ZYPREXA RELPREVV is indicated for the treatment of schizophrenia. Efficacy was established in two clinical trials in patients with schizophrenia: one 8-week trial in adults and one maintenance trial in adults [see Clinical Studies (14.1)].

ZYPREXA RELPREVV is intended for deep intramuscular gluteal injection only and should not be administered intravenously or subcutaneously.

Be aware that there are two ZYPREXA intramuscular formulations with different dosing schedules. ZYPREXA IntraMuscular (10 mg/vial) is a short-acting formulation and should not be confused with ZYPREXA RELPREVV. Refer to the package insert for ZYPREXA IntraMuscular for more information about that product.

Establish tolerability with oral olanzapine prior to initiating treatment.

ZYPREXA RELPREVV should be administered by a healthcare professional every 2 to 4 weeks by deep intramuscular gluteal injection using a 19-gauge, 1.5-inch needle. Following insertion of the needle into the muscle, aspiration should be maintained for several seconds to ensure that no blood is drawn into the syringe. If any blood is aspirated into the syringe, it should be discarded and fresh drug should be prepared using a new convenience kit. The injection should be performed at a steady, continuous pressure. Do not massage the injection site.

Dose Selection — The efficacy of ZYPREXA RELPREVV has been demonstrated within the range of 150 mg to 300 mg administered every 2 weeks and with 405 mg administered every 4 weeks. Dose recommendations considering oral ZYPREXA and ZYPREXA RELPREVV are shown in Table 1.

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 1: Recommended Dosing for ZYPREXA RELPREVV Based on Correspondence to Oral ZYPREXA Doses</span> </caption> <col align="left" width="33.333%"/> <col align="left" width="33.333%"/> <col align="left" width="33.333%"/> <tbody class="Headless"> <tr class="First"> <td align="center" class="Botrule Lrule Rrule Toprule" valign="top"><span class="Bold"> <br/>Target Oral ZYPREXA Dose</span></td><td align="center" class="Botrule Rrule Toprule" valign="top"><span class="Bold">Dosing of ZYPREXA RELPREVV During the First 8 Weeks</span></td><td align="center" class="Botrule Rrule Toprule" valign="top"><span class="Bold">Maintenance Dose After 8 Weeks of ZYPREXA RELPREVV Treatment</span></td> </tr> <tr> <td align="center" class="Lrule Rrule" valign="top">10 mg/day</td><td align="center" class="Rrule" valign="top">210 mg/2 weeks or</td><td align="center" class="Rrule" valign="top">150 mg/2 weeks or</td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top">405 mg/4 weeks</td><td align="center" class="Botrule Rrule" valign="top">300 mg/4 weeks</td> </tr> <tr> <td align="center" class="Lrule Rrule" valign="top">15 mg/day</td><td align="center" class="Rrule" valign="top">300 mg/2 weeks</td><td align="center" class="Rrule" valign="top">210 mg/2 weeks or</td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top">405 mg/4 weeks</td> </tr> <tr class="Last"> <td align="center" class="Botrule Lrule Rrule" valign="top">20 mg/day</td><td align="center" class="Botrule Rrule" valign="top">300 mg/2 weeks</td><td align="center" class="Botrule Rrule" valign="top">300 mg/2 weeks</td> </tr> </tbody> </table></div>

ZYPREXA RELPREVV doses greater than 405 mg every 4 weeks or 300 mg every 2 weeks have not been evaluated in clinical trials.

Post-Injection Delirium/Sedation Syndrome — During premarketing clinical studies, adverse events that presented with signs and symptoms consistent with olanzapine overdose, in particular, sedation (including coma) and/or delirium, were reported in patients following an injection of ZYPREXA RELPREVV [see Boxed Warning, Warnings and Precautions (5.1), and Overdosage (10.1)]. Patients should be informed of this risk and how to recognize related symptoms [see Patient Counseling Information (17)]. ZYPREXA RELPREVV must be administered in a registered healthcare facility with ready access to emergency response services. After each ZYPREXA RELPREVV injection, a healthcare professional must continuously observe the patient at the healthcare facility for at least 3 hours for symptoms consistent with olanzapine overdose, including sedation (ranging from mild in severity to coma) and/or delirium (including confusion, disorientation, agitation, anxiety, and other cognitive impairment). Other symptoms noted include extrapyramidal symptoms, dysarthria, ataxia, aggression, dizziness, weakness, hypertension, and convulsion. The potential for onset of an event is greatest within the first hour. The majority of cases have occurred within the first 3 hours after injection; however, the event has occurred after 3 hours. Following the 3-hour observation period, healthcare professionals must confirm that the patient is alert, oriented, and absent of any signs and symptoms of post-injection delirium/sedation syndrome prior to being released. All patients must be accompanied to their destination upon leaving the facility. For the remainder of the day of each injection, patients should not drive or operate heavy machinery, and should be advised to be vigilant for symptoms of post-injection delirium/sedation syndrome and be able to obtain medical assistance if needed. If post-injection delirium/sedation syndrome is suspected, close medical supervision and monitoring should be instituted in a facility capable of resuscitation [see Overdosage (10)].

Dosing in Specific Populations — Tolerance of oral ZYPREXA should be established prior to initiating treatment with ZYPREXA RELPREVV. The recommended starting dose is ZYPREXA RELPREVV 150 mg/4 wks in patients who are debilitated, who have a predisposition to hypotensive reactions, who otherwise exhibit a combination of factors that may result in slower metabolism of olanzapine (e.g., nonsmoking female patients ≥65 years of age), or who may be more pharmacodynamically sensitive to olanzapine. When indicated, dose escalation should be undertaken with caution in these patients [see Warnings and Precautions (5.18), Drug Interactions (7), and Clinical Pharmacology (12.3)].

ZYPREXA RELPREVV has not been studied in subjects under 18 years of age [see Warnings and Precautions (5.7)].

Maintenance Treatment — Although no controlled studies have been conducted to determine how long patients should be treated with ZYPREXA RELPREVV, efficacy has been demonstrated over a period of 24 weeks in patients with stabilized schizophrenia. Additionally, oral ZYPREXA has been shown to be effective in maintenance of treatment response in schizophrenia in longer-term use. Patients should be periodically reassessed to determine the need for continued treatment.

Switching from Other Antipsychotics — There are no systematically collected data to specifically address how to switch patients with schizophrenia from other antipsychotics to ZYPREXA RELPREVV.

For deep intramuscular gluteal injection only. Not to be injected intravenously or subcutaneously.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Step 1: Preparing Materials

Convenience kit includes:

ZYPREXA RELPREVV must be suspended using only the diluent supplied in the convenience kit.

It is recommended that gloves are used when reconstituting, as ZYPREXA RELPREVV may be irritating to the skin. Flush with water if contact is made with skin.

See additional insert entitled "Instructions to Reconstitute and Administer ZYPREXA RELPREVV" (included) for more information regarding the safe and effective use of the Hypodermic Needle-Pro syringe and needle.

Step 2: Determining Reconstitution Volume

Refer to the table below to determine the amount of diluent to be added to powder for reconstitution of each vial strength.

It is important to note that there is more diluent in the vial than is needed to reconstitute.

<div class="scrollingtable"><table width="100%"> <colgroup> <col align="left" width="33.333%"/> <col align="left" width="33.333%"/> <col align="left" width="33.333%"/> </colgroup> <tbody class="Headless"> <tr class="First"> <td align="center" class="Botrule Lrule Rrule Toprule" valign="top"><span class="Bold">Dose</span></td><td align="center" class="Botrule Rrule Toprule" valign="top"><span class="Bold">Vial Strength</span></td><td align="center" class="Botrule Rrule Toprule" valign="top"><span class="Bold">Diluent to Add</span></td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top">150 mg</td><td align="center" class="Botrule Rrule" valign="top">210 mg</td><td align="center" class="Botrule Rrule" valign="top">1.3 mL</td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top">210 mg</td><td align="center" class="Botrule Rrule" valign="top">210 mg</td><td align="center" class="Botrule Rrule" valign="top">1.3 mL</td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top">300 mg</td><td align="center" class="Botrule Rrule" valign="top">300 mg</td><td align="center" class="Botrule Rrule" valign="top">1.8 mL</td> </tr> <tr class="Last"> <td align="center" class="Botrule Lrule Rrule" valign="top">405 mg</td><td align="center" class="Botrule Rrule" valign="top">405 mg</td><td align="center" class="Botrule Rrule" valign="top">2.3 mL</td> </tr> </tbody> </table></div>

Step 3: Reconstituting ZYPREXA RELPREVV

Please read the Hypodermic Needle-Pro Instructions for Use before proceeding with Step 3. Failure to follow these instructions may result in a needlestick injury.

Loosen the powder by lightly tapping the vial.

Open the prepackaged Hypodermic Needle-Pro syringe and needle with needle protection device.

Withdraw the pre-determined diluent volume (Step 2) into the syringe.

Inject the diluent into the powder vial.

Withdraw air to equalize the pressure in the vial by pulling back slightly on the plunger in the syringe.

Remove the needle from the vial, holding the vial upright to prevent any loss of material.

Engage the needle safety device (refer to complete Hypodermic Needle-Pro Instructions for Use).

Pad a hard surface to cushion impact (see Figure 1). Tap the vial firmly and repeatedly on the surface until no powder is visible.

<div class="scrollingtable"><table width="100%"> <colgroup> <col align="left" width="100.000%"/> </colgroup> <tbody class="Headless"> <tr class="First"> <td align="center" valign="top"><img alt="Figure 1" src="/dailymed/image.cfm?name=Relprevv-f001-v1.jpg&amp;setid=11544cba-64a9-49cb-8d74-da228053b252"/></td> </tr> <tr class="Last"> <td align="center" valign="top"><span class="Bold">Figure 1:</span> Tap firmly to mix.</td> </tr> </tbody> </table></div>

Visually check the vial for clumps. Unsuspended powder appears as yellow, dry clumps clinging to the vial. Additional tapping may be required if large clumps remain (see Figure 2).

<div class="scrollingtable"><table width="100%"> <colgroup> <col align="left" width="100.000%"/> </colgroup> <tbody class="Headless"> <tr class="First"> <td align="center" valign="top"><img alt="Figure 2" src="/dailymed/image.cfm?name=Relprevv-f002-v2.jpg&amp;setid=11544cba-64a9-49cb-8d74-da228053b252"/></td> </tr> <tr class="Last"> <td align="center" valign="top"><span class="Bold">Figure 2:</span> Check for unsuspended powder and repeat tapping if needed.</td> </tr> </tbody> </table></div>

Shake the vial vigorously until the suspension appears smooth and is consistent in color and texture. The suspended product will be yellow and opaque (see Figure 3).

<div class="scrollingtable"><table width="100%"> <colgroup> <col align="left" width="100.000%"/> </colgroup> <tbody class="Headless"> <tr class="First"> <td align="center" valign="top"><img alt="Figure 3" src="/dailymed/image.cfm?name=Relprevv-f003-v2.jpg&amp;setid=11544cba-64a9-49cb-8d74-da228053b252"/></td> </tr> <tr class="Last"> <td align="center" valign="top"><span class="Bold">Figure 3:</span> Vigorously shake vial.</td> </tr> </tbody> </table></div>

If foam forms, let vial stand to allow foam to dissipate.

If the product is not used right away, it should be shaken vigorously to re-suspend. Reconstituted ZYPREXA RELPREVV remains stable at room temperature for up to 24 hours in the vial.

Step 4: Injecting ZYPREXA RELPREVV

Before administering the injection, confirm there will be someone to accompany the patient after the 3-hour observation period. If this cannot be confirmed, do not give the injection.

Refer to the table below to determine the final volume to inject. Suspension concentration is 150 mg/mL ZYPREXA RELPREVV.

<div class="scrollingtable"><table width="100%"> <colgroup> <col align="left" width="50.000%"/> <col align="left" width="50.000%"/> </colgroup> <tbody class="Headless"> <tr class="First"> <td align="center" class="Botrule Lrule Rrule Toprule" valign="top"><span class="Bold">Dose</span></td><td align="center" class="Botrule Rrule Toprule" valign="top"><span class="Bold">Final Volume to Inject</span></td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top">150 mg</td><td align="center" class="Botrule Rrule" valign="top">1 mL</td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top">210 mg</td><td align="center" class="Botrule Rrule" valign="top">1.4 mL</td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top">300 mg</td><td align="center" class="Botrule Rrule" valign="top">2 mL</td> </tr> <tr class="Last"> <td align="center" class="Botrule Lrule Rrule" valign="top">405 mg</td><td align="center" class="Botrule Rrule" valign="top">2.7 mL</td> </tr> </tbody> </table></div>

Attach a new safety needle to the syringe.

Slowly withdraw the desired amount into the syringe.

Some excess product will remain in the vial.

Engage the needle safety device and remove the needle from syringe.

For administration, select the 19-gauge, 1.5-inch (38 mm) Hypodermic Needle-Pro needle with needle protection device. For obese patients, a 2-inch (50 mm), 19-gauge or larger needle (not included in convenience kit) may be used. To help prevent clogging, a 19-gauge or larger needle must be used.

Attach the new safety needle to the syringe prior to injection. Once the suspension has been removed from the vial, it should be injected immediately.

For deep intramuscular gluteal injection only. Do not inject intravenously or subcutaneously.

Select and prepare a site for injection in the gluteal area.

After insertion of the needle into the muscle, aspirate for several seconds to ensure that no blood appears. If any blood is drawn into the syringe, discard the syringe and the dose and begin with a new convenience kit. The injection should be performed with steady, continuous pressure.

Do not massage the injection site.

Engage the needle safety device.

Dispose of the vials, needles, and syringe appropriately after injection. The vial is for single-dose only.

ZYPREXA RELPREVV is a powder for suspension for intramuscular use only. ZYPREXA RELPREVV is present as a yellow solid in a glass vial equivalent to 210, 300, or 405 mg olanzapine single-dose per vial. The diluent is a clear, colorless to slightly yellow solution in a glass vial [see Description (11) and How Supplied/Storage and Handling (16)]. The reconstituted suspension will be yellow and opaque [see Dosage and Administration (2.2)].

{ "type": "p", "children": [], "text": "ZYPREXA RELPREVV is a powder for suspension for intramuscular use only. ZYPREXA RELPREVV is present as a yellow solid in a glass vial equivalent to 210, 300, or 405 mg olanzapine single-dose per vial. The diluent is a clear, colorless to slightly yellow solution in a glass vial [see Description (11) and How Supplied/Storage and Handling (16)]. The reconstituted suspension will be yellow and opaque [see Dosage and Administration (2.2)]." }

None.

{ "type": "p", "children": [], "text": "None." }

During premarketing clinical studies of ZYPREXA RELPREVV, adverse events that presented with signs and symptoms consistent with olanzapine overdose, in particular, sedation (including coma) and/or delirium, were reported in patients following an injection of ZYPREXA RELPREVV [see Boxed Warning and Dosage and Administration (2.1)]. These events occurred in <0.1% of injections and in approximately 2% of patients who received injections for up to 46 months. These events were correlated with an unintentional rapid increase in serum olanzapine concentrations to supra-therapeutic ranges in some cases. While a rapid and greater than expected increase in serum olanzapine concentration has been observed in some patients with these events, the exact mechanism by which the drug was unintentionally introduced into the blood stream is not known. Clinical signs and symptoms included dizziness, confusion, disorientation, slurred speech, altered gait, difficulty ambulating, weakness, agitation, extrapyramidal symptoms, hypertension, convulsion, and reduced level of consciousness ranging from mild sedation to coma. Time after injection to event ranged from soon after injection to greater than 3 hours after injection. The majority of patients were hospitalized and some required supportive care, including intubation, in several cases. All patients had largely recovered by 72 hours. The risk of an event is the same at each injection, so the risk per patient is cumulative (i.e., increases with the number of injections) [see Overdosage (10.1)].

Healthcare professionals are advised to discuss this potential risk with patients each time they prescribe and administer ZYPREXA RELPREVV [see Patient Counseling Information (17)].

ZYPREXA RELPREVV is available only through a restricted distribution program [see Boxed Warning, Indications and Usage (1), and Patient Counseling Information (17)]. ZYPREXA RELPREVV must not be dispensed directly to a patient. For a patient to receive treatment, the prescriber, healthcare facility, patient, and pharmacy must all be enrolled in the ZYPREXA RELPREVV Patient Care Program. To enroll, call 1-877-772-9390.

ZYPREXA RELPREVV must be administered in a registered healthcare facility (such as a hospital, clinic, residential treatment center, or community healthcare center) with ready access to emergency response services. After each ZYPREXA RELPREVV injection, a healthcare professional must continuously observe the patient at the healthcare facility for at least 3 hours and must confirm that the patient is alert, oriented, and absent of any signs and symptoms of post-injection delirium/sedation syndrome prior to being released. All patients must be accompanied to their destination upon leaving the facility. For the remainder of the day of each injection, patients should not drive or operate heavy machinery, and should be advised to be vigilant for symptoms of post-injection delirium/sedation syndrome and be able to obtain medical assistance if needed. If post-injection delirium/sedation syndrome is suspected, close medical supervision and monitoring should be instituted in a facility capable of resuscitation [see Overdosage (10)]. If parenteral benzodiazepines are required for patient management during an event of post-injection delirium/sedation syndrome, careful evaluation of clinical status for excessive sedation and cardiorespiratory depression is recommended.

Increased Mortality

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. ZYPREXA RELPREVV is not approved for the treatment of patients with dementia-related psychosis[see Boxed Warning, Use in Specific Populations (8.5), and Patient Counseling Information (17)].

In placebo-controlled oral olanzapine clinical trials of elderly patients with dementia-related psychosis, the incidence of death in olanzapine-treated patients was significantly greater than placebo-treated patients (3.5% vs 1.5%, respectively).

Cerebrovascular Adverse Events (CVAE), Including Stroke

Cerebrovascular adverse events (e.g., stroke, transient ischemic attack), including fatalities, were reported in patients in trials of oral olanzapine in elderly patients with dementia-related psychosis. In placebo-controlled trials, there was a significantly higher incidence of cerebrovascular adverse events in patients treated with oral olanzapine compared to patients treated with placebo. ZYPREXA RELPREVV is not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning and Patient Counseling Information (17)].

The possibility of a suicide attempt is inherent in schizophrenia, and close supervision of high-risk patients should accompany drug therapy.

A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with administration of antipsychotic drugs, including olanzapine. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis and cardiac dysrhythmia). Additional signs may include elevated creatinine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure.

The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a diagnosis, it is important to exclude cases where the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever, and primary central nervous system pathology.

The management of NMS should include: 1) immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy; 2) intensive symptomatic treatment and medical monitoring; and 3) treatment of any concomitant serious medical problems for which specific treatments are available. There is no general agreement about specific pharmacological treatment regimens for NMS.

If a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of drug therapy should be carefully considered and tolerability with oral olanzapine should be established prior to initiating treatment with ZYPREXA RELPREVV [see Dosage and Administration (2.1)]. The patient should be carefully monitored, since recurrences of NMS have been reported [see Patient Counseling Information (17)].

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported with olanzapine exposure. DRESS may present with a cutaneous reaction (such as rash or exfoliative dermatitis), eosinophilia, fever, and/or lymphadenopathy with systemic complications such as hepatitis, nephritis, pneumonitis, myocarditis, and/or pericarditis. DRESS is sometimes fatal. Discontinue ZYPREXA RELPREVV if DRESS is suspected [see Patient Counseling Information (17)].

Atypical antipsychotic drugs have been associated with metabolic changes including hyperglycemia, dyslipidemia, and weight gain. Metabolic changes may be associated with increased cardiovascular/cerebrovascular risk. Olanzapine's specific metabolic profile is presented below.

Hyperglycemia and Diabetes Mellitus

Healthcare providers should consider the risks and benefits when prescribing olanzapine to patients with an established diagnosis of diabetes mellitus, or having borderline increased blood glucose level (fasting 100-126 mg/dL, nonfasting 140-200 mg/dL). Patients taking olanzapine should be monitored regularly for worsening of glucose control. Patients starting treatment with olanzapine should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics should undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of anti-diabetic treatment despite discontinuation of the suspect drug [see Patient Counseling Information (17)].

Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics including olanzapine. Assessment of the relationship between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population. Epidemiological studies suggest an increased risk of treatment-emergent hyperglycemia-related adverse reactions in patients treated with the atypical antipsychotics. While relative risk estimates are inconsistent, the association between atypical antipsychotics and increases in glucose levels appears to fall on a continuum and olanzapine appears to have a greater association than some other atypical antipsychotics.

Mean increases in blood glucose have been observed in patients treated (median exposure of 9.2 months) with olanzapine in phase 1 of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE). The mean increase of serum glucose (fasting and nonfasting samples) from baseline to the average of the 2 highest serum concentrations was 15.0 mg/dL.

In a study of healthy volunteers, subjects who received olanzapine (N=22) for 3 weeks had a mean increase compared to baseline in fasting blood glucose of 2.3 mg/dL. Placebo-treated subjects (N=19) had a mean increase in fasting blood glucose compared to baseline of 0.34 mg/dL.

Olanzapine Monotherapy in Adults — In an analysis of 5 placebo-controlled adult olanzapine monotherapy studies with a median treatment duration of approximately 3 weeks, olanzapine was associated with a greater mean change in fasting glucose levels compared to placebo (2.76 mg/dL versus 0.17 mg/dL). The difference in mean changes between olanzapine and placebo was greater in patients with evidence of glucose dysregulation at baseline (patients diagnosed with diabetes mellitus or related adverse reactions, patients treated with anti-diabetic agents, patients with a baseline random glucose level ≥200 mg/dL, and/or a baseline fasting glucose level ≥126 mg/dL).

Olanzapine-treated patients had a greater mean HbA1c increase from baseline of 0.04% (median exposure 21 days), compared to a mean HbA1c decrease of 0.06% in placebo-treated subjects (median exposure 17 days).

In an analysis of 8 placebo-controlled studies (median treatment exposure 4-5 weeks), 6.1% of olanzapine-treated subjects (N=855) had treatment-emergent glycosuria compared to 2.8% of placebo-treated subjects (N=599). Table 2 shows short-term and long-term changes in fasting glucose levels from adult olanzapine monotherapy studies.

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 2: Changes in Fasting Glucose Levels from Adult Olanzapine Monotherapy Studies</span> </caption> <col align="left" width="13.229%"/> <col align="left" width="39.200%"/> <col align="left" width="11.429%"/> <col align="left" width="9.029%"/> <col align="left" width="9.043%"/> <col align="left" width="9.029%"/> <col align="left" width="9.043%"/> <tfoot> <tr class="First Last"> <td align="left" colspan="7" valign="top"> <p class="First Footnote"> <span class="Sup">a</span> Not Applicable.</p> </td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td align="center" class="Botrule Lrule Toprule" valign="top"></td><td align="center" class="Botrule Toprule" valign="top"></td><td align="center" class="Botrule Rrule Toprule" valign="top"></td><td align="center" class="Botrule Rrule Toprule" colspan="2" valign="top"><span class="Bold">Up to 12 weeks exposure</span></td><td align="center" class="Botrule Rrule Toprule" colspan="2" valign="top"><span class="Bold">At least 48 weeks exposure</span></td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"><span class="Bold">Laboratory Analyte</span></td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold">Category Change (at least once)<br/>from Baseline</span></td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold">Treatment Arm</span></td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold"> <br/>N</span></td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold"> <br/>Patients</span></td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold"> <br/>N</span></td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold"> <br/>Patients</span></td> </tr> <tr> <td align="center" class="Lrule Rrule" valign="top"></td><td align="center" class="Rrule" valign="top">Normal to High</td><td align="center" class="Botrule Rrule" valign="top">Olanzapine</td><td align="center" class="Botrule Rrule" valign="top">543</td><td align="center" class="Botrule Rrule" valign="top">2.2%</td><td align="center" class="Botrule Rrule" valign="top">345</td><td align="center" class="Botrule Rrule" valign="top">12.8%</td> </tr> <tr> <td align="center" class="Lrule Rrule" valign="top">Fasting</td><td align="center" class="Botrule Rrule" valign="top">(&lt;100 mg/dL to ≥126 mg/dL)</td><td align="center" class="Botrule Rrule" valign="top">Placebo</td><td align="center" class="Botrule Rrule" valign="top">293</td><td align="center" class="Botrule Rrule" valign="top">3.4%</td><td align="center" class="Botrule Rrule" valign="top">NA<span class="Sup">a</span></td><td align="center" class="Botrule Rrule" valign="top">NA<span class="Sup">a</span></td> </tr> <tr> <td align="center" class="Lrule Rrule" valign="top">Glucose</td><td align="center" class="Rrule" valign="top">Borderline to High</td><td align="center" class="Botrule Rrule" valign="top">Olanzapine</td><td align="center" class="Botrule Rrule" valign="top">178</td><td align="center" class="Botrule Rrule" valign="top">17.4%</td><td align="center" class="Botrule Rrule" valign="top">127</td><td align="center" class="Botrule Rrule" valign="top">26.0%</td> </tr> <tr class="Last"> <td align="center" class="Botrule Lrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top">(≥100 mg/dL and &lt;126 mg/dL to ≥126 mg/dL)</td><td align="center" class="Botrule Rrule" valign="top">Placebo</td><td align="center" class="Botrule Rrule" valign="top">96</td><td align="center" class="Botrule Rrule" valign="top">11.5%</td><td align="center" class="Botrule Rrule" valign="top">NA<span class="Sup">a</span></td><td align="center" class="Botrule Rrule" valign="top">NA<span class="Sup">a</span></td> </tr> </tbody> </table></div>

The mean change in fasting glucose for patients exposed at least 48 weeks was 4.2 mg/dL (N=487). In analyses of patients who completed 9-12 months of olanzapine therapy, mean change in fasting and nonfasting glucose levels continued to increase over time.

Olanzapine Monotherapy in Adolescents — The safety and efficacy of ZYPREXA RELPREVV have not been established in patients under the age of 18 years.

In an analysis of 3 placebo-controlled oral olanzapine monotherapy studies of adolescent patients (13-17 years), including those with schizophrenia (6 weeks) or bipolar I disorder (manic or mixed episodes) (3 weeks), olanzapine was associated with a greater mean change from baseline in fasting glucose levels compared to placebo (2.68 mg/dL versus -2.59 mg/dL). The mean change in fasting glucose for adolescents exposed at least 24 weeks was 3.1 mg/dL (N=121). Table 3 shows short-term and long-term changes in fasting blood glucose from adolescent oral olanzapine monotherapy studies.

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 3: Changes in Fasting Glucose Levels from Adolescent Oral Olanzapine Monotherapy Studies</span> </caption> <col align="left" width="13.229%"/> <col align="left" width="39.200%"/> <col align="left" width="11.429%"/> <col align="left" width="9.029%"/> <col align="left" width="9.043%"/> <col align="left" width="9.029%"/> <col align="left" width="9.043%"/> <tfoot> <tr class="First Last"> <td align="left" colspan="7" valign="top"> <p class="First Footnote"> <span class="Sup">a</span> Not Applicable.</p> </td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td align="center" class="Botrule Lrule Toprule" valign="top"></td><td align="center" class="Botrule Toprule" valign="top"></td><td align="center" class="Botrule Rrule Toprule" valign="top"></td><td align="center" class="Botrule Rrule Toprule" colspan="2" valign="top"><span class="Bold">Up to 12 weeks exposure</span></td><td align="center" class="Botrule Rrule Toprule" colspan="2" valign="top"><span class="Bold">At least 24 weeks exposure</span></td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"><span class="Bold">Laboratory Analyte</span></td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold">Category Change (at least once)<br/>from Baseline</span></td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold">Treatment Arm</span></td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold"> <br/>N</span></td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold"> <br/>Patients</span></td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold"> <br/>N</span></td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold"> <br/>Patients</span></td> </tr> <tr> <td align="center" class="Lrule Rrule" valign="top"></td><td align="center" class="Rrule" valign="top">Normal to High</td><td align="center" class="Botrule Rrule" valign="top">Olanzapine</td><td align="center" class="Botrule Rrule" valign="top">124</td><td align="center" class="Botrule Rrule" valign="top">0%</td><td align="center" class="Botrule Rrule" valign="top">108</td><td align="center" class="Botrule Rrule" valign="top">0.9%</td> </tr> <tr> <td align="center" class="Lrule Rrule" valign="top">Fasting</td><td align="center" class="Botrule Rrule" valign="top">(&lt;100 mg/dL to ≥126 mg/dL)</td><td align="center" class="Botrule Rrule" valign="top">Placebo</td><td align="center" class="Botrule Rrule" valign="top">53</td><td align="center" class="Botrule Rrule" valign="top">1.9%</td><td align="center" class="Botrule Rrule" valign="top">NA<span class="Sup">a</span></td><td align="center" class="Botrule Rrule" valign="top">NA<span class="Sup">a</span></td> </tr> <tr> <td align="center" class="Lrule Rrule" valign="top">Glucose</td><td align="center" class="Rrule" valign="top">Borderline to High</td><td align="center" class="Botrule Rrule" valign="top">Olanzapine</td><td align="center" class="Botrule Rrule" valign="top">14</td><td align="center" class="Botrule Rrule" valign="top">14.3%</td><td align="center" class="Botrule Rrule" valign="top">13</td><td align="center" class="Botrule Rrule" valign="top">23.1%</td> </tr> <tr class="Last"> <td align="center" class="Botrule Lrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top">(≥100 mg/dL and &lt;126 mg/dL to ≥126 mg/dL)</td><td align="center" class="Botrule Rrule" valign="top">Placebo</td><td align="center" class="Botrule Rrule" valign="top">13</td><td align="center" class="Botrule Rrule" valign="top">0%</td><td align="center" class="Botrule Rrule" valign="top">NA<span class="Sup">a</span></td><td align="center" class="Botrule Rrule" valign="top">NA<span class="Sup">a</span></td> </tr> </tbody> </table></div>

Dyslipidemia

Undesirable alterations in lipids have been observed with olanzapine use. Clinical monitoring, including baseline and periodic follow-up lipid evaluations in patients using olanzapine, is recommended [see Patient Counseling Information (17)].

Clinically significant, and sometimes very high (>500 mg/dL), elevations in triglyceride levels have been observed with olanzapine use. Modest mean increases in total cholesterol have also been seen with olanzapine use.

Olanzapine Monotherapy in Adults — In an analysis of 5 placebo-controlled olanzapine monotherapy studies with treatment duration up to 12 weeks, olanzapine-treated patients had increases from baseline in mean fasting total cholesterol, LDL cholesterol, and triglycerides of 5.3 mg/dL, 3.0 mg/dL, and 20.8 mg/dL respectively compared to decreases from baseline in mean fasting total cholesterol, LDL cholesterol, and triglycerides of 6.1 mg/dL, 4.3 mg/dL, and 10.7 mg/dL for placebo-treated patients. For fasting HDL cholesterol, no clinically meaningful differences were observed between olanzapine-treated patients and placebo-treated patients. Mean increases in fasting lipid values (total cholesterol, LDL cholesterol, and triglycerides) were greater in patients without evidence of lipid dysregulation at baseline, where lipid dysregulation was defined as patients diagnosed with dyslipidemia or related adverse reactions, patients treated with lipid lowering agents, or patients with high baseline lipid levels.

In long-term studies (at least 48 weeks), patients had increases from baseline in mean fasting total cholesterol, LDL cholesterol, and triglycerides of 5.6 mg/dL, 2.5 mg/dL, and 18.7 mg/dL, respectively, and a mean decrease in fasting HDL cholesterol of 0.16 mg/dL. In an analysis of patients who completed 12 months of therapy, the mean nonfasting total cholesterol did not increase further after approximately 4-6 months.

The proportion of patients who had changes (at least once) in total cholesterol, LDL cholesterol or triglycerides from normal or borderline to high, or changes in HDL cholesterol from normal or borderline to low, was greater in long-term studies (at least 48 weeks) as compared with short-term studies. Table 4 shows categorical changes in fasting lipids values.

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 4: Changes in Fasting Lipids Values from Adult Olanzapine Monotherapy Studies </span> </caption> <colgroup> <col align="left" width="13.229%"/> <col align="left" width="39.200%"/> <col align="left" width="11.429%"/> <col align="left" width="9.029%"/> <col align="left" width="9.043%"/> <col align="left" width="9.029%"/> <col align="left" width="9.043%"/> </colgroup> <tfoot> <tr class="First First Last Last"> <td align="left" colspan="7" valign="top"> <p class="First First Footnote"> <span class="Sup">a</span> Not Applicable.</p> </td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td align="center" class="Botrule Lrule Toprule" valign="top"></td><td align="center" class="Botrule Toprule" valign="top"></td><td align="center" class="Botrule Rrule Toprule" valign="top"></td><td align="center" class="Botrule Rrule Toprule" colspan="2" valign="top"><span class="Bold">Up to 12 weeks exposure</span></td><td align="center" class="Botrule Rrule Toprule" colspan="2" valign="top"><span class="Bold">At least 48 weeks exposure</span></td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"><span class="Bold">Laboratory Analyte</span></td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold">Category Change (at least once)<br/>from Baseline</span></td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold">Treatment Arm</span></td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold"> <br/>N</span></td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold"> <br/>Patients</span></td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold"> <br/>N</span></td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold"> <br/>Patients</span></td> </tr> <tr> <td align="center" class="Lrule Rrule" valign="top"></td><td align="center" class="Rrule" valign="top">Increase by ≥50 mg/dL</td><td align="center" class="Botrule Rrule" valign="top">Olanzapine</td><td align="center" class="Botrule Rrule" valign="top">745</td><td align="center" class="Botrule Rrule" valign="top">39.6%</td><td align="center" class="Botrule Rrule" valign="top">487</td><td align="center" class="Botrule Rrule" valign="top">61.4%</td> </tr> <tr> <td align="center" class="Lrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top">Placebo</td><td align="center" class="Botrule Rrule" valign="top">402</td><td align="center" class="Botrule Rrule" valign="top">26.1%</td><td align="center" class="Botrule Rrule" valign="top">NA<span class="Sup">a</span></td><td align="center" class="Botrule Rrule" valign="top">NA<span class="Sup">a</span></td> </tr> <tr> <td align="center" class="Lrule Rrule" valign="top">Fasting</td><td align="center" class="Rrule" valign="top">Normal to High</td><td align="center" class="Botrule Rrule" valign="top">Olanzapine</td><td align="center" class="Botrule Rrule" valign="top">457</td><td align="center" class="Botrule Rrule" valign="top">9.2%</td><td align="center" class="Botrule Rrule" valign="top">293</td><td align="center" class="Botrule Rrule" valign="top">32.4%</td> </tr> <tr> <td align="center" class="Lrule Rrule" valign="top">Triglycerides</td><td align="center" class="Botrule Rrule" valign="top">(&lt;150 mg/dL to ≥200 mg/dL)</td><td align="center" class="Botrule Rrule" valign="top">Placebo</td><td align="center" class="Botrule Rrule" valign="top">251</td><td align="center" class="Botrule Rrule" valign="top">4.4%</td><td align="center" class="Botrule Rrule" valign="top">NA<span class="Sup">a</span></td><td align="center" class="Botrule Rrule" valign="top">NA<span class="Sup">a</span></td> </tr> <tr> <td align="center" class="Lrule Rrule" valign="top"></td><td align="center" class="Rrule" valign="top">Borderline to High</td><td align="center" class="Botrule Rrule" valign="top">Olanzapine</td><td align="center" class="Botrule Rrule" valign="top">135</td><td align="center" class="Botrule Rrule" valign="top">39.3%</td><td align="center" class="Botrule Rrule" valign="top">75</td><td align="center" class="Botrule Rrule" valign="top">70.7%</td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top">(≥150 mg/dL and &lt;200 mg/dL to ≥200 mg/dL)</td><td align="center" class="Botrule Rrule" valign="top">Placebo</td><td align="center" class="Botrule Rrule" valign="top">65</td><td align="center" class="Botrule Rrule" valign="top">20.0%</td><td align="center" class="Botrule Rrule" valign="top">NA<span class="Sup">a</span></td><td align="center" class="Botrule Rrule" valign="top">NA<span class="Sup">a</span></td> </tr> <tr> <td align="center" class="Botrule Lrule" valign="top"></td><td align="center" class="Botrule" valign="top"></td><td align="center" class="Botrule" valign="top"></td><td align="center" class="Botrule" valign="top"></td><td align="center" class="Botrule" valign="top"></td><td align="center" class="Botrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"></td> </tr> <tr> <td align="center" class="Lrule Rrule" valign="top"></td><td align="center" class="Rrule" valign="top">Increase by ≥40 mg/dL</td><td align="center" class="Botrule Rrule" valign="top">Olanzapine</td><td align="center" class="Botrule Rrule" valign="top">745</td><td align="center" class="Botrule Rrule" valign="top">21.6%</td><td align="center" class="Botrule Rrule" valign="top">489</td><td align="center" class="Botrule Rrule" valign="top">32.9%</td> </tr> <tr> <td align="center" class="Lrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top">Placebo</td><td align="center" class="Botrule Rrule" valign="top">402</td><td align="center" class="Botrule Rrule" valign="top">9.5%</td><td align="center" class="Botrule Rrule" valign="top">NA<span class="Sup">a</span></td><td align="center" class="Botrule Rrule" valign="top">NA<span class="Sup">a</span></td> </tr> <tr> <td align="center" class="Lrule Rrule" valign="top">Fasting Total</td><td align="center" class="Rrule" valign="top">Normal to High</td><td align="center" class="Botrule Rrule" valign="top">Olanzapine</td><td align="center" class="Botrule Rrule" valign="top">392</td><td align="center" class="Botrule Rrule" valign="top">2.8%</td><td align="center" class="Botrule Rrule" valign="top">283</td><td align="center" class="Botrule Rrule" valign="top">14.8%</td> </tr> <tr> <td align="center" class="Lrule Rrule" valign="top">Cholesterol</td><td align="center" class="Botrule Rrule" valign="top">(&lt;200 mg/dL to ≥240 mg/dL)</td><td align="center" class="Botrule Rrule" valign="top">Placebo</td><td align="center" class="Botrule Rrule" valign="top">207</td><td align="center" class="Botrule Rrule" valign="top">2.4%</td><td align="center" class="Botrule Rrule" valign="top">NA<span class="Sup">a</span></td><td align="center" class="Botrule Rrule" valign="top">NA<span class="Sup">a</span></td> </tr> <tr> <td align="center" class="Lrule Rrule" valign="top"></td><td align="center" class="Rrule" valign="top">Borderline to High</td><td align="center" class="Botrule Rrule" valign="top">Olanzapine</td><td align="center" class="Botrule Rrule" valign="top">222</td><td align="center" class="Botrule Rrule" valign="top">23.0%</td><td align="center" class="Botrule Rrule" valign="top">125</td><td align="center" class="Botrule Rrule" valign="top">55.2%</td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top">(≥200 mg/dL and &lt;240 mg/dL to ≥240 mg/dL)</td><td align="center" class="Botrule Rrule" valign="top">Placebo</td><td align="center" class="Botrule Rrule" valign="top">112</td><td align="center" class="Botrule Rrule" valign="top">12.5%</td><td align="center" class="Botrule Rrule" valign="top">NA<span class="Sup">a</span></td><td align="center" class="Botrule Rrule" valign="top">NA<span class="Sup">a</span></td> </tr> <tr> <td align="center" class="Botrule Lrule" valign="top"></td><td align="center" class="Botrule" valign="top"></td><td align="center" class="Botrule" valign="top"></td><td align="center" class="Botrule" valign="top"></td><td align="center" class="Botrule" valign="top"></td><td align="center" class="Botrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"></td> </tr> <tr> <td align="center" class="Lrule Rrule" valign="top"></td><td align="center" class="Rrule" valign="top">Increase by ≥30 mg/dL</td><td align="center" class="Botrule Rrule" valign="top">Olanzapine</td><td align="center" class="Botrule Rrule" valign="top">536</td><td align="center" class="Botrule Rrule" valign="top">23.7%</td><td align="center" class="Botrule Rrule" valign="top">483</td><td align="center" class="Botrule Rrule" valign="top">39.8%</td> </tr> <tr> <td align="center" class="Lrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top">Placebo</td><td align="center" class="Botrule Rrule" valign="top">304</td><td align="center" class="Botrule Rrule" valign="top">14.1%</td><td align="center" class="Botrule Rrule" valign="top">NA<span class="Sup">a</span></td><td align="center" class="Botrule Rrule" valign="top">NA<span class="Sup">a</span></td> </tr> <tr> <td align="center" class="Lrule Rrule" valign="top">Fasting LDL</td><td align="center" class="Rrule" valign="top">Normal to High</td><td align="center" class="Botrule Rrule" valign="top">Olanzapine</td><td align="center" class="Botrule Rrule" valign="top">154</td><td align="center" class="Botrule Rrule" valign="top">0%</td><td align="center" class="Botrule Rrule" valign="top">123</td><td align="center" class="Botrule Rrule" valign="top">7.3%</td> </tr> <tr> <td align="center" class="Lrule Rrule" valign="top">Cholesterol</td><td align="center" class="Botrule Rrule" valign="top">(&lt;100 mg/dL to ≥160 mg/dL)</td><td align="center" class="Botrule Rrule" valign="top">Placebo</td><td align="center" class="Botrule Rrule" valign="top">82</td><td align="center" class="Botrule Rrule" valign="top">1.2%</td><td align="center" class="Botrule Rrule" valign="top">NA<span class="Sup">a</span></td><td align="center" class="Botrule Rrule" valign="top">NA<span class="Sup">a</span></td> </tr> <tr> <td align="center" class="Lrule Rrule" valign="top"></td><td align="center" class="Rrule" valign="top">Borderline to High</td><td align="center" class="Botrule Rrule" valign="top">Olanzapine</td><td align="center" class="Botrule Rrule" valign="top">302</td><td align="center" class="Botrule Rrule" valign="top">10.6%</td><td align="center" class="Botrule Rrule" valign="top">284</td><td align="center" class="Botrule Rrule" valign="top">31.0%</td> </tr> <tr class="Last"> <td align="center" class="Botrule Lrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top">(≥100 mg/dL and &lt;160 mg/dL to ≥160 mg/dL)</td><td align="center" class="Botrule Rrule" valign="top">Placebo</td><td align="center" class="Botrule Rrule" valign="top">173</td><td align="center" class="Botrule Rrule" valign="top">8.1%</td><td align="center" class="Botrule Rrule" valign="top">NA<span class="Sup">a</span></td><td align="center" class="Botrule Rrule" valign="top">NA<span class="Sup">a</span></td> </tr> </tbody> </table></div>

In phase 1 of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE), over a median exposure of 9.2 months, the mean increase in triglycerides in patients taking olanzapine was 40.5 mg/dL. In phase 1 of CATIE, the mean increase in total cholesterol was 9.4 mg/dL.

Dose group differences with respect to increases in fasting triglycerides have been observed. In a 24-week randomized, double-blind, fixed-dose study with ZYPREXA RELPREVV, statistically significant differences among dose groups have been observed for fasting triglycerides. Incidence of changes from normal to high levels of fasting triglycerides at any time during the trial indicated significant differences between the highest dose group (300 mg/2 weeks, 24.5% [13/53]) and the lower dose groups (150 mg/2 weeks, 6.5% [4/62]; 405 mg/4 weeks, 9.8% [13/133]).

Olanzapine Monotherapy in Adolescents — The safety and efficacy of ZYPREXA RELPREVV have not been established in patients under the age of 18 years.

In an analysis of 3 placebo-controlled oral olanzapine monotherapy studies of adolescents (13-17 years), including those with schizophrenia (6 weeks) or bipolar I disorder (manic or mixed episodes) (3 weeks), olanzapine-treated adolescents had increases from baseline in mean fasting total cholesterol, LDL cholesterol, and triglycerides of 12.9 mg/dL, 6.5 mg/dL, and 28.4 mg/dL, respectively, compared to increases from baseline in mean fasting total cholesterol and LDL cholesterol of 1.3 mg/dL and 1.0 mg/dL, and a decrease in triglycerides of 1.1 mg/dL for placebo-treated adolescents. For fasting HDL cholesterol, no clinically meaningful differences were observed between olanzapine-treated adolescents and placebo-treated adolescents.

In long-term studies (at least 24 weeks), adolescents had increases from baseline in mean fasting total cholesterol, LDL cholesterol, and triglycerides of 5.5 mg/dL, 5.4 mg/dL, and 20.5 mg/dL, respectively, and a mean decrease in fasting HDL cholesterol of 4.5 mg/dL. Table 5 shows categorical changes in fasting lipids values in adolescents.

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 5: Changes in Fasting Lipids Values from Adolescent Oral Olanzapine Monotherapy Studies </span> </caption> <colgroup> <col align="left" width="13.229%"/> <col align="left" width="39.200%"/> <col align="left" width="11.429%"/> <col align="left" width="9.029%"/> <col align="left" width="9.043%"/> <col align="left" width="9.029%"/> <col align="left" width="9.043%"/> </colgroup> <tfoot> <tr class="First First Last Last"> <td align="left" colspan="7" valign="top"> <p class="First First Footnote"> <span class="Sup">a</span> Not Applicable.</p> </td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td align="center" class="Botrule Lrule Toprule" valign="top"></td><td align="center" class="Botrule Toprule" valign="top"></td><td align="center" class="Botrule Rrule Toprule" valign="top"></td><td align="center" class="Botrule Rrule Toprule" colspan="2" valign="top"><span class="Bold">Up to 6 weeks exposure</span></td><td align="center" class="Botrule Rrule Toprule" colspan="2" valign="top"><span class="Bold">At least 24 weeks exposure</span></td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"><span class="Bold">Laboratory Analyte</span></td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold">Category Change (at least once)<br/>from Baseline</span></td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold">Treatment Arm</span></td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold"> <br/>N</span></td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold"> <br/>Patients</span></td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold"> <br/>N</span></td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold"> <br/>Patients</span></td> </tr> <tr> <td align="center" class="Lrule Rrule" valign="top"></td><td align="center" class="Rrule" valign="top">Increase by ≥50 mg/dL</td><td align="center" class="Botrule Rrule" valign="top">Olanzapine</td><td align="center" class="Botrule Rrule" valign="top">138</td><td align="center" class="Botrule Rrule" valign="top">37.0%</td><td align="center" class="Botrule Rrule" valign="top">122</td><td align="center" class="Botrule Rrule" valign="top">45.9%</td> </tr> <tr> <td align="center" class="Lrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top">Placebo</td><td align="center" class="Botrule Rrule" valign="top">66</td><td align="center" class="Botrule Rrule" valign="top">15.2%</td><td align="center" class="Botrule Rrule" valign="top">NA<span class="Sup">a</span></td><td align="center" class="Botrule Rrule" valign="top">NA<span class="Sup">a</span></td> </tr> <tr> <td align="center" class="Lrule Rrule" valign="top">Fasting</td><td align="center" class="Rrule" valign="top">Normal to High</td><td align="center" class="Botrule Rrule" valign="top">Olanzapine</td><td align="center" class="Botrule Rrule" valign="top">67</td><td align="center" class="Botrule Rrule" valign="top">26.9%</td><td align="center" class="Botrule Rrule" valign="top">66</td><td align="center" class="Botrule Rrule" valign="top">36.4%</td> </tr> <tr> <td align="center" class="Lrule Rrule" valign="top">Triglycerides</td><td align="center" class="Botrule Rrule" valign="top">(&lt;90 mg/dL to &gt;130 mg/dL)</td><td align="center" class="Botrule Rrule" valign="top">Placebo</td><td align="center" class="Botrule Rrule" valign="top">28</td><td align="center" class="Botrule Rrule" valign="top">10.7%</td><td align="center" class="Botrule Rrule" valign="top">NA<span class="Sup">a</span></td><td align="center" class="Botrule Rrule" valign="top">NA<span class="Sup">a</span></td> </tr> <tr> <td align="center" class="Lrule Rrule" valign="top"></td><td align="center" class="Rrule" valign="top">Borderline to High</td><td align="center" class="Botrule Rrule" valign="top">Olanzapine</td><td align="center" class="Botrule Rrule" valign="top">37</td><td align="center" class="Botrule Rrule" valign="top">59.5%</td><td align="center" class="Botrule Rrule" valign="top">31</td><td align="center" class="Botrule Rrule" valign="top">64.5%</td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top">(≥90 mg/dL and ≤130 mg/dL to &gt;130 mg/dL)</td><td align="center" class="Botrule Rrule" valign="top">Placebo</td><td align="center" class="Botrule Rrule" valign="top">17</td><td align="center" class="Botrule Rrule" valign="top">35.3%</td><td align="center" class="Botrule Rrule" valign="top">NA<span class="Sup">a</span></td><td align="center" class="Botrule Rrule" valign="top">NA<span class="Sup">a</span></td> </tr> <tr> <td align="center" class="Botrule Lrule" valign="top"></td><td align="center" class="Botrule" valign="top"></td><td align="center" class="Botrule" valign="top"></td><td align="center" class="Botrule" valign="top"></td><td align="center" class="Botrule" valign="top"></td><td align="center" class="Botrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"></td> </tr> <tr> <td align="center" class="Lrule Rrule" valign="top"></td><td align="center" class="Rrule" valign="top">Increase by ≥40 mg/dL</td><td align="center" class="Botrule Rrule" valign="top">Olanzapine</td><td align="center" class="Botrule Rrule" valign="top">138</td><td align="center" class="Botrule Rrule" valign="top">14.5%</td><td align="center" class="Botrule Rrule" valign="top">122</td><td align="center" class="Botrule Rrule" valign="top">14.8%</td> </tr> <tr> <td align="center" class="Lrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top">Placebo</td><td align="center" class="Botrule Rrule" valign="top">66</td><td align="center" class="Botrule Rrule" valign="top">4.5%</td><td align="center" class="Botrule Rrule" valign="top">NA<span class="Sup">a</span></td><td align="center" class="Botrule Rrule" valign="top">NA<span class="Sup">a</span></td> </tr> <tr> <td align="center" class="Lrule Rrule" valign="top">Fasting Total</td><td align="center" class="Rrule" valign="top">Normal to High</td><td align="center" class="Botrule Rrule" valign="top">Olanzapine</td><td align="center" class="Botrule Rrule" valign="top">87</td><td align="center" class="Botrule Rrule" valign="top">6.9%</td><td align="center" class="Botrule Rrule" valign="top">78</td><td align="center" class="Botrule Rrule" valign="top">7.7%</td> </tr> <tr> <td align="center" class="Lrule Rrule" valign="top">Cholesterol</td><td align="center" class="Botrule Rrule" valign="top">(&lt;170 mg/dL to ≥200 mg/dL)</td><td align="center" class="Botrule Rrule" valign="top">Placebo</td><td align="center" class="Botrule Rrule" valign="top">43</td><td align="center" class="Botrule Rrule" valign="top">2.3%</td><td align="center" class="Botrule Rrule" valign="top">NA<span class="Sup">a</span></td><td align="center" class="Botrule Rrule" valign="top">NA<span class="Sup">a</span></td> </tr> <tr> <td align="center" class="Lrule Rrule" valign="top"></td><td align="center" class="Rrule" valign="top">Borderline to High</td><td align="center" class="Botrule Rrule" valign="top">Olanzapine</td><td align="center" class="Botrule Rrule" valign="top">36</td><td align="center" class="Botrule Rrule" valign="top">38.9%</td><td align="center" class="Botrule Rrule" valign="top">33</td><td align="center" class="Botrule Rrule" valign="top">57.6%</td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top">(≥170 mg/dL and &lt;200 mg/dL to ≥200 mg/dL)</td><td align="center" class="Botrule Rrule" valign="top">Placebo</td><td align="center" class="Botrule Rrule" valign="top">13</td><td align="center" class="Botrule Rrule" valign="top">7.7%</td><td align="center" class="Botrule Rrule" valign="top">NA<span class="Sup">a</span></td><td align="center" class="Botrule Rrule" valign="top">NA<span class="Sup">a</span></td> </tr> <tr> <td align="center" class="Botrule Lrule" valign="top"></td><td align="center" class="Botrule" valign="top"></td><td align="center" class="Botrule" valign="top"></td><td align="center" class="Botrule" valign="top"></td><td align="center" class="Botrule" valign="top"></td><td align="center" class="Botrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"></td> </tr> <tr> <td align="center" class="Lrule Rrule" valign="top"></td><td align="center" class="Rrule" valign="top">Increase by ≥30 mg/dL</td><td align="center" class="Botrule Rrule" valign="top">Olanzapine</td><td align="center" class="Botrule Rrule" valign="top">137</td><td align="center" class="Botrule Rrule" valign="top">17.5%</td><td align="center" class="Botrule Rrule" valign="top">121</td><td align="center" class="Botrule Rrule" valign="top">22.3%</td> </tr> <tr> <td align="center" class="Lrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top">Placebo</td><td align="center" class="Botrule Rrule" valign="top">63</td><td align="center" class="Botrule Rrule" valign="top">11.1%</td><td align="center" class="Botrule Rrule" valign="top">NA<span class="Sup">a</span></td><td align="center" class="Botrule Rrule" valign="top">NA<span class="Sup">a</span></td> </tr> <tr> <td align="center" class="Lrule Rrule" valign="top">Fasting LDL</td><td align="center" class="Rrule" valign="top">Normal to High</td><td align="center" class="Botrule Rrule" valign="top">Olanzapine</td><td align="center" class="Botrule Rrule" valign="top">98</td><td align="center" class="Botrule Rrule" valign="top">5.1%</td><td align="center" class="Botrule Rrule" valign="top">92</td><td align="center" class="Botrule Rrule" valign="top">10.9%</td> </tr> <tr> <td align="center" class="Lrule Rrule" valign="top">Cholesterol</td><td align="center" class="Botrule Rrule" valign="top">(&lt;110 mg/dL to ≥130 mg/dL)</td><td align="center" class="Botrule Rrule" valign="top">Placebo</td><td align="center" class="Botrule Rrule" valign="top">44</td><td align="center" class="Botrule Rrule" valign="top">4.5%</td><td align="center" class="Botrule Rrule" valign="top">NA<span class="Sup">a</span></td><td align="center" class="Botrule Rrule" valign="top">NA<span class="Sup">a</span></td> </tr> <tr> <td align="center" class="Lrule Rrule" valign="top"></td><td align="center" class="Rrule" valign="top">Borderline to High</td><td align="center" class="Botrule Rrule" valign="top">Olanzapine</td><td align="center" class="Botrule Rrule" valign="top">29</td><td align="center" class="Botrule Rrule" valign="top">48.3%</td><td align="center" class="Botrule Rrule" valign="top">21</td><td align="center" class="Botrule Rrule" valign="top">47.6%</td> </tr> <tr class="Last"> <td align="center" class="Botrule Lrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top">(≥110 mg/dL and &lt;130 mg/dL to ≥130 mg/dL)</td><td align="center" class="Botrule Rrule" valign="top">Placebo</td><td align="center" class="Botrule Rrule" valign="top">9</td><td align="center" class="Botrule Rrule" valign="top">0%</td><td align="center" class="Botrule Rrule" valign="top">NA<span class="Sup">a</span></td><td align="center" class="Botrule Rrule" valign="top">NA<span class="Sup">a</span></td> </tr> </tbody> </table></div>

Weight Gain

Potential consequences of weight gain should be considered prior to starting olanzapine. Patients receiving olanzapine should receive regular monitoring of weight [see Patient Counseling Information (17)].

Olanzapine Monotherapy in Adults — In an analysis of 13 placebo-controlled olanzapine monotherapy studies, olanzapine-treated patients gained an average of 2.6 kg (5.7 lb) compared to an average 0.3 kg (0.6 lb) weight loss in placebo-treated patients with a median exposure of 6 weeks; 22.2% of olanzapine-treated patients gained at least 7% of their baseline weight, compared to 3% of placebo-treated patients, with a median exposure to event of 8 weeks; 4.2% of olanzapine-treated patients gained at least 15% of their baseline weight, compared to 0.3% of placebo-treated patients, with a median exposure to event of 12 weeks. Clinically significant weight gain was observed across all baseline Body Mass Index (BMI) categories. Discontinuation due to weight gain occurred in 0.2% of olanzapine-treated patients and in 0% of placebo-treated patients.

In long-term studies (at least 48 weeks), the mean weight gain was 5.6 kg (12.3 lb) (median exposure of 573 days, N=2021). The percentages of patients who gained at least 7%, 15%, or 25% of their baseline body weight with long-term exposure were 64%, 32%, and 12%, respectively. Discontinuation due to weight gain occurred in 0.4% of olanzapine-treated patients following at least 48 weeks of exposure.

Table 6 includes data on adult weight gain with olanzapine pooled from 86 clinical trials. The data in each column represent data for those patients who completed treatment periods of the durations specified.

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 6: Weight Gain with Olanzapine Use in Adults</span> </caption> <col align="left" width="20.950%"/> <col align="left" width="15.800%"/> <col align="left" width="15.817%"/> <col align="left" width="15.800%"/> <col align="left" width="15.817%"/> <col align="left" width="15.817%"/> <tbody class="Headless"> <tr class="First"> <td align="center" class="Lrule Rrule Toprule" valign="top"></td><td align="center" class="Rrule Toprule" valign="top"><span class="Bold">6 Weeks</span></td><td align="center" class="Rrule Toprule" valign="top"><span class="Bold">6 Months</span></td><td align="center" class="Rrule Toprule" valign="top"><span class="Bold">12 Months</span></td><td align="center" class="Rrule Toprule" valign="top"><span class="Bold">24 Months</span></td><td align="center" class="Rrule Toprule" valign="top"><span class="Bold">36 Months</span></td> </tr> <tr> <td align="center" class="Lrule Rrule" valign="top"><span class="Bold">Amount Gained</span></td><td align="center" class="Rrule" valign="top"><span class="Bold">(N=7465)</span></td><td align="center" class="Rrule" valign="top"><span class="Bold">(N=4162)</span></td><td align="center" class="Rrule" valign="top"><span class="Bold">(N=1345)</span></td><td align="center" class="Rrule" valign="top"><span class="Bold">(N=474)</span></td><td align="center" class="Rrule" valign="top"><span class="Bold">(N=147)</span></td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"><span class="Bold">kg (lb)</span></td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold">(%)</span></td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold">(%)</span></td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold">(%)</span></td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold">(%)</span></td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold">(%)</span></td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top">≤0</td><td align="center" class="Botrule Rrule" valign="top">26.2</td><td align="center" class="Botrule Rrule" valign="top">24.3</td><td align="center" class="Botrule Rrule" valign="top">20.8</td><td align="center" class="Botrule Rrule" valign="top">23.2</td><td align="center" class="Botrule Rrule" valign="top">17.0</td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top">0 to ≤5 (0-11 lb)</td><td align="center" class="Botrule Rrule" valign="top">57.0</td><td align="center" class="Botrule Rrule" valign="top">36.0</td><td align="center" class="Botrule Rrule" valign="top">26.0</td><td align="center" class="Botrule Rrule" valign="top">23.4</td><td align="center" class="Botrule Rrule" valign="top">25.2</td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top">&gt;5 to ≤10 (11-22 lb)</td><td align="center" class="Botrule Rrule" valign="top">14.9</td><td align="center" class="Botrule Rrule" valign="top">24.6</td><td align="center" class="Botrule Rrule" valign="top">24.2</td><td align="center" class="Botrule Rrule" valign="top">24.1</td><td align="center" class="Botrule Rrule" valign="top">18.4</td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top">&gt;10 to ≤15 (22-33 lb)</td><td align="center" class="Botrule Rrule" valign="top">1.8</td><td align="center" class="Botrule Rrule" valign="top">10.9</td><td align="center" class="Botrule Rrule" valign="top">14.9</td><td align="center" class="Botrule Rrule" valign="top">11.4</td><td align="center" class="Botrule Rrule" valign="top">17.0</td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top">&gt;15 to ≤20 (33-44 lb)</td><td align="center" class="Botrule Rrule" valign="top">0.1</td><td align="center" class="Botrule Rrule" valign="top">3.1</td><td align="center" class="Botrule Rrule" valign="top">8.6</td><td align="center" class="Botrule Rrule" valign="top">9.3</td><td align="center" class="Botrule Rrule" valign="top">11.6</td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top">&gt;20 to ≤25 (44-55 lb)</td><td align="center" class="Botrule Rrule" valign="top">0</td><td align="center" class="Botrule Rrule" valign="top">0.9</td><td align="center" class="Botrule Rrule" valign="top">3.3</td><td align="center" class="Botrule Rrule" valign="top">5.1</td><td align="center" class="Botrule Rrule" valign="top">4.1</td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top">&gt;25 to ≤30 (55-66 lb)</td><td align="center" class="Botrule Rrule" valign="top">0</td><td align="center" class="Botrule Rrule" valign="top">0.2</td><td align="center" class="Botrule Rrule" valign="top">1.4</td><td align="center" class="Botrule Rrule" valign="top">2.3</td><td align="center" class="Botrule Rrule" valign="top">4.8</td> </tr> <tr class="Last"> <td align="center" class="Botrule Lrule Rrule" valign="top">&gt;30 (&gt;66 lb)</td><td align="center" class="Botrule Rrule" valign="top">0</td><td align="center" class="Botrule Rrule" valign="top">0.1</td><td align="center" class="Botrule Rrule" valign="top">0.8</td><td align="center" class="Botrule Rrule" valign="top">1.2</td><td align="center" class="Botrule Rrule" valign="top">2</td> </tr> </tbody> </table></div>

Dose group differences with respect to weight gain have been observed in some studies. In a 24-week randomized, double-blind, fixed-dose study with ZYPREXA RELPREVV, mean baseline-to-endpoint increase in weight (150 mg/2 weeks, n=140: 0.67 kg; 405 mg/4 weeks, n=315: 0.89 kg; 300 mg/2 weeks, n=140: 1.70 kg) was observed with significant differences between the lowest and highest dose groups (150 vs 300 mg/2 weeks). In a single 8-week randomized, double-blind, fixed-dose study comparing 10 (N=199), 20 (N=200) and 40 (N=200) mg/day of oral olanzapine in adult patients with schizophrenia or schizoaffective disorder, mean baseline to endpoint increase in weight (10 mg/day: 1.9 kg; 20 mg/day: 2.3 kg; 40 mg/day: 3 kg) was observed with significant differences between 10 vs 40 mg/day.

Olanzapine Monotherapy in Adolescents — The safety and efficacy of ZYPREXA RELPREVV have not been established in patients under the age of 18 years.

Mean increase in weight in adolescents was greater than in adults. In 4 placebo-controlled trials, discontinuation due to weight gain occurred in 1% of olanzapine-treated patients, compared to 0% of placebo-treated patients.

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 7: Weight Gain with Oral Olanzapine Use in Adolescents from 4 Placebo-Controlled Trials</span> </caption> <col align="left" width="33.333%"/> <col align="left" width="33.333%"/> <col align="left" width="33.333%"/> <tbody class="Headless"> <tr class="First"> <td align="left" class="Botrule Lrule Rrule Toprule" valign="top"></td><td align="center" class="Botrule Rrule Toprule" valign="top"><span class="Bold">Olanzapine-treated patients</span></td><td align="center" class="Botrule Rrule Toprule" valign="top"><span class="Bold">Placebo-treated patients</span></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">Mean change in body weight from baseline (median exposure = 3 weeks)</td><td align="center" class="Botrule Rrule" valign="top">4.6 kg (10.1 lb)</td><td align="center" class="Botrule Rrule" valign="top">0.3 kg (0.7 lb)</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" rowspan="2" valign="top">Percentage of patients who gained at least 7% of baseline body weight</td><td align="center" class="Rrule" valign="top">40.6%</td><td align="center" class="Rrule" valign="top">9.8%</td> </tr> <tr> <td align="center" class="Botrule Rrule" valign="top">(median exposure to 7% = 4 weeks)</td><td align="center" class="Botrule Rrule" valign="top">(median exposure to 7% = 8 weeks)</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" rowspan="2" valign="top">Percentage of patients who gained at least 15% of baseline body weight</td><td align="center" class="Rrule" valign="top">7.1%</td><td align="center" class="Rrule" valign="top">2.7%</td> </tr> <tr class="Last"> <td align="center" class="Botrule Rrule" valign="top">(median exposure to 15% = 19 weeks)</td><td align="center" class="Botrule Rrule" valign="top">(median exposure to 15% = 8 weeks)</td> </tr> </tbody> </table></div>

In long-term studies (at least 24 weeks), the mean weight gain was 11.2 kg (24.6 lb); (median exposure of 201 days, N=179). The percentages of adolescents who gained at least 7%, 15%, or 25% of their baseline body weight with long-term exposure were 89%, 55%, and 29%, respectively. Among adolescent patients, mean weight gain by baseline BMI category was 11.5 kg (25.3 lb), 12.1 kg (26.6 lb), and 12.7 kg (27.9 lb), respectively, for normal (N=106), overweight (N=26) and obese (N=17). Discontinuation due to weight gain occurred in 2.2% of olanzapine-treated patients following at least 24 weeks of exposure.

Table 8 shows data on adolescent weight gain with olanzapine pooled from 6 clinical trials. The data in each column represent data for those patients who completed treatment periods of the durations specified. Little clinical trial data is available on weight gain in adolescents with olanzapine beyond 6 months of treatment.

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 8: Weight Gain with Olanzapine Use in Adolescents</span> </caption> <col align="left" width="33.333%"/> <col align="left" width="33.333%"/> <col align="left" width="33.333%"/> <tbody class="Headless"> <tr class="First"> <td align="center" class="Lrule Rrule Toprule" valign="top"></td><td align="center" class="Rrule Toprule" valign="top"><span class="Bold">6 Weeks</span></td><td align="center" class="Rrule Toprule" valign="top"><span class="Bold">6 Months</span></td> </tr> <tr> <td align="center" class="Lrule Rrule" valign="top"><span class="Bold">Amount Gained</span></td><td align="center" class="Rrule" valign="top"><span class="Bold">(N=243)</span></td><td align="center" class="Rrule" valign="top"><span class="Bold">(N=191)</span></td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"><span class="Bold">kg (lb)</span></td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold">(%)</span></td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold">(%)</span></td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top">≤0</td><td align="center" class="Botrule Rrule" valign="top">2.9</td><td align="center" class="Botrule Rrule" valign="top">2.1</td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top">0 to ≤5 (0-11 lb)</td><td align="center" class="Botrule Rrule" valign="top">47.3</td><td align="center" class="Botrule Rrule" valign="top">24.6</td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top">&gt;5 to ≤10 (11-22 lb)</td><td align="center" class="Botrule Rrule" valign="top">42.4</td><td align="center" class="Botrule Rrule" valign="top">26.7</td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top">&gt;10 to ≤15 (22-33 lb)</td><td align="center" class="Botrule Rrule" valign="top">5.8</td><td align="center" class="Botrule Rrule" valign="top">22.0</td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top">&gt;15 to ≤20 (33-44 lb)</td><td align="center" class="Botrule Rrule" valign="top">0.8</td><td align="center" class="Botrule Rrule" valign="top">12.6</td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top">&gt;20 to ≤25 (44-55 lb)</td><td align="center" class="Botrule Rrule" valign="top">0.8</td><td align="center" class="Botrule Rrule" valign="top">9.4</td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top">&gt;25 to ≤30 (55-66 lb)</td><td align="center" class="Botrule Rrule" valign="top">0</td><td align="center" class="Botrule Rrule" valign="top">2.1</td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top">&gt;30 to ≤35 (66-77 lb)</td><td align="center" class="Botrule Rrule" valign="top">0</td><td align="center" class="Botrule Rrule" valign="top">0</td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top">&gt;35 to ≤40 (77-88 lb)</td><td align="center" class="Botrule Rrule" valign="top">0</td><td align="center" class="Botrule Rrule" valign="top">0</td> </tr> <tr class="Last"> <td align="center" class="Botrule Lrule Rrule" valign="top">&gt;40 (&gt;88 lb)</td><td align="center" class="Botrule Rrule" valign="top">0</td><td align="center" class="Botrule Rrule" valign="top">0.5</td> </tr> </tbody> </table></div>

A syndrome of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with antipsychotic drugs. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to rely upon prevalence estimates to predict, at the inception of antipsychotic treatment, which patients are likely to develop the syndrome. Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown.

The risk of developing tardive dyskinesia and the likelihood that it will become irreversible are believed to increase as the duration of treatment and the total cumulative dose of antipsychotic drugs administered to the patient increase. However, the syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses or may even arise after discontinuation of treatment.

Tardive dyskinesia may remit, partially or completely, if antipsychotic treatment is withdrawn. Antipsychotic treatment, itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome and thereby may possibly mask the underlying process. The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown.

Given these considerations, olanzapine should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia. Chronic antipsychotic treatment should generally be reserved for patients (1) who suffer from a chronic illness that is known to respond to antipsychotic drugs, and (2) for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate. In patients who do require chronic treatment, the smallest dose and the shortest duration of treatment producing a satisfactory clinical response should be sought. The need for continued treatment should be reassessed periodically.

If signs and symptoms of tardive dyskinesia appear in a patient on olanzapine, drug discontinuation should be considered. However, some patients may require treatment with olanzapine despite the presence of the syndrome.

ZYPREXA RELPREVV may induce orthostatic hypotension associated with dizziness, tachycardia, bradycardia and, in some patients, syncope, probably reflecting its α1-adrenergic antagonistic properties [see Patient Counseling Information (17)]. Syncope-related adverse reactions were reported in 0.1% of patients treated with ZYPREXA RELPREVV in clinical studies.

From an analysis of the vital sign data in an integrated database of 41 completed clinical studies in adult patients treated with oral olanzapine, orthostatic hypotension was recorded in ≥20% (1277/6030) of patients.

Olanzapine should be used with particular caution in patients with known cardiovascular disease (history of myocardial infarction or ischemia, heart failure, or conduction abnormalities), cerebrovascular disease, and conditions which would predispose patients to hypotension (dehydration, hypovolemia, and treatment with antihypertensive medications) where the occurrence of syncope, or hypotension and/or bradycardia might put the patient at increased medical risk. For patients in this population who have never taken oral olanzapine, tolerability should be established with oral olanzapine prior to initiating treatment with ZYPREXA RELPREVV [see Dosage and Administration (2.1)].

Caution is necessary in patients who receive treatment with other drugs having effects that can induce hypotension, bradycardia, respiratory or central nervous system depression [see Drug Interactions (7)].

ZYPREXA RELPREVV may cause somnolence, postural hypotension, motor and sensory instability, which may lead to falls and, consequently, fractures or other injuries. For patients with diseases, conditions, or medications that could exacerbate these effects, complete fall risk assessments when initiating antipsychotic treatment and recurrently for patients on long-term antipsychotic therapy.

Class Effect — In clinical trial and/or postmarketing experience, events of leukopenia/neutropenia have been reported temporally related to antipsychotic agents, including ZYPREXA. Agranulocytosis has also been reported.

Possible risk factors for leukopenia/neutropenia include pre-existing low white blood cell count (WBC) and history of drug-induced leukopenia/neutropenia. Patients with a history of a clinically significant low WBC or drug induced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and discontinuation of ZYPREXA RELPREVV should be considered at the first sign of a clinically significant decline in WBC in the absence of other causative factors.

Patients with clinically significant neutropenia should be carefully monitored for fever or other symptoms or signs of infection and treated promptly if such symptoms or signs occur. Patients with severe neutropenia (absolute neutrophil count <1000/mm3) should discontinue ZYPREXA RELPREVV and have their WBC followed until recovery.

Esophageal dysmotility and aspiration have been associated with antipsychotic drug use. Aspiration pneumonia is a common cause of morbidity and mortality in patients with advanced Alzheimer's disease. Olanzapine is not approved for the treatment of patients with Alzheimer's disease.

During premarketing testing of ZYPREXA RELPREVV, seizures occurred in 0.15% of patients. During premarketing testing of oral olanzapine, seizures occurred in 0.9% of olanzapine-treated patients. There were confounding factors that may have contributed to the occurrence of seizures in many of these cases.

Olanzapine should be used cautiously in patients with a history of seizures or with conditions that potentially lower the seizure threshold, e.g., Alzheimer's dementia. Olanzapine is not approved for the treatment of patients with Alzheimer's disease. Conditions that lower the seizure threshold may be more prevalent in a population of 65 years or older.

Sedation was a commonly reported adverse reaction associated with ZYPREXA RELPREVV treatment, occurring at an incidence of 8% in ZYPREXA RELPREVV patients compared to 2% in placebo patients. Somnolence and sedation adverse reactions led to discontinuation in 0.6% of patients in the premarketing ZYPREXA RELPREVV database.

Since olanzapine has the potential to impair judgment, thinking, or motor skills, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that olanzapine therapy does not affect them adversely. However, due to the risk of post-injection delirium/sedation syndrome after each injection, patients should not drive or operate heavy machinery for the remainder of the day of each injection [see Dosage and Administration (2.1), Warnings and Precautions (5.1), and Patient Counseling Information (17)].

Disruption of the body's ability to reduce core body temperature has been attributed to antipsychotic agents. Appropriate care is advised when prescribing ZYPREXA RELPREVV for patients who will be experiencing conditions which may contribute to an elevation in core body temperature, e.g., exercising strenuously, exposure to extreme heat, receiving concomitant medication with anticholinergic activity, or being subject to dehydration [see Patient Counseling Information (17)].

Olanzapine exhibits in vitro muscarinic receptor affinity [see Clinical Pharmacology 12.2]. In premarketing clinical trials with oral olanzapine, olanzapine was associated with constipation, dry mouth, and tachycardia, all adverse reactions possibly related to cholinergic antagonism. Such adverse reactions were not often the basis for discontinuations from olanzapine, but olanzapine should be used with caution in patients with a current diagnosis or prior history of urinary retention, clinically significant prostatic hypertrophy, constipation, or a history of paralytic ileus or related conditions. In post marketing experience, the risk for severe adverse reactions (including fatalities) was increased with concomitant use of anticholinergic medications [see Drug Interactions (7.1)].

As with other drugs that antagonize dopamine D2 receptors, olanzapine elevates prolactin levels, and the elevation persists during chronic administration. Hyperprolactinemia may suppress hypothalamic GnRH, resulting in reduced pituitary gonadotropin secretion. This, in turn, may inhibit reproductive function by impairing gonadal steroidogenesis in both female and male patients. Galactorrhea, amenorrhea, gynecomastia, and impotence have been reported in patients receiving prolactin-elevating compounds. Long-standing hyperprolactinemia when associated with hypogonadism may lead to decreased bone density in both female and male subjects.

Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin dependent in vitro, a factor of potential importance if the prescription of these drugs is contemplated in a patient with previously detected breast cancer. As is common with compounds which increase prolactin release, an increase in mammary gland neoplasia was observed in the oral olanzapine carcinogenicity studies conducted in mice and rats [see Nonclinical Toxicology (13.1)]. Published epidemiologic studies have shown inconsistent results when exploring the potential association between hyperprolactinemia and breast cancer.

In placebo-controlled olanzapine clinical studies (up to 12 weeks), changes from normal to high in prolactin concentrations were observed in 30% of adults treated with olanzapine as compared to 10.5% of adults treated with placebo. In a pooled analysis from clinical studies including 8136 adults treated with olanzapine, potentially associated clinical manifestations included menstrual-related events1 (2% [49/3240] of females), sexual function-related events2 (2% [150/8136] of females and males), and breast-related events3 (0.7% [23/3240] of females, 0.2% [9/4896] of males).

In placebo-controlled olanzapine monotherapy studies in adolescent patients (up to 6 weeks) with schizophrenia or bipolar I disorder (manic or mixed episodes), changes from normal to high in prolactin concentrations were observed in 47% of olanzapine-treated patients compared to 7% of placebo-treated patients. In a pooled analysis from clinical trials including 454 adolescents treated with olanzapine, potentially associated clinical manifestations included menstrual-related events1 (1% [2/168] of females), sexual function-related events2 (0.7% [3/454] of females and males), and breast-related events3 (2% [3/168] of females, 2% [7/286] of males) [see Use in Specific Populations (8.4)].

1 Based on a search of the following terms: amenorrhea, hypomenorrhea, menstruation delayed, and oligomenorrhea.

2 Based on a search of the following terms: anorgasmia, delayed ejaculation, erectile dysfunction, decreased libido, loss of libido, abnormal orgasm, and sexual dysfunction.

3 Based on a search of the following terms: breast discharge, enlargement or swelling, galactorrhea, gynecomastia, and lactation disorder.

Dose group differences with respect to prolactin elevation have been observed in some studies. In a 24-week randomized, double-blind, fixed-dose study with ZYPREXA RELPREVV, statistically significant differences among dose groups were observed for prolactin levels, with a mean baseline-to-endpoint increase observed in the highest dose group (300 mg/2 weeks, n=115: 3.57 ng/mL) relative to mean decreases in the lower dose groups (150 mg/2 weeks, n=109: -5.61 ng/mL; 405 mg/4 weeks, n=259: -2.76 ng/mL). In a single 8-week randomized, double-blind, fixed-dose study comparing 10 (N=199), 20 (N=200) and 40 (N=200) mg/day of oral olanzapine in adult patients with schizophrenia or schizoaffective disorder, incidence of prolactin elevation >24.2 ng/mL (female) or >18.77 ng/mL (male) at any time during the trial (10 mg/day: 31.2%; 20 mg/day: 42.7%; 40 mg/day: 61.1%) indicated significant differences between 10 vs 40 mg/day and 20 vs 40 mg/day.

Fasting blood glucose testing and lipid profile at the beginning of, and periodically during, treatment is recommended [see Warnings and Precautions (5.7) and Patient Counseling Information (17)].

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect or predict the rates observed in practice.

The information below for ZYPREXA RELPREVV is derived primarily from a clinical trial database consisting of 2058 patients with approximately 1948 patient years of exposure to ZYPREXA RELPREVV. This database includes safety data from 6 open-label studies and 2 double-blind comparator studies, conducted in patients with schizophrenia or schizoaffective disorder. Additionally, data obtained from patients treated with oral olanzapine are also presented below. Adverse reactions were assessed by the collection of adverse reactions, vital signs, weights, laboratory analytes, ECGs, and the results of physical and ophthalmologic examinations. In the tables and tabulations that follow for ZYPREXA RELPREVV, the MedDRA terminology has been used to classify reported adverse reactions. Data obtained from oral olanzapine studies was reported using the COSTART and MedDRA dictionaries.

The stated frequencies of adverse reactions represent the proportion of individuals who experienced, at least once, a treatment-emergent adverse reaction of the type listed. A reaction was considered treatment emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation. Reactions listed elsewhere in labeling may not be repeated below. The entire label should be read to gain a complete understanding of the safety profile of ZYPREXA RELPREVV.

