UZEDY is indicated for the treatment of schizophrenia in adults.

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For patients who have never taken risperidone, establish tolerability with oral risperidone prior to initiating UZEDY.

UZEDY must be administered by a healthcare professional as an abdominal or upper arm subcutaneous injection. Do not administer UZEDY by any other route.

For detailed preparation and administration instructions, see Dosage and Administration (2.4).

To start UZEDY, switch from oral daily risperidone. Initiate UZEDY, as either a once monthly injection or a once every 2 month injection, the day after the last dose of oral therapy. See Table 1 to determine how to switch from oral risperidone to UZEDY once monthly (50 mg, 75 mg, 100 mg, or 125 mg) or once every 2 months (100 mg, 150 mg, 200 mg, or 250 mg) given via abdominal or upper arm subcutaneous injection. Neither a loading dose nor supplemental oral risperidone doses are recommended when switching. 

<div class="scrollingtable"><table width="411px"> <caption> <span>Table 1: Dosage Recommendations for Switching from Daily Oral Risperidone to UZEDY</span> </caption> <col/> <col/> <col/> <tbody class="Headless"> <tr class="First"> <td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First"> <span class="Bold">Prior Therapy</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First"> <span class="Bold">UZEDY Dosage</span> </p> <p> <span class="Bold">Once Monthly</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First"> <span class="Bold">UZEDY Dosage</span> </p> <p> <span class="Bold">Once Every 2 Months</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule">2 mg of oral risperidone per day</td><td align="center" class="Botrule Lrule Rrule Toprule">50 mg</td><td align="center" class="Botrule Lrule Rrule Toprule">100 mg </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule">3 mg of oral risperidone per day </td><td align="center" class="Botrule Lrule Rrule Toprule">75 mg</td><td align="center" class="Botrule Lrule Rrule Toprule">150 mg</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule">4 mg of oral risperidone per day</td><td align="center" class="Botrule Lrule Rrule Toprule">100 mg</td><td align="center" class="Botrule Lrule Rrule Toprule">200 mg</td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule">5 mg of oral risperidone per day </td><td align="center" class="Botrule Lrule Rrule Toprule">125 mg</td><td align="center" class="Botrule Lrule Rrule Toprule">250 mg </td> </tr> </tbody> </table></div>

Patients can switch between doses of UZEDY once monthly and once every 2 months by administering the first dose of the new dosing regimen on the next scheduled date of administration in the original dosing regimen. Revise the dose administration schedule to reflect the change.

When a dose of UZEDY is missed, administer the next UZEDY injection as soon as possible. Do not administer more frequently than recommended.

Prior to initiating UZEDY in patients with renal or hepatic impairment, titrate with oral risperidone to at least 2 mg once daily. Following oral titration, and based on clinical response and tolerability, the recommended dosage of UZEDY is 50 mg once monthly [see Use in Specific Populations (8.6, 8.7) and Clinical Pharmacology (12.3)].

Concomitant Use with Strong CYP2D6 Inhibitors

When initiation of fluoxetine or paroxetine is considered, place patients on a lower dose of UZEDY prior to the planned start of fluoxetine or paroxetine therapy to adjust for the expected increase in plasma concentrations of risperidone.

When fluoxetine or paroxetine is initiated in patients receiving the recommended dose of 50 mg once monthly or 100 mg once every 2 months of UZEDY, continue treatment with these doses unless clinical judgment necessitates interruption of UZEDY [see Drug Interactions (7.1)].

Concomitant Use with Strong CYP3A4 Inducers

At the initiation of therapy with strong CYP3A4 inducers (such as carbamazepine), patients should be closely monitored during the first 4 to 8 weeks since the dose of UZEDY may need to be adjusted. A dose increase, or additional oral risperidone, may be considered.

On discontinuation of a strong CYP3A4 inducer, re-evaluated the dosage of UZEDY or any additional oral risperidone therapy and, if necessary, decrease to adjust for the expected increase in plasma concentration of risperidone.

On discontinuation of a strong CYP3A4 inducer in a patient treated with UZEDY 50 mg once monthly or 100 mg once every 2 months, continue treatment with these doses unless clinical judgment necessitates interruption of UZEDY [see Drug Interactions (7.1)].

STEP 1

Check to make sure UZEDY kit contains:

Do not substitute any components of the kit for administration.

STEP 2

Remove the kit from refrigerated storage and allow the package to sit at room temperature (20°C to 25°C [68°F to 77°F]) for at least 30 minutes.

Note: UZEDY is a solid at refrigerated temperatures and must reach room temperature prior to administration. Do not warm any other way and keep protected from light.

 STEP 3

Check that the drug in the syringe is white to off-white, opaque in color, and free from non-white particulate matter. Check that the pouch label states the needle size is 21G x 5/8”.

Do not use if any component of the kit is damaged or if the expiration date has passed.

 STEP 4

Expose the safety needle hub by peeling back the paper tab of the needle pouch. Set aside for use in Step 7.

STEP 5

<div class="scrollingtable"><table width="470px"> <col/> <tbody class="Headless"> <tr class="First Last"> <td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">IMPORTANT:</span> This step must be performed to ensure complete dosing. UZEDY is viscous and forceful downward flicks are required to move the bubble to the cap of the syringe. Failure to move the bubble to the cap of the syringe could result in incomplete dosage.</p> </td> </tr> </tbody> </table></div>

Firmly hold the syringe by the white collar.

Flick Syringe Forcefully Three Times to Move the Bubble to the Cap

Note: Standing while you do this may help achieve required force.

Check that the Bubble is at the Cap of the Syringe

STEP 6

Hold the syringe vertically by the white collar. Bend and snap off the cap.

Do not touch the syringe tip to avoid contamination.

STEP 7

Attach the Needle to the Syringe

Inspect the needle connection to check that the hub is not damaged.

STEP 8

Select Injection Site from the Following Areas:

Do not inject UZEDY anywhere except in the areas specified above.

Do not inject UZEDY into an area that is tender, red, bruised, callused, tattooed, hard, or has scars or stretch marks.

 STEP 9

Clean the Injection Site with an alcohol wipe.

STEP 10

Remove the needle sheath by pulling the needle sheath away from the green hub to expose the needle.

Do not expel any visible air bubble.

 STEP 11

Pinch at least 1 inch of the area of cleaned skin with your free hand.

 STEP 12

Insert the needle into subcutaneous tissue (actual angle of injection will depend on the amount of subcutaneous tissue). Do not apply pressure to the plunger.

 STEP 13

Release the pinched skin once the needle is in the subcutaneous tissue.

 STEP 14

Inject the Medication

IMPORTANT: UZEDY is viscous. Resistance will be experienced during dose delivery. Do not use excessive force in an attempt to deliver UZEDY faster.

STEP 15

Wait 2-3 seconds after the entire dose is delivered before removing the needle. Slowly pull the needle out from the injection site at the same angle as insertion.

 STEP 16

Activate (lock) the safety needle shield using one of the following methods:

There will be an audible click when the needle safety shield is locked.

Dispose of all syringe components in a suitable sharps container. 

Extended-release injectable suspension: sterile, white to off-white opaque viscous suspension available in the following strengths: 50 mg/0.14 mL, 75 mg/0.21 mL, 100 mg/0.28 mL, 125 mg/0.35 mL, 150 mg/0.42 mL, 200 mg/0.56 mL, and 250 mg/0.7 mL.

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Each strength is provided as a kit, which includes: one single-dose prefilled syringe and one 21 gauge, 5/8-inch needle.

{ "type": "p", "children": [], "text": "Each strength is provided as a kit, which includes: one single-dose prefilled syringe and one 21 gauge, 5/8-inch needle." }

UZEDY is contraindicated in patients with a known hypersensitivity to risperidone, its metabolite, paliperidone, or to any of its components. Hypersensitivity reactions, including anaphylactic reactions and angioedema, have been reported in patients treated with risperidone or paliperidone.

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Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Analyses of 17 placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of between 1.6- to 1.7-times the risk of death in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality. The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear.

In two of four placebo-controlled trials in elderly patients with dementia-related psychosis, a higher incidence of mortality was observed in patients treated with furosemide plus oral risperidone when compared to patients treated with oral risperidone alone or with placebo plus furosemide. No pathological mechanism has been identified to explain this finding, and no consistent pattern for cause of death was observed.

UZEDY is not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning and Warnings and Precautions (5.2)].

Cerebrovascular adverse reactions (e.g., stroke, transient ischemic attack), including fatalities, were reported in patients (mean age 85 years; range 73 to 97 years) in trials of oral risperidone in elderly patients with dementia-related psychosis. In placebo-controlled trials, there was a significantly higher incidence of cerebrovascular adverse reactions in patients treated with oral risperidone compared to patients treated with placebo. UZEDY is not approved for the treatment of patients with dementia-related psychosis [see Warnings and Precautions (5.1)].

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

If NMS is suspected, immediately discontinue UZEDY and provide symptomatic treatment and monitoring.

Tardive dyskinesia, a syndrome consisting 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 predict, which patients will 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 with the duration of treatment and the cumulative dose. The syndrome can develop, after relatively brief treatment periods, even at low doses. It may also occur after discontinuation of treatment.

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

Given these considerations, UZEDY 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, use the lowest dose and the shortest duration of treatment producing a satisfactory clinical response. Periodically reassess the need for continued treatment.

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

Atypical antipsychotic drugs have been associated with metabolic changes that may increase cardiovascular/cerebrovascular risk. These metabolic changes include hyperglycemia, dyslipidemia, and body weight gain. While all of the drugs in the class have been shown to produce some metabolic changes, each drug has its own specific risk profile.

Hyperglycemia and Diabetes Mellitus

Hyperglycemia and diabetes mellitus, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, have been reported in patients treated with atypical antipsychotics including risperidone. 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. Given these confounders, the relationship between atypical antipsychotic use and hyperglycemia-related adverse events is not completely understood. However, epidemiological studies suggest an increased risk of treatment-emergent hyperglycemia-related adverse events in patients treated with the atypical antipsychotics. Precise risk estimates for hyperglycemia-related adverse events in patients treated with atypical antipsychotics are not available.

Patients with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics, including UZEDY, should be monitored regularly for worsening of glucose control. Patients with risk factors for diabetes mellitus (e.g., obesity, family history of diabetes) who are starting treatment with atypical antipsychotics, including UZEDY, should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Any patient treated with atypical antipsychotics, including UZEDY, should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics, including UZEDY, should undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic, including risperidone, was discontinued; however, some patients required continuation of antidiabetic treatment despite discontinuation of risperidone.

Pooled data from three double-blind, placebo-controlled schizophrenia studies and four double-blind, placebo-controlled studies in another indication with oral risperidone are presented in Table 2.

<div class="scrollingtable"><table width="481px"> <caption> <span>Table 2: Change in Random Glucose from Seven Placebo-Controlled, 3- to 8-Week, Fixed- or Flexible-Dose Studies in Adults with Schizophrenia or Another Indication with Oral Risperidone</span> </caption> <col/> <col/> <col/> <col/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" colspan="2" valign="bottom"> <br/> <span class="Bold"> <br/> </span></td><td align="center" class="Botrule Lrule Rrule Toprule" colspan="2" valign="bottom"><span class="Bold">Oral Risperidone</span> <br/> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> </td><td align="center" class="Botrule Lrule Rrule Toprule"><span class="Bold"> Placebo</span></td><td align="center" class="Botrule Lrule Rrule Toprule"> <span class="Bold">1 mg to 8 mg per day</span></td><td align="center" class="Botrule Lrule Rrule Toprule"><span class="Bold"> &gt;8 mg to 16mg per day</span></td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> </td><td align="center" class="Botrule Lrule Rrule Toprule" colspan="3"> <span class="Bold">Mean change from baseline (mg/dL)</span></td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold"> </span> </p> <p> <span class="Bold">Serum Glucose</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">N=555</span> </p> <p>-1.4</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">N=748</span> </p> <p>0.8</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">N=164</span> </p> <p>0.6</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> </td><td align="center" class="Botrule Lrule Rrule Toprule" colspan="3"><span class="Bold">Proportion of Patients with Shifts </span></td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">Serum Glucose</span> </p> <p> (&lt;140 mg/dL to ≥200 mg/dL)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First"> 0.6%</p> <p>(3/525)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First"> 0.4%</p> <p>(3/702)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First"> 0%</p> <p>(0/158)</p> </td> </tr> </tbody> </table></div>

In longer-term, controlled and uncontrolled studies in adults, oral risperidone was associated with a mean change in glucose of +2.8 mg/dL at Week 24 (N=151) and +4.1 mg/dL at Week 48 (N=50).

Dyslipidemia

Undesirable alterations in lipids have been observed in patients treated with atypical antipsychotics. Before or soon after initiation of antipsychotic medications, obtain a fasting lipid profile at baseline and monitor periodically during treatment.

Pooled data from 7 placebo-controlled, 3- to 8- week, fixed- or flexible-dose studies in adults with schizophrenia or another indication with oral risperidone are presented in Table 3.

<div class="scrollingtable"><table width="492px"> <caption> <span>Table 3: Change in Random Lipids from Seven Placebo-Controlled, 3- to 8-Week, Fixed- or Flexible-Dose Studies in Adults with Schizophrenia or Another Indication with Oral Risperidone</span> </caption> <col/> <col/> <col/> <col/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" colspan="2" valign="bottom"><span class="Bold"> <br/> </span></td><td align="center" class="Botrule Lrule Rrule Toprule" colspan="2" valign="bottom"> <p class="First"> <span class="Bold">Oral Risperidone</span><span class="Bold"> <br/> </span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <br/> </td><td align="center" class="Botrule Lrule Rrule Toprule"><span class="Bold">Placebo</span> <br/> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <span class="Bold">1 mg to 8 mg per day</span></td><td align="center" class="Botrule Lrule Rrule Toprule"><span class="Bold"> &gt;8 mg to 16mg per day</span></td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> </td><td align="center" class="Botrule Lrule Rrule Toprule" colspan="3"> <p class="First"> <span class="Bold">Mean change from baseline (mg/dL)</span> <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">Cholesterol</span> </p> <p>Change from baseline</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">N=559</span> </p> <p>0.6 </p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">N=742</span> </p> <p>6.9</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">N=156</span> </p> <p>1.8 </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">Triglycerides</span> </p> <p>Change from baseline</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">N=183</span> </p> <p>-17.4 </p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">N=307</span> </p> <p>-4.9</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">N=123</span> </p> <p>-8.3<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> </td><td align="center" class="Botrule Lrule Rrule Toprule" colspan="3"><span class="Bold"> Proportion of Patients with Shifts</span></td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">Cholesterol</span> </p> <p>(&lt;200 mg/dL to ≥240 mg/dL) </p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">2.7%</p> <p>(10/368) </p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First"> 4.3%</p> <p>(22/156)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First"> 6.3%</p> <p>(6/96)</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">Triglycerides</span> </p> <p>(&lt;500 mg/dL to ≥500 mg/dL) </p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">1.1%</p> <p>(2/180) </p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First"> 2.7%</p> <p>(8/301)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First"> 2.5%</p> <p>(3/121)</p> </td> </tr> </tbody> </table></div>

In longer-term, controlled and uncontrolled studies, oral risperidone was associated with a mean change in (a) non-fasting cholesterol of +4.4 mg/dL at Week 24 (N=231) and +5.5 mg/dL at Week 48 (N=86); and (b) non-fasting triglycerides of +19.9 mg/dL at Week 24 (N=52).

Weight Gain

Weight gain has been observed with atypical antipsychotic use. Clinical monitoring of weight is recommended.

Data on mean changes in body weight and the proportion of subjects meeting a weight gain criterion of 7% or greater of body weight from 7 placebo-controlled, 3- to 8- week, fixed- or flexible-dose studies in adults with schizophrenia or another indication with oral risperidone are presented in Table 4.

<div class="scrollingtable"><table> <caption> <span>Table 4: Mean Change in Body Weight (kg) and the Proportion of Subjects with ≥7% Gain in Body Weight From Seven Placebo-Controlled, 3- to 8-Week, Fixed- or Flexible-Dose Studies in Adults With Schizophrenia or Another Indication with Oral Risperidone</span> </caption> <col/> <col/> <col/> <col/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" colspan="2"> <br/> </td><td align="center" class="Botrule Lrule Rrule Toprule" colspan="2"><span class="Bold">Oral Risperidone</span></td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">Placebo </span> </p> <p> <span class="Bold">(n=597)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">1 mg to 8 mg per day </span> </p> <p> <span class="Bold">(n=769)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold"> &gt;8 mg to 16mg per day </span> </p> <p> <span class="Bold">(n=158)</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">Weight (kg)</span> </p> <p>Change from baseline </p> </td><td align="center" class="Botrule Lrule Rrule Toprule">-0.3 </td><td align="center" class="Botrule Lrule Rrule Toprule"> 0.7</td><td align="center" class="Botrule Lrule Rrule Toprule"> 2.2</td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">Weight Gain </span> </p> <p>≥7% increase from baseline<span class="Bold"> </span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> 2.9%</td><td align="center" class="Botrule Lrule Rrule Toprule">8.7% </td><td align="center" class="Botrule Lrule Rrule Toprule">  20.9%</td> </tr> </tbody> </table></div>

In longer-term, controlled and uncontrolled studies, oral risperidone was associated with a mean change in weight of +4.3 kg at Week 24 (n=395) and +5.3 kg at Week 48 (n=203).

As with other drugs that antagonize dopamine D2 receptors, risperidone elevates prolactin levels and the elevation persists during chronic administration. Risperidone is associated with higher levels of prolactin elevation than other antipsychotic agents.

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 may lead to decreased bone density in both female and male patients.

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. An increase in pituitary gland, mammary gland, and pancreatic islet cell neoplasia (mammary adenocarcinomas, pituitary and pancreatic adenomas) was observed in the risperidone 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.

UZEDY may induce orthostatic hypotension associated with dizziness, tachycardia, and in some patients, syncope, probably reflecting its alpha-adrenergic antagonistic properties. Syncope was reported in 0.2% (6/2607) of patients treated with oral risperidone in Phase 2 and 3 studies in adults with schizophrenia.

UZEDY should be used with particular caution in (1) 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, e.g., dehydration and hypovolemia and (2) in the elderly and patients with renal or hepatic impairment. Monitoring of orthostatic vital signs should be considered in all such patients, and a dose reduction should be considered if hypotension occurs. Clinically significant hypotension has been observed with concomitant use of oral risperidone and antihypertensive medication.

Antipsychotics, including UZEDY, may cause somnolence, postural hypotension, motor and sensory instability which may lead to falls and, consequently, fractures or other fall-related injuries. Somnolence, postural hypotension, motor and sensory instability have been reported with the use of risperidone. For patients, particularly the elderly, with diseases, conditions, or medications that could exacerbate these effects, assess the risk of falls when initiating antipsychotic treatment and recurrently for patients on long-term antipsychotic therapy.

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

Possible risk factors for leukopenia/neutropenia include pre-existing low white blood cell count (WBC) and a history of drug-induced leukopenia/neutropenia. In patients with a pre-existing history of a clinically significant low WBC or ANC or a history of drug-induced leukopenia or neutropenia, perform a complete blood count (CBC) frequently during the first few months of therapy. In such patients, consider discontinuation of UZEDY at the first sign of a clinically significant decline in WBC in the absence of other causative factors.

Monitor patients with clinically significant neutropenia for fever or other symptoms or signs of infection and treated promptly if such symptoms or signs occur. Discontinue UZEDY in patients with absolute neutrophil count <1000/mm3 and follow their WBC followed until recovery.

UZEDY, like other antipsychotics, may cause somnolence and has the potential to impair judgement, thinking, and motor skills. Somnolence was a commonly reported adverse reaction associated with oral risperidone treatment, especially when ascertained by direct questioning of patients. This adverse reaction is dose-related, and in a study utilizing a checklist to detect adverse reactions, 41% of the high-dose patients (oral risperidone 16 mg/day) reported somnolence compared to 16% of placebo patients. Direct questioning is more sensitive for detecting adverse reactions than spontaneous reporting, by which 8% of oral risperidone 16 mg/day patients and 1% of placebo patients reported somnolence as an adverse reaction.

Patients should be cautioned about operating hazardous machinery, including motor vehicles, until they are reasonably certain that treatment with UZEDY does not affect them adversely.

During premarketing studies of oral risperidone in adult patients with schizophrenia, seizures occurred in 0.3% of patients (9 out of 2,607 patients), two in association with hyponatremia. Use UZEDY cautiously in patients with a history of seizures or other conditions that potentially lower the seizure threshold.

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 dementia. Antipsychotic drugs, including UZEDY, should be used cautiously in patients at risk for aspiration.

Priapism has been reported during postmarketing surveillance for other risperidone products. A case of priapism was reported in premarket studies of UZEDY. Severe priapism may require surgical intervention.

Disruption of the body’s ability to reduce core body temperature has been attributed to antipsychotic agents. Both hyperthermia and hypothermia have been reported in association with oral risperidone use. Strenuous exercise, exposure to extreme heat, dehydration, and anticholinergic medications may contribute to an elevation in core body temperature; use UZEDY with caution in patients who may experience these conditions.

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 the rates observed in clinical practice.

The safety of UZEDY for the treatment of schizophrenia in adults is based on adequate and well-controlled studies of oral risperidone in studies of patients with schizophrenia and other indications. The results of those adequate and well-controlled studies are presented below.

The data described in this section are derived from a clinical trial database consisting of 9,803 patients exposed to one or more doses of oral risperidone for the treatment of schizophrenia and other psychiatric disorders. Of these 9,803 patients, 2,687 were patients who received oral risperidone while participating in double-blind, placebo-controlled trials. The conditions and duration of treatment with oral risperidone varied greatly and included (in overlapping categories) double-blind, fixed- and flexible-dose, placebo- or active-controlled studies and open-label phases of studies, inpatients and outpatients, and short-term (up to 12 weeks) and longer-term (up to 3 years) exposures. Safety was assessed by collecting adverse reactions and performing physical examinations, vital signs, body weights, laboratory analyses, and ECGs.

Injection site reactions for UZEDY presented in this section (see “Injection Site Reactions with UZEDY” below) are based on a randomized withdrawal study in patients with schizophrenia consisting of a 12-week open-label oral risperidone (2 mg to 5 mg) stabilization phase, followed by a placebo-controlled phase in which patients were randomized to UZEDY (once monthly or once every 2 months) or placebo for a variable time until impending relapse or study completion [see Clinical Studies (14)].

The safety of UZEDY was evaluated in a total of 740 adult patients with schizophrenia who received at least 1 dose of UZEDY during the clinical development program. A total of 351 patients were exposed to UZEDY for at least 6 months, of which 221 patients were exposed to UZEDY for at least 12 months, which included 112 patients exposed to once monthly and 109 patients to once every 2 months dosing regimens. In addition, 32 patients were exposed to UZEDY for at least 24 months.

Adverse Reactions in Studies with Oral Risperidone

The most common adverse reactions in clinical trials of oral risperidone (>5% and twice placebo) were parkinsonism, akathisia, dystonia, tremor, sedation, dizziness, anxiety, blurred vision, nausea, vomiting, upper abdominal pain, stomach discomfort, dyspepsia, diarrhea, salivary hypersecretion, constipation, dry mouth, increased appetite, increased weight, fatigue, rash, nasal congestion, upper respiratory tract infection, nasopharyngitis, and pharyngolaryngeal pain.

Commonly-Observed Adverse Reactions in Double-Blind, Placebo-Controlled Clinical Trials – Adult Patients with Schizophrenia Treated with Oral Risperidone

Table 5 lists the adverse reactions reported in 2% or more of oral risperidone-treated adult patients with schizophrenia in three 4- to 8-week, double-blind, placebo-controlled trials.

<div class="scrollingtable"><table> <caption> <span>Table 5: Adverse Reactions in ≥2% of Oral Risperidone-Treated Adult Patients (and greater than placebo) with Schizophrenia in Double-Blind, Placebo-Controlled Trials</span> </caption> <col/> <col/> <col/> <col/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" valign="bottom"> </td><td align="center" class="Botrule Lrule Rrule Toprule" colspan="3" valign="bottom"><span class="Bold">Percentage of Patients Reporting Reaction</span> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="bottom"> </td><td align="center" class="Botrule Lrule Rrule Toprule" colspan="2" valign="bottom"><span class="Bold">Oral Risperidone </span></td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First"> <span class="Bold"> System/Organ Class</span> </p>   Adverse Reaction</td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First"> <span class="Bold">2 mg to 8 mg per day<br/> (N=366)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First"> <span class="Bold">&gt;8 mg to 16 mg per day<br/> (N=198)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First"> <span class="Bold">Placebo<br/> (N=225)</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="4"> <span class="Bold">Cardiac Disorders</span></td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> Tachycardia</td><td align="center" class="Botrule Lrule Rrule Toprule"> 1</td><td align="center" class="Botrule Lrule Rrule Toprule"> 3</td><td align="center" class="Botrule Lrule Rrule Toprule"> 0</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="4"> <span class="Bold">Eye Disorders</span></td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> Vision blurred</td><td align="center" class="Botrule Lrule Rrule Toprule"> 3</td><td align="center" class="Botrule Lrule Rrule Toprule"> 1</td><td align="center" class="Botrule Lrule Rrule Toprule"> 1</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="4"><span class="Bold"> Gastrointestinal Disorders</span> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> Nausea</td><td align="center" class="Botrule Lrule Rrule Toprule"> 9</td><td align="center" class="Botrule Lrule Rrule Toprule"> 4</td><td align="center" class="Botrule Lrule Rrule Toprule">4</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> Constipation</td><td align="center" class="Botrule Lrule Rrule Toprule"> 8</td><td align="center" class="Botrule Lrule Rrule Toprule"> 9</td><td align="center" class="Botrule Lrule Rrule Toprule">6</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> Dyspepsia </td><td align="center" class="Botrule Lrule Rrule Toprule"> 8</td><td align="center" class="Botrule Lrule Rrule Toprule"> 6</td><td align="center" class="Botrule Lrule Rrule Toprule">5 </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> Dry mouth</td><td align="center" class="Botrule Lrule Rrule Toprule"> 4</td><td align="center" class="Botrule Lrule Rrule Toprule"> 0</td><td align="center" class="Botrule Lrule Rrule Toprule">1</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> Abdominal discomfort</td><td align="center" class="Botrule Lrule Rrule Toprule"> 3</td><td align="center" class="Botrule Lrule Rrule Toprule"> 1</td><td align="center" class="Botrule Lrule Rrule Toprule">1 </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> Salivary hypersecretion </td><td align="center" class="Botrule Lrule Rrule Toprule">2</td><td align="center" class="Botrule Lrule Rrule Toprule">1</td><td align="center" class="Botrule Lrule Rrule Toprule">&lt;1</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> Diarrhea</td><td align="center" class="Botrule Lrule Rrule Toprule">2</td><td align="center" class="Botrule Lrule Rrule Toprule"> 1</td><td align="center" class="Botrule Lrule Rrule Toprule">1</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="4"> <span class="Bold">General Disorders</span></td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> Fatigue</td><td align="center" class="Botrule Lrule Rrule Toprule"> 3</td><td align="center" class="Botrule Lrule Rrule Toprule"> 1</td><td align="center" class="Botrule Lrule Rrule Toprule"> 0</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> Chest pain</td><td align="center" class="Botrule Lrule Rrule Toprule"> 2</td><td align="center" class="Botrule Lrule Rrule Toprule"> 2</td><td align="center" class="Botrule Lrule Rrule Toprule"> 1</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> Asthenia</td><td align="center" class="Botrule Lrule Rrule Toprule"> 2</td><td align="center" class="Botrule Lrule Rrule Toprule"> 1</td><td align="center" class="Botrule Lrule Rrule Toprule"> &lt;1</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="4"><span class="Bold"> Infections and Infestations</span> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> Nasopharyngitis </td><td align="center" class="Botrule Lrule Rrule Toprule">3 </td><td align="center" class="Botrule Lrule Rrule Toprule">4</td><td align="center" class="Botrule Lrule Rrule Toprule">3</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> Upper respiratory tract infection </td><td align="center" class="Botrule Lrule Rrule Toprule">2</td><td align="center" class="Botrule Lrule Rrule Toprule">3</td><td align="center" class="Botrule Lrule Rrule Toprule">1</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> Sinusitis</td><td align="center" class="Botrule Lrule Rrule Toprule">1 </td><td align="center" class="Botrule Lrule Rrule Toprule"> 2</td><td align="center" class="Botrule Lrule Rrule Toprule">1 </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> Urinary tract infection </td><td align="center" class="Botrule Lrule Rrule Toprule">1</td><td align="center" class="Botrule Lrule Rrule Toprule">3</td><td align="center" class="Botrule Lrule Rrule Toprule">0</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="4"> <span class="Bold">Investigations</span></td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> Blood creatine phosphokinase increased</td><td align="center" class="Botrule Lrule Rrule Toprule"> 1</td><td align="center" class="Botrule Lrule Rrule Toprule"> 2</td><td align="center" class="Botrule Lrule Rrule Toprule"> &lt;1</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> Heart rate increased</td><td align="center" class="Botrule Lrule Rrule Toprule"> &lt;1</td><td align="center" class="Botrule Lrule Rrule Toprule"> 2</td><td align="center" class="Botrule Lrule Rrule Toprule"> 0</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="4"> <span class="Bold">Musculoskeletal and Connective Tissue Disorders</span></td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> Back pain</td><td align="center" class="Botrule Lrule Rrule Toprule"> 4</td><td align="center" class="Botrule Lrule Rrule Toprule"> 1</td><td align="center" class="Botrule Lrule Rrule Toprule"> 1</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> Arthralgia</td><td align="center" class="Botrule Lrule Rrule Toprule"> 2</td><td align="center" class="Botrule Lrule Rrule Toprule"> 3</td><td align="center" class="Botrule Lrule Rrule Toprule"> &lt;1</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> Pain in extremity</td><td align="center" class="Botrule Lrule Rrule Toprule"> 2</td><td align="center" class="Botrule Lrule Rrule Toprule"> 1</td><td align="center" class="Botrule Lrule Rrule Toprule"> 1</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="4"> <span class="Bold">Nervous System Disorders</span></td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> Parkinsonism*</td><td align="center" class="Botrule Lrule Rrule Toprule"> 14</td><td align="center" class="Botrule Lrule Rrule Toprule"> 17</td><td align="center" class="Botrule Lrule Rrule Toprule"> 8</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> Akathisia*</td><td align="center" class="Botrule Lrule Rrule Toprule"> 10</td><td align="center" class="Botrule Lrule Rrule Toprule"> 10</td><td align="center" class="Botrule Lrule Rrule Toprule"> 3</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> Sedation</td><td align="center" class="Botrule Lrule Rrule Toprule"> 10</td><td align="center" class="Botrule Lrule Rrule Toprule"> 5</td><td align="center" class="Botrule Lrule Rrule Toprule"> 2</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> Dizziness</td><td align="center" class="Botrule Lrule Rrule Toprule"> 7</td><td align="center" class="Botrule Lrule Rrule Toprule"> 4</td><td align="center" class="Botrule Lrule Rrule Toprule"> 2</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> Dystonia*</td><td align="center" class="Botrule Lrule Rrule Toprule"> 3</td><td align="center" class="Botrule Lrule Rrule Toprule"> 4</td><td align="center" class="Botrule Lrule Rrule Toprule"> 2</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> Tremor*</td><td align="center" class="Botrule Lrule Rrule Toprule"> 2</td><td align="center" class="Botrule Lrule Rrule Toprule"> 3</td><td align="center" class="Botrule Lrule Rrule Toprule"> 1</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> Dizziness postural</td><td align="center" class="Botrule Lrule Rrule Toprule"> 2</td><td align="center" class="Botrule Lrule Rrule Toprule"> 0</td><td align="center" class="Botrule Lrule Rrule Toprule"> 0</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="4"> <span class="Bold">Psychiatric Disorders</span></td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> Insomnia</td><td align="center" class="Botrule Lrule Rrule Toprule"> 32</td><td align="center" class="Botrule Lrule Rrule Toprule"> 25</td><td align="center" class="Botrule Lrule Rrule Toprule"> 27</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> Anxiety</td><td align="center" class="Botrule Lrule Rrule Toprule"> 16</td><td align="center" class="Botrule Lrule Rrule Toprule"> 11</td><td align="center" class="Botrule Lrule Rrule Toprule"> 11</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="4"> <span class="Bold">Respiratory, Thoracic and Mediastinal Disorders</span></td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> Nasal congestion</td><td align="center" class="Botrule Lrule Rrule Toprule"> 4</td><td align="center" class="Botrule Lrule Rrule Toprule"> 6</td><td align="center" class="Botrule Lrule Rrule Toprule"> 2</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> Dyspnea</td><td align="center" class="Botrule Lrule Rrule Toprule"> 1</td><td align="center" class="Botrule Lrule Rrule Toprule"> 2</td><td align="center" class="Botrule Lrule Rrule Toprule"> 0</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> Epistaxis</td><td align="center" class="Botrule Lrule Rrule Toprule"> &lt;1</td><td align="center" class="Botrule Lrule Rrule Toprule"> 2</td><td align="center" class="Botrule Lrule Rrule Toprule"> 0</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="4"><span class="Bold"> Skin and Subcutaneous Tissue Disorders</span> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> Rash </td><td align="center" class="Botrule Lrule Rrule Toprule">1</td><td align="center" class="Botrule Lrule Rrule Toprule">4</td><td align="center" class="Botrule Lrule Rrule Toprule">1</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> Dry skin</td><td align="center" class="Botrule Lrule Rrule Toprule"> 1</td><td align="center" class="Botrule Lrule Rrule Toprule"> 3</td><td align="center" class="Botrule Lrule Rrule Toprule"> 0</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="4"> <span class="Bold">Vascular Disorders</span></td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule"> Orthostatic hypotension </td><td align="center" class="Botrule Lrule Rrule Toprule"> 2</td><td align="center" class="Botrule Lrule Rrule Toprule"> 1</td><td align="center" class="Botrule Lrule Rrule Toprule"> 0</td> </tr> </tbody> </table></div>

* Parkinsonism includes extrapyramidal disorder, musculoskeletal stiffness, parkinsonism, cogwheel rigidity, akinesia, bradykinesia, hypokinesia, masked facies, muscle rigidity, and Parkinson’s disease. Akathisia includes akathisia and restlessness. Dystonia includes dystonia, muscle spasms, muscle contractions involuntary, muscle contracture, oculogyration, tongue paralysis. Tremor includes tremor and parkinsonian rest tremor.

Other Adverse Reactions Observed During the Clinical Trial Evaluations of Oral Risperidone

The following is a list of additional adverse drug reactions that have been reported during the clinical trial evaluation of oral risperidone:

Blood and Lymphatic System Disorders: anemia, granulocytopenia, neutropenia

Cardiac Disorders:  sinus bradycardia, sinus tachycardia, atrioventricular block first degree, bundle branch block left, bundle branch block right, atrioventricular block

Ear and Labyrinth Disorders: ear pain, tinnitus

Endocrine Disorders: hyperprolactinemia

Eye Disorders: ocular hyperemia, eye discharge, conjunctivitis, eye rolling, eyelid edema, eye swelling, eyelid margin crusting, dry eye, lacrimation increased, photophobia, glaucoma, visual acuity reduced

Gastrointestinal Disorders:  dysphagia, fecaloma, fecal incontinence, gastritis, lip swelling, cheilitis, aptyalism

General Disorders:  edema peripheral, thirst, gait disturbance, chest discomfort, chest pain, influenza-like illness, pitting edema, edema, chills, sluggishness, malaise, face edema, discomfort, generalized edema, drug withdrawal syndrome, peripheral coldness, feeling abnormal

Immune System Disorders:  drug hypersensitivity

Infections and Infestations:  pneumonia, influenza, ear infection, viral infection, pharyngitis, tonsillitis, bronchitis, eye infection, localized infection, cystitis, cellulitis, otitis media, onychomycosis, acarodermatitis, bronchopneumonia, respiratory tract infection, tracheobronchitis, otitis media chronic

Investigations:  body temperature increased, blood prolactin increased, alanine aminotransferase increased, electrocardiogram abnormal, eosinophil count increased, white blood cell count decreased, blood glucose increased, hemoglobin decreased, hematocrit decreased, body temperature decreased, blood pressure decreased, transaminases increased

Metabolism and Nutrition Disorders:  decreased appetite, polydipsia, anorexia

Musculoskeletal, Connective Tissue, and Bone Disorders:  joint swelling, joint stiffness, musculoskeletal chest pain, posture abnormal, myalgia, neck pain, muscular weakness, muscle rigidity, rhabdomyolysis

Nervous System Disorders:  balance disorder, disturbance in attention, dysarthria, unresponsive to stimuli, depressed level of consciousness, movement disorder, transient ischemic attack, coordination abnormal, cerebrovascular accident, speech disorder, syncope, loss of consciousness, hypoesthesia, tardive dyskinesia, cerebral ischemia, cerebrovascular disorder, neuroleptic malignant syndrome, diabetic coma, head titubation

Psychiatric Disorders:  agitation, blunted affect, confusional state, middle insomnia, nervousness, sleep disorder, listlessness, libido decreased, anorgasmia

Renal and Urinary Disorders:  enuresis, dysuria, pollakiuria, urinary incontinence

Reproductive System and Breast Disorders:  menstruation irregular, amenorrhea, gynecomastia, galactorrhea, vaginal discharge, menstrual disorder, erectile dysfunction, retrograde ejaculation, ejaculation disorder, sexual dysfunction, breast enlargement

Respiratory, Thoracic, and Mediastinal Disorders:  wheezing, pneumonia aspiration, sinus congestion, dysphonia, productive cough, pulmonary congestion, respiratory tract congestion, rales, respiratory disorder, hyperventilation, nasal edema

Skin and Subcutaneous Tissue Disorders:  erythema, skin discoloration, skin lesion, pruritus, skin disorder, rash erythematous, rash papular, acne, hyperkeratosis, seborrheic dermatitis, rash generalized, rash maculopapular

Vascular Disorders:  hypotension, flushing

Discontinuations Due to Adverse Drug Reactions with Oral Risperidone

Approximately 7% (39/564) of oral risperidone-treated patients in double-blind, placebo-controlled trials discontinued treatment due to an adverse reaction, compared with 4% (10/225) who were receiving placebo. The adverse reactions associated with discontinuation in 2 or more oral risperidone-treated patients were:

<div class="scrollingtable"><table> <caption> <span>Table 6: Adverse Reactions Associated with Discontinuation in ≥2% of Oral Risperidone-Treated Adult Patients in Schizophrenia Trials</span> </caption> <col/> <col/> <col/> <col/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule"> </td><td align="center" class="Botrule Lrule Rrule Toprule" colspan="2"> <span class="Bold">Oral Risperidone</span></td><td class="Botrule Lrule Rrule Toprule"> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold"> Adverse Reaction</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">2 mg to 8 mg per day</span> </p> <p> <span class="Bold">(N=366) </span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">&gt;8 mg to 16 mg per day</span> </p> <p> <span class="Bold">(N=198)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">Placebo</span> </p> <p> <span class="Bold">(N=225)</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> Dizziness</td><td align="center" class="Botrule Lrule Rrule Toprule"> 1.4%</td><td align="center" class="Botrule Lrule Rrule Toprule"> 1%</td><td align="center" class="Botrule Lrule Rrule Toprule">0% </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> Nausea</td><td align="center" class="Botrule Lrule Rrule Toprule"> 1.4%</td><td align="center" class="Botrule Lrule Rrule Toprule"> 0% </td><td align="center" class="Botrule Lrule Rrule Toprule">0%</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> Vomiting</td><td align="center" class="Botrule Lrule Rrule Toprule"> 0.8%</td><td align="center" class="Botrule Lrule Rrule Toprule"> 0%</td><td align="center" class="Botrule Lrule Rrule Toprule">0%</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> Parkinsonism</td><td align="center" class="Botrule Lrule Rrule Toprule"> 0.8%</td><td align="center" class="Botrule Lrule Rrule Toprule"> 0%</td><td align="center" class="Botrule Lrule Rrule Toprule">0%</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> Somnolence</td><td align="center" class="Botrule Lrule Rrule Toprule"> 0.8%</td><td align="center" class="Botrule Lrule Rrule Toprule"> 0%</td><td align="center" class="Botrule Lrule Rrule Toprule"> 0% </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> Dystonia</td><td align="center" class="Botrule Lrule Rrule Toprule"> 0.5%</td><td align="center" class="Botrule Lrule Rrule Toprule"> 0%</td><td align="center" class="Botrule Lrule Rrule Toprule">0%</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> Agitation</td><td align="center" class="Botrule Lrule Rrule Toprule"> 0.5%</td><td align="center" class="Botrule Lrule Rrule Toprule"> 0%</td><td align="center" class="Botrule Lrule Rrule Toprule"> 0%</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> Abdominal pain</td><td align="center" class="Botrule Lrule Rrule Toprule"> 0.5%</td><td align="center" class="Botrule Lrule Rrule Toprule"> 0%</td><td align="center" class="Botrule Lrule Rrule Toprule"> 0%</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> Orthostatic hypotension</td><td align="center" class="Botrule Lrule Rrule Toprule"> 0.3%</td><td align="center" class="Botrule Lrule Rrule Toprule"> 0.5%</td><td align="center" class="Botrule Lrule Rrule Toprule"> 0%</td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule"> Akathisia</td><td align="center" class="Botrule Lrule Rrule Toprule"> 0.3%</td><td align="center" class="Botrule Lrule Rrule Toprule"> 2%</td><td align="center" class="Botrule Lrule Rrule Toprule"> 0%</td> </tr> </tbody> </table></div>

Discontinuation for extrapyramidal symptoms (including Parkinsonism, akathisia, dystonia, and tardive dyskinesia) was 1% in placebo-treated patients, and 3.4% in active control-treated patients in a double-blind, placebo- and active-controlled trial.

Dose Dependency of Adverse Reactions in Clinical Trials of Oral Risperidone

Extrapyramidal Symptoms

Data from two fixed-dose trials in adults with schizophrenia provided evidence of dose-relatedness for extrapyramidal symptoms associated with oral risperidone treatment. Two methods were used to measure extrapyramidal symptoms (EPS) in an 8-week trial comparing 4 fixed doses of oral risperidone (2, 6, 10, and 16 mg/day), including (1) a Parkinsonism score (mean change from baseline) from the Extrapyramidal Symptom Rating Scale, and (2) incidence of spontaneous complaints of EPS:

<div class="scrollingtable"><table> <caption> <span>Table 7: Extrapyramidal Symptoms Associated with Oral Risperidone-Treated Adult Patients in an 8-Week Fixed Dose Schizophrenia Trial </span> </caption> <col/> <col/> <col/> <col/> <col/> <col/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">Dose Groups</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">Placebo</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">Oral Risperidone</span> </p> <p> <span class="Bold">2 mg </span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">Oral Risperidone</span> </p> <p> <span class="Bold">6 mg</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">Oral Risperidone</span> </p> <p> <span class="Bold">10 mg</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">Oral Risperidone</span> </p> <p> <span class="Bold">16 mg </span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> Parkinsonism</td><td align="center" class="Botrule Lrule Rrule Toprule"> 1.2</td><td align="center" class="Botrule Lrule Rrule Toprule"> 0.9</td><td align="center" class="Botrule Lrule Rrule Toprule"> 1.8</td><td align="center" class="Botrule Lrule Rrule Toprule"> 2.4</td><td align="center" class="Botrule Lrule Rrule Toprule"> 2.6</td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule"> EPS Incidence</td><td align="center" class="Botrule Lrule Rrule Toprule"> 13%</td><td align="center" class="Botrule Lrule Rrule Toprule"> 17%</td><td align="center" class="Botrule Lrule Rrule Toprule"> 21%</td><td align="center" class="Botrule Lrule Rrule Toprule"> 21%</td><td align="center" class="Botrule Lrule Rrule Toprule"> 35%</td> </tr> </tbody> </table></div>

Similar methods were used to measure extrapyramidal symptoms (EPS) in an 8-week trial comparing 5 fixed doses of oral risperidone (1, 4, 8, 12, and 16 mg/day):

<div class="scrollingtable"><table> <caption> <span>Table 8: Extrapyramidal Symptoms Associated with Oral Risperidone-Treated Adult Patients in an 8-Week Fixed Dose Schizophrenia Trial</span> </caption> <col/> <col/> <col/> <col/> <col/> <col/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule"><span class="Bold">Dose Groups</span> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">Oral Risperidone</span> </p> <p> <span class="Bold">1 mg</span> </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">Oral Risperidone</span> </p> <p> <span class="Bold">4 mg</span> </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">Oral Risperidone</span> </p> <p> <span class="Bold">8 mg</span> </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">Oral Risperidone</span> </p> <p> <span class="Bold">12 mg</span> </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">Oral Risperidone</span> </p> <p> <span class="Bold">16 mg</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> Parkinsonism</td><td align="center" class="Botrule Lrule Rrule Toprule"> 0.6</td><td align="center" class="Botrule Lrule Rrule Toprule"> 1.7</td><td align="center" class="Botrule Lrule Rrule Toprule"> 2.4</td><td align="center" class="Botrule Lrule Rrule Toprule"> 2.9</td><td align="center" class="Botrule Lrule Rrule Toprule"> 4.1</td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule"> EPS Incidence</td><td align="center" class="Botrule Lrule Rrule Toprule"> 7%</td><td align="center" class="Botrule Lrule Rrule Toprule"> 12%</td><td align="center" class="Botrule Lrule Rrule Toprule"> 17%</td><td align="center" class="Botrule Lrule Rrule Toprule"> 18%</td><td align="center" class="Botrule Lrule Rrule Toprule"> 20%</td> </tr> </tbody> </table></div>

Changes in Body Weight

Weight gain was observed in short-term, controlled trials and longer-term uncontrolled studies in adults [see Warnings and Precautions (5.5) and Adverse Reactions (6)].

Dystonia

 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, they occur more frequently and with greater severity with high potency and at higher doses of first generation antipsychotic drugs. An elevated risk of acute dystonia is observed in males and younger age groups.

Other Adverse Reactions

Adverse reaction data elicited by a checklist for side effects from a large study comparing 5 fixed doses of oral risperidone (1, 4, 8, 12, and 16 mg/day) were explored for dose-relatedness of adverse events. A Cochran-Armitage Test for trend in these data revealed a positive trend (p<0.05) for the following adverse reactions: somnolence, vision abnormal, dizziness, palpitations, weight increase, erectile dysfunction, ejaculation disorder, sexual function abnormal, fatigue, and skin discoloration.

Changes in ECG

Between-group comparisons for pooled placebo-controlled trials of oral risperidone in adults revealed no statistically significant differences between oral risperidone and placebo in mean changes from baseline in ECG parameters, including QT, QTc, and PR intervals, and heart rate. When all oral risperidone doses were pooled from randomized controlled trials in several indications, there was a mean increase in heart rate of 1 beat per minute compared to no change for placebo patients. In short-term schizophrenia trials, higher doses of oral risperidone were associated with a higher mean increase in heart rate compared to placebo (4 to 6 beats per minute).

Injection Site Reactions with UZEDY

Local tolerability assessments were administered to patients who reported injection site adverse reactions in a randomized withdrawal study with UZEDY in adult patients with schizophrenia. The injection site was assessed by appropriately trained personnel throughout the clinical development program.

All injection site reactions (nodule, pruritus, erythema, mass, and swelling) were mild to moderate in severity with the exception of 1 case of severe pruritus which resolved after 6 days. Injection site reactions were reported in 22 patients (13%) in the placebo group, 36 patients (20%) in the UZEDY once monthly group, and 37 patients (21%) in the UZEDY once every 2 months group. The most common injection site reactions were: nodule (7% in each UZEDY-treated group and 3% in the placebo group) and pruritus (5% and 3% in the UZEDY-treated once monthly and once every 2 months groups, respectively, and 2% in the placebo group).

The following adverse reactions have been identified during post-approval use of oral risperidone. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

These adverse reactions include: alopecia, anaphylactic reaction, angioedema, atrial fibrillation, cardiopulmonary arrest, catatonia, diabetic ketoacidosis in patients with impaired glucose metabolism, dysgeusia, hypoglycemia, hypothermia, ileus, inappropriate antidiuretic hormone secretion, intestinal obstruction, jaundice, mania, pancreatitis, pituitary adenoma, precocious puberty, pulmonary embolism, QT prolongation, sleep apnea syndrome, somnambulism, Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN), sudden death, thrombocytopenia, thrombotic thrombocytopenic purpura, urinary retention, and water intoxication.

Postmarketing cases of extrapyramidal symptoms (dystonia and dyskinesia) have been reported in patients concomitantly taking methylphenidate and risperidone when there was an increase or decrease in dosage, initiation, or discontinuation of either or both medications.

Table 9 includes clinically significant drug interactions with UZEDY.

<div class="scrollingtable"><table> <caption> <span>Table 9: Clinically Important Drug Interactions with UZEDY</span> </caption> <col/> <col/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" colspan="2"><span class="Bold">Strong CYP2D6 Inhibitors</span> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"><span class="Italics">Clinical Impact:</span> </td><td class="Botrule Lrule Rrule Toprule">Concomitant use of UZEDY with strong CYP2D6 inhibitors may increase the plasma exposure of risperidone and lower the plasma exposure of a major active metabolite, 9-hydroxyrisperidone <span class="Italics">[see Clinical Pharmacology (<a href="#www.splportal.comLINK_2918cb2b-1703-46cc-9d3e-43426ca8d455">12.3</a>)]</span>. </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"><span class="Italics">Intervention:</span></td><td class="Botrule Lrule Rrule Toprule">When initiation of strong CYP2D6 inhibitors is considered, patients may be placed on the lowest dose (50 mg once monthly or 100 mg once every 2 months) of UZEDY prior to the planned start of strong CYP2D6 inhibitors to adjust for the expected increase in plasma concentrations of risperidone. When strong CYP2D6 inhibitors are initiated in patients receiving UZEDY 50 mg once monthly or 100 mg once every 2 months, it is recommended to continue treatment with the same dose unless clinical judgment necessitates interruption of UZEDY treatment. The effects of discontinuation of strong CYP2D6 inhibitors on the pharmacokinetics of risperidone and 9-hydroxyrisperidone have not been studied <span class="Italics">[see Clinical Pharmacology (<a href="#www.splportal.comLINK_2918cb2b-1703-46cc-9d3e-43426ca8d455">12.3</a>)]</span>. </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="2"><span class="Bold">Strong CYP3A4 Inducers</span> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"><span class="Italics">Clinical Impact:</span> </td><td class="Botrule Lrule Rrule Toprule">Concomitant use of UZEDY and a strong CYP3A4 inducer may cause decreases in the combined plasma concentrations of risperidone and 9-hydroxyrisperidone which could lead to decreased efficacy of UZEDY <span class="Italics">[see Clinical Pharmacology (<a href="#www.splportal.comLINK_2918cb2b-1703-46cc-9d3e-43426ca8d455">12.3</a>)]</span>. </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"><span class="Italics">Intervention:</span> </td><td class="Botrule Lrule Rrule Toprule">Changes in efficacy and safety should be carefully monitored with any dose adjustment of UZEDY. At the initiation of therapy with a strong CYP3A4 inducer, patients should be closely monitored during the first 4 to 8 weeks. In patients receiving UZEDY at a specific dose, consider increasing the dose to the next highest dose. In patients receiving UZEDY 125 mg once monthly or 250 mg once every 2 months, additional oral risperidone therapy may need to be considered. On discontinuation of a strong CYP3A4 inducer, the dosage of UZEDY or any additional oral risperidone therapy should be reevaluated and, if necessary, decreased to adjust for the expected increase in plasma concentration of risperidone and 9-hydroxyrisperidone. For patients treated with UZEDY 50 mg once monthly or UZEDY 100 mg once every 2 months discontinuing from a strong CYP3A4 inducer, it is recommended to continue treatment with the same dose unless clinical judgment necessitates interruption of UZEDY treatment <span class="Italics">[see Dosage and Administration (<a href="#www.splportal.comLINK_8633168c-93de-4a9b-a39d-f2288f38db8e">2.3</a>)]</span>. </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="2"><span class="Bold">Centrally-Acting Drugs and Alcohol</span> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"><span class="Italics">Clinical Impact:</span> </td><td class="Botrule Lrule Rrule Toprule">Due to additive pharmacologic effects, the concomitant use of centrally-acting drugs, including alcohol, may increase nervous system disorders. </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"><span class="Italics">Intervention:</span> </td><td class="Botrule Lrule Rrule Toprule">Caution should be used when UZEDY is administered in combination with other centrally-acting drugs or alcohol. </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="2"><span class="Bold">Hypotensive Agents</span> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"><span class="Italics">Clinical Impact:</span> </td><td class="Botrule Lrule Rrule Toprule">Because of its potential for inducing hypotension, UZEDY may enhance the hypotensive effects of other therapeutic agents with this potential. </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"><span class="Italics">Intervention:</span> </td><td class="Botrule Lrule Rrule Toprule">Caution should be used when UZEDY is administered with other therapeutic effects of other therapeutic agents with this potential. </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="2"><span class="Bold">Dopamine Agonists</span> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"><span class="Italics">Clinical Impact:</span> </td><td class="Botrule Lrule Rrule Toprule">Agents with central antidopaminergic activity such as UZEDY may antagonize the pharmacologic effects of dopamine agonists. </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"><span class="Italics">Intervention:</span> </td><td class="Botrule Lrule Rrule Toprule">Caution should be used when UZEDY is administered in combination with levodopa and dopamine agonists. </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="2"><span class="Bold">Methylphenidate</span> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"><span class="Italics">Clinical Impact:</span> </td><td class="Botrule Lrule Rrule Toprule">Concomitant use with methylphenidate, when there is change in dosage of either medication, may increase the risk of extrapyramidal symptoms (EPS) <span class="Italics">[see Adverse Reactions (<a href="#www.splportal.comLINK_f4863eb1-824c-49db-92dd-1b8a13418332">6.2</a>)]</span>. </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule"><span class="Italics">Intervention:</span> </td><td class="Botrule Lrule Rrule Toprule">Monitor for symptoms of EPS with concomitant use of UZEDY and methylphenidate. </td> </tr> </tbody> </table></div>

Based on pharmacokinetic studies with oral risperidone, no dosage adjustment of UZEDY is required when administered concomitantly with amitriptyline, cimetidine, ranitidine, clozapine, topiramate, and moderate CYP3A4 inhibitors (erythromycin). Additionally, no dosage adjustment is necessary for lithium, valproate, topiramate, digoxin, and CYP2D6 substrates (donepezil and galantamine) when co-administered with UZEDY [see Clinical Pharmacology (12.3)].

Pregnancy Exposure Registry

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

Risk Summary

Neonates exposed to antipsychotic drugs during the third trimester of pregnancy 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 risperidone 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 and with exposure to antipsychotics, including UZEDY, during pregnancy (see Clinical Considerations).

Oral administration of risperidone to pregnant mice caused cleft palate at doses 3- to 4-times the oral maximum recommended human dose (MRHD) of 16 mg/day with maternal toxicity observed at 4-times MRHD based on mg/m2 body surface area. Risperidone was not teratogenic in rats or rabbits at doses up to 6-times the oral MRHD based on mg/m2 body surface area. Increased stillbirths and decreased birth weight occurred after oral risperidone administration to pregnant rats at 1.5-times the oral MRHD based on mg/m2 body surface area. Learning was impaired in offspring of rats when the dams were dosed at 0.6-times the oral MRHD and offspring mortality increased at doses 0.1- to 3-times the oral MRHD based on mg/m2 body surface area.

The background risks of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, 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/or embryo/fetal risk

There is a risk to the mother from untreated schizophrenia, including increased risk of relapse, hospitalization, and suicide. Schizophrenia is 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 risperidone, 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

Published data from observational studies, birth registries, and case reports on the use of atypical antipsychotics during pregnancy do not report a clear association with antipsychotics and major birth defects. A prospective observational study including 6 women treated with risperidone demonstrated placental passage of risperidone. 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. There was a small increase in the risk of major birth defects (RR = 1.26, 95% CI = 1.02 to 1.56) and of cardiac malformations (RR = 1.26, 95% CI = 0.88 to 1.81) in a subgroup of 1566 women exposed to risperidone during the first trimester of pregnancy; however, there is no mechanism of action to explain the difference in malformation rates.

Animal data

No developmental toxicity studies were conducted with subcutaneous risperidone suspension.

Oral administration of risperidone to pregnant mice during organogenesis caused cleft palate at 10 mg/kg/day which is 3-times the oral MRHD of 16 mg/day based on mg/m2 body surface area; maternal toxicity occurred at 4-times the oral MRHD. Risperidone was not teratogenic when administered orally to rats at 0.6 to 10 mg/kg/day and rabbits at 0.3 to 5 mg/kg/day, which are up to 6-times the oral MRHD of 16 mg/day risperidone based on mg/m2 body surface area. Learning was impaired in offspring of rats dosed orally throughout pregnancy at 1 mg/kg/day which is 0.6-times the oral MRHD and neuronal cell death increased in fetal brains of offspring of rats dosed during pregnancy at 1 and 2 mg/kg/day which are 0.6- and 1.2-times the oral MRHD based on mg/m2 body surface area; postnatal development and growth of the offspring were also delayed.

Rat offspring mortality increased during the first 4 days of lactation when pregnant rats were dosed throughout gestation at 0.16 to 5 mg/kg/day which are 0.1- to 3-times the oral MRHD of 16 mg/day based on mg/m2 body surface area. It is not known whether these deaths were due to a direct effect on the fetuses or pups or to effects on the dams; a no-effect dose could not be determined. The rate of stillbirths was increased at 2.5 mg/kg or 1.5-times the oral MRHD based on mg/m2 body surface area.

In a rat cross-fostering study the number of live offspring was decreased, the number of stillbirths increased, and the birth weight was decreased in offspring of drug-treated pregnant rats. In addition, the number of deaths increased by Day 1 among offspring of drug-treated pregnant rats, regardless of whether or not the offspring were cross-fostered. Risperidone also appeared to impair maternal behavior in that offspring body weight gain and survival (from Day 1 to 4 of lactation) were reduced in offspring born to control but reared by drug-treated dams. All of these effects occurred at 5 mg/kg which is 3-times the oral MRHD based on mg/m2 and the only dose tested in the study.

Risk Summary

Limited data from published literature reports the presence of risperidone and its metabolite, 9-hydroxyrisperidone, in human breast milk at relative infant dose ranging between 2.3 and 4.7% of the maternal weight-adjusted dosage. There are reports of sedation, failure to thrive, jitteriness, and extrapyramidal symptoms (tremors and abnormal muscle movements) in breastfed infants exposed to risperidone (see Clinical Considerations).

There is no information on the effects of risperidone on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for UZEDY and any potential adverse effects on the breastfed child from UZEDY or from the mother’s underlying condition.

Clinical Considerations

Infants exposed to UZEDY through breastmilk should be monitored for excess sedation, failure to thrive, jitteriness, and extrapyramidal symptoms (tremors and abnormal muscle movements).

Infertility

Females

Based on the pharmacologic action of risperidone (D2 receptor antagonism), treatment with UZEDY 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 (5.6)].

The safety and effectiveness of UZEDY have not been established in pediatric patients.

Juvenile Animal Toxicity Data

No juvenile animal studies were conducted with subcutaneous risperidone suspension.

Juvenile dogs were treated with oral risperidone from weeks 10 to 50 of age (equivalent to the period of childhood through adolescence in humans), at doses of 0.31, 1.25, or 5 mg/kg/day. Bone length and density were decreased with a no-effect dose of 0.31 mg/kg/day; this dose produced plasma AUC of risperidone plus its active metabolite paliperidone (9-hydroxyrisperidone) that were similar to those in children and adolescents receiving the oral MRHD of 6 mg/day. In addition, sexual maturation was delayed at all doses in both males and females. The above effects showed little or no reversibility in females after a 12 week drug-free recovery period.

Juvenile rats, treated with oral risperidone from days 12 to 50 of age (equivalent to the period of infancy through adolescence in humans) showed impaired learning and memory performance (reversible only in females), with a no-effect dose of 0.63 mg/kg/day which is 0.5 times the oral MRHD of 6 mg/day for children, based on mg/m2 body surface area. This dose produced plasma AUC of risperidone plus paliperidone about half the exposure observed in humans at the oral MRHD. No other consistent effects on neurobehavioral or reproductive development were seen up to the highest tested dose of 1.25 mg/kg/day which is 1 time the oral MRHD and produced plasma AUC of risperidone plus paliperidone that were about two thirds of those observed in humans at the oral MRHD of 6 mg/day for children.

Clinical studies of UZEDY in the treatment of schizophrenia did not include patients older than 65 years to determine whether or not they respond differently from younger patients.

In general, dose selection for geriatric patients should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

UZEDY is substantially excreted by the kidneys, and the risk of reactions may be greater in patients with impaired renal function. Because geriatric patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function [see Warnings and Precautions (5.7) and Clinical Pharmacology (12.3)].

Elderly patients with dementia-related psychosis treated with UZEDY are at an increased risk of death compared to placebo. UZEDY is not approved for the treatment of patients with dementia‑related psychosis [see Boxed Warning and Warnings and Precautions (5.1, 5.2)].

In patients with renal impairment, titrate with oral risperidone (up to at least 2 mg daily) before initiating treatment with UZEDY [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)].

UZEDY was not studied in patients with renal impairment.

In patients with hepatic impairment, titrate with oral risperidone (up to at least 2 mg daily) before initiating treatment with UZEDY [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)].

UZEDY has not been studied in patients with hepatic impairment; however, such effect has been investigated with oral risperidone.

Patients with Parkinson’s disease or dementia with Lewy bodies can experience increased sensitivity to UZEDY. Manifestations can include confusion, obtundation, postural instability with frequent falls, extrapyramidal symptoms, and clinical features consistent with neuroleptic malignant syndrome.

Human Experience

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

No cases of overdose were reported in premarketing studies with UZEDY.

{ "type": "p", "children": [], "text": "No cases of overdose were reported in premarketing studies with UZEDY." }

In premarketing experience with oral risperidone, there were eight reports of acute risperidone overdosage with estimated doses ranging from 20 to 300 mg and no fatalities. In general, reported signs and symptoms were those resulting from an exaggeration of the drug's known pharmacological effects, i.e., drowsiness and sedation, tachycardia and hypotension, and extrapyramidal symptoms. One case, involving an estimated overdose of 240 mg, was associated with hyponatremia, hypokalemia, prolonged QT, and widened QRS. Another case, involving an estimated overdose of 36 mg, was associated with a seizure.

{ "type": "p", "children": [], "text": "In premarketing experience with oral risperidone, there were eight reports of acute risperidone overdosage with estimated doses ranging from 20 to 300 mg and no fatalities. In general, reported signs and symptoms were those resulting from an exaggeration of the drug's known pharmacological effects, i.e., drowsiness and sedation, tachycardia and hypotension, and extrapyramidal symptoms. One case, involving an estimated overdose of 240 mg, was associated with hyponatremia, hypokalemia, prolonged QT, and widened QRS. Another case, involving an estimated overdose of 36 mg, was associated with a seizure." }

Postmarketing experience with oral risperidone included reports of acute overdosage with estimated doses of up to 360 mg. In general, the most frequently reported signs and symptoms are those resulting from an exaggeration of the drug's known pharmacological effects, i.e., drowsiness, sedation, tachycardia, hypotension, and extrapyramidal symptoms. Other postmarketing adverse reactions related to oral risperidone overdose include prolonged QT interval and convulsions. Torsade de pointes has been reported in association with combined overdose of oral risperidone and paroxetine.

{ "type": "p", "children": [], "text": "Postmarketing experience with oral risperidone included reports of acute overdosage with estimated doses of up to 360 mg. In general, the most frequently reported signs and symptoms are those resulting from an exaggeration of the drug's known pharmacological effects, i.e., drowsiness, sedation, tachycardia, hypotension, and extrapyramidal symptoms. Other postmarketing adverse reactions related to oral risperidone overdose include prolonged QT interval and convulsions. Torsade de pointes has been reported in association with combined overdose of oral risperidone and paroxetine." }

Management of Overdosage

{ "type": "p", "children": [], "text": "\nManagement of Overdosage\n" }

There is no specific antidote to risperidone. Provide supportive care including close medical supervision and monitoring. Treatment should consist of general measures employed in the management of overdosage with any drug. Consider the possibility of multiple drug overdosage. Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm and vital signs.

{ "type": "p", "children": [], "text": "There is no specific antidote to risperidone. Provide supportive care including close medical supervision and monitoring. Treatment should consist of general measures employed in the management of overdosage with any drug. Consider the possibility of multiple drug overdosage. Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm and vital signs." }

Consider contacting the Poison Help Line (1-800-222-1222) or medical toxicologist for additional overdosage management recommendations.

