SUSTOL is indicated in combination with other antiemetics in adults for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of moderately emetogenic chemotherapy (MEC) or anthracycline and cyclophosphamide (AC) combination chemotherapy regimens.

{ "type": "p", "children": [], "text": "SUSTOL is indicated in combination with other antiemetics in adults for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of moderately emetogenic chemotherapy (MEC) or anthracycline and cyclophosphamide (AC) combination chemotherapy regimens." }

Preparation

Administration

The recommended dosage of SUSTOL is 10 mg administered subcutaneously. Administer SUSTOL in combination with dexamethasone at least 30 minutes before the initiation of MEC or AC combination chemotherapy. Administer SUSTOL on Day 1 of chemotherapy and not more frequently than once every 7 days because of the extended-release properties of the formulation.

For patients receiving MEC, the recommended dexamethasone dosage is 8 mg intravenously on Day 1. For patients receiving AC combination chemotherapy regimens, the recommended dexamethasone dosage is 20 mg intravenously on Day 1, followed by 8 mg orally, twice a day, on Days 2, 3 and 4.

If SUSTOL is administered with an NK1 receptor antagonist, see the prescribing information of the NK1 receptor antagonist for the recommended dexamethasone dosage.

In patients with moderate renal impairment (creatinine clearance of 30 to 59 mL/min), administer SUSTOL on Day 1 of chemotherapy and not more frequently than once every 14 days. Avoid SUSTOL in patients with severe renal impairment (creatinine clearance of less than 30 mL/min) [see Use in Specific Populations (8.6)].

SUSTOL is supplied as a clear, colorless to slightly yellow, viscous liquid and is available as an:

{ "type": "p", "children": [], "text": "SUSTOL is supplied as a clear, colorless to slightly yellow, viscous liquid and is available as an:" }

{ "type": "ul", "children": [ "Extended-Release Injection: 10 mg/0.4 mL in a single-dose pre-filled syringe." ], "text": "" }

SUSTOL is contraindicated in patients with hypersensitivity to granisetron, any of the components of SUSTOL, or to any of the other 5-HT3 receptor antagonists [see Warnings and Precautions (5.3), Description (11)].

{ "type": "p", "children": [], "text": "SUSTOL is contraindicated in patients with hypersensitivity to granisetron, any of the components of SUSTOL, or to any of the other 5-HT3 receptor antagonists [see Warnings and Precautions (5.3), Description (11)]." }

Infections

Infections at the injection site occurred in 0.4% (7 of 1814) of patients with cancer and 0.2% (1 of 412) of healthy subjects in clinical trials. Infections had a median onset of 9 days (range 7 to 16 days) following SUSTOL administration. One patient who was neutropenic at the time of the infection was hospitalized. All patients with infection were treated with antibiotics and had complete resolution.

Bruising and/or hematomas

Bruising and/or hematomas at the injection site occurred in 426 of 1131 (38%) patients treated with SUSTOL 10 mg with a median time to onset of 2 days. Bruising and/or hematomas with a delayed onset (onset 5 or more days following SUSTOL administration) were reported in 175 (15%) patients. Severe bruising or hematoma (e.g., greater than 4 cm bruise or hematoma) occurred in 3% of patients. Patients receiving concomitant anticoagulant and antiplatelet medications were at greater risk for severe injection site bruising and hematomas.

Bleeding

Bleeding at the injection site occurred in 70 of 1814 (4%) patients treated with SUSTOL. One patient required emergency management. Bleeding for longer than 5 days was reported in 23 (1%) patients.

Pain and Tenderness

In a clinical trial that collected information about injection site pain and tenderness from patient diaries, pain with or without tenderness at the injection site was reported by 91 of 456 (20%) of patients treated with SUSTOL 10 mg, and an additional 50 of 456 (11%) of patients reported tenderness without pain. Pain and/or tenderness severe enough to require taking pain medication, interfere with patient activity level, or cause significant discomfort at rest was reported in 2% of patients. Among all patients who reported pain and/or tenderness with SUSTOL 10 mg in clinical trials, the median duration was 5 days, and pain lasting longer than 7 days occurred in 6% of patients.

Nodules

Nodules at the injection site occurred in 203 of 1131 (18%) of patients treated with SUSTOL 10 mg. Nodules persisted for a median of 15 days and 73 patients (6%) had nodules with durations longer than 21 days.

Management of ISRs

Constipation

In clinical trials, 224 of 1131 (20%) of patients treated with SUSTOL 10 mg reported constipation compared to 13% to 15% in the 5-HT3 receptor antagonist control arms. Hospitalization due to constipation or fecal impaction was reported in 5 SUSTOL-treated patients (0.3%). Monitor patients for the development of constipation while receiving treatment with SUSTOL taking into consideration the extended-release properties of the SUSTOL polymer formulation over at least 5 to 7 days, particularly in patients receiving opioid medications. Consider optimizing bowel regimens in patients using SUSTOL.

Progressive Ileus and Gastric Distention

SUSTOL may mask a progressive ileus and/or gastric distention. This should be particularly considered before use of SUSTOL in patients who have had recent abdominal surgery. Monitor for decreased bowel activity, particularly in patients with risk factors for gastrointestinal obstruction.

Hypersensitivity reactions, including anaphylaxis, have been reported in granisetron-treated patients who have exhibited hypersensitivity to other 5-HT3 receptor antagonists [see Contraindications (4)]. Avoid SUSTOL in patients who have had hypersensitivity reactions to other 5-HT3 receptor antagonists [see Contraindications (4)].

Due to the extended-release properties of the SUSTOL polymer formulation, exposure to granisetron may continue for 5 to 7 days following administration. Hypersensitivity reactions may occur up to 7 days or longer following SUSTOL administration and may have an extended course. Inform patients of the signs and symptoms of anaphylaxis, and instruct them to seek immediate medical care should signs and symptoms occur. If hypersensitivity reactions occur, administer appropriate treatment and monitor patients until signs and symptoms resolve.

The development of serotonin syndrome has been reported with 5-HT3 receptor antagonists. Most reports have been associated with concomitant use of serotonergic drugs (e.g., selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), monoamine oxidase inhibitors, mirtazapine, fentanyl, lithium, tramadol, and intravenous methylene blue). Some of the reported cases were fatal. Serotonin syndrome occurring with overdose of another 5-HT3 receptor antagonist alone has also been reported. The majority of reports of serotonin syndrome related to 5-HT3 receptor antagonist use occurred in a post-anesthesia care unit or an infusion center.

Symptoms associated with serotonin syndrome may include the following combination of signs and symptoms: mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, with or without gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Patients should be monitored for the emergence of serotonin syndrome, especially with concomitant use of SUSTOL and other serotonergic drugs. If symptoms of serotonin syndrome occur, discontinue SUSTOL and initiate supportive treatment. Patients should be informed of the increased risk of serotonin syndrome, especially if SUSTOL is used concomitantly with other serotonergic drugs [see Drug Interactions (7.1)].

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 practice.

SUSTOL

The safety of a 10 mg subcutaneous dose of SUSTOL was evaluated in two double-blind, randomized, active-controlled studies, in which 210 patients (23%) received MEC and 467 patients (51%) received AC combination chemotherapy. The data described below reflect exposure to a single 10 mg dose of SUSTOL in 924 patients whose mean age was 56 years (range 19 to 91 years); 76% of patients were female; 70% of patients were Caucasian, 16% Asian, 10% Black, and 4% other races. Dexamethasone was co-administered with SUSTOL in Study 1 and Study 2 and an NK1 receptor antagonist was co-administered with SUSTOL in Study 2.

Table 1 lists the most common adverse reactions reported in at least 3% of patients following a single-dose of SUSTOL 10 mg in Study 1 and/or Study 2. Overall, injection site reactions (ISRs) were the most common group of adverse reactions in SUSTOL-treated patients. Specific types of ISRs reported by SUSTOL-treated patients are shown in Table 2.

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 1. Adverse Reactions Occurring in at Least 3% of Patients Treated with SUSTOL 10 mg in Study 1 and/or Study 2</span> </caption> <colgroup> <col align="left" width="24%"/> <col align="center" width="19%"/> <col align="center" width="19%"/> <col align="center" width="19%"/> <col align="center" width="19%"/> </colgroup> <thead> <tr class="First"> <th align="left" class="Rrule"></th><th align="center" class="Botrule Rrule" colspan="2" valign="top">Study 1</th><th align="center" class="Botrule Lrule" colspan="2" valign="top">Study 2</th> </tr> <tr class="Last"> <th align="center" class="Botrule Rrule" valign="bottom">Adverse Reaction</th><th align="center" class="Botrule Rrule" valign="middle">SUSTOL<br/>10 mg<br/>subcutaneous<br/>(N=468)<br/>%</th><th align="center" class="Botrule Rrule" valign="middle">Palonosetron<br/>hydrochloride<br/>0.25 mg<br/>intravenous<br/>(N=463)<br/>%</th><th align="center" class="Botrule Rrule" valign="middle">SUSTOL<br/>10 mg<br/>subcutaneous<br/>(N=456)<br/>%</th><th align="center" class="Botrule" valign="middle">Ondansetron<br/>0.15 mg/kg<br/>intravenous<br/>(N=459)<br/>%</th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="5"> <dl class="Footnote"> <dt> <a href="#footnote-reference-1" name="footnote-1">*</a> </dt> <dd>Rates of individual injection site reactions (ISRs) are shown in <a href="#t2">Table 2</a> </dd> <dt> <a href="#footnote-reference-2" name="footnote-2">†</a> </dt> <dd>The placebo subcutaneous injection for Study 1 was normal saline and for Study 2 was a SUSTOL-matched control consisting of the SUSTOL polymer vehicle without active drug.</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="First"> <td align="left" class="Botrule Rrule">Injection Site Reactions, any<a class="Sup" href="#footnote-1" name="footnote-reference-1">*</a></td><td align="center" class="Botrule Rrule">37</td><td align="center" class="Botrule Rrule">15<a class="Sup" href="#footnote-2" name="footnote-reference-2">†</a></td><td align="center" class="Botrule Rrule">62</td><td align="center" class="Botrule">See footnote<a class="Sup" href="#footnote-2">†</a></td> </tr> <tr> <td align="left" class="Botrule Rrule">Constipation</td><td align="center" class="Botrule Rrule">14</td><td align="center" class="Botrule Rrule">11</td><td align="center" class="Botrule Rrule">22</td><td align="center" class="Botrule">15</td> </tr> <tr> <td align="left" class="Botrule Rrule">Fatigue</td><td align="center" class="Botrule Rrule">11</td><td align="center" class="Botrule Rrule">10</td><td align="center" class="Botrule Rrule">21</td><td align="center" class="Botrule">24</td> </tr> <tr> <td align="left" class="Botrule Rrule">Headache</td><td align="center" class="Botrule Rrule">9</td><td align="center" class="Botrule Rrule">9</td><td align="center" class="Botrule Rrule">13</td><td align="center" class="Botrule">19</td> </tr> <tr> <td align="left" class="Botrule Rrule">Diarrhea</td><td align="center" class="Botrule Rrule">8</td><td align="center" class="Botrule Rrule">7</td><td align="center" class="Botrule Rrule">9</td><td align="center" class="Botrule">8</td> </tr> <tr> <td align="left" class="Botrule Rrule">Abdominal Pain</td><td align="center" class="Botrule Rrule">7</td><td align="center" class="Botrule Rrule">7</td><td align="center" class="Botrule Rrule">7</td><td align="center" class="Botrule">4</td> </tr> <tr> <td align="left" class="Botrule Rrule">Insomnia</td><td align="center" class="Botrule Rrule">4</td><td align="center" class="Botrule Rrule">2</td><td align="center" class="Botrule Rrule">5</td><td align="center" class="Botrule">6</td> </tr> <tr> <td align="left" class="Botrule Rrule">Dyspepsia</td><td align="center" class="Botrule Rrule">3</td><td align="center" class="Botrule Rrule">3</td><td align="center" class="Botrule Rrule">6</td><td align="center" class="Botrule">7</td> </tr> <tr> <td align="left" class="Botrule Rrule">Dizziness</td><td align="center" class="Botrule Rrule">3</td><td align="center" class="Botrule Rrule">2</td><td align="center" class="Botrule Rrule">5</td><td align="center" class="Botrule">5</td> </tr> <tr> <td align="left" class="Botrule Rrule">Asthenia</td><td align="center" class="Botrule Rrule">4</td><td align="center" class="Botrule Rrule">6</td><td align="center" class="Botrule Rrule">2</td><td align="center" class="Botrule">2</td> </tr> <tr class="Last"> <td align="left" class="Botrule Rrule">Gastroesophageal Reflux</td><td align="center" class="Botrule Rrule">1</td><td align="center" class="Botrule Rrule">1</td><td align="center" class="Botrule Rrule">5</td><td align="center" class="Botrule">4</td> </tr> </tbody> </table></div>

Injection Site Reactions (ISRs)

Injection site reactions occurred in 37% (175/468) in Study 1, Cycle 1 only, and 62% (281/456) in Study 2 of SUSTOL-treated patients. The ISR manifestations included pain, erythema, mass/nodule, swelling/induration, and bleeding. The incidence of individual ISRs is shown in Table 2. Patients may have experienced one or more types of injection site reactions; a total of 213 of 924 patients had three or more.

ISR reporting procedures included both investigator- and patient-reported outcomes in Study 2, while Study 1 used only investigator reporting.