The prescriber should be aware that the figures in the tables and tabulations cannot be used to predict the incidence of side effects in the course of usual medical practice where patient characteristics and other factors differ from those that prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators. The cited figures, however, do provide the prescribing healthcare provider with some basis for estimating the relative contribution of drug and nondrug factors to the adverse reaction incidence in the population studied.

Adverse Reactions Associated with Discontinuation of Treatment in a Short-Term, Placebo-Controlled Trial

Overall, there was no difference in the incidence of discontinuation due to adverse reactions between ZYPREXA RELPREVV (4%; 13/306 patients) and placebo (5%; 5/98 patients) in an 8-week trial.

Commonly Observed Adverse Reactions in a Short-Term, Placebo-Controlled Trial

In an 8-week trial, treatment-emergent adverse reactions with an incidence of 5% or greater in at least one of the ZYPREXA RELPREVV treatment groups (210 mg/2 weeks, 405 mg/4 weeks, or 300 mg/2 weeks) and greater than placebo were: headache, sedation, weight gain, cough, diarrhea, back pain, nausea, somnolence, dry mouth, nasopharyngitis, increased appetite, and vomiting.

Adverse Reactions Occurring at an Incidence of 2% or More among ZYPREXA RELPREVV-Treated Patients in a Short-Term, Placebo-Controlled Trial

Table 9 enumerates the incidence, rounded to the nearest percent, of treatment-emergent adverse reactions that occurred in 2% or more of patients treated with ZYPREXA RELPREVV and with incidence greater than placebo who participated in the 8-week, placebo-controlled trial.

<div class="scrollingtable"><table class="Noautorules" width="100%"> <caption> <span>Table 9: Treatment-Emergent Adverse Reactions: Incidence in a Short-Term, Placebo-Controlled Clinical Trial with ZYPREXA RELPREVV</span> </caption> <col align="left" width="43.460%"/> <col align="left" width="11.540%"/> <col align="left" width="15.000%"/> <col align="left" width="15.000%"/> <col align="left" width="15.000%"/> <tfoot> <tr> <td align="left" colspan="5" valign="top"> <p class="First Footnote"> <span class="Sup">a</span> The term abdominal pain upper was combined under abdominal pain.</p> </td> </tr> <tr> <td align="left" colspan="5" valign="top"> <p class="First Footnote"> <span class="Sup">b</span> The term tooth abscess was combined under tooth infection.</p> </td> </tr> <tr> <td align="left" colspan="5" valign="top"> <p class="First Footnote"> <span class="Sup">c</span> The terms alanine aminotransferase increased, aspartate aminotransferase increased, and gamma-glutamyltransferase increased were combined under hepatic enzyme increased.</p> </td> </tr> <tr> <td align="left" colspan="5" valign="top"> <p class="First Footnote"> <span class="Sup">d</span> The term tension headache was combined under headache.</p> </td> </tr> <tr> <td align="left" colspan="5" valign="top"> <p class="First Footnote"> <span class="Sup">e</span> The term somnolence was combined under sedation.</p> </td> </tr> <tr> <td align="left" colspan="5" valign="top"> <p class="First Footnote"> <span class="Sup">f</span> The term sinus congestion was combined under nasal congestion.</p> </td> </tr> </tfoot> <tbody class="Headless"> <tr> <td align="left" valign="top"></td><td align="center" class="Botrule" colspan="4" valign="top"><span class="Bold">Percentage of Patients Reporting Adverse Event</span></td> </tr> <tr> <td align="left" valign="top"></td><td align="center" valign="top"></td><td align="center" valign="top"><span class="Bold">ZYPREXA RELPREVV</span></td><td align="center" valign="top"><span class="Bold">ZYPREXA RELPREVV</span></td><td align="center" valign="top"><span class="Bold">ZYPREXA RELPREVV</span></td> </tr> <tr> <td align="left" valign="top"></td><td align="center" valign="top"><span class="Bold">Placebo</span></td><td align="center" valign="top"><span class="Bold">405 mg/4 wks</span></td><td align="center" valign="top"><span class="Bold">210 mg/2 wks</span></td><td align="center" valign="top"><span class="Bold">300 mg/2 wks</span></td> </tr> <tr> <td align="left" class="Botrule" valign="top"><span class="Bold">Body System/Adverse Reaction</span></td><td align="center" class="Botrule" valign="top"><span class="Bold">(N=98)</span></td><td align="center" class="Botrule" valign="top"><span class="Bold">(N=100)</span></td><td align="center" class="Botrule" valign="top"><span class="Bold">(N=106)</span></td><td align="center" class="Botrule" valign="top"><span class="Bold">(N=100)</span></td> </tr> <tr> <td align="left" valign="top"><span class="Bold">Ear and Labyrinth Disorders</span></td><td align="center" valign="top"></td><td align="center" valign="top"></td><td align="center" valign="top"></td><td align="center" valign="top"></td> </tr> <tr> <td align="left" class="Botrule" valign="top">Ear pain</td><td align="center" class="Botrule" valign="top">2</td><td align="center" class="Botrule" valign="top">1</td><td align="center" class="Botrule" valign="top">1</td><td align="center" class="Botrule" valign="top">4</td> </tr> <tr> <td align="left" valign="top"><span class="Bold">Gastrointestinal Disorders</span></td><td align="center" valign="top"></td><td align="center" valign="top"></td><td align="center" valign="top"></td><td align="center" valign="top"></td> </tr> <tr> <td align="left" valign="top">Abdominal pain<span class="Sup">a</span></td><td align="center" valign="top">2</td><td align="center" valign="top">3</td><td align="center" valign="top">3</td><td align="center" valign="top">3</td> </tr> <tr> <td align="left" valign="top">Diarrhea</td><td align="center" valign="top">4</td><td align="center" valign="top">2</td><td align="center" valign="top">7</td><td align="center" valign="top">5</td> </tr> <tr> <td align="left" valign="top">Dry mouth</td><td align="center" valign="top">1</td><td align="center" valign="top">2</td><td align="center" valign="top">6</td><td align="center" valign="top">4</td> </tr> <tr> <td align="left" valign="top">Flatulence</td><td align="center" valign="top">0</td><td align="center" valign="top">2</td><td align="center" valign="top">2</td><td align="center" valign="top">1</td> </tr> <tr> <td align="left" valign="top">Nausea</td><td align="center" valign="top">2</td><td align="center" valign="top">5</td><td align="center" valign="top">5</td><td align="center" valign="top">4</td> </tr> <tr> <td align="left" valign="top">Toothache</td><td align="center" valign="top">0</td><td align="center" valign="top">3</td><td align="center" valign="top">4</td><td align="center" valign="top">3</td> </tr> <tr> <td align="left" class="Botrule" valign="top">Vomiting</td><td align="center" class="Botrule" valign="top">2</td><td align="center" class="Botrule" valign="top">6</td><td align="center" class="Botrule" valign="top">1</td><td align="center" class="Botrule" valign="top">2</td> </tr> <tr> <td align="left" valign="top"><span class="Bold">General Disorders and Administration Site Conditions</span></td><td align="center" valign="top"></td><td align="center" valign="top"></td><td align="center" valign="top"></td><td align="center" valign="top"></td> </tr> <tr> <td align="left" valign="top">Fatigue</td><td align="center" valign="top">2</td><td align="center" valign="top">4</td><td align="center" valign="top">2</td><td align="center" valign="top">3</td> </tr> <tr> <td align="left" valign="top">Injection site pain</td><td align="center" valign="top">0</td><td align="center" valign="top">2</td><td align="center" valign="top">3</td><td align="center" valign="top">2</td> </tr> <tr> <td align="left" valign="top">Pain</td><td align="center" valign="top">0</td><td align="center" valign="top">0</td><td align="center" valign="top">2</td><td align="center" valign="top">3</td> </tr> <tr> <td align="left" class="Botrule" valign="top">Pyrexia</td><td align="center" class="Botrule" valign="top">0</td><td align="center" class="Botrule" valign="top">2</td><td align="center" class="Botrule" valign="top">0</td><td align="center" class="Botrule" valign="top">0</td> </tr> <tr> <td align="left" valign="top"><span class="Bold">Infections and Infestations</span></td><td align="center" valign="top"></td><td align="center" valign="top"></td><td align="center" valign="top"></td><td align="center" valign="top"></td> </tr> <tr> <td align="left" valign="top">Nasopharyngitis</td><td align="center" valign="top">2</td><td align="center" valign="top">3</td><td align="center" valign="top">6</td><td align="center" valign="top">1</td> </tr> <tr> <td align="left" valign="top">Tooth infection<span class="Sup">b</span></td><td align="center" valign="top">0</td><td align="center" valign="top">4</td><td align="center" valign="top">0</td><td align="center" valign="top">0</td> </tr> <tr> <td align="left" valign="top">Upper respiratory tract infection</td><td align="center" valign="top">2</td><td align="center" valign="top">3</td><td align="center" valign="top">1</td><td align="center" valign="top">4</td> </tr> <tr> <td align="left" class="Botrule" valign="top">Viral infection</td><td align="center" class="Botrule" valign="top">0</td><td align="center" class="Botrule" valign="top">0</td><td align="center" class="Botrule" valign="top">0</td><td align="center" class="Botrule" valign="top">2</td> </tr> <tr> <td align="left" valign="top"><span class="Bold">Injury, Poisoning and Procedural Complications</span></td><td align="center" valign="top"></td><td align="center" valign="top"></td><td align="center" valign="top"></td><td align="center" valign="top"></td> </tr> <tr> <td align="left" class="Botrule" valign="top">Procedural pain</td><td align="center" class="Botrule" valign="top">0</td><td align="center" class="Botrule" valign="top">2</td><td align="center" class="Botrule" valign="top">0</td><td align="center" class="Botrule" valign="top">0</td> </tr> <tr> <td align="left" valign="top"><span class="Bold">Investigations</span></td><td align="center" valign="top"></td><td align="center" valign="top"></td><td align="center" valign="top"></td><td align="center" valign="top"></td> </tr> <tr> <td align="left" valign="top">Electrocardiogram QT-corrected interval prolonged</td><td align="center" valign="top">1</td><td align="center" valign="top">0</td><td align="center" valign="top">0</td><td align="center" valign="top">2</td> </tr> <tr> <td align="left" valign="top">Hepatic enzyme increased<span class="Sup">c</span></td><td align="center" valign="top">1</td><td align="center" valign="top">4</td><td align="center" valign="top">1</td><td align="center" valign="top">3</td> </tr> <tr> <td align="left" class="Botrule" valign="top">Weight increased</td><td align="center" class="Botrule" valign="top">5</td><td align="center" class="Botrule" valign="top">5</td><td align="center" class="Botrule" valign="top">6</td><td align="center" class="Botrule" valign="top">7</td> </tr> <tr> <td align="left" valign="top"><span class="Bold">Metabolism and Nutrition Disorders</span></td><td align="center" valign="top"></td><td align="center" valign="top"></td><td align="center" valign="top"></td><td align="center" valign="top"></td> </tr> <tr> <td align="left" class="Botrule" valign="top">Increased appetite</td><td align="center" class="Botrule" valign="top">0</td><td align="center" class="Botrule" valign="top">1</td><td align="center" class="Botrule" valign="top">4</td><td align="center" class="Botrule" valign="top">6</td> </tr> <tr> <td align="left" valign="top"><span class="Bold">Musculoskeletal and Connective Tissue Disorders</span></td><td align="center" valign="top"></td><td align="center" valign="top"></td><td align="center" valign="top"></td><td align="center" valign="top"></td> </tr> <tr> <td align="left" valign="top">Arthralgia</td><td align="center" valign="top">0</td><td align="center" valign="top">3</td><td align="center" valign="top">3</td><td align="center" valign="top">3</td> </tr> <tr> <td align="left" valign="top">Back pain</td><td align="center" valign="top">4</td><td align="center" valign="top">4</td><td align="center" valign="top">3</td><td align="center" valign="top">5</td> </tr> <tr> <td align="left" valign="top">Muscle spasms</td><td align="center" valign="top">0</td><td align="center" valign="top">3</td><td align="center" valign="top">1</td><td align="center" valign="top">2</td> </tr> <tr> <td align="left" class="Botrule" valign="top">Musculoskeletal stiffness</td><td align="center" class="Botrule" valign="top">1</td><td align="center" class="Botrule" valign="top">1</td><td align="center" class="Botrule" valign="top">4</td><td align="center" class="Botrule" valign="top">4</td> </tr> <tr> <td align="left" valign="top"><span class="Bold">Nervous System Disorders</span></td><td align="center" valign="top"></td><td align="center" valign="top"></td><td align="center" valign="top"></td><td align="center" valign="top"></td> </tr> <tr> <td align="left" valign="top">Dizziness</td><td align="center" valign="top">2</td><td align="center" valign="top">4</td><td align="center" valign="top">4</td><td align="center" valign="top">1</td> </tr> <tr> <td align="left" valign="top">Dysarthria</td><td align="center" valign="top">0</td><td align="center" valign="top">0</td><td align="center" valign="top">1</td><td align="center" valign="top">2</td> </tr> <tr> <td align="left" valign="top">Headache<span class="Sup">d</span></td><td align="center" valign="top">8</td><td align="center" valign="top">13</td><td align="center" valign="top">15</td><td align="center" valign="top">18</td> </tr> <tr> <td align="left" valign="top">Sedation<span class="Sup">e</span></td><td align="center" valign="top">7</td><td align="center" valign="top">13</td><td align="center" valign="top">8</td><td align="center" valign="top">13</td> </tr> <tr> <td align="left" class="Botrule" valign="top">Tremor</td><td align="center" class="Botrule" valign="top">1</td><td align="center" class="Botrule" valign="top">3</td><td align="center" class="Botrule" valign="top">0</td><td align="center" class="Botrule" valign="top">1</td> </tr> <tr> <td align="left" valign="top"><span class="Bold">Psychiatric Disorders</span></td><td align="center" valign="top"></td><td align="center" valign="top"></td><td align="center" valign="top"></td><td align="center" valign="top"></td> </tr> <tr> <td align="left" valign="top">Abnormal dreams</td><td align="center" valign="top">0</td><td align="center" valign="top">0</td><td align="center" valign="top">0</td><td align="center" valign="top">2</td> </tr> <tr> <td align="left" valign="top">Hallucination, auditory</td><td align="center" valign="top">2</td><td align="center" valign="top">3</td><td align="center" valign="top">1</td><td align="center" valign="top">0</td> </tr> <tr> <td align="left" valign="top">Restlessness</td><td align="center" valign="top">2</td><td align="center" valign="top">2</td><td align="center" valign="top">3</td><td align="center" valign="top">1</td> </tr> <tr> <td align="left" valign="top">Sleep disorder</td><td align="center" valign="top">1</td><td align="center" valign="top">0</td><td align="center" valign="top">0</td><td align="center" valign="top">2</td> </tr> <tr> <td align="left" class="Botrule" valign="top">Thinking abnormal</td><td align="center" class="Botrule" valign="top">1</td><td align="center" class="Botrule" valign="top">3</td><td align="center" class="Botrule" valign="top">0</td><td align="center" class="Botrule" valign="top">0</td> </tr> <tr> <td align="left" valign="top"><span class="Bold">Reproductive System and Breast Disorders</span></td><td align="center" valign="top"></td><td align="center" valign="top"></td><td align="center" valign="top"></td><td align="center" valign="top"></td> </tr> <tr> <td align="left" class="Botrule" valign="top">Vaginal discharge</td><td align="center" class="Botrule" valign="top">0</td><td align="center" class="Botrule" valign="top">0</td><td align="center" class="Botrule" valign="top">4</td><td align="center" class="Botrule" valign="top">4</td> </tr> <tr> <td align="left" valign="top"><span class="Bold">Respiratory, Thoracic and Mediastinal Disorders</span></td><td align="center" valign="top"></td><td align="center" valign="top"></td><td align="center" valign="top"></td><td align="center" valign="top"></td> </tr> <tr> <td align="left" valign="top">Cough</td><td align="center" valign="top">5</td><td align="center" valign="top">3</td><td align="center" valign="top">5</td><td align="center" valign="top">9</td> </tr> <tr> <td align="left" valign="top">Nasal congestion<span class="Sup">f</span></td><td align="center" valign="top">3</td><td align="center" valign="top">2</td><td align="center" valign="top">1</td><td align="center" valign="top">7</td> </tr> <tr> <td align="left" valign="top">Pharyngolaryngeal pain</td><td align="center" valign="top">2</td><td align="center" valign="top">2</td><td align="center" valign="top">3</td><td align="center" valign="top">3</td> </tr> <tr> <td align="left" class="Botrule" valign="top">Sneezing</td><td align="center" class="Botrule" valign="top">0</td><td align="center" class="Botrule" valign="top">0</td><td align="center" class="Botrule" valign="top">0</td><td align="center" class="Botrule" valign="top">2</td> </tr> <tr> <td align="left" valign="top"><span class="Bold">Skin and Subcutaneous Tissue Disorders</span></td><td align="center" valign="top"></td><td align="center" valign="top"></td><td align="center" valign="top"></td><td align="center" valign="top"></td> </tr> <tr> <td align="left" class="Botrule" valign="top">Acne</td><td align="center" class="Botrule" valign="top">0</td><td align="center" class="Botrule" valign="top">2</td><td align="center" class="Botrule" valign="top">0</td><td align="center" class="Botrule" valign="top">2</td> </tr> <tr> <td align="left" valign="top"><span class="Bold">Vascular Disorders</span></td><td align="center" valign="top"></td><td align="center" valign="top"></td><td align="center" valign="top"></td><td align="center" valign="top"></td> </tr> <tr> <td align="left" class="Botrule" valign="top">Hypertension</td><td align="center" class="Botrule" valign="top">0</td><td align="center" class="Botrule" valign="top">3</td><td align="center" class="Botrule" valign="top">2</td><td align="center" class="Botrule" valign="top">0</td> </tr> </tbody> </table></div>

Dose Dependency of Adverse Reactions

Dose group differences have been observed for weight, fasting triglycerides and prolactin elevation for ZYPREXA RELPREVV [see Warnings and Precautions (5.7, 5.17)].

A dose group difference for oral olanzapine has been observed for fatigue, dizziness, weight gain and prolactin elevation. In a single 8-week randomized, double-blind, fixed-dose study comparing 10 (N=199), 20 (N=200) and 40 (N=200) mg/day of oral olanzapine in adult patients with schizophrenia or schizoaffective disorder, incidence of fatigue (10 mg/day: 1.5%; 20 mg/day: 2.1%; 40 mg/day: 6.6%) was observed with significant differences between 10 vs 40 and 20 vs 40 mg/day. The incidence of dizziness (10 mg/day: 2.6%; 20 mg/day: 1.6%; 40 mg/day: 6.6%) was observed with significant differences between 20 vs 40 mg. Dose group differences were also noted for weight gain and prolactin elevation [see Warnings and Precautions (5.7, 5.17)].

Extrapyramidal Symptoms

The following table enumerates the percentage of patients with treatment-emergent extrapyramidal symptoms as assessed by categorical analyses of formal rating scales during acute therapy in a controlled clinical trial comparing oral olanzapine at 3 fixed doses with placebo in the treatment of schizophrenia in a 6-week trial.

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 10: Treatment-Emergent Extrapyramidal Symptoms Assessed by Rating Scales Incidence in a Fixed Dosage Range, Placebo-Controlled Clinical Trial of Oral Olanzapine in Schizophrenia — Acute Phase</span> </caption> <col align="left" width="20.000%"/> <col align="left" width="20.000%"/> <col align="left" width="20.000%"/> <col align="left" width="20.000%"/> <col align="left" width="20.000%"/> <tfoot> <tr class="First"> <td align="left" colspan="5" valign="top"> <p class="First Footnote"> <span class="Sup">a</span> Percentage of patients with a Simpson-Angus Scale total score &gt;3.</p> </td> </tr> <tr class="Last"> <td align="left" colspan="5" valign="top"> <p class="First Footnote"> <span class="Sup">b</span> Percentage of patients with a Barnes Akathisia Scale global score ≥2.</p> </td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td align="left" class="Lrule Rrule Toprule" valign="top"></td><td align="center" class="Botrule Rrule Toprule" colspan="4" valign="top"><span class="Bold">Percentage of Patients Reporting Event</span></td> </tr> <tr> <td align="left" class="Lrule Rrule" valign="top"></td><td align="center" class="Rrule" valign="top"></td><td align="center" class="Rrule" valign="top"><span class="Bold">Olanzapine</span></td><td align="center" class="Rrule" valign="top"><span class="Bold">Olanzapine</span></td><td align="center" class="Rrule" valign="top"><span class="Bold">Olanzapine</span></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold">Placebo</span></td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold">5 ± 2.5 mg/day</span></td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold">10 ± 2.5 mg/day</span></td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold">15 ± 2.5 mg/day</span></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">Parkinsonism<span class="Sup">a</span></td><td align="center" class="Botrule Rrule" valign="top">15</td><td align="center" class="Botrule Rrule" valign="top">14</td><td align="center" class="Botrule Rrule" valign="top">12</td><td align="center" class="Botrule Rrule" valign="top">14</td> </tr> <tr class="Last"> <td align="left" class="Botrule Lrule Rrule" valign="top">Akathisia<span class="Sup">b</span></td><td align="center" class="Botrule Rrule" valign="top">23</td><td align="center" class="Botrule Rrule" valign="top">16</td><td align="center" class="Botrule Rrule" valign="top">19</td><td align="center" class="Botrule Rrule" valign="top">27</td> </tr> </tbody> </table></div>

The following table enumerates the percentage of patients with treatment-emergent extrapyramidal symptoms as assessed by spontaneously reported adverse reactions during acute therapy in the same controlled clinical trial comparing olanzapine at 3 fixed doses with placebo in the treatment of schizophrenia in a 6-week trial.

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 11: Treatment-Emergent Extrapyramidal Symptoms Assessed by Adverse Reactions Incidence in a Fixed Dosage Range, Placebo-Controlled Clinical Trial of Oral Olanzapine in Schizophrenia — Acute Phase</span> </caption> <col align="left" width="23.680%"/> <col align="left" width="19.080%"/> <col align="left" width="19.080%"/> <col align="left" width="19.080%"/> <col align="left" width="19.080%"/> <tfoot> <tr class="First"> <td align="left" colspan="5" valign="top"> <p class="First Footnote"> <span class="Sup">a</span> Patients with the following COSTART terms were counted in this category: dystonia, generalized spasm, neck rigidity, oculogyric crisis, opisthotonos, torticollis.</p> </td> </tr> <tr> <td align="left" colspan="5" valign="top"> <p class="First Footnote"> <span class="Sup">b</span> Patients with the following COSTART terms were counted in this category: akinesia, cogwheel rigidity, extrapyramidal syndrome, hypertonia, hypokinesia, masked facies, tremor.</p> </td> </tr> <tr> <td align="left" colspan="5" valign="top"> <p class="First Footnote"> <span class="Sup">c</span> Patients with the following COSTART terms were counted in this category: akathisia, hyperkinesia.</p> </td> </tr> <tr> <td align="left" colspan="5" valign="top"> <p class="First Footnote"> <span class="Sup">d</span> Patients with the following COSTART terms were counted in this category: buccoglossal syndrome, choreoathetosis, dyskinesia, tardive dyskinesia.</p> </td> </tr> <tr class="Last"> <td align="left" colspan="5" valign="top"> <p class="First Footnote"> <span class="Sup">e</span> Patients with the following COSTART terms were counted in this category: movement disorder, myoclonus, twitching.</p> </td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td align="left" class="Lrule Rrule Toprule" valign="top"></td><td align="center" class="Botrule Rrule Toprule" colspan="4" valign="top"><span class="Bold">Percentage of Patients Reporting Event</span></td> </tr> <tr> <td align="left" class="Lrule Rrule" valign="top"></td><td align="center" class="Rrule" valign="top"></td><td align="center" class="Rrule" valign="top"><span class="Bold">Olanzapine</span></td><td align="center" class="Rrule" valign="top"><span class="Bold">Olanzapine</span></td><td align="center" class="Rrule" valign="top"><span class="Bold">Olanzapine</span></td> </tr> <tr> <td align="left" class="Lrule Rrule" valign="top"></td><td align="center" class="Rrule" valign="top"><span class="Bold">Placebo</span></td><td align="center" class="Rrule" valign="top"><span class="Bold">5 ± 2.5 mg/day</span></td><td align="center" class="Rrule" valign="top"><span class="Bold">10 ± 2.5 mg/day</span></td><td align="center" class="Rrule" valign="top"><span class="Bold">15 ± 2.5 mg/day</span></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold">(N=68)</span></td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold">(N=65)</span></td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold">(N=64)</span></td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold">(N=69)</span></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">Dystonic events<span class="Sup">a</span></td><td align="center" class="Botrule Rrule" valign="top">1</td><td align="center" class="Botrule Rrule" valign="top">3</td><td align="center" class="Botrule Rrule" valign="top">2</td><td align="center" class="Botrule Rrule" valign="top">3</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">Parkinsonism events<span class="Sup">b</span></td><td align="center" class="Botrule Rrule" valign="top">10</td><td align="center" class="Botrule Rrule" valign="top">8</td><td align="center" class="Botrule Rrule" valign="top">14</td><td align="center" class="Botrule Rrule" valign="top">20</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">Akathisia events<span class="Sup">c</span></td><td align="center" class="Botrule Rrule" valign="top">1</td><td align="center" class="Botrule Rrule" valign="top">5</td><td align="center" class="Botrule Rrule" valign="top">11</td><td align="center" class="Botrule Rrule" valign="top">10</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">Dyskinetic events<span class="Sup">d</span></td><td align="center" class="Botrule Rrule" valign="top">4</td><td align="center" class="Botrule Rrule" valign="top">0</td><td align="center" class="Botrule Rrule" valign="top">2</td><td align="center" class="Botrule Rrule" valign="top">1</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">Residual events<span class="Sup">e</span></td><td align="center" class="Botrule Rrule" valign="top">1</td><td align="center" class="Botrule Rrule" valign="top">2</td><td align="center" class="Botrule Rrule" valign="top">5</td><td align="center" class="Botrule Rrule" valign="top">1</td> </tr> <tr class="Last"> <td align="left" class="Botrule Lrule Rrule" valign="top">Any extrapyramidal event</td><td align="center" class="Botrule Rrule" valign="top">16</td><td align="center" class="Botrule Rrule" valign="top">15</td><td align="center" class="Botrule Rrule" valign="top">25</td><td align="center" class="Botrule Rrule" valign="top">32</td> </tr> </tbody> </table></div>

Dystonia, Class Effect: Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include: spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur at low doses, the frequency and severity are greater with high potency and at higher doses of first generation antipsychotic drugs. In general, an elevated risk of acute dystonia may be observed in males and younger age groups receiving antipsychotics; however, events of dystonia have been reported infrequently (<1%) with olanzapine use.

Other Adverse Reactions

Local Injection Site Reactions

Eleven ZYPREXA RELPREVV-treated patients (3.6%) and 0 placebo-treated patients experienced treatment-emergent injection-related adverse reactions (injection site pain, buttock pain, injection site mass, induration, injection site induration) in the placebo-controlled database. The most frequently occurring treatment-emergent adverse reaction was injection site pain (2.3% ZYPREXA RELPREVV-treated; 0% placebo-treated).

Other Adverse Reactions Observed During the Clinical Trial Evaluation of Olanzapine for Extended-Release Injectable Suspension

Injection site abscess has been reported in clinical trials with ZYPREXA RELPREVV therapy. Isolated cases required surgical intervention.

Commonly Observed Adverse Reactions During the Clinical Trial Evaluation of Oral Olanzapine

In clinical trials of oral olanzapine monotherapy for the treatment of schizophrenia in adult patients, treatment-emergent adverse reactions with an incidence of 5% or greater in the olanzapine treatment arm and at least twice that of placebo were: postural hypotension, constipation, weight gain, dizziness, personality disorder, and akathisia.

Other Adverse Reactions Observed During the Clinical Trial Evaluation of Oral Olanzapine

Following is a list of treatment-emergent adverse reactions reported by patients treated with oral olanzapine (at multiple doses ≥1 mg/day) in clinical trials. This listing is not intended to include reactions (1) already listed in previous tables or elsewhere in labeling, (2) for which a drug cause was remote, (3) which were so general as to be uninformative, (4) which were not considered to have significant clinical implications, or (5) which occurred at a rate equal to or less than placebo. Reactions are classified by body system using the following definitions: frequent adverse reactions are those occurring in at least 1/100 patients; infrequent adverse reactions are those occurring in 1/100 to 1/1000 patients; rare adverse reactions are those occurring in fewer than 1/1000 patients.

Body as a Whole — Infrequent: chills, face edema, photosensitivity reaction, suicide attempt1; Rare: chills and fever, hangover effect, sudden death1.

Cardiovascular System — Infrequent: cerebrovascular accident, vasodilatation.

Digestive System — Infrequent: abdominal distension, nausea and vomiting, tongue edema; Rare: ileus, intestinal obstruction, liver fatty deposit.

Hemic and Lymphatic System — Infrequent: thrombocytopenia.

Metabolic and Nutritional Disorders — Frequent: alkaline phosphatase increased; Infrequent: bilirubinemia, hypoproteinemia.

Musculoskeletal System — Rare: osteoporosis.

Nervous System — Infrequent: ataxia, dysarthria, libido decreased, stupor; Rare: coma.

Respiratory System — Infrequent: epistaxis; Rare: lung edema.

Skin and Appendages — Infrequent: alopecia.

Special Senses — Infrequent: abnormality of accommodation, dry eyes; Rare: mydriasis.

Urogenital System — Infrequent: amenorrhea2, breast pain, decreased menstruation, impotence2, increased menstruation2, menorrhagia2, metrorrhagia2, polyuria2, urinary frequency, urinary retention, urinary urgency, urination impaired.

1 These terms represent serious adverse events but do not meet the definition for adverse drug reactions. They are included here because of their seriousness.

2 Adjusted for gender.

Vital Signs and Laboratory Studies

Laboratory Changes

ZYPREXA RELPREVV in Adults: Statistically significant within group mean changes for ZYPREXA RELPREVV, which were also significantly different from placebo, were observed for the following: eosinophils, monocytes, cholesterol, low-density lipoprotein (LDL), triglycerides, and direct bilirubin. There were no statistically significant differences between ZYPREXA RELPREVV and placebo in the incidence of potentially clinically significant changes in any of the laboratory values studied.

Statistically significant within group mean changes for ZYPREXA RELPREVV, which were also significantly different from oral olanzapine (in a 24-week double-blind study), were observed for the following: gamma-glutamyltransferase (GGT) and sodium.

From an analysis of the laboratory data in an integrated database of 41 completed clinical studies in adult patients treated with oral olanzapine, high GGT levels were recorded in ≥1% (88/5245) of patients.

Statistically significant differences were observed between ZYPREXA RELPREVV and oral olanzapine for the incidence of treatment-emergent low platelet count (0% ZYPREXA RELPREVV vs 1% oral olanzapine); and low total bilirubin (2.8% ZYPREXA RELPREVV vs 0.7% for oral olanzapine). There was a statistically significant difference between ZYPREXA RELPREVV and oral olanzapine in potentially clinically significant changes for high leukocyte count (0% ZYPREXA RELPREVV vs 1% oral olanzapine).

Changes in aminotransferases observed with ZYPREXA RELPREVV treatment were similar to those reported with ZYPREXA treatment. In placebo-controlled ZYPREXA RELPREVV studies, clinically significant ALT elevations (≥3 times the upper limit of the normal range) were observed in 2.7% (8/291) of patients exposed to olanzapine compared to 3.2% (3/94) of the placebo patients. None of these patients experienced jaundice. In 3 of these patients, liver enzymes reverted to the normal range despite continued treatment, and in 5 cases enzymes values decreased, but were still above the normal range at the end of therapy.

Within the larger premarketing ZYPREXA RELPREVV database of 1886 patients with baseline ALT ≤90 IU/L, the incidence of ALT elevation to >200 IU/L was 0.8%. None of these patients experienced jaundice or other symptoms attributable to liver impairment and most had transient changes that tended to normalize while ZYPREXA RELPREVV treatment was continued.

From an analysis of the laboratory data in an integrated database of 41 completed clinical studies in adult patients treated with oral olanzapine, elevated uric acid was recorded in ≥3% (171/4641) of patients.

Olanzapine Monotherapy in Adults: An assessment of the premarketing experience for oral olanzapine revealed an association with asymptomatic increases in ALT, AST, and GGT. Within the original premarketing database of about 2400 adult patients with baseline ALT ≤90 IU/L, the incidence of ALT elevations to >200 IU/L was 2% (50/2381). None of these patients experienced jaundice or other symptoms attributable to liver impairment and most had transient changes that tended to normalize while olanzapine treatment was continued.

In placebo-controlled oral olanzapine monotherapy studies in adults, clinically significant ALT elevations (change from <3 times the upper limit of normal [ULN] at baseline to ≥3 times ULN) were observed in 5% (77/1426) of patients exposed to olanzapine compared to 1% (10/1187) of patients exposed to placebo. ALT elevations ≥5 times ULN were observed in 2% (29/1438) of olanzapine-treated patients, compared to 0.3% (4/1196) of placebo-treated patients. ALT values returned to normal, or were decreasing, at last follow-up in the majority of patients who either continued treatment with olanzapine or discontinued olanzapine. No patient with elevated ALT values experienced jaundice, liver failure, or met the criteria for Hy's Rule.

Caution should be exercised in patients with signs and symptoms of hepatic impairment, in patients with pre-existing conditions associated with limited hepatic functional reserve, and in patients who are being treated with potentially hepatotoxic drugs.

Oral olanzapine administration was also associated with increases in serum prolactin [see Warnings and Precautions (5.17)], with an asymptomatic elevation of the eosinophil count in 0.3% of patients, and with an increase in CPK.

ECG Changes — Comparison of ZYPREXA RELPREVV and oral olanzapine, in a 24 week study, revealed no significant differences on ECG changes. Between-group comparisons for pooled placebo-controlled trials revealed no significant oral olanzapine/placebo differences in the proportions of patients experiencing potentially important changes in ECG parameters, including QT, QTc, and PR intervals. Oral olanzapine use was associated with a mean increase in heart rate of 2.4 beats per minute compared to no change among placebo patients. This slight tendency to tachycardia may be related to olanzapine's potential for inducing orthostatic changes [see Warnings and Precautions (5.11)].

The following adverse reactions have been identified during post-approval use of ZYPREXA and ZYPREXA RELPREVV. Because these reactions are reported voluntarily from a population of uncertain size, it is difficult to reliably estimate their frequency or evaluate a causal relationship to drug exposure.

Adverse reactions reported since market introduction that were temporally (but not necessarily causally) related to ZYPREXA therapy include the following: allergic reaction (e.g., anaphylactoid reaction, angioedema, pruritus or urticaria), cholestatic or mixed liver injury, diabetic coma, diabetic ketoacidosis, discontinuation reaction (diaphoresis, nausea, or vomiting), drug reaction with eosinophilia and systemic symptoms (DRESS), hepatitis, jaundice, neutropenia, pancreatitis, priapism, rash, restless legs syndrome, rhabdomyolysis, salivary hypersecretion, stuttering1, venous thromboembolic events (including pulmonary embolism and deep venous thrombosis), fecal incontinence, and somnambulism. Random cholesterol levels of ≥240 mg/dL and random triglyceride levels of ≥1000 mg/dL have been reported. Additionally, injection site abscess has been reported in postmarketing reports with ZYPREXA RELPREVV therapy. Isolated cases required surgical intervention.

1 Stuttering was only studied in oral and long acting injection (LAI) formulations.

Diazepam — The co-administration of diazepam with olanzapine potentiated the orthostatic hypotension observed with olanzapine [see Drug Interactions (7.2)].

Inducers of CYP1A2 — Carbamazepine therapy (200 mg bid) causes an approximately 50% increase in the clearance of olanzapine. This increase is likely due to the fact that carbamazepine is a potent inducer of CYP1A2 activity. Higher daily doses of carbamazepine may cause an even greater increase in olanzapine clearance.

Alcohol — Ethanol (45 mg/70 kg single dose) did not have an effect on olanzapine pharmacokinetics. The co-administration of alcohol (i.e., ethanol) with olanzapine potentiated the orthostatic hypotension observed with olanzapine [see Drug Interactions (7.2)].

Inhibitors of CYP1A2 — Fluvoxamine, a CYP1A2 inhibitor, decreases the clearance of olanzapine. This results in a mean increase in olanzapine Cmax following fluvoxamine of 54% in female nonsmokers and 77% in male smokers. The mean increase in olanzapine AUC is 52% and 108%, respectively. Lower doses of olanzapine should be considered in patients receiving concomitant treatment with fluvoxamine.

Inhibitors of CYP2D6 — Fluoxetine caused a small decrease in olanzapine clearance leading to a minimal change in olanzapine steady-state concentrations and, therefore dose modification is not routinely recommended.

Warfarin — Warfarin (20 mg single dose) did not affect olanzapine pharmacokinetics [see Drug Interactions (7.2)].

Inducers of CYP1A2 or Glucuronyl Transferase Enzymes — Omeprazole and rifampin may cause an increase in olanzapine clearance.

Anticholinergic Drugs — Concomitant treatment with olanzapine and other drugs with anticholinergic activity can increase the risk for severe gastrointestinal adverse reactions related to hypomotility. ZYPREXA RELPREVV should be used with caution in patients receiving medications having anticholinergic (antimuscarinic) effects [see Warnings and Precautions (5.16)].

CNS Acting Drugs — Given the primary CNS effects of olanzapine, caution should be used when olanzapine is taken in combination with other centrally acting drugs and alcohol.

Antihypertensive Agents — Olanzapine, because of its potential for inducing hypotension, may enhance the effects of certain antihypertensive agents.

Levodopa and Dopamine Agonists — Olanzapine may antagonize the effects of levodopa and dopamine agonists.

Lorazepam (IM) — Co-administration of lorazepam does not significantly affect the pharmacokinetics of olanzapine, unconjugated lorazepam, or total lorazepam. However, this co-administration of lorazepam with olanzapine potentiated the somnolence observed with either drug alone.

Lithium — Multiple doses of olanzapine (10 mg for 8 days) did not influence the kinetics of lithium. Therefore, concomitant olanzapine administration does not require dosage adjustment of lithium.

Valproate — Olanzapine (10 mg daily for 2 weeks) did not affect the steady-state plasma concentrations of valproate. Therefore, concomitant olanzapine administration does not require dosage adjustment of valproate.

Effect of Olanzapine on Drug Metabolizing Enzymes — In vitro studies utilizing human liver microsomes suggest that olanzapine has little potential to inhibit CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A. Thus, olanzapine is unlikely to cause clinically important drug interactions mediated by these enzymes.

Imipramine — Single doses of olanzapine did not affect the pharmacokinetics of imipramine or its active metabolite desipramine.

Warfarin — Single doses of olanzapine did not affect the pharmacokinetics of warfarin [see Drug Interactions (7.1)].

Diazepam — Olanzapine did not influence the pharmacokinetics of diazepam or its active metabolite N-desmethyldiazepam. However, diazepam co-administered with olanzapine increased the orthostatic hypotension observed with either drug given alone [see Drug Interactions (7.1)].

Alcohol — Multiple doses of olanzapine did not influence the kinetics of ethanol [see Drug Interactions (7.1)].

Biperiden — Multiple doses of olanzapine did not influence the kinetics of biperiden.

Theophylline — Multiple doses of olanzapine did not affect the pharmacokinetics of theophylline or its metabolites.

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to atypical antipsychotics, including ZYPREXA RELPREVV, during pregnancy. Healthcare providers are encouraged to register patients by contacting the National Pregnancy Registry for Atypical Antipsychotics at 1-866-961-2388 or visit http://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/.

Risk Summary

Neonates exposed to antipsychotic drugs, including ZYPREXA RELPREVV, during the third trimester are at risk for extrapyramidal and/or withdrawal symptoms following delivery (see Clinical Considerations). Overall available data from published epidemiologic studies of pregnant women exposed to olanzapine have not established a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes (see Data). There are risks to the mother associated with untreated schizophrenia or bipolar I disorder and with exposure to antipsychotics, including ZYPREXA RELPREVV, during pregnancy (see Clinical Considerations).

Olanzapine was not teratogenic when administered orally to pregnant rats and rabbits at doses that are 9- and 30-times the daily oral maximum recommended human dose (MRHD), based on mg/m2 body surface area; some fetal toxicities were observed at these doses (see Data).

The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defects, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Clinical Considerations

Disease-associated maternal and embryo/fetal risk

There is a risk to the mother from untreated schizophrenia or bipolar I disorder, including increased risk of relapse, hospitalization, and suicide. Schizophrenia and bipolar I disorder are associated with increased adverse perinatal outcomes, including preterm birth. It is not known if this is a direct result of the illness or other comorbid factors.

Fetal/Neonatal adverse reactions

Extrapyramidal and/or withdrawal symptoms, including agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder have been reported in neonates who were exposed to antipsychotic drugs, including ZYPREXA RELPREVV, during the third trimester of pregnancy. These symptoms have varied in severity. Monitor neonates for extrapyramidal and/or withdrawal symptoms and manage symptoms appropriately. Some neonates recovered within hours or days without specific treatment; others required prolonged hospitalization.

Data

Human Data

Placental passage has been reported in published study reports; however, the placental passage ratio was highly variable ranging between 7% to 167% at birth following exposure during pregnancy. The clinical relevance of this finding is unknown.

Published data from observational studies, birth registries, case reports and meta-analyses that have evaluated the use of atypical antipsychotics during pregnancy do not establish an increased risk of major birth defects. A retrospective cohort study from a Medicaid database of 9258 women exposed to antipsychotics during pregnancy did not indicate an overall increased risk for major birth defects.

Animal Data

In oral reproduction studies in rats at doses up to 18 mg/kg/day and in rabbits at doses up to 30 mg/kg/day (9 and 30 times the daily oral MRHD based on mg/m2 body surface area, respectively), no evidence of teratogenicity was observed. In an oral rat teratology study, early resorptions and increased numbers of nonviable fetuses were observed at a dose of 18 mg/kg/day (9 times the daily oral MRHD based on mg/m2 body surface area), and gestation was prolonged at 10 mg/kg/day (5 times the daily oral MRHD based on mg/m2 body surface area). In an oral rabbit teratology study, fetal toxicity manifested as increased resorptions and decreased fetal weight, occurred at a maternally toxic dose of 30 mg/kg/day (30 times the daily oral MRHD based on mg/m2 body surface area). No evidence of teratogenicity or embryo-fetal toxicity was observed in rats or rabbits with olanzapine at intramuscular doses up to 75 mg/kg (1 and 2 times the MRHD of 300 mg every 2 weeks, respectively, based on mg/m2 body surface area).

Risk Summary

Olanzapine pamoate is present in human milk. There are reports of excess sedation, irritability, poor feeding, and extrapyramidal symptoms (tremors and abnormal muscle movements) in infants exposed to olanzapine pamoate through breast milk (see Clinical Considerations). There is no information on the effects of olanzapine pamoate on milk production.

The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for ZYPREXA RELPREVV and any potential adverse effects on the breastfed child from ZYPREXA RELPREVV or from the mother's underlying condition.

Infants exposed to ZYPREXA RELPREVV should be monitored for excess sedation, irritability, poor feeding, and extrapyramidal symptoms (tremors and abnormal muscle movements).

Infertility

Females

Based on the pharmacologic action of olanzapine (D2 receptor antagonism), treatment with ZYPREXA RELPREVV may result in an increase in serum prolactin levels, which may lead to a reversible reduction in fertility in females of reproductive potential [see Warnings and Precautions (5.17)].

Safety and effectiveness of ZYPREXA RELPREVV in children and adolescent patients have not been established [see Warnings and Precautions (5.7)].

Compared to patients from adult clinical trials, adolescents treated with oral ZYPREXA were likely to gain more weight, experience increased sedation, and have greater increases in total cholesterol, triglycerides, LDL cholesterol, prolactin and hepatic aminotransferase levels.

Clinical studies of ZYPREXA RELPREVV did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In the premarketing clinical studies with oral olanzapine, there was no indication of any different tolerability of olanzapine in elderly patients compared to younger patients with schizophrenia. Oral olanzapine studies in elderly patients with dementia-related psychosis have suggested that there may be a different tolerability profile in this population compared to younger patients with schizophrenia. Elderly patients with dementia-related psychosis treated with olanzapine are at an increased risk of death compared to placebo. In placebo-controlled studies of olanzapine in elderly patients with dementia-related psychosis, there was a higher incidence of cerebrovascular adverse events (e.g., stroke, transient ischemic attack) in patients treated with olanzapine compared to patients treated with placebo. In 5 placebo-controlled studies of olanzapine in elderly patients with dementia-related psychosis (n=1184), the following adverse reactions were reported in olanzapine-treated patients at an incidence of at least 2% and significantly greater than placebo-treated patients: falls, somnolence, peripheral edema, abnormal gait, urinary incontinence, lethargy, increased weight, asthenia, pyrexia, pneumonia, dry mouth and visual hallucinations. The rate of discontinuation due to adverse reactions was greater with olanzapine than placebo (13% vs 7%). Elderly patients with dementia-related psychosis treated with olanzapine are at an increased risk of death compared to placebo. Olanzapine is not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning, Warnings and Precautions (5.3), and Patient Counseling Information (17)]. Olanzapine is not approved for the treatment of patients with dementia-related psychosis. Also, the presence of factors that might decrease pharmacokinetic clearance or increase the pharmacodynamic response to olanzapine should lead to consideration of a lower starting dose for any geriatric patient [see Boxed Warning, Dosage and Administration (2.1), and Warnings and Precautions (5.3)].

In studies prospectively designed to assess abuse and dependence potential, olanzapine was shown to have acute depressive CNS effects but little or no potential of abuse or physical dependence in rats administered oral doses up to 15 times the daily oral MRHD (20 mg) and rhesus monkeys administered oral doses up to 8 times the daily oral MRHD based on mg/m2 body surface area.

Olanzapine has not been systematically studied in humans for its potential for abuse, tolerance, or physical dependence. Because ZYPREXA RELPREVV is to be administered by healthcare professionals, the potential for misuse or abuse by patients is low.

During premarketing clinical studies of ZYPREXA RELPREVV, adverse reactions that presented with signs and symptoms consistent with olanzapine overdose, in particular, sedation (including coma) and/or delirium, were reported in patients following an injection of ZYPREXA RELPREVV [see Boxed Warning and Dosage and Administration (2.1)]. These reactions occurred in <0.1% of injections and in approximately 2% of patients who received injections for up to 46 months. These reactions were correlated with an unintentional rapid increase in serum olanzapine concentrations to supra-therapeutic ranges in some cases. While a rapid and greater than expected increase in serum olanzapine concentration has been observed in some patients with these reactions, the exact mechanism by which the drug was unintentionally introduced into the blood stream is not known. Clinical signs and symptoms included dizziness, confusion, disorientation, slurred speech, altered gait, difficulty ambulating, weakness, agitation, extrapyramidal symptoms, hypertension, convulsion, and reduced level of consciousness ranging from mild sedation to coma. Time after injection to event ranged from soon after injection to greater than 3 hours after injection. The majority of patients were hospitalized and some required supportive care, including intubation, in several cases. All patients had largely recovered by 72 hours. The risk of an event is the same at each injection, so the risk per patient is cumulative (i.e., increases with the number of injections) [see Warnings and Precautions (5.1)].

In postmarketing reports of overdose with oral olanzapine alone, symptoms have been reported in the majority of cases. In symptomatic patients, symptoms with ≥10% incidence included agitation/aggressiveness, dysarthria, tachycardia, various extrapyramidal symptoms, and reduced level of consciousness ranging from sedation to coma. Among less commonly reported symptoms were the following potentially medically serious reactions: aspiration, cardiopulmonary arrest, cardiac arrhythmias (such as supraventricular tachycardia and 1 patient experiencing sinus pause with spontaneous resumption of normal rhythm), delirium, possible neuroleptic malignant syndrome, respiratory depression/arrest, convulsion, hypertension, and hypotension. Eli Lilly and Company has received reports of fatality in association with overdose of oral olanzapine alone. In 1 case of death, the amount of acutely ingested oral olanzapine was reported to be possibly as low as 450 mg of oral olanzapine; however, in another case, a patient was reported to survive an acute olanzapine ingestion of approximately 2 g of oral olanzapine.

Post-injection delirium/sedation syndrome may occur with each injection of ZYPREXA RELPREVV. Signs and symptoms consistent with olanzapine overdose have been observed, and access to emergency response services must be readily available for safe use [see Boxed Warning and Warnings and Precautions (5.1)].

There is no specific antidote to olanzapine. Therefore, appropriate supportive measures should be initiated. Hypotension and circulatory collapse should be treated with appropriate measures such as intravenous fluids and/or sympathomimetic agents. (Do not use epinephrine, dopamine, or other sympathomimetics with beta-agonist activity, since beta stimulation may worsen hypotension in the setting of olanzapine-induced alpha blockade.) Respiratory support, including ventilation, may be required. Close medical supervision and monitoring should continue until the patient recovers.

The possibility of multiple drug involvement should be considered. In case of acute overdosage, establish and maintain an airway and ensure adequate oxygenation and ventilation, which may include intubation. The possibility of obtundation, seizures, or dystonic reaction of the head and neck following overdose may create a risk of aspiration with induced emesis. Cardiovascular monitoring should commence immediately and should include continuous electrocardiographic monitoring to detect possible arrhythmias.

ZYPREXA RELPREVV is an atypical antipsychotic that belongs to the thienobenzodiazepine class. The chemical designation is 10H-thieno[2,3-b][1,5]benzodiazepine, 2-methyl-4-(4-methyl-1-piperazinyl)-,4,4′-methylenebis[3-hydroxy-2-naphthalenecarboxylate] (1:1), monohydrate. The formula is C17H22N4S•C23H14O6•H2O, which corresponds to a molecular weight of 718.8. The chemical structure is:

{ "type": "p", "children": [], "text": "ZYPREXA RELPREVV is an atypical antipsychotic that belongs to the thienobenzodiazepine class. The chemical designation is 10H-thieno[2,3-b][1,5]benzodiazepine, 2-methyl-4-(4-methyl-1-piperazinyl)-,4,4′-methylenebis[3-hydroxy-2-naphthalenecarboxylate] (1:1), monohydrate. The formula is C17H22N4S•C23H14O6•H2O, which corresponds to a molecular weight of 718.8. The chemical structure is:" }

ZYPREXA RELPREVV is a long-acting form of olanzapine and is intended for deep intramuscular gluteal injection only.

{ "type": "p", "children": [], "text": "ZYPREXA RELPREVV is a long-acting form of olanzapine and is intended for deep intramuscular gluteal injection only." }

ZYPREXA RELPREVV includes a single-dose vial of the drug product and a vial of the sterile diluent for ZYPREXA RELPREVV.

{ "type": "p", "children": [], "text": "ZYPREXA RELPREVV includes a single-dose vial of the drug product and a vial of the sterile diluent for ZYPREXA RELPREVV." }

The drug product is olanzapine pamoate monohydrate, present as a yellow solid in a glass vial equivalent to 210, 300, or 405 mg olanzapine base per vial. The diluent for ZYPREXA RELPREVV is a clear, colorless to slightly yellow solution in a glass vial and is composed of carboxymethylcellulose sodium, mannitol, polysorbate 80, sodium hydroxide and/or hydrochloric acid for pH adjustment, and water for injection. The drug product is suspended in the diluent for ZYPREXA RELPREVV to a target concentration of 150 mg olanzapine per mL prior to intramuscular injection.

{ "type": "p", "children": [], "text": "The drug product is olanzapine pamoate monohydrate, present as a yellow solid in a glass vial equivalent to 210, 300, or 405 mg olanzapine base per vial. The diluent for ZYPREXA RELPREVV is a clear, colorless to slightly yellow solution in a glass vial and is composed of carboxymethylcellulose sodium, mannitol, polysorbate 80, sodium hydroxide and/or hydrochloric acid for pH adjustment, and water for injection. The drug product is suspended in the diluent for ZYPREXA RELPREVV to a target concentration of 150 mg olanzapine per mL prior to intramuscular injection." }

The mechanism of action of olanzapine, in the listed indications is unclear. However, the efficacy of olanzapine in schizophrenia could be mediated through a combination of dopamine and serotonin type 2 (5HT2) antagonism.

Olanzapine binds with high affinity to the following receptors: serotonin 5HT2A/2C, 5HT6 (Ki=4, 11, and 5 nM, respectively), dopamine D1-4 (Ki=11-31 nM), histamine H1 (Ki=7 nM), and adrenergic α1 receptors (Ki=19 nM). Olanzapine is an antagonist with moderate affinity binding for serotonin 5HT3 (Ki=57 nM) and muscarinic M1-5 (Ki=73, 96, 132, 32, and 48 nM, respectively). Olanzapine binds with low affinity to GABAA, BZD, and β-adrenergic receptors (Ki>10 μM).

The fundamental pharmacokinetic properties of olanzapine are similar for ZYPREXA RELPREVV and orally administered olanzapine. Refer to the section below describing the pharmacokinetics of orally administered olanzapine for details.

Slow dissolution of ZYPREXA RELPREVV, a practically insoluble salt, after a deep intramuscular gluteal injection of a dose of ZYPREXA RELPREVV results in prolonged systemic olanzapine plasma concentrations that are sustained over a period of weeks to months. An injection every 2 or 4 weeks provides olanzapine plasma concentrations that are similar to those achieved by daily doses of oral olanzapine. The steady-state plasma concentrations for ZYPREXA RELPREVV for doses of 150 mg to 405 mg every 2 or 4 weeks are within the range of steady-state olanzapine plasma concentration known to have been associated with oral doses of 5 mg to 20 mg olanzapine once daily. The change to a slow release, rate-controlled absorption process is the only fundamental pharmacokinetic difference between the administration of ZYPREXA RELPREVV and orally administered olanzapine. The effective half-life for olanzapine after intramuscular ZYPREXA RELPREVV administration is approximately 30 days as compared to a half-life after oral administration of approximately 30 hours. Exposure to olanzapine may persist for a period of months after a ZYPREXA RELPREVV injection. The long persistence of systemic concentrations of olanzapine may be an important consideration for the long-term clinical management of the patient. Typical systemic olanzapine plasma concentrations reach a peak within the first week after injection and are at trough level immediately prior to the next injection. The olanzapine plasma concentration fluctuation between the peak and trough is comparable to the peak and trough fluctuations associated with once daily oral dosing.

Dose Proportionality and Oral Dose Correspondence — ZYPREXA RELPREVV provides a dose of 150, 210, 300, or 405 mg olanzapine. An injection of a larger dose produces a dose-proportional increase in the systemic exposure. The olanzapine exposure after doses of ZYPREXA RELPREVV corresponds to exposure for oral doses of olanzapine. A ZYPREXA RELPREVV dose of 300 mg olanzapine injected every two weeks delivers approximately 20 mg olanzapine per day and a ZYPREXA RELPREVV dose of 150 mg olanzapine injected every two weeks delivers approximately 10 mg per day. These ZYPREXA RELPREVV doses sustain steady-state olanzapine concentrations over long periods of treatment.

Pharmacokinetic Impact of Switching to ZYPREXA RELPREVV from Oral Olanzapine — The switch from oral olanzapine to ZYPREXA RELPREVV changes the pharmacokinetics from an elimination-rate-controlled to an absorption-rate-controlled process. The switch to ZYPREXA RELPREVV may require treatment for a period of approximately 3 months to re-establish steady-state conditions. Initial treatment with ZYPREXA RELPREVV is recommended at a dose corresponding to the mg/day oral dose [see Dosage and Administration (2.1)]. Plasma concentrations of olanzapine during the first injection interval may be lower than those maintained by a corresponding oral dose. Even though the concentrations are lower, the olanzapine concentrations remained within a therapeutically effective range and supplementation with orally administered olanzapine was generally not necessary in clinical trials.

Olanzapine is extensively distributed throughout the body, with a volume of distribution of approximately 1000 L. It is 93% bound to plasma proteins over the concentration range of 7 to 1100 ng/mL, binding primarily to albumin and α1-acid glycoprotein.

Metabolism and Elimination — Following a single oral dose of 14C labeled olanzapine, 7% of the dose of olanzapine was recovered in the urine as unchanged drug, indicating that olanzapine is highly metabolized. Approximately 57% and 30% of the dose was recovered in the urine and feces, respectively. In the plasma, olanzapine accounted for only 12% of the AUC for total radioactivity, indicating significant exposure to metabolites. After multiple dosing, the major circulating metabolites were the 10-N-glucuronide, present at steady state at 44% of the concentration of olanzapine, and 4′-N-desmethyl olanzapine, present at steady state at 31% of the concentration of olanzapine. Both metabolites lack pharmacological activity at the concentrations observed.

Direct glucuronidation and cytochrome P450 (CYP) mediated oxidation are the primary metabolic pathways for olanzapine. In vitro studies suggest that CYPs 1A2 and 2D6, and the flavin-containing monooxygenase system are involved in olanzapine oxidation. CYP2D6 mediated oxidation appears to be a minor metabolic pathway in vivo, because the clearance of olanzapine is not reduced in subjects who are deficient in this enzyme.

Intramuscular Formulations — There are two formulations of ZYPREXA which are available for intramuscular injection. One form (ZYPREXA RELPREVV) is described in this package insert. The other formulation (ZYPREXA IntraMuscular) is a solution of olanzapine. When ZYPREXA IntraMuscular is injected intramuscularly, olanzapine (as the free base) is rapidly absorbed and peak plasma concentrations occur within 15 to 45 minutes. With the exception of higher maximum plasma concentrations, the pharmacokinetics of olanzapine after ZYPREXA IntraMuscular are similar to those for orally administered olanzapine. Refer to the package insert for ZYPREXA IntraMuscular for additional information.

Specific Populations — In general, the decision to use ZYPREXA RELPREVV in specific populations should be thoughtfully considered. For patients who have never taken oral olanzapine, tolerability should be established with oral olanzapine prior to initiating treatment with ZYPREXA RELPREVV. The recommended starting dose is ZYPREXA RELPREVV 150 mg/4 wks, in patients who are debilitated, who have a predisposition to hypotensive reactions, who otherwise exhibit a combination of factors that may result in slower metabolism of olanzapine (e.g., nonsmoking female patients >65 years of age), or who may be more pharmacodynamically sensitive to olanzapine. When indicated, dose escalation should be performed with caution in these patients [see Dosage and Administration (2.1)]. Precautions noted below need to be carefully weighed.

Renal Impairment — Because olanzapine is highly metabolized before excretion and only 7% of the drug is excreted unchanged, renal dysfunction alone is unlikely to have a major impact on the pharmacokinetics of olanzapine. The pharmacokinetic characteristics of orally administered olanzapine were similar in patients with severe renal impairment and normal subjects, indicating that dosage adjustment based upon the degree of renal impairment is not required. In addition, olanzapine is not removed by dialysis. The effect of renal impairment on metabolite elimination has not been studied.

Hepatic Impairment — Although the presence of hepatic impairment may be expected to reduce the clearance of olanzapine, a study of the effect of impaired liver function in subjects (n=6) with clinically significant (Childs Pugh Classification A and B) cirrhosis revealed little effect on the pharmacokinetics of orally administered olanzapine.

Geriatric — In a study involving 24 healthy subjects, the mean elimination half-life of orally administered olanzapine was about 1.5 times greater in elderly (≥65 years) than in nonelderly subjects (<65 years). Caution should be used in dosing the elderly, especially if there are other factors that might additively influence drug metabolism and/or pharmacodynamic sensitivity [see Dosage and Administration (2.1)].

Gender — For both oral ZYPREXA and ZYPREXA RELPREVV higher average plasma concentrations of olanzapine were observed in women than in men. There were, however, no apparent differences between men and women in effectiveness or adverse effects. Dosage modifications based on gender should not be needed.

Smoking Status — For both oral ZYPREXA and ZYPREXA RELPREVV, studies have demonstrated that the clearance of olanzapine is higher in smokers than in nonsmokers, although dosage modifications are not routinely recommended.

Race — In vivo studies of orally administered olanzapine have shown that exposures are similar among Japanese, Chinese and Caucasians, especially after normalization for body weight differences. Dosage modifications for race are, therefore, not recommended.

Combined Effects — The combined effects of age, smoking, and gender could lead to substantial pharmacokinetic differences in populations. The clearance in young smoking males, for example, may be 3 times higher than that in elderly nonsmoking females. Dosing modification may be necessary in patients who exhibit a combination of factors that may result in slower metabolism of olanzapine [see Dosage and Administration (2.1)].

Carcinogenesis — Oral carcinogenicity studies were conducted in mice and rats. Olanzapine was administered to mice in two 78-week studies at doses of 3, 10, 30/20 mg/kg/day (equivalent to 0.8-5 times the daily oral MRHD based on mg/m2 body surface area) and 0.25, 2, 8 mg/kg/day (equivalent to 0.06-2 times the daily oral MRHD based on mg/m2 body surface area). Rats were dosed for 2 years at doses of 0.25, 1, 2.5, 4 mg/kg/day (males) and 0.25, 1, 4, 8 mg/kg/day (females) (equivalent to 0.13-2 and 0.13-4 times the daily oral MRHD based on mg/m2 body surface area, respectively). The incidence of liver hemangiomas and hemangiosarcomas was significantly increased in 1 mouse study in female mice at 2 times the daily oral MRHD based on mg/m2 body surface area. These tumors were not increased in another mouse study in females dosed up to 2-5 times the daily oral MRHD based on mg/m2 body surface area; in this study, there was a high incidence of early mortalities in males of the 30/20 mg/kg/day group. The incidence of mammary gland adenomas and adenocarcinomas was significantly increased in female mice dosed at ≥2 mg/kg/day and in female rats dosed at ≥4 mg/kg/day (0.5 and 2 times the daily oral MRHD based on mg/m2 body surface area, respectively). Rats were also treated intramuscularly with ZYPREXA RELPREVV once a month for 2 years at doses of 5, 10, 20 mg/kg (males) and 10, 25, 50 mg/kg (females) (equivalent to 0.08-0.8 times the daily oral MRHD of 300 mg every 2 weeks based on mg/m2 body surface area; dosing was limited due to local reactions at the IM injection site). The incidence of tumors in this study was not altered when compared to solution for ZYPREXA RELPREVV control or pamoic acid treated animals. Antipsychotic drugs have been shown to chronically elevate prolactin levels in rodents. Serum prolactin levels were not measured during the olanzapine carcinogenicity studies; however, measurements during subchronic toxicity studies showed that olanzapine elevated serum prolactin levels up to 4-fold in rats at the same doses used in the carcinogenicity study. An increase in mammary gland neoplasms has been found in rodents after chronic administration of other antipsychotic drugs and is considered to be prolactin mediated. The relevance for human risk of the finding of prolactin mediated endocrine tumors in rodents is unknown [see Warnings and Precautions (5.17)].

Mutagenesis — No evidence of genotoxic potential for olanzapine was found in the Ames reverse mutation test, in vivo micronucleus test in mice, the chromosomal aberration test in Chinese hamster ovary cells, unscheduled DNA synthesis test in rat hepatocytes, induction of forward mutation test in mouse lymphoma cells, or in vivo sister chromatid exchange test in bone marrow of Chinese hamsters.

Impairment of Fertility — In an oral fertility and reproductive performance study in rats, male mating performance, but not fertility, was impaired at a dose of 22.4 mg/kg/day and female fertility was decreased at a dose of 3 mg/kg/day (11 and 1.5 times the daily oral MRHD based on mg/m2 body surface area, respectively). Discontinuance of olanzapine treatment reversed the effects on male mating performance. In female rats, the precoital period was increased and the mating index reduced at 5 mg/kg/day (2.5 times the daily oral MRHD based on mg/m2 body surface area). Diestrous was prolonged and estrous delayed at 1.1 mg/kg/day (0.6 times the daily oral MRHD based on mg/m2 body surface area); therefore olanzapine may produce a delay in ovulation.

In animal studies with olanzapine, the principal hematologic findings were reversible peripheral cytopenias in individual dogs dosed at 10 mg/kg (17 times the daily oral MRHD based on mg/m2 body surface area), dose-related decreases in lymphocytes and neutrophils in mice, and lymphopenia in rats. A few dogs treated with 10 mg/kg developed reversible neutropenia and/or reversible hemolytic anemia between 1 and 10 months of treatment. Dose-related decreases in lymphocytes and neutrophils were seen in mice given doses of 10 mg/kg (equal to 2 times the daily oral MRHD based on mg/m2 body surface area) in studies of 3 months' duration. Nonspecific lymphopenia, consistent with decreased body weight gain, occurred in rats receiving 22.5 mg/kg (11 times the daily oral MRHD based on mg/m2 body surface area) for 3 months or 16 mg/kg (8 times the daily oral MRHD based on mg/m2 body surface area) for 6 or 12 months. No evidence of bone marrow cytotoxicity was found in any of the species examined. Bone marrows were normocellular or hypercellular, indicating that the reductions in circulating blood cells were probably due to peripheral (non-marrow) factors.

The short-term effectiveness of ZYPREXA RELPREVV was established in an 8-week, placebo-controlled trial in adult patients (n=404) who were experiencing psychotic symptoms and met DSM-IV or DSM-IV-TR criteria for schizophrenia. Patients were randomized to receive injections of ZYPREXA RELPREVV 210 mg every 2 weeks, ZYPREXA RELPREVV 405 mg every 4 weeks, ZYPREXA RELPREVV 300 mg every 2 weeks, or placebo every 2 weeks. Patients were discontinued from their previous antipsychotics and underwent a 2-7 day washout period. No oral antipsychotic supplementation was allowed throughout the trial. The primary efficacy measure was change from baseline to endpoint in total Positive and Negative Syndrome Scale (PANSS) score (mean baseline total PANSS score 101). Total PANSS scores showed statistically significant improvement from baseline to endpoint with each dose of ZYPREXA RELPREVV (210 mg every 2 weeks, 405 mg every 4 weeks, and 300 mg every 2 weeks) as compared to placebo. The effectiveness of ZYPREXA RELPREVV in the treatment of schizophrenia is further supported by the established effectiveness of the oral formulation of olanzapine.

A longer-term trial enrolled patients with schizophrenia (n=1065) who had remained stable for 4 to 8 weeks on open-label treatment with oral olanzapine (mean baseline total PANSS score 56) and were then randomized to continue their current oral olanzapine dose (10, 15, or 20 mg/day); or to ZYPREXA RELPREVV 150 mg every 2 weeks (405 mg every 4 weeks, 300 mg every 2 weeks, or 45 mg every 4 weeks). No oral antipsychotic supplementation was allowed throughout the trial. The primary efficacy measure was time to exacerbation of symptoms of schizophrenia defined in terms of increases in Brief Psychiatric Rating Scale (BPRS) positive symptoms or hospitalization. ZYPREXA RELPREVV doses of 150 mg every 2 weeks, 405 mg every 4 weeks, and 300 mg every 2 weeks were each statistically significantly superior to low dose ZYPREXA RELPREVV (45 mg every 4 weeks).

ZYPREXA RELPREVV convenience kit is supplied in single dose cartons. Each carton includes one vial of olanzapine pamoate monohydrate in dosage strengths that are equivalent to 210 mg olanzapine (483 mg olanzapine pamoate monohydrate), 300 mg olanzapine (690 mg olanzapine pamoate monohydrate), and 405 mg olanzapine (931 mg olanzapine pamoate monohydrate) per vial; one vial of approximately 3 mL of diluent for ZYPREXA RELPREVV used to suspend the drug product; one 3-mL syringe with pre-attached 19-gauge, 1.5-inch (38 mm) Hypodermic Needle-Pro needle with needle protection device; and two 19-gauge, 1.5-inch (38 mm) Hypodermic Needle-Pro needles with needle protection device.

Needle-Pro® is a registered trademark of Smiths Medical.

NDC 61269-660-20 — single-dose convenience kit: 210 mg vial (VL7635) with rust flip-off cap and 3-mL vial of sterile diluent (VL7622) with gray flip-off cap

NDC 61269-661-20 — single-dose convenience kit: 300 mg vial (VL7636) with olive flip-off cap and 3-mL vial of sterile diluent (VL7622) with gray flip-off cap

NDC 61269-662-20 — single-dose convenience kit: 405 mg vial (VL7637) with steel blue flip-off cap and 3-mL vial of sterile diluent (VL7622) with gray flip-off cap

ZYPREXA RELPREVV should be stored at room temperature not to exceed 30°C (86°F).

When the drug product is suspended in the solution for ZYPREXA RELPREVV, it may be held at room temperature for 24 hours. The vial should be agitated immediately prior to product withdrawal. Once the suspension is withdrawn into the syringe, it should be used immediately [see Dosage and Administration (2.2)].

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

{ "type": "p", "children": [], "text": "Advise the patient to read the FDA-approved patient labeling (Medication Guide)." }

Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking ZYPREXA RELPREVV. Patients should be advised to call their doctor if they do not think they are getting better or have concerns about their condition.

{ "type": "p", "children": [], "text": "Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking ZYPREXA RELPREVV. Patients should be advised to call their doctor if they do not think they are getting better or have concerns about their condition." }

Post-Injection Delirium/Sedation Syndrome

{ "type": "p", "children": [], "text": "\nPost-Injection Delirium/Sedation Syndrome\n" }

During premarketing clinical studies, reactions that presented with signs and symptoms consistent with olanzapine overdose have been reported in patients following an injection of ZYPREXA RELPREVV. It is mandatory that patients be enrolled in the ZYPREXA RELPREVV Patient Care Program to receive ZYPREXA RELPREVV treatment. Patients should be advised of the risk of post-injection delirium/sedation syndrome each time they receive an injection [see Warnings and Precautions (5.1, 5.2)]. Patient and caregivers should be advised that after each ZYPREXA RELPREVV injection, patients must be observed at the healthcare facility for at least 3 hours and must be accompanied to their destination upon leaving the facility. The Medication Guide should be distributed each time patients receive an injection.

{ "type": "p", "children": [], "text": "During premarketing clinical studies, reactions that presented with signs and symptoms consistent with olanzapine overdose have been reported in patients following an injection of ZYPREXA RELPREVV. It is mandatory that patients be enrolled in the ZYPREXA RELPREVV Patient Care Program to receive ZYPREXA RELPREVV treatment. Patients should be advised of the risk of post-injection delirium/sedation syndrome each time they receive an injection [see Warnings and Precautions (5.1, 5.2)]. Patient and caregivers should be advised that after each ZYPREXA RELPREVV injection, patients must be observed at the healthcare facility for at least 3 hours and must be accompanied to their destination upon leaving the facility. The Medication Guide should be distributed each time patients receive an injection." }

Elderly Patients with Dementia-Related Psychosis: Increased Mortality and Cerebrovascular Adverse Events (CVAE), Including Stroke

{ "type": "p", "children": [], "text": "\nElderly Patients with Dementia-Related Psychosis: Increased Mortality and Cerebrovascular Adverse Events (CVAE), Including Stroke \n" }

Patients and caregivers should be advised that elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Patients and caregivers should be advised that elderly patients with dementia-related psychosis treated with ZYPREXA had a significantly higher incidence of cerebrovascular adverse events (e.g., stroke, transient ischemic attack) compared with placebo.

{ "type": "p", "children": [], "text": "Patients and caregivers should be advised that elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Patients and caregivers should be advised that elderly patients with dementia-related psychosis treated with ZYPREXA had a significantly higher incidence of cerebrovascular adverse events (e.g., stroke, transient ischemic attack) compared with placebo." }

ZYPREXA RELPREVV is not approved for elderly patients with dementia-related psychosis [see Boxed Warning and Warnings and Precautions (5.3)].

{ "type": "p", "children": [], "text": "ZYPREXA RELPREVV is not approved for elderly patients with dementia-related psychosis [see Boxed Warning and Warnings and Precautions (5.3)]." }

Neuroleptic Malignant Syndrome (NMS)

{ "type": "p", "children": [], "text": "\nNeuroleptic Malignant Syndrome (NMS)\n" }

Patients and caregivers should be counseled that a potentially fatal symptom complex sometimes referred to as NMS has been reported in association with administration of antipsychotic drugs, including ZYPREXA. Signs and symptoms of NMS include hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia) [see Warnings and Precautions (5.5)].

{ "type": "p", "children": [], "text": "Patients and caregivers should be counseled that a potentially fatal symptom complex sometimes referred to as NMS has been reported in association with administration of antipsychotic drugs, including ZYPREXA. Signs and symptoms of NMS include hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia) [see Warnings and Precautions (5.5)]." }

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)

{ "type": "p", "children": [], "text": "\nDrug Reaction with Eosinophilia and Systemic Symptoms (DRESS)\n" }

Patients should be advised to report to their health care provider at the earliest onset of any signs or symptoms that may be associated with Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) [see Warnings and Precautions (5.6)].

{ "type": "p", "children": [], "text": "Patients should be advised to report to their health care provider at the earliest onset of any signs or symptoms that may be associated with Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) [see Warnings and Precautions (5.6)]." }

Hyperglycemia and Diabetes Mellitus

{ "type": "p", "children": [], "text": "\nHyperglycemia and Diabetes Mellitus\n" }

Patients should be advised of the potential risk of hyperglycemia-related adverse reactions related to ZYPREXA RELPREVV. Patients should be monitored regularly for worsening of glucose control. Patients who have diabetes should follow their doctor's instructions about how often to check their blood sugar while taking ZYPREXA RELPREVV [see Warnings and Precautions (5.7)].

{ "type": "p", "children": [], "text": "Patients should be advised of the potential risk of hyperglycemia-related adverse reactions related to ZYPREXA RELPREVV. Patients should be monitored regularly for worsening of glucose control. Patients who have diabetes should follow their doctor's instructions about how often to check their blood sugar while taking ZYPREXA RELPREVV [see Warnings and Precautions (5.7)]." }

Dyslipidemia

{ "type": "p", "children": [], "text": "\nDyslipidemia\n" }

Patients should be counseled that dyslipidemia has occurred during treatment with ZYPREXA RELPREVV. Patients should have their lipid profile monitored regularly [see Warnings and Precautions (5.7)].

{ "type": "p", "children": [], "text": "Patients should be counseled that dyslipidemia has occurred during treatment with ZYPREXA RELPREVV. Patients should have their lipid profile monitored regularly [see Warnings and Precautions (5.7)]." }

Weight Gain

{ "type": "p", "children": [], "text": "\nWeight Gain\n" }

Patients should be counseled that weight gain has occurred during treatment with ZYPREXA RELPREVV. Patients should have their weight monitored regularly [see Warnings and Precautions (5.7)].

{ "type": "p", "children": [], "text": "Patients should be counseled that weight gain has occurred during treatment with ZYPREXA RELPREVV. Patients should have their weight monitored regularly [see Warnings and Precautions (5.7)]." }

Orthostatic Hypotension

{ "type": "p", "children": [], "text": "\nOrthostatic Hypotension\n" }

Patients should be advised of the risk of orthostatic hypotension, and in association with the use of concomitant drugs that may potentiate the orthostatic effect of ZYPREXA RELPREVV, e.g., diazepam or alcohol [see Warnings and Precautions (5.9) and Drug Interactions (7)]. Patients should be advised to change positions carefully to help prevent orthostatic hypotension, and to lie down if they feel dizzy or faint, until they feel better. Patients should be advised to call their doctor if they experience any of the following signs and symptoms associated with orthostatic hypotension: dizziness, fast or slow heartbeat, or fainting.

{ "type": "p", "children": [], "text": "Patients should be advised of the risk of orthostatic hypotension, and in association with the use of concomitant drugs that may potentiate the orthostatic effect of ZYPREXA RELPREVV, e.g., diazepam or alcohol [see Warnings and Precautions (5.9) and Drug Interactions (7)]. Patients should be advised to change positions carefully to help prevent orthostatic hypotension, and to lie down if they feel dizzy or faint, until they feel better. Patients should be advised to call their doctor if they experience any of the following signs and symptoms associated with orthostatic hypotension: dizziness, fast or slow heartbeat, or fainting." }

Potential for Cognitive and Motor Impairment

{ "type": "p", "children": [], "text": "\nPotential for Cognitive and Motor Impairment\n" }

Because ZYPREXA RELPREVV has the potential to impair judgment, thinking, or motor skills, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that ZYPREXA RELPREVV therapy does not affect them adversely. Additionally, due to the risk of post-injection delirium/sedation syndrome, patients should not drive or operate heavy machinery for the remainder of the day of each injection [see Dosage and Administration (2.1) and Warnings and Precautions (5.1, 5.14)].

{ "type": "p", "children": [], "text": "Because ZYPREXA RELPREVV has the potential to impair judgment, thinking, or motor skills, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that ZYPREXA RELPREVV therapy does not affect them adversely. Additionally, due to the risk of post-injection delirium/sedation syndrome, patients should not drive or operate heavy machinery for the remainder of the day of each injection [see Dosage and Administration (2.1) and Warnings and Precautions (5.1, 5.14)]." }

Body Temperature Regulation

{ "type": "p", "children": [], "text": "\nBody Temperature Regulation\n" }

Patients should be advised regarding appropriate care in avoiding overheating and dehydration. Patients should be advised to call their doctor right away if they become severely ill and have some or all of these symptoms of dehydration: sweating too much or not at all, dry mouth, feeling very hot, feeling thirsty, not able to produce urine [see Warnings and Precautions (5.15)].

{ "type": "p", "children": [], "text": "Patients should be advised regarding appropriate care in avoiding overheating and dehydration. Patients should be advised to call their doctor right away if they become severely ill and have some or all of these symptoms of dehydration: sweating too much or not at all, dry mouth, feeling very hot, feeling thirsty, not able to produce urine [see Warnings and Precautions (5.15)]." }

Concomitant Medication

{ "type": "p", "children": [], "text": "\nConcomitant Medication\n" }

Patients should be advised to inform their healthcare providers if they are taking, or plan to take, ZYPREXA or Symbyax® (olanzapine/fluoxetine combination). Patients should also be advised to inform their healthcare providers if they are taking, plan to take, or have stopped taking any prescription or over-the-counter drugs, including herbal supplements, since there is a potential for interactions [see Drug Interactions (7)].