{ "type": "p", "children": [], "text": "Consider contacting the Poison Help Line (1-800-222-1222) or medical toxicologist for additional overdosage management recommendations." }

UZEDY contains risperidone, an atypical antipsychotic. Risperidone belongs to the chemical class of benzisoxazole derivatives. The chemical designation 3-[2-[4-(6-fluoro-1,2-benzoxazol-3-yl) piperidin-1yl] ethyl]-2-methyl-6,7,8,9-tetrahydropyrido[1,2-a] pyrimidin-4-one. Its molecular formula is C23H27FN4O2 and its molecular weight is 410.5 g/mol.

{ "type": "p", "children": [], "text": "UZEDY contains risperidone, an atypical antipsychotic. Risperidone belongs to the chemical class of benzisoxazole derivatives. The chemical designation 3-[2-[4-(6-fluoro-1,2-benzoxazol-3-yl) piperidin-1yl] ethyl]-2-methyl-6,7,8,9-tetrahydropyrido[1,2-a] pyrimidin-4-one. Its molecular formula is C23H27FN4O2 and its molecular weight is 410.5 g/mol." }

The structural formula is:

{ "type": "p", "children": [], "text": "The structural formula is:" }

Risperidone is a white to off-white powder. It is practically insoluble in water and soluble in methanol and 0.1 N HCl. It has the following pKa values: 8.28 (piperidine moiety) and 3.12 (pyrimidine moiety).

{ "type": "p", "children": [], "text": "Risperidone is a white to off-white powder. It is practically insoluble in water and soluble in methanol and 0.1 N HCl. It has the following pKa values: 8.28 (piperidine moiety) and 3.12 (pyrimidine moiety).\n" }

UZEDY is a sterile, white to off-white opaque viscous extended-release injectable suspension, intended for subcutaneous administration in the following strengths of risperidone (and deliverable volumes from a single-dose prefilled syringe): 50 mg (0.14 mL), 75 mg (0.21 mL), 100 mg (0.28 mL), 125 mg (0.35 mL), 150 mg (0.42 mL), 200 mg (0.56 mL), and 250 mg (0.7 mL). The inactive ingredients include dimethyl sulfoxide (45% w/w), methoxy-poly(ethylene glycol)-co-poly(D,L-lactide) (15% w/w), and poly(D,L-lactide)-co-poly(ethylene glycol)-co-poly(D,L-lactide) (10% w/w).

{ "type": "p", "children": [], "text": "UZEDY is a sterile, white to off-white opaque viscous extended-release injectable suspension, intended for subcutaneous administration in the following strengths of risperidone (and deliverable volumes from a single-dose prefilled syringe): 50 mg (0.14 mL), 75 mg (0.21 mL), 100 mg (0.28 mL), 125 mg (0.35 mL), 150 mg (0.42 mL), 200 mg (0.56 mL), and 250 mg (0.7 mL). The inactive ingredients include dimethyl sulfoxide (45% w/w), methoxy-poly(ethylene glycol)-co-poly(D,L-lactide) (15% w/w), and poly(D,L-lactide)-co-poly(ethylene glycol)-co-poly(D,L-lactide) (10% w/w).\n" }

The mechanism of action of risperidone, in schizophrenia, is unclear. The drug’s therapeutic activity in schizophrenia could be mediated through a combination of dopamine Type 2 (D2) and serotonin Type 2 (5HT2) receptor antagonism. The clinical effect from risperidone results from the combined concentrations of risperidone and its major metabolite, 9-hydroxyrisperidone (paliperidone) [see Clinical Pharmacology (12.3)]. Antagonism at receptors other than D2 and 5HT2 may explain some of the other effects of risperidone.

Risperidone is a monoaminergic antagonist with high affinity (Ki of 0.12 to 7.3 nM) for the serotonin Type 2 (5HT2), dopamine Type 2 (D2), α1 and α2 adrenergic, and H1 histaminergic receptors. Risperidone showed low to moderate affinity (Ki of 47 to 253 nM) for the serotonin 5HT1C, 5HT1D, and 5HT1A receptors, weak affinity (Ki of 620 to 800 nM) for the dopamine D1 and haloperidol-sensitive sigma site, and no affinity (when tested at concentrations >10-5 M) for cholinergic muscarinic or β1 and β2 adrenergic receptors.

The pharmacokinetics of the risperidone and 9-hydroxyrisperidone combined and the individual components (risperidone and 9-hydroxyrisperidone), following subcutaneous injection of UZEDY, were evaluated in both healthy subjects (n = 53) and in patients with clinically stable schizophrenia and schizoaffective disorder after single doses (12.5 to 225 mg, n = 195) and 3 repeated monthly doses (75 mg and 150 mg, n=24).

For all doses, steady-state levels of risperidone and 9-hydroxyrisperidone were approached within 2 months of UZEDY initiation. Steady-state plasma exposure values of risperidone, 9-hydroxyrisperidone, and risperidone and 9-hydroxyrisperidone combined following once monthly administration of UZEDY are approximately 2- to 2.5-fold higher than single dose exposure, while the values for UZEDY administered once every 2 months are about 1.5-fold higher than the respective single dose exposure. After administration of UZEDY, plasma levels of risperidone, 9-hydroxyrisperidone, and risperidone and 9-hydroxyrisperidone combined (AUC0-tau and Cmax) increase in a dose-proportional manner.

The average exposure values (Cavg,ss ) over the dosing period are comparable for UZEDY administered once monthly and once every 2 months at corresponding doses. Following both once monthly (50 mg to 125 mg) and once every 2 months dosing (100 mg to 250 mg), the mean exposure of risperidone and 9-hydroxyrisperidone combined (AUC0-tau) of UZEDY corresponds to that of oral risperidone (2 mg to 5 mg/day) administered over an equivalent dosing period (see Table 1). 

Absorption

UZEDY contains risperidone in a liquid delivery system. Following subcutaneous injection, a depot forms which provides a sustained plasma levels of risperidone and 9-hydroxyrisperidone combined over one month or two months. All UZEDY doses, administered once monthly or once every 2 months, showed two absorption peaks for risperidone in plasma. After subcutaneous administration, median tmax for the risperidone and 9-hydroxyrisperidone combined ranges from 8 to 14 days. Therapeutic concentrations in plasma are within 6 to 24 hours following the first subcutaneous injection.

UZEDY administered in the abdomen and upper arm results in similar pharmacokinetic profiles for all UZEDY doses, permitting either injection site to be used interchangeably.

Distribution

Once absorbed, risperidone is rapidly distributed. The volume of distribution is 1 to 2 L/kg. Risperidone is bound to albumin and α1-acid glycoprotein. The plasma protein binding of risperidone is approximately 90%, and that of its major metabolite, 9-hydroxyrisperidone, is 77%. Neither risperidone nor 9-hydroxyrisperidone displace each other from plasma binding sites.

Elimination

The combined clearance of the risperidone and 9-hydroxyrisperidone following UZEDY administration is 14.3 L/h at steady state. The mean apparent half-life (t½) of UZEDY ranges between 14 to 22 days for risperidone, 9-hydroxyrisperidone, and risperidone and 9-hydroxyrisperidone combined.

Metabolism

Risperidone is extensively metabolized in the liver. The main metabolic pathway is through hydroxylation of risperidone to 9-hydroxyrisperidone by the enzyme cytochrome CYP2D6 with minor contribution by CYP3A4. A minor metabolic pathway is through N-dealkylation. The main metabolite, 9-hydroxyrisperidone, has similar pharmacological activity as risperidone. Consequently, the clinical effect of the drug results from the combined concentrations of risperidone plus 9-hydroxyrisperidone).

CYP2D6 is the enzyme responsible for metabolism of many neuroleptics, antidepressants, antiarrhythmics, and other drugs. CYP2D6 is subject to genetic polymorphism (about 6 to 8% of Caucasians, and a very low percentage of Asians, have little or no activity and are “poor metabolizers”) and to inhibition by a variety of substrates and some non-substrates, notably quinidine. Extensive CYP2D6 metabolizers convert risperidone rapidly into 9-hydroxyrisperidone; whereas, poor CYP2D6 metabolizers convert it much more slowly.

Population PK analysis demonstrates that plasma exposure to risperidone and 9-hydroxyrisperidone combined was similar in CYP2D6 extensive, intermediate, poor and non-poor metabolizers following subcutaneous injection with UZEDY.

Excretion

Risperidone and its metabolites are eliminated via the urine and, to a much lesser extent, via the feces. As illustrated by a mass balance study of a single 1 mg oral dose of 14C-risperidone administered as a solution to three healthy male volunteers, total recovery of radioactivity at 1-week was 84%, including 70% in the urine and 14% in the feces.

Specific Populations

Based on population pharmacokinetic analyses, age, sex, race and weight do not have a clinically meaningful effect on the pharmacokinetics of UZEDY.

Patients with Renal Impairment

UZEDY was not studied in patients with renal impairment; however, such effect has been investigated with oral risperidone. In patients with moderate to severe renal disease treated with oral risperidone, the apparent clearance (CL/F) of risperidone and 9-hydroxyrisperidone combined was decreased by 60% in patients with moderate to severe renal disease compared with young healthy subjects [see Use in Specific Populations (8.6)].

Patients with Hepatic Impairment

The effect of hepatic impairment on the pharmacokinetics of UZEDY has not been studied.

The effect of hepatic impairment on the pharmacokinetics of oral risperidone has been evaluated in a phase I study. While the pharmacokinetics of risperidone in subjects with liver disease were comparable to those in young healthy subjects, the mean free fraction of risperidone in plasma was increased by about 35% because of the diminished concentration of both albumin and α1-acid glycoprotein [see Use in Specific Populations (8.7)].

Drug Interaction Studies

No specific drug interaction studies have been performed with UZEDY. The drug interaction data provided in this section is based on studies with oral risperidone. Effects of other drugs on the exposures of risperidone, 9-hydroxyrisperidone, and risperidone and 9-hydroxyrisperidone combined as well as the effects of risperidone on the exposures of other drugs is summarized below.

Effects of Other Drugs on Risperidone, 9-hydroxyrisperidone, and Risperidone and 9-hydroxyrisperidone Combined Pharmacokinetics

Strong CYP2D6 Inhibitors (Fluoxetine and Paroxetine)

Fluoxetine (20 mg once daily) and paroxetine (20 mg once daily), potent CYP2D6 inhibitors, have been shown to increase the plasma concentration of risperidone by 2.5- to 2.8-fold and 3- to 9-fold, respectively. Fluoxetine did not affect the plasma concentration of 9-hydroxyrisperidone. Paroxetine lowered the concentration of 9-hydroxyrisperidone by about 10%. The effects of discontinuation of concomitant fluoxetine or paroxetine therapy on the pharmacokinetics of risperidone and 9-hydroxyrisperidone have not been studied.

Moderate CYP3A4 Inhibitor (Erythromycin)

There were no significant interactions between oral risperidone and erythromycin, a moderate CYP3A4 inhibitor.

Strong CYP3A4 Inducer (Carbamazepine)

Carbamazepine co-administration with oral risperidone decreased the steady-state plasma concentrations of risperidone and 9-hydroxyrisperidone by about 50%. Plasma concentrations of carbamazepine did not appear to be affected. Co-administration of other known CYP3A4 enzyme inducers (e.g., phenytoin, rifampin, and phenobarbital) with risperidone may cause similar decreases in the combined plasma concentrations of risperidone and 9-hydroxyrisperidone, which could lead to decreased efficacy of UZEDY treatment.

Amitriptyline, Cimetidine, Ranitidine, Clozapine

Clinically meaningful pharmacokinetic interaction between UZEDY and other drugs, such as amitriptyline, cimetidine, ranitidine, and clozapine, is not expected.

Effects of Oral Risperidone on Pharmacokinetics of Other Drugs

Lithium

Repeated doses of oral risperidone (3 mg twice daily) did not affect the exposure (AUC) or peak plasma concentrations (Cmax) of lithium (n = 13).

Valproate

Repeated doses of oral risperidone (4 mg once daily) did not affect the predose or average plasma concentrations and exposure (AUC) of valproate (1000 mg/day in three divided doses) compared to placebo (n = 21). However, there was a 20% increase in valproate peak plasma concentration (Cmax) after concomitant administration of oral risperidone.

Topiramate

Oral risperidone administered at doses from 1 to 6 mg/day concomitantly with topiramate 400 mg/day resulted in a 23% decrease in risperidone Cmax and a 33% decrease in risperidone AUC0‑12 hour at steady state. Minimal reductions in the exposure to risperidone and 9-hydroxyrisperidone combined, and no change for 9-hydroxyrisperidone were observed. This interaction is unlikely to be of clinical significance. There was no clinically relevant effect of oral risperidone on the pharmacokinetics of topiramate.

Digoxin

Oral risperidone (0.25 mg twice daily) did not show a clinically relevant effect on the pharmacokinetics of digoxin.

CYP2D6 Substrates

In vitro studies indicate that risperidone is a relatively weak inhibitor of CYP2D6. Therefore, UZEDY is not expected to substantially inhibit the clearance of drugs that are metabolized by this enzymatic pathway. In drug interaction studies, oral risperidone did not significantly affect the pharmacokinetics of donepezil and galantamine, which are metabolized by CYP2D6.

Carcinogenesis

No carcinogenicity studies were conducted with subcutaneous risperidone suspension. Carcinogenicity studies were conducted with oral risperidone in mice and rats. Risperidone was administered in the diet at doses of 0.63, 2.5, and 10 mg/kg for 18-months to mice and for 25-months to rats. These doses are equivalent to approximately 0.2-, 0.75-, and 3-times (mice) and 0.4-, 1.5-, and 6-times (rats) the oral MRHD of 16 mg/day, based on a mg/m2 body surface area. A maximum tolerated dose was not achieved in male mice. There were statistically significant increases in pituitary gland adenomas, endocrine pancreas adenomas, and mammary gland adenocarcinomas. The table below summarizes the multiples of the human dose on a mg/m2 (mg/kg) basis at which these tumors occurred.

<div class="scrollingtable"><table> <caption> <span>Table 10: Summary of Tumor Occurrence at the Multiples of the Human Oral Dose on a mg/m<span class="Sup">2</span> (mg/kg) Basis with Oral Risperidone Dosing</span> </caption> <col/> <col/> <col/> <col/> <col/> <tbody class="Headless"> <tr class="First"> <td align="center" class="Botrule Lrule Rrule Toprule" rowspan="2"> <br/> <span class="Bold">Tumor Type </span> </td><td align="center" class="Botrule Lrule Rrule Toprule" rowspan="2"> <br/> <span class="Bold">Species</span> </td><td align="center" class="Botrule Lrule Rrule Toprule" rowspan="2"> <br/> <span class="Bold">Sex</span> </td><td align="center" class="Botrule Lrule Rrule Toprule" colspan="2"> <span class="Bold">Multiples of Maximum Human Dose in mg/m<span class="Sup">2</span> (mg/kg)</span></td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule Toprule"><span class="Bold">Lowest Effect Level</span> </td><td align="center" class="Botrule Lrule Rrule Toprule"><span class="Bold">Highest No-Effect Level </span></td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule">Pituitary adenomas </td><td align="center" class="Botrule Lrule Rrule Toprule">mouse </td><td align="center" class="Botrule Lrule Rrule Toprule">Female </td><td align="center" class="Botrule Lrule Rrule Toprule">0.75 (9.4) </td><td align="center" class="Botrule Lrule Rrule Toprule">0.2 (2.4) </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Endocrine pancreas </p> <p>adenomas </p> </td><td align="center" class="Botrule Lrule Rrule Toprule">rat </td><td align="center" class="Botrule Lrule Rrule Toprule">Male</td><td align="center" class="Botrule Lrule Rrule Toprule">1.5 (9.4) </td><td align="center" class="Botrule Lrule Rrule Toprule">0.4 (2.4) </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Mammary gland </p> <p>adenocarcinomas </p> </td><td align="center" class="Botrule Lrule Rrule Toprule">mouse </td><td align="center" class="Botrule Lrule Rrule Toprule">Female </td><td align="center" class="Botrule Lrule Rrule Toprule">0.2 (2.4) </td><td align="center" class="Botrule Lrule Rrule Toprule">none </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> </td><td align="center" class="Botrule Lrule Rrule Toprule">rat </td><td align="center" class="Botrule Lrule Rrule Toprule">Female </td><td align="center" class="Botrule Lrule Rrule Toprule">0.4 (2.4) </td><td align="center" class="Botrule Lrule Rrule Toprule">none </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> </td><td align="center" class="Botrule Lrule Rrule Toprule">rat </td><td align="center" class="Botrule Lrule Rrule Toprule">Male </td><td align="center" class="Botrule Lrule Rrule Toprule">6.0 (37.5) </td><td align="center" class="Botrule Lrule Rrule Toprule">1.5 (9.4) </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Mammary gland </p> <p>neoplasm, Total</p> </td><td align="center" class="Botrule Lrule Rrule Toprule">rat </td><td align="center" class="Botrule Lrule Rrule Toprule">Male </td><td align="center" class="Botrule Lrule Rrule Toprule">1.5 (9.4) </td><td align="center" class="Botrule Lrule Rrule Toprule">0.4 (2.4) </td> </tr> </tbody> </table></div>

Antipsychotic drugs have been shown to chronically elevate prolactin levels in rodents. Serum prolactin levels were not measured during the risperidone carcinogenicity studies; however, measurements during subchronic toxicity studies showed that risperidone elevated serum prolactin levels 5- to 6-fold in mice and rats at the same doses used in the carcinogenicity studies. An increase in mammary, pituitary, and endocrine pancreas 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 findings of prolactin-mediated endocrine tumors in rodents is unclear [see Warnings and Precautions (5.6)]. 

Mutagenesis

No evidence of mutagenic or clastogenic potential for risperidone was found in the in vitro tests of Ames gene mutation, the mouse lymphoma assay, rat hepatocyte DNA-repair assay, the chromosomal aberration test in human lymphocytes, Chinese hamster ovary cells, or in the in vivo oral micronucleus test in mice and the sex-linked recessive lethal test in Drosophila.

No evidence of mutagenic potential was found in the in vitro Ames reverse mutation test for the copolymer mixture of methoxy-poly(ethylene glycol)-co-poly(D,L-lactide) and poly(D,L-lactide)-co-poly(ethylene glycol)-co-poly(D,L-lactide) dissolved in dimethyl sulfoxide.

Impairment of Fertility

No mating and fertility studies were conducted with subcutaneous risperidone suspension. Oral risperidone (0.16 to 5 mg/kg) impaired mating, but not fertility, in rat reproductive studies at doses 0.1- to 3-times the oral MRHD, of 16 mg/day based on mg/m2 body surface area. The effect appeared to be in females, since impaired mating behavior was not noted in the male fertility study. In a subchronic study in Beagle dogs in which risperidone was administered orally at doses of 0.31 to 5 mg/kg, sperm motility and concentration were decreased at doses 0.6- to 10-times the oral MRHD based on mg/m2 body surface area. Dose-related decreases were also noted in serum testosterone at the same doses. Serum testosterone and sperm parameters partially recovered, but remained decreased after treatment was discontinued. A no-effect dose could not be determined in either rat or dog.

The efficacy of UZEDY for the treatment of schizophrenia in adults is based, in part, on the established effectiveness of oral risperidone as well as in a randomized withdrawal study (Study 1: NCT03503318) with UZEDY in adults who met the DSM-5 criteria for schizophrenia. The results from Study 1 are presented below.

{ "type": "p", "children": [], "text": "The efficacy of UZEDY for the treatment of schizophrenia in adults is based, in part, on the established effectiveness of oral risperidone as well as in a randomized withdrawal study (Study 1: NCT03503318) with UZEDY in adults who met the DSM-5 criteria for schizophrenia. The results from Study 1 are presented below." }

Study 1 was a randomized withdrawal study in patients with schizophrenia consisting of a 12-week open-label oral risperidone (2 mg to 5 mg) stabilization phase, followed by a placebo-controlled phase in which patients were randomized to UZEDY (once monthly or once every 2 months) or placebo for a variable time until impending relapse or study completion.

{ "type": "p", "children": [], "text": "Study 1 was a randomized withdrawal study in patients with schizophrenia consisting of a 12-week open-label oral risperidone (2 mg to 5 mg) stabilization phase, followed by a placebo-controlled phase in which patients were randomized to UZEDY (once monthly or once every 2 months) or placebo for a variable time until impending relapse or study completion." }

UZEDY was administered once monthly or once every 2 months at doses of 50 mg to 250 mg compared with monthly placebo injections in adult patients meeting DSM-5 criteria for schizophrenia. Patients were required to have a Positive and Negative Syndrome Scale (PANSS) total score lower than 100 at the screening visit. Eligible screened patients were enrolled into an oral conversion and stabilization stage (12 weeks). Patients were administered oral risperidone (2 mg to 5 mg per day) to establish stability and tolerability. Eligible patients were randomized into the double-blind period of the study if they met the following randomization criteria for at least 4 consecutive weeks prior to the baseline visit: outpatient status, PANSS total ≤80, Minimal presence of specific psychotic symptoms on the PANSS, as measured by a score of ≤4 on each of the following items: conceptual disorganization, suspiciousness, hallucinatory behavior, and unusual thought content [CGI-S score ≤4 (moderately ill); CGI-SS score ≤2 (mildly suicidal) on Part 1 and ≤5 (minimally worsened) on Part 2].

{ "type": "p", "children": [], "text": "UZEDY was administered once monthly or once every 2 months at doses of 50 mg to 250 mg compared with monthly placebo injections in adult patients meeting DSM-5 criteria for schizophrenia. Patients were required to have a Positive and Negative Syndrome Scale (PANSS) total score lower than 100 at the screening visit. Eligible screened patients were enrolled into an oral conversion and stabilization stage (12 weeks). Patients were administered oral risperidone (2 mg to 5 mg per day) to establish stability and tolerability. Eligible patients were randomized into the double-blind period of the study if they met the following randomization criteria for at least 4 consecutive weeks prior to the baseline visit: outpatient status, PANSS total ≤80, Minimal presence of specific psychotic symptoms on the PANSS, as measured by a score of ≤4 on each of the following items: conceptual disorganization, suspiciousness, hallucinatory behavior, and unusual thought content [CGI-S score ≤4 (moderately ill); CGI-SS score ≤2 (mildly suicidal) on Part 1 and ≤5 (minimally worsened) on Part 2]." }

In the double-blind stage (variable in duration), patients were randomized to receive placebo, once monthly UZEDY, or once every 2 months UZEDY in doses based on the oral dose on which they were previously stabilized in the oral conversion and stabilization stage.

{ "type": "p", "children": [], "text": "In the double-blind stage (variable in duration), patients were randomized to receive placebo, once monthly UZEDY, or once every 2 months UZEDY in doses based on the oral dose on which they were previously stabilized in the oral conversion and stabilization stage." }

The primary efficacy endpoint was time to impending relapse. Relapse was defined as one or more of the following items:

{ "type": "p", "children": [], "text": "The primary efficacy endpoint was time to impending relapse. Relapse was defined as one or more of the following items:" }

{ "type": "ul", "children": [ "Clinical Global Impression–Improvement (CGI-I) of ≥5 (greater than or equal to minimally worse, i.e., minimally worse, much worse or very much worse), AND" ], "text": "" }

{ "type": "ul", "children": [ "an increase of any of the following individual Positive and Negative Syndrome Scale (PANSS) items: conceptual disorganization, hallucinatory behavior, suspiciousness, and unusual thought content, to a score of >4 with an absolute increase of ≥2 on that specific item since randomization, OR", "an increase in any of the following 4 individual PANSS items: conceptual disorganization, hallucinatory behavior, suspiciousness, and unusual thought content, to a score of >4 and an absolute increase of ≥4 on the combined score of these 4 PANSS items (conceptual disorganization, hallucinatory behavior, suspiciousness, and unusual thought content) since randomization" ], "text": "" }

{ "type": "ul", "children": [ "hospitalization due to worsening of psychotic symptoms (including partial hospitalization programs), excluding hospitalization for psychosocial reasons", "Clinical Global Impression-Severity of Suicidality (CGI-SS) of 4 (severely suicidal) or 5 (attempted suicide) on Part 1 and/or 6 (much worse) or 7 (very much worse) on Part 2", "violent behavior resulting in clinically significant self-injury, injury to another person, or property damage" ], "text": "" }

The mean baseline PANSS total score was similar across the groups (approximately 61 in each group). Most patients were male (61% per group) and the median age was 52 years. Most patients in this study were black or African American (57% to 61% per group). Of the 544 patients randomized to treatment, 543 were included in the intent-to-treat (ITT) population.

{ "type": "p", "children": [], "text": "The mean baseline PANSS total score was similar across the groups (approximately 61 in each group). Most patients were male (61% per group) and the median age was 52 years. Most patients in this study were black or African American (57% to 61% per group). Of the 544 patients randomized to treatment, 543 were included in the intent-to-treat (ITT) population." }

The study met its prespecified primary endpoint for both the UZEDY once monthly and once every 2 months dosing regimens. Time to relapse was statistically significantly longer in the UZEDY-treated groups compared to the placebo group. The cumulative percentage of relapse over time was calculated using Kaplan-Meier product limit estimate of the time to relapse during the randomized withdrawal trial as shown in Figure 1.

{ "type": "p", "children": [], "text": "The study met its prespecified primary endpoint for both the UZEDY once monthly and once every 2 months dosing regimens. Time to relapse was statistically significantly longer in the UZEDY-treated groups compared to the placebo group. The cumulative percentage of relapse over time was calculated using Kaplan-Meier product limit estimate of the time to relapse during the randomized withdrawal trial as shown in Figure 1." }

Subgroup analyses by gender, age, and race did not suggest any clear evidence of differential responsiveness to UZEDY.

{ "type": "p", "children": [], "text": "Subgroup analyses by gender, age, and race did not suggest any clear evidence of differential responsiveness to UZEDY." }

Figure 1:         Kaplan-Meier Curve of Cumulative Proportion of UZEDY-Treated Patients with Relapse Over Time

{ "type": "p", "children": [], "text": "\nFigure 1:         Kaplan-Meier Curve of Cumulative Proportion of UZEDY-Treated Patients with Relapse Over Time\n" }

How Supplied

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

UZEDY (risperidone) extended-release injectable suspension, for subcutaneous use is a sterile, white to off-white opaque viscous suspension.

{ "type": "p", "children": [], "text": "UZEDY (risperidone) extended-release injectable suspension, for subcutaneous use is a sterile, white to off-white opaque viscous suspension.\n" }

UZEDY is supplied in single-dose kits as follows:

{ "type": "p", "children": [], "text": "UZEDY is supplied in single-dose kits as follows:" }

{ "type": "ul", "children": [ "50 mg/0.14 mL single-dose prefilled syringe, packaged in a carton with one 21 gauge, 5/8-inch needle (NDC 51759-305-10)", "75 mg/0.21 mL single-dose prefilled syringe, packaged in a carton with one 21 gauge, 5/8-inch needle (NDC 51759-410-10)", "100 mg/0.28 mL single-dose prefilled syringe, packaged in a carton with one 21 gauge, 5/8-inch needle (NDC 51759-520-10)", "125 mg/0.35 mL single-dose prefilled syringe, packaged in a carton with one 21 gauge, 5/8-inch needle (NDC 51759-630-10)", "150 mg/0.42 mL single-dose prefilled syringe, packaged in a carton with one 21 gauge, 5/8-inch needle (NDC 51759-740-10)", "200 mg/0.56 mL single-dose prefilled syringe, packaged in a carton with one 21 gauge, 5/8-inch needle (NDC 51759-850-10)", "250 mg/0.7 mL single-dose prefilled syringe, packaged in a carton with one 21 gauge, 5/8-inch needle (NDC 51759-960-10)" ], "text": "" }

The prefilled syringe cap is not made with natural rubber latex.

{ "type": "p", "children": [], "text": "The prefilled syringe cap is not made with natural rubber latex." }

Storage and Handling

{ "type": "p", "children": [], "text": "\nStorage and Handling\n" }

Store in refrigerator at 2°C to 8°C (36°F to 46°F) in the original carton to protect from light.

{ "type": "p", "children": [], "text": "Store in refrigerator at 2°C to 8°C (36°F to 46°F) in the original carton to protect from light.\n" }

UZEDY may be stored in unopened original packaging at room temperature, 20°C to 25°C (68°F to 77°F), for up to 90 days. If unopened, UZEDY may be returned to refrigerated storage within 90 days. Once the carton is opened, administer UZEDY or discard.

{ "type": "p", "children": [], "text": "UZEDY may be stored in unopened original packaging at room temperature, 20°C to 25°C (68°F to 77°F), for up to 90 days. If unopened, UZEDY may be returned to refrigerated storage within 90 days. Once the carton is opened, administer UZEDY or discard.\n" }

Neuroleptic Malignant Syndrome (NMS)

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

Counsel patients about a potentially fatal adverse reaction, Neuroleptic Malignant Syndrome (NMS) that has been reported in association with administration of antipsychotic drugs. Advise patients, family members, or caregivers to contact the healthcare provider or report to the emergency room if they experience signs and symptoms of NMS [see Warnings and Precautions (5.3)]. 

{ "type": "p", "children": [], "text": "Counsel patients about a potentially fatal adverse reaction, Neuroleptic Malignant Syndrome (NMS) that has been reported in association with administration of antipsychotic drugs. Advise patients, family members, or caregivers to contact the healthcare provider or report to the emergency room if they experience signs and symptoms of NMS [see Warnings and Precautions (5.3)]. " }

Tardive Dyskinesia

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

Counsel patients on the signs and symptoms of tardive dyskinesia and to contact their healthcare provider if these abnormal movements occur [see Warnings and Precautions (5.4)]. 

{ "type": "p", "children": [], "text": "Counsel patients on the signs and symptoms of tardive dyskinesia and to contact their healthcare provider if these abnormal movements occur [see Warnings and Precautions (5.4)]. " }

Metabolic Changes

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

Educate patients about the risk of metabolic changes, how to recognize symptoms of hyperglycemia and diabetes mellitus and the need for specific monitoring, including blood glucose, lipids, and weight [see Warnings and Precautions (5.5)]. 

{ "type": "p", "children": [], "text": "Educate patients about the risk of metabolic changes, how to recognize symptoms of hyperglycemia and diabetes mellitus and the need for specific monitoring, including blood glucose, lipids, and weight [see Warnings and Precautions (5.5)]. " }

Hyperprolactinemia

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

Counsel patients on signs and symptoms of hyperprolactinemia that may be associated with chronic use of UZEDY. Advise them to seek medical attention if they experience any of the following: amenorrhea or galactorrhea in females, erectile dysfunction, or gynecomastia in males [see Warnings and Precautions (5.6)].

{ "type": "p", "children": [], "text": "Counsel patients on signs and symptoms of hyperprolactinemia that may be associated with chronic use of UZEDY. Advise them to seek medical attention if they experience any of the following: amenorrhea or galactorrhea in females, erectile dysfunction, or gynecomastia in males [see Warnings and Precautions (5.6)]." }

Orthostatic Hypotension and Syncope

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

Educate patients about the risk of orthostatic hypotension and syncope, particularly at the time of initiating treatment, re-initiating treatment or increasing the dose [see Warnings and Precautions (5.7)].

{ "type": "p", "children": [], "text": "Educate patients about the risk of orthostatic hypotension and syncope, particularly at the time of initiating treatment, re-initiating treatment or increasing the dose [see Warnings and Precautions (5.7)].\n" }

Leukopenia/Neutropenia

{ "type": "p", "children": [], "text": "\nLeukopenia/Neutropenia\n" }

Advise patients with a pre-existing low WBC or a history of drug-induced leukopenia/neutropenia that they should have their CBC monitored while being treated with UZEDY [see Warnings and Precautions (5.9)].

{ "type": "p", "children": [], "text": "Advise patients with a pre-existing low WBC or a history of drug-induced leukopenia/neutropenia that they should have their CBC monitored while being treated with UZEDY [see Warnings and Precautions (5.9)]." }

Potential for Cognitive and Motor Impairment

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

Inform patients that UZEDY has the potential to impair judgement, thinking, and motor skills. Caution patients about performing activities requiring mental alertness, such as operating hazardous machinery, or operating a motor vehicle, until they are reasonably certain that UZEDY therapy does not affect them adversely [see Warnings and Precautions (5.10)].

{ "type": "p", "children": [], "text": "Inform patients that UZEDY has the potential to impair judgement, thinking, and motor skills. Caution patients about performing activities requiring mental alertness, such as operating hazardous machinery, or operating a motor vehicle, until they are reasonably certain that UZEDY therapy does not affect them adversely [see Warnings and Precautions (5.10)].\n" }

Priapism

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

Advise patients of the possibility of painful or prolonged penile erections (priapism). Instruct the patient to seek immediate medical attention in the event of priapism [see Warnings and Precautions (5.13)]. 

{ "type": "p", "children": [], "text": "Advise patients of the possibility of painful or prolonged penile erections (priapism). Instruct the patient to seek immediate medical attention in the event of priapism [see Warnings and Precautions (5.13)]. " }

Heat Exposure and Dehydration

{ "type": "p", "children": [], "text": "\nHeat Exposure and Dehydration\n" }

Educate patients regarding appropriate care in avoiding overheating and dehydration [see Warnings and Precautions (5.14)]. 

{ "type": "p", "children": [], "text": "Educate patients regarding appropriate care in avoiding overheating and dehydration [see Warnings and Precautions (5.14)]. " }

Concomitant Medication

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

Advise patients to inform their healthcare providers if they are taking, or plan to take, any prescription or over-the-counter drugs, as there is a potential for interaction [see Drug Interactions (7)].

{ "type": "p", "children": [], "text": "Advise patients to inform their healthcare providers if they are taking, or plan to take, any prescription or over-the-counter drugs, as there is a potential for interaction [see Drug Interactions (7)].\n" }

Alcohol

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

Advise patients to avoid alcohol during treatment with UZEDY [see Drug Interactions (7.1)]. 

{ "type": "p", "children": [], "text": "Advise patients to avoid alcohol during treatment with UZEDY [see Drug Interactions (7.1)]. " }

Pregnancy

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

Advise patients to notify their healthcare professional if they become pregnant or intend to become pregnant during treatment with UZEDY. Advise patients that UZEDY 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 registry that monitors pregnancy outcomes in women exposed to UZEDY during pregnancy [see Use in Specific Populations (8.1)]. 

{ "type": "p", "children": [], "text": "Advise patients to notify their healthcare professional if they become pregnant or intend to become pregnant during treatment with UZEDY. Advise patients that UZEDY 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 registry that monitors pregnancy outcomes in women exposed to UZEDY during pregnancy [see Use in Specific Populations (8.1)]. " }

Lactation

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

Advise breastfeeding women using UZEDY to monitor infants for somnolence, failure to thrive, jitteriness, 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": "Advise breastfeeding women using UZEDY to monitor infants for somnolence, failure to thrive, jitteriness, 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

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

Advise females of reproductive potential that UZEDY 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": "Advise females of reproductive potential that UZEDY may impair fertility due to an increase in serum prolactin levels. The effects on fertility are reversible [see Use in Specific Populations (8.3)].\n" }

UZE-004

{ "type": "p", "children": [], "text": "UZE-004" }

Manufactured for: Teva Neuroscience, Inc. Parsippany, NJ 07054

{ "type": "p", "children": [], "text": "Manufactured for:\nTeva Neuroscience, Inc.\nParsippany, NJ 07054" }

©2025 Teva Neuroscience, Inc.

{ "type": "p", "children": [], "text": "©2025 Teva Neuroscience, Inc." }

1 month dosing 

{ "type": "p", "children": [], "text": "\n1 month dosing \n" }

 For administration by a healthcare professional

{ "type": "p", "children": [], "text": "\n For administration by a healthcare professional\n" }

Rx Only

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

UZEDY® (risperiDONE) extended-release injectable suspension

{ "type": "p", "children": [], "text": "\nUZEDY® (risperiDONE) extended-release injectable suspension" }

FOR SUBCUTANEOUS USE ONLY

{ "type": "p", "children": [], "text": "\nFOR SUBCUTANEOUS USE ONLY\n" }

NDC 51759-305-10 One single-dose prefilled syringe 50 mg/0.14 mL administered every one month

{ "type": "p", "children": [], "text": "\nNDC 51759-305-10\nOne single-dose prefilled syringe\n50 mg/0.14 mL administered every one month" }

Store in refrigerator at 2°C to 8°C (36°F to 46°F) in the original carton to protect from light.

{ "type": "p", "children": [], "text": "\nStore in refrigerator at 2°C to 8°C (36°F to 46°F) in the original carton to protect from light." }

Allow UZEDY to sit in its packaging at room temperature at 20°C to 25°C(68°F to 77°F) for at least 30 minutes prior to administration.

{ "type": "p", "children": [], "text": "Allow UZEDY to sit in its packaging at room temperature at 20°C to 25°C(68°F to 77°F) for at least 30 minutes prior to administration." }

UZEDY may be stored in unopened original packaging at room temperature, 20°C to 25°C (68°F to 77°F), for up to 90 days. If unopened, UZEDY may be returned to refrigerated storage within 90 days.

{ "type": "p", "children": [], "text": "UZEDY may be stored in unopened original packaging at room temperature, 20°C to 25°C (68°F to 77°F), for up to 90 days. If unopened, UZEDY may be returned to refrigerated storage within 90 days. " }

Once the carton is opened, administer UZEDY or discard.

{ "type": "p", "children": [], "text": "Once the carton is opened, administer UZEDY or discard." }

OPEN HERE teva

{ "type": "p", "children": [], "text": "\nOPEN HERE\nteva\n" }

1 month dosing

{ "type": "p", "children": [], "text": "\n1 month dosing\n" }

For administration by a healthcare professional

{ "type": "p", "children": [], "text": "\nFor administration by a healthcare professional\n" }

Rx Only

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

UZEDY® (risperiDONE) extended-release injectable suspension FOR SUBCUTANEOUS USE ONLY

{ "type": "p", "children": [], "text": "\nUZEDY® (risperiDONE) extended-release injectable suspension\n\nFOR SUBCUTANEOUS USE ONLY\n" }

NDC 51759-410-10 One single-dose prefilled syringe 75 mg/0.21 mL administered every one month

{ "type": "p", "children": [], "text": "\nNDC 51759-410-10\nOne single-dose prefilled syringe\n75 mg/0.21 mL administered every one month" }

Store in refrigerator at 2°C to 8°C (36°F to 46°F) in the original carton to protect from light.

{ "type": "p", "children": [], "text": "\nStore in refrigerator at 2°C to 8°C (36°F to 46°F) in the original carton to protect from light." }

Allow UZEDY to sit in its packaging at room temperature at 20°C to 25°C(68°F to 77°F) for at least 30 minutes prior to administration.

{ "type": "p", "children": [], "text": "Allow UZEDY to sit in its packaging at room temperature at 20°C to 25°C(68°F to 77°F) for at least 30 minutes prior to administration." }

UZEDY may be stored in unopened original packaging at room temperature, 20°C to 25°C (68°F to 77°F), for up to 90 days. If unopened, UZEDY may be returned to refrigerated storage within 90 days.

{ "type": "p", "children": [], "text": "UZEDY may be stored in unopened original packaging at room temperature, 20°C to 25°C (68°F to 77°F), for up to 90 days. If unopened, UZEDY may be returned to refrigerated storage within 90 days." }

Once the carton is opened, administer UZEDY or discard.

{ "type": "p", "children": [], "text": "Once the carton is opened, administer UZEDY or discard." }

OPEN HERE teva

{ "type": "p", "children": [], "text": "\nOPEN HERE\nteva\n" }

FOR ADMINISTRATION BY A HEALTHCARE PROFESSIONAL 

{ "type": "p", "children": [], "text": "\nFOR ADMINISTRATION BY A HEALTHCARE PROFESSIONAL \n" }

1 month dosing OR 2 month dosing                        Rx Only 

{ "type": "p", "children": [], "text": "\n1 month dosing OR 2 month dosing                        Rx Only \n" }

 UZEDY® (risperiDONE) extended-release injectable suspension FOR SUBCUTANEOUS USE ONLY

{ "type": "p", "children": [], "text": "\n UZEDY® (risperiDONE) extended-release injectable suspension\n\nFOR SUBCUTANEOUS USE ONLY\n" }

NDC 51759-520-10 One single-dose prefilled syringe 100 mg/0.28 mL administered every one or two months

{ "type": "p", "children": [], "text": "\nNDC 51759-520-10\nOne single-dose prefilled syringe\n100 mg/0.28 mL administered every one or two months" }

Store in refrigerator at 2°C to 8°C (36°F to 46°F) in the original carton to protect from light.

{ "type": "p", "children": [], "text": "\nStore in refrigerator at 2°C to 8°C (36°F to 46°F) in the original carton to protect from light." }

Allow UZEDY to sit in its packaging at room temperature at 20°C to 25°C(68°F to 77°F) for at least 30 minutes prior to administration.

{ "type": "p", "children": [], "text": "Allow UZEDY to sit in its packaging at room temperature at 20°C to 25°C(68°F to 77°F) for at least 30 minutes prior to administration." }

UZEDY may be stored in unopened original packaging at room temperature, 20°C to 25°C (68°F to 77°F), for up to 90 days. If unopened, UZEDY may be returned to refrigerated storage within 90 days.

{ "type": "p", "children": [], "text": "UZEDY may be stored in unopened original packaging at room temperature, 20°C to 25°C (68°F to 77°F), for up to 90 days. If unopened, UZEDY may be returned to refrigerated storage within 90 days." }

Once the carton is opened, administer UZEDY or discard.

{ "type": "p", "children": [], "text": "Once the carton is opened, administer UZEDY or discard." }

OPEN HERE teva

{ "type": "p", "children": [], "text": "\nOPEN HERE\nteva\n" }

1 month dosing

{ "type": "p", "children": [], "text": "\n1 month dosing\n" }

For administration by a healthcare professional

{ "type": "p", "children": [], "text": "\nFor administration by a healthcare professional\n" }

Rx Only

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

UZEDY® (risperiDONE) extended-release injectable suspension FOR SUBCUTANEOUS USE ONLY

{ "type": "p", "children": [], "text": "\nUZEDY® (risperiDONE) extended-release injectable suspension\n\nFOR SUBCUTANEOUS USE ONLY\n" }

NDC 51759-630-10 One single-dose prefilled syringe 125 mg/0.35 mL administered every one month

{ "type": "p", "children": [], "text": "\nNDC 51759-630-10\nOne single-dose prefilled syringe\n125 mg/0.35 mL administered every one month" }

Store in refrigerator at 2°C to 8°C (36°F to 46°F) in the original carton to protect from light.

{ "type": "p", "children": [], "text": "\nStore in refrigerator at 2°C to 8°C (36°F to 46°F) in the original carton to protect from light." }

Allow UZEDY to sit in its packaging at room temperature at 20°C to 25°C(68°F to 77°F) for at least 30 minutes prior to administration.

{ "type": "p", "children": [], "text": "Allow UZEDY to sit in its packaging at room temperature at 20°C to 25°C(68°F to 77°F) for at least 30 minutes prior to administration." }

UZEDY may be stored in unopened original packaging at room temperature, 20°C to 25°C (68°F to 77°F), for up to 90 days. If unopened, UZEDY may be returned to refrigerated storage within 90 days.

{ "type": "p", "children": [], "text": "UZEDY may be stored in unopened original packaging at room temperature, 20°C to 25°C (68°F to 77°F), for up to 90 days. If unopened, UZEDY may be returned to refrigerated storage within 90 days." }

Once the carton is opened, administer UZEDY or discard.

{ "type": "p", "children": [], "text": "Once the carton is opened, administer UZEDY or discard." }

OPEN HERE teva

{ "type": "p", "children": [], "text": "\nOPEN HERE\nteva\n" }

2 month dosing

{ "type": "p", "children": [], "text": "\n2 month dosing\n" }

For administration by a healthcare professional

{ "type": "p", "children": [], "text": "\nFor administration by a healthcare professional\n" }

Rx Only

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

UZEDY® (risperiDONE) extended-release injectable suspension FOR SUBCUTANEOUS USE ONLY

{ "type": "p", "children": [], "text": "\nUZEDY® (risperiDONE) extended-release injectable suspension\n\nFOR SUBCUTANEOUS USE ONLY\n" }

NDC 51759-740-10 One single-dose prefilled syringe 150 mg/0.42 mL administered every two months

{ "type": "p", "children": [], "text": "\nNDC 51759-740-10\nOne single-dose prefilled syringe\n150 mg/0.42 mL administered every two months" }

Store in refrigerator at 2°C to 8°C (36°F to 46°F) in the original carton to protect from light.

{ "type": "p", "children": [], "text": "\nStore in refrigerator at 2°C to 8°C (36°F to 46°F) in the original carton to protect from light." }

Allow UZEDY to sit in its packaging at room temperature at 20°C to 25°C(68°F to 77°F) for at least 30 minutes prior to administration.

{ "type": "p", "children": [], "text": "Allow UZEDY to sit in its packaging at room temperature at 20°C to 25°C(68°F to 77°F) for at least 30 minutes prior to administration." }

UZEDY may be stored in unopened original packaging at room temperature, 20°C to 25°C (68°F to 77°F), for up to 90 days. If unopened, UZEDY may be returned to refrigerated storage within 90 days.

{ "type": "p", "children": [], "text": "UZEDY may be stored in unopened original packaging at room temperature, 20°C to 25°C (68°F to 77°F), for up to 90 days. If unopened, UZEDY may be returned to refrigerated storage within 90 days." }

Once the carton is opened, administer UZEDY or discard.

{ "type": "p", "children": [], "text": "Once the carton is opened, administer UZEDY or discard." }

OPEN HERE teva

{ "type": "p", "children": [], "text": "\nOPEN HERE\nteva\n" }

2 month dosing

{ "type": "p", "children": [], "text": "\n2 month dosing\n" }

For administration by a healthcare professional

{ "type": "p", "children": [], "text": "\nFor administration by a healthcare professional\n" }

Rx Only

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

UZEDY® (risperiDONE) extended-release injectable suspension FOR SUBCUTANEOUS USE ONLY

{ "type": "p", "children": [], "text": "\nUZEDY® (risperiDONE) extended-release injectable suspension\n\nFOR SUBCUTANEOUS USE ONLY\n" }

NDC 51759-850-10 One single-dose prefilled syringe 200 mg/0.56 mL administered every two months

{ "type": "p", "children": [], "text": "\nNDC 51759-850-10\nOne single-dose prefilled syringe\n200 mg/0.56 mL administered every two months" }

Store in refrigerator at 2°C to 8°C (36°F to 46°F) in the original carton to protect from light.

{ "type": "p", "children": [], "text": "\nStore in refrigerator at 2°C to 8°C (36°F to 46°F) in the original carton to protect from light." }

Allow UZEDY to sit in its packaging at room temperature at 20°C to 25°C(68°F to 77°F) for at least 30 minutes prior to administration.

{ "type": "p", "children": [], "text": "Allow UZEDY to sit in its packaging at room temperature at 20°C to 25°C(68°F to 77°F) for at least 30 minutes prior to administration." }

UZEDY may be stored in unopened original packaging at room temperature, 20°C to 25°C (68°F to 77°F), for up to 90 days. If unopened, UZEDY may be returned to refrigerated storage within 90 days.

{ "type": "p", "children": [], "text": "UZEDY may be stored in unopened original packaging at room temperature, 20°C to 25°C (68°F to 77°F), for up to 90 days. If unopened, UZEDY may be returned to refrigerated storage within 90 days." }

Once the carton is opened, administer UZEDY or discard.

{ "type": "p", "children": [], "text": "Once the carton is opened, administer UZEDY or discard." }

OPEN HERE teva

{ "type": "p", "children": [], "text": "\nOPEN HERE\nteva\n" }

2 month dosing

{ "type": "p", "children": [], "text": "\n2 month dosing\n" }

For administration by a healthcare professional

{ "type": "p", "children": [], "text": "\nFor administration by a healthcare professional\n" }

Rx Only

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

UZEDY® (risperiDONE) extended-release injectable suspension FOR SUBCUTANEOUS USE ONLY

{ "type": "p", "children": [], "text": "\nUZEDY® (risperiDONE) extended-release injectable suspension\n\nFOR SUBCUTANEOUS USE ONLY\n" }

NDC 51759-960-10 One single-dose prefilled syringe 250 mg/0.7 mL administered every two months

{ "type": "p", "children": [], "text": "\nNDC 51759-960-10\nOne single-dose prefilled syringe\n250 mg/0.7 mL administered every two months" }

Store in refrigerator at 2°C to 8°C (36°F to 46°F) in the original carton to protect from light.

{ "type": "p", "children": [], "text": "\nStore in refrigerator at 2°C to 8°C (36°F to 46°F) in the original carton to protect from light." }

Allow UZEDY to sit in its packaging at room temperature at 20°C to 25°C(68°F to 77°F) for at least 30 minutes prior to administration.

{ "type": "p", "children": [], "text": "Allow UZEDY to sit in its packaging at room temperature at 20°C to 25°C(68°F to 77°F) for at least 30 minutes prior to administration." }

UZEDY may be stored in unopened original packaging at room temperature, 20°C to 25°C (68°F to 77°F), for up to 90 days. If unopened, UZEDY may be returned to refrigerated storage within 90 days.

{ "type": "p", "children": [], "text": "UZEDY may be stored in unopened original packaging at room temperature, 20°C to 25°C (68°F to 77°F), for up to 90 days. If unopened, UZEDY may be returned to refrigerated storage within 90 days." }

Once the carton is opened, administer UZEDY or discard.

{ "type": "p", "children": [], "text": "Once the carton is opened, administer UZEDY or discard." }

OPEN HERE teva

{ "type": "p", "children": [], "text": "\nOPEN HERE\nteva\n" }

RISPERDAL CONSTA (risperidone) is indicated for the treatment of schizophrenia [see Clinical Studies (14.1)].

RISPERDAL CONSTA is indicated as monotherapy or as adjunctive therapy to lithium or valproate for the maintenance treatment of Bipolar I Disorder [see Clinical Studies (14.2, 14.3)] .

The recommended dose for the treatment of schizophrenia is 25 mg IM every 2 weeks. Although dose response for effectiveness has not been established for RISPERDAL CONSTA, some patients not responding to 25 mg may benefit from a higher dose of 37.5 mg or 50 mg. The maximum dose should not exceed 50 mg RISPERDAL CONSTA every 2 weeks. No additional benefit was observed with dosages greater than 50 mg RISPERDAL CONSTA; however, a higher incidence of adverse effects was observed.

The efficacy of RISPERDAL CONSTA in the treatment of schizophrenia has not been evaluated in controlled clinical trials for longer than 12 weeks. Although controlled studies have not been conducted to answer the question of how long patients with schizophrenia should be treated with RISPERDAL CONSTA, oral risperidone has been shown to be effective in delaying time to relapse in longer-term use. It is recommended that responding patients be continued on treatment with RISPERDAL CONSTA at the lowest dose needed. The physician who elects to use RISPERDAL CONSTA for extended periods should periodically re-evaluate the long-term risks and benefits of the drug for the individual patient.

The recommended dose for monotherapy or adjunctive therapy to lithium or valproate for the maintenance treatment of Bipolar I Disorder is 25 mg IM every 2 weeks. Some patients may benefit from a higher dose of 37.5 mg or 50 mg. Dosages above 50 mg have not been studied in this population. The physician who elects to use RISPERDAL CONSTA for extended periods should periodically re-evaluate the long-term risks and benefits of the drug for the individual patient.

A lower initial dose of 12.5 mg may be appropriate when clinical factors warrant dose adjustment, such as in patients with hepatic or renal impairment, for certain drug interactions that increase risperidone plasma concentrations [see Drug Interactions (7.11)] or in patients who have a history of poor tolerability to psychotropic medications. The efficacy of the 12.5 mg dose has not been investigated in clinical trials.

Oral RISPERDAL (or another antipsychotic medication) should be given with the first injection of RISPERDAL CONSTA and continued for 3 weeks (and then discontinued) to ensure that adequate therapeutic plasma concentrations are maintained prior to the main release phase of risperidone from the injection site [see Clinical Pharmacology (12.3)] .

Upward dose adjustment should not be made more frequently than every 4 weeks. The clinical effects of this dose adjustment should not be anticipated earlier than 3 weeks after the first injection with the higher dose.

In patients with clinical factors such as hepatic or renal impairment or certain drug interactions that increase risperidone plasma concentrations [see Drug Interactions (7.11)] , dose reduction as low as 12.5 mg may be appropriate. The efficacy of the 12.5 mg dose has not been investigated in clinical trials.

Do not combine two different dose strengths of RISPERDAL CONSTA in a single administration.

Elderly

For elderly patients treated with RISPERDAL CONSTA, the recommended dosage is 25 mg IM every 2 weeks. Oral RISPERDAL (or another antipsychotic medication) should be given with the first injection of RISPERDAL CONSTA and should be continued for 3 weeks to ensure that adequate therapeutic plasma concentrations are maintained prior to the main release phase of risperidone from the injection site [see Clinical Pharmacology (12.3)] .

Renal or Hepatic Impairment

Patients with renal or hepatic impairment should be treated with titrated doses of oral RISPERDAL prior to initiating treatment with RISPERDAL CONSTA. The recommended starting dose is 0.5 mg oral RISPERDAL twice daily during the first week, which can be increased to 1 mg twice daily or 2 mg once daily during the second week. If a total daily dose of at least 2 mg oral RISPERDAL is well tolerated, an injection of 25 mg RISPERDAL CONSTA can be administered every 2 weeks. Oral supplementation should be continued for 3 weeks after the first injection until the main release of risperidone from the injection site has begun. In some patients, slower titration may be medically appropriate. Alternatively, a starting dose of RISPERDAL CONSTA of 12.5 mg may be appropriate. The efficacy of the 12.5 mg dose has not been investigated in clinical trials.

Patients with renal impairment may have less ability to eliminate risperidone than normal adults. Patients with impaired hepatic function may have an increase in the free fraction of the risperidone, possibly resulting in an enhanced effect [see Clinical Pharmacology (12.3)] . Elderly patients and patients with a predisposition to hypotensive reactions or for whom such reactions would pose a particular risk should be instructed in nonpharmacologic interventions that help to reduce the occurrence of orthostatic hypotension (e.g., sitting on the edge of the bed for several minutes before attempting to stand in the morning and slowly rising from a seated position). These patients should avoid sodium depletion or dehydration, and circumstances that accentuate hypotension (alcohol intake, high ambient temperature, etc.). Monitoring of orthostatic vital signs should be considered [see Warnings and Precautions (5.7)] .

There are no data to specifically address reinitiation of treatment. When restarting patients who have had an interval off treatment with RISPERDAL CONSTA, supplementation with oral RISPERDAL (or another antipsychotic medication) should be administered.

There are no systematically collected data to specifically address switching patients from other antipsychotics to RISPERDAL CONSTA, or concerning concomitant administration with other antipsychotics. Previous antipsychotics should be continued for 3 weeks after the first injection of RISPERDAL CONSTA to ensure that therapeutic concentrations are maintained until the main release phase of risperidone from the injection site has begun [see Clinical Pharmacology (12.3)] . For patients who have never taken oral RISPERDAL, it is recommended to establish tolerability with oral RISPERDAL prior to initiating treatment with RISPERDAL CONSTA. As recommended with other antipsychotic medications, the need for continuing existing EPS medication should be re-evaluated periodically.

Co-administration of carbamazepine and other CYP 3A4 enzyme inducers (e.g., phenytoin, rifampin, phenobarbital) with risperidone would be expected to cause decreases in the plasma concentrations of the sum of risperidone and 9-hydroxyrisperidone combined, which could lead to decreased efficacy of RISPERDAL CONSTA treatment. The dose of risperidone needs to be titrated accordingly for patients receiving these enzyme inducers, especially during initiation or discontinuation of therapy with these inducers [see Drug Interactions (7.11)] . At the initiation of therapy with carbamazepine or other known CYP 3A4 hepatic enzyme inducers, patients should be closely monitored during the first 4–8 weeks, since the dose of RISPERDAL CONSTA may need to be adjusted. A dose increase, or additional oral RISPERDAL, may need to be considered. On discontinuation of carbamazepine or other CYP 3A4 hepatic enzyme inducers, the dosage of RISPERDAL CONSTA should be re-evaluated and, if necessary, decreased. Patients may be placed on a lower dose of RISPERDAL CONSTA between 2 to 4 weeks before the planned discontinuation of carbamazepine or other CYP 3A4 inducers to adjust for the expected increase in plasma concentrations of risperidone plus 9-hydroxyrisperidone. For patients treated with the recommended dose of 25 mg RISPERDAL CONSTA and discontinuing from carbamazepine or other CYP3A4 enzyme inducers, it is recommended to continue treatment with the 25-mg dose unless clinical judgment necessitates lowering the RISPERDAL CONSTA dose to 12.5 mg or necessitates interruption of RISPERDAL CONSTA treatment. The efficacy of the 12.5 mg dose has not been investigated in clinical trials.

Fluoxetine and paroxetine, CYP 2D6 inhibitors, have been shown to increase the plasma concentration of risperidone 2.5–2.8 fold and 3–9 fold respectively. Fluoxetine did not affect the plasma concentration of 9-hydroxyrisperidone. Paroxetine lowered the concentration of 9-hydroxyrisperidone by about 10%. The dose of risperidone needs to be titrated accordingly when fluoxetine or paroxetine is co-administered. When either concomitant fluoxetine or paroxetine is initiated or discontinued, the physician should re-evaluate the dose of RISPERDAL CONSTA. When initiation of fluoxetine or paroxetine is considered, patients may be placed on a lower dose of RISPERDAL CONSTA between 2 to 4 weeks before the planned start of fluoxetine or paroxetine therapy to adjust for the expected increase in plasma concentrations of risperidone. When fluoxetine or paroxetine is initiated in patients receiving the recommended dose of 25 mg RISPERDAL CONSTA, it is recommended to continue treatment with the 25 mg dose unless clinical judgment necessitates lowering the RISPERDAL CONSTA dose to 12.5 mg or necessitates interruption of RISPERDAL CONSTA treatment. When RISPERDAL CONSTA is initiated in patients already receiving fluoxetine or paroxetine, a starting dose of 12.5 mg can be considered. The efficacy of the 12.5 mg dose has not been investigated in clinical trials. The effects of discontinuation of concomitant fluoxetine or paroxetine therapy on the pharmacokinetics of risperidone and 9-hydroxyrisperidone have not been studied. [see Drug Interactions (7.11)] .

For deltoid or gluteal intramuscular injection only

IMPORTANT RESOURCES

For additional information, visit www.risperdalconsta.com or call Janssen Pharmaceuticals, Inc. at 1-800-526-7736.

Important Information

RISPERDAL CONSTA requires close attention to these step-by-step Instructions for Use to help ensure successful administration.

Use components provided

The components in this dose pack are specifically designed for use with RISPERDAL CONSTA. RISPERDAL CONSTA must be reconstituted only in the diluent supplied in the dose pack.

Do notsubstitute ANY components of the dose pack.

Do not store suspension after reconstitution

Administer dose as soon as possible after reconstitution to avoid settling.

Proper dosing

The entire contents of the vial must be administered to ensure intended dose of RISPERDAL CONSTA is delivered.

SINGLE-USE DEVICE

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.