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 2. Injection Site Adverse Reactions Following a Single 10 mg SUSTOL Dose</span> </caption> <colgroup> <col align="left" width="30%"/> <col align="center" width="23.33%"/> <col align="center" width="23.33%"/> <col align="center" width="23.33%"/> </colgroup> <thead> <tr class="First"> <th align="center" class="Rrule" rowspan="2">Injection Site Reaction</th><th align="center" class="Botrule Rrule" colspan="2" valign="top">Study 1<br/>Treatment Arm (Subcutaneous Injection)</th><th align="center" class="Botrule Lrule" rowspan="2" valign="middle">Study 2<a class="Sup" href="#footnote-3" name="footnote-reference-3">*</a><span class="Sup">,</span><a class="Sup" href="#footnote-4" name="footnote-reference-4">†</a> <br/>SUSTOL<br/>(N=456)<br/>%</th> </tr> <tr class="Last"> <th align="center" class="Botrule Rrule" valign="bottom">SUSTOL<br/>(N=468)<br/>%</th><th align="center" class="Botrule Rrule" valign="top">Saline Control<br/>(N=463)<br/>%</th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="4"> <dl class="Footnote"> <dt> <a href="#footnote-reference-3" name="footnote-3">*</a> </dt> <dd>Patient diary was used in Study 2 to collect ISR information daily.</dd> <dt> <a href="#footnote-reference-4" name="footnote-4">†</a> </dt> <dd>The placebo subcutaneous injection for Study 2 was a SUSTOL-matched control consisting of the SUSTOL polymer vehicle without active drug. ISR data for this group are not shown.</dd> <dt> <a href="#footnote-reference-5" name="footnote-5">‡</a> </dt> <dd>Other includes injection site discoloration, vesicles, irritation, lipoma, paresthesia, pruritus, rash, reaction, scab, scar, and warmth.</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="First"> <td align="left" class="Botrule Rrule">Total Subjects with at least 1 ISR</td><td align="center" class="Botrule Rrule">37</td><td align="center" class="Botrule Rrule">15</td><td align="center" class="Botrule">62</td> </tr> <tr> <td align="left" class="Botrule Rrule">Pain</td><td align="center" class="Botrule Rrule">3</td><td align="center" class="Botrule Rrule">1</td><td align="center" class="Botrule">20</td> </tr> <tr> <td align="left" class="Botrule Rrule">Tenderness</td><td align="center" class="Botrule Rrule">4</td><td align="center" class="Botrule Rrule">1</td><td align="center" class="Botrule">27</td> </tr> <tr> <td align="left" class="Botrule Rrule">Bruising/Hematoma</td><td align="center" class="Botrule Rrule">22</td><td align="center" class="Botrule Rrule">10</td><td align="center" class="Botrule">45</td> </tr> <tr> <td align="left" class="Botrule Rrule">Bleeding</td><td align="center" class="Botrule Rrule">2</td><td align="center" class="Botrule Rrule">1</td><td align="center" class="Botrule">4</td> </tr> <tr> <td align="left" class="Botrule Rrule">Erythema/Redness</td><td align="center" class="Botrule Rrule">11</td><td align="center" class="Botrule Rrule">3</td><td align="center" class="Botrule">17</td> </tr> <tr> <td align="left" class="Botrule Rrule">Swelling/Induration</td><td align="center" class="Botrule Rrule">1</td><td align="center" class="Botrule Rrule">0</td><td align="center" class="Botrule">10</td> </tr> <tr> <td align="left" class="Botrule Rrule">Mass/Nodule</td><td align="center" class="Botrule Rrule">11</td><td align="center" class="Botrule Rrule">1</td><td align="center" class="Botrule">18</td> </tr> <tr> <td align="left" class="Botrule Rrule">Infection at injection site</td><td align="center" class="Botrule Rrule">&lt;1</td><td align="center" class="Botrule Rrule">0</td><td align="center" class="Botrule">1</td> </tr> <tr class="Last"> <td align="left" class="Botrule Rrule">Other<a class="Sup" href="#footnote-5" name="footnote-reference-5">‡</a></td><td align="center" class="Botrule Rrule">2</td><td align="center" class="Botrule Rrule">1</td><td align="center" class="Botrule">1</td> </tr> </tbody> </table></div>

Less common adverse reactions reported in less than 3% of SUSTOL-treated patients in clinical trials are syncope, elevation of serum transaminase levels, pancreatitis, atrial fibrillation, somnolence, flushing, and hypersensitivity reactions (e.g., anaphylaxis, urticaria).

The following adverse reactions have been identified during post-approval use of other formulations of granisetron. 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.

<div class="scrollingtable"><table width="100%"> <colgroup> <col align="left" valign="middle" width="50%"/> <col align="left" valign="middle" width="50%"/> </colgroup> <thead> <tr class="First First Last Last"> <th align="left" class="Botrule Rrule">  System Organ Class</th><th align="left" class="Botrule">  Adverse Reactions</th> </tr> </thead> <tbody> <tr class="First First Last Last"> <td align="left" class="Botrule Rrule"><span class="Italics">  Cardiovascular</span></td><td align="left" class="Botrule">  bradycardia, chest pain, palpitations, sick sinus syndrome</td> </tr> </tbody> </table></div>

Serotonin syndrome (including altered mental status, autonomic instability, and neuromuscular symptoms) has been described following the concomitant use of 5-HT3 receptor antagonists and other serotonergic drugs, including selective serotonin reuptake inhibitors (SSRIs) and serotonin and noradrenaline reuptake inhibitors (SNRIs). Monitor for the emergence of serotonin syndrome. If symptoms occur, discontinue SUSTOL and initiate supportive treatment [see Warnings and Precautions (5.4)].

Risk Summary

There are no available data on the use of SUSTOL in pregnant women. Limited published data on granisetron use during pregnancy are not sufficient to inform a drug-associated risk. In animal reproduction studies, no adverse developmental effects were observed in pregnant rats and rabbits administered granisetron hydrochloride during organogenesis at intravenous doses up to 61 times and 41 times respectively the maximum recommended human dose (MRHD) of SUSTOL 10 mg/week [see Data].

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.

Data

Animal Data

Reproduction studies with granisetron hydrochloride have been performed in pregnant rats following administration during the period of organogenesis at intravenous doses up to 9 mg/kg/day (approximately 61 times the maximum recommended human dose (MRHD) of SUSTOL 10 mg/week, based on body surface area) and oral doses up to 125 mg/kg/day (approximately 851 times the MRHD of SUSTOL 10 mg/week, based on body surface area). Reproduction studies have been performed in pregnant rabbits in which granisetron hydrochloride was administered during the period of organogenesis at intravenous doses up to 3 mg/kg/day (approximately 41 times the MRHD of SUSTOL 10 mg/week, based on body surface area) and at oral doses up to 32 mg/kg/day (approximately 436 times the MRHD of SUSTOL 10 mg/week, based on body surface area). These studies did not reveal any evidence of impaired fertility or harm to the fetus due to granisetron hydrochloride.

Reproduction studies with the polymer vehicle for SUSTOL have been performed in pregnant rats and rabbits following administration of the polymer vehicle during the period of organogenesis at subcutaneous doses up to 0.295 and 1.18 g per day, respectively, (approximately 45 and 36 times, respectively the amount of polymer vehicle present in the maximum recommended /weekly single human dose of SUSTOL, based on body surface area). These studies did not reveal any evidence of impaired fertility or harm to the fetus due to the polymer vehicle. A pre and postnatal development study with the polymer vehicle for SUSTOL in rats showed no evidence of any adverse effects on pre and postnatal development at subcutaneous doses (administered on gestation days 7 through lactation day 20) up to 0.295 g per day (approximately 45 times the amount of polymer vehicle present in the maximum recommended /weekly single human dose of SUSTOL, based on body surface area).

Risk Summary

There are no data on the presence of SUSTOL in human milk, the effects of SUSTOL on the breastfed infant, or the effects of SUSTOL on milk production. The lack of clinical data during lactation precludes a clear determination of the risk of SUSTOL to an infant during lactation; therefore, the developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for SUSTOL and any potential adverse effects on the breastfed infant from SUSTOL or from the underlying maternal condition.

The safety and effectiveness of SUSTOL in pediatric patients under 18 years of age have not been established.

SUSTOL is not recommended for use in pediatric patients less than 12 years of age because the product administration requires a large gauge needle and an extended administration time.

Of the 738 patients administered 10 mg of SUSTOL in the comparator controlled studies, 177 (24%) were 65 and over while 39 (5%) were 75 and over. No overall differences in safety or effectiveness were observed between these patients and younger patients; and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Breakdown products of the polymer vehicle in SUSTOL can be detected in urine of healthy subjects [see Clinical Pharmacology (12.3)]. There are no pharmacokinetic data regarding elimination of the polymer vehicle of SUSTOL in patients with renal impairment and the clinical significance of potential prolonged elimination is not known. Avoid SUSTOL in patients with severe renal impairment. In patients with moderate renal impairment, administer SUSTOL not more frequently than once every 14 days [see Dosage and Administration (2.3)].

There is no specific antidote for granisetron overdosage. In the case of overdosage, symptomatic treatment should be given. Overdosage of up to 38.5 mg of granisetron hydrochloride, as a single intravenous injection, has been reported without symptoms or with only the occurrence of headache.

{ "type": "p", "children": [], "text": "There is no specific antidote for granisetron overdosage. In the case of overdosage, symptomatic treatment should be given. Overdosage of up to 38.5 mg of granisetron hydrochloride, as a single intravenous injection, has been reported without symptoms or with only the occurrence of headache." }

SUSTOL (granisetron) extended-release injection, contains granisetron, a serotonin-3 (5-HT3) receptor antagonist. Granisetron is 1-methyl-N-[(1R,3r,5S)-9-methyl-9-azabicyclo[3.3.1]non-3-yl]-1H-indazole-3-carboxamide with a molecular weight of 312.4. Its empirical formula is C18H24N4O, with the following chemical structure:

{ "type": "p", "children": [], "text": "SUSTOL (granisetron) extended-release injection, contains granisetron, a serotonin-3 (5-HT3) receptor antagonist. Granisetron is 1-methyl-N-[(1R,3r,5S)-9-methyl-9-azabicyclo[3.3.1]non-3-yl]-1H-indazole-3-carboxamide with a molecular weight of 312.4. Its empirical formula is C18H24N4O, with the following chemical structure:" }

Granisetron is a white to off-white crystalline solid that is insoluble in water.

{ "type": "p", "children": [], "text": "Granisetron is a white to off-white crystalline solid that is insoluble in water." }

SUSTOL is a sterile, clear, colorless to slightly yellow, viscous liquid supplied in a single-dose, pre-filled syringe. Each syringe contains 10 mg granisetron incorporated in an extended-release polymer formulation; the inactive ingredients are triethylene glycol poly(orthoester) polymer, 392 mg and polyethylene glycol monomethyl ether, NF, 98 mg.

{ "type": "p", "children": [], "text": "SUSTOL is a sterile, clear, colorless to slightly yellow, viscous liquid supplied in a single-dose, pre-filled syringe. Each syringe contains 10 mg granisetron incorporated in an extended-release polymer formulation; the inactive ingredients are triethylene glycol poly(orthoester) polymer, 392 mg and polyethylene glycol monomethyl ether, NF, 98 mg." }

Granisetron is a selective 5-hydroxytryptamine3 (5-HT3) receptor antagonist with little or no affinity for other serotonin receptors, including 5-HT1, 5-HT1A, 5-HT1B/C, 5-HT2; for alpha1-, alpha2-, or beta-adrenoreceptors; for dopamine-D2; or for histamine-H1; benzodiazepine; picrotoxin or opioid receptors.

Serotonin receptors of the 5-HT3 type are located peripherally on vagal nerve terminals and centrally in the chemoreceptor trigger zone of the area postrema. During chemotherapy that induces vomiting, mucosal enterochromaffin cells release serotonin, which stimulates 5-HT3 receptors. This evokes vagal afferent discharge, inducing vomiting. Animal studies demonstrate that, in binding to 5-HT3 receptors, granisetron blocks serotonin stimulation and subsequent vomiting after emetogenic stimuli such as cisplatin. In the ferret animal model, a single granisetron injection prevented vomiting due to high-dose cisplatin or arrested vomiting within 5 to 30 seconds.

Cardiac Electrophysiology

The effect of SUSTOL on QTc prolongation was evaluated in a double-blind randomized, four-way crossover, placebo and positive (moxifloxacin) controlled study in 51 adult male and female healthy subjects. At 2-fold the recommended dosage of SUSTOL, there was no significant effect on the QTcF interval.

In 142 cancer patients, 24-hour Holter monitoring and 12-lead ECGs were evaluated. QTcF greater than 450 msec were seen in a total of 20 (19%) patients administered SUSTOL and 9 (31%) patients administered intravenous palonosetron hydrochloride. In the SUSTOL group, one patient had a QTcF interval greater than 500 msec and 4 patients had a change from baseline QTcF greater than 60 msec.

Absorption

SUSTOL is an extended-release injection formulation of granisetron using a polymer-based drug delivery system. Following a single-dose administration in healthy subjects, granisetron is released from the polymer over an extended period of time and remains detectable in plasma for 7 days post-dose (Figure 1). A mean concentration of 3.5 ng/mL (range 0 to 14 ng/mL) was observed at 5 days post-dose [see Warnings and Precautions (5.3)].

<div class="scrollingtable"><table width="100%"> <caption> <span>Figure 1. Plasma Concentrations of Granisetron Over 7 Days after a Single Subcutaneous Injection of SUSTOL in Healthy Subjects</span> </caption> <tbody class="Headless"> <tr class="First First Last Last"> <td align="center"><img alt="image of figure 1" src="/dailymed/image.cfm?name=sustol-02.jpg&amp;setid=f7c7ffdd-8270-4030-bc1e-a1cb28a6de56"/></td> </tr> </tbody> </table></div>

The granisetron pharmacokinetic parameters following injection of SUSTOL were similar between the abdomen and upper arm injection sites as shown in Table 3.

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 3. Granisetron Pharmacokinetic Parameters Following a Single 10 mg Subcutaneous Injection of SUSTOL in Healthy Subjects by Injection Site Location</span> </caption> <colgroup> <col align="left" width="35%"/> <col align="center" width="32.5%"/> <col align="center" width="32.5%"/> </colgroup> <thead> <tr class="First"> <th align="left" class="Rrule" rowspan="2">Parameter<a class="Sup" href="#footnote-6" name="footnote-reference-6">*</a></th><th align="center" class="Botrule" colspan="2" valign="top">Injection Site Location</th> </tr> <tr class="Last"> <th align="center" class="Botrule Rrule" valign="top">Abdomen<br/>N=113</th><th align="center" class="Botrule" valign="top">Upper Arm<br/>N=113</th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="3"> <dl class="Footnote"> <dt> <a href="#footnote-reference-6" name="footnote-6">*</a> </dt> <dd>Values shown are mean ± SD, except for T<span class="Sub">max</span> where median [range] are shown.</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="First"> <td align="left" class="Botrule Rrule">C<span class="Sub">max</span> (ng/mL)</td><td align="center" class="Botrule Rrule">9.8 ± 4.8</td><td align="center" class="Botrule">10.8 ± 4.6</td> </tr> <tr> <td align="left" class="Botrule Rrule">T<span class="Sub">max</span> (hours) [range]</td><td align="center" class="Botrule Rrule">12 [1 to 144]</td><td align="center" class="Botrule">11 [1 to 120]</td> </tr> <tr class="Last"> <td align="left" class="Botrule Rrule">AUC<span class="Sub">inf</span>, ng.h/mL</td><td align="center" class="Botrule Rrule">680 ± 362</td><td align="center" class="Botrule">720 ± 366</td> </tr> </tbody> </table></div>

In patients, peak plasma granisetron concentrations were delayed compared to healthy subjects with a median Tmax of approximately 24 hours.

Distribution

Plasma protein binding of granisetron is approximately 65% and granisetron distributes freely between plasma and red blood cells.

Metabolism

Published data suggests that granisetron is metabolized by CYP1A1 and CYP3A4. Granisetron metabolism involves N-demethylation and aromatic ring oxidation followed by conjugation.

Elimination

Metabolism: Following a single 10 mg subcutaneous injection of SUSTOL, the terminal elimination half-life of granisetron was approximately 24 hours and was comparable between healthy subjects and patients.

Granisetron clearance is predominantly by hepatic metabolism.

Excretion: Approximately 12% of a granisetron dose, following intravenous administration of granisetron hydrochloride, is eliminated unchanged in the urine in 48 hours. The remainder of the dose is excreted as metabolites, 49% in the urine and 34% in the feces.

Specific Populations

Age: Geriatric Population: In a pooled analysis of samples collected from 56 cancer patients in 3 clinical studies, the mean Cmax and mean AUC0-inf for granisetron following subcutaneous administration of a 10 mg dose of SUSTOL was 39% and 76% higher in patients 65 years of age and older than in patients less than 65 years of age. These pharmacokinetic differences are not considered clinically meaningful taking into consideration the small number of patients 65 years of age and older in the analysis (n = 16) and the high inter-patient variability.

Sex: In a pooled analysis of samples collected from 56 cancer patients in 3 clinical studies, the mean Cmax and mean AUC0-inf for granisetron following subcutaneous administration of a 10 mg dose of SUSTOL was 34% and 132% higher in males than in females. These pharmacokinetic differences are not considered meaningful taking into consideration the small number of males in the analysis (n = 13) and the high inter-patient variability.