{ "type": "p", "children": [], "text": "Patients should be advised to inform their healthcare providers if they are taking, or plan to take, ZYPREXA or Symbyax® (olanzapine/fluoxetine combination). Patients should also be advised to inform their healthcare providers if they are taking, plan to take, or have stopped taking any prescription or over-the-counter drugs, including herbal supplements, since there is a potential for interactions [see Drug Interactions (7)]." }

Alcohol

{ "type": "p", "children": [], "text": "\nAlcohol\n" }

Patients should be advised to avoid alcohol while taking ZYPREXA RELPREVV [see Drug Interactions (7.1)].

{ "type": "p", "children": [], "text": "Patients should be advised to avoid alcohol while taking ZYPREXA RELPREVV [see Drug Interactions (7.1)]." }

Use in Specific Populations

{ "type": "p", "children": [], "text": "\nUse in Specific Populations\n" }

Pregnancy — Advise women to notify their healthcare provider if they become pregnant or intend to become pregnant during treatment with ZYPREXA RELPREVV. Advise patients that ZYPREXA RELPREVV may cause extrapyramidal and/or withdrawal symptoms (agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder) in a neonate. Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ZYPREXA RELPREVV during pregnancy [see Use in Specific Populations (8.1)].

{ "type": "p", "children": [], "text": "\nPregnancy — Advise women to notify their healthcare provider if they become pregnant or intend to become pregnant during treatment with ZYPREXA RELPREVV. Advise patients that ZYPREXA RELPREVV may cause extrapyramidal and/or withdrawal symptoms (agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder) in a neonate. Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ZYPREXA RELPREVV during pregnancy [see Use in Specific Populations (8.1)]." }

Lactation — Advise breastfeeding women using ZYPREXA RELPREVV to monitor infants for excess sedation, irritability, poor feeding and extrapyramidal symptoms (tremors and abnormal muscle movements) and to seek medical care if they notice these signs [see Use in Specific Populations (8.2)].

{ "type": "p", "children": [], "text": "\nLactation — Advise breastfeeding women using ZYPREXA RELPREVV to monitor infants for excess sedation, irritability, poor feeding and extrapyramidal symptoms (tremors and abnormal muscle movements) and to seek medical care if they notice these signs [see Use in Specific Populations (8.2)]." }

Infertility — Advise females of reproductive potential that ZYPREXA RELPREVV may impair fertility due to an increase in serum prolactin levels. The effects on fertility are reversible [see Use in Specific Populations (8.3)].

{ "type": "p", "children": [], "text": "\nInfertility — Advise females of reproductive potential that ZYPREXA RELPREVV may impair fertility due to an increase in serum prolactin levels. The effects on fertility are reversible [see Use in Specific Populations (8.3)]." }

Pediatric Use — Safety and effectiveness of ZYPREXA RELPREVV in patients under 18 years have not been established [see Use in Specific Populations (8.4)].

{ "type": "p", "children": [], "text": "\nPediatric Use — Safety and effectiveness of ZYPREXA RELPREVV in patients under 18 years have not been established [see Use in Specific Populations (8.4)]." }

Distributed by: H2-Pharma, LLC Montgomery, AL 36117, USA

{ "type": "p", "children": [], "text": "Distributed by: H2-Pharma, LLC\nMontgomery, AL 36117, USA" }

Licensed by: CHEPLAPHARM Registration GmbH, Weilerstr. 5e, 79540 Lörrach, Germany

{ "type": "p", "children": [], "text": "Licensed by: CHEPLAPHARM Registration GmbH, Weilerstr. 5e, 79540 Lörrach, Germany" }

CHEPLAPHARM Registration GmbH under the license of CHEPLAPHARM Schweiz GmbH

{ "type": "p", "children": [], "text": "CHEPLAPHARM Registration GmbH under the license of CHEPLAPHARM Schweiz GmbH" }

Medication Guide

{ "type": "p", "children": [], "text": "\nMedication Guide\n" }

ZYPREXA® RELPREVV™ (zy-PREX-a REL-prev)

{ "type": "p", "children": [], "text": "\nZYPREXA® RELPREVV™ (zy-PREX-a REL-prev)\n" }

(olanzapine)

{ "type": "p", "children": [], "text": "\n(olanzapine)\n" }

For Extended Release Injectable Suspension

{ "type": "p", "children": [], "text": "\nFor Extended Release Injectable Suspension\n" }

Read the Medication Guide that comes with ZYPREXA RELPREVV before you start taking it and each time before you get an injection. There may be new information. This Medication Guide does not take the place of talking to your doctor about your medical condition or treatment. Talk with your doctor if there is something you do not understand or you want to learn more about ZYPREXA RELPREVV.

{ "type": "p", "children": [], "text": "Read the Medication Guide that comes with ZYPREXA RELPREVV before you start taking it and each time before you get an injection. There may be new information. This Medication Guide does not take the place of talking to your doctor about your medical condition or treatment. Talk with your doctor if there is something you do not understand or you want to learn more about ZYPREXA RELPREVV." }

What is the most important information I should know about ZYPREXA RELPREVV?

{ "type": "p", "children": [], "text": "\nWhat is the most important information I should know about ZYPREXA RELPREVV?\n" }

Before you receive ZYPREXA RELPREVV treatment you must:

{ "type": "p", "children": [], "text": "\nBefore you receive ZYPREXA RELPREVV treatment you must:\n" }

{ "type": "ul", "children": [ "\nunderstand the risks and benefits of ZYPREXA RELPREVV treatment. Your doctor will talk to you about the risks and benefits of ZYPREXA RELPREVV treatment.\n", "\nregister in the ZYPREXA RELPREVV Patient Care Program. You must agree to the rules of the ZYPREXA RELPREVV Patient Care Program before you register.\n" ], "text": "" }

ZYPREXA RELPREVV may cause serious side effects, including:

{ "type": "p", "children": [], "text": "\nZYPREXA RELPREVV may cause serious side effects, including:\n" }

{ "type": "", "children": [], "text": "" }

These serious side effects are described below.

{ "type": "p", "children": [], "text": "\nThese serious side effects are described below.\n" }

{ "type": "", "children": [], "text": "" }

What is ZYPREXA RELPREVV?

{ "type": "p", "children": [], "text": "\nWhat is ZYPREXA RELPREVV?\n" }

ZYPREXA RELPREVV is a long-acting prescription medicine given by injection and used to treat schizophrenia in adults. The symptoms of schizophrenia include:

{ "type": "p", "children": [], "text": "ZYPREXA RELPREVV is a long-acting prescription medicine given by injection and used to treat schizophrenia in adults. The symptoms of schizophrenia include:" }

{ "type": "ul", "children": [ "hearing voices", "seeing things that are not there", "having beliefs that are not true", "being suspicious or withdrawn" ], "text": "" }

Some of your symptoms of schizophrenia may improve with treatment with ZYPREXA RELPREVV. If you do not think you are getting better, call your doctor.

{ "type": "p", "children": [], "text": "Some of your symptoms of schizophrenia may improve with treatment with ZYPREXA RELPREVV. If you do not think you are getting better, call your doctor." }

It is not known if ZYPREXA RELPREVV is safe and effective in children under 18 years of age.

{ "type": "p", "children": [], "text": "It is not known if ZYPREXA RELPREVV is safe and effective in children under 18 years of age." }

What should I tell my doctor before taking ZYPREXA RELPREVV?

{ "type": "p", "children": [], "text": "\nWhat should I tell my doctor before taking ZYPREXA RELPREVV?\n" }

ZYPREXA RELPREVV may not be right for you. Before starting ZYPREXA RELPREVV, tell your doctor if you have or had:

{ "type": "p", "children": [], "text": "ZYPREXA RELPREVV may not be right for you. Before starting ZYPREXA RELPREVV, tell your doctor if you have or had:" }

{ "type": "ul", "children": [ "heart problems", "seizures", "diabetes or high blood sugar levels (hyperglycemia)", "high cholesterol or triglyceride levels in your blood", "liver problems", "low or high blood pressure", "strokes or \"mini-strokes\" also called transient ischemic attacks (TIAs)", "Alzheimer's disease", "narrow-angle glaucoma", "enlarged prostate in men", "bowel obstruction", "breast cancer", "thoughts of suicide or hurting yourself", "any other medical condition", "are pregnant or plan to become pregnant. It is not known if ZYPREXA RELPREVV will harm your unborn baby.\nIf you become pregnant while receiving ZYPREXA, talk to your healthcare provider about registering with the National Pregnancy Registry for Atypical Antipsychotics. You can register by calling 1-866-961-2388 or go to http://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/.\n\n", "are breast-feeding or plan to breast-feed. ZYPREXA RELPREVV passes into your breast milk. Talk to your doctor about the best way to feed your baby if you take ZYPREXA RELPREVV." ], "text": "" }

Tell your doctor if you exercise a lot or are in hot places often.

{ "type": "p", "children": [], "text": "Tell your doctor if you exercise a lot or are in hot places often." }

The symptoms of schizophrenia may include thoughts of suicide or of hurting yourself or others. If you have these thoughts at any time, tell your doctor or go to an emergency room right away.

{ "type": "p", "children": [], "text": "The symptoms of schizophrenia may include thoughts of suicide or of hurting yourself or others. If you have these thoughts at any time, tell your doctor or go to an emergency room right away." }

Tell your doctor about all the medicines that you take, including prescription and nonprescription medicines, vitamins, and herbal supplements. ZYPREXA RELPREVV and some medicines may interact with each other and may not work as well, or cause possible serious side effects. Your doctor can tell you if it is safe to take ZYPREXA RELPREVV with your other medicines. Do not start or stop any medicine while taking ZYPREXA RELPREVV without talking to your doctor first.

{ "type": "p", "children": [], "text": "\nTell your doctor about all the medicines that you take, including prescription and nonprescription medicines, vitamins, and herbal supplements. ZYPREXA RELPREVV and some medicines may interact with each other and may not work as well, or cause possible serious side effects. Your doctor can tell you if it is safe to take ZYPREXA RELPREVV with your other medicines. Do not start or stop any medicine while taking ZYPREXA RELPREVV without talking to your doctor first." }

How should I receive ZYPREXA RELPREVV?

{ "type": "p", "children": [], "text": "\nHow should I receive ZYPREXA RELPREVV?\n" }

{ "type": "ul", "children": [ "ZYPREXA RELPREVV will be injected into the muscle in your buttock (gluteus) by your doctor or nurse at the clinic.", "After receiving ZYPREXA RELPREVV, you will need to stay at the clinic for at least 3 hours.", "When you leave the clinic, someone must be with you.", "Call your doctor if you do not think you are getting better or have any concerns about your condition while taking ZYPREXA RELPREVV." ], "text": "" }

What should I avoid while receiving ZYPREXA RELPREVV?

{ "type": "p", "children": [], "text": "\nWhat should I avoid while receiving ZYPREXA RELPREVV?\n" }

{ "type": "ul", "children": [ "ZYPREXA RELPREVV can cause sleepiness and may affect your ability to make decisions, think clearly, or react quickly. Do not drive, operate heavy machinery, or do other dangerous activities until you know how ZYPREXA RELPREVV affects you. You should not drive or operate heavy machinery for the rest of the day after each injection.", "Avoid drinking alcohol while taking ZYPREXA RELPREVV. Drinking alcohol while you take ZYPREXA RELPREVV may make you sleepier than if you take ZYPREXA RELPREVV alone." ], "text": "" }

What are the possible side effects of ZYPREXA RELPREVV?

{ "type": "p", "children": [], "text": "\nWhat are the possible side effects of ZYPREXA RELPREVV?\n" }

Serious side effects may happen when you take ZYPREXA RELPREVV, including:

{ "type": "p", "children": [], "text": "\nSerious side effects may happen when you take ZYPREXA RELPREVV, including:\n" }

{ "type": "ul", "children": [ "\nSee \"What is the most important information I should know about ZYPREXA RELPREVV?\", which describes the risk of post-injection delirium sedation syndrome (PDSS), increased risk of death in elderly people with dementia-related psychosis and the risks of high blood sugar, high cholesterol and triglyceride levels, and weight gain.\n", "\nIncreased incidence of stroke or \"mini-strokes\" called transient ischemic attacks (TIAs) in elderly people with dementia-related psychosis (elderly people who have lost touch with reality due to confusion and memory loss). ZYPREXA RELPREVV is not approved for these patients.", "\nNeuroleptic Malignant Syndrome (NMS):NMS is a rare but very serious condition that can happen in people who take antipsychotic medicines, including ZYPREXA RELPREVV. NMS can cause death and must be treated in a hospital. Call your doctor right away if you become severely ill and have any of these symptoms:\nhigh fever\nexcessive sweating\nrigid muscles\nconfusion\nchanges in your breathing, heartbeat, and blood pressure\n\n", "\nDrug Reaction with Eosinophilia and Systemic Symptoms (DRESS): DRESS can occur with ZYPREXA RELPREVV. Features of DRESS may include rash, fever, swollen glands and other internal organ involvement such as liver, kidney, lung and heart. DRESS is sometimes fatal; therefore, tell your doctor immediately if you experience any of these signs.", "\nTardive Dyskinesia: This condition causes body movements that keep happening and that you can not control. These movements usually affect the face and tongue. Tardive dyskinesia may not go away, even if you stop taking ZYPREXA RELPREVV. It may also start after you stop taking ZYPREXA RELPREVV. Tell your doctor if you get any body movements that you can not control.", "\nDecreased blood pressure when you change positions, with symptoms of dizziness, fast or slow heartbeat, or fainting.\n", "\nDifficulty swallowing, that can cause food or liquid to get into your lungs.\n", "\nSeizures: Tell your doctor if you have a seizure during treatment with ZYPREXA RELPREVV.\n", "\nProblems with control of body temperature:You could become very hot, for instance when you exercise a lot or stay in an area that is very hot. It is important for you to drink water to avoid dehydration. Call your doctor right away if you become severely ill and have any of these symptoms of dehydration:\nsweating too much or not at all\ndry mouth\nfeeling very hot\nfeeling thirsty\nnot able to produce urine\n\n" ], "text": "" }

Common side effects of ZYPREXA RELPREVV include: headache, sleepiness or drowsiness, weight gain, dry mouth, diarrhea, nausea, common cold, eating more (increased appetite), vomiting, cough, back pain, or pain at the injection site.

{ "type": "p", "children": [], "text": "\nCommon side effects of ZYPREXA RELPREVV include: headache, sleepiness or drowsiness, weight gain, dry mouth, diarrhea, nausea, common cold, eating more (increased appetite), vomiting, cough, back pain, or pain at the injection site." }

Tell your doctor about any side effect that bothers you or that does not go away.

{ "type": "p", "children": [], "text": "Tell your doctor about any side effect that bothers you or that does not go away." }

These are not all the possible side effects with ZYPREXA RELPREVV. For more information, ask your doctor or pharmacist.

{ "type": "p", "children": [], "text": "These are not all the possible side effects with ZYPREXA RELPREVV. For more information, ask your doctor or pharmacist." }

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

{ "type": "p", "children": [], "text": "Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088." }

General information about ZYPREXA RELPREVV

{ "type": "p", "children": [], "text": "\nGeneral information about ZYPREXA RELPREVV\n" }

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide.

{ "type": "p", "children": [], "text": "Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide." }

This Medication Guide summarizes the most important information about ZYPREXA RELPREVV. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about ZYPREXA RELPREVV that was written for healthcare professionals. For more information about ZYPREXA RELPREVV call 1-866-770-9010.

{ "type": "p", "children": [], "text": "This Medication Guide summarizes the most important information about ZYPREXA RELPREVV. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about ZYPREXA RELPREVV that was written for healthcare professionals. For more information about ZYPREXA RELPREVV call 1-866-770-9010." }

What are the ingredients in ZYPREXA RELPREVV?

{ "type": "p", "children": [], "text": "\nWhat are the ingredients in ZYPREXA RELPREVV?\n" }

Active ingredient: olanzapine

{ "type": "p", "children": [], "text": "Active ingredient: olanzapine" }

Inactive ingredients: carboxymethylcellulose sodium, mannitol, polysorbate 80, sodium hydroxide and/or hydrochloric acid for pH adjustment, and water for injection

{ "type": "p", "children": [], "text": "Inactive ingredients: carboxymethylcellulose sodium, mannitol, polysorbate 80, sodium hydroxide and/or hydrochloric acid for pH adjustment, and water for injection" }

This Medication Guide has been approved by the U.S. Food and Drug Administration.

{ "type": "p", "children": [], "text": "\nThis Medication Guide has been approved by the U.S. Food and Drug Administration.\n" }

Medication Guide revised October, 2023

{ "type": "p", "children": [], "text": "Medication Guide revised October, 2023" }

Distributed by: H2-Pharma, LLC Montgomery, AL 36117, USA

{ "type": "p", "children": [], "text": "Distributed by: H2-Pharma, LLC\nMontgomery, AL 36117, USA" }

Licensed by: CHEPLAPHARM Registration GmbH Weilerstr. 5e, 79540 Lörrach, Germany

{ "type": "p", "children": [], "text": "Licensed by:\nCHEPLAPHARM Registration GmbH\nWeilerstr. 5e, 79540 Lörrach, Germany" }

CHEPLAPHARM Registration GmbH under the license of CHEPLAPHARM Schweiz GmbH

{ "type": "p", "children": [], "text": "CHEPLAPHARM Registration GmbH under the license of CHEPLAPHARM Schweiz GmbH" }

<div class="scrollingtable"><table width="100%"> <colgroup> <col align="left" width="6.766%"/> <col align="left" width="48.861%"/> <col align="left" width="10%"/> <col align="left" width="1.878%"/> <col align="left" width="10%"/> <col align="left" width="11.277%"/> <col align="left" width="9.021%"/> <col align="left" width="7.899%"/> <col align="left" width="12.410%"/> </colgroup> <tbody class="Headless"> <tr class="First"> <td align="left" colspan="9" valign="top">Instructions to Reconstitute and Administer Single-Dose vial of Zyprexa<span class="Sup">®</span> Relprevv<span class="Sup">®</span></td> </tr> <tr> <td align="left" colspan="9" valign="top"></td> </tr> <tr> <td align="left" colspan="9" valign="top"><span class="Bold">FOR DEEP INTRAMUSCULAR GLUTEAL INJECTION ONLY.</span></td> </tr> <tr> <td align="left" colspan="9" valign="top"><span class="Bold">NOT TO BE INJECTED INTRAVENOUSLY OR SUBCUTANEOUSLY.</span></td> </tr> <tr> <td align="left" colspan="9" valign="top"></td> </tr> <tr> <td align="left" colspan="9" valign="top"><span class="Bold">STEP 1</span></td> </tr> <tr> <td align="left" colspan="9" valign="top"><span class="Bold">PREPARING MATERIALS</span></td> </tr> <tr> <td align="left" colspan="9" valign="top"></td> </tr> <tr> <td align="left" colspan="2" valign="top"><span class="Bold">Convenience kit includes:</span></td><td align="left" colspan="2" valign="top"></td><td align="left" colspan="5" rowspan="6" valign="top"> <br/> <img alt="Figure 1" src="/dailymed/image.cfm?name=zr-um-f1-v1.jpg&amp;setid=11544cba-64a9-49cb-8d74-da228053b252"/></td> </tr> <tr> <td align="left" colspan="2" valign="top"><span class="Italics">(see <a href="#f06">Figure 1</a> on right)</span></td><td align="left" colspan="2" valign="top"></td> </tr> <tr> <td align="left" colspan="2" valign="top"></td><td align="left" colspan="2" valign="top"></td> </tr> <tr> <td align="left" colspan="2" valign="top"> <ul class="Disc"> <li>Single-dose vial of Zyprexa Relprevv powder</li> </ul> </td><td align="left" colspan="2" valign="top"></td> </tr> <tr> <td align="left" colspan="2" valign="top"> <ul class="Disc"> <li>3-mL vial of diluent</li> </ul> </td><td align="left" colspan="2" valign="top"></td> </tr> <tr> <td align="left" colspan="2" valign="top"> <ul class="Disc"> <li>One 3-mL syringe with pre-attached 19-gauge, 1.5-inch (38 mm) Hypodermic Needle-Pro<span class="Sup">®</span> needle with needle protection device</li> </ul> </td><td align="left" colspan="2" valign="top"></td> </tr> <tr> <td align="left" colspan="2" rowspan="3" valign="top"> <ul class="Disc"> <li>Two 19-gauge, 1.5-inch (38 mm) Hypodermic Needle-Pro needles with needle protection device</li> </ul> </td><td align="left" colspan="2" rowspan="3" valign="top"></td><td align="left" colspan="5" valign="top"></td> </tr> <tr> <td align="left" colspan="5" valign="top"></td> </tr> <tr> <td align="left" colspan="5" valign="top"></td> </tr> <tr> <td align="left" colspan="9" valign="top">— For obese patients, a 2-inch (50 mm), 19-gauge or larger needle (not included in convenience kit) may be used for administration.</td> </tr> <tr> <td align="left" colspan="9" valign="top"></td> </tr> <tr> <td align="left" valign="top"> <br/> <p class="First"> <img alt="Figure 2" src="/dailymed/image.cfm?name=zr-um-exclamation.jpg&amp;setid=11544cba-64a9-49cb-8d74-da228053b252"/></p> </td><td align="left" colspan="8" valign="middle"><span class="Italics">Zyprexa Relprevv must be suspended using only the diluent supplied in the convenience kit.</span></td> </tr> <tr> <td align="left" colspan="9" valign="top"></td> </tr> <tr> <td align="left" colspan="9" valign="top">It is recommended that gloves are used when reconstituting, as Zyprexa Relprevv may be irritating to the skin. Flush with water if contact is made with skin.</td> </tr> <tr> <td align="left" colspan="9" valign="top"></td> </tr> <tr> <td align="left" colspan="9" valign="top"> <p class="First"> <a name="p02"></a><span class="Bold">STEP 2</span> </p> </td> </tr> <tr> <td align="left" colspan="9" valign="top"><span class="Bold">DETERMINING RECONSTITUTION VOLUME</span></td> </tr> <tr> <td align="left" colspan="9" valign="top"></td> </tr> <tr> <td align="left" colspan="4" valign="top">Refer to the table at right to determine the amount of diluent to be added to powder for reconstitution of each vial strength.</td><td align="center" colspan="5" rowspan="2" valign="top"><img alt="Table" src="/dailymed/image.cfm?name=zr-um-f2-v1.jpg&amp;setid=11544cba-64a9-49cb-8d74-da228053b252"/></td> </tr> <tr> <td align="left" valign="top"> <br/> <p class="First"> <img alt="Figure 2" src="/dailymed/image.cfm?name=zr-um-exclamation.jpg&amp;setid=11544cba-64a9-49cb-8d74-da228053b252"/></p> </td><td align="left" colspan="3" valign="middle"><span class="Italics">It is important to note that there is more diluent in the vial than is needed to reconstitute.</span></td> </tr> <tr> <td align="left" colspan="9" valign="top"></td> </tr> <tr> <td align="left" colspan="9" valign="top"><span class="Bold">STEP 3</span></td> </tr> <tr> <td align="left" colspan="9" valign="top"><span class="Bold">RECONSTITUTING ZYPREXA RELPREVV</span></td> </tr> <tr> <td align="left" colspan="9" valign="top"></td> </tr> <tr> <td align="left" colspan="9" valign="top">Please read the Hypodermic Needle-Pro Instructions for Use before proceeding with Step 3. Failure to follow these instructions may result in a needle stick injury.</td> </tr> <tr> <td align="left" valign="top"></td><td align="left" colspan="2" valign="top"></td><td align="left" colspan="2" valign="top"></td><td align="left" colspan="4" valign="top"></td> </tr> <tr> <td align="left" valign="top">3.1</td><td align="left" colspan="2" valign="top">Loosen the powder by lightly tapping the vial.</td><td align="left" colspan="2" valign="top"></td><td align="left" colspan="4" valign="top"> <br/> <img alt="Figure 4" src="/dailymed/image.cfm?name=zr-um-f3-v1.jpg&amp;setid=11544cba-64a9-49cb-8d74-da228053b252"/></td> </tr> <tr> <td align="left" valign="top"></td><td align="left" colspan="2" valign="top"></td><td align="left" colspan="2" valign="top"></td><td align="left" colspan="4" valign="top"></td> </tr> <tr> <td align="left" valign="top"></td><td align="left" colspan="2" valign="top"></td><td align="left" colspan="2" valign="top"></td><td align="left" colspan="4" valign="top"></td> </tr> <tr> <td align="left" valign="top">3.2</td><td align="left" colspan="2" valign="top">Open the prepackaged Hypodermic Needle-Pro syringe and needle with needle protection device.</td><td align="left" colspan="2" valign="top"></td><td align="left" colspan="4" valign="top"></td> </tr> <tr> <td align="left" valign="top"></td><td align="left" colspan="2" valign="top"></td><td align="left" colspan="2" valign="top"></td><td align="left" colspan="4" valign="top"></td> </tr> <tr> <td align="left" valign="top">3.3</td><td align="left" colspan="2" valign="top">Withdraw the pre-determined diluent volume (<a href="#p02">Step 2</a>) into the syringe.</td><td align="left" colspan="2" valign="top"></td><td align="left" colspan="4" valign="top"></td> </tr> <tr> <td align="left" valign="top"></td><td align="left" colspan="2" valign="top"></td><td align="left" colspan="2" valign="top"></td><td align="left" colspan="4" valign="top"></td> </tr> <tr> <td align="left" valign="top">3.4</td><td align="left" colspan="2" valign="top">Inject the diluent into the powder vial.</td><td align="left" colspan="2" valign="top"></td><td align="left" colspan="4" valign="top"></td> </tr> <tr> <td align="left" valign="top"></td><td align="left" colspan="2" valign="top"></td><td align="left" colspan="2" valign="top"></td><td align="left" colspan="4" valign="top"></td> </tr> <tr> <td align="left" valign="top">3.5</td><td align="left" colspan="2" valign="top">Withdraw air to equalize the pressure in the vial by pulling back slightly on the plunger in the syringe.</td><td align="left" colspan="2" valign="top"></td><td align="left" colspan="4" valign="top"></td> </tr> <tr> <td align="left" valign="top"></td><td align="left" colspan="2" valign="top"></td><td align="left" colspan="2" valign="top"></td><td align="left" colspan="4" valign="top"></td> </tr> <tr> <td align="left" valign="top">3.6</td><td align="left" colspan="2" valign="top">Remove the needle from the vial, holding the vial upright to prevent any loss of material.</td><td align="left" colspan="2" valign="top"></td><td align="left" colspan="4" valign="top"></td> </tr> <tr> <td align="left" valign="top"></td><td align="left" colspan="2" valign="top"></td><td align="left" colspan="2" valign="top"></td><td align="left" colspan="4" valign="top"></td> </tr> <tr> <td align="left" valign="top">3.7</td><td align="left" colspan="2" valign="top">Engage the needle safety device (refer to complete Hypodermic Needle-Pro Instructions for Use).</td><td align="left" colspan="2" valign="top"></td><td align="left" colspan="4" valign="top"></td> </tr> <tr> <td align="left" valign="top"></td><td align="left" colspan="2" valign="top"></td><td align="left" colspan="2" valign="top"></td><td align="left" colspan="4" valign="top"></td> </tr> <tr> <td align="left" valign="top">3.8</td><td align="left" colspan="2" valign="top">Pad a hard surface to cushion impact <span class="Italics">(see <a href="#f08">Figure 2</a>)</span>. Tap the vial firmly and repeatedly on the surface until no powder is visible.</td><td align="left" colspan="2" valign="top"></td><td align="left" colspan="4" valign="top"></td> </tr> <tr> <td align="left" valign="top"></td><td align="left" colspan="2" valign="top"></td><td align="left" colspan="2" valign="top"></td><td align="left" colspan="4" valign="top"></td> </tr> <tr> <td align="left" rowspan="2" valign="top">3.9</td><td align="left" colspan="2" rowspan="2" valign="top">Visually check the vial for clumps. Unsuspended powder appears as yellow, dry clumps clinging to the vial. Additional tapping may be required if large clumps remain <span class="Italics">(see <a href="#f09">Figure 3</a>)</span>.</td><td align="left" colspan="2" rowspan="2" valign="top"></td><td align="left" colspan="4" valign="top"></td> </tr> <tr> <td align="left" colspan="4" valign="top"> <br/> <img alt="Figure" src="/dailymed/image.cfm?name=zr-um-f4-v1.jpg&amp;setid=11544cba-64a9-49cb-8d74-da228053b252"/></td> </tr> <tr> <td align="left" valign="top"></td><td align="left" colspan="2" valign="top"></td><td align="left" colspan="2" valign="top"></td><td align="left" colspan="4" valign="top"></td> </tr> <tr> <td align="left" valign="top"></td><td align="left" colspan="2" valign="top"></td><td align="left" colspan="2" valign="top"></td><td align="left" colspan="4" valign="top"></td> </tr> <tr> <td align="left" valign="top"></td><td align="left" colspan="2" valign="top"></td><td align="left" colspan="2" valign="top"></td><td align="left" colspan="4" valign="top"></td> </tr> <tr> <td align="left" valign="top"></td><td align="left" colspan="2" valign="top"></td><td align="left" colspan="2" valign="top"></td><td align="left" colspan="4" valign="top"></td> </tr> <tr> <td align="left" valign="top">3.10</td><td align="left" colspan="2" valign="top">Shake the vial vigorously until the suspension appears smooth and is consistent in color and texture. The suspended product will be yellow and opaque <span class="Italics">(see <a href="#f11">Figure 4</a>)</span>.</td><td align="left" colspan="2" valign="top"></td><td align="left" colspan="4" valign="top"> <br/> <img alt="Figure" src="/dailymed/image.cfm?name=zr-um-f5-v1.jpg&amp;setid=11544cba-64a9-49cb-8d74-da228053b252"/></td> </tr> <tr> <td align="left" valign="top"></td><td align="left" colspan="2" valign="top"></td><td align="left" colspan="2" valign="top"></td><td align="left" colspan="4" valign="top"></td> </tr> <tr> <td align="left" valign="top"></td><td align="left" colspan="2" valign="top"></td><td align="left" colspan="2" valign="top"></td><td align="left" colspan="4" valign="top"></td> </tr> <tr> <td align="left" colspan="9" valign="top"><span class="Bold">If foam forms,</span> let vial stand to allow foam to dissipate.</td> </tr> <tr> <td align="left" colspan="9" valign="top"></td> </tr> <tr> <td align="left" colspan="9" valign="top"><span class="Bold">If the product is not used right away,</span> it should be shaken vigorously to re-suspend. Reconstituted Zyprexa Relprevv remains stable at room temperature for up to 24 hours in the vial.</td> </tr> <tr> <td align="left" colspan="9" valign="top"></td> </tr> <tr> <td align="left" colspan="9" valign="top"></td> </tr> <tr> <td align="left" colspan="9" valign="top"><span class="Bold">STEP 4</span></td> </tr> <tr> <td align="left" colspan="9" valign="top"><span class="Bold">INJECTING ZYPREXA RELPREVV</span></td> </tr> <tr> <td align="left" valign="top"></td><td align="left" colspan="8" valign="top"></td> </tr> <tr> <td align="left" valign="top"> <br/> <p class="First"> <img alt="Figure 2" src="/dailymed/image.cfm?name=zr-um-exclamation.jpg&amp;setid=11544cba-64a9-49cb-8d74-da228053b252"/></p> </td><td align="left" colspan="8" valign="middle"><span class="Italics">IMPORTANT</span></td> </tr> <tr> <td align="left" colspan="9" valign="top"><span class="Italics">Before administering the injection, confirm there will be someone to accompany the patient after the 3-hour observation period. If this cannot be confirmed, do not give the injection.</span></td> </tr> <tr> <td align="left" valign="top"></td><td align="left" colspan="8" valign="top"></td> </tr> <tr> <td align="left" colspan="3" valign="top">Refer to the table at right to determine the final volume to inject. <span class="Bold">Suspension concentration is 150 mg/mL Zyprexa Relprevv.</span></td><td align="center" colspan="6" valign="top"><img alt="Figure" src="/dailymed/image.cfm?name=zr-um-f6-v1.jpg&amp;setid=11544cba-64a9-49cb-8d74-da228053b252"/></td> </tr> <tr> <td align="left" valign="top"></td><td align="left" colspan="8" valign="top"></td> </tr> <tr> <td align="left" valign="top">4.1</td><td align="left" colspan="8" valign="top">Attach a new safety needle to the syringe.</td> </tr> <tr> <td align="left" valign="top"></td><td align="left" colspan="8" valign="top"></td> </tr> <tr> <td align="left" valign="top">4.2</td><td align="left" colspan="8" valign="top">Slowly withdraw the desired amount into the syringe.</td> </tr> <tr> <td align="left" valign="top"></td><td align="left" colspan="8" valign="top"></td> </tr> <tr> <td align="left" valign="top"> <br/> <p class="First"> <img alt="Figure 2" src="/dailymed/image.cfm?name=zr-um-exclamation.jpg&amp;setid=11544cba-64a9-49cb-8d74-da228053b252"/></p> </td><td align="left" colspan="8" valign="middle"><span class="Italics">SOME EXCESS PRODUCT WILL REMAIN IN THE VIAL.</span></td> </tr> <tr> <td align="left" valign="top"></td><td align="left" colspan="8" valign="top"></td> </tr> <tr> <td align="left" valign="top">4.3</td><td align="left" colspan="8" valign="top">Engage the needle safety device and remove the needle from syringe.</td> </tr> <tr> <td align="left" valign="top"></td><td align="left" colspan="8" valign="top"></td> </tr> <tr> <td align="left" valign="top">4.4</td><td align="left" colspan="8" valign="top">For administration, select the 19-gauge, 1.5-inch (38 mm) Hypodermic Needle-Pro needle with needle protection device. For obese patients, a 2-inch (50 mm), 19-gauge or larger needle (not included in convenience kit) may be used. <span class="Bold">To help prevent clogging, a 19-gauge or larger needle must be used.</span></td> </tr> <tr> <td align="left" valign="top"></td><td align="left" colspan="8" valign="top"></td> </tr> <tr> <td align="left" valign="top">4.5</td><td align="left" colspan="8" valign="top">Attach the new safety needle to the syringe prior to injection. Once the suspension has been removed from the vial, it should be injected immediately.</td> </tr> <tr> <td align="left" valign="top"></td><td align="left" colspan="8" valign="top"></td> </tr> <tr> <td align="left" valign="top"> <br/> <p class="First"> <img alt="Figure 2" src="/dailymed/image.cfm?name=zr-um-exclamation.jpg&amp;setid=11544cba-64a9-49cb-8d74-da228053b252"/></p> </td><td align="left" colspan="8" valign="middle"><span class="Bold">FOR DEEP INTRAMUSCULAR GLUTEAL INJECTION ONLY.</span></td> </tr> <tr> <td align="left" valign="top"></td><td align="left" colspan="8" valign="top"><span class="Italics">DO NOT INJECT INTRAVENOUSLY OR SUBCUTANEOUSLY.</span></td> </tr> <tr> <td align="left" valign="top"></td><td align="left" colspan="8" valign="top"></td> </tr> <tr> <td align="left" valign="top">4.6</td><td align="left" colspan="8" valign="top">Select and prepare a site for injection in the <span class="Bold">gluteal</span> area.</td> </tr> <tr> <td align="left" valign="top"></td><td align="left" colspan="8" valign="top"></td> </tr> <tr> <td align="left" valign="top">4.7</td><td align="left" colspan="8" valign="top"> <p class="First">After insertion of the needle into the muscle, <img alt="Figure 2" src="/dailymed/image.cfm?name=zr-um-exclamation.jpg&amp;setid=11544cba-64a9-49cb-8d74-da228053b252"/><span class="Italics">aspirate for several seconds to ensure that no blood appears.</span> If any blood is drawn into the syringe, discard the syringe and the dose and begin with a new convenience kit. The injection should be performed with steady, continuous pressure.</p> </td> </tr> <tr> <td align="left" valign="top"></td><td align="left" colspan="8" valign="top"></td> </tr> <tr> <td align="left" valign="top"> <br/> <p class="First"> <img alt="Figure 2" src="/dailymed/image.cfm?name=zr-um-exclamation.jpg&amp;setid=11544cba-64a9-49cb-8d74-da228053b252"/></p> </td><td align="left" colspan="8" valign="middle"><span class="Italics">DO NOT MASSAGE THE INJECTION SITE.</span></td> </tr> <tr> <td align="left" valign="top"></td><td align="left" colspan="8" valign="top"></td> </tr> <tr> <td align="left" valign="top">4.8</td><td align="left" colspan="8" valign="top">Engage the needle safety device.</td> </tr> <tr> <td align="left" valign="top"></td><td align="left" colspan="8" valign="top"></td> </tr> <tr> <td align="left" valign="top">4.9</td><td align="left" colspan="8" valign="top">Dispose of the vials, needles, and syringe appropriately after injection. The vial is for single-dose only.</td> </tr> <tr> <td align="left" colspan="9" valign="top"></td> </tr> <tr> <td align="right" colspan="8" valign="top"></td><td align="right" valign="top"> <p class="First"> <img alt="Figure" src="/dailymed/image.cfm?name=zr-CP-Logo.jpg&amp;setid=11544cba-64a9-49cb-8d74-da228053b252"/></p> </td> </tr> <tr> <td align="left" colspan="9" valign="top"></td> </tr> <tr> <td align="right" colspan="8" valign="top"></td><td align="right" valign="top"> <p class="First"> <img alt="Figure" src="/dailymed/image.cfm?name=zr-um-logo-v1.jpg&amp;setid=11544cba-64a9-49cb-8d74-da228053b252"/></p> </td> </tr> <tr> <td align="left" colspan="9" valign="top"></td> </tr> <tr> <td align="left" colspan="9" valign="top">Zyprexa<span class="Sup">®</span> Relprevv<span class="Sup">®</span> is a registered trademark of CHEPLAPHARM.</td> </tr> <tr> <td align="left" colspan="9" valign="top"></td> </tr> <tr> <td align="left" colspan="9" valign="top">CHEPLAPHARM Registration GmbH under the license of CHEPLAPHARM Schweiz GmbH</td> </tr> <tr> <td align="left" colspan="9" valign="top"></td> </tr> <tr> <td align="left" colspan="9" valign="top">Literature revised: October, 2023</td> </tr> <tr> <td align="left" colspan="9" valign="top"></td> </tr> <tr> <td align="left" colspan="9" valign="top"><span class="Bold">Smiths Medical </span> <br/> <span class="Bold">Jelco<span class="Sup">®</span></span> <br/> <span class="Bold">Hypodermic Needle-Pro<span class="Sup">®</span> Needle</span> <br/> <span class="Bold">With Needle Protection Device</span></td> </tr> <tr> <td align="left" valign="top"></td><td align="left" colspan="8" valign="top"></td> </tr> <tr> <td align="left" valign="top"><span class="Bold">1.</span></td><td align="left" colspan="8" valign="top"><span class="Bold">DESCRIPTION:</span></td> </tr> <tr> <td align="left" valign="top"></td><td align="left" colspan="8" valign="top"></td> </tr> <tr> <td align="left" valign="top"></td><td align="left" colspan="8" valign="top">The Hypodermic Needle-Pro<span class="Sup">®</span> device is a sterile, single use device. It includes a needle and needle safety sheath. The Needle-Pro<span class="Sup">®</span> device can be used with a Luer slip or Luer lock syringe.</td> </tr> <tr> <td align="left" valign="top"></td><td align="left" colspan="8" valign="top"></td> </tr> <tr> <td align="left" valign="top"><span class="Bold">2.</span></td><td align="left" colspan="8" valign="top"><span class="Bold">INDICATIONS FOR USE:</span></td> </tr> <tr> <td align="left" valign="top"></td><td align="left" colspan="8" valign="top"></td> </tr> <tr> <td align="left" valign="top"></td><td align="left" colspan="8" valign="top">This device is intended for injection or aspiration of fluids. The needle protection device covers the needle after use to help prevent needle sticks.</td> </tr> <tr> <td align="left" valign="top"></td><td align="left" colspan="8" valign="top"></td> </tr> <tr> <td align="left" valign="top"><span class="Bold">3.</span></td><td align="left" colspan="8" valign="top"><span class="Bold">CONTRAINDICATIONS:</span></td> </tr> <tr> <td align="left" valign="top"></td><td align="left" colspan="8" valign="top"></td> </tr> <tr> <td align="left" valign="top"></td><td align="left" colspan="8" valign="top">None known.</td> </tr> <tr> <td align="left" valign="top"></td><td align="left" colspan="8" valign="top"></td> </tr> <tr> <td align="left" valign="top"><span class="Bold">4.</span></td><td align="left" colspan="8" valign="top"><span class="Bold Underline">WARNINGS:</span></td> </tr> <tr> <td align="left" valign="top"></td><td align="left" colspan="8" valign="top"></td> </tr> <tr> <td align="left" valign="top">4.1</td><td align="left" colspan="8" valign="top">A needle stick with a contaminated needle may cause infectious diseases.</td> </tr> <tr> <td align="left" valign="top"></td><td align="left" colspan="8" valign="top"></td> </tr> <tr> <td align="left" valign="top">4.2</td><td align="left" colspan="8" valign="top">Intentional disengagement of the Needle-Pro<span class="Sup">®</span> device may result in a needle stick with a contaminated needle.</td> </tr> <tr> <td align="left" valign="top"></td><td align="left" colspan="8" valign="top"></td> </tr> <tr> <td align="left" valign="top">4.3</td><td align="left" colspan="8" valign="top">Bent or damaged needles can result in breakage or damage to the tissue or accidental needle puncture. If the needle is bent or damaged, no attempt should be made to straighten the needle or engage the Needle-Pro<span class="Sup">®</span> device. The Needle-Pro<span class="Sup">®</span> device may not properly contain a bent needle and/or the needle could puncture the needle protection device which may result in a needle stick with a contaminated needle.</td> </tr> <tr> <td align="left" valign="top"></td><td align="left" colspan="8" valign="top"></td> </tr> <tr> <td align="left" valign="top">4.4</td><td align="left" colspan="8" valign="top">Mishandling of the needle protection device may cause needles, especially short or small gauge needles, to bend whereby they protrude from the needle protector sheath which may result in a contaminated needle stick.</td> </tr> <tr> <td align="left" valign="top"></td><td align="left" colspan="8" valign="top"></td> </tr> <tr> <td align="left" valign="top">4.5</td><td align="left" colspan="8" valign="top">Do not use with Paraldehyde.</td> </tr> <tr> <td align="left" valign="top"></td><td align="left" colspan="8" valign="top"></td> </tr> <tr> <td align="left" valign="top"><span class="Bold">5.</span></td><td align="left" colspan="8" valign="top"><span class="Bold Underline">CAUTION:</span></td> </tr> <tr> <td align="left" valign="top"></td><td align="left" colspan="8" valign="top"></td> </tr> <tr> <td align="left" valign="top">5.1</td><td align="left" colspan="8" valign="top">Do Not Reuse: Medical devices require specific material characteristics to perform as intended. These characteristics have been verified for single use only. Any attempt to re-process the device for subsequent re-use may adversely affect the integrity of the device or lead to deterioration in performance.</td> </tr> <tr> <td align="left" valign="top"></td><td align="left" colspan="8" valign="top"></td> </tr> <tr> <td align="left" valign="top">5.2</td><td align="left" colspan="8" valign="top">Follow standard infection control procedures as specified by the Centers for Disease Control and Prevention (USA) or local equivalent.</td> </tr> <tr> <td align="left" valign="top"></td><td align="left" colspan="8" valign="top"></td> </tr> <tr> <td align="left" valign="top"><span class="Bold">6.</span></td><td align="left" colspan="8" valign="top"><span class="Bold">INSTRUCTIONS FOR USE:</span></td> </tr> <tr> <td align="left" valign="top"></td><td align="left" colspan="8" valign="top"></td> </tr> <tr> <td align="left" valign="top">6.1</td><td align="left" colspan="8" valign="top">Peel blister pouch and remove device.</td> </tr> <tr> <td align="left" valign="top"></td><td align="left" colspan="8" valign="top"></td> </tr> <tr> <td align="left" valign="top">6.2</td><td align="left" colspan="8" valign="top">Attach a syringe (if not already attached) to the Luer connection of the Needle-Pro<span class="Sup">®</span> device with an easy twisting motion. Seat the needle firmly on the Needle-Pro<span class="Sup">®</span> device with a push and a clockwise twist, then pull the needle cap straight away from the needle.</td> </tr> <tr> <td align="left" valign="top"></td><td align="left" colspan="8" valign="top"></td> </tr> <tr> <td align="left" valign="top">6.3</td><td align="left" colspan="8" valign="top">After procedure is completed, press the needle into the sheath using a one-handed technique. Perform a one-handed technique by gently pressing the sheath against a flat surface. As The Sheath Is Pressed (<a href="#f17">Fig. 1</a>), The Needle Is Firmly Engaged Into The Sheath (<a href="#f17">Fig. 2</a>).</td> </tr> <tr> <td align="left" valign="top"></td><td align="left" colspan="8" valign="top"></td> </tr> <tr> <td align="center" colspan="9" valign="top"> <br/> <img alt="Figure" src="/dailymed/image.cfm?name=zr-needle-um-f1-v3.jpg&amp;setid=11544cba-64a9-49cb-8d74-da228053b252"/></td> </tr> <tr> <td align="left" valign="top"></td><td align="left" colspan="8" valign="top"></td> </tr> <tr> <td align="left" valign="top">6.4</td><td align="left" colspan="8" valign="top">Visually confirm that the needle is fully engaged into the needle protection sheath.</td> </tr> <tr> <td align="left" valign="top"></td><td align="left" colspan="8" valign="top"></td> </tr> <tr> <td align="left" valign="top">6.5</td><td align="left" colspan="8" valign="top">Only remove the Needle-Pro<span class="Sup">®</span> device with engaged needle from the syringe when required by a specific medical procedure. Remove by grasping the Luer hub of the needle protection device with thumb and forefinger, keeping the free fingers clear of the end of the device containing the needle point. (See <a href="#f09">Fig. 3</a>)</td> </tr> <tr> <td align="left" valign="top"></td><td align="left" colspan="8" valign="top"></td> </tr> <tr> <td align="center" colspan="9" valign="top"> <br/> <img alt="Figure" src="/dailymed/image.cfm?name=zr-needle-um-f3-v1.jpg&amp;setid=11544cba-64a9-49cb-8d74-da228053b252"/></td> </tr> <tr> <td align="left" valign="top"></td><td align="left" colspan="8" valign="top"></td> </tr> <tr> <td align="left" valign="top">6.6</td><td align="left" colspan="8" valign="top">After use, place sharps in a suitable sharps container. Dispose of contaminated product in a safe manner according to Centers for Disease Control and Prevention, USA and Federal/State/Local regulations (EPA, OSHA) and health care facility guidelines or local equivalent.</td> </tr> <tr> <td align="left" valign="top"></td><td align="left" colspan="8" valign="top"></td> </tr> <tr> <td align="left" valign="top"></td><td align="left" colspan="8" valign="top"><span class="Bold Italics">NOTE:</span> Additional dead space added by Needle-Pro<span class="Sup">®</span> device averages 0.036 mL.</td> </tr> <tr> <td align="left" colspan="9" valign="top"></td> </tr> <tr> <td align="left" colspan="9" valign="top"></td> </tr> <tr> <td align="left" colspan="9" valign="top">Needle-Pro; and the color orange applied to the needle protection device, Jelco design mark and Smiths Medical design mark are trademarks of Smiths Medical. The symbol ® indicates the trademark is registered in the U.S. Patent and Trademark Office and certain other countries.</td> </tr> <tr> <td align="left" colspan="9" valign="top"></td> </tr> <tr> <td align="left" colspan="9" valign="top">© 2019 Smiths Medical. All rights reserved.</td> </tr> <tr> <td align="left" colspan="9" valign="top"><img alt="Figure" src="/dailymed/image.cfm?name=zr-um-f7-v1.jpg&amp;setid=11544cba-64a9-49cb-8d74-da228053b252"/><span class="Bold">Caution</span> • <img alt="Figure" src="/dailymed/image.cfm?name=zr-um-f8-v1.jpg&amp;setid=11544cba-64a9-49cb-8d74-da228053b252"/> Do Not Reuse • <img alt="Figure" src="/dailymed/image.cfm?name=zr-um-f9-v1.jpg&amp;setid=11544cba-64a9-49cb-8d74-da228053b252"/>Not made with natural rubber latex • <img alt="Figure" src="/dailymed/image.cfm?name=zr-um-f10-v1.jpg&amp;setid=11544cba-64a9-49cb-8d74-da228053b252"/> Do not use if package is damaged • <img alt="Figure" src="/dailymed/image.cfm?name=zr-um-f11-v1.jpg&amp;setid=11544cba-64a9-49cb-8d74-da228053b252"/>Sterilized using ethylene oxide • <img alt="Figure" src="/dailymed/image.cfm?name=zr-um-f12-v1.jpg&amp;setid=11544cba-64a9-49cb-8d74-da228053b252"/> Non-pyrogenic fluid path • <img alt="Figure" src="/dailymed/image.cfm?name=zr-um-f13-v1.jpg&amp;setid=11544cba-64a9-49cb-8d74-da228053b252"/><span class="Bold">Caution:</span> Federal (USA) law restricts this device to sale by or on the order of a physician • <img alt="Figure" src="/dailymed/image.cfm?name=zr-um-f14-v1.jpg&amp;setid=11544cba-64a9-49cb-8d74-da228053b252"/>Catalogue Number • <img alt="Figure" src="/dailymed/image.cfm?name=zr-um-f15-v1.jpg&amp;setid=11544cba-64a9-49cb-8d74-da228053b252"/>Batch Code • <img alt="Figure" src="/dailymed/image.cfm?name=zr-um-f16-v1.jpg&amp;setid=11544cba-64a9-49cb-8d74-da228053b252"/>Date of Manufacture • <img alt="Figure" src="/dailymed/image.cfm?name=zr-um-f17-v1.jpg&amp;setid=11544cba-64a9-49cb-8d74-da228053b252"/>Use by • <img alt="Figure" src="/dailymed/image.cfm?name=zr-um-f18-v1.jpg&amp;setid=11544cba-64a9-49cb-8d74-da228053b252"/>Quantity • <img alt="Figure" src="/dailymed/image.cfm?name=zr-um-f19-v1.jpg&amp;setid=11544cba-64a9-49cb-8d74-da228053b252"/>Manufacturer • <img alt="Figure" src="/dailymed/image.cfm?name=zr-um-f20-v1.jpg&amp;setid=11544cba-64a9-49cb-8d74-da228053b252"/>Authorized Representative in the European Community • <img alt="Figure" src="/dailymed/image.cfm?name=zr-um-f21-v1.jpg&amp;setid=11544cba-64a9-49cb-8d74-da228053b252"/>Keep dry • <img alt="Figure" src="/dailymed/image.cfm?name=zr-um-f22-v1.jpg&amp;setid=11544cba-64a9-49cb-8d74-da228053b252"/>Keep away from sunlight</td> </tr> <tr> <td align="left" colspan="9" valign="top"></td> </tr> <tr> <td align="left" colspan="9" valign="top"><img alt="Figure" src="/dailymed/image.cfm?name=zr-um-f19-v1.jpg&amp;setid=11544cba-64a9-49cb-8d74-da228053b252"/>Manufacturer:<br/> <span class="Bold">Smiths Medical ASD, Inc.</span> <br/> 6000 Nathan Lane North<br/> Minneapolis, MN 55442 USA<br/> Tel: 1 800 258 5361 (US/CA) <br/> Tel: +1 614 210 7300</td> </tr> <tr> <td align="left" colspan="9" valign="top"></td> </tr> <tr> <td align="left" colspan="9" valign="top">www.smiths-medical.com</td> </tr> <tr> <td align="left" colspan="9" valign="top"> Rx ONLY</td> </tr> <tr> <td align="left" colspan="9" valign="top">CE<br/> 2797</td> </tr> <tr class="Last"> <td align="left" colspan="9" valign="top"> <br/> <br/>ZYPR-0002-SM10018196-002-IFU-20200204</td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table width=\"100%\">\n<colgroup>\n<col align=\"left\" width=\"6.766%\"/>\n<col align=\"left\" width=\"48.861%\"/>\n<col align=\"left\" width=\"10%\"/>\n<col align=\"left\" width=\"1.878%\"/>\n<col align=\"left\" width=\"10%\"/>\n<col align=\"left\" width=\"11.277%\"/>\n<col align=\"left\" width=\"9.021%\"/>\n<col align=\"left\" width=\"7.899%\"/>\n<col align=\"left\" width=\"12.410%\"/>\n</colgroup>\n<tbody class=\"Headless\">\n<tr class=\"First\">\n<td align=\"left\" colspan=\"9\" valign=\"top\">Instructions to Reconstitute and Administer Single-Dose vial of Zyprexa<span class=\"Sup\">®</span> Relprevv<span class=\"Sup\">®</span></td>\n</tr>\n<tr>\n<td align=\"left\" colspan=\"9\" valign=\"top\"></td>\n</tr>\n<tr>\n<td align=\"left\" colspan=\"9\" valign=\"top\"><span class=\"Bold\">FOR DEEP INTRAMUSCULAR GLUTEAL INJECTION ONLY.</span></td>\n</tr>\n<tr>\n<td align=\"left\" colspan=\"9\" valign=\"top\"><span class=\"Bold\">NOT TO BE INJECTED INTRAVENOUSLY OR SUBCUTANEOUSLY.</span></td>\n</tr>\n<tr>\n<td align=\"left\" colspan=\"9\" valign=\"top\"></td>\n</tr>\n<tr>\n<td align=\"left\" colspan=\"9\" valign=\"top\"><span class=\"Bold\">STEP 1</span></td>\n</tr>\n<tr>\n<td align=\"left\" colspan=\"9\" valign=\"top\"><span class=\"Bold\">PREPARING MATERIALS</span></td>\n</tr>\n<tr>\n<td align=\"left\" colspan=\"9\" valign=\"top\"></td>\n</tr>\n<tr>\n<td align=\"left\" colspan=\"2\" valign=\"top\"><span class=\"Bold\">Convenience kit includes:</span></td><td align=\"left\" colspan=\"2\" valign=\"top\"></td><td align=\"left\" colspan=\"5\" rowspan=\"6\" valign=\"top\">\n<br/>\n<img alt=\"Figure 1\" src=\"/dailymed/image.cfm?name=zr-um-f1-v1.jpg&amp;setid=11544cba-64a9-49cb-8d74-da228053b252\"/></td>\n</tr>\n<tr>\n<td align=\"left\" colspan=\"2\" valign=\"top\"><span class=\"Italics\">(see <a href=\"#f06\">Figure 1</a> on right)</span></td><td align=\"left\" colspan=\"2\" valign=\"top\"></td>\n</tr>\n<tr>\n<td align=\"left\" colspan=\"2\" valign=\"top\"></td><td align=\"left\" colspan=\"2\" valign=\"top\"></td>\n</tr>\n<tr>\n<td align=\"left\" colspan=\"2\" valign=\"top\">\n<ul class=\"Disc\">\n<li>Single-dose vial of Zyprexa Relprevv powder</li>\n</ul>\n</td><td align=\"left\" colspan=\"2\" valign=\"top\"></td>\n</tr>\n<tr>\n<td align=\"left\" colspan=\"2\" valign=\"top\">\n<ul class=\"Disc\">\n<li>3-mL vial of diluent</li>\n</ul>\n</td><td align=\"left\" colspan=\"2\" valign=\"top\"></td>\n</tr>\n<tr>\n<td align=\"left\" colspan=\"2\" valign=\"top\">\n<ul class=\"Disc\">\n<li>One 3-mL syringe with pre-attached 19-gauge, 1.5-inch (38 mm) Hypodermic Needle-Pro<span class=\"Sup\">®</span> needle with needle protection device</li>\n</ul>\n</td><td align=\"left\" colspan=\"2\" valign=\"top\"></td>\n</tr>\n<tr>\n<td align=\"left\" colspan=\"2\" rowspan=\"3\" valign=\"top\">\n<ul class=\"Disc\">\n<li>Two 19-gauge, 1.5-inch (38 mm) Hypodermic Needle-Pro needles with needle protection device</li>\n</ul>\n</td><td align=\"left\" colspan=\"2\" rowspan=\"3\" valign=\"top\"></td><td align=\"left\" colspan=\"5\" valign=\"top\"></td>\n</tr>\n<tr>\n<td align=\"left\" colspan=\"5\" valign=\"top\"></td>\n</tr>\n<tr>\n<td align=\"left\" colspan=\"5\" valign=\"top\"></td>\n</tr>\n<tr>\n<td align=\"left\" colspan=\"9\" valign=\"top\">— For obese patients, a 2-inch (50 mm), 19-gauge or larger needle (not included in convenience kit) may be used for administration.</td>\n</tr>\n<tr>\n<td align=\"left\" colspan=\"9\" valign=\"top\"></td>\n</tr>\n<tr>\n<td align=\"left\" valign=\"top\">\n<br/>\n<p class=\"First\">\n<img alt=\"Figure 2\" src=\"/dailymed/image.cfm?name=zr-um-exclamation.jpg&amp;setid=11544cba-64a9-49cb-8d74-da228053b252\"/></p>\n</td><td align=\"left\" colspan=\"8\" valign=\"middle\"><span class=\"Italics\">Zyprexa Relprevv must be suspended using only the diluent supplied in the convenience kit.</span></td>\n</tr>\n<tr>\n<td align=\"left\" colspan=\"9\" valign=\"top\"></td>\n</tr>\n<tr>\n<td align=\"left\" colspan=\"9\" valign=\"top\">It is recommended that gloves are used when reconstituting, as Zyprexa Relprevv may be irritating to the skin. Flush with water if contact is made with skin.</td>\n</tr>\n<tr>\n<td align=\"left\" colspan=\"9\" valign=\"top\"></td>\n</tr>\n<tr>\n<td align=\"left\" colspan=\"9\" valign=\"top\">\n<p class=\"First\">\n<a name=\"p02\"></a><span class=\"Bold\">STEP 2</span>\n</p>\n</td>\n</tr>\n<tr>\n<td align=\"left\" colspan=\"9\" valign=\"top\"><span class=\"Bold\">DETERMINING RECONSTITUTION VOLUME</span></td>\n</tr>\n<tr>\n<td align=\"left\" colspan=\"9\" valign=\"top\"></td>\n</tr>\n<tr>\n<td align=\"left\" colspan=\"4\" valign=\"top\">Refer to the table at right to determine the amount of diluent to be added to powder for reconstitution of each vial strength.</td><td align=\"center\" colspan=\"5\" rowspan=\"2\" valign=\"top\"><img alt=\"Table\" src=\"/dailymed/image.cfm?name=zr-um-f2-v1.jpg&amp;setid=11544cba-64a9-49cb-8d74-da228053b252\"/></td>\n</tr>\n<tr>\n<td align=\"left\" valign=\"top\">\n<br/>\n<p class=\"First\">\n<img alt=\"Figure 2\" src=\"/dailymed/image.cfm?name=zr-um-exclamation.jpg&amp;setid=11544cba-64a9-49cb-8d74-da228053b252\"/></p>\n</td><td align=\"left\" colspan=\"3\" valign=\"middle\"><span class=\"Italics\">It is important to note that there is more diluent in the vial than is needed to reconstitute.</span></td>\n</tr>\n<tr>\n<td align=\"left\" colspan=\"9\" valign=\"top\"></td>\n</tr>\n<tr>\n<td align=\"left\" colspan=\"9\" valign=\"top\"><span class=\"Bold\">STEP 3</span></td>\n</tr>\n<tr>\n<td align=\"left\" colspan=\"9\" valign=\"top\"><span class=\"Bold\">RECONSTITUTING ZYPREXA RELPREVV</span></td>\n</tr>\n<tr>\n<td align=\"left\" colspan=\"9\" valign=\"top\"></td>\n</tr>\n<tr>\n<td align=\"left\" colspan=\"9\" valign=\"top\">Please read the Hypodermic Needle-Pro Instructions for Use before proceeding with Step 3. Failure to follow these instructions may result in a needle stick injury.</td>\n</tr>\n<tr>\n<td align=\"left\" valign=\"top\"></td><td align=\"left\" colspan=\"2\" valign=\"top\"></td><td align=\"left\" colspan=\"2\" valign=\"top\"></td><td align=\"left\" colspan=\"4\" valign=\"top\"></td>\n</tr>\n<tr>\n<td align=\"left\" valign=\"top\">3.1</td><td align=\"left\" colspan=\"2\" valign=\"top\">Loosen the powder by lightly tapping the vial.</td><td align=\"left\" colspan=\"2\" valign=\"top\"></td><td align=\"left\" colspan=\"4\" valign=\"top\">\n<br/>\n<img alt=\"Figure 4\" src=\"/dailymed/image.cfm?name=zr-um-f3-v1.jpg&amp;setid=11544cba-64a9-49cb-8d74-da228053b252\"/></td>\n</tr>\n<tr>\n<td align=\"left\" valign=\"top\"></td><td align=\"left\" colspan=\"2\" valign=\"top\"></td><td align=\"left\" colspan=\"2\" valign=\"top\"></td><td align=\"left\" colspan=\"4\" valign=\"top\"></td>\n</tr>\n<tr>\n<td align=\"left\" valign=\"top\"></td><td align=\"left\" colspan=\"2\" valign=\"top\"></td><td align=\"left\" colspan=\"2\" valign=\"top\"></td><td align=\"left\" colspan=\"4\" valign=\"top\"></td>\n</tr>\n<tr>\n<td align=\"left\" valign=\"top\">3.2</td><td align=\"left\" colspan=\"2\" valign=\"top\">Open the prepackaged Hypodermic Needle-Pro syringe and needle with needle protection device.</td><td align=\"left\" colspan=\"2\" valign=\"top\"></td><td align=\"left\" colspan=\"4\" valign=\"top\"></td>\n</tr>\n<tr>\n<td align=\"left\" valign=\"top\"></td><td align=\"left\" colspan=\"2\" valign=\"top\"></td><td align=\"left\" colspan=\"2\" valign=\"top\"></td><td align=\"left\" colspan=\"4\" valign=\"top\"></td>\n</tr>\n<tr>\n<td align=\"left\" valign=\"top\">3.3</td><td align=\"left\" colspan=\"2\" valign=\"top\">Withdraw the pre-determined diluent volume (<a href=\"#p02\">Step 2</a>) into the syringe.</td><td align=\"left\" colspan=\"2\" valign=\"top\"></td><td align=\"left\" colspan=\"4\" valign=\"top\"></td>\n</tr>\n<tr>\n<td align=\"left\" valign=\"top\"></td><td align=\"left\" colspan=\"2\" valign=\"top\"></td><td align=\"left\" colspan=\"2\" valign=\"top\"></td><td align=\"left\" colspan=\"4\" valign=\"top\"></td>\n</tr>\n<tr>\n<td align=\"left\" valign=\"top\">3.4</td><td align=\"left\" colspan=\"2\" valign=\"top\">Inject the diluent into the powder vial.</td><td align=\"left\" colspan=\"2\" valign=\"top\"></td><td align=\"left\" colspan=\"4\" valign=\"top\"></td>\n</tr>\n<tr>\n<td align=\"left\" valign=\"top\"></td><td align=\"left\" colspan=\"2\" valign=\"top\"></td><td align=\"left\" colspan=\"2\" valign=\"top\"></td><td align=\"left\" colspan=\"4\" valign=\"top\"></td>\n</tr>\n<tr>\n<td align=\"left\" valign=\"top\">3.5</td><td align=\"left\" colspan=\"2\" valign=\"top\">Withdraw air to equalize the pressure in the vial by pulling back slightly on the plunger in the syringe.</td><td align=\"left\" colspan=\"2\" valign=\"top\"></td><td align=\"left\" colspan=\"4\" valign=\"top\"></td>\n</tr>\n<tr>\n<td align=\"left\" valign=\"top\"></td><td align=\"left\" colspan=\"2\" valign=\"top\"></td><td align=\"left\" colspan=\"2\" valign=\"top\"></td><td align=\"left\" colspan=\"4\" valign=\"top\"></td>\n</tr>\n<tr>\n<td align=\"left\" valign=\"top\">3.6</td><td align=\"left\" colspan=\"2\" valign=\"top\">Remove the needle from the vial, holding the vial upright to prevent any loss of material.</td><td align=\"left\" colspan=\"2\" valign=\"top\"></td><td align=\"left\" colspan=\"4\" valign=\"top\"></td>\n</tr>\n<tr>\n<td align=\"left\" valign=\"top\"></td><td align=\"left\" colspan=\"2\" valign=\"top\"></td><td align=\"left\" colspan=\"2\" valign=\"top\"></td><td align=\"left\" colspan=\"4\" valign=\"top\"></td>\n</tr>\n<tr>\n<td align=\"left\" valign=\"top\">3.7</td><td align=\"left\" colspan=\"2\" valign=\"top\">Engage the needle safety device (refer to complete Hypodermic Needle-Pro Instructions for Use).</td><td align=\"left\" colspan=\"2\" valign=\"top\"></td><td align=\"left\" colspan=\"4\" valign=\"top\"></td>\n</tr>\n<tr>\n<td align=\"left\" valign=\"top\"></td><td align=\"left\" colspan=\"2\" valign=\"top\"></td><td align=\"left\" colspan=\"2\" valign=\"top\"></td><td align=\"left\" colspan=\"4\" valign=\"top\"></td>\n</tr>\n<tr>\n<td align=\"left\" valign=\"top\">3.8</td><td align=\"left\" colspan=\"2\" valign=\"top\">Pad a hard surface to cushion impact <span class=\"Italics\">(see <a href=\"#f08\">Figure 2</a>)</span>. Tap the vial firmly and repeatedly on the surface until no powder is visible.</td><td align=\"left\" colspan=\"2\" valign=\"top\"></td><td align=\"left\" colspan=\"4\" valign=\"top\"></td>\n</tr>\n<tr>\n<td align=\"left\" valign=\"top\"></td><td align=\"left\" colspan=\"2\" valign=\"top\"></td><td align=\"left\" colspan=\"2\" valign=\"top\"></td><td align=\"left\" colspan=\"4\" valign=\"top\"></td>\n</tr>\n<tr>\n<td align=\"left\" rowspan=\"2\" valign=\"top\">3.9</td><td align=\"left\" colspan=\"2\" rowspan=\"2\" valign=\"top\">Visually check the vial for clumps. Unsuspended powder appears as yellow, dry clumps clinging to the vial. Additional tapping may be required if large clumps remain <span class=\"Italics\">(see <a href=\"#f09\">Figure 3</a>)</span>.</td><td align=\"left\" colspan=\"2\" rowspan=\"2\" valign=\"top\"></td><td align=\"left\" colspan=\"4\" valign=\"top\"></td>\n</tr>\n<tr>\n<td align=\"left\" colspan=\"4\" valign=\"top\">\n<br/>\n<img alt=\"Figure\" src=\"/dailymed/image.cfm?name=zr-um-f4-v1.jpg&amp;setid=11544cba-64a9-49cb-8d74-da228053b252\"/></td>\n</tr>\n<tr>\n<td align=\"left\" valign=\"top\"></td><td align=\"left\" colspan=\"2\" valign=\"top\"></td><td align=\"left\" colspan=\"2\" valign=\"top\"></td><td align=\"left\" colspan=\"4\" valign=\"top\"></td>\n</tr>\n<tr>\n<td align=\"left\" valign=\"top\"></td><td align=\"left\" colspan=\"2\" valign=\"top\"></td><td align=\"left\" colspan=\"2\" valign=\"top\"></td><td align=\"left\" colspan=\"4\" valign=\"top\"></td>\n</tr>\n<tr>\n<td align=\"left\" valign=\"top\"></td><td align=\"left\" colspan=\"2\" valign=\"top\"></td><td align=\"left\" colspan=\"2\" valign=\"top\"></td><td align=\"left\" colspan=\"4\" valign=\"top\"></td>\n</tr>\n<tr>\n<td align=\"left\" valign=\"top\"></td><td align=\"left\" colspan=\"2\" valign=\"top\"></td><td align=\"left\" colspan=\"2\" valign=\"top\"></td><td align=\"left\" colspan=\"4\" valign=\"top\"></td>\n</tr>\n<tr>\n<td align=\"left\" valign=\"top\">3.10</td><td align=\"left\" colspan=\"2\" valign=\"top\">Shake the vial vigorously until the suspension appears smooth and is consistent in color and texture. The suspended product will be yellow and opaque <span class=\"Italics\">(see <a href=\"#f11\">Figure 4</a>)</span>.</td><td align=\"left\" colspan=\"2\" valign=\"top\"></td><td align=\"left\" colspan=\"4\" valign=\"top\">\n<br/>\n<img alt=\"Figure\" src=\"/dailymed/image.cfm?name=zr-um-f5-v1.jpg&amp;setid=11544cba-64a9-49cb-8d74-da228053b252\"/></td>\n</tr>\n<tr>\n<td align=\"left\" valign=\"top\"></td><td align=\"left\" colspan=\"2\" valign=\"top\"></td><td align=\"left\" colspan=\"2\" valign=\"top\"></td><td align=\"left\" colspan=\"4\" valign=\"top\"></td>\n</tr>\n<tr>\n<td align=\"left\" valign=\"top\"></td><td align=\"left\" colspan=\"2\" valign=\"top\"></td><td align=\"left\" colspan=\"2\" valign=\"top\"></td><td align=\"left\" colspan=\"4\" valign=\"top\"></td>\n</tr>\n<tr>\n<td align=\"left\" colspan=\"9\" valign=\"top\"><span class=\"Bold\">If foam forms,</span> let vial stand to allow foam to dissipate.</td>\n</tr>\n<tr>\n<td align=\"left\" colspan=\"9\" valign=\"top\"></td>\n</tr>\n<tr>\n<td align=\"left\" colspan=\"9\" valign=\"top\"><span class=\"Bold\">If the product is not used right away,</span> it should be shaken vigorously to re-suspend. Reconstituted Zyprexa Relprevv remains stable at room temperature for up to 24 hours in the vial.</td>\n</tr>\n<tr>\n<td align=\"left\" colspan=\"9\" valign=\"top\"></td>\n</tr>\n<tr>\n<td align=\"left\" colspan=\"9\" valign=\"top\"></td>\n</tr>\n<tr>\n<td align=\"left\" colspan=\"9\" valign=\"top\"><span class=\"Bold\">STEP 4</span></td>\n</tr>\n<tr>\n<td align=\"left\" colspan=\"9\" valign=\"top\"><span class=\"Bold\">INJECTING ZYPREXA RELPREVV</span></td>\n</tr>\n<tr>\n<td align=\"left\" valign=\"top\"></td><td align=\"left\" colspan=\"8\" valign=\"top\"></td>\n</tr>\n<tr>\n<td align=\"left\" valign=\"top\">\n<br/>\n<p class=\"First\">\n<img alt=\"Figure 2\" src=\"/dailymed/image.cfm?name=zr-um-exclamation.jpg&amp;setid=11544cba-64a9-49cb-8d74-da228053b252\"/></p>\n</td><td align=\"left\" colspan=\"8\" valign=\"middle\"><span class=\"Italics\">IMPORTANT</span></td>\n</tr>\n<tr>\n<td align=\"left\" colspan=\"9\" valign=\"top\"><span class=\"Italics\">Before administering the injection, confirm there will be someone to accompany the patient after the 3-hour observation period. If this cannot be confirmed, do not give the injection.</span></td>\n</tr>\n<tr>\n<td align=\"left\" valign=\"top\"></td><td align=\"left\" colspan=\"8\" valign=\"top\"></td>\n</tr>\n<tr>\n<td align=\"left\" colspan=\"3\" valign=\"top\">Refer to the table at right to determine the final volume to inject. <span class=\"Bold\">Suspension concentration is 150 mg/mL Zyprexa Relprevv.</span></td><td align=\"center\" colspan=\"6\" valign=\"top\"><img alt=\"Figure\" src=\"/dailymed/image.cfm?name=zr-um-f6-v1.jpg&amp;setid=11544cba-64a9-49cb-8d74-da228053b252\"/></td>\n</tr>\n<tr>\n<td align=\"left\" valign=\"top\"></td><td align=\"left\" colspan=\"8\" valign=\"top\"></td>\n</tr>\n<tr>\n<td align=\"left\" valign=\"top\">4.1</td><td align=\"left\" colspan=\"8\" valign=\"top\">Attach a new safety needle to the syringe.</td>\n</tr>\n<tr>\n<td align=\"left\" valign=\"top\"></td><td align=\"left\" colspan=\"8\" valign=\"top\"></td>\n</tr>\n<tr>\n<td align=\"left\" valign=\"top\">4.2</td><td align=\"left\" colspan=\"8\" valign=\"top\">Slowly withdraw the desired amount into the syringe.</td>\n</tr>\n<tr>\n<td align=\"left\" valign=\"top\"></td><td align=\"left\" colspan=\"8\" valign=\"top\"></td>\n</tr>\n<tr>\n<td align=\"left\" valign=\"top\">\n<br/>\n<p class=\"First\">\n<img alt=\"Figure 2\" src=\"/dailymed/image.cfm?name=zr-um-exclamation.jpg&amp;setid=11544cba-64a9-49cb-8d74-da228053b252\"/></p>\n</td><td align=\"left\" colspan=\"8\" valign=\"middle\"><span class=\"Italics\">SOME EXCESS PRODUCT WILL REMAIN IN THE VIAL.</span></td>\n</tr>\n<tr>\n<td align=\"left\" valign=\"top\"></td><td align=\"left\" colspan=\"8\" valign=\"top\"></td>\n</tr>\n<tr>\n<td align=\"left\" valign=\"top\">4.3</td><td align=\"left\" colspan=\"8\" valign=\"top\">Engage the needle safety device and remove the needle from syringe.</td>\n</tr>\n<tr>\n<td align=\"left\" valign=\"top\"></td><td align=\"left\" colspan=\"8\" valign=\"top\"></td>\n</tr>\n<tr>\n<td align=\"left\" valign=\"top\">4.4</td><td align=\"left\" colspan=\"8\" valign=\"top\">For administration, select the 19-gauge, 1.5-inch (38 mm) Hypodermic Needle-Pro needle with needle protection device. For obese patients, a 2-inch (50 mm), 19-gauge or larger needle (not included in convenience kit) may be used. <span class=\"Bold\">To help prevent clogging, a 19-gauge or larger needle must be used.</span></td>\n</tr>\n<tr>\n<td align=\"left\" valign=\"top\"></td><td align=\"left\" colspan=\"8\" valign=\"top\"></td>\n</tr>\n<tr>\n<td align=\"left\" valign=\"top\">4.5</td><td align=\"left\" colspan=\"8\" valign=\"top\">Attach the new safety needle to the syringe prior to injection. Once the suspension has been removed from the vial, it should be injected immediately.</td>\n</tr>\n<tr>\n<td align=\"left\" valign=\"top\"></td><td align=\"left\" colspan=\"8\" valign=\"top\"></td>\n</tr>\n<tr>\n<td align=\"left\" valign=\"top\">\n<br/>\n<p class=\"First\">\n<img alt=\"Figure 2\" src=\"/dailymed/image.cfm?name=zr-um-exclamation.jpg&amp;setid=11544cba-64a9-49cb-8d74-da228053b252\"/></p>\n</td><td align=\"left\" colspan=\"8\" valign=\"middle\"><span class=\"Bold\">FOR DEEP INTRAMUSCULAR GLUTEAL INJECTION ONLY.</span></td>\n</tr>\n<tr>\n<td align=\"left\" valign=\"top\"></td><td align=\"left\" colspan=\"8\" valign=\"top\"><span class=\"Italics\">DO NOT INJECT INTRAVENOUSLY OR SUBCUTANEOUSLY.</span></td>\n</tr>\n<tr>\n<td align=\"left\" valign=\"top\"></td><td align=\"left\" colspan=\"8\" valign=\"top\"></td>\n</tr>\n<tr>\n<td align=\"left\" valign=\"top\">4.6</td><td align=\"left\" colspan=\"8\" valign=\"top\">Select and prepare a site for injection in the <span class=\"Bold\">gluteal</span> area.</td>\n</tr>\n<tr>\n<td align=\"left\" valign=\"top\"></td><td align=\"left\" colspan=\"8\" valign=\"top\"></td>\n</tr>\n<tr>\n<td align=\"left\" valign=\"top\">4.7</td><td align=\"left\" colspan=\"8\" valign=\"top\">\n<p class=\"First\">After insertion of the needle into the muscle, <img alt=\"Figure 2\" src=\"/dailymed/image.cfm?name=zr-um-exclamation.jpg&amp;setid=11544cba-64a9-49cb-8d74-da228053b252\"/><span class=\"Italics\">aspirate for several seconds to ensure that no blood appears.</span> If any blood is drawn into the syringe, discard the syringe and the dose and begin with a new convenience kit. The injection should be performed with steady, continuous pressure.</p>\n</td>\n</tr>\n<tr>\n<td align=\"left\" valign=\"top\"></td><td align=\"left\" colspan=\"8\" valign=\"top\"></td>\n</tr>\n<tr>\n<td align=\"left\" valign=\"top\">\n<br/>\n<p class=\"First\">\n<img alt=\"Figure 2\" src=\"/dailymed/image.cfm?name=zr-um-exclamation.jpg&amp;setid=11544cba-64a9-49cb-8d74-da228053b252\"/></p>\n</td><td align=\"left\" colspan=\"8\" valign=\"middle\"><span class=\"Italics\">DO NOT MASSAGE THE INJECTION SITE.</span></td>\n</tr>\n<tr>\n<td align=\"left\" valign=\"top\"></td><td align=\"left\" colspan=\"8\" valign=\"top\"></td>\n</tr>\n<tr>\n<td align=\"left\" valign=\"top\">4.8</td><td align=\"left\" colspan=\"8\" valign=\"top\">Engage the needle safety device.</td>\n</tr>\n<tr>\n<td align=\"left\" valign=\"top\"></td><td align=\"left\" colspan=\"8\" valign=\"top\"></td>\n</tr>\n<tr>\n<td align=\"left\" valign=\"top\">4.9</td><td align=\"left\" colspan=\"8\" valign=\"top\">Dispose of the vials, needles, and syringe appropriately after injection. The vial is for single-dose only.</td>\n</tr>\n<tr>\n<td align=\"left\" colspan=\"9\" valign=\"top\"></td>\n</tr>\n<tr>\n<td align=\"right\" colspan=\"8\" valign=\"top\"></td><td align=\"right\" valign=\"top\">\n<p class=\"First\">\n<img alt=\"Figure\" src=\"/dailymed/image.cfm?name=zr-CP-Logo.jpg&amp;setid=11544cba-64a9-49cb-8d74-da228053b252\"/></p>\n</td>\n</tr>\n<tr>\n<td align=\"left\" colspan=\"9\" valign=\"top\"></td>\n</tr>\n<tr>\n<td align=\"right\" colspan=\"8\" valign=\"top\"></td><td align=\"right\" valign=\"top\">\n<p class=\"First\">\n<img alt=\"Figure\" src=\"/dailymed/image.cfm?name=zr-um-logo-v1.jpg&amp;setid=11544cba-64a9-49cb-8d74-da228053b252\"/></p>\n</td>\n</tr>\n<tr>\n<td align=\"left\" colspan=\"9\" valign=\"top\"></td>\n</tr>\n<tr>\n<td align=\"left\" colspan=\"9\" valign=\"top\">Zyprexa<span class=\"Sup\">®</span> Relprevv<span class=\"Sup\">®</span> is a registered trademark of CHEPLAPHARM.</td>\n</tr>\n<tr>\n<td align=\"left\" colspan=\"9\" valign=\"top\"></td>\n</tr>\n<tr>\n<td align=\"left\" colspan=\"9\" valign=\"top\">CHEPLAPHARM Registration GmbH under the license of CHEPLAPHARM Schweiz GmbH</td>\n</tr>\n<tr>\n<td align=\"left\" colspan=\"9\" valign=\"top\"></td>\n</tr>\n<tr>\n<td align=\"left\" colspan=\"9\" valign=\"top\">Literature revised: October, 2023</td>\n</tr>\n<tr>\n<td align=\"left\" colspan=\"9\" valign=\"top\"></td>\n</tr>\n<tr>\n<td align=\"left\" colspan=\"9\" valign=\"top\"><span class=\"Bold\">Smiths Medical </span>\n<br/>\n<span class=\"Bold\">Jelco<span class=\"Sup\">®</span></span>\n<br/>\n<span class=\"Bold\">Hypodermic Needle-Pro<span class=\"Sup\">®</span> Needle</span>\n<br/>\n<span class=\"Bold\">With Needle Protection Device</span></td>\n</tr>\n<tr>\n<td align=\"left\" valign=\"top\"></td><td align=\"left\" colspan=\"8\" valign=\"top\"></td>\n</tr>\n<tr>\n<td align=\"left\" valign=\"top\"><span class=\"Bold\">1.</span></td><td align=\"left\" colspan=\"8\" valign=\"top\"><span class=\"Bold\">DESCRIPTION:</span></td>\n</tr>\n<tr>\n<td align=\"left\" valign=\"top\"></td><td align=\"left\" colspan=\"8\" valign=\"top\"></td>\n</tr>\n<tr>\n<td align=\"left\" valign=\"top\"></td><td align=\"left\" colspan=\"8\" valign=\"top\">The Hypodermic Needle-Pro<span class=\"Sup\">®</span> device is a sterile, single use device. It includes a needle and needle safety sheath. The Needle-Pro<span class=\"Sup\">®</span> device can be used with a Luer slip or Luer lock syringe.</td>\n</tr>\n<tr>\n<td align=\"left\" valign=\"top\"></td><td align=\"left\" colspan=\"8\" valign=\"top\"></td>\n</tr>\n<tr>\n<td align=\"left\" valign=\"top\"><span class=\"Bold\">2.</span></td><td align=\"left\" colspan=\"8\" valign=\"top\"><span class=\"Bold\">INDICATIONS FOR USE:</span></td>\n</tr>\n<tr>\n<td align=\"left\" valign=\"top\"></td><td align=\"left\" colspan=\"8\" valign=\"top\"></td>\n</tr>\n<tr>\n<td align=\"left\" valign=\"top\"></td><td align=\"left\" colspan=\"8\" valign=\"top\">This device is intended for injection or aspiration of fluids. The needle protection device covers the needle after use to help prevent needle sticks.</td>\n</tr>\n<tr>\n<td align=\"left\" valign=\"top\"></td><td align=\"left\" colspan=\"8\" valign=\"top\"></td>\n</tr>\n<tr>\n<td align=\"left\" valign=\"top\"><span class=\"Bold\">3.</span></td><td align=\"left\" colspan=\"8\" valign=\"top\"><span class=\"Bold\">CONTRAINDICATIONS:</span></td>\n</tr>\n<tr>\n<td align=\"left\" valign=\"top\"></td><td align=\"left\" colspan=\"8\" valign=\"top\"></td>\n</tr>\n<tr>\n<td align=\"left\" valign=\"top\"></td><td align=\"left\" colspan=\"8\" valign=\"top\">None known.</td>\n</tr>\n<tr>\n<td align=\"left\" valign=\"top\"></td><td align=\"left\" colspan=\"8\" valign=\"top\"></td>\n</tr>\n<tr>\n<td align=\"left\" valign=\"top\"><span class=\"Bold\">4.</span></td><td align=\"left\" colspan=\"8\" valign=\"top\"><span class=\"Bold Underline\">WARNINGS:</span></td>\n</tr>\n<tr>\n<td align=\"left\" valign=\"top\"></td><td align=\"left\" colspan=\"8\" valign=\"top\"></td>\n</tr>\n<tr>\n<td align=\"left\" valign=\"top\">4.1</td><td align=\"left\" colspan=\"8\" valign=\"top\">A needle stick with a contaminated needle may cause infectious diseases.</td>\n</tr>\n<tr>\n<td align=\"left\" valign=\"top\"></td><td align=\"left\" colspan=\"8\" valign=\"top\"></td>\n</tr>\n<tr>\n<td align=\"left\" valign=\"top\">4.2</td><td align=\"left\" colspan=\"8\" valign=\"top\">Intentional disengagement of the Needle-Pro<span class=\"Sup\">®</span> device may result in a needle stick with a contaminated needle.</td>\n</tr>\n<tr>\n<td align=\"left\" valign=\"top\"></td><td align=\"left\" colspan=\"8\" valign=\"top\"></td>\n</tr>\n<tr>\n<td align=\"left\" valign=\"top\">4.3</td><td align=\"left\" colspan=\"8\" valign=\"top\">Bent or damaged needles can result in breakage or damage to the tissue or accidental needle puncture. If the needle is bent or damaged, no attempt should be made to straighten the needle or engage the Needle-Pro<span class=\"Sup\">®</span> device. The Needle-Pro<span class=\"Sup\">®</span> device may not properly contain a bent needle and/or the needle could puncture the needle protection device which may result in a needle stick with a contaminated needle.</td>\n</tr>\n<tr>\n<td align=\"left\" valign=\"top\"></td><td align=\"left\" colspan=\"8\" valign=\"top\"></td>\n</tr>\n<tr>\n<td align=\"left\" valign=\"top\">4.4</td><td align=\"left\" colspan=\"8\" valign=\"top\">Mishandling of the needle protection device may cause needles, especially short or small gauge needles, to bend whereby they protrude from the needle protector sheath which may result in a contaminated needle stick.</td>\n</tr>\n<tr>\n<td align=\"left\" valign=\"top\"></td><td align=\"left\" colspan=\"8\" valign=\"top\"></td>\n</tr>\n<tr>\n<td align=\"left\" valign=\"top\">4.5</td><td align=\"left\" colspan=\"8\" valign=\"top\">Do not use with Paraldehyde.</td>\n</tr>\n<tr>\n<td align=\"left\" valign=\"top\"></td><td align=\"left\" colspan=\"8\" valign=\"top\"></td>\n</tr>\n<tr>\n<td align=\"left\" valign=\"top\"><span class=\"Bold\">5.</span></td><td align=\"left\" colspan=\"8\" valign=\"top\"><span class=\"Bold Underline\">CAUTION:</span></td>\n</tr>\n<tr>\n<td align=\"left\" valign=\"top\"></td><td align=\"left\" colspan=\"8\" valign=\"top\"></td>\n</tr>\n<tr>\n<td align=\"left\" valign=\"top\">5.1</td><td align=\"left\" colspan=\"8\" valign=\"top\">Do Not Reuse: Medical devices require specific material characteristics to perform as intended. These characteristics have been verified for single use only. Any attempt to re-process the device for subsequent re-use may adversely affect the integrity of the device or lead to deterioration in performance.</td>\n</tr>\n<tr>\n<td align=\"left\" valign=\"top\"></td><td align=\"left\" colspan=\"8\" valign=\"top\"></td>\n</tr>\n<tr>\n<td align=\"left\" valign=\"top\">5.2</td><td align=\"left\" colspan=\"8\" valign=\"top\">Follow standard infection control procedures as specified by the Centers for Disease Control and Prevention (USA) or local equivalent.</td>\n</tr>\n<tr>\n<td align=\"left\" valign=\"top\"></td><td align=\"left\" colspan=\"8\" valign=\"top\"></td>\n</tr>\n<tr>\n<td align=\"left\" valign=\"top\"><span class=\"Bold\">6.</span></td><td align=\"left\" colspan=\"8\" valign=\"top\"><span class=\"Bold\">INSTRUCTIONS FOR USE:</span></td>\n</tr>\n<tr>\n<td align=\"left\" valign=\"top\"></td><td align=\"left\" colspan=\"8\" valign=\"top\"></td>\n</tr>\n<tr>\n<td align=\"left\" valign=\"top\">6.1</td><td align=\"left\" colspan=\"8\" valign=\"top\">Peel blister pouch and remove device.</td>\n</tr>\n<tr>\n<td align=\"left\" valign=\"top\"></td><td align=\"left\" colspan=\"8\" valign=\"top\"></td>\n</tr>\n<tr>\n<td align=\"left\" valign=\"top\">6.2</td><td align=\"left\" colspan=\"8\" valign=\"top\">Attach a syringe (if not already attached) to the Luer connection of the Needle-Pro<span class=\"Sup\">®</span> device with an easy twisting motion. Seat the needle firmly on the Needle-Pro<span class=\"Sup\">®</span> device with a push and a clockwise twist, then pull the needle cap straight away from the needle.</td>\n</tr>\n<tr>\n<td align=\"left\" valign=\"top\"></td><td align=\"left\" colspan=\"8\" valign=\"top\"></td>\n</tr>\n<tr>\n<td align=\"left\" valign=\"top\">6.3</td><td align=\"left\" colspan=\"8\" valign=\"top\">After procedure is completed, press the needle into the sheath using a one-handed technique. Perform a one-handed technique by gently pressing the sheath against a flat surface. As The Sheath Is Pressed (<a href=\"#f17\">Fig. 1</a>), The Needle Is Firmly Engaged Into The Sheath (<a href=\"#f17\">Fig. 2</a>).</td>\n</tr>\n<tr>\n<td align=\"left\" valign=\"top\"></td><td align=\"left\" colspan=\"8\" valign=\"top\"></td>\n</tr>\n<tr>\n<td align=\"center\" colspan=\"9\" valign=\"top\">\n<br/>\n<img alt=\"Figure\" src=\"/dailymed/image.cfm?name=zr-needle-um-f1-v3.jpg&amp;setid=11544cba-64a9-49cb-8d74-da228053b252\"/></td>\n</tr>\n<tr>\n<td align=\"left\" valign=\"top\"></td><td align=\"left\" colspan=\"8\" valign=\"top\"></td>\n</tr>\n<tr>\n<td align=\"left\" valign=\"top\">6.4</td><td align=\"left\" colspan=\"8\" valign=\"top\">Visually confirm that the needle is fully engaged into the needle protection sheath.</td>\n</tr>\n<tr>\n<td align=\"left\" valign=\"top\"></td><td align=\"left\" colspan=\"8\" valign=\"top\"></td>\n</tr>\n<tr>\n<td align=\"left\" valign=\"top\">6.5</td><td align=\"left\" colspan=\"8\" valign=\"top\">Only remove the Needle-Pro<span class=\"Sup\">®</span> device with engaged needle from the syringe when required by a specific medical procedure. Remove by grasping the Luer hub of the needle protection device with thumb and forefinger, keeping the free fingers clear of the end of the device containing the needle point. (See <a href=\"#f09\">Fig. 3</a>)</td>\n</tr>\n<tr>\n<td align=\"left\" valign=\"top\"></td><td align=\"left\" colspan=\"8\" valign=\"top\"></td>\n</tr>\n<tr>\n<td align=\"center\" colspan=\"9\" valign=\"top\">\n<br/>\n<img alt=\"Figure\" src=\"/dailymed/image.cfm?name=zr-needle-um-f3-v1.jpg&amp;setid=11544cba-64a9-49cb-8d74-da228053b252\"/></td>\n</tr>\n<tr>\n<td align=\"left\" valign=\"top\"></td><td align=\"left\" colspan=\"8\" valign=\"top\"></td>\n</tr>\n<tr>\n<td align=\"left\" valign=\"top\">6.6</td><td align=\"left\" colspan=\"8\" valign=\"top\">After use, place sharps in a suitable sharps container. Dispose of contaminated product in a safe manner according to Centers for Disease Control and Prevention, USA and Federal/State/Local regulations (EPA, OSHA) and health care facility guidelines or local equivalent.</td>\n</tr>\n<tr>\n<td align=\"left\" valign=\"top\"></td><td align=\"left\" colspan=\"8\" valign=\"top\"></td>\n</tr>\n<tr>\n<td align=\"left\" valign=\"top\"></td><td align=\"left\" colspan=\"8\" valign=\"top\"><span class=\"Bold Italics\">NOTE:</span> Additional dead space added by Needle-Pro<span class=\"Sup\">®</span> device averages 0.036 mL.</td>\n</tr>\n<tr>\n<td align=\"left\" colspan=\"9\" valign=\"top\"></td>\n</tr>\n<tr>\n<td align=\"left\" colspan=\"9\" valign=\"top\"></td>\n</tr>\n<tr>\n<td align=\"left\" colspan=\"9\" valign=\"top\">Needle-Pro; and the color orange applied to the needle protection device, Jelco design mark and Smiths Medical design mark are trademarks of Smiths Medical. The symbol ® indicates the trademark is registered in the U.S. Patent and Trademark Office and certain other countries.</td>\n</tr>\n<tr>\n<td align=\"left\" colspan=\"9\" valign=\"top\"></td>\n</tr>\n<tr>\n<td align=\"left\" colspan=\"9\" valign=\"top\">© 2019 Smiths Medical. All rights reserved.</td>\n</tr>\n<tr>\n<td align=\"left\" colspan=\"9\" valign=\"top\"><img alt=\"Figure\" src=\"/dailymed/image.cfm?name=zr-um-f7-v1.jpg&amp;setid=11544cba-64a9-49cb-8d74-da228053b252\"/><span class=\"Bold\">Caution</span> • <img alt=\"Figure\" src=\"/dailymed/image.cfm?name=zr-um-f8-v1.jpg&amp;setid=11544cba-64a9-49cb-8d74-da228053b252\"/> Do Not Reuse • <img alt=\"Figure\" src=\"/dailymed/image.cfm?name=zr-um-f9-v1.jpg&amp;setid=11544cba-64a9-49cb-8d74-da228053b252\"/>Not made with natural rubber latex • <img alt=\"Figure\" src=\"/dailymed/image.cfm?name=zr-um-f10-v1.jpg&amp;setid=11544cba-64a9-49cb-8d74-da228053b252\"/> Do not use if package is damaged • <img alt=\"Figure\" src=\"/dailymed/image.cfm?name=zr-um-f11-v1.jpg&amp;setid=11544cba-64a9-49cb-8d74-da228053b252\"/>Sterilized using ethylene oxide • <img alt=\"Figure\" src=\"/dailymed/image.cfm?name=zr-um-f12-v1.jpg&amp;setid=11544cba-64a9-49cb-8d74-da228053b252\"/> Non-pyrogenic fluid path • <img alt=\"Figure\" src=\"/dailymed/image.cfm?name=zr-um-f13-v1.jpg&amp;setid=11544cba-64a9-49cb-8d74-da228053b252\"/><span class=\"Bold\">Caution:</span> Federal (USA) law restricts this device to sale by or on the order of a physician • <img alt=\"Figure\" src=\"/dailymed/image.cfm?name=zr-um-f14-v1.jpg&amp;setid=11544cba-64a9-49cb-8d74-da228053b252\"/>Catalogue Number • <img alt=\"Figure\" src=\"/dailymed/image.cfm?name=zr-um-f15-v1.jpg&amp;setid=11544cba-64a9-49cb-8d74-da228053b252\"/>Batch Code • <img alt=\"Figure\" src=\"/dailymed/image.cfm?name=zr-um-f16-v1.jpg&amp;setid=11544cba-64a9-49cb-8d74-da228053b252\"/>Date of Manufacture • <img alt=\"Figure\" src=\"/dailymed/image.cfm?name=zr-um-f17-v1.jpg&amp;setid=11544cba-64a9-49cb-8d74-da228053b252\"/>Use by • <img alt=\"Figure\" src=\"/dailymed/image.cfm?name=zr-um-f18-v1.jpg&amp;setid=11544cba-64a9-49cb-8d74-da228053b252\"/>Quantity • <img alt=\"Figure\" src=\"/dailymed/image.cfm?name=zr-um-f19-v1.jpg&amp;setid=11544cba-64a9-49cb-8d74-da228053b252\"/>Manufacturer • <img alt=\"Figure\" src=\"/dailymed/image.cfm?name=zr-um-f20-v1.jpg&amp;setid=11544cba-64a9-49cb-8d74-da228053b252\"/>Authorized Representative in the European Community • <img alt=\"Figure\" src=\"/dailymed/image.cfm?name=zr-um-f21-v1.jpg&amp;setid=11544cba-64a9-49cb-8d74-da228053b252\"/>Keep dry • <img alt=\"Figure\" src=\"/dailymed/image.cfm?name=zr-um-f22-v1.jpg&amp;setid=11544cba-64a9-49cb-8d74-da228053b252\"/>Keep away from sunlight</td>\n</tr>\n<tr>\n<td align=\"left\" colspan=\"9\" valign=\"top\"></td>\n</tr>\n<tr>\n<td align=\"left\" colspan=\"9\" valign=\"top\"><img alt=\"Figure\" src=\"/dailymed/image.cfm?name=zr-um-f19-v1.jpg&amp;setid=11544cba-64a9-49cb-8d74-da228053b252\"/>Manufacturer:<br/>\n<span class=\"Bold\">Smiths Medical ASD, Inc.</span>\n<br/> 6000 Nathan Lane North<br/> Minneapolis, MN 55442 USA<br/> Tel: 1 800 258 5361 (US/CA) <br/> Tel: +1 614 210 7300</td>\n</tr>\n<tr>\n<td align=\"left\" colspan=\"9\" valign=\"top\"></td>\n</tr>\n<tr>\n<td align=\"left\" colspan=\"9\" valign=\"top\">www.smiths-medical.com</td>\n</tr>\n<tr>\n<td align=\"left\" colspan=\"9\" valign=\"top\"> Rx ONLY</td>\n</tr>\n<tr>\n<td align=\"left\" colspan=\"9\" valign=\"top\">CE<br/> 2797</td>\n</tr>\n<tr class=\"Last\">\n<td align=\"left\" colspan=\"9\" valign=\"top\">\n<br/>\n<br/>ZYPR-0002-SM10018196-002-IFU-20200204</td>\n</tr>\n</tbody>\n</table></div>" }