Dose pack contents

<div class="scrollingtable"><table class="Noautorules" width="100%"> <col align="left" valign="top" width="25%"/> <col align="left" valign="top" width="25%"/> <col align="left" valign="top" width="25%"/> <col align="left" valign="top" width="25%"/> <thead> <tr> <th align="left" colspan="4"><span class="Underline">Step 1</span><span class="Underline">Assemble components</span></th> </tr> <tr class="Botrule"> <th align="left" colspan="4">Take out dose pack Connect vial adapter to vial</th> </tr> </thead> <tbody> <tr> <td align="left"> <p class="First"> <img alt="Figure" src="/dailymed/image.cfm?name=risperdal-02.jpg&amp;setid=bb34ee82-d2c2-43b8-ba21-2825c0954691"/></p> </td><td align="left"> <p class="First"> <img alt="Figure" src="/dailymed/image.cfm?name=risperdal-03.jpg&amp;setid=bb34ee82-d2c2-43b8-ba21-2825c0954691"/></p> </td><td align="left"> <p class="First"> <img alt="Figure" src="/dailymed/image.cfm?name=risperdal-04.jpg&amp;setid=bb34ee82-d2c2-43b8-ba21-2825c0954691"/></p> </td><td align="left"> <p class="First"> <img alt="Figure" src="/dailymed/image.cfm?name=risperdal-05.jpg&amp;setid=bb34ee82-d2c2-43b8-ba21-2825c0954691"/></p> </td> </tr> <tr> <td align="left"><span class="Bold">Wait 30 minutes</span> <br/> Remove dose pack from the refrigerator and allow to sit at room temperature for at least <span class="Bold">30 minutes</span>before reconstituting. <br/> <br/> <span class="Bold">Do not</span>warm any other way. </td><td align="left"><span class="Bold">Remove cap from vial</span> <br/> Flip off colored cap from vial. <br/> <br/> Wipe top of the grey stopper with an <span class="Underline">alcohol swab</span>. Allow to air dry. <br/> <br/> <span class="Bold">Do not</span>remove grey rubber stopper. </td><td align="left"><span class="Bold">Prepare vial adapter</span> <br/> Hold sterile blister as shown. Peel back and remove paper backing. <br/> <br/> <span class="Bold">Do not</span>remove vial adapter from blister. <br/> <br/> <span class="Bold">Do not</span>touch spike tip at any time. This will result in contamination. </td><td align="left"><span class="Bold">Connect vial adapter to vial</span> <br/> Place vial on a hard surface and hold by the base. Center vial adapter over the grey rubber stopper. Push vial adapter straight down onto vial top until it snaps securely into place. <br/> <br/> <span class="Bold">Do not</span>place vial adapter on at an angle or diluent may leak upon transfer to the vial. <p class="First"> <img alt="Figure" src="/dailymed/image.cfm?name=risperdal-06.jpg&amp;setid=bb34ee82-d2c2-43b8-ba21-2825c0954691"/></p> </td> </tr> <tr class="Botrule"> <td align="left" colspan="4"><span class="Bold">Connect prefilled syringe to vial adapter</span></td> </tr> <tr> <td align="left"> <p class="First"> <img alt="Figure" src="/dailymed/image.cfm?name=risperdal-07.jpg&amp;setid=bb34ee82-d2c2-43b8-ba21-2825c0954691"/></p> </td><td align="left" class="Lrule"> <p class="First"> <img alt="Figure" src="/dailymed/image.cfm?name=risperdal-09.jpg&amp;setid=bb34ee82-d2c2-43b8-ba21-2825c0954691"/></p> </td><td align="left" class="Lrule"> <p class="First"> <img alt="Figure" src="/dailymed/image.cfm?name=risperdal-11.jpg&amp;setid=bb34ee82-d2c2-43b8-ba21-2825c0954691"/></p> </td><td align="left" class="Lrule"> <p class="First"> <img alt="Figure" src="/dailymed/image.cfm?name=risperdal-13.jpg&amp;setid=bb34ee82-d2c2-43b8-ba21-2825c0954691"/></p> </td> </tr> <tr> <td align="left"><span class="Bold">Remove sterile blister</span> <p class="First"> <img alt="Figure" src="/dailymed/image.cfm?name=risperdal-08.jpg&amp;setid=bb34ee82-d2c2-43b8-ba21-2825c0954691"/></p> <br/> Keep vial vertical to prevent leakage. <br/> Hold base of vial and pull up on the sterile blister to remove. <br/> <br/> <span class="Bold">Do not</span>shake. <br/> <br/> <span class="Bold">Do not</span>touch exposed luer opening on vial adapter. <br/> This will result in contamination. </td><td align="left" class="Lrule"><span class="Bold">Use proper grip</span> <br/> Hold by white collar at the tip of the syringe. <br/> <br/> <span class="Bold">Do not</span>hold syringe by the glass barrel during assembly. <p class="First"> <img alt="Figure" src="/dailymed/image.cfm?name=risperdal-10.jpg&amp;setid=bb34ee82-d2c2-43b8-ba21-2825c0954691"/></p> </td><td align="left" class="Lrule"><span class="Bold">Remove cap</span> <br/> Holding the white collar, snap off the white cap. <br/> <br/> <span class="Bold">Do not</span>twist or cut off the white cap. <br/> <br/> <span class="Bold">Do not</span>touch syringe tip. This will result in contamination. <p class="First"> <img alt="Figure" src="/dailymed/image.cfm?name=risperdal-12.jpg&amp;setid=bb34ee82-d2c2-43b8-ba21-2825c0954691"/></p>The broken-off cap can be discarded. </td><td align="left" class="Lrule"><span class="Bold">Connect syringe to vial adapter</span> <br/> Hold vial adapter by skirt to keep stationary. <br/> <br/> <span class="Bold">Hold syringe by white collar</span>then insert tip into the luer opening of the vial adapter. <br/> <br/> <span class="Bold">Do not</span>hold the glass syringe barrel. This may cause the white collar to loosen or detach. <br/> <br/> Attach the syringe to the vial adapter with a firm <span class="Bold"><span class="Underline">clockwise twisting motion</span></span>until it feels snug. <br/> <br/> <span class="Bold">Do not</span>over-tighten. Over-tightening may cause the syringe tip to break. </td> </tr> </tbody> </table></div>

<div class="scrollingtable"><table class="Noautorules" width="100%"> <col align="left" valign="top" width="25%"/> <col align="left" valign="top" width="25%"/> <col align="left" valign="top" width="25%"/> <col align="left" valign="top" width="25%"/> <thead> <tr> <th align="left" colspan="4"><span class="Underline">Step 2</span><span class="Underline">Reconstitute microspheres</span></th> </tr> </thead> <tbody> <tr> <td align="left"> <p class="First"> <img alt="Figure" src="/dailymed/image.cfm?name=risperdal-14.jpg&amp;setid=bb34ee82-d2c2-43b8-ba21-2825c0954691"/></p> </td><td align="left"> <p class="First"> <img alt="Figure" src="/dailymed/image.cfm?name=risperdal-16.jpg&amp;setid=bb34ee82-d2c2-43b8-ba21-2825c0954691"/></p> </td><td align="left"> <p class="First"> <img alt="Figure" src="/dailymed/image.cfm?name=risperdal-17.jpg&amp;setid=bb34ee82-d2c2-43b8-ba21-2825c0954691"/></p> </td><td align="left"> <p class="First"> <img alt="Figure" src="/dailymed/image.cfm?name=risperdal-18.jpg&amp;setid=bb34ee82-d2c2-43b8-ba21-2825c0954691"/></p> </td> </tr> <tr> <td align="left"><span class="Bold">Inject diluent</span> <br/> Inject entire amount of diluent from syringe into the vial. <p class="First"> <img alt="Figure" src="/dailymed/image.cfm?name=risperdal-15.jpg&amp;setid=bb34ee82-d2c2-43b8-ba21-2825c0954691"/></p> </td><td align="left"><span class="Bold">Suspend microspheres in diluent</span> <br/> Continuing to hold down the plunger rod, <span class="Bold">shake vigorously for at least 10 seconds</span>, as shown. <br/> <br/> <span class="Underline">Check the suspension</span>. When properly mixed, the suspension appears uniform, thick and milky in color. Microspheres will be visible in the liquid. <br/> <br/> Immediately proceed to the next step so suspension does not settle. </td><td align="left"><span class="Bold">Transfer suspension to syringe</span> <br/> Invert vial completely. Slowly pull plunger rod down to withdraw entire contents from the vial into the syringe. </td><td align="left"><span class="Bold">Remove vial adapter</span> <br/> Hold white collar on the syringe and unscrew from vial adapter. <br/> <br/> Tear section of the vial label at the perforation. Apply detached label to the syringe for identification purposes. <br/> <br/> Discard both vial and vial adapter appropriately. </td> </tr> </tbody> </table></div>

<div class="scrollingtable"><table class="Noautorules" width="100%"> <col align="left" valign="top" width="34%"/> <col align="left" valign="top" width="33%"/> <col align="left" valign="top" width="33%"/> <thead> <tr> <th align="left" colspan="3"><span class="Underline">Step 3</span><span class="Underline">Attach needle</span></th> </tr> </thead> <tbody> <tr> <td align="left"> <p class="First"> <img alt="Figure" src="/dailymed/image.cfm?name=risperdal-19.jpg&amp;setid=bb34ee82-d2c2-43b8-ba21-2825c0954691"/></p> </td><td align="left"> <p class="First"> <img alt="Figure" src="/dailymed/image.cfm?name=risperdal-20.jpg&amp;setid=bb34ee82-d2c2-43b8-ba21-2825c0954691"/></p> </td><td align="left"> <p class="First"> <img alt="Figure" src="/dailymed/image.cfm?name=risperdal-21.jpg&amp;setid=bb34ee82-d2c2-43b8-ba21-2825c0954691"/></p> </td> </tr> <tr> <td align="left"><span class="Bold">Select appropriate needle</span> <br/> Choose needle based on injection location (gluteal or deltoid). </td><td align="left"><span class="Bold">Attach needle</span> <br/> Peel blister pouch open part way and use to grasp the base of the needle, as shown. <br/> <br/> <span class="Bold">Holding the white collar on the syringe</span>, attach syringe to needle luer connection with a firm <span class="Bold"><span class="Underline">clockwise twisting motion</span></span>until snug. <br/> <br/> <span class="Bold">Do not</span>touch needle luer opening. This will result in contamination. </td><td align="left"><span class="Bold">Resuspend microspheres</span> <br/> Fully remove the blister pouch. <br/> <br/> Just before injection, shake syringe vigorously again, as some settling will have occurred. </td> </tr> </tbody> </table></div>

<div class="scrollingtable"><table class="Noautorules" width="100%"> <col align="left" valign="top" width="20%"/> <col align="left" valign="top" width="20%"/> <col align="left" valign="top" width="20%"/> <col align="left" valign="top" width="20%"/> <col align="left" valign="top" width="20%"/> <thead> <tr> <th align="left" colspan="5"><span class="Underline">Step 4</span><span class="Underline">Inject dose</span></th> </tr> </thead> <tbody> <tr> <td align="left"> <p class="First"> <img alt="Figure" src="/dailymed/image.cfm?name=risperdal-22.jpg&amp;setid=bb34ee82-d2c2-43b8-ba21-2825c0954691"/></p> </td><td align="left"> <p class="First"> <img alt="Figure" src="/dailymed/image.cfm?name=risperdal-23.jpg&amp;setid=bb34ee82-d2c2-43b8-ba21-2825c0954691"/></p> </td><td align="left"> <p class="First"> <img alt="Figure" src="/dailymed/image.cfm?name=risperdal-24.jpg&amp;setid=bb34ee82-d2c2-43b8-ba21-2825c0954691"/></p> </td><td align="left"> <p class="First"> <img alt="Figure" src="/dailymed/image.cfm?name=risperdal-25.jpg&amp;setid=bb34ee82-d2c2-43b8-ba21-2825c0954691"/></p> </td><td align="left"> <p class="First"> <img alt="Figure" src="/dailymed/image.cfm?name=risperdal-26.jpg&amp;setid=bb34ee82-d2c2-43b8-ba21-2825c0954691"/></p> </td> </tr> <tr> <td align="left"><span class="Bold">Remove transparent needle protector</span> <br/> Move the needle safety device back towards the syringe, as shown. Then hold white collar on syringe and carefully pull the transparent needle protector straight off. <br/> <br/> <span class="Bold">Do not</span>twist transparent needle protector, as the luer connection may loosen. </td><td align="left"><span class="Bold">Remove air bubbles</span> <br/> Hold needle upright and tap gently to make any air bubbles rise to the top. <br/> Slowly and carefully press plunger rod upward to remove air. </td><td align="left"><span class="Bold">Inject</span> <br/> Immediately inject entire contents of syringe intramuscularly (IM) into the gluteal or deltoid muscle of the patient. <br/> <br/> Gluteal injection should be made into the upper-outer quadrant of the gluteal area. <br/> <br/> <span class="Bold">Do not administer intravenously.</span></td><td align="left"><span class="Bold">Secure needle in safety device</span> <br/> Using <span class="Underline">one hand</span>, place needle safety device at a 45-degree angle on a hard, flat surface. Press down with a firm, quick motion until needle is fully engaged in safety device. <br/> <br/> <span class="Bold">Avoid needle stick injury:</span> <br/> <br/> <span class="Bold">Do not</span>use two hands. <br/> <br/> <span class="Bold">Do not</span>intentionally disengage or mishandle the needle safety device. <br/> <br/> <span class="Bold">Do not</span>attempt to straighten the needle or engage the safety device if the needle is bent or damaged. </td><td align="left"><span class="Bold">Properly dispose of needles</span> <br/> Check to confirm needle safety device is fully engaged. <br/> Discard in an approved sharps container. <br/> <br/> Also discard the unused needle provided in the dose pack. </td> </tr> </tbody> </table></div>

RISPERDAL CONSTA is available in dosage strengths of 12.5 mg, 25 mg, 37.5 mg, and 50 mg risperidone. It is provided as a single-use dose pack, consisting of a vial containing the risperidone microspheres, a pre-filled syringe containing 2 mL of diluent for RISPERDAL CONSTA, a vial adapter, and two Terumo SurGuard 3 Needles for intramuscular injection (a 21 G UTW 1-inch needle with needle protection device for deltoid administration and a 20 G TW 2-inch needle with needle protection device for gluteal administration).

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RISPERDAL CONSTA is contraindicated in patients with a known hypersensitivity to either risperidone or paliperidone, or to any of the excipients in the RISPERDAL CONSTA formulation. Hypersensitivity reactions, including anaphylactic reactions and angioedema, have been reported in patients treated with risperidone and in patients treated with paliperidone. Paliperidone is a metabolite of risperidone.

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Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Analyses of 17 placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality. The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear.

RISPERDAL CONSTA (risperidone) is not approved for the treatment of dementia-related psychosis [see Boxed Warning] .

Cerebrovascular adverse events (e.g., stroke, transient ischemic attack), including fatalities, were reported in patients (mean age 85 years; range 73–97) in trials of oral risperidone 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 risperidone compared to patients treated with placebo. RISPERDAL CONSTA is not approved for the treatment of patients with dementia-related psychosis. [See also Boxed Warningand Warnings and Precautions (5.1)]

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

If NMS is suspected, immediately discontinue RISPERDAL CONSTA and provide symptomatic treatment and monitoring.

Tardive dyskinesia, a syndrome consisting 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 predict which patients will 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 increase with the duration of treatment and the cumulative dose. The syndrome can develop after relatively brief treatment periods, even at low doses. It may also occur after discontinuation of treatment.

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

Given these considerations, RISPERDAL CONSTA 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 lowest dose and the shortest duration of treatment producing a satisfactory clinical response. Periodically reassess the need for continued treatment.

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

Atypical antipsychotic drugs have been associated with metabolic changes that may increase cardiovascular/cerebrovascular risk. These metabolic changes include hyperglycemia, dyslipidemia, and body weight gain. While all of the drugs in the class have been shown to produce some metabolic changes, each drug has its own specific risk profile.

Hyperglycemia and Diabetes Mellitus

Hyperglycemia and diabetes mellitus, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, have been reported in patients treated with atypical antipsychotics including RISPERDAL. 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. Given these confounders, the relationship between atypical antipsychotic use and hyperglycemia-related adverse events is not completely understood. However, epidemiological studies suggest an increased risk of treatment-emergent hyperglycemia-related adverse events in patients treated with the atypical antipsychotics. Precise risk estimates for hyperglycemia-related adverse events in patients treated with atypical antipsychotics are not available.

Patients with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics, including RISPERDAL, should be monitored regularly for worsening of glucose control. Patients with risk factors for diabetes mellitus (e.g., obesity, family history of diabetes) who are starting treatment with atypical antipsychotics, including RISPERDAL, should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Any patient treated with atypical antipsychotics, including RISPERDAL, should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics, including RISPERDAL, should undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic, including RISPERDAL, was discontinued; however, some patients required continuation of anti-diabetic treatment despite discontinuation of RISPERDAL.

Pooled data from 3 double-blind, placebo-controlled studies in subjects with schizophrenia and 4 double-blind, placebo-controlled monotherapy studies in subjects with bipolar mania with oral risperidone are presented in Table 1.

<div class="scrollingtable"><table width="80%"> <caption> <span>Table 1. Change in Random Glucose From Seven Placebo-Controlled, 3- to 8-Week, Fixed- or Flexible-Dose Studies in Adult Subjects With Schizophrenia or Bipolar Mania With Oral Risperidone</span> </caption> <col align="left" valign="middle" width="40%"/> <col align="center" valign="middle" width="20%"/> <col align="center" valign="middle" width="20%"/> <col align="center" valign="middle" width="20%"/> <thead> <tr class="First"> <th align="left"></th><th align="center"></th><th align="center" colspan="2">RISPERDAL</th> </tr> <tr class="Last"> <th align="left"></th><th align="center">Placebo</th><th align="center">1–8 mg/day</th><th align="center">&gt;8–16 mg/day</th> </tr> </thead> <tbody> <tr class="First"> <td align="left"></td><td align="center" colspan="3"><span class="Bold">Mean change from baseline (mg/dL)</span></td> </tr> <tr> <td align="left"></td><td align="center"><span class="Bold">N=555</span></td><td align="center"><span class="Bold">N=748</span></td><td align="center"><span class="Bold">N=164</span></td> </tr> <tr> <td align="left">Serum Glucose</td><td align="center">-1.4</td><td align="center">0.8</td><td align="center">0.6</td> </tr> <tr> <td align="left"></td><td align="center" colspan="3"><span class="Bold">Proportion of patients with shifts</span></td> </tr> <tr> <td align="left">Serum Glucose</td><td align="center">0.6%</td><td align="center">0.4%</td><td align="center">0%</td> </tr> <tr class="Last"> <td align="left">(&lt;140 mg/dL to ≥200 mg/dL)</td><td align="center">(3/525)</td><td align="center">(3/702)</td><td align="center">(0/158)</td> </tr> </tbody> </table></div>

In longer-term, controlled and uncontrolled studies in adult subjects, RISPERDAL was associated with a mean change in glucose of +2.8 mg/dL at Week 24 (N=151) and +4.1 mg/dL at Week 48 (N=50).

Dyslipidemia

Undesirable alterations in lipids have been observed in patients treated with atypical antipsychotics.

Pooled data from 7 placebo-controlled, 3- to 8- week, fixed- or flexible-dose studies in adult subjects with schizophrenia or bipolar mania are presented in Table 2.

<div class="scrollingtable"><table width="80%"> <caption> <span>Table 2. Change in Random Lipids From Seven Placebo-Controlled, 3- to 8-Week, Fixed- or Flexible-Dose Studies in Adult Subjects With Schizophrenia or Bipolar Mania With Oral Risperidone</span> </caption> <col align="left" valign="middle" width="40%"/> <col align="center" valign="middle" width="20%"/> <col align="center" valign="middle" width="20%"/> <col align="center" valign="middle" width="20%"/> <thead> <tr class="First"> <th align="left"></th><th align="center"></th><th align="center" colspan="2">RISPERDAL</th> </tr> <tr class="Last"> <th align="left"></th><th align="center">Placebo</th><th align="center">1–8 mg/day</th><th align="center">&gt;8–16 mg/day</th> </tr> </thead> <tbody> <tr class="First"> <td align="left"></td><td align="center" colspan="3"><span class="Bold">Mean change from baseline (mg/dL)</span></td> </tr> <tr> <td align="left"><span class="Bold">Cholesterol</span></td><td align="center"><span class="Bold">N=559</span></td><td align="center"><span class="Bold">N=742</span></td><td align="center"><span class="Bold">N=156</span></td> </tr> <tr> <td align="left">Change from baseline</td><td align="center">0.6</td><td align="center">6.9</td><td align="center">1.8</td> </tr> <tr> <td align="left"><span class="Bold">Triglycerides</span></td><td align="center"><span class="Bold">N=183</span></td><td align="center"><span class="Bold">N=307</span></td><td align="center"><span class="Bold">N=123</span></td> </tr> <tr> <td align="left">Change from baseline</td><td align="center">-17.4</td><td align="center">-4.9</td><td align="center">-8.3</td> </tr> <tr> <td align="left"></td><td align="center" colspan="3"><span class="Bold">Proportion of patients With Shifts</span></td> </tr> <tr> <td align="left"><span class="Bold">Cholesterol</span></td><td align="center">2.7%</td><td align="center">4.3%</td><td align="center">6.3%</td> </tr> <tr> <td align="left">(&lt;200 mg/dL to ≥240 mg/dL)</td><td align="center">(10/368)</td><td align="center">(22/516)</td><td align="center">(6/96)</td> </tr> <tr> <td align="left"><span class="Bold">Triglycerides</span></td><td align="center">1.1%</td><td align="center">2.7%</td><td align="center">2.5%</td> </tr> <tr class="Last"> <td align="left">(&lt;500 mg/dL to ≥500 mg/dL)</td><td align="center">(2/180)</td><td align="center">(8/301)</td><td align="center">(3/121)</td> </tr> </tbody> </table></div>

In longer-term, controlled and uncontrolled studies, RISPERDAL was associated with a mean change in (a) non-fasting cholesterol of +4.4 mg/dL at Week 24 (N=231) and +5.5 mg/dL at Week 48 (N=86); and (b) non-fasting triglycerides of +19.9 mg/dL at Week 24 (N=52).

Weight Gain

Weight gain has been observed with atypical antipsychotic use. Clinical monitoring of weight is recommended.

Data from a placebo-controlled, 12-week, fixed-dose study in adult subjects with schizophrenia are presented in Table 3.

<div class="scrollingtable"><table width="80%"> <caption> <span>Table 3. Mean Change in Body Weight (kg) and the Proportion of Subjects With ≥7% Gain in Body Weight From a Placebo-Controlled, 12-Week, Fixed-Dose Study in Adult Subjects With Schizophrenia</span> </caption> <col align="left" valign="middle" width="40%"/> <col align="center" valign="middle" width="20%"/> <col align="center" valign="middle" width="20%"/> <col align="center" valign="middle" width="20%"/> <thead> <tr class="First"> <th align="left"></th><th align="center"></th><th align="center" colspan="2">RISPERDAL CONSTA</th> </tr> <tr class="Last"> <th align="left"></th><th align="center">Placebo <br/> (N=83) </th><th align="center">25 mg <br/> (N=90) </th><th align="center">50 mg <br/> (N=87) </th> </tr> </thead> <tbody> <tr class="First"> <td align="left"><span class="Bold">Weight (kg)</span></td><td align="center"></td><td align="center"></td><td align="center"></td> </tr> <tr> <td align="left">Change from baseline</td><td align="center">-1.4</td><td align="center">0.5</td><td align="center">1.2</td> </tr> <tr> <td align="left"><span class="Bold">Weight Gain</span></td><td align="center"></td><td align="center"></td><td align="center"></td> </tr> <tr class="Last"> <td align="left">≥7% increase from baseline</td><td align="center">6%</td><td align="center">10%</td><td align="center">8%</td> </tr> </tbody> </table></div>

In an uncontrolled, longer-term, open-label study, RISPERDAL CONSTA was associated with a mean change in weight of +2.1 kg at Week 24 (N=268) and +2.8 kg at Week 50 (N=199).

As with other drugs that antagonize dopamine D 2receptors, risperidone elevates prolactin levels and the elevation persists during chronic administration. Risperidone is associated with higher levels of prolactin elevation than other antipsychotic agents.

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. An increase in pituitary gland, mammary gland, and pancreatic islet cell neoplasia (mammary adenocarcinomas, pituitary and pancreatic adenomas) was observed in the risperidone 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.

RISPERDAL CONSTA may induce orthostatic hypotension associated with dizziness, tachycardia, and in some patients, syncope, especially during the initial dose-titration period with oral risperidone, probably reflecting its alpha-adrenergic antagonistic properties. Syncope was reported in 0.8% (12/1499 patients) of patients treated with RISPERDAL CONSTA in multiple-dose studies. Patients should be instructed in nonpharmacologic interventions that help to reduce the occurrence of orthostatic hypotension (e.g., sitting on the edge of the bed for several minutes before attempting to stand in the morning and slowly rising from a seated position).

RISPERDAL CONSTA should be used with particular caution in (1) 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, e.g., dehydration and hypovolemia, and (2) in the elderly and patients with renal or hepatic impairment. Monitoring of orthostatic vital signs should be considered in all such patients, and a dose reduction should be considered if hypotension occurs. Clinically significant hypotension has been observed with concomitant use of oral RISPERDAL and antihypertensive medication.

Somnolence, postural hypotension, motor and sensory instability have been reported with the use of antipsychotics, including RISPERDAL CONSTA, which may lead to falls and, consequently, fractures or other fall-related injuries. For patients, particularly the elderly, with diseases, conditions, or medications that could exacerbate these effects, assess the risk of falls 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 RISPERDAL CONSTA. Agranulocytosis has also been reported.

Possible risk factors for leukopenia/neutropenia include pre-existing low white blood cell count (WBC) and a history of drug-induced leukopenia/neutropenia. Patients with a history of a clinically significant low WBC or a drug-induced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and discontinuation of RISPERDAL CONSTA 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 RISPERDAL CONSTA and have their WBC followed until recovery.

Somnolence was reported by 5% of patients treated with RISPERDAL CONSTA in multiple-dose trials. Since risperidone 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 treatment with RISPERDAL CONSTA does not affect them adversely.

During premarketing testing, seizures occurred in 0.3% (5/1499 patients) of patients treated with RISPERDAL CONSTA. Therefore, RISPERDAL CONSTA should be used cautiously in patients with a history of seizures.

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 dementia. RISPERDAL CONSTA and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia. [see also Boxed Warningand Warnings and Precautions (5.1)]

Priapism has been reported during postmarketing surveillance [see Adverse Reactions (6.2)] . Severe priapism may require surgical intervention.

Disruption of body temperature regulation has been attributed to antipsychotic agents. Both hyperthermia and hypothermia have been reported in association with oral RISPERDAL or RISPERDAL CONSTA use. Caution is advised when prescribing RISPERDAL CONSTA for patients who will be exposed to temperature extremes.

RISPERDAL CONSTA should be injected into the deltoid or gluteal muscle, and care must be taken to avoid inadvertent injection into a blood vessel. [see Dosage and Administration (2)and Adverse Reactions (6)] .

RISPERDAL CONSTA produced osteodystrophy in male and female rats in a 1-year toxicity study and a 2-year carcinogenicity study at a dose of 40 mg/kg administered IM every 2 weeks.

RISPERDAL CONSTA produced renal tubular tumors (adenoma, adenocarcinoma) and adrenomedullary pheochromocytomas in male rats in the 2-year carcinogenicity study at 40 mg/kg administered IM every 2 weeks. In addition, RISPERDAL CONSTA produced an increase in a marker of cellular proliferation in renal tissue in males in the 1-year toxicity study and in renal tumor-bearing males in the 2-year carcinogenicity study at 40 mg/kg administered IM every 2 weeks. (Cellular proliferation was not measured at the low dose or in females in either study.)

The effect dose for osteodystrophy and the tumor findings is 8 times the IM maximum recommended human dose (MRHD) (50 mg) on a mg/m 2basis and is associated with a plasma exposure (AUC) 2 times the expected plasma exposure (AUC) at the IM MRHD. The no-effect dose for these findings was 5 mg/kg (equal to the IM MRHD on a mg/m 2basis). Plasma exposure (AUC) at the no-effect dose was one third the expected plasma exposure (AUC) at the IM MRHD.

Neither the renal or adrenal tumors, nor osteodystrophy, were seen in studies of orally administered risperidone.Osteodystrophy was not observed in dogs at doses up to 14 times (based on AUC) the IM MRHD in a 1-year toxicity study.

The renal tubular and adrenomedullary tumors in male rats and other tumor findings are described in more detail in Section 13.1 (Carcinogenicity, Mutagenesis, Impairment of Fertility).

The relevance of these findings to human risk is unknown.

Commonly-Observed Adverse Reactions in Double-Blind, Placebo-Controlled Clinical Trials - Schizophrenia

Table 4 lists the adverse reactions reported in 2% or more of RISPERDAL CONSTA-treated patients with schizophrenia in one 12-week double-blind, placebo-controlled trial.

<div class="scrollingtable"><table width="80%"> <caption> <span>Table 4. Adverse Reactions in ≥2% of RISPERDAL CONSTA-Treated Patients with Schizophrenia in a 12-Week Double-Blind, Placebo-Controlled Trial</span> </caption> <col align="left" valign="top" width="40%"/> <col align="center" valign="top" width="20%"/> <col align="center" valign="top" width="20%"/> <col align="center" valign="top" width="20%"/> <thead> <tr class="First"> <th align="left"></th><th align="center" colspan="3">Percentage of Patients Reporting Event</th> </tr> <tr> <th align="left"></th><th align="center" colspan="2">RISPERDAL CONSTA</th><th align="center">Placebo</th> </tr> <tr> <th align="left">System/Organ Class</th><th align="center">25 mg</th><th align="center">50 mg</th><th align="center"></th> </tr> <tr class="Last"> <th align="left">  Adverse Reaction</th><th align="center">(N=99)</th><th align="center">(N=103)</th><th align="center">(N=98)</th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="4"> <dl class="Footnote"> <dt> <a href="#footnote-reference-1" name="footnote-1">*</a> </dt> <dd>Fatigue includes fatigue and asthenia. Parkinsonism includes extrapyramidal disorder, musculoskeletal stiffness, muscle rigidity, and bradykinesia. Akathisia includes akathisia and restlessness. Sedation includes sedation and somnolence.</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="First"> <td align="left"><span class="Bold">Eye disorders</span></td><td align="center"></td><td align="center"></td><td align="center"></td> </tr> <tr> <td align="left">  Vision blurred</td><td align="center">2</td><td align="center">3</td><td align="center">0</td> </tr> <tr> <td align="left" colspan="4"><span class="Bold">Gastrointestinal disorders</span></td> </tr> <tr> <td align="left">  Constipation</td><td align="center">5</td><td align="center">7</td><td align="center">1</td> </tr> <tr> <td align="left">  Dry mouth</td><td align="center">0</td><td align="center">7</td><td align="center">1</td> </tr> <tr> <td align="left">  Dyspepsia</td><td align="center">6</td><td align="center">6</td><td align="center">0</td> </tr> <tr> <td align="left">  Nausea</td><td align="center">3</td><td align="center">4</td><td align="center">5</td> </tr> <tr> <td align="left">  Toothache</td><td align="center">1</td><td align="center">3</td><td align="center">0</td> </tr> <tr> <td align="left">  Salivary hypersecretion</td><td align="center">4</td><td align="center">1</td><td align="center">0</td> </tr> <tr> <td align="left" colspan="4"><span class="Bold">General disorders and administration site conditions</span></td> </tr> <tr> <td align="left">  Fatigue <a class="Sup" href="#footnote-1" name="footnote-reference-1">*</a></td><td align="center">3</td><td align="center">9</td><td align="center">0</td> </tr> <tr> <td align="left">  Edema peripheral</td><td align="center">2</td><td align="center">3</td><td align="center">1</td> </tr> <tr> <td align="left">  Pain</td><td align="center">4</td><td align="center">1</td><td align="center">0</td> </tr> <tr> <td align="left">  Pyrexia</td><td align="center">2</td><td align="center">1</td><td align="center">0</td> </tr> <tr> <td align="left" colspan="4"><span class="Bold">Infections and infestations</span></td> </tr> <tr> <td align="left">  Upper respiratory tract infection</td><td align="center">2</td><td align="center">0</td><td align="center">1</td> </tr> <tr> <td align="left" colspan="4"><span class="Bold">Investigations</span></td> </tr> <tr> <td align="left">  Weight increased</td><td align="center">5</td><td align="center">4</td><td align="center">2</td> </tr> <tr> <td align="left">  Weight decreased</td><td align="center">4</td><td align="center">1</td><td align="center">1</td> </tr> <tr> <td align="left" colspan="4"><span class="Bold">Musculoskeletal and connective tissue disorders</span></td> </tr> <tr> <td align="left">  Pain in extremity</td><td align="center">6</td><td align="center">2</td><td align="center">1</td> </tr> <tr> <td align="left" colspan="4"><span class="Bold">Nervous system disorders</span></td> </tr> <tr> <td align="left">  Headache</td><td align="center">15</td><td align="center">21</td><td align="center">12</td> </tr> <tr> <td align="left">  Parkinsonism <a class="Sup" href="#footnote-1">*</a></td><td align="center">8</td><td align="center">15</td><td align="center">9</td> </tr> <tr> <td align="left">  Dizziness</td><td align="center">7</td><td align="center">11</td><td align="center">6</td> </tr> <tr> <td align="left">  Akathisia <a class="Sup" href="#footnote-1">*</a></td><td align="center">4</td><td align="center">11</td><td align="center">6</td> </tr> <tr> <td align="left">  Sedation <a class="Sup" href="#footnote-1">*</a></td><td align="center">5</td><td align="center">6</td><td align="center">3</td> </tr> <tr> <td align="left">  Tremor</td><td align="center">0</td><td align="center">3</td><td align="center">0</td> </tr> <tr> <td align="left">  Syncope</td><td align="center">2</td><td align="center">1</td><td align="center">0</td> </tr> <tr> <td align="left">  Hypoesthesia</td><td align="center">2</td><td align="center">0</td><td align="center">0</td> </tr> <tr> <td align="left" colspan="4"><span class="Bold">Respiratory, thoracic and mediastinal disorders</span></td> </tr> <tr> <td align="left">  Cough</td><td align="center">4</td><td align="center">2</td><td align="center">3</td> </tr> <tr> <td align="left">  Sinus congestion</td><td align="center">2</td><td align="center">0</td><td align="center">0</td> </tr> <tr> <td align="left" colspan="4"><span class="Bold">Skin and subcutaneous tissue disorders</span></td> </tr> <tr> <td align="left">  Acne</td><td align="center">2</td><td align="center">2</td><td align="center">0</td> </tr> <tr class="Last"> <td align="left">  Dry skin</td><td align="center">2</td><td align="center">0</td><td align="center">0</td> </tr> </tbody> </table></div>

Commonly-Observed Adverse Reactions in Double-Blind, Placebo-Controlled Clinical Trials – Bipolar Disorder

Table 5 lists the treatment-emergent adverse reactions reported in 2% or more of RISPERDAL CONSTA-treated patients in the 24-month double-blind, placebo-controlled treatment period of the trial assessing the efficacy and safety of RISPERDAL CONSTA when administered as monotherapy for maintenance treatment in patients with Bipolar I Disorder.

<div class="scrollingtable"><table width="80%"> <caption> <span>Table 5. Adverse Reactions in ≥2% of Patients with Bipolar I Disorder Treated with RISPERDAL CONSTA as Monotherapy in a 24-Month Double-Blind, Placebo-Controlled Trial</span> </caption> <col align="left" valign="top" width="40%"/> <col align="center" valign="top" width="30%"/> <col align="center" valign="top" width="30%"/> <thead> <tr class="First"> <th align="left"></th><th align="center" colspan="2">Percentage of Patients Reporting Event</th> </tr> <tr class="Last"> <th align="left" valign="bottom">System/Organ Class <br/>   Adverse Reaction </th><th align="center">RISPERDAL CONSTA <br/> (N=154) </th><th align="center">Placebo <br/> (N=149) </th> </tr> </thead> <tbody> <tr class="First"> <td align="left" colspan="3"><span class="Bold">Investigations</span></td> </tr> <tr> <td align="left">  Weight increased</td><td align="center">5</td><td align="center">1</td> </tr> <tr> <td align="left" colspan="3"><span class="Bold">Nervous system disorders</span></td> </tr> <tr> <td align="left">  Dizziness</td><td align="center">3</td><td align="center">1</td> </tr> <tr> <td align="left" colspan="3"><span class="Bold">Vascular disorders</span></td> </tr> <tr class="Last"> <td align="left">  Hypertension</td><td align="center">3</td><td align="center">1</td> </tr> </tbody> </table></div>

Table 6 lists the treatment-emergent adverse reactions reported in 4% or more of patients in the 52-week double-blind, placebo-controlled treatment phase of a trial assessing the efficacy and safety of RISPERDAL CONSTA when administered as adjunctive maintenance treatment in patients with bipolar disorder.

<div class="scrollingtable"><table width="80%"> <caption> <span>Table 6. Adverse Reactions in ≥ 4% of Patients with Bipolar Disorder Treated with RISPERDAL CONSTA as Adjunctive Therapy in a 52-Week Double-Blind, Placebo-Controlled Trial</span> </caption> <col align="left" valign="top" width="40%"/> <col align="center" valign="top" width="30%"/> <col align="center" valign="top" width="30%"/> <thead> <tr class="First"> <th align="left"></th><th align="center" colspan="2">Percentage of Patients Reporting Event</th> </tr> <tr class="Botrule Last"> <th align="left" valign="bottom">System/Organ Class <br/>   Adverse Reaction </th><th align="center" valign="bottom">RISPERDAL CONSTA + Treatment as Usual <a class="Sup" href="#footnote-2" name="footnote-reference-2">*</a> <br/> (N=72) </th><th align="center" valign="bottom">Placebo + Treatment as Usual <a class="Sup" href="#footnote-2">*</a> <br/> (N=67) </th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="3"> <dl class="Footnote"> <dt> <a href="#footnote-reference-2" name="footnote-2">*</a> </dt> <dd>Patients received double-blind RISPERDAL CONSTA or placebo in addition to continuing their treatment as usual, which included mood stabilizers, antidepressants, and/or anxiolytics. </dd> <dt> <a href="#footnote-reference-3" name="footnote-3">†</a> </dt> <dd>Parkinsonism includes muscle rigidity, hypokinesia, cogwheel rigidity, and bradykinesia. Dyskinesia includes muscle twitching and dyskinesia.</dd> <dt> <a href="#footnote-reference-4" name="footnote-4">‡</a> </dt> <dd>Sedation includes sedation and somnolence.</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="First"> <td align="left" colspan="3"><span class="Bold">General disorders and administration site conditions</span></td> </tr> <tr> <td align="left">  Gait abnormal</td><td align="center">4</td><td align="center">0</td> </tr> <tr> <td align="left" colspan="3"><span class="Bold">Infections and infestations</span></td> </tr> <tr> <td align="left">  Upper respiratory tract infection</td><td align="center">6</td><td align="center">3</td> </tr> <tr> <td align="left" colspan="3"><span class="Bold">Investigations</span></td> </tr> <tr> <td align="left">  Weight increased</td><td align="center">7</td><td align="center">1</td> </tr> <tr> <td align="left" colspan="3"><span class="Bold">Metabolism and nutrition disorders</span></td> </tr> <tr> <td align="left">  Decreased appetite</td><td align="center">6</td><td align="center">1</td> </tr> <tr> <td align="left">  Increased appetite</td><td align="center">4</td><td align="center">0</td> </tr> <tr> <td align="left" colspan="3"><span class="Bold">Musculoskeletal and connective tissue disorders</span></td> </tr> <tr> <td align="left">  Arthralgia</td><td align="center">4</td><td align="center">3</td> </tr> <tr> <td align="left" colspan="3"><span class="Bold">Nervous system disorders</span></td> </tr> <tr> <td align="left">  Tremor</td><td align="center">24</td><td align="center">16</td> </tr> <tr> <td align="left">  Parkinsonism <a class="Sup" href="#footnote-3" name="footnote-reference-3">†</a></td><td align="center">15</td><td align="center">6</td> </tr> <tr> <td align="left">  Dyskinesia <a class="Sup" href="#footnote-3">†</a></td><td align="center">6</td><td align="center">3</td> </tr> <tr> <td align="left">  Sedation <a class="Sup" href="#footnote-4" name="footnote-reference-4">‡</a></td><td align="center">7</td><td align="center">1</td> </tr> <tr> <td align="left">  Disturbance in attention</td><td align="center">4</td><td align="center">0</td> </tr> <tr> <td align="left" colspan="3"><span class="Bold">Reproductive system and breast disorders</span></td> </tr> <tr> <td align="left">  Amenorrhea</td><td align="center">4</td><td align="center">1</td> </tr> <tr> <td align="left" colspan="3"><span class="Bold">Respiratory, thoracic and mediastinal disorders</span></td> </tr> <tr class="Last"> <td align="left">  Cough</td><td align="center">4</td><td align="center">1</td> </tr> </tbody> </table></div>

Other Adverse Reactions Observed During the Clinical Trial Evaluation of Risperidone

The following additional adverse reactions occurred in < 2% of the RISPERDAL CONSTA-treated patients in the above schizophrenia double-blind, placebo-controlled trial dataset, in < 2% of the RISPERDAL CONSTA-treated patients in the above double-blind, placebo-controlled period of the monotherapy bipolar disorder trial dataset, or in < 4% of the RISPERDAL CONSTA-treated patients in the above double-blind, placebo-controlled period of the adjunctive treatment bipolar disorder trial dataset. The following also includes additional adverse reactions reported at any frequency in RISPERDAL CONSTA-treated patients who participated in the open-label phases of the above bipolar disorder studies and in other studies, including double-blind, active controlled and open-label studies in schizophrenia and bipolar disorder.

Blood and lymphatic system disorders:anemia, neutropenia

Cardiac disorders:tachycardia, atrioventricular block first degree, palpitations, sinus bradycardia, bundle branch block left, bradycardia, sinus tachycardia, bundle branch block right

Ear and labyrinth disorders:ear pain, vertigo

Endocrine disorders:hyperprolactinemia

Eye disorders:conjunctivitis, visual acuity reduced

Gastrointestinal disorders:diarrhea, vomiting, abdominal pain upper, abdominal pain, stomach discomfort, gastritis

General disorders and administration site conditions:injection site pain, chest discomfort, chest pain, influenza like illness, sluggishness, malaise, induration, injection site induration, injection site swelling, injection site reaction, face edema

Immune system disorders:hypersensitivity

Infections and infestations:nasopharyngitis, influenza, bronchitis, urinary tract infection, rhinitis, respiratory tract infection, ear infection, pneumonia, lower respiratory tract infection, pharyngitis, sinusitis, viral infection, infection, localized infection, cystitis, gastroenteritis, subcutaneous abscess

Injury and poisoning:fall, procedural pain

Investigations:blood prolactin increased, alanine aminotransferase increased, electrocardiogram abnormal, gamma-glutamyl transferase increased, blood glucose increased, hepatic enzyme increased, aspartate aminotransferase increased, electrocardiogram QT prolonged, glucose urine present

Metabolism and nutritional disorders:anorexia, hyperglycemia

Musculoskeletal, connective tissue and bone disorders:posture abnormal, myalgia, back pain, buttock pain, muscular weakness, neck pain, musculoskeletal chest pain

Nervous system disorders:coordination abnormal, dystonia, tardive dyskinesia, drooling, paresthesia, dizziness postural, convulsion, akinesia, hypokinesia, dysarthria

Psychiatric disorders:insomnia, agitation, anxiety, sleep disorder, depression, initial insomnia, libido decreased, nervousness

Renal and urinary disorders:urinary incontinence

Reproductive system and breast disorders:galactorrhea, oligomenorrhea, erectile dysfunction, sexual dysfunction, ejaculation disorder, gynecomastia, breast discomfort, menstruation irregular, menstruation delayed, menstrual disorder, ejaculation delayed

Respiratory, thoracic and mediastinal disorders:nasal congestion, pharyngolaryngeal pain, dyspnea, rhinorrhea

Skin and subcutaneous tissue disorders:rash, eczema, pruritus generalized, pruritus

Vascular disorders:hypotension, orthostatic hypotension

Additional Adverse Reactions Reported with Oral RISPERDAL

The following is a list of additional adverse reactions that have been reported during the clinical trial evaluation of oral RISPERDAL, regardless of frequency of occurrence:

Blood and Lymphatic Disorders:granulocytopenia

Cardiac Disorders:atrioventricular block

Ear and Labyrinth Disorders:tinnitus

Eye Disorders:ocular hyperemia, eye discharge, eye rolling, eyelid edema, eye swelling, eyelid margin crusting, dry eye, lacrimation increased, photophobia, glaucoma

Gastrointestinal Disorders:abdominal pain upper, dysphagia, fecaloma, abdominal discomfort, fecal incontinence, lip swelling, cheilitis, aptyalism

General Disorders:thirst, feeling abnormal, gait disturbance, pitting edema, edema, chills, discomfort, generalized edema, drug withdrawal syndrome, peripheral coldness

Immune System Disorders:drug hypersensitivity

Infections and Infestations:tonsillitis, eye infection, cellulitis, otitis media, onychomycosis, acarodermatitis, bronchopneumonia, respiratory tract infection, tracheobronchitis, otitis media chronic

Investigations:body temperature increased, heart rate increased, eosinophil count increased, white blood cell count decreased, hemoglobin decreased, blood creatine phosphokinase increased, hematocrit decreased, body temperature decreased, blood pressure decreased, transaminases increased

Metabolism and Nutrition Disorders:polydipsia

Musculoskeletal, Connective Tissue, and Bone Disorders:joint swelling, joint stiffness, rhabdomyolysis, torticollis

Nervous System Disorders:hypertonia, balance disorder, dysarthria, unresponsive to stimuli, depressed level of consciousness, movement disorder, hypokinesia, parkinsonian rest tremor, transient ischemic attack, cerebrovascular accident, masked facies, speech disorder, loss of consciousness, muscle contractions involuntary, akinesia, cerebral ischemia, cerebrovascular disorder, neuroleptic malignant syndrome, diabetic coma, head titubation

Psychiatric Disorders:blunted affect, confusional state, middle insomnia, listlessness, anorgasmia

Renal and Urinary Disorders:enuresis, dysuria, pollakiuria

Reproductive System and Breast Disorders:vaginal discharge, retrograde ejaculation, ejaculation disorder, ejaculation failure, breast enlargement

Respiratory, Thoracic, and Mediastinal Disorders:epistaxis, wheezing, pneumonia aspiration, dysphonia, productive cough, pulmonary congestion, respiratory tract congestion, rales, respiratory disorder, hyperventilation, nasal edema

Skin and Subcutaneous Tissue Disorders:erythema, skin discoloration, skin lesion, skin disorder, rash erythematous, rash papular, hyperkeratosis, dandruff, seborrheic dermatitis, rash generalized, rash maculopapular

Vascular Disorders:flushing

Discontinuations Due to Adverse Reactions

Schizophrenia

Approximately 11% (22/202) of RISPERDAL CONSTA-treated patients in the 12-week double-blind, placebo-controlled schizophrenia trial discontinued treatment due to an adverse event, compared with 13% (13/98) who received placebo. The adverse reactions associated with discontinuation in two or more RISPERDAL CONSTA-treated patients were: agitation (3%), depression (2%), anxiety (1%), and akathisia (1%).

Bipolar Disorder

In the 24-month double-blind, placebo-controlled treatment period of the trial assessing the efficacy and safety of RISPERDAL CONSTA when administered as monotherapy for maintenance treatment in patients with bipolar I disorder, 1 (0.6%) of 154 RISPERDAL CONSTA-treated patients discontinued due to an adverse reaction (hyperglycemia).

In the 52-week double-blind phase of the placebo-controlled trial in which RISPERDAL CONSTA was administered as adjunctive therapy to patients with bipolar disorder in addition to continuing with their treatment as usual, approximately 4% (3/72) of RISPERDAL CONSTA-treated patients discontinued treatment due to an adverse event, compared with 1.5% (1/67) of placebo-treated patients. Adverse reactions associated with discontinuation in RISPERDAL CONSTA-treated patients were: hypokinesia (one patient) and tardive dyskinesia (one patient).

Dose Dependency of Adverse Reactions in Clinical Trials

Extrapyramidal Symptoms

Two methods were used to measure extrapyramidal symptoms (EPS) in the 12-week double-blind, placebo-controlled trial comparing three doses of RISPERDAL CONSTA (25 mg, 50 mg, and 75 mg) with placebo in patients with schizophrenia, including: (1) the incidence of spontaneous reports of EPS symptoms; and (2) the change from baseline to endpoint on the total score (sum of the subscale scores for parkinsonism, dystonia, and dyskinesia) of the Extrapyramidal Symptom Rating Scale (ESRS).

As shown in Table 1, the overall incidence of EPS-related adverse reactions (akathisia, dystonia, parkinsonism, and tremor) in patients treated with 25 mg RISPERDAL CONSTA was comparable to that of patients treated with placebo; the incidence of EPS-related adverse reactions was higher in patients treated with 50 mg RISPERDAL CONSTA.

The median change from baseline to endpoint in total ESRS score showed no worsening in patients treated with RISPERDAL CONSTA compared with patients treated with placebo: 0 (placebo group); -1 (25-mg group, significantly less than the placebo group); and 0 (50-mg group).

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, they occur more frequently and with greater severity with high potency and at higher doses of first generation antipsychotic drugs. An elevated risk of acute dystonia is observed in males and younger age groups.

Changes in ECG

The electrocardiograms of 202 schizophrenic patients treated with 25 mg or 50 mg RISPERDAL CONSTA and 98 schizophrenic patients treated with placebo in the 12-week double-blind, placebo-controlled trial were evaluated. Compared with placebo, there were no statistically significant differences in QTc intervals (using Fridericia's and linear correction factors) during treatment with RISPERDAL CONSTA.

The electrocardiograms of 227 patients with Bipolar I Disorder were evaluated in the 24-month double-blind, placebo-controlled period. There were no clinically relevant differences in QTc intervals (using Fridericia's and linear correction factors) during treatment with RISPERDAL CONSTA compared to placebo.

The electrocardiograms of 85 patients with bipolar disorder were evaluated in the 52-week double-blind, placebo-controlled trial. There were no statistically significant differences in QTc intervals (using Fridericia's and linear correction factors) during treatment with RISPERDAL CONSTA 25 mg, 37.5 mg, or 50 mg when administered as adjunctive treatment in addition to continuing treatment as usual compared to placebo.

Pain Assessment and Local Injection Site Reactions

The mean intensity of injection pain reported by patients with schizophrenia using a visual analog scale (0 = no pain to 100 = unbearably painful) decreased in all treatment groups from the first to the last injection (placebo: 16.7 to 12.6; 25 mg: 12.0 to 9.0; 50 mg: 18.2 to 11.8). After the sixth injection (Week 10), investigator ratings indicated that 1% of patients treated with 25 mg or 50 mg RISPERDAL CONSTA experienced redness, swelling, or induration at the injection site.

In a separate study to observe local-site tolerability in which RISPERDAL CONSTA was administered into the deltoid muscle every 2 weeks over a period of 8 weeks, no patient discontinued treatment due to local injection site pain or reaction. Clinician ratings indicated that only mild redness, swelling, or induration at the injection site was observed in subjects treated with 37.5 mg or 50 mg RISPERDAL CONSTA at 2 hours after deltoid injection. All ratings returned to baseline at the predose assessment of the next injection 2 weeks later. No moderate or severe reactions were observed in any subject.

The following adverse reactions have been identified during postapproval use of risperidone; because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency: agranulocytosis, alopecia, anaphylactic reaction, angioedema, atrial fibrillation, blood cholesterol increased, blood triglycerides increased, catatonia, diabetes mellitus, diabetic ketoacidosis in patients with impaired glucose metabolism, drug withdrawal syndrome neonatal, dysgeusia, hypoglycemia, hypothermia, ileus, inappropriate antidiuretic hormone secretion, intestinal obstruction, jaundice, mania, pancreatitis, priapism, QT prolongation, sleep apnea syndrome, somnambulism, Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN), thrombocytopenia, thrombotic thrombocytopenic purpura, urinary retention, and water intoxication. In addition, the following adverse reactions have been observed during postapproval use of RISPERDAL CONSTA: cerebrovascular disorders, including cerebrovascular accidents, and diabetes mellitus aggravated.

Retinal artery occlusion after injection of RISPERDAL CONSTA has been reported during postmarketing surveillance. This has been reported in the presence of abnormal arteriovenous anastomosis.

Serious injection site reactions including abscess, cellulitis, cyst, hematoma, necrosis, nodule, and ulcer have been reported with RISPERDAL CONSTA during postmarketing surveillance. Isolated cases required surgical intervention.

Very rarely, cases of anaphylactic reaction after injection with RISPERDAL CONSTA have been reported during postmarketing experience in patients who have previously tolerated oral risperidone.

Postmarketing cases of extrapyramidal symptoms (dystonia and dyskinesia) have been reported in patients concomitantly taking methylphenidate and risperidone when there was an increase or decrease in dosage, initiation, or discontinuation of either or both medications.

Given the primary CNS effects of risperidone, caution should be used when RISPERDAL CONSTA is administered in combination with other centrally-acting drugs or alcohol.

Because of its potential for inducing hypotension, RISPERDAL CONSTA may enhance the hypotensive effects of other therapeutic agents with this potential.

RISPERDAL CONSTA may antagonize the effects of levodopa and dopamine agonists.

Amitriptyline did not affect the pharmacokinetics of risperidone or of risperidone and 9-hydroxyrisperidone combined following concomitant administration with oral RISPERDAL.

Cimetidine and ranitidine increased the bioavailability of oral risperidone by 64% and 26%, respectively. However, cimetidine did not affect the AUC of risperidone and 9-hydroxyrisperidone combined, whereas ranitidine increased the AUC of risperidone and 9-hydroxyrisperidone combined by 20%.

Concomitant use with methylphenidate, when there is change in dosage of either medication, may increase the risk of extrapyramidal symptoms (EPS). Monitor for symptoms of EPS with concomitant use of RISPERDAL CONSTA and methylphenidate [see Adverse Reactions (6.2)] .

Chronic administration of clozapine with risperidone may decrease the clearance of risperidone.

Repeated doses of oral RISPERDAL (3 mg twice daily) did not affect the exposure (AUC) or peak plasma concentrations (C max) of lithium (N=13).

Repeated doses of oral RISPERDAL (4 mg once daily) did not affect the pre-dose or average plasma concentrations and exposure (AUC) of valproate (1000 mg/day in three divided doses) compared to placebo (N=21). However, there was a 20% increase in valproate peak plasma concentration (C max) after concomitant administration of oral RISPERDAL.

Oral RISPERDAL (0.25 mg twice daily) did not show a clinically relevant effect on the pharmacokinetics of digoxin.

Oral RISPERDAL administered at doses from 1–6 mg/day concomitantly with topiramate 400 mg/day resulted in a 23% decrease in risperidone C max and a 33% decrease in risperidone AUC 0–12 hour at steady state. Minimal reductions in the exposure to risperidone and 9-hydroxyrisperidone combined, and no change for 9-hydroxyrisperidone were observed. This interaction is unlikely to be of clinical significance. There was no clinically relevant effect of oral RISPERDAL on the pharmacokinetics of topiramate.

Risperidone is metabolized to 9-hydroxyrisperidone by CYP 2D6, an enzyme that is polymorphic in the population and that can be inhibited by a variety of psychotropic and other drugs [see Clinical Pharmacology (12.3)] . Drug interactions that reduce the metabolism of risperidone to 9-hydroxyrisperidone would increase the plasma concentrations of risperidone and lower the concentrations of 9-hydroxyrisperidone. Analysis of clinical studies involving a modest number of poor metabolizers (n≅70 patients) does not suggest that poor and extensive metabolizers have different rates of adverse effects. No comparison of effectiveness in the two groups has been made.

In vitrostudies showed that drugs metabolized by other CYP isozymes, including 1A1, 1A2, 2C9, 2C19, and 3A4, are only weak inhibitors of risperidone metabolism.

Fluoxetine and Paroxetine

Fluoxetine (20 mg once daily) and paroxetine (20 mg once daily), CYP 2D6 inhibitors, have been shown to increase the plasma concentration of risperidone 2.5–2.8 fold and 3–9 fold respectively. Fluoxetine did not affect the plasma concentration of 9-hydroxyrisperidone. Paroxetine lowered the concentration of 9-hydroxyrisperidone by about 10%. When either concomitant fluoxetine or paroxetine is initiated or discontinued, the physician should re-evaluate the dose of RISPERDAL CONSTA. When initiation of fluoxetine or paroxetine is considered, patients may be placed on a lower dose of RISPERDAL CONSTA between 2 to 4 weeks before the planned start of fluoxetine or paroxetine therapy to adjust for the expected increase in plasma concentrations of risperidone. When fluoxetine or paroxetine is initiated in patients receiving the recommended dose of 25 mg RISPERDAL CONSTA, it is recommended to continue treatment with the 25-mg dose unless clinical judgment necessitates lowering the RISPERDAL CONSTA dose to 12.5 mg or necessitates interruption of RISPERDAL CONSTA treatment. When RISPERDAL CONSTA is initiated in patients already receiving fluoxetine or paroxetine, a starting dose of 12.5 mg can be considered. The efficacy of the 12.5 mg dose has not been investigated in clinical trials. [see also Dosage and Administration (2.5)] . The effects of discontinuation of concomitant fluoxetine or paroxetine therapy on the pharmacokinetics of risperidone and 9-hydroxyrisperidone have not been studied.

Erythromycin

There were no significant interactions between oral RISPERDAL and erythromycin.

Carbamazepine co-administration with oral RISPERDAL decreased the steady-state plasma concentrations of risperidone and 9-hydroxyrisperidone by about 50%. Plasma concentrations of carbamazepine did not appear to be affected. Co-administration of other known CYP 3A4 enzyme inducers (e.g., phenytoin, rifampin, and phenobarbital) with risperidone may cause similar decreases in the combined plasma concentrations of risperidone and 9-hydroxyrisperidone, which could lead to decreased efficacy of RISPERDAL CONSTA treatment. At the initiation of therapy with carbamazepine or other known hepatic enzyme inducers, patients should be closely monitored during the first 4–8 weeks, since the dose of RISPERDAL CONSTA may need to be adjusted. A dose increase, or additional oral RISPERDAL, may need to be considered. On discontinuation of carbamazepine or other CYP 3A4 hepatic enzyme inducers, the dosage of RISPERDAL CONSTA should be re-evaluated and, if necessary, decreased. Patients may be placed on a lower dose of RISPERDAL CONSTA between 2 to 4 weeks before the planned discontinuation of carbamazepine or other CYP 3A4 enzyme inducers to adjust for the expected increase in plasma concentrations of risperidone plus 9-hydroxyrisperidone. For patients treated with the recommended dose of 25 mg RISPERDAL CONSTA and discontinuing from carbamazepine or other CYP 3A4 enzyme inducers, it is recommended to continue treatment with the 25-mg dose unless clinical judgment necessitates lowering the RISPERDAL CONSTA dose to 12.5 mg or necessitates interruption of RISPERDAL CONSTA treatment. The efficacy of the 12.5 mg dose has not been investigated in clinical trials. [see also Dosage and Administration (2.5)]

In vitrostudies indicate that risperidone is a relatively weak inhibitor of CYP 2D6. Therefore, RISPERDAL CONSTA is not expected to substantially inhibit the clearance of drugs that are metabolized by this enzymatic pathway. In drug interaction studies, oral RISPERDAL did not significantly affect the pharmacokinetics of donepezil and galantamine, which are metabolized by CYP 2D6.

Pregnancy Exposure Registry

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

Risk Summary

Neonates exposed to antipsychotic drugs during the third trimester of pregnancy 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 risperidone 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 RISPERDAL CONSTA, during pregnancy (see Clinical Considerations) . Risperidone has been detected in plasma in adult subjects up to 8 weeks after a single-dose administration of RISPERDAL CONSTA [see Clinical Pharmacology (12.3)] . The clinical significance of RISPERDAL CONSTA administered before pregnancy or anytime during pregnancy is not known.

Oral administration of risperidone to pregnant mice caused cleft palate at doses 3 to 4 times the maximum recommended human dose (MRHD) with maternal toxicity observed at 4-times the MRHD based on mg/m 2 body surface area. Risperidone was not teratogenic in rats or rabbits at doses up to 6-times the MRHD based on mg/m 2 body surface area. Increased stillbirths and decreased birth weight occurred after oral risperidone administration to pregnant rats at 1.5-times the MRHD based on mg/m 2 body surface area. Learning was impaired in offspring of rats when the dams were dosed at 0.6-times the MRHD and offspring mortality increased at doses 0.1 to 3 times the MRHD based on mg/m 2 body surface area.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, 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 2–4% and 15–20%, respectively.

Clinical Considerations

Disease-associated Maternal and/or 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 RISPERDAL CONSTA, 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

Published data from observational studies, birth registries, and case reports on the use of atypical antipsychotics during pregnancy do not report a clear association with antipsychotics and major birth defects. A prospective observational study including 6 women treated with risperidone demonstrated placental passage of risperidone. 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. There was a small increase in the risk major of birth defects (RR=1.26, 95% CI 1.02–1.56) and of cardiac malformations (RR=1.26, 95% CI 0.88–1.81) in a subgroup of 1566 women exposed to risperidone during the first trimester of pregnancy; however, there is no mechanism of action to explain the difference in malformation rates.

Animal Data

Oral administration of risperidone to pregnant mice during organogenesis caused cleft palate at 10 mg/kg/day which is 3 times the MRHD of 16 mg/day based on mg/m 2 body surface area; maternal toxicity occurred at 4 times the MRHD. Risperidone was not teratogenic when administered orally to rats at 0.6 to 10 mg/kg/day and rabbits at 0.3 to 5 mg/kg/day, which are up to 6 times the MRHD of 16 mg/day risperidone based on mg/m 2 body surface area. Learning was impaired in offspring of rats dosed orally throughout pregnancy at 1 mg/kg/day which is 0.6 times the MRHD and neuronal cell death increased in fetal brains of offspring of rats dosed during pregnancy at 1 and 2 mg/kg/day which are 0.6 and 1.2 times the MRHD based on mg/m 2 body surface area; postnatal development and growth of the offspring were also delayed.

Rat offspring mortality increased during the first 4 days of lactation when pregnant rats were dosed throughout gestation at 0.16 to 5 mg/kg/day which are 0.1 to 3 times the MRHD of 16 mg/day based on mg/m 2 body surface area. It is not known whether these deaths were due to a direct effect on the fetuses or pups or to effects on the dams; a no-effect dose could not be determined. The rate of stillbirths was increased at 2.5 mg/kg or 1.5 times the MRHD based on mg/m 2 body surface area.

In a rat cross-fostering study the number of live offspring was decreased, the number of stillbirths increased, and the birth weight was decreased in offspring of drug-treated pregnant rats. In addition, the number of deaths increased by Day 1 among offspring of drug-treated pregnant rats, regardless of whether or not the offspring were cross-fostered. Risperidone also appeared to impair maternal behavior in that offspring body weight gain and survival (from Day 1 to 4 of lactation) were reduced in offspring born to control but reared by drug-treated dams. All of these effects occurred at 5 mg/kg which is 3 times the MRHD based on mg/m 2 and the only dose tested in the study.

Risk Summary

Limited data from published literature reports the presence of risperidone and its metabolite, 9-hydroxyrisperidone, in human breast milk at relative infant dose ranging between 2.3% and 4.7% of the maternal weight-adjusted dosage. There are reports of sedation, failure to thrive, jitteriness, and extrapyramidal symptoms (tremors and abnormal muscle movements) in breastfed infants exposed to risperidone (see Clinical Considerations). Risperidone has been detected in plasma in adult subjects up to 8 weeks after a single-dose administration of RISPERDAL CONSTA [see Clinical Pharmacology (12.3)] , and the clinical significance on the breastfed infant is not known. There is no information on the effects of risperidone on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for RISPERDAL CONSTA and any potential adverse effects on the breastfed child from RISPERDAL CONSTA or from the mother's underlying condition.

Clinical Considerations

Infants exposed to RISPERDAL CONSTA through breastmilk should be monitored for excess sedation, failure to thrive, jitteriness, and extrapyramidal symptoms (tremors and abnormal muscle movements).

Infertility

Females

Based on the pharmacologic action of risperidone (D 2 receptor antagonism), treatment with RISPERDAL CONSTA 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 (5.6)].

Safety and effectiveness of RISPERDAL CONSTA in pediatric patients have not been established. However, juvenile animal toxicology studies have been conducted with oral risperidone.

Juvenile Animal Studies

Juvenile dogs were treated with oral risperidone from weeks 10 to 50 of age (equivalent to the period of childhood through adolescence in humans), at doses of 0.31, 1.25, or 5 mg/kg/day, which are 1.2, 3.4 and 13.5 times the MRHD of 6 mg/day for children, based on mg/m 2 body surface area. Bone length and density were decreased with a no-effect dose of 0.31 mg/kg/day; this dose produced plasma AUC of risperidone plus its active metabolite paliperidone (9-hydroxy-risperidone) that were similar to those in children and adolescents receiving the MRHD of 6 mg/day. In addition, sexual maturation was delayed at all doses in both males and females. The above effects showed little or no reversibility in females after a 12 week drug-free recovery period. Juvenile rats, treated with oral risperidone from days 12 to 50 of age (equivalent to the period of infancy through adolescence in humans) showed impaired learning and memory performance (reversible only in females), with a no-effect dose of 0.63 mg/kg/day which is 0.5 times the MRHD of 6 mg/day for children, based on mg/m 2body surface area. This dose produced plasma AUC of risperidone plus paliperidone about half the exposure observed in humans at the MRHD. No other consistent effects on neurobehavioral or reproductive development were seen up to the highest tested dose of 1.25 mg/kg/day which is 1 time the MRHD and produced plasma AUC of risperidone plus paliperidone that were about two thirds of those observed in humans at the MRHD of 6 mg/day for children.

In an open-label study, 57 clinically stable, elderly patients (≥ 65 years old) with schizophrenia or schizoaffective disorder received RISPERDAL CONSTA every 2 weeks for up to 12 months. In general, no differences in the tolerability of RISPERDAL CONSTA were observed between otherwise healthy elderly and nonelderly patients. Therefore, dosing recommendations for otherwise healthy elderly patients are the same as for nonelderly patients. Because elderly patients exhibit a greater tendency to orthostatic hypotension than nonelderly patients, elderly patients should be instructed in nonpharmacologic interventions that help to reduce the occurrence of orthostatic hypotension (e.g., sitting on the edge of the bed for several minutes before attempting to stand in the morning and slowly rising from a seated position). In addition, monitoring of orthostatic vital signs should be considered in elderly patients for whom orthostatic hypotension is of concern [see Warnings and Precautions (5.7)] .

Concomitant use with Furosemide in Elderly Patients with Dementia-Related Psychosis

In two of four placebo-controlled trials in elderly patients with dementia-related psychosis, a higher incidence of mortality was observed in patients treated with furosemide plus oral risperidone when compared to patients treated with oral risperidone alone or with oral placebo plus furosemide. No pathological mechanism has been identified to explain this finding, and no consistent pattern for cause of death was observed. An increase of mortality in elderly patients with dementia-related psychosis was seen with the use of oral risperidone regardless of concomitant use with furosemide. RISPERDAL CONSTA is not approved for the treatment of patients with dementia-related psychosis. [see Boxed Warningand Warnings and Precautions (5.1)] .

In patients with renal or hepatic impairment, carefully titrate with oral risperidone prior to initiating treatment with RISPERDAL CONSTA [see Dosage and Administration (2.4)].

Patients with renal impairment may have less ability to eliminate risperidone than patients with normal renal function. Patients with impaired hepatic function may have an increase in the free fraction of risperidone, possibly resulting in an enhanced effect [see Clinical Pharmacology (12.3)] .

Patients with Parkinson's Disease or Dementia with Lewy Bodies can experience increased sensitivity to RISPERDAL CONSTA. Manifestations can include confusion, obtundation, postural instability with frequent falls, extrapyramidal symptoms, and clinical features consistent with neuroleptic malignant syndrome.

RISPERDAL CONSTA (risperidone) is not a controlled substance.

RISPERDAL CONSTA has not been systematically studied in animals or humans for its potential for abuse. Because RISPERDAL CONSTA is to be administered by health care professionals, the potential for misuse or abuse by patients is low.

RISPERDAL CONSTA has not been systematically studied in animals or humans for its potential for tolerance or physical dependence.

No cases of overdose were reported in premarketing studies with RISPERDAL CONSTA. Because RISPERDAL CONSTA is to be administered by health care professionals, the potential for overdosage by patients is low.

In premarketing experience with oral RISPERDAL, there were eight reports of acute RISPERDAL overdosage, with estimated doses ranging from 20 to 300 mg and no fatalities. In general, reported signs and symptoms were those resulting from an exaggeration of the drug's known pharmacological effects, i.e., drowsiness and sedation, tachycardia and hypotension, and extrapyramidal symptoms. One case, involving an estimated overdose of 240 mg, was associated with hyponatremia, hypokalemia, prolonged QT, and widened QRS. Another case, involving an estimated overdose of 36 mg, was associated with a seizure.

Postmarketing experience with oral RISPERDAL includes reports of acute overdose, with estimated doses of up to 360 mg. In general, the most frequently reported signs and symptoms are those resulting from an exaggeration of the drug's known pharmacological effects, i.e., drowsiness, sedation, tachycardia, hypotension, and extrapyramidal symptoms. Other adverse reactions reported since market introduction related to oral RISPERDAL overdose include prolonged QT interval and convulsions. Torsade de pointes has been reported in association with combined overdose of oral RISPERDAL and paroxetine.