Renal Impairment: The total clearance of granisetron was similar in patients with severe renal failure compared to patients with normal renal function following a single 40 mcg/kg intravenous dose of granisetron hydrochloride.

Breakdown products of the polymer vehicle in SUSTOL can be detected in urine of healthy subjects [see Clinical Pharmacology (12.3)]. There are no pharmacokinetic data regarding elimination of the polymer vehicle of SUSTOL in patients with renal impairment [see Dosage and Administration (2.3), Use in Specific Populations (8.6)].

Hepatic Impairment: The total clearance of granisetron was approximately 50% lower in patients with hepatic impairment (neoplastic liver disease) compared to patients with normal hepatic function following a single 40 mcg/kg intravenous dose of granisetron hydrochloride. The high inter-subject variability in the pharmacokinetic parameters of granisetron in patients with hepatic impairment limits the interpretation of these findings.

Drug Interaction Studies

Effect of Other Drugs on Granisetron

Granisetron is metabolized by the hepatic cytochrome P-450 drug-metabolizing enzymes CYP1A1 and CYP3A4. Inducers or inhibitors of CYP1A1 and CYP3A4 enzymes may affect the clearance and half-life of granisetron. In in vitro human microsomal studies, ketoconazole inhibited ring oxidation of granisetron. However, the potential for an in vivo pharmacokinetic interaction with ketoconazole is not known.

Phenobarbital: Administration of intravenous granisetron hydrochloride with phenobarbital, an enzyme inducer, resulted in a 25% increase in total plasma clearance of granisetron. The clinical significance of this interaction is not known.

Effect of Granisetron on Other Drugs

Granisetron does not induce or inhibit the cytochrome P-450 drug-metabolizing enzyme system in vitro. In addition, the in vitro activity of the cytochrome P-450 subfamily 3A4, which is involved in the metabolism of some narcotic analgesics, is not modified by granisetron.

Polymer Breakdown Products

In a metabolic fate study conducted in healthy subjects, breakdown products of the triethylene glycol poly(orthoester) polymer vehicle of the SUSTOL formulation including triethylene glycol (TEG), pentaerythritol (PE), and the oxidative metabolite of TEG, triethylene glycol monocarboxylic acid (TEG acid) were detected in urine with incomplete recovery by the end of study period (10 days). Accumulation of these metabolites in plasma was not noted. The recovery of the polymer load was incomplete in this study and could be due to insufficient sampling and assay sensitivity issues preventing detection of additional metabolites [see Dosage and Administration (2.3), Use in Specific Populations (8.6)].

In a 24-month carcinogenicity study of granisetron hydrochloride, rats were treated orally with 1, 5 or 50 mg/kg/day. The 50 mg/kg/day dose was reduced to 25 mg/kg/day during week 59 due to toxicity. For a 60 kg person, the 1, 5, and 25 mg/kg/day doses represent approximately 7, 34 and 169 times, respectively, the maximum recommended human dose (MRHD) (10 mg granisetron/week, approximately 6.2 mg/m2/week) of SUSTOL 10 mg/week, based on body surface area. There was a statistically significant increase in the incidence of hepatocellular carcinomas and adenomas in male rats treated with 5 mg/kg/day (approximately 34 times the MRHD of SUSTOL 10 mg/week, based on body surface area) and above, and in female rats treated with 25 mg/kg/day (approximately 169 times the MRHD of SUSTOL 10 mg/week, based on body surface area). No increase in liver tumors was observed at a dose of 1 mg/kg/day (approximately 7 times the MRHD of SUSTOL 10 mg/week, based on body surface area) in male rats and 5 mg/kg/day (approximately 34 times the MRHD of SUSTOL 10 mg/week, based on body surface area) in female rats.

A 24-month subcutaneous carcinogenicity study in rats evaluated the carcinogenic potenial of the polymer vehicle in SUSTOL. There were no drug-related neoplasms up to 0.295 g/week (approximately 9 to 30 times the amounnt of polymer vehicle present in the MRHD of SUSTOL 10 mg/week, based on body surface area).

In a 12-month oral toxicity study with granisetron hydrochloride, rats were treated at 100 mg/kg/day (approximately 677 times the MRHD of SUSTOL 10 mg/week, based on body surface area). This dose produced hepatocellular adenomas in male and female rats while no such tumors were found in the control rats. A 24-month mouse carcinogenicity study of granisetron did not show a statistically significant increase in tumor incidence, but the study was not conclusive. Because of the tumor findings in rat studies, SUSTOL should be prescribed only at the dose and for the indication recommended [see Indications and Usage (1), Dosage and Administration (2.2)].

Granisetron hydrochloride was not mutagenic in an in vitro Ames test and mouse lymphoma cell forward mutation assay, and in vivo mouse micronucleus test and in vitro and ex vivo rat hepatocyte unscheduled DNA synthesis (UDS) assays. However, granisetron hydrochloride was positive in a mouse lymphoma assay with metabolic activation and produced a significant increase in UDS in HeLa cells in vitro and a significant increased incidence of cells with polyploidy in an in vitro human lymphocyte chromosomal aberration test.

Neither SUSTOL nor the polymer vehicle for SUSTOL was mutagenic in the Ames test, mouse lymphoma assay, and the in vivo rat bone marrow micronucleus test.

Granisetron hydrochloride at subcutaneous doses up to 6 mg/kg/day (approximately 40 times the MRHD of SUSTOL 10 mg/week, based on body surface area), and oral doses up to 100 mg/kg/day (approximately 677 times the MRHD of SUSTOL 10 mg/week, based on body surface area) was found to have no effect on fertility and reproductive performance of male and female rats.

The polymer vehicle for SUSTOL at subcutaneous doses up to 0.295 g per day (approximately 137 times the amount of polymer vehicle present in the maximum recommended /weekly single human dose of SUSTOL, based on body surface area) was found to have no adverse effect on fertility and reproductive performance of male and female rats.

In a randomized, multicenter, double-blind, parallel group study, a single 10 mg subcutaneous dose of SUSTOL was compared to a single 0.25 mg intravenous dose of palonosetron hydrochloride in cancer patients administered moderately emetogenic (MEC) or anthracycline plus cyclophosphamide (AC) combination chemotherapy. SUSTOL or palonosetron hydrochloride was administered 30 minutes prior to chemotherapy on Day 1. Patients also received either 8 or 20 mg intravenous dexamethasone on Day 1 depending on chemotherapy regimen. Patients who received 20 mg of intravenous dexamethasone also received oral dexamethasone 8 mg twice daily on Days 2, 3, and 4.

{ "type": "p", "children": [], "text": "In a randomized, multicenter, double-blind, parallel group study, a single 10 mg subcutaneous dose of SUSTOL was compared to a single 0.25 mg intravenous dose of palonosetron hydrochloride in cancer patients administered moderately emetogenic (MEC) or anthracycline plus cyclophosphamide (AC) combination chemotherapy. SUSTOL or palonosetron hydrochloride was administered 30 minutes prior to chemotherapy on Day 1. Patients also received either 8 or 20 mg intravenous dexamethasone on Day 1 depending on chemotherapy regimen. Patients who received 20 mg of intravenous dexamethasone also received oral dexamethasone 8 mg twice daily on Days 2, 3, and 4." }

In this study of 733 patients (371 in the SUSTOL 10 mg arm and 362 in the palonosetron arm), 79% of patients were female and 63% were Caucasian. The mean age was 57 years (range 22 to 91 years), 55% received MEC and 45% received AC combination chemotherapy regimens. The most common MEC regimens were carboplatin/paclitaxel (31%).

{ "type": "p", "children": [], "text": "In this study of 733 patients (371 in the SUSTOL 10 mg arm and 362 in the palonosetron arm), 79% of patients were female and 63% were Caucasian. The mean age was 57 years (range 22 to 91 years), 55% received MEC and 45% received AC combination chemotherapy regimens. The most common MEC regimens were carboplatin/paclitaxel (31%)." }

The primary endpoints were proportion of patients with complete response (CR) [defined as no emetic episodes (vomiting or retching) and no use of rescue medication] during the acute phase (0 to 24 hours) and the delayed phase (>24 to 120 hours) following the administration of chemotherapy in Cycle 1. The study design allowed for assessment of non-inferiority of SUSTOL to palonosetron hydrochloride in the acute and delayed phase of MEC and of AC combination chemotherapy.

{ "type": "p", "children": [], "text": "The primary endpoints were proportion of patients with complete response (CR) [defined as no emetic episodes (vomiting or retching) and no use of rescue medication] during the acute phase (0 to 24 hours) and the delayed phase (>24 to 120 hours) following the administration of chemotherapy in Cycle 1. The study design allowed for assessment of non-inferiority of SUSTOL to palonosetron hydrochloride in the acute and delayed phase of MEC and of AC combination chemotherapy." }

Non-inferiority of SUSTOL to palonosetron hydrochloride was demonstrated in the acute and delayed phases of MEC and of AC combination chemotherapy [Table 4].

{ "type": "p", "children": [], "text": "Non-inferiority of SUSTOL to palonosetron hydrochloride was demonstrated in the acute and delayed phases of MEC and of AC combination chemotherapy [Table 4]." }

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 4. Number and Percentage of Patients Who Achieved Complete Response with MEC or AC Combination Chemotherapy<a class="Sup" href="#footnote-7" name="footnote-reference-7">*</a></span> </caption> <col align="left" width="35%"/> <col align="center" width="21.66%"/> <col align="center" width="21.66%"/> <col align="center" width="21.66%"/> <thead> <tr class="First"> <td align="left" class="Botrule" colspan="4" valign="bottom"><span class="Bold Italics">Moderately Emetogenic Chemotherapy</span></td> </tr> <tr class="Last"> <th align="center" class="Botrule Rrule" valign="middle">Complete Response</th><th align="center" class="Botrule Rrule" valign="middle">SUSTOL<br/>10 mg<br/>subcutaneous <br/>N=200<br/>n (%)</th><th align="center" class="Botrule Rrule" valign="middle">Palonosetron<br/>hydrochloride,<br/>0.25 mg<br/>intravenous<br/>N=206<br/>n (%)</th><th align="center" class="Botrule" valign="middle">Difference<br/>(95% CI <a class="Sup" href="#footnote-8" name="footnote-reference-8">†</a>):<br/>SUSTOL minus<br/>Palonosetron</th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="4"> <dl class="Footnote"> <dt> <a href="#footnote-reference-7" name="footnote-7">*</a> </dt> <dd>Complete response defined as no emetic episodes and no use of rescue medications.</dd> <dt> <a href="#footnote-reference-8" name="footnote-8">†</a> </dt> <dd>This study was designed to show non-inferiority in the acute phase or delayed phase for patients receiving moderately emetogenic chemotherapy. A lower bound greater than -15% demonstrates non-inferiority between SUSTOL and comparator.</dd> <dt> <a href="#footnote-reference-9" name="footnote-9">‡</a> </dt> <dd>This study was designed to show non-inferiority in the acute phase and superiority in the delayed phase. A lower bound greater than -15% demonstrates non-inferiority between SUSTOL and comparator. Because a lower bound did not exceed 0%, superiority was not demonstrated between SUSTOL and comparator.</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="First"> <td align="left" class="Botrule Rrule">Acute Phase (0 – 24 hours)</td><td align="center" class="Botrule Rrule" valign="top">166 (83)</td><td align="center" class="Botrule Rrule" valign="top">183 (89)</td><td align="center" class="Botrule" valign="top">-6 (-13, 1)</td> </tr> <tr> <td align="left" class="Rrule">Delayed Phase (&gt;24 – 120 hours)</td><td align="center" class="Rrule" valign="top">137 (69)</td><td align="center" class="Rrule" valign="top">144 (70)</td><td align="center" valign="top">-1 (-10, 8)</td> </tr> <tr> <td align="left" class="Botrule Toprule" colspan="4" valign="bottom"><span class="Bold Italics">AC Combination Chemotherapy</span></td> </tr> <tr> <td align="center" class="Botrule Rrule" valign="middle">Complete Response</td><td align="center" class="Botrule Rrule" valign="middle">SUSTOL<br/>10 mg<br/>subcutaneous <br/>N=171<br/>n (%)</td><td align="center" class="Botrule Rrule" valign="middle">Palonosetron<br/>hydrochloride,<br/>0.25 mg<br/>intravenous<br/>N=156<br/>n (%)</td><td align="center" class="Botrule" valign="middle">Difference<br/>(95% CI <a class="Sup" href="#footnote-9" name="footnote-reference-9">‡</a>):<br/>SUSTOL minus<br/>Palonosetron</td> </tr> <tr> <td align="left" class="Botrule Rrule">Acute Phase (0 – 24 hours)</td><td align="center" class="Botrule Rrule" valign="top">120 (70)</td><td align="center" class="Botrule Rrule" valign="top">99 (64)</td><td align="center" class="Botrule" valign="top">6 (-3, 17)</td> </tr> <tr class="Last"> <td align="left" class="Rrule">Delayed Phase (&gt;24 – 120 hours)</td><td align="center" class="Rrule" valign="top">85 (50)</td><td align="center" class="Rrule" valign="top">74 (47)</td><td align="center" valign="top">2 (-9, 13)</td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table width=\"100%\">\n<caption>\n<span>Table 4. Number and Percentage of Patients Who Achieved Complete Response with MEC or AC Combination Chemotherapy<a class=\"Sup\" href=\"#footnote-7\" name=\"footnote-reference-7\">*</a></span>\n</caption>\n<col align=\"left\" width=\"35%\"/>\n<col align=\"center\" width=\"21.66%\"/>\n<col align=\"center\" width=\"21.66%\"/>\n<col align=\"center\" width=\"21.66%\"/>\n<thead>\n<tr class=\"First\">\n<td align=\"left\" class=\"Botrule\" colspan=\"4\" valign=\"bottom\"><span class=\"Bold Italics\">Moderately Emetogenic Chemotherapy</span></td>\n</tr>\n<tr class=\"Last\">\n<th align=\"center\" class=\"Botrule Rrule\" valign=\"middle\">Complete Response</th><th align=\"center\" class=\"Botrule Rrule\" valign=\"middle\">SUSTOL<br/>10 mg<br/>subcutaneous <br/>N=200<br/>n (%)</th><th align=\"center\" class=\"Botrule Rrule\" valign=\"middle\">Palonosetron<br/>hydrochloride,<br/>0.25 mg<br/>intravenous<br/>N=206<br/>n (%)</th><th align=\"center\" class=\"Botrule\" valign=\"middle\">Difference<br/>(95% CI <a class=\"Sup\" href=\"#footnote-8\" name=\"footnote-reference-8\">†</a>):<br/>SUSTOL minus<br/>Palonosetron</th>\n</tr>\n</thead>\n<tfoot>\n<tr>\n<td align=\"left\" colspan=\"4\">\n<dl class=\"Footnote\">\n<dt>\n<a href=\"#footnote-reference-7\" name=\"footnote-7\">*</a>\n</dt>\n<dd>Complete response defined as no emetic episodes and no use of rescue medications.</dd>\n<dt>\n<a href=\"#footnote-reference-8\" name=\"footnote-8\">†</a>\n</dt>\n<dd>This study was designed to show non-inferiority in the acute phase or delayed phase for patients receiving moderately emetogenic chemotherapy. A lower bound greater than -15% demonstrates non-inferiority between SUSTOL and comparator.</dd>\n<dt>\n<a href=\"#footnote-reference-9\" name=\"footnote-9\">‡</a>\n</dt>\n<dd>This study was designed to show non-inferiority in the acute phase and superiority in the delayed phase. A lower bound greater than -15% demonstrates non-inferiority between SUSTOL and comparator. Because a lower bound did not exceed 0%, superiority was not demonstrated between SUSTOL and comparator.</dd>\n</dl>\n</td>\n</tr>\n</tfoot>\n<tbody>\n<tr class=\"First\">\n<td align=\"left\" class=\"Botrule Rrule\">Acute Phase (0 – 24 hours)</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">166 (83)</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">183 (89)</td><td align=\"center\" class=\"Botrule\" valign=\"top\">-6 (-13, 1)</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Rrule\">Delayed Phase (&gt;24 – 120 hours)</td><td align=\"center\" class=\"Rrule\" valign=\"top\">137 (69)</td><td align=\"center\" class=\"Rrule\" valign=\"top\">144 (70)</td><td align=\"center\" valign=\"top\">-1 (-10, 8)</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Toprule\" colspan=\"4\" valign=\"bottom\"><span class=\"Bold Italics\">AC Combination Chemotherapy</span></td>\n</tr>\n<tr>\n<td align=\"center\" class=\"Botrule Rrule\" valign=\"middle\">Complete Response</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"middle\">SUSTOL<br/>10 mg<br/>subcutaneous <br/>N=171<br/>n (%)</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"middle\">Palonosetron<br/>hydrochloride,<br/>0.25 mg<br/>intravenous<br/>N=156<br/>n (%)</td><td align=\"center\" class=\"Botrule\" valign=\"middle\">Difference<br/>(95% CI <a class=\"Sup\" href=\"#footnote-9\" name=\"footnote-reference-9\">‡</a>):<br/>SUSTOL minus<br/>Palonosetron</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Rrule\">Acute Phase (0 – 24 hours)</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">120 (70)</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">99 (64)</td><td align=\"center\" class=\"Botrule\" valign=\"top\">6 (-3, 17)</td>\n</tr>\n<tr class=\"Last\">\n<td align=\"left\" class=\"Rrule\">Delayed Phase (&gt;24 – 120 hours)</td><td align=\"center\" class=\"Rrule\" valign=\"top\">85 (50)</td><td align=\"center\" class=\"Rrule\" valign=\"top\">74 (47)</td><td align=\"center\" valign=\"top\">2 (-9, 13)</td>\n</tr>\n</tbody>\n</table></div>" }