PACKAGE LABEL - ZYPREXA Relprevv 210 mg

{ "type": "p", "children": [], "text": "\nPACKAGE LABEL - ZYPREXA Relprevv 210 mg\n" }

NDC 61269-660-20

{ "type": "p", "children": [], "text": "NDC 61269-660-20" }

ZYPREXA® Relprevv™

{ "type": "p", "children": [], "text": "ZYPREXA® Relprevv™\n" }

(olanzapine)

{ "type": "p", "children": [], "text": "(olanzapine)" }

For Extended Release Injectable Suspension

{ "type": "p", "children": [], "text": "For Extended Release Injectable Suspension" }

210 mg/vial Single-Dose Vial Convenience Kit

{ "type": "p", "children": [], "text": "210 mg/vial Single-Dose Vial Convenience Kit" }

Medication Guide is to be dispensed to patients.

{ "type": "p", "children": [], "text": "Medication Guide is to be dispensed to patients." }

VL7635/VL7622

{ "type": "p", "children": [], "text": "VL7635/VL7622" }

Convenience kit includes:

{ "type": "p", "children": [], "text": "Convenience kit includes:" }

Single-Dose vial of Zyprexa® Relprevv™ 210 mg/vial

{ "type": "p", "children": [], "text": "Single-Dose vial of Zyprexa® Relprevv™ 210 mg/vial" }

One 3-mL vial of diluent

{ "type": "p", "children": [], "text": "One 3-mL vial of diluent" }

One 3-mL syringe with pre-attached 19-gauge, 1.5-inch Hypodermic Needle-Pro® needle with needle protection device

{ "type": "p", "children": [], "text": "One 3-mL syringe with pre-attached 19-gauge, 1.5-inch Hypodermic Needle-Pro® needle with needle protection device" }

Two 19-gauge, 1.5-inch Hypodermic Needle-Pro needles with needle protection device

{ "type": "p", "children": [], "text": "Two 19-gauge, 1.5-inch Hypodermic Needle-Pro needles with needle protection device" }

Hypodermic Needle-Pro is a registered trademark of Smiths Medical.

{ "type": "p", "children": [], "text": "Hypodermic Needle-Pro is a registered trademark of Smiths Medical." }

Reconstitute each vial with 1.3 mL of enclosed diluent. The resultant solution will contain 150 mg/mL.

{ "type": "p", "children": [], "text": "Reconstitute each vial with 1.3 mL of enclosed diluent. The resultant solution will contain 150 mg/mL." }

Rx only

{ "type": "p", "children": [], "text": "Rx only" }

FOR DEEP INTRAMUSCULAR GLUTEAL INJECTION ONLY.

{ "type": "p", "children": [], "text": "FOR DEEP INTRAMUSCULAR GLUTEAL INJECTION ONLY." }

Dosing Frequency: Once every two weeks

{ "type": "p", "children": [], "text": "Dosing Frequency: Once every two weeks" }

CHEPLAPHARM

{ "type": "p", "children": [], "text": "CHEPLAPHARM" }

PACKAGE LABEL - ZYPREXA Relprevv 300 mg

{ "type": "p", "children": [], "text": "\nPACKAGE LABEL - ZYPREXA Relprevv 300 mg \n" }

NDC 61269-661-20

{ "type": "p", "children": [], "text": "NDC 61269-661-20" }

ZYPREXA® Relprevv™

{ "type": "p", "children": [], "text": "ZYPREXA® Relprevv™\n" }

(olanzapine)

{ "type": "p", "children": [], "text": "(olanzapine)" }

For Extended Release Injectable Suspension

{ "type": "p", "children": [], "text": "For Extended Release Injectable Suspension" }

300 mg/vial Single-Dose Vial Convenience Kit

{ "type": "p", "children": [], "text": "300 mg/vial Single-Dose Vial Convenience Kit" }

Medication Guide is to be dispensed to patients.

{ "type": "p", "children": [], "text": "Medication Guide is to be dispensed to patients." }

VL7636/VL7622

{ "type": "p", "children": [], "text": "VL7636/VL7622" }

Convenience kit includes:

{ "type": "p", "children": [], "text": "Convenience kit includes:" }

Single-Dose vial of Zyprexa® Relprevv™ 300 mg/vial

{ "type": "p", "children": [], "text": "Single-Dose vial of Zyprexa® Relprevv™ 300 mg/vial" }

One 3-mL vial of diluent

{ "type": "p", "children": [], "text": "One 3-mL vial of diluent" }

One 3-mL syringe with pre-attached 19-gauge, 1.5-inch Hypodermic Needle-Pro® needle with needle protection device

{ "type": "p", "children": [], "text": "One 3-mL syringe with pre-attached 19-gauge, 1.5-inch Hypodermic Needle-Pro® needle with needle protection device" }

Two 19-gauge, 1.5-inch Hypodermic Needle-Pro needles with needle protection device

{ "type": "p", "children": [], "text": "Two 19-gauge, 1.5-inch Hypodermic Needle-Pro needles with needle protection device" }

Hypodermic Needle-Pro is a registered trademark of Smiths Medical.

{ "type": "p", "children": [], "text": "Hypodermic Needle-Pro is a registered trademark of Smiths Medical." }

Reconstitute each vial with 1.8 mL of enclosed diluent. The resultant solution will contain 150 mg/mL.

{ "type": "p", "children": [], "text": "Reconstitute each vial with 1.8 mL of enclosed diluent. The resultant solution will contain 150 mg/mL." }

Rx only

{ "type": "p", "children": [], "text": "Rx only" }

FOR DEEP INTRAMUSCULAR GLUTEAL INJECTION ONLY.

{ "type": "p", "children": [], "text": "FOR DEEP INTRAMUSCULAR GLUTEAL INJECTION ONLY." }

Dosing Frequency: Once every two or four weeks

{ "type": "p", "children": [], "text": "Dosing Frequency: Once every two or four weeks" }

CHEPLPHARM

{ "type": "p", "children": [], "text": "CHEPLPHARM" }

PACKAGE LABEL - ZYPREXA Relprevv 405 mg

{ "type": "p", "children": [], "text": "\nPACKAGE LABEL - ZYPREXA Relprevv 405 mg \n" }

NDC 61269-662-20

{ "type": "p", "children": [], "text": "NDC 61269-662-20" }

ZYPREXA® Relprevv™

{ "type": "p", "children": [], "text": "ZYPREXA® Relprevv™\n" }

(olanzapine)

{ "type": "p", "children": [], "text": "(olanzapine)" }

For Extended Release Injectable Suspension

{ "type": "p", "children": [], "text": "For Extended Release Injectable Suspension" }

405 mg/vial Single-Dose Vial Convenience Kit

{ "type": "p", "children": [], "text": "405 mg/vial Single-Dose Vial Convenience Kit" }

Medication Guide is to be dispensed to patients.

{ "type": "p", "children": [], "text": "Medication Guide is to be dispensed to patients." }

VL7637/VL7622

{ "type": "p", "children": [], "text": "VL7637/VL7622" }

Convenience kit includes:

{ "type": "p", "children": [], "text": "Convenience kit includes:" }

Single-Dose vial of Zyprexa® Relprevv™ 405 mg/vial

{ "type": "p", "children": [], "text": "Single-Dose vial of Zyprexa® Relprevv™ 405 mg/vial" }

One 3-mL vial of diluent

{ "type": "p", "children": [], "text": "One 3-mL vial of diluent" }

One 3-mL syringe with pre-attached 19-gauge, 1.5-inch Hypodermic Needle-Pro® needle with needle protection device

{ "type": "p", "children": [], "text": "One 3-mL syringe with pre-attached 19-gauge, 1.5-inch Hypodermic Needle-Pro® needle with needle protection device" }

Two 19-gauge, 1.5-inch Hypodermic Needle-Pro needles with needle protection device

{ "type": "p", "children": [], "text": "Two 19-gauge, 1.5-inch Hypodermic Needle-Pro needles with needle protection device" }

Hypodermic Needle-Pro is a registered trademark of Smiths Medical.

{ "type": "p", "children": [], "text": "Hypodermic Needle-Pro is a registered trademark of Smiths Medical." }

Reconstitute each vial with 2.3 mL of enclosed diluent. The resultant solution will contain 150 mg/mL.

{ "type": "p", "children": [], "text": "Reconstitute each vial with 2.3 mL of enclosed diluent. The resultant solution will contain 150 mg/mL." }

Rx only

{ "type": "p", "children": [], "text": "Rx only" }

FOR DEEP INTRAMUSCULAR GLUTEAL INJECTION ONLY.

{ "type": "p", "children": [], "text": "FOR DEEP INTRAMUSCULAR GLUTEAL INJECTION ONLY." }

Dosing Frequency: Once every four weeks

{ "type": "p", "children": [], "text": "Dosing Frequency: Once every four weeks" }

CHEPLAPHARM

{ "type": "p", "children": [], "text": "CHEPLAPHARM" }

Olanzapine for Injection is indicated for the treatment of acute agitation associated with schizophrenia and bipolar I mania.

Efficacy was demonstrated in 3 short-term (24 hours of IM treatment) placebo-controlled trials in agitated adult inpatients with: schizophrenia or bipolar I disorder (manic or mixed episodes) [see Clinical Studies (14.3)].

“Psychomotor agitation” is defined in DSM-IV as “excessive motor activity associated with a feeling of inner tension.” Patients experiencing agitation often manifest behaviors that interfere with their diagnosis and care, e.g., threatening behaviors, escalating or urgently distressing behavior, or self-exhausting behavior, leading clinicians to the use of intramuscular antipsychotic medications to achieve immediate control of the agitation.

Dose Selection for Agitated Adult Patients with Schizophrenia and Bipolar I Mania — The efficacy of intramuscular olanzapine for injection in controlling agitation in these disorders was demonstrated in a dose range of 2.5 mg to 10 mg. The recommended dose in these patients is 10 mg. A lower dose of 5 or 7.5 mg may be considered when clinical factors warrant [see Clinical Studies (14.3)]. If agitation warranting additional intramuscular doses persists following the initial dose, subsequent doses up to 10 mg may be given. However, the efficacy of repeated doses of intramuscular olanzapine for injection in agitated patients has not been systematically evaluated in controlled clinical trials. Also, the safety of total daily doses greater than 30 mg, or 10 mg injections given more frequently than 2 hours after the initial dose, and 4 hours after the second dose have not been evaluated in clinical trials. Maximal dosing of intramuscular olanzapine (e.g., 3 doses of 10 mg administered 2-4 hours apart) may be associated with a substantial occurrence of significant orthostatic hypotension [see Warnings and Precautions (5.7)]. Thus, it is recommended that patients requiring subsequent intramuscular injections be assessed for orthostatic hypotension prior to the administration of any subsequent doses of intramuscular olanzapine for injection. The administration of an additional dose to a patient with a clinically significant postural change in systolic blood pressure is not recommended.

If ongoing olanzapine therapy is clinically indicated, oral olanzapine may be initiated in a range of 5-20 mg/day as soon as clinically appropriate.

Intramuscular Dosing in Special Populations — A dose of 5 mg/injection should be considered for geriatric patients or when other clinical factors warrant. A lower dose of 2.5 mg/injection should be considered for patients who otherwise might be debilitated, be predisposed to hypotensive reactions, or be more pharmacodynamically sensitive to olanzapine [see Warnings and Precautions (5.14), Drug Interactions (7), and Clinical Pharmacology (12.3)].

Administration of Olanzapine for Injection — Olanzapine for Injection is intended for intramuscular use only. Do not administer intravenously or subcutaneously. Inject slowly, deep into the muscle mass.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Directions for Preparation of Olanzapine for Injection with Sterile Water for Injection — Dissolve the contents of the vial using 2.1 mL of Sterile Water for Injection to provide a solution containing approximately 5 mg/mL of olanzapine. The resulting solution should appear clear and yellow. Olanzapine for Injection reconstituted with Sterile Water for Injection should be used immediately (within 1 hour) after reconstitution. Discard any unused portion.

The following table provides injection volumes for delivering various doses of intramuscular olanzapine for injection reconstituted with Sterile Water for Injection.

<div class="scrollingtable"><table width="100%"> <colgroup> <col align="left" width="50.000%"/> <col align="left" width="50.000%"/> </colgroup> <tbody class="Headless"> <tr class="First"> <td align="center" valign="top"><span class="Underline">Dose, mg Olanzapine</span></td><td align="center" valign="top"><span class="Underline">Volume of Injection, mL</span></td> </tr> <tr> <td align="center" valign="top">10</td><td align="center" valign="top">Withdraw total contents of vial</td> </tr> <tr> <td align="center" valign="top">7.5</td><td align="center" valign="top">1.5</td> </tr> <tr> <td align="center" valign="top">5</td><td align="center" valign="top">1</td> </tr> <tr class="Last"> <td align="center" valign="top">2.5</td><td align="center" valign="top">0.5</td> </tr> </tbody> </table></div>

Physical Incompatibility Information — Olanzapine for Injection should be reconstituted only with Sterile Water for Injection. Olanzapine for Injection should not be combined in a syringe with diazepam injection because precipitation occurs when these products are mixed. Lorazepam injection should not be used to reconstitute Olanzapine for Injection as this combination results in a delayed reconstitution time. Olanzapine for Injection should not be combined in a syringe with haloperidol injection because the resulting low pH has been shown to degrade olanzapine over time.

Olanzapine for Injection is available as single-dose 10 mg vial (1s).

{ "type": "p", "children": [], "text": "\n\nOlanzapine for Injection is available as single-dose 10 mg vial (1s).\n" }

{ "type": "ul", "children": [ "None with olanzapine monotherapy.", "For specific information about the contraindications of lithium or valproate, refer to the Contraindications section of the package inserts for these other products." ], "text": "" }

Increased Mortality — Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Olanzapine for injection is not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning, Use in Specific Populations (8.5), and Patient Counseling Information (17)].

In placebo-controlled clinical trials of elderly patients with dementia-related psychosis, the incidence of death in olanzapine-treated patients was significantly greater than placebo-treated patients (3.5% vs 1.5%, respectively).

Cerebrovascular Adverse Events (CVAE), Including Stroke — Cerebrovascular adverse events (e.g., stroke, transient ischemic attack), including fatalities, were reported in patients in trials of olanzapine in elderly patients with dementia-related psychosis. In placebo-controlled trials, there was a significantly higher incidence of cerebrovascular adverse events in patients treated with olanzapine compared to patients treated with placebo. Olanzapine is not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning and Patient Counseling Information (17)].

The possibility of a suicide attempt is inherent in schizophrenia and in bipolar I disorder, and close supervision of high-risk patients should accompany drug therapy. Prescriptions for olanzapine should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose.

A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with administration of antipsychotic drugs, including olanzapine. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis and cardiac dysrhythmia). Additional signs may include elevated creatinine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure.

The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a diagnosis, it is important to exclude cases where the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever, and primary central nervous system pathology.

The management of NMS should include: 1) immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy; 2) intensive symptomatic treatment and medical monitoring; and 3) treatment of any concomitant serious medical problems for which specific treatments are available. There is no general agreement about specific pharmacological treatment regimens for NMS.

If a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of drug therapy should be carefully considered. The patient should be carefully monitored, since recurrences of NMS have been reported [see Patient Counseling Information (17)].

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported with olanzapine exposure. DRESS may present with a cutaneous reaction (such as rash or exfoliative dermatitis), eosinophilia, fever, and/or lymphadenopathy with systemic complications such as hepatitis, nephritis, pneumonitis, myocarditis, and/or pericarditis. DRESS is sometimes fatal. Discontinue olanzapine if DRESS is suspected [see Patient Counseling Information (17)].

Atypical antipsychotic drugs have been associated with metabolic changes including hyperglycemia, dyslipidemia, and weight gain. Metabolic changes may be associated with increased cardiovascular/cerebrovascular risk. Olanzapine's specific metabolic profile is presented below.

Hyperglycemia and Diabetes Mellitus

Healthcare providers should consider the risks and benefits when prescribing olanzapine to patients with an established diagnosis of diabetes mellitus, or having borderline increased blood glucose level (fasting 100-126 mg/dL, nonfasting 140-200 mg/dL). Patients taking olanzapine should be monitored regularly for worsening of glucose control. Patients starting treatment with olanzapine should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics should undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of anti-diabetic treatment despite discontinuation of the suspect drug [see Patient Counseling Information (17)].

Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics including olanzapine. Assessment of the relationship between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population. Epidemiological studies suggest an increased risk of treatment-emergent hyperglycemia-related adverse reactions in patients treated with the atypical antipsychotics. While relative risk estimates are inconsistent, the association between atypical antipsychotics and increases in glucose levels appears to fall on a continuum and olanzapine appears to have a greater association than some other atypical antipsychotics.

Mean increases in blood glucose have been observed in patients treated (median exposure of 9.2 months) with olanzapine in phase 1 of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE). The mean increase of serum glucose (fasting and nonfasting samples) from baseline to the average of the 2 highest serum concentrations was 15 mg/dL.

In a study of healthy volunteers, subjects who received olanzapine (N=22) for 3 weeks had a mean increase compared to baseline in fasting blood glucose of 2.3 mg/dL. Placebo-treated subjects (N=19) had a mean increase in fasting blood glucose compared to baseline of 0.34 mg/dL.

Olanzapine Monotherapy in Adults — In an analysis of 5 placebo-controlled adult olanzapine monotherapy studies with a median treatment duration of approximately 3 weeks, olanzapine was associated with a greater mean change in fasting glucose levels compared to placebo (2.76 mg/dL versus 0.17 mg/dL). The difference in mean changes between olanzapine and placebo was greater in patients with evidence of glucose dysregulation at baseline (patients diagnosed with diabetes mellitus or related adverse reactions, patients treated with anti-diabetic agents, patients with a baseline random glucose level ≥200 mg/dL, and/or a baseline fasting glucose level ≥126 mg/dL). Olanzapine-treated patients had a greater mean HbA1c increase from baseline of 0.04% (median exposure 21 days), compared to a mean HbA1c decrease of 0.06% in placebo-treated subjects (median exposure 17 days).

In an analysis of 8 placebo-controlled studies (median treatment exposure 4-5 weeks), 6.1% of olanzapine-treated subjects (N=855) had treatment-emergent glycosuria compared to 2.8% of placebo-treated subjects (N=599). Table 2 shows short-term and long-term changes in fasting glucose levels from adult olanzapine monotherapy studies.

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 2: Changes in Fasting Glucose Levels from Adult Olanzapine Monotherapy Studies </span> </caption> <colgroup> <col align="left" width="14.276%"/> <col align="left" width="39.354%"/> <col align="left" width="12.704%"/> <col align="left" width="8.417%"/> <col align="left" width="8.417%"/> <col align="left" width="8.417%"/> <col align="left" width="8.417%"/> </colgroup> <tfoot> <tr class="First First Last Last"> <td align="left" colspan="7" valign="top"> <p class="First First Footnote"> <span class="Sup">a</span> Not Applicable.</p> </td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td align="center" class="Botrule Lrule" valign="top"></td><td align="center" class="Botrule Toprule" valign="top"></td><td align="center" class="Botrule Rrule Toprule" valign="top"></td><td align="center" class="Botrule Rrule Toprule" colspan="2" valign="top"><span class="Bold">Up to 12 weeks exposure</span></td><td align="center" class="Botrule Rrule Toprule" colspan="2" valign="top"><span class="Bold">At least 48 weeks exposure</span></td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"><span class="Bold">Laboratory Analyte</span></td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold">Category Change (at least once)<br/>from Baseline</span></td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold">Treatment Arm</span></td><td align="center" class="Botrule Rrule" valign="bottom"><span class="Bold">N</span></td><td align="center" class="Botrule Rrule" valign="bottom"><span class="Bold">Patients</span></td><td align="center" class="Botrule Rrule" valign="bottom"><span class="Bold">N</span></td><td align="center" class="Botrule Rrule" valign="bottom"><span class="Bold">Patients</span></td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" rowspan="4" valign="middle">Fasting<br/>Glucose</td><td align="center" class="Botrule Rrule" rowspan="2" valign="top">Normal to High<br/>(&lt;100 mg/dL to ≥126 mg/dL)</td><td align="center" class="Botrule Rrule" valign="top">Olanzapine</td><td align="center" class="Botrule Rrule" valign="top">543</td><td align="center" class="Botrule Rrule" valign="top">2.2%</td><td align="center" class="Botrule Rrule" valign="top">345</td><td align="center" class="Botrule Rrule" valign="top">12.8%</td> </tr> <tr> <td align="center" class="Botrule Rrule" valign="top">Placebo</td><td align="center" class="Botrule Rrule" valign="top">293</td><td align="center" class="Botrule Rrule" valign="top">3.4%</td><td align="center" class="Botrule Rrule" valign="top">NA<span class="Sup">a</span></td><td align="center" class="Botrule Rrule" valign="top">NA<span class="Sup">a</span></td> </tr> <tr> <td align="center" class="Botrule Rrule" rowspan="2" valign="top">Borderline to High<br/>(≥100 mg/dL and &lt;126 mg/dL to ≥126 mg/dL)</td><td align="center" class="Botrule Rrule" valign="top">Olanzapine</td><td align="center" class="Botrule Rrule" valign="top">178</td><td align="center" class="Botrule Rrule" valign="top">17.4%</td><td align="center" class="Botrule Rrule" valign="top">127</td><td align="center" class="Botrule Rrule" valign="top">26%</td> </tr> <tr class="Last"> <td align="center" class="Botrule Rrule" valign="top">Placebo</td><td align="center" class="Botrule Rrule" valign="top">96</td><td align="center" class="Botrule Rrule" valign="top">11.5%</td><td align="center" class="Botrule Rrule" valign="top">NA<span class="Sup">a</span></td><td align="center" class="Botrule Rrule" valign="top">NA<span class="Sup">a</span></td> </tr> </tbody> </table></div>

The mean change in fasting glucose for patients exposed at least 48 weeks was 4.2 mg/dL (N=487). In analyses of patients who completed 9-12 months of olanzapine therapy, mean change in fasting and nonfasting glucose levels continued to increase over time.

Olanzapine Monotherapy in Adolescents — The safety and efficacy of olanzapine have not been established in patients under the age of 13 years. In an analysis of 3 placebo-controlled olanzapine monotherapy studies of adolescent patients, including those with schizophrenia (6 weeks) or bipolar I disorder (manic or mixed episodes) (3 weeks), olanzapine was associated with a greater mean change from baseline in fasting glucose levels compared to placebo (2.68 mg/dL versus -2.59 mg/dL). The mean change in fasting glucose for adolescents exposed at least 24 weeks was 3.1 mg/dL (N=121). Table 3 shows short-term and long-term changes in fasting blood glucose from adolescent olanzapine monotherapy studies.

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 3: Changes in Fasting Glucose Levels from Adolescent Olanzapine Monotherapy Studies </span> </caption> <colgroup> <col align="left" width="14.276%"/> <col align="left" width="39.354%"/> <col align="left" width="12.704%"/> <col align="left" width="8.417%"/> <col align="left" width="8.417%"/> <col align="left" width="8.417%"/> <col align="left" width="8.417%"/> </colgroup> <tfoot> <tr class="First First Last Last"> <td align="left" colspan="7" valign="top"> <p class="First First Footnote"> <span class="Sup">a</span> Not Applicable.</p> </td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td align="center" class="Botrule Lrule" valign="top"></td><td align="center" class="Botrule Toprule" valign="top"></td><td align="center" class="Botrule Rrule Toprule" valign="top"></td><td align="center" class="Botrule Rrule Toprule" colspan="2" valign="top"><span class="Bold">Up to 12 weeks exposure</span></td><td align="center" class="Botrule Rrule Toprule" colspan="2" valign="top"><span class="Bold">At least 24 weeks exposure</span></td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"><span class="Bold">Laboratory Analyte</span></td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold">Category Change (at least once)<br/>from Baseline</span></td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold">Treatment Arm</span></td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold">N</span></td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold">Patients</span></td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold">N</span></td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold">Patients</span></td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" rowspan="4" valign="middle">Fasting<br/>Glucose</td><td align="center" class="Botrule Rrule" rowspan="2" valign="top">Normal to High<br/>(&lt;100 mg/dL to ≥126 mg/dL)</td><td align="center" class="Botrule Rrule" valign="top">Olanzapine</td><td align="center" class="Botrule Rrule" valign="top">124</td><td align="center" class="Botrule Rrule" valign="top">0%</td><td align="center" class="Botrule Rrule" valign="top">108</td><td align="center" class="Botrule Rrule" valign="top">0.9%</td> </tr> <tr> <td align="center" class="Botrule Rrule" valign="top">Placebo</td><td align="center" class="Botrule Rrule" valign="top">53</td><td align="center" class="Botrule Rrule" valign="top">1.9%</td><td align="center" class="Botrule Rrule" valign="top">NA<span class="Sup">a</span></td><td align="center" class="Botrule Rrule" valign="top">NA<span class="Sup">a</span></td> </tr> <tr> <td align="center" class="Botrule Rrule" rowspan="2" valign="top">Borderline to High<br/>(≥100 mg/dL and &lt;126 mg/dL to ≥126 mg/dL)</td><td align="center" class="Botrule Rrule" valign="top">Olanzapine</td><td align="center" class="Botrule Rrule" valign="top">14</td><td align="center" class="Botrule Rrule" valign="top">14.3%</td><td align="center" class="Botrule Rrule" valign="top">13</td><td align="center" class="Botrule Rrule" valign="top">23.1%</td> </tr> <tr class="Last"> <td align="center" class="Botrule Rrule" valign="top">Placebo</td><td align="center" class="Botrule Rrule" valign="top">13</td><td align="center" class="Botrule Rrule" valign="top">0%</td><td align="center" class="Botrule Rrule" valign="top">NA<span class="Sup">a</span></td><td align="center" class="Botrule Rrule" valign="top">NA<span class="Sup">a</span></td> </tr> </tbody> </table></div>

Dyslipidemia

Undesirable alterations in lipids have been observed with olanzapine use. Clinical monitoring, including baseline and periodic follow-up lipid evaluations in patients using olanzapine, is recommended [see Patient Counseling Information (17)].

Clinically significant, and sometimes very high (>500 mg/dL), elevations in triglyceride levels have been observed with olanzapine use. Modest mean increases in total cholesterol have also been seen with olanzapine use.

Olanzapine Monotherapy in Adults — In an analysis of 5 placebo-controlled olanzapine monotherapy studies with treatment duration up to 12 weeks, olanzapine-treated patients had increases from baseline in mean fasting total cholesterol, LDL cholesterol, and triglycerides of 5.3 mg/dL, 3 mg/dL, and 20.8 mg/dL respectively compared to decreases from baseline in mean fasting total cholesterol, LDL cholesterol, and triglycerides of 6.1 mg/dL, 4.3 mg/dL, and 10.7 mg/dL for placebo-treated patients. For fasting HDL cholesterol, no clinically meaningful differences were observed between olanzapine-treated patients and placebo-treated patients. Mean increases in fasting lipid values (total cholesterol, LDL cholesterol, and triglycerides) were greater in patients without evidence of lipid dysregulation at baseline, where lipid dysregulation was defined as patients diagnosed with dyslipidemia or related adverse reactions, patients treated with lipid lowering agents, or patients with high baseline lipid levels.

In long-term studies (at least 48 weeks), patients had increases from baseline in mean fasting total cholesterol, LDL cholesterol, and triglycerides of 5.6 mg/dL, 2.5 mg/dL, and 18.7 mg/dL, respectively, and a mean decrease in fasting HDL cholesterol of 0.16 mg/dL. In an analysis of patients who completed 12 months of therapy, the mean nonfasting total cholesterol did not increase further after approximately 4-6 months.

The proportion of patients who had changes (at least once) in total cholesterol, LDL cholesterol or triglycerides from normal or borderline to high, or changes in HDL cholesterol from normal or borderline to low, was greater in long-term studies (at least 48 weeks) as compared with short-term studies. Table 4 shows categorical changes in fasting lipids values.

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 4: Changes in Fasting Lipids Values from Adult Olanzapine Monotherapy Studies </span> </caption> <colgroup> <col align="left" width="14.276%"/> <col align="left" width="39.354%"/> <col align="left" width="12.704%"/> <col align="left" width="8.417%"/> <col align="left" width="8.417%"/> <col align="left" width="8.417%"/> <col align="left" width="8.417%"/> </colgroup> <tfoot> <tr class="First First Last Last"> <td align="left" colspan="7" valign="top"> <p class="First First Footnote"> <span class="Sup">a</span> Not Applicable.</p> </td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td align="center" class="Botrule Lrule" valign="top"></td><td align="center" class="Botrule Toprule" valign="top"></td><td align="center" class="Botrule Rrule Toprule" valign="top"></td><td align="center" class="Botrule Rrule Toprule" colspan="2" valign="top"><span class="Bold">Up to 12 weeks exposure</span></td><td align="center" class="Botrule Rrule Toprule" colspan="2" valign="top"><span class="Bold">At least 48 weeks exposure</span></td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"><span class="Bold">Laboratory Analyte</span></td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold">Category Change (at least once)<br/>from Baseline</span></td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold">Treatment Arm</span></td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold"> <br/>N</span></td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold"> <br/>Patients</span></td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold"> <br/>N</span></td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold"> <br/>Patients</span></td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" rowspan="6" valign="middle">Fasting<br/>Triglycerides</td><td align="center" class="Botrule Rrule" rowspan="2" valign="top">Increase by ≥50 mg/dL</td><td align="center" class="Botrule Rrule" valign="top">Olanzapine</td><td align="center" class="Botrule Rrule" valign="top">745</td><td align="center" class="Botrule Rrule" valign="top">39.6%</td><td align="center" class="Botrule Rrule" valign="top">487</td><td align="center" class="Botrule Rrule" valign="top">61.4%</td> </tr> <tr> <td align="center" class="Botrule Rrule" valign="top">Placebo</td><td align="center" class="Botrule Rrule" valign="top">402</td><td align="center" class="Botrule Rrule" valign="top">26.1%</td><td align="center" class="Botrule Rrule" valign="top">NA<span class="Sup">a</span></td><td align="center" class="Botrule Rrule" valign="top">NA<span class="Sup">a</span></td> </tr> <tr> <td align="center" class="Botrule Rrule" rowspan="2" valign="top">Normal to High<br/>(&lt;150 mg/dL to ≥200 mg/dL)</td><td align="center" class="Botrule Rrule" valign="top">Olanzapine</td><td align="center" class="Botrule Rrule" valign="top">457</td><td align="center" class="Botrule Rrule" valign="top">9.2%</td><td align="center" class="Botrule Rrule" valign="top">293</td><td align="center" class="Botrule Rrule" valign="top">32.4%</td> </tr> <tr> <td align="center" class="Botrule Rrule" valign="top">Placebo</td><td align="center" class="Botrule Rrule" valign="top">251</td><td align="center" class="Botrule Rrule" valign="top">4.4%</td><td align="center" class="Botrule Rrule" valign="top">NA<span class="Sup">a</span></td><td align="center" class="Botrule Rrule" valign="top">NA<span class="Sup">a</span></td> </tr> <tr> <td align="center" class="Botrule Rrule" rowspan="2" valign="top">Borderline to High<br/>(≥150 mg/dL and &lt;200 mg/dL to ≥200 mg/dL)</td><td align="center" class="Botrule Rrule" valign="top">Olanzapine</td><td align="center" class="Botrule Rrule" valign="top">135</td><td align="center" class="Botrule Rrule" valign="top">39.3%</td><td align="center" class="Botrule Rrule" valign="top">75</td><td align="center" class="Botrule Rrule" valign="top">70.7%</td> </tr> <tr> <td align="center" class="Botrule Rrule" valign="top">Placebo</td><td align="center" class="Botrule Rrule" valign="top">65</td><td align="center" class="Botrule Rrule" valign="top">20%</td><td align="center" class="Botrule Rrule" valign="top">NA<span class="Sup">a</span></td><td align="center" class="Botrule Rrule" valign="top">NA<span class="Sup">a</span></td> </tr> <tr> <td align="center" class="Botrule Lrule" valign="top"></td><td align="center" class="Botrule" valign="top"></td><td align="center" class="Botrule" valign="top"></td><td align="center" class="Botrule" valign="top"></td><td align="center" class="Botrule" valign="top"></td><td align="center" class="Botrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"></td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" rowspan="6" valign="middle">Fasting Total<br/>Cholesterol</td><td align="center" class="Botrule Rrule" rowspan="2" valign="top">Increase by ≥40 mg/dL</td><td align="center" class="Botrule Rrule" valign="top">Olanzapine</td><td align="center" class="Botrule Rrule" valign="top">745</td><td align="center" class="Botrule Rrule" valign="top">21.6%</td><td align="center" class="Botrule Rrule" valign="top">489</td><td align="center" class="Botrule Rrule" valign="top">32.9%</td> </tr> <tr> <td align="center" class="Botrule Rrule" valign="top">Placebo</td><td align="center" class="Botrule Rrule" valign="top">402</td><td align="center" class="Botrule Rrule" valign="top">9.5%</td><td align="center" class="Botrule Rrule" valign="top">NA<span class="Sup">a</span></td><td align="center" class="Botrule Rrule" valign="top">NA<span class="Sup">a</span></td> </tr> <tr> <td align="center" class="Botrule Rrule" rowspan="2" valign="top">Normal to High<br/>(&lt;200 mg/dL to ≥240 mg/dL)</td><td align="center" class="Botrule Rrule" valign="top">Olanzapine</td><td align="center" class="Botrule Rrule" valign="top">392</td><td align="center" class="Botrule Rrule" valign="top">2.8%</td><td align="center" class="Botrule Rrule" valign="top">283</td><td align="center" class="Botrule Rrule" valign="top">14.8%</td> </tr> <tr> <td align="center" class="Botrule Rrule" valign="top">Placebo</td><td align="center" class="Botrule Rrule" valign="top">207</td><td align="center" class="Botrule Rrule" valign="top">2.4%</td><td align="center" class="Botrule Rrule" valign="top">NA<span class="Sup">a</span></td><td align="center" class="Botrule Rrule" valign="top">NA<span class="Sup">a</span></td> </tr> <tr> <td align="center" class="Botrule Rrule" rowspan="2" valign="top">Borderline to High<br/>(≥200 mg/dL and &lt;240 mg/dL to ≥240 mg/dL)</td><td align="center" class="Botrule Rrule" valign="top">Olanzapine</td><td align="center" class="Botrule Rrule" valign="top">222</td><td align="center" class="Botrule Rrule" valign="top">23%</td><td align="center" class="Botrule Rrule" valign="top">125</td><td align="center" class="Botrule Rrule" valign="top">55.2%</td> </tr> <tr> <td align="center" class="Botrule Rrule" valign="top">Placebo</td><td align="center" class="Botrule Rrule" valign="top">112</td><td align="center" class="Botrule Rrule" valign="top">12.5%</td><td align="center" class="Botrule Rrule" valign="top">NA<span class="Sup">a</span></td><td align="center" class="Botrule Rrule" valign="top">NA<span class="Sup">a</span></td> </tr> <tr> <td align="center" class="Botrule Lrule" valign="top"></td><td align="center" class="Botrule" valign="top"></td><td align="center" class="Botrule" valign="top"></td><td align="center" class="Botrule" valign="top"></td><td align="center" class="Botrule" valign="top"></td><td align="center" class="Botrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"></td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" rowspan="6" valign="middle">Fasting LDL<br/>Cholesterol</td><td align="center" class="Botrule Rrule" rowspan="2" valign="top">Increase by ≥30 mg/dL</td><td align="center" class="Botrule Rrule" valign="top">Olanzapine</td><td align="center" class="Botrule Rrule" valign="top">536</td><td align="center" class="Botrule Rrule" valign="top">23.7%</td><td align="center" class="Botrule Rrule" valign="top">483</td><td align="center" class="Botrule Rrule" valign="top">39.8%</td> </tr> <tr> <td align="center" class="Botrule Rrule" valign="top">Placebo</td><td align="center" class="Botrule Rrule" valign="top">304</td><td align="center" class="Botrule Rrule" valign="top">14.1%</td><td align="center" class="Botrule Rrule" valign="top">NA<span class="Sup">a</span></td><td align="center" class="Botrule Rrule" valign="top">NA<span class="Sup">a</span></td> </tr> <tr> <td align="center" class="Botrule Rrule" rowspan="2" valign="top">Normal to High<br/>(&lt;100 mg/dL to ≥160 mg/dL)</td><td align="center" class="Botrule Rrule" valign="top">Olanzapine</td><td align="center" class="Botrule Rrule" valign="top">154</td><td align="center" class="Botrule Rrule" valign="top">0%</td><td align="center" class="Botrule Rrule" valign="top">123</td><td align="center" class="Botrule Rrule" valign="top">7.3%</td> </tr> <tr> <td align="center" class="Botrule Rrule" valign="top">Placebo</td><td align="center" class="Botrule Rrule" valign="top">82</td><td align="center" class="Botrule Rrule" valign="top">1.2%</td><td align="center" class="Botrule Rrule" valign="top">NA<span class="Sup">a</span></td><td align="center" class="Botrule Rrule" valign="top">NA<span class="Sup">a</span></td> </tr> <tr> <td align="center" class="Botrule Rrule" rowspan="2" valign="top">Borderline to High<br/>(≥100 mg/dL and &lt;160 mg/dL to ≥160 mg/dL)</td><td align="center" class="Botrule Rrule" valign="top">Olanzapine</td><td align="center" class="Botrule Rrule" valign="top">302</td><td align="center" class="Botrule Rrule" valign="top">10.6%</td><td align="center" class="Botrule Rrule" valign="top">284</td><td align="center" class="Botrule Rrule" valign="top">31%</td> </tr> <tr class="Last"> <td align="center" class="Botrule Rrule" valign="top">Placebo</td><td align="center" class="Botrule Rrule" valign="top">173</td><td align="center" class="Botrule Rrule" valign="top">8.1%</td><td align="center" class="Botrule Rrule" valign="top">NA<span class="Sup">a</span></td><td align="center" class="Botrule Rrule" valign="top">NA<span class="Sup">a</span></td> </tr> </tbody> </table></div>

In phase 1 of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE), over a median exposure of 9.2 months, the mean increase in triglycerides in patients taking olanzapine was 40.5 mg/dL. In phase 1 of CATIE, the mean increase in total cholesterol was 9.4 mg/dL.

Olanzapine Monotherapy in Adolescents — The safety and efficacy of olanzapine have not been established in patients under the age of 13 years. In an analysis of 3 placebo-controlled olanzapine monotherapy studies of adolescents, including those with schizophrenia (6 weeks) or bipolar I disorder (manic or mixed episodes) (3 weeks), olanzapine-treated adolescents had increases from baseline in mean fasting total cholesterol, LDL cholesterol, and triglycerides of 12.9 mg/dL, 6.5 mg/dL, and 28.4 mg/dL, respectively, compared to increases from baseline in mean fasting total cholesterol and LDL cholesterol of 1.3 mg/dL and 1 mg/dL, and a decrease in triglycerides of 1.1 mg/dL for placebo-treated adolescents. For fasting HDL cholesterol, no clinically meaningful differences were observed between olanzapine-treated adolescents and placebo-treated adolescents.

In long-term studies (at least 24 weeks), adolescents had increases from baseline in mean fasting total cholesterol, LDL cholesterol, and triglycerides of 5.5 mg/dL, 5.4 mg/dL, and 20.5 mg/dL, respectively, and a mean decrease in fasting HDL cholesterol of 4.5 mg/dL. Table 5 shows categorical changes in fasting lipids values in adolescents.

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 5: Changes in Fasting Lipids Values from Adolescent Olanzapine Monotherapy Studies </span> </caption> <colgroup> <col align="left" width="14.276%"/> <col align="left" width="39.354%"/> <col align="left" width="12.704%"/> <col align="left" width="8.417%"/> <col align="left" width="8.417%"/> <col align="left" width="8.417%"/> <col align="left" width="8.417%"/> </colgroup> <tfoot> <tr class="First First Last Last"> <td align="left" colspan="7" valign="top"> <p class="First First Footnote"> <span class="Sup">a</span> Not Applicable.</p> </td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td align="center" class="Botrule Lrule" valign="top"></td><td align="center" class="Botrule Toprule" valign="top"></td><td align="center" class="Botrule Rrule Toprule" valign="top"></td><td align="center" class="Botrule Rrule Toprule" colspan="2" valign="top"><span class="Bold">Up to 6 weeks exposure</span></td><td align="center" class="Botrule Rrule Toprule" colspan="2" valign="top"><span class="Bold">At least 24 weeks exposure</span></td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"><span class="Bold">Laboratory Analyte</span></td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold">Category Change (at least once)<br/>from Baseline</span></td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold">Treatment Arm</span></td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold"> <br/>N</span></td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold"> <br/>Patients</span></td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold"> <br/>N</span></td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold"> <br/>Patients</span></td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" rowspan="6" valign="middle">Fasting<br/>Triglycerides</td><td align="center" class="Botrule Rrule" rowspan="2" valign="top">Increase by ≥50 mg/dL</td><td align="center" class="Botrule Rrule" valign="top">Olanzapine</td><td align="center" class="Botrule Rrule" valign="top">138</td><td align="center" class="Botrule Rrule" valign="top">37%</td><td align="center" class="Botrule Rrule" valign="top">122</td><td align="center" class="Botrule Rrule" valign="top">45.9%</td> </tr> <tr> <td align="center" class="Botrule Rrule" valign="top">Placebo</td><td align="center" class="Botrule Rrule" valign="top">66</td><td align="center" class="Botrule Rrule" valign="top">15.2%</td><td align="center" class="Botrule Rrule" valign="top">NA<span class="Sup">a</span></td><td align="center" class="Botrule Rrule" valign="top">NA<span class="Sup">a</span></td> </tr> <tr> <td align="center" class="Botrule Rrule" rowspan="2" valign="top">Normal to High<br/>(&lt;90 mg/dL to &gt;130 mg/dL)</td><td align="center" class="Botrule Rrule" valign="top">Olanzapine</td><td align="center" class="Botrule Rrule" valign="top">67</td><td align="center" class="Botrule Rrule" valign="top">26.9%</td><td align="center" class="Botrule Rrule" valign="top">66</td><td align="center" class="Botrule Rrule" valign="top">36.4%</td> </tr> <tr> <td align="center" class="Botrule Rrule" valign="top">Placebo</td><td align="center" class="Botrule Rrule" valign="top">28</td><td align="center" class="Botrule Rrule" valign="top">10.7%</td><td align="center" class="Botrule Rrule" valign="top">NA<span class="Sup">a</span></td><td align="center" class="Botrule Rrule" valign="top">NA<span class="Sup">a</span></td> </tr> <tr> <td align="center" class="Botrule Rrule" rowspan="2" valign="top">Borderline to High<br/>(≥90 mg/dL and ≤130 mg/dL to &gt;130 mg/dL)</td><td align="center" class="Botrule Rrule" valign="top">Olanzapine</td><td align="center" class="Botrule Rrule" valign="top">37</td><td align="center" class="Botrule Rrule" valign="top">59.5%</td><td align="center" class="Botrule Rrule" valign="top">31</td><td align="center" class="Botrule Rrule" valign="top">64.5%</td> </tr> <tr> <td align="center" class="Botrule Rrule" valign="top">Placebo</td><td align="center" class="Botrule Rrule" valign="top">17</td><td align="center" class="Botrule Rrule" valign="top">35.3%</td><td align="center" class="Botrule Rrule" valign="top">NA<span class="Sup">a</span></td><td align="center" class="Botrule Rrule" valign="top">NA<span class="Sup">a</span></td> </tr> <tr> <td align="center" class="Botrule Lrule" valign="top"></td><td align="center" class="Botrule" valign="top"></td><td align="center" class="Botrule" valign="top"></td><td align="center" class="Botrule" valign="top"></td><td align="center" class="Botrule" valign="top"></td><td align="center" class="Botrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"></td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" rowspan="6" valign="middle">Fasting Total<br/>Cholesterol</td><td align="center" class="Botrule Rrule" rowspan="2" valign="top">Increase by ≥40 mg/dL</td><td align="center" class="Botrule Rrule" valign="top">Olanzapine</td><td align="center" class="Botrule Rrule" valign="top">138</td><td align="center" class="Botrule Rrule" valign="top">14.5%</td><td align="center" class="Botrule Rrule" valign="top">122</td><td align="center" class="Botrule Rrule" valign="top">14.8%</td> </tr> <tr> <td align="center" class="Botrule Rrule" valign="top">Placebo</td><td align="center" class="Botrule Rrule" valign="top">66</td><td align="center" class="Botrule Rrule" valign="top">4.5%</td><td align="center" class="Botrule Rrule" valign="top">NA<span class="Sup">a</span></td><td align="center" class="Botrule Rrule" valign="top">NA<span class="Sup">a</span></td> </tr> <tr> <td align="center" class="Botrule Rrule" rowspan="2" valign="top">Normal to High<br/>(&lt;170 mg/dL to ≥200 mg/dL)</td><td align="center" class="Botrule Rrule" valign="top">Olanzapine</td><td align="center" class="Botrule Rrule" valign="top">87</td><td align="center" class="Botrule Rrule" valign="top">6.9%</td><td align="center" class="Botrule Rrule" valign="top">78</td><td align="center" class="Botrule Rrule" valign="top">7.7%</td> </tr> <tr> <td align="center" class="Botrule Rrule" valign="top">Placebo</td><td align="center" class="Botrule Rrule" valign="top">43</td><td align="center" class="Botrule Rrule" valign="top">2.3%</td><td align="center" class="Botrule Rrule" valign="top">NA<span class="Sup">a</span></td><td align="center" class="Botrule Rrule" valign="top">NA<span class="Sup">a</span></td> </tr> <tr> <td align="center" class="Botrule Rrule" rowspan="2" valign="top">Borderline to High<br/>(≥170 mg/dL and &lt;200 mg/dL to ≥200 mg/dL)</td><td align="center" class="Botrule Rrule" valign="top">Olanzapine</td><td align="center" class="Botrule Rrule" valign="top">36</td><td align="center" class="Botrule Rrule" valign="top">38.9%</td><td align="center" class="Botrule Rrule" valign="top">33</td><td align="center" class="Botrule Rrule" valign="top">57.6%</td> </tr> <tr> <td align="center" class="Botrule Rrule" valign="top">Placebo</td><td align="center" class="Botrule Rrule" valign="top">13</td><td align="center" class="Botrule Rrule" valign="top">7.7%</td><td align="center" class="Botrule Rrule" valign="top">NA<span class="Sup">a</span></td><td align="center" class="Botrule Rrule" valign="top">NA<span class="Sup">a</span></td> </tr> <tr> <td align="center" class="Botrule Lrule" valign="top"></td><td align="center" class="Botrule" valign="top"></td><td align="center" class="Botrule" valign="top"></td><td align="center" class="Botrule" valign="top"></td><td align="center" class="Botrule" valign="top"></td><td align="center" class="Botrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"></td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" rowspan="6" valign="middle">Fasting LDL<br/>Cholesterol</td><td align="center" class="Botrule Rrule" rowspan="2" valign="top">Increase by ≥30 mg/dL</td><td align="center" class="Botrule Rrule" valign="top">Olanzapine</td><td align="center" class="Botrule Rrule" valign="top">137</td><td align="center" class="Botrule Rrule" valign="top">17.5%</td><td align="center" class="Botrule Rrule" valign="top">121</td><td align="center" class="Botrule Rrule" valign="top">22.3%</td> </tr> <tr> <td align="center" class="Botrule Rrule" valign="top">Placebo</td><td align="center" class="Botrule Rrule" valign="top">63</td><td align="center" class="Botrule Rrule" valign="top">11.1%</td><td align="center" class="Botrule Rrule" valign="top">NA<span class="Sup">a</span></td><td align="center" class="Botrule Rrule" valign="top">NA<span class="Sup">a</span></td> </tr> <tr> <td align="center" class="Botrule Rrule" rowspan="2" valign="top">Normal to High<br/>(&lt;110 mg/dL to ≥130 mg/dL)</td><td align="center" class="Botrule Rrule" valign="top">Olanzapine</td><td align="center" class="Botrule Rrule" valign="top">98</td><td align="center" class="Botrule Rrule" valign="top">5.1%</td><td align="center" class="Botrule Rrule" valign="top">92</td><td align="center" class="Botrule Rrule" valign="top">10.9%</td> </tr> <tr> <td align="center" class="Botrule Rrule" valign="top">Placebo</td><td align="center" class="Botrule Rrule" valign="top">44</td><td align="center" class="Botrule Rrule" valign="top">4.5%</td><td align="center" class="Botrule Rrule" valign="top">NA<span class="Sup">a</span></td><td align="center" class="Botrule Rrule" valign="top">NA<span class="Sup">a</span></td> </tr> <tr> <td align="center" class="Botrule Rrule" rowspan="2" valign="top">Borderline to High<br/>(≥110 mg/dL and &lt;130 mg/dL to ≥130 mg/dL)</td><td align="center" class="Botrule Rrule" valign="top">Olanzapine</td><td align="center" class="Botrule Rrule" valign="top">29</td><td align="center" class="Botrule Rrule" valign="top">48.3%</td><td align="center" class="Botrule Rrule" valign="top">21</td><td align="center" class="Botrule Rrule" valign="top">47.6%</td> </tr> <tr class="Last"> <td align="center" class="Botrule Rrule" valign="top">Placebo</td><td align="center" class="Botrule Rrule" valign="top">9</td><td align="center" class="Botrule Rrule" valign="top">0%</td><td align="center" class="Botrule Rrule" valign="top">NA<span class="Sup">a</span></td><td align="center" class="Botrule Rrule" valign="top">NA<span class="Sup">a</span></td> </tr> </tbody> </table></div>

Weight Gain

Potential consequences of weight gain should be considered prior to starting olanzapine. Patients receiving olanzapine should receive regular monitoring of weight [see Patient Counseling Information (17)].

Olanzapine Monotherapy in Adults — In an analysis of 13 placebo-controlled olanzapine monotherapy studies, olanzapine-treated patients gained an average of 2.6 kg (5.7 lb) compared to an average 0.3 kg (0.6 lb) weight loss in placebo-treated patients with a median exposure of 6 weeks; 22.2% of olanzapine-treated patients gained at least 7% of their baseline weight, compared to 3% of placebo-treated patients, with a median exposure to event of 8 weeks; 4.2% of olanzapine-treated patients gained at least 15% of their baseline weight, compared to 0.3% of placebo-treated patients, with a median exposure to event of 12 weeks. Clinically significant weight gain was observed across all baseline Body Mass Index (BMI) categories. Discontinuation due to weight gain occurred in 0.2% of olanzapine-treated patients and in 0% of placebo-treated patients.

In long-term studies (at least 48 weeks), the mean weight gain was 5.6 kg (12.3 lb) (median exposure of 573 days, N=2021). The percentages of patients who gained at least 7%, 15%, or 25% of their baseline body weight with long-term exposure were 64%, 32%, and 12%, respectively. Discontinuation due to weight gain occurred in 0.4% of olanzapine-treated patients following at least 48 weeks of exposure.

Table 6 includes data on adult weight gain with olanzapine pooled from 86 clinical trials. The data in each column represent data for those patients who completed treatment periods of the durations specified.

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 6: Weight Gain with Olanzapine Use in Adults </span> </caption> <colgroup> <col align="left" width="20.950%"/> <col align="left" width="15.800%"/> <col align="left" width="15.817%"/> <col align="left" width="15.800%"/> <col align="left" width="15.817%"/> <col align="left" width="15.817%"/> </colgroup> <tbody class="Headless"> <tr class="First"> <td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"><span class="Bold">Amount Gained<br/>kg (lb)</span></td><td align="center" class="Botrule Rrule Toprule" valign="top"><span class="Bold">6 Weeks<br/>(N=7465)<br/>(%)</span></td><td align="center" class="Botrule Rrule Toprule" valign="top"><span class="Bold">6 Months<br/>(N=4162)<br/>(%)</span></td><td align="center" class="Botrule Rrule Toprule" valign="top"><span class="Bold">12 Months<br/>(N=1345)<br/>(%)</span></td><td align="center" class="Botrule Rrule Toprule" valign="top"><span class="Bold">24 Months<br/>(N=474)<br/>(%)</span></td><td align="center" class="Botrule Rrule Toprule" valign="top"><span class="Bold">36 Months<br/>(N=147)<br/>(%)</span></td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top">≤0</td><td align="center" class="Botrule Rrule" valign="top">26.2</td><td align="center" class="Botrule Rrule" valign="top">24.3</td><td align="center" class="Botrule Rrule" valign="top">20.8</td><td align="center" class="Botrule Rrule" valign="top">23.2</td><td align="center" class="Botrule Rrule" valign="top">17</td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top">0 to ≤5 (0-11 lb)</td><td align="center" class="Botrule Rrule" valign="top">57</td><td align="center" class="Botrule Rrule" valign="top">36</td><td align="center" class="Botrule Rrule" valign="top">26</td><td align="center" class="Botrule Rrule" valign="top">23.4</td><td align="center" class="Botrule Rrule" valign="top">25.2</td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top">&gt;5 to ≤10 (11-22 lb)</td><td align="center" class="Botrule Rrule" valign="top">14.9</td><td align="center" class="Botrule Rrule" valign="top">24.6</td><td align="center" class="Botrule Rrule" valign="top">24.2</td><td align="center" class="Botrule Rrule" valign="top">24.1</td><td align="center" class="Botrule Rrule" valign="top">18.4</td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top">&gt;10 to ≤15 (22-33 lb)</td><td align="center" class="Botrule Rrule" valign="top">1.8</td><td align="center" class="Botrule Rrule" valign="top">10.9</td><td align="center" class="Botrule Rrule" valign="top">14.9</td><td align="center" class="Botrule Rrule" valign="top">11.4</td><td align="center" class="Botrule Rrule" valign="top">17</td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top">&gt;15 to ≤20 (33-44 lb)</td><td align="center" class="Botrule Rrule" valign="top">0.1</td><td align="center" class="Botrule Rrule" valign="top">3.1</td><td align="center" class="Botrule Rrule" valign="top">8.6</td><td align="center" class="Botrule Rrule" valign="top">9.3</td><td align="center" class="Botrule Rrule" valign="top">11.6</td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top">&gt;20 to ≤25 (44-55 lb)</td><td align="center" class="Botrule Rrule" valign="top">0</td><td align="center" class="Botrule Rrule" valign="top">0.9</td><td align="center" class="Botrule Rrule" valign="top">3.3</td><td align="center" class="Botrule Rrule" valign="top">5.1</td><td align="center" class="Botrule Rrule" valign="top">4.1</td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top">&gt;25 to ≤30 (55-66 lb)</td><td align="center" class="Botrule Rrule" valign="top">0</td><td align="center" class="Botrule Rrule" valign="top">0.2</td><td align="center" class="Botrule Rrule" valign="top">1.4</td><td align="center" class="Botrule Rrule" valign="top">2.3</td><td align="center" class="Botrule Rrule" valign="top">4.8</td> </tr> <tr class="Last"> <td align="center" class="Botrule Lrule Rrule" valign="top">&gt;30 (&gt;66 lb)</td><td align="center" class="Botrule Rrule" valign="top">0</td><td align="center" class="Botrule Rrule" valign="top">0.1</td><td align="center" class="Botrule Rrule" valign="top">0.8</td><td align="center" class="Botrule Rrule" valign="top">1.2</td><td align="center" class="Botrule Rrule" valign="top">2</td> </tr> </tbody> </table></div>

Dose group differences with respect to weight gain have been observed. In a single 8-week randomized, double-blind, fixed-dose study comparing 10 (N=199), 20 (N=200) and 40 (N=200) mg/day of oral olanzapine in adult patients with schizophrenia or schizoaffective disorder, mean baseline to endpoint increase in weight (10 mg/day: 1.9 kg; 20 mg/day: 2.3 kg; 40 mg/day: 3 kg) was observed with significant differences between 10 vs 40 mg/day.

Olanzapine Monotherapy in Adolescents — The safety and efficacy of olanzapine have not been established in patients under the age of 13 years. Mean increase in weight in adolescents was greater than in adults. In 4 placebo-controlled trials, discontinuation due to weight gain occurred in 1% of olanzapine-treated patients, compared to 0% of placebo-treated patients.

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 7: Weight Gain with Olanzapine Use in Adolescents from 4 Placebo-Controlled Trials </span> </caption> <colgroup> <col align="left" width="33.333%"/> <col align="left" width="33.333%"/> <col align="left" width="33.333%"/> </colgroup> <tbody class="Headless"> <tr class="First"> <td align="left" class="Botrule Lrule Rrule Toprule" valign="top"></td><td align="center" class="Botrule Rrule Toprule" valign="top"><span class="Bold">Olanzapine-treated patients</span></td><td align="center" class="Botrule Rrule Toprule" valign="top"><span class="Bold">Placebo-treated patients</span></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">Mean change in body weight from baseline (median exposure = 3 weeks)</td><td align="center" class="Botrule Rrule" valign="top">4.6 kg (10.1 lb)</td><td align="center" class="Botrule Rrule" valign="top">0.3 kg (0.7 lb)</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" rowspan="2" valign="top">Percentage of patients who gained at least 7% of baseline body weight</td><td align="center" class="Rrule" valign="top">40.6%</td><td align="center" class="Rrule" valign="top">9.8%</td> </tr> <tr> <td align="center" class="Botrule Rrule" valign="top">(median exposure to 7% = 4 weeks)</td><td align="center" class="Botrule Rrule" valign="top">(median exposure to 7% = 8 weeks)</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" rowspan="2" valign="top">Percentage of patients who gained at least 15% of baseline body weight</td><td align="center" class="Rrule" valign="top">7.1%</td><td align="center" class="Rrule" valign="top">2.7%</td> </tr> <tr class="Last"> <td align="center" class="Botrule Rrule" valign="top">(median exposure to 15% = 19 weeks)</td><td align="center" class="Botrule Rrule" valign="top">(median exposure to 15% = 8 weeks)</td> </tr> </tbody> </table></div>

In long-term studies (at least 24 weeks), the mean weight gain was 11.2 kg (24.6 lb); (median exposure of 201 days, N=179). The percentages of adolescents who gained at least 7%, 15%, or 25% of their baseline body weight with long-term exposure were 89%, 55%, and 29%, respectively. Among adolescent patients, mean weight gain by baseline BMI category was 11.5 kg (25.3 lb), 12.1 kg (26.6 lb), and 12.7 kg (27.9 lb), respectively, for normal (N=106), overweight (N=26) and obese (N=17). Discontinuation due to weight gain occurred in 2.2% of olanzapine-treated patients following at least 24 weeks of exposure.

Table 8 shows data on adolescent weight gain with olanzapine pooled from 6 clinical trials. The data in each column represent data for those patients who completed treatment periods of the durations specified. Little clinical trial data is available on weight gain in adolescents with olanzapine beyond 6 months of treatment.