In case of acute overdosage, 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. If antiarrhythmic therapy is administered, disopyramide, procainamide, and quinidine carry a theoretical hazard of QT prolonging effects that might be additive to those of risperidone. Similarly, it is reasonable to expect that the alpha-blocking properties of bretylium might be additive to those of risperidone, resulting in problematic hypotension.

There is no specific antidote to risperidone. Therefore, appropriate supportive measures should be instituted. The possibility of multiple drug involvement should be considered. Hypotension and circulatory collapse should be treated with appropriate measures, such as intravenous fluids and/or sympathomimetic agents (epinephrine and dopamine should not be used, since beta stimulation may worsen hypotension in the setting of risperidone-induced alpha blockade). In cases of severe extrapyramidal symptoms, anticholinergic medication should be administered. Close medical supervision and monitoring should continue until the patient recovers.

RISPERDAL CONSTA ®contains risperidone, an atypical antipsychotic belonging to the chemical class of benzisoxazole derivatives. The chemical designation is 3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one. Its molecular formula is C 23 H 27 FN 4O 2 and its molecular weight is 410.49. The structural formula is:

{ "type": "p", "children": [], "text": "RISPERDAL CONSTA \n ®contains risperidone, an atypical antipsychotic belonging to the chemical class of benzisoxazole derivatives. The chemical designation is 3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one. Its molecular formula is C\n 23 H\n 27 FN\n 4O\n 2 and its molecular weight is 410.49. The structural formula is:\n " }

Risperidone is practically insoluble in water, freely soluble in methylene chloride, and soluble in methanol and 0.1 NHCl.

{ "type": "p", "children": [], "text": "Risperidone is practically insoluble in water, freely soluble in methylene chloride, and soluble in methanol and 0.1 \n NHCl.\n " }

RISPERDAL CONSTA (risperidone) Long-Acting Injection is a combination of extended-release microspheres for injection and diluent for parenteral use.

{ "type": "p", "children": [], "text": "RISPERDAL CONSTA (risperidone) Long-Acting Injection is a combination of extended-release microspheres for injection and diluent for parenteral use." }

The extended-release microspheres formulation is a white to off-white, free-flowing powder that is available in dosage strengths of 12.5 mg, 25 mg, 37.5 mg, or 50 mg risperidone per vial. Risperidone is micro-encapsulated in 7525 polylactide-co-glycolide (PLG) at a concentration of 381 mg risperidone per gram of microspheres.

{ "type": "p", "children": [], "text": "The extended-release microspheres formulation is a white to off-white, free-flowing powder that is available in dosage strengths of 12.5 mg, 25 mg, 37.5 mg, or 50 mg risperidone per vial. Risperidone is micro-encapsulated in 7525 polylactide-co-glycolide (PLG) at a concentration of 381 mg risperidone per gram of microspheres." }

The diluent for parenteral use is a clear, colorless solution. Composition of the diluent includes 1 mg/mL citric acid anhydrous, 1.27 mg/mL disodium hydrogen phosphate dihydrate, 1 mg/mL polysorbate 20, 22.5 mg/mL sodium carboxymethyl cellulose, 6 mg/mL sodium chloride, 0.54 mg/mL sodium hydroxide, and water for injection. The microspheres are suspended in the diluent prior to injection.

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RISPERDAL CONSTA is provided as a single-use dose pack, consisting of a vial containing the microspheres, a pre-filled syringe containing the diluent, a vial adapter, and two Terumo SurGuard 3 Needles (a 21 G UTW 1-inch needle with needle protection device for deltoid administration and a 20 G TW 2-inch needle with needle protection device for gluteal administration).

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The mechanism of action of risperidone in schizophrenia is unclear. The drug's therapeutic activity in schizophrenia could be mediated through a combination of dopamine Type 2 (D 2) and serotonin Type 2 (5HT 2) receptor antagonism. The clinical effect from risperidone results from the combined concentrations of risperidone and its major active metabolite, 9-hydroxyrisperidone (paliperidone) [see Clinical Pharmacology (12.3)] . Antagonism at receptors other than D 2 and 5HT 2 may explain some of the other effects of risperidone [see Clinical Pharmacology (12.1)] .

Risperidone is a monoaminergic antagonist with high affinity (Ki of 0.12 to 7.3 nM) for the serotonin Type 2 (5HT 2), dopamine Type 2 (D 2), α1 and α2 adrenergic, and H 1 histaminergic receptors. Risperidone showed low to moderate affinity (Ki of 47 to 253 nM) for the serotonin 5HT 1C, 5HT 1D, and 5HT 1A receptors, weak affinity (Ki of 620 to 800 nM) for the dopamine D 1 and haloperidol-sensitive sigma site, and no affinity (when tested at concentrations >10 -5 M) for cholinergic muscarinic or β1 and β2 adrenergic receptors.

Absorption

After a single intramuscular (gluteal) injection of RISPERDAL CONSTA, there is a small initial release of the drug (< 1% of the dose), followed by a lag time of 3 weeks. The main release of the drug starts from 3 weeks onward, is maintained from 4 to 6 weeks, and subsides by 7 weeks following the intramuscular (IM) injection. Therefore, oral antipsychotic supplementation should be given during the first 3 weeks of treatment with RISPERDAL CONSTA to maintain therapeutic levels until the main release of risperidone from the injection site has begun [see Dosage and Administration (2)] . Following single doses of RISPERDAL CONSTA, the pharmacokinetics of risperidone, 9-hydroxyrisperidone (the major metabolite), and risperidone plus 9-hydroxyrisperidone were linear in the dosing range of 12.5 mg to 50 mg.

The combination of the release profile and the dosage regimen (IM injections every 2 weeks) of RISPERDAL CONSTA results in sustained therapeutic concentrations. Steady-state plasma concentrations are reached after 4 injections and are maintained for 4 to 6 weeks after the last injection. Following multiple doses of 25 mg and 50 mg RISPERDAL CONSTA, plasma concentrations of risperidone, 9-hydroxyrisperidone, and risperidone plus 9-hydroxyrisperidone were linear.

Deltoid and gluteal intramuscular injections at the same doses are bioequivalent and, therefore, interchangeable.

Distribution

Once absorbed, risperidone is rapidly distributed. The volume of distribution is 1–2 L/kg. In plasma, risperidone is bound to albumin and α1-acid glycoprotein. The plasma protein binding of risperidone is approximately 90%, and that of its major metabolite, 9-hydroxyrisperidone, is 77%. Neither risperidone nor 9-hydroxyrisperidone displaces each other from plasma binding sites. High therapeutic concentrations of sulfamethazine (100 mcg/mL), warfarin (10 mcg/mL), and carbamazepine (10 mcg/mL) caused only a slight increase in the free fraction of risperidone at 10 ng/mL and of 9-hydroxyrisperidone at 50 ng/mL, changes of unknown clinical significance.

Metabolism and Drug Interactions

Risperidone is extensively metabolized in the liver. The main metabolic pathway is through hydroxylation of risperidone to 9-hydroxyrisperidone by the enzyme, CYP 2D6. A minor metabolic pathway is through N-dealkylation. The main metabolite, 9-hydroxyrisperidone, has similar pharmacological activity as risperidone. Consequently, the clinical effect of the drug results from the combined concentrations of risperidone plus 9-hydroxyrisperidone.

CYP 2D6, also called debrisoquin hydroxylase, is the enzyme responsible for metabolism of many neuroleptics, antidepressants, antiarrhythmics, and other drugs. CYP 2D6 is subject to genetic polymorphism (about 6%–8% of Caucasians, and a very low percentage of Asians, have little or no activity and are "poor metabolizers") and to inhibition by a variety of substrates and some non-substrates, notably quinidine. Extensive CYP 2D6 metabolizers convert risperidone rapidly into 9-hydroxyrisperidone, whereas poor CYP 2D6 metabolizers convert it much more slowly. Although extensive metabolizers have lower risperidone and higher 9-hydroxyrisperidone concentrations than poor metabolizers, the pharmacokinetics of risperidone and 9-hydroxyrisperidone combined, after single and multiple doses, are similar in extensive and poor metabolizers.

The interactions of RISPERDAL CONSTA with coadministration of other drugs have not been systematically evaluated in human subjects. Drug interactions are based primarily on experience with oral RISPERDAL. Risperidone could be subject to two kinds of drug-drug interactions. First, inhibitors of CYP 2D6 interfere with conversion of risperidone to 9-hydroxyrisperidone [see Drug Interactions (7.11)] . This occurs with quinidine, giving essentially all recipients a risperidone pharmacokinetic profile typical of poor metabolizers. The therapeutic benefits and adverse effects of RISPERDAL in patients receiving quinidine have not been evaluated, but observations in a modest number (n≅70) of poor metabolizers given oral RISPERDAL do not suggest important differences between poor and extensive metabolizers. Second, co-administration of carbamazepine and other known enzyme inducers (e.g., phenytoin, rifampin, and phenobarbital) with oral RISPERDAL cause a decrease in the combined plasma concentrations of risperidone and 9-hydroxyrisperidone [see Drug Interactions (7.12)] . It would also be possible for risperidone to interfere with metabolism of other drugs metabolized by CYP 2D6. Relatively weak binding of risperidone to the enzyme suggests this is unlikely [see Drug Interactions (7.11)] .

Excretion

Risperidone and its metabolites are eliminated via the urine and, to a much lesser extent, via the feces. As illustrated by a mass balance study of a single 1 mg oral dose of 14C-risperidone administered as solution to three healthy male volunteers, total recovery of radioactivity at 1 week was 84%, including 70% in the urine and 14% in the feces.

The apparent half-life of risperidone plus 9-hydroxyrisperidone following RISPERDAL CONSTA administration is 3 to 6 days, and is associated with a monoexponential decline in plasma concentrations. This half-life of 3–6 days is related to the erosion of the microspheres and subsequent absorption of risperidone. The clearance of risperidone and risperidone plus 9-hydroxyrisperidone was 13.7 L/h and 5.0 L/h in extensive CYP 2D6 metabolizers, and 3.3 L/h and 3.2 L/h in poor CYP 2D6 metabolizers, respectively. No accumulation of risperidone was observed during long-term use (up to 12 months) in patients treated every 2 weeks with 25 mg or 50 mg RISPERDAL CONSTA. The elimination phase is complete approximately 7 to 8 weeks after the last injection.

Renal Impairment

In patients with moderate to severe renal disease treated with oral RISPERDAL, clearance of the sum of risperidone and its active metabolite decreased by 60% compared with young healthy subjects. Although patients with renal impairment were not studied with RISPERDAL CONSTA, it is recommended that patients with renal impairment be carefully titrated on oral RISPERDAL before treatment with RISPERDAL CONSTA is initiated at a dose of 25 mg. A lower initial dose of 12.5 mg may be appropriate when clinical factors warrant dose adjustment, such as in patients with renal impairment [see Dosage and Administration (2.4)] .

Hepatic Impairment

While the pharmacokinetics of oral RISPERDAL in subjects with liver disease were comparable to those in young healthy subjects, the mean free fraction of risperidone in plasma was increased by about 35% because of the diminished concentration of both albumin and α1-acid glycoprotein. Although patients with hepatic impairment were not studied with RISPERDAL CONSTA, it is recommended that patients with hepatic impairment be carefully titrated on oral RISPERDAL before treatment with RISPERDAL CONSTA is initiated at a dose of 25 mg. A lower initial dose of 12.5 mg may be appropriate when clinical factors warrant dose adjustment, such as in patients with hepatic impairment [see Dosage and Administration (2.4)] .

Elderly

In an open-label trial, steady-state concentrations of risperidone plus 9-hydroxyrisperidone in otherwise healthy elderly patients (≥ 65 years old) treated with RISPERDAL CONSTA for up to 12 months fell within the range of values observed in otherwise healthy nonelderly patients. Dosing recommendations are the same for otherwise healthy elderly patients and nonelderly patients [see Dosage and Administration (2)] .

Race and Gender Effects

No specific pharmacokinetic study was conducted to investigate race and gender effects, but a population pharmacokinetic analysis did not identify important differences in the disposition of risperidone due to gender (whether or not corrected for body weight) or race.

Carcinogenesis - Oral

Risperidone was administered in the diet at doses of 0.63, 2.5, and 10 mg/kg for 18 months to mice and for 25 months to rats. These doses are equivalent to approximately 0.2, 0.75, and 3 times (mice) and 0.4, 1.5, and 6 times (rats) the MRHD of 16 mg/day, based on mg/m 2 body surface area. A maximum tolerated dose was not achieved in male mice. There was a significant increase in pituitary gland adenomas, endocrine pancreatic adenomas, and mammary gland adenocarcinomas. The table below summarizes the multiples of the human dose on mg/m 2 (mg/kg) basis at which these tumors occurred.

<div class="scrollingtable"><table width="90%"> <colgroup> <col align="left" valign="top" width="28%"/> <col align="center" valign="top" width="16%"/> <col align="center" valign="top" width="16%"/> <col align="center" valign="top" width="20%"/> <col align="center" valign="top" width="20%"/> </colgroup> <thead> <tr class="First"> <th align="left"></th><th align="center"></th><th align="center"></th><th align="center" class="Botrule" colspan="2">Multiples of Maximum Human Dose in mg/m <span class="Sup">2 </span>(mg/kg) </th> </tr> <tr class="Last"> <th align="left">Tumor Type</th><th align="center">Species</th><th align="center">Sex</th><th align="center">Lowest Effect Level</th><th align="center">Highest No-Effect Level</th> </tr> </thead> <tbody> <tr class="First"> <td align="left">Pituitary adenomas</td><td align="center">mouse</td><td align="center">Female</td><td align="center">0.75 (9.4)</td><td align="center">0.2 (2.4)</td> </tr> <tr> <td align="left">Endocrine pancreas adenomas</td><td align="center">rat</td><td align="center">Male</td><td align="center">1.5 (9.4)</td><td align="center">0.4 (2.4)</td> </tr> <tr> <td align="left">Mammary gland adenocarcinomas</td><td align="center">mouse</td><td align="center">Female</td><td align="center">0.2 (2.4)</td><td align="center">none</td> </tr> <tr> <td align="left"></td><td align="center">rat</td><td align="center">Female</td><td align="center">0.4 (2.4)</td><td align="center">none</td> </tr> <tr> <td align="left"></td><td align="center">rat</td><td align="center">Male</td><td align="center">6.0 (37.5)</td><td align="center">1.5 (9.4)</td> </tr> <tr class="Last"> <td align="left">Mammary gland neoplasm, Total</td><td align="center">rat</td><td align="center">Male</td><td align="center">1.5 (9.4)</td><td align="center">0.4 (2.4)</td> </tr> </tbody> </table></div>

Antipsychotic drugs have been shown to chronically elevate prolactin levels in rodents. Serum prolactin levels were not measured during the risperidone carcinogenicity studies; however, measurements during subchronic toxicity studies showed that risperidone elevated serum prolactin levels 5–6 fold in mice and rats at the same doses used in the carcinogenicity studies. An increase in mammary, pituitary, and endocrine pancreas 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 findings of prolactin-mediated endocrine tumors in rodents is unclear [see Warnings and Precautions (5.6)] .

Carcinogenesis - Intramuscular

Risperidone was evaluated in a 24-month carcinogenicity study in which SPF Wistar rats were treated every 2 weeks with intramuscular (IM) injections of either 5 mg/kg or 40 mg/kg of risperidone. These doses are 1 and 8 times the MRHD (50 mg) on a mg/m 2 basis. A control group received injections of 0.9% NaCl, and a vehicle control group was injected with placebo microspheres. There was a significant increase in pituitary gland adenomas, endocrine pancreas adenomas, and adrenomedullary pheochromocytomas at 8 times the IM MRHD on a mg/m 2 basis. The incidence of mammary gland adenocarcinomas was significantly increased in female rats at both doses (1 and 8 times the IM MRHD on a mg/m 2 basis). A significant increase in renal tubular tumors (adenoma, adenocarcinomas) was observed in male rats at 8 times the IM MRHD on a mg/m 2 basis. Plasma exposures (AUC) in rats were 0.3 and 2 times (at 5 and 40 mg/kg, respectively) the expected plasma exposure (AUC) at the IM MRHD.

Dopamine D 2 receptor antagonists have been shown to chronically elevate prolactin levels in rodents. Serum prolactin levels were not measured during the carcinogenicity studies of oral risperidone; however, measurements taken during subchronic toxicity studies showed that oral risperidone elevated serum prolactin levels 5- to 6-fold in mice and rats at the same doses used in the oral carcinogenicity studies. Serum prolactin levels increased in a dose-dependent manner up to 6- and 1.5-fold in male and female rats, respectively, at the end of the 24-month treatment with risperidone every 2 weeks IM. Increases in the incidence of pituitary gland, endocrine pancreas, and mammary gland neoplasms have been found in rodents after chronic administration of other antipsychotic drugs and may be prolactin-mediated.

The relevance for human risk of the findings of prolactin-mediated endocrine tumors in rodents is unknown [see Warnings and Precautions (5.6)] .

Mutagenesis

No evidence of mutagenic or clastogenic potential for risperidone was found in the in vitrotests of Ames gene mutation, the mouse lymphoma assay, rat hepatocyte DNA-repair assay, the chromosomal aberration test in human lymphocytes, Chinese hamster ovary cells, or in the in vivomicronucleus test in mice, and the sex-linked recessive lethal test in Drosophila.

In addition, no evidence of mutagenic potential was found in the in vitroAmes reverse mutation test for RISPERDAL CONSTA.

Impairment of Fertility

Oral risperidone (0.16 to 5 mg/kg) impaired mating, but not fertility, in rat reproductive studies at doses 0.1 to 3 times the oral maximum recommended human dose (MRHD of 16 mg/day) based on mg/m 2 body surface area. The effect appeared to be in females, since impaired mating behavior was not noted in the male fertility study. In a subchronic study in Beagle dogs in which oral risperidone was administered at doses of 0.31 to 5 mg/kg, sperm motility and concentration were decreased at doses 0.6 to 10 times the oral MRHD on mg/m 2 basis. Dose-related decreases were also noted in serum testosterone at the same doses. Serum testosterone and sperm parameters partially recovered, but remained decreased after treatment was discontinued. A no-effect dose could not be determined in either rat or dog.

The effectiveness of RISPERDAL CONSTA in the treatment of schizophrenia was established, in part, on the basis of extrapolation from the established effectiveness of the oral formulation of risperidone. In addition, the effectiveness of RISPERDAL CONSTA in the treatment of schizophrenia was established in a 12-week, placebo-controlled trial in adult psychotic inpatients and outpatients who met the DSM-IV criteria for schizophrenia.

Efficacy data were obtained from 400 patients with schizophrenia who were randomized to receive injections of 25 mg, 50 mg, or 75 mg RISPERDAL CONSTA or placebo every 2 weeks. During a 1-week run-in period, patients were discontinued from other antipsychotics and were titrated to a dose of 4 mg oral RISPERDAL. Patients who received RISPERDAL CONSTA were given doses of oral RISPERDAL (2 mg for patients in the 25-mg group, 4 mg for patients in the 50-mg group, and 6 mg for patients in the 75-mg group) for the 3 weeks after the first injection to provide therapeutic plasma concentrations until the main release phase of risperidone from the injection site had begun. Patients who received placebo injections were given placebo tablets.

Efficacy was evaluated using the Positive and Negative Syndrome Scale (PANSS), a validated, multi-item inventory, composed of five subscales to evaluate positive symptoms, negative symptoms, disorganized thoughts, uncontrolled hostility/excitement, and anxiety/depression.

The primary efficacy variable in this trial was change from baseline to endpoint in the total PANSS score. The mean total PANSS score at baseline for schizophrenic patients in this study was 81.5.

Total PANSS scores showed significant improvement in the change from baseline to endpoint in schizophrenic patients treated with each dose of RISPERDAL CONSTA (25 mg, 50 mg, or 75 mg) compared with patients treated with placebo. While there were no statistically significant differences between the treatment effects for the three dose groups, the effect size for the 75 mg dose group was actually numerically less than that observed for the 50 mg dose group.

Subgroup analyses did not indicate any differences in treatment outcome as a function of age, race, or gender.

The effectiveness of RISPERDAL CONSTA for the maintenance treatment of Bipolar I Disorder was established in a multicenter, double-blind, placebo-controlled study of adult patients who met DSM-IV criteria for Bipolar Disorder Type I, who were stable on medications or experiencing an acute manic or mixed episode.

A total of 501 patients were treated during a 26-week open-label period with RISPERDAL CONSTA (starting dose of 25 mg, and titrated, if deemed clinically desirable, to 37.5 mg or 50 mg; in patients not tolerating the 25 mg dose, the dose could be reduced to 12.5 mg). In the open-label phase, 303 (60%) patients were judged to be stable and were randomized to double-blind treatment with either the same dose of RISPERDAL CONSTA or placebo and monitored for relapse. The primary endpoint was time to relapse to any mood episode (depression, mania, hypomania, or mixed).

Time to relapse was delayed in patients receiving RISPERDAL CONSTA monotherapy as compared to placebo. The majority of relapses were due to manic rather than depressive symptoms. Based on their bipolar disorder history, subjects entering this study had had, on average, more manic episodes than depressive episodes.

The effectiveness of RISPERDAL CONSTA as an adjunct to treatment with lithium or valproate for the maintenance treatment of Bipolar Disorder was established in a multi-center, randomized, double-blind, placebo-controlled study of adult patients who met DSM-IV criteria for Bipolar Disorder Type I and who experienced at least 4 episodes of mood disorder requiring psychiatric/clinical intervention in the previous 12 months, including at least 2 episodes in the 6 months prior to the start of the study.

A total of 240 patients were treated during a 16-week open-label period with RISPERDAL CONSTA (starting dose of 25 mg, and titrated, if deemed clinically desirable, to 37.5 mg or 50 mg), as adjunctive therapy in addition to continuing their treatment as usual for their bipolar disorder, which consisted of mood stabilizers (primarily lithium and valproate), antidepressants, and/or anxiolytics. All oral antipsychotics were discontinued after the first three weeks of the initial RISPERDAL CONSTA injection. In the open-label phase, 124 (51.7%) were judged to be stable for at least the last 4 weeks and were randomized to double-blind treatment with either the same dose of RISPERDAL CONSTA or placebo in addition to continuing their treatment as usual and monitored for relapse during a 52-week period. The primary endpoint was time to relapse to any new mood episode (depression, mania, hypomania, or mixed).

Time to relapse was delayed in patients receiving adjunctive therapy with RISPERDAL CONSTA as compared to placebo. The relapse types were about half depressive and half manic or mixed episodes.

Storage and Handling

The entire dose pack should be stored in the refrigerator (36 °F to 46 °F; 2 °C to 8 °C) and protected from light.

If refrigeration is unavailable, RISPERDAL CONSTA can be stored at temperatures not exceeding 77 °F (25 °C) for no more than 7 days prior to administration. Do not expose unrefrigerated product to temperatures above 77 °F (25 °C).

Keep out of reach of children.

Neuroleptic Malignant Syndrome (NMS)

Counsel patients about a potentially fatal adverse reaction, Neuroleptic Malignant Syndrome (NMS), that has been reported in association with administration of antipsychotic drugs. Advise patients, family members, or caregivers to contact the healthcare provider or report to the emergency room if they experience signs and symptoms of NMS, including hyperpyrexia, muscle rigidity, altered mental status including delirium, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia) [see Warnings and Precautions (5.3)] .

Tardive Dyskinesia

Counsel patients on the signs and symptoms of tardive dyskinesia and to contact their healthcare provider if these abnormal movements occur [see Warnings and Precautions (5.4)] .

Metabolic Changes

Educate patients about the risk of metabolic changes, how to recognize symptoms of hyperglycemia and diabetes mellitus and the need for specific monitoring, including blood glucose, lipids, and weight [see Warnings and Precautions (5.5)] .

Orthostatic Hypotension

Educate patients about the risk of orthostatic hypotension and syncope, particularly at the time of initiating treatment, re-initiating treatment, or increasing the dose. [see Warnings and Precautions (5.7)] .

Leukopenia/Neutropenia

Advise patients with a pre-existing low WBC or a history of drug induced leukopenia/neutropenia that they should have their CBC monitored while being treated with RISPERDAL CONSTA [see Warnings and Precautions (5.9)] .

Hyperprolactinemia

Counsel patients on signs and symptoms of hyperprolactinemia that may be associated with chronic use of RISPERDAL CONSTA. Advise them to seek medical attention if they experience any of the following: amenorrhea or galactorrhea in females, erectile dysfunction or gynecomastia in males. [See Warnings and Precautions (5.6)] .

Interference with Cognitive and Motor Performance

Caution patients about performing activities requiring mental alertness, such as operating hazardous machinery, or operating a motor vehicle, until they are reasonably certain that RISPERDAL CONSTA therapy does not affect them adversely [see Warnings and Precautions (5.10)] .

Priapism

Advise patients of the possibility of painful or prolonged penile erections (priapism). Instruct the patient to seek immediate medical attention in the event of priapism [Warnings and Precautions (5.13)].

Heat Exposure and Dehydration

Counsel patients regarding appropriate care in avoiding overheating and dehydration [see Warnings and Precautions (5.14)] .

Concomitant Medication

Advise patients to inform their healthcare providers if they are taking, or plan to take any prescription or over-the-counter drugs, as there is a potential for interactions [see Drug Interactions (7)] .

Alcohol

Advise patients to avoid alcohol during treatment with RISPERDAL CONSTA [see Drug Interactions (7.1)] .

Pregnancy

Advise patients to notify their healthcare provider if they become pregnant or intend to become pregnant during treatment with RISPERDAL CONSTA. Advise patients that RISPERDAL CONSTA may cause extrapyramidal and/or withdrawal symptoms in a neonate. Advise patients that there is a pregnancy registry that monitors pregnancy outcomes in women exposed to RISPERDAL CONSTA during pregnancy [see Use in Specific Populations (8.1)] .

Lactation

Advise breastfeeding women using RISPERDAL CONSTA to monitor infants for somnolence, failure to thrive, jitteriness, 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 RISPERDAL CONSTA may impair fertility due to an increase in serum prolactin levels. The effects on fertility are reversible [see Use in Specific Populations (8.3)].

Manufactured for: Janssen Pharmaceuticals, Inc. Titusville, NJ 08560, USA

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For patent information: www.janssenpatents.com

{ "type": "p", "children": [], "text": "For patent information: www.janssenpatents.com" }

© Johnson & Johnson and its affiliates 2007

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RISPERDAL CONSTA® (risperidone) Long-Acting Injection 12.5 mg, 25 mg, 37.5 mg, 50 mg

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For deltoid or gluteal intramuscular injection only Each injection should be administered by a healthcare professional.

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IMPORTANT RESOURCES For additional information, visit www.risperdalconsta.com or call Janssen Pharmaceuticals, Inc. at 1-800-526-7736.

{ "type": "p", "children": [], "text": "IMPORTANT RESOURCES\n \nFor additional information, visit www.risperdalconsta.com or call Janssen Pharmaceuticals, Inc. at 1-800-526-7736.\n " }

Manufactured for: Janssen Pharmaceuticals, Inc. Titusville, NJ 08560, USA

{ "type": "p", "children": [], "text": "Manufactured for:\n \nJanssen Pharmaceuticals, Inc.\n \nTitusville, NJ 08560, USA\n " }

For patent information: www.janssenpatents.com

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© Johnson & Johnson and its affiliates 2007

{ "type": "p", "children": [], "text": "© Johnson & Johnson and its affiliates 2007" }

Revised: 4/2025

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Instructions for use

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RISPERDAL CONSTA ® requires close attention to these step-by-step Instructions for Use to help ensure successful administration.

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SINGLE-USE DEVICE

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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.

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Important Information

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Use components provided

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The components in this dose pack are specifically designed for use with RISPERDAL CONSTA ®. RISPERDAL CONSTA ® must be reconstituted only in the diluent supplied in the dose pack.

{ "type": "p", "children": [], "text": "The components in this dose pack are specifically designed for use with RISPERDAL CONSTA\n ®. RISPERDAL CONSTA\n ® must be reconstituted only in the diluent supplied in the dose pack.\n " }

Do not substitute ANY components of the dose pack.

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Do not store suspension after reconstitution

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Administer dose as soon as possible after reconstitution to avoid settling.

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Proper dosing

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The entire contents of the vial must be administered to ensure intended dose of RISPERDAL CONSTA ®is delivered.

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Dose pack contents

{ "type": "p", "children": [], "text": "\nDose pack contents\n" }

<div class="scrollingtable"><table class="Noautorules" width="100%"> <colgroup> <col align="left" valign="top" width="25%"/> <col align="left" valign="top" width="25%"/> <col align="left" valign="top" width="25%"/> <col align="left" valign="top" width="25%"/> </colgroup> <thead> <tr> <th align="left" colspan="4">Step 1 Assemble components</th> </tr> <tr class="Botrule"> <th align="left">Take out dose pack</th><th align="left" colspan="3">Connect vial adapter to vial</th> </tr> </thead> <tbody> <tr> <td align="left"> <p class="First"> <img alt="Figure" src="/dailymed/image.cfm?name=risperdal-29.jpg&amp;setid=bb34ee82-d2c2-43b8-ba21-2825c0954691"/></p> </td><td align="left"> <p class="First"> <img alt="Figure" src="/dailymed/image.cfm?name=risperdal-30.jpg&amp;setid=bb34ee82-d2c2-43b8-ba21-2825c0954691"/></p> </td><td align="left"> <p class="First"> <img alt="Figure" src="/dailymed/image.cfm?name=risperdal-31.jpg&amp;setid=bb34ee82-d2c2-43b8-ba21-2825c0954691"/></p> </td><td align="left"> <p class="First"> <img alt="Figure" src="/dailymed/image.cfm?name=risperdal-32.jpg&amp;setid=bb34ee82-d2c2-43b8-ba21-2825c0954691"/></p> </td> </tr> <tr> <td align="left"><span class="Bold">Wait 30 minutes</span> <br/> Remove dose pack from the refrigerator and allow to sit at room temperature for at least <span class="Bold">30 minutes </span>before reconstituting. <br/> <br/> <span class="Bold">Do not </span>warm any other way. </td><td align="left"><span class="Bold">Remove cap from vial</span> <br/> Flip off colored cap from vial. <br/> <br/> Wipe top of the grey stopper with an <span class="Underline">alcohol swab</span>. Allow to air dry. <br/> <br/> <span class="Bold">Do not </span>remove grey rubber stopper. </td><td align="left"><span class="Bold">Prepare vial adapter</span> <br/> Hold sterile blister as shown. Peel back and remove paper backing. <br/> <br/> <span class="Bold">Do not </span>remove vial adapter from blister. <br/> <br/> <span class="Bold">Do not </span>touch spike tip at any time. This will result in contamination. </td><td align="left"><span class="Bold">Connect vial adapter to vial</span> <br/> Place vial on a hard surface and hold by the base. Center vial adapter over the grey rubber stopper. Push vial adapter straight down onto vial top until it snaps securely into place. <br/> <br/> <span class="Bold">Do not </span>place vial adapter on at an angle or diluent may leak upon transfer to the vial. <p class="First"> <img alt="Figure" src="/dailymed/image.cfm?name=risperdal-33.jpg&amp;setid=bb34ee82-d2c2-43b8-ba21-2825c0954691"/></p> </td> </tr> <tr class="Botrule"> <td align="left" colspan="4"><span class="Bold">Connect prefilled syringe to vial adapter</span></td> </tr> <tr> <td align="left"> <p class="First"> <img alt="Figure" src="/dailymed/image.cfm?name=risperdal-34.jpg&amp;setid=bb34ee82-d2c2-43b8-ba21-2825c0954691"/></p> </td><td align="left"> <p class="First"> <img alt="Figure" src="/dailymed/image.cfm?name=risperdal-35.jpg&amp;setid=bb34ee82-d2c2-43b8-ba21-2825c0954691"/></p> </td><td align="left"> <p class="First"> <img alt="Figure" src="/dailymed/image.cfm?name=risperdal-36.jpg&amp;setid=bb34ee82-d2c2-43b8-ba21-2825c0954691"/></p> </td><td align="left"> <p class="First"> <img alt="Figure" src="/dailymed/image.cfm?name=risperdal-37.jpg&amp;setid=bb34ee82-d2c2-43b8-ba21-2825c0954691"/></p> </td> </tr> <tr> <td align="left"><span class="Bold">Remove sterile blister</span> <p class="First"> <img alt="Figure" src="/dailymed/image.cfm?name=risperdal-38.jpg&amp;setid=bb34ee82-d2c2-43b8-ba21-2825c0954691"/></p> <br/> Keep vial vertical to prevent leakage. <br/> Hold base of vial and pull up on the sterile blister to remove. <br/> <br/> <span class="Bold">Do not </span>shake. <br/> <br/> <span class="Bold">Do not </span>touch exposed luer opening on vial adapter. <br/> This will result in contamination. </td><td align="left"><span class="Bold">Use proper grip</span> <br/> Hold by white collar at the tip of the syringe. <br/> <br/> <span class="Bold">Do not </span>hold syringe by the glass barrel during assembly. <p class="First"> <img alt="Figure" src="/dailymed/image.cfm?name=risperdal-39.jpg&amp;setid=bb34ee82-d2c2-43b8-ba21-2825c0954691"/></p> </td><td align="left"><span class="Bold">Remove cap</span> <br/> Holding the white collar, snap off the white cap. <br/> <br/> <span class="Bold">Do not </span>twist or cut off the white cap. <br/> <br/> <span class="Bold">Do not </span>touch syringe tip. This will result in contamination. <p class="First"> <img alt="Figure" src="/dailymed/image.cfm?name=risperdal-40.jpg&amp;setid=bb34ee82-d2c2-43b8-ba21-2825c0954691"/></p> The broken-off cap can be discarded. </td><td align="left"><span class="Bold">Connect syringe to vial adapter</span> <br/> Hold vial adapter by skirt to keep stationary. <br/> <br/> <span class="Bold">Hold syringe by white collar</span>then insert tip into the luer opening of the vial adapter. <br/> <br/> <span class="Bold">Do not </span>hold the glass syringe barrel. This may cause the white collar to loosen or detach. <br/> <br/> Attach the syringe to the vial adapter with a firm <span class="Bold"><span class="Underline">clockwise twisting motion</span></span>until it feels snug. <br/> <br/> <span class="Bold">Do not </span>over-tighten. Over-tightening may cause the syringe tip to break. </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table class=\"Noautorules\" width=\"100%\">\n<colgroup>\n<col align=\"left\" valign=\"top\" width=\"25%\"/>\n<col align=\"left\" valign=\"top\" width=\"25%\"/>\n<col align=\"left\" valign=\"top\" width=\"25%\"/>\n<col align=\"left\" valign=\"top\" width=\"25%\"/>\n</colgroup>\n<thead>\n<tr>\n<th align=\"left\" colspan=\"4\">Step 1 Assemble components</th>\n</tr>\n<tr class=\"Botrule\">\n<th align=\"left\">Take out dose pack</th><th align=\"left\" colspan=\"3\">Connect vial adapter to vial</th>\n</tr>\n</thead>\n<tbody>\n<tr>\n<td align=\"left\">\n<p class=\"First\">\n<img alt=\"Figure\" src=\"/dailymed/image.cfm?name=risperdal-29.jpg&amp;setid=bb34ee82-d2c2-43b8-ba21-2825c0954691\"/></p>\n</td><td align=\"left\">\n<p class=\"First\">\n<img alt=\"Figure\" src=\"/dailymed/image.cfm?name=risperdal-30.jpg&amp;setid=bb34ee82-d2c2-43b8-ba21-2825c0954691\"/></p>\n</td><td align=\"left\">\n<p class=\"First\">\n<img alt=\"Figure\" src=\"/dailymed/image.cfm?name=risperdal-31.jpg&amp;setid=bb34ee82-d2c2-43b8-ba21-2825c0954691\"/></p>\n</td><td align=\"left\">\n<p class=\"First\">\n<img alt=\"Figure\" src=\"/dailymed/image.cfm?name=risperdal-32.jpg&amp;setid=bb34ee82-d2c2-43b8-ba21-2825c0954691\"/></p>\n</td>\n</tr>\n<tr>\n<td align=\"left\"><span class=\"Bold\">Wait 30 minutes</span>\n<br/>\n\t\t\tRemove dose pack from the refrigerator and allow to sit at room temperature for at least \n <span class=\"Bold\">30 minutes </span>before reconstituting.\n <br/>\n<br/>\n<span class=\"Bold\">Do not </span>warm any other way.\n </td><td align=\"left\"><span class=\"Bold\">Remove cap from vial</span>\n<br/>\n\t\t\tFlip off colored cap from vial.\n <br/>\n<br/>\n\t\t\tWipe top of the grey stopper with an \n <span class=\"Underline\">alcohol swab</span>. Allow to air dry.\n <br/>\n<br/>\n<span class=\"Bold\">Do not </span>remove grey rubber stopper.\n </td><td align=\"left\"><span class=\"Bold\">Prepare vial adapter</span>\n<br/>\n\t\t\tHold sterile blister as shown. Peel back and remove paper backing.\n <br/>\n<br/>\n<span class=\"Bold\">Do not </span>remove vial adapter from blister.\n <br/>\n<br/>\n<span class=\"Bold\">Do not </span>touch spike tip at any time. This will result in contamination.\n </td><td align=\"left\"><span class=\"Bold\">Connect vial adapter to vial</span>\n<br/>\n\t\t\tPlace vial on a hard surface and hold by the base. Center vial adapter over the grey rubber stopper. Push vial adapter straight down onto vial top until it snaps securely into place.\n <br/>\n<br/>\n<span class=\"Bold\">Do not </span>place vial adapter on at an angle or diluent may leak upon transfer to the vial.\n\t\t\t\n <p class=\"First\">\n<img alt=\"Figure\" src=\"/dailymed/image.cfm?name=risperdal-33.jpg&amp;setid=bb34ee82-d2c2-43b8-ba21-2825c0954691\"/></p>\n</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" colspan=\"4\"><span class=\"Bold\">Connect prefilled syringe to vial adapter</span></td>\n</tr>\n<tr>\n<td align=\"left\">\n<p class=\"First\">\n<img alt=\"Figure\" src=\"/dailymed/image.cfm?name=risperdal-34.jpg&amp;setid=bb34ee82-d2c2-43b8-ba21-2825c0954691\"/></p>\n</td><td align=\"left\">\n<p class=\"First\">\n<img alt=\"Figure\" src=\"/dailymed/image.cfm?name=risperdal-35.jpg&amp;setid=bb34ee82-d2c2-43b8-ba21-2825c0954691\"/></p>\n</td><td align=\"left\">\n<p class=\"First\">\n<img alt=\"Figure\" src=\"/dailymed/image.cfm?name=risperdal-36.jpg&amp;setid=bb34ee82-d2c2-43b8-ba21-2825c0954691\"/></p>\n</td><td align=\"left\">\n<p class=\"First\">\n<img alt=\"Figure\" src=\"/dailymed/image.cfm?name=risperdal-37.jpg&amp;setid=bb34ee82-d2c2-43b8-ba21-2825c0954691\"/></p>\n</td>\n</tr>\n<tr>\n<td align=\"left\"><span class=\"Bold\">Remove sterile blister</span>\n<p class=\"First\">\n<img alt=\"Figure\" src=\"/dailymed/image.cfm?name=risperdal-38.jpg&amp;setid=bb34ee82-d2c2-43b8-ba21-2825c0954691\"/></p>\n<br/>\n\t\t\tKeep vial vertical to prevent leakage.\n <br/>\n\t\t\tHold base of vial and pull up on the sterile blister to remove.\n <br/>\n<br/>\n<span class=\"Bold\">Do not </span>shake.\n <br/>\n<br/>\n<span class=\"Bold\">Do not </span>touch exposed luer opening on vial adapter.\n <br/>\n\t\t\tThis will result in contamination.\n </td><td align=\"left\"><span class=\"Bold\">Use proper grip</span>\n<br/>\n\t\t\tHold by white collar at the tip of the syringe.\n <br/>\n<br/>\n<span class=\"Bold\">Do not </span>hold syringe by the glass barrel during assembly.\n\t\t\t\n <p class=\"First\">\n<img alt=\"Figure\" src=\"/dailymed/image.cfm?name=risperdal-39.jpg&amp;setid=bb34ee82-d2c2-43b8-ba21-2825c0954691\"/></p>\n</td><td align=\"left\"><span class=\"Bold\">Remove cap</span>\n<br/>\n\t\t\tHolding the white collar, snap off the white cap.\n <br/>\n<br/>\n<span class=\"Bold\">Do not </span>twist or cut off the white cap.\n <br/>\n<br/>\n<span class=\"Bold\">Do not </span>touch syringe tip. This will result in contamination.\n\t\t\t\n <p class=\"First\">\n<img alt=\"Figure\" src=\"/dailymed/image.cfm?name=risperdal-40.jpg&amp;setid=bb34ee82-d2c2-43b8-ba21-2825c0954691\"/></p>\n\t\t\tThe broken-off cap can be discarded.\n </td><td align=\"left\"><span class=\"Bold\">Connect syringe to vial adapter</span>\n<br/>\n\t\t\tHold vial adapter by skirt to keep stationary.\n <br/>\n<br/>\n<span class=\"Bold\">Hold syringe by white collar</span>then insert tip into the luer opening of the vial adapter.\n <br/>\n<br/>\n<span class=\"Bold\">Do not </span>hold the glass syringe barrel. This may cause the white collar to loosen or detach.\n <br/>\n<br/>\n\t\t\tAttach the syringe to the vial adapter with a firm \n <span class=\"Bold\"><span class=\"Underline\">clockwise twisting motion</span></span>until it feels snug.\n <br/>\n<br/>\n<span class=\"Bold\">Do not </span>over-tighten. Over-tightening may cause the syringe tip to break.\n </td>\n</tr>\n</tbody>\n</table></div>" }

<div class="scrollingtable"><table class="Noautorules" width="100%"> <colgroup> <col align="left" valign="top" width="25%"/> <col align="left" valign="top" width="25%"/> <col align="left" valign="top" width="25%"/> <col align="left" valign="top" width="25%"/> </colgroup> <thead> <tr> <th align="left" colspan="4">Step 2 Reconstitute microspheres</th> </tr> </thead> <tbody> <tr> <td align="left"> <p class="First"> <img alt="Figure" src="/dailymed/image.cfm?name=risperdal-41.jpg&amp;setid=bb34ee82-d2c2-43b8-ba21-2825c0954691"/></p> </td><td align="left"> <p class="First"> <img alt="Figure" src="/dailymed/image.cfm?name=risperdal-42.jpg&amp;setid=bb34ee82-d2c2-43b8-ba21-2825c0954691"/></p> </td><td align="left"> <p class="First"> <img alt="Figure" src="/dailymed/image.cfm?name=risperdal-43.jpg&amp;setid=bb34ee82-d2c2-43b8-ba21-2825c0954691"/></p> </td><td align="left"> <p class="First"> <img alt="Figure" src="/dailymed/image.cfm?name=risperdal-44.jpg&amp;setid=bb34ee82-d2c2-43b8-ba21-2825c0954691"/></p> </td> </tr> <tr> <td align="left"><span class="Bold">Inject diluent</span> <br/> Inject entire amount of diluent from syringe into the vial. <p class="First"> <img alt="Figure" src="/dailymed/image.cfm?name=risperdal-45.jpg&amp;setid=bb34ee82-d2c2-43b8-ba21-2825c0954691"/></p> </td><td align="left"><span class="Bold">Suspend microspheres in diluent</span> <br/> Continuing to hold down the plunger rod, <span class="Bold">shake vigorously for at least 10 seconds</span>, as shown. <br/> <br/> <span class="Underline">Check the suspension</span>. When properly mixed, the suspension appears uniform, thick and milky in color. Microspheres will be visible in the liquid. <br/> <br/> Immediately proceed to the next step so suspension does not settle. </td><td align="left"><span class="Bold">Transfer suspension to syringe</span> <br/> Invert vial completely. Slowly pull plunger rod down to withdraw entire contents from the vial into the syringe. </td><td align="left"><span class="Bold">Remove vial adapter</span> <br/> Hold white collar on the syringe and unscrew from vial adapter. <br/> <br/> Tear section of the vial label at the perforation. Apply detached label to the syringe for identification purposes. <br/> <br/> Discard both vial and vial adapter appropriately. </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table class=\"Noautorules\" width=\"100%\">\n<colgroup>\n<col align=\"left\" valign=\"top\" width=\"25%\"/>\n<col align=\"left\" valign=\"top\" width=\"25%\"/>\n<col align=\"left\" valign=\"top\" width=\"25%\"/>\n<col align=\"left\" valign=\"top\" width=\"25%\"/>\n</colgroup>\n<thead>\n<tr>\n<th align=\"left\" colspan=\"4\">Step 2 Reconstitute microspheres</th>\n</tr>\n</thead>\n<tbody>\n<tr>\n<td align=\"left\">\n<p class=\"First\">\n<img alt=\"Figure\" src=\"/dailymed/image.cfm?name=risperdal-41.jpg&amp;setid=bb34ee82-d2c2-43b8-ba21-2825c0954691\"/></p>\n</td><td align=\"left\">\n<p class=\"First\">\n<img alt=\"Figure\" src=\"/dailymed/image.cfm?name=risperdal-42.jpg&amp;setid=bb34ee82-d2c2-43b8-ba21-2825c0954691\"/></p>\n</td><td align=\"left\">\n<p class=\"First\">\n<img alt=\"Figure\" src=\"/dailymed/image.cfm?name=risperdal-43.jpg&amp;setid=bb34ee82-d2c2-43b8-ba21-2825c0954691\"/></p>\n</td><td align=\"left\">\n<p class=\"First\">\n<img alt=\"Figure\" src=\"/dailymed/image.cfm?name=risperdal-44.jpg&amp;setid=bb34ee82-d2c2-43b8-ba21-2825c0954691\"/></p>\n</td>\n</tr>\n<tr>\n<td align=\"left\"><span class=\"Bold\">Inject diluent</span>\n<br/>\n\t\t\tInject entire amount of diluent from syringe into the vial.\n\t\t\t\n <p class=\"First\">\n<img alt=\"Figure\" src=\"/dailymed/image.cfm?name=risperdal-45.jpg&amp;setid=bb34ee82-d2c2-43b8-ba21-2825c0954691\"/></p>\n</td><td align=\"left\"><span class=\"Bold\">Suspend microspheres in diluent</span>\n<br/>\n\t\t\tContinuing to hold down the plunger rod, \n <span class=\"Bold\">shake vigorously for at least 10 seconds</span>, as shown.\n <br/>\n<br/>\n<span class=\"Underline\">Check the suspension</span>. When properly mixed, the suspension appears uniform, thick and milky in color. Microspheres will be visible in the liquid.\n <br/>\n<br/>\n\t\t\tImmediately proceed to the next step so suspension does not settle.\n </td><td align=\"left\"><span class=\"Bold\">Transfer suspension to syringe</span>\n<br/>\n\t\t\tInvert vial completely. Slowly pull plunger rod down to withdraw entire contents from the vial into the syringe.\n </td><td align=\"left\"><span class=\"Bold\">Remove vial adapter</span>\n<br/>\n\t\t\tHold white collar on the syringe and unscrew from vial adapter.\n <br/>\n<br/>\n\t\t\tTear section of the vial label at the perforation. Apply detached label to the syringe for identification purposes.\n <br/>\n<br/>\n\t\t\tDiscard both vial and vial adapter appropriately.\n </td>\n</tr>\n</tbody>\n</table></div>" }

<div class="scrollingtable"><table class="Noautorules" width="100%"> <colgroup> <col align="left" valign="top" width="34%"/> <col align="left" valign="top" width="33%"/> <col align="left" valign="top" width="33%"/> </colgroup> <thead> <tr> <th align="left" colspan="3">Step 3 Attach needle</th> </tr> </thead> <tbody> <tr> <td align="left"> <p class="First"> <img alt="Figure" src="/dailymed/image.cfm?name=risperdal-46.jpg&amp;setid=bb34ee82-d2c2-43b8-ba21-2825c0954691"/></p> </td><td align="left"> <p class="First"> <img alt="Figure" src="/dailymed/image.cfm?name=risperdal-47.jpg&amp;setid=bb34ee82-d2c2-43b8-ba21-2825c0954691"/></p> </td><td align="left"> <p class="First"> <img alt="Figure" src="/dailymed/image.cfm?name=risperdal-48.jpg&amp;setid=bb34ee82-d2c2-43b8-ba21-2825c0954691"/></p> </td> </tr> <tr> <td align="left"><span class="Bold">Select appropriate needle</span> <br/> Choose needle based on injection location (gluteal or deltoid). </td><td align="left"><span class="Bold">Attach needle</span> <br/> Peel blister pouch open part way and use to grasp the base of the needle, as shown. <br/> <br/> <span class="Bold">Holding the white collar on the syringe</span>, attach syringe to needle luer connection with a firm <span class="Bold"><span class="Underline">clockwise twisting motion</span></span>until snug. <br/> <br/> <span class="Bold">Do not </span>touch needle luer opening. This will result in contamination. </td><td align="left"><span class="Bold">Resuspend microspheres</span> <br/> Fully remove the blister pouch. <br/> <br/> Just before injection, shake syringe vigorously again, as some settling will have occurred. </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table class=\"Noautorules\" width=\"100%\">\n<colgroup>\n<col align=\"left\" valign=\"top\" width=\"34%\"/>\n<col align=\"left\" valign=\"top\" width=\"33%\"/>\n<col align=\"left\" valign=\"top\" width=\"33%\"/>\n</colgroup>\n<thead>\n<tr>\n<th align=\"left\" colspan=\"3\">Step 3 Attach needle</th>\n</tr>\n</thead>\n<tbody>\n<tr>\n<td align=\"left\">\n<p class=\"First\">\n<img alt=\"Figure\" src=\"/dailymed/image.cfm?name=risperdal-46.jpg&amp;setid=bb34ee82-d2c2-43b8-ba21-2825c0954691\"/></p>\n</td><td align=\"left\">\n<p class=\"First\">\n<img alt=\"Figure\" src=\"/dailymed/image.cfm?name=risperdal-47.jpg&amp;setid=bb34ee82-d2c2-43b8-ba21-2825c0954691\"/></p>\n</td><td align=\"left\">\n<p class=\"First\">\n<img alt=\"Figure\" src=\"/dailymed/image.cfm?name=risperdal-48.jpg&amp;setid=bb34ee82-d2c2-43b8-ba21-2825c0954691\"/></p>\n</td>\n</tr>\n<tr>\n<td align=\"left\"><span class=\"Bold\">Select appropriate needle</span>\n<br/>\n\t\t\tChoose needle based on injection location (gluteal or deltoid).\n </td><td align=\"left\"><span class=\"Bold\">Attach needle</span>\n<br/>\n\t\t\tPeel blister pouch open part way and use to grasp the base of the needle, as shown.\n <br/>\n<br/>\n<span class=\"Bold\">Holding the white collar on the syringe</span>, attach syringe to needle luer connection with a firm \n <span class=\"Bold\"><span class=\"Underline\">clockwise twisting motion</span></span>until snug.\n <br/>\n<br/>\n<span class=\"Bold\">Do not </span>touch needle luer opening. This will result in contamination.\n </td><td align=\"left\"><span class=\"Bold\">Resuspend microspheres</span>\n<br/>\n\t\t\tFully remove the blister pouch.\n <br/>\n<br/>\n\t\t\tJust before injection, shake syringe vigorously again, as some settling will have occurred.\n </td>\n</tr>\n</tbody>\n</table></div>" }

<div class="scrollingtable"><table class="Noautorules" width="100%"> <colgroup> <col align="left" valign="top" width="20%"/> <col align="left" valign="top" width="20%"/> <col align="left" valign="top" width="20%"/> <col align="left" valign="top" width="20%"/> <col align="left" valign="top" width="20%"/> </colgroup> <thead> <tr> <th align="left" colspan="5">Step 4 Inject dose</th> </tr> </thead> <tbody> <tr> <td align="left"> <p class="First"> <img alt="Figure" src="/dailymed/image.cfm?name=risperdal-49.jpg&amp;setid=bb34ee82-d2c2-43b8-ba21-2825c0954691"/></p> </td><td align="left"> <p class="First"> <img alt="Figure" src="/dailymed/image.cfm?name=risperdal-50.jpg&amp;setid=bb34ee82-d2c2-43b8-ba21-2825c0954691"/></p> </td><td align="left"> <p class="First"> <img alt="Figure" src="/dailymed/image.cfm?name=risperdal-51.jpg&amp;setid=bb34ee82-d2c2-43b8-ba21-2825c0954691"/></p> </td><td align="left"> <p class="First"> <img alt="Figure" src="/dailymed/image.cfm?name=risperdal-52.jpg&amp;setid=bb34ee82-d2c2-43b8-ba21-2825c0954691"/></p> </td><td align="left"> <p class="First"> <img alt="Figure" src="/dailymed/image.cfm?name=risperdal-53.jpg&amp;setid=bb34ee82-d2c2-43b8-ba21-2825c0954691"/></p> </td> </tr> <tr> <td align="left"><span class="Bold">Remove transparent needle protector</span> <br/> Move the needle safety device back towards the syringe, as shown. <br/> Then hold white collar on syringe and carefully pull the transparent needle protector straight off. <br/> <br/> <span class="Bold">Do not </span>twist transparent needle protector, as the luer connection may loosen. </td><td align="left"><span class="Bold">Remove air bubbles</span> <br/> Hold needle upright and tap gently to make any air bubbles rise to the top. <br/> Slowly and carefully press plunger rod upward to remove air. </td><td align="left"><span class="Bold">Inject</span> <br/> Immediately inject entire contents of syringe intramuscularly (IM) into the gluteal or deltoid muscle of the patient. <br/> <br/> Gluteal injection should be made into the upper-outer quadrant of the gluteal area. <br/> <br/> <span class="Bold">Do not administer intravenously.</span></td><td align="left"><span class="Bold">Secure needle in safety device</span> <br/> Using <span class="Underline">one hand</span>, place needle safety device at a 45-degree angle on a hard, flat surface. Press down with a firm, quick motion until needle is fully engaged in safety device. <br/> <br/> <span class="Bold">Avoid needle stick injury:</span> <br/> <br/> <span class="Bold">Do not </span>use two hands. <br/> <br/> <span class="Bold">Do not </span>intentionally disengage or mishandle the needle safety device. <br/> <br/> <span class="Bold">Do not </span>attempt to straighten the needle or engage the safety device if the needle is bent or damaged. </td><td align="left"><span class="Bold">Properly dispose of needles</span> <br/> Check to confirm needle safety device is fully engaged. <br/> Discard in an approved sharps container. <br/> <br/> Also discard the unused needle provided in the dose pack. </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table class=\"Noautorules\" width=\"100%\">\n<colgroup>\n<col align=\"left\" valign=\"top\" width=\"20%\"/>\n<col align=\"left\" valign=\"top\" width=\"20%\"/>\n<col align=\"left\" valign=\"top\" width=\"20%\"/>\n<col align=\"left\" valign=\"top\" width=\"20%\"/>\n<col align=\"left\" valign=\"top\" width=\"20%\"/>\n</colgroup>\n<thead>\n<tr>\n<th align=\"left\" colspan=\"5\">Step 4 Inject dose</th>\n</tr>\n</thead>\n<tbody>\n<tr>\n<td align=\"left\">\n<p class=\"First\">\n<img alt=\"Figure\" src=\"/dailymed/image.cfm?name=risperdal-49.jpg&amp;setid=bb34ee82-d2c2-43b8-ba21-2825c0954691\"/></p>\n</td><td align=\"left\">\n<p class=\"First\">\n<img alt=\"Figure\" src=\"/dailymed/image.cfm?name=risperdal-50.jpg&amp;setid=bb34ee82-d2c2-43b8-ba21-2825c0954691\"/></p>\n</td><td align=\"left\">\n<p class=\"First\">\n<img alt=\"Figure\" src=\"/dailymed/image.cfm?name=risperdal-51.jpg&amp;setid=bb34ee82-d2c2-43b8-ba21-2825c0954691\"/></p>\n</td><td align=\"left\">\n<p class=\"First\">\n<img alt=\"Figure\" src=\"/dailymed/image.cfm?name=risperdal-52.jpg&amp;setid=bb34ee82-d2c2-43b8-ba21-2825c0954691\"/></p>\n</td><td align=\"left\">\n<p class=\"First\">\n<img alt=\"Figure\" src=\"/dailymed/image.cfm?name=risperdal-53.jpg&amp;setid=bb34ee82-d2c2-43b8-ba21-2825c0954691\"/></p>\n</td>\n</tr>\n<tr>\n<td align=\"left\"><span class=\"Bold\">Remove transparent needle protector</span>\n<br/>\n\t\t\tMove the needle safety device back towards the syringe, as shown.\n <br/>\n\t\t\tThen hold white collar on syringe and carefully pull the transparent needle protector straight off.\n <br/>\n<br/>\n<span class=\"Bold\">Do not </span>twist transparent needle protector, as the luer connection may loosen.\n </td><td align=\"left\"><span class=\"Bold\">Remove air bubbles</span>\n<br/>\n\t\t\tHold needle upright and tap gently to make any air bubbles rise to the top.\n <br/>\n\t\t\tSlowly and carefully press plunger rod upward to remove air.\n </td><td align=\"left\"><span class=\"Bold\">Inject</span>\n<br/>\n\t\t\tImmediately inject entire contents of syringe intramuscularly (IM) into the gluteal or deltoid muscle of the patient.\n <br/>\n<br/>\n\t\t\tGluteal injection should be made into the upper-outer quadrant of the gluteal area.\n <br/>\n<br/>\n<span class=\"Bold\">Do not administer intravenously.</span></td><td align=\"left\"><span class=\"Bold\">Secure needle in safety device</span>\n<br/>\n\t\t\tUsing \n <span class=\"Underline\">one hand</span>, place needle safety device at a 45-degree angle on a hard, flat surface. Press down with a firm, quick motion until needle is fully engaged in safety device.\n <br/>\n<br/>\n<span class=\"Bold\">Avoid needle stick injury:</span>\n<br/>\n<br/>\n<span class=\"Bold\">Do not </span>use two hands.\n <br/>\n<br/>\n<span class=\"Bold\">Do not </span>intentionally disengage or mishandle the needle safety device.\n <br/>\n<br/>\n<span class=\"Bold\">Do not </span>attempt to straighten the needle or engage the safety device if the needle is bent or damaged.\n </td><td align=\"left\"><span class=\"Bold\">Properly dispose of needles</span>\n<br/>\n\t\t\tCheck to confirm needle safety device is fully engaged.\n <br/>\n\t\t\tDiscard in an approved sharps container.\n <br/>\n<br/>\n\t\t\tAlso discard the unused needle provided in the dose pack.\n </td>\n</tr>\n</tbody>\n</table></div>" }

12.5 mg Dose Pack

{ "type": "p", "children": [], "text": "\n12.5 mg\n \nDose Pack\n \n" }

Store Package in Refrigerator (see bottom panel for storage conditions)

{ "type": "p", "children": [], "text": "\nStore Package\n \nin Refrigerator\n \n(see bottom panel for\n \nstorage conditions)\n \n" }

Rx only Single use only

{ "type": "p", "children": [], "text": "\nRx only\n \nSingle use only\n \n" }

NDC50458-309-11

{ "type": "p", "children": [], "text": "\nNDC50458-309-11\n " }

Risperdal CONSTA® risperiDONE Long-Acting Injection

{ "type": "p", "children": [], "text": "\nRisperdal \n CONSTA®\n\nrisperiDONE Long-Acting Injection\n " }

DOSE PACK CONTENTS:

{ "type": "p", "children": [], "text": "\nDOSE PACK CONTENTS:\n" }

{ "type": "ul", "children": [ "One 12.5 mg vial of risperidone extended-release microspheres for injection", "One pre-filled syringe containing 2 mL of diluent", "One Vial Adapter", "One 21-gauge UTW 1\" Terumo SurGuard \n ®3 safety needle for deltoid injection\n ", "One 20-gauge TW 2\" Terumo SurGuard \n ®3 safety needle for gluteal injection\n " ], "text": "" }

Do not substitute any components of the dose pack.

{ "type": "p", "children": [], "text": "\nDo not substitute any components of the dose pack.\n" }

For deltoid or gluteal intramuscular injection only Each injection should be administered by a healthcare professional.

{ "type": "p", "children": [], "text": "\nFor deltoid or gluteal intramuscular injection only\n \nEach injection should be administered by a healthcare professional.\n \n" }

PLEASE READ COMPLETE INSTRUCTIONS PRIOR TO USE.

{ "type": "p", "children": [], "text": "\nPLEASE READ COMPLETE INSTRUCTIONS PRIOR TO USE.\n" }

25 mg Dose Pack

{ "type": "p", "children": [], "text": "\n25 mg\n \nDose Pack\n \n" }

Store Package in Refrigerator (see bottom panel for storage conditions)

{ "type": "p", "children": [], "text": "\nStore Package\n \nin Refrigerator\n \n(see bottom panel for\n \nstorage conditions)\n \n" }

Rx only Single use only

{ "type": "p", "children": [], "text": "\nRx only\n \nSingle use only\n \n" }

NDC50458-306-11

{ "type": "p", "children": [], "text": "\nNDC50458-306-11\n " }

Risperdal CONSTA® risperiDONE Long-Acting Injection

{ "type": "p", "children": [], "text": "\nRisperdal \n CONSTA®\n\nrisperiDONE Long-Acting Injection\n " }

DOSE PACK CONTENTS:

{ "type": "p", "children": [], "text": "\nDOSE PACK CONTENTS:\n" }

{ "type": "ul", "children": [ "One 25 mg vial of risperidone extended-release microspheres for injection", "One pre-filled syringe containing 2 mL of diluent", "One Vial Adapter", "One 21-gauge UTW 1\" Terumo SurGuard \n ®3 safety needle for deltoid injection\n ", "One 20-gauge TW 2\" Terumo SurGuard \n ®3 safety needle for gluteal injection\n " ], "text": "" }

Do not substitute any components of the dose pack.

{ "type": "p", "children": [], "text": "\nDo not substitute any components of the dose pack.\n" }

For deltoid or gluteal intramuscular injection only Each injection should be administered by a healthcare professional.

{ "type": "p", "children": [], "text": "\nFor deltoid or gluteal intramuscular injection only\n \nEach injection should be administered by a healthcare professional.\n \n" }

PLEASE READ COMPLETE INSTRUCTIONS PRIOR TO USE.

{ "type": "p", "children": [], "text": "\nPLEASE READ COMPLETE INSTRUCTIONS PRIOR TO USE.\n" }

37.5 mg Dose Pack

{ "type": "p", "children": [], "text": "\n37.5 mg\n \nDose Pack\n \n" }

Store Package in Refrigerator (see bottom panel for storage conditions)

{ "type": "p", "children": [], "text": "\nStore Package\n \nin Refrigerator\n \n(see bottom panel for\n \nstorage conditions)\n \n" }

Rx only Single use only

{ "type": "p", "children": [], "text": "\nRx only\n \nSingle use only\n \n" }

NDC50458-307-11

{ "type": "p", "children": [], "text": "\nNDC50458-307-11\n " }

Risperdal CONSTA® risperiDONE Long-Acting Injection

{ "type": "p", "children": [], "text": "\nRisperdal \n CONSTA®\n\nrisperiDONE Long-Acting Injection\n " }

DOSE PACK CONTENTS:

{ "type": "p", "children": [], "text": "\nDOSE PACK CONTENTS:\n" }

{ "type": "ul", "children": [ "One 37.5 mg vial of risperidone extended-release microspheres for injection", "One pre-filled syringe containing 2 mL of diluent", "One Vial Adapter", "One 21-gauge UTW 1\" Terumo SurGuard \n ®3 safety needle for deltoid injection\n ", "One 20-gauge TW 2\" Terumo SurGuard \n ®3 safety needle for gluteal injection\n " ], "text": "" }

Do not substitute any components of the dose pack.

{ "type": "p", "children": [], "text": "\nDo not substitute any components of the dose pack.\n" }

For deltoid or gluteal intramuscular injection only Each injection should be administered by a healthcare professional.

{ "type": "p", "children": [], "text": "\nFor deltoid or gluteal intramuscular injection only\n \nEach injection should be administered by a healthcare professional.\n \n" }

PLEASE READ COMPLETE INSTRUCTIONS PRIOR TO USE.

{ "type": "p", "children": [], "text": "\nPLEASE READ COMPLETE INSTRUCTIONS PRIOR TO USE.\n" }

50 mg Dose Pack

{ "type": "p", "children": [], "text": "\n50 mg\n \nDose Pack\n \n" }

Store Package in Refrigerator (see bottom panel for storage conditions)

{ "type": "p", "children": [], "text": "\nStore Package\n \nin Refrigerator\n \n(see bottom panel for\n \nstorage conditions)\n \n" }

Rx only Single use only

{ "type": "p", "children": [], "text": "\nRx only\n \nSingle use only\n \n" }

NDC50458-308-11

{ "type": "p", "children": [], "text": "\nNDC50458-308-11\n " }

Risperdal CONSTA® risperiDONE Long-Acting Injection

{ "type": "p", "children": [], "text": "\nRisperdal \n CONSTA®\n\nrisperiDONE Long-Acting Injection\n " }

DOSE PACK CONTENTS:

{ "type": "p", "children": [], "text": "\nDOSE PACK CONTENTS:\n" }

{ "type": "ul", "children": [ "One 50 mg vial of risperidone extended-release microspheres for injection", "One pre-filled syringe containing 2 mL of diluent", "One Vial Adapter", "One 21-gauge UTW 1\" Terumo SurGuard \n ®3 safety needle for deltoid injection\n ", "One 20-gauge TW 2\" Terumo SurGuard \n ®3 safety needle for gluteal injection\n " ], "text": "" }

Do not substitute any components of the dose pack.

{ "type": "p", "children": [], "text": "\nDo not substitute any components of the dose pack.\n" }

For deltoid or gluteal intramuscular injection only Each injection should be administered by a healthcare professional.

{ "type": "p", "children": [], "text": "\nFor deltoid or gluteal intramuscular injection only\n \nEach injection should be administered by a healthcare professional.\n \n" }

PLEASE READ COMPLETE INSTRUCTIONS PRIOR TO USE.

{ "type": "p", "children": [], "text": "\nPLEASE READ COMPLETE INSTRUCTIONS PRIOR TO USE.\n" }

Risperidone oral solution is indicated for the treatment of schizophrenia. Efficacy was established in 4 short-term trials in adults, 2 short-term trials in adolescents (ages 13 to 17 years), and one long-term maintenance trial in adults [ seeClinical Studies (14.1)].

Monotherapy

Risperidone oral solution is indicated for the treatment of acute manic or mixed episodes associated with Bipolar I Disorder. Efficacy was established in 2 short-term trials in adults and one short-term trial in children and adolescents (ages 10 to 17 years) [ seeClinical Studies (14.2)].

Adjunctive Therapy

Risperidone oral solution adjunctive therapy with lithium or valproate is indicated for the treatment of acute manic or mixed episodes associated with Bipolar I Disorder. Efficacy was established in one short-term trial in adults [ seeClinical Studies (14.3)].

Risperidone oral solution is indicated for the treatment of irritability associated with autistic disorder, including symptoms of aggression towards others, deliberate self-injuriousness, temper tantrums, and quickly changing moods. Efficacy was established in 3 short-term trials in children and adolescents (ages 5 to 17 years) [ seeClinical Studies (14.4)].

Adults

Usual Initial Dose

Risperidone oral solution can be administered once or twice daily. Initial dosing is 2 mg per day. May increase the dose at intervals of 24 hours or greater, in increments of 1 to 2 mg per day, as tolerated, to a recommended dose of 4 to 8 mg per day. In some patients, slower titration may be appropriate. Efficacy has been demonstrated in a range of 4 mg to 16 mg per day. However, doses above 6 mg per day for twice daily dosing were not demonstrated to be more efficacious than lower doses, were associated with more extrapyramidal symptoms and other adverse effects, and are generally not recommended. In a single study supporting once-daily dosing, the efficacy results were generally stronger for 8 mg than for 4 mg. The safety of doses above 16 mg per day has not been evaluated in clinical trials [ seeClinical Studies (14.1)].

Adolescents

The initial dose is 0.5 mg once daily, administered as a single-daily dose in the morning or evening. The dose may be adjusted at intervals of 24 hours or greater, in increments of 0.5 mg or 1 mg per day, as tolerated, to a recommended dose of 3 mg per day. Although efficacy has been demonstrated in studies of adolescent patients with schizophrenia at doses between 1 mg to 6 mg per day, no additional benefit was observed above 3 mg per day, and higher doses were associated with more adverse events. Doses higher than 6 mg per day have not been studied.

Patients experiencing persistent somnolence may benefit from administering half the daily dose twice daily.

Maintenance Therapy

While it is unknown how long a patient with schizophrenia should remain on risperidone, the effectiveness of risperidone 2 mg per day to 8 mg per day at delaying relapse was demonstrated in a controlled trial in adult patients who had been clinically stable for at least 4 weeks and were then followed for a period of 1 to 2 years [ seeClinical Studies (14.1)]. Both adult and adolescent patients who respond acutely should generally be maintained on their effective dose beyond the acute episode. Patients should be periodically reassessed to determine the need for maintenance treatment.

Reinitiation of Treatment in Patients Previously Discontinued

Although there are no data to specifically address reinitiation of treatment, it is recommended that after an interval off risperidone, the initial titration schedule should be followed.

Switching From Other Antipsychotics

There are no systematically collected data to specifically address switching schizophrenic patients from other antipsychotics to risperidone, or treating patients with concomitant antipsychotics.

Usual Dose

Adults

The initial dose range is 2 mg to 3 mg per day. The dose may be adjusted at intervals of 24 hours or greater, in increments of 1 mg per day. The effective dose range is 1 mg to 6 mg per day, as studied in the short-term, placebo-controlled trials. In these trials, short-term (3 week) anti-manic efficacy was demonstrated in a flexible dosage range of 1 mg to 6 mg per day [ see Clinical Studies(14.2,14.3)]. Risperidone doses higher than 6 mg per day were not studied.

Pediatrics

The initial dose is 0.5 mg once daily, administered as a single-daily dose in the morning or evening. The dose may be adjusted at intervals of 24 hours or greater, in increments of 0.5 mg or 1 mg per day, as tolerated, to the recommended target dose of 1 mg to 2.5 mg per day. Although efficacy has been demonstrated in studies of pediatric patients with bipolar mania at doses between 0.5 mg and 6 mg per day, no additional benefit was observed above 2.5 mg per day, and higher doses were associated with more adverse events. Doses higher than 6 mg per day have not been studied.

Patients experiencing persistent somnolence may benefit from administering half the daily dose twice daily.

Maintenance Therapy

There is no body of evidence available from controlled trials to guide a clinician in the longer-term management of a patient who improves during treatment of an acute manic episode with risperidone.  While it is generally agreed that pharmacological treatment beyond an acute response in mania is desirable, both for maintenance of the initial response and for prevention of new manic episodes, there are no systematically obtained data to support the use of risperidone in such longer-term treatment (i.e., beyond 3 weeks). The physician who elects to use risperidone for extended periods should periodically re-evaluate the long-term risks and benefits of the drug for the individual patient.

The dosage of risperidone should be individualized according to the response and tolerability of the patient. The total daily dose of risperidone can be administered once daily, or half the total daily dose can be administered twice daily.

For patients with body weight less than 20 kg, initiate dosing at 0.25 mg per day. For patients with body weight greater than or equal to 20 kg, initiate dosing at 0.5 mg per day. After a minimum of four days, the dose may be increased to the recommended dose of 0.5 mg per day for patients less than 20 kg and 1 mg per day for patients greater than or equal to 20 kg. Maintain this dose for a minimum of 14 days. In patients not achieving sufficient clinical response, the dose may be increased at intervals of 2 weeks or greater, in increments of 0.25 mg per day for patients less than 20 kg, or increments of 0.5 mg per day for patients greater than or equal to 20 kg. The effective dose range is 0.5 mg to 3 mg per day. No dosing data are available for children who weigh less than 15 kg.

Once sufficient clinical response has been achieved and maintained, consider gradually lowering the dose to achieve the optimal balance of efficacy and safety. The physician who elects to use risperidone for extended periods should periodically re-evaluate the long-term risks and benefits of the drug for the individual patient.

Patients experiencing persistent somnolence may benefit from a once-daily dose administered at bedtime or administering half the daily dose twice daily, or a reduction of the dose.

For patients with severe renal impairment (CLcr< 30 mL/min) or hepatic impairment (10 to 15 points on Child Pugh System), the initial starting dose is 0.5 mg twice daily. The dose may be increased in increments of 0.5 mg or less, administered twice daily. For doses above 1.5 mg twice daily, increase in intervals of one week or greater [ seeUse in Specific Populations( 8.6and 8.7)].

When risperidone is co-administered with enzyme inducers (e.g., carbamazepine), the dose of risperidone should be increased up to double the patient’s usual dose. It may be necessary to decrease the risperidone dose when enzyme inducers such as carbamazepine are discontinued [ seeDrug Interactions (7.1)]. Similar effect may be expected with co-administration of risperidone with other enzyme inducers (e.g., phenytoin, rifampin, and phenobarbital).

When fluoxetine or paroxetine is co-administered with risperidone, the dose of risperidone should be reduced. The risperidone dose should not exceed 8 mg per day in adults when co-administered with these drugs. When initiating therapy, risperidone should be titrated slowly. It may be necessary to increase the risperidone dose when enzyme inhibitors such as fluoxetine or paroxetine are discontinued [ seeDrug Interactions (7.1)].

Risperidone oral solution can be administered directly from the calibrated oral dosing syringe, or can be mixed with a beverage prior to administration. Risperidone oral solution is compatible in the following beverages: water, coffee, orange juice, and low-fat milk; it is NOT compatible with either cola or tea.

Risperidone oral solution is available in a 1 mg/mL strength.

{ "type": "p", "children": [], "text": "Risperidone oral solution is available in a 1 mg/mL strength." }

Risperidone oral solution is contraindicated in patients with a known hypersensitivity to either risperidone or paliperidone, or to any of the excipients in the risperidone formulation. Hypersensitivity reactions, including anaphylactic reactions and angioedema, have been reported in patients treated with risperidone and in patients treated with paliperidone. Paliperidone is a metabolite of risperidone.

{ "type": "p", "children": [], "text": "Risperidone oral solution is contraindicated in patients with a known hypersensitivity to either risperidone or paliperidone, or to any of the excipients in the risperidone formulation. Hypersensitivity reactions, including anaphylactic reactions and angioedema, have been reported in patients treated with risperidone and in patients treated with paliperidone. Paliperidone is a metabolite of risperidone." }

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Analyses of 17 placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality. The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear.

In two of four placebo-controlled trials in elderly patients with dementia-related psychosis, a higher incidence of mortality was observed in patients treated with furosemide plus risperidone when compared to patients treated with risperidone alone or with placebo plus furosemide. No pathological mechanism has been identified to explain this finding, and no consistent pattern for cause of death was observed.

Risperidone is not approved for the treatment of dementia-related psychosis [ seeBoxed Warning].

Cerebrovascular adverse reactions (e.g., stroke, transient ischemic attack), including fatalities, were reported in patients (mean age 85 years; range 73 to 97) in trials of risperidone 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 risperidone compared to patients treated with placebo. Risperidone is not approved for the treatment of patients with dementia-related psychosis [ seeBoxed WarningandWarnings and Precautions (5.1)].

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

If NMS is suspected, immediately discontinue Risperidone Oral Solution and provide symptomatic treatment and monitoring.

Tardive dyskinesia, a syndrome consisting 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 predict which patients will 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 increase with the duration of treatment and the cumulative dose. The syndrome can develop after relatively brief treatment periods, even at low doses. It may also occur after discontinuation of treatment.

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

Given these considerations, risperidone 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, use the lowest dose and the shortest duration of treatment producing a satisfactory clinical response. Periodically reassess the need for continued treatment.

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

Atypical antipsychotic drugs have been associated with metabolic changes that may increase cardiovascular/cerebrovascular risk. These metabolic changes include hyperglycemia, dyslipidemia, and body weight gain. While all of the drugs in the class have been shown to produce some metabolic changes, each drug has its own specific risk profile.

Hyperglycemia and Diabetes Mellitus

Hyperglycemia and diabetes mellitus, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, have been reported in patients treated with atypical antipsychotics including risperidone. 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. Given these confounders, the relationship between atypical antipsychotic use and hyperglycemia-related adverse events is not completely understood. However, epidemiological studies suggest an increased risk of treatment-emergent hyperglycemia-related adverse events in patients treated with the atypical antipsychotics. Precise risk estimates for hyperglycemia-related adverse events in patients treated with atypical antipsychotics are not available.

Patients with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics, including risperidone, should be monitored regularly for worsening of glucose control. Patients with risk factors for diabetes mellitus (e.g., obesity, family history of diabetes) who are starting treatment with atypical antipsychotics, including risperidone, should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Any patient treated with atypical antipsychotics, including risperidone, should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics, including risperidone, should undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic, including risperidone, was discontinued; however, some patients required continuation of anti-diabetic treatment despite discontinuation of risperidone.

Pooled data from three double-blind, placebo-controlled schizophrenia studies and four double-blind, placebo-controlled bipolar monotherapy studies are presented in Table 2.

<div class="scrollingtable"><table> <caption> <span>Table 2.  Change in Random Glucose from Seven Placebo-Controlled, 3- to 8-Week, Fixed- or Flexible-Dose Studies in Adult Subjects with Schizophrenia or Bipolar Mania</span> </caption> <col/> <col/> <col/> <col/> <thead> <tr class="First"> <td class="Toprule" valign="top"></td><td class="Toprule" colspan="3" valign="top"><span class="Bold"> Risperidone</span></td> </tr> <tr class="Last"> <td class="Botrule" valign="top"><span class="Bold"></span></td><td class="Botrule" valign="top"><span class="Bold">  Placebo</span></td><td class="Botrule" valign="top"><span class="Bold">  1 to 8 mg/day</span></td><td class="Botrule" valign="top"><span class="Bold">  &gt;8 to 16 mg/day</span></td> </tr> </thead> <tbody> <tr class="First"> <td align="center" class="Toprule" colspan="4" valign="top"><span class="Bold">Mean change from baseline (mg/dL)</span></td> </tr> <tr> <td valign="top"></td><td valign="top"><span class="Bold">n = 555</span></td><td valign="top"><span class="Bold">n = 748</span></td><td valign="top"><span class="Bold">n = 164</span></td> </tr> <tr> <td valign="top"> Serum Glucose</td><td valign="top"> -1.4</td><td valign="top"> 0.8</td><td valign="top"> 0.6</td> </tr> <tr> <td valign="top"></td><td colspan="3" valign="top"><span class="Bold">Proportion of patients with shifts</span></td> </tr> <tr class="Last"> <td class="Botrule" valign="top"> <p class="First"> Serum Glucose</p> <p>(&lt;140 mg/dL to ≥ 200 mg/dL)</p> </td><td class="Botrule" valign="top"> <p class="First"> 0.6%</p> <p>(3/525)</p> </td><td class="Botrule" valign="top"> <p class="First">0.4%</p> <p>(3/702)</p> </td><td class="Botrule" valign="top"> <p class="First">0%</p> <p>(0/158)</p> </td> </tr> </tbody> </table></div>

In longer-term, controlled and uncontrolled studies, risperidone was associated with a mean change in glucose of +2.8 mg/dL at Week 24 (n = 151) and +4.1 mg/dL at Week 48 (n = 50).

Data from the placebo-controlled 3- to 6-week study in children and adolescents with schizophrenia (13 to 17 years of age), bipolar mania (10 to 17 years of age), or autistic disorder (5 to 17 years of age) are presented in Table 3.

Table 3.  Change in Fasting Glucose from Three Placebo-Controlled, 3- to 6-Week, Fixed-Dose Studies in Children and Adolescents with Schizophrenia (13 to 17 years of age), Bipolar Mania (10 to 17 years of age), or Autistic Disorder (5 to 17 years of age)

<div class="scrollingtable"><table> <col/> <col/> <col/> <col/> <thead> <tr class="First"> <td class="Toprule" colspan="2" valign="top"></td><td class="Toprule" colspan="2" valign="top"><span class="Bold">       Risperidone</span></td> </tr> <tr class="Last"> <td class="Botrule" valign="top"><span class="Bold"></span></td><td class="Botrule" colspan="2" valign="top"><span class="Bold">  Placebo</span></td><td class="Botrule" valign="top"><span class="Bold">  0.5 to 6 mg/day</span></td> </tr> </thead> <tbody> <tr class="First"> <td class="Toprule" valign="top"></td><td class="Toprule" colspan="3" valign="top"><span class="Bold">Mean change from baseline (mg/dL)</span></td> </tr> <tr> <td valign="top"></td><td colspan="2" valign="top"><span class="Bold">n = 76</span></td><td valign="top"><span class="Bold">n = 135</span></td> </tr> <tr> <td valign="top"> Serum Glucose</td><td colspan="2" valign="top"> -1.3</td><td valign="top"> 2.6</td> </tr> <tr> <td valign="top"></td><td colspan="3" valign="top"><span class="Bold">Proportion of patients with shifts</span></td> </tr> <tr class="Last"> <td valign="top"> <p class="First"> Serum Glucose</p> <p>(&lt;100 mg/dL to ≥126 mg/dL)</p> </td><td colspan="2" valign="top"> <p class="First"> 0%</p> <p>(0/64)</p> </td><td valign="top"> <p class="First"> 0.8%</p> <p>(1/120)</p> </td> </tr> </tbody> </table></div>

In longer-term, uncontrolled, open-label extension pediatric studies, risperidone was associated with a mean change in fasting glucose of +5.2 mg/dL at Week 24 (n = 119).

Dyslipidemia

Undesirable alterations in lipids have been observed in patients treated with atypical antipsychotics.

Pooled data from 7 placebo-controlled, 3- to 8- week, fixed- or flexible-dose studies in adult subjects with schizophrenia or bipolar mania are presented in Table 4.

<div class="scrollingtable"><table> <caption> <span>Table 4.  Change in Random Lipids from Seven Placebo-Controlled, 3- to 8-Week, Fixed- or Flexible-Dose Studies in Adult Subjects with Schizophrenia or Bipolar Mania</span> </caption> <col/> <col/> <col/> <col/> <thead> <tr class="First"> <td class="Toprule" valign="top"></td><td class="Toprule" colspan="3" valign="top"><span class="Bold">Risperidone</span></td> </tr> <tr class="Last"> <td class="Botrule" valign="top"><span class="Bold"></span></td><td class="Botrule" valign="top"><span class="Bold">  Placebo</span></td><td class="Botrule" valign="top"><span class="Bold">  1 to 8 mg/day</span></td><td class="Botrule" valign="top"><span class="Bold">  &gt;8 to16 mg/day</span></td> </tr> </thead> <tbody> <tr class="First"> <td align="center" class="Toprule" colspan="4" valign="top"><span class="Bold">Mean change from baseline (mg/dL)</span></td> </tr> <tr> <td valign="top"> <p class="First"> <span class="Bold">Cholesterol</span> </p> <p> <span class="Bold"></span>Change from baseline </p> </td><td valign="top"> <p class="First"> <span class="Bold">n = 559</span> </p> <p> <span class="Bold"></span>0.6 </p> </td><td valign="top"> <p class="First"> <span class="Bold">n = 742</span> </p> <p> <span class="Bold"></span>6.9 </p> </td><td valign="top"> <p class="First"> <span class="Bold">n = 156</span> </p> <p> <span class="Bold"></span>1.8 </p> </td> </tr> <tr> <td valign="top"> <p class="First"> <span class="Bold">Triglycerides</span> </p> <p> <span class="Bold"></span>Change from baseline </p> </td><td valign="top"> <p class="First"> <span class="Bold">n = 183</span> </p> <p> <span class="Bold"></span>-17.4 </p> </td><td valign="top"> <p class="First"> <span class="Bold">n = 307</span> </p> <p> <span class="Bold"></span>-4.9 </p> </td><td valign="top"> <p class="First"> <span class="Bold">n = 123</span> </p> <p> <span class="Bold"></span>-8.3 </p> </td> </tr> <tr> <td align="center" colspan="4" valign="top"><span class="Bold">Proportion of patients with shifts</span></td> </tr> <tr> <td valign="top"> <p class="First"> <span class="Bold">Cholesterol</span> </p> <p> <span class="Bold"></span>(&lt;200 mg/dL to ≥240 mg/dL) </p> </td><td valign="top"> <p class="First"> 2.7%</p> <p>(10/368)</p> </td><td valign="top"> <p class="First"> 4.3%</p> <p>(22/516)</p> </td><td valign="top"> <p class="First"> 6.3%</p> <p>(6/96)</p> </td> </tr> <tr class="Last"> <td valign="top"> <p class="First"> <span class="Bold">Triglycerides</span> </p> <p> <span class="Bold"></span>(&lt;500 mg/dL to ≥500 mg/dL) </p> </td><td valign="top"> <p class="First"> 1.1%</p> <p>(2/180)</p> </td><td valign="top"> <p class="First"> 2.7%</p> <p>(8/301)</p> </td><td valign="top"> <p class="First"> 2.5%</p> <p>(3/121)</p> </td> </tr> </tbody> </table></div>

In longer-term, controlled and uncontrolled studies, risperidone was associated with a mean change in (a) non-fasting cholesterol of +4.4 mg/dL at Week 24 (n = 231) and +5.5 mg/dL at Week 48 (n = 86); and (b) non-fasting triglycerides of +19.9 mg/dL at Week 24 (n = 52).

Pooled data from 3 placebo-controlled, 3- to 6-week, fixed-dose studies in children and adolescents with schizophrenia (13 to 17 years of age), bipolar mania (10 to 17 years of age), or autistic disorder (5 to 17 years of age) are presented in Table 5.

<div class="scrollingtable"><table width="368.6px"> <caption> <span>Table 5.  Change in Fasting Lipids from Three Placebo-Controlled, 3- to 6-Week, Fixed-Dose Studies in Children and Adolescents with Schizophrenia (13 to 17 Years of Age), Bipolar Mania (10 to 17 Years of Age), or Autistic Disorder (5 to 17 Years of Age)</span> </caption> <col/> <col/> <col/> <thead> <tr class="First Last"> <td class="Botrule Toprule" valign="top"></td><td class="Botrule Toprule" valign="top"><span class="Bold">Placebo </span></td><td class="Botrule Toprule" valign="top"> <p class="First"> <span class="Bold">  Risperidone</span> </p> <p> <span class="Bold">0.5 to 6 mg/day</span> </p> </td> </tr> </thead> <tbody> <tr class="First"> <td align="right" class="Toprule" colspan="3" valign="top"><span class="Bold">Mean change from baseline (mg/dL)</span></td> </tr> <tr> <td valign="top"> <p class="First"> <span class="Bold">Cholesterol</span> </p> <p> <span class="Bold"></span>Change from baseline </p> </td><td valign="top"> <p class="First"> <span class="Bold">n = 74</span> </p> <p> <span class="Bold"></span>0.3 </p> </td><td valign="top"> <p class="First"> <span class="Bold">n = 133</span> </p> <p> <span class="Bold"></span>-0.3 </p> </td> </tr> <tr> <td valign="top"> <p class="First"> <span class="Bold">LDL</span> </p> <p> <span class="Bold"></span>Change from baseline </p> </td><td valign="top"> <p class="First"> <span class="Bold">n = 22</span> </p> <p> <span class="Bold"></span>3.7 </p> </td><td valign="top"> <p class="First"> <span class="Bold">n = 22</span> </p> <p> <span class="Bold"></span>0.5 </p> </td> </tr> <tr> <td valign="top"> <p class="First"> <span class="Bold">HDL</span> </p> <p> <span class="Bold"></span>Change from baseline </p> </td><td valign="top"> <p class="First"> <span class="Bold">n = 22</span> </p> <p> <span class="Bold"></span>1.6 </p> </td><td valign="top"> <p class="First"> <span class="Bold">n = 22</span> </p> <p> <span class="Bold"></span>-1.9 </p> </td> </tr> <tr> <td valign="top"> <p class="First"> <span class="Bold">Triglycerides</span> </p> <p>Change from baseline</p> </td><td valign="top"> <p class="First"> <span class="Bold">n = 77</span> </p> <p> <span class="Bold"></span>-9 </p> </td><td valign="top"> <p class="First"> <span class="Bold">n = 138</span> </p> <p> <span class="Bold"></span>-2.6 </p> </td> </tr> <tr> <td align="right" colspan="3" valign="top"><span class="Bold">Proportion of patients with shifts</span></td> </tr> <tr> <td valign="top"> <p class="First"> <span class="Bold">Cholesterol</span> </p> <p> <span class="Bold"></span>(&lt;170 mg/dL to ≥200 mg/dL) </p> </td><td valign="top"> <p class="First"> 2.4%</p> <p>(1/42)</p> </td><td valign="top"> <p class="First"> 3.8%</p> <p>(3/80)</p> </td> </tr> <tr> <td valign="top"> <p class="First"> <span class="Bold">LDL</span> </p> <p> <span class="Bold"></span>(&lt;110 mg/dL to ≥130 mg/dL) </p> </td><td valign="top"> <p class="First"> 0%</p> <p>(0/16)</p> </td><td valign="top"> <p class="First"> 0%</p> <p>(0/16)</p> </td> </tr> <tr> <td valign="top"> <p class="First"> <span class="Bold">HDL</span> </p> <p> <span class="Bold"></span>(≥40 mg/dL to &lt;40 mg/dL) </p> </td><td valign="top"> <p class="First"> 0%</p> <p>(0/19)</p> </td><td valign="top"> <p class="First"> 10%</p> <p>(2/20)</p> </td> </tr> <tr class="Last"> <td class="Botrule" valign="top"> <p class="First"> <span class="Bold">Triglycerides</span> </p> <p> <span class="Bold"></span>(&lt;150 mg/dL to ≥200 mg/dL) </p> </td><td class="Botrule" valign="top"> <p class="First"> 1.5%</p> <p>(1/65)</p> </td><td class="Botrule" valign="top"> <p class="First"> 7.1%</p> <p>(8/113)</p> </td> </tr> </tbody> </table></div>

In longer-term, uncontrolled, open-label extension pediatric studies, risperidone was associated with a mean change in (a) fasting cholesterol of +2.1 mg/dL at Week 24 (n = 114); (b) fasting LDL of -0.2 mg/dL at Week 24 (n = 103); (c) fasting HDL of +0.4 mg/dL at Week 24 (n = 103); and (d) fasting triglycerides of +6.8 mg/dL at Week 24 (n = 120).

Weight Gain

Weight gain has been observed with atypical antipsychotic use. Clinical monitoring of weight is recommended.

Data on mean changes in body weight and the proportion of subjects meeting a weight gain criterion of 7% or greater of body weight from 7 placebo-controlled, 3- to 8- week, fixed- or flexible-dose studies in adult subjects with schizophrenia or bipolar mania are presented in Table 6.

<div class="scrollingtable"><table> <caption> <span>Table 6.  Mean Change in Body Weight (kg) and the Proportion of Subjects with ≥ 7% Gain in Body Weight From Seven Placebo-Controlled, 3- to 8-Week, Fixed- or Flexible-Dose Studies in Adult Subjects With Schizophrenia or Bipolar Mania</span> </caption> <col/> <col/> <col/> <col/> <thead> <tr class="First"> <td class="Toprule" valign="top"></td><td class="Toprule" valign="top"></td><td class="Toprule" colspan="2" valign="top"><span class="Bold">Risperidone</span></td> </tr> <tr class="Last"> <td class="Botrule" valign="top"><span class="Bold"></span></td><td align="center" class="Botrule" valign="top"> <p class="First"> <span class="Bold"> Placebo</span> </p> <p> <span class="Bold">(n = 597)</span> </p> </td><td align="center" class="Botrule" valign="top"> <p class="First"> <span class="Bold">  1 to 8 mg/day</span> </p> <p> <span class="Bold">(n = 769)</span> </p> </td><td align="center" class="Botrule" valign="top"> <p class="First"> <span class="Bold">  &gt;8 to16 mg/day</span> </p> <p> <span class="Bold">(n = 158)</span> </p> </td> </tr> </thead> <tbody> <tr class="First"> <td class="Toprule" valign="top"> <p class="First"> <span class="Bold">Weight (kg)</span> </p> <p> <span class="Bold"></span>Change from baseline </p> </td><td class="Toprule" valign="top"> -0.3</td><td class="Toprule" valign="top"> 0.7</td><td class="Toprule" valign="top"> 2.2</td> </tr> <tr class="Last"> <td class="Botrule" valign="top"> <p class="First"> <span class="Bold">Weight Gain</span> </p> <p> <span class="Bold"></span>≥7% increase from baseline </p> </td><td class="Botrule" valign="top"> 2.9%</td><td class="Botrule" valign="top"> 8.7%</td><td class="Botrule" valign="top"> 20.9%</td> </tr> </tbody> </table></div>

In longer-term, controlled and uncontrolled studies, risperidone was associated with a mean change in weight of +4.3 kg at Week 24 (n = 395) and +5.3 kg at Week 48 (n = 203).

Data on mean changes in body weight and the proportion of subjects meeting the criterion of ≥7% gain in body weight from nine placebo-controlled, 3- to 8-week, fixed-dose studies in children and adolescents with schizophrenia (13 to 17 years of age), bipolar mania (10 to 17 years of age), autistic disorder (5 to 17 years of age), or other psychiatric disorders (5 to 17 years of age) are presented in Table 7.

<div class="scrollingtable"><table> <caption> <span>Table 7.  Mean Change in Body Weight (kg) and the Proportion of Subjects With ≥7% Gain in Body Weight From Nine Placebo-Controlled, 3- to 8-Week, Fixed-Dose Studies in Children and Adolescents With Schizophrenia (13 to 17 Years of Age), Bipolar Mania (10 to 17 Years of Age), Autistic Disorder (5 to 17 Years of Age) or Other Psychiatric Disorders (5 to 17 Years of Age)</span> </caption> <col/> <col/> <col/> <thead> <tr class="First Last"> <td align="center" class="Botrule Toprule" valign="top"></td><td align="center" class="Botrule Toprule" valign="top"> <p class="First"> <span class="Bold">Placebo</span> </p> <p> <span class="Bold">(n = 375)</span> </p> </td><td align="center" class="Botrule Toprule" valign="top"> <p class="First"> <span class="Bold">  Risperidone 0.5 to 6 mg/day</span> </p> <p> <span class="Bold">(n = 448)</span> </p> </td> </tr> </thead> <tbody> <tr class="First"> <td class="Toprule" valign="top"> <p class="First"> <span class="Bold">Weight (kg)</span> </p> <p> <span class="Bold"></span>Change from baseline </p> </td><td align="center" class="Toprule" valign="top"> 0.6%</td><td align="center" class="Toprule" valign="top"> 2%</td> </tr> <tr class="Last"> <td class="Botrule" valign="top"> <p class="First"> <span class="Bold">Weight Gain</span> </p> <p> <span class="Bold"></span>≥7% increase from baseline </p> </td><td align="center" class="Botrule" valign="top"> 6.9%</td><td align="center" class="Botrule" valign="top"> 32.6%</td> </tr> </tbody> </table></div>

In longer-term, uncontrolled, open-label extension pediatric studies, risperidone was associated with a mean change in weight of +5.5 kg at Week 24 (n = 748) and +8 kg at Week 48 (n=242).

In a long-term, open-label extension study in adolescent patients with schizophrenia, weight increase was reported as a treatment-emergent adverse event in 14% of patients. In 103 adolescent patients with schizophrenia, a mean increase of 9 kg was observed after 8 months of risperidone treatment. The majority of that increase was observed within the first 6 months. The average percentiles at baseline and 8 months, respectively, were 56 and 72 for weight, 55 and 58 for height, and 51 and 71 for body mass index.

In long-term, open-label trials (studies in patients with autistic disorder or other psychiatric disorders), a mean increase of 7.5 kg after 12 months of risperidone treatment was observed, which was higher than the expected normal weight gain (approximately 3 to 3.5 kg per year adjusted for age, based on Centers for Disease Control and Prevention normative data). The majority of that increase occurred within the first 6 months of exposure to risperidone. The average percentiles at baseline and 12 months, respectively, were 49 and 60 for weight, 48 and 53 for height, and 50 and 62 for body mass index.

In one 3-week, placebo-controlled trial in children and adolescent patients with acute manic or mixed episodes of bipolar I disorder, increases in body weight were higher in the risperidone groups than the placebo group, but not dose related (1.90 kg in the risperidone 0.5 to 2.5 mg group, 1.44 kg in the risperidone 3 to 6 mg group, and 0.65 kg in the placebo group). A similar trend was observed in the mean change from baseline in body mass index.

When treating pediatric patients with risperidone for any indication, weight gain should be assessed against that expected with normal growth.

As with other drugs that antagonize dopamine D 2receptors, risperidone elevates prolactin levels and the elevation persists during chronic administration. Risperidone is associated with higher levels of prolactin elevation than other antipsychotic agents.

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. An increase in pituitary gland, mammary gland, and pancreatic islet cell neoplasia (mammary adenocarcinomas, pituitary and pancreatic adenomas) was observed in the risperidone carcinogenicity studies conducted in mice and rats [ seeNonclinical Toxicology (13.1)]. Neither clinical studies nor epidemiologic studies conducted to date have shown an association between chronic administration of this class of drugs and tumorigenesis in humans; the available evidence is considered too limited to be conclusive at this time.

Risperidone may induce orthostatic hypotension associated with dizziness, tachycardia, and in some patients, syncope, especially during the initial dose-titration period, probably reflecting its alpha-adrenergic antagonistic properties. Syncope was reported in 0.2% (6/2607) of risperidone-treated patients in Phase 2 and 3 studies in adults with schizophrenia. The risk of orthostatic hypotension and syncope may be minimized by limiting the initial dose to 2 mg total (either once daily or 1 mg twice daily) in normal adults and 0.5 mg twice daily in the elderly and patients with renal or hepatic impairment [ see Dosage and Administration(2.1,2.4)].

Monitoring of orthostatic vital signs should be considered in patients for whom this is of concern. A dose reduction should be considered if hypotension occurs. Risperidone 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, e.g., dehydration and hypovolemia and in the elderly patients with renal or hepatic impairment. Monitoring of orthostatic vital signs should be considered if hypotension occurs. Clinically significant hypotension has been observed with concomitant use of risperidone and antihypertensive medication.

Somnolence, postural hypotension, motor and sensory instability have been reported with the use of antipsychotics, including risperidone, which may lead to falls and, consequently, fractures or other fall-related injuries. For patients, particularly the elderly, with diseases, conditions, or medications that could exacerbate these effects, assess the risk of falls 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 risperidone. 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 a drug-induced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and discontinuation of risperidone 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 risperidone and have their WBC followed until recovery.

Somnolence was a commonly reported adverse reaction associated with risperidone treatment, especially when ascertained by direct questioning of patients. This adverse reaction is dose-related, and in a study utilizing a checklist to detect adverse events, 41% of the high-dose patients (risperidone 16 mg/day) reported somnolence compared to 16% of placebo patients. Direct questioning is more sensitive for detecting adverse events than spontaneous reporting, by which 8% of risperidone 16 mg/day patients and 1% of placebo patients reported somnolence as an adverse reaction. Since risperidone 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 risperidone therapy does not affect them adversely.

During premarketing testing in adult patients with schizophrenia, seizures occurred in 0.3% (9/2607) of risperidone-treated patients, two in association with hyponatremia. Risperidone should be used cautiously in patients with a history of seizures.

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 dementia. Risperidone and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia [ seeBoxed Warningand Warnings and Precautions (5.1)].

Priapism has been reported during postmarketing surveillance. Severe priapism may require surgical intervention.

Disruption of body temperature regulation has been attributed to antipsychotic agents. Both hyperthermia and hypothermia have been reported in association with oral risperidone use. Caution is advised when prescribing for patients who will be exposed to temperature extremes.

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 the rates observed in clinical practice.

Commonly-Observed Adverse Reactions in Double-Blind, Placebo-Controlled Clinical Trials – Schizophrenia

Adult Patients with Schizophrenia

Table 8 lists the adverse reactions reported in 2% or more of risperidone-treated adult patients with schizophrenia in three 4- to 8-week, double-blind, placebo-controlled trials.

Table 8.  Adverse Reactions in ≥ 2% of Risperidone-Treated Adult Patients (and greater than placebo) with Schizophrenia in Double-Blind, Placebo-Controlled Trials

<div class="scrollingtable"><table border="1" cellpadding="0" cellspacing="0"> <col/> <col/> <col/> <col/> <tbody class="Headless"> <tr class="First"> <td align="center" class="Botrule Lrule Rrule Toprule" colspan="4"> <p class="First"> <span class="Bold">Percentage of Patients Reporting Reaction</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"></td><td colspan="3"> <p class="First"> <span class="Bold">                        R</span><span class="Bold">isperidone</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">System/Organ Class</span> </p> <p>Adverse Reaction</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">2 to 8 mg per day</span> </p> <p> <span class="Bold">(n = 366)</span> </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">&gt; 8 to 16 mg per day</span> </p> <p> <span class="Bold">(n = 198)</span> </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">Placebo</span> </p> <p> <span class="Bold">(n = 225)</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="4"> <p class="First"> <span class="Bold">Cardiac Disorders</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Tachycardia</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">1</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">3</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="4"> <p class="First"> <span class="Bold">Eye Disorders</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Vision blurred</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">3</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">1</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">1</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="4"> <p class="First"> <span class="Bold">Gastrointestinal Disorders</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Nausea</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">9</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">4</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">4</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Constipation</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">8</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">9</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">6</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Dyspepsia</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">8</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">6</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">5</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Dry mouth</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">4</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">0</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">1</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Abdominal discomfort</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">3</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">1</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">1</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Salivary hypersecretion</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">2</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">1</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">&lt;1</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Diarrhea</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">2</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">1</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">1</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="4"> <p class="First"> <span class="Bold">General Disorders</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Fatigue</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">3</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">1</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Chest pain</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">2</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">2</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">1</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Asthenia</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">2</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">1</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">&lt;1</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="4"> <p class="First"> <span class="Bold">Infections and Infestations</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Nasopharyngitis</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">3</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">4</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">3</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Upper respiratory tract infection</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">2</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">3</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">1</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Sinusitis</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">1</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">2</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">1</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Urinary tract infection</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">1</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">3</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">Investigations</span> </p> </td><td class="Botrule Lrule Rrule Toprule"></td><td></td><td></td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Blood creatine phosphokinase increased</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">1</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">2</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">&lt;1</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Heart rate increased</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">&lt;1</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">2</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="4"> <p class="First"> <span class="Bold">Musculoskeletal and Connective Tissue Disorders</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Back pain</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">4</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">1</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">1</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Arthralgia</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">2</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">3</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">&lt;1</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Pain in extremity</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">2</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">1</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">1</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="4"> <p class="First"> <span class="Bold">Nervous System Disorders</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Parkinsonism*</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">14</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">17</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">8</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Akathisia*</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">10</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">10</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">3</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Sedation</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">10</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">5</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">2</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Dizziness</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">7</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">4</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">2</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Dystonia*</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">3</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">4</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">2</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Tremor*</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">2</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">3</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">1</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Dizziness postural</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">2</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">0</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="4"> <p class="First"> <span class="Bold">Psychiatric Disorders</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Insomnia</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">32</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">25</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">27</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Anxiety</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">16</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">11</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">11</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="4"> <p class="First"> <span class="Bold">Respiratory, Thoracic and Mediastinal Disorders</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Nasal congestion</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">4</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">6</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">2</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Dyspnea</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">1</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">2</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Epistaxis</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">&lt;1</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">2</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="4"> <p class="First"> <span class="Bold">Skin and Subcutaneous Tissue Disorders</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Rash</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">1</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">4</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">1</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Dry skin</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">1</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">3</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="4"> <p class="First"> <span class="Bold">Vascular Disorders</span> </p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Orthostatic hypotension</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">2</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">1</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">0</p> </td> </tr> </tbody> </table></div>

*Parkinsonism includes extrapyramidal disorder, musculoskeletal stiffness, parkinsonism, cogwheel rigidity, akinesia, bradykinesia, hypokinesia, masked facies, muscle rigidity, and Parkinson’s disease. Akathisia includes akathisia and restlessness. Dystonia includes dystonia, muscle spasms, muscle contractions involuntary, muscle contracture, oculogyration, tongue paralysis. Tremor includes tremor and parkinsonian rest tremor.

Pediatric Patients with Schizophrenia

Table 9 lists the adverse reactions reported in 5% or more of risperidone-treated pediatric patients with schizophrenia in a 6-week double-blind, placebo-controlled trial.

Table 9.  Adverse Reactions in ≥ 5% of Risperidone-Treated Pediatric Patients (and greater than placebo) with Schizophrenia in a Double-Blind Trial

<div class="scrollingtable"><table border="1" cellpadding="0" cellspacing="0"> <col/> <col/> <col/> <col/> <tbody class="Headless"> <tr class="First"> <td align="center" class="Botrule Lrule Rrule Toprule" colspan="4"> <p class="First"> <span class="Bold">Percentage of Patients Reporting Reaction</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"></td><td colspan="3"> <p class="First"> <span class="Bold">                               Risperidone</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">System/Organ Class</span> </p> <p>Adverse Reaction</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">1 to 3 mg per day</span> </p> <p> <span class="Bold">(n = 55)</span> </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">4 to 6 mg per day</span> </p> <p> <span class="Bold">(n = 51)</span> </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">Placebo</span> </p> <p> <span class="Bold">(n = 54)</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="4"> <p class="First"> <span class="Bold">Gastrointestinal Disorders</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Salivary hypersecretion</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">0</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">10</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">2</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="4"> <p class="First"> <span class="Bold">Nervous System Disorders</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Sedation</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">24</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">12</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">4</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Parkinsonism*</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">16</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">28</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">11</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Tremor</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">11</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">10</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">6</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Akathisia*</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">9</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">10</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">4</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Dizziness</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">7</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">14</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">2</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Dystonia*</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">2</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">6</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="4"> <p class="First"> <span class="Bold">Psychiatric Disorders</span> </p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Anxiety</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">7</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">6</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">0</p> </td> </tr> </tbody> </table></div>

* Parkinsonism includes extrapyramidal disorder, muscle rigidity, musculoskeletal stiffness, and hypokinesia. Akathisia includes akathisia and restlessness. Dystonia includes dystonia and oculogyration.

Commonly-Observed Adverse Reactions in Double-Blind, Placebo-Controlled Clinical Trials – Bipolar Mania

Adult Patients with Bipolar Mania

Table 10 lists the adverse reactions reported in 2% or more of risperidone-treated adult patients with bipolar mania in four 3-week, double-blind, placebo-controlled monotherapy trials.

Table 10.  Adverse Reactions in ≥ 2% of Risperidone-Treated Adult Patients (and greater than placebo) with Bipolar Mania in Double-Blind, Placebo-Controlled Monotherapy Trials

<div class="scrollingtable"><table border="1" cellpadding="0" cellspacing="0"> <col/> <col/> <col/> <tbody class="Headless"> <tr class="First"> <td align="center" class="Botrule Lrule Rrule Toprule" colspan="3"> <p class="First"> <span class="Bold">Percentage of Patients Reporting Reaction</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">System/Organ Class</span> </p> <p>Adverse Reaction</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">Risperidone</span> </p> <p> <span class="Bold">1 to 6 mg per day</span> </p> <p> <span class="Bold">(n = 448)</span> </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">Placebo</span> </p> <p> <span class="Bold">(n = 424)</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="3"> <p class="First"> <span class="Bold">Eye Disorders</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Vision blurred</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">2</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">1</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="3"> <p class="First"> <span class="Bold">Gastrointestinal Disorders</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Nausea</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">5</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">2</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Diarrhea</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">3</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">2</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Salivary hypersecretion</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">3</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">1</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Stomach discomfort</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">2</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">&lt;1</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="3"> <p class="First"> <span class="Bold">General Disorders</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Fatigue</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">2</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">1</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="3"> <p class="First"> <span class="Bold">Nervous System Disorders</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Parkinsonism*</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">25</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">9</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Sedation</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">11</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">4</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Akathisia*</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">9</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">3</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Tremor*</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">6</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">3</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Dizziness</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">6</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">5</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Dystonia*</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">5</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">1</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Lethargy</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">2</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">1</p> </td> </tr> </tbody> </table></div>

* Parkinsonism includes extrapyramidal disorder, parkinsonism, musculoskeletal stiffness, hypokinesia, muscle rigidity, muscle tightness, bradykinesia, cogwheel rigidity. Akathisia includes akathisia and restlessness. Tremor includes tremor and parkinsonian rest tremor. Dystonia includes dystonia, muscle spasms, oculogyration, torticollis.

Table 11 lists the adverse reactions reported in 2% or more of risperidone-treated adult patients with bipolar mania in two 3-week, double-blind, placebo-controlled adjuvant therapy trials.

Table 11.  Adverse Reactions in ≥ 2% of Risperidone-Treated Adult Patients (and greater than placebo) with Bipolar Mania in Double-Blind, Placebo-Controlled Adjunctive Therapy Trials

<div class="scrollingtable"><table border="1" cellpadding="0" cellspacing="0"> <col/> <col/> <col/> <tbody class="Headless"> <tr class="First"> <td align="center" class="Botrule Lrule Rrule Toprule" colspan="3"> <p class="First"> <span class="Bold">Percentage of Patients Reporting Reaction</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">System/Organ Class</span> </p> <p>Adverse Reaction</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">Risperidone +</span> </p> <p> <span class="Bold">Mood Stabilizer</span> </p> <p> <span class="Bold">(n = 127)</span> </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">Placebo +</span> </p> <p> <span class="Bold">Mood Stabilizer</span> </p> <p> <span class="Bold">(n = 126)</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="3"> <p class="First"> <span class="Bold">Cardiac Disorders</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Palpitations</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">2</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="3"> <p class="First"> <span class="Bold">Gastrointestinal Disorders</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Dyspepsia</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">9</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">8</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Nausea</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">6</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">4</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Diarrhea</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">6</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">4</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Salivary hypersecretion</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">2</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="3"> <p class="First"> <span class="Bold">General Disorders</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Chest pain</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">2</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">1</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="3"> <p class="First"> <span class="Bold">Infections and Infestations</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Urinary tract infection</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">2</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">1</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="3"> <p class="First"> <span class="Bold">Nervous System Disorders</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Parkinsonism*</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">14</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">4</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Sedation</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">9</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">4</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Akathisia*</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">8</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Dizziness</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">7</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">2</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Tremor</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">6</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">2</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Lethargy</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">2</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">1</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">Psychiatric Disorders</span> </p> </td><td class="Botrule Lrule Rrule Toprule" colspan="2"></td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Anxiety</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">3</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">2</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="3"> <p class="First"> <span class="Bold">Respiratory, Thoracic and Mediastinal Disorders</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Pharyngolaryngeal pain</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">5</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">2</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Cough</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">2</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">0</p> </td> </tr> </tbody> </table></div>

* Parkinsonism includes extrapyramidal disorder, hypokinesia and bradykinesia. Akathisia includes hyperkinesia and akathisia.

Pediatric Patients with Bipolar Mania

Table 12 lists the adverse reactions reported in 5% or more of risperidone-treated pediatric patients with bipolar mania in a 3-week double-blind, placebo-controlled trial.

Table 12.  Adverse Reactions in≥ 5% of Risperidone-Treated Pediatric Patients (and greater than placebo) with Bipolar Mania in Double-Blind, Placebo-Controlled Trials

<div class="scrollingtable"><table border="1" cellpadding="0" cellspacing="0"> <col/> <col/> <col/> <col/> <tbody class="Headless"> <tr class="First"> <td align="center" class="Botrule Lrule Rrule Toprule" colspan="4"> <p class="First"> <span class="Bold">Percentage of Patients Reporting</span><span class="Bold">Reaction</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"></td><td> <p class="First"> <span class="Bold">Risperidone</span> </p> </td><td class="Botrule Lrule Rrule Toprule" colspan="2"></td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">System/Organ Class</span> </p> <p>Adverse Reaction</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">0.5 to 2.5 mg per day</span> </p> <p> <span class="Bold">(n = 50)</span> </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">3 to 6 mg per day</span> </p> <p> <span class="Bold">(n = 61)</span> </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">Placebo</span> </p> <p> <span class="Bold">(n = 58)</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="4"> <p class="First"> <span class="Bold">Eye Disorders</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Vision blurred</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">4</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">7</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="4"> <p class="First"> <span class="Bold">Gastrointestinal Disorders</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Abdominal pain upper</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">16</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">13</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">5</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Nausea</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">16</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">13</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">7</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Vomiting</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">10</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">10</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">5</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Diarrhea</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">8</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">7</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">2</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Dyspepsia</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">10</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">3</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">2</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Stomach discomfort</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">6</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">0</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">2</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="4"> <p class="First"> <span class="Bold">General Disorders</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Fatigue</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">18</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">30</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">3</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="4"> <p class="First"> <span class="Bold">Metabolism and Nutrition Disorders</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Increased appetite</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">4</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">7</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">2</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="4"> <p class="First"> <span class="Bold">Nervous System Disorders</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Sedation</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">42</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">56</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">19</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Dizziness</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">16</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">13</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">5</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Parkinsonism*</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">6</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">12</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">3</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Dystonia*</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">6</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">5</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Akathisia*</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">0</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">8</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">2</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="4"> <p class="First"> <span class="Bold">Psychiatric Disorders</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Anxiety</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">0</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">8</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">3</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="4"> <p class="First"> <span class="Bold">Respiratory, Thoracic and Mediastinal Disorders</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Pharyngolaryngeal pain</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">10</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">3</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">5</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="4"> <p class="First"> <span class="Bold">Skin and Subcutaneous Tissue Disorders</span> </p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Rash</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">0</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">7</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">2</p> </td> </tr> </tbody> </table></div>

* Parkinsonism includes musculoskeletal stiffness, extrapyramidal disorder, bradykinesia, and nuchal rigidity. Dystonia includes dystonia, laryngospasm, and muscle spasms. Akathisia includes restlessness and akathisia.

Commonly-Observed Adverse Reactions in Double-Blind, Placebo-Controlled Clinical Trials - Autistic Disorder

Table 13 lists the adverse reactions reported in 5% or more of risperidone-treated pediatric patients treated for irritability associated with autistic disorder in two 8-week, double-blind, placebo-controlled trials and one 6-week double-blind, placebo-controlled study.

Table 13.  Adverse Reactions in≥5% of Risperidone-Treated Pediatric Patients (and greater than placebo) Treated for Irritability Associated with Autistic Disorder in Double-Blind, Placebo-Controlled Trials

<div class="scrollingtable"><table border="1" cellpadding="0" cellspacing="0"> <col/> <col/> <col/> <tbody class="Headless"> <tr class="First"> <td align="center" class="Botrule Lrule Rrule Toprule" colspan="3"> <p class="First"> <span class="Bold">Percentage of Patients Reporting Reaction</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">System/Organ Class</span> </p> <p> <span class="Bold">Adverse Reaction</span> </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">Risperidone</span> </p> <p> <span class="Bold">0.5 to 4 mg/day</span> </p> <p> <span class="Bold">(n = 107)</span> </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">Placebo</span> </p> <p> <span class="Bold">(n = 115)</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="3"> <p class="First"> <span class="Bold">Gastrointestinal Disorders</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Vomiting</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">20</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">17</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Constipation</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">17</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">6</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Dry mouth</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">10</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">4</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Nausea</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">8</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">5</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Salivary hypersecretion</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">7</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">1</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="3"> <p class="First"> <span class="Bold">General Disorders and Administration Site Conditions</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Fatigue</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">31</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">9</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Pyrexia</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">16</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">13</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Thirst</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">7</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">4</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="3"> <p class="First"> <span class="Bold">Infections and Infestations</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Nasopharyngitis</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">19</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">9</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Rhinitis</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">9</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">7</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Upper respiratory tract infection</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">8</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">3</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="3"> <p class="First"> <span class="Bold">Investigations</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Weight increased</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">8</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">2</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="3"> <p class="First"> <span class="Bold">Metabolism and Nutrition Disorders</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Increased appetite</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">44</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">15</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="3"> <p class="First"> <span class="Bold">Nervous System Disorders</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Sedation</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">63</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">15</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Drooling</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">12</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">4</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Headache</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">12</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">10</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Tremor</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">8</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">1</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Dizziness</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">8</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">2</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Parkinsonism*</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">8</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">1</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="3"> <p class="First"> <span class="Bold">Renal and Urinary Disorders</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Enuresis</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">16</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">10</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="3"> <p class="First"> <span class="Bold">Respiratory, Thoracic and Mediastinal Disorders</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Cough</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">17</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">12</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Rhinorrhea</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">12</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">10</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Nasal congestion</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">10</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">4</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="3"> <p class="First"> <span class="Bold">Skin and Subcutaneous Tissue Disorders</span> </p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Rash</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">8</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">5</p> </td> </tr> </tbody> </table></div>

*Parkinsonism includes musculoskeletal stiffness, extrapyramidal disorder, muscle rigidity, cogwheel rigidity, and muscle tightness.

Other Adverse Reactions Observed During the Clinical Trial Evaluation of Risperidone

The following additional adverse reactions occurred across all placebo-controlled, active-controlled, and open-label studies of risperidone in adults and pediatric patients.

Blood and Lymphatic System Disorders: anemia, granulocytopenia, neutropenia

Cardiac Disorders: sinus bradycardia, sinus tachycardia, atrioventricular block first degree, bundle branch block left, bundle branch block right, atrioventricular block

Ear and Labyrinth Disorders: ear pain, tinnitus

Endocrine Disorders: hyperprolactinemia

Eye Disorders: ocular hyperemia, eye discharge, conjunctivitis, eye rolling, eyelid edema, eye swelling, eyelid margin crusting, dry eye, lacrimation increased, photophobia, glaucoma, visual acuity reduced

Gastrointestinal Disorders: dysphagia, fecaloma, fecal incontinence, gastritis, lip swelling, cheilitis, aptyalism

General Disorders: edema peripheral, thirst, gait disturbance, influenza-like illness, pitting edema, edema, chills, sluggishness, malaise, chest discomfort, face edema, discomfort, generalized edema, drug withdrawal syndrome, peripheral coldness, feeling abnormal

Immune System Disorders: drug hypersensitivity

Infections and Infestations: pneumonia, influenza, ear infection, viral infection, pharyngitis, tonsillitis, bronchitis, eye infection, localized infection, cystitis, cellulitis, otitis media, onychomycosis, acarodermatitis, bronchopneumonia, respiratory tract infection, tracheobronchitis, otitis media chronic

Investigations: body temperature increased, blood prolactin increased, alanine aminotransferase increased, electrocardiogram abnormal, eosinophil count increased, white blood cell count decreased, blood glucose increased, hemoglobin decreased, hematocrit decreased, body temperature decreased, blood pressure decreased, transaminases increased

Metabolism and Nutrition Disorders: decreased appetite, polydipsia, anorexia

Musculoskeletal and Connective Tissue Disorders: joint stiffness, joint swelling, musculoskeletal chest pain, posture abnormal, myalgia, neck pain, muscular weakness, rhabdomyolysis

Nervous System Disorders: balance disorder, disturbance in attention, dysarthria, unresponsive to stimuli, depressed level of consciousness, movement disorder, transient ischemic attack, coordination abnormal, cerebrovascular accident, speech disorder, syncope, loss of consciousness, hypoesthesia, tardive dyskinesia, dyskinesia, cerebral ischemia, cerebrovascular disorder, neuroleptic malignant syndrome, diabetic coma, head titubation

Psychiatric Disorders: agitation, blunted affect, confusional state, middle insomnia, nervousness, sleep disorder, listlessness, libido decreased, and anorgasmia

Renal and Urinary Disorders: enuresis, dysuria, pollakiuria, urinary incontinence

Reproductive System and Breast Disorders: menstruation irregular, amenorrhea, gynecomastia, galactorrhea, vaginal discharge, menstrual disorder, erectile dysfunction, retrograde ejaculation, ejaculation disorder, sexual dysfunction, breast enlargement

Respiratory, Thoracic, and Mediastinal Disorders: wheezing, pneumonia aspiration, sinus congestion, dysphonia, productive cough, pulmonary congestion, respiratory tract congestion, rales, respiratory disorder, hyperventilation, nasal edema

Skin and Subcutaneous Tissue Disorders: erythema, skin discoloration, skin lesion, pruritus, skin disorder, rash erythematous, rash papular, rash generalized, rash maculopapular, acne, hyperkeratosis, seborrheic dermatitis

Vascular Disorders: hypotension, flushing

Discontinuations Due to Adverse Reactions

Schizophrenia - Adults

Approximately 7% (39/564) of risperidone-treated patients in double-blind, placebo-controlled trials discontinued treatment due to an adverse reaction, compared with 4% (10/225) who were receiving placebo. The adverse reactions associated with discontinuation in 2 or more risperidone-treated patients were:

Table 14.  Adverse Reactions Associated With Discontinuation in 2 or More Risperidone-Treated Adult Patients in Schizophrenia Trials

<div class="scrollingtable"><table border="1" cellpadding="0" cellspacing="0"> <col/> <col/> <col/> <col/> <tbody class="Headless"> <tr class="First"> <td align="center" class="Botrule Lrule Rrule Toprule" colspan="4"> <p class="First"> <span class="Bold">Risperidone</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">Adverse Reaction</span> </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">2 to 8 mg/day</span> </p> <p> <span class="Bold">(n = 366)</span> </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">&gt; 8 to 16 mg/day</span> </p> <p> <span class="Bold">(n = 198)</span> </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">Placebo</span> </p> <p> <span class="Bold">(n = 225)</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Dizziness</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">1.4%</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">1%</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">0%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Nausea</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">1.4%</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">0%</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">0%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Vomiting</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">0.8%</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">0%</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">0%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Parkinsonism</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">0.8%</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">0%</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">0%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Somnolence</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">0.8%</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">0%</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">0%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Dystonia</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">0.5%</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">0%</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">0%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Agitation</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">0.5%</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">0%</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">0%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Abdominal pain</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">0.5%</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">0%</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">0%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Orthostatic hypotension</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">0.3%</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">0.5%</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">0%</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Akathisia</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">0.3%</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">2%</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">0%</p> </td> </tr> </tbody> </table></div>

Discontinuation for extrapyramidal symptoms (including Parkinsonism, akathisia, dystonia, and tardive dyskinesia) was 1% in placebo-treated patients, and 3.4% in active control-treated patients in a double-blind, placebo- and active-controlled trial.

Schizophrenia - Pediatrics

Approximately 7% (7/106), of risperidone-treated patients discontinued treatment due to an adverse reaction in a double-blind, placebo-controlled trial, compared with 4% (2/54) placebo-treated patients. The adverse reactions associated with discontinuation for at least one risperidone-treated patient were dizziness (2%), somnolence (1%), sedation (1%), lethargy (1%), anxiety (1%), balance disorder (1%), hypotension (1%), and palpitation (1%).

Bipolar Mania – Adults

In double-blind, placebo-controlled trials with risperidone as monotherapy, approximately 6% (25/448) of risperidone-treated patients discontinued treatment due to an adverse event, compared with approximately 5% (19/424) of placebo-treated patients. The adverse reactions associated with discontinuation in risperidone-treated patients were:

Table 15.  Adverse Reactions Associated With Discontinuation in 2 or More Risperidone-Treated Adult Patients in Bipolar Mania Clinical Trials

<div class="scrollingtable"><table border="1" cellpadding="0" cellspacing="0"> <col/> <col/> <col/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">Adverse Reaction</span> </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">Risperidone</span> </p> <p> <span class="Bold">1 to 6 mg/day</span> </p> <p> <span class="Bold">(n = 448)</span> </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">Placebo</span> </p> <p> <span class="Bold">(n = 424)</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Parkinsonism</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">0.4%</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">0%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Lethargy</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">0.2%</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">0%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Dizziness</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">0.2%</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">0%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Alanine aminotransferase increased</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">0.2%</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">0.2%</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Aspartate aminotransferase increased</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">0.2%</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">0.2%</p> </td> </tr> </tbody> </table></div>

Bipolar Mania - Pediatrics

In a double-blind, placebo-controlled trial 12% (13/111) of risperidone-treated patients discontinued due to an adverse reaction, compared with 7% (4/58) of placebo-treated patients. The adverse reactions associated with discontinuation in more than one risperidone-treated pediatric patient were nausea (3%), somnolence (2%), sedation (2%), and vomiting (2%).

Autistic Disorder - Pediatrics

In the two 8-week, placebo-controlled trials in pediatric patients treated for irritability associated with autistic disorder (n = 156), one risperidone-treated patient discontinued due to an adverse reaction (Parkinsonism), and one placebo-treated patient discontinued due to an adverse event.

Dose Dependency of Adverse Reactions in Clinical Trials

Extrapyramidal Symptoms

Data from two fixed-dose trials in adults with schizophrenia provided evidence of dose-relatedness for extrapyramidal symptoms associated with risperidone treatment.

Two methods were used to measure extrapyramidal symptoms (EPS) in an 8-week trial comparing 4 fixed doses of risperidone (2, 6, 10, and 16 mg/day), including (1) a Parkinsonism score (mean change from baseline) from the Extrapyramidal Symptom Rating Scale, and (2) incidence of spontaneous complaints of EPS:

Table 16.

<div class="scrollingtable"><table border="1" cellpadding="0" cellspacing="0"> <col/> <col/> <col/> <col/> <col/> <col/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">Dose Groups</span> </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">Placebo</span> </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">Risperidone</span> </p> <p> <span class="Bold">2 mg</span> </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">Risperidone</span> </p> <p> <span class="Bold">6 mg</span> </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">Risperidone</span> </p> <p> <span class="Bold">10 mg</span> </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">Risperidone</span> </p> <p> <span class="Bold">16 mg</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Parkinsonism</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">1.2</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">0.9</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">1.8</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">2.4</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">2.6</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule"> <p class="First">EPS Incidence</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">13%</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">17%</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">21%</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">21%</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">35%</p> </td> </tr> </tbody> </table></div>

Similar methods were used to measure extrapyramidal symptoms (EPS) in an 8-week trial comparing 5 fixed doses of risperidone (1, 4, 8, 12, and 16 mg/day):

Table 17.

<div class="scrollingtable"><table border="1" cellpadding="0" cellspacing="0"> <col/> <col/> <col/> <col/> <col/> <col/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">Dose Groups</span> </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">Risperidone</span> </p> <p> <span class="Bold">1 mg</span> </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">Risperidone</span> </p> <p> <span class="Bold">4 mg</span> </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">Risperidone</span> </p> <p> <span class="Bold">8 mg</span> </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">Risperidone</span> </p> <p> <span class="Bold">12 mg</span> </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">Risperidone</span> </p> <p> <span class="Bold">16 mg</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Parkinsonism</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">0.6</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">1.7</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">2.4</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">2.9</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">4.1</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule"> <p class="First">EPS Incidence</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">7%</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">12%</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">17%</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">18%</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">20%</p> </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, they occur more frequently and with greater severity with high potency and at higher doses of first generation antipsychotic drugs. An elevated risk of acute dystonia is observed in males and younger age groups.

Other Adverse Reactions

Adverse event data elicited by a checklist for side effects from a large study comparing 5 fixed doses of risperidone (1, 4, 8, 12, and 16 mg/day) were explored for dose-relatedness of adverse events. A Cochran-Armitage Test for trend in these data revealed a positive trend (p<0.05) for the following adverse reactions: somnolence, vision abnormal, dizziness, palpitations, weight increase, erectile dysfunction, ejaculation disorder, sexual function abnormal, fatigue, and skin discoloration.

Changes in Body Weight

Weight gain was observed in short-term, controlled trials and longer-term uncontrolled studies in adult and pediatric patients [ see Warnings and Precautions(5.5),Adverse Reactions(6),and Use in Specific Populations(8.4)].

Changes in ECG Parameters

Between-group comparisons for pooled placebo-controlled trials in adults revealed no statistically significant differences between risperidone and placebo in mean changes from baseline in ECG parameters, including QT, QTc, and PR intervals, and heart rate. When all risperidone doses were pooled from randomized controlled trials in several indications, there was a mean increase in heart rate of 1 beat per minute compared to no change for placebo patients. In short-term schizophrenia trials, higher doses of risperidone (8 to 16 mg/day) were associated with a higher mean increase in heart rate compared to placebo (4 to 6 beats per minute). In pooled placebo-controlled acute mania trials in adults, there were small decreases in mean heart rate, similar among all treatment groups.

In the two placebo-controlled trials in children and adolescents with autistic disorder (aged 5 to 16 years) mean changes in heart rate were an increase of 8.4 beats per minute in the risperidone groups and 6.5 beats per minute in the placebo group. There were no other notable ECG changes.

In a placebo-controlled acute mania trial in children and adolescents (aged 10 to 17 years), there were no significant changes in ECG parameters, other than the effect of risperidone to transiently increase pulse rate (< 6 beats per minute). In two controlled schizophrenia trials in adolescents (aged 13 to 17 years), there were no clinically meaningful changes in ECG parameters including corrected QT intervals between treatment groups or within treatment groups over time.

The following adverse reactions have been identified during postapproval use of risperidone. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These adverse reactions include: alopecia, anaphylactic reaction, angioedema, atrial fibrillation, cardiopulmonary arrest, catatonia, diabetic ketoacidosis in patients with impaired glucose metabolism, dysgeusia, hypoglycemia, hypothermia, ileus, inappropriate antidiuretic hormone secretion, intestinal obstruction, jaundice, mania, pancreatitis, pituitary adenoma, precocious puberty, pulmonary embolism, QT prolongation, sleep apnea syndrome, somnambulism, Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN), sudden death, thrombocytopenia, thrombotic thrombocytopenic purpura, urinary retention, and water intoxication.

Postmarketing cases of extrapyramidal symptoms (dystonia and dyskinesia) have been reported in patients concomitantly taking methylphenidate and risperidone when there was an increase or decrease in dosage, initiation, or discontinuation of either or both medications.

The dose of risperidone should be adjusted when used in combination with CYP2D6 enzyme inhibitors (e.g., fluoxetine, and paroxetine) and enzyme inducers (e.g., carbamazepine) [ see Table 18 and Dosage and Administration (2.5)]. Dose adjustment is not recommended for risperidone when co-administered with ranitidine, cimetidine, amitriptyline, or erythromycin [ seeT able 18].

<div class="scrollingtable"><table> <caption> <span>Table 18.  Summary of Effect of Co-administered Drugs on Exposure to Active Moiety (Risperidone + 9-HydroxyRisperidone) in Healthy Subjects or Patients with Schizophrenia</span> </caption> <col/> <col/> <col/> <col/> <col/> <col/> <thead> <tr class="First Last"> <td class="Botrule Lrule Rrule Toprule" valign="top"><span class="Bold">Co-administered Drug</span></td><td class="Botrule Lrule Rrule Toprule" colspan="2" valign="top"><span class="Bold">  Dosing Schedule</span></td><td class="Botrule Lrule Rrule Toprule" colspan="2" valign="top"> <p class="First"> <span class="Bold">Effect on Active Moiety</span> </p> <p> <span class="Bold">(Risperidone + 9- Hydroxy-Risperidone (Ratio*)</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"><span class="Bold">  Risperidone Dose Recommendation</span></td> </tr> </thead> <tbody> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" valign="top"></td><td class="Botrule Lrule Rrule Toprule" valign="top"> Co-administered Drug</td><td class="Botrule Lrule Rrule Toprule" valign="top"> Risperidone</td><td class="Botrule Lrule Rrule Toprule" valign="top"> AUC</td><td class="Botrule Lrule Rrule Toprule" valign="top"> C <span class="Sub">max</span></td><td class="Botrule Lrule Rrule Toprule" valign="top"></td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="6" valign="top"> Enzyme (CYP2D6) Inhibitors</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> Fluoxetine</td><td class="Botrule Lrule Rrule Toprule" valign="top"> 20 mg/day</td><td class="Botrule Lrule Rrule Toprule" valign="top"> 2 or 3 mg twice daily</td><td class="Botrule Lrule Rrule Toprule" valign="top"> 1.4</td><td class="Botrule Lrule Rrule Toprule" valign="top"> 1.5</td><td class="Botrule Lrule Rrule Toprule" valign="top"> Re-evaluate dosing. Do not exceed 8 mg/day</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" rowspan="3" valign="top"> Paroxetine</td><td class="Botrule Lrule Rrule Toprule" valign="top"> 10 mg/day</td><td class="Botrule Lrule Rrule Toprule" valign="top"> 4 mg/day</td><td class="Botrule Lrule Rrule Toprule" valign="top"> 1.3</td><td class="Botrule Lrule Rrule Toprule" valign="top"> -</td><td class="Botrule Lrule Rrule Toprule" rowspan="3" valign="top"> Re-evaluate dosing. Do not exceed 8 mg/day</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> 20 mg/day</td><td class="Botrule Lrule Rrule Toprule" valign="top"> 4 mg/day</td><td class="Botrule Lrule Rrule Toprule" valign="top"> 1.6</td><td class="Botrule Lrule Rrule Toprule" valign="top"> -</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> 40 mg/day</td><td class="Botrule Lrule Rrule Toprule" valign="top"> 4 mg/day</td><td class="Botrule Lrule Rrule Toprule" valign="top"> 1.8</td><td class="Botrule Lrule Rrule Toprule" valign="top"> -</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="6" valign="top"> Enzyme (CYP3A/ PgP inducers) Inducers</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> Carbamazepine</td><td class="Botrule Lrule Rrule Toprule" valign="top"> 573 ± 168 mg/day</td><td class="Botrule Lrule Rrule Toprule" valign="top"> 3 mg twice daily</td><td class="Botrule Lrule Rrule Toprule" valign="top"> 0.51</td><td class="Botrule Lrule Rrule Toprule" valign="top"> 0.55</td><td class="Botrule Lrule Rrule Toprule" valign="top"> Titrate dose upwards. Do not exceed twice the patient’s usual dose</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="6" valign="top"> Enzyme (CYP3A) Inhibitors</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> Ranitidine</td><td class="Botrule Lrule Rrule Toprule" valign="top"> 150 mg twice daily</td><td class="Botrule Lrule Rrule Toprule" valign="top"> 1 mg single dose</td><td class="Botrule Lrule Rrule Toprule" valign="top"> 1.2</td><td class="Botrule Lrule Rrule Toprule" valign="top"> 1.4</td><td class="Botrule Lrule Rrule Toprule" valign="top"> Dose adjustment not needed</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> Cimetidine</td><td class="Botrule Lrule Rrule Toprule" valign="top"> 400 mg twice daily</td><td class="Botrule Lrule Rrule Toprule" valign="top"> 1 mg single dose</td><td class="Botrule Lrule Rrule Toprule" valign="top"> 1.1</td><td class="Botrule Lrule Rrule Toprule" valign="top"> 1.3</td><td class="Botrule Lrule Rrule Toprule" valign="top"> Dose adjustment not needed</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> Erythromycin</td><td class="Botrule Lrule Rrule Toprule" valign="top"> 500 mg four times daily</td><td class="Botrule Lrule Rrule Toprule" valign="top"> 1 mg single dose</td><td class="Botrule Lrule Rrule Toprule" valign="top"> 1.1</td><td class="Botrule Lrule Rrule Toprule" valign="top"> 0.94</td><td class="Botrule Lrule Rrule Toprule" valign="top"> Dose adjustment not needed</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="6" valign="top"> Other Drugs</td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule" valign="top"> Amitriptyline</td><td class="Botrule Lrule Rrule Toprule" valign="top"> 50 mg twice daily</td><td class="Botrule Lrule Rrule Toprule" valign="top"> 3 mg twice daily</td><td class="Botrule Lrule Rrule Toprule" valign="top"> 1.2</td><td class="Botrule Lrule Rrule Toprule" valign="top"> 1.1</td><td class="Botrule Lrule Rrule Toprule" valign="top"> Dose adjustment not needed</td> </tr> </tbody> </table></div>

*Change relative to reference

Effect of Risperidone on other drugs

Lithium

Repeated oral doses of risperidone (3 mg twice daily) did not affect the exposure (AUC) or peak plasma concentrations (C max) of lithium (n = 13). Dose adjustment for lithium is not recommended.

Valproate

Repeated oral doses of risperidone (4 mg once daily) did not affect the pre-dose or average plasma concentrations and exposure (AUC) of valproate (1000 mg/day in three divided doses) compared to placebo (n = 21). However, there was a 20% increase in valproate peak plasma concentration (C max) after concomitant administration of risperidone. Dose adjustment for valproate is not recommended.

Digoxin

Risperidone (0.25 mg twice daily) did not show a clinically relevant effect on the pharmacokinetics of digoxin. Dose adjustment for digoxin is not recommended.

Centrally Acting Drugs and Alcohol

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

Drugs with Hypotensive Effects

Because of its potential for inducing hypotension, risperidone may enhance the hypotensive effects of other therapeutic agents with this potential.

Levodopa and Dopamine Agonists

Risperidone may antagonize the effects of levodopa and dopamine agonists.

Methylphenidate

Concomitant use with methylphenidate, when there is change in dosage of either medication, may increase the risk of extrapyramidal symptoms (EPS). Monitor for symptoms of EPS with concomitant use of risperidone and methylphenidate [ see Adverse Reactions (6.2)].

Clozapine

Chronic administration of clozapine with risperidone may decrease the clearance of risperidone.

Pregnancy Exposure Registry

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

Risk Summary

Neonates exposed to antipsychotic drugs during the third trimester of pregnancy 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 risperidone 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 risperidone, during pregnancy ( see Clinical Considerations).

Oral administration of risperidone to pregnant mice caused cleft palate at doses 3 to 4 times the maximum recommended human dose (MRHD) with maternal toxicity observed at 4-times MRHD based on mg/m 2body surface area. Risperidone was not teratogenic in rats or rabbits at doses up to 6-times the MRHD based on mg/m 2body surface area. Increased stillbirths and decreased birth weight occurred after oral risperidone administration to pregnant rats at 1.5-times the MRHD based on mg/m 2body surface area. Learning was impaired in offspring of rats when the dams were dosed at 0.6-times the MRHD and offspring mortality increased at doses 0.1 to 3 times the MRHD based on mg/m 2body surface area.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, 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/or embryo/fetal riskThere 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 risperidone, 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

Published data from observational studies, birth registries, and case reports on the use of atypical antipsychotics during pregnancy do not report a clear association with antipsychotics and major birth defects. A prospective observational study including 6 women treated with risperidone demonstrated placental passage of risperidone. 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. There was a small increase in the risk of major birth defects (RR=1.26, 95% CI 1.02-1.56) and of cardiac malformations (RR=1.26, 95% CI 0.88- 1.81) in a subgroup of 1566 women exposed to risperidone during the first trimester of pregnancy; however, there is no mechanism of action to explain the difference in malformation rates.

Animal Data

Oral administration of risperidone to pregnant mice during organogenesis caused cleft palate at 10 mg/kg/day which is 3 times the MRHD of 16 mg/day based on mg/m 2body surface area: maternal toxicity occurred at 4 times the MRHD. Risperidone was not teratogenic when administered orally to rats at 0.6 to 10 mg/kg/day and rabbits at 0.3 to 5 mg/kg/day, which are up to 6 times the MRHD of 16 mg/day risperidone based on mg/m 2body surface area. Learning was impaired in offspring of rats dosed orally throughout pregnancy at 1 mg/kg/day which is 0.6 times the MRHD and neuronal cell death increased in fetal brains of offspring of rats dosed during pregnancy at 1 and 2 mg/kg/day which are 0.6 and 1.2 times the MRHD based on mg/m 2body surface area; postnatal development and growth of the offspring were also delayed.

Rat offspring mortality increased during the first 4 days of lactation when pregnant rats were dosed throughout gestation at 0.16 to 5 mg/kg/day which are 0.1 to 3 times the MRHD of 16 mg/day based on mg/m 2body surface area. It is not known whether these deaths were due to a direct effect on the fetuses or pups or to effects on the dams; a no-effect dose could not be determined. The rate of stillbirths was increased at 2.5 mg/kg or 1.5 times the MRHD based on mg/m 2body surface area.

In a rat cross-fostering study the number of live offspring was decreased, the number of stillbirths increased, and the birth weight was decreased in offspring of drug-treated pregnant rats. In addition, the number of deaths increased by Day 1 among offspring of drug-treated pregnant rats, regardless of whether or not the offspring were cross-fostered. Risperidone also appeared to impair maternal behavior in that offspring body weight gain and survival (from Day 1 to 4 of lactation) were reduced in offspring born to control but reared by drug-treated dams. All of these effects occurred at 5 mg/kg which is 3 times the MRHD based on mg/m 2and the only dose tested in the study.

Risk Summary

Limited data from published literature reports the presence of risperidone and its metabolite, 9- hydroxyrisperidone, in human breast milk at relative infant dose ranging between 2.3% and 4.7% of the maternal weight-adjusted dosage. There are reports of sedation, failure to thrive, jitteriness, and extrapyramidal symptoms (tremors and abnormal muscle movements) in breastfed infants exposed to risperidone ( see Clinical Considerations). There is no information on the effects of risperidone on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for risperidone and any potential adverse effects on the breastfed child from Risperidone or from the mother’s underlying condition.

Clinical Considerations

Infants exposed to risperidone through breastmilk should be monitored for excess sedation, failure to thrive, jitteriness, and extrapyramidal symptoms (tremors and abnormal muscle movements).

Infertility

Females

Based on the pharmacologic action of risperidone (D2 receptor antagonism), treatment with risperidone 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 (5.6)].

Approved Pediatric Indications

Schizophrenia

The efficacy and safety of risperidone in the treatment of schizophrenia were demonstrated in 417 adolescents, aged 13 to 17 years, in two short-term (6 and 8 weeks, respectively) double-blind controlled trials [ seeIndications and Usage(1.1),Adverse Reactions(6.1),and Clinical Studies(14.1)]. Additional safety and efficacy information was also assessed in one long-term (6-month) open-label extension study in 284 of these adolescent patients with schizophrenia.

Safety and effectiveness of risperidone in children less than 13 years of age with schizophrenia have not been established.

Bipolar I Disorder

The efficacy and safety of risperidone in the short-term treatment of acute manic or mixed episodes associated with Bipolar I Disorder in 169 children and adolescent patients, aged 10 to 17 years, were demonstrated in one double-blind, placebo-controlled, 3-week trial [ seeIndications and Usage (1.2),Adverse Reactions (6.1),and Clinical Studies (14.2)].

Safety and effectiveness of risperidone in children less than 10 years of age with bipolar disorder have not been established.

Autistic Disorder

The efficacy and safety of risperidone in the treatment of irritability associated with autistic disorder were established in two 8-week, double-blind, placebo-controlled trials in 156 children and adolescent patients, aged 5 to 16 years [ seeIndications and Usage (1.3),Adverse Reactions (6.1)and Clinical Studies (14.4)]. Additional safety information was also assessed in a long-term study in patients with autistic disorder, or in short- and long-term studies in more than 1200 pediatric patients with psychiatric disorders other than autistic disorder, schizophrenia, or bipolar mania who were of similar age and weight, and who received similar dosages of risperidone as patients treated for irritability associated with autistic disorder.

A third study was a 6-week, multicenter, randomized, double-blind, placebo-controlled, fixed-dose study to evaluate the efficacy and safety of a lower than recommended dose of risperidone in subjects 5 to 17 years of age with autistic disorder and associated irritability, and related behavioral symptoms. There were two weight-based, fixed doses of risperidone (high-dose and low-dose). The high dose was 1.25 mg per day for patients weighing 20 to < 45 kg, and it was 1.75 mg per day for patients weighing ≥ 45 kg. The low dose was 0.125 mg per day for patients weighing 20 to < 45 kg, and it was 0.175 mg per day for patients weighing ≥ 45 kg. The study demonstrated the efficacy of high-dose risperidone, but it did not demonstrate efficacy for low-dose risperidone.

Adverse Reactions in Pediatric Patients

Tardive Dyskinesia

In clinical trials in 1885 children and adolescents treated with risperidone, 2 (0.1%) patients were reported to have tardive dyskinesia, which resolved on discontinuation of risperidone treatment [ see alsoWarnings and Precautions (5.4)].

Weight Gain

Weight gain has been observed in children and adolescents during treatment with risperidone. Clinical monitoring of weight is recommended during treatment.

Data derive from short-term placebo-controlled trials and longer-term uncontrolled studies in pediatric patients (ages 5 to 17 years) with schizophrenia, bipolar disorder, autistic disorder, or other psychiatric disorders. In the short-term trials (3 to 8 weeks), the mean weight gain for risperidone-treated patients was 2 kg, compared to 0.6 kg for placebo-treated patients. In these trials, approximately 33% of the risperidone group had weight gain ≥7%, compared to 7% in the placebo group. In longer-term, uncontrolled, open-label pediatric studies, the mean weight gain was 5.5 kg at Week 24 and 8 kg at Week 48 [ seeWarnings and Precautions (5.5)and Adverse Reactions (6.1)].

Somnolence

Somnolence was frequently observed in placebo-controlled clinical trials of pediatric patients with autistic disorder. Most cases were mild or moderate in severity. These events were most often of early onset with peak incidence occurring during the first two weeks of treatment, and transient with a median duration of 16 days. Somnolence was the most commonly observed adverse reaction in the clinical trial of bipolar disorder in children and adolescents, as well as in the schizophrenia trials in adolescents. As was seen in the autistic disorder trials, these adverse reactions were most often of early onset and transient in duration [ seeAdverse Reactions(6.1and 6.2)]. Patients experiencing persistent somnolence may benefit from a change in dosing regimen [ seeDosage and Administration(2.1,2.2,and 2.3)].

Hyperprolactinemia

Risperidone has been shown to elevate prolactin levels in children and adolescents as well as in adults [ seeWarnings and Precautions (5.6)]. In double-blind, placebo-controlled studies of up to 8 weeks duration in children and adolescents (aged 5 to 17 years) with autistic disorder or psychiatric disorders other than autistic disorder, schizophrenia, or bipolar mania, 49% of patients who received risperidone had elevated prolactin levels compared to 2% of patients who received placebo. Similarly, in placebo-controlled trials in children and adolescents (aged 10 to 17 years) with bipolar disorder, or adolescents (aged 13 to 17 years) with schizophrenia, 82 to 87% of patients who received risperidone had elevated levels of prolactin compared to 3 to 7% of patients on placebo. Increases were dose-dependent and generally greater in females than in males across indications.

In clinical trials in 1885 children and adolescents, galactorrhea was reported in 0.8% of risperidone-treated patients and gynecomastia was reported in 2.3% of risperidone-treated patients.

Growth and Sexual Maturation

The long-term effects of risperidone on growth and sexual maturation have not been fully evaluated in children and adolescents.

Juvenile Animal Studies

Juvenile dogs were treated with oral risperidone from weeks 10 to 50 of age (equivalent to the period of childhood through adolescence in humans), at doses of 0.31, 1.25, or 5 mg/kg/day, which are 1.2, 3.4, and 13.5 times the MRHD of 6 mg/day for children, based on mg/m 2body surface area. Bone length and density were decreased with a no-effect dose of 0.31 mg/kg/day; this dose produced plasma AUC of risperidone plus its active metabolite paliperidone (9- hydroxyrisperidone) that were similar to those in children and adolescents receiving the MRHD of 6 mg/day. In addition, sexual maturation was delayed at all doses in both males and females. The above effects showed little or no reversibility in females after a 12 week drug-free recovery period.

Juvenile rats, treated with oral risperidone from days 12 to 50 of age (equivalent to the period of infancy through adolescence in humans) showed impaired learning and memory performance (reversible only in females), with a no-effect dose of 0.63 mg/kg/day which is 0.5 times the MRHD of 6 mg/day for children, based on mg/m 2body surface area. This dose produced plasma AUC of risperidone plus paliperidone about half the exposure observed in humans at the MRHD. No other consistent effects on neurobehavioral or reproductive development were seen up to the highest tested dose of 1.25 mg/kg/day which is 1 time the MRHD and produced plasma AUC of risperidone plus paliperidone that were about two thirds of those observed in humans at the MRHD of 6 mg/ day for children.

Clinical studies of risperidone in the treatment of schizophrenia did not include sufficient numbers of patients aged 65 and over to determine whether or not they respond differently than younger patients. Other reported clinical experience has not identified differences in responses between elderly and younger patients. In general, a lower starting dose is recommended for an elderly patient, reflecting a decreased pharmacokinetic clearance in the elderly, as well as a greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy [ seeClinical Pharmacology (12.3)and Dosage and Administration(2.4,2.5)]. While elderly patients exhibit a greater tendency to orthostatic hypotension, its risk in the elderly may be minimized by limiting the initial dose to 0.5 mg twice daily followed by careful titration [ seeWarnings and Precautions (5.7)]. Monitoring of orthostatic vital signs should be considered in patients for whom this is of concern.

This drug is substantially excreted by the kidneys, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function [ seeDosage and Administration (2.4)].

In patients with moderate to severe (Clcr 59 to 15 mL/min) renal disease, clearance of the sum of risperidone and its active metabolite decreased by 60%, compared to young healthy subjects. Risperidone doses should be reduced in patients with renal disease [ seeDosage and Administration (2.4)].

While the pharmacokinetics of risperidone in subjects with liver disease were comparable to those in young healthy subjects, the mean free fraction of risperidone in plasma was increased by about 35% because of the diminished concentration of both albumin and α 1-acid glycoprotein. Risperidone doses should be reduced in patients with liver disease [ seeDosage and Administration (2.4)].

Patients with Parkinson’s Disease or Dementia with Lewy Bodies can experience increased sensitivity to risperidone. Manifestations can include confusion, obtundation, postural instability with frequent falls, extrapyramidal symptoms, and clinical features consistent with neuroleptic malignant syndrome.

Risperidone oral solution is not a controlled substance.

Risperidone has not been systematically studied in animals or humans for its potential for abuse. 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 risperidone misuse or abuse (e.g., development of tolerance, increases in dose, drug-seeking behavior).

Risperidone has not been systematically studied in animals or humans for its potential for tolerance or physical dependence.

Premarketing experience included eight reports of acute risperidone overdosage with estimated doses ranging from 20 to 300 mg and no fatalities. In general, reported signs and symptoms were those resulting from an exaggeration of the drug's known pharmacological effects, i.e., drowsiness and sedation, tachycardia and hypotension, and extrapyramidal symptoms. One case, involving an estimated overdose of 240 mg, was associated with hyponatremia, hypokalemia, prolonged QT, and widened QRS. Another case, involving an estimated overdose of 36 mg, was associated with a seizure.

Postmarketing experience includes reports of acute risperidone overdosage, with estimated doses of up to 360 mg. In general, the most frequently reported signs and symptoms are those resulting from an exaggeration of the drug's known pharmacological effects, i.e., drowsiness, sedation, tachycardia, hypotension, and extrapyramidal symptoms. Other adverse reactions reported since market introduction related to risperidone overdose include prolonged QT interval and convulsions. Torsade de pointes has been reported in association with combined overdose of risperidone and paroxetine.

For the most up to date information on the management of risperidone overdosage, contact a certified poison control center (1-800-222-1222 or www.poison.org). Provide supportive care including close medical supervision and monitoring. Treatment should consist of general measures employed in the management of overdosage with any drug. Consider the possibility of multiple drug overdosage. Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm and vital signs. Use supportive and symptomatic measures. There is no specific antidote to risperidone.

Risperidone oral solution contains risperidone, an atypical antipsychotic belonging to the chemical class of benzisoxazole derivatives. The chemical designation is 3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)- 1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one. Its molecular formula is C 23H 27FN 4O 2and its molecular weight is 410.49. The structural formula is:

{ "type": "p", "children": [], "text": "Risperidone oral solution contains risperidone, an atypical antipsychotic belonging to the chemical class of benzisoxazole derivatives. The chemical designation is 3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)- 1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one. Its molecular formula is C\n \n 23H\n \n 27FN\n \n 4O\n \n 2and its molecular weight is 410.49. The structural formula is:\n\n " }

Risperidone is a white to slightly beige powder. It is practically insoluble in water, freely soluble in methylene chloride, and soluble in methanol and 0.1 NHCl.

{ "type": "p", "children": [], "text": "Risperidone is a white to slightly beige powder. It is practically insoluble in water, freely soluble in methylene chloride, and soluble in methanol and 0.1\n \n NHCl.\n\n " }

Risperidone is also available as a 1 mg/mL oral solution. Risperidone Oral Solution contains the following inactive ingredients: benzoic acid, sodium hydroxide, sorbitol solution, tartaric acid, and purified water.

{ "type": "p", "children": [], "text": "Risperidone is also available as a 1 mg/mL oral solution. Risperidone Oral Solution contains the following inactive ingredients: benzoic acid, sodium hydroxide, sorbitol solution, tartaric acid, and purified water." }

The mechanism of action of risperidone in schizophrenia is unclear. The drug's therapeutic activity in schizophrenia could be mediated through a combination of dopamine Type 2 (D 2) and serotonin Type 2 (5HT 2) receptor antagonism. The clinical effect from risperidone results from the combined concentrations of risperidone and its major metabolite, 9-hydroxyrisperidone (paliperidone) [ seeClinical Pharmacology (12.3)]. Antagonism at receptors other than D 2and 5HT 2may explain some of the other effects of risperidone [ seeClinical Pharmacology (12.1)].

Risperidone is a monoaminergic antagonist with high affinity (Ki of 0.12 to 7.3 nM) for the serotonin Type 2 (5HT 2), dopamine Type 2 (D 2), α 1and α 2adrenergic, and H 1histaminergic receptors. Risperidone showed low to moderate affinity (Ki of 47 to 253 nM) for the serotonin 5HT 1C, 5HT 1D, and 5HT 1Areceptors, weak affinity (Ki of 620 to 800 nM) for the dopamine D 1and haloperidol-sensitive sigma site, and no affinity (when tested at concentrations >10 -5M) for cholinergic muscarinic or β 1and β 2adrenergic receptors.

Absorption

Risperidone is well absorbed. The absolute oral bioavailability of risperidone is 70% (CV = 25%). The relative oral bioavailability of risperidone from a tablet is 94% (CV = 10%) when compared to a solution.

Pharmacokinetic studies showed that Risperidone Orally Disintegrating Tablets and Risperidone Oral Solution are bioequivalent to Risperidone Tablets.

Plasma concentrations of risperidone, its major metabolite, 9-hydroxyrisperidone, and risperidone plus 9-hydroxyrisperidone are dose proportional over the dosing range of 1 to 16 mg daily (0.5 to 8 mg twice daily). Following oral administration of solution or tablet, mean peak plasma concentrations of risperidone occurred at about 1 hour. Peak concentrations of 9-hydroxyrisperidone occurred at about 3 hours in extensive metabolizers, and 17 hours in poor metabolizers. Steady-state concentrations of risperidone are reached in 1 day in extensive metabolizers and would be expected to reach steady-state in about 5 days in poor metabolizers. Steady-state concentrations of 9-hydroxyrisperidone are reached in 5 to 6 days (measured in extensive metabolizers).

Food Effect

Food does not affect either the rate or extent of absorption of risperidone. Thus, risperidone oral solution can be given with or without meals.

Distribution

Risperidone is rapidly distributed. The volume of distribution is 1 to 2 L/kg. In plasma, risperidone is bound to albumin and α 1-acid glycoprotein. The plasma protein binding of risperidone is approximately 90%, and that of its major metabolite, 9-hydroxyrisperidone, is 77%. Neither risperidone nor 9-hydroxyrisperidone displaces each other from plasma binding sites. High therapeutic concentrations of sulfamethazine (100 mcg/mL), warfarin (10 mcg/mL), and carbamazepine (10 mcg/mL) caused only a slight increase in the free fraction of risperidone at 10 ng/mL and 9-hydroxyrisperidone at 50 ng/mL, changes of unknown clinical significance.

Elimination

Metabolism

Risperidone is extensively metabolized in the liver. The main metabolic pathway is through hydroxylation of risperidone to 9-hydroxyrisperidone by the enzyme, CYP 2D6. A minor metabolic pathway is through N-dealkylation. The main metabolite, 9-hydroxyrisperidone, has similar pharmacological activity as risperidone. Consequently, the clinical effect of the drug results from the combined concentrations of risperidone plus 9-hydroxyrisperidone.

CYP 2D6, also called debrisoquin hydroxylase, is the enzyme responsible for metabolism of many neuroleptics, antidepressants, antiarrhythmics, and other drugs. CYP 2D6 is subject to genetic polymorphism (about 6% to 8% of Caucasians, and a very low percentage of Asians, have little or no activity and are “poor metabolizers”) and to inhibition by a variety of substrates and some non-substrates, notably quinidine. Extensive CYP 2D6 metabolizers convert risperidone rapidly into 9-hydroxyrisperidone, whereas poor CYP 2D6 metabolizers convert it much more slowly. Although extensive metabolizers have lower risperidone and higher 9-hydroxyrisperidone concentrations than poor metabolizers, the pharmacokinetics of risperidone and 9-hydroxyrisperidone combined, after single and multiple doses, are similar in extensive and poor metabolizers.

Excretion

Risperidone and its metabolites are eliminated via the urine and, to a much lesser extent, via the feces. As illustrated by a mass balance study of a single 1 mg oral dose of 14C-risperidone administered as solution to three healthy male volunteers, total recovery of radioactivity at 1 week was 84%, including 70% in the urine and 14% in the feces.

The apparent half-life of risperidone was 3 hours (CV = 30%) in extensive metabolizers and 20 hours (CV = 40%) in poor metabolizers. The apparent half-life of 9-hydroxyrisperidone was about 21 hours (CV = 20%) in extensive metabolizers and 30 hours (CV = 25%) in poor metabolizers. The pharmacokinetics of risperidone and 9-hydroxyrisperidone combined, after single and multiple doses, were similar in extensive and poor metabolizers, with an overall mean elimination half-life of about 20 hours.

Drug Interaction Studies

Risperidone could be subject to two kinds of drug-drug interactions. First, inhibitors of CYP 2D6 interfere with conversion of risperidone to 9-hydroxyrisperidone [ seeDrug Interactions (7)]. This occurs with quinidine, giving essentially all recipients a risperidone pharmacokinetic profile typical of poor metabolizers. The therapeutic benefits and adverse effects of risperidone in patients receiving quinidine have not been evaluated, but observations in a modest number (n≅70) of poor metabolizers given risperidone do not suggest important differences between poor and extensive metabolizers. Second, co-administration of known enzyme inducers (e.g., carbamazepine, phenytoin, rifampin, and phenobarbital) with risperidone may cause a decrease in the combined plasma concentrations of risperidone and 9-hydroxyrisperidone [ seeDrug Interactions (7)]. It would also be possible for risperidone to interfere with metabolism of other drugs metabolized by CYP 2D6. Relatively weak binding of risperidone to the enzyme suggests this is unlikely [ seeDrug Interactions (7)].

In vitrostudies indicate that risperidone is a relatively weak inhibitor of CYP 2D6. Therefore, risperidone is not expected to substantially inhibit the clearance of drugs that are metabolized by this enzymatic pathway. In drug interaction studies, risperidone did not significantly affect the pharmacokinetics of donepezil and galantamine, which are metabolized by CYP 2D6.

In vitrostudies demonstrated that drugs metabolized by other CYP isozymes, including 1A1, 1A2, 2C9, 2C19, and 3A4, are only weak inhibitors of risperidone metabolism.

Specific Populations

Renal and Hepatic Impairment

[ See Use in Specific Populations(8.6and 8.7) ].

Elderly

In healthy elderly subjects, renal clearance of both risperidone and 9-hydroxyrisperidone was decreased, and elimination half-lives were prolonged compared to young healthy subjects. Dosing should be modified accordingly in the elderly patients [ seeUse in Specific Populations (8.5)].

Pediatric

The pharmacokinetics of risperidone and 9-hydroxyrisperidone in children were similar to those in adults after correcting for the difference in body weight.

Race and Gender Effects

No specific pharmacokinetic study was conducted to investigate race and gender effects, but a population pharmacokinetic analysis did not identify important differences in the disposition of risperidone due to gender (whether corrected for body weight or not) or race.

Carcinogenesis

Risperidone was administered in the diet at doses of 0.63, 2.5, and 10 mg/kg for 18 months to mice and for 25 months to rats. These doses are equivalent to approximately 0.2, 0.75, and 3 times (mice) and 0.4, 1.5, and 6 times (rats) the MRHD of 16 mg/day, based on mg/m 2body surface area. A maximum tolerated dose was not achieved in male mice. There were statistically significant increases in pituitary gland adenomas, endocrine pancreas adenomas, and mammary gland adenocarcinomas. The table below summarizes the multiples of the human dose on a mg/m 2(mg/kg) basis at which these tumors occurred.

<div class="scrollingtable"><table> <col/> <col/> <col/> <col/> <col/> <thead> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" valign="top"></td><td align="center" class="Botrule Lrule Rrule Toprule" colspan="4" valign="top"><span class="Bold">  Multiples of Maximum Human Dose in mg/m <span class="Sup">2</span> <br/> (mg/kg) </span></td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule" valign="top"><span class="Bold">  Tumor Type</span></td><td class="Botrule Lrule Rrule Toprule" valign="top"><span class="Bold">  Species</span></td><td class="Botrule Lrule Rrule Toprule" valign="top"><span class="Bold">  Sex</span></td><td class="Botrule Lrule Rrule Toprule" valign="top"><span class="Bold">  Lowest Effect Level</span></td><td class="Botrule Lrule Rrule Toprule" valign="top"><span class="Bold">  Highest No-Effect Level</span></td> </tr> </thead> <tbody> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" valign="top"> Pituitary adenomas</td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> mouse</td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> Female</td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 0.75 (9.4)</td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 0.2 (2.4)</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> Endocrine pancreas adenomas</td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> rat</td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> Male</td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 1.5 (9.4)</td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 0.4 (2.4)</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> Mammary gland adenocarcinomas</td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> mouse</td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> Female</td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 0.2 (2.4)</td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> none</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"></td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> rat</td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> Female</td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 0.4 (2.4)</td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> none</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"></td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> rat</td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> Male</td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 6 (37.5)</td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 1.5 (9.4)</td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule" valign="top"> Mammary gland neoplasm, Total</td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> rat</td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> Male</td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 1.5 (9.4)</td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 0.4 (2.4)</td> </tr> </tbody> </table></div>

Antipsychotic drugs have been shown to chronically elevate prolactin levels in rodents. Serum prolactin levels were not measured during the risperidone carcinogenicity studies; however, measurements during subchronic toxicity studies showed that risperidone elevated serum prolactin levels 5 to 6 fold in mice and rats at the same doses used in the carcinogenicity studies. An increase in mammary, pituitary, and endocrine pancreas 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 findings of prolactin-mediated endocrine tumors in rodents is unclear [ seeWarnings and Precautions (5.6)].

Mutagenesis

No evidence of mutagenic or clastogenic potential for risperidone was found in the in vitrotests of Ames gene mutation, the mouse lymphoma assay, rat hepatocyte DNA-repair assay, the chromosomal aberration test in human lymphocytes, Chinese hamster ovary cells, or in the in vivooral micronucleus test in mice and the sex-linked recessive lethal test in Drosophila.

Impairment of Fertility

Oral risperidone (0.16 to 5 mg/kg) impaired mating, but not fertility, in rat reproductive studies at doses 0.1 to 3 times the MRHD of 16 mg/day based on mg/m 2body surface area. The effect appeared to be in females, since impaired mating behavior was not noted in the male fertility study. In a subchronic study in Beagle dogs in which risperidone was administered orally at doses of 0.31 to 5 mg/kg, sperm motility and concentration were decreased at doses 0.6 to 10 times the MRHD based on mg/m 2body surface area. Dose-related decreases were also noted in serum testosterone at the same doses. Serum testosterone and sperm parameters partially recovered, but remained decreased after treatment was discontinued. A no-effect dose could not be determined in either rat or dog.

Adults

Short-Term Efficacy

The efficacy of risperidone in the treatment of schizophrenia was established in four short-term (4- to 8-week) controlled trials of psychotic inpatients who met DSM-III-R criteria for schizophrenia.

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, the Positive and Negative Syndrome Scale (PANSS) and the Scale for Assessing Negative Symptoms (SANS) were employed.

The results of the trials follow:

(1) In a 6-week, placebo-controlled trial (n = 160) involving titration of risperidone in doses up to 10 mg/day (twice-daily schedule), risperidone was generally superior to placebo on the BPRS total score, on the BPRS psychosis cluster, and marginally superior to placebo on the SANS.

(2) In an 8-week, placebo-controlled trial (n = 513) involving 4 fixed doses of risperidone (2 mg/day, 6 mg/day, 10 mg/day, and 16 mg/day, on a twice-daily schedule), all 4 risperidone groups were generally superior to placebo on the BPRS total score, BPRS psychosis cluster, and CGI severity score; the 3 highest risperidone dose groups were generally superior to placebo on the PANSS negative subscale. The most consistently positive responses on all measures were seen for the 6 mg dose group, and there was no suggestion of increased benefit from larger doses.

(3) In an 8-week, dose comparison trial (n = 1356) involving 5 fixed doses of risperidone (1 mg/day, 4 mg/day, 8 mg/day, 12 mg/day, and 16 mg/day, on a twice-daily schedule), the four highest risperidone dose groups were generally superior to the 1 mg risperidone dose group on BPRS total score, BPRS psychosis cluster, and CGI severity score. None of the dose groups were superior to the 1 mg group on the PANSS negative subscale. The most consistently positive responses were seen for the 4 mg dose group.

(4) In a 4-week, placebo-controlled dose comparison trial (n = 246) involving 2 fixed doses of risperidone (4 and 8 mg/day on a once-daily schedule), both risperidone dose groups were generally superior to placebo on several PANSS measures, including a response measure (>20% reduction in PANSS total score), PANSS total score, and the BPRS psychosis cluster (derived from PANSS). The results were generally stronger for the 8 mg than for the 4 mg dose group.

Long-Term Efficacy

In a longer-term trial, 365 adult outpatients predominantly meeting DSM-IV criteria for schizophrenia and who had been clinically stable for at least 4 weeks on an antipsychotic medication were randomized to risperidone (2 to 8 mg/day) or to an active comparator, for 1 to 2 years of observation for relapse. Patients receiving risperidone experienced a significantly longer time to relapse over this time period compared to those receiving the active comparator.

Pediatrics

The efficacy of risperidone in the treatment of schizophrenia in adolescents aged 13 to 17 years was demonstrated in two short-term (6 and 8 weeks), double-blind controlled trials. All patients met DSM-IV diagnostic criteria for schizophrenia and were experiencing an acute episode at time of enrollment. In the first trial (study #1), patients were randomized into one of three treatment groups: risperidone 1 to 3 mg/day (n = 55, mean modal dose = 2.6 mg), risperidone 4 to 6 mg/day (n = 51, mean modal dose = 5.3 mg), or placebo (n = 54). In the second trial (study #2), patients were randomized to either risperidone 0.15 to 0.6 mg/day (n = 132, mean modal dose = 0.5 mg) or risperidone 1.5 to 6 mg/day (n = 125, mean modal dose = 4 mg). In all cases, study medication was initiated at 0.5 mg/day (with the exception of the 0.15 to 0.6 mg/day group in study #2, where the initial dose was 0.05 mg/day) and titrated to the target dosage range by approximately Day 7. Subsequently, dosage was increased to the maximum tolerated dose within the target dose range by Day 14. The primary efficacy variable in all studies was the mean change from baseline in total PANSS score.

Results of the studies demonstrated efficacy of risperidone in all dose groups from 1 to 6 mg/day compared to placebo, as measured by significant reduction of total PANSS score. The efficacy on the primary parameter in the 1 to 3 mg/day group was comparable to the 4 to 6 mg/day group in study #1, and similar to the efficacy demonstrated in the 1.5 to 6 mg/day group in study #2. In study #2, the efficacy in the 1.5 to 6 mg/day group was statistically significantly greater than that in the 0.15 to 0.6 mg/day group. Doses higher than 3 mg/day did not reveal any trend towards greater efficacy.

Adults

The efficacy of risperidone in the treatment of acute manic or mixed episodes was established in two short-term (3-week) placebo-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.

The primary rating instrument used for assessing manic symptoms in these trials was the Young Mania Rating Scale (YMRS), 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 YMRS total score. The results of the trials follow:

(1) In one 3-week placebo-controlled trial (n = 246), limited to patients with manic episodes,  which involved a dose range of risperidone 1 to 6 mg/day, once daily, starting at 3 mg/day  (mean modal dose was 4.1 mg/day), risperidone was superior to placebo in the reduction  of YMRS total score.

(2) In another 3-week placebo-controlled trial (n = 286), which involved a dose range of 1 to 6 mg/day, once daily, starting at 3 mg/day (mean modal dose was 5.6 mg/day), risperidone was superior to placebo in the reduction of YMRS total score.

Pediatrics 

The efficacy of risperidone in the treatment of mania in children or adolescents with Bipolar I  disorder was demonstrated in a 3-week, randomized, double-blind, placebo-controlled,  multicenter trial including patients ranging in ages from 10 to 17 years who were experiencing a  manic or mixed episode of bipolar I disorder. Patients were randomized into one of three treatment groups: risperidone 0.5 to 2.5 mg/day (n = 50, mean modal dose = 1.9 mg), risperidone 3 to 6 mg/day (n = 61, mean modal dose = 4.7 mg), or placebo (n = 58). In all cases, study medication was initiated at 0.5 mg/day and titrated to the target dosage range by Day 7, with further increases in dosage to the maximum tolerated dose within the targeted dose range by Day 10. The primary rating instrument used for assessing efficacy in this study was the mean change from baseline in the total YMRS score.

Results of this study demonstrated efficacy of risperidone in both dose groups compared with placebo, as measured by significant reduction of total YMRS score. The efficacy on the primary parameter in the 3 to 6 mg/day dose group was comparable to the 0.5 to 2.5 mg/day dose group.  Doses higher than 2.5 mg/day did not reveal any trend towards greater efficacy.

The efficacy of risperidone with concomitant lithium or valproate in the treatment of acute manic or mixed episodes was established in one controlled trial in adult patients who met the DSM-IV criteria for Bipolar I Disorder. This trial included patients with or without psychotic features and with or without a rapid-cycling course.

(1) In this 3-week placebo-controlled combination trial, 148 in- or outpatients on lithium or valproate therapy with inadequately controlled manic or mixed symptoms were randomized to receive risperidone, placebo, or an active comparator, in combination with their original therapy. Risperidone, in a dose range of 1 to 6 mg/day, once daily, starting at 2 mg/day (mean modal dose of 3.8 mg/day), combined with lithium or valproate (in a therapeutic range of 0.6 mEq/L to 1.4 mEq/L or 50 mcg/mL to 120 mcg/mL, respectively) was superior to lithium or valproate alone in the reduction of YMRS total score.

(2) In a second 3-week placebo-controlled combination trial, 142 in- or outpatients on lithium, valproate, or carbamazepine therapy with inadequately controlled manic or mixed symptoms were randomized to receive risperidone or placebo, in combination with their original therapy. Risperidone, in a dose range of 1 to 6 mg/day, once daily, starting at 2 mg/day (mean modal dose of 3.7 mg/day), combined with lithium, valproate, or carbamazepine (in therapeutic ranges of 0.6 mEq/L to 1.4 mEq/L for lithium, 50 mcg/mL to 125 mcg/mL for valproate, or 4 to 12 mcg/mL for carbamazepine, respectively) was not superior to lithium, valproate, or carbamazepine alone in the reduction of YMRS total score. A possible explanation for the failure of this trial was induction of risperidone and 9-hydroxyrisperidone clearance by carbamazepine, leading to subtherapeutic levels of risperidone and 9-hydroxyrisperidone.

Short-Term Efficacy

The efficacy of risperidone in the treatment of irritability associated with autistic disorder was established in two 8-week, placebo-controlled trials in children and adolescents (aged 5 to 16 years) who met the DSM-IV criteria for autistic disorder. Over 90% of these subjects were under 12 years of age and most weighed over 20 kg (16 to 104.3 kg).

Efficacy was evaluated using two assessment scales: the Aberrant Behavior Checklist (ABC) and the Clinical Global Impression - Change (CGI-C) scale. The primary outcome measure in both trials was the change from baseline to endpoint in the Irritability subscale of the ABC (ABC-I).  The ABC-I subscale measured the emotional and behavioral symptoms of autism, including  aggression towards others, deliberate self-injuriousness, temper tantrums, and quickly changing  moods. The CGI-C rating at endpoint was a co-primary outcome measure in one of the studies.

The results of these trials are as follows:

(1) In one of the 8-week, placebo-controlled trials, children and adolescents with autistic disorder (n = 101), aged 5 to 16 years, received twice daily doses of placebo or risperidone 0.5 to 3.5 mg/day on a weight-adjusted basis. Risperidone, starting at 0.25 mg/day or 0.5 mg/day depending on baseline weight (< 20 kg and ≥ 20 kg, respectively) and titrated to clinical response (mean modal dose of 1.9 mg/day, equivalent to 0.06 mg/kg/day), significantly improved scores on the ABC-I subscale and on the CGI-C scale compared with placebo.

(2) In the other 8-week, placebo-controlled trial in children with autistic disorder (n = 55), aged 5 to 12 years, risperidone 0.02 to 0.06 mg/kg/day given once or twice daily, starting at 0.01 mg/kg/day and titrated to clinical response (mean modal dose of 0.05 mg/kg/day, equivalent to 1.4 mg/day), significantly improved scores on the ABC-I subscale compared with placebo.

A third trial was a 6-week, multicenter, randomized, double-blind, placebo-controlled, fixed-dose study to evaluate the efficacy and safety of a lower than recommended dose of risperidone in subjects (N = 96) 5 to 17 years of age with autistic disorder (defined by DSM-IV criteria) and associated irritability and related behavioral symptoms. Approximately 77% of patients were younger than 12 years of age (mean age = 9), and 88% were male. Most patients (73%) weighed less than 45 kg (mean weight = 40 kg). Approximately 90% of patients were antipsychotic-naïve before entering the study.

There were two weight-based, fixed doses of risperidone (high-dose and low-dose). The high dose was 1.25 mg per day for patients weighing 20 to < 45 kg, and it was 1.75 mg per day for patients weighing ≥ 45 kg. The low dose was 0.125 mg per day for patients weighing 20 to < 45 kg, and it was 0.175 mg per day for patients weighing ≥ 45 kg. The dose was administered once daily in the morning, or in the evening if sedation occurred.

The primary efficacy endpoint was the mean change in the Aberrant Behavior Checklist – Irritability subscale (ABC-I) score from baseline to the end of Week 6. The study demonstrated the efficacy of high-dose risperidone, as measured by the mean change in ABC-I score. It did not demonstrate efficacy for low-dose risperidone. The mean baseline ABC-I scores were 29 in the placebo group (n = 35), 27 in the risperidone low-dose group (n = 30), and 28 in the risperidone high-dose group (n = 31). The mean changes in ABC-I scores were -3.5, -7.4, and -12.4 in the placebo, low-dose, and high-dose group respectively. The results in the high-dose group were statistically significant (p< 0.001) but not in the low-dose group (p = 0.164).

Long-Term Efficacy

Following completion of the first 8-week double-blind study, 63 patients entered an open-label study extension where they were treated with risperidone for 4 or 6 months (depending on whether they received risperidone or placebo in the double-blind study). During this open-label treatment period, patients were maintained on a mean modal dose of risperidone of 1.8 to 2.1 mg/day (equivalent to 0.05 - 0.07 mg/kg/day).

Patients who maintained their positive response to risperidone (response was defined as ≥ 25% improvement on the ABC-I subscale and a CGI-C rating of ‘much improved’ or ‘very much improved’) during the 4 to 6 month open-label treatment phase for about 140 days, on average, were randomized to receive risperidone or placebo during an 8-week, double-blind withdrawal study (n = 39 of the 63 patients). A pre-planned interim analysis of data from patients who completed the withdrawal study (n = 32), undertaken by an independent Data Safety

Monitoring Board, demonstrated a significantly lower relapse rate in the risperidone group compared with the placebo group. Based on the interim analysis results, the study was terminated due to demonstration of a statistically significant effect on relapse prevention. Relapse was defined as ≥ 25% worsening on the most recent assessment of the ABC-I subscale (in relation to baseline of the randomized withdrawal phase).

Risperidone Oral Solution, USP 1 mg/mL is supplied as follow: 

NDC 17856-1002-01 RISPERIDONE 1 MG/ML - 1 ML ENFIT SYRINGE 120 ct UD

NDC 17856-1002-02 RISPERIDONE 1 MG/ML - 1 ML SYRINGE 120 ct UD

NDC 17856-1002-03 RISPERIDONE 1 MG/ML - 2 ML ENFIT SYRINGE 120 ct UD

Risperidone Oral Solution, USP 1 mg/mL should be stored at controlled room temperature 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. Protect from light and freezing.

Light Sensitive:Store in carton, away from direct sunlight. Keep out of reach of children.

Advise patients using Risperidone oral solution to read the FDA-approved patient labeling (Instructions for Use) for Risperidone oral solution.

{ "type": "p", "children": [], "text": "Advise patients using Risperidone oral solution to read the FDA-approved patient labeling (Instructions for Use) for Risperidone oral solution." }

Physicians are advised to discuss the following issues with patients for whom they prescribe risperidone.

{ "type": "p", "children": [], "text": "Physicians are advised to discuss the following issues with patients for whom they prescribe risperidone." }

Neuroleptic Malignant Syndrome (NMS)

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

Counsel patients about a potentially fatal adverse reaction, Neuroleptic Malignant Syndrome (NMS), that has been reported in association with administration of antipsychotic drugs. Advise patients, family members, or caregivers to contact the healthcare provider or report to the emergency room if they experience signs and symptoms of NMS, including hyperpyrexia, muscle rigidity, altered mental status including delirium, 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": "Counsel patients about a potentially fatal adverse reaction, Neuroleptic Malignant Syndrome (NMS), that has been reported in association with administration of antipsychotic drugs. Advise patients, family members, or caregivers to contact the healthcare provider or report to the emergency room if they experience signs and symptoms of NMS, including hyperpyrexia, muscle rigidity, altered mental status including delirium, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia) [\n \n see\n \n Warnings and Precautions (5.3)].\n\n " }

Tardive Dyskinesia

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

Counsel patients on the signs and symptoms of tardive dyskinesia and to contact their healthcare provider if these abnormal movements occur [ see Warnings and Precautions (5.4)].

{ "type": "p", "children": [], "text": "Counsel patients on the signs and symptoms of tardive dyskinesia and to contact their healthcare provider if these abnormal movements occur [\n \n see\n \n Warnings and Precautions (5.4)].\n\n " }

Metabolic Changes

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

Educate patients about the risk of metabolic changes, how to recognize symptoms of hyperglycemia and diabetes mellitus, and the need for specific monitoring, including blood glucose, lipids, and weight [ see Warnings and Precautions (5.5)].

{ "type": "p", "children": [], "text": "Educate patients about the risk of metabolic changes, how to recognize symptoms of hyperglycemia and diabetes mellitus, and the need for specific monitoring, including blood glucose, lipids, and weight [\n \n see\n \n Warnings and Precautions (5.5)].\n\n " }

Orthostatic Hypotension

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

Educate patients about the risk of orthostatic hypotension and syncope, particularly at the time of initiating treatment, re-initiating treatment, or increasing the dose [ see Warnings and Precautions (5.7)].

{ "type": "p", "children": [], "text": "Educate patients about the risk of orthostatic hypotension and syncope, particularly at the time of initiating treatment, re-initiating treatment, or increasing the dose [\n \n see\n \n Warnings and Precautions (5.7)].\n\n " }

Leukopenia/Neutropenia

{ "type": "p", "children": [], "text": "\nLeukopenia/Neutropenia\n" }

Advise patients with a pre-existing low WBC or a history of drug induced leukopenia/neutropenia they should have their CBC monitored while taking risperidone [ see Warnings and Precautions (5.9)].

{ "type": "p", "children": [], "text": "Advise patients with a pre-existing low WBC or a history of drug induced leukopenia/neutropenia they should have their CBC monitored while taking risperidone [\n \n see\n \n Warnings and Precautions (5.9)].\n\n " }

Hyperprolactinemia

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

Counsel patients on signs and symptoms of hyperprolactinemia that may be associated with chronic use of risperidone. Advise them to seek medical attention if they experience any of the following: amenorrhea or galactorrhea in females, erectile dysfunction or gynecomastia in males. [See Warnings and Precautions (5.6)] .

{ "type": "p", "children": [], "text": "Counsel patients on signs and symptoms of hyperprolactinemia that may be associated with chronic use of risperidone. Advise them to seek medical attention if they experience any of the following: amenorrhea or galactorrhea in females, erectile dysfunction or gynecomastia in males.\n \n [See\n \n Warnings and Precautions (5.6)]\n \n .\n\n " }

Interference with Cognitive and Motor Performance

{ "type": "p", "children": [], "text": "\nInterference with Cognitive and Motor Performance\n" }

Caution patients about performing activities requiring mental alertness, such as operating hazardous machinery, or operating a motor vehicle until they are reasonably certain that risperidone therapy does not affect them adversely [ see Warnings and Precautions (5.10)].

{ "type": "p", "children": [], "text": "Caution patients about performing activities requiring mental alertness, such as operating hazardous machinery, or operating a motor vehicle until they are reasonably certain that risperidone therapy does not affect them adversely [\n \n see\n \n Warnings and Precautions (5.10)].\n\n " }

Priapism

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

Advise patients of the possibility of painful or prolonged penile erections (priapism). Instruct the patient to seek immediate medical attention in the event of priapism [see  Warnings and Precautions (5.13)].

{ "type": "p", "children": [], "text": "Advise patients of the possibility of painful or prolonged penile erections (priapism). Instruct the patient to seek immediate medical attention in the event of priapism [see \n \n Warnings and Precautions (5.13)].\n\n " }

Heat Exposure and Dehydration

{ "type": "p", "children": [], "text": "\nHeat Exposure and Dehydration\n" }

Counsel patients regarding appropriate care in avoiding overheating and dehydration [ see Warnings and Precautions (5.14)].

{ "type": "p", "children": [], "text": "Counsel patients regarding appropriate care in avoiding overheating and dehydration [\n \n see\n \n Warnings and Precautions (5.14)].\n\n " }

Concomitant Medication

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

Advise patients to inform their healthcare providers if they are taking, or plan to take any prescription or over-the-counter drugs, as a potential for interactions [ seeDrug Interactions (7)].

{ "type": "p", "children": [], "text": "Advise patients to inform their healthcare providers if they are taking, or plan to take any prescription or over-the-counter drugs, as a potential for interactions [\n \n seeDrug Interactions (7)].\n\n " }

Alcohol

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

Advise patients to avoid alcohol while taking risperidone [ seeDrug Interactions (7.2)].

{ "type": "p", "children": [], "text": "Advise patients to avoid alcohol while taking risperidone [\n \n seeDrug Interactions (7.2)].\n\n " }

Pregnancy

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

Advise patients to notify their healthcare provider if they become pregnant or intend to become pregnant during treatment with risperidone. Advise patients that risperidone may cause extrapyramidal and/or withdrawal symptoms in a neonate. Advise patients that there is a pregnancy registry that monitors pregnancy outcomes in women exposed to risperidone during pregnancy [ seeUse in Specific Populations (8.1)].

{ "type": "p", "children": [], "text": "Advise patients to notify their healthcare provider if they become pregnant or intend to become pregnant during treatment with risperidone. Advise patients that risperidone may cause extrapyramidal and/or withdrawal symptoms in a neonate. Advise patients that there is a pregnancy registry that monitors pregnancy outcomes in women exposed to risperidone during pregnancy [\n \n seeUse in Specific Populations (8.1)].\n\n " }

Lactation

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

Advise breastfeeding women using risperidone to monitor infants for somnolence, failure to thrive, jitteriness, 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": "Advise breastfeeding women using risperidone to monitor infants for somnolence, failure to thrive, jitteriness, and extrapyramidal symptoms (tremors and \n abnormal muscle movements) and to seek medical care if they notice these signs [\n \n see\n \n Use in Specific Populations (8.2)].\n\n " }

Infertility

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

Advise females of reproductive potential that risperidone 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": "Advise females of reproductive potential that risperidone may impair fertility due to an increase in serum prolactin levels. The effects on fertility are reversible \n [\n \n see\n \n Use in Specific Populations (8.3)].\n\n " }

Manufactured by:

{ "type": "p", "children": [], "text": "Manufactured by:" }

Tris Pharma, Inc.

{ "type": "p", "children": [], "text": "Tris Pharma, Inc." }

Monmouth Junction, NJ 08852

{ "type": "p", "children": [], "text": "Monmouth Junction, NJ 08852" }

www.trispharma.com

{ "type": "p", "children": [], "text": "www.trispharma.com" }

LB8017 

{ "type": "p", "children": [], "text": "LB8017 " }

Rev. 09 04/2023

{ "type": "p", "children": [], "text": "Rev. 09 04/2023" }

DISTRIBUTED BY:

{ "type": "p", "children": [], "text": "DISTRIBUTED BY:" }

ATLANTIC BIOLOGICALS CORP.

{ "type": "p", "children": [], "text": "ATLANTIC BIOLOGICALS CORP." }

MIAMI, FL 33179

{ "type": "p", "children": [], "text": "MIAMI, FL 33179" }

Risperidone tablets are indicated for the treatment of schizophrenia. Efficacy was established in 4 short-term trials in adults, 2 short-term trials in adolescents (ages 13 to 17 years), and one long-term maintenance trial in adults [see Clinical Studies (14.1)] .

Monotherapy

Risperidone tablets are indicated for the treatment of acute manic or mixed episodes associated with Bipolar I Disorder. Efficacy was established in 2 short-term trials in adults and one short-term trial in children and adolescents (ages 10 to 17 years) [see Clinical Studies (14.2)] . 

Adjunctive Therapy

Risperidone tablets adjunctive therapy with lithium or valproate is indicated for the treatment of acute manic or mixed episodes associated with Bipolar I Disorder. Efficacy was established in one short-term trial in adults [see Clinical Studies (14.3)] .

Risperidone tablets are indicated for the treatment of irritability associated with autistic disorder, including symptoms of aggression towards others, deliberate self-injuriousness, temper tantrums, and quickly changing moods. Efficacy was established in 3 short-term trials in children and adolescents (ages 5 to 17 years)   [see Clinical Studies (14.4)] .

Adults

Usual Initial Dose

Risperidone tablets can be administered once or twice daily. Initial dosing is 2 mg per day. May increase the dose at intervals of 24 hours or greater, in increments of 1 to 2 mg per day, as tolerated, to a recommended dose of 4 to 8 mg per day. In some patients, slower titration may be appropriate. Efficacy has been demonstrated in a range of 4 mg to 16 mg per day .However, doses above 6 mg per day for twice daily dosing were not demonstrated to be more efficacious than lower doses, were associated with more extrapyramidal symptoms and other adverse effects, and are generally not recommended. In a single study supporting once-daily dosing, the efficacy results were generally stronger for 8 mg than for 4 mg. The safety of doses above 16 mg per day has not been evaluated in clinical trials [see Clinical Studies (14.1)].

Adolescents

The initial dose is 0.5 mg once daily, administered as a single-daily dose in the morning or evening. The dose may be adjusted at intervals of 24 hours or greater, in increments of 0.5 mg or 1 mg per day, as tolerated, to a recommended dose of 3 mg per day. Although efficacy has been demonstrated in studies of adolescent patients with schizophrenia at doses between 1 mg and 6 mg per day, no additional benefit was observed above 3 mg per day, and higher doses were associated with more adverse events. Doses higher than 6 mg per day have not been studied.

Patients experiencing persistent somnolence may benefit from administering half the daily dose twice daily.

Maintenance Therapy

While it is unknown how long a patient with schizophrenia should remain on risperidone tablets, the effectiveness of risperidone tablets 2 mg per day to 8 mg per day at delaying relapse was demonstrated in a controlled trial in adult patients who had been clinically stable for at least 4 weeks and were then followed for a period of 1 to 2 years [see Clinical Studies (14.1)] . Both adult and adolescent patients who respond acutely should generally be maintained on their effective dose beyond the acute episode. Patients should be periodically reassessed to determine the need for maintenance treatment.

Reinitiation of Treatment in Patients Previously Discontinued

Although there are no data to specifically address reinitiation of treatment, it is recommended that after an interval off risperidone tablets, the initial titration schedule should be followed.

Switching From Other Antipsychotics

There are no systematically collected data to specifically address switching schizophrenic patients from other antipsychotics to risperidone tablets, or treating patients with concomitant antipsychotics.

Usual Dose

Adults

The inital dose range is 2 mg to 3 mg per day. The dose may be adjusted at intervals of 24 hours or greater, in increments of 1 mg per day. The effective dose range is 1 mg to 6 mg per day, as studied in the short-term, placebo-controlled trials. In these trials, short-term (3 week) anti-manic efficacy was demonstrated in a flexible dosage range of 1 mg to 6 mg per day [see Clinical Studies (14.2, 14.3)] . Risperidone tablets doses higher than 6 mg per day were not studied.

Pediatrics

The inital dose is 0.5 mg once daily, administered as a single-daily dose in the morning or evening. The dose may be adjusted at intervals of 24 hours or greater, in increments of 0.5 mg or 1 mg per day, as tolerated, to the recommended target dose of 1 mg to 2.5 mg per day. Although efficacy has been demonstrated in studies of pediatric patients with bipolar mania at doses between 0.5 mg and 6 mg per day, no additional benefit was observed above 2.5 mg per day, and higher doses were associated with more adverse events. Doses higher than 6 mg per day have not been studied.

Patients experiencing persistent somnolence may benefit from administering half the daily dose twice daily.

Maintenance Therapy

There is no body of evidence available from controlled trials to guide a clinician in the longer-term management of a patient who improves during treatment of an acute manic episode with risperidone tablets. While it is generally agreed that pharmacological treatment beyond an acute response in mania is desirable, both for maintenance of the initial response and for prevention of new manic episodes, there are no systematically obtained data to support the use of risperidone tablets in such longer-term treatment (i.e., beyond 3 weeks). The physician who elects to use risperidone tablets for extended periods should periodically re-evaluate the long-term risks and benefits of the drug for the individual patient.

The dosage of risperidone tablets should be individualized according to the response and tolerability of the patient. The total daily dose of risperidone tablets can be administered once daily, or half the total daily dose can be administered twice daily.

For patients with body weight less than 20 kg, initiate dosing at 0.25 mg per day. For patients with body weight greater than or equal to 20 kg, initiate dosing at 0.5 mg per day. After a minimum of four days, the dose may be increased to the recommended dose of 0.5 mg per day for patients less than 20 kg and 1.0 mg per day for patients greater than or equal to 20 kg. Maintain this dose for a minimum of 14 days. In patients not achieving sufficient clinical response, the dose may be increased at intervals of 2 weeks or greater, in increments of 0.25 mg per day for patients less than 20 kg, or increments of 0.5 mg per day for patients greater than or equal to 20 kg. The effective dose range is 0.5 mg to 3 mg per day. No dosing data are available for children who weigh less than 15 kg.

Once sufficient clinical response has been achieved and maintained, consider gradually lowering the dose to achieve the optimal balance of efficacy and safety. The physician who elects to use risperidone tablets for extended periods should periodically re-evaluate the long-term risks and benefits of the drug for the individual patient.

Patients experiencing persistent somnolence may benefit from a once-daily dose administered at bedtime or administering half the daily dose twice daily, or a reduction of the dose.

For patients with severe renal impairment (Clcr < 30 mL/min) or hepatic impairment (10-15 points on Child Pugh System), the initial starting dose is 0.5 mg twice daily. The dose may be increased in increments of 0.5 mg or less, administered twice daily. For doses above 1.5 mg twice daily, increase in intervals of one week or greater [see Use in Specific Populations (8.6and 8.7)] .

When risperidone tablets are co-administered with enzyme inducers (e.g., carbamazepine), the dose of risperidone tablets should be increased up to double the patient’s usual dose. It may be necessary to decrease the risperidone tablets dose when enzyme inducers such as carbamazepine are discontinued [see Drug Interactions (7.1)] . Similar effect may be expected with co-administration of risperidone tablets with other enzyme inducers (e.g., phenytoin, rifampin, and phenobarbital).

When fluoxetine or paroxetine is co-administered with risperidone tablets, the dose of risperidone tablets should be reduced. The risperidone tablets dose should not exceed 8 mg per day in adults when co-administered with these drugs. When initiating therapy, risperidone tablets should be titrated slowly. It may be necessary to increase the risperidone tablets dose when enzyme inhibitors such as fluoxetine or paroxetine are discontinued [see Drug Interactions (7.1)] .

Risperidone tablets, USP are available in the following strengths and colors:2 mg (yellow), are circular shaped. Risperidone tablets, USP are engraved with “RI4” on one side on “2” and plain on other side.

{ "type": "p", "children": [], "text": "Risperidone tablets, USP are available in the following strengths and colors:2 mg (yellow), are circular shaped. Risperidone tablets, USP are engraved with “RI4” on one side on “2” and plain on other side." }

Risperidone tablets are contraindicated in patients with a known hypersensitivity to either risperidone or paliperidone, or to any of the excipients in the risperidone tablets formulation. Hypersensitivity reactions, including anaphylactic reactions and angioedema, have been reported in patients treated with risperidone and in patients treated with paliperidone. Paliperidone is a metabolite of risperidone.

{ "type": "p", "children": [], "text": "Risperidone tablets are contraindicated in patients with a known hypersensitivity to either risperidone or paliperidone, or to any of the excipients in the risperidone tablets formulation. Hypersensitivity reactions, including anaphylactic reactions and angioedema, have been reported in patients treated with risperidone and in patients treated with paliperidone. Paliperidone is a metabolite of risperidone." }

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Analyses of 17 placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality. The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear.

In two of four placebo-controlled trials in elderly patients with dementia-related psychosis, a higher incidence of mortality was observed in patients treated with furosemide plus risperidone tablets when compared to patients treated with risperidone tablets alone or with placebo plus furosemide. No pathological mechanism has been identified to explain this finding, and no consistent pattern for cause of death was observed.

Risperidone tablets are not approved for the treatment of dementia-related psychosis [see Boxed Warning] .

Cerebrovascular adverse reactions (e.g., stroke, transient ischemic attack), including fatalities, were reported in patients (mean age 85 years; range 73-97) in trials of risperidone 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 risperidone compared to patients treated with placebo. Risperidone tablets are not approved for the treatment of patients with dementia-related psychosis. [see Boxed Warning and Warnings and Precautions (5.1)] .

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

If NMS is suspected, immediately discontinue risperidone tablets and provide symptomatic treatment and monitoring.

Tardive dyskinesia, a syndrome consisting 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 predict which patients will 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 increase with the duration of treatment and the cumulative dose. The syndrome can develop after relatively brief treatment periods, even at low doses. It may also occur after discontinuation of treatment.

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

Given these considerations, risperidone tablets  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, use the lowest dose and the shortest duration of treatment producing a satisfactory clinical response. Periodically reassess the need for continued treatment.

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

Atypical antipsychotic drugs have been associated with metabolic changes that may increase cardiovascular/cerebrovascular risk. These metabolic changes include hyperglycemia, dyslipidemia, and body weight gain. While all of the drugs in the class have been shown to produce some metabolic changes, each drug has its own specific risk profile.

Hyperglycemia and Diabetes Mellitus

Hyperglycemia and diabetes mellitus, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, have been reported in patients treated with atypical antipsychotics including risperidone tablets. 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. Given these confounders, the relationship between atypical antipsychotic use and hyperglycemia-related adverse events is not completely understood. However, epidemiological studies suggest an increased risk of treatment-emergent hyperglycemia-related adverse events in patients treated with the atypical antipsychotics. Precise risk estimates for hyperglycemia-related adverse events in patients treated with atypical antipsychotics are not available.

Patients with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics, including risperidone tablets, should be monitored regularly for worsening of glucose control. Patients with risk factors for diabetes mellitus (e.g., obesity, family history of diabetes) who are starting treatment with atypical antipsychotics, including risperidone tablets, should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Any patient treated with atypical antipsychotics, including risperidone tablets, should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics, including risperidone tablets, should undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic, including risperidone tablets, was discontinued; however, some patients required continuation of anti-diabetic treatment despite discontinuation of risperidone tablets.

Pooled data from three double-blind, placebo-controlled schizophrenia studies and four double-blind, placebo-controlled bipolar monotherapy studies are presented in Table 2.

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="100%"> <caption> <span>Table 2.    Change in Random Glucose from Seven Placebo-Controlled, 3- to 8-Week, Fixed- or Flexible-Dose Studies in Adult Subjects with Schizophrenia or Bipolar Mania</span> </caption> <col width="30.58%"/> <col width="21.16%"/> <col width="18.84%"/> <col width="29.42%"/> <tbody class="Headless"> <tr class="Botrule First"> <td align="justify" class="Lrule Rrule" colspan="2" valign="top">  <br/> </td><td align="center" class="Rrule" colspan="2" valign="top">Risperidone Tablets <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  <br/> </td><td align="center" class="Rrule" valign="top">Placebo <br/> </td><td align="center" class="Rrule" valign="top">1–8 mg/day <br/> </td><td align="center" class="Rrule" valign="top">&gt;8–16 mg/day <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  <br/> </td><td align="center" class="Rrule" colspan="3" valign="top"><span class="Bold">Mean change from baseline (mg/dL)</span> <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  <br/>   <br/> Serum Glucose <br/> </td><td align="center" class="Rrule" valign="top"><span class="Bold">n=555</span> <br/> - 1.4 <br/> </td><td align="center" class="Rrule" valign="top"><span class="Bold">n=748</span> <br/>   <br/> 0.8 <br/> </td><td align="center" class="Rrule" valign="top"><span class="Bold">n=164</span> <br/>   <br/> 0.6 <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  <br/> </td><td align="center" class="Rrule" colspan="3" valign="top"><span class="Bold">Proportion of patients with shifts</span> <br/> </td> </tr> <tr class="Last"> <td align="justify" class="Lrule Rrule" valign="top">Serum Glucose <br/> (&lt;140 mg/dL to ≥200 mg/dL) <br/> </td><td align="center" class="Rrule" valign="top">  <br/> 0.6% <br/> (3/525) <br/> </td><td align="center" class="Rrule" valign="top">  <br/> 0.4% <br/> (3/702) <br/> </td><td align="center" class="Rrule" valign="top">  <br/> 0% <br/> (0/158) <br/> </td> </tr> </tbody> </table></div>

In longer-term, controlled and uncontrolled studies, risperidone tablets were associated with a mean change in glucose of +2.8 mg/dL at Week 24 (n=151) and +4.1 mg/dL at Week 48 (n=50).

Data from the placebo-controlled 3- to 6-week study in children and adolescents with schizophrenia (13–17 years of age), bipolar mania (10–17 years of age), or autistic disorder (5 to 17 years of age) are presented in Table 3. 

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="100%"> <caption> <span>Table 3.  Change in Fasting Glucose from Three Placebo-Controlled, 3- to 6-Week, Fixed-Dose   Studies in Children and Adolescents with Schizophrenia (13–17 years of age), Bipolar Mania (10–17 years of age), or Autistic Disorder (5 to 17 years of age)</span> </caption> <col width="33.14%"/> <col width="24.22%"/> <col width="42.64%"/> <tbody class="Headless"> <tr class="Botrule First"> <td align="justify" class="Lrule Rrule" colspan="2" valign="top">  <br/> </td><td align="center" class="Rrule" valign="top">Risperidone Tablets <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  <br/> </td><td align="center" class="Rrule" valign="top">Placebo <br/> </td><td align="center" class="Rrule" valign="top">0.5-6 mg/day <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  <br/> </td><td align="center" class="Rrule" colspan="2" valign="top"><span class="Bold">Mean change from baseline (mg/dL)</span> <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  <br/>   <br/> Serum Glucose <br/> </td><td align="center" class="Rrule" valign="top"><span class="Bold">n=76</span> <br/>   <br/> -1.3 <br/> </td><td align="center" class="Rrule" valign="top"><span class="Bold">n=135</span> <br/>   <br/> 2.6 <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  <br/> </td><td align="center" class="Rrule" colspan="2" valign="top"><span class="Bold">Proportion of patients with shifts</span> <br/> </td> </tr> <tr class="Last"> <td align="justify" class="Lrule Rrule" valign="top">Serum Glucose <br/> (&lt;100 mg/dL to ≥126 mg/dL) <br/> </td><td align="center" class="Rrule" valign="top">  <br/> 0% <br/> (0/64) <br/> </td><td align="center" class="Rrule" valign="top">  <br/> 0.8% <br/> (1/120) <br/> </td> </tr> </tbody> </table></div>

In longer-term, uncontrolled, open-label extension pediatric studies, risperidone tablets were associated with a mean change in fasting glucose of +5.2 mg/dL at Week 24 (n=119).

Dyslipidemia

Undesirable alterations in lipids have been observed in patients treated with atypical antipsychotics.

Pooled data from 7 placebo-controlled, 3- to 8- week, fixed- or flexible-dose studies in adult subjects with schizophrenia or bipolar mania are presented in Table 4.

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="100%"> <caption> <span>Table 4. Change in Random Lipids from Seven Placebo-Controlled, 3- to 8-Week, Fixed- or Flexible -Dose Studies in Adult Subjects with Schizophrenia or Bipolar Mania</span> </caption> <col width="36.46%"/> <col width="10.56%"/> <col width="24.96%"/> <col width="28.02%"/> <tbody class="Headless"> <tr class="Botrule First"> <td align="justify" class="Lrule Rrule" colspan="2" valign="top">  <br/> </td><td align="center" class="Rrule" colspan="2" valign="top">Risperidone Tablets <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  <br/> </td><td align="center" class="Rrule" valign="top">Placebo <br/> </td><td align="center" class="Rrule" valign="top">1–8 mg/day <br/> </td><td align="center" class="Rrule" valign="top">&gt;8–16 mg/day <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  <br/> </td><td align="center" class="Rrule" colspan="3" valign="top"><span class="Bold">Mean change from baseline (mg/dL)</span> <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"><span class="Bold">Cholesterol</span> <br/> </td><td align="center" class="Rrule" valign="top"><span class="Bold">n=559</span> <br/> </td><td align="center" class="Rrule" valign="top"><span class="Bold">n=742</span> <br/> </td><td align="center" class="Rrule" valign="top"><span class="Bold">n=156</span> <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Change from baseline <br/> </td><td align="center" class="Rrule" valign="top">0.6 <span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">6.9 <span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">1.8 <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"><span class="Bold">Triglycerides</span> <br/> </td><td align="center" class="Rrule" valign="top"><span class="Bold">n=183</span> <br/> </td><td align="center" class="Rrule" valign="top"><span class="Bold">n=307</span> <br/> </td><td align="center" class="Rrule" valign="top"><span class="Bold">n=123</span> <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Change from baseline <br/> </td><td align="center" class="Rrule" valign="top">-17.4 <br/> </td><td align="center" class="Rrule" valign="top">-4.9 <br/> </td><td align="center" class="Rrule" valign="top">-8.3 <br/>   <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  <br/> </td><td align="center" class="Rrule" colspan="3" valign="top"><span class="Bold">Proportion of patients with shifts</span> <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"><span class="Bold">Cholesterol</span> <br/> (&lt;200 mg/dL to ≥240 mg/dL) <br/> </td><td align="center" class="Rrule" valign="top">  <br/> 2.7% <br/> (10/368) <br/> </td><td align="center" class="Rrule" valign="top">  <br/> 4.3% <br/> (22/516) <br/> </td><td align="center" class="Rrule" valign="top">  <br/> 6.3% <br/> (6/96) <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"><span class="Bold">Triglycerides</span> <br/> </td><td align="center" class="Rrule" valign="top">1.1% <br/> </td><td align="center" class="Rrule" valign="top">2.7% <br/> </td><td align="center" class="Rrule" valign="top">2.5% <br/> </td> </tr> <tr class="Last"> <td align="justify" class="Lrule Rrule" valign="top">(&lt;500 mg/dL to ≥500 mg/dL) <span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">(2/180) <br/> </td><td align="center" class="Rrule" valign="top">(8/301) <br/> </td><td align="center" class="Rrule" valign="top">(3/121) <br/> </td> </tr> </tbody> </table></div>

In longer-term, controlled and uncontrolled studies, risperidone tablets were associated with a mean change in (a) non-fasting cholesterol of +4.4 mg/dL at Week 24 (n=231) and +5.5 mg/dL at Week 48 (n=86); and (b) non-fasting triglycerides of +19.9 mg/dL at Week 24 (n=52).

Pooled data from 3 placebo-controlled, 3- to 6-week, fixed-dose studies in children and adolescents with schizophrenia (13–17 years of age), bipolar mania (10–17 years of age), or autistic disorder (5–17 years of age) are presented in Table 5.

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="100%"> <caption> <span>Table 5.    Change in Fasting Lipids from Three Placebo-Controlled, 3- to 6-Week, Fixed-Dose Studies in Children and Adolescents with Schizophrenia (13–17 Years of Age), Bipolar Mania (10–17 Years of Age), or Autistic Disorder (5 to 17 Years of Age)</span> </caption> <col width="35.72%"/> <col width="29.6%"/> <col width="34.68%"/> <tbody class="Headless"> <tr class="Botrule First"> <td align="justify" class="Lrule Rrule" colspan="2" valign="top">  <br/> </td><td align="center" class="Rrule" valign="top">Risperidone Tablets <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  <br/> </td><td align="center" class="Rrule" valign="top">Placebo <br/> </td><td align="center" class="Rrule" valign="top">0.5-6 mg/day <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  <br/> </td><td align="center" class="Rrule" colspan="2" valign="top"><span class="Bold">Mean change from baseline (mg/dL)</span> <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"><span class="Bold">Cholesterol</span> <br/> </td><td align="center" class="Rrule" valign="top"><span class="Bold">n=74</span> <br/> </td><td align="center" class="Rrule" valign="top"><span class="Bold">n=133</span> <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Change from baseline <br/> </td><td align="center" class="Rrule" valign="top">0.3 <br/>   <br/> </td><td align="center" class="Rrule" valign="top">-0.3 <br/>   <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"><span class="Bold">LDL</span> <br/> </td><td align="center" class="Rrule" valign="top"><span class="Bold">n=22</span> <br/> </td><td align="center" class="Rrule" valign="top"><span class="Bold">n=22</span> <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Change from baseline <span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">3.7 <br/>   <br/> </td><td align="center" class="Rrule" valign="top">0.5 <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"><span class="Bold">HDL</span> <br/> </td><td align="center" class="Rrule" valign="top"><span class="Bold">n=22</span> <br/> </td><td align="center" class="Rrule" valign="top"><span class="Bold">n=22</span> <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Change from baseline <span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">1.6 <br/>   <br/> </td><td align="center" class="Rrule" valign="top">-1.9 <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"><span class="Bold">Triglycerides</span> <br/> </td><td align="center" class="Rrule" valign="top"><span class="Bold">n=77</span> <br/> </td><td align="center" class="Rrule" valign="top"><span class="Bold">n=138</span> <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Change from baseline <span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">-9.0 <br/> </td><td align="center" class="Rrule" valign="top">-2.6 <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  <br/> </td><td align="center" class="Rrule" colspan="2" valign="top"><span class="Bold">Proportion of patients with shifts</span> <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"><span class="Bold">Cholesterol</span> <br/> </td><td align="center" class="Rrule" valign="top">2.4% <br/> </td><td align="center" class="Rrule" valign="top">3.8% <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">(&lt;170 mg/dL to ≥200 mg/dL) <br/> </td><td align="center" class="Rrule" valign="top">(1/42) <br/> </td><td align="center" class="Rrule" valign="top">(3/80) <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"><span class="Bold">LDL</span> <br/> </td><td align="center" class="Rrule" valign="top">0% <br/> </td><td align="center" class="Rrule" valign="top">0% <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">(&lt;110 mg/dL to ≥130 mg/dL) <span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">(0/16) <br/> </td><td align="center" class="Rrule" valign="top">(0/16) <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"><span class="Bold">HDL</span> <br/> </td><td align="center" class="Rrule" valign="top">0% <br/> </td><td align="center" class="Rrule" valign="top">10% <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">(≥40 mg/dL to &lt;40 mg/dL) <span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">(0/19) <br/> </td><td align="center" class="Rrule" valign="top">(2/20) <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"><span class="Bold">Triglycerides</span> <br/> </td><td align="center" class="Rrule" valign="top">1.5% <br/> </td><td align="center" class="Rrule" valign="top">7.1% <br/> </td> </tr> <tr class="Last"> <td align="justify" class="Lrule Rrule" valign="top">(&lt;150 mg/dL to ≥200 mg/dL) <span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">(1/65) <br/> </td><td align="center" class="Rrule" valign="top">(8/113) <br/> </td> </tr> </tbody> </table></div>

In longer-term, uncontrolled, open-label extension pediatric studies, risperidone tablets were associated with a mean change in (a) fasting cholesterol of +2.1 mg/dL at Week 24 (n=114); (b) fasting LDL of -0.2 mg/dL at Week 24 (n=103); (c) fasting HDL of +0.4 mg/dL at Week 24 (n=103); and (d) fasting triglycerides of +6.8 mg/dL at Week 24 (n=120).

Weight Gain

Weight gain has been observed with atypical antipsychotic use. Clinical monitoring of weight is recommended.

Data on mean changes in body weight and the proportion of subjects meeting a weight gain criterion of 7% or greater of body weight from 7 placebo-controlled, 3- to 8- week, fixed- or flexible-dose studies in adult subjects with schizophrenia or bipolar mania are presented in Table 6.

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="100%"> <caption> <span>Table 6. Mean Change in Body Weight (kg) and the Proportion of Subjects with =7% Gain in Body Weight From Seven Placebo-Controlled, 3- to 8-Week, Fixed- or Flexible-Dose Studies in Adult Subjects With Schizophrenia or Bipolar Mania</span> </caption> <col width="31.38%"/> <col width="16.66%"/> <col width="21.56%"/> <col width="30.4%"/> <tbody class="Headless"> <tr class="Botrule First"> <td align="justify" class="Lrule Rrule" colspan="2" valign="top">  <br/> </td><td align="center" class="Rrule" colspan="2" valign="top">Risperidone Tablets <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  <br/> </td><td align="center" class="Rrule" valign="top">Placebo <br/> (n=597) <br/> </td><td align="center" class="Rrule" valign="top">1–8 mg/day <br/> (n=769) <br/> </td><td align="center" class="Rrule" valign="top">&gt;8–16 mg/day <br/> (n=158) <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"><span class="Bold">Weight (kg)</span> <br/> </td><td align="center" class="Rrule" valign="top"></td><td align="center" class="Rrule" valign="top"></td><td align="center" class="Rrule" valign="top"></td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Change from baseline <br/> </td><td align="center" class="Rrule" valign="top">-0.3 <span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">0.7 <span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">2.2 <span class="Bold"></span> <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"><span class="Bold">Weight Gain</span> <br/> </td><td align="center" class="Rrule" valign="top">  <br/> </td><td align="center" class="Rrule" valign="top">  <br/> </td><td align="center" class="Rrule" valign="top">  <br/> </td> </tr> <tr class="Last"> <td align="justify" class="Lrule Rrule" valign="top">≥7% increase from baseline <br/> </td><td align="center" class="Rrule" valign="top">2.9% <br/> </td><td align="center" class="Rrule" valign="top">8.7% <br/> </td><td align="center" class="Rrule" valign="top">20.9% <br/> </td> </tr> </tbody> </table></div>

In longer-term, controlled and uncontrolled studies, risperidone tablets were associated with a mean change in weight of +4.3 kg at Week 24 (n=395) and +5.3 kg at Week 48 (n=203).

Data on mean changes in body weight and the proportion of subjects meeting the criterion of ≥7% gain in body weight from nine placebo-controlled, 3- to 8-week, fixed-dose studies in children and adolescents with schizophrenia (13–17 years of age), bipolar mania (10–17 years of age), autistic disorder (5–17 years of age), or other psychiatric disorders (5–17 years of age) are presented in Table 7.

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="100%"> <caption> <span>Table 7.   Mean Change in Body Weight (kg) and the Proportion of Subjects With =7% Gain in Body Weight From Nine Placebo-Controlled, 3- to 8-Week, Fixed-Dose Studies in Children and Adolescents With Schizophrenia (13–17 Years of Age), Bipolar Mania (10–17 Years of Age), Autistic Disorder (5 to 17 Years of Age) or Other Psychiatric Disorders (5–17 Years of Age)</span> </caption> <col width="27.72%"/> <col width="27.74%"/> <col width="44.54%"/> <tbody class="Headless"> <tr class="Botrule First"> <td align="center" class="Lrule Rrule" valign="middle">  <br/> </td><td align="center" class="Rrule" valign="middle"><span class="Bold">Placebo</span> <br/> </td><td align="center" class="Rrule" valign="middle"><span class="Bold">Risperidone Tablets</span> <br/> <span class="Bold">0.5–6 mg/day</span> <br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="middle">  <br/> </td><td align="center" class="Rrule" valign="middle"><span class="Bold">(n=375)</span> <br/> </td><td align="center" class="Rrule" valign="middle"><span class="Bold">(n=448)</span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle"><span class="Bold">Weight (kg)</span> <br/> </td><td align="center" class="Rrule" valign="middle"></td><td align="center" class="Rrule" valign="middle"></td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">Change from baseline <br/> </td><td align="center" class="Rrule" valign="middle">0.6 <span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="middle">2.0 <span class="Bold"></span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle"><span class="Bold">Weight Gain</span> <br/> </td><td align="center" class="Rrule" valign="middle">  <br/> </td><td align="center" class="Rrule" valign="middle">  <br/> </td> </tr> <tr class="Last"> <td class="Lrule Rrule" valign="middle">≥7% increase from baseline <br/> </td><td align="center" class="Rrule" valign="middle">6.9% <br/> </td><td align="center" class="Rrule" valign="middle">32.6% <br/> </td> </tr> </tbody> </table></div>

In longer-term, uncontrolled, open-label extension pediatric studies, risperidone tablets were associated with a mean change in weight of +5.5 kg at Week 24 (n=748) and +8.0 kg at Week 48 (n=242).

In a long-term, open-label extension study in adolescent patients with schizophrenia, weight increase was reported as a treatment-emergent adverse event in 14% of patients. In 103 adolescent patients with schizophrenia, a mean increase of 9.0 kg was observed after 8 months of risperidone tablets treatment. The majority of that increase was observed within the first 6 months. The average percentiles at baseline and 8 months, respectively, were 56 and 72 for weight, 55 and 58 for height, and 51 and 71 for body mass index.

In long-term, open-label trials (studies in patients with autistic disorder or other psychiatric disorders), a mean increase of 7.5 kg after 12 months of risperidone tablets treatment was observed, which was higher than the expected normal weight gain (approximately 3 to 3.5 kg per year adjusted for age, based on Centers for Disease Control and Prevention normative data). The majority of that increase occurred within the first 6 months of exposure to risperidone tablets. The average percentiles at baseline and 12 months, respectively, were 49 and 60 for weight, 48 and 53 for height, and 50 and 62 for body mass index.

In one 3-week, placebo-controlled trial in children and adolescent patients with acute manic or mixed episodes of bipolar I disorder, increases in body weight were higher in the risperidone tablets groups than the placebo group, but not dose related (1.90 kg in the risperidone tablets 0.5–2.5 mg group, 1.44 kg in the risperidone tablets 3–6 mg group, and 0.65 kg in the placebo group). A similar trend was observed in the mean change from baseline in body mass index.

When treating pediatric patients with risperidone tablets for any indication, weight gain should be assessed against that expected with normal growth.

As with other drugs that antagonize dopamine D2 receptors, risperidone tablets elevates prolactin levels and the elevation persists during chronic administration. Risperidone tablets are associated with higher levels of prolactin elevation than other antipsychotic agents.

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.

Tissuecultureexperiments 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. An increase in pituitary gland, mammary gland, and pancreatic islet cell neoplasia (mammary adenocarcinomas, pituitary and pancreatic adenomas) was observed in the risperidone 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.

Risperidone tablets may induce orthostatic hypotension associated with dizziness, tachycardia, and in some patients, syncope, especially during the initial dose-titration period, probably reflecting its alpha-adrenergic antagonistic properties. Syncope was reported in 0.2% (6/2607) of risperidone tablets-treated patients in Phase 2 and 3 studies in adults with schizophrenia. The risk of orthostatic hypotension and syncope may be minimized by limiting the initial dose to 2 mg total (either once daily or 1 mg twice daily) in normal adults and 0.5 mg twice daily in the elderly and patients with renal or hepatic impairment [see Dosage and Administration ( 2.1, 2.4)] .

Monitoring of orthostatic vital signs should be considered in patients for whom this is of concern. A dose reduction should be considered if hypotension occurs. Risperidone tablets 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, e.g., dehydration and hypovolemia, and in the elderly and patients with renal or hepatic impairment. Monitoring of orthostatic vital signs should be considered if hypotension occurs. Clinically significant hypotension has been observed with concomitant use of risperidone tablets and antihypertensive medication.

Somnolence, postural hypotension, motor and sensory instability have been reported with the use of antipsychotics, including risperidone tablets, which may lead to falls and, consequently, fractures or other fall-related injuries. For patients, particularly the elderly, with diseases, conditions, or medications that could exacerbate these effects, assess the risk of falls 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 risperidone tablets. 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 a drug-induced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and discontinuation of risperidone tablets 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 risperidone tablets and have their WBC followed until recovery.

Somnolence was a commonly reported adverse reactions associated with risperidone tablets treatment, especially when ascertained by direct questioning of patients. This adverse reaction is dose-related, and in a study utilizing a checklist to detect adverse events, 41% of the high-dose patients (risperidone tablets 16 mg/day) reported somnolence compared to 16% of placebo patients. Direct questioning is more sensitive for detecting adverse events than spontaneous reporting, by which 8% of risperidone tablets 16 mg/day patients and 1% of placebo patients reported somnolence as an adverse reation. Since risperidone tablets have 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 risperidone tablets therapy does not affect them adversely.

During premarketing testing in adult patients with schizophrenia, seizures occurred in 0.3% (9/2607) of risperidone tablets-treated patients, two in association with hyponatremia. Risperidone tablets should be used cautiously in patients with a history of seizures.

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 dementia. Risperidone tablets and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia. [see  Boxed Warningand Warnings and Precautions (5.1)].

Priapism has been reported during postmarketing surveillance. Severe priapism may require surgical intervention.

Disruption of body temperature regulation has been attributed to antipsychotic agents. Both hyperthermia and hypothermia have been reported in association with oral risperidone tablets use. Caution is advised when prescribing for patients who will be exposed to temperature extremes.

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 the rates observed in clinical practice.

Commonly-Observed Adverse Reactions in Double-Blind, Placebo-Controlled Clinical Trials – Schizophrenia Adult Patients with Schizophrenia Table 8 lists the adverse reactions reported in 2% or more of risperidone tablets-treated adult patients with schizophrenia in three 4- to 8-week, double-blind, placebo-controlled trials.

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="100%"> <caption> <span>Table  8.  Adverse Reactions in ≥2% of Risperidone Tablets-Treated Adult Patients (and greater than placebo) with Schizophrenia in Double-Blind, Placebo-Controlled Trials</span> </caption> <col width="43.82%"/> <col width="23.5%"/> <col width="19.32%"/> <col width="13.36%"/> <tfoot> <tr class="First Last"> <td colspan="202"><span class="Sup">*</span>Parkinsonism includes extrapyramidal disorder, musculoskeletal stiffness, parkinsonism, cogwheel    rigidity, akinesia, bradykinesia, hypokinesia, masked facies, muscle rigidity, and Parkinson's disease.   Akathisia includes akathisia and restlessness. Dystonia includes dystonia, muscle spasms, muscle   contractions involuntary, muscle contracture, oculogyration, tongue paralysis. Tremor includes tremor and parkinsonian rest tremor. </td> </tr> </tfoot> <tbody class="Headless"> <tr class="Botrule First"> <td class="Lrule Rrule" rowspan="3" valign="bottom"><span class="Bold"> <br/> System/Organ Class </span> <br/> <span class="Bold"> </span>Adverse Reaction <br/> </td><td align="center" class="Rrule" colspan="3" valign="top"><span class="Bold">Percentage of Patients Reporting Reaction</span> <br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" colspan="2" valign="top"><span class="Bold">Risperidone</span>  <span class="Bold">Tablets </span> <br/> </td><td class="Rrule" valign="top">  <br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="middle"><span class="Bold">2–8 mg per day</span> <br/> <span class="Bold">(N=366)</span> <br/> </td><td align="center" class="Rrule" valign="middle"><span class="Bold">&gt;8–16 mg per day</span> <br/> <span class="Bold">(N=198)</span> <br/> </td><td align="center" class="Rrule" valign="middle"><span class="Bold">Placebo</span> <br/> <span class="Bold">(N=225)</span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" colspan="4" valign="top"><span class="Bold">Cardiac Disorders</span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  Tachycardia <br/> </td><td align="center" class="Rrule" valign="top">1 <br/> </td><td align="center" class="Rrule" valign="top">3 <br/> </td><td align="center" class="Rrule" valign="top">0 <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" colspan="4" valign="top"><span class="Bold">Eye Disorders</span>  <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  Vision blurred <br/> </td><td align="center" class="Rrule" valign="top">3 <br/> </td><td align="center" class="Rrule" valign="top">1 <br/> </td><td align="center" class="Rrule" valign="top">1 <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" colspan="4" valign="top"><span class="Bold">Gastrointestinal Disorders</span>  <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  Nausea <br/> </td><td align="center" class="Rrule" valign="top">9 <br/> </td><td align="center" class="Rrule" valign="top">4 <br/> </td><td align="center" class="Rrule" valign="top">4 <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  Constipation <br/> </td><td align="center" class="Rrule" valign="top">8 <br/> </td><td align="center" class="Rrule" valign="top">9 <br/> </td><td align="center" class="Rrule" valign="top">6 <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  Dyspepsia <br/> </td><td align="center" class="Rrule" valign="top">8 <br/> </td><td align="center" class="Rrule" valign="top">6 <br/> </td><td align="center" class="Rrule" valign="top">5 <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  Dry mouth <br/> </td><td align="center" class="Rrule" valign="top">4 <br/> </td><td align="center" class="Rrule" valign="top">0 <br/> </td><td align="center" class="Rrule" valign="top">1 <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  Abdominal discomfort <br/> </td><td align="center" class="Rrule" valign="top">3 <br/> </td><td align="center" class="Rrule" valign="top">1 <br/> </td><td align="center" class="Rrule" valign="top">1 <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  Salivary hypersecretion <br/> </td><td align="center" class="Rrule" valign="top">2 <br/> </td><td align="center" class="Rrule" valign="top">1 <br/> </td><td align="center" class="Rrule" valign="top">&lt;1 <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  Diarrhea <br/> </td><td align="center" class="Rrule" valign="top">2 <br/> </td><td align="center" class="Rrule" valign="top">1 <br/> </td><td align="center" class="Rrule" valign="top">1 <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" colspan="4" valign="top"><span class="Bold">General Disorders</span>  <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  Fatigue <br/> </td><td align="center" class="Rrule" valign="top">3 <br/> </td><td align="center" class="Rrule" valign="top">1 <br/> </td><td align="center" class="Rrule" valign="top">0 <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  Chest pain <br/> </td><td align="center" class="Rrule" valign="top">2 <br/> </td><td align="center" class="Rrule" valign="top">2 <br/> </td><td align="center" class="Rrule" valign="top">1 <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  Asthenia <br/> </td><td align="center" class="Rrule" valign="top">2 <br/> </td><td align="center" class="Rrule" valign="top">1 <br/> </td><td align="center" class="Rrule" valign="top">&lt;1 <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" colspan="4" valign="top"><span class="Bold">Infections and Infestations</span>  <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  Nasopharyngitis <br/> </td><td align="center" class="Rrule" valign="top">3 <br/> </td><td align="center" class="Rrule" valign="top">4 <br/> </td><td align="center" class="Rrule" valign="top">3 <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  Upper respiratory tract infection <br/> </td><td align="center" class="Rrule" valign="top">2 <br/> </td><td align="center" class="Rrule" valign="top">3 <br/> </td><td align="center" class="Rrule" valign="top">1 <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  Sinusitis <br/> </td><td align="center" class="Rrule" valign="top">1 <br/> </td><td align="center" class="Rrule" valign="top">2 <br/> </td><td align="center" class="Rrule" valign="top">1 <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  Urinary tract infection <br/> </td><td align="center" class="Rrule" valign="top">1 <br/> </td><td align="center" class="Rrule" valign="top">3 <br/> </td><td align="center" class="Rrule" valign="top">0 <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" colspan="4" valign="top"><span class="Bold">Investigations</span>  <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  Blood creatine phosphokinase increased <br/> </td><td align="center" class="Rrule" valign="top">1 <br/> </td><td align="center" class="Rrule" valign="top">2 <br/> </td><td align="center" class="Rrule" valign="top">&lt;1 <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  Heart rate increased <br/> </td><td align="center" class="Rrule" valign="top">&lt;1 <br/> </td><td align="center" class="Rrule" valign="top">2 <br/> </td><td align="center" class="Rrule" valign="top">0 <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" colspan="4" valign="top"><span class="Bold">Musculoskeletal and Connective Tissue</span> <br/> <span class="Bold">Disorders</span>  <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  Back pain <br/> </td><td align="center" class="Rrule" valign="top">4 <br/> </td><td align="center" class="Rrule" valign="top">1 <br/> </td><td align="center" class="Rrule" valign="top">1 <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  Arthralgia <br/> </td><td align="center" class="Rrule" valign="top">2 <br/> </td><td align="center" class="Rrule" valign="top">3 <br/> </td><td align="center" class="Rrule" valign="top">&lt;1 <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  Pain in extremity <br/> </td><td align="center" class="Rrule" valign="top">2 <br/> </td><td align="center" class="Rrule" valign="top">1 <br/> </td><td align="center" class="Rrule" valign="top">1 <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" colspan="4" valign="top"><span class="Bold">Nervous System Disorders</span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  Parkinsonism <span class="Sup">*</span> <br/> </td><td align="center" class="Rrule" valign="top">14 <br/> </td><td align="center" class="Rrule" valign="top">17 <br/> </td><td align="center" class="Rrule" valign="top">8 <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  Akathisia <span class="Sup">*</span> <br/> </td><td align="center" class="Rrule" valign="top">10 <br/> </td><td align="center" class="Rrule" valign="top">10 <br/> </td><td align="center" class="Rrule" valign="top">3 <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  Sedation <br/> </td><td align="center" class="Rrule" valign="top">10  <br/> </td><td align="center" class="Rrule" valign="top">5 <br/> </td><td align="center" class="Rrule" valign="top">2 <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  Dizziness <br/> </td><td align="center" class="Rrule" valign="top">7 <br/> </td><td align="center" class="Rrule" valign="top">4 <br/> </td><td align="center" class="Rrule" valign="top">2 <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  Dystonia <span class="Sup">*</span> <br/> </td><td align="center" class="Rrule" valign="top">3 <br/> </td><td align="center" class="Rrule" valign="top">4 <br/> </td><td align="center" class="Rrule" valign="top">2 <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  Tremor <span class="Sup">*</span> <br/> </td><td align="center" class="Rrule" valign="top">2 <br/> </td><td align="center" class="Rrule" valign="top">3 <br/> </td><td align="center" class="Rrule" valign="top">1 <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  Dizziness postural <br/> </td><td align="center" class="Rrule" valign="top">2 <br/> </td><td align="center" class="Rrule" valign="top">0 <br/> </td><td align="center" class="Rrule" valign="top">0 <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" colspan="4" valign="top"><span class="Bold">Psychiatric Disorders</span>  <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  Insomnia <br/> </td><td align="center" class="Rrule" valign="top">32 <br/> </td><td align="center" class="Rrule" valign="top">25 <br/> </td><td align="center" class="Rrule" valign="top">27 <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  Anxiety <br/> </td><td align="center" class="Rrule" valign="top">16 <br/> </td><td align="center" class="Rrule" valign="top">11 <br/> </td><td align="center" class="Rrule" valign="top">11 <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" colspan="4" valign="top"><span class="Bold">Respiratory, Thoracic and Mediastinal</span> <br/> <span class="Bold">Disorders</span>  <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  Nasal congestion <br/> </td><td align="center" class="Rrule" valign="top">4 <br/> </td><td align="center" class="Rrule" valign="top">6 <br/> </td><td align="center" class="Rrule" valign="top">2 <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  Dyspnea <br/> </td><td align="center" class="Rrule" valign="top">1 <br/> </td><td align="center" class="Rrule" valign="top">2 <br/> </td><td align="center" class="Rrule" valign="top">0 <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  Epistaxis <br/> </td><td align="center" class="Rrule" valign="top">&lt;1 <br/> </td><td align="center" class="Rrule" valign="top">2 <br/> </td><td align="center" class="Rrule" valign="top">0 <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" colspan="4" valign="top"><span class="Bold">Skin and Subcutaneous Tissue Disorders</span>  <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  Rash <br/> </td><td align="center" class="Rrule" valign="top">1 <br/> </td><td align="center" class="Rrule" valign="top">4 <br/> </td><td align="center" class="Rrule" valign="top">1 <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  Dry skin <br/> </td><td align="center" class="Rrule" valign="top">1 <br/> </td><td align="center" class="Rrule" valign="top">3 <br/> </td><td align="center" class="Rrule" valign="top">0 <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" colspan="4" valign="top"><span class="Bold">Vascular Disorders</span> <br/> </td> </tr> <tr class="Last"> <td class="Lrule Rrule" valign="top">  Orthostatic hypotension <br/> </td><td align="center" class="Rrule" valign="top">2 <br/> </td><td align="center" class="Rrule" valign="top">1 <br/> </td><td align="center" class="Rrule" valign="top">0 <br/> </td> </tr> </tbody> </table></div>

Pediatric Patients with Schizophrenia

Table 9 lists the adverse reactions reported in 5% or more of risperidone tablets-treated pediatric patients with schizophrenia in a 6-week double-blind, placebo-controlled trial.  

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="100%"> <caption> <span>Table 9. Adverse Reactions in ≥5% of Risperidone Tablets-Treated Pediatric Patients (and greater than placebo) with Schizophrenia in a Double-Blind Trial</span> </caption> <col width="34.02%"/> <col width="25.42%"/> <col width="25.42%"/> <col width="15.16%"/> <tfoot> <tr class="First Last"> <td colspan="54"><span class="Sup">*</span>Parkinsonism includes extrapyramidal disorder, muscle rigidity, musculoskeletal stiffness, and hypokinesia. Akathisia includes akathisia and restlessness. Dystonia includes dystonia and oculogyration. </td> </tr> </tfoot> <tbody class="Headless"> <tr class="Botrule First"> <td class="Lrule Rrule" rowspan="3" valign="bottom"><span class="Bold"> <br/> <br/> System/Organ Class </span> <br/> <span class="Bold"> </span>Adverse Reaction <br/> </td><td align="center" class="Rrule" colspan="3" valign="middle"><span class="Bold">Percentage of Patients Reporting Reaction</span> <br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" colspan="2" valign="middle"><span class="Bold">Risperidone</span>  <span class="Bold">Tablets </span> <br/> </td><td class="Rrule" valign="top"><span class="Bold"> </span> <br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="middle"><span class="Bold">1–3 mg per day</span> <br/> <span class="Bold">(N=55)</span> <br/> </td><td align="center" class="Rrule" valign="middle"><span class="Bold">4–6 mg per day</span> <br/> <span class="Bold">(N=51)</span> <br/> </td><td align="center" class="Rrule" valign="middle"><span class="Bold">Placebo</span> <br/> <span class="Bold">(N=54)</span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" colspan="4" valign="top"><span class="Bold">Gastrointestinal Disorders</span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  Salivary hypersecretion <span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">0 <span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">10 <span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">2 <span class="Bold"></span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" colspan="4" valign="top"><span class="Bold">Nervous System Disorders</span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">  Sedation <br/> </td><td align="center" class="Rrule" valign="top">24 <span class="Bold"> </span> <br/> </td><td align="center" class="Rrule" valign="top">12 <span class="Bold"> </span> <br/> </td><td align="center" class="Rrule" valign="top">4 <span class="Bold"> </span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">  Parkinsonism <span class="Sup">*</span> <br/> </td><td align="center" class="Rrule" valign="top">16 <span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">28 <span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">11 <span class="Bold"></span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">  Tremor <br/> </td><td align="center" class="Rrule" valign="top">11 <span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">10 <span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">6 <span class="Bold"></span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">  Akathisia <span class="Sup">*</span> <br/> </td><td align="center" class="Rrule" valign="top">9 <span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">10 <span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">4 <span class="Bold"></span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">  Dizziness <br/> </td><td align="center" class="Rrule" valign="top">7 <span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">14 <span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">2 <span class="Bold"></span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">  Dystonia <span class="Sup">*</span> <br/> </td><td align="center" class="Rrule" valign="top">2 <span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">6 <span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">0 <span class="Bold"></span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" colspan="4" valign="top"><span class="Bold">Psychiatric Disorders</span> <br/> </td> </tr> <tr class="Last"> <td class="Lrule Rrule" valign="top">  Anxiety <span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">7 <span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">6 <span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">0 <span class="Bold"></span> <br/> </td> </tr> </tbody> </table></div>

Commonly-Observed Adverse Reactions in Double-Blind, Placebo-Controlled Clinical Trials – Bipolar Mania

Adult Patients with Bipolar Mania

Table 10 lists the adverse reactions reported in 2% or more of risperidone tablets-treated adult patients with bipolar mania in four 3-week, double-blind, placebo-controlled monotherapy trials.

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="100%"> <caption> <span>Table 10. Adverse Reactions in ≥2% of Risperidone Tablets-Treated Adult Patients (and greater than placebo) with Bipolar Mania in Double-Blind, Placebo-Controlled Monotherapy Trials</span> </caption> <col width="48.16%"/> <col width="31.1%"/> <col width="20.74%"/> <tfoot> <tr class="First Last"> <td colspan="56"><span class="Sup">*</span>Parkinsonism includes extrapyramidal disorder, parkinsonism, musculoskeletal stiffness, hypokinesia,    muscle rigidity, muscle tightness, bradykinesia, cogwheel rigidity. Akathisia includes akathisia and    restlessness. Tremor includes tremor and parkinsonian rest tremor. Dystonia includes dystonia, muscle   spasms, oculogyration, torticollis. </td> </tr> </tfoot> <tbody class="Headless"> <tr class="Botrule First"> <td class="Lrule Rrule" rowspan="2" valign="middle"><span class="Bold"> <br/> <br/> System/Organ Class </span> <br/> Adverse Reaction <br/> </td><td align="center" class="Rrule" colspan="2" valign="top"><span class="Bold">Percentage of Patients Reporting Reaction</span> <br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="middle"><span class="Bold">Risperidone</span><span class="Bold">Tablets </span> <br/> <span class="Bold">1–6 mg per day</span> <br/> <span class="Bold">(N=448)</span> <br/> </td><td align="center" class="Rrule" valign="middle"><span class="Bold">Placebo</span> <br/> <span class="Bold">(N=424)</span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" colspan="3" valign="top"><span class="Bold">Eye Disorders</span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  Vision blurred <span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">2 <span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">1 <span class="Bold"></span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" colspan="3" valign="top"><span class="Bold">Gastrointestinal Disorders</span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  Nausea <br/> </td><td align="center" class="Rrule" valign="top">5 <span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">2 <span class="Bold"></span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  Diarrhea <br/> </td><td align="center" class="Rrule" valign="top">3 <span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">2 <span class="Bold"></span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  Salivary hypersecretion <br/> </td><td align="center" class="Rrule" valign="top">3 <span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">1 <span class="Bold"></span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  Stomach discomfort <br/> </td><td align="center" class="Rrule" valign="top">2 <span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">&lt;1 <span class="Bold"></span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" colspan="3" valign="top"><span class="Bold">General Disorders</span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  Fatigue <br/> </td><td align="center" class="Rrule" valign="top">2 <span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">1 <span class="Bold"></span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" colspan="3" valign="top"><span class="Bold">Nervous System Disorders</span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  Parkinsonism <span class="Sup">*</span> <br/> </td><td align="center" class="Rrule" valign="top">25 <span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">9 <span class="Bold"></span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  Sedation <br/> </td><td align="center" class="Rrule" valign="top">11 <span class="Bold"> </span> <br/> </td><td align="center" class="Rrule" valign="top">4 <span class="Bold"></span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  Akathisia <span class="Sup">*</span> <br/> </td><td align="center" class="Rrule" valign="top">9 <span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">3 <span class="Bold"></span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  Tremor <span class="Sup">*</span> <br/> </td><td align="center" class="Rrule" valign="top">6 <span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">3 <span class="Bold"></span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  Dizziness <br/> </td><td align="center" class="Rrule" valign="top">6 <span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">5 <span class="Bold"></span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  Dystonia <span class="Sup">*</span> <br/> </td><td align="center" class="Rrule" valign="top">5 <span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">1 <span class="Bold"></span> <br/> </td> </tr> <tr class="Last"> <td class="Lrule Rrule" valign="top">  Lethargy <br/> </td><td align="center" class="Rrule" valign="top">2 <span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">1 <span class="Bold"></span> <br/> </td> </tr> </tbody> </table></div>

Table 11 lists the adverse reactions reported in 2% or more of risperidone tablets-treated adult patients with bipolar mania in two 3-week, double-blind, placebo-controlled adjuvant therapy trials.  

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="100%"> <caption> <span>Table 11. Adverse Reactions in ≥2% of Risperidone Tablets-Treated Adult Patients (and greater than placebo) with Bipolar Mania in Double-Blind, Placebo-Controlled Adjunctive Therapy Trials </span> </caption> <col width="31.1%"/> <col width="44.94%"/> <col width="23.96%"/> <tfoot> <tr class="First Last"> <td colspan="74">  <span class="Sup">*</span>Parkinsonism includes extrapyramidal disorder, hypokinesia and bradykinesia. Akathisia includes hyperkinesia and akathisia. </td> </tr> </tfoot> <tbody class="Headless"> <tr class="Botrule First"> <td class="Lrule Rrule" rowspan="2" valign="bottom"><span class="Bold"> <br/> <br/> System/Organ Class </span> <br/> Adverse Reaction <br/> </td><td align="center" class="Rrule" colspan="2" valign="top"><span class="Bold">Percentage of Patients Reporting Reaction</span> <br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="middle"><span class="Bold">Risperidone</span><span class="Bold">Tablets + Mood Stabilizer</span> <br/> <span class="Bold"> </span><span class="Bold">(N=127)</span> <br/> </td><td align="center" class="Rrule" valign="middle"><span class="Bold">Placebo + Mood Stabilizer</span> <br/> <span class="Bold">(N=126)</span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" colspan="3" valign="top"><span class="Bold">Cardiac Disorders</span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  Palpitations <span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">2 <span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">0 <span class="Bold"></span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" colspan="3" valign="top"><span class="Bold">Gastrointestinal Disorders</span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  Dyspepsia <br/> </td><td align="center" class="Rrule" valign="top">9 <span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">8 <span class="Bold"></span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  Nausea <br/> </td><td align="center" class="Rrule" valign="top">6 <span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">4 <span class="Bold"></span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  Diarrhea <br/> </td><td align="center" class="Rrule" valign="top">6 <span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">4 <span class="Bold"></span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  Salivary hypersecretion <br/> </td><td align="center" class="Rrule" valign="top">2 <span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">0 <span class="Bold"></span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" colspan="3" valign="top"><span class="Bold">General Disorders</span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  Chest pain <br/> </td><td align="center" class="Rrule" valign="top">2 <span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">1 <span class="Bold"></span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" colspan="3" valign="top"><span class="Bold">Infections and Infestations</span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  Urinary tract infection <span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">2 <span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">1 <span class="Bold"></span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" colspan="3" valign="top"><span class="Bold">Nervous System Disorders</span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  Parkinsonism <span class="Sup">*</span> <br/> </td><td align="center" class="Rrule" valign="top">14 <span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">4 <span class="Bold"></span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  Sedation <br/> </td><td align="center" class="Rrule" valign="top">9 <span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">4 <span class="Bold"> </span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  Akathisia <span class="Sup">*</span> <br/> </td><td align="center" class="Rrule" valign="top">8 <span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">0 <span class="Bold"></span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  Dizziness <br/> </td><td align="center" class="Rrule" valign="top">7 <span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">2 <span class="Bold"></span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  Tremor <br/> </td><td align="center" class="Rrule" valign="top">6 <span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">2 <span class="Bold"></span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  Lethargy <br/> </td><td align="center" class="Rrule" valign="top">2 <span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">1 <span class="Bold"></span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" colspan="3" valign="top"><span class="Bold">Psychiatric Disorders</span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  Anxiety <br/> </td><td align="center" class="Rrule" valign="top">3 <span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">2 <span class="Bold"></span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" colspan="3" valign="top"><span class="Bold">Respiratory, Thoracic and</span> <br/> <span class="Bold">Mediastinal Disorders</span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  Pharyngolaryngeal pain <br/> </td><td align="center" class="Rrule" valign="top">5 <span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">2 <span class="Bold"></span> <br/> </td> </tr> <tr class="Last"> <td class="Lrule Rrule" valign="top">  Cough <br/> </td><td align="center" class="Rrule" valign="top">2 <span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">0 <span class="Bold"></span> <br/> </td> </tr> </tbody> </table></div>

 Pediatric Patients with Bipolar Mania Table 12 lists the adverse reactions reported in 5% or more of risperidone tablets-treated pediatric patients with bipolar mania in a 3-week double-blind, placebo-controlled trial.

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="100%"> <caption> <span>Table 12.  Adverse Reactions in ≥5% of Risperidone Tablets-Treated Pediatric Patients (and greater than placebo) with Bipolar Mania in Double-Blind, Placebo-Controlled Trials</span> </caption> <col width="35.72%"/> <col width="27.02%"/> <col width="23.28%"/> <col width="13.98%"/> <tfoot> <tr class="First Last"> <td colspan="109"><span class="Sup">*</span>Parkinsonism includes musculoskeletal stiffness, extrapyramidal disorder, bradykinesia, and nuchal rigidity. Dystonia includes dystonia, laryngospasm, and muscle spasms. Akathisia includes restlessness and akathisia. </td> </tr> </tfoot> <tbody class="Headless"> <tr class="Botrule First"> <td class="Lrule Rrule" rowspan="3" valign="middle"><span class="Bold"> <br/> <br/> System/Organ Class </span> <br/>   Adverse Reaction <br/> </td><td align="center" class="Rrule" colspan="3" valign="middle"><span class="Bold">Percentage of Patients Reporting Reaction</span> <br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" colspan="2" valign="middle"><span class="Bold">Risperidone</span>  <span class="Bold">Tablets </span> <br/> </td><td align="center" class="Rrule" rowspan="2" valign="middle"><span class="Bold">Placebo</span> <br/> <span class="Bold">(N=58)</span>  <br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="middle"><span class="Bold">0.5–2.5 mg per day</span> <br/> <span class="Bold">(N=50)</span>  <br/> </td><td align="center" class="Rrule" valign="middle"><span class="Bold">3–6 mg per day</span> <br/> <span class="Bold">(N=61)</span>  <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" colspan="4" valign="top"><span class="Bold">Eye Disorders</span>  <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  Vision blurred <br/> </td><td align="center" class="Rrule" valign="top">4 <br/> </td><td align="center" class="Rrule" valign="top">7 <br/> </td><td align="center" class="Rrule" valign="top">0 <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" colspan="4" valign="top"><span class="Bold">Gastrointestinal Disorders</span>  <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  Abdominal pain upper <br/> </td><td align="center" class="Rrule" valign="top">16 <br/> </td><td align="center" class="Rrule" valign="top">13 <br/> </td><td align="center" class="Rrule" valign="top">5 <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  Nausea <br/> </td><td align="center" class="Rrule" valign="top">16 <br/> </td><td align="center" class="Rrule" valign="top">13 <br/> </td><td align="center" class="Rrule" valign="top">7 <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  Vomiting <br/> </td><td align="center" class="Rrule" valign="top">10 <br/> </td><td align="center" class="Rrule" valign="top">10 <br/> </td><td align="center" class="Rrule" valign="top">5 <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  Diarrhea <br/> </td><td align="center" class="Rrule" valign="top">8 <br/> </td><td align="center" class="Rrule" valign="top">7 <br/> </td><td align="center" class="Rrule" valign="top">2 <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  Dyspepsia <br/> </td><td align="center" class="Rrule" valign="top">10 <br/> </td><td align="center" class="Rrule" valign="top">3 <br/> </td><td align="center" class="Rrule" valign="top">2 <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  Stomach discomfort <br/> </td><td align="center" class="Rrule" valign="top">6 <br/> </td><td align="center" class="Rrule" valign="top">0 <br/> </td><td align="center" class="Rrule" valign="top">2 <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" colspan="4" valign="top"><span class="Bold">General Disorders</span>  <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  Fatigue <br/> </td><td align="center" class="Rrule" valign="top">18 <br/> </td><td align="center" class="Rrule" valign="top">30 <br/> </td><td align="center" class="Rrule" valign="top">3 <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" colspan="4" valign="top"><span class="Bold">Metabolism and Nutrition Disorders</span>  <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  Increased appetite <br/> </td><td align="center" class="Rrule" valign="top">4 <br/> </td><td align="center" class="Rrule" valign="top">7 <br/> </td><td align="center" class="Rrule" valign="top">2 <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" colspan="4" valign="top"><span class="Bold">Nervous System Disorders</span>  <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  Sedation <br/> </td><td align="center" class="Rrule" valign="top">42 <br/> </td><td align="center" class="Rrule" valign="top">56 <br/> </td><td align="center" class="Rrule" valign="top">19 <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  Dizziness <br/> </td><td align="center" class="Rrule" valign="top">16 <br/> </td><td align="center" class="Rrule" valign="top">13 <br/> </td><td align="center" class="Rrule" valign="top">5 <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  Parkinsonism <span class="Sup">*</span> <br/> </td><td align="center" class="Rrule" valign="top">6 <br/> </td><td align="center" class="Rrule" valign="top">12 <br/> </td><td align="center" class="Rrule" valign="top">3 <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  Dystonia <span class="Sup">*</span> <br/> </td><td align="center" class="Rrule" valign="top">6 <br/> </td><td align="center" class="Rrule" valign="top">5 <br/> </td><td align="center" class="Rrule" valign="top">0 <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  Akathisia <span class="Sup">*</span> <br/> </td><td align="center" class="Rrule" valign="top">0 <br/> </td><td align="center" class="Rrule" valign="top">8 <br/> </td><td align="center" class="Rrule" valign="top">2 <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" colspan="4" valign="top"><span class="Bold">Psychiatric Disorders</span>  <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  Anxiety <br/> </td><td align="center" class="Rrule" valign="top">0 <br/> </td><td align="center" class="Rrule" valign="top">8 <br/> </td><td align="center" class="Rrule" valign="top">3 <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" colspan="4" valign="top"><span class="Bold">Respiratory, Thoracic and Mediastinal Disorders</span>  <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  Pharyngolaryngeal pain <br/> </td><td align="center" class="Rrule" valign="top">10 <br/> </td><td align="center" class="Rrule" valign="top">3 <br/> </td><td align="center" class="Rrule" valign="top">5 <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" colspan="4" valign="top"><span class="Bold">Skin and Subcutaneous Tissue Disorders</span>  <br/> </td> </tr> <tr class="Last"> <td class="Lrule Rrule" valign="top">  Rash <br/> </td><td align="center" class="Rrule" valign="top">0 <br/> </td><td align="center" class="Rrule" valign="top">7 <br/> </td><td align="center" class="Rrule" valign="top">2 <br/> </td> </tr> </tbody> </table></div>

Commonly-Observed Adverse Reactions in Double-Blind, Placebo-Controlled Clinical Trials - Autistic Disorder

Table 13 lists the adverse reactions reported in 5% or more of risperidone tablets-treated pediatric patients treated for irritability associated with autistic disorder in two 8-week, double-blind, placebo-controlled trials and one 6-week double-blind, placebo-controlled study.

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="100%"> <caption> <span>Table 13.   Adverse Reactions in ≥ 5% of Risperidone Tablets-Treated Pediatric Patients (and greater than placebo) Treated for Irritability Associated with Autistic Disorder in Double-Blind, Placebo-Controlled Trials</span> </caption> <col width="60.22%"/> <col width="23.46%"/> <col width="16.32%"/> <tfoot> <tr class="First Last"> <td colspan="104"><span class="Sup">*</span>Parkinsonism includes musculoskeletal stiffness, extrapyramidal disorder, muscle rigidity, cogwheel rigidity, and muscle tightness. </td> </tr> </tfoot> <tbody class="Headless"> <tr class="Botrule First"> <td class="Lrule Rrule" rowspan="2" valign="bottom">   <br/> <span class="Bold">System/Organ Class</span> <br/>   Adverse Reaction  <br/> </td><td align="center" class="Rrule" colspan="2" valign="middle"><span class="Bold">Percentage of Patients Reporting Reaction</span>  <br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="middle"><span class="Bold">Risperidone</span><span class="Bold">Tablets </span> <br/> <span class="Bold">0.5–4.0 mg per day</span> <br/> <span class="Bold">(N=107)</span>  <br/> </td><td align="center" class="Rrule" valign="middle"><span class="Bold"> <br/> Placebo </span> <br/> <span class="Bold">(N=115)</span>  <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" colspan="3" valign="top"><span class="Bold">Gastrointestinal Disorders</span>  <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  Vomiting  <br/> </td><td align="center" class="Rrule" valign="top">20 <br/> </td><td align="center" class="Rrule" valign="top">17 <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  Constipation <br/> </td><td align="center" class="Rrule" valign="top">17 <br/> </td><td align="center" class="Rrule" valign="top">6 <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  Dry mouth <br/> </td><td align="center" class="Rrule" valign="top">10 <br/> </td><td align="center" class="Rrule" valign="top">4   <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  Nausea <br/> </td><td align="center" class="Rrule" valign="top">8 <br/> </td><td align="center" class="Rrule" valign="top">5 <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  Salivary hypersecretion <br/> </td><td align="center" class="Rrule" valign="top">7 <br/> </td><td align="center" class="Rrule" valign="top">1 <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top"><span class="Bold">General Disorders and Administration Site Conditions</span>  <br/> </td><td class="Rrule" valign="top">  <br/> </td><td class="Rrule" valign="top">  <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  Fatigue <br/> </td><td align="center" class="Rrule" valign="top">31 <br/> </td><td align="center" class="Rrule" valign="top">9 <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  Pyrexia <br/> </td><td align="center" class="Rrule" valign="top">16 <br/> </td><td align="center" class="Rrule" valign="top">13 <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  Thirst <br/> </td><td align="center" class="Rrule" valign="top">7 <br/> </td><td align="center" class="Rrule" valign="top">4 <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" colspan="3" valign="top"><span class="Bold">Infections and Infestations</span>  <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  Nasopharyngitis <br/> </td><td align="center" class="Rrule" valign="top">19 <br/> </td><td align="center" class="Rrule" valign="top">9 <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  Rhinitis <br/> </td><td align="center" class="Rrule" valign="top">9 <br/> </td><td align="center" class="Rrule" valign="top">7 <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  Upper respiratory tract infection <br/> </td><td align="center" class="Rrule" valign="top">8 <br/> </td><td align="center" class="Rrule" valign="top">3 <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" colspan="3" valign="top"><span class="Bold">Investigations</span>  <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  Weight increased <br/> </td><td align="center" class="Rrule" valign="top">8 <br/> </td><td align="center" class="Rrule" valign="top">2 <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" colspan="3" valign="top"><span class="Bold">Metabolism and Nutrition Disorders</span>  <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  Increased appetite <br/> </td><td align="center" class="Rrule" valign="top">44 <br/> </td><td align="center" class="Rrule" valign="top">15 <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" colspan="3" valign="top"><span class="Bold">Nervous System Disorders</span>  <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  Sedation <br/> </td><td align="center" class="Rrule" valign="top">63 <br/> </td><td align="center" class="Rrule" valign="top">15 <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  Drooling <br/> </td><td align="center" class="Rrule" valign="top">12 <br/> </td><td align="center" class="Rrule" valign="top">4 <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  Headache <br/> </td><td align="center" class="Rrule" valign="top">12 <br/> </td><td align="center" class="Rrule" valign="top">10 <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  Tremor <br/> </td><td align="center" class="Rrule" valign="top">8 <br/> </td><td align="center" class="Rrule" valign="top">1 <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  Dizziness <br/> </td><td align="center" class="Rrule" valign="top">8 <br/> </td><td align="center" class="Rrule" valign="top">2 <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  Parkinsonism <span class="Sup">*</span> <br/> </td><td align="center" class="Rrule" valign="top">8 <br/> </td><td align="center" class="Rrule" valign="top">1 <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" colspan="3" valign="top"><span class="Bold">Renal and Urinary Disorders </span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  Enuresis <br/> </td><td align="center" class="Rrule" valign="top">16 <br/> </td><td align="center" class="Rrule" valign="top">10 <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" colspan="3" valign="top"><span class="Bold">Respiratory, Thoracic and Mediastinal Disorders</span>  <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  Cough <br/> </td><td align="center" class="Rrule" valign="top">17 <br/> </td><td align="center" class="Rrule" valign="top">12 <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  Rhinorrhea <br/> </td><td align="center" class="Rrule" valign="top">12 <br/> </td><td align="center" class="Rrule" valign="top">10 <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  Nasal congestion <br/> </td><td align="center" class="Rrule" valign="top">10 <br/> </td><td align="center" class="Rrule" valign="top">4 <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" colspan="3" valign="top"><span class="Bold">Skin and Subcutaneous Tissue Disorders</span>  <br/> </td> </tr> <tr class="Last"> <td class="Lrule Rrule" valign="top">  Rash <br/> </td><td align="center" class="Rrule" valign="top">8 <br/> </td><td align="center" class="Rrule" valign="top">5 <br/> </td> </tr> </tbody> </table></div>

Other Adverse Reactions Observed During the Clinical Trial Evaluation of Risperidone

The following additional adverse reactions occurred across all placebo-controlled, active-controlled, and open-label studies of risperidone tablets in adults and pediatric patients.

Blood and Lymphatic System Disorders: anemia, granulocytopenia, neutropenia

Cardiac Disorders: sinus bradycardia, sinus tachycardia, atrioventricular block first degree, bundle branch block left, bundle branch block right, atrioventricular block

Ear and Labyrinth Disorders: ear pain, tinnitus

Endocrine Disorders: hyperprolactinemia

Eye Disorders: ocular hyperemia, eye discharge, conjunctivitis, eye rolling, eyelid edema, eye swelling, eyelid margin crusting, dry eye, lacrimation increased, photophobia, glaucoma, visual acuity reduced

Gastrointestinal Disorders: dysphagia, fecaloma, fecal incontinence, gastritis, lip swelling, cheilitis, aptyalism

General Disorders: edema peripheral, thirst, gait disturbance, influenza-like illness, pitting edema, edema, chills, sluggishness, malaise, chest discomfort, face edema, discomfort, generalized edema, drug withdrawal syndrome, peripheral coldness, feeling abnormal

Immune System Disorders: drug hypersensitivity

Infections and Infestations: pneumonia, influenza, ear infection, viral infection, pharyngitis, tonsillitis, bronchitis, eye infection, localized infection, cystitis, cellulitis, otitis media, onychomycosis, acarodermatitis, bronchopneumonia, respiratory tract infection, tracheobronchitis, otitis media chronic

Investigations: body temperature increased, blood prolactin increased, alanine aminotransferase increased, electrocardiogram abnormal, eosinophil count increased, white blood cell count decreased, blood glucose increased, hemoglobin decreased, hematocrit decreased, body temperature decreased, blood pressure decreased, transaminases increased

Metabolism and Nutrition Disorders: decreased appetite, polydipsia, anorexia

Musculoskeletal and Connective Tissue Disorders: joint stiffness, joint swelling, musculoskeletal chest pain, posture abnormal, myalgia, neck pain, muscular weakness, rhabdomyolysis

Nervous System Disorders: balance disorder, disturbance in attention, dysarthria, unresponsive to stimuli, depressed level of consciousness, movement disorder, transient ischemic attack, coordination abnormal, cerebrovascular accident, speech disorder, syncope,  loss of consciousness, hypoesthesia, tardive dyskinesia, dyskinesia, cerebral ischemia, cerebrovascular disorder, neuroleptic malignant syndrome, diabetic coma, head titubation

Psychiatric Disorders: agitation, blunted affect, confusional state, middle insomnia, nervousness, sleep disorder, listlessness, libido decreased, and anorgasmia

Renal and Urinary Disorders: enuresis, dysuria, pollakiuria, urinary incontinence

Reproductive System and Breast Disorders: menstruation irregular, amenorrhea, gynecomastia, galactorrhea, vaginal discharge, menstrual disorder, erectile dysfunction, retrograde ejaculation, ejaculation disorder, sexual dysfunction, breast enlargement

Respiratory, Thoracic, and Mediastinal Disorders: wheezing, pneumonia aspiration, sinus congestion, dysphonia, productive cough, pulmonary congestion, respiratory tract congestion, rales, respiratory disorder, hyperventilation, nasal edema

Skin and Subcutaneous Tissue Disorders: erythema, skin discoloration, skin lesion, pruritus, skin disorder, rash erythematous, rash papular, rash generalized, rash maculopapular, acne, hyperkeratosis, seborrheic dermatitis

Vascular Disorders: hypotension, flushing

Discontinuations Due to Adverse Reactions Schizophrenia - Adults  

Approximately 7% (39/564) of risperidone tablets-treated patients in double-blind, placebo-controlled trials discontinued treatment due to an adverse reaction, compared with 4% (10/225) who were receiving placebo. The adverse reactions associated with discontinuation in 2 or more risperidone tablets-treated patients were:

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="100%"> <caption> <span>Table 14.  Adverse Reactions Associated With Discontinuation in 2 or More Risperidone Tablets-Treated Adult Patients in Schizophrenia Trials</span> </caption> <col width="32.16%"/> <col width="22.9%"/> <col width="25.52%"/> <col width="19.42%"/> <tbody class="Headless"> <tr class="Botrule First"> <td class="Lrule Rrule" rowspan="2" valign="bottom"><span class="Bold">Adverse Reaction</span> <br/> </td><td align="center" class="Rrule" colspan="2" valign="middle"><span class="Bold">Risperidone</span>  <span class="Bold">Tablets </span> <br/> </td><td align="center" class="Rrule" rowspan="2" valign="middle"><span class="Bold"> <br/> Placebo    <br/> (N=225 </span><span class="Bold">)</span><span class="Bold"> </span> <br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="middle"><span class="Bold">2-8 mg/day <br/> (N=366) </span> <br/> </td><td align="center" class="Rrule" valign="middle"><span class="Bold">&gt;8-16 mg/day <br/> (N=198) </span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Dizziness                                <span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">1.4% <span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">1.0% <span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">0% <span class="Bold"></span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Nausea                                    <span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">1.4% <span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">0% <span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">0% <span class="Bold"></span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Vomiting <br/> </td><td align="center" class="Rrule" valign="top">0.8% <span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">0% <span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">0% <span class="Bold"></span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Parkinsonism                        <span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">0.8% <span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">0% <span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">0% <span class="Bold"></span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Somnolence                          <span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">0.8% <span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">0% <span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">0% <span class="Bold"></span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Dystonia                               <span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">0.5% <span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">0% <span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">0% <span class="Bold"></span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Agitation                                  <span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">0.5% <span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">0% <span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">0% <span class="Bold"></span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Abdominal pain <span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">0.5% <span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">0% <span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">0% <span class="Bold"></span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Orthostatic hypotension  <span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">0.3% <span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">0.5% <span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">0% <span class="Bold"></span> <br/> </td> </tr> <tr class="Last"> <td class="Lrule Rrule" valign="top">Akathisia                                <span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">0.3% <span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">2.0% <span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">0% <span class="Bold"></span> <br/> </td> </tr> </tbody> </table></div>

Discontinuation for extrapyramidal symptoms (including Parkinsonism, akathisia, dystonia, and tardive dyskinesia) was 1% in placebo-treated patients, and 3.4% in active control-treated patients in a double-blind, placebo- and active-controlled trial.

Schizophrenia – Pediatrics Approximately 7% (7/106), of risperidone tablets-treated patients discontinued treatment due to an adverse reaction in a double-blind, placebo-controlled trial, compared with 4% (2/54) placebo-treated patients. The adverse reactions associated with discontinuation for at least one risperidone tablets-treated patient were dizziness (2%), somnolence (1%), sedation (1%), lethargy (1%), anxiety (1%), balance disorder (1%), hypotension (1%), and palpitation (1%).

Bipolar Mania – Adults In double-blind, placebo-controlled trials with risperidone tablets as monotherapy, approximately 6% (25/448) of risperidone tablets-treated patients discontinued treatment due to an adverse event, compared with approximately 5% (19/424) of placebo-treated patients. The adverse reactions associated with discontinuation in risperidone tablets-treated patients were:

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="100%"> <caption> <span>Table 15. Adverse Reactions Associated With Discontinuation in 2 or More Risperidone Tablets-Treated Adult Patients in Bipolar Mania Clinical Trials</span> </caption> <col width="56.52%"/> <col width="24.98%"/> <col width="18.5%"/> <tbody class="Headless"> <tr class="Botrule First"> <td class="Lrule Rrule" valign="bottom"><span class="Bold"> <br/> <br/> Adverse Reaction </span>  <br/> </td><td align="center" class="Rrule" valign="bottom"><span class="Bold">Risperidone</span>  <span class="Bold">Tablets       <br/> 1-6 mg/day <br/> (N=448) </span> <br/> </td><td align="center" class="Rrule" valign="bottom"><span class="Bold"> <br/> Placebo <br/> (N=448) </span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">Parkinsonism <span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="middle">0.4% <span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="middle">0% <span class="Bold"></span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">Lethargy                                            <span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="middle">0.2% <span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="middle">0% <span class="Bold"></span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">Dizziness                                                 <span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="middle">0.2% <span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="middle">0% <span class="Bold"></span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">Alanine aminotransferase increased <span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="middle">0.2% <span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="middle">0.2% <span class="Bold"></span> <br/> </td> </tr> <tr class="Last"> <td class="Lrule Rrule" valign="middle">Aspartate aminotransferase increased <span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="middle">0.2% <span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="middle">0.2% <span class="Bold"></span> <br/> </td> </tr> </tbody> </table></div>

Bipolar Mania – Pediatrics In a double-blind, placebo-controlled trial 12% (13/111) of risperidone tablets-treated patients discontinued due to an adverse reaction, compared with 7% (4/58) of placebo-treated patients. The adverse reactions associated with discontinuation in more than one risperidone tablets-treated pediatric patient were nausea (3%), somnolence (2%), sedation (2%), and vomiting (2%).

Autistic Disorder – Pediatrics

In the two 8-week, placebo-controlled trials in pediatric patients treated for irritability associated with autistic disorder (n = 156), one risperidone tablets-treated patient discontinued due to an adverse reaction (Parkinsonism), and one placebo-treated patient discontinued due to an adverse event.

Dose Dependency of Adverse Reactions in Clinical Trials Extrapyramidal Symptoms Data from two fixed-dose trials in adults with schizophrenia provided evidence of dose-relatedness for extrapyramidal symptoms associated with risperidone tablets treatment.

Two methods were used to measure extrapyramidal symptoms (EPS) in an 8-week trial comparing 4 fixed doses of risperidone tablets (2, 6, 10, and 16 mg/day), including (1) a Parkinsonism score (mean change from baseline) from the Extrapyramidal Symptom Rating Scale, and (2) incidence of spontaneous complaints of EPS: 

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="100%"> <caption> <span>Table 16.</span> </caption> <col width="21.06%"/> <col width="15.46%"/> <col width="15.86%"/> <col width="15.86%"/> <col width="15.86%"/> <col width="15.86%"/> <tbody class="Headless"> <tr class="Botrule First"> <td align="justify" class="Lrule Rrule" valign="top"><span class="Bold">Dose Groups</span><span class="Bold"> </span> <br/> </td><td align="center" class="Rrule" valign="top"><span class="Bold">Placebo</span><span class="Bold"> </span> <br/> </td><td align="center" class="Rrule" valign="top"><span class="Bold">Risperidone</span>  <span class="Bold">Tablets</span><span class="Bold"> <br/> 2 mg </span><span class="Bold"> </span> <br/> </td><td align="center" class="Rrule" valign="top"><span class="Bold">Risperidone</span><span class="Bold">Tablets</span><span class="Bold"> <br/> 6 mg </span><span class="Bold"> </span> <br/> </td><td align="center" class="Rrule" valign="top"><span class="Bold">Risperidone</span><span class="Bold">Tablets</span><span class="Bold"> <br/> 10 mg </span><span class="Bold"> </span> <br/> </td><td align="center" class="Rrule" valign="top"><span class="Bold">Risperidone</span><span class="Bold">Tablets</span><span class="Bold"> <br/> 16 mg </span><span class="Bold"> </span> <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Parkinsonism  <br/> </td><td align="center" class="Rrule" valign="top">1.2  <br/> </td><td align="center" class="Rrule" valign="top">0.9  <br/> </td><td align="center" class="Rrule" valign="top">1.8  <br/> </td><td align="center" class="Rrule" valign="top">2.4  <br/> </td><td align="center" class="Rrule" valign="top">2.6  <br/> </td> </tr> <tr class="Last"> <td align="justify" class="Lrule Rrule" valign="top">EPS Incidence <br/> </td><td align="center" class="Rrule" valign="top">13%  <br/> </td><td align="center" class="Rrule" valign="top">17%  <br/> </td><td align="center" class="Rrule" valign="top">21%  <br/> </td><td align="center" class="Rrule" valign="top">21%  <br/> </td><td align="center" class="Rrule" valign="top">35%  <br/> </td> </tr> </tbody> </table></div>

Similar methods were used to measure extrapyramidal symptoms (EPS) in an 8-week trial comparing 5 fixed doses of risperidone tablets (1, 4, 8, 12, and 16 mg/day):         

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="100%"> <caption> <span>Table 17.</span> </caption> <col width="21.06%"/> <col width="15.48%"/> <col width="15.86%"/> <col width="15.86%"/> <col width="15.86%"/> <col width="15.86%"/> <tbody class="Headless"> <tr class="Botrule First"> <td align="justify" class="Lrule Rrule" valign="top"><span class="Bold">Dose Groups</span><span class="Bold"> </span> <br/> </td><td align="center" class="Rrule" valign="top"><span class="Bold">Risperidone</span><span class="Bold">Tablets</span><span class="Bold"> <br/> 1 mg </span><span class="Bold"> </span> <br/> </td><td align="center" class="Rrule" valign="top"><span class="Bold">Risperidone</span><span class="Bold">Tablets</span><span class="Bold"> <br/> 4 mg </span><span class="Bold"> </span> <br/> </td><td align="center" class="Rrule" valign="top"><span class="Bold">Risperidone</span><span class="Bold">Tablet</span><span class="Bold">s <br/> 8 mg </span><span class="Bold"> </span> <br/> </td><td align="center" class="Rrule" valign="top"><span class="Bold">Risperidone</span><span class="Bold">Tablets</span><span class="Bold"> <br/> 12 mg </span><span class="Bold"> </span> <br/> </td><td align="center" class="Rrule" valign="top"><span class="Bold">Risperidone</span><span class="Bold">Tablets</span><span class="Bold"> <br/> 16 mg </span><span class="Bold"> </span> <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Parkinsonism  <br/> </td><td align="center" class="Rrule" valign="top">0.6  <br/> </td><td align="center" class="Rrule" valign="top">1.7  <br/> </td><td align="center" class="Rrule" valign="top">2.4  <br/> </td><td align="center" class="Rrule" valign="top">2.9  <br/> </td><td align="center" class="Rrule" valign="top">4.1  <br/> </td> </tr> <tr class="Last"> <td align="justify" class="Lrule Rrule" valign="top">EPS Incidence <br/> </td><td align="center" class="Rrule" valign="top">7%  <br/> </td><td align="center" class="Rrule" valign="top">12%  <br/> </td><td align="center" class="Rrule" valign="top">17%  <br/> </td><td align="center" class="Rrule" valign="top">18%  <br/> </td><td align="center" class="Rrule" valign="top">20%  <br/> </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, they occur more frequently and with greater severity with high potency and at higher doses of first generation antipsychotic drugs. An elevated risk of acute dystonia is observed in males and younger age groups.

Other Adverse Reactions Adverse event data elicited by a checklist for side effects from a large study comparing 5 fixed doses of risperidone tablets (1, 4, 8, 12, and 16 mg/day) were explored for dose-relatedness of adverse events. A Cochran-Armitage Test for trend in these data revealed a positive trend (p<0.05) for the following adverse reactions: somnolence, vision abnormal, dizziness, palpitations, weight increase, erectile dysfunction, ejaculation disorder, sexual function abnormal, fatigue, and skin discoloration.

Changes in Body Weight

Weight gain was observed in short-term, controlled trials and longer-term uncontrolled studies in adult and pediatric patients [see Warnings and Precautions (5.5), Adverse Reactions (6), and Use in Specific Populations (8.4)].

Changes in ECG Parameters Between-group comparisons for pooled placebo-controlled trials in adults revealed no statistically significant differences between risperidone and placebo in mean changes from baseline in ECG parameters, including QT, QTc, and PR intervals, and heart rate. When all risperidone tablets doses were pooled from randomized controlled trials in several indications, there was a mean increase in heart rate of 1 beat per minute compared to no change for placebo patients. In short-term schizophrenia trials, higher doses of risperidone (8-16 mg/day) were associated with a higher mean increase in heart rate compared to placebo (4-6 beats per minute). In pooled placebo-controlled acute mania trials in adults, there were small decreases in mean heart rate, similar among all treatment groups.

In the two placebo-controlled trials in children and adolescents with autistic disorder (aged 5 – 16 years) mean changes in heart rate were an increase of 8.4 beats per minute in the risperidone tablets groups and 6.5 beats per minute in the placebo group. There were no other notable ECG changes.

In a placebo-controlled acute mania trial in children and adolescents (aged 10 – 17 years), there were no significant changes in ECG parameters, other than the effect of risperidone tablets to transiently increase pulse rate (< 6 beats per minute). In two controlled schizophrenia trials in adolescents (aged 13 – 17 years), there were no clinically meaningful changes in ECG parameters including corrected QT intervals between treatment groups or within treatment groups over time.

The following adverse reactions have been identified during postapproval use of risperidone. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These adverse reactions include: alopecia, anaphylactic reaction, angioedema, atrial fibrillation, cardiopulmonary arrest, catatonia, diabetic ketoacidosis in patients with impaired glucose metabolism, dysgeusia, hypoglycemia, hypothermia, ileus, inappropriate antidiuretic hormone secretion, intestinal obstruction, jaundice, mania, pancreatitis, pituitary adenoma, precocious puberty, pulmonary embolism, QT prolongation, sleep apnea syndrome, somnambulism, Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN), sudden death, thrombocytopenia, thrombotic thrombocytopenic purpura, urinary retention, and water intoxication.

Postmarketing cases of extrapyramidal symptoms (dystonia and dyskinesia) have been reported in patients concomitantly taking methylphenidate and risperidone when there was an increase or decrease in dosage, initiation, or discontinuation of either or both medications.

The dose of risperidone tablets should be adjusted when used in combination with CYP2D6 enzyme inhibitors (e.g., fluoxetine, and paroxetine) and enzyme inducers (e.g., carbamazepine) [see Table 18 and Dosage and Administration (2.5)]. Dose adjustment is not recommended for risperidone tablets when co-administered with ranitidine, cimetidine, amitriptyline, or erythromycin [see Table 18 ].

Table 18. Summary of Effect of Coadministered Drugs on Exposure to Active Moiety (Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia Coadministered Drug Dosing Schedule Effect on Active Moiety (Risperidone + 9- Hydroxy- Risperidone (Ratio*) Risperidone Dose Recommendation Coadministered Drug Risperidone AUC C max Enzyme (CYP2D6) inhibitors Fluoxetine 20 mg/day 2 or 3 mg twice daily 1.4 1.5 Re-evaluate dosing. Do not exceed 8 mg/day Paroxetine 10 mg/day 4 mg/day 1.3 - Re-evaluate dosing. Do not exceed 8 mg/day 20 mg/day 4 mg/day 1.6 - 40 mg/day 4 mg/day 1.8 - Enzyme (CYP3A/ PgP inducers) Inducers Carbamazepine 573 ± 168 mg/day 3 mg twice daily 0.51 0.55 Titrate dose upwards. Do not exceed twice the patient’s usual dose Enzyme (CYP3A) inhibitors Ranitidine 150 mg twice daily 1 mg single dose 1.2 1.4 Dose adjustment not needed Cimetidine 400 mg twice daily 1 mg single dose 1.1 1.3 Dose adjustment not needed Erythromycin 500 mg four times daily 1 mg single dose 1.1 0.94 Dose adjustment not needed Other Drugs Amitriptyline 50 mg twice daily 3 mg twice daily 1.2 1.1 Dose adjustment not Needed *Change relative to reference

Effect of Risperidone on other drugs

Lithium

Repeated oral doses of risperidone tablets (3 mg twice daily) did not affect the exposure (AUC) or peak plasma concentrations (C max) of lithium (n=13). Dose adjustment for lithium is not recommended.

Valproate

Repeated oral doses of risperidone tablets (4 mg once daily) did not affect the pre-dose or average plasma concentrations and exposure (AUC) of valproate (1000 mg/day in three divided doses) compared to placebo (n=21). However, there was a 20% increase in valproate peak plasma concentration (C max) after concomitant administration of risperidone tablets. Dose adjustment for valproate is not recommended.

Digoxin

Risperidone tablets (0.25 mg twice daily) did not show a clinically relevant effect on the pharmacokinetics of digoxin. Dose adjustment for digoxin is not recommended.

Centrally Acting Drugs and Alcohol

Given the primary CNS effects of risperidone, caution should be used when risperidone tablets are taken in combination with other centrally acting drugs and alcohol.

Drugs with Hypotensive Effects

Because of its potential for inducing hypotension, risperidone tablets may enhance the hypotensive effects of other therapeutic agents with this potential.

Levodopa and Dopamine Agonists

Risperidone tablets may antagonize the effects of levodopa and dopamine agonists.

Methylphenidate Concomitant use with methylphenidate, when there is change in dosage of either medication, may increase the risk of extrapyramidal symptoms (EPS). Monitor for symptoms of EPS with concomitant use of risperidone tablets  and methylphenidate [see Adverse Reactions ( 6.2)].

Clozapine 

Chronic administration of clozapine with risperidone tablets may decrease the clearance of risperidone.

PregnancyExposure Registry

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

Risk Summary

Neonates exposed to antipsychotic drugs during the third trimester of pregnancy 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 risperidone 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 risperidone, during pregnancy (see Clinical Considerations).

Oral administration of risperidone to pregnant mice caused cleft palate at doses 3 to 4 times the maximum recommended human dose (MRHD) with maternal toxicity observed at 4-times MRHD based on mg/m 2body surface area. Risperidone was not teratogenic in rats or rabbits at doses up to 6-times the MRHD based on mg/m 2body surface area. Increased stillbirths and decreased birth weight occurred after oral risperidone administration to pregnant rats at 1.5-times the MRHD based on mg/m 2body surface area. Learning was impaired in offspring of rats when the dams were dosed at 0.6-times the MRHD and offspring mortality increased at doses 0.1 to 3 times the MRHD based on mg/m 2body surface area.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, 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 2-4% and 15-20%, respectively.

Clinical Considerations

Disease-associated maternal and/or 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 risperidone, 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

Published data from observational studies, birth registries, and case reports on the use of atypical antipsychotics during pregnancy do not report a clear association with antipsychotics and major birth defects. A prospective observational study including 6 women treated with risperidone demonstrated placental passage of risperidone. 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. There was a small increase in the risk of major birth defects (RR=1.26, 95% CI 1.02-1.56) and of cardiac malformations (RR=1.26, 95% CI 0.88-1.81) in a subgroup of 1566 women exposed to risperidone during the first trimester of pregnancy; however, there is no mechanism of action to explain the difference in malformation rates.

Animal Data

Oral administration of risperidone to pregnant mice during organogenesis caused cleft palate at 10 mg/kg/day which is 3 times the MRHD of 16 mg/day based on mg/m 2body surface area: maternal toxicity occurred at 4 times the MRHD. Risperidone was not teratogenic when administered orally to rats at 0.6 to 10 mg/kg/day and rabbits at 0.3 to 5 mg/kg/day, which are up to 6 times the MRHD of 16 mg/day risperidone based on mg/m 2body surface area. Learning was impaired in offspring of rats dosed orally throughout pregnancy at 1 mg/kg/day which is 0.6 times the MRHD and neuronal cell death increased in fetal brains of offspring of rats dosed during pregnancy at 1 and 2 mg/kg/day which are 0.6 and 1.2 times the MRHD based on mg/m 2body surface area; postnatal development and growth of the offspring were also delayed.

Rat offspring mortality increased during the first 4 days of lactation when pregnant rats were dosed throughout gestation at 0.16 to 5 mg/kg/day which are 0.1 to 3 times the MRHD of 16 mg/day based on mg/m 2body surface area. It is not known whether these deaths were due to a direct effect on the fetuses or pups or to effects on the dams; a no-effect dose could not be determined. The rate of stillbirths was increased at 2.5 mg/kg or 1.5 times the MRHD based on mg/m 2body surface area.

In a rat cross-fostering study the number of live offspring was decreased, the number of stillbirths increased, and the birth weight was decreased in offspring of drug-treated pregnant rats. In addition, the number of deaths increased by Day 1 among offspring of drug-treated pregnant rats, regardless of whether or not the offspring were cross-fostered. Risperidone also appeared to impair maternal behavior in that offspring body weight gain and survival (from Day 1 to 4 of lactation) were reduced in offspring born to control but reared by drug-treated dams. All of these effects occurred at 5 mg/kg which is 3 times the MRHD based on mg/m 2and the only dose tested in the study.

Risk Summary

Limited data from published literature reports the presence of risperidone and its metabolite, 9-hydroxyrisperidone, in human breast milk at relative infant dose ranging between 2.3% and 4.7% of the maternal weight-adjusted dosage. There are reports of sedation, failure to thrive, jitteriness, and extrapyramidal symptoms (tremors and abnormal muscle movements) in breastfed infants exposed to risperidone (see Clinical Considerations).There is no information on the effects of risperidone on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for risperidone  and any potential adverse effects on the breastfed child from risperidone or from the mother’s underlying condition. Clinical Considerations Infants exposed to risperidone through breastmilk should be monitored for excess sedation, failure to thrive, jitteriness, and extrapyramidal symptoms (tremors and abnormal muscle movements).

Infertility

Females

Based on the pharmacologic action of risperidone (D 2receptor antagonism), treatment with risperidone 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 ( 5.6)].

Approved Pediatric Indications

Schizophrenia

The efficacy and safety of risperidone tablets in the treatment of schizophrenia were demonstrated in 417 adolescents, aged 13 to 17 years, in two short-term (6 and 8 weeks, respectively) double-blind controlled trials [see Indications and Usage (1.1), Adverse Reactions (6.1), and Clinical Studies (14.1)] . Additional safety and efficacy information was also assessed in one long-term (6-month) open-label extension study in 284 of these adolescent patients with schizophrenia.

Safety and effectiveness of risperidone tablets in children less than 13 years of age with schizophrenia have not been established.

Bipolar I Disorder

The efficacy and safety of risperidone tablets in the short-term treatment of acute manic or mixed episodes associated with Bipolar I Disorder in 169 children and adolescent patients, aged 10 to 17 years, were demonstrated in one double-blind, placebo-controlled, 3-week trial [see Indications and Usage (1.2), Adverse Reactions (6.2), and Clinical Studies (14.2)] .

Safety and effectiveness of risperidone tablets in children less than 10 years of age with bipolar disorder have not been established.

Autistic Disorder

The efficacy and safety of risperidone tablets in the treatment of irritability associated with autistic disorder were established in two 8-week, double-blind, placebo-controlled trials in 156 children and adolescent patients, aged 5 to 16 years [see Indications and Usage (1.3),  Adverse Reactions (6.1)and Clinical Studies (14.4)] . Additional safety information was also assessed in a long-term study in patients with autistic disorder, or in short- and long-term studies in more than 1200 pediatric patients with psychiatric disorders other than autistic disorder, schizophrenia, or bipolar mania who were of similar age and weight, and who received similar dosages of risperidone tablets as patients treated for irritability associated with autistic disorder.

A third study was a 6-week, multicenter, randomized, double-blind, placebo-controlled, fixed-dose study to evaluate the efficacy and safety of a lower than recommended dose of risperidone in subjects 5 to 17 years of age with autistic disorder and associated irritability, and related behavioral symptoms. There were two weight-based, fixed doses of risperidone (high-dose and low-dose). The high dose was 1.25 mg per day for patients weighing 20 to < 45 kg, and it was 1.75 mg per day for patients weighing ≥ 45 kg.The low dose was 0.125 mg per day for patients weighing 20 to < 45 kg, and it was 0.175 mg per day for patients weighing ≥ 45 kg. The study demonstrated the efficacy of high-dose risperidone, but it did not demonstrate efficacy for low-dose risperidone.

Adverse Reactions in Pediatric Patients

Tardive Dyskinesia

In clinical trials in 1885 children and adolescents treated with risperidone tablets, 2 (0.1%) patients were reported to have tardive dyskinesia, which resolved on discontinuation of risperidone tablets treatment [see also Warnings and Precautions (5.4)] .

Weight Gain

Weight gain has been observed in children and adolescents during treatment with risperidone tablets. Clinical monitoring of weight is recommended during treatment.

Data derive from short-term placebo-controlled trials and longer-term uncontrolled studies in pediatric patients (ages 5 to 17 years) with schizophrenia, bipolar disorder, autistic disorder, or other psychiatric disorders. In the short-term trials (3 to 8 weeks), the mean weight gain for risperidone tablets-treated patients was 2 kg, compared to 0.6 kg for placebo-treated patients. In these trials, approximately 33% of the risperidone tablets group had weight gain ≥7%, compared to 7% in the placebo group. In longer-term, uncontrolled, open-label pediatric studies, the mean weight gain was 5.5 kg at Week 24 and 8 kg at Week 48 [see Warnings and Precautions (5.5)and Adverse Reactions (6.1)].

Somnolence

Somnolence was frequently observed in placebo-controlled clinical trials of pediatric patients with autistic disorder. Most cases were mild or moderate in severity. These events were most often of early onset with peak incidence occurring during the first two weeks of treatment, and transient with a median duration of 16 days. Somnolence was the most commonly observed adverse reaction in the clinical trial of bipolar disorder in children and adolescents, as well as in the schizophrenia trials in adolescents. As was seen in the autistic disorder trials, these adverse reactions were most often of early onset and transient in duration  [see  Adverse Reactions (6.1, 6.2)] . Patients experiencing persistent somnolence may benefit from a change in dosing regimen [see Dosage & Administration (2.1, 2.2, and 2.3)] .

Hyperprolactinemia

Risperidone tablets have been shown to elevate prolactin levels in children and adolescents as well as in adults [see Warnings and Precautions (5.6)] . In double-blind, placebo-controlled studies of up to 8 weeks duration in children and adolescents (aged 5 to 17 years) with autistic disorder or psychiatric disorders other than autistic disorder, schizophrenia, or bipolar mania, 49% of patients who received risperidone tablets had elevated prolactin levels compared to 2% of patients who received placebo. Similarly, in placebo-controlled trials in children and adolescents (aged 10 to 17 years) with bipolar disorder, or adolescents (aged 13 to 17 years) with schizophrenia, 82–87% of patients who received risperidone tablets had elevated levels of prolactin compared to 3–7% of patients on placebo. Increases were dose-dependent and generally greater in females than in males across indications.

In clinical trials in 1885 children and adolescents, galactorrhea was reported in 0.8% of risperidone tablets-treated patients and gynecomastia was reported in 2.3% of risperidone tablets-treated patients.

Growth and Sexual Maturation

The long-term effects of risperidone tablets on growth and sexual maturation have not been fully evaluated in children and adolescents.

Juvenile Animal Studies

Juvenile dogs were treated with oral risperidone from weeks 10 to 50 of age (equivalent to the period of childhood through adolescence in humans), at doses of 0.31, 1.25, or 5 mg/kg/day, which are 1.2, 3.4, and 13.5 times the MRHD of  6 mg/day for children, based on mg/m 2body surface area. Bone length and density were decreased with a no-effect dose of 0.31 mg/kg/day; this dose produced plasma AUC of risperidone plus its active metabolite paliperidone (9-hydroxy-risperidone) that were similar to those in children and adolescents receiving the MRHD of 6 mg/day. In addition, sexual maturation was delayed at all doses in both males and females. The above effects showed little or no reversibility in females after a 12 week drug-free recovery period.

Juvenile rats, treated with oral risperidone from days 12 to 50 of age (equivalent to the period of infancy through adolescence in humans) showed impaired learning and memory performance (reversible only in females), with a no-effect dose of 0.63 mg/kg/day which is 0.5 times the MRHD of 6 mg/day for children, based on mg/m 2body surface area. This dose produced plasma AUC of risperidone plus paliperidone about half the exposure observed in humans at the MRHD. No other consistent effects on neurobehavioral or reproductive development were seen up to the highest tested dose of 1.25 mg/kg/day which is 1 time the MRHD and produced plasma AUC of risperidone plus paliperidone that were about two thirds of those observed in humans at the MRHD of 6 mg/day for children.

Clinical studies of risperidone tablets in the treatment of schizophrenia did not include sufficient numbers of patients aged 65 and over to determine whether or not they respond differently than younger patients. Other reported clinical experience has not identified differences in responses between elderly and younger patients. In general, a lower starting dose is recommended for an elderly patient, reflecting a decreased pharmacokinetic clearance in the elderly, as well as a greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy [see Clinical Pharmacology (12.3)and Dosage & Administration (2.4, 2.5)] . While elderly patients exhibit a greater tendency to orthostatic hypotension, its risk in the elderly may be minimized by limiting the initial dose to 0.5 mg twice daily followed by careful titration [see Warnings and Precautions (5.7)] . Monitoring of orthostatic vital signs should be considered in patients for whom this is of concern.

This drug is substantially excreted by the kidneys, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function [see Dosage & Administration (2.4)] .

In patients with moderate to severe (Clcr 59 to 15 mL/min) renal disease, clearance of the sum of risperidone and its active metabolite decreased by 60%, compared to young healthy subjects. Risperidone tablets doses should be reduced in patients with renal disease [see Dosage and Administration (2.4)] .

While the pharmacokinetics of risperidone in subjects with liver disease were comparable to those in young healthy subjects, the mean free fraction of risperidone in plasma was increased by about 35% because of the diminished concentration of both albumin and α 1-acid glycoprotein. Risperidone tablets doses should be reduced in patients with liver disease [see Dosage and Administration (2.4)] .

Patients with Parkinsons Disease or Dementia with Lewy Bodies can experience increased sensitivity to risperidone tablets. Manifestations can include confusion, obtundation, postural instability with frequent falls, extrapyramidal symptoms, and clinical features consistent with neuroleptic malignant syndrome.

Risperidone tablets are not a controlled substance.

Risperidone tablets have not been systematically studied in animals or humans for its potential for abuse. 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 risperidone tablets misuse or abuse (e.g., development of tolerance, increases in dose, drug-seeking behavior).

Risperidone tablets have not been systematically studied in animals or humans for its potential for tolerance or physical dependence.

Premarketing experience included eight reports of acute risperidone tablets overdosage with estimated doses ranging from 20 to 300 mg and no fatalities. In general, reported signs and symptoms were those resulting from an exaggeration of the drug's known pharmacological effects, i.e., drowsiness and sedation, tachycardia and hypotension, and extrapyramidal symptoms. One case, involving an estimated overdose of 240 mg, was associated with hyponatremia, hypokalemia, prolonged QT, and widened QRS. Another case, involving an estimated overdose of 36 mg, was associated with a seizure.

Postmarketing experience includes reports of acute risperidone tablets overdosage, with estimated doses of up to 360 mg. In general, the most frequently reported signs and symptoms are those resulting from an exaggeration of the drug's known pharmacological effects, i.e., drowsiness, sedation, tachycardia, hypotension, and extrapyramidal symptoms. Other adverse reactions reported since market introduction related to risperidone tablets overdose include prolonged QT interval and convulsions. Torsade de pointes has been reported in association with combined overdose of risperidone tablets and paroxetine.

For the most up to date information on the management of risperidone tablets overdosage, contact a certified poison control center (1-800-222-1222 or www.poison.org). Provide supportive care including close medical supervision and monitoring. Treatment should consist of general measures employed in the management of overdosage with any drug. Consider the possibility of multiple drug overdosage. Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm and vital signs. Use supportive and symptomatic measures. There is no specific antidote to risperidone tablets.

Risperidone tablets, USP contain risperidone USP, an atypical antipsychotic belonging to the chemical class of benzisoxazole derivatives. The chemical designation is 3-[2-[4-(6-fluoro-1,2- benzisoxazol-3-yl)-1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one. Its molecular formula is C 23H 27FN 4O 2and its molecular weight is 410.49. The structural formula is:

{ "type": "p", "children": [], "text": "Risperidone tablets, USP contain risperidone USP, an atypical antipsychotic belonging to the chemical class of benzisoxazole derivatives. The chemical designation is 3-[2-[4-(6-fluoro-1,2- benzisoxazol-3-yl)-1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one. Its molecular formula is C\n \n 23H\n \n 27FN\n \n 4O\n \n 2and its molecular weight is 410.49. The structural formula is:\n\n " }

Risperidone USP is a white to slightly beige powder. It is practically insoluble in water, freely soluble in methylene chloride, and soluble in methanol and 0.1 NHCl.

{ "type": "p", "children": [], "text": "Risperidone USP is a white to slightly beige powder. It is practically insoluble in water, freely soluble in methylene chloride, and soluble in methanol and 0.1\n \n NHCl.\n\n " }

Risperidone tablets, USP are for oral administration and available in 0.25 mg (orange), 0.5 mg (orange), 1 mg (white), 2 mg (yellow), 3 mg (orange), and 4 mg (brown) strengths. Risperidone tablets contain the following inactive ingredients: colloidal silicon dioxide, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, propylene glycol (except 1 mg), sodium lauryl sulphate, sodium starch glycolate and polyethylene glycol (1 mg). Tablets of 0.25 mg, 0.5 mg, 2 mg, 3 mg, and 4 mg also contain talc and titanium dioxide. 0.25 mg, 0.5 mg, and 3 mg tablets contain FD&C Yellow # 6 aluminum lake, the 2 mg tablets contain yellow iron oxide; the 4 mg tablets contain iron oxide red.

{ "type": "p", "children": [], "text": "Risperidone tablets, USP are for oral administration and available in 0.25 mg (orange), 0.5 mg (orange), 1 mg (white), 2 mg (yellow), 3 mg (orange), and 4 mg (brown) strengths. Risperidone tablets contain the following inactive ingredients: colloidal silicon dioxide, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, propylene glycol (except 1 mg), sodium lauryl sulphate, sodium starch glycolate and polyethylene glycol (1 mg). Tablets of 0.25 mg, 0.5 mg, 2 mg, 3 mg, and 4 mg also contain talc and titanium dioxide. 0.25 mg, 0.5 mg, and 3 mg tablets contain FD&C Yellow # 6 aluminum lake, the 2 mg tablets contain yellow iron oxide; the 4 mg tablets contain iron oxide red." }

The mechanism of action of risperidone in schizophrenia is unclear. The drug's therapeutic activity in schizophrenia could be mediated through a combination of dopamine Type 2 (D 2) and serotonin Type 2 (5HT 2) receptor antagonism. The clinical effect from risperidone results from the combined concentrations of risperidone and its major metabolite, 9-hydroxyrisperidone (paliperidone) [see Clinical Pharmacology ( 12.3)] . Antagonism at receptors other than D 2and 5HT 2may explain some of the other effects of risperidone [see Clinical Pharmacology ( 12.1)] .

Risperidone is a monoaminergic antagonist with high affinity (Ki of 0.12 to 7.3 nM) for the serotonin Type 2 (5HT 2), dopamine Type 2 (D 2), α 1and α 2adrenergic, and H 1histaminergic receptors. Risperidone showed low to moderate affinity (Ki of 47 to 253 nM) for the serotonin 5HT 1C, 5HT 1D, and 5HT 1Areceptors, weak affinity (Ki of 620 to 800 nM) for the dopamine D 1and haloperidol-sensitive sigma site, and no affinity (when tested at concentrations >10 -5M) for cholinergic muscarinic or β 1and β 2adrenergic receptors.

Absorption

Risperidone is well absorbed. The absolute oral bioavailability of risperidone is 70% (CV=25%). The relative oral bioavailability of risperidone from a tablet is 94% (CV=10%) when compared to a solution.

Plasma concentrations of risperidone, its major metabolite, 9-hydroxyrisperidone, and risperidone plus 9-hydroxyrisperidone are dose proportional over the dosing range of 1 to 16 mg daily (0.5 to 8 mg twice daily). Following oral administration of tablet, mean peak plasma concentrations of risperidone occurred at about 1 hour. Peak concentrations of 9-hydroxyrisperidone occurred at about 3 hours in extensive metabolizers, and 17 hours in poor metabolizers. Steady-state concentrations of risperidone are reached in 1 day in extensive metabolizers and would be expected to reach steady-state in about 5 days in poor metabolizers. Steady-state concentrations of 9-hydroxyrisperidone are reached in 5-6 days (measured in extensive metabolizers). 

Food Effect

Food does not affect either the rate or extent of absorption of risperidone. Thus, risperidone tablets can be given with or without meals. 

Distribution

Risperidone is rapidly distributed. The volume of distribution is 1-2 L/kg. In plasma, risperidone is bound to albumin and α 1-acid glycoprotein. The plasma protein binding of risperidone is approximately 90%, and that of its major metabolite, 9-hydroxyrisperidone, is 77%. Neither risperidone nor 9-hydroxyrisperidone displaces each other from plasma binding sites. High therapeutic concentrations of sulfamethazine (100 mcg/mL), warfarin (10 mcg/mL), and carbamazepine (10 mcg/mL) caused only a slight increase in the free fraction of risperidone at 10 ng/mL and 9-hydroxyrisperidone at 50 ng/mL, changes of unknown clinical significance. 

Elimination

Metabolism

Risperidone is extensively metabolized in the liver. The main metabolic pathway is through hydroxylation of risperidone to 9-hydroxyrisperidone by the enzyme, CYP 2D6. A minor metabolic pathway is through N-dealkylation. The main metabolite, 9-hydroxyrisperidone, has similar pharmacological activity as risperidone. Consequently, the clinical effect of the drug results from the combined concentrations of risperidone plus 9-hydroxyrisperidone.

CYP 2D6, also called debrisoquin hydroxylase, is the enzyme responsible for metabolism of many neuroleptics, antidepressants, antiarrhythmics, and other drugs. CYP 2D6 is subject to genetic polymorphism (about 6%-8% of Caucasians, and a very low percentage of Asians, have little or no activity and are “poor metabolizers”) and to inhibition by a variety of substrates and some non-substrates, notably quinidine. Extensive CYP 2D6 metabolizers convert risperidone rapidly into 9-hydroxyrisperidone, whereas poor CYP 2D6 metabolizers convert it much more slowly. Although extensive metabolizers have lower risperidone and higher 9-hydroxyrisperidone concentrations than poor metabolizers, the pharmacokinetics of risperidone and 9-hydroxyrisperidone combined, after single and multiple doses, are similar in extensive and poor metabolizers.

Excretion

Risperidone and its metabolites are eliminated via the urine and, to a much lesser extent, via the feces. As illustrated by a mass balance study of a single 1 mg oral dose of 14C-risperidone administered as solution to three healthy male volunteers, total recovery of radioactivity at 1 week was 84%, including 70% in the urine and 14% in the feces. 

The apparent half-life of risperidone was 3 hours (CV=30%) in extensive metabolizers and 20 hours (CV=40%) in poor metabolizers. The apparent half-life of 9-hydroxyrisperidone was about 21 hours (CV=20%) in extensive metabolizers and 30 hours (CV=25%) in poor metabolizers. The pharmacokinetics of risperidone and 9-hydroxyrisperidone combined, after single and multiple doses, were similar in extensive and poor metabolizers, with an overall mean elimination half-life of about 20 hours. 

Drug Interaction Studies Risperidone could be subject to two kinds of drug-drug interactions. First, inhibitors of CYP 2D6 interfere with conversion of risperidone to 9-hydroxyrisperidone [see Drug Interactions ( 7)]. This occurs with quinidine, giving essentially all recipients a risperidone pharmacokinetic profile typical of poor metabolizers. The therapeutic benefits and adverse effects of risperidone in patients receiving quinidine have not been evaluated, but observations in a modest number (n≅70) of poor metabolizers given risperidone tablets do not suggest important differences between poor and extensive metabolizers. Second, co-administration of known enzyme inducers (e.g., carbamazepine, phenytoin, rifampin, and phenobarbital) with risperidone tablets may cause a decrease in the combined plasma concentrations of risperidone and 9-hydroxyrisperidone [see Drug Interactions ( 7)]. It would also be possible for risperidone to interfere with metabolism of other drugs metabolized by CYP 2D6. Relatively weak binding of risperidone to the enzyme suggests this is unlikely [see Drug Interactions ( 7)].

In vitrostudies indicate that risperidone is a relatively weak inhibitor of CYP 2D6. Therefore, risperidone tablets are not expected to substantially inhibit the clearance of drugs that are metabolized by this enzymatic pathway. In drug interaction studies, risperidone tablets did not significantly affect the pharmacokinetics of donepezil and galantamine, which are metabolized by CYP 2D6.

In vitrostudies demonstrated that drugs metabolized by other CYP isozymes, including 1A1, 1A2, 2C9, 2C19, and 3A4, are only weak inhibitors of risperidone metabolism.

Specific Populations

Renal and Hepatic Impairment

[SeeUse in Specific Populations (8.6 and 8.7)].

Elderly

In healthy elderly subjects, renal clearance of both risperidone and 9-hydroxyrisperidone was decreased, and elimination half-lives were prolonged compared to young healthy subjects. Dosing should be modified accordingly in the elderly patients [see Use in Specific Populations (8.5)] . 

Pediatric

The pharmacokinetics of risperidone and 9-hydroxyrisperidone in children were similar to those in adults after correcting for the difference in body weight. 

Race and Gender Effects

No specific pharmacokinetic study was conducted to investigate race and gender effects, but a population pharmacokinetic analysis did not identify important differences in the disposition of risperidone due to gender (whether corrected for body weight or not) or race.

Carcinogenesis 

Risperidone was administered in the diet at doses of 0.63, 2.5, and 10 mg/kg for 18 months to mice and for 25 months to rats. These doses are equivalent to approximately 0.2, 0.75, and 3 times (mice) and 0.4, 1.5, and 6 times (rats) the MRHD of 16 mg/day, based on mg/m 2  body surface area. A maximum tolerated dose was not achieved in male mice. There were statistically significant increases in pituitary gland adenomas, endocrine pancreas adenomas, and mammary gland adenocarcinomas. The table below summarizes the multiples of the human dose on a mg/m 2  (mg/kg) basis at which these tumors occurred.         

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="100%"> <col width="38.7%"/> <col width="11.98%"/> <col width="11.7%"/> <col width="18.66%"/> <col width="18.98%"/> <tbody class="Headless"> <tr class="Botrule First"> <td align="justify" class="Lrule Rrule" valign="top">        <br/> <br/> </td><td align="justify" class="Rrule" valign="top">  <br/> </td><td align="justify" class="Rrule" valign="top">  <br/> </td><td align="center" class="Rrule" colspan="2" valign="top"><span class="Bold">Multiples of Maximum Human <br/> Dose in mg/m² (mg/kg) </span><span class="Bold"></span> <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"><span class="Bold">Tumor Type</span><span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top"><span class="Bold">Species</span><span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top"><span class="Bold">Sex</span><span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top"><span class="Bold">Lowest Effect <br/> Level </span><span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top"><span class="Bold">Highest No- <br/> Effect Level </span><span class="Bold"></span> <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Pituitary adenomas <br/> </td><td align="center" class="Rrule" valign="top">mouse <br/> </td><td align="center" class="Rrule" valign="top">Female <br/> </td><td align="center" class="Rrule" valign="top">0.75 (9.4) <br/> </td><td align="center" class="Rrule" valign="top">0.2 (2.4) <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Endocrine pancreas adenomas <br/> </td><td align="center" class="Rrule" valign="top">rat <br/> </td><td align="center" class="Rrule" valign="top">Male <br/> </td><td align="center" class="Rrule" valign="top">1.5 (9.4) <br/> </td><td align="center" class="Rrule" valign="top">0.4 (2.4) <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Mammary gland adenocarcinomas <br/> </td><td align="center" class="Rrule" valign="top">mouse <br/> </td><td align="center" class="Rrule" valign="top">Female <br/> </td><td align="center" class="Rrule" valign="top">0.2 (2.4) <br/> </td><td align="center" class="Rrule" valign="top">none <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  <br/> </td><td align="center" class="Rrule" valign="top">rat <br/> </td><td align="center" class="Rrule" valign="top">Female <br/> </td><td align="center" class="Rrule" valign="top">0.4 (2.4) <br/> </td><td align="center" class="Rrule" valign="top">none <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  <br/> </td><td align="center" class="Rrule" valign="top">rat <br/> </td><td align="center" class="Rrule" valign="top">Male <br/> </td><td align="center" class="Rrule" valign="top">6.0 (37.5) <br/> </td><td align="center" class="Rrule" valign="top">1.5 (9.4) <br/> </td> </tr> <tr class="Last"> <td align="justify" class="Lrule Rrule" valign="top">Mammary gland neoplasm, Total <br/> </td><td align="center" class="Rrule" valign="top">rat <br/> </td><td align="center" class="Rrule" valign="top">Male <br/> </td><td align="center" class="Rrule" valign="top">1.5 (9.4) <br/> </td><td align="center" class="Rrule" valign="top">0.4 (2.4) <br/> </td> </tr> </tbody> </table></div>

Antipsychotic drugs have been shown to chronically elevate prolactin levels in rodents. Serum prolactin levels were not measured during the risperidone carcinogenicity studies; however, measurements during subchronic toxicity studies showed that risperidone elevated serum prolactin levels 5-6 fold in mice and rats at the same doses used in the carcinogenicity studies. An increase in mammary, pituitary, and endocrine pancreas 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 findings of prolactin-mediated endocrine tumors in rodents is unclear [see Warnings and Precautions ( 5.6)] .

Mutagenesis

No evidence of mutagenic or clastogenic potential for risperidone was found in the in vitrotests of Ames gene mutation, the mouse lymphoma assay, rat hepatocyte DNA-repair assay, the chromosomal aberration test in human lymphocytes, Chinese hamster ovary cells, or in the in vivooral micronucleus test in mice and the sex-linked recessive lethal test in Drosophila.

Impairment of Fertility

Oral risperidone (0.16 to 5 mg/kg) impaired mating, but not fertility, in rat reproductive studies at doses 0.1 to 3 times the MRHD of 16 mg/day based on mg/m 2body surface area. The effect appeared to be in females, since impaired mating behavior was not noted in the male fertility study. In a subchronic study in Beagle dogs in which risperidone was administered orally at doses of 0.31 to 5 mg/kg, sperm motility and concentration were decreased at doses 0.6 to 10 times the MRHD based on  mg/m 2body surface area. Dose-related decreases were also noted in serum testosterone at the same doses. Serum testosterone and sperm parameters partially recovered, but remained decreased after treatment was discontinued. A no-effect dose could not be determined in either rat or dog.

Adults

Short-Term Efficacy

The efficacy of risperidone tablets in the treatment of schizophrenia was established in four short-term (4- to 8-week) controlled trials of psychotic inpatients who met DSM-III-R criteria for schizophrenia.

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, the Positive and Negative Syndrome Scale (PANSS) and the Scale for Assessing Negative Symptoms (SANS) were employed. 

The results of the trials follow:

Long-Term Efficacy

In a longer-term trial, 365 adult outpatients predominantly meeting DSM-IV criteria for schizophrenia and who had been clinically stable for at least 4 weeks on an antipsychotic medication were randomized to risperidone tablets (2-8 mg/day) or to an active comparator, for 1 to 2 years of observation for relapse. Patients receiving risperidone tablets experienced a significantly longer time to relapse over this time period compared to those receiving the active comparator. 

Pediatrics

The efficacy of risperidone tablets in the treatment of schizophrenia in adolescents aged 13–17 years was demonstrated in two short-term (6 and 8 weeks), double-blind controlled trials. All patients met DSM-IV diagnostic criteria for schizophrenia and were experiencing an acute episode at time of enrollment. In the first trial (study #1), patients were randomized into one of three treatment groups: Risperidone tablets 1-3 mg/day (n = 55, mean modal dose = 2.6 mg), risperidone tablets 4-6 mg/day (n = 51, mean modal dose = 5.3 mg), or placebo (n = 54). In the second trial (study #2), patients were randomized to either risperidone tablets 0.15-0.6 mg/day (n = 132, mean modal dose = 0.5 mg) or risperidone tablets 1.5–6 mg/day (n = 125, mean modal dose = 4 mg). In all cases, study medication was initiated at 0.5 mg/day (with the exception of the 0.15-0.6 mg/day group in study #2, where the initial dose was 0.05 mg/day) and titrated to the target dosage range by approximately Day 7. Subsequently, dosage was increased to the maximum tolerated dose within the target dose range by Day 14. The primary efficacy variable in all studies was the mean change from baseline in total PANSS score.

Results of the studies demonstrated efficacy of risperidone tablets in all dose groups from 1-6 mg/day compared to placebo, as measured by significant reduction of total PANSS score. The efficacy on the primary parameter in the 1-3 mg/day group was comparable to the 4-6 mg/day group in study #1, and similar to the efficacy demonstrated in the 1.5–6 mg/day group in study #2. In study #2, the efficacy in the 1.5-6 mg/day group was statistically significantly greater than that in the 0.15-0.6 mg/day group. Doses higher than 3 mg/day did not reveal any trend towards greater efficacy.

Adults

The efficacy of risperidone tablets in the treatment of acute manic or mixed episodes was established in two short-term (3-week) placebo-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.

The primary rating instrument used for assessing manic symptoms in these trials was the Young Mania Rating Scale (YMRS), 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 YMRS total score. The results of the trials follow:

Pediatrics

The efficacy of risperidone tablets in the treatment of mania in children or adolescents with Bipolar I disorder was demonstrated in a 3-week, randomized, double-blind, placebo-controlled, multicenter trial including patients ranging in ages from 10 to 17 years who were experiencing a manic or mixed episode of bipolar I disorder. Patients were randomized into one of three treatment groups: Risperidone tablets 0.5-2.5 mg/day (n = 50, mean modal dose = 1.9 mg), risperidone tablets 3-6 mg/day (n = 61, mean modal dose = 4.7 mg), or placebo (n = 58). In all cases, study medication was initiated at 0.5 mg/day and titrated to the target dosage range by Day 7, with further increases in dosage to the maximum tolerated dose within the targeted dose range by Day 10. The primary rating instrument used for assessing efficacy in this study was the mean change from baseline in the total YMRS score.

Results of this study demonstrated efficacy of risperidone tablets in both dose groups compared with placebo, as measured by significant reduction of total YMRS score. The efficacy on the primary parameter in the 3-6 mg/day dose group was comparable to the 0.5-2.5 mg/day dose group. Doses higher than 2.5 mg/day did not reveal any trend towards greater efficacy.

The efficacy of risperidone tablets with concomitant lithium or valproate in the treatment of acute manic or mixed episodes was established in one controlled trial in adult patients who met the DSM-IV criteria for Bipolar I Disorder. This trial included patients with or without psychotic features and with or without a rapid-cycling course. 

Short-Term Efficacy

The efficacy of risperidone tablets in the treatment of irritability associated with autistic disorder was established in two 8-week, placebo-controlled trials in children and adolescents (aged 5 to 16 years) who met the DSM-IV criteria for autistic disorder. Over 90% of these subjects were under 12 years of age and most weighed over 20 kg (16-104.3 kg).

Efficacy was evaluated using two assessment scales: the Aberrant Behavior Checklist (ABC) and the Clinical Global Impression - Change (CGI-C) scale. The primary outcome measure in both trials was the change from baseline to endpoint in the Irritability subscale of the ABC (ABC-I). The ABC-I subscale measured the emotional and behavioral symptoms of autism, including aggression towards others, deliberate self-injuriousness, temper tantrums, and quickly changing moods. The CGI-C rating at endpoint was a co-primary outcome measure in one of the studies.

The results of these trials are as follows:

A third trial was a 6-week, multicenter, randomized, double blind, placebo-controlled, fixed-dose study to evaluate the efficacy and safety of a lower than recommended dose of risperidone in subjects (N=96) 5 to 17 years of age with autistic disorder (defined by DSM-IV criteria) and associated irritability and related behavioral symptoms. Approximately 77% of patients were younger than 12 years of age (mean age = 9), and 88% were male. Most patients (73%) weighed less than 45 kg (mean weight = 40 kg). Approximately 90% of patients were antipsychotic-naïve before entering the study.

There were two weight-based, fixed doses of risperidone (high-dose and low-dose). The high dose was 1.25 mg per day for patients weighing 20 to < 45 kg, and it was 1.75 mg per day for patients weighing ≥ 45 kg. The low dose was 0.125 mg per day for patients weighing 20 to < 45 kg, and it was 0.175 mg per day for patients weighing ≥ 45 kg. The dose was administered once daily in the morning, or in the evening if sedation occurred.

The primary efficacy endpoint was the mean change in the Aberrant Behavior Checklist – Irritability subscale (ABC-I) score from baseline to the end of Week 6. The study demonstrated the efficacy of high-dose risperidone, as measured by the mean change in ABC-I score. It did not demonstrate efficacy for low-dose risperidone. The mean baseline ABC-I scores were 29 in the placebo group (n = 35), 27 in the risperidone low-dose group (n = 30), and 28 in the risperidone high-dose group (n = 31). The mean changes in ABC-I scores were -3.5, -7.4, and -12.4 in the placebo, low-dose, and high-dose group respectively. The results in the high-dose group were statistically significant (p< 0.001) but not in the low-dose group (p=0.164).

Long-Term Efficacy

Following completion of the first 8-week double-blind study, 63 patients entered an open-label study extension where they were treated with risperidone tablets for 4 or 6 months (depending on whether they received risperidone tablets or placebo in the double-blind study). During this open-label treatment period, patients were maintained on a mean modal dose of risperidone tablets of 1.8-2.1 mg/day (equivalent to 0.05 - 0.07 mg/kg/day).

Patients who maintained their positive response to risperidone tablets (response was defined as ≥ 25% improvement on the ABC-I subscale and a CGI-C rating of ‘much improved’ or ‘very much improved’) during the 4-6 month open-label treatment phase for about 140 days, on average, were randomized to receive risperidone tablets or placebo during an 8-week, double-blind withdrawal study (n=39 of the 63 patients). A pre-planned interim analysis of data from patients who completed the withdrawal study (n=32), undertaken by an independent Data Safety Monitoring Board, demonstrated a significantly lower relapse rate in the risperidone tablets group compared with the placebo group. Based on the interim analysis results, the study was terminated due to demonstration of a statistically significant effect on relapse prevention. Relapse was defined as ≥ 25% worsening on the most recent assessment of the ABC-I subscale (in relation to baseline of the randomized withdrawal phase).

Risperidone Tablets, USP 2 mg are yellow, circular, biconvex film-coated tablets, engraved with 'RI4' on one side and plain on other and are supplied as follows:

{ "type": "p", "children": [], "text": "Risperidone Tablets, USP 2 mg are yellow, circular, biconvex film-coated tablets, engraved with 'RI4' on one side and plain on other and are supplied as follows:" }

NDC: 70518-1568-00

{ "type": "p", "children": [], "text": "NDC: 70518-1568-00" }

PACKAGING: 30 in 1 BLISTER PACK

{ "type": "p", "children": [], "text": "PACKAGING: 30 in 1 BLISTER PACK" }

Risperidone tablets should be stored at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F) [see USP controlled room temperature]. Protect from light and moisture.

{ "type": "p", "children": [], "text": "Risperidone tablets should be stored at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F) [see USP controlled room temperature]. Protect from light and moisture." }

Keep out of reach of children.

{ "type": "p", "children": [], "text": "Keep out of reach of children." }

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" }

Physicians are advised to discuss the following issues with patients for whom they prescribe risperidone tablets.

{ "type": "p", "children": [], "text": "Physicians are advised to discuss the following issues with patients for whom they prescribe risperidone tablets." }

Neuroleptic Malignant Syndrome (NMS)

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

Counsel patients about a potentially fatal adverse reaction, Neuroleptic Malignant Syndrome (NMS), that has been reported in association with administration of antipsychotic drugs. Advise patients, family members, or caregivers to contact the healthcare provider or report to the emergency room if they experience signs and symptoms of NMS, including hyperpyrexia, muscle rigidity, altered mental status including delirium, 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": "Counsel patients about a potentially fatal adverse reaction, Neuroleptic Malignant Syndrome (NMS), that has been reported in association with administration of antipsychotic drugs. Advise patients, family members, or caregivers to contact the healthcare provider or report to the emergency room if they experience signs and symptoms of NMS, including hyperpyrexia, muscle rigidity, altered mental status including delirium, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia) \n [see Warnings and Precautions ( \n 5.3)] \n .\n " }

Tardive Dyskinesia

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

Counsel patients on the signs and symptoms of tardive dyskinesia and to contact their healthcare provider if these abnormal movements occur [see Warnings and Precautions ( 5.4)] .

{ "type": "p", "children": [], "text": "Counsel patients on the signs and symptoms of tardive dyskinesia and to contact their healthcare provider if these abnormal movements occur \n [see Warnings and Precautions ( \n 5.4)] \n .\n " }

Metabolic Changes

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

Educate patients about the risk of metabolic changes, how to recognize symptoms of hyperglycemia and diabetes mellitus, and the need for specific monitoring, including blood glucose, lipids, and weight [see Warnings and Precautions ( 5.5)] .

{ "type": "p", "children": [], "text": "Educate patients about the risk of metabolic changes, how to recognize symptoms of hyperglycemia and diabetes mellitus, and the need for specific monitoring, including blood glucose, lipids, and weight \n [see Warnings and Precautions ( \n 5.5)] \n .\n " }

Orthostatic Hypotension

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

Educate patients about the risk of orthostatic hypotension and syncope, particularly at the time of initiating treatment, re-initiating treatment, or increasing the dose [see Warnings and Precautions ( 5.7)] .

{ "type": "p", "children": [], "text": "Educate patients about the risk of orthostatic hypotension and syncope, particularly at the time of initiating treatment, re-initiating treatment, or increasing the dose \n [see Warnings and Precautions ( \n 5.7)] \n .\n " }

Leukopenia/Neutropenia

{ "type": "p", "children": [], "text": "\nLeukopenia/Neutropenia\n" }

Advise patients with a pre-existing low WBC or a history of drug induced leukopenia/neutropenia they should have their CBC monitored while taking risperdione tablets [see Warnings and Precautions ( 5.9)] .

{ "type": "p", "children": [], "text": "Advise patients with a pre-existing low WBC or a history of drug induced leukopenia/neutropenia they should have their CBC monitored while taking risperdione tablets \n [see Warnings and Precautions ( \n 5.9)] \n .\n " }

Hyperprolactinemia

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

Counsel patients on signs and symptoms of hyperprolactinemia that may be associated with chronic use of risperdione tablets. Advise them to seek medical attention if they experience any of the following: amenorrhea or galactorrhea in females, erectile dysfunction or gynecomastia in males. [See Warnings and Precautions ( 5.6)] .

{ "type": "p", "children": [], "text": "Counsel patients on signs and symptoms of hyperprolactinemia that may be associated with chronic use of risperdione tablets. Advise them to seek medical attention if they experience any of the following: amenorrhea or galactorrhea in females, erectile dysfunction or gynecomastia in males. \n [See Warnings and Precautions ( \n 5.6)] \n .\n " }

Interference with Cognitive and Motor Performance

{ "type": "p", "children": [], "text": "\nInterference with Cognitive and Motor Performance\n" }

Caution patients about performing activities requiring mental alertness, such as operating hazardous machinery, or operating a motor vehicle until they are reasonably certain that risperdione tablets therapy does not affect them adversely [see Warnings and Precautions ( 5.10)] .

{ "type": "p", "children": [], "text": "Caution patients about performing activities requiring mental alertness, such as operating hazardous machinery, or operating a motor vehicle until they are reasonably certain that risperdione tablets therapy does not affect them adversely \n [see Warnings and Precautions ( \n 5.10)] \n .\n " }

Priapism

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

Advise patients of the possibility of painful or prolonged penile erections (priapism). Instruct the patient to seek immediate medical attention in the event of priapism [Warnings and Precautions ( 5.13)] .

{ "type": "p", "children": [], "text": "Advise patients of the possibility of painful or prolonged penile erections (priapism). Instruct the patient to seek immediate medical attention in the event of priapism \n [Warnings and Precautions ( \n 5.13)] \n .\n " }

Heat Exposure and Dehydration

{ "type": "p", "children": [], "text": "\nHeat Exposure and Dehydration\n" }

Counsel patients regarding appropriate care in avoiding overheating and dehydration [see Warnings and Precautions ( 5.14)] .

{ "type": "p", "children": [], "text": "Counsel patients regarding appropriate care in avoiding overheating and dehydration \n [see Warnings and Precautions ( \n 5.14)] \n .\n " }

Concomitant Medication

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

Advise patients to inform their healthcare providers if they are taking, or plan to take any prescription or over-the-counter drugs, as there is a potential for interactions [see Drug Interactions ( 7)] .

{ "type": "p", "children": [], "text": "Advise patients to inform their healthcare providers if they are taking, or plan to take any prescription or over-the-counter drugs, as there is a potential for interactions \n [see Drug Interactions ( \n 7)] \n .\n " }

Alcohol

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

Advise patients to avoid alcohol while taking risperdione tablets [see Drug Interactions ( 7.2)] .

{ "type": "p", "children": [], "text": "Advise patients to avoid alcohol while taking risperdione tablets \n [see Drug Interactions ( \n 7.2)] \n .\n " }

Pregnancy

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

Advise patients to notify their healthcare provider if they become pregnant or intend to become pregnant during treatment with risperdione tablets. Advise patients that risperdione tablets may cause extrapyramidal and/or withdrawal symptoms in a neonate. Advise patients that there is a pregnancy registry that monitors pregnancy outcomes in women exposed to risperdione tablets during pregnancy [see Use in Specific Populations ( 8.1)] .

{ "type": "p", "children": [], "text": "Advise patients to notify their healthcare provider if they become pregnant or intend to become pregnant during treatment with risperdione tablets. Advise patients that risperdione tablets \n may cause extrapyramidal and/or withdrawal symptoms in a neonate. Advise patients that there is a pregnancy registry that monitors pregnancy outcomes in women exposed to risperdione tablets \n during pregnancy \n [see Use in Specific Populations ( \n 8.1)] \n .\n " }

Lactation

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

Advise breastfeeding women using risperdione tablets to monitor infants for somnolence, failure to thrive, jitteriness, 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": "Advise breastfeeding women using risperdione tablets to monitor infants for somnolence, failure to thrive, jitteriness, and extrapyramidal symptoms (tremors and abnormal muscle movements) and to seek medical care if they notice these signs \n [see Use in Specific Populations ( \n 8.2)] \n .\n " }

Infertility

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

Advise females of reproductive potential that risperdione tablets 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": "Advise females of reproductive potential that risperdione tablets \n may impair fertility due to an increase in serum prolactin levels. The effects on fertility are reversible \n [see Use in Specific Populations ( \n 8.3)]. \n \n" }

Risperidone Tablets, USP

{ "type": "p", "children": [], "text": "Risperidone Tablets, USP" }

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: RISPERIDONE

{ "type": "p", "children": [], "text": "DRUG: RISPERIDONE" }

GENERIC: RISPERIDONE

{ "type": "p", "children": [], "text": "GENERIC: RISPERIDONE" }

DOSAGE: TABLET

{ "type": "p", "children": [], "text": "DOSAGE: TABLET" }

ADMINSTRATION: ORAL

{ "type": "p", "children": [], "text": "ADMINSTRATION: ORAL" }

NDC: 70518-1568-0

{ "type": "p", "children": [], "text": "NDC: 70518-1568-0" }

COLOR: yellow

{ "type": "p", "children": [], "text": "COLOR: yellow" }

SHAPE: ROUND

{ "type": "p", "children": [], "text": "SHAPE: ROUND" }

SCORE: No score

{ "type": "p", "children": [], "text": "SCORE: No score" }

SIZE: 8 mm

{ "type": "p", "children": [], "text": "SIZE: 8 mm" }

IMPRINT: RI4

{ "type": "p", "children": [], "text": "IMPRINT: RI4" }

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": [ "RISPERIDONE 2mg in 1" ], "text": "" }

INACTIVE INGREDIENT(S):

{ "type": "p", "children": [], "text": "INACTIVE INGREDIENT(S):" }

{ "type": "ul", "children": [ "SILICON DIOXIDE", "HYPROMELLOSE, UNSPECIFIED", "MAGNESIUM STEARATE", "MICROCRYSTALLINE CELLULOSE", "PROPYLENE GLYCOL", "SODIUM LAURYL SULFATE", "SODIUM STARCH GLYCOLATE TYPE A POTATO", "TALC", "TITANIUM DIOXIDE", "FERRIC OXIDE YELLOW", "LACTOSE MONOHYDRATE" ], "text": "" }