SUSTOL extended-release injection is supplied in cartons of six kits (NDC 47426-101-06) each kit contains:

{ "type": "p", "children": [], "text": "SUSTOL extended-release injection is supplied in cartons of six kits (NDC 47426-101-06) each kit contains:" }

{ "type": "ul", "children": [ "One sterile single-dose amber colored glass syringe which contains 10 mg granisetron/0.4 mL,", "One sterile 18 Ga x 5/8\" special thin walled administration needle,", "Two sodium acetate syringe warming pouches,", "One Point Lok needle protection device." ], "text": "" }

Storage

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

Store SUSTOL in the refrigerator at 2°C to 8°C (36°F to 46°F).

{ "type": "p", "children": [], "text": "Store SUSTOL in the refrigerator at 2°C to 8°C (36°F to 46°F)." }

SUSTOL can be placed back in the refrigerator after being kept at room temperature. SUSTOL can remain at room temperature for up to a maximum of 7 days.

{ "type": "p", "children": [], "text": "SUSTOL can be placed back in the refrigerator after being kept at room temperature. SUSTOL can remain at room temperature for up to a maximum of 7 days." }

Protect from light. Do not freeze.

{ "type": "p", "children": [], "text": "Protect from light. Do not freeze." }

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

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

Administration

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

{ "type": "ul", "children": [ "SUSTOL is intended for subcutaneous injection by a health care provider." ], "text": "" }

Injection Site Reactions [see Warnings and Precautions (5.1)]

{ "type": "p", "children": [], "text": "\nInjection Site Reactions [see Warnings and Precautions (5.1)]\n" }

{ "type": "ul", "children": [ "Inform the patient that ISRs may occur and may include infections, bruising and/or hematomas, bleeding, pain and tenderness, and nodules.", "Inform the patient that some ISRs (infections, bruising, and hematoma) may occur up to 2 weeks or more after SUSTOL administration.", "Instruct the patient to seek immediate medical care for the following ISRs:   ο  signs of infection at the injection site.   ο  injection site bleeding that is severe or lasts for longer than one day.", "Advise the patient to tell their healthcare provider if they experience:   ο  pain or tenderness severe enough to require treatment with pain medication or interfere with daily activity.   ο  bruising and/or hematoma or a persistent nodule at the injection site." ], "text": "" }

Gastrointestinal

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

Advise the patient to report new or worsening constipation to their healthcare provider and seek immediate medical care if signs and symptoms of an ileus occur [see Warnings and Precautions (5.2)].

{ "type": "p", "children": [], "text": "Advise the patient to report new or worsening constipation to their healthcare provider and seek immediate medical care if signs and symptoms of an ileus occur [see Warnings and Precautions (5.2)]." }

Hypersensitivity reactions

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

Advise the patient that hypersensitivity reactions may occur up to 7 days or longer following SUSTOL administration. Inform the patient of the signs and symptoms of hypersensitivity reactions, and have them seek immediate medical care should signs and symptoms occur [see Warnings and Precautions (5.1, 5.3)].

{ "type": "p", "children": [], "text": "Advise the patient that hypersensitivity reactions may occur up to 7 days or longer following SUSTOL administration. Inform the patient of the signs and symptoms of hypersensitivity reactions, and have them seek immediate medical care should signs and symptoms occur [see Warnings and Precautions (5.1, 5.3)]." }

Serotonin Syndrome

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

Advise the patient of the possibility of serotonin syndrome, especially with concomitant use of SUSTOL and another serotonergic agent such as medications to treat depression and migraines. Advise the patient to seek immediate medical attention if the following symptoms occur: changes in mental status, autonomic instability, neuromuscular symptoms with or without gastrointestinal symptoms [see Warnings and Precautions (5.4)].

{ "type": "p", "children": [], "text": "Advise the patient of the possibility of serotonin syndrome, especially with concomitant use of SUSTOL and another serotonergic agent such as medications to treat depression and migraines. Advise the patient to seek immediate medical attention if the following symptoms occur: changes in mental status, autonomic instability, neuromuscular symptoms with or without gastrointestinal symptoms [see Warnings and Precautions (5.4)]." }

Manufactured for: Heron Therapeutics, Inc., San Diego, CA 92121, USAPatent: https://www.herontx.com/patents/

{ "type": "p", "children": [], "text": "Manufactured for: Heron Therapeutics, Inc., San Diego, CA 92121, USAPatent: https://www.herontx.com/patents/" }

SUSTOL® is a registered trademark of Heron Therapeutics, Inc.Copyright © 2017-2023 Heron Therapeutics, Inc.

{ "type": "p", "children": [], "text": "SUSTOL® is a registered trademark of Heron Therapeutics, Inc.Copyright © 2017-2023 Heron Therapeutics, Inc.\n" }

All rights reserved.

{ "type": "p", "children": [], "text": "All rights reserved." }

MEDICATION GUIDE

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

SUSTOL® (sus' tol)

{ "type": "p", "children": [], "text": "SUSTOL® (sus' tol)" }

(granisetron)

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

extended-release injection, for subcutaneous use

{ "type": "p", "children": [], "text": "extended-release injection, for subcutaneous use" }

What is the most important information I should know about SUSTOL?

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

SUSTOL can cause serious side effects, including:

{ "type": "p", "children": [], "text": "\nSUSTOL can cause serious side effects, including:\n" }

{ "type": "ul", "children": [ "\nInjection site reactions. Some injection site reactions may be serious and require medical care. Injection site reactions may include infections, bruising, swelling that is caused by blood that collects under the skin (hematoma), bleeding, pain and tenderness, and small bumps (nodules) at the injection site. Infections, bruising, and hematomas can happen up to 2 weeks or more after receiving SUSTOL.Tell your healthcare provider if you have:   ο  pain or tenderness that you need to take pain medicine for or if you have pain that interferes with your daily activity.   ο  bruising, hematoma, or a nodule at the injection site that does not go away. Your risk of severe bruising and hematomas at the injection site is increased if you take a blood thinner medicine (anticoagulant or antiplatelet medicine).Get medical care right away if you have:   ο  signs of an infection at the injection site, including continued redness or warmth, or if you have a fever.   ο  bleeding at the injection site that is severe or lasts for longer than 24 hours.", "\nStomach and intestinal problems. Problems having a bowel movement (constipation) that may be serious, can happen up to 7 days after treatment with SUSTOL. These problems may be more likely in people taking opioid pain medicines. SUSTOL can make it harder to identify certain stomach and bowel problems you may have. Tell your healthcare provider if you have constipation or your constipation worsens after you receive SUSTOL. Get medical care right away if you have pain or swelling in your stomach-area (abdomen).", "\nSerious allergic reactions. Serious allergic reactions have happened in people who receive SUSTOL and who have had allergic reactions to other medicines used to help prevent nausea and vomiting called 5-HT3 receptor antagonists. Serious allergic reactions can happen up to 7 days or longer after treatment. Get emergency medical help right away if you have any signs or symptoms of a serious allergic reaction, including:   ο  hives   ο  breathing trouble   ο  swollen face   ο  chest pain" ], "text": "" }

What is SUSTOL?

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

{ "type": "ul", "children": [ "SUSTOL is a prescription medicine called an \"antiemetic.\"", "SUSTOL is used in adults to help prevent the nausea and vomiting that happens right away or later with certain anti-cancer medicines (chemotherapy)." ], "text": "" }

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

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

Who should not receive SUSTOL?

{ "type": "p", "children": [], "text": "\nWho should not receive SUSTOL?\n" }

Do not receive SUSTOL if you are allergic to:

{ "type": "p", "children": [], "text": "\nDo not receive SUSTOL if you are allergic to:\n" }

{ "type": "ul", "children": [ "granisetron or any of the ingredients in SUSTOL. See the end of this Medication Guide for a complete list of ingredients in SUSTOL.", "any other 5-HT3 receptor antagonist medicine used to help prevent nausea and vomiting." ], "text": "" }

What should I tell my healthcare provider before receiving SUSTOL?

{ "type": "p", "children": [], "text": "\nWhat should I tell my healthcare provider before receiving SUSTOL?\n" }

Before receiving SUSTOL, tell your healthcare provider about all of your medical conditions, including if you:

{ "type": "p", "children": [], "text": "\nBefore receiving SUSTOL, tell your healthcare provider about all of your medical conditions, including if you:\n" }

{ "type": "ul", "children": [ "have constipation", "have had recent stomach-area (abdominal) surgery", "have kidney problems", "are pregnant or plan to become pregnant. It is not known if SUSTOL will harm your unborn baby.", "are breastfeeding or plan to breastfeed. It is not known if SUSTOL passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby if you will receive SUSTOL." ], "text": "" }

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Using SUSTOL with certain other medicines can cause serious side effects.

{ "type": "p", "children": [], "text": "\nTell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Using SUSTOL with certain other medicines can cause serious side effects." }

Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine.

{ "type": "p", "children": [], "text": "Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine." }

How will I receive SUSTOL?

{ "type": "p", "children": [], "text": "\nHow will I receive SUSTOL?\n" }

{ "type": "ul", "children": [ "SUSTOL will be given to you by an injection under your skin (subcutaneously) in the back of your upper arm or in your stomach-area (abdomen) on Day 1 of your chemotherapy cycle.", "SUSTOL will be given to you by a healthcare provider.", "SUSTOL is usually given about 30 minutes before you receive your anti-cancer medicine (chemotherapy).", "You should not receive SUSTOL more often than 1 time every 7 days." ], "text": "" }

What are the possible side effects of SUSTOL?

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

SUSTOL may cause serious side effects, including:

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

{ "type": "ul", "children": [ "See \"What is the most important information I should know about SUSTOL?\"\n", "\nSerotonin Syndrome. A possible life-threatening problem called serotonin syndrome can happen with medicines called 5-HT3 receptor antagonists, including SUSTOL, especially when used with medicines used to treat depression and migraine headaches called serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), monoamine oxidase inhibitors (MAOIs), and certain other medicines. Tell your healthcare provider or nurse right away if you have any of the following symptoms of serotonin syndrome:   ο  agitation, seeing things that are not there (hallucinations), confusion, or coma   ο  fast heartbeat or unusual and frequent changes in your blood pressure   ο  dizziness, sweating, flushing, or fever   ο  tremors, stiff muscles, muscle twitching, overactive reflexes, or loss of coordination   ο  seizures   ο  nausea, vomiting, or diarrhea" ], "text": "" }

The most common side effects of SUSTOL include: injection site reactions, constipation, fatigue, headache, diarrhea, stomach-area (abdominal) pain, trouble sleeping or falling asleep, indigestion, dizziness, weakness, and heartburn.

{ "type": "p", "children": [], "text": "The most common side effects of SUSTOL include: injection site reactions, constipation, fatigue, headache, diarrhea, stomach-area (abdominal) pain, trouble sleeping or falling asleep, indigestion, dizziness, weakness, and heartburn." }

These are not all the possible side effects of SUSTOL. Tell your healthcare provider if you have any side effect that bothers you or does not go away.

{ "type": "p", "children": [], "text": "These are not all the possible side effects of SUSTOL. Tell your healthcare provider if you have any side effect that bothers you or does not go away." }

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

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

General Information about the safe and effective use of SUSTOL

{ "type": "p", "children": [], "text": "\nGeneral Information about the safe and effective use of SUSTOL\n" }

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use SUSTOL for a condition for which it was not prescribed. Do not give SUSTOL to other people, even if they have the same symptoms that you have. It may harm them.You can ask your healthcare provider or pharmacist for information about SUSTOL that is written for health professionals.

{ "type": "p", "children": [], "text": "Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use SUSTOL for a condition for which it was not prescribed. Do not give SUSTOL to other people, even if they have the same symptoms that you have. It may harm them.You can ask your healthcare provider or pharmacist for information about SUSTOL that is written for health professionals." }

What are the ingredients in SUSTOL?

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

Active ingredient: granisetron

{ "type": "p", "children": [], "text": "\nActive ingredient: granisetron" }

Inactive ingredients: triethylene glycol poly(orthoester) polymer and polyethylene glycol monomethyl ether

{ "type": "p", "children": [], "text": "\nInactive ingredients: triethylene glycol poly(orthoester) polymer and polyethylene glycol monomethyl ether" }

Manufactured for: Heron Therapeutics, Inc., San Diego, CA 92121

{ "type": "p", "children": [], "text": "\nManufactured for: Heron Therapeutics, Inc., San Diego, CA 92121\n" }

Patent: https://www.herontx.com/patents/

{ "type": "p", "children": [], "text": "Patent: https://www.herontx.com/patents/" }

SUSTOL® is a registered trademark of Heron Therapeutics, Inc. Copyright © 2017-2023 Heron Therapeutics, Inc.

{ "type": "p", "children": [], "text": "SUSTOL® is a registered trademark of Heron Therapeutics, Inc.\nCopyright © 2017-2023 Heron Therapeutics, Inc.\n" }

All rights reserved.

{ "type": "p", "children": [], "text": "All rights reserved." }

For more information, go to www.SUSTOL.com or call 1-844-437-6611.