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 8: Weight Gain with Olanzapine Use in Adolescents </span> </caption> <colgroup> <col align="left" width="33.333%"/> <col align="left" width="33.333%"/> <col align="left" width="33.333%"/> </colgroup> <tbody class="Headless"> <tr class="First"> <td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"><span class="Bold">Amount Gained<br/>kg (lb)</span></td><td align="center" class="Botrule Rrule Toprule" valign="top"><span class="Bold">6 Weeks<br/>(N=243)<br/>(%)</span></td><td align="center" class="Botrule Rrule Toprule" valign="top"><span class="Bold">6 Months<br/>(N=191)<br/>(%)</span></td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top">≤0</td><td align="center" class="Botrule Rrule" valign="top">2.9</td><td align="center" class="Botrule Rrule" valign="top">2.1</td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top">0 to ≤5 (0-11 lb)</td><td align="center" class="Botrule Rrule" valign="top">47.3</td><td align="center" class="Botrule Rrule" valign="top">24.6</td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top">&gt;5 to ≤10 (11-22 lb)</td><td align="center" class="Botrule Rrule" valign="top">42.4</td><td align="center" class="Botrule Rrule" valign="top">26.7</td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top">&gt;10 to ≤15 (22-33 lb)</td><td align="center" class="Botrule Rrule" valign="top">5.8</td><td align="center" class="Botrule Rrule" valign="top">22</td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top">&gt;15 to ≤20 (33-44 lb)</td><td align="center" class="Botrule Rrule" valign="top">0.8</td><td align="center" class="Botrule Rrule" valign="top">12.6</td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top">&gt;20 to ≤25 (44-55 lb)</td><td align="center" class="Botrule Rrule" valign="top">0.8</td><td align="center" class="Botrule Rrule" valign="top">9.4</td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top">&gt;25 to ≤30 (55-66 lb)</td><td align="center" class="Botrule Rrule" valign="top">0</td><td align="center" class="Botrule Rrule" valign="top">2.1</td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top">&gt;30 to ≤35 (66-77 lb)</td><td align="center" class="Botrule Rrule" valign="top">0</td><td align="center" class="Botrule Rrule" valign="top">0</td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top">&gt;35 to ≤40 (77-88 lb)</td><td align="center" class="Botrule Rrule" valign="top">0</td><td align="center" class="Botrule Rrule" valign="top">0</td> </tr> <tr class="Last"> <td align="center" class="Botrule Lrule Rrule" valign="top">&gt;40 (&gt;88 lb)</td><td align="center" class="Botrule Rrule" valign="top">0</td><td align="center" class="Botrule Rrule" valign="top">0.5</td> </tr> </tbody> </table></div>

A syndrome of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with antipsychotic drugs. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to rely upon prevalence estimates to predict, at the inception of antipsychotic treatment, which patients are likely to develop the syndrome. Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown.

The risk of developing tardive dyskinesia and the likelihood that it will become irreversible are believed to increase as the duration of treatment and the total cumulative dose of antipsychotic drugs administered to the patient increase. However, the syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses or may even arise after discontinuation of treatment.

Tardive dyskinesia may remit, partially or completely, if antipsychotic treatment is withdrawn. Antipsychotic treatment, itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome and thereby may possibly mask the underlying process. The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown.

Given these considerations, olanzapine should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia. Chronic antipsychotic treatment should generally be reserved for patients (1) who suffer from a chronic illness that is known to respond to antipsychotic drugs, and (2) for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate. In patients who do require chronic treatment, the smallest dose and the shortest duration of treatment producing a satisfactory clinical response should be sought. The need for continued treatment should be reassessed periodically.

If signs and symptoms of tardive dyskinesia appear in a patient on olanzapine, drug discontinuation should be considered. However, some patients may require treatment with olanzapine despite the presence of the syndrome.

For specific information about the warnings of lithium or valproate, refer to the Warnings section of the package inserts for these other products.

Olanzapine may induce orthostatic hypotension associated with dizziness, tachycardia, bradycardia and, in some patients, syncope, especially during the initial dose-titration period, probably reflecting its α1-adrenergic antagonistic properties [see Patient Counseling Information (17)].

From an analysis of the vital sign data in an integrated database of 41 completed clinical studies in adult patients treated with oral olanzapine, orthostatic hypotension was recorded in ≥20% (1277/6030) of patients.

Hypotension, bradycardia with or without hypotension, tachycardia, and syncope were also reported during the clinical trials with intramuscular olanzapine for injection. In an open-label clinical pharmacology study in nonagitated patients with schizophrenia in which the safety and tolerability of intramuscular olanzapine were evaluated under a maximal dosing regimen (three 10 mg doses administered 4 hours apart), approximately one-third of these patients experienced a significant orthostatic decrease in systolic blood pressure (i.e., decrease ≥30 mmHg) [see Dosage and Administration (2.4)]. Syncope was reported in 0.6% (15/2500) of olanzapine-treated patients in phase 2-3 oral olanzapine studies and in 0.3% (2/722) of olanzapine-treated patients with agitation in the intramuscular olanzapine for injection studies. Three normal volunteers in phase 1 studies with intramuscular olanzapine experienced hypotension, bradycardia, and sinus pauses of up to 6 seconds that spontaneously resolved (in 2 cases the reactions occurred on intramuscular olanzapine, and in 1 case, on oral olanzapine). The risk for this sequence of hypotension, bradycardia, and sinus pause may be greater in nonpsychiatric patients compared to psychiatric patients who are possibly more adapted to certain effects of psychotropic drugs. For intramuscular olanzapine for injection therapy, patients should remain recumbent if drowsy or dizzy after injection until examination has indicated that they are not experiencing postural hypotension, bradycardia, and/or hypoventilation.

Olanzapine should be used with particular caution in patients with known cardiovascular disease (history of myocardial infarction or ischemia, heart failure, or conduction abnormalities), cerebrovascular disease, and conditions which would predispose patients to hypotension (dehydration, hypovolemia, and treatment with antihypertensive medications) where the occurrence of syncope, or hypotension and/or bradycardia might put the patient at increased medical risk.

Caution is necessary in patients who receive treatment with other drugs having effects that can induce hypotension, bradycardia, respiratory or central nervous system depression [see Drug Interactions (7)]. Concomitant administration of intramuscular olanzapine and parenteral benzodiazepine is not recommended due to the potential for excessive sedation and cardiorespiratory depression.

Olanzapine may cause somnolence, postural hypotension, motor and sensory instability, which may lead to falls and, consequently, fractures or other injuries. For patients with diseases, conditions, or medications that could exacerbate these effects, complete fall risk assessments when initiating antipsychotic treatment and recurrently for patients on long-term antipsychotic therapy.

Class Effect — In clinical trial and/or postmarketing experience, events of leukopenia/neutropenia have been reported temporally related to antipsychotic agents, including olanzapine. Agranulocytosis has also been reported.

Possible risk factors for leukopenia/neutropenia include pre-existing low white blood cell count (WBC) and history of drug induced leukopenia/neutropenia. Patients with a history of a clinically significant low WBC or drug induced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and discontinuation of olanzapine should be considered at the first sign of a clinically significant decline in WBC in the absence of other causative factors.

Patients with clinically significant neutropenia should be carefully monitored for fever or other symptoms or signs of infection and treated promptly if such symptoms or signs occur. Patients with severe neutropenia (absolute neutrophil count <1000/mm3) should discontinue olanzapine and have their WBC followed until recovery.

Esophageal dysmotility and aspiration have been associated with antipsychotic drug use. Aspiration pneumonia is a common cause of morbidity and mortality in patients with advanced Alzheimer's disease. Olanzapine is not approved for the treatment of patients with Alzheimer's disease.

During premarketing testing, seizures occurred in 0.9% (22/2500) of olanzapine-treated patients. There were confounding factors that may have contributed to the occurrence of seizures in many of these cases. Olanzapine should be used cautiously in patients with a history of seizures or with conditions that potentially lower the seizure threshold, e.g., Alzheimer's dementia. Olanzapine is not approved for the treatment of patients with Alzheimer's disease. Conditions that lower the seizure threshold may be more prevalent in a population of 65 years or older.

Somnolence was a commonly reported adverse reaction associated with olanzapine treatment, occurring at an incidence of 26% in olanzapine patients compared to 15% in placebo patients. This adverse reaction was also dose related. Somnolence led to discontinuation in 0.4% (9/2500) of patients in the premarketing database.

Since olanzapine has the potential to impair judgment, thinking, or motor skills, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that olanzapine therapy does not affect them adversely [see Patient Counseling Information (17)].

Disruption of the body's ability to reduce core body temperature has been attributed to antipsychotic agents. Appropriate care is advised when prescribing olanzapine for patients who will be experiencing conditions which may contribute to an elevation in core body temperature, e.g., exercising strenuously, exposure to extreme heat, receiving concomitant medication with anticholinergic activity, or being subject to dehydration [see Patient Counseling Information (17)].

Olanzapine exhibits in vitro muscarinic receptor affinity [see Clinical Pharmacology 12.2]. In premarketing clinical trials, olanzapine was associated with constipation, dry mouth, and tachycardia, all adverse reactions possibly related to cholinergic antagonism. Such adverse reactions were not often the basis for discontinuations, but olanzapine should be used with caution in patients with a current diagnosis or prior history of urinary retention, clinically significant prostatic hypertrophy, constipation, or a history of paralytic ileus or related conditions. In post marketing experience, the risk for severe adverse reactions (including fatalities) was increased with concomitant use of anticholinergic medications [see Drug Interactions (7.1)].

As with other drugs that antagonize dopamine D2 receptors, olanzapine elevates prolactin levels, and the elevation persists during chronic administration. Hyperprolactinemia may suppress hypothalamic GnRH, resulting in reduced pituitary gonadotropin secretion. This, in turn, may inhibit reproductive function by impairing gonadal steroidogenesis in both female and male patients. Galactorrhea, amenorrhea, gynecomastia, and impotence have been reported in patients receiving prolactin-elevating compounds. Long-standing hyperprolactinemia when associated with hypogonadism may lead to decreased bone density in both female and male subjects.

Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin dependent in vitro, a factor of potential importance if the prescription of these drugs is contemplated in a patient with previously detected breast cancer. As is common with compounds which increase prolactin release, an increase in mammary gland neoplasia was observed in the olanzapine carcinogenicity studies conducted in mice and rats [see Nonclinical Toxicology (13.1)]. Published epidemiologic studies have shown inconsistent results when exploring the potential association between hyperprolactinemia and breast cancer.

In placebo-controlled olanzapine clinical studies (up to 12 weeks), changes from normal to high in prolactin concentrations were observed in 30% of adults treated with olanzapine as compared to 10.5% of adults treated with placebo. In a pooled analysis from clinical studies including 8136 adults treated with olanzapine, potentially associated clinical manifestations included menstrual-related events1 (2% [49/3240] of females), sexual function-related events2 (2% [150/8136] of females and males), and breast-related events3 (0.7% [23/3240] of females, 0.2% [9/4896] of males).

In placebo-controlled olanzapine monotherapy studies in adolescent patients (up to 6 weeks) with schizophrenia or bipolar I disorder (manic or mixed episodes), changes from normal to high in prolactin concentrations were observed in 47% of olanzapine-treated patients compared to 7% of placebo-treated patients. In a pooled analysis from clinical trials including 454 adolescents treated with olanzapine, potentially associated clinical manifestations included menstrual-related events1 (1% [2/168] of females), sexual function-related events2 (0.7% [3/454] of females and males), and breast-related events3 (2% [3/168] of females, 2% [7/286] of males) [see Use in Specific Populations (8.4)].

1 Based on a search of the following terms: amenorrhea, hypomenorrhea, menstruation delayed, and oligomenorrhea. 2 Based on a search of the following terms: anorgasmia, delayed ejaculation, erectile dysfunction, decreased libido, loss of libido, abnormal orgasm, and sexual dysfunction. 3 Based on a search of the following terms: breast discharge, enlargement or swelling, galactorrhea, gynecomastia, and lactation disorder.

Dose group differences with respect to prolactin elevation have been observed. In a single 8-week randomized, double-blind, fixed-dose study comparing 10 (N=199), 20 (N=200) and 40 (N=200) mg/day of oral olanzapine in adult patients with schizophrenia or schizoaffective disorder, incidence of prolactin elevation >24.2 ng/mL (female) or >18.77 ng/mL (male) at any time during the trial (10 mg/day: 31.2%; 20 mg/day: 42.7%; 40 mg/day: 61.1%) indicated significant differences between 10 vs 40 mg/day and 20 vs 40 mg/day.

When using olanzapine in combination with lithium or valproate, the prescriber should refer to the Warnings and Precautions sections of the package inserts for lithium or valproate [see Drug Interactions (7)].

Fasting blood glucose testing and lipid profile at the beginning of, and periodically during, treatment is recommended [see Warnings and Precautions (5.5) and Patient Counseling Information (17)].

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect or predict the rates observed in practice.

Clinical Trials in Adults

The information below for olanzapine is derived from a clinical trial database for olanzapine consisting of 10,504 adult patients with approximately 4765 patient-years of exposure to olanzapine plus 722 patients with exposure to intramuscular olanzapine for injection. This database includes: (1) 2500 patients who participated in multiple-dose oral olanzapine premarketing trials in schizophrenia and Alzheimer's disease representing approximately 1122 patient-years of exposure as of February 14, 1995; (2) 182 patients who participated in oral olanzapine premarketing bipolar I disorder (manic or mixed episodes) trials representing approximately 66 patient-years of exposure; (3) 191 patients who participated in an oral olanzapine trial of patients having various psychiatric symptoms in association with Alzheimer's disease representing approximately 29 patient-years of exposure; (4) 5788 additional patients from 88 oral olanzapine clinical trials as of December 31, 2001; (5) 1843 additional patients from 41 olanzapine clinical trials as of October 31, 2011; and (6) 722 patients who participated in intramuscular olanzapine for injection premarketing trials in agitated patients with schizophrenia, bipolar I disorder (manic or mixed episodes), or dementia. Also included below is information from the premarketing 6-week clinical study database for olanzapine in combination with lithium or valproate, consisting of 224 patients who participated in bipolar I disorder (manic or mixed episodes) trials with approximately 22 patient-years of exposure.

The conditions and duration of treatment with olanzapine varied greatly and included (in overlapping categories) open-label and double-blind phases of studies, inpatients and outpatients, fixed-dose and dose-titration studies, and short-term or longer-term exposure. Adverse reactions were assessed by collecting adverse reactions, results of physical examinations, vital signs, weights, laboratory analytes, ECGs, chest x-rays, and results of ophthalmologic examinations.

Certain portions of the discussion below relating to objective or numeric safety parameters, namely, dose-dependent adverse reactions, vital sign changes, weight gain, laboratory changes, and ECG changes are derived from studies in patients with schizophrenia and have not been duplicated for bipolar I disorder (manic or mixed episodes) or agitation. However, this information is also generally applicable to bipolar I disorder (manic or mixed episodes) and agitation.

Adverse reactions during exposure were obtained by spontaneous report and recorded by clinical investigators using terminology of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse reactions without first grouping similar types of reactions into a smaller number of standardized reaction categories. In the tables and tabulations that follow, MedDRA and COSTART Dictionary terminology has been used to classify reported adverse reactions.

The stated frequencies of adverse reactions represent the proportion of individuals who experienced, at least once, a treatment-emergent adverse reaction of the type listed. A reaction was considered treatment emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation. The reported reactions do not include those reaction terms that were so general as to be uninformative. Reactions listed elsewhere in labeling may not be repeated below. It is important to emphasize that, although the reactions occurred during treatment with olanzapine, they were not necessarily caused by it. The entire label should be read to gain a complete understanding of the safety profile of olanzapine.

The prescriber should be aware that the figures in the tables and tabulations cannot be used to predict the incidence of side effects in the course of usual medical practice where patient characteristics and other factors differ from those that prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators. The cited figures, however, do provide the prescribing healthcare provider with some basis for estimating the relative contribution of drug and nondrug factors to the adverse reactions incidence in the population studied.

Incidence of Adverse Reactions in Short-Term, Placebo-Controlled and Combination Trials

The following findings are based on premarketing trials of (1) oral olanzapine for schizophrenia, bipolar I disorder (manic or mixed episodes), a subsequent trial of patients having various psychiatric symptoms in association with Alzheimer's disease, and premarketing combination trials, and (2) intramuscular olanzapine for injection in agitated patients with schizophrenia or bipolar I mania.

Adverse Reactions Associated with Discontinuation of Treatment in Short-Term, Placebo-Controlled Trials

Schizophrenia — Overall, there was no difference in the incidence of discontinuation due to adverse reactions (5% for oral olanzapine vs 6% for placebo). However, discontinuations due to increases in ALT were considered to be drug related (2% for oral olanzapine vs 0% for placebo).

Bipolar I Disorder (Manic or Mixed Episodes) Monotherapy — Overall, there was no difference in the incidence of discontinuation due to adverse reactions (2% for oral olanzapine vs 2% for placebo).

Agitation — Overall, there was no difference in the incidence of discontinuation due to adverse reactions (0.4% for intramuscular olanzapine for injection vs 0% for placebo).

Adverse Reactions Associated with Discontinuation of Treatment in Short-Term Combination Trials

Bipolar I Disorder (Manic or Mixed Episodes), Olanzapine as Adjunct to Lithium or Valproate — In a study of patients who were already tolerating either lithium or valproate as monotherapy, discontinuation rates due to adverse reactions were 11% for the combination of oral olanzapine with lithium or valproate compared to 2% for patients who remained on lithium or valproate monotherapy. Discontinuations with the combination of oral olanzapine and lithium or valproate that occurred in more than 1 patient were: somnolence (3%), weight gain (1%), and peripheral edema (1%).

Commonly Observed Adverse Reactions in Short-Term, Placebo-Controlled Trials

The most commonly observed adverse reactions associated with the use of oral olanzapine (incidence of 5% or greater) and not observed at an equivalent incidence among placebo-treated patients (olanzapine incidence at least twice that for placebo) were:

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 9: Common Treatment-Emergent Adverse Reactions Associated with the Use of Oral Olanzapine in 6-Week Trials — SCHIZOPHRENIA </span> </caption> <colgroup> <col align="left" width="33.333%"/> <col align="left" width="33.333%"/> <col align="left" width="33.333%"/> </colgroup> <tfoot> <tr class="First First Last Last"> <td align="left" colspan="3" valign="top"> <p class="First First Footnote"> <span class="Sup">a</span> Personality disorder is the COSTART term for designating nonaggressive objectionable behavior.</p> </td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td align="left" class="Botrule" rowspan="2" valign="bottom"><span class="Bold">Adverse Reaction</span></td><td align="center" class="Botrule" colspan="2" valign="top"><span class="Bold">Percentage of Patients Reporting Event</span></td> </tr> <tr> <td align="center" class="Botrule" valign="top"><span class="Bold">Olanzapine<br/>(N=248)</span></td><td align="center" class="Botrule" valign="top"><span class="Bold">Placebo<br/>(N=118)</span></td> </tr> <tr> <td align="left" valign="top">Postural hypotension</td><td align="center" valign="top">5</td><td align="center" valign="top">2</td> </tr> <tr> <td align="left" valign="top">Constipation</td><td align="center" valign="top">9</td><td align="center" valign="top">3</td> </tr> <tr> <td align="left" valign="top">Weight gain</td><td align="center" valign="top">6</td><td align="center" valign="top">1</td> </tr> <tr> <td align="left" valign="top">Dizziness</td><td align="center" valign="top">11</td><td align="center" valign="top">4</td> </tr> <tr> <td align="left" valign="top">Personality disorder<span class="Sup">a</span></td><td align="center" valign="top">8</td><td align="center" valign="top">4</td> </tr> <tr class="Last"> <td align="left" class="Botrule" valign="top">Akathisia</td><td align="center" class="Botrule" valign="top">5</td><td align="center" class="Botrule" valign="top">1</td> </tr> </tbody> </table></div>

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 10: Common Treatment-Emergent Adverse Reactions Associated with the Use of Oral Olanzapine in 3-Week and 4-Week Trials — Bipolar I Disorder (Manic or Mixed Episodes) </span> </caption> <colgroup> <col align="left" width="33.333%"/> <col align="left" width="33.333%"/> <col align="left" width="33.333%"/> </colgroup> <tbody class="Headless"> <tr class="First"> <td align="left" class="Botrule" rowspan="2" valign="bottom"><span class="Bold">Adverse Reaction</span></td><td align="center" class="Botrule" colspan="2" valign="top"><span class="Bold">Percentage of Patients Reporting Event</span></td> </tr> <tr> <td align="center" class="Botrule" valign="top"><span class="Bold">Olanzapine<br/>(N=125)</span></td><td align="center" class="Botrule" valign="top"><span class="Bold">Placebo<br/>(N=129)</span></td> </tr> <tr> <td align="left" valign="top">Asthenia</td><td align="center" valign="top">15</td><td align="center" valign="top">6</td> </tr> <tr> <td align="left" valign="top">Dry mouth</td><td align="center" valign="top">22</td><td align="center" valign="top">7</td> </tr> <tr> <td align="left" valign="top">Constipation</td><td align="center" valign="top">11</td><td align="center" valign="top">5</td> </tr> <tr> <td align="left" valign="top">Dyspepsia</td><td align="center" valign="top">11</td><td align="center" valign="top">5</td> </tr> <tr> <td align="left" valign="top">Increased appetite</td><td align="center" valign="top">6</td><td align="center" valign="top">3</td> </tr> <tr> <td align="left" valign="top">Somnolence</td><td align="center" valign="top">35</td><td align="center" valign="top">13</td> </tr> <tr> <td align="left" valign="top">Dizziness</td><td align="center" valign="top">18</td><td align="center" valign="top">6</td> </tr> <tr class="Last"> <td align="left" class="Botrule" valign="top">Tremor</td><td align="center" class="Botrule" valign="top">6</td><td align="center" class="Botrule" valign="top">3</td> </tr> </tbody> </table></div>

Olanzapine Intramuscular — There was 1 adverse reaction (somnolence) observed at an incidence of 5% or greater among intramuscular olanzapine for injection-treated patients and not observed at an equivalent incidence among placebo-treated patients (olanzapine incidence at least twice that for placebo) during the placebo-controlled premarketing studies. The incidence of somnolence during the 24 hour IM treatment period in clinical trials in agitated patients with schizophrenia or bipolar I mania was 6% for intramuscular olanzapine for injection and 3% for placebo.

Adverse Reactions Occurring at an Incidence of 2% or More among Oral Olanzapine-Treated Patients in Short-Term, Placebo-Controlled Trials

Table 11 enumerates the incidence, rounded to the nearest percent, of treatment-emergent adverse reactions that occurred in 2% or more of patients treated with oral olanzapine (doses ≥2.5 mg/day) and with incidence greater than placebo who participated in the acute phase of placebo-controlled trials.

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 11: Treatment-Emergent Adverse Reactions: Incidence in Short-Term, Placebo-Controlled Clinical Trials with Oral Olanzapine </span> </caption> <colgroup> <col align="left" width="33.333%"/> <col align="left" width="33.333%"/> <col align="left" width="33.333%"/> </colgroup> <tbody class="Headless"> <tr class="First"> <td align="left" class="Botrule" rowspan="2" valign="bottom"><span class="Bold">Body System/Adverse Reaction</span></td><td align="center" class="Botrule" colspan="2" valign="top"><span class="Bold">Percentage of Patients Reporting Event</span></td> </tr> <tr> <td align="center" class="Botrule" valign="top"><span class="Bold">Olanzapine<br/>(N=532)</span></td><td align="center" class="Botrule" valign="top"><span class="Bold">Placebo<br/>(N=294)</span></td> </tr> <tr> <td align="left" valign="top"><span class="Bold">Body as a Whole</span></td><td align="center" valign="top"></td><td align="center" valign="top"></td> </tr> <tr> <td align="left" valign="top">Accidental injury</td><td align="center" valign="top">12</td><td align="center" valign="top">8</td> </tr> <tr> <td align="left" valign="top">Asthenia</td><td align="center" valign="top">10</td><td align="center" valign="top">9</td> </tr> <tr> <td align="left" valign="top">Fever</td><td align="center" valign="top">6</td><td align="center" valign="top">2</td> </tr> <tr> <td align="left" valign="top">Back pain</td><td align="center" valign="top">5</td><td align="center" valign="top">2</td> </tr> <tr> <td align="left" class="Botrule" valign="top">Chest pain</td><td align="center" class="Botrule" valign="top">3</td><td align="center" class="Botrule" valign="top">1</td> </tr> <tr> <td align="left" valign="top"><span class="Bold">Cardiovascular System</span></td><td align="center" valign="top"></td><td align="center" valign="top"></td> </tr> <tr> <td align="left" valign="top">Postural hypotension</td><td align="center" valign="top">3</td><td align="center" valign="top">1</td> </tr> <tr> <td align="left" valign="top">Tachycardia</td><td align="center" valign="top">3</td><td align="center" valign="top">1</td> </tr> <tr> <td align="left" class="Botrule" valign="top">Hypertension</td><td align="center" class="Botrule" valign="top">2</td><td align="center" class="Botrule" valign="top">1</td> </tr> <tr> <td align="left" valign="top"><span class="Bold">Digestive System</span></td><td align="center" valign="top"></td><td align="center" valign="top"></td> </tr> <tr> <td align="left" valign="top">Dry mouth</td><td align="center" valign="top">9</td><td align="center" valign="top">5</td> </tr> <tr> <td align="left" valign="top">Constipation</td><td align="center" valign="top">9</td><td align="center" valign="top">4</td> </tr> <tr> <td align="left" valign="top">Dyspepsia</td><td align="center" valign="top">7</td><td align="center" valign="top">5</td> </tr> <tr> <td align="left" valign="top">Vomiting</td><td align="center" valign="top">4</td><td align="center" valign="top">3</td> </tr> <tr> <td align="left" class="Botrule" valign="top">Increased appetite</td><td align="center" class="Botrule" valign="top">3</td><td align="center" class="Botrule" valign="top">2</td> </tr> <tr> <td align="left" valign="top"><span class="Bold">Hemic and Lymphatic System</span></td><td align="center" valign="top"></td><td align="center" valign="top"></td> </tr> <tr> <td align="left" class="Botrule" valign="top">Ecchymosis</td><td align="center" class="Botrule" valign="top">5</td><td align="center" class="Botrule" valign="top">3</td> </tr> <tr> <td align="left" valign="top"><span class="Bold">Metabolic and Nutritional Disorders</span></td><td align="center" valign="top"></td><td align="center" valign="top"></td> </tr> <tr> <td align="left" valign="top">Weight gain</td><td align="center" valign="top">5</td><td align="center" valign="top">3</td> </tr> <tr> <td align="left" class="Botrule" valign="top">Peripheral edema</td><td align="center" class="Botrule" valign="top">3</td><td align="center" class="Botrule" valign="top">1</td> </tr> <tr> <td align="left" valign="top"><span class="Bold">Musculoskeletal System</span></td><td align="center" valign="top"></td><td align="center" valign="top"></td> </tr> <tr> <td align="left" valign="top">Extremity pain (other than joint)</td><td align="center" valign="top">5</td><td align="center" valign="top">3</td> </tr> <tr> <td align="left" class="Botrule" valign="top">Joint pain</td><td align="center" class="Botrule" valign="top">5</td><td align="center" class="Botrule" valign="top">3</td> </tr> <tr> <td align="left" valign="top"><span class="Bold">Nervous System</span></td><td align="center" valign="top"></td><td align="center" valign="top"></td> </tr> <tr> <td align="left" valign="top">Somnolence</td><td align="center" valign="top">29</td><td align="center" valign="top">13</td> </tr> <tr> <td align="left" valign="top">Insomnia</td><td align="center" valign="top">12</td><td align="center" valign="top">11</td> </tr> <tr> <td align="left" valign="top">Dizziness</td><td align="center" valign="top">11</td><td align="center" valign="top">4</td> </tr> <tr> <td align="left" valign="top">Abnormal gait</td><td align="center" valign="top">6</td><td align="center" valign="top">1</td> </tr> <tr> <td align="left" valign="top">Tremor</td><td align="center" valign="top">4</td><td align="center" valign="top">3</td> </tr> <tr> <td align="left" valign="top">Akathisia</td><td align="center" valign="top">3</td><td align="center" valign="top">2</td> </tr> <tr> <td align="left" valign="top">Hypertonia</td><td align="center" valign="top">3</td><td align="center" valign="top">2</td> </tr> <tr> <td align="left" class="Botrule" valign="top">Articulation impairment</td><td align="center" class="Botrule" valign="top">2</td><td align="center" class="Botrule" valign="top">1</td> </tr> <tr> <td align="left" valign="top"><span class="Bold">Respiratory System</span></td><td align="center" valign="top"></td><td align="center" valign="top"></td> </tr> <tr> <td align="left" valign="top">Rhinitis</td><td align="center" valign="top">7</td><td align="center" valign="top">6</td> </tr> <tr> <td align="left" valign="top">Cough increased</td><td align="center" valign="top">6</td><td align="center" valign="top">3</td> </tr> <tr> <td align="left" class="Botrule" valign="top">Pharyngitis</td><td align="center" class="Botrule" valign="top">4</td><td align="center" class="Botrule" valign="top">3</td> </tr> <tr> <td align="left" valign="top"><span class="Bold">Special Senses</span></td><td align="center" valign="top"></td><td align="center" valign="top"></td> </tr> <tr> <td align="left" class="Botrule" valign="top">Amblyopia</td><td align="center" class="Botrule" valign="top">3</td><td align="center" class="Botrule" valign="top">2</td> </tr> <tr> <td align="left" valign="top"><span class="Bold">Urogenital System</span></td><td align="center" valign="top"></td><td align="center" valign="top"></td> </tr> <tr> <td align="left" valign="top">Urinary incontinence</td><td align="center" valign="top">2</td><td align="center" valign="top">1</td> </tr> <tr class="Last"> <td align="left" class="Botrule" valign="top">Urinary tract infection</td><td align="center" class="Botrule" valign="top">2</td><td align="center" class="Botrule" valign="top">1</td> </tr> </tbody> </table></div>

Dose Dependency of Adverse Reactions

A dose group difference has been observed for fatigue, dizziness, weight gain and prolactin elevation. In a single 8-week randomized, double-blind, fixed-dose study comparing 10 (N=199), 20 (N=200) and 40 (N=200) mg/day of oral olanzapine in adult patients with schizophrenia or schizoaffective disorder, incidence of fatigue (10 mg/day: 1.5%; 20 mg/day: 2.1%; 40 mg/day: 6.6%) was observed with significant differences between 10 vs 40 and 20 vs 40 mg/day. The incidence of dizziness (10 mg/day: 2.6%; 20 mg/day: 1.6%; 40 mg/day: 6.6%) was observed with significant differences between 20 vs 40 mg. Dose group differences were also noted for weight gain and prolactin elevation [see Warnings and Precautions (5.5, 5.15)].

The following table addresses dose relatedness for other adverse reactions using data from a schizophrenia trial involving fixed dosage ranges of oral olanzapine. It enumerates the percentage of patients with treatment-emergent adverse reactions for the 3 fixed-dose range groups and placebo. The data were analyzed using the Cochran-Armitage test, excluding the placebo group, and the table includes only those adverse reactions for which there was a trend.

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 12: Percentage of Patients from a Schizophrenia Trial with Treatment-Emergent Adverse Reactions for the 3 Dose Range Groups and Placebo </span> </caption> <colgroup> <col align="left" width="23.680%"/> <col align="left" width="19.080%"/> <col align="left" width="19.080%"/> <col align="left" width="19.080%"/> <col align="left" width="19.080%"/> </colgroup> <tbody class="Headless"> <tr class="First"> <td align="left" class="Lrule Rrule Toprule" valign="top"></td><td align="center" class="Botrule Rrule Toprule" colspan="4" valign="top"><span class="Bold">Percentage of Patients Reporting Event</span></td> </tr> <tr> <td align="left" class="Lrule Rrule" valign="top"></td><td align="center" class="Rrule" valign="top"></td><td align="center" class="Rrule" valign="top"><span class="Bold">Olanzapine</span></td><td align="center" class="Rrule" valign="top"><span class="Bold">Olanzapine</span></td><td align="center" class="Rrule" valign="top"><span class="Bold">Olanzapine</span></td> </tr> <tr> <td align="left" class="Lrule Rrule" valign="top"></td><td align="center" class="Rrule" valign="top"><span class="Bold">Placebo</span></td><td align="center" class="Rrule" valign="top"><span class="Bold">5 ± 2.5 mg/day</span></td><td align="center" class="Rrule" valign="top"><span class="Bold">10 ± 2.5 mg/day</span></td><td align="center" class="Rrule" valign="top"><span class="Bold">15 ± 2.5 mg/day</span></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"><span class="Bold">Adverse Reaction</span></td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold">(N=68)</span></td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold">(N=65)</span></td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold">(N=64)</span></td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold">(N=69)</span></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">Asthenia</td><td align="center" class="Botrule Rrule" valign="top">15</td><td align="center" class="Botrule Rrule" valign="top">8</td><td align="center" class="Botrule Rrule" valign="top">9</td><td align="center" class="Botrule Rrule" valign="top">20</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">Dry mouth</td><td align="center" class="Botrule Rrule" valign="top">4</td><td align="center" class="Botrule Rrule" valign="top">3</td><td align="center" class="Botrule Rrule" valign="top">5</td><td align="center" class="Botrule Rrule" valign="top">13</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">Nausea</td><td align="center" class="Botrule Rrule" valign="top">9</td><td align="center" class="Botrule Rrule" valign="top">0</td><td align="center" class="Botrule Rrule" valign="top">2</td><td align="center" class="Botrule Rrule" valign="top">9</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">Somnolence</td><td align="center" class="Botrule Rrule" valign="top">16</td><td align="center" class="Botrule Rrule" valign="top">20</td><td align="center" class="Botrule Rrule" valign="top">30</td><td align="center" class="Botrule Rrule" valign="top">39</td> </tr> <tr class="Last"> <td align="left" class="Botrule Lrule Rrule" valign="top">Tremor</td><td align="center" class="Botrule Rrule" valign="top">3</td><td align="center" class="Botrule Rrule" valign="top">0</td><td align="center" class="Botrule Rrule" valign="top">5</td><td align="center" class="Botrule Rrule" valign="top">7</td> </tr> </tbody> </table></div>

Commonly Observed Adverse Reactions in Short-Term Trials of Oral Olanzapine as Adjunct to Lithium or Valproate

In the bipolar I disorder (manic or mixed episodes) adjunct placebo-controlled trials, the most commonly observed adverse reactions associated with the combination of olanzapine and lithium or valproate (incidence of ≥5% and at least twice placebo) were:

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 13: Common Treatment-Emergent Adverse Reactions Associated with the Use of Oral Olanzapine in 6-Week Adjunct to Lithium or Valproate Trials — Bipolar I Disorder (Manic or Mixed Episodes) </span> </caption> <colgroup> <col align="left" width="33.333%"/> <col align="left" width="33.333%"/> <col align="left" width="33.333%"/> </colgroup> <tbody class="Headless"> <tr class="First"> <td align="left" class="Botrule" rowspan="2" valign="bottom"><span class="Bold">Adverse Reaction</span></td><td align="center" class="Botrule" colspan="2" valign="top"><span class="Bold">Percentage of Patients Reporting Event</span></td> </tr> <tr> <td align="center" class="Botrule" valign="top"><span class="Bold">Olanzapine with lithium or valproate<br/>(N=229)</span></td><td align="center" class="Botrule" valign="top"><span class="Bold">Placebo with lithium or valproate<br/>(N=115)</span></td> </tr> <tr> <td align="left" valign="top">Dry mouth</td><td align="center" valign="top">32</td><td align="center" valign="top">9</td> </tr> <tr> <td align="left" valign="top">Weight gain</td><td align="center" valign="top">26</td><td align="center" valign="top">7</td> </tr> <tr> <td align="left" valign="top">Increased appetite</td><td align="center" valign="top">24</td><td align="center" valign="top">8</td> </tr> <tr> <td align="left" valign="top">Dizziness</td><td align="center" valign="top">14</td><td align="center" valign="top">7</td> </tr> <tr> <td align="left" valign="top">Back pain</td><td align="center" valign="top">8</td><td align="center" valign="top">4</td> </tr> <tr> <td align="left" valign="top">Constipation</td><td align="center" valign="top">8</td><td align="center" valign="top">4</td> </tr> <tr> <td align="left" valign="top">Speech disorder</td><td align="center" valign="top">7</td><td align="center" valign="top">1</td> </tr> <tr> <td align="left" valign="top">Increased salivation</td><td align="center" valign="top">6</td><td align="center" valign="top">2</td> </tr> <tr> <td align="left" valign="top">Amnesia</td><td align="center" valign="top">5</td><td align="center" valign="top">2</td> </tr> <tr class="Last"> <td align="left" class="Botrule" valign="top">Paresthesia</td><td align="center" class="Botrule" valign="top">5</td><td align="center" class="Botrule" valign="top">2</td> </tr> </tbody> </table></div>

Adverse Reactions Occurring at an Incidence of 2% or More among Oral Olanzapine-Treated Patients in Short-Term Trials of Olanzapine as Adjunct to Lithium or Valproate

Table 14 enumerates the incidence, rounded to the nearest percent, of treatment-emergent adverse reactions that occurred in 2% or more of patients treated with the combination of olanzapine (doses ≥5 mg/day) and lithium or valproate and with incidence greater than lithium or valproate alone who participated in the acute phase of placebo-controlled combination trials.

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 14: Treatment-Emergent Adverse Reactions: Incidence in Short-Term, Placebo-Controlled Clinical Trials of Oral Olanzapine as Adjunct to Lithium or Valproate </span> </caption> <colgroup> <col align="left" width="33.333%"/> <col align="left" width="33.333%"/> <col align="left" width="33.333%"/> </colgroup> <tfoot> <tr class="First First Last Last"> <td align="left" colspan="3" valign="top"> <p class="First First Footnote"> <span class="Sup">a</span> Denominator used was for females only (olanzapine, N=128; placebo, N=51).</p> </td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td align="left" class="Botrule" rowspan="2" valign="bottom"><span class="Bold">Body System/Adverse Reaction</span></td><td align="center" class="Botrule" colspan="2" valign="top"><span class="Bold">Percentage of Patients Reporting Event</span></td> </tr> <tr> <td align="center" class="Botrule" valign="top"><span class="Bold">Olanzapine with lithium or valproate<br/>(N=229)</span></td><td align="center" class="Botrule" valign="top"><span class="Bold">Placebo with lithium or valproate<br/>(N=115)</span></td> </tr> <tr> <td align="left" valign="top"><span class="Bold">Body as a Whole</span></td><td align="center" valign="top"></td><td align="center" valign="top"></td> </tr> <tr> <td align="left" valign="top">Asthenia</td><td align="center" valign="top">18</td><td align="center" valign="top">13</td> </tr> <tr> <td align="left" valign="top">Back pain</td><td align="center" valign="top">8</td><td align="center" valign="top">4</td> </tr> <tr> <td align="left" valign="top">Accidental injury</td><td align="center" valign="top">4</td><td align="center" valign="top">2</td> </tr> <tr> <td align="left" class="Botrule" valign="top">Chest pain</td><td align="center" class="Botrule" valign="top">3</td><td align="center" class="Botrule" valign="top">2</td> </tr> <tr> <td align="left" valign="top"><span class="Bold">Cardiovascular System</span></td><td align="center" valign="top"></td><td align="center" valign="top"></td> </tr> <tr> <td align="left" class="Botrule" valign="top">Hypertension</td><td align="center" class="Botrule" valign="top">2</td><td align="center" class="Botrule" valign="top">1</td> </tr> <tr> <td align="left" valign="top"><span class="Bold">Digestive System</span></td><td align="center" valign="top"></td><td align="center" valign="top"></td> </tr> <tr> <td align="left" valign="top">Dry mouth</td><td align="center" valign="top">32</td><td align="center" valign="top">9</td> </tr> <tr> <td align="left" valign="top">Increased appetite</td><td align="center" valign="top">24</td><td align="center" valign="top">8</td> </tr> <tr> <td align="left" valign="top">Thirst</td><td align="center" valign="top">10</td><td align="center" valign="top">6</td> </tr> <tr> <td align="left" valign="top">Constipation</td><td align="center" valign="top">8</td><td align="center" valign="top">4</td> </tr> <tr> <td align="left" class="Botrule" valign="top">Increased salivation</td><td align="center" class="Botrule" valign="top">6</td><td align="center" class="Botrule" valign="top">2</td> </tr> <tr> <td align="left" valign="top"><span class="Bold">Metabolic and Nutritional Disorders</span></td><td align="center" valign="top"></td><td align="center" valign="top"></td> </tr> <tr> <td align="left" valign="top">Weight gain</td><td align="center" valign="top">26</td><td align="center" valign="top">7</td> </tr> <tr> <td align="left" valign="top">Peripheral edema</td><td align="center" valign="top">6</td><td align="center" valign="top">4</td> </tr> <tr> <td align="left" class="Botrule" valign="top">Edema</td><td align="center" class="Botrule" valign="top">2</td><td align="center" class="Botrule" valign="top">1</td> </tr> <tr> <td align="left" valign="top"><span class="Bold">Nervous System</span></td><td align="center" valign="top"></td><td align="center" valign="top"></td> </tr> <tr> <td align="left" valign="top">Somnolence</td><td align="center" valign="top">52</td><td align="center" valign="top">27</td> </tr> <tr> <td align="left" valign="top">Tremor</td><td align="center" valign="top">23</td><td align="center" valign="top">13</td> </tr> <tr> <td align="left" valign="top">Depression</td><td align="center" valign="top">18</td><td align="center" valign="top">17</td> </tr> <tr> <td align="left" valign="top">Dizziness</td><td align="center" valign="top">14</td><td align="center" valign="top">7</td> </tr> <tr> <td align="left" valign="top">Speech disorder</td><td align="center" valign="top">7</td><td align="center" valign="top">1</td> </tr> <tr> <td align="left" valign="top">Amnesia</td><td align="center" valign="top">5</td><td align="center" valign="top">2</td> </tr> <tr> <td align="left" valign="top">Paresthesia</td><td align="center" valign="top">5</td><td align="center" valign="top">2</td> </tr> <tr> <td align="left" valign="top">Apathy</td><td align="center" valign="top">4</td><td align="center" valign="top">3</td> </tr> <tr> <td align="left" valign="top">Confusion</td><td align="center" valign="top">4</td><td align="center" valign="top">1</td> </tr> <tr> <td align="left" valign="top">Euphoria</td><td align="center" valign="top">3</td><td align="center" valign="top">2</td> </tr> <tr> <td align="left" class="Botrule" valign="top">Incoordination</td><td align="center" class="Botrule" valign="top">2</td><td align="center" class="Botrule" valign="top">0</td> </tr> <tr> <td align="left" valign="top"><span class="Bold">Respiratory System</span></td><td align="center" valign="top"></td><td align="center" valign="top"></td> </tr> <tr> <td align="left" valign="top">Pharyngitis</td><td align="center" valign="top">4</td><td align="center" valign="top">1</td> </tr> <tr> <td align="left" class="Botrule" valign="top">Dyspnea</td><td align="center" class="Botrule" valign="top">3</td><td align="center" class="Botrule" valign="top">1</td> </tr> <tr> <td align="left" valign="top"><span class="Bold">Skin and Appendages</span></td><td align="center" valign="top"></td><td align="center" valign="top"></td> </tr> <tr> <td align="left" valign="top">Sweating</td><td align="center" valign="top">3</td><td align="center" valign="top">1</td> </tr> <tr> <td align="left" valign="top">Acne</td><td align="center" valign="top">2</td><td align="center" valign="top">0</td> </tr> <tr> <td align="left" class="Botrule" valign="top">Dry skin</td><td align="center" class="Botrule" valign="top">2</td><td align="center" class="Botrule" valign="top">0</td> </tr> <tr> <td align="left" valign="top"><span class="Bold">Special Senses</span></td><td align="center" valign="top"></td><td align="center" valign="top"></td> </tr> <tr> <td align="left" valign="top">Amblyopia</td><td align="center" valign="top">9</td><td align="center" valign="top">5</td> </tr> <tr> <td align="left" class="Botrule" valign="top">Abnormal vision</td><td align="center" class="Botrule" valign="top">2</td><td align="center" class="Botrule" valign="top">0</td> </tr> <tr> <td align="left" valign="top"><span class="Bold">Urogenital System</span></td><td align="center" valign="top"></td><td align="center" valign="top"></td> </tr> <tr> <td align="left" valign="top">Dysmenorrhea<span class="Sup">a</span></td><td align="center" valign="top">2</td><td align="center" valign="top">0</td> </tr> <tr class="Last"> <td align="left" class="Botrule" valign="top">Vaginitis<span class="Sup">a</span></td><td align="center" class="Botrule" valign="top">2</td><td align="center" class="Botrule" valign="top">0</td> </tr> </tbody> </table></div>

For specific information about the adverse reactions observed with lithium or valproate, refer to the Adverse Reactions section of the package inserts for these other products.

Adverse Reactions Occurring at an Incidence of 1% or More among Intramuscular Olanzapine for Injection-Treated Patients in Short-Term, Placebo-Controlled Trials

Table 15 enumerates the incidence, rounded to the nearest percent, of treatment-emergent adverse reactions that occurred in 1% or more of patients treated with intramuscular olanzapine for injection (dose range of 2.5-10 mg/injection) and with incidence greater than placebo who participated in the short-term, placebo-controlled trials in agitated patients with schizophrenia or bipolar I mania.

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 15: Treatment-Emergent Adverse Reactions: Incidence in Short-Term (24 Hour), Placebo-Controlled Clinical Trials with Intramuscular Olanzapine for Injection in Agitated Patients with Schizophrenia or Bipolar I Mania </span> </caption> <colgroup> <col align="left" width="33.333%"/> <col align="left" width="33.333%"/> <col align="left" width="33.333%"/> </colgroup> <tbody class="Headless"> <tr class="First"> <td align="left" class="Botrule" rowspan="2" valign="bottom"><span class="Bold">Body System/Adverse Reaction</span></td><td align="center" class="Botrule" colspan="2" valign="top"><span class="Bold">Percentage of Patients Reporting Event</span></td> </tr> <tr> <td align="center" class="Botrule" valign="top"><span class="Bold">Olanzapine<br/>(N=415)</span></td><td align="center" class="Botrule" valign="top"><span class="Bold">Placebo<br/>(N=150)</span></td> </tr> <tr> <td align="left" valign="top"><span class="Bold">Body as a Whole</span></td><td align="center" valign="top"></td><td align="center" valign="top"></td> </tr> <tr> <td align="left" class="Botrule" valign="top">Asthenia</td><td align="center" class="Botrule" valign="top">2</td><td align="center" class="Botrule" valign="top">1</td> </tr> <tr> <td align="left" valign="top"><span class="Bold">Cardiovascular System</span></td><td align="center" valign="top"></td><td align="center" valign="top"></td> </tr> <tr> <td align="left" valign="top">Hypotension</td><td align="center" valign="top">2</td><td align="center" valign="top">0</td> </tr> <tr> <td align="left" class="Botrule" valign="top">Postural hypotension</td><td align="center" class="Botrule" valign="top">1</td><td align="center" class="Botrule" valign="top">0</td> </tr> <tr> <td align="left" valign="top"><span class="Bold">Nervous System</span></td><td align="center" valign="top"></td><td align="center" valign="top"></td> </tr> <tr> <td align="left" valign="top">Somnolence</td><td align="center" valign="top">6</td><td align="center" valign="top">3</td> </tr> <tr> <td align="left" valign="top">Dizziness</td><td align="center" valign="top">4</td><td align="center" valign="top">2</td> </tr> <tr class="Last"> <td align="left" class="Botrule" valign="top">Tremor</td><td align="center" class="Botrule" valign="top">1</td><td align="center" class="Botrule" valign="top">0</td> </tr> </tbody> </table></div>

Extrapyramidal Symptoms

The following table enumerates the percentage of patients with treatment-emergent extrapyramidal symptoms as assessed by categorical analyses of formal rating scales during acute therapy in a controlled clinical trial comparing oral olanzapine at 3 fixed doses with placebo in the treatment of schizophrenia in a 6-week trial.

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 16: Treatment-Emergent Extrapyramidal Symptoms Assessed by Rating Scales Incidence in a Fixed Dosage Range, Placebo-Controlled Clinical Trial of Oral Olanzapine in Schizophrenia — Acute Phase </span> </caption> <colgroup> <col align="left" width="20.000%"/> <col align="left" width="20.000%"/> <col align="left" width="20.000%"/> <col align="left" width="20.000%"/> <col align="left" width="20.000%"/> </colgroup> <tfoot> <tr class="First"> <td align="left" colspan="5" valign="top"> <p class="First First Footnote"> <span class="Sup">a</span> Percentage of patients with a Simpson-Angus Scale total score &gt;3.</p> </td> </tr> <tr class="Last"> <td align="left" colspan="5" valign="top"> <p class="First First Footnote"> <span class="Sup">b</span> Percentage of patients with a Barnes Akathisia Scale global score ≥2.</p> </td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td align="left" class="Botrule Lrule Rrule Toprule" rowspan="2" valign="top"></td><td align="center" class="Botrule Rrule Toprule" colspan="4" valign="top"><span class="Bold">Percentage of Patients Reporting Event</span></td> </tr> <tr> <td align="center" class="Botrule Rrule" valign="bottom"><span class="Bold">Placebo</span></td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold">Olanzapine<br/>5 ± 2.5 mg/day</span></td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold">Olanzapine<br/>10 ± 2.5 mg/day</span></td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold">Olanzapine<br/>15 ± 2.5 mg/day</span></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">Parkinsonism<span class="Sup">a</span></td><td align="center" class="Botrule Rrule" valign="top">15</td><td align="center" class="Botrule Rrule" valign="top">14</td><td align="center" class="Botrule Rrule" valign="top">12</td><td align="center" class="Botrule Rrule" valign="top">14</td> </tr> <tr class="Last"> <td align="left" class="Botrule Lrule Rrule" valign="top">Akathisia<span class="Sup">b</span></td><td align="center" class="Botrule Rrule" valign="top">23</td><td align="center" class="Botrule Rrule" valign="top">16</td><td align="center" class="Botrule Rrule" valign="top">19</td><td align="center" class="Botrule Rrule" valign="top">27</td> </tr> </tbody> </table></div>

The following table enumerates the percentage of patients with treatment-emergent extrapyramidal symptoms as assessed by spontaneously reported adverse reactions during acute therapy in the same controlled clinical trial comparing olanzapine at 3 fixed doses with placebo in the treatment of schizophrenia in a 6-week trial.

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 17: Treatment-Emergent Extrapyramidal Symptoms Assessed by Adverse Reactions Incidence in a Fixed Dosage Range, Placebo-Controlled Clinical Trial of Oral Olanzapine in Schizophrenia — Acute Phase </span> </caption> <colgroup> <col align="left" width="23.680%"/> <col align="left" width="19.080%"/> <col align="left" width="19.080%"/> <col align="left" width="19.080%"/> <col align="left" width="19.080%"/> </colgroup> <tfoot> <tr class="First"> <td align="left" colspan="5" valign="top"> <p class="First First Footnote"> <span class="Sup">a</span> Patients with the following COSTART terms were counted in this category: dystonia, generalized spasm, neck rigidity, oculogyric crisis, opisthotonos, torticollis.</p> </td> </tr> <tr> <td align="left" colspan="5" valign="top"> <p class="First First Footnote"> <span class="Sup">b</span> Patients with the following COSTART terms were counted in this category: akinesia, cogwheel rigidity, extrapyramidal syndrome, hypertonia, hypokinesia, masked facies, tremor.</p> </td> </tr> <tr> <td align="left" colspan="5" valign="top"> <p class="First First Footnote"> <span class="Sup">c</span> Patients with the following COSTART terms were counted in this category: akathisia, hyperkinesia.</p> </td> </tr> <tr> <td align="left" colspan="5" valign="top"> <p class="First First Footnote"> <span class="Sup">d</span> Patients with the following COSTART terms were counted in this category: buccoglossal syndrome, choreoathetosis, dyskinesia, tardive dyskinesia.</p> </td> </tr> <tr class="Last"> <td align="left" colspan="5" valign="top"> <p class="First First Footnote"> <span class="Sup">e</span> Patients with the following COSTART terms were counted in this category: movement disorder, myoclonus, twitching.</p> </td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td align="left" class="Botrule Lrule Rrule Toprule" rowspan="2" valign="top"></td><td align="center" class="Botrule Rrule Toprule" colspan="4" valign="top"><span class="Bold">Percentage of Patients Reporting Event</span></td> </tr> <tr> <td align="center" class="Botrule Rrule" valign="bottom"><span class="Bold">Placebo<br/>(N=68)</span></td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold">Olanzapine<br/>5 ± 2.5 mg/day<br/>(N=65)</span></td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold">Olanzapine<br/>10 ± 2.5 mg/day<br/>(N=64)</span></td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold">Olanzapine<br/>15 ± 2.5 mg/day<br/>(N=69)</span></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">Dystonic events<span class="Sup">a</span></td><td align="center" class="Botrule Rrule" valign="top">1</td><td align="center" class="Botrule Rrule" valign="top">3</td><td align="center" class="Botrule Rrule" valign="top">2</td><td align="center" class="Botrule Rrule" valign="top">3</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">Parkinsonism events<span class="Sup">b</span></td><td align="center" class="Botrule Rrule" valign="top">10</td><td align="center" class="Botrule Rrule" valign="top">8</td><td align="center" class="Botrule Rrule" valign="top">14</td><td align="center" class="Botrule Rrule" valign="top">20</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">Akathisia events<span class="Sup">c</span></td><td align="center" class="Botrule Rrule" valign="top">1</td><td align="center" class="Botrule Rrule" valign="top">5</td><td align="center" class="Botrule Rrule" valign="top">11</td><td align="center" class="Botrule Rrule" valign="top">10</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">Dyskinetic events<span class="Sup">d</span></td><td align="center" class="Botrule Rrule" valign="top">4</td><td align="center" class="Botrule Rrule" valign="top">0</td><td align="center" class="Botrule Rrule" valign="top">2</td><td align="center" class="Botrule Rrule" valign="top">1</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">Residual events<span class="Sup">e</span></td><td align="center" class="Botrule Rrule" valign="top">1</td><td align="center" class="Botrule Rrule" valign="top">2</td><td align="center" class="Botrule Rrule" valign="top">5</td><td align="center" class="Botrule Rrule" valign="top">1</td> </tr> <tr class="Last"> <td align="left" class="Botrule Lrule Rrule" valign="top">Any extrapyramidal event</td><td align="center" class="Botrule Rrule" valign="top">16</td><td align="center" class="Botrule Rrule" valign="top">15</td><td align="center" class="Botrule Rrule" valign="top">25</td><td align="center" class="Botrule Rrule" valign="top">32</td> </tr> </tbody> </table></div>

The following table enumerates the percentage of adolescent patients with treatment-emergent extrapyramidal symptoms as assessed by spontaneously reported adverse reactions during acute therapy (dose range: 2.5 to 20 mg/day).

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 18: Treatment-Emergent Extrapyramidal Symptoms Assessed by Adverse Reactions Incidence in Placebo-Controlled Clinical Trials of Oral Olanzapine in Schizophrenia and Bipolar I Disorder — Adolescents </span> </caption> <colgroup> <col align="left" width="33.333%"/> <col align="left" width="33.333%"/> <col align="left" width="33.333%"/> </colgroup> <tfoot> <tr class="First First Last Last"> <td align="left" colspan="3" valign="top"> <p class="First First Footnote"> <span class="Sup">a</span> Categories are based on Standard MedDRA Queries (SMQ) for extrapyramidal symptoms as defined in MedDRA version 12.0.</p> </td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td align="left" class="Lrule Rrule Toprule" valign="top"></td><td align="center" class="Botrule Rrule Toprule" colspan="2" valign="top"><span class="Bold">Percentage of Patients Reporting Event</span></td> </tr> <tr> <td align="left" class="Lrule Rrule" valign="top"></td><td align="center" class="Rrule" valign="top"><span class="Bold">Placebo</span></td><td align="center" class="Rrule" valign="top"><span class="Bold">Olanzapine</span></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"><span class="Bold">Categories<span class="Sup">a</span></span></td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold">(N=89)</span></td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold">(N=179)</span></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">Dystonic events</td><td align="center" class="Botrule Rrule" valign="top">0</td><td align="center" class="Botrule Rrule" valign="top">1</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">Parkinsonism events</td><td align="center" class="Botrule Rrule" valign="top">2</td><td align="center" class="Botrule Rrule" valign="top">1</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">Akathisia events</td><td align="center" class="Botrule Rrule" valign="top">4</td><td align="center" class="Botrule Rrule" valign="top">6</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">Dyskinetic events</td><td align="center" class="Botrule Rrule" valign="top">0</td><td align="center" class="Botrule Rrule" valign="top">1</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">Nonspecific events</td><td align="center" class="Botrule Rrule" valign="top">0</td><td align="center" class="Botrule Rrule" valign="top">4</td> </tr> <tr class="Last"> <td align="left" class="Botrule Lrule Rrule" valign="top">Any extrapyramidal event</td><td align="center" class="Botrule Rrule" valign="top">6</td><td align="center" class="Botrule Rrule" valign="top">10</td> </tr> </tbody> </table></div>

The following table enumerates the percentage of patients with treatment-emergent extrapyramidal symptoms as assessed by categorical analyses of formal rating scales during controlled clinical trials comparing fixed doses of intramuscular olanzapine for injection with placebo in agitation. Patients in each dose group could receive up to 3 injections during the trials [see Clinical Studies (14.3)]. Patient assessments were conducted during the 24 hours following the initial dose of intramuscular olanzapine for injection.

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 19: Treatment-Emergent Extrapyramidal Symptoms Assessed by Rating Scales Incidence in a Fixed Dose, Placebo-Controlled Clinical Trial of Intramuscular Olanzapine for Injection in Agitated Patients with Schizophrenia </span> </caption> <colgroup> <col align="left" width="16.667%"/> <col align="left" width="16.667%"/> <col align="left" width="16.667%"/> <col align="left" width="16.667%"/> <col align="left" width="16.667%"/> <col align="left" width="16.667%"/> </colgroup> <tfoot> <tr class="First"> <td align="left" colspan="6" valign="top"> <p class="First First Footnote"> <span class="Sup">a</span> Percentage of patients with a Simpson-Angus Scale total score &gt;3.</p> </td> </tr> <tr class="Last"> <td align="left" colspan="6" valign="top"> <p class="First First Footnote"> <span class="Sup">b</span> Percentage of patients with a Barnes Akathisia Scale global score ≥2.</p> </td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td align="left" class="Botrule Lrule Rrule Toprule" rowspan="2" valign="top"></td><td align="center" class="Botrule Rrule Toprule" colspan="5" valign="top"><span class="Bold">Percentage of Patients Reporting Event</span></td> </tr> <tr> <td align="center" class="Botrule Rrule" valign="bottom"><span class="Bold">Placebo</span></td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold">Olanzapine<br/>IM<br/>2.5 mg</span></td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold">Olanzapine<br/>IM<br/>5 mg</span></td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold">Olanzapine<br/>IM<br/>7.5 mg</span></td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold">Olanzapine<br/>IM<br/>10 mg</span></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">Parkinsonism<span class="Sup">a</span></td><td align="center" class="Botrule Rrule" valign="top">0</td><td align="center" class="Botrule Rrule" valign="top">0</td><td align="center" class="Botrule Rrule" valign="top">0</td><td align="center" class="Botrule Rrule" valign="top">0</td><td align="center" class="Botrule Rrule" valign="top">3</td> </tr> <tr class="Last"> <td align="left" class="Botrule Lrule Rrule" valign="top">Akathisia<span class="Sup">b</span></td><td align="center" class="Botrule Rrule" valign="top">0</td><td align="center" class="Botrule Rrule" valign="top">0</td><td align="center" class="Botrule Rrule" valign="top">5</td><td align="center" class="Botrule Rrule" valign="top">0</td><td align="center" class="Botrule Rrule" valign="top">0</td> </tr> </tbody> </table></div>

The following table enumerates the percentage of patients with treatment-emergent extrapyramidal symptoms as assessed by spontaneously reported adverse reactions in the same controlled clinical trial comparing fixed doses of intramuscular olanzapine for injection with placebo in agitated patients with schizophrenia.

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 20: Treatment-Emergent Extrapyramidal Symptoms Assessed by Adverse Reactions Incidence in a Fixed Dose, Placebo-Controlled Clinical Trial of Intramuscular Olanzapine for Injection in Agitated Patients with Schizophrenia </span> </caption> <colgroup> <col align="left" width="22.770%"/> <col align="left" width="15.436%"/> <col align="left" width="15.453%"/> <col align="left" width="15.436%"/> <col align="left" width="15.453%"/> <col align="left" width="15.453%"/> </colgroup> <tfoot> <tr class="First"> <td align="left" colspan="6" valign="top"> <p class="First First Footnote"> <span class="Sup">a</span> Patients with the following COSTART terms were counted in this category: dystonia, generalized spasm, neck rigidity, oculogyric crisis, opisthotonos, torticollis.</p> </td> </tr> <tr> <td align="left" colspan="6" valign="top"> <p class="First First Footnote"> <span class="Sup">b</span> Patients with the following COSTART terms were counted in this category: akinesia, cogwheel rigidity, extrapyramidal syndrome, hypertonia, hypokinesia, masked facies, tremor.</p> </td> </tr> <tr> <td align="left" colspan="6" valign="top"> <p class="First First Footnote"> <span class="Sup">c</span> Patients with the following COSTART terms were counted in this category: akathisia, hyperkinesia.</p> </td> </tr> <tr> <td align="left" colspan="6" valign="top"> <p class="First First Footnote"> <span class="Sup">d</span> Patients with the following COSTART terms were counted in this category: buccoglossal syndrome, choreoathetosis, dyskinesia, tardive dyskinesia.</p> </td> </tr> <tr class="Last"> <td align="left" colspan="6" valign="top"> <p class="First First Footnote"> <span class="Sup">e</span> Patients with the following COSTART terms were counted in this category: movement disorder, myoclonus, twitching.</p> </td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td align="left" class="Botrule Lrule Rrule Toprule" rowspan="2" valign="top"></td><td align="center" class="Botrule Rrule Toprule" colspan="5" valign="top"><span class="Bold">Percentage of Patients Reporting Event</span></td> </tr> <tr> <td align="center" class="Botrule Rrule" valign="bottom"><span class="Bold">Placebo </span> <br/> <span class="Bold">(N=45)</span></td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold">Olanzapine<br/>IM<br/>2.5 mg<br/>(N=48)</span></td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold">Olanzapine<br/>IM<br/>5 mg<br/>(N=45)</span></td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold">Olanzapine<br/>IM<br/>7.5 mg<br/>(N=46)</span></td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold">Olanzapine<br/>IM<br/>10 mg<br/>(N=46)</span></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">Dystonic events<span class="Sup">a</span></td><td align="center" class="Botrule Rrule" valign="top">0</td><td align="center" class="Botrule Rrule" valign="top">0</td><td align="center" class="Botrule Rrule" valign="top">0</td><td align="center" class="Botrule Rrule" valign="top">0</td><td align="center" class="Botrule Rrule" valign="top">0</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">Parkinsonism events<span class="Sup">b</span></td><td align="center" class="Botrule Rrule" valign="top">0</td><td align="center" class="Botrule Rrule" valign="top">4</td><td align="center" class="Botrule Rrule" valign="top">2</td><td align="center" class="Botrule Rrule" valign="top">0</td><td align="center" class="Botrule Rrule" valign="top">0</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">Akathisia events<span class="Sup">c</span></td><td align="center" class="Botrule Rrule" valign="top">0</td><td align="center" class="Botrule Rrule" valign="top">2</td><td align="center" class="Botrule Rrule" valign="top">0</td><td align="center" class="Botrule Rrule" valign="top">0</td><td align="center" class="Botrule Rrule" valign="top">0</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">Dyskinetic events<span class="Sup">d</span></td><td align="center" class="Botrule Rrule" valign="top">0</td><td align="center" class="Botrule Rrule" valign="top">0</td><td align="center" class="Botrule Rrule" valign="top">0</td><td align="center" class="Botrule Rrule" valign="top">0</td><td align="center" class="Botrule Rrule" valign="top">0</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">Residual events<span class="Sup">e</span></td><td align="center" class="Botrule Rrule" valign="top">0</td><td align="center" class="Botrule Rrule" valign="top">0</td><td align="center" class="Botrule Rrule" valign="top">0</td><td align="center" class="Botrule Rrule" valign="top">0</td><td align="center" class="Botrule Rrule" valign="top">0</td> </tr> <tr class="Last"> <td align="left" class="Botrule Lrule Rrule" valign="top">Any extrapyramidal events</td><td align="center" class="Botrule Rrule" valign="top">0</td><td align="center" class="Botrule Rrule" valign="top">4</td><td align="center" class="Botrule Rrule" valign="top">2</td><td align="center" class="Botrule Rrule" valign="top">0</td><td align="center" class="Botrule Rrule" valign="top">0</td> </tr> </tbody> </table></div>

Dystonia, Class Effect: Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include: spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur at low doses, the frequency and severity are greater with high potency and at higher doses of first generation antipsychotic drugs. In general, an elevated risk of acute dystonia may be observed in males and younger age groups receiving antipsychotics; however, events of dystonia have been reported infrequently (<1%) with olanzapine use.

Other Adverse Reactions

Other Adverse Reactions Observed During the Clinical Trial Evaluation of Oral Olanzapine

Following is a list of treatment-emergent adverse reactions reported by patients treated with oral olanzapine (at multiple doses ≥1 mg/day) in clinical trials. This listing is not intended to include reactions (1) already listed in previous tables or elsewhere in labeling, (2) for which a drug cause was remote, (3) which were so general as to be uninformative, (4) which were not considered to have significant clinical implications, or (5) which occurred at a rate equal to or less than placebo. Reactions are classified by body system using the following definitions: frequent adverse reactions are those occurring in at least 1/100 patients; infrequent adverse reactions are those occurring in 1/100 to 1/1000 patients; rare reactions are those occurring in fewer than 1/1000 patients.

Body as a Whole — Infrequent: chills, face edema, photosensitivity reaction, suicide attempt1; Rare: chills and fever, hangover effect, sudden death1.

Cardiovascular System — Infrequent: cerebrovascular accident, vasodilatation.

Digestive System — Infrequent: abdominal distension, nausea and vomiting, tongue edema; Rare: ileus, intestinal obstruction, liver fatty deposit.

Hemic and Lymphatic System — Infrequent: thrombocytopenia.

Metabolic and Nutritional Disorders — Frequent: alkaline phosphatase increased; Infrequent: bilirubinemia, hypoproteinemia.

Musculoskeletal System — Rare: osteoporosis.

Nervous System — Infrequent: ataxia, dysarthria, libido decreased, stupor; Rare: coma.

Respiratory System — Infrequent: epistaxis; Rare: lung edema.

Skin and Appendages — Infrequent: alopecia.

Special Senses — Infrequent: abnormality of accommodation, dry eyes; Rare: mydriasis.

Urogenital System — Infrequent: amenorrhea2, breast pain, decreased menstruation, impotence2, increased menstruation2, menorrhagia2, metrorrhagia2, polyuria2, urinary frequency, urinary retention, urinary urgency, urination impaired.

1 These terms represent serious adverse events but do not meet the definition for adverse drug reactions. They are included here because of their seriousness.

2 Adjusted for gender.

Other Adverse Reactions Observed During the Clinical Trial Evaluation of Intramuscular Olanzapine for Injection

Following is a list of treatment-emergent adverse reactions reported by patients treated with intramuscular olanzapine for injection (at 1 or more doses ≥2.5 mg/injection) in clinical trials. This listing is not intended to include reactions (1) already listed in previous tables or elsewhere in labeling, (2) for which a drug cause was remote, (3) which were so general as to be uninformative, (4) which were not considered to have significant clinical implications, or (5) for which occurred at a rate equal to or less than placebo. Reactions are classified by body system using the following definitions: frequent adverse reactions are those occurring in at least 1/100 patients; infrequent adverse reactions are those occurring in 1/100 to 1/1000 patients.

Body as a Whole — Frequent: injection site pain.

Cardiovascular System — Infrequent: syncope.

Digestive System — Infrequent: nausea.

Metabolic and Nutritional Disorders — Infrequent:creatine phosphokinase increased.

Clinical Trials in Adolescent Patients (age 13 to 17 years)

Commonly Observed Adverse Reactions in Oral Olanzapine Short-Term, Placebo-Controlled Trials

Adverse reactions in adolescent patients treated with oral olanzapine (doses ≥2.5 mg) reported with an incidence of 5% or more and reported at least twice as frequently as placebo-treated patients are listed in Table 21.

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 21: Treatment-Emergent Adverse Reactions of ≥5% Incidence among Adolescents (13-17 Years Old) with Schizophrenia or Bipolar I Disorder (Manic or Mixed Episodes) </span> </caption> <colgroup> <col align="left" width="20.000%"/> <col align="left" width="20.000%"/> <col align="left" width="20.000%"/> <col align="left" width="20.000%"/> <col align="left" width="20.000%"/> </colgroup> <tfoot> <tr class="First"> <td align="left" colspan="5" valign="top"> <p class="First First Footnote"> <span class="Sup">a</span> Patients with the following MedDRA terms were counted in this category: hypersomnia, lethargy, sedation, somnolence.</p> </td> </tr> <tr class="Last"> <td align="left" colspan="5" valign="top"> <p class="First First Footnote"> <span class="Sup">b</span> Patients with the following MedDRA terms were counted in this category: abdominal pain, abdominal pain lower, abdominal pain upper.</p> </td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td align="left" class="Botrule Lrule Rrule Toprule" rowspan="3" valign="bottom"><span class="Bold">Adverse Reactions</span></td><td align="center" class="Botrule Rrule Toprule" colspan="4" valign="top"><span class="Bold">Percentage of Patients Reporting Event</span></td> </tr> <tr> <td align="center" class="Botrule Rrule" colspan="2" valign="top"><span class="Bold">6 Week Trial<br/>% Schizophrenia Patients</span></td><td align="center" class="Botrule Rrule" colspan="2" valign="top"><span class="Bold">3 Week Trial<br/>% Bipolar Patients</span></td> </tr> <tr> <td align="center" class="Botrule Rrule" valign="top"><span class="Bold">Olanzapine<br/>(N=72)</span></td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold">Placebo<br/>(N=35)</span></td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold">Olanzapine<br/>(N=107)</span></td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold">Placebo<br/>(N=54)</span></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">Sedation<span class="Sup">a</span></td><td align="center" class="Botrule Rrule" valign="top">39</td><td align="center" class="Botrule Rrule" valign="top">9</td><td align="center" class="Botrule Rrule" valign="top">48</td><td align="center" class="Botrule Rrule" valign="top">9</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">Weight increased</td><td align="center" class="Botrule Rrule" valign="top">31</td><td align="center" class="Botrule Rrule" valign="top">9</td><td align="center" class="Botrule Rrule" valign="top">29</td><td align="center" class="Botrule Rrule" valign="top">4</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">Headache</td><td align="center" class="Botrule Rrule" valign="top">17</td><td align="center" class="Botrule Rrule" valign="top">6</td><td align="center" class="Botrule Rrule" valign="top">17</td><td align="center" class="Botrule Rrule" valign="top">17</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">Increased appetite</td><td align="center" class="Botrule Rrule" valign="top">17</td><td align="center" class="Botrule Rrule" valign="top">9</td><td align="center" class="Botrule Rrule" valign="top">29</td><td align="center" class="Botrule Rrule" valign="top">4</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">Dizziness</td><td align="center" class="Botrule Rrule" valign="top">8</td><td align="center" class="Botrule Rrule" valign="top">3</td><td align="center" class="Botrule Rrule" valign="top">7</td><td align="center" class="Botrule Rrule" valign="top">2</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">Abdominal pain<span class="Sup">b</span></td><td align="center" class="Botrule Rrule" valign="top">6</td><td align="center" class="Botrule Rrule" valign="top">3</td><td align="center" class="Botrule Rrule" valign="top">6</td><td align="center" class="Botrule Rrule" valign="top">7</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">Pain in extremity</td><td align="center" class="Botrule Rrule" valign="top">6</td><td align="center" class="Botrule Rrule" valign="top">3</td><td align="center" class="Botrule Rrule" valign="top">5</td><td align="center" class="Botrule Rrule" valign="top">0</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">Fatigue</td><td align="center" class="Botrule Rrule" valign="top">3</td><td align="center" class="Botrule Rrule" valign="top">3</td><td align="center" class="Botrule Rrule" valign="top">14</td><td align="center" class="Botrule Rrule" valign="top">6</td> </tr> <tr class="Last"> <td align="left" class="Botrule Lrule Rrule" valign="top">Dry mouth</td><td align="center" class="Botrule Rrule" valign="top">4</td><td align="center" class="Botrule Rrule" valign="top">0</td><td align="center" class="Botrule Rrule" valign="top">7</td><td align="center" class="Botrule Rrule" valign="top">0</td> </tr> </tbody> </table></div>

Adverse Reactions Occurring at an Incidence of 2% or More among Oral Olanzapine-Treated Patients in Short-Term (3-6 weeks), Placebo-Controlled Trials

Adverse reactions in adolescent patients treated with oral olanzapine (doses ≥2.5 mg) reported with an incidence of 2% or more and greater than placebo are listed in Table 22.

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 22: Treatment-Emergent Adverse Reactions of ≥2% Incidence among Adolescents (13-17 Years Old) (Combined Incidence from Short-Term, Placebo-Controlled Clinical Trials of Schizophrenia or Bipolar I Disorder [Manic or Mixed Episodes]) </span> </caption> <colgroup> <col align="left" width="33.333%"/> <col align="left" width="33.333%"/> <col align="left" width="33.333%"/> </colgroup> <tfoot> <tr class="First"> <td align="left" colspan="3" valign="top"> <p class="First First Footnote"> <span class="Sup">a</span> Patients with the following MedDRA terms were counted in this category: hypersomnia, lethargy, sedation, somnolence.</p> </td> </tr> <tr> <td align="left" colspan="3" valign="top"> <p class="First First Footnote"> <span class="Sup">b</span> The terms alanine aminotransferase (ALT), aspartate aminotransferase (AST), and hepatic enzyme were combined under liver enzymes.</p> </td> </tr> <tr class="Last"> <td align="left" colspan="3" valign="top"> <p class="First First Footnote"> <span class="Sup">c</span> Patients with the following MedDRA terms were counted in this category: lower respiratory tract infection, respiratory tract infection, respiratory tract infection viral, upper respiratory tract infection, viral upper respiratory tract infection.</p> </td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td align="left" class="Botrule" rowspan="2" valign="bottom"><span class="Bold">Adverse Reaction</span></td><td align="center" class="Botrule" colspan="2" valign="top"><span class="Bold">Percentage of Patients Reporting Event</span></td> </tr> <tr> <td align="center" class="Botrule" valign="top"><span class="Bold">Olanzapine<br/>(N=179)</span></td><td align="center" class="Botrule" valign="top"><span class="Bold">Placebo<br/>(N=89)</span></td> </tr> <tr> <td align="left" valign="top">Sedation<span class="Sup">a</span></td><td align="center" valign="top">44</td><td align="center" valign="top">9</td> </tr> <tr> <td align="left" valign="top">Weight increased</td><td align="center" valign="top">30</td><td align="center" valign="top">6</td> </tr> <tr> <td align="left" valign="top">Increased appetite</td><td align="center" valign="top">24</td><td align="center" valign="top">6</td> </tr> <tr> <td align="left" valign="top">Headache</td><td align="center" valign="top">17</td><td align="center" valign="top">12</td> </tr> <tr> <td align="left" valign="top">Fatigue</td><td align="center" valign="top">9</td><td align="center" valign="top">4</td> </tr> <tr> <td align="left" valign="top">Dizziness</td><td align="center" valign="top">7</td><td align="center" valign="top">2</td> </tr> <tr> <td align="left" valign="top">Dry mouth</td><td align="center" valign="top">6</td><td align="center" valign="top">0</td> </tr> <tr> <td align="left" valign="top">Pain in extremity</td><td align="center" valign="top">5</td><td align="center" valign="top">1</td> </tr> <tr> <td align="left" valign="top">Constipation</td><td align="center" valign="top">4</td><td align="center" valign="top">0</td> </tr> <tr> <td align="left" valign="top">Nasopharyngitis</td><td align="center" valign="top">4</td><td align="center" valign="top">2</td> </tr> <tr> <td align="left" valign="top">Diarrhea</td><td align="center" valign="top">3</td><td align="center" valign="top">0</td> </tr> <tr> <td align="left" valign="top">Restlessness</td><td align="center" valign="top">3</td><td align="center" valign="top">2</td> </tr> <tr> <td align="left" valign="top">Liver enzymes increased<span class="Sup">b</span></td><td align="center" valign="top">8</td><td align="center" valign="top">1</td> </tr> <tr> <td align="left" valign="top">Dyspepsia</td><td align="center" valign="top">3</td><td align="center" valign="top">1</td> </tr> <tr> <td align="left" valign="top">Epistaxis</td><td align="center" valign="top">3</td><td align="center" valign="top">0</td> </tr> <tr> <td align="left" valign="top">Respiratory tract infection<span class="Sup">c</span></td><td align="center" valign="top">3</td><td align="center" valign="top">2</td> </tr> <tr> <td align="left" valign="top">Sinusitis</td><td align="center" valign="top">3</td><td align="center" valign="top">0</td> </tr> <tr> <td align="left" valign="top">Arthralgia</td><td align="center" valign="top">2</td><td align="center" valign="top">0</td> </tr> <tr class="Last"> <td align="left" class="Botrule" valign="top">Musculoskeletal stiffness</td><td align="center" class="Botrule" valign="top">2</td><td align="center" class="Botrule" valign="top">0</td> </tr> </tbody> </table></div>

Vital Signs and Laboratory Studies

Vital Sign Changes — Oral olanzapine was associated with orthostatic hypotension and tachycardia in clinical trials. Intramuscular olanzapine for injection was associated with bradycardia, hypotension, and tachycardia in clinical trials [see Warnings and Precautions (5)].

Laboratory Changes

Olanzapine Monotherapy in Adults: An assessment of the premarketing experience for olanzapine revealed an association with asymptomatic increases in ALT, AST, and GGT. Within the original premarketing database of about 2400 adult patients with baseline ALT ≤90 IU/L, the incidence of ALT elevations to >200 IU/L was 2% (50/2381). None of these patients experienced jaundice or other symptoms attributable to liver impairment and most had transient changes that tended to normalize while olanzapine treatment was continued.

In placebo-controlled olanzapine monotherapy studies in adults, clinically significant ALT elevations (change from <3 times the upper limit of normal [ULN] at baseline to ≥3 times ULN) were observed in 5% (77/1426) of patients exposed to olanzapine compared to 1% (10/1187) of patients exposed to placebo. ALT elevations ≥5 times ULN were observed in 2% (29/1438) of olanzapine-treated patients, compared to 0.3% (4/1196) of placebo-treated patients. ALT values returned to normal, or were decreasing, at last follow-up in the majority of patients who either continued treatment with olanzapine or discontinued olanzapine. No patient with elevated ALT values experienced jaundice, liver failure, or met the criteria for Hy's Rule.

From an analysis of the laboratory data in an integrated database of 41 completed clinical studies in adult patients treated with oral olanzapine, high GGT levels were recorded in ≥1% (88/5245) of patients.

Caution should be exercised in patients with signs and symptoms of hepatic impairment, in patients with pre-existing conditions associated with limited hepatic functional reserve, and in patients who are being treated with potentially hepatotoxic drugs.

Olanzapine administration was also associated with increases in serum prolactin [see Warnings and Precautions (5.15)], with an asymptomatic elevation of the eosinophil count in 0.3% of patients, and with an increase in CPK.

From an analysis of the laboratory data in an integrated database of 41 completed clinical studies in adult patients treated with oral olanzapine, elevated uric acid was recorded in ≥3% (171/4641) of patients.

Olanzapine Monotherapy in Adolescents: In placebo-controlled clinical trials of adolescent patients with schizophrenia or bipolar I disorder (manic or mixed episodes), greater frequencies for the following treatment-emergent findings, at anytime, were observed in laboratory analytes compared to placebo: elevated ALT (≥3X ULN in patients with ALT at baseline <3X ULN), (12% vs 2%); elevated AST (28% vs 4%); low total bilirubin (22% vs 7%); elevated GGT (10% vs 1%); and elevated prolactin (47% vs 7%).

In placebo-controlled olanzapine monotherapy studies in adolescents, clinically significant ALT elevations (change from <3 times ULN at baseline to ≥3 times ULN) were observed in 12% (22/192) of patients exposed to olanzapine compared to 2% (2/109) of patients exposed to placebo. ALT elevations ≥5 times ULN were observed in 4% (8/192) of olanzapine-treated patients, compared to 1% (1/109) of placebo-treated patients. ALT values returned to normal, or were decreasing, at last follow-up in the majority of patients who either continued treatment with olanzapine or discontinued olanzapine. No adolescent patient with elevated ALT values experienced jaundice, liver failure, or met the criteria for Hy's Rule.

ECG Changes — In pooled studies of adults as well as pooled studies of adolescents, there were no significant differences between olanzapine and placebo in the proportions of patients experiencing potentially important changes in ECG parameters, including QT, QTc (Fridericia corrected), and PR intervals. Olanzapine use was associated with a mean increase in heart rate compared to placebo (adults: +2.4 beats per minute vs no change with placebo; adolescents: +6.3 beats per minute vs -5.1 beats per minute with placebo). This increase in heart rate may be related to olanzapine's potential for inducing orthostatic changes [see Warnings and Precautions (5.7)].

The following adverse reactions have been identified during post-approval use of olanzapine. Because these reactions are reported voluntarily from a population of uncertain size, it is difficult to reliably estimate their frequency or evaluate a causal relationship to drug exposure.

Adverse reactions reported since market introduction that were temporally (but not necessarily causally) related to olanzapine therapy include the following: allergic reaction (e.g., anaphylactoid reaction, angioedema, pruritus or urticaria), cholestatic or mixed liver injury, diabetic coma, diabetic ketoacidosis, discontinuation reaction (diaphoresis, nausea or vomiting), Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), hepatitis, jaundice, neutropenia, pancreatitis, priapism, rash, restless legs syndrome, rhabdomyolysis, salivary hypersecretion, stuttering1, venous thromboembolic events (including pulmonary embolism and deep venous thrombosis), fecal incontinence, and somnambulism. Random cholesterol levels of ≥240 mg/dL and random triglyceride levels of ≥1000 mg/dL have been reported.

1 Stuttering was only studied in oral and long acting injection (LAI) formulations.

Diazepam — The co-administration of diazepam with olanzapine potentiated the orthostatic hypotension observed with olanzapine [see Drug Interactions (7.2)].

Cimetidine and Antacids — Single doses of cimetidine (800 mg) or aluminum- and magnesium-containing antacids did not affect the oral bioavailability of olanzapine.

Inducers of CYP1A2 — Carbamazepine therapy (200 mg bid) causes an approximately 50% increase in the clearance of olanzapine. This increase is likely due to the fact that carbamazepine is a potent inducer of CYP1A2 activity. Higher daily doses of carbamazepine may cause an even greater increase in olanzapine clearance.

Alcohol — Ethanol (45 mg/70 kg single dose) did not have an effect on olanzapine pharmacokinetics. The co-administration of alcohol (i.e., ethanol) with olanzapine potentiated the orthostatic hypotension observed with olanzapine [see Drug Interactions (7.2)].

Inhibitors of CYP1A2

Fluvoxamine: Fluvoxamine, a CYP1A2 inhibitor, decreases the clearance of olanzapine. This results in a mean increase in olanzapine Cmax following fluvoxamine of 54% in female nonsmokers and 77% in male smokers. The mean increase in olanzapine AUC is 52% and 108%, respectively. Lower doses of olanzapine should be considered in patients receiving concomitant treatment with fluvoxamine.

Inhibitors of CYP2D6

Fluoxetine: Fluoxetine (60 mg single dose or 60 mg daily dose for 8 days) causes a small (mean 16%) increase in the maximum concentration of olanzapine and a small (mean 16%) decrease in olanzapine clearance. The magnitude of the impact of this factor is small in comparison to the overall variability between individuals, and therefore dose modification is not routinely recommended.

Warfarin — Warfarin (20 mg single dose) did not affect olanzapine pharmacokinetics [see Drug Interactions (7.2)].

Inducers of CYP1A2 or Glucuronyl Transferase — Omeprazole and rifampin may cause an increase in olanzapine clearance.

Charcoal — The administration of activated charcoal (1 g) reduced the Cmax and AUC of oral olanzapine by about 60%. As peak olanzapine levels are not typically obtained until about 6 hours after dosing, charcoal may be a useful treatment for olanzapine overdose.

Anticholinergic Drugs — Concomitant treatment with olanzapine and other drugs with anticholinergic activity can increase the risk for severe gastrointestinal adverse reactions related to hypomotility. Olanzapine should be used with caution in patients receiving medications having anticholinergic (antimuscarinic) effects [see Warnings and Precautions (5.14)].

CNS Acting Drugs — Given the primary CNS effects of olanzapine, caution should be used when olanzapine is taken in combination with other centrally acting drugs and alcohol.

Antihypertensive Agents — Olanzapine, because of its potential for inducing hypotension, may enhance the effects of certain antihypertensive agents.

Levodopa and Dopamine Agonists — Olanzapine may antagonize the effects of levodopa and dopamine agonists.

Lorazepam (IM) — Administration of intramuscular lorazepam (2 mg) 1 hour after intramuscular olanzapine for injection (5 mg) did not significantly affect the pharmacokinetics of olanzapine, unconjugated lorazepam, or total lorazepam. However, this co-administration of intramuscular lorazepam and intramuscular olanzapine for injection added to the somnolence observed with either drug alone [see Warnings and Precautions (5.7)].

Lithium — Multiple doses of olanzapine (10 mg for 8 days) did not influence the kinetics of lithium. Therefore, concomitant olanzapine administration does not require dosage adjustment of lithium [see Warnings and Precautions (5.16)].

Valproate — Olanzapine (10 mg daily for 2 weeks) did not affect the steady state plasma concentrations of valproate. Therefore, concomitant olanzapine administration does not require dosage adjustment of valproate [see Warnings and Precautions (5.16)].

Effect of Olanzapine on Drug Metabolizing Enzymes — In vitro studies utilizing human liver microsomes suggest that olanzapine has little potential to inhibit CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A. Thus, olanzapine is unlikely to cause clinically important drug interactions mediated by these enzymes.

Imipramine — Single doses of olanzapine did not affect the pharmacokinetics of imipramine or its active metabolite desipramine.

Warfarin — Single doses of olanzapine did not affect the pharmacokinetics of warfarin [see Drug Interactions (7.1)].

Diazepam — Olanzapine did not influence the pharmacokinetics of diazepam or its active metabolite N-desmethyldiazepam. However, diazepam co-administered with olanzapine increased the orthostatic hypotension observed with either drug given alone [see Drug Interactions (7.1)].

Alcohol — Multiple doses of olanzapine did not influence the kinetics of ethanol [see Drug Interactions (7.1)].

Biperiden — Multiple doses of olanzapine did not influence the kinetics of biperiden.

Theophylline — Multiple doses of olanzapine did not affect the pharmacokinetics of theophylline or its metabolites.

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to atypical antipsychotics, including olanzapine, during pregnancy. Healthcare providers are encouraged to register patients by contacting the National Pregnancy Registry for Atypical Antipsychotics at 1-866-961-2388 or visit http://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/.

Risk Summary

Neonates exposed to antipsychotic drugs, including olanzapine, during the third trimester are at risk for extrapyramidal and/or withdrawal symptoms following delivery (see Clinical Considerations). Overall available data from published epidemiologic studies of pregnant women exposed to olanzapine have not established a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes (see Data). There are risks to the mother associated with untreated schizophrenia or bipolar I disorder and with exposure to antipsychotics, including olanzapine, during pregnancy (see Clinical Considerations).

Olanzapine was not teratogenic when administered orally to pregnant rats and rabbits at doses that are 9- and 30-times the daily oral maximum recommended human dose (MRHD), based on mg/m2 body surface area; some fetal toxicities were observed at these doses (see Data).

The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defects, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Clinical Considerations

Disease-associated maternal and embryo/fetal risk

There is a risk to the mother from untreated schizophrenia or bipolar I disorder, including increased risk of relapse, hospitalization, and suicide. Schizophrenia and bipolar I disorder are associated with increased adverse perinatal outcomes, including preterm birth. It is not known if this is a direct result of the illness or other comorbid factors.

Fetal/Neonatal adverse reactions

Extrapyramidal and/or withdrawal symptoms, including agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder have been reported in neonates who were exposed to antipsychotic drugs, including olanzapine, during the third trimester of pregnancy. These symptoms have varied in severity. Monitor neonates for extrapyramidal and/or withdrawal symptoms and manage symptoms appropriately. Some neonates recovered within hours or days without specific treatment; others required prolonged hospitalization.

Data

Human Data

Placental passage has been reported in published study reports; however, the placental passage ratio was highly variable ranging between 7% to 167% at birth following exposure during pregnancy. The clinical relevance of this finding is unknown.

Published data from observational studies, birth registries, and case reports that have evaluated the use of atypical antipsychotics during pregnancy do not establish an increased risk of major birth defects. A retrospective cohort study from a Medicaid database of 9258 women exposed to antipsychotics during pregnancy did not indicate an overall increased risk for major birth defects.

Animal Data

In oral reproduction studies in rats at doses up to 18 mg/kg/day and in rabbits at doses up to 30 mg/kg/day (9 and 30 times the daily oral MRHD based on mg/m2 body surface area, respectively), no evidence of teratogenicity was observed. In an oral rat teratology study, early resorptions and increased numbers of nonviable fetuses were observed at a dose of 18 mg/kg/day (9 times the daily oral MRHD based on mg/m2 body surface area), and gestation was prolonged at 10 mg/kg/day (5 times the daily oral MRHD based on mg/m2 body surface area). In an oral rabbit teratology study, fetal toxicity manifested as increased resorptions and decreased fetal weight, occurred at a maternally toxic dose of 30 mg/kg/day (30 times the daily oral MRHD based on mg/m2 body surface area).

Risk Summary

Olanzapine is present in human milk. There are reports of excess sedation, irritability, poor feeding and extrapyramidal symptoms (tremors and abnormal muscle movements) in infants exposed to olanzapine through breast milk (see Clinical Considerations). There is no information on the effects of olanzapine on milk production.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for olanzapine and any potential adverse effects on the breastfed child from olanzapine or from the mother’s underlying condition.

Clinical Considerations

Infants exposed to olanzapine should be monitored for excess sedation, irritability, poor feeding, and extrapyramidal symptoms (tremors and abnormal muscle movements).

Infertility

Females

Based on the pharmacologic action of olanzapine (D2 receptor antagonism), treatment with olanzapine may result in an increase in serum prolactin levels, which may lead to a reversible reduction in fertility in females of reproductive potential [see Warnings and Precautions (5.15)].

Compared to patients from adult clinical trials, adolescents were likely to gain more weight, experience increased sedation, and have greater increases in total cholesterol, triglycerides, LDL cholesterol, prolactin and hepatic aminotransferase levels [see Warnings and Precautions (5.5, 5.15, 5.17) and Adverse Reactions (6.1)]. When deciding among the alternative treatments available for adolescents, clinicians should consider the increased potential (in adolescents as compared with adults) for weight gain and dyslipidemia. Clinicians should consider the potential long-term risks when prescribing to adolescents, and in many cases this may lead them to consider prescribing other drugs first in adolescents.

Safety and effectiveness of olanzapine in children <13 years of age have not been established [see Patient Counseling Information (17)].

Of the 2500 patients in premarketing clinical studies with oral olanzapine, 11% (263) were 65 years of age or over. In patients with schizophrenia, there was no indication of any different tolerability of olanzapine in the elderly compared to younger patients. Studies in elderly patients with dementia-related psychosis have suggested that there may be a different tolerability profile in this population compared to younger patients with schizophrenia. Elderly patients with dementia-related psychosis treated with olanzapine are at an increased risk of death compared to placebo. In placebo-controlled studies of olanzapine in elderly patients with dementia-related psychosis, there was a higher incidence of cerebrovascular adverse events (e.g., stroke, transient ischemic attack) in patients treated with olanzapine compared to patients treated with placebo. In 5 placebo-controlled studies of olanzapine in elderly patients with dementia-related psychosis (n=1184), the following adverse reactions were reported in olanzapine-treated patients at an incidence of at least 2% and significantly greater than placebo-treated patients: falls, somnolence, peripheral edema, abnormal gait, urinary incontinence, lethargy, increased weight, asthenia, pyrexia, pneumonia, dry mouth and visual hallucinations. The rate of discontinuation due to adverse reactions was greater with olanzapine than placebo (13% vs 7%). Elderly patients with dementia-related psychosis treated with olanzapine are at an increased risk of death compared to placebo. Olanzapine is not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning, Warnings and Precautions (5.1), and Patient Counseling Information (17)]. Olanzapine is not approved for the treatment of patients with dementia-related psychosis. Also, the presence of factors that might decrease pharmacokinetic clearance or increase the pharmacodynamic response to olanzapine should lead to consideration of a lower starting dose for any geriatric patient [see Boxed Warning, and Warnings and Precautions (5.1)].

In studies prospectively designed to assess abuse and dependence potential, olanzapine was shown to have acute depressive CNS effects but little or no potential of abuse or physical dependence in rats administered oral doses up to 15 times the daily oral MRHD (20 mg) and rhesus monkeys administered oral doses up to 8 times the daily oral MRHD based on mg/m2 body surface area.

Olanzapine has not been systematically studied in humans for its potential for abuse, tolerance, or physical dependence. While the clinical trials did not reveal any tendency for any drug-seeking behavior, these observations were not systematic, and it is not possible to predict on the basis of this limited experience the extent to which a CNS-active drug will be misused, diverted, and/or abused once marketed. Consequently, patients should be evaluated carefully for a history of drug abuse, and such patients should be observed closely for signs of misuse or abuse of olanzapine (e.g., development of tolerance, increases in dose, drug-seeking behavior).

In premarketing trials involving more than 3100 patients and/or normal subjects, accidental or intentional acute overdosage of olanzapine was identified in 67 patients. In the patient taking the largest identified amount, 300 mg, the only symptoms reported were drowsiness and slurred speech. In the limited number of patients who were evaluated in hospitals, including the patient taking 300 mg, there were no observations indicating an adverse change in laboratory analytes or ECG. Vital signs were usually within normal limits following overdoses.

In postmarketing reports of overdose with olanzapine alone, symptoms have been reported in the majority of cases. In symptomatic patients, symptoms with ≥10% incidence included agitation/aggressiveness, dysarthria, tachycardia, various extrapyramidal symptoms, and reduced level of consciousness ranging from sedation to coma. Among less commonly reported symptoms were the following potentially medically serious reactions: aspiration, cardiopulmonary arrest, cardiac arrhythmias (such as supraventricular tachycardia and 1 patient experiencing sinus pause with spontaneous resumption of normal rhythm), delirium, possible neuroleptic malignant syndrome, respiratory depression/arrest, convulsion, hypertension, and hypotension. Company has received reports of fatality in association with overdose of olanzapine alone. In 1 case of death, the amount of acutely ingested olanzapine was reported to be possibly as low as 450 mg of oral olanzapine; however, in another case, a patient was reported to survive an acute olanzapine ingestion of approximately 2 g of oral olanzapine.

There is no specific antidote to an overdose of olanzapine. The possibility of multiple drug involvement should be considered. Establish and maintain an airway and ensure adequate oxygenation and ventilation. Cardiovascular monitoring should commence immediately and should include continuous electrocardiographic monitoring to detect possible arrhythmias.

Contact a Certified Poison Control Center for the most up to date information on the management of overdosage (1-800-222-1222).

For specific information about overdosage with lithium or valproate, refer to the Overdosage section of the prescribing information for those products.

Olanzapine is an atypical antipsychotic that belongs to the thienobenzodiazepine class. The chemical designation is 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b] [1,5]benzodiazepine. The molecular formula is C17H20N4S, which corresponds to a molecular weight of 312.44. The chemical structure is:

{ "type": "p", "children": [], "text": "Olanzapine is an atypical antipsychotic that belongs to the thienobenzodiazepine class. The chemical designation is 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b] [1,5]benzodiazepine. The molecular formula is C17H20N4S, which corresponds to a molecular weight of 312.44. The chemical structure is:" }

Olanzapine is a yellow crystalline solid, which is practically insoluble in water.

{ "type": "p", "children": [], "text": "Olanzapine is a yellow crystalline solid, which is practically insoluble in water." }

Olanzapine for injection is intended for intramuscular use only.

{ "type": "p", "children": [], "text": "\nOlanzapine for injection is intended for intramuscular use only.\n" }

Each single-dose vial provides for the administration of 10 mg (32 μmol) olanzapine with inactive ingredients 50 mg lactose monohydrate and 3.5 mg tartaric acid. Diluted hydrochloric acid and/or sodium hydroxide may have been added during manufacturing to adjust pH.

{ "type": "p", "children": [], "text": "Each single-dose vial provides for the administration of 10 mg (32 μmol) olanzapine with inactive ingredients 50 mg lactose monohydrate and 3.5 mg tartaric acid. Diluted hydrochloric acid and/or sodium hydroxide may have been added during manufacturing to adjust pH." }

The mechanism of action of olanzapine, in the listed indications is unclear. However, the efficacy of olanzapine in schizophrenia could be mediated through a combination of dopamine and serotonin type 2 (5HT2) antagonism.

Olanzapine binds with high affinity to the following receptors: serotonin 5HT2A/2C, 5HT6 (Ki=4, 11, and 5 nM, respectively), dopamine D1-4 (Ki=11-31 nM), histamine H1 (Ki=7 nM), and adrenergic α1 receptors (Ki=19 nM). Olanzapine is an antagonist with moderate affinity binding for serotonin 5HT3 (Ki=57 nM) and muscarinic M1-5 (Ki=73, 96, 132, 32, and 48 nM, respectively). Olanzapine binds with low affinity to GABAA, BZD, and β-adrenergic receptors (Ki>10 μM).

Oral Administration, Monotherapy — Olanzapine is well absorbed and reaches peak concentrations in approximately 6 hours following an oral dose. It is eliminated extensively by first pass metabolism, with approximately 40% of the dose metabolized before reaching the systemic circulation. Food does not affect the rate or extent of olanzapine absorption. Pharmacokinetic studies showed that Zyprexa tablets and Zyprexa Zydis dosage forms of olanzapine are bioequivalent.

Olanzapine displays linear kinetics over the clinical dosing range. Its half-life ranges from 21 to 54 hours (5th to 95th percentile; mean of 30 hr), and apparent plasma clearance ranges from 12 to 47 L/hr (5th to 95th percentile; mean of 25 L/hr).

Administration of olanzapine once daily leads to steady-state concentrations in about 1 week that are approximately twice the concentrations after single doses. Plasma concentrations, half-life, and clearance of olanzapine may vary between individuals on the basis of smoking status, gender, and age.

Olanzapine is extensively distributed throughout the body, with a volume of distribution of approximately 1000 L. It is 93% bound to plasma proteins over the concentration range of 7 to 1100 ng/mL, binding primarily to albumin and α1-acid glycoprotein.

Metabolism and Elimination — Following a single oral dose of 14C labeled olanzapine, 7% of the dose of olanzapine was recovered in the urine as unchanged drug, indicating that olanzapine is highly metabolized. Approximately 57% and 30% of the dose was recovered in the urine and feces, respectively. In the plasma, olanzapine accounted for only 12% of the AUC for total radioactivity, indicating significant exposure to metabolites. After multiple dosing, the major circulating metabolites were the 10-N-glucuronide, present at steady state at 44% of the concentration of olanzapine, and 4′-N-desmethyl olanzapine, present at steady state at 31% of the concentration of olanzapine. Both metabolites lack pharmacological activity at the concentrations observed.

Direct glucuronidation and cytochrome P450 (CYP) mediated oxidation are the primary metabolic pathways for olanzapine. In vitro studies suggest that CYPs 1A2 and 2D6, and the flavin-containing monooxygenase system are involved in olanzapine oxidation. CYP2D6 mediated oxidation appears to be a minor metabolic pathway in vivo, because the clearance of olanzapine is not reduced in subjects who are deficient in this enzyme.

Intramuscular Administration — Olanzapine for Injection results in rapid absorption with peak plasma concentrations occurring within 15 to 45 minutes. Based upon a pharmacokinetic study in healthy volunteers, a 5 mg dose of intramuscular olanzapine for injection produces, on average, a maximum plasma concentration approximately 5 times higher than the maximum plasma concentration produced by a 5 mg dose of oral olanzapine. Area under the curve achieved after an intramuscular dose is similar to that achieved after oral administration of the same dose. The half-life observed after intramuscular administration is similar to that observed after oral dosing. The pharmacokinetics are linear over the clinical dosing range. Metabolic profiles after intramuscular administration are qualitatively similar to metabolic profiles after oral administration.

Specific Populations

Renal Impairment — Because olanzapine is highly metabolized before excretion and only 7% of the drug is excreted unchanged, renal dysfunction alone is unlikely to have a major impact on the pharmacokinetics of olanzapine. The pharmacokinetic characteristics of olanzapine were similar in patients with severe renal impairment and normal subjects, indicating that dosage adjustment based upon the degree of renal impairment is not required. In addition, olanzapine is not removed by dialysis. The effect of renal impairment on metabolite elimination has not been studied.

Hepatic Impairment — Although the presence of hepatic impairment may be expected to reduce the clearance of olanzapine, a study of the effect of impaired liver function in subjects (n=6) with clinically significant (Childs Pugh Classification A and B) cirrhosis revealed little effect on the pharmacokinetics of olanzapine.

Geriatric — In a study involving 24 healthy subjects, the mean elimination half-life of olanzapine was about 1.5 times greater in elderly (≥65 years) than in nonelderly subjects (<65 years). Caution should be used in dosing the elderly, especially if there are other factors that might additively influence drug metabolism and/or pharmacodynamic sensitivity [see Dosage and Administration (2)].

Gender — Clearance of olanzapine is approximately 30% lower in women than in men. There were, however, no apparent differences between men and women in effectiveness or adverse effects. Dosage modifications based on gender should not be needed.

Smoking Status — Olanzapine clearance is about 40% higher in smokers than in nonsmokers, although dosage modifications are not routinely recommended.

Race — In vivo studies have shown that exposures are similar among Japanese, Chinese and Caucasians, especially after normalization for body weight differences. Dosage modifications for race are, therefore, not recommended.

Combined Effects — The combined effects of age, smoking, and gender could lead to substantial pharmacokinetic differences in populations. The clearance in young smoking males, for example, may be 3 times higher than that in elderly nonsmoking females. Dosing modification may be necessary in patients who exhibit a combination of factors that may result in slower metabolism of olanzapine [see Dosage and Administration (2)].

Adolescents (ages 13 to 17 years) — In clinical studies, most adolescents were nonsmokers and this population had a lower average body weight, which resulted in higher average olanzapine exposure compared to adults.

Carcinogenesis — Oral carcinogenicity studies were conducted in mice and rats. Olanzapine was administered to mice in two 78-week studies at doses of 3, 10, 30/20 mg/kg/day (equivalent to 0.8-5 times the daily oral MRHD based on mg/m2 body surface area) and 0.25, 2, 8 mg/kg/day (equivalent to 0.06-2 times the daily oral MRHD based on mg/m2 body surface area). Rats were dosed for 2 years at doses of 0.25, 1, 2.5, 4 mg/kg/day (males) and 0.25, 1, 4, 8 mg/kg/day (females) (equivalent to 0.13-2 and 0.13-4 times the daily oral MRHD based on mg/m2 body surface area, respectively). The incidence of liver hemangiomas and hemangiosarcomas was significantly increased in 1 mouse study in female mice at 2 times the daily oral MRHD based on mg/m2 body surface area. These tumors were not increased in another mouse study in females dosed up to 2-5 times the daily oral MRHD based on mg/m2 body surface area; in this study, there was a high incidence of early mortalities in males of the 30/20 mg/kg/day group. The incidence of mammary gland adenomas and adenocarcinomas was significantly increased in female mice dosed at ≥2 mg/kg/day and in female rats dosed at ≥4 mg/kg/day (0.5 and 2 times the daily oral MRHD based on mg/m2 body surface area, respectively). Antipsychotic drugs have been shown to chronically elevate prolactin levels in rodents. Serum prolactin levels were not measured during the olanzapine carcinogenicity studies; however, measurements during subchronic toxicity studies showed that olanzapine elevated serum prolactin levels up to 4-fold in rats at the same doses used in the carcinogenicity study. An increase in mammary gland neoplasms has been found in rodents after chronic administration of other antipsychotic drugs and is considered to be prolactin mediated. The relevance for human risk of the finding of prolactin mediated endocrine tumors in rodents is unknown [see Warnings and Precautions (5.15)].

Mutagenesis — No evidence of genotoxic potential for olanzapine was found in the Ames reverse mutation test, in vivo micronucleus test in mice, the chromosomal aberration test in Chinese hamster ovary cells, unscheduled DNA synthesis test in rat hepatocytes, induction of forward mutation test in mouse lymphoma cells, or in vivo sister chromatid exchange test in bone marrow of Chinese hamsters.

Impairment of Fertility — In an oral fertility and reproductive performance study in rats, male mating performance, but not fertility, was impaired at a dose of 22.4 mg/kg/day and female fertility was decreased at a dose of 3 mg/kg/day (11 and 1.5 times the daily oral MRHD based on mg/m2 body surface area, respectively). Discontinuance of olanzapine treatment reversed the effects on male mating performance. In female rats, the precoital period was increased and the mating index reduced at 5 mg/kg/day (2.5 times the daily oral MRHD based on mg/m2 body surface area). Diestrous was prolonged and estrous delayed at 1.1 mg/kg/day (0.6 times the daily oral MRHD based on mg/m2 body surface area); therefore olanzapine may produce a delay in ovulation.

In animal studies with olanzapine, the principal hematologic findings were reversible peripheral cytopenias in individual dogs dosed at 10 mg/kg (17 times the daily oral MRHD based on mg/m2 body surface area), dose-related decreases in lymphocytes and neutrophils in mice, and lymphopenia in rats. A few dogs treated with 10 mg/kg developed reversible neutropenia and/or reversible hemolytic anemia between 1 and 10 months of treatment. Dose-related decreases in lymphocytes and neutrophils were seen in mice given doses of 10 mg/kg (equal to 2 times the daily oral MRHD based on mg/m2 body surface area) in studies of 3 months' duration. Nonspecific lymphopenia, consistent with decreased body weight gain, occurred in rats receiving 22.5 mg/kg (11 times the daily oral MRHD based on mg/m2 body surface area) for 3 months or 16 mg/kg (8 times the daily oral MRHD based on mg/m2 body surface area) for 6 or 12 months. No evidence of bone marrow cytotoxicity was found in any of the species examined. Bone marrows were normocellular or hypercellular, indicating that the reductions in circulating blood cells were probably due to peripheral (non-marrow) factors.

The efficacy of intramuscular olanzapine for injection for the treatment of agitation was established in 3 short-term (24 hours of IM treatment) placebo-controlled trials in agitated adult inpatients from 2 diagnostic groups: schizophrenia and bipolar I disorder (manic or mixed episodes). Each of the trials included a single active comparator treatment arm of either haloperidol injection (schizophrenia studies) or lorazepam injection (bipolar I mania study). Patients enrolled in the trials needed to be: (1) judged by the clinical investigators as clinically agitated and clinically appropriate candidates for treatment with intramuscular medication, and (2) exhibiting a level of agitation that met or exceeded a threshold score of ≥14 on the 5 items comprising the Positive and Negative Syndrome Scale (PANSS) Excited Component (i.e., poor impulse control, tension, hostility, uncooperativeness and excitement items) with at least 1 individual item score ≥4 using a 1-7 scoring system (1=absent, 4=moderate, 7=extreme). In the studies, the mean baseline PANSS Excited Component score was 18.4, with scores ranging from 13 to 32 (out of a maximum score of 35), thus suggesting predominantly moderate levels of agitation with some patients experiencing mild or severe levels of agitation. The primary efficacy measure used for assessing agitation signs and symptoms in these trials was the change from baseline in the PANSS Excited Component at 2 hours post-injection. Patients could receive up to 3 injections during the 24 hour IM treatment periods; however, patients could not receive the second injection until after the initial 2 hour period when the primary efficacy measure was assessed. The results of the trials follow:

(1) In a placebo-controlled trial in agitated inpatients meeting DSM-IV criteria for schizophrenia (n=270), 4 fixed intramuscular olanzapine for injection doses of 2.5 mg, 5 mg, 7.5 mg and 10 mg were evaluated. All doses were statistically superior to placebo on the PANSS Excited Component at 2 hours post-injection. However, the effect was larger and more consistent for the 3 highest doses. There were no significant pairwise differences for the 7.5 and 10 mg doses over the 5 mg dose.

(2) In a second placebo-controlled trial in agitated inpatients meeting DSM-IV criteria for schizophrenia (n=311), 1 fixed intramuscular olanzapine for injection dose of 10 mg was evaluated. Olanzapine for injection was statistically superior to placebo on the PANSS Excited Component at 2 hours post-injection.

(3) In a placebo-controlled trial in agitated inpatients meeting DSM-IV criteria for bipolar I disorder (and currently displaying an acute manic or mixed episode with or without psychotic features) (n=201), 1 fixed intramuscular olanzapine for injection dose of 10 mg was evaluated. Olanzapine for injection was statistically superior to placebo on the PANSS Excited Component at 2 hours post-injection.

Examination of population subsets (age, race, and gender) did not reveal any differential responsiveness on the basis of these subgroupings.

Olanzapine for Injection is available in:

NDC 0143-9199-01 – 10 mg single-dose vial (1s)

Store Olanzapine for Injection vials (before reconstitution) at controlled room temperature, 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. Reconstituted Olanzapine for Injection may be stored at controlled room temperature, 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature] for up to 1 hour if necessary. Discard any unused portion of reconstituted Olanzapine for Injection. The USP defines controlled room temperature as a temperature maintained thermostatically that encompasses the usual and customary working environment of 20° to 25°C (68° to 77°F); that results in a mean kinetic temperature calculated to be not more than 25°C; and that allows for excursions between 15° and 30°C (59° and 86°F) that are experienced in pharmacies, hospitals, and warehouses.

Protect Olanzapine for Injection from light, do not freeze.

Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking olanzapine as monotherapy. If you do not think you are getting better or have any concerns about your condition while taking olanzapine, call your doctor.

{ "type": "p", "children": [], "text": "Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking olanzapine as monotherapy. If you do not think you are getting better or have any concerns about your condition while taking olanzapine, call your doctor." }

Elderly Patients with Dementia-Related Psychosis: Increased Mortality and Cerebrovascular Adverse Events (CVAE), Including Stroke

{ "type": "p", "children": [], "text": "\nElderly Patients with Dementia-Related Psychosis: Increased Mortality and Cerebrovascular Adverse Events (CVAE), Including Stroke\n" }

Patients and caregivers should be advised that elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Patients and caregivers should be advised that elderly patients with dementia-related psychosis treated with olanzapine had a significantly higher incidence of cerebrovascular adverse events (e.g., stroke, transient ischemic attack) compared with placebo.

{ "type": "p", "children": [], "text": "Patients and caregivers should be advised that elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Patients and caregivers should be advised that elderly patients with dementia-related psychosis treated with olanzapine had a significantly higher incidence of cerebrovascular adverse events (e.g., stroke, transient ischemic attack) compared with placebo." }

Olanzapine is not approved for elderly patients with dementia-related psychosis [see Boxed Warning and Warnings and Precautions (5.1)].

{ "type": "p", "children": [], "text": "Olanzapine is not approved for elderly patients with dementia-related psychosis [see Boxed Warning and Warnings and Precautions (5.1)]." }

Neuroleptic Malignant Syndrome (NMS)

{ "type": "p", "children": [], "text": "\nNeuroleptic Malignant Syndrome (NMS)\n" }

Patients and caregivers should be counseled that a potentially fatal symptom complex sometimes referred to as NMS has been reported in association with administration of antipsychotic drugs, including olanzapine. Signs and symptoms of NMS include hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia) [see Warnings and Precautions (5.3)].

{ "type": "p", "children": [], "text": "Patients and caregivers should be counseled that a potentially fatal symptom complex sometimes referred to as NMS has been reported in association with administration of antipsychotic drugs, including olanzapine. Signs and symptoms of NMS include hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia) [see Warnings and Precautions (5.3)]." }

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)

{ "type": "p", "children": [], "text": "\nDrug Reaction with Eosinophilia and Systemic Symptoms (DRESS)\n" }

Patients should be advised to report to their health care provider at the earliest onset of any signs and symptoms that may be associated with Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) [see Warnings and Precautions (5.4)].

{ "type": "p", "children": [], "text": "Patients should be advised to report to their health care provider at the earliest onset of any signs and symptoms that may be associated with Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) [see Warnings and Precautions (5.4)]." }

Hyperglycemia and Diabetes Mellitus

{ "type": "p", "children": [], "text": "\nHyperglycemia and Diabetes Mellitus\n" }

Patients should be advised of the potential risk of hyperglycemia-related adverse reactions. Patients should be monitored regularly for worsening of glucose control. Patients who have diabetes should follow their doctor's instructions about how often to check their blood sugar while taking olanzapine [see Warnings and Precautions (5.5)].

{ "type": "p", "children": [], "text": "Patients should be advised of the potential risk of hyperglycemia-related adverse reactions. Patients should be monitored regularly for worsening of glucose control. Patients who have diabetes should follow their doctor's instructions about how often to check their blood sugar while taking olanzapine [see Warnings and Precautions (5.5)]." }

Dyslipidemia

{ "type": "p", "children": [], "text": "\nDyslipidemia\n" }

Patients should be counseled that dyslipidemia has occurred during treatment with olanzapine. Patients should have their lipid profile monitored regularly [see Warnings and Precautions (5.5)].

{ "type": "p", "children": [], "text": "Patients should be counseled that dyslipidemia has occurred during treatment with olanzapine. Patients should have their lipid profile monitored regularly [see Warnings and Precautions (5.5)]." }

Weight Gain

{ "type": "p", "children": [], "text": "\nWeight Gain\n" }

Patients should be counseled that weight gain has occurred during treatment with olanzapine. Patients should have their weight monitored regularly [see Warnings and Precautions (5.5)].

{ "type": "p", "children": [], "text": "Patients should be counseled that weight gain has occurred during treatment with olanzapine. Patients should have their weight monitored regularly [see Warnings and Precautions (5.5)]." }

Orthostatic Hypotension

{ "type": "p", "children": [], "text": "\nOrthostatic Hypotension\n" }

Patients should be advised of the risk of orthostatic hypotension, especially during the period of initial dose titration and in association with the use of concomitant drugs that may potentiate the orthostatic effect of olanzapine, e.g., diazepam or alcohol [see Warnings and Precautions (5.7) and Drug Interactions (7)]. Patients should be advised to change positions carefully to help prevent orthostatic hypotension, and to lie down if they feel dizzy or faint, until they feel better. Patients should be advised to call their doctor if they experience any of the following signs and symptoms associated with orthostatic hypotension: dizziness, fast or slow heartbeat, or fainting.

{ "type": "p", "children": [], "text": "Patients should be advised of the risk of orthostatic hypotension, especially during the period of initial dose titration and in association with the use of concomitant drugs that may potentiate the orthostatic effect of olanzapine, e.g., diazepam or alcohol [see Warnings and Precautions (5.7) and Drug Interactions (7)]. Patients should be advised to change positions carefully to help prevent orthostatic hypotension, and to lie down if they feel dizzy or faint, until they feel better. Patients should be advised to call their doctor if they experience any of the following signs and symptoms associated with orthostatic hypotension: dizziness, fast or slow heartbeat, or fainting." }

Potential for Cognitive and Motor Impairment

{ "type": "p", "children": [], "text": "\nPotential for Cognitive and Motor Impairment\n" }

Because olanzapine has the potential to impair judgment, thinking, or motor skills, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that olanzapine therapy does not affect them adversely [see Warnings and Precautions (5.12)].

{ "type": "p", "children": [], "text": "Because olanzapine has the potential to impair judgment, thinking, or motor skills, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that olanzapine therapy does not affect them adversely [see Warnings and Precautions (5.12)]." }

Body Temperature Regulation

{ "type": "p", "children": [], "text": "\nBody Temperature Regulation\n" }

Patients should be advised regarding appropriate care in avoiding overheating and dehydration. Patients should be advised to call their doctor right away if they become severely ill and have some or all of these symptoms of dehydration: sweating too much or not at all, dry mouth, feeling very hot, feeling thirsty, not able to produce urine [see Warnings and Precautions (5.13)].

{ "type": "p", "children": [], "text": "Patients should be advised regarding appropriate care in avoiding overheating and dehydration. Patients should be advised to call their doctor right away if they become severely ill and have some or all of these symptoms of dehydration: sweating too much or not at all, dry mouth, feeling very hot, feeling thirsty, not able to produce urine [see Warnings and Precautions (5.13)]." }

Concomitant Medication

{ "type": "p", "children": [], "text": "\nConcomitant Medication\n" }

Patients should be advised to inform their healthcare providers if they are taking, or plan to take, Symbyax. Patients should also be advised to inform their healthcare providers if they are taking, plan to take, or have stopped taking any prescription or over-the-counter drugs, including herbal supplements, since there is a potential for interactions [see Drug Interactions (7)].

{ "type": "p", "children": [], "text": "Patients should be advised to inform their healthcare providers if they are taking, or plan to take, Symbyax. Patients should also be advised to inform their healthcare providers if they are taking, plan to take, or have stopped taking any prescription or over-the-counter drugs, including herbal supplements, since there is a potential for interactions [see Drug Interactions (7)]." }

Alcohol

{ "type": "p", "children": [], "text": "\nAlcohol\n" }

Patients should be advised to avoid alcohol while taking olanzapine [see Drug Interactions (7)].

{ "type": "p", "children": [], "text": "Patients should be advised to avoid alcohol while taking olanzapine [see Drug Interactions (7)]." }

Use in Specific Populations

{ "type": "p", "children": [], "text": "\nUse in Specific Populations\n" }

Pregnancy — Advise women to notify their healthcare provider if they become pregnant or intend to become pregnant during treatment with olanzapine. Advise patients that olanzapine may cause extrapyramidal and/or withdrawal symptoms (agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder) in a neonate. Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to olanzapine during pregnancy [see Use in Specific Populations (8.1)].

{ "type": "p", "children": [], "text": "\nPregnancy — Advise women to notify their healthcare provider if they become pregnant or intend to become pregnant during treatment with olanzapine. Advise patients that olanzapine may cause extrapyramidal and/or withdrawal symptoms (agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder) in a neonate. Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to olanzapine during pregnancy [see Use in Specific Populations (8.1)]." }

Lactation — Advise breastfeeding women using olanzapine to monitor infants for excess sedation, irritability, poor feeding and extrapyramidal symptoms (tremors and abnormal muscle movements) and to seek medical care if they notice these signs [see Use in Specific Populations (8.3)].

{ "type": "p", "children": [], "text": "\nLactation — Advise breastfeeding women using olanzapine to monitor infants for excess sedation, irritability, poor feeding and extrapyramidal symptoms (tremors and abnormal muscle movements) and to seek medical care if they notice these signs [see Use in Specific Populations (8.3)]." }

Infertility — Advise females of reproductive potential that olanzapine may impair fertility due to an increase in serum prolactin levels. The effects on fertility are reversible [see Use in Specific Populations (8.3)].

{ "type": "p", "children": [], "text": "\nInfertility — Advise females of reproductive potential that olanzapine may impair fertility due to an increase in serum prolactin levels. The effects on fertility are reversible [see Use in Specific Populations (8.3)]." }

Pediatric Use — Compared to patients from adult clinical trials, adolescents were likely to gain more weight, experience increased sedation, and have greater increases in total cholesterol, triglycerides, LDL cholesterol, prolactin, and hepatic aminotransferase levels. Patients should be counseled about the potential long-term risks associated with olanzapine and advised that these risks may lead them to consider other drugs first. Safety and effectiveness of olanzapine in patients under 13 years of age have not been established [see Warnings and Precautions (5.5) and Use in Specific Populations (8.4)].

{ "type": "p", "children": [], "text": "\nPediatric Use — Compared to patients from adult clinical trials, adolescents were likely to gain more weight, experience increased sedation, and have greater increases in total cholesterol, triglycerides, LDL cholesterol, prolactin, and hepatic aminotransferase levels. Patients should be counseled about the potential long-term risks associated with olanzapine and advised that these risks may lead them to consider other drugs first. Safety and effectiveness of olanzapine in patients under 13 years of age have not been established [see Warnings and Precautions (5.5) and Use in Specific Populations (8.4)]." }

Need for Comprehensive Treatment Program in Pediatric Patients

{ "type": "p", "children": [], "text": "\nNeed for Comprehensive Treatment Program in Pediatric Patients\n" }

Olanzapine is indicated as an integral part of a total treatment program for pediatric patients with schizophrenia and bipolar disorder that may include other measures (psychological, educational, social) for patients with the disorder. Effectiveness and safety of olanzapine have not been established in pediatric patients less than 13 years of age. Atypical antipsychotics are not intended for use in the pediatric patient who exhibits symptoms secondary to environmental factors and/or other primary psychiatric disorders. Appropriate educational placement is essential and psychosocial intervention is often helpful. The decision to prescribe atypical antipsychotic medication will depend upon the healthcare provider's assessment of the chronicity and severity of the patient's symptoms.

{ "type": "p", "children": [], "text": "Olanzapine is indicated as an integral part of a total treatment program for pediatric patients with schizophrenia and bipolar disorder that may include other measures (psychological, educational, social) for patients with the disorder. Effectiveness and safety of olanzapine have not been established in pediatric patients less than 13 years of age. Atypical antipsychotics are not intended for use in the pediatric patient who exhibits symptoms secondary to environmental factors and/or other primary psychiatric disorders. Appropriate educational placement is essential and psychosocial intervention is often helpful. The decision to prescribe atypical antipsychotic medication will depend upon the healthcare provider's assessment of the chronicity and severity of the patient's symptoms." }

All Product/Brand names are the trademarks of their respective owners.

{ "type": "p", "children": [], "text": "All Product/Brand names are the trademarks of their respective owners." }

Manufactured by: Qilu Pharmaceutical Co., Ltd., Jinan, 250104, China

{ "type": "p", "children": [], "text": "Manufactured by: Qilu Pharmaceutical Co., Ltd., Jinan, 250104, China" }

Distributed by: Hikma Pharmaceuticals USA Inc., Berkeley Heights, NJ 07922

{ "type": "p", "children": [], "text": "Distributed by: Hikma Pharmaceuticals USA Inc., Berkeley Heights, NJ 07922" }

Code number：34040150111A

{ "type": "p", "children": [], "text": "Code number：34040150111A" }

NDC 0143-9199-01  

{ "type": "p", "children": [], "text": "\nNDC 0143-9199-01  \n" }

Olanzapine for Injection

{ "type": "p", "children": [], "text": "\nOlanzapine for Injection\n" }

10 mg/vial

{ "type": "p", "children": [], "text": "\n10 mg/vial\n" }

Sterile Single-Dose Vial

{ "type": "p", "children": [], "text": "Sterile Single-Dose Vial" }

For intramuscular use only.

{ "type": "p", "children": [], "text": "\nFor intramuscular use only.\n" }

1 Vial      Rx only

{ "type": "p", "children": [], "text": "\n1 Vial      Rx only\n" }

NDC 0143-9199-01

{ "type": "p", "children": [], "text": "NDC 0143-9199-01" }

Olanzapine for Injection

{ "type": "p", "children": [], "text": "Olanzapine for Injection" }

10 mg/vial

{ "type": "p", "children": [], "text": "10 mg/vial" }

Sterile Single-Dose Vial

{ "type": "p", "children": [], "text": "Sterile Single-Dose Vial" }

For intramuscular use only.

{ "type": "p", "children": [], "text": "For intramuscular use only." }

1 Vial Rx only

{ "type": "p", "children": [], "text": "1 Vial Rx only" }

Oral olanzapine is indicated for the treatment of schizophrenia. Efficacy was established in three clinical trials in adult patients with schizophrenia: two 6-week trials and one maintenance trial. In adolescent patients with schizophrenia (ages 13 to 17), efficacy was established in one 6-week trial  [see Clinical Studies ( 14.1)].   

When deciding among the alternative treatments available for adolescents, clinicians should consider the increased potential (in adolescents as compared with adults) for weight gain and dyslipidemia. Clinicians should consider the potential long-term risks  when prescribing to adolescents, and in many cases this may lead them to consider prescribing other drugs first in adolescents [see   Warnings and Precautions ( 5.5)]. 

Oral olanzapine is indicated for the acute treatment of manic or mixed episodes associated with bipolar I disorder and maintenance treatment of bipolar I disorder. Efficacy was established in three clinical trials in adult patients with manic or mixed episodes of bipolar I disorder: two 3- to 4-week trials and one monotherapy maintenance trial. In adolescent patients with manic or mixed episodes associated with bipolar I disorder (ages 13 to 17), efficacy was established in one 3-week trial [see Clinical Studies ( 14.2) ]. 

When deciding among the alternative treatments available for adolescents, clinicians should consider the increased potential (in adolescents as compared with adults) for weight gain and dyslipidemia. Clinicians should consider the potential long-term risks when prescribing to adolescents, and in many cases this may lead them  to consider prescribing other drugs first in adolescents [see Warnings and Precautions ( 5.5) ].

Oral olanzapine is indicated for the treatment of manic or mixed episodes associated with bipolar I disorder as an adjunct to lithium or valproate. Efficacy was established in two 6-week clinical trials in adults. The effectiveness of adjunctive therapy for longer-term use has not been systematically evaluated in controlled trials [see Clinical Studies (14.2)].

Pediatric schizophrenia and bipolar I disorder are serious mental disorders; however, diagnosis can be challenging. For pediatric schizophrenia, symptom profiles can be variable, and for bipolar I disorder, pediatric patients may have variable patterns of periodicity of manic or mixed symptoms. It is recommended that medication therapy for pediatric schizophrenia and bipolar I disorder be initiated only after a thorough diagnostic evaluation has been performed and careful consideration given to the risks associated with medication treatment. Medication treatment for both pediatric schizophrenia and bipolar I disorder should be part of a total treatment program that often includes psychological, educational and social interventions.

Oral olanzapine and fluoxetine in combination is indicated for the treatment of depressive episodes associated with bipolar I disorder, based on clinical studies. When using olanzapine and fluoxetine in combination, refer to the Clinical Studies section of the package insert for Symbyax.

Olanzapine monotheraphy is not indicated for the treatment of depressive episodes associated with bipolar I disorder.

Oral olanzapine and fluoxetine in combination is indicated for the treatment of treatment resistant depression (major depressive disorder in patients who do not respond to 2 separate trials of different antidepressants of adequate dose and duration in the current episode), based on clinical studies in adult patients. When using olanzapine and fluoxetine in combination, refer to the Clinical Studies section of the package insert for Symbyax.  

Olanzapine monotherapy is not indicated for the treatment of treatment resistant depression. 

Adults

Dose Selection— Oral olanzapine should be administered on a once-a-day schedule without regard to meals, generally beginning with 5 to 10 mg initially, with a target dose of 10 mg/day within several days. Further dosage adjustments, if indicated, should 4 generally occur at intervals of not less than 1 week, since steady state for olanzapine would not be achieved for approximately 1 week in the typical patient. When dosage adjustments are necessary, dose increments/decrements of 5 mg QD are recommended. 

Efficacy in schizophrenia was demonstrated in a dose range of 10 to 15 mg/day in clinical trials. However, doses above 10 mg/day were not demonstrated to be more efficacious than the 10 mg/day dose. An increase to a dose greater than the target dose of 10 mg/day (i.e., to a dose of 15 mg/day or greater) is recommended only after clinical assessment. Olanzapine is not indicated for use in doses above 20 mg/day. 

Dosing in Special Populations— The recommended starting dose is 5 mg in patients who are debilitated, who have a predisposition to hypotensive reactions, who otherwise exhibit a combination of factors that may result in slower metabolism of olanzapine (e.g., nonsmoking female patients ≥65 years of age), or who may be more pharmacodynamically sensitive to olanzapine [see Warnings and Precautions (5.14), Drug Interactions (7), and Clinical Pharmacology (12.3)]. When indicated, dose escalation should be performed with caution in these patients. 

Maintenance Treatment—The effectiveness of oral olanzapine, 10 mg/day to 20 mg/day, in maintaining treatment response in schizophrenic patients who had been stable on olanzapine for approximately 8 weeks and were then followed for relapse has been demonstrated in a placebo-controlled trial [see Clinical Studies (14.1)]. The healthcare provider who elects to use olanzapine for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient. 

Adolescents

Dose Selection— Oral olanzapine should be administered on a once-a-day schedule without regard to meals with a recommended starting dose of 2.5 or 5 mg, with a target dose of 10 mg/day. Efficacy in adolescents with schizophrenia was demonstrated based on a flexible dose range of 2.5 to 20 mg/day in clinical trials, with a mean modal dose of 12.5 mg/day (mean dose of 11.1 mg/day). When dosage adjustments are necessary, dose increments/decrements of 2.5 or 5 mg are recommended.  

The safety and effectiveness of doses above 20 mg/day have not been evaluated in clinical trials [see Clinical Studies ( 14.1) ].

Maintenance Treatment— The efficacy of olanzapine for the maintenance treatment of schizophrenia in the adolescent population has not been systematically evaluated; however, maintenance efficacy can be extrapolated from adult data along with comparisons of olanzapine pharmacokinetic parameters in adult and adolescent patients. Thus, it is generally recommended that responding patients be continued beyond the acute response, but at the lowest dose needed to maintain remission. Patients should be periodically reassessed to determine the need for maintenance treatment.

Adults

Dose Selection for Monotherapy— Oral olanzapine should be administered on a once-a-day schedule without regard to meals, generally beginning with 10 or 15 mg. Dosage adjustments, if indicated, should generally occur at intervals of not less than 24 hours, reflecting the procedures in the placebo-controlled trials. When dosage adjustments are necessary, dose increments/decrements of 5 mg QD are recommended. 

Short-term (3 to 4 weeks) antimanic efficacy was demonstrated in a dose range of 5 mg to 20 mg/day in clinical trials. The safety of doses above 20 mg/day has not been evaluated in clinical trials [see Clinical Studies (14.2)]. 

Maintenance Monotherapy— The benefit of maintaining bipolar I patients on monotherapy with oral olanzapine at a dose of 5 to 20 mg/day, after achieving a responder status for an average duration of 2 weeks, was demonstrated in a controlled trial [see Clinical Studies ( 14.2) ]. The healthcare provider who elects to use olanzapine for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient. 

Dose Selection for Adjunctive Treatment — When administered as adjunctive treatment to lithium or valproate, oral olanzapine dosing should generally begin with 10 mg once-a-day without regard to meals. 

Antimanic efficacy was demonstrated in a dose range of 5 mg to 20 mg/day in clinical trials [see Clinical Studies ( 14.2) ]. The safety of doses above 20 mg/day has not been evaluated in clinical trials. 

Adolescents

Dose Selection— Oral olanzapine should be administered on a once-a-day schedule without regard to meals with a recommended starting dose of 2.5 or 5 mg, with a target dose of 10 mg/day. Efficacy in adolescents with bipolar I disorder (manic or mixed episodes) was demonstrated based on a flexible dose range of 2.5 to 20 mg/day in clinical trials, with a mean modal dose of 10.7 mg/day (mean dose of 8.9 mg/day). When dosage adjustments are necessary, dose increments/decrements of 2.5 or 5 mg are recommended.  

The safety and effectiveness of doses above 20 mg/day have not been evaluated in clinical trials [see Clinical Studies ( 14.2) ].  

Maintenance Treatment— The efficacy of olanzapine for the maintenance treatment of bipolar I disorder in the adolescent population has not been evaluated; however, maintenance efficacy can be extrapolated from adult data along with comparisons of olanzapine pharmacokinetic parameters in adult and adolescent patients. Thus, it is generally recommended that responding patients be continued beyond the acute response, but at the lowest dose needed to maintain remission. Patients should be periodically reassessed to determine the need for maintenance treatment.

When using olanzapine and fluoxetine in combination, also refer to the Clinical Studies section of the package insert for Symbyax. 

Adults

Oral olanzapine should be administered in combination with fluoxetine once daily in the evening, without regard to meals, generally beginning with 5 mg of oral olanzapine and 20 mg of fluoxetine. Dosage adjustments, if indicated, can be made according to efficacy and tolerability within dose ranges of oral olanzapine 5 to 12.5 mg and fluoxetine 20 to 50 mg. Antidepressant efficacy was demonstrated with olanzapine and fluoxetine in combination in adult patients with a dose range of olanzapine 6 to 12 mg and fluoxetine 25 to 50 mg.  Safety of co-administration of doses above 18 mg olanzapine with 75 mg fluoxetine has not been evaluated in clinical studies.

Children and Adolescents (10 to 17 years of age)

Oral olanzapine should be administered in combination with fluoxetine once daily in the evening, without regard to meals, generally beginning with 2.5 mg of oral olanzapine and 20 mg of fluoxetine. Dosage adjustments, if indicated, can be made according to efficacy and tolerability. Safety of co-administration of doses above 12 mg olanzapine with 50 mg fluoxetine has not been evaluated in pediatric clinical studies. 

Safety and efficacy of olanzapine and fluoxetine in combination was determined in clinical trials supporting approval of Symbyax (fixed dose combination of olanzapine and fluoxetine). Symbyax is dosed between 3 mg/25 mg (olanzapine/fluoxetine) per day and 12 mg/50 mg (olanzapine/fluoxetine) per day. The following table demonstrates the appropriate individual component doses of olanzapine and fluoxetine versus Symbyax. Dosage adjustments, if indicated, should be made with the individual components according to efficacy and tolerability. 

Table 1: Approximate Dose Correspondence Between Symbyax aand the Combination of Olanzapine and Fluoxetine  

<div class="scrollingtable"><table border="1" cellpadding="4" cellspacing="0"> <tbody class="Headless"> <tr class="First"> <td valign="top"> </td><td colspan="2" valign="top"><span class="Bold">Use in Combination</span></td> </tr> <tr> <td><span class="Bold">For Symbyax</span><span class="Bold">(mg/day)</span></td><td><span class="Bold">Olanzapine</span><span class="Bold">(mg/day)</span></td><td><span class="Bold">Fluoxetine</span><span class="Bold">(mg/day)</span></td> </tr> <tr> <td>3 mg olanzapine/25 mg fluoxetine</td><td>2.5</td><td>20</td> </tr> <tr> <td>6 mg olanzapine/25 mg fluoxetine</td><td>5</td><td>20</td> </tr> <tr> <td>12 mg olanzapine/25 mg fluoxetine</td><td>10+2.5</td><td>20</td> </tr> <tr> <td>6 mg olanzapine/50 mg fluoxetine</td><td>5</td><td>40+10</td> </tr> <tr class="Last"> <td>12 mg olanzapine/50 mg fluoxetine</td><td>10+2.5</td><td>40+10</td> </tr> </tbody> </table></div>

aSymbyax (olanzapine/fluoxetine HCl) is a fixed-dose combination of olanzapine and fluoxetine.  

While there is no body of evidence to answer the question of how long a patient treated with olanzapine and fluoxetine in combination should remain on it, it is generally accepted that bipolar I disorder, including the depressive episodes associated with bipolar I disorder, is a chronic illness requiring chronic treatment. The healthcare provider should periodically reexamine the need for continued pharmacotherapy. 

Olanzapine monotherapy is not indicated for the treatment of depressive episodes associated with bipolar I disorder.

When using olanzapine and fluoxetine in combination, also refer to the Clinical Studies section of the package insert for Symbyax.  

Oral olanzapine should be administered in combination with fluoxetine once daily in the evening, without regard to meals, generally beginning with 5 mg of oral olanzapine and 20 mg of fluoxetine. Dosage adjustments, if indicated, can be made according to efficacy and tolerability within dose ranges of oral olanzapine 5 to 20 mg and fluoxetine 20 to 50 mg. Antidepressant efficacy was demonstrated with olanzapine and fluoxetine in combination in adult patients with a dose range of olanzapine 6 to 18 mg and fluoxetine 25 to 50 mg.  

Safety and efficacy of olanzapine in combination with fluoxetine was determined in clinical trials supporting approval of Symbyax (fixed dose combination of olanzapine and fluoxetine). Symbyax is dosed between 3 mg/25 mg (olanzapine/fluoxetine) per day and 12 mg/50 mg (olanzapine/fluoxetine) per day. Table 1 above demonstrates the appropriate individual component doses of olanzapine and fluoxetine versus Symbyax. Dosage adjustments, if indicated, should be made with the individual components according to efficacy and tolerability.  

While there is no body of evidence to answer the question of how long a patient treated with olanzapine and fluoxetine in combination should remain on it, it is generally accepted that treatment resistant depression (major depressive disorder in adult patients who do not respond to 2 separate trials of different antidepressants of adequate dose and duration in the current episode) is a chronic illness requiring chronic treatment. The healthcare provider should periodically reexamine the need for continued pharmacotherapy.  

Safety of co-administration of doses above 18 mg olanzapine with 75 mg fluoxetine has not been evaluated in clinical studies.  

Olanzapine monotherapy is not indicated for treatment of treatment resistant depression (major depressive disorder in patients who do not respond to 2 antidepressants of adequate dose and duration in the current episode).  

The starting dose of oral olanzapine 2.5 to 5 mg with fluoxetine 20 mg should be used for patients with a predisposition to hypotensive reactions, patients with hepatic impairment, or patients who exhibit a combination of factors that may slow the metabolism of olanzapine or fluoxetine in combination (female gender, geriatric age, nonsmoking status), or those patients who may be pharmacodynamically sensitive to olanzapine. Dosing modification may be necessary in patients who exhibit a combination of factors that may slow metabolism. When indicated, dose escalation should be performed with caution in these patients. Olanzapine and fluoxetine in combination have not been systematically studied in patients over 65 years of age or in patients under < 10 years of age. [see Warnings and Precautions (5.14), Drug Interactions ( 7), and Clinical Pharmacology ( 12.3)].

Olanzapine Tablets USP, 20 mg are white, film coated, oval, biconvex tablets with “R”

{ "type": "p", "children": [], "text": "Olanzapine Tablets USP, 20 mg are white, film coated, oval, biconvex tablets with “R”" }

20

{ "type": "p", "children": [], "text": "20" }

debossed on one side and “0168” on other side.

{ "type": "p", "children": [], "text": "debossed on one side and “0168” on other side." }

{ "type": "ul", "children": [ "None with olanzapine monotherapy.", "When using olanzapine and fluoxetine in combination, also refer to the Contraindications section of the package insert for Symbyax.", "For specific information about the contraindications of lithium or valproate, refer to the Contraindications section of the package inserts for these other products." ], "text": "" }

Elderly patients with dementiarelated psychosis treated with antipsychotic drugs are at an increased risk of death. Olanzapine is not approved for the treatment of patients with dementia-related psychosis. [see Boxed Warning, Use in Specific Populations (8.5), and Patient Counseling Information (17)].

In placebo-controlled clinical trials of elderly patients with dementia-related psychosis, the incidence of death in olanzapine-treated patients was significantly greater than placebo-treated patients (3.5% vs 1.5%, respectively).

Cerebrovascular adverse events (e.g., stroke, transient ischemic attack), including fatalities, were reported in patients in trials of olanzapine in elderly patients with dementia-related psychosis. In placebo-controlled trials, there was a significantly higher incidence of cerebrovascular adverse events in patients treated with olanzapine compared to patients treated with placebo. Olanzapine is not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning and Patient Counseling Information (17)].

The possibility of a suicide attempt is inherent in schizophrenia and in bipolar I disorder, and close supervision of high-risk patients should accompany drug therapy. Prescriptions for olanzapine should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose.

A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with administration of antipsychotic drugs, including olanzapine. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis and cardiac dysrhythmia). Additional signs may include elevated creatinine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure. 

The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a diagnosis, it is important to exclude cases where the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever, and primary central nervous system pathology. 

The management of NMS should include: 1) immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy; 2) intensive symptomatic treatment and medical monitoring; and 3) treatment of any concomitant serious medical problems for which specific treatments are available. There is no general agreement about specific pharmacological treatment regimens for NMS. 

If a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of drug therapy should be carefully considered. The patient should be carefully monitored, since recurrences of NMS have been reported. [see Patient Counseling Information (17)].

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported with olanzapine exposure. DRESS may present with a cutaneous reaction (such as rash or exfoliative dermatitis), eosinophilia, fever, and/or lymphadenopathy with systemic complications such as hepatitis, nephritis, pneumonitis, myocarditis, and/or pericarditis. DRESS is sometimes fatal. Discontinue olanzapine if DRESS is suspected [see Patient Counseling Information ( 17.4)].

Atypical antipsychotic drugs have been associated with metabolic changes including hyperglycemia, dyslipidemia, and weight gain. Metabolic changes may be associated with increased cardiovascular/cerebrovascular risk. Olanzapine’s specific metabolic profile is presented below. 

Hyperglycemia and Diabetes Mellitus

Healthcare providers should consider the risks and benefits when prescribing olanzapine to patients with an established diagnosis of diabetes mellitus, or having borderline increased blood glucose level (fasting 100 to 126 mg/dL, nonfasting 140 to 200 mg/dL). Patients taking olanzapine should be monitored regularly for worsening of glucose control. Patients starting treatment with olanzapine should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics should undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of anti-diabetic treatment despite discontinuation of the suspect drug. [see Patient Counseling Information ( 17) ].

Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics including olanzapine. Assessment of the relationship between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population. Epidemiological studies suggest an increased risk of treatment-emergent hyperglycemia-related adverse reactions in patients treated with the atypical antipsychotics. While relative risk estimates are inconsistent, the association between atypical antipsychotics and increases in glucose levels appears to fall on a continuum and olanzapine appears to have a greater association than some other atypical antipsychotics.

Mean increases in blood glucose have been observed in patients treated (median exposure of 9.2 months) with olanzapine in phase 1 of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE). The mean increase of serum glucose (fasting and nonfasting samples) from baseline to the average of the 2 highest serum concentrations was 15 mg/dL.

In a study of healthy volunteers, subjects who received olanzapine (N=22) for 3 weeks had a mean increase compared to baseline in fasting blood glucose of 2.3 mg/dL. Placebo-treated subjects (N=19) had a mean increase in fasting blood glucose compared to baseline of 0.34 mg/dL.

Olanzapine Monotherapy in Adults — In an analysis of 5 placebo-controlled adult olanzapine monotherapy studies with a median treatment duration of approximately 3 weeks, olanzapine was associated with a greater mean change in fasting glucose levels compared to placebo (2.76 mg/dL versus 0.17 mg/dL). The difference in mean changes between olanzapine and placebo was greater in patients with evidence of glucose dysregulation at baseline (patients diagnosed with diabetes mellitus or related adverse reactions, patients treated with anti-diabetic agents, patients with a baseline random glucose level ≥200 mg/dL, and/or a baseline fasting glucose level ≥126 mg/dL). Olanzapine-treated patients had a greater mean HbA1c increase from baseline of 0.04% (median exposure 21 days), compared to a mean HbA1c decrease of 0.06% in placebo-treated subjects (median exposure 17 days).

In an analysis of 8 placebo-controlled studies (median treatment exposure 4 to 5 weeks), 6.1% of olanzapine-treated subjects (N=855) had treatment-emergent glycosuria compared to 2.8% of placebo-treated subjects (N=599). Table 2 shows short-term and long-term changes in fasting glucose levels from adult olanzapine monotherapy studies.

Table 2: Changes in Fasting Glucose Levels from Adult Olanzapine Monotherapy Studies

<div class="scrollingtable"><table border="1" cellpadding="3" width="85%"> <tbody class="Headless"> <tr class="First"> <td colspan="3"> </td><td colspan="2"><span class="Bold">Up to 12 weeks exposure</span><span class="Bold"> </span></td><td colspan="2"><span class="Bold">At least 48 weeks exposure</span></td> </tr> <tr> <td><span class="Bold">Laboratory Analyte</span><span class="Bold"> </span></td><td><span class="Bold">Category Change (at least once) from Baseline</span></td><td><span class="Bold">Treatment Arm</span><span class="Bold"> </span></td><td><span class="Bold">N</span><span class="Bold"> </span></td><td><span class="Bold">Patients</span><span class="Bold"> </span></td><td><span class="Bold">N</span><span class="Bold"> </span></td><td><span class="Bold">Patients</span><span class="Bold"> </span></td> </tr> <tr> <td rowspan="4">  Fasting Glucose </td><td rowspan="2">Normal to High(&lt;100 mg/dL to ≥126 mg/dL)</td><td>Olanzapine </td><td>543</td><td>2.2%</td><td>345</td><td>12.8%</td> </tr> <tr> <td>Placebo </td><td>293</td><td>3.4%</td><td>NA <span class="Sup">a</span>  </td><td>NA <span class="Sup">a</span>  </td> </tr> <tr> <td rowspan="2">Borderline to High(≥100 mg/dL and &lt;126 mg/dL to ≥126 mg/dL) </td><td>Olanzapine </td><td>178</td><td>17.4%</td><td>127</td><td>26%</td> </tr> <tr class="Last"> <td>Placebo</td><td>96</td><td>11.5%</td><td>NA <span class="Sup">a</span>  </td><td>NA <span class="Sup">a</span></td> </tr> </tbody> </table></div>

aNot Applicable. 

The mean change in fasting glucose for patients exposed at least 48 weeks was 4.2 mg/dL (N=487). In analyses of patients who completed 9 to 12 months of olanzapine therapy, mean change in fasting and nonfasting glucose levels continued to increase over time.

Olanzapine Monotherapy in Adolescents — The safety and efficacy of olanzapine have not been established in patients under the age of 13 years. In an analysis of 3 placebo-controlled olanzapine monotherapy studies of adolescent patients, including those with schizophrenia (6 weeks) or bipolar I disorder (manic or mixed episodes) (3 weeks), olanzapine was associated with a greater mean change from baseline in fasting glucose levels compared to placebo (2.68 mg/dL versus -2.59 mg/dL). The mean change in fasting glucose for adolescents exposed at least 24 weeks was 3.1 mg/dL (N=121). Table 3 shows short-term and long-term changes in fasting blood glucose from adolescent olanzapine monotherapy studies.

Table 3: Changes in Fasting Glucose Levels from Adolescent Olanzapine Monotherapy Studies

<div class="scrollingtable"><table border="1" cellpadding="3" width="85%"> <tbody class="Headless"> <tr class="First"> <td colspan="3"> </td><td colspan="2"><span class="Bold">Up to 12 weeks exposure</span><span class="Bold"> </span></td><td colspan="2"><span class="Bold">At least 24 weeks exposure</span></td> </tr> <tr> <td><span class="Bold">Laboratory Analyte</span><span class="Bold"> </span></td><td><span class="Bold">Category Change (at least once) from Baseline</span></td><td><span class="Bold">Treatment Arm</span><span class="Bold"> </span></td><td><span class="Bold">N</span><span class="Bold"> </span></td><td><span class="Bold">Patients</span><span class="Bold"> </span></td><td><span class="Bold">N</span><span class="Bold"> </span></td><td><span class="Bold">Patients</span><span class="Bold"> </span></td> </tr> <tr> <td rowspan="4">  Fasting Glucose </td><td rowspan="2">Normal to High(&lt;100 mg/dL to ≥126 mg/dL)</td><td>Olanzapine </td><td>124</td><td>0%</td><td>108</td><td>0.9%</td> </tr> <tr> <td>Placebo </td><td>53</td><td>1.9%</td><td>NA <span class="Sup">a</span>  </td><td>NA <span class="Sup">a</span>  </td> </tr> <tr> <td rowspan="2">Borderline to High(≥100 mg/dL and &lt;126 mg/dL to ≥126 mg/dL) </td><td>Olanzapine </td><td>14</td><td>14.3%</td><td>13</td><td>23.1%</td> </tr> <tr class="Last"> <td>Placebo</td><td>13</td><td>0%</td><td>NA <span class="Sup">a</span>  </td><td>NA <span class="Sup">a</span></td> </tr> </tbody> </table></div>

aNot Applicable. 

Dyslipidemia

Undesirable alterations in lipids have been observed with olanzapine use. Clinical monitoring, including baseline and periodic follow-up lipid evaluations in patients using olanzapine, is recommended. [see Patient Counseling Information ( 17) ].

Clinically significant, and sometimes very high (>500 mg/dL), elevations in triglyceride levels have been observed with olanzapine use. Modest mean increases in total cholesterol have also been seen with olanzapine use.

Olanzapine Monotherapy in Adults — In an analysis of 5 placebo-controlled olanzapine monotherapy studies with treatment duration up to 12 weeks, olanzapine-treated patients had increases from baseline in mean fasting total cholesterol, LDL cholesterol, and triglycerides of 5.3 mg/dL, 3 mg/dL, and 20.8 mg/dL respectively compared to decreases from baseline in mean fasting total cholesterol, LDL cholesterol, and triglycerides of 6.1 mg/dL, 4.3 mg/dL, and 10.7 mg/dL for placebo-treated patients. For fasting HDL cholesterol, no clinically meaningful differences were observed between olanzapine-treated patients and placebo-treated patients. Mean increases in fasting lipid values (total cholesterol, LDL cholesterol, and triglycerides) were greater in patients without evidence of lipid dysregulation at baseline, where lipid dysregulation was defined as patients diagnosed with dyslipidemia or related adverse reactions, patients treated with lipid lowering agents, or patients with high baseline lipid levels.

In long-term studies (at least 48 weeks), patients had increases from baseline in mean fasting total cholesterol, LDL cholesterol, and triglycerides of 5.6 mg/dL, 2.5 mg/dL, and 18.7 mg/dL, respectively, and a mean decrease in fasting HDL cholesterol of 0.16 mg/dL. In an analysis of patients who completed 12 months of therapy, the mean nonfasting total cholesterol did not increase further after approximately 4 to 6 months.

The proportion of patients who had changes (at least once) in total cholesterol, LDL cholesterol or triglycerides from normal or borderline to high, or changes in HDL cholesterol from normal or borderline to low, was greater in long-term studies (at least 48 weeks) as compared with short-term studies. Table 4 shows categorical changes in fasting lipids values.

Table 4: Changes in Fasting Lipids Values from Adult Olanzapine Monotherapy Studies

<div class="scrollingtable"><table border="1" cellpadding="3" width="85%"> <tbody class="Headless"> <tr class="First"> <td colspan="3"> </td><td colspan="2"><span class="Bold">Up to 12 weeks exposure</span><span class="Bold"> </span></td><td colspan="2"><span class="Bold">At least 48 weeks exposure</span></td> </tr> <tr> <td><span class="Bold">Laboratory Analyte</span><span class="Bold"> </span></td><td><span class="Bold">Category Change (at least once) from Baseline</span></td><td><span class="Bold">Treatment Arm</span><span class="Bold"> </span></td><td><span class="Bold">N</span><span class="Bold"> </span></td><td><span class="Bold">Patients</span><span class="Bold"> </span></td><td><span class="Bold">N</span><span class="Bold"> </span></td><td><span class="Bold">Patients</span><span class="Bold"> </span></td> </tr> <tr> <td rowspan="6">     Fasting Triglycerides   </td><td rowspan="2"> Increase by ≥50 mg/dL </td><td>Olanzapine </td><td>745</td><td>39.6%</td><td>487</td><td>61.4%</td> </tr> <tr> <td>Placebo </td><td>402</td><td>26.1%</td><td>NA <span class="Sup">a</span>  </td><td>NA <span class="Sup">a</span>  </td> </tr> <tr> <td rowspan="2">Normal to High (&lt;150 mg/dL to ≥200 mg/dL) </td><td>Olanzapine </td><td>457</td><td>9.2%</td><td>293</td><td>32.4%</td> </tr> <tr> <td>Placebo</td><td>251</td><td>4.4%</td><td>NA <span class="Sup">a</span>  </td><td>NA <span class="Sup">a</span></td> </tr> <tr> <td rowspan="2">Borderline to High (≥150 mg/dL and &lt;200 mg/dL to ≥200 mg/dL)</td><td>Olanzapine </td><td>135</td><td>39.3%</td><td>75</td><td>70.7%</td> </tr> <tr> <td>Placebo</td><td>65</td><td>20%</td><td>NA <span class="Sup">a</span>  </td><td>NA <span class="Sup">a</span>  </td> </tr> <tr> <td colspan="7"> </td> </tr> <tr> <td rowspan="6">  Fasting Total Cholesterol  </td><td rowspan="2">Increase by ≥40 mg/dL </td><td>Olanzapine </td><td>745</td><td>21.6%</td><td>489</td><td>32.9%</td> </tr> <tr> <td>Placebo</td><td>402</td><td>9.5%</td><td>NA <span class="Sup">a</span>  </td><td>NA <span class="Sup">a</span>  </td> </tr> <tr> <td rowspan="2">Normal to High(&lt;200 mg/dL to ≥240 mg/dL) </td><td>Olanzapine </td><td>392</td><td>2.8%</td><td>283</td><td>14.8%</td> </tr> <tr> <td>Placebo</td><td>207</td><td>2.4%</td><td>NA <span class="Sup">a</span>  </td><td>NA <span class="Sup">a</span></td> </tr> <tr> <td rowspan="2">Borderline to High (≥200 mg/dL and &lt;240 mg/dL to ≥240 mg/dL)</td><td>Olanzapine </td><td>222</td><td>23%</td><td>125</td><td>55.2%</td> </tr> <tr> <td>Placebo</td><td>112</td><td>12.5%</td><td>NA <span class="Sup">a</span>  </td><td>NA <span class="Sup">a</span>  </td> </tr> <tr> <td colspan="7"> </td> </tr> <tr> <td rowspan="6">   Fasting LDL Cholesterol </td><td rowspan="2">Increase by ≥30 mg/dL </td><td>Olanzapine </td><td>536</td><td>23.7%</td><td>483</td><td>39.8%</td> </tr> <tr> <td>Placebo</td><td>304</td><td>14.1%</td><td>NA <span class="Sup">a</span>  </td><td>NA <span class="Sup">a</span>  </td> </tr> <tr> <td rowspan="2">Normal to High (&lt;100 mg/dL to ≥160 mg/dL) </td><td>Olanzapine </td><td>154</td><td>0%</td><td>123</td><td>7.3%</td> </tr> <tr> <td>Placebo</td><td>82</td><td>1.2%</td><td>NA <span class="Sup">a</span>  </td><td>NA <span class="Sup">a</span></td> </tr> <tr> <td rowspan="2">Borderline to High (≥100 mg/dL and &lt;160 mg/dL to ≥160 mg/dL)</td><td>Olanzapine </td><td>302</td><td>10.6%</td><td>284</td><td>31%</td> </tr> <tr class="Last"> <td>Placebo</td><td>173</td><td>8.1%</td><td>NA <span class="Sup">a</span>  </td><td>NA <span class="Sup">a</span>  </td> </tr> </tbody> </table></div>

aNot Applicable. 

In phase 1 of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE), over a median exposure of 9.2 months, the mean increase in triglycerides in patients taking olanzapine was 40.5 mg/dL. In phase 1 of CATIE, the mean increase in total cholesterol was 9.4 mg/dL. 

Olanzapine Monotherapy in Adolescents — The safety and efficacy of olanzapine have not been established in patients under the age of 13 years. In an analysis of 3 placebo-controlled olanzapine monotherapy studies of adolescents, including those with schizophrenia (6 weeks) or bipolar I disorder (manic or mixed episodes) (3 weeks), olanzapine-treated adolescents had increases from baseline in mean fasting total cholesterol, LDL cholesterol, and triglycerides of 12.9 mg/dL, 6.5 mg/dL, and 28.4 mg/dL, respectively, compared to increases from baseline in mean fasting total cholesterol and LDL cholesterol of 1.3 mg/dL and 1 mg/dL, and a decrease in triglycerides of 1.1 mg/dL for placebo-treated adolescents. For fasting HDL cholesterol, no clinically meaningful differences were observed between olanzapine-treated adolescents and placebo-treated adolescents.

In long-term studies (at least 24 weeks), adolescents had increases from baseline in mean fasting total cholesterol, LDL cholesterol, and triglycerides of 5.5 mg/dL, 5.4 mg/dL, and 20.5 mg/dL, respectively, and a mean decrease in fasting HDL cholesterol of 4.5 mg/dL. Table 5 shows categorical changes in fasting lipids values in adolescents.

Table 5: Changes in Fasting Lipids Values from Adolescent Olanzapine Monotherapy Studies

<div class="scrollingtable"><table border="1" cellpadding="3" width="85%"> <tbody class="Headless"> <tr class="First"> <td colspan="3"> </td><td colspan="2"><span class="Bold">Up to 6 weeks exposure</span><span class="Bold"> </span></td><td colspan="2"><span class="Bold">At least 24 weeks exposure</span></td> </tr> <tr> <td><span class="Bold">Laboratory Analyte</span><span class="Bold"> </span></td><td><span class="Bold">Category Change (at least once) from Baseline</span></td><td><span class="Bold">Treatment Arm</span><span class="Bold"> </span></td><td><span class="Bold">N</span><span class="Bold"> </span></td><td><span class="Bold">Patients</span><span class="Bold"> </span></td><td><span class="Bold">N</span><span class="Bold"> </span></td><td><span class="Bold">Patients</span><span class="Bold"> </span></td> </tr> <tr> <td rowspan="6">     Fasting Triglycerides   </td><td rowspan="2"> Increase by ≥50 mg/dL </td><td>Olanzapine </td><td>138</td><td>37%</td><td>122</td><td>45.9%</td> </tr> <tr> <td>Placebo </td><td>66</td><td>15.2%</td><td>NA <span class="Sup">a</span>  </td><td>NA <span class="Sup">a</span>  </td> </tr> <tr> <td rowspan="2">Normal to High (&lt;90 mg/dL to &gt;130 mg/dL) </td><td>Olanzapine </td><td>67</td><td>26.9%</td><td>66</td><td>36.4%</td> </tr> <tr> <td>Placebo</td><td>28</td><td>10.7%</td><td>NA <span class="Sup">a</span>  </td><td>NA <span class="Sup">a</span></td> </tr> <tr> <td rowspan="2">Borderline to High (≥90 mg/dL and ≤130 mg/dL to &gt;130 mg/dL) </td><td>Olanzapine </td><td>37</td><td>59.5%</td><td>31</td><td>64.5%</td> </tr> <tr> <td>Placebo</td><td>17</td><td>35.3%</td><td>NA <span class="Sup">a</span>  </td><td>NA <span class="Sup">a</span>  </td> </tr> <tr> <td colspan="7"> </td> </tr> <tr> <td rowspan="6">  Fasting Total Cholesterol  </td><td rowspan="2">Increase by ≥40 mg/dL </td><td>Olanzapine </td><td>138</td><td>14.5%</td><td>122</td><td>14.8%</td> </tr> <tr> <td>Placebo</td><td>66</td><td>4.5%</td><td>NA <span class="Sup">a</span>  </td><td>NA <span class="Sup">a</span>  </td> </tr> <tr> <td rowspan="2">Normal to High(&lt;170 mg/dL to ≥200 mg/dL) </td><td>Olanzapine </td><td>87</td><td>6.9%</td><td>78</td><td>7.7%</td> </tr> <tr> <td>Placebo</td><td>43</td><td>2.3%</td><td>NA <span class="Sup">a</span>  </td><td>NA <span class="Sup">a</span></td> </tr> <tr> <td rowspan="2">Borderline to High (≥170 mg/dL and &lt;200 mg/dL to ≥200 mg/dL) </td><td>Olanzapine </td><td>36</td><td>38.9%</td><td>33</td><td>57.6%</td> </tr> <tr> <td>Placebo</td><td>13</td><td>7.7%</td><td>NA <span class="Sup">a</span>  </td><td>NA <span class="Sup">a</span>  </td> </tr> <tr> <td colspan="7"> </td> </tr> <tr> <td rowspan="6">   Fasting LDL Cholesterol </td><td rowspan="2">Increase by ≥30 mg/dL  </td><td>Olanzapine </td><td>137</td><td>17.5%</td><td>121</td><td>22.3%</td> </tr> <tr> <td>Placebo</td><td>63</td><td>11.1%</td><td>NA <span class="Sup">a</span>  </td><td>NA <span class="Sup">a</span>  </td> </tr> <tr> <td rowspan="2">Normal to High (&lt;110 mg/dL to ≥130 mg/dL) </td><td>Olanzapine </td><td>98</td><td>5.1%</td><td>92</td><td>10.9%</td> </tr> <tr> <td>Placebo</td><td>44</td><td>4.5%</td><td>NA <span class="Sup">a</span>  </td><td>NA <span class="Sup">a</span></td> </tr> <tr> <td rowspan="2">Borderline to High (≥110 mg/dL and &lt;130 mg/dL to ≥130 mg/dL) </td><td>Olanzapine </td><td>29</td><td>48.3%</td><td>21</td><td>47.6%</td> </tr> <tr class="Last"> <td>Placebo</td><td>9</td><td>0%</td><td>NA <span class="Sup">a</span>  </td><td>NA <span class="Sup">a</span>  </td> </tr> </tbody> </table></div>

aNot Applicable. 

Weight Gain

Potential consequences of weight gain should be considered prior to starting olanzapine. Patients receiving olanzapine should receive regular monitoring of weight. [see Patient Counseling Information ( 17) ]

Olanzapine Monotherapy in Adults — In an analysis of 13 placebo-controlled olanzapine monotherapy studies, olanzapine-treated patients gained an average of 2.6 kg (5.7 lb), compared to an average 0.3 kg (0.6 lb) weight loss in placebo-treated patients with a median exposure of 6 weeks; 22.2% of olanzapine-treated patients gained at least 7% of their baseline weight, compared to 3% of placebo-treated patients, with a median exposure to event of 8 weeks; 4.2% of olanzapine-treated patients gained at least 15% of their baseline weight, compared to 0.3% of placebo-treated patients, with a median exposure to event of 12 weeks. Clinically significant weight gain was observed across all baseline Body Mass Index (BMI) categories. Discontinuation due to weight gain occurred in 0.2% of olanzapine-treated patients and in 0% of placebo-treated patients.

In long-term studies (at least 48 weeks), the mean weight gain was 5.6 kg (12.3 lb) (median exposure of 573 days, N=2021). The percentages of patients who gained at least 7%, 15%, or 25% of their baseline body weight with long-term exposure were 64%, 32%, and 12%, respectively. Discontinuation due to weight gain occurred in 0.4% of olanzapine-treated patients following at least 48 weeks of exposure.

Table 6 includes data on adult weight gain with olanzapine pooled from 86 clinical trials. The data in each column represent data for those patients who completed treatment periods of the durations specified. 

Table 6: Weight Gain with Olanzapine Use in Adults

<div class="scrollingtable"><table border="1" cellpadding="3" width="85%"> <tbody class="Headless"> <tr class="First"> <td>Amount Gained kg (lb) </td><td>6 Weeks (N=7465)(%)</td><td>6 Months (N=4162)(%)</td><td>12 Months (N=1345)(%)</td><td>24 Months (N=474)(%)</td><td>36 Months (N=147)(%)</td> </tr> <tr> <td>≤0</td><td>26.2</td><td>24.3</td><td>20.8</td><td>23.2</td><td>17</td> </tr> <tr> <td>0 to ≤5 (0-11 lb)</td><td>57</td><td>36</td><td>26</td><td>23.4</td><td>25.2</td> </tr> <tr> <td>&gt;5 to ≤10 (11-22 lb)</td><td>14.9</td><td>24.6</td><td>24.2</td><td>24.1</td><td>18.4</td> </tr> <tr> <td>&gt;10 to ≤15 (22-33 lb)</td><td>1.8</td><td>10.9</td><td>14.9</td><td>11.4</td><td>17</td> </tr> <tr> <td>&gt;15 to ≤20 (33-44 lb)</td><td>0.1</td><td>3.1</td><td>8.6</td><td>9.3</td><td>11.6</td> </tr> <tr> <td>&gt;20 to ≤25 (44-55 lb)</td><td>0</td><td>0.9</td><td>3.3</td><td>5.1</td><td>4.1</td> </tr> <tr> <td>&gt;25 to ≤30 (55-66 lb)</td><td>0</td><td>0.2</td><td>1.4</td><td>2.3</td><td>4.8</td> </tr> <tr class="Last"> <td>&gt;30 (&gt;66 lb)</td><td>0</td><td>0.1</td><td>0.8</td><td>1.2</td><td>2</td> </tr> </tbody> </table></div>

Dose group differences with respect to weight gain have been observed. In a single 8-week randomized, double-blind, fixed-dose study comparing 10 (N=199), 20 (N=200) and 40 (N=200) mg/day of oral olanzapine in adult patients with schizophrenia or schizoaffective disorder, mean baseline to endpoint increase in weight (10 mg/day: 1.9 kg; 20 mg/day: 2.3 kg; 40 mg/day: 3 kg) was observed with significant differences between 10 vs 40 mg/day. 

Olanzapine Monotherapy in Adolescents — The safety and efficacy of olanzapine have not been established in patients under the age of 13 years. Mean increase in weight in adolescents was greater than in adults. In 4 placebo-controlled trials, discontinuation due to weight gain occurred in 1% of olanzapine-treated patients, compared to 0% of placebo-treated patients.

Table 7: Weight Gain with Olanzapine Use in Adolescents from 4 Placebo-Controlled Trials

<div class="scrollingtable"><table border="1" cellpadding="3" cellspacing="0" width="85%"> <tbody class="Headless"> <tr class="First"> <td><span class="Bold"> </span></td><td><span class="Bold">Olanzapine-treated patients</span></td><td><span class="Bold">Placebo-treated patients</span></td> </tr> <tr> <td>Mean change in body weight from baseline (median exposure = 3 weeks)</td><td>4.6 kg (10.1 lb)</td><td>0.3 kg (0.7 lb)</td> </tr> <tr> <td>Percentage of patients who gained at least 7% of baseline body weight</td><td>40.6% <br/> (median exposure to 7% = 4 weeks) </td><td>9.8%( median exposure to 7% = 8 weeks)</td> </tr> <tr class="Last"> <td>Percentage of patients who gained at least 15% of baseline body weight</td><td>7.1% <br/> (median exposure to 15% = 19 weeks) </td><td>2.7% (median exposure to 15% = 8 weeks)</td> </tr> </tbody> </table></div>

In long-term studies (at least 24 weeks), the mean weight gain was 11.2 kg (24.6 lb); (median exposure of 201 days, N=179). The percentages of adolescents who gained at least 7%, 15%, or 25% of their baseline body weight with long-term exposure were 89%, 55%, and 29%, respectively. Among adolescent patients, mean weight gain by baseline BMI category was 11.5 kg (25.3 lb), 12.1 kg (26.6 lb), and 12.7 kg (27.9 lb), respectively, for normal (N=106), overweight (N=26) and obese (N=17). Discontinuation due to weight gain occurred in 2.2% of olanzapine-treated patients following at least 24 weeks of exposure.

Table 8 shows data on adolescent weight gain with olanzapine pooled from 6 clinical trials. The data in each column represent data for those patients who completed treatment periods of the durations specified. Little clinical trial data is available on weight gain in adolescents with olanzapine beyond 6 months of treatment.

Table 8: Weight Gain with Olanzapine Use in Adolescents

<div class="scrollingtable"><table border="1" cellpadding="4" cellspacing="0" width="85%"> <tbody class="Headless"> <tr class="First"> <td><span class="Bold"> </span><span class="Bold">Amount Gained kg (lb)</span></td><td><span class="Bold">6 Weeks</span><span class="Bold">(N=243)</span><span class="Bold">(%)</span></td><td><span class="Bold">6 Months</span><span class="Bold">(N=191)</span><span class="Bold">(%)</span></td> </tr> <tr> <td>≤0</td><td>2.9</td><td>2.1</td> </tr> <tr> <td>0 to ≤5 (0-11 lb)</td><td>47.3</td><td>24.6</td> </tr> <tr> <td>&gt;5 to ≤10 (11-22 lb)</td><td>42.4</td><td>26.7</td> </tr> <tr> <td>&gt;10 to ≤15 (22-33 lb)</td><td>5.8</td><td>22</td> </tr> <tr> <td>&gt;15 to ≤20 (33-44 lb)</td><td>0.8</td><td>12.6</td> </tr> <tr> <td>&gt;20 to ≤25 (44-55 lb)</td><td>0.8</td><td>9.4</td> </tr> <tr> <td>&gt;25 to ≤30 (55-66 lb)</td><td>0</td><td>2.1</td> </tr> <tr> <td>&gt;30 to ≤35 (66-77 lb)</td><td>0</td><td>0</td> </tr> <tr> <td>&gt;35 to ≤40 (77-88 lb)</td><td>0</td><td>0</td> </tr> <tr class="Last"> <td>&gt;40 (&gt;88 lb)</td><td>0</td><td>0.5</td> </tr> </tbody> </table></div>

A syndrome of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with antipsychotic drugs. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to rely upon prevalence estimates to predict, at the inception of antipsychotic treatment, which patients are likely to develop the syndrome. Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown. 

The risk of developing tardive dyskinesia and the likelihood that it will become irreversible are believed to increase as the duration of treatment and the total cumulative dose of antipsychotic drugs administered to the patient increase. However, the syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses or may even arise after discontinuation of treatment. 

Tardive dyskinesia may remit, partially or completely, if antipsychotic treatment is withdrawn. Antipsychotic treatment, itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome and thereby may possibly mask the underlying process. The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown. 

Given these considerations, olanzapine should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia. Chronic antipsychotic treatment should generally be reserved for patients who suffer from a chronic illness that is known to respond to antipsychotic drugs, and (2) for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate. In patients who do require chronic treatment, the smallest dose and the shortest duration of treatment producing a satisfactory clinical response should be sought. The need for continued treatment should be reassessed periodically. 

If signs and symptoms of tardive dyskinesia appear in a patient on olanzapine, drug discontinuation should be considered. However, some patients may require treatment with olanzapine despite the presence of the syndrome. 

For specific information about the warnings of lithium or valproate, refer to the Warnings section of the package inserts for these other products.

Olanzapine may induce orthostatic hypotension associated with dizziness, tachycardia, bradycardia and, in some patients, syncope, especially during the initial dose-titration period, probably reflecting its α 1-adrenergic antagonistic properties. [see Patient Counseling Information (17)]

From an analysis of the vital sign data in an integrated database of 41 completed clinical studies in adult patients treated with oral olanzapine, orthostatic hypotension was recorded in ≥20% (1277/6030) of patients.

For oral olanzapine therapy, the risk of orthostatic hypotension and syncope may be minimized by initiating therapy with 5 mg QD [see Dosage and Administration (2)]. A more gradual titration to the target dose should be considered if hypotension occurs. 

Syncope was reported in 0.6% (15/2500) of olanzapine-treated patients in phase 2-3 oral olanzapine studies. The risk for this sequence of hypotension, bradycardia, and sinus pause  may be greater in nonpsychiatric patients compared to psychiatric patients who are possibly more adapted to certain effects of  psychotropic drugs. 

Olanzapine should be used with particular caution in patients with known cardiovascular disease (history of myocardial infarction or ischemia, heart failure, or conduction abnormalities), cerebrovascular disease, and conditions which would predispose patients to hypotension (dehydration, hypovolemia, and treatment with antihypertensive medications) where the occurrence of syncope, or hypotension and/or bradycardia might put the patient at increased medical risk. 

Caution is necessary in patients who receive treatment with other drugs having effects that can induce hypotension, bradycardia, respiratory or central nervous system depression [see Drug Interactions (7)].

Olanzapine may cause somnolence, postural hypotension, motor and sensory instability, which may lead to falls and, consequently, fractures or other injuries. For patients with diseases, conditions, or medications that could exacerbate these effects, complete fall risk assessments when initiating antipsychotic treatment and recurrently for patients on long-term antipsychotic therapy. 

Class Effect— In clinical trial and/or postmarketing experience, events of leukopenia/neutropenia have been reported temporally related to antipsychotic agents, including olanzapine. Agranulocytosis has also been reported.  

Possible risk factors for leukopenia/neutropenia include pre-existing low white blood cell count (WBC) and history of drug induced leukopenia/neutropenia. Patients with a history of a clinically significant low WBC or drug induced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and discontinuation of olanzapine should be considered at the first sign of a clinically significant decline in WBC in the absence of other causative factors.  

Patients with clinically significant neutropenia should be carefully monitored for fever or other symptoms or signs of infection and treated promptly if such symptoms or signs occur. Patients with severe neutropenia (absolute neutrophil count <1000/mm 3) should discontinue olanzapine and have their WBC followed until recovery.

Esophageal dysmotility and aspiration have been associated with antipsychotic drug use. Aspiration pneumonia is a common cause of morbidity and mortality in patients with advanced Alzheimer’s disease. Olanzapine is not approved for the treatment of patients with Alzheimer’s disease.

During premarketing testing, seizures occurred in 0.9% (22/2500) of olanzapine-treated patients. There were confounding factors that may have contributed to the occurrence of seizures in many of these cases. Olanzapine should be used cautiously in patients with a history of seizures or with conditions that potentially lower the seizure threshold, e.g., Alzheimer’s dementia. Olanzapine is not approved for the treatment of patients with Alzheimer’s disease. Conditions that lower the seizure threshold may be more prevalent in a population of 65 years or older.

Somnolence was a commonly reported adverse reaction associated with olanzapine treatment, occurring at an incidence of 26% in olanzapine patients compared to 15% in placebo patients. This adverse reaction was also dose related. Somnolence led to discontinuation in 0.4% (9/2500) of patients in the premarketing database. 

Since olanzapine has the potential to impair judgment, thinking, or motor skills, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that olanzapine therapy does not affect them adversely. [ see Patient Counseling Information ( 17) ].

Disruption of the body’s ability to reduce core body temperature has been attributed to antipsychotic agents. Appropriate care is advised when prescribing olanzapine for patients who will be experiencing conditions which may contribute to an elevation in core body temperature, e.g., exercising strenuously, exposure to extreme heat, receiving concomitant medication with anticholinergic activity, or being subject to dehydration. [ see Patient Counseling Information ( 17) ].

Olanzapine exhibits in vitro muscarinic receptor affinity [see Clinical Pharmacology12.2]. In premarketing clinical trials, olanzapine was associated with constipation, dry mouth, and tachycardia, all adverse reactions possibly related to cholinergic antagonism. Such adverse reactions were not often the basis for discontinuations, but olanzapine should be used with caution in patients with a current diagnosis or prior history of urinary retention, clinically significant prostatic hypertrophy, constipation, or a history of paralytic ileus or related conditions. In post marketing experience, the risk for severe adverse reactions (including fatalities) was increased with concomitant use of anticholinergic medications [see Drug Interactions( 7.1)].

As with other drugs that antagonize dopamine D 2receptors, olanzapine elevates prolactin levels, and the elevation persists during chronic administration. Hyperprolactinemia may suppress hypothalamic GnRH, resulting in reduced pituitary gonadotropin secretion. This, in turn, may inhibit reproductive function by impairing gonadal steroidogenesis in both female and male patients. Galactorrhea, amenorrhea, gynecomastia, and impotence have been reported in patients receiving prolactin-elevating compounds. Long-standing hyperprolactinemia when associated with hypogonadism may lead to decreased bone density in both female and male subjects. 

Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin dependent in vitro, a factor of potential importance if the prescription of these drugs is contemplated in a patient with previously detected breast cancer. As is common with compounds which increase prolactin release, an increase in mammary gland neoplasia was observed in the olanzapine carcinogenicity studies conducted in mice and rats [see Nonclinical Toxicology (13.1)]. Published epidemiologic studies have shown inconsistent results when exploring the potential association between hyperprolactinemia and breast cancer.

 In placebo-controlled olanzapine clinical studies (up to 12 weeks), changes from normal to high in prolactin concentrations were observed in 30% of adults treated with olanzapine as compared to 10.5% of adults treated with placebo. In a pooled analysis from clinical studies including 8136 adults treated with olanzapine, potentially associated clinical manifestations included menstrual-related events 1(2% [49/3240] of females), sexual function-related events 2(2% [150/8136] of females and males), and breast-related events 3(0.7% [23/3240] of females, 0.2% [9/4896] of males).  

In placebo-controlled olanzapine monotherapy studies in adolescent patients (up to 6 weeks) with schizophrenia or bipolar I disorder (manic or mixed episodes), changes from normal to high in prolactin concentrations were observed in 47% of olanzapinetreated patients compared to 7% of placebo-treated patients. In a pooled analysis from clinical trials including 454 adolescents treated with olanzapine, potentially associated clinical manifestations included menstrual-related events 1(1% [2/168] of females), sexual function-related events 2(0.7% [3/454] of females and males), and breast-related events 3(2% [3/168] of females, 2% [7/286] of males) [see Use in Specific Populations(8.4)]. 

1Based on a search of the following terms: amenorrhea, hypomenorrhea, menstruation delayed, and oligomenorrhea.

2Based on a search of the following terms: anorgasmia, delayed ejaculation, erectile dysfunction, decreased libido, loss of libido, abnormal orgasm, and sexual dysfunction.

3Based on a search of the following terms: breast discharge, enlargement or swelling, galactorrhea, gynecomastia, and lactation disorder.

Dose group differences with respect to prolactin elevation have been observed. In a single 8-week randomized, double-blind, fixed-dose study comparing 10 (N=199), 20 (N=200) and 40 (N=200) mg/day of oral olanzapine in adult patients with schizophrenia or schizoaffective disorder, incidence of prolactin elevation >24.2 ng/mL (female) or >18.77 ng/mL (male) at any time during the trial (10 mg/day: 31.2%; 20 mg/day: 42.7%; 40 mg/day: 61.1%) indicated significant differences between 10 vs 40 mg/day and 20 vs 40 mg/day. 

When using olanzapine and fluoxetine in combination, the prescriber should also refer to the Warnings and Precautions section of the package insert for Symbyax. When using olanzapine in combination with lithium or valproate, the prescriber should refer to the Warnings and Precautions sections of the package inserts for lithium or valproate. [See Drug Interactions (7)].

Fasting blood glucose testing and lipid profile at the beginning of, and periodically during, treatment is recommended [see Warnings and Precautions ( 5.4), and Patient Counseling Information ( 17)].

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect or predict the rates observed in practice.

Clinical Trials in Adults

The information below for olanzapine is derived from a clinical trial database for olanzapine consisting of 10,504 adult patients with approximately 4765 patient-years of exposure to oral olanzapine. This database includes: (1) 2500 patients who participated in multiple-dose oral olanzapine premarketing trials in schizophrenia and Alzheimer’s disease representing approximately 1122 patient-years of exposure as of February 14, 1995; (2) 182 patients who participated in oral olanzapine premarketing bipolar I disorder (manic or mixed episodes) trials representing approximately 66 patient-years of exposure; (3) 191 patients who participated in an oral olanzapine trial of patients having various psychiatric symptoms in association with Alzheimer’s disease representing approximately 29 patient-years of exposure; (4) 5788 additional patients from 88 oral olanzapine clinical trials as of December 31, 2001; (5) 1843 additional patients from 41 olanzapine clinical trials as of October 31, 2011. Also included below is information from the premarketing 6-week clinical study database for olanzapine in combination with lithium or valproate, consisting of 224 patients who participated in bipolar I disorder (manic or mixed episodes) trials with approximately 22 patient-years of exposure. 

The conditions and duration of treatment with olanzapine varied greatly and included (in overlapping categories) open-label and double-blind phases of studies, inpatients and outpatients, fixed-dose and dose-titration studies, and short-term or longer-term exposure. Adverse reactions were assessed by collecting adverse reactions, results of physical examinations, vital signs, weights, laboratory analytes, ECGs, chest x-rays, and results of ophthalmologic examinations. 

Certain portions of the discussion below relating to objective or numeric safety parameters, namely, dose-dependent adverse reactions, vital sign changes, weight gain, laboratory changes, and ECG changes are derived from studies in patients with schizophrenia and have not been duplicated for bipolar I disorder (manic or mixed episodes). However, this information is also generally applicable to bipolar I disorder (manic or mixed episodes). 

Adverse reactions during exposure were obtained by spontaneous report and recorded by clinical investigators using terminology of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse reactions without first grouping similar types of reactions into a smaller number of standardized reaction categories. In the tables and tabulations that follow, MedDRA and COSTART Dictionary terminology has been used to classify reported adverse reactions.

 The stated frequencies of adverse reactions represent the proportion of individuals who experienced, at least once, a treatment-emergent adverse reaction of the type listed. A reaction was considered treatment emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation. The reported reactions do not include those reaction terms that were so general as to be uninformative. Reactions listed elsewhere in labeling may not be repeated below. It is important to emphasize that, although the reactions occurred during treatment with olanzapine, they were not necessarily caused by it. The entire label should be read to gain a complete understanding of the safety profile of olanzapine. 

The prescriber should be aware that the figures in the tables and tabulations cannot be used to predict the incidence of side effects in the course of usual medical practice where patient characteristics and other factors differ from those that prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators. The cited figures, however, do provide the prescribing healthcare provider with some basis for estimating the relative contribution of drug and nondrug factors to the adverse reactions incidence in the population studied.

 Incidence of Adverse Reactions in Short-Term, Placebo-Controlled and Combination Trials

The following findings are based on premarketing trials of oral olanzapine for Schizophrenia, Bipolar I Disorder (manic or mixed episodes), a subsequent trial of patients having various psychiatric symptoms in association with Alzheimer’s disease, and premarketing combination trials.

 Adverse Reactions Associated with Discontinuation of Treatment in Short-Term, Placebo-Controlled Trials

Schizophrenia— Overall, there was no difference in the incidence of discontinuation due to adverse reactions (5% for oral olanzapine vs 6% for placebo). However, discontinuations due to increases in ALT were considered to be drug related (2% for oral olanzapine vs 0% for placebo). 

Bipolar I Disorder (Manic or Mixed Episodes) Monotherapy— Overall, there was no difference in the incidence of discontinuation due to adverse reactions (2% for oral olanzapine vs 2% for placebo). 

Adverse Reactions Associated with Discontinuation of Treatment in Short-Term Combination Trials

Bipolar I Disorder (Manic or Mixed Episodes), Olanzapine as Adjunct to Lithium or Valproate— In a study of patients who were already tolerating either lithium or valproate as monotherapy, discontinuation rates due to adverse reactions were 11% for the combination of oral olanzapine with lithium or valproate compared to 2% for patients who remained on lithium or valproate monotherapy. Discontinuations with the combination of oral olanzapine and lithium or valproate that occurred in more than 1 patient were: somnolence (3%), weight gain (1%), and peripheral edema (1%). 

Commonly Observed Adverse Reactions in Short-Term, Placebo-Controlled Trials

The most commonly observed adverse reactions associated with the use of oral olanzapine (incidence of 5% or greater) and not observed at an equivalent incidence among placebo-treated patients (olanzapine incidence at least twice that for placebo) were: 

Table 9: Common Treatment-Emergent Adverse Reactions Associated with the Use of OralOlanzapine in 6-Week Trials — SCHIZOPHRENIA

<div class="scrollingtable"><table border="1" cellpadding="4" cellspacing="0" width="640"> <tbody class="Headless"> <tr class="First"> <td rowspan="2" valign="bottom"><span class="Bold">Adverse Reaction</span></td><td colspan="2" valign="top"><span class="Bold">Percentage of Patients Reporting Event</span></td> </tr> <tr> <td valign="top"><span class="Bold">Olanzapine</span></td><td valign="top"><span class="Bold">Placebo</span></td> </tr> <tr> <td valign="top"> </td><td valign="top"><span class="Bold">(N=248)</span></td><td valign="top"><span class="Bold">(N=118)</span></td> </tr> <tr> <td valign="top">Postural hypotension</td><td valign="top">5</td><td valign="top">2</td> </tr> <tr> <td valign="top">Constipation</td><td valign="top">9</td><td valign="top">3</td> </tr> <tr> <td valign="top">Weight gain</td><td valign="top">6</td><td valign="top">1</td> </tr> <tr> <td valign="top">Dizziness</td><td valign="top">11</td><td valign="top">4</td> </tr> <tr> <td valign="top">Personality disorder <span class="Sup">a</span></td><td valign="top">8</td><td valign="top">4</td> </tr> <tr class="Last"> <td valign="top">Akathisia</td><td valign="top">5</td><td valign="top">1</td> </tr> </tbody> </table></div>

aPersonality disorder is the COSTART term for designating non-aggressive objectionable behavior.

Table 10: Common Treatment-Emergent Adverse Reactions Associated with the Use of Oral Olanzapine in 3-Week and 4-Week Trials — Bipolar I Disorder (Manic or Mixed Episodes)

<div class="scrollingtable"><table border="1" cellpadding="4" cellspacing="0" width="634"> <tbody class="Headless"> <tr class="First"> <td rowspan="2" valign="top"><span class="Bold"> </span><span class="Bold">Adverse</span><span class="Bold">Reaction</span></td><td colspan="2" valign="top"><span class="Bold">Percentage of Patients Reporting Event</span></td> </tr> <tr> <td valign="top">Olanzapine <br/> <span class="Bold">(N=125)</span></td><td valign="top">Placebo <br/> <span class="Bold">(N=129)</span></td> </tr> <tr> <td valign="top">Asthenia</td><td valign="top">15</td><td valign="top">6</td> </tr> <tr> <td valign="top">Dry mouth</td><td valign="top">22</td><td valign="top">7</td> </tr> <tr> <td valign="top">Constipation</td><td valign="top">11</td><td valign="top">5</td> </tr> <tr> <td valign="top">Dyspepsia</td><td valign="top">11</td><td valign="top">5</td> </tr> <tr> <td valign="top">Increased appetite</td><td valign="top">6</td><td valign="top">3</td> </tr> <tr> <td valign="top">Somnolence</td><td valign="top">35</td><td valign="top">13</td> </tr> <tr> <td valign="top">Dizziness</td><td valign="top">18</td><td valign="top">6</td> </tr> <tr class="Last"> <td valign="top">Tremor</td><td valign="top">6</td><td valign="top">3</td> </tr> </tbody> </table></div>

Adverse Reactions Occurring at an Incidence of 2% or More Among Oral Olanzapine-Treated Patients in Short-Term, Placebo-Controlled Trials 

Table 11 enumerates the incidence, rounded to the nearest percent, of treatment-emergent adverse reactions that occurred in 2% or more of patients treated with oral olanzapine (doses ≥2.5 mg/day) and with incidence greater than placebo who participated in the acute phase of placebo-controlled trials.

Table 11: Treatment-Emergent Adverse Reactions:Incidence in Short-Term, Placebo-Controlled Clinical Trials with Oral Olanzapine

<div class="scrollingtable"><table width="100%"> <caption> <span></span> </caption> <col align="left" char="." charoff="50" span="1" width="46%"/> <col align="left" char="." charoff="50" span="1" width="27%"/> <col align="left" char="." charoff="50" span="1" width="27%"/> <tbody class="Headless" valign="top"> <tr class="First" valign="middle"> <td align="left" char="." charoff="50" colspan="1" rowspan="1" valign="top"></td><td align="center" char="." charoff="50" colspan="2" rowspan="1" valign="top"> <p class="First"> <span class="Bold">Percentage of Patients Reporting Event</span> </p> </td> </tr> <tr valign="middle"> <td align="left" char="." charoff="50" colspan="1" rowspan="1" valign="top"></td><td align="center" char="." charoff="50" colspan="1" rowspan="1" valign="top"> <p class="First"> <span class="Bold">Olanzapine</span> </p> </td><td align="center" char="." charoff="50" colspan="1" rowspan="1" valign="top"> <p class="First"> <span class="Bold">Placebo</span> </p> </td> </tr> <tr valign="middle"> <td align="left" char="." charoff="50" colspan="1" rowspan="1" valign="top"> <p class="First"> <span class="Bold">Body System/Adverse Event</span> </p> </td><td align="center" char="." charoff="50" colspan="1" rowspan="1" valign="top"> <p class="First"> <span class="Bold">(N=532)</span> </p> </td><td align="center" char="." charoff="50" colspan="1" rowspan="1" valign="top"> <p class="First"> <span class="Bold">(N=294)</span> </p> </td> </tr> <tr valign="middle"> <td align="left" char="." charoff="50" colspan="1" rowspan="1" valign="top"> <p class="First"> <span class="Bold">Body as a Whole</span> </p> </td><td align="center" char="." charoff="50" colspan="1" rowspan="1" valign="top"></td><td align="center" char="." charoff="50" colspan="1" rowspan="1" valign="top"></td> </tr> <tr valign="middle"> <td align="left" char="." charoff="50" colspan="1" rowspan="1" valign="top"> <p class="First">Accidental injury</p> </td><td align="center" char="." charoff="50" colspan="1" rowspan="1" valign="top"> <p class="First">12</p> </td><td align="center" char="." charoff="50" colspan="1" rowspan="1" valign="top"> <p class="First">8</p> </td> </tr> <tr valign="middle"> <td align="left" char="." charoff="50" colspan="1" rowspan="1" valign="top"> <p class="First">Asthenia</p> </td><td align="center" char="." charoff="50" colspan="1" rowspan="1" valign="top"> <p class="First">10</p> </td><td align="center" char="." charoff="50" colspan="1" rowspan="1" valign="top"> <p class="First">9</p> </td> </tr> <tr valign="middle"> <td align="left" char="." charoff="50" colspan="1" rowspan="1" valign="top"> <p class="First">Fever</p> </td><td align="center" char="." charoff="50" colspan="1" rowspan="1" valign="top"> <p class="First">6</p> </td><td align="center" char="." charoff="50" colspan="1" rowspan="1" valign="top"> <p class="First">2</p> </td> </tr> <tr valign="middle"> <td align="left" char="." charoff="50" colspan="1" rowspan="1" valign="top"> <p class="First">Back pain</p> </td><td align="center" char="." charoff="50" colspan="1" rowspan="1" valign="top"> <p class="First">5</p> </td><td align="center" char="." charoff="50" colspan="1" rowspan="1" valign="top"> <p class="First">2</p> </td> </tr> <tr valign="middle"> <td align="left" char="." charoff="50" colspan="1" rowspan="1" valign="top"> <p class="First">Chest pain</p> </td><td align="center" char="." charoff="50" colspan="1" rowspan="1" valign="top"> <p class="First">3</p> </td><td align="center" char="." charoff="50" colspan="1" rowspan="1" valign="top"> <p class="First">1</p> </td> </tr> <tr valign="middle"> <td align="left" char="." charoff="50" colspan="1" rowspan="1" valign="top"> <p class="First"> <span class="Bold">Cardiovascular System</span> </p> </td><td align="center" char="." charoff="50" colspan="1" rowspan="1" valign="top"></td><td align="center" char="." charoff="50" colspan="1" rowspan="1" valign="top"></td> </tr> <tr valign="middle"> <td align="left" char="." charoff="50" colspan="1" rowspan="1" valign="top"> <p class="First">Postural hypotension</p> </td><td align="center" char="." charoff="50" colspan="1" rowspan="1" valign="top"> <p class="First">3</p> </td><td align="center" char="." charoff="50" colspan="1" rowspan="1" valign="top"> <p class="First">1</p> </td> </tr> <tr valign="middle"> <td align="left" char="." charoff="50" colspan="1" rowspan="1" valign="top"> <p class="First">Tachycardia</p> </td><td align="center" char="." charoff="50" colspan="1" rowspan="1" valign="top"> <p class="First">3</p> </td><td align="center" char="." charoff="50" colspan="1" rowspan="1" valign="top"> <p class="First">1</p> </td> </tr> <tr valign="middle"> <td align="left" char="." charoff="50" colspan="1" rowspan="1" valign="top"> <p class="First">Hypertension</p> </td><td align="center" char="." charoff="50" colspan="1" rowspan="1" valign="top"> <p class="First">2</p> </td><td align="center" char="." charoff="50" colspan="1" rowspan="1" valign="top"> <p class="First">1</p> </td> </tr> <tr valign="middle"> <td align="left" char="." charoff="50" colspan="1" rowspan="1" valign="top"> <p class="First"> <span class="Bold">Digestive System</span> </p> </td><td align="center" char="." charoff="50" colspan="1" rowspan="1" valign="top"></td><td align="center" char="." charoff="50" colspan="1" rowspan="1" valign="top"></td> </tr> <tr valign="middle"> <td align="left" char="." charoff="50" colspan="1" rowspan="1" valign="top"> <p class="First">Dry mouth</p> </td><td align="center" char="." charoff="50" colspan="1" rowspan="1" valign="top"> <p class="First">9</p> </td><td align="center" char="." charoff="50" colspan="1" rowspan="1" valign="top"> <p class="First">5</p> </td> </tr> <tr valign="middle"> <td align="left" char="." charoff="50" colspan="1" rowspan="1" valign="top"> <p class="First">Constipation</p> </td><td align="center" char="." charoff="50" colspan="1" rowspan="1" valign="top"> <p class="First">9</p> </td><td align="center" char="." charoff="50" colspan="1" rowspan="1" valign="top"> <p class="First">4</p> </td> </tr> <tr valign="middle"> <td align="left" char="." charoff="50" colspan="1" rowspan="1" valign="top"> <p class="First">Dyspepsia</p> </td><td align="center" char="." charoff="50" colspan="1" rowspan="1" valign="top"> <p class="First">7</p> </td><td align="center" char="." charoff="50" colspan="1" rowspan="1" valign="top"> <p class="First">5</p> </td> </tr> <tr valign="middle"> <td align="left" char="." charoff="50" colspan="1" rowspan="1" valign="top"> <p class="First">Vomiting</p> </td><td align="center" char="." charoff="50" colspan="1" rowspan="1" valign="top"> <p class="First">4</p> </td><td align="center" char="." charoff="50" colspan="1" rowspan="1" valign="top"> <p class="First">3</p> </td> </tr> <tr valign="middle"> <td align="left" char="." charoff="50" colspan="1" rowspan="1" valign="top"> <p class="First">Increased appetite</p> </td><td align="center" char="." charoff="50" colspan="1" rowspan="1" valign="top"> <p class="First">3</p> </td><td align="center" char="." charoff="50" colspan="1" rowspan="1" valign="top"> <p class="First">2</p> </td> </tr> <tr valign="middle"> <td align="left" char="." charoff="50" colspan="1" rowspan="1" valign="top"> <p class="First"> <span class="Bold">Hemic and Lymphatic System</span> </p> </td><td align="center" char="." charoff="50" colspan="1" rowspan="1" valign="top"></td><td align="center" char="." charoff="50" colspan="1" rowspan="1" valign="top"></td> </tr> <tr valign="middle"> <td align="left" char="." charoff="50" colspan="1" rowspan="1" valign="top"> <p class="First">Ecchymosis</p> </td><td align="center" char="." charoff="50" colspan="1" rowspan="1" valign="top"> <p class="First">5</p> </td><td align="center" char="." charoff="50" colspan="1" rowspan="1" valign="top"> <p class="First">3</p> </td> </tr> <tr valign="middle"> <td align="left" char="." charoff="50" colspan="1" rowspan="1" valign="top"> <p class="First"> <span class="Bold">Metabolic and Nutritional Disorders</span> </p> </td><td align="center" char="." charoff="50" colspan="1" rowspan="1" valign="top"></td><td align="center" char="." charoff="50" colspan="1" rowspan="1" valign="top"></td> </tr> <tr valign="middle"> <td align="left" char="." charoff="50" colspan="1" rowspan="1" valign="top"> <p class="First">Weight gain</p> </td><td align="center" char="." charoff="50" colspan="1" rowspan="1" valign="top"> <p class="First">5</p> </td><td align="center" char="." charoff="50" colspan="1" rowspan="1" valign="top"> <p class="First">3</p> </td> </tr> <tr valign="middle"> <td align="left" char="." charoff="50" colspan="1" rowspan="1" valign="top"> <p class="First">Peripheral edema</p> </td><td align="center" char="." charoff="50" colspan="1" rowspan="1" valign="top"> <p class="First">3</p> </td><td align="center" char="." charoff="50" colspan="1" rowspan="1" valign="top"> <p class="First">1</p> </td> </tr> <tr valign="middle"> <td align="left" char="." charoff="50" colspan="1" rowspan="1" valign="top"> <p class="First"> <span class="Bold">Musculoskeletal System</span> </p> </td><td align="center" char="." charoff="50" colspan="1" rowspan="1" valign="top"></td><td align="center" char="." charoff="50" colspan="1" rowspan="1" valign="top"></td> </tr> <tr valign="middle"> <td align="left" char="." charoff="50" colspan="1" rowspan="1" valign="top"> <p class="First">Extremity pain (other than joint)</p> </td><td align="center" char="." charoff="50" colspan="1" rowspan="1" valign="top"> <p class="First">5</p> </td><td align="center" char="." charoff="50" colspan="1" rowspan="1" valign="top"> <p class="First">3</p> </td> </tr> <tr valign="middle"> <td align="left" char="." charoff="50" colspan="1" rowspan="1" valign="top"> <p class="First">Joint pain</p> </td><td align="center" char="." charoff="50" colspan="1" rowspan="1" valign="top"> <p class="First">5</p> </td><td align="center" char="." charoff="50" colspan="1" rowspan="1" valign="top"> <p class="First">3</p> </td> </tr> <tr valign="middle"> <td align="left" char="." charoff="50" colspan="1" rowspan="1" valign="top"> <p class="First"> <span class="Bold">Nervous System</span> </p> </td><td align="center" char="." charoff="50" colspan="1" rowspan="1" valign="top"></td><td align="center" char="." charoff="50" colspan="1" rowspan="1" valign="top"></td> </tr> <tr valign="middle"> <td align="left" char="." charoff="50" colspan="1" rowspan="1" valign="top"> <p class="First">Somnolence</p> </td><td align="center" char="." charoff="50" colspan="1" rowspan="1" valign="top"> <p class="First">29</p> </td><td align="center" char="." charoff="50" colspan="1" rowspan="1" valign="top"> <p class="First">13</p> </td> </tr> <tr valign="middle"> <td align="left" char="." charoff="50" colspan="1" rowspan="1" valign="top"> <p class="First">Insomnia</p> </td><td align="center" char="." charoff="50" colspan="1" rowspan="1" valign="top"> <p class="First">12</p> </td><td align="center" char="." charoff="50" colspan="1" rowspan="1" valign="top"> <p class="First">11</p> </td> </tr> <tr valign="middle"> <td align="left" char="." charoff="50" colspan="1" rowspan="1" valign="top"> <p class="First">Dizziness</p> </td><td align="center" char="." charoff="50" colspan="1" rowspan="1" valign="top"> <p class="First">11</p> </td><td align="center" char="." charoff="50" colspan="1" rowspan="1" valign="top"> <p class="First">4</p> </td> </tr> <tr valign="middle"> <td align="left" char="." charoff="50" colspan="1" rowspan="1" valign="top"> <p class="First">Abnormal gait</p> </td><td align="center" char="." charoff="50" colspan="1" rowspan="1" valign="top"> <p class="First">6</p> </td><td align="center" char="." charoff="50" colspan="1" rowspan="1" valign="top"> <p class="First">1</p> </td> </tr> <tr valign="middle"> <td align="left" char="." charoff="50" colspan="1" rowspan="1" valign="top"> <p class="First">Tremor</p> </td><td align="center" char="." charoff="50" colspan="1" rowspan="1" valign="top"> <p class="First">4</p> </td><td align="center" char="." charoff="50" colspan="1" rowspan="1" valign="top"> <p class="First">3</p> </td> </tr> <tr valign="middle"> <td align="left" char="." charoff="50" colspan="1" rowspan="1" valign="top"> <p class="First">Akathisia</p> </td><td align="center" char="." charoff="50" colspan="1" rowspan="1" valign="top"> <p class="First">3</p> </td><td align="center" char="." charoff="50" colspan="1" rowspan="1" valign="top"> <p class="First">2</p> </td> </tr> <tr valign="middle"> <td align="left" char="." charoff="50" colspan="1" rowspan="1" valign="top"> <p class="First">Hypertonia</p> </td><td align="center" char="." charoff="50" colspan="1" rowspan="1" valign="top"> <p class="First">3</p> </td><td align="center" char="." charoff="50" colspan="1" rowspan="1" valign="top"> <p class="First">2</p> </td> </tr> <tr valign="middle"> <td align="left" char="." charoff="50" colspan="1" rowspan="1" valign="top"> <p class="First">Articulation impairment</p> </td><td align="center" char="." charoff="50" colspan="1" rowspan="1" valign="top"> <p class="First">2</p> </td><td align="center" char="." charoff="50" colspan="1" rowspan="1" valign="top"> <p class="First">1</p> </td> </tr> <tr valign="middle"> <td align="left" char="." charoff="50" colspan="1" rowspan="1" valign="top"> <p class="First"> <span class="Bold">Respiratory System</span> </p> </td><td align="center" char="." charoff="50" colspan="1" rowspan="1" valign="top"></td><td align="center" char="." charoff="50" colspan="1" rowspan="1" valign="top"></td> </tr> <tr valign="middle"> <td align="left" char="." charoff="50" colspan="1" rowspan="1" valign="top"> <p class="First">Rhinitis</p> </td><td align="center" char="." charoff="50" colspan="1" rowspan="1" valign="top"> <p class="First">7</p> </td><td align="center" char="." charoff="50" colspan="1" rowspan="1" valign="top"> <p class="First">6</p> </td> </tr> <tr valign="middle"> <td align="left" char="." charoff="50" colspan="1" rowspan="1" valign="top"> <p class="First">Cough increased</p> </td><td align="center" char="." charoff="50" colspan="1" rowspan="1" valign="top"> <p class="First">6</p> </td><td align="center" char="." charoff="50" colspan="1" rowspan="1" valign="top"> <p class="First">3</p> </td> </tr> <tr valign="middle"> <td align="left" char="." charoff="50" colspan="1" rowspan="1" valign="top"> <p class="First">Pharyngitis</p> </td><td align="center" char="." charoff="50" colspan="1" rowspan="1" valign="top"> <p class="First">4</p> </td><td align="center" char="." charoff="50" colspan="1" rowspan="1" valign="top"> <p class="First">3</p> </td> </tr> <tr valign="middle"> <td align="left" char="." charoff="50" colspan="1" rowspan="1" valign="top"> <p class="First"> <span class="Bold">Special Senses</span> </p> </td><td align="center" char="." charoff="50" colspan="1" rowspan="1" valign="top"></td><td align="center" char="." charoff="50" colspan="1" rowspan="1" valign="top"></td> </tr> <tr valign="middle"> <td align="left" char="." charoff="50" colspan="1" rowspan="1" valign="top"> <p class="First">Amblyopia</p> </td><td align="center" char="." charoff="50" colspan="1" rowspan="1" valign="top"> <p class="First">3</p> </td><td align="center" char="." charoff="50" colspan="1" rowspan="1" valign="top"> <p class="First">2</p> </td> </tr> <tr valign="middle"> <td align="left" char="." charoff="50" colspan="1" rowspan="1" valign="top"> <p class="First"> <span class="Bold">Urogenital System</span> </p> </td><td align="center" char="." charoff="50" colspan="1" rowspan="1" valign="top"></td><td align="center" char="." charoff="50" colspan="1" rowspan="1" valign="top"></td> </tr> <tr valign="middle"> <td align="left" char="." charoff="50" colspan="1" rowspan="1" valign="top"> <p class="First">Urinary incontinence</p> </td><td align="center" char="." charoff="50" colspan="1" rowspan="1" valign="top"> <p class="First">2</p> </td><td align="center" char="." charoff="50" colspan="1" rowspan="1" valign="top"> <p class="First">1</p> </td> </tr> <tr class="Last" valign="middle"> <td align="left" char="." charoff="50" colspan="1" rowspan="1" valign="top"> <p class="First">Urinary tract infection</p> </td><td align="center" char="." charoff="50" colspan="1" rowspan="1" valign="top"> <p class="First">2</p> </td><td align="center" char="." charoff="50" colspan="1" rowspan="1" valign="top"> <p class="First">1</p> </td> </tr> </tbody> </table></div>

Dose Dependency of Adverse Reactions A dose group difference has been observed for fatigue, dizziness, weight gain and prolactin elevation. In a single 8-week randomized, double-blind, fixed-dose study comparing 10 (N=199), 20 (N=200) and 40 (N=200) mg/day of oral olanzapine in adult patients with schizophrenia or schizoaffective disorder, incidence of fatigue (10 mg/day: 1.5%; 20 mg/day: 2.1%; 40 mg/day: 6.6%) was observed with significant differences between 10 vs 40 and 20 vs 40 mg/day. The incidence of dizziness (10 mg/day: 2.6%; 20 mg/day: 1.6%; 40 mg/day: 6.6%) was observed with significant differences between 20 vs 40 mg. Dose group differences were also noted for weight gain and prolactin elevation [see Warnings and Precautions (5.5, 5.15)].  

The following table addresses dose relatedness for other adverse reactions using data from a schizophrenia trial involving fixed dosage ranges of oral olanzapine. It enumerates the percentage of patients with treatment-emergent adverse reactions for the 3 fixed-dose range groups and placebo. The data were analyzed using the Cochran-Armitage test, excluding the placebo group, and the table includes only those adverse reactions for which there was a trend.

Table 12: Percentage of Patients from a Schizophrenia Trial with Treatment-Emergent Adverse Reactions for the 3 Dose Range Groups and Placebo

<div class="scrollingtable"><table> <tbody class="Headless"> <tr class="First"> <td><span class="Bold"> </span></td><td colspan="5"><span class="Bold">Percentage of Patients Reporting Event</span>  </td> </tr> <tr> <td><span class="Bold">Adverse Reaction</span></td><td><span class="Bold">Placebo</span><span class="Bold">(N=68)</span></td><td><span class="Bold">Olanzapine</span><span class="Bold">5±2.5 mg/day</span><span class="Bold">(N=65)</span></td><td><span class="Bold">Olanzapine</span><span class="Bold">10 ±2.5 mg/day</span><span class="Bold">(N=64)</span></td><td colspan="2"><span class="Bold">Olanzapine</span><span class="Bold">15±2.5 mg/day</span><span class="Bold">(N=69)</span></td> </tr> <tr> <td>Asthenia</td><td>15</td><td>8</td><td>9</td><td>20</td><td> </td> </tr> <tr> <td>Dry mouth</td><td>4</td><td>3</td><td>5</td><td>13</td><td> </td> </tr> <tr> <td>Nausea</td><td>9</td><td>0</td><td>2</td><td>9</td><td> </td> </tr> <tr> <td>Somnolence</td><td>16</td><td>20</td><td>30</td><td>39</td><td> </td> </tr> <tr class="Last"> <td>Tremor</td><td>3</td><td>0</td><td>5</td><td>7</td><td> </td> </tr> </tbody> </table></div>

Commonly Observed Adverse Reactions in Short-Term Trials of Oral Olanzapine as Adjunct  to Lithium or Valproate

In the bipolar I disorder (manic or mixed episodes) adjunct placebo-controlled trials, the most commonly observed adverse reactions associated with the combination of olanzapine and lithium or valproate (incidence of ≥5% and at least twice placebo) were:

Table 13: Common Treatment-Emergent Adverse Reactions Associated with the Use of Oral Olanzapine in 6-Week Adjunct to Lithium or Valproate  Trials — Bipolar I Disorder (Manic or Mixed Episodes)

<div class="scrollingtable"><table border="1" cellpadding="4" cellspacing="0"> <tbody class="Headless"> <tr class="First"> <td rowspan="2" valign="top">   <span class="Bold">Adverse Reaction</span></td><td colspan="2" valign="top"><span class="Bold">Percentage of Patients Reporting Event</span></td> </tr> <tr> <td valign="top"><span class="Bold">Olanzapine with</span><span class="Bold">lithium or valproate</span> <br/> <span class="Bold">(N=229)</span></td><td valign="top"><span class="Bold">Placebo with</span><span class="Bold">lithium or valproate</span> <br/> <span class="Bold">(N=115)</span></td> </tr> <tr> <td valign="top">Dry mouth</td><td valign="top">32</td><td valign="top">9</td> </tr> <tr> <td valign="top">Weight gain</td><td valign="top">26</td><td valign="top">7</td> </tr> <tr> <td valign="top">Increased appetite</td><td valign="top">24</td><td valign="top">8</td> </tr> <tr> <td valign="top">Dizziness</td><td valign="top">14</td><td valign="top">7</td> </tr> <tr> <td valign="top">Back pain</td><td valign="top">8</td><td valign="top">4</td> </tr> <tr> <td valign="top">Constipation</td><td valign="top">8</td><td valign="top">4</td> </tr> <tr> <td valign="top">Speech disorder</td><td valign="top">7</td><td valign="top">1</td> </tr> <tr> <td valign="top">Increased salivation</td><td valign="top">6</td><td valign="top">2</td> </tr> <tr> <td valign="top">Amnesia</td><td valign="top">5</td><td valign="top">2</td> </tr> <tr class="Last"> <td valign="top">Paresthesia</td><td valign="top">5</td><td valign="top">2</td> </tr> </tbody> </table></div>

Adverse Reactions Occurring at an Incidence of 2% or More Among Oral Olanzapine-Treated Patients in Short-Term Trials of Olanzapine as Adjunct  to Lithium or Valproate 

Table 14 enumerates the incidence, rounded to the nearest percent, of treatment-emergent adverse reactions that occurred in 2% or more of patients treated with the combination of olanzapine (doses ≥5 mg/day) and lithium or valproate and with incidence greater than lithium or valproate alone who participated in the acute phase of placebo-controlled combination trials.

Table 14: Treatment-Emergent Adverse Reactions: Incidence in Short-Term, Placebo-Controlled Clinical Trials of Oral Olanzapine in as Adjunct to with Lithium or Valproate

<div class="scrollingtable"><table border="1" cellpadding="3" cellspacing="0" width="641"> <tbody class="Headless"> <tr class="First"> <td rowspan="2" valign="bottom"><span class="Bold">Body System/Adverse Reaction</span></td><td colspan="2" valign="top">Percentage of Patients Reporting Event</td> </tr> <tr> <td valign="top">Olanzapine with <span class="Bold">lithium or valproate</span><span class="Bold">(N=229)</span></td><td valign="top">Placebo with <span class="Bold">lithium or valproate</span><span class="Bold">(N=115)</span></td> </tr> <tr> <td valign="top">Body as a Whole</td><td> </td><td> </td> </tr> <tr> <td valign="top">Asthenia</td><td>18</td><td>13</td> </tr> <tr> <td valign="top">Back pain</td><td>8</td><td>4</td> </tr> <tr> <td valign="top">Accidental injury</td><td>4</td><td>2</td> </tr> <tr> <td valign="top">Chest pain</td><td>3</td><td>2</td> </tr> <tr> <td valign="top">Cardiovascular System</td><td> </td><td> </td> </tr> <tr> <td valign="top">Hypertension</td><td>2</td><td>1</td> </tr> <tr> <td valign="top">Digestive System</td><td> </td><td> </td> </tr> <tr> <td valign="top">Dry mouth</td><td>32</td><td>9</td> </tr> <tr> <td valign="top">Increased appetite</td><td>24</td><td>8</td> </tr> <tr> <td valign="top">Thirst</td><td>10</td><td>6</td> </tr> <tr> <td valign="top">Constipation</td><td>8</td><td>4</td> </tr> <tr> <td valign="top">Increased salivation</td><td>6</td><td>2</td> </tr> <tr> <td valign="top">Metabolic and Nutritional Disorders</td><td> </td><td> </td> </tr> <tr> <td valign="top">Weight gain</td><td>26</td><td>7</td> </tr> <tr> <td valign="top">Peripheral edema</td><td>6</td><td>4</td> </tr> <tr> <td valign="top">Edema</td><td>2</td><td>1</td> </tr> <tr> <td valign="top">Nervous System</td><td> </td><td> </td> </tr> <tr> <td valign="top">Somnolence</td><td>52</td><td>27</td> </tr> <tr> <td valign="top">Tremor</td><td>23</td><td>13</td> </tr> <tr> <td valign="top">Depression</td><td>18</td><td>17</td> </tr> <tr> <td valign="top">Dizziness</td><td>14</td><td>7</td> </tr> <tr> <td valign="top">Speech disorder</td><td>7</td><td>1</td> </tr> <tr> <td valign="top">Amnesia</td><td>5</td><td>2</td> </tr> <tr> <td valign="top">Paresthesia</td><td>5</td><td>2</td> </tr> <tr> <td valign="top">Apathy</td><td>4</td><td>3</td> </tr> <tr> <td valign="top">Confusion</td><td>4</td><td>1</td> </tr> <tr> <td valign="top">Euphoria</td><td>3</td><td>2</td> </tr> <tr> <td valign="top">Incoordination</td><td>2</td><td>0</td> </tr> <tr> <td valign="top">Respiratory System</td><td> </td><td> </td> </tr> <tr> <td valign="top">Pharyngitis</td><td>4</td><td>1</td> </tr> <tr> <td valign="top">Dyspnea</td><td>3</td><td>1</td> </tr> <tr> <td valign="top">Skin and Appendages</td><td> </td><td> </td> </tr> <tr> <td valign="top">Sweating</td><td>3</td><td>1</td> </tr> <tr> <td valign="top">Acne</td><td>2</td><td>0</td> </tr> <tr> <td valign="top">Dry skin</td><td>2</td><td>0</td> </tr> <tr> <td valign="top">Special Senses</td><td> </td><td> </td> </tr> <tr> <td valign="top">Amblyopia</td><td>9</td><td>5</td> </tr> <tr> <td valign="top">Abnormal vision</td><td>2</td><td>0</td> </tr> <tr> <td valign="top">Urogenital System</td><td> </td><td> </td> </tr> <tr> <td valign="top">Dysmenorrhea <span class="Sup">a</span></td><td>2</td><td>0</td> </tr> <tr class="Last"> <td valign="top">Vagiitis <span class="Sup">a</span></td><td>2</td><td>0</td> </tr> </tbody> </table></div>

aDenominator used was for females only (olanzapine, N=128; placebo, N=51). 

For specific information about the adverse reactions observed with lithium or valproate, refer to the Adverse Reactions section of the package inserts for these other products. 

The following table enumerates the percentage of patients with treatment-emergent extrapyramidal symptoms as assessed by categorical analyses of formal rating scales during acute therapy in a controlled clinical trial comparing oral olanzapine at 3 fixed doses with placebo in the treatment of schizophrenia in a 6-week trial. 

Table 16: Treatment-Emergent Extrapyramidal Symptoms Assessed by Rating Scales Incidence in a Fixed Dosage Range, Placebo-Controlled Clinical Trial of Oral Olanzapine in Schizophrenia — Acute Phase

<div class="scrollingtable"><table border="1" cellpadding="4" cellspacing="0" width="102%"> <tbody class="Headless"> <tr class="First"> <td valign="top"> </td><td colspan="4" valign="top"><span class="Bold">Percentage of Patients Reporting Event</span></td> </tr> <tr> <td valign="top"> </td><td valign="top">  <span class="Bold">Placebo</span></td><td valign="top"><span class="Bold">Olanzapine</span><span class="Bold">5 ± 2.5 mg/day</span></td><td valign="top"><span class="Bold">Olanzapine</span><span class="Bold">10 ± 2.5 mg/day</span></td><td valign="top"><span class="Bold">Olanzapine</span><span class="Bold">15 ± 2.5 mg/day</span></td> </tr> <tr> <td valign="top">Parkinsonism <span class="Sup">a</span></td><td valign="top">15</td><td valign="top">14</td><td valign="top">12</td><td valign="top">14</td> </tr> <tr class="Last"> <td valign="top">Akathisia <span class="Sup">b</span></td><td valign="top">23</td><td valign="top">16</td><td valign="top">19</td><td valign="top">27</td> </tr> </tbody> </table></div>

aPercentage of patients with a Simpson-Angus Scale total score >3.  

bPercentage of patients with a Barnes Akathisia Scale global score ≥2. 

The following table enumerates the percentage of patients with treatment-emergent extrapyramidal symptoms as assessed by spontaneously reported adverse reactions during acute therapy in the same controlled clinical trial comparing olanzapine at 3 fixed doses with placebo in the treatment of schizophrenia in a 6-week trial. 

Table 17: Treatment-Emergent Extrapyramidal Symptoms Assessed by Adverse Reactions Incidence in a Fixed Dosage Range, Placebo-Controlled Clinical Trial of Oral Olanzapine in Schizophrenia — Acute Phase

<div class="scrollingtable"><table border="1" cellpadding="4" cellspacing="0" width="100%"> <tbody class="Headless"> <tr class="First"> <td valign="top"> </td><td colspan="4" valign="top">Percentage of Patients Reporting Event</td> </tr> <tr> <td valign="top"> </td><td valign="top"> Placebo(N=68)</td><td valign="top">Olanzapine5 ± 2.5 mg/day(N=65)</td><td valign="top">Olanzapine10 ± 2.5 mg/day(N=64)</td><td valign="top">Olanzapine15 ± 2.5 mg/day(N=69)</td> </tr> <tr> <td valign="top">Dystonic events <span class="Sup">a</span></td><td valign="top">1</td><td valign="top">3</td><td valign="top">2</td><td valign="top">3</td> </tr> <tr> <td valign="top">Parkinsonism events <span class="Sup">b</span></td><td valign="top">10</td><td valign="top">8</td><td valign="top">14</td><td valign="top">20</td> </tr> <tr> <td valign="top">Akathisia events <span class="Sup">c</span></td><td valign="top">1</td><td valign="top">5</td><td valign="top">11</td><td valign="top">10</td> </tr> <tr> <td valign="top">Dyskinetic events <span class="Sup">d</span></td><td valign="top">4</td><td valign="top">0</td><td valign="top">2</td><td valign="top">1</td> </tr> <tr> <td valign="top">Residual events <span class="Sup">e</span></td><td valign="top">1</td><td valign="top">2</td><td valign="top">5</td><td valign="top">1</td> </tr> <tr class="Last"> <td valign="top">Any extrapyramidal event</td><td valign="top">16</td><td valign="top">15</td><td valign="top">25</td><td valign="top">32</td> </tr> </tbody> </table></div>

aPatients with the following COSTART terms were counted in this category: dystonia, generalized spasm, neck rigidity, oculogyric crisis, opisthotonos, torticollis.

bPatients with the following COSTART terms were counted in this category: akinesia, cogwheel rigidity, extrapyramidal syndrome, hypertonia, hypokinesia, masked facies, tremor.

CPatients with the following COSTART terms were counted in this category: akathisia, hyperkinesia.

dPatients with the following COSTART terms were counted in this category: buccoglossal syndrome, choreoathetosis, dyskinesia, tardive dyskinesia.

ePatients with the following COSTART terms were counted in this category: movement disorder, myoclonus, twitching.

The following table enumerates the percentage of adolescent patients with treatment-emergent extrapyramidal symptoms as assessed by spontaneously reported adverse reactions during acute therapy (dose range: 2.5 to 20 mg/day).  

Table 18: Treatment-Emergent Extrapyramidal Symptoms Assessed by Adverse Reactions Incidencein Placebo-Controlled Clinical Trials of Oral Olanzapine in Schizophrenia and Bipolar I Disorder — Adolescents 

<div class="scrollingtable"><table border="1" cellpadding="4" cellspacing="0" width="600"> <tbody class="Headless"> <tr class="First"> <td valign="top"><span class="Bold"> </span></td><td colspan="2" valign="top"><span class="Bold">Percentage of Patients Reporting Event</span></td> </tr> <tr> <td valign="top"><span class="Bold">Categories <span class="Sup">a</span></span></td><td valign="top"><span class="Bold">Placebo</span> <br/> <span class="Bold">(N=89)</span></td><td valign="top"><span class="Bold">Olanzapine</span> <br/> <span class="Bold">(N=179)</span></td> </tr> <tr> <td valign="top">Dystonic events <span class="Bold"></span></td><td valign="top">0</td><td valign="top">1</td> </tr> <tr> <td valign="top">Parkinsonism events <span class="Bold"></span></td><td valign="top">2</td><td valign="top">1</td> </tr> <tr> <td valign="top">Akathisia events <span class="Bold"></span></td><td valign="top">4</td><td valign="top">6</td> </tr> <tr> <td valign="top">Dyskinetic events <span class="Bold"></span></td><td valign="top">0</td><td valign="top">1</td> </tr> <tr> <td valign="top">Nonspecific events <span class="Bold"></span></td><td valign="top">0</td><td valign="top">4</td> </tr> <tr class="Last"> <td valign="top">Any extrapyramidal event <span class="Bold"></span></td><td valign="top">6</td><td valign="top">10</td> </tr> </tbody> </table></div>

aCategories are based on Standard MedDRA Queries (SMQ) for extrapyramidal symptoms as defined in MedDRA version 12.

Dystonia, Class Effect:Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include: spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur at low doses, the frequency and severity are greater with high potency and at higher doses of first generation antipsychotic drugs. In general, an elevated risk of acute dystonia may be observed in males and younger age groups receiving antipsychotics; however, events of dystonia have been reported infrequently (<1%) with olanzapine use. 

Other Adverse Reactions Observed During the Clinical Trial Evaluation of Oral Olanzapine

Following is a list of treatment-emergent adverse reactions reported by patients treated with oral olanzapine (at multiple doses ≥1 mg/day) in clinical trials. This listing is not intended to include reactions (1) already listed in previous tables or elsewhere in labeling, (2) for which a drug cause was remote, (3) which were so general as to be uninformative, (4) which were not considered to have significant clinical implications, or (5) which occurred at a rate equal to or less than placebo. Reactions are classified by body system using the following definitions: frequent adverse reactions are those occurring in at least 1/100 patients; infrequent adverse reactions are those occurring in 1/100 to 1/1000 patients; rare reactions are those occurring in fewer than 1/1000 patients.

Body as a Whole — Infrequent: chills, face edema, photosensitivity reaction, suicide attempt1; Rare: chills and fever, hangover effect, sudden death1.

Cardiovascular System — Infrequent: cerebrovascular accident, vasodilatation.

Digestive System — Infrequent: abdominal distension, nausea and vomiting, tongue edema; Rare: ileus, intestinal obstruction, liver fatty deposit.

Hemic and Lymphatic System — Infrequent: thrombocytopenia.

Metabolic and Nutritional Disorders — Frequent: alkaline phosphatase increased, Infrequent: bilirubinemia, hypoproteinemia.

Musculoskeletal System — Rare: osteoporosis.

Nervous System — Infrequent: ataxia, dysarthria, libido decreased, stupor; Rare: coma.

Respiratory System — Infrequent: epistaxis; Rare: lung edema. Skin and Appendages — Infrequent: alopecia.

Special Senses — Infrequent: abnormality of accommodation, dry eyes; Rare: mydriasis.

Urogenital System — Infrequent: amenorrhea 2, breast pain, decreased menstruation, impotence2, increased menstruation2, menorrhagia2, metrorrhagia2, polyuria2, urinary frequency, urinary retention, urinary urgency, urination impaired.

1 These terms represent serious adverse events but do not meet the definition for adverse drug reactions. They are included here because of their seriousness.

2 Adjusted for gender.

Clinical Trials in Adolescent Patients (age 13 to 17 years)

Commonly Observed Adverse Reactions in Oral Olanzapine Short-Term, Placebo-Controlled Trials: Adverse reactions in adolescent patients treated with oral olanzapine (doses ≥2.5 mg) reported with an incidence of 5% or more and reported at least twice as frequently as placebo-treated patients are listed in Table 21.

Table 21: Treatment-Emergent Adverse Reactions of ≥5% Incidence among Adolescents (13 to 17 Years Old) with Schizophrenia or Bipolar I Disorder (Manic or Mixed Episodes) ­

<div class="scrollingtable"><table> <tbody class="Headless"> <tr class="First"> <td rowspan="3"><span class="Bold"> </span>  <span class="Bold"> </span>  <span class="Bold">Adverse Reactions</span>  <span class="Bold"> </span>  </td><td colspan="4"><span class="Bold">Percentage of Patients Reporting Event</span>  </td> </tr> <tr> <td colspan="2"><span class="Bold">6 Week Trial</span>  <span class="Bold">% Schizophrenia Patients</span>  </td><td colspan="2"><span class="Bold">3 Week Trial</span>  <span class="Bold">% Bipolar Patients</span>  </td> </tr> <tr> <td><span class="Bold">Olanzapine</span>  <span class="Bold">(N=72)</span>  </td><td><span class="Bold">Placebo</span>  <span class="Bold">(N=35)</span>  </td><td><span class="Bold">Olanzapine</span>  <span class="Bold">(N=107)</span>  </td><td><span class="Bold">Placebo</span>  <span class="Bold">(N=54)</span>  </td> </tr> <tr> <td>Sedationa </td><td>39</td><td>9</td><td>48</td><td>9</td> </tr> <tr> <td>Weight increased</td><td>31</td><td>9</td><td>29</td><td>4</td> </tr> <tr> <td>Headache</td><td>17</td><td>6</td><td>17</td><td>17</td> </tr> <tr> <td>Increased appetite</td><td>17</td><td>9</td><td>29</td><td>4</td> </tr> <tr> <td>Dizziness</td><td>8</td><td>3</td><td>7</td><td>2</td> </tr> <tr> <td>Abdominal painb </td><td>6</td><td>3</td><td>6</td><td>7</td> </tr> <tr> <td>Pain in extremity</td><td>6</td><td>3</td><td>5</td><td>0</td> </tr> <tr> <td>Fatigue</td><td>3</td><td>3</td><td>14</td><td>6</td> </tr> <tr class="Last"> <td>Dry mouth</td><td>4</td><td>0</td><td>7</td><td>0</td> </tr> </tbody> </table></div>

aPatients with the following MedDRA terms were counted in this category: hypersomnia, lethargy, sedation, somnolence. 

bPatients with the following MedDRA terms were counted in this category: abdominal pain, abdominal pain lower, abdominal pain upper.

Adverse Reactions Occurring at an Incidence of 2% or More among Oral Olanzapine-Treated Patients in Short-Term (3 to 6 weeks), Placebo-Controlled Trials: Adverse reactions in adolescent patients treated with oral olanzapine (doses ≥2.5 mg) reported with an incidence of 2% or more and greater than placebo are listed in Table 22.

Table 22: Treatment-Emergent Adverse Reactions of ≥2% Incidence among Adolescents (13 to 17 Years Old) (Combined Incidence from Short-Term, Placebo-Controlled Clinical Trials of Schizophrenia or Bipolar I Disorder [Manic or Mixed Episodes])

<div class="scrollingtable"><table> <tbody class="Headless"> <tr class="First"> <td colspan="3"><span class="Bold">Percentage of Patients Reporting Event</span>  </td> </tr> <tr> <td><span class="Bold">Adverse Reaction</span>  <span class="Bold"> </span>  </td><td><span class="Bold">Olanzapine</span>   <span class="Bold">(N=179)</span>  </td><td><span class="Bold">Placebo</span>   <span class="Bold">(N=89)</span>  </td> </tr> <tr> <td>Sedationa </td><td>44</td><td>9</td> </tr> <tr> <td>Weight increased</td><td>30</td><td>6</td> </tr> <tr> <td>Increased appetite</td><td>24</td><td>6</td> </tr> <tr> <td>Headache</td><td>17</td><td>12</td> </tr> <tr> <td>Fatigue</td><td>9</td><td>4</td> </tr> <tr> <td>Dizziness</td><td>7</td><td>2</td> </tr> <tr> <td>Dry mouth</td><td>6</td><td>0</td> </tr> <tr> <td>Pain in extremity</td><td>5</td><td>1</td> </tr> <tr> <td>Constipation</td><td>4</td><td>0</td> </tr> <tr> <td>Nasopharyngitis</td><td>4</td><td>2</td> </tr> <tr> <td>Diarrhea</td><td>3</td><td>0</td> </tr> <tr> <td>Restlessness</td><td>3</td><td>2</td> </tr> <tr> <td>Liver enzymes increasedb </td><td>8</td><td>1</td> </tr> <tr> <td>Dyspepsia</td><td>3</td><td>1</td> </tr> <tr> <td>Epistaxis</td><td>3</td><td>0</td> </tr> <tr> <td>Respiratory tract infectionc </td><td>3</td><td>2</td> </tr> <tr> <td>Sinusitis</td><td>3</td><td>0</td> </tr> <tr> <td>Arthralgia</td><td>2</td><td>0</td> </tr> <tr class="Last"> <td>Musculoskeletal stiffness</td><td>2</td><td>0</td> </tr> </tbody> </table></div>

aPatients with the following MedDRA terms were counted in this category: hypersomnia, lethargy, sedation, somnolence. bThe terms alanine aminotransferase (ALT), aspartate aminotransferase (AST), and hepatic enzyme were combined under liver enzymes. cPatients with the following MedDRA terms were counted in this category: lower respiratory tract infection, respiratory tract infection, respiratory tract infection viral, upper respiratory tract infection, viral upper respiratory tract infection.

Vital Signs and Laboratory Studies

Vital Sign Changes — Oral olanzapine was associated with orthostatic hypotension and tachycardia in clinical trials. [see Warnings and Precautions (5)].

Laboratory Changes 

Olanzapine Monotherapy in Adults:  An assessment of the premarketing experience for olanzapine revealed an association with asymptomatic increases in ALT, AST, and GGT. Within the original premarketing database of about 2400 adult patients with baseline ALT ≤90 IU/L, the incidence of ALT elevations to >200 IU/L was 2% (50/2381). None of these patients experienced jaundice or other symptoms attributable to liver impairment and most had transient changes that tended to normalize while olanzapine treatment was continued.

In placebo-controlled olanzapine monotherapy studies in adults, clinically significant ALT elevations (change from <3 times the upper limit of normal [ULN] at baseline to ≥3 times ULN) were observed in 5% (77/1426) of patients exposed to olanzapine compared to 1% (10/1187) of patients exposed to placebo. ALT elevations ≥5 times ULN were observed in 2% (29/1438) of olanzapine-treated patients, compared to 0.3% (4/1196) of placebo-treated patients. ALT values returned to normal, or were decreasing, at last follow-up in the majority of patients who either continued treatment with olanzapine or discontinued olanzapine. No patient with elevated ALT values experienced jaundice, liver failure, or met the criteria for Hy’s Rule.

From an analysis of the laboratory data in an integrated database of 41 completed clinical studies in adult patients treated with oral olanzapine, high GGT levels were recorded in ≥1% (88/5245) of patients.

Caution should be exercised in patients with signs and symptoms of hepatic impairment, in patients with pre-existing conditions associated with limited hepatic functional reserve, and in patients who are being treated with potentially hepatotoxic drugs.

Olanzapine administration was also associated with increases in serum prolactin [see Warnings and Precautions ( 5.15) ], with an asymptomatic elevation of the eosinophil count in 0.3% of patients, and with an increase in CPK.

From an analysis of the laboratory data in an integrated database of 41 completed clinical studies in adult patients treated with oral olanzapine, elevated uric acid was recorded in ≥3% (171/4641) of patients.

Olanzapine Monotherapy in Adolescents: In placebo-controlled clinical trials of adolescent patients with schizophrenia or bipolar I disorder (manic or mixed episodes), greater frequencies for the following treatment-emergent findings, at anytime, were observed in laboratory analytes compared to placebo: elevated ALT (≥3 X ULN in patients with ALT at baseline <3 X ULN), (12% vs 2%); elevated AST (28% vs 4%); low total bilirubin (22% vs 7%); elevated GGT (10 % vs 1%); and elevated prolactin (47% vs 7%).

In placebo-controlled olanzapine monotherapy studies in adolescents, clinically significant ALT elevations (change from <3 times ULN at baseline to ≥3 times ULN) were observed in 12% (22/192) of patients exposed to olanzapine compared to 2% (2/109) of patients exposed to placebo. ALT elevations ≥5 times ULN were observed in 4% (8/192) of olanzapine-treated patients, compared to 1% (1/109) of placebo-treated patients. ALT values returned to normal, or were decreasing, at last follow-up in the majority of patients who either continued treatment with olanzapine or discontinued olanzapine. No adolescent patient with elevated ALT values experienced jaundice, liver failure, or met the criteria for Hy’s Rule.

ECG Changes — In pooled studies of adults as well as pooled studies of adolescents, there were no significant differences between olanzapine and placebo in the proportions of patients experiencing potentially important changes in ECG parameters, including QT, QTc (Fridericia corrected), and PR intervals. Olanzapine use was associated with a mean increase in heart rate compared to placebo (adults: +2.4 beats per minute vs no change with placebo; adolescents: +6.3 beats per minute vs -5.1 beats per minute with placebo). This increase in heart rate may be related to olanzapine’s potential for inducing orthostatic changes [see Warnings and Precautions ( 5.7) ].

The following adverse reactions have been identified during post-approval use of olanzapine. Because these reactions are reported voluntarily from a population of uncertain size, it is difficult to reliably estimate their frequency or evaluate a causal relationship to drug exposure. 

Adverse reactions reported since market introduction that were temporally (but not necessarily causally) related to olanzapine therapy include the following: allergic reaction (e.g., anaphylactoid reaction, angioedema, pruritus or urticaria), cholestatic or mixed liver injury, diabetic coma, diabetic ketoacidosis, discontinuation reaction (diaphoresis, nausea or vomiting), Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), hepatitis, jaundice, neutropenia, pancreatitis, priapism, rash, restless legs syndrome, rhabdomyolysis, salivary hypersecretion, stuttering 1venous thromboembolic events (including pulmonary embolism and deep venous thrombosis), fecal incontinence, and somnambulism. Random cholesterol levels of ≥240 mg/dL and random triglyceride levels of ≥1000 mg/dL have been reported.

1Stuttering was only studied in oral and long acting injection (LAI) formulations.

Diazepam — The co-administration of diazepam with olanzapine potentiated the orthostatic hypotension observed with olanzapine [see Drug Interactions (7.2)]. 

Cimetidine and Antacids — Single doses of cimetidine (800 mg) or aluminum- and magnesium-containing antacids did not affect the oral bioavailability of olanzapine. 

Inducers of CYP1A2 — Carbamazepine therapy (200 mg bid) causes an approximately 50% increase in the clearance of olanzapine. This increase is likely due to the fact that carbamazepine is a potent inducer of CYP1A2 activity. Higher daily doses of carbamazepine may cause an even greater increase in olanzapine clearance. 

Alcohol — Ethanol (45 mg/70 kg single dose) did not have an effect on olanzapine pharmacokinetics. The co-administration of alcohol (i.e., ethanol) with olanzapine potentiated the orthostatic hypotension observed with olanzapine [see Drug Interactions (7.2)]. 

Inhibitors of CYP1A2

Fluvoxamine: Fluvoxamine, a CYP1A2 inhibitor, decreases the clearance of olanzapine. This results in a mean increase in olanzapine Cmax following fluvoxamine of 54% in female nonsmokers and 77% in male smokers. The mean increase in olanzapine AUC is 52% and 108%, respectively. Lower doses of olanzapine should be considered in patients receiving concomitant treatment with fluvoxamine. 

Inhibitors of CYP2D6

Fluoxetine: Fluoxetine (60 mg single dose or 60 mg daily dose for 8 days) causes a small (mean 16%) increase in the maximum concentration of olanzapine and a small (mean 16%) decrease in olanzapine clearance. The magnitude of the impact of this factor is small in comparison to the overall variability between individuals, and therefore dose modification is not routinely recommended. When using olanzapine and fluoxetine in combination, also refer to the Drug Interactions section of the package insert for Symbyax.

 Warfarin — Warfarin (20 mg single dose) did not affect olanzapine pharmacokinetics [see Drug Interactions (7.2) ]. 

Inducers of CYP1A2 or Glucuronyl Transferase — Omeprazole and rifampin, may cause an increase in olanzapine clearance. 

Charcoal — The administration of activated charcoal (1 g) reduced the Cmax and AUC of oral olanzapine by about 60%. As peak olanzapine levels are not typically obtained until about 6 hours after dosing, charcoal may be a useful treatment for olanzapine overdose.

Anticholinergic Drugs — Concomitant treatment with olanzapine and other drugs with anticholinergic activity can increase the risk for severe gastrointestinal adverse reactions related to hypomotility. Olanzapine should be used with caution in patients receiving medications having anticholinergic (antimuscarinic) effects [see Warnings and Precautions ( 5.14)].

CNS Acting Drugs — Given the primary CNS effects of olanzapine, caution should be used when olanzapine is taken in combination with other centrally acting drugs and alcohol. 

Antihypertensive Agents — Olanzapine, because of its potential for inducing hypotension, may enhance the effects of certain antihypertensive agents. 

Levodopa and Dopamine Agonists — Olanzapine may antagonize the effects of levodopa and dopamine agonists. 

Lithium — Multiple doses of olanzapine (10 mg for 8 days) did not influence the kinetics of lithium. Therefore, concomitant olanzapine administration does not require dosage adjustment of lithium. [see Warnings and Precautions (5.16)].

Valproate —Olanzapine (10 mg daily for 2 weeks) did not affect the steady state plasma concentrations of valproate. Therefore, concomitant olanzapine administration does not require dosage adjustment of valproate. [see Warnings and Precautions (5.16)].

Effect of Olanzapine on Drug Metabolizing Enzymes — In vitrostudies utilizing human liver microsomes suggest that olanzapine has little potential to inhibit CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A. Thus, olanzapine is unlikely to cause clinically important drug interactions mediated by these enzymes. 

Imipramine — Single doses of olanzapine did not affect the pharmacokinetics of imipramine or its active metabolite desipramine. 

Warfarin — Single doses of olanzapine did not affect the pharmacokinetics of warfarin [see Drug Interactions (7.1)]. 

Diazepam — Olanzapine did not influence the pharmacokinetics of diazepam or its active metabolite N-desmethyldiazepam. However, diazepam co-administered with olanzapine increased the orthostatic hypotension observed with either drug given alone. [see Drug Interactions (7.1)].

Alcohol — Multiple doses of olanzapine did not influence the kinetics of ethanol [see Drug Interactions (7.1)]. 

Biperiden — Multiple doses of olanzapine did not influence the kinetics of biperiden. 

Theophylline — Multiple doses of olanzapine did not affect the pharmacokinetics of theophylline or its metabolites.

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to atypical antipsychotics, including olanzapine, during pregnancy. Healthcare providers are encouraged to register patients by contacting the National Pregnancy Registry for Atypical Antipsychotics at 1-866-961-2388 or visit http://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/.

Risk Summary

Neonates exposed to antipsychotic drugs, including olanzapine, during the third trimester are at risk for extrapyramidal and/or withdrawal symptoms following delivery ( see Clinical Considerations). Overall available data from published epidemiologic studies of pregnant women exposed to olanzapine have not established a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes ( see Data). There are risks to the mother associated with untreated schizophrenia or bipolar I disorder and with exposure to antipsychotics, including olanzapine, during pregnancy ( see Clinical Considerations).

Olanzapine was not teratogenic when administered orally to pregnant rats and rabbits at doses that are 9- and 30-times the daily oral maximum recommended human dose (MRHD), based on mg/m 2body surface area; some fetal toxicities were observed at these doses ( see Data).

The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defects, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Clinical Considerations

Disease-associated maternal and embryo/fetal risk

There is a risk to the mother from untreated schizophrenia or bipolar I disorder, including increased risk of relapse, hospitalization, and suicide. Schizophrenia and bipolar I disorder are associated with increased adverse perinatal outcomes, including preterm birth. It is not known if this is a direct result of the illness or other comorbid factors.

Fetal/Neonatal adverse reactions

Extrapyramidal and/or withdrawal symptoms, including agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder have been reported in neonates who were exposed to antipsychotic drugs, including olanzapine, during the third trimester of pregnancy. These symptoms have varied in severity. Monitor neonates for extrapyramidal and/or withdrawal symptoms and manage symptoms appropriately. Some neonates recovered within hours or days without specific treatment; others required prolonged hospitalization.

Data

Human Data

Placental passage has been reported in published study reports; however, the placental passage ratio was highly variable ranging between 7% to 167% at birth following exposure during pregnancy. The clinical relevance of this finding is unknown.

Published data from observational studies, birth registries, and case reports that have evaluated the use of atypical antipsychotics during pregnancy do not establish an increased risk of major birth defects. A retrospective cohort study from a Medicaid database of 9258 women exposed to antipsychotics during pregnancy did not indicate an overall increased risk for major birth defects.

Animal Data

In oral reproduction studies in rats at doses up to 18 mg/kg/day and in rabbits at doses up to 30 mg/kg/day (9 and 30 times the daily oral MRHD based on mg/m 2body surface area, respectively), no evidence of teratogenicity was observed. In an oral rat teratology study, early resorptions and increased numbers of nonviable fetuses were observed at a dose of 18 mg/kg/day (9 times the daily oral MRHD based on mg/m 2body surface area), and gestation was prolonged at 10 mg/kg/day (5 times the daily oral MRHD based on mg/m 2body surface area). In an oral rabbit teratology study, fetal toxicity manifested as increased resorptions and decreased fetal weight, occurred at a maternally toxic dose of 30 mg/kg/day (30 times the daily oral MRHD based on mg/m 2body surface area).

Risk Summary

Olanzapine is present in human milk. There are reports of excess sedation, irritability, poor feeding and extrapyramidal symptoms (tremors and abnormal muscle movements) in infants exposed to olanzapine through breast milk ( see Clinical Considerations). There is no information on the effects of olanzapine on milk production.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for olanzapine and any potential adverse effects on the breastfed child from olanzapine or from the mother’s underlying condition.

Clinical Considerations

Infants exposed to olanzapine should be monitored for excess sedation, irritability, poor feeding, and extrapyramidal symptoms (tremors and abnormal muscle movements).

Infertility

Females

Based on the pharmacologic action of olanzapine (D 2receptor antagonism), treatment with olanzapine may result in an increase in serum prolactin levels, which may lead to a reversible reduction in fertility in females of reproductive potential [see Warnings and Precautions (5.15)].

The safety and effectiveness of oral olanzapine in the treatment of schizophrenia and manic or mixed episodes associated with bipolar I disorder were established in short-term studies in adolescents (ages 13 to 17 years). Use of olanzapine in adolescents is supported by evidence from adequate and well-controlled studies of olanzapine in which 268 adolescents received olanzapine in a range of 2.5 to 20 mg/day [see Clinical Studies (14.1, 14.2)]. Recommended starting dose for adolescents is lower than that for adults [see Dosage and Administration ( 2.1, 2.2)]. Compared to patients from adult clinical trials, adolescents were likely to gain more weight, experience increased sedation, and have greater increases in total cholesterol, triglycerides, LDL cholesterol, prolactin and hepatic aminotransferase levels [see Warnings and Precautions ( 5.5, 5.15, 5.17) and Adverse Reactions (6.1)]. When deciding among the alternative treatments available for adolescents, clinicians should consider the increased potential (in adolescents as compared with adults) for weight gain and dyslipidemia. Clinicians should consider the potential long-term risks when prescribing to adolescents, and in many cases this may lead them to consider prescribing other drugs first in adolescents [see Indications and Usage ( 1.1, 1.2) ]. 

Safety and effectiveness of olanzapine in children <13 years of age have not been established [see Patient Counseling Information ( 17) ].

Safety and efficacy of olanzapine and fluoxetine in combination in children and adolescents (10 to 17 years of age) have been established for the acute treatment of depressive episodes associated with bipolar I disorder.

Safety and effectiveness of olanzapine and fluoxetine in combination in children <10 years of age have not been established.  

Of the 2500 patients in premarketing clinical studies with oral olanzapine, 11% (263) were 65 years of age or over. In patients with schizophrenia, there was no indication of any different tolerability of olanzapine in the elderly compared to younger patients. Studies in elderly patients with dementia-related psychosis have suggested that there may be a different tolerability profile in this population compared to younger patients with schizophrenia. Elderly patients with dementia-related psychosis treated with olanzapine are at an increased risk of death compared to placebo. In placebo-controlled studies of olanzapine in elderly patients with dementia-related psychosis, there was a higher incidence of cerebrovascular adverse events (e.g., stroke, transient ischemic attack) in patients treated with olanzapine compared to patients treated with placebo. In 5 placebo-controlled studies of olanzapine in elderly patients with dementia-related psychosis (n=1184), the following adverse reactions were reported in olanzapine-treated patients at an incidence of at least 2% and significantly greater than placebo-treated patients: falls, somnolence, peripheral edema, abnormal gait, urinary incontinence, lethargy, increased weight, asthenia, pyrexia, pneumonia, dry mouth and visual hallucinations. The rate of discontinuation due to adverse reactions was greater with olanzapine than placebo (13% vs 7%). Elderly patients with dementia-related psychosis treated with olanzapine are at an increased risk of death compared to placebo. Olanzapine is not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning, Warnings and Precautions ( 5.1), and Patient Counseling Information ( 17)]. Olanzapine is not approved for the treatment of patients with dementia-related psychosis. Also, the presence of factors that might decrease pharmacokinetic clearance or increase the pharmacodynamic response to olanzapine should lead to consideration of a lower starting dose for any geriatric patient [see Boxed Warning, Warnings and Precautions (5.1), and Dosage and Administration (2.1)]. 

Clinical studies of olanzapine and fluoxetine in combination did not include sufficient numbers of patients ≥65 years of age to determine whether they respond differently from younger patients.

In studies prospectively designed to assess abuse and dependence potential, olanzapine was shown to have acute depressive CNS effects but little or no potential of abuse or physical dependence in rats administered oral doses up to 15 times the daily oral MRHD (20 mg) and rhesus monkeys administered oral doses up to 8 times the daily oral MRHD based on mg/m 2body surface area. 

Olanzapine has not been systematically studied in humans for its potential for abuse, tolerance, or physical dependence. While the clinical trials did not reveal any tendency for any drug-seeking behavior, these observations were not systematic, and it is not possible to predict on the basis of this limited experience the extent to which a CNS-active drug will be misused, diverted, and/or abused once marketed. Consequently, patients should be evaluated carefully for a history of drug abuse, and such patients should be observed closely for signs of misuse or abuse of olanzapine (e.g., development of tolerance, increases in dose, drug-seeking behavior).

In premarketing trials involving more than 3100 patients and/or normal subjects, accidental or intentional acute overdosage of olanzapine was identified in 67 patients. In the patient taking the largest identified amount, 300 mg, the only symptoms reported were drowsiness and slurred speech. In the limited number of patients who were evaluated in hospitals, including the patient taking 300 mg, there were no observations indicating an adverse change in laboratory analytes or ECG. Vital signs were usually within normal limits following overdoses. 

In postmarketing reports of overdose with olanzapine alone, symptoms have been reported in the majority of cases. In symptomatic patients, symptoms with ≥10% incidence included agitation/aggressiveness, dysarthria, tachycardia, various extrapyramidal symptoms, and reduced level of consciousness ranging from sedation to coma. Among less commonly reported symptoms were the following potentially medically serious reactions: aspiration, cardiopulmonary arrest, cardiac arrhythmias (such as supraventricular tachycardia and 1 patient experiencing sinus pause with spontaneous resumption of normal rhythm), delirium, possible neuroleptic malignant syndrome, respiratory depression/arrest, convulsion, hypertension, and hypotension. Reports of fatality in association with overdose of olanzapine alone have been received .In 1 case of death, the amount of acutely ingested olanzapine was reported to be possibly as low as 450 mg of oral olanzapine; however, in another case, a patient was reported to survive an acute olanzapine ingestion of approximately 2 g of oral olanzapine.

There is no specific antidote to an overdose of olanzapine. The possibility of multiple drug involvement should be considered. Establish and maintain an airway and ensure adequate oxygenation and ventilation. Cardiovascular monitoring should commence immediately and should include continuous electrocardiographic monitoring to detect possible arrhythmias.

Contact a Certified Poison Control Center for the most up to date information on the management of overdosage (1-800-222- 1222).

For specific information about overdosage with lithium or valproate, refer to the Overdosage section of the prescribing information for those products. For specific information about overdosage with olanzapine and fluoxetine in combination, refer to the Overdosage section of the Symbyax prescribing information.

Olanzapine  USP is an atypical antipsychotic that belongs to the thienobenzodiazepine class. The chemical designation is 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b] [1,5]benzodiazepine. The molecular formula is C 17H 20N 4S, which corresponds to a molecular weight of 312.44. The chemical structure is:

{ "type": "p", "children": [], "text": "Olanzapine  USP is an atypical antipsychotic that belongs to the thienobenzodiazepine class. The chemical designation is 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b] [1,5]benzodiazepine. The molecular formula is C\n \n 17H\n \n 20N\n \n 4S, which corresponds to a molecular weight of 312.44. The chemical structure is:\n\n " }

Olanzapine USP is a yellow crystalline solid, which is practically insoluble in water. 

{ "type": "p", "children": [], "text": "Olanzapine USP is a yellow crystalline solid, which is practically insoluble in water. " }

Olanzapine tablets USP are intended for oral administration only. 

{ "type": "p", "children": [], "text": "Olanzapine tablets USP are intended for oral administration only. " }

Each tablet contains olanzapine USP equivalent to 15 mg (48 μmol) and 20 mg (64 µmol). Inactive ingredients are crospovidone, hydroxypropyl cellulose, lactose monohydrate, magnesium stearate, microcrystalline cellulose (Avicel PH 101) and microcrystalline cellulose (Avicel PH 102). The color coating contains hypromellose, polyethylene glycol 400 and titanium dioxide.

{ "type": "p", "children": [], "text": "Each tablet contains olanzapine USP equivalent to 15 mg (48 μmol) and 20 mg (64 µmol). Inactive ingredients are crospovidone, hydroxypropyl cellulose, lactose monohydrate, magnesium stearate, microcrystalline cellulose (Avicel PH 101) and microcrystalline cellulose (Avicel PH 102). The color coating contains hypromellose, polyethylene glycol 400 and titanium dioxide." }

The mechanism of action of olanzapine, in the listed indications is unclear. However, the efficacy of olanzapine in schizophrenia could be mediated through a combination of dopamine and serotonin type 2 (5HT 2) antagonism.

Olanzapine binds with high affinity to the following receptors: serotonin 5HT 2A/2C, 5HT 6(K i=4, 11, and 5 nM, respectively), dopamine D 1-4(K i=11-31 nM), histamine H 1(K i=7 nM), and adrenergic α 1receptors (K i=19 nM). Olanzapine is an antagonist with moderate affinity binding for serotonin 5HT 3(K i=57 nM) and muscarinic M 1-5(K i=73, 96, 132, 32, and 48 nM, respectively). Olanzapine binds with low affinity to GABA A, BZD, and β adrenergic receptors (K i>10 μM). 

Oral Administration, Monotherapy — Olanzapine is well absorbed and reaches peak concentrations in approximately 6 hours following an oral dose. It is eliminated extensively by first pass metabolism, with approximately 40% of the dose metabolized before reaching the systemic circulation. Food does not affect the rate or extent of olanzapine absorption.  

Olanzapine displays linear kinetics over the clinical dosing range. Its half-life ranges from 21 to 54 hours (5th to 95th percentile; mean of 30 hr), and apparent plasma clearance ranges from 12 to 47 L/hr (5th to 95th percentile; mean of 25 L/hr). Administration of olanzapine once daily leads to steady-state concentrations in about 1 week that are approximately twice the concentrations after single doses. Plasma concentrations, half-life, and clearance of olanzapine may vary between individuals on the basis of smoking status, gender, and age.

Olanzapine is extensively distributed throughout the body, with a volume of distribution of approximately 1000 L. It is 93% bound to plasma proteins over the concentration range of 7 to 1100 ng/mL, binding primarily to albumin and α 1-acid glycoprotein. 

Metabolism and Elimination — Following a single oral dose of 14C labeled olanzapine, 7% of the dose of olanzapine was recovered in the urine as unchanged drug, indicating that olanzapine is highly metabolized. Approximately 57% and 30% of the dose was recovered in the urine and feces, respectively. In the plasma, olanzapine accounted for only 12% of the AUC for total radioactivity, indicating significant exposure to metabolites. After multiple dosing, the major circulating metabolites were the 10-N-glucuronide, present at steady state at 44% of the concentration of olanzapine, and 4´-N-desmethyl olanzapine, present at steady state at 31% of the concentration of olanzapine. Both metabolites lack pharmacological activity at the concentrations observed. Direct glucuronidation and cytochrome P450 (CYP) mediated oxidation are the primary metabolic pathways for olanzapine. In vitrostudies suggest that CYPs 1A2 and 2D6, and the flavin-containing monooxygenase system are involved in olanzapine oxidation. CYP2D6 mediated oxidation appears to be a minor metabolic pathway in vivo, because the clearance of olanzapine is not reduced in subjects who are deficient in this enzyme. 

Specific Populations

Renal Impairment— Because olanzapine is highly metabolized before excretion and only 7% of the drug is excreted unchanged, renal dysfunction alone is unlikely to have a major impact on the pharmacokinetics of olanzapine. The pharmacokinetic characteristics of olanzapine were similar in patients with severe renal impairment and normal subjects, indicating that dosage adjustment based upon the degree of renal impairment is not required. In addition, olanzapine is not removed by dialysis. The effect of renal impairment on metabolite elimination has not been studied. 

Hepatic Impairment— Although the presence of hepatic impairment may be expected to reduce the clearance of olanzapine, a study of the effect of impaired liver function in subjects (n=6) with clinically significant (Childs Pugh Classification A and B) cirrhosis revealed little effect on the pharmacokinetics of olanzapine. 

Geriatric— In a study involving 24 healthy subjects, the mean elimination half-life of olanzapine was about 1.5 times greater in elderly (≥65 years) than in non-elderly subjects (<65 years). Caution should be used in dosing the elderly, especially if there are other factors that might additively influence drug metabolism and/or pharmacodynamic sensitivity [see Dosage and Administration (2)]. 

Gender— Clearance of olanzapine is approximately 30% lower in women than in men. There were, however, no apparent differences between men and women in effectiveness or adverse effects. Dosage modifications based on gender should not be needed. 

Smoking Status— Olanzapine clearance is about 40% higher in smokers than in nonsmokers, although dosage modifications are not routinely recommended. 

Race— In vivostudies have shown that exposures are similar among Japanese, Chinese and Caucasians, especially after normalization for body weight differences. Dosage modifications for race are, therefore, not recommended. 

Combined Effects— The combined effects of age, smoking, and gender could lead to substantial pharmacokinetic differences in populations. The clearance in young smoking males, for example, may be 3 times higher than that in elderly nonsmoking females. Dosing modification may be necessary in patients who exhibit a combination of factors that may result in slower metabolism of olanzapine [see Dosage and Administration (2)]. 

Adolescents (ages 13 to 17 years)—In clinical studies, most adolescents were nonsmokers and this population had a lower average body weight, which resulted in higher average olanzapine exposure compared to adults.

Carcinogenesis — Oral carcinogenicity studies were conducted in mice and rats. Olanzapine was administered to mice in two 78-week studies at doses of 3, 10, 30/20 mg/kg/day (equivalent to 0.8 to 5 times the daily oral MRHD based on mg/m 2body surface area) and 0.25, 2, 8 mg/kg/day (equivalent to 0.06 to 2 times the daily oral MRHD based on mg/m 2body surface area). Rats were dosed for 2 years at doses of 0.25, 1, 2.5, 4 mg/kg/day (males) and 0.25, 1, 4, 8 mg/kg/day (females) (equivalent to 0.13-2 and 0.13-4 times the daily oral MRHD based on mg/m2 body surface area, respectively). The incidence of liver hemangiomas and hemangiosarcomas was significantly increased in 1 mouse study in female mice at 2 times the daily oral MRHD based on mg/m 2body surface area. These tumors were not increased in another mouse study in females dosed up to 2-5 times the daily oral MRHD based on mg/m 2body surface area; in this study, there was a high incidence of early mortalities in males of the 30/20 mg/kg/day group. The incidence of mammary gland adenomas and adenocarcinomas was significantly increased in female mice dosed at ≥2 mg/kg/day and in female rats dosed at ≥4 mg/kg/day (0.5 and 2 times the daily oral MRHD based on mg/m 2body surface area, respectively). Antipsychotic drugs have been shown to chronically elevate prolactin levels in rodents. Serum prolactin levels were not measured during the olanzapine carcinogenicity studies; however, measurements during subchronic toxicity studies showed that olanzapine elevated serum prolactin levels up to 4-fold in rats at the same doses used in the carcinogenicity study. An increase in mammary gland neoplasms has been found in rodents after chronic administration of other antipsychotic drugs and is considered to be prolactin mediated. The relevance for human risk of the finding of prolactin mediated endocrine tumors in rodents is unknown [see Warnings and Precautions (5.15)].

Mutagenesis — No evidence of genotoxic potential for olanzapine was found in the Ames reverse mutation test, in vivomicronucleus test in mice, the chromosomal aberration test in Chinese hamster ovary cells, unscheduled DNA synthesis test in rat hepatocytes, induction of forward mutation test in mouse lymphoma cells, or in vivosister chromatid exchange test in bone marrow of Chinese hamsters. 

Impairment of Fertility — In an oral fertility and reproductive performance study in rats, male mating performance, but not fertility, was impaired at a dose of 22.4 mg/kg/day and female fertility was decreased at a dose of 3 mg/kg/day (11 and 1.5 times the daily oral MRHD based on mg/m 2body surface area, respectively). Discontinuance of olanzapine treatment reversed the effects on male mating performance. In female rats, the precoital period was increased and the mating index reduced at 5 mg/kg/day (2.5 times the daily oral MRHD based on mg/m 2body surface area. Diestrous was prolonged and estrous delayed at 1.1 mg/kg/day (0.6 times the daily oral MRHD based on mg/m 2body surface area); therefore olanzapine may produce a delay in ovulation.

In animal studies with olanzapine, the principal hematologic findings were reversible peripheral cytopenias in individual dogs dosed at 10 mg/kg (17 times the daily oral MRHD based on mg/m 2body surface area), dose-related decreases in lymphocytes and neutrophils in mice, and lymphopenia in rats. A few dogs treated with 10 mg/kg developed reversible neutropenia and/or reversible hemolytic anemia between 1 and 10 months of treatment. Dose-related decreases in lymphocytes and neutrophils were seen in mice given doses of 10 mg/kg (equal to 2 times the daily oral MRHD based on mg/m 2body surface area) in studies of 3 months’ duration. Nonspecific lymphopenia, consistent with decreased body weight gain, occurred in rats receiving 22.5 mg/kg (11 times the daily oral MRHD based on mg/m 2body surface area) for 3 months or 16 mg/kg (8 times the daily oral MRHD based on mg/m 2body surface area) for 6 or 12 months. No evidence of bone marrow cytotoxicity was found in any of the species examined. Bone marrows were normocellular or hypercellular, indicating that the reductions in circulating blood cells were probably due to peripheral (non-marrow) factors.

Adults

The efficacy of oral olanzapine in the treatment of schizophrenia was established in 2 short-term (6-week) controlled trials of adult inpatients who met DSM III-R criteria for schizophrenia. A single haloperidol arm was included as a comparative treatment in 1 of the 2 trials, but this trial did not compare these 2 drugs on the full range of clinically relevant doses for both. 

Several instruments were used for assessing psychiatric signs and symptoms in these studies, among them the Brief Psychiatric Rating Scale (BPRS), a multi-item inventory of general psychopathology traditionally used to evaluate the effects of drug treatment in schizophrenia. The BPRS psychosis cluster (conceptual disorganization, hallucinatory behavior, suspiciousness, and unusual thought content) is considered a particularly useful subset for assessing actively psychotic schizophrenic patients. A second traditional assessment, the Clinical Global Impression (CGI), reflects the impression of a skilled observer, fully familiar with the manifestations of schizophrenia, about the overall clinical state of the patient. In addition, 2 more recently developed scales were employed; these included the 30-item Positive and Negative Symptoms Scale (PANSS), in which are embedded the 18 items of the BPRS, and the Scale for Assessing Negative Symptoms (SANS). The trial summaries below focus on the following outcomes: PANSS total and/or BPRS total; BPRS psychosis cluster; PANSS negative subscale or SANS; and CGI Severity. The results of the trials follow:

1) In a 6-week, placebo-controlled trial (n=149) involving 2 fixed olanzapine doses of 1 and 10 mg/day (once daily schedule), olanzapine, at 10 mg/day (but not at 1 mg/day), was superior toplacebo on the PANSS total score (also on the extracted BPRS total), on the BPRS psychosis cluster, on the PANSS Negative subscale, and on CGI Severity.

2) In a 6-week, placebo-controlled trial (n=253) involving 3 fixed dose ranges of olanzapine (5 ± 2.5 mg/day, 10 ± 2.5 mg/day, and 15 ± 2.5 mg/day) on a once daily schedule, the 2 highest olanzapine dose groups (actual mean doses of 12 and 16 mg/day, respectively) were superior to placebo on BPRS total score, BPRS psychosis cluster, and CGI severity score; the highest olanzapine dose group was superior to placebo on the SANS. There was no clear advantage for the high-dose group over the medium-dose group. 

3) In a longer-term trial, adult outpatients (n=326) who predominantly met DSM-IV criteria for schizophrenia and who remained stable on olanzapine during open-label treatment for at least 8 weeks were randomized to continuation on their current olanzapine doses (ranging from 10 to   20 mg/day) or to placebo. The follow-up period to observe patients for relapse, defined in terms of increases in BPRS positive symptoms or hospitalization, was planned for 12 months, however, criteria were met for stopping the trial early due to an excess of placebo relapses compared to olanzapine relapses, and olanzapine was superior to placebo on time to relapse, the primary outcome for this study. Thus, olanzapine was more effective than placebo at maintaining efficacy in patients stabilized for approximately 8 weeks and followed for an observation period of up to 8 months.

Examination of population subsets (race and gender) did not reveal any differential responsiveness on the basis of these subgroupings.

Adolescents

The efficacy of oral olanzapine in the acute treatment of schizophrenia in adolescents (ages 13 to 17 years) was established in a 6-week double-blind, placebo-controlled, randomized trial of inpatients and outpatients with schizophrenia (n=107) who met diagnostic criteria according to DSM-IV-TR and confirmed by the Kiddie Schedule for Affective Disorders and schizophrenia for School Aged Children-Present and Lifetime Version (K-SADS-PL).  

The primary rating instrument used for assessing psychiatric signs and symptoms in this trial was the Anchored Version of the Brief Psychiatric Rating Scale for Children (BPRS-C) total score.  

In this flexible-dose trial, olanzapine 2.5 to 20 mg/day (mean modal dose 12.5 mg/day, mean dose of 11.1 mg/day) was more effective than placebo in the treatment of adolescents diagnosed with schizophrenia, as supported by the statistically significantly greater mean reduction in BPRS-C total score for patients in the olanzapine treatment group than in the placebo group.  

While there is no body of evidence available to answer the question of how long the adolescent patient treated with olanzapine should be maintained, maintenance efficacy can be extrapolated from adult data along with comparisons of olanzapine pharmacokinetic parameters in adult and adolescent patients. It is generally recommended that responding patients be continued beyond the acute response, but at the lowest dose needed to maintain remission. Patients should be periodically reassessed to determine the need for maintenance treatment.

Adults

Monotherapy— The efficacy of oral olanzapine in the treatment of manic or mixed episodes was established in 2 short-term (one 3-week and one 4-week) placebo-controlled trials in adult patients who met the DSM-IV criteria for bipolar I disorder with manic or mixed episodes. These trials included patients with or without psychotic features and with or without a rapid-cycling course. 

The primary rating instrument used for assessing manic symptoms in these trials was the Young Mania Rating Scale (Y-MRS), an 11-item clinician-rated scale traditionally used to assess the degree of manic symptomatology (irritability, disruptive/aggressive behavior, sleep, elevated mood, speech, increased activity, sexual interest, language/thought disorder, thought content, appearance, and insight) in a range from 0 (no manic features) to 60 (maximum score). The primary outcome in these trials was change from baseline in the Y-MRS total score. The results of the trials follow:

(1) In one 3-week placebo-controlled trial (n=67) which involved a dose range of olanzapine (5-20 mg/day, once daily, starting at 10 mg/day), olanzapine was superior to placebo in the reduction of Y-MRS total score. In an identically designed trial conducted simultaneously with the first trial, olanzapine demonstrated a similar treatment difference, but possibly due to sample size and site variability, was not shown to be superior to placebo on this outcome.

(2) In a 4-week placebo-controlled trial (n=115) which involved a dose range of olanzapine (5 to 20 mg/day, once daily, starting at 15 mg/day), olanzapine was superior to placebo in the reduction of Y-MRS total score.

(3) In another trial, 361 patients meeting DSM-IV criteria for a manic or mixed episode of bipolar I disorder who had responded during an initial open-label treatment phase for about 2 weeks, on average, to olanzapine 5 to 20 mg/day were randomized to either continuation of olanzapine at their same dose (n=225) or to placebo (n=136), for observation of relapse. Approximately 50% of the patients had discontinued from the olanzapine group by day 59 and 50% of the placebo group had discontinued by day 23 of double-blind treatment. Response during the open-label phase was defined by having a decrease of the Y-MRS total score to ≤12 and HAM-D 21 to ≤8. Relapse during the double-blind phase was defined as an increase of the Y-MRS or HAM-D 21 total score to ≥15, or being hospitalized for either mania or depression. In the randomized phase, patients receiving continued olanzapine experienced a significantly longer time to relapse. 

Adjunct to Lithium or Valproate — The efficacy of oral olanzapine with concomitant lithium or valproate in the treatment of acute manic or mixed episodes was established in 2 controlled trials in patients who met the DSM-IV criteria for bipolar I disorder with manic or mixed episodes. These trials included patients with or without psychotic features and with or without a rapid-cycling course. The results of the trials follow:

(1) In one 6-week placebo-controlled combination trial, 175 outpatients on lithium or valproate therapy with inadequately controlled manic or mixed symptoms (Y-MRS ≥16) were randomized to receive either olanzapine or placebo, in combination with their original therapy. Olanzapine (in a dose range of 5 to 20 mg/day, once daily, starting at 10 mg/day) combined with lithium or valproate (in a therapeutic range of 0.6 mEq/L to 1.2 mEq/L or 50 mcg/ mL to 125 mcg/mL, respectively) was superior to lithium or valproate alone in the reduction of Y-MRS total score.

(2) In a second 6-week placebo-controlled combination trial, 169 outpatients on lithium or valproate therapy with inadequately controlled manic or mixed symptoms (Y-MRS ≥16) were randomized to receive either olanzapine or placebo, in combination with their original therapy. Olanzapine (in a dose range of 5 to 20 mg/day, once daily, starting at 10 mg/day) combined with lithium or valproate (in a therapeutic range of 0.6 mEq/L to 1.2 mEq/L or 50 mcg/mL to 125 mcg/mL, respectively) was superior to lithium or valproate alone in the reduction of Y-MRS total score.

Adolescents

Acute Monotherapy —The efficacy of oral olanzapine in the treatment of acute manic or mixed episodes in adolescents (ages 13 to 17 years) was established in a 3-week, double-blind, placebo-controlled, randomized trial of adolescent inpatients and outpatients who met the diagnostic criteria for manic or mixed episodes associated with bipolar I disorder (with or without psychotic features) according to the DSM-IV-TR (n=161). Diagnosis was confirmed by the K-SADS-PL.  

The primary rating instrument used for assessing manic symptoms in this trial was the Adolescent Structured Young-Mania Rating Scale (Y-MRS) total score.  

In this flexible-dose trial, olanzapine 2.5 to 20 mg/day (mean modal dose 10.7 mg/day, mean dose of 8.9 mg/day) was more effective than placebo in the treatment of adolescents with manic or mixed episodes associated with bipolar I disorder, as supported by the statistically significantly greater mean reduction in Y-MRS total score for patients in the olanzapine treatment group than in the placebo group.  

While there is no body of evidence available to answer the question of how long the adolescent patient treated with olanzapine should be maintained, maintenance efficacy can be extrapolated from adult data along with comparisons of olanzapine pharmacokinetic parameters in adult and adolescent patients. It is generally recommended that responding patients be continued beyond the acute response, but at the lowest dose needed to maintain remission. Patients should be periodically reassessed to determine the need for maintenance treatment.

Olanzapine Tablets USP, 20 mg are white, film coated, oval, biconvex tablets with “R” debossed on

{ "type": "p", "children": [], "text": "Olanzapine Tablets USP, 20 mg are white, film coated, oval, biconvex tablets with “R” debossed on" }

20 one side and “0168” on other side and are supplied in

{ "type": "p", "children": [], "text": "20 one side and “0168” on other side and are supplied in" }

NDC: 70518-1582-00

{ "type": "p", "children": [], "text": "NDC: 70518-1582-00" }

PACKAGING: 30 in 1 BLISTER PACK

{ "type": "p", "children": [], "text": "PACKAGING: 30 in 1 BLISTER PACK" }

Store olanzapine tablets at controlled room temperature, 20° to 25°C (68° to 77°F) [see USP]. The USP defines controlled room temperature as a temperature maintained thermostatically that encompasses the usual and customary working environment of 20° to 25°C (68° to 77°F); that results in a mean kinetic temperature calculated to be not more than 25°C; and that allows for excursions between 15° and 30°C (59° and 86°F) that are experienced in pharmacies, hospitals, and warehouses.

{ "type": "p", "children": [], "text": "Store olanzapine tablets at controlled room temperature, 20° to 25°C (68° to 77°F) [see USP]. The USP defines controlled room temperature as a temperature maintained thermostatically that encompasses the usual and customary working environment of 20° to 25°C (68° to 77°F); that results in a mean kinetic temperature calculated to be not more than 25°C; and that allows for excursions between 15° and 30°C (59° and 86°F) that are experienced in pharmacies, hospitals, and warehouses." }

Protect olanzapine tablets from light and moisture.

{ "type": "p", "children": [], "text": "Protect olanzapine tablets from light and moisture." }

Repackaged and Distributed By:

{ "type": "p", "children": [], "text": "Repackaged and Distributed By:" }

Remedy Repack, Inc.

{ "type": "p", "children": [], "text": "Remedy Repack, Inc." }

625 Kolter Dr. Suite #4 Indiana, PA 1-724-465-8762

{ "type": "p", "children": [], "text": "625 Kolter Dr. Suite #4 Indiana, PA 1-724-465-8762" }

Advise the patient to read the FDA-approved patient labeling (Medication Guide) for the oral formulations.

{ "type": "p", "children": [], "text": "Advise the patient to read the FDA-approved patient labeling (Medication Guide) for the oral formulations. " }

Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking olanzapine as monotherapy or in combination with fluoxetine. If you do not think you are getting better or have any concerns about your condition while taking olanzapine, call your doctor. When using olanzapine and fluoxetine in combination, also refer to the Patient Counseling Information section of the package insert for Symbyax.

{ "type": "p", "children": [], "text": "Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking olanzapine as monotherapy or in combination with fluoxetine. If you do not think you are getting better or have any concerns about your condition while taking olanzapine, call your doctor. When using olanzapine and fluoxetine in combination, also refer to the Patient Counseling Information section of the package insert for Symbyax." }

Elderly Patients with Dementia-Related Psychosis: Increased Mortality and Cerebrovascular Adverse Events (CVAE), Including Stroke

{ "type": "p", "children": [], "text": "\nElderly Patients with Dementia-Related Psychosis: Increased Mortality and Cerebrovascular Adverse Events (CVAE), Including Stroke\n" }

Patients and caregivers should be advised that elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Patients and caregivers should be advised that elderly patients with dementia-related psychosis treated with olanzapine had a significantly higher incidence of cerebrovascular adverse events (e.g., stroke, transient ischemic attack) compared with placebo.

{ "type": "p", "children": [], "text": "Patients and caregivers should be advised that elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Patients and caregivers should be advised that elderly patients with dementia-related psychosis treated with olanzapine had a significantly higher incidence of cerebrovascular adverse events (e.g., stroke, transient ischemic attack) compared with placebo." }

Olanzapine is not approved for elderly patients with dementia-related psychosis [see Boxed Warning and Warnings and Precautions ( 5.1) ].

{ "type": "p", "children": [], "text": "Olanzapine is not approved for elderly patients with dementia-related psychosis [see \n Boxed Warning and Warnings and Precautions ( \n 5.1) \n ].\n " }

Neuroleptic Malignant Syndrome (NMS)

{ "type": "p", "children": [], "text": "\nNeuroleptic Malignant Syndrome (NMS)\n" }

Patients and caregivers should be counseled that a potentially fatal symptom complex sometimes referred to as NMS has been reported in association with administration of antipsychotic drugs, including olanzapine. Signs and symptoms of NMS include hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia) [see Warnings and Precautions ( 5.3) ].

{ "type": "p", "children": [], "text": "Patients and caregivers should be counseled that a potentially fatal symptom complex sometimes referred to as NMS has been reported in association with administration of antipsychotic drugs, including olanzapine. Signs and symptoms of NMS include hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia) [see \n Warnings and Precautions ( \n 5.3) \n ].\n " }

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)

{ "type": "p", "children": [], "text": "\nDrug Reaction with Eosinophilia and Systemic Symptoms (DRESS)\n" }

Patients should be advised to report to their health care provider at the earliest onset of any signs and symptoms that may be associated with Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) [see Warnings and Precautions ( 5.4) ].

{ "type": "p", "children": [], "text": "Patients should be advised to report to their health care provider at the earliest onset of any signs and symptoms that may be associated with Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) [see \n Warnings and Precautions ( \n 5.4) \n ].\n " }

Hyperglycemia and Diabetes Mellitus

{ "type": "p", "children": [], "text": "\nHyperglycemia and Diabetes Mellitus\n" }

Patients should be advised of the potential risk of hyperglycemia-related adverse reactions. Patients should be monitored regularly for worsening of glucose control. Patients who have diabetes should follow their doctor’s instructions about how often to check their blood sugar while taking olanzapine [see Warnings and Precautions ( 5.5) ].

{ "type": "p", "children": [], "text": "Patients should be advised of the potential risk of hyperglycemia-related adverse reactions. Patients should be monitored regularly for worsening of glucose control. Patients who have diabetes should follow their doctor’s instructions about how often to check their blood sugar while taking olanzapine [see \n Warnings and Precautions ( \n 5.5) \n ].\n " }

Dyslipidemia

{ "type": "p", "children": [], "text": "\nDyslipidemia\n" }

Patients should be counseled that dyslipidemia has occurred during treatment with olanzapine. Patients should have their lipid profile monitored regularly [see Warnings and Precautions ( 5.5) ].

{ "type": "p", "children": [], "text": "Patients should be counseled that dyslipidemia has occurred during treatment with olanzapine. Patients should have their lipid profile monitored regularly [see \n Warnings and Precautions ( \n 5.5) \n ].\n " }

Weight Gain

{ "type": "p", "children": [], "text": "\nWeight Gain\n" }

Patients should be counseled that weight gain has occurred during treatment with olanzapine. Patients should have their weight monitored regularly [see Warnings and Precautions ( 5.5) ].

{ "type": "p", "children": [], "text": "Patients should be counseled that weight gain has occurred during treatment with olanzapine. Patients should have their weight monitored regularly [see \n Warnings and Precautions ( \n 5.5) \n ].\n " }

Orthostatic Hypotension

{ "type": "p", "children": [], "text": "\nOrthostatic Hypotension\n" }

Patients should be advised of the risk of orthostatic hypotension, especially during the period of initial dose titration and in association with the use of concomitant drugs that may potentiate the orthostatic effect of olanzapine, e.g., diazepam or alcohol [see Warnings and Precautions (5.7) and Drug Interactions ( 7) ]. Patients should be advised to change positions carefully to help prevent orthostatic hypotension, and to lie down if they feel dizzy or faint, until they feel better. Patients should be advised to call their doctor if they experience any of the following signs and symptoms associated with orthostatic hypotension: dizziness, fast or slow heart beat, or fainting.

{ "type": "p", "children": [], "text": "Patients should be advised of the risk of orthostatic hypotension, especially during the period of initial dose titration and in association with the use of concomitant drugs that may potentiate the orthostatic effect of olanzapine, e.g., diazepam or alcohol [see \n Warnings and Precautions (5.7) and Drug Interactions ( \n 7) \n ]. Patients should be advised to change positions carefully to help prevent orthostatic hypotension, and to lie down if they feel dizzy or faint, until they feel better. Patients should be advised to call their doctor if they experience any of the following signs and symptoms associated with orthostatic hypotension: dizziness, fast or slow heart beat, or fainting.\n " }

Potential for Cognitive and Motor Impairment

{ "type": "p", "children": [], "text": "\nPotential for Cognitive and Motor Impairment\n" }

Because olanzapine has the potential to impair judgment, thinking, or motor skills, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that olanzapine therapy does not affect them adversely [see Warnings and Precautions ( 5.12) ].

{ "type": "p", "children": [], "text": "Because olanzapine has the potential to impair judgment, thinking, or motor skills, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that olanzapine therapy does not affect them adversely [see \n Warnings and Precautions ( \n 5.12) \n ].\n " }

Body Temperature RegulationPatients should be advised regarding appropriate care in avoiding overheating and dehydration. Patients should be advised to call their doctor right away if they become severely ill and have some or all of these symptoms of dehydration: sweating too much or not at all, dry mouth, feeling very hot, feeling thirsty, not able to produce urine [see Warnings and Precautions (5.13)].

{ "type": "p", "children": [], "text": "\nBody Temperature RegulationPatients should be advised regarding appropriate care in avoiding overheating and dehydration. Patients should be advised to call their doctor right away if they become severely ill and have some or all of these symptoms of dehydration: sweating too much or not at all, dry mouth, feeling very hot, feeling thirsty, not able to produce urine [see \n Warnings and Precautions (5.13)].\n " }

Concomitant Medication

{ "type": "p", "children": [], "text": "\nConcomitant Medication\n" }

Patients should be advised to inform their healthcare providers if they are taking, or plan to take, Symbyax ®(olanzapine and fluoxetine hydrochloride). Patients should also be advised to inform their healthcare providers if they are taking, plan to take, or have stopped taking any prescription or over-the-counter drugs, including herbal supplements, since there is a potential for interactions [see Drug Interactions (7)].

{ "type": "p", "children": [], "text": "Patients should be advised to inform their healthcare providers if they are taking, or plan to take, Symbyax \n ®(olanzapine and fluoxetine hydrochloride). Patients should also be advised to inform their healthcare providers if they are taking, plan to take, or have stopped taking any prescription or over-the-counter drugs, including herbal supplements, since there is a potential for interactions [see \n Drug Interactions (7)].\n " }

AlcoholPatients should be advised to avoid alcohol while taking olanzapine [see Drug Interactions ( 7) ].

{ "type": "p", "children": [], "text": "\nAlcoholPatients should be advised to avoid alcohol while taking olanzapine [see \n Drug Interactions ( \n 7) \n ].\n " }

Use in Specific Populations

{ "type": "p", "children": [], "text": "\nUse in Specific Populations\n" }

Pregnancy — Advise women to notify their healthcare provider if they become pregnant or intend to become pregnant during treatment with olanzapine. Advise patients that olanzapine may cause extrapyramidal and/or withdrawal symptoms (agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder) in a neonate. Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to olanzapine during pregnancy [see Use in Specific Populations ( 8.1) ].

{ "type": "p", "children": [], "text": "Pregnancy — Advise women to notify their healthcare provider if they become pregnant or intend to become pregnant during treatment with olanzapine. Advise patients that olanzapine may cause extrapyramidal and/or withdrawal symptoms (agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder) in a neonate. Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to olanzapine during pregnancy [see \n Use in Specific Populations ( \n 8.1) \n ].\n " }

Lactation — Advise breastfeeding women using olanzapine to monitor infants for excess sedation, irritability, poor feeding and extrapyramidal symptoms (tremors and abnormal muscle movements) and to seek medical care if they notice these signs. [see Use in Specific Populations ( 8.2) ].

{ "type": "p", "children": [], "text": "Lactation — Advise breastfeeding women using olanzapine to monitor infants for excess sedation, irritability, poor feeding and extrapyramidal symptoms (tremors and abnormal muscle movements) and to seek medical care if they notice these signs. [see \n Use in Specific Populations ( \n 8.2) \n ].\n " }

Infertility — Advise females of reproductive potential that olanzapine may impair fertility due to an increase in serum prolactin levels. The effects on fertility are reversible [see Use in Specific Populations ( 8.3) ].

{ "type": "p", "children": [], "text": "Infertility — Advise females of reproductive potential that olanzapine may impair fertility due to an increase in serum prolactin levels. The effects on fertility are reversible [see \n Use in Specific Populations ( \n 8.3) \n ].\n " }

Pediatric Use — Olanzapine is indicated for treatment of schizophrenia and manic or mixed episodes associated with bipolar I disorder in adolescents 13 to 17 years of age. Compared to patients from adult clinical trials, adolescents were likely to gain more weight, experience increased sedation, and have greater increases in total cholesterol, triglycerides, LDL cholesterol, prolactin, and hepatic aminotransferase levels. Patients should be counseled about the potential long-term risks associated with olanzapine and advised that these risks may lead them to consider other drugs first [ see Indications and Usage ( 1.1, 1.2) ]. Safety and effectiveness of olanzapine in patients under 13 years of age have not been established. Safety and efficacy of olanzapine and fluoxetine in combination in patients 10 to 17 years of age have been established for the acute treatment of depressive episodes associated with bipolar I disorder. Safety and effectiveness of olanzapine and fluoxetine in combination in patients < 10 years of age have not been established [see Warnings and Precautions ( 5.5) and Use in Specific Populations ( 8.4) ].

{ "type": "p", "children": [], "text": "Pediatric Use — Olanzapine is indicated for treatment of schizophrenia and manic or mixed episodes associated with bipolar I disorder in adolescents 13 to 17 years of age. Compared to patients from adult clinical trials, adolescents were likely to gain more weight, experience increased sedation, and have greater increases in total cholesterol, triglycerides, LDL cholesterol, prolactin, and hepatic aminotransferase levels. Patients should be counseled about the potential long-term risks associated with olanzapine and advised that these risks may lead them to consider other drugs first [ \n see Indications and Usage ( \n 1.1, \n 1.2) \n ]. Safety and effectiveness of olanzapine in patients under 13 years of age have not been established. Safety and efficacy of olanzapine and fluoxetine in combination in patients 10 to 17 years of age have been established for the acute treatment of depressive episodes associated with bipolar I disorder. Safety and effectiveness of olanzapine and fluoxetine in combination in patients < 10 years of age have not been established [see \n Warnings and Precautions ( \n 5.5) \n and \n Use in Specific Populations ( \n 8.4) \n ].\n " }

Need for Comprehensive Treatment Program in Pediatric Patients

{ "type": "p", "children": [], "text": "\nNeed for Comprehensive Treatment Program in Pediatric Patients\n" }

Olanzapine is indicated as an integral part of a total treatment program for pediatric patients with schizophrenia and bipolar disorder that may include other measures (psychological, educational, social) for patients with the disorder. Effectiveness and safety of olanzapine have not been established in pediatric patients less than 13 years of age. Atypical antipsychotics are not intended for use in the pediatric patient who exhibits symptoms secondary to environmental factors and/or other primary psychiatric disorders. Appropriate educational placement is essential and psychosocial intervention is often helpful. The decision to prescribe atypical antipsychotic medication will depend upon the healthcare provider’s assessment of the chronicity and severity of the patient’s symptoms [see Indications and Usage ( 1.3)] .

{ "type": "p", "children": [], "text": "Olanzapine is indicated as an integral part of a total treatment program for pediatric patients with schizophrenia and bipolar disorder that may include other measures (psychological, educational, social) for patients with the disorder. Effectiveness and safety of olanzapine have not been established in pediatric patients less than 13 years of age. Atypical antipsychotics are not intended for use in the pediatric patient who exhibits symptoms secondary to environmental factors and/or other primary psychiatric disorders. Appropriate educational placement is essential and psychosocial intervention is often helpful. The decision to prescribe atypical antipsychotic medication will depend upon the healthcare provider’s assessment of the chronicity and severity of the patient’s symptoms [see \n Indications and Usage ( \n 1.3)] \n .\n" }

Symbyax ®(olanzapine and fluoxetine hydrochloride) is a trademark of Eli Lilly company.

{ "type": "p", "children": [], "text": "Symbyax \n ®(olanzapine and fluoxetine hydrochloride) is a trademark of Eli Lilly company.\n " }

Rx Only

{ "type": "p", "children": [], "text": "Rx Only" }

Repackaged By / Distributed By: RemedyRepack Inc.

{ "type": "p", "children": [], "text": "Repackaged By / Distributed By: RemedyRepack Inc." }

625 Kolter Drive, Indiana, PA 15701

{ "type": "p", "children": [], "text": "625 Kolter Drive, Indiana, PA 15701" }

(724) 465-8762

{ "type": "p", "children": [], "text": "(724) 465-8762" }

Medication Guide

{ "type": "p", "children": [], "text": "\nMedication Guide\n" }

Olanzapine Tablets USP

{ "type": "p", "children": [], "text": "\nOlanzapine Tablets USP\n" }

(oh lan' za peen)

{ "type": "p", "children": [], "text": "\n(oh lan' za peen)\n" }

Read the Medication Guide that comes with olanzapine tablets before you start taking them and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking to your doctor about your medical condition or treatment. Talk with your doctor or pharmacist if there is something you do not understand or you want to learn more about olanzapine tablets.

{ "type": "p", "children": [], "text": "Read the Medication Guide that comes with olanzapine tablets before you start taking them and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking to your doctor about your medical condition or treatment. Talk with your doctor or pharmacist if there is something you do not understand or you want to learn more about olanzapine tablets." }

What is the most important information I should know about olanzapine tablets?

{ "type": "p", "children": [], "text": "\nWhat is the most important information I should know about olanzapine tablets? \n" }

Olanzapine tablets may cause serious side effects, including:

{ "type": "p", "children": [], "text": "\nOlanzapine tablets may cause serious side effects, including: \n" }

1. Increased risk of death in elderly people who are confused, have memory loss and have lost touch with reality (dementia-related psychosis).

{ "type": "p", "children": [], "text": "\n1. Increased risk of death in elderly people who are confused, have memory loss and have lost touch with reality (dementia-related psychosis). \n" }

2. High blood sugar (hyperglycemia).

{ "type": "p", "children": [], "text": "\n2. High blood sugar (hyperglycemia). \n" }

3. High fat levels in your blood (increased cholesterol and triglycerides), especially in teenagers age 13 to 17, or when used in combination with fluoxetine in children age 10 to 17.

{ "type": "p", "children": [], "text": "\n3. High fat levels in your blood (increased cholesterol and triglycerides), especially in teenagers age 13 to 17, or when used in combination with fluoxetine in children age 10 to 17.\n" }

4. Weight gain, especially in teenagers age 13 to 17, or when used in combination with fluoxetine in children age 10 to 17.

{ "type": "p", "children": [], "text": "\n4. Weight gain, especially in teenagers age 13 to 17, or when used in combination with fluoxetine in children age 10 to 17. \n" }

These serious side effects are described below.

{ "type": "p", "children": [], "text": "\nThese serious side effects are described below. \n" }

1. Increased risk of death in elderly people who are confused, have memory loss and have lost touch with reality (dementia-related psychosis).Olanzapine tablets are not approved for treating psychosis in elderly people with dementia.

{ "type": "p", "children": [], "text": "\n1. Increased risk of death in elderly people who are confused, have memory loss and have lost touch with reality (dementia-related psychosis).Olanzapine tablets are not approved for treating psychosis in elderly people with dementia. \n " }

2. High blood sugar (hyperglycemia).High blood sugar can happen if you have diabetes already or if you have never had diabetes. High blood sugar could lead to:

{ "type": "p", "children": [], "text": "\n2. High blood sugar (hyperglycemia).High blood sugar can happen if you have diabetes already or if you have never had diabetes. High blood sugar could lead to:\n " }

• a build up of acid in your blood due to ketones (ketoacidosis)

{ "type": "p", "children": [], "text": "• a build up of acid in your blood due to ketones (ketoacidosis)" }

• coma

{ "type": "p", "children": [], "text": "• coma" }

• death

{ "type": "p", "children": [], "text": "• death" }

Your doctor should do tests to check your blood sugar before you start taking olanzapine tablets and during treatment. In people who do not have diabetes, sometimes high blood sugar goes away when olanzapine tablets are stopped. People with diabetes and some people who did not have diabetes before taking olanzapine tablets need to take medicine for high blood sugar even after they stop taking olanzapine tablets.

{ "type": "p", "children": [], "text": "Your doctor should do tests to check your blood sugar before you start taking olanzapine tablets and during treatment. In people who do not have diabetes, sometimes high blood sugar goes away when olanzapine tablets are stopped. People with diabetes and some people who did not have diabetes before taking olanzapine tablets need to take medicine for high blood sugar even after they stop taking olanzapine tablets." }

If you have diabetes, follow your doctor’s instructions about how often to check your blood sugar while taking olanzapine tablets.

{ "type": "p", "children": [], "text": "If you have diabetes, follow your doctor’s instructions about how often to check your blood sugar while taking olanzapine tablets." }

Call your doctorif you have any of these symptoms of high blood sugar (hyperglycemia) while taking olanzapine tablets:

{ "type": "p", "children": [], "text": "\nCall your doctorif you have any of these symptoms of high blood sugar (hyperglycemia) while taking olanzapine tablets:\n " }

• feel very thirsty

{ "type": "p", "children": [], "text": "• feel very thirsty" }

• need to urinate more than usual

{ "type": "p", "children": [], "text": "• need to urinate more than usual" }

• feel very hungry

{ "type": "p", "children": [], "text": "• feel very hungry" }

• feel weak or tired

{ "type": "p", "children": [], "text": "• feel weak or tired" }

• feel sick to your stomach

{ "type": "p", "children": [], "text": "• feel sick to your stomach" }

• feel confused or your breath smells fruity

{ "type": "p", "children": [], "text": "• feel confused or your breath smells fruity" }

3. High fat levels in your blood (cholesterol and triglycerides).High fat levels may happen in people treated with olanzapine tablets, especially in teenagers (13 to 17 years old), or when used in combination with fluoxetine in children (10 to 17 years old). You may not have any symptoms, so your doctor should do blood tests to check your cholesterol and triglyceride levels before you start taking olanzapine tablets and during treatment.

{ "type": "p", "children": [], "text": "\n3. High fat levels in your blood (cholesterol and triglycerides).High fat levels may happen in people treated with olanzapine tablets, especially in teenagers (13 to 17 years old), or when used in combination with fluoxetine in children (10 to 17 years old). You may not have any symptoms, so your doctor should do blood tests to check your cholesterol and triglyceride levels before you start taking olanzapine tablets and during treatment.\n " }

4. Weight gain.Weight gain is very common in people who take olanzapine tablets. Teenagers (13 to 17 years old) are more likely to gain weight and to gain more weight than adults. Children (10 to 17 years old) are also more likely to gain weight and to gain more weight than adults when olanzapine is used in combination with fluoxetine. Some people may gain a lot of weight while taking olanzapine tablets, so you and your doctor should check your weight regularly. Talk to your doctor about ways to control weight gain, such as eating a healthy, balanced diet, and exercising.

{ "type": "p", "children": [], "text": "\n4. Weight gain.Weight gain is very common in people who take olanzapine tablets. Teenagers (13 to 17 years old) are more likely to gain weight and to gain more weight than adults. Children (10 to 17 years old) are also more likely to gain weight and to gain more weight than adults when olanzapine is used in combination with fluoxetine. Some people may gain a lot of weight while taking olanzapine tablets, so you and your doctor should check your weight regularly. Talk to your doctor about ways to control weight gain, such as eating a healthy, balanced diet, and exercising.\n " }

What are Olanzapine tablets?

{ "type": "p", "children": [], "text": "\nWhat are Olanzapine tablets?\n" }

Olanzapine tablets are prescription medicine used to treat:

{ "type": "p", "children": [], "text": "Olanzapine tablets are prescription medicine used to treat:" }

• schizophrenia in people age 13 or older.

{ "type": "p", "children": [], "text": "• schizophrenia in people age 13 or older." }

• bipolar disorder, including:

{ "type": "p", "children": [], "text": "• bipolar disorder, including:" }

• manic or mixed episodes that happen with bipolar I disorder in people age 13 or older.

{ "type": "p", "children": [], "text": "• manic or mixed episodes that happen with bipolar I disorder in people age 13 or older." }

• manic or mixed episodes that happen with bipolar I disorder, when used with the medicine lithium or valproate, in adults.

{ "type": "p", "children": [], "text": "• manic or mixed episodes that happen with bipolar I disorder, when used with the medicine lithium or valproate, in adults." }

• long-term treatment of bipolar I disorder in adults.

{ "type": "p", "children": [], "text": "• long-term treatment of bipolar I disorder in adults." }

• episodes of depression that happen with bipolar I disorder, when used with the medicine fluoxetine (Prozac®), in people age 10 or older.

{ "type": "p", "children": [], "text": "• episodes of depression that happen with bipolar I disorder, when used with the medicine fluoxetine (Prozac®), in people age 10 or older." }

• Episodes of depression that do not get better after 2 other medicines, also called treatment resistant depression, when used with the medicine fluoxetine (Prozac), in adults.

{ "type": "p", "children": [], "text": "• Episodes of depression that do not get better after 2 other medicines, also called treatment resistant depression, when used with the medicine fluoxetine (Prozac), in adults." }

Olanzapine tablets have not been approved for use in children under 13 years of age. Olanzapine in combination with fluoxetine has not been approved for use in children under 10 years of age.

{ "type": "p", "children": [], "text": "Olanzapine tablets have not been approved for use in children under 13 years of age. Olanzapine in combination with fluoxetine has not been approved for use in children under 10 years of age. " }

The symptoms of schizophrenia include hearing voices, seeing things that are not there, having beliefs that are not true, and being suspicious or withdrawn.

{ "type": "p", "children": [], "text": "The symptoms of schizophrenia include hearing voices, seeing things that are not there, having beliefs that are not true, and being suspicious or withdrawn." }

The symptoms of bipolar I disorder include alternating periods of depression and high or irritable mood, increased activity and restlessness, racing thoughts, talking fast, impulsive behavior, and a decreased need for sleep.

{ "type": "p", "children": [], "text": "The symptoms of bipolar I disorder include alternating periods of depression and high or irritable mood, increased activity and restlessness, racing thoughts, talking fast, impulsive behavior, and a decreased need for sleep." }

The symptoms of treatment resistant depression include decreased mood, decreased interest, increased guilty feelings, decreased energy, decreased concentration, changes in appetite, and suicidal thoughts or behavior.

{ "type": "p", "children": [], "text": "The symptoms of treatment resistant depression include decreased mood, decreased interest, increased guilty feelings, decreased energy, decreased concentration, changes in appetite, and suicidal thoughts or behavior." }

Some of your symptoms may improve with treatment. If you do not think you are getting better, call your doctor.

{ "type": "p", "children": [], "text": "Some of your symptoms may improve with treatment. If you do not think you are getting better, call your doctor." }

What should I tell my doctor before taking olanzapinetablets?

{ "type": "p", "children": [], "text": "\nWhat should I tell my doctor before taking olanzapinetablets?\n" }

Olanzapine tablets may not be right for you. Before starting olanzapine tablets, tell your doctor if you have or had:

{ "type": "p", "children": [], "text": "Olanzapine tablets may not be right for you. Before starting olanzapine tablets, tell your doctor if you have or had:" }

• heart problems

{ "type": "p", "children": [], "text": "• heart problems" }

• seizures

{ "type": "p", "children": [], "text": "• seizures" }

• diabetes or high blood sugar levels (hyperglycemia)

{ "type": "p", "children": [], "text": "• diabetes or high blood sugar levels (hyperglycemia)" }

• high cholesterol or triglyceride levels in your blood

{ "type": "p", "children": [], "text": "• high cholesterol or triglyceride levels in your blood" }

• liver problems

{ "type": "p", "children": [], "text": "• liver problems" }

• low or high blood pressure

{ "type": "p", "children": [], "text": "• low or high blood pressure" }

• strokes or “mini-strokes” also called transient ischemic attacks (TIAs)

{ "type": "p", "children": [], "text": "• strokes or “mini-strokes” also called transient ischemic attacks (TIAs)" }

• Alzheimer’s disease

{ "type": "p", "children": [], "text": "• Alzheimer’s disease" }

• narrow-angle glaucoma

{ "type": "p", "children": [], "text": "• narrow-angle glaucoma" }

• enlarged prostate in men

{ "type": "p", "children": [], "text": "• enlarged prostate in men" }

• bowel obstruction

{ "type": "p", "children": [], "text": "• bowel obstruction" }

• breast cancer

{ "type": "p", "children": [], "text": "• breast cancer" }

• thoughts of suicide or hurting yourself

{ "type": "p", "children": [], "text": "• thoughts of suicide or hurting yourself" }

• any other medical condition

{ "type": "p", "children": [], "text": "• any other medical condition" }

• are pregnant or plan to become pregnant. It is not known if olanzapine tablets will harm your unborn baby.

{ "type": "p", "children": [], "text": "• are pregnant or plan to become pregnant. It is not known if olanzapine tablets will harm your unborn baby." }

• If you become pregnant while receiving olanzapine tablets, talk to your healthcare provider about registering with the National Pregnancy Registry for Atypical Antipsychotics. You can register by calling 1-866-961-2388 or go to http://womensmentalhealth.org/clinical-and­research-programs/pregnancyregistry/.

{ "type": "p", "children": [], "text": "• If you become pregnant while receiving olanzapine tablets, talk to your healthcare provider about registering with the National Pregnancy Registry for Atypical Antipsychotics. You can register by calling 1-866-961-2388 or go to http://womensmentalhealth.org/clinical-and­research-programs/pregnancyregistry/." }

• are breast-feeding or plan to breast-feed. Olanzapine passes into your breast milk. Talk to your doctor about the best way to feed your baby if you take olanzapine tablets.

{ "type": "p", "children": [], "text": "• are breast-feeding or plan to breast-feed. Olanzapine passes into your breast milk. Talk to your doctor about the best way to feed your baby if you take olanzapine tablets." }

Tell your doctor if you exercise a lot or are in hot places often.

{ "type": "p", "children": [], "text": "Tell your doctor if you exercise a lot or are in hot places often." }

The symptoms of bipolar I disorder or schizophrenia may include thoughts of suicideor of hurting yourself or others. If you have these thoughts at any time, tell your doctor or go to an emergency room right away.

{ "type": "p", "children": [], "text": "The symptoms of bipolar I disorder or schizophrenia may include \n thoughts of suicideor of hurting yourself or others. If you have these thoughts at any time, tell your doctor or go to an emergency room right away. \n " }

Tell your doctor about all the medicines that you take,including prescription and non-prescription medicines, vitamins, and herbal supplements. Olanzapine tablets and some medicines may interact with each other and may not work as well, or cause possible serious side effects. Your doctor can tell you if it is safe to take olanzapine tablets with your other medicines. Do not start or stop any medicine while taking olanzapine tablets without talking to your doctor first.

{ "type": "p", "children": [], "text": "\nTell your doctor about all the medicines that you take,including prescription and non-prescription medicines, vitamins, and herbal supplements. Olanzapine tablets and some medicines may interact with each other and may not work as well, or cause possible serious side effects. Your doctor can tell you if it is safe to take olanzapine tablets with your other medicines. Do not start or stop any medicine while taking olanzapine tablets without talking to your doctor first.\n " }

How should I take olanzapinetablets?

{ "type": "p", "children": [], "text": "\nHow should I take olanzapinetablets?\n" }

• Take olanzapine tablets exactly as prescribed. Your doctor may need to change (adjust) the dose of olanzapine tablets until it is right for you.

{ "type": "p", "children": [], "text": "• Take olanzapine tablets exactly as prescribed. Your doctor may need to change (adjust) the dose of olanzapine tablets until it is right for you." }

• If you miss a dose of olanzapine tablets, take the missed dose as soon as you remember. If it is almost time for the next dose, just skip the missed dose and take your next dose at the regular time. Do not take two doses of olanzapine tablets at the same time.

{ "type": "p", "children": [], "text": "• If you miss a dose of olanzapine tablets, take the missed dose as soon as you remember. If it is almost time for the next dose, just skip the missed dose and take your next dose at the regular time. Do not take two doses of olanzapine tablets at the same time." }

• To prevent serious side effects, do not stop taking olanzapine tablets suddenly. If you need to stop taking olanzapinetablets, your doctor can tell you how to safely stop taking it.

{ "type": "p", "children": [], "text": "• \n To prevent serious side effects, do not stop taking olanzapine tablets suddenly. If you need to stop taking olanzapinetablets, your doctor can tell you how to safely stop taking it. \n" }

• If you take too much olanzapinetablets, call your doctor or poison control center at 1-800-222-1222 right away, or get emergency treatment.

{ "type": "p", "children": [], "text": "• \n If you take too much olanzapinetablets, call your doctor or poison control center at 1-800-222-1222 right away, or get emergency treatment.\n" }

• Olanzapine tablets can be taken with or without food.

{ "type": "p", "children": [], "text": "• Olanzapine tablets can be taken with or without food." }

• Olanzapine tablets are usually taken one time each day

{ "type": "p", "children": [], "text": "• Olanzapine tablets are usually taken one time each day" }

• Call your doctor if you do not think you are getting better or have any concerns about your condition while taking olanzapine tablets, .

{ "type": "p", "children": [], "text": "• Call your doctor if you do not think you are getting better or have any concerns about your condition while taking olanzapine tablets, ." }

What should I avoid while taking olanzapine tablets?

{ "type": "p", "children": [], "text": "\nWhat should I avoid while taking olanzapine tablets?\n" }

• Olanzapine tablets can cause sleepiness and may affect your ability to make decisions, think clearly, or react quickly. You should not drive, operate heavy machinery, or do other dangerous activities until you know how olanzapine tablets affects you.

{ "type": "p", "children": [], "text": "• Olanzapine tablets can cause sleepiness and may affect your ability to make decisions, think clearly, or react quickly. You should not drive, operate heavy machinery, or do other dangerous activities until you know how olanzapine tablets affects you." }

• Avoid drinking alcohol while taking olanzapine tablets. Drinking alcohol while you take olanzapine tablets may make you sleepier than if you take olanzapine tablets alone.

{ "type": "p", "children": [], "text": "• Avoid drinking alcohol while taking olanzapine tablets. Drinking alcohol while you take olanzapine tablets may make you sleepier than if you take olanzapine tablets alone." }

What are the possible side effects of olanzapinetablets?

{ "type": "p", "children": [], "text": "\nWhat are the possible side effects of olanzapinetablets?\n" }

Serious side effects may happen when you take olanzapine tablets, including:

{ "type": "p", "children": [], "text": "\nSerious side effects may happen when you take olanzapine tablets, including:\n" }

• See “What is the most important information I should know about olanzapine tablets?”, which describes the increased risk of death in elderly people with dementia-related psychosis and the risks of high blood sugar, high cholesterol and triglyceride levels, and weight gain.

{ "type": "p", "children": [], "text": "\n• See “What is the most important information I should know about olanzapine tablets?”, which describes the increased risk of death in elderly people with dementia-related psychosis and the risks of high blood sugar, high cholesterol and triglyceride levels, and weight gain.\n" }

• Increased incidence of stroke or “mini-strokes” called transient ischemic attacks (TIAs) in elderly people with dementia-related psychosis(elderly people who have lost touch with reality due to confusion and memory loss). Olanzapine tablets are not approved for these patients.

{ "type": "p", "children": [], "text": "\n• Increased incidence of stroke or “mini-strokes” called transient ischemic attacks (TIAs) in elderly people with dementia-related psychosis(elderly people who have lost touch with reality due to confusion and memory loss). Olanzapine tablets are not approved for these patients.\n " }

• Neuroleptic Malignant Syndrome (NMS): NMS is a rare but very serious condition that can happen in people who take antipsychotic medicines, including olanzapine tablets. NMS can cause death and must be treated in a hospital. Call your doctor right away if you become severely ill and have any of these symptoms:

{ "type": "p", "children": [], "text": "\n• Neuroleptic Malignant Syndrome (NMS): NMS is a rare but very serious condition that can happen in people who take antipsychotic medicines, including olanzapine tablets. NMS can cause death and must be treated in a hospital. Call your doctor right away if you become severely ill and have any of these symptoms:\n " }

• high fever

{ "type": "p", "children": [], "text": "• high fever" }

• excessive sweating

{ "type": "p", "children": [], "text": "• excessive sweating" }

• rigid muscles

{ "type": "p", "children": [], "text": "• rigid muscles" }

• confusion

{ "type": "p", "children": [], "text": "• confusion" }

• changes in your breathing, heartbeat, and blood pressure

{ "type": "p", "children": [], "text": "• changes in your breathing, heartbeat, and blood pressure" }

• Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS):DRESS can occur with olanzapine. Features of DRESS may include rash, fever, swollen glands and other internal organ involvement such as liver, kidney, lung and heart. DRESS is sometimes fatal; therefore, tell your doctor immediately if you experience any of these signs.

{ "type": "p", "children": [], "text": "• \n Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS):DRESS can occur with olanzapine. Features of DRESS may include rash, fever, swollen glands and other internal organ involvement such as liver, kidney, lung and heart. DRESS is sometimes fatal; therefore, tell your doctor immediately if you experience any of these signs.\n " }

• Tardive Dyskinesia: This condition causes body movements that keep happening and that you can not control. These movements usually affect the face and tongue. Tardive dyskinesia may not go away, even if you stop taking olanzapine tablets. It may also start after you stop taking olanzapine tablets. Tell your doctor if you get any body movements that you can not control.

{ "type": "p", "children": [], "text": "\n• Tardive Dyskinesia: This condition causes body movements that keep happening and that you can not control. These movements usually affect the face and tongue. Tardive dyskinesia may not go away, even if you stop taking olanzapine tablets. It may also start after you stop taking olanzapine tablets. Tell your doctor if you get any body movements that you can not control.\n " }

• Decreased blood pressure when you change positions, with symptoms of dizziness, fast or slow heartbeat, or fainting.

{ "type": "p", "children": [], "text": "\n• Decreased blood pressure when you change positions, with symptoms of dizziness, fast or slow heartbeat, or fainting. \n" }

• Difficulty swallowing, that can cause food or liquid to get into your lungs.

{ "type": "p", "children": [], "text": "\n• Difficulty swallowing, that can cause food or liquid to get into your lungs.\n" }

• Seizures : Tell your doctor if you have a seizure during treatment with olanzapine tablets.

{ "type": "p", "children": [], "text": "\n• Seizures : Tell your doctor if you have a seizure during treatment with olanzapine tablets. \n" }

• Problems with control of body temperature:You could become very hot, for instance when you exercise a lot or stay in an area that is very hot. It is important for you to drink water to avoid dehydration. Call your doctor right away if you become severely ill and have any of these symptoms of dehydration:

{ "type": "p", "children": [], "text": "\n• Problems with control of body temperature:You could become very hot, for instance when you exercise a lot or stay in an area that is very hot. It is important for you to drink water to avoid dehydration. Call your doctor right away if you become severely ill and have any of these symptoms of dehydration:\n " }

• sweating too much or not at all

{ "type": "p", "children": [], "text": "• sweating too much or not at all" }

• dry mouth

{ "type": "p", "children": [], "text": "• dry mouth" }

• feeling very hot

{ "type": "p", "children": [], "text": "• feeling very hot" }

• feeling thirsty

{ "type": "p", "children": [], "text": "• feeling thirsty" }

• not able to produce urine

{ "type": "p", "children": [], "text": "• not able to produce urine" }

Common side effects of olanzapine tablets include:lack of energy, dry mouth, increased appetite, sleepiness, tremor (shakes), having hard or infrequent stools, dizziness, changes in behavior, or restlessness.

{ "type": "p", "children": [], "text": "\nCommon side effects of olanzapine tablets include:lack of energy, dry mouth, increased appetite, sleepiness, tremor (shakes), having hard or infrequent stools, dizziness, changes in behavior, or restlessness.\n " }

Other common side effects in teenagers (13 to 17 years old) include:headache, stomach-area (abdominal) pain, pain in your arms or legs, or tiredness. Teenagers experienced greater increases in prolactin, liver enzymes, and sleepiness, as compared with adults.

{ "type": "p", "children": [], "text": "\nOther common side effects in teenagers (13 to 17 years old) include:headache, stomach-area (abdominal) pain, pain in your arms or legs, or tiredness. Teenagers experienced greater increases in prolactin, liver enzymes, and sleepiness, as compared with adults.\n " }

Tell your doctor about any side effect that bothers you or that does not go away.

{ "type": "p", "children": [], "text": "Tell your doctor about any side effect that bothers you or that does not go away." }

These are not all the possible side effects with olanzapine tablets. For more information, ask your doctor or pharmacist.

{ "type": "p", "children": [], "text": "These are not all the possible side effects with olanzapine tablets. For more information, ask your doctor or pharmacist." }

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

{ "type": "p", "children": [], "text": "Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088." }

How should I store olanzapinetablets?

{ "type": "p", "children": [], "text": "\nHow should I store olanzapinetablets?\n" }

• Store olanzapine tablets at room temperature, between 68°F to 77°F (20°C to 25°C).

{ "type": "p", "children": [], "text": "• Store olanzapine tablets at room temperature, between 68°F to 77°F (20°C to 25°C)." }

• Keep olanzapine tablets away from light.

{ "type": "p", "children": [], "text": "• Keep olanzapine tablets away from light." }

• Keep olanzapine tablets dry and away from moisture.

{ "type": "p", "children": [], "text": "• Keep olanzapine tablets dry and away from moisture." }

Keep olanzapine tablets and all medicines out of the reach of children.

{ "type": "p", "children": [], "text": "\nKeep olanzapine tablets and all medicines out of the reach of children.\n" }

General information about olanzapinetablets

{ "type": "p", "children": [], "text": "\nGeneral information about olanzapinetablets\n" }

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use olanzapine tablets for a condition for which it was not prescribed. Do not give olanzapine tablets to other people, even if they have the same condition. It may harm them.

{ "type": "p", "children": [], "text": "Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use olanzapine tablets for a condition for which it was not prescribed. Do not give olanzapine tablets to other people, even if they have the same condition. It may harm them." }

This Medication Guide summarizes the most important information about olanzapine tablets. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about olanzapine tablets that was written for healthcare professionals.

{ "type": "p", "children": [], "text": "This Medication Guide summarizes the most important information about olanzapine tablets. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about olanzapine tablets that was written for healthcare professionals." }

For more information about olanzapine tablets call 1-888-375-3784.

{ "type": "p", "children": [], "text": "For more information about olanzapine tablets call 1-888-375-3784." }

What are the ingredients in olanzapine tablets?

{ "type": "p", "children": [], "text": "\nWhat are the ingredients in olanzapine tablets?\n" }

Active ingredient:olanzapine

{ "type": "p", "children": [], "text": "\nActive ingredient:olanzapine\n " }

Inactive ingredients:Tablets — crospovidone, hydroxypropyl cellulose, lactose monohydrate, magnesium stearate, microcrystalline cellulose (Avicel PH 101) and microcrystalline cellulose (Avicel PH 102). The color coating contains hypromellose, polyethylene glycol 400 and titanium dioxide.

{ "type": "p", "children": [], "text": "\nInactive ingredients:Tablets — crospovidone, hydroxypropyl cellulose, lactose monohydrate, magnesium stearate, microcrystalline cellulose (Avicel PH 101) and microcrystalline cellulose (Avicel PH 102). The color coating contains hypromellose, polyethylene glycol 400 and titanium dioxide.\n " }

This Medication Guide has been approved by the U.S. Food and Drug Administration.

{ "type": "p", "children": [], "text": "This Medication Guide has been approved by the U.S. Food and Drug Administration." }

Rx Only

{ "type": "p", "children": [], "text": "Rx Only" }

Repackaged By / Distributed By: RemedyRepack Inc.

{ "type": "p", "children": [], "text": "Repackaged By / Distributed By: RemedyRepack Inc." }

625 Kolter Drive, Indiana, PA 15701

{ "type": "p", "children": [], "text": "625 Kolter Drive, Indiana, PA 15701" }

(724) 465-8762

{ "type": "p", "children": [], "text": "(724) 465-8762" }

DRUG: Olanzapine

{ "type": "p", "children": [], "text": "DRUG: Olanzapine" }

GENERIC: Olanzapine

{ "type": "p", "children": [], "text": "GENERIC: Olanzapine" }

DOSAGE: TABLET, FILM COATED

{ "type": "p", "children": [], "text": "DOSAGE: TABLET, FILM COATED" }

ADMINSTRATION: ORAL

{ "type": "p", "children": [], "text": "ADMINSTRATION: ORAL" }

NDC: 70518-1582-0

{ "type": "p", "children": [], "text": "NDC: 70518-1582-0" }

COLOR: white

{ "type": "p", "children": [], "text": "COLOR: white" }

SHAPE: OVAL

{ "type": "p", "children": [], "text": "SHAPE: OVAL" }

SCORE: No score

{ "type": "p", "children": [], "text": "SCORE: No score" }

SIZE: 15 mm

{ "type": "p", "children": [], "text": "SIZE: 15 mm" }

IMPRINT: R20;0168

{ "type": "p", "children": [], "text": "IMPRINT: R20;0168" }

PACKAGING: 30 in 1 BLISTER PACK

{ "type": "p", "children": [], "text": "PACKAGING: 30 in 1 BLISTER PACK" }

ACTIVE INGREDIENT(S):

{ "type": "p", "children": [], "text": "ACTIVE INGREDIENT(S):" }

{ "type": "ul", "children": [ "olanzapine 20mg in 1" ], "text": "" }

INACTIVE INGREDIENT(S):

{ "type": "p", "children": [], "text": "INACTIVE INGREDIENT(S):" }

{ "type": "ul", "children": [ "Crospovidone", "HYDROXYPROPYL CELLULOSE (110000 WAMW)", "lactose monohydrate", "magnesium stearate", "CELLULOSE, MICROCRYSTALLINE", "hypromelloses", "POLYETHYLENE GLYCOL 400", "titanium dioxide" ], "text": "" }