{ "type": "p", "children": [], "text": "For more information, go to www.SUSTOL.com or call 1-844-437-6611." }

This Medication Guide has been approved by the U.S. Food and Drug Administration Revised: 06/2023

{ "type": "p", "children": [], "text": "This Medication Guide has been approved by the U.S. Food and Drug Administration\nRevised: 06/2023" }

<div class="scrollingtable"><table width="100%"> <colgroup> <col align="left" valign="top" width="47.5%"/> <col align="center" valign="middle" width="5%"/> <col align="left" valign="middle" width="47.5%"/> </colgroup> <thead> <tr class="First First Last Last"> <th align="left" class="Botrule">SUSTOL<span class="Sup">®</span> <br/>(granisetron) extended-release injection 10 mg/0.4 mL<br/> <br/>Instructions for Use</th><th align="left" class="Botrule" colspan="2">You must read these complete instructions before you administer SUSTOL for the first time.<br/> <br/>SUSTOL must be administered by a healthcare provider.</th> </tr> </thead> <tbody> <tr class="First"> <td align="left" class="Botrule Rrule" valign="top">What is SUSTOL?</td><td align="left" class="Botrule" colspan="2">SUSTOL is a subcutaneous injection that provides long-acting antiemetic medication to patients receiving chemotherapy. SUSTOL contains a highly viscous polymer that provides sustained release of granisetron.<br/> <br/>SUSTOL is supplied as part of an administration kit.</td> </tr> <tr> <td align="left" class="Botrule Rrule" valign="top">When should you administer SUSTOL?</td><td align="left" class="Botrule" colspan="2">Administer SUSTOL at least 30 minutes before chemotherapy on Day 1 of chemotherapy treatment and not more frequently than once every 7 days, because of the extended-release properties of the formulation.</td> </tr> <tr> <td align="left" class="Botrule Rrule" rowspan="2" valign="top">Before you begin to prepare SUSTOL Injection</td><td align="left" colspan="2"><span class="Bold">Read these critical instructions.</span> <br/> <br/> <span class="Italics">Do not substitute any of the components from the kit for administration.</span> <br/> <br/>Check to make sure the SUSTOL kit contains:</td> </tr> <tr> <td align="left" class="Botrule" colspan="2"> <ul> <li>One sterile single-dose glass syringe which contains 10 mg granisetron</li> <li>One sterile 18G x 5/8" administration needle</li> <li>Two sodium acetate warming pouches</li> <li>One Point-Lok<span class="Sup">®</span> needle protection device</li> <li>Instructions for Use, Package Insert and Medication Guide</li> </ul> </td> </tr> <tr> <td align="left" class="Botrule Rrule">Bring SUSTOL to room temperature</td><td align="center" class="Botrule Rrule">STEP</td><td align="left" class="Botrule">To bring SUSTOL to room temperature:</td> </tr> <tr> <td align="center" class="Botrule Rrule"><img alt="Image of iFU Instruction 1" src="/dailymed/image.cfm?name=sustol-05.jpg&amp;setid=f7c7ffdd-8270-4030-bc1e-a1cb28a6de56"/></td><td align="center" class="Botrule Rrule" valign="top">1</td><td align="left" class="Botrule">Remove SUSTOL kit from refrigeration. Open carton and remove tray. Open tray and unpack warming pouches. Wait a minimum of <span class="Bold">60 minutes</span> prior to use to allow SUSTOL and the warming pouches to warm to room temperature.<br/> <br/>SUSTOL may be left out at room temperature overnight, and for up to 7 days, before it must be discarded. SUSTOL may be re-refrigerated if not used within the 7 day period.<br/> <br/>Warming SUSTOL prior to injection decreases the viscosity and makes administration easier. Bringing SUSTOL to room temperature prior to warming with the sodium acetate warming pouch will facilitate warming of SUSTOL to body temperature.</td> </tr> <tr> <td align="left" class="Botrule Rrule">Prepare the syringe</td><td align="center" class="Botrule Rrule">STEP</td><td align="left" class="Botrule">Follow these steps to prepare SUSTOL for use:</td> </tr> <tr> <td align="left" class="Botrule Rrule"></td><td align="center" class="Botrule Rrule" valign="top">1</td><td align="left" class="Botrule"><img alt="Image of iFU Instruction - Caution" src="/dailymed/image.cfm?name=sustol-17c.jpg&amp;setid=f7c7ffdd-8270-4030-bc1e-a1cb28a6de56"/>Examine all contents of the package. Do not use if any component is damaged.</td> </tr> <tr> <td align="left" class="Botrule Rrule"></td><td align="center" class="Botrule Rrule" valign="top">2</td><td align="left" class="Botrule">Check the expiration date on the syringe. Do not use if the expiration date has passed.</td> </tr> <tr> <td align="left" class="Botrule Rrule"></td><td align="center" class="Botrule Rrule" valign="top">3</td><td align="left" class="Botrule"><img alt="Image of iFU Instruction - Optional" src="/dailymed/image.cfm?name=sustol-18o.jpg&amp;setid=f7c7ffdd-8270-4030-bc1e-a1cb28a6de56"/>Remove the perforated flag label from the plunger rod.</td> </tr> <tr> <td align="center" class="Botrule Rrule"><img alt="Image of iFU Instruction 2" src="/dailymed/image.cfm?name=sustol-06.jpg&amp;setid=f7c7ffdd-8270-4030-bc1e-a1cb28a6de56"/></td><td align="center" class="Botrule Rrule" valign="top">4</td><td align="left" class="Botrule">To ensure that the syringe contains the full dose, check that the gray stopper is close to or below the black line on the syringe barrel label as shown in the illustration.<br/> <br/>Do <span class="Bold">NOT</span> expel air bubbles. For a subcutaneous injection, air bubbles in the syringe will not harm the patient.</td> </tr> <tr> <td align="center" class="Botrule Rrule"><img alt="Image of iFU Instruction 3" src="/dailymed/image.cfm?name=sustol-07.jpg&amp;setid=f7c7ffdd-8270-4030-bc1e-a1cb28a6de56"/></td><td align="center" class="Botrule Rrule" valign="top">5</td><td align="left" class="Botrule"><span class="Bold">Unscrew</span> the tip cap from the end of the pre-filled glass syringe.<br/> <br/>Do <span class="Bold">NOT</span> use if the tip cap is missing or has been tampered with. Do <span class="Bold">NOT</span> use if the Luer fitting is missing or dislodged.</td> </tr> <tr> <td align="left" class="Botrule Rrule"></td><td align="center" class="Botrule Rrule" valign="top">6</td><td align="left" class="Botrule">Remove the hub cover from the 18G x 5/8" needle supplied with the syringe. Attach the needle to the syringe and seat the needle securely. Do <span class="Bold">NOT</span> remove the blue needle cover. <span class="Bold">Do not substitute with any other needle</span> <br/> <img alt="Image of iFU Instruction - Caution" src="/dailymed/image.cfm?name=sustol-17c.jpg&amp;setid=f7c7ffdd-8270-4030-bc1e-a1cb28a6de56"/><span class="Bold">Use ONLY the 18G x 5/8" needle provided with the syringe because of the highly viscous nature of the medication.</span></td> </tr> <tr> <td align="left" class="Botrule Rrule">Warm SUSTOL to body temperature</td><td align="center" class="Botrule Rrule" valign="top">STEP</td><td align="left" class="Botrule">Just prior to administering the injection, follow these steps:</td> </tr> <tr> <td align="center" class="Botrule Rrule"><img alt="Image of iFU Instruction 4" src="/dailymed/image.cfm?name=sustol-08.jpg&amp;setid=f7c7ffdd-8270-4030-bc1e-a1cb28a6de56"/></td><td align="center" class="Botrule Rrule"></td><td align="left" class="Botrule">SUSTOL must be warmed to body temperature immediately prior to injection to reduce viscosity and facilitate administration.<br/> <br/>SUSTOL is packaged with two warming pouches. The warming pouches use a non- toxic solution of sodium acetate to create an exothermic (warming) reaction. The second warming pouch can be used if SUSTOL is not immediately administered within the 15 minutes provided by the first warming pouch and needs to be re-warmed. <br/> <br/>Before activating the warming pouch, make sure that the SUSTOL kit was removed from the refrigerator and that the warming pouches were unpacked from the kit at least 60 minutes prior to use to allow SUSTOL and the warming pouches to warm to room temperature.</td> </tr> <tr> <td align="center" class="Botrule Rrule"><img alt="Image of iFU Instruction 5" src="/dailymed/image.cfm?name=sustol-09.jpg&amp;setid=f7c7ffdd-8270-4030-bc1e-a1cb28a6de56"/></td><td align="center" class="Botrule Rrule" valign="top">1</td><td align="left" class="Botrule">To activate the warming pouch, locate the metal disc and grasp with thumb and forefingers of both hands. Flex (bend) the disc rapidly until crystals begin to form (fluid will start to turn white). Massage warming pouch for a few seconds to soften and to increase the activation rate.</td> </tr> <tr> <td align="center" class="Botrule Rrule"><img alt="Image of iFU Instruction 6" src="/dailymed/image.cfm?name=sustol-10.jpg&amp;setid=f7c7ffdd-8270-4030-bc1e-a1cb28a6de56"/></td><td align="center" class="Botrule Rrule" valign="top">2</td><td align="left" class="Botrule">Wrap the SUSTOL syringe and needle in the syringe warming pouch. Use the outline on the warming pouch label as a placement guide for the syringe and needle. Fold the warming pouch over the syringe and press fastening strips together.<br/> <br/>Allow SUSTOL to warm for 5 - 6 minutes in the warming pouch.<br/> <br/>SUSTOL must be warmed to body temperature immediately prior to injection to reduce viscosity and facilitate administration.</td> </tr> <tr> <td align="center" class="Botrule Rrule"><img alt="Image of iFU Instruction 7" src="/dailymed/image.cfm?name=sustol-11.jpg&amp;setid=f7c7ffdd-8270-4030-bc1e-a1cb28a6de56"/></td><td align="center" class="Botrule Rrule" valign="top">3</td><td align="left" class="Botrule">Keep the SUSTOL syringe and needle in the warming pouch until you are ready to administer SUSTOL. The warming pouch will keep the SUSTOL syringe at body temperature for 10 - 15 minutes. If more than 15 minutes has elapsed since warming the SUSTOL syringe, then re-warm the syringe using the second warming pouch prior to injecting SUSTOL.<br/> <img alt="Image of iFU Instruction - Caution" src="/dailymed/image.cfm?name=sustol-17c.jpg&amp;setid=f7c7ffdd-8270-4030-bc1e-a1cb28a6de56"/>Sodium acetate is a non-toxic salt. In case of a puncture to a warming pouch and the spilling of the solution or crystals, clean up with soap and water. In case of eye contact, flush with water for 15 minutes. In case of skin contact, wash with soap and water. Seek medical attention if irritation develops or persists.<br/> <br/>Used warming pouches may be safely disposed of in the trash.</td> </tr> <tr> <td align="left" class="Botrule Rrule">Select an injection site</td><td align="center" class="Botrule Rrule" valign="top">STEP</td><td align="left" class="Botrule">To select an injection site, use these guidelines:</td> </tr> <tr> <td align="center" class="Botrule Rrule"><img alt="Image of iFU Instruction 8" src="/dailymed/image.cfm?name=sustol-12.jpg&amp;setid=f7c7ffdd-8270-4030-bc1e-a1cb28a6de56"/></td><td align="center" class="Botrule Rrule" valign="top">1</td><td align="left" class="Botrule">Use the <span class="Bold">skin of the abdomen at least one inch from the umbilicus</span> or the <span class="Bold">skin of the back of the upper arms</span> as sites for subcutaneous injections.<br/> <img alt="Image of iFU Instruction - Warning" src="/dailymed/image.cfm?name=sustol-19w.jpg&amp;setid=f7c7ffdd-8270-4030-bc1e-a1cb28a6de56"/>For <span class="Bold">SUBCUTANEOUS</span> injection only.<br/> <br/>Do <span class="Bold">NOT</span> inject within 1 inch of the umbilicus or anywhere the skin is:<br/>• Burned • Hardened • Inflamed • Swollen • Compromised<br/> <br/>For subsequent injections, use the same general area of the body. However, be sure not to inject in the exact same place. Administer new injections at least 1 inch from the previous site.</td> </tr> <tr> <td align="left" class="Botrule Rrule">Inject SUSTOL</td><td align="center" class="Botrule Rrule" valign="top">STEP</td><td align="left" class="Botrule">Follow these steps to inject SUSTOL:</td> </tr> <tr> <td align="left" class="Botrule Rrule"></td><td align="center" class="Botrule Rrule" valign="top">1</td><td align="left" class="Botrule">Remove the syringe from the warming pouch.<br/> <img alt="Image of iFU Instruction - Caution" src="/dailymed/image.cfm?name=sustol-17c.jpg&amp;setid=f7c7ffdd-8270-4030-bc1e-a1cb28a6de56"/>The white finger flange on the syringe provides better control when administering SUSTOL. Do <span class="Bold">NOT</span> remove white finger flange.</td> </tr> <tr> <td align="left" class="Botrule Rrule"></td><td align="center" class="Botrule Rrule" valign="top">2</td><td align="left" class="Botrule">Remove the blue needle cover. Use standard sharps safety techniques to avoid needle sticks.</td> </tr> <tr> <td align="center" class="Botrule Rrule"><img alt="Image of iFU Instruction 9" src="/dailymed/image.cfm?name=sustol-13.jpg&amp;setid=f7c7ffdd-8270-4030-bc1e-a1cb28a6de56"/></td><td align="center" class="Botrule Rrule" valign="top">3</td><td align="left">Use standard aseptic technique when performing the injection.<br/> <br/>Pinch the skin and underlying subcutaneous tissue with your non-dominant hand to create a "tent."<br/> <br/>Insert the needle into the subcutaneous tissue at a 30° - 45° angle with your dominant hand.<br/> <img alt="Image of iFU Instruction - Warning" src="/dailymed/image.cfm?name=sustol-19w.jpg&amp;setid=f7c7ffdd-8270-4030-bc1e-a1cb28a6de56"/>Administer SUSTOL <span class="Bold">ONLY</span> as a subcutaneous injection. <span class="Bold">NEVER</span> administer intravenously, intramuscularly or intraperitoneally.</td> </tr> <tr> <td align="center" class="Botrule Rrule"><img alt="Image of iFU Instruction 10" src="/dailymed/image.cfm?name=sustol-14.jpg&amp;setid=f7c7ffdd-8270-4030-bc1e-a1cb28a6de56"/></td><td align="center" class="Botrule Rrule" valign="top">4</td><td align="left" class="Botrule"><img alt="Image of iFU Instruction - Optional" src="/dailymed/image.cfm?name=sustol-18o.jpg&amp;setid=f7c7ffdd-8270-4030-bc1e-a1cb28a6de56"/>For additional stability, once the needle is inserted into the subcutaneous tissue, release the "tent" and hold the syringe barrel with your non-dominant hand.</td> </tr> <tr> <td align="left" class="Botrule Rrule"></td><td align="center" class="Botrule Rrule" valign="top">5</td><td align="left" class="Botrule">Press the plunger using a slow, firm, and steady push until you have delivered the entire dose. Do not use excessive force to inject the material more quickly, as this will only result in greater difficulty with the injection.<br/> <img alt="Image of iFU Instruction - Caution" src="/dailymed/image.cfm?name=sustol-17c.jpg&amp;setid=f7c7ffdd-8270-4030-bc1e-a1cb28a6de56"/>Due to the high viscosity of SUSTOL, you will experience resistance when injecting SUSTOL. Apply firm and steady pressure to the plunger for about <span class="Bold">20-30 seconds</span>. Pressing harder will <span class="Bold">NOT</span> expel SUSTOL faster.<br/> <br/> <span class="Bold">Do NOT advance or reposition the syringe in the subcutaneous tissue during the injection.</span></td> </tr> <tr> <td align="center" class="Botrule Rrule"><img alt="Image of iFU Instruction 11" src="/dailymed/image.cfm?name=sustol-15.jpg&amp;setid=f7c7ffdd-8270-4030-bc1e-a1cb28a6de56"/></td><td align="center" class="Botrule Rrule" valign="top">6</td><td align="left" class="Botrule">Because SUSTOL is highly viscous, before withdrawing the needle, make sure that the medication is completely expelled by checking the position of the stopper at the base of the syringe barrel.</td> </tr> <tr> <td align="center" class="Botrule Rrule"><img alt="Image of iFU Instruction 12" src="/dailymed/image.cfm?name=sustol-16.jpg&amp;setid=f7c7ffdd-8270-4030-bc1e-a1cb28a6de56"/></td><td align="center" class="Botrule Rrule" valign="top">7</td><td align="left" class="Botrule">Withdraw the needle. Do not remove the needle from the syringe. Use the enclosed Point-Lok<span class="Sup">®</span> device to prevent needle sticks.<br/> <br/>Place the Point-Lok needle protection device, supplied within the SUSTOL kit, on a secured flat surface. <span class="Bold">Do not hold the Point-Lok device in your hand</span>. Carefully insert the exposed needle into the opening at the top of the Point-Lok device and push down until the needle is fully seated in the Point-Lok device. This action will seal the needle tip and lock the needle firmly into the Point-Lok device. Discard the protected needle and attached syringe using your organization's standard sharps disposal procedures.</td> </tr> <tr> <td align="left" class="Botrule Rrule"></td><td align="center" class="Botrule Rrule" valign="top">8</td><td align="left" class="Botrule">Dispense enclosed Medication Guide to each Patient.</td> </tr> <tr class="Last"> <td align="left" valign="middle">Marketed by: Heron Therapeutics, Inc.<br/>4242 Campus Point Court, Suite 200<br/>San Diego, CA 92121<br/> <br/>© 2017 Heron Therapeutics, Inc.<br/>Revision Date: May 2017</td><td align="center"></td><td align="left"><span class="Bold">Questions about how to use SUSTOL?</span> <br/> <br/>Call the support line toll-free at 844-HERON11 (844-437-6611) or visit www.SUSTOL.com<br/> <br/>LAM-0000363</td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table width=\"100%\">\n<colgroup>\n<col align=\"left\" valign=\"top\" width=\"47.5%\"/>\n<col align=\"center\" valign=\"middle\" width=\"5%\"/>\n<col align=\"left\" valign=\"middle\" width=\"47.5%\"/>\n</colgroup>\n<thead>\n<tr class=\"First First Last Last\">\n<th align=\"left\" class=\"Botrule\">SUSTOL<span class=\"Sup\">®</span>\n<br/>(granisetron) extended-release injection 10 mg/0.4 mL<br/>\n<br/>Instructions for Use</th><th align=\"left\" class=\"Botrule\" colspan=\"2\">You must read these complete instructions before you administer SUSTOL for the first time.<br/>\n<br/>SUSTOL must be administered by a healthcare provider.</th>\n</tr>\n</thead>\n<tbody>\n<tr class=\"First\">\n<td align=\"left\" class=\"Botrule Rrule\" valign=\"top\">What is SUSTOL?</td><td align=\"left\" class=\"Botrule\" colspan=\"2\">SUSTOL is a subcutaneous injection that provides long-acting antiemetic medication to patients receiving chemotherapy. SUSTOL contains a highly viscous polymer that provides sustained release of granisetron.<br/>\n<br/>SUSTOL is supplied as part of an administration kit.</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Rrule\" valign=\"top\">When should you administer SUSTOL?</td><td align=\"left\" class=\"Botrule\" colspan=\"2\">Administer SUSTOL at least 30 minutes before chemotherapy on Day 1 of chemotherapy treatment and not more frequently than once every 7 days, because of the extended-release properties of the formulation.</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Rrule\" rowspan=\"2\" valign=\"top\">Before you begin to prepare SUSTOL Injection</td><td align=\"left\" colspan=\"2\"><span class=\"Bold\">Read these critical instructions.</span>\n<br/>\n<br/>\n<span class=\"Italics\">Do not substitute any of the components from the kit for administration.</span>\n<br/>\n<br/>Check to make sure the SUSTOL kit contains:</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule\" colspan=\"2\">\n<ul>\n<li>One sterile single-dose glass syringe which contains 10 mg granisetron</li>\n<li>One sterile 18G x 5/8\" administration needle</li>\n<li>Two sodium acetate warming pouches</li>\n<li>One Point-Lok<span class=\"Sup\">®</span> needle protection device</li>\n<li>Instructions for Use, Package Insert and Medication Guide</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Rrule\">Bring SUSTOL to room temperature</td><td align=\"center\" class=\"Botrule Rrule\">STEP</td><td align=\"left\" class=\"Botrule\">To bring SUSTOL to room temperature:</td>\n</tr>\n<tr>\n<td align=\"center\" class=\"Botrule Rrule\"><img alt=\"Image of iFU Instruction 1\" src=\"/dailymed/image.cfm?name=sustol-05.jpg&amp;setid=f7c7ffdd-8270-4030-bc1e-a1cb28a6de56\"/></td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">1</td><td align=\"left\" class=\"Botrule\">Remove SUSTOL kit from refrigeration. Open carton and remove tray. Open tray and unpack warming pouches. Wait a minimum of <span class=\"Bold\">60 minutes</span> prior to use to allow SUSTOL and the warming pouches to warm to room temperature.<br/>\n<br/>SUSTOL may be left out at room temperature overnight, and for up to 7 days, before it must be discarded. SUSTOL may be re-refrigerated if not used within the 7 day period.<br/>\n<br/>Warming SUSTOL prior to injection decreases the viscosity and makes administration easier. Bringing SUSTOL to room temperature prior to warming with the sodium acetate warming pouch will facilitate warming of SUSTOL to body temperature.</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Rrule\">Prepare the syringe</td><td align=\"center\" class=\"Botrule Rrule\">STEP</td><td align=\"left\" class=\"Botrule\">Follow these steps to prepare SUSTOL for use:</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Rrule\"></td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">1</td><td align=\"left\" class=\"Botrule\"><img alt=\"Image of iFU Instruction - Caution\" src=\"/dailymed/image.cfm?name=sustol-17c.jpg&amp;setid=f7c7ffdd-8270-4030-bc1e-a1cb28a6de56\"/>Examine all contents of the package. Do not use if any component is damaged.</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Rrule\"></td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">2</td><td align=\"left\" class=\"Botrule\">Check the expiration date on the syringe. Do not use if the expiration date has passed.</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Rrule\"></td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">3</td><td align=\"left\" class=\"Botrule\"><img alt=\"Image of iFU Instruction - Optional\" src=\"/dailymed/image.cfm?name=sustol-18o.jpg&amp;setid=f7c7ffdd-8270-4030-bc1e-a1cb28a6de56\"/>Remove the perforated flag label from the plunger rod.</td>\n</tr>\n<tr>\n<td align=\"center\" class=\"Botrule Rrule\"><img alt=\"Image of iFU Instruction 2\" src=\"/dailymed/image.cfm?name=sustol-06.jpg&amp;setid=f7c7ffdd-8270-4030-bc1e-a1cb28a6de56\"/></td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">4</td><td align=\"left\" class=\"Botrule\">To ensure that the syringe contains the full dose, check that the gray stopper is close to or below the black line on the syringe barrel label as shown in the illustration.<br/>\n<br/>Do <span class=\"Bold\">NOT</span> expel air bubbles. For a subcutaneous injection, air bubbles in the syringe will not harm the patient.</td>\n</tr>\n<tr>\n<td align=\"center\" class=\"Botrule Rrule\"><img alt=\"Image of iFU Instruction 3\" src=\"/dailymed/image.cfm?name=sustol-07.jpg&amp;setid=f7c7ffdd-8270-4030-bc1e-a1cb28a6de56\"/></td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">5</td><td align=\"left\" class=\"Botrule\"><span class=\"Bold\">Unscrew</span> the tip cap from the end of the pre-filled glass syringe.<br/>\n<br/>Do <span class=\"Bold\">NOT</span> use if the tip cap is missing or has been tampered with. Do <span class=\"Bold\">NOT</span> use if the Luer fitting is missing or dislodged.</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Rrule\"></td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">6</td><td align=\"left\" class=\"Botrule\">Remove the hub cover from the 18G x 5/8\" needle supplied with the syringe. Attach the needle to the syringe and seat the needle securely. Do <span class=\"Bold\">NOT</span> remove the blue needle cover. <span class=\"Bold\">Do not substitute with any other needle</span>\n<br/>\n<img alt=\"Image of iFU Instruction - Caution\" src=\"/dailymed/image.cfm?name=sustol-17c.jpg&amp;setid=f7c7ffdd-8270-4030-bc1e-a1cb28a6de56\"/><span class=\"Bold\">Use ONLY the 18G x 5/8\" needle provided with the syringe because of the highly viscous nature of the medication.</span></td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Rrule\">Warm SUSTOL to body temperature</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">STEP</td><td align=\"left\" class=\"Botrule\">Just prior to administering the injection, follow these steps:</td>\n</tr>\n<tr>\n<td align=\"center\" class=\"Botrule Rrule\"><img alt=\"Image of iFU Instruction 4\" src=\"/dailymed/image.cfm?name=sustol-08.jpg&amp;setid=f7c7ffdd-8270-4030-bc1e-a1cb28a6de56\"/></td><td align=\"center\" class=\"Botrule Rrule\"></td><td align=\"left\" class=\"Botrule\">SUSTOL must be warmed to body temperature immediately prior to injection to reduce viscosity and facilitate administration.<br/>\n<br/>SUSTOL is packaged with two warming pouches. The warming pouches use a non- toxic solution of sodium acetate to create an exothermic (warming) reaction. The second warming pouch can be used if SUSTOL is not immediately administered within the 15 minutes provided by the first warming pouch and needs to be re-warmed. <br/>\n<br/>Before activating the warming pouch, make sure that the SUSTOL kit was removed from the refrigerator and that the warming pouches were unpacked from the kit at least 60 minutes prior to use to allow SUSTOL and the warming pouches to warm to room temperature.</td>\n</tr>\n<tr>\n<td align=\"center\" class=\"Botrule Rrule\"><img alt=\"Image of iFU Instruction 5\" src=\"/dailymed/image.cfm?name=sustol-09.jpg&amp;setid=f7c7ffdd-8270-4030-bc1e-a1cb28a6de56\"/></td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">1</td><td align=\"left\" class=\"Botrule\">To activate the warming pouch, locate the metal disc and grasp with thumb and forefingers of both hands. Flex (bend) the disc rapidly until crystals begin to form (fluid will start to turn white). Massage warming pouch for a few seconds to soften and to increase the activation rate.</td>\n</tr>\n<tr>\n<td align=\"center\" class=\"Botrule Rrule\"><img alt=\"Image of iFU Instruction 6\" src=\"/dailymed/image.cfm?name=sustol-10.jpg&amp;setid=f7c7ffdd-8270-4030-bc1e-a1cb28a6de56\"/></td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">2</td><td align=\"left\" class=\"Botrule\">Wrap the SUSTOL syringe and needle in the syringe warming pouch. Use the outline on the warming pouch label as a placement guide for the syringe and needle. Fold the warming pouch over the syringe and press fastening strips together.<br/>\n<br/>Allow SUSTOL to warm for 5 - 6 minutes in the warming pouch.<br/>\n<br/>SUSTOL must be warmed to body temperature immediately prior to injection to reduce viscosity and facilitate administration.</td>\n</tr>\n<tr>\n<td align=\"center\" class=\"Botrule Rrule\"><img alt=\"Image of iFU Instruction 7\" src=\"/dailymed/image.cfm?name=sustol-11.jpg&amp;setid=f7c7ffdd-8270-4030-bc1e-a1cb28a6de56\"/></td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">3</td><td align=\"left\" class=\"Botrule\">Keep the SUSTOL syringe and needle in the warming pouch until you are ready to administer SUSTOL. The warming pouch will keep the SUSTOL syringe at body temperature for 10 - 15 minutes. If more than 15 minutes has elapsed since warming the SUSTOL syringe, then re-warm the syringe using the second warming pouch prior to injecting SUSTOL.<br/>\n<img alt=\"Image of iFU Instruction - Caution\" src=\"/dailymed/image.cfm?name=sustol-17c.jpg&amp;setid=f7c7ffdd-8270-4030-bc1e-a1cb28a6de56\"/>Sodium acetate is a non-toxic salt. In case of a puncture to a warming pouch and the spilling of the solution or crystals, clean up with soap and water. In case of eye contact, flush with water for 15 minutes. In case of skin contact, wash with soap and water. Seek medical attention if irritation develops or persists.<br/>\n<br/>Used warming pouches may be safely disposed of in the trash.</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Rrule\">Select an injection site</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">STEP</td><td align=\"left\" class=\"Botrule\">To select an injection site, use these guidelines:</td>\n</tr>\n<tr>\n<td align=\"center\" class=\"Botrule Rrule\"><img alt=\"Image of iFU Instruction 8\" src=\"/dailymed/image.cfm?name=sustol-12.jpg&amp;setid=f7c7ffdd-8270-4030-bc1e-a1cb28a6de56\"/></td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">1</td><td align=\"left\" class=\"Botrule\">Use the <span class=\"Bold\">skin of the abdomen at least one inch from the umbilicus</span> or the <span class=\"Bold\">skin of the back of the upper arms</span> as sites for subcutaneous injections.<br/>\n<img alt=\"Image of iFU Instruction - Warning\" src=\"/dailymed/image.cfm?name=sustol-19w.jpg&amp;setid=f7c7ffdd-8270-4030-bc1e-a1cb28a6de56\"/>For <span class=\"Bold\">SUBCUTANEOUS</span> injection only.<br/>\n<br/>Do <span class=\"Bold\">NOT</span> inject within 1 inch of the umbilicus or anywhere the skin is:<br/>• Burned • Hardened • Inflamed • Swollen • Compromised<br/>\n<br/>For subsequent injections, use the same general area of the body. However, be sure not to inject in the exact same place. Administer new injections at least 1 inch from the previous site.</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Rrule\">Inject SUSTOL</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">STEP</td><td align=\"left\" class=\"Botrule\">Follow these steps to inject SUSTOL:</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Rrule\"></td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">1</td><td align=\"left\" class=\"Botrule\">Remove the syringe from the warming pouch.<br/>\n<img alt=\"Image of iFU Instruction - Caution\" src=\"/dailymed/image.cfm?name=sustol-17c.jpg&amp;setid=f7c7ffdd-8270-4030-bc1e-a1cb28a6de56\"/>The white finger flange on the syringe provides better control when administering SUSTOL. Do <span class=\"Bold\">NOT</span> remove white finger flange.</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Rrule\"></td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">2</td><td align=\"left\" class=\"Botrule\">Remove the blue needle cover. Use standard sharps safety techniques to avoid needle sticks.</td>\n</tr>\n<tr>\n<td align=\"center\" class=\"Botrule Rrule\"><img alt=\"Image of iFU Instruction 9\" src=\"/dailymed/image.cfm?name=sustol-13.jpg&amp;setid=f7c7ffdd-8270-4030-bc1e-a1cb28a6de56\"/></td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">3</td><td align=\"left\">Use standard aseptic technique when performing the injection.<br/>\n<br/>Pinch the skin and underlying subcutaneous tissue with your non-dominant hand to create a \"tent.\"<br/>\n<br/>Insert the needle into the subcutaneous tissue at a 30° - 45° angle with your dominant hand.<br/>\n<img alt=\"Image of iFU Instruction - Warning\" src=\"/dailymed/image.cfm?name=sustol-19w.jpg&amp;setid=f7c7ffdd-8270-4030-bc1e-a1cb28a6de56\"/>Administer SUSTOL <span class=\"Bold\">ONLY</span> as a subcutaneous injection. <span class=\"Bold\">NEVER</span> administer intravenously, intramuscularly or intraperitoneally.</td>\n</tr>\n<tr>\n<td align=\"center\" class=\"Botrule Rrule\"><img alt=\"Image of iFU Instruction 10\" src=\"/dailymed/image.cfm?name=sustol-14.jpg&amp;setid=f7c7ffdd-8270-4030-bc1e-a1cb28a6de56\"/></td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">4</td><td align=\"left\" class=\"Botrule\"><img alt=\"Image of iFU Instruction - Optional\" src=\"/dailymed/image.cfm?name=sustol-18o.jpg&amp;setid=f7c7ffdd-8270-4030-bc1e-a1cb28a6de56\"/>For additional stability, once the needle is inserted into the subcutaneous tissue, release the \"tent\" and hold the syringe barrel with your non-dominant hand.</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Rrule\"></td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">5</td><td align=\"left\" class=\"Botrule\">Press the plunger using a slow, firm, and steady push until you have delivered the entire dose. Do not use excessive force to inject the material more quickly, as this will only result in greater difficulty with the injection.<br/>\n<img alt=\"Image of iFU Instruction - Caution\" src=\"/dailymed/image.cfm?name=sustol-17c.jpg&amp;setid=f7c7ffdd-8270-4030-bc1e-a1cb28a6de56\"/>Due to the high viscosity of SUSTOL, you will experience resistance when injecting SUSTOL. Apply firm and steady pressure to the plunger for about <span class=\"Bold\">20-30 seconds</span>. Pressing harder will <span class=\"Bold\">NOT</span> expel SUSTOL faster.<br/>\n<br/>\n<span class=\"Bold\">Do NOT advance or reposition the syringe in the subcutaneous tissue during the injection.</span></td>\n</tr>\n<tr>\n<td align=\"center\" class=\"Botrule Rrule\"><img alt=\"Image of iFU Instruction 11\" src=\"/dailymed/image.cfm?name=sustol-15.jpg&amp;setid=f7c7ffdd-8270-4030-bc1e-a1cb28a6de56\"/></td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">6</td><td align=\"left\" class=\"Botrule\">Because SUSTOL is highly viscous, before withdrawing the needle, make sure that the medication is completely expelled by checking the position of the stopper at the base of the syringe barrel.</td>\n</tr>\n<tr>\n<td align=\"center\" class=\"Botrule Rrule\"><img alt=\"Image of iFU Instruction 12\" src=\"/dailymed/image.cfm?name=sustol-16.jpg&amp;setid=f7c7ffdd-8270-4030-bc1e-a1cb28a6de56\"/></td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">7</td><td align=\"left\" class=\"Botrule\">Withdraw the needle. Do not remove the needle from the syringe. Use the enclosed Point-Lok<span class=\"Sup\">®</span> device to prevent needle sticks.<br/>\n<br/>Place the Point-Lok needle protection device, supplied within the SUSTOL kit, on a secured flat surface. <span class=\"Bold\">Do not hold the Point-Lok device in your hand</span>. Carefully insert the exposed needle into the opening at the top of the Point-Lok device and push down until the needle is fully seated in the Point-Lok device. This action will seal the needle tip and lock the needle firmly into the Point-Lok device. Discard the protected needle and attached syringe using your organization's standard sharps disposal procedures.</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Rrule\"></td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">8</td><td align=\"left\" class=\"Botrule\">Dispense enclosed Medication Guide to each Patient.</td>\n</tr>\n<tr class=\"Last\">\n<td align=\"left\" valign=\"middle\">Marketed by: Heron Therapeutics, Inc.<br/>4242 Campus Point Court, Suite 200<br/>San Diego, CA 92121<br/>\n<br/>© 2017 Heron Therapeutics, Inc.<br/>Revision Date: May 2017</td><td align=\"center\"></td><td align=\"left\"><span class=\"Bold\">Questions about how to use SUSTOL?</span>\n<br/>\n<br/>Call the support line toll-free at 844-HERON11 (844-437-6611) or visit www.SUSTOL.com<br/>\n<br/>LAM-0000363</td>\n</tr>\n</tbody>\n</table></div>" }

NDC: 47426-101-06

{ "type": "p", "children": [], "text": "NDC: 47426-101-06" }

sustol® (granisetron) extended-release injection 10 mg/0.4mL

{ "type": "p", "children": [], "text": "sustol®\n(granisetron) extended-release injection 10 mg/0.4mL" }

Contains: 6 single-dose PRE-FILLED syringe units

{ "type": "p", "children": [], "text": "Contains: 6 single-dose PRE-FILLED syringe units " }

FOR SUBCUTANEOUS USE ONLY.

{ "type": "p", "children": [], "text": "FOR SUBCUTANEOUS USE ONLY." }

REMOVE CARTON FROM REFRIGERATOR AND UNPACK ALL CONTENTS AT LEAST 60 MINUTES PRIOR TO USE.

{ "type": "p", "children": [], "text": "REMOVE CARTON FROM REFRIGERATOR AND UNPACK ALL CONTENTS AT LEAST 60 MINUTES PRIOR TO USE." }

Each single-dose unit contains: One sterile single-dose glass syringe which contains 10 mg granisetronOne sterile 18Gx5/8" administration needleTwo sodium acetate warming pouchesOne Point-Lok® needle protection deviceInstructions for Use and Package Insert

{ "type": "p", "children": [], "text": "Each single-dose unit contains: One sterile single-dose glass syringe which contains 10 mg granisetronOne sterile 18Gx5/8\" administration needleTwo sodium acetate warming pouchesOne Point-Lok® needle protection deviceInstructions for Use and Package Insert" }

Must be refrigeratedStore at 2°C to 8°C (36°F to 46°F); DO NOT FREEZE.Protect from Light.

{ "type": "p", "children": [], "text": "Must be refrigeratedStore at 2°C to 8°C (36°F to 46°F); DO NOT FREEZE.Protect from Light." }

SUSTOL is to be administered once weekly.

{ "type": "p", "children": [], "text": "SUSTOL is to be administered once weekly." }

Rx only

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

HERONTHERAPEUTICS

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

Granisetron hydrochloride injection,  is a serotonin-3 (5-HT3) receptor antagonist indicated for:

{ "type": "p", "children": [], "text": "Granisetron hydrochloride injection,  is a serotonin-3 (5-HT3) receptor antagonist indicated for:" }

{ "type": "ul", "children": [ "The prevention of nausea and/or vomiting associated with initial and repeat courses of emetogenic cancer therapy, including high-dose cisplatin.", "The prevention and treatment of postoperative nausea and vomiting in adults. As with other antiemetics, routine prophylaxis is not recommended in patients in whom there is little expectation that nausea and/or vomiting will occur postoperatively. In patients where nausea and/or vomiting must be avoided during the postoperative period, granisetron hydrochloride injection is recommended even where the incidence of postoperative nausea and/or vomiting is low. " ], "text": "" }

Adult Patients   The recommended dosage for granisetron hydrochloride injection, is 10 mcg/kg administered intravenously within 30 minutes before initiation of chemotherapy, and only on the day(s) chemotherapy is given. Infusion Preparation  Granisetron hydrochloride injection, may be administered intravenously either undiluted over 30 seconds, or diluted with 0.9% Sodium Chloride or 5% Dextrose and infused over 5 minutes. Stability  Intravenous infusion of granisetron hydrochloride injection, should be prepared at the time of administration. However, granisetron hydrochloride injection, has been shown to be stable for at least 24 hours when diluted in 0.9% Sodium Chloride or 5% Dextrose and stored at room temperature under normal lighting conditions. As a general precaution, granisetron hydrochloride injection, should not be mixed in solution with other drugs. Parenteral drug products should be inspected visually for particulate matter and discoloration before administration whenever solution and container permit. Pediatric Patients

The recommended dose in pediatric patients 2 to 16 years of age is 10 mcg/kg [see Clinical Studies (14)]. Pediatric patients under 2 years of age have not been studied.

Adult Patients The recommended dosage for prevention of postoperative nausea and vomiting is 1 mg of granisetron hydrochloride injection, undiluted, administered intravenously over 30 seconds, before induction of anesthesia or immediately before reversal of anesthesia. The recommended dosage for the treatment of nausea and/or vomiting after surgery is 1 mg of granisetron hydrochloride injection, undiluted, administered intravenously over 30 seconds.

Single-Dose Vials for Injection: 1 mg/mL Multiple-Dose Vials for Injection: 4 mg/4 mL

{ "type": "p", "children": [], "text": "Single-Dose Vials for Injection: 1 mg/mL\n Multiple-Dose Vials for Injection: 4 mg/4 mL" }

Granisetron hydrochloride injection is contraindicated in patients with known hypersensitivity (e.g., anaphylaxis, shortness of breath, hypotension, urticaria) to the drug or to any of its components.

{ "type": "p", "children": [], "text": "Granisetron hydrochloride injection is contraindicated in patients with known hypersensitivity (e.g., anaphylaxis, shortness of breath, hypotension, urticaria) to the drug or to any of its components." }

Granisetron hydrochloride is not a drug that stimulates gastric or intestinal peristalsis. It should not be used instead of nasogastric suction. The use of granisetron hydrochloride in patients following abdominal surgery or in patients with chemotherapy-induced nausea and vomiting may mask a progressive ileus and/or gastric distention.

An adequate QT assessment has not been conducted, but QT prolongation has been reported with granisetron hydrochloride. Therefore, granisetron hydrochloride should be used with caution in patients with pre-existing arrhythmias or cardiac conduction disorders, as this might lead to clinical consequences. Patients with cardiac disease, on cardio-toxic chemotherapy, with concomitant electrolyte abnormalities and/or on concomitant medications that prolong the QT interval are particularly at risk.

Hypersensitivity reactions (e.g., anaphylaxis, shortness of breath, hypotension, urticaria) may occur in patients who have exhibited hypersensitivity to other selective 5-HT3 receptor antagonists.

The development of serotonin syndrome has been reported with 5-HT3 receptor antagonists. Most reports have been associated with concomitant use of serotonergic drugs (e.g., selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), monoamine oxidase inhibitors, mirtazapine, fentanyl, lithium, tramadol, and intravenous methylene blue). Some of the reported cases were fatal. Serotonin syndrome occurring with overdose of another 5-HT3 receptor antagonist alone has also been reported. The majority of reports of serotonin syndrome related to 5-HT3 receptor antagonist use occurred in a post-anesthesia care unit or an infusion center. Symptoms associated with serotonin syndrome may include the following combination of signs and symptoms: mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, with or without gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Patients should be monitored for the emergence of serotonin syndrome, especially with concomitant use of granisetron and other serotonergic drugs. If symptoms of serotonin syndrome occur, discontinue granisetron and initiate supportive treatment. Patients should be informed of the increased risk of serotonin syndrome, especially if granisetron is used concomitantly with other serotonergic drugs [see Drug Interactions (7), Patient Counseling Information (17.1)].

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 patients. Chemotherapy-Induced Nausea and Vomiting The following have been reported during controlled clinical trials or in the routine management of patients. The percentage figures are based on clinical trial experience only. Table 1 gives the comparative frequencies of the two most commonly reported adverse reactions (≥ 3%) in patients receiving granisetron hydrochloride injection, in single-day chemotherapy trials. These patients received chemotherapy, primarily cisplatin, and intravenous fluids during the 24-hour period following granisetron hydrochloride injection administration. Reactions were generally recorded over seven days post-granisetron hydrochloride injection administration.

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="813.96"> <caption> <span>Table 1 Principal Adverse Reactions in Clinical Trials — Single-Day Chemotherapy </span> </caption> <colgroup> <col width="22.5490196078431%"/> <col width="44.7712418300654%"/> <col width="32.6797385620915%"/> </colgroup> <tfoot> <tr class="First Last"> <td colspan="3"><span class="Sup">1</span> Metoclopramide/dexamethasone and phenothiazines/dexamethasone.<br/> </td> </tr> </tfoot> <tbody class="Headless"> <tr class="Botrule First"> <td class="Lrule Rrule" colspan="3" valign="top"><span class="Bold">                                                                                          Percent of Patients With Reaction</span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top"></td><td align="center" class="Rrule" valign="top"><span class="Bold"> G</span><span class="Bold">ranisetron Hydrochlorid</span><span class="Bold">e Injection</span> <br/> <span class="Bold">40 mcg/kg</span> <br/> <span class="Bold">(n = 1268)</span> <br/> </td><td align="center" class="Rrule" valign="middle"><span class="Bold">Comparator<span class="Sup">1</span></span> <br/> <span class="Bold">(n = 422)</span> <br/> </td> </tr> <tr class="Last"> <td class="Lrule Rrule" valign="top">   Headache<br/>   Constipation<span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">14%<br/>3%<span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">6%<br/>3%<span class="Bold"></span> <br/> </td> </tr> </tbody> </table></div>

Additional adverse events reported in clinical trials were asthenia, somnolence and diarrhea. In over 3,000 patients receiving granisetron hydrochloride injection (2 to 160 mcg/kg) in single-day and multiple-day clinical trials with emetogenic cancer therapies, adverse events, other than those adverse reactions listed in Table 1, were observed; attribution of many of these events to granisetron hydrochloride is uncertain. Hepatic: In comparative trials, mainly with cisplatin regimens, elevations of AST and ALT (> 2 times the upper limit of normal) following administration of granisetron hydrochloride injection occurred in 2.8% and 3.3% of patients, respectively. These frequencies were not significantly different from those seen with comparators (AST: 2.1%; ALT: 2.4%). Cardiovascular: Hypertension (2%); hypotension, arrhythmias such as sinus bradycardia, atrial fibrillation, varying degrees of A-V block, ventricular ectopy including non-sustained tachycardia, and ECG abnormalities have been observed rarely. Central Nervous System: Agitation, anxiety, CNS stimulation and insomnia were seen in less than 2% of patients. Extrapyramidal syndrome occurred rarely and only in the presence of other drugs associated with this syndrome. Hypersensitivity: Rare cases of hypersensitivity reactions, sometimes severe (e.g., anaphylaxis, shortness of breath, hypotension, urticaria) have been reported. Other: Fever (3%), taste disorder (2%), skin rashes (1%). In multiple-day comparative studies, fever occurred more frequently with granisetron hydrochloride injection (8.6%) than with comparative drugs (3.4%, P < 0.014), which usually included dexamethasone. Postoperative Nausea and Vomiting The adverse reactions listed in Table 2 were reported in ≥ 2% of adults receiving granisetron hydrochloride injection 1 mg during controlled clinical trials.

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="100%"> <caption> <span>Table 2 Adverse Reactions in Controlled Clinical Trials in Postoperative Nausea and Vomiting (Reported in ≥ 2% of Adults Receiving Granisetron Hydrochloride Injection 1 mg)      </span> </caption> <colgroup> <col width="42.86%"/> <col width="30.96%"/> <col width="26.18%"/> </colgroup> <tbody class="Headless"> <tr class="Botrule First"> <td align="center" class="Lrule Rrule" colspan="3" valign="top"><span class="Bold">Percent of Patients With Reaction</span> <br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top"></td><td align="center" class="Rrule" valign="top"><span class="Bold">Granisetron Hydrochloride Injection</span> <br/> <span class="Bold">1 mg</span> <br/> <span class="Bold">(n=267)</span> <br/> </td><td align="center" class="Rrule" valign="top"><span class="Bold">Placebo</span> <br/> <span class="Bold">(n=266)</span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">Pain<br/> </td><td align="center" class="Rrule" valign="middle">10.1<br/> </td><td align="center" class="Rrule" valign="middle">8.3<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">Headache<br/> </td><td align="center" class="Rrule" valign="middle">8.6<br/> </td><td align="center" class="Rrule" valign="middle">7.1<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">Fever<br/> </td><td align="center" class="Rrule" valign="middle">7.9<br/> </td><td align="center" class="Rrule" valign="middle">4.5<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">Abdominal Pain<br/> </td><td align="center" class="Rrule" valign="middle">6<br/> </td><td align="center" class="Rrule" valign="middle">6<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">Hepatic Enzymes Increased<br/> </td><td align="center" class="Rrule" valign="middle">5.6<br/> </td><td align="center" class="Rrule" valign="middle">4.1<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">Dizziness<br/> </td><td align="center" class="Rrule" valign="middle">4.1<br/> </td><td align="center" class="Rrule" valign="middle">3.4<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">Diarrhea<br/> </td><td align="center" class="Rrule" valign="middle">3.4<br/> </td><td align="center" class="Rrule" valign="middle">1.1<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">Flatulence<br/> </td><td align="center" class="Rrule" valign="middle">3<br/> </td><td align="center" class="Rrule" valign="middle">3<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">Dyspepsia<br/> </td><td align="center" class="Rrule" valign="middle">3<br/> </td><td align="center" class="Rrule" valign="middle">1.9<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">Oliguria<br/> </td><td align="center" class="Rrule" valign="middle">2.2<br/> </td><td align="center" class="Rrule" valign="middle">1.5<br/> </td> </tr> <tr class="Last"> <td class="Lrule Rrule" valign="middle">Coughing<br/> </td><td align="center" class="Rrule" valign="middle">2.2<br/> </td><td align="center" class="Rrule" valign="middle">1.1<br/> </td> </tr> </tbody> </table></div>

Additional adverse events reported in clinical trials were constipation, anemia, insomnia, bradycardia, leukocytosis, anxiety, hypotension, infection, hypertension, and urinary tract infection. In a clinical study conducted in Japan, the types of adverse events differed notably from those reported above in Table 2. The adverse events in the Japanese study that occurred in ≥ 2% of patients and were more frequent with granisetron hydrochloride injection 1 mg than with placebo were: fever (56% to 50%), sputum increased (2.7% to 1.7%), and dermatitis (2.7% to 0%).

The following adverse reactions have been identified during post approval use of granisetron hydrochloride. 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 granisetron hydrochloride exposure. QT prolongation has been reported with granisetron hydrochloride [see Warnings and Precautions (5.2) and Drug Interactions (7)].

Granisetron does not induce or inhibit the cytochrome P-450 drug-metabolizing enzyme system in vitro. There have been no definitive drug-drug interaction studies to examine pharmacokinetic or pharmacodynamic interaction with other drugs; however, in humans, granisetron hydrochloride injection has been safely administered with drugs representing benzodiazepines, neuroleptics and anti-ulcer medications commonly prescribed with antiemetic treatments. Granisetron hydrochloride injection also does not appear to interact with emetogenic cancer chemotherapies. Because granisetron is metabolized by hepatic cytochrome P-450 drug-metabolizing enzymes, inducers or inhibitors of these enzymes may change the clearance and, hence, the half-life of granisetron. No specific interaction studies have been conducted in anesthetized patients. In addition, the activity of the cytochrome P-450 subfamily 3A4 (involved in the metabolism of some of the main narcotic analgesic agents) is not modified by granisetron hydrochloride in vitro. In in vitro human microsomal studies, ketoconazole inhibited ring oxidation of granisetron hydrochloride. However, the clinical significance of in vivo pharmacokinetic interactions with ketoconazole is not known. In a human pharmacokinetic study, hepatic enzyme induction with phenobarbital resulted in a 25% increase in total plasma clearance of intravenous granisetron hydrochloride. The clinical significance of this change is not known. QT prolongation has been reported with granisetron hydrochloride. Use of granisetron hydrochloride in patients concurrently treated with drugs known to prolong the QT interval and/or are arrhythmogenic may result in clinical consequences. Serotonin syndrome (including altered mental status, autonomic instability, and neuromuscular symptoms) has been described following the concomitant use of 5-HT3 receptor antagonists and other serotonergic drugs, including selective serotonin reuptake inhibitors (SSRIs) and serotonin and norepinephrine reuptake inhibitors (SNRIs) [see Warnings and Precautions (5.4)].

{ "type": "p", "children": [], "text": "Granisetron does not induce or inhibit the cytochrome P-450 drug-metabolizing enzyme system in vitro. There have been no definitive drug-drug interaction studies to examine pharmacokinetic or pharmacodynamic interaction with other drugs; however, in humans, granisetron hydrochloride injection has been safely administered with drugs representing benzodiazepines, neuroleptics and anti-ulcer medications commonly prescribed with antiemetic treatments. Granisetron hydrochloride injection also does not appear to interact with emetogenic cancer chemotherapies. Because granisetron is metabolized by hepatic cytochrome P-450 drug-metabolizing enzymes, inducers or inhibitors of these enzymes may change the clearance and, hence, the half-life of granisetron. No specific interaction studies have been conducted in anesthetized patients. In addition, the activity of the cytochrome P-450 subfamily 3A4 (involved in the metabolism of some of the main narcotic analgesic agents) is not modified by granisetron hydrochloride in vitro.\n In in vitro human microsomal studies, ketoconazole inhibited ring oxidation of granisetron hydrochloride. However, the clinical significance of in vivo pharmacokinetic interactions with ketoconazole is not known. In a human pharmacokinetic study, hepatic enzyme induction with phenobarbital resulted in a 25% increase in total plasma clearance of intravenous granisetron hydrochloride. The clinical significance of this change is not known.\n QT prolongation has been reported with granisetron hydrochloride. Use of granisetron hydrochloride in patients concurrently treated with drugs known to prolong the QT interval and/or are arrhythmogenic may result in clinical consequences.\n Serotonin syndrome (including altered mental status, autonomic instability, and neuromuscular symptoms) has been described following the concomitant use of 5-HT3 receptor antagonists and other serotonergic drugs, including selective serotonin reuptake inhibitors (SSRIs) and serotonin and norepinephrine reuptake inhibitors (SNRIs) [see Warnings and Precautions (5.4)]." }

Teratogenic Effects

Reproduction studies have been performed in pregnant rats at intravenous doses up to 9 mg/kg/day (54 mg/m2/day, 146 times the recommended human dose based on body surface area) and pregnant rabbits at intravenous doses up to 3 mg/kg/day (35.4 mg/m2/day, 96 times the recommended human dose based on body surface area) and have revealed no evidence of impaired fertility or harm to the fetus due to granisetron. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

It is not known whether granisetron is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when granisetron hydrochloride injection is administered to a nursing woman.

Chemotherapy-Induced Nausea and Vomiting [See Dosage and Administration (2)] for use in chemotherapy-induced nausea and vomiting in pediatric patients 2 to 16 years of age. Safety and effectiveness in pediatric patients under 2 years of age have not been established. Postoperative Nausea and Vomiting Safety and efficacy have not been established in pediatric patients for the prevention of postoperative nausea and vomiting (PONV). Granisetron has been evaluated in a pediatric patient clinical trial for use in the prevention of PONV. Due to the lack of efficacy and the QT prolongation observed in this trial, use of granisetron for the prevention of PONV in children is not recommended. The trial was a prospective, multicenter, randomized, double-blind, parallel-group trial that evaluated 157 children aged 2 to 16 years who were undergoing elective surgery for tonsillectomy or adenotonsillectomy. The purpose of the trial was to assess two dose levels (20 mcg/kg and 40 mcg/kg) of intravenous granisetron in the prevention of PONV. There was no active comparator or placebo. The primary endpoint was total control of nausea and vomiting (defined as no nausea, vomiting/retching, or use of rescue medication) in the 24 hours following surgery. Efficacy was not established due to lack of a dose response. The trial also included standard 12 lead ECGs performed pre-dose and after the induction of anesthesia. ECGs were repeated at the end of surgery after the administration of granisetron and just prior to reversal of anesthesia. QT prolongation was seen at both dose levels. Five patients in this trial experienced an increase of ≥ 60 msec in QTcF. In addition, there were two patients whose QTcF was ≥ 500 msec. Interpretation of the QTcF prolongation was confounded by multiple factors, including the use of concomitant medication and the lack of either a placebo or active control. A thorough QT trial in adults has not been performed. Other adverse events that occurred in the study included: vomiting (5 to 8%), post-procedural hemorrhage (3 to 5%), and dehydration (0 to 5%). Pediatric patients under 2 years of age have not been studied.

During chemotherapy clinical trials, 713 patients 65 years of age or older received granisetron hydrochloride injection. The safety and effectiveness were similar in patients of various ages. During postoperative nausea and vomiting clinical trials, 168 patients 65 years of age or older, of which 47 were 75 years of age or older, received granisetron hydrochloride injection. Clinical studies of granisetron hydrochloride injection did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients.

There is no specific antidote for granisetron hydrochloride injection overdosage. In case of overdosage, symptomatic treatment should be given. Overdosage of up to 38.5 mg of granisetron hydrochloride injection has been reported without symptoms or only the occurrence of a slight headache.

{ "type": "p", "children": [], "text": "There is no specific antidote for granisetron hydrochloride injection overdosage. In case of overdosage, symptomatic treatment should be given. Overdosage of up to 38.5 mg of granisetron hydrochloride injection has been reported without symptoms or only the occurrence of a slight headache." }

Granisetron hydrochloride injection, USP is a serotonin-3 (5-HT3) receptor antagonist. Chemically it is endo-N-(9-methyl-9-azabicyclo [3.3.1] non-3-yl)-1-methyl-1H-indazole-3-carboxamide hydrochloride with a molecular weight of 348.9 (312.4 free base). Its molecular formula is C18H24N4O•HCl, while its chemical structure is:

{ "type": "p", "children": [], "text": "Granisetron hydrochloride injection, USP is a serotonin-3 (5-HT3) receptor antagonist. Chemically it is endo-N-(9-methyl-9-azabicyclo [3.3.1] non-3-yl)-1-methyl-1H-indazole-3-carboxamide hydrochloride with a molecular weight of 348.9 (312.4 free base). Its molecular formula is C18H24N4O•HCl, while its chemical structure is:" }

Granisetron hydrochloride USP is a white or almost white powder that is readily soluble in water and normal saline at 20°C. Granisetron hydrochloride injection, USP is a clear, colorless, sterile, nonpyrogenic, aqueous solution for intravenous administration. Granisetron hydrochloride injection, USP 1 mg/mL is available in 1 mL single-dose and 4 mL multiple-dose vials. Each mL contains 1.12 mg granisetron hydrochloride USP equivalent to granisetron 1 mg; sodium chloride, 9 mg; citric acid, 2 mg; methylparaben, 1.8 mg and propylparaben, 0.2 mg, as preservatives, water for injection, q.s., sodium hydroxide and hydrochloric acid, as pH adjusters. The solution's pH ranges from 4.0 to 6.0.

{ "type": "p", "children": [], "text": "Granisetron hydrochloride USP is a white or almost white powder that is readily soluble in water and normal saline at 20°C. Granisetron hydrochloride injection, USP is a clear, colorless, sterile, nonpyrogenic, aqueous solution for intravenous administration.\n Granisetron hydrochloride injection, USP 1 mg/mL is available in 1 mL single-dose and 4 mL multiple-dose vials.\n Each mL contains 1.12 mg granisetron hydrochloride USP equivalent to granisetron 1 mg; sodium chloride, 9 mg; citric acid, 2 mg; methylparaben, 1.8 mg and propylparaben, 0.2 mg, as preservatives, water for injection, q.s., sodium hydroxide and hydrochloric acid, as pH adjusters. The solution's pH ranges from 4.0 to 6.0." }

Granisetron is a selective 5-hydroxytryptamine3 (5-HT3) receptor antagonist with little or no affinity for other serotonin receptors, including 5-HT1; 5-HT1A; 5-HT1B/C; 5-HT2; for alpha1-, alpha2- or beta-adrenoreceptors; for dopamine-D2; or for histamine-H1; benzodiazepine; picrotoxin or opioid receptors. Serotonin receptors of the 5-HT3 type are located peripherally on vagal nerve terminals and centrally in the chemoreceptor trigger zone of the area postrema. During chemotherapy-induced vomiting, mucosal enterochromaffin cells release serotonin, which stimulates 5-HT3 receptors. This evokes vagal afferent discharge and may induce vomiting. Animal studies demonstrate that, in binding to 5-HT3 receptors, granisetron blocks serotonin stimulation and subsequent vomiting after emetogenic stimuli such as cisplatin. In the ferret animal model, a single granisetron injection prevented vomiting due to high-dose cisplatin or arrested vomiting within 5 to 30 seconds. In most human studies, granisetron has had little effect on blood pressure, heart rate or ECG. No evidence of an effect on plasma prolactin or aldosterone concentrations has been found in other studies. Granisetron hydrochloride injection exhibited no effect on oro-cecal transit time in normal volunteers given a single intravenous infusion of 50 mcg/kg or 200 mcg/kg. Single and multiple oral doses slowed colonic transit in normal volunteers.

Chemotherapy-Induced Nausea and Vomiting In adult cancer patients undergoing chemotherapy and in volunteers, mean pharmacokinetic data obtained from an infusion of a single 40 mcg/kg dose of granisetron hydrochloride injection are shown in Table 3.

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="829.92"> <caption> <span>Table 3 Pharmacokinetic Parameters in Adult Cancer Patients Undergoing Chemotherapy and in Volunteers, Following a Single Intravenous 40 mcg/kg Dose of Granisetron Hydrochloride Injection </span> </caption> <colgroup> <col width="21.1538461538462%"/> <col width="19.2307692307692%"/> <col width="22.1153846153846%"/> <col width="20.1923076923077%"/> <col width="17.3076923076923%"/> </colgroup> <tfoot> <tr class="First Last"> <td colspan="5"><span class="Sup">*</span> 5-minute infusion. <br/> <span class="Sup">†</span> 3-minute infusion.<br/> </td> </tr> </tfoot> <tbody class="Headless"> <tr class="Botrule First"> <td class="Lrule Rrule" valign="top"></td><td align="center" class="Rrule" valign="top"><span class="Bold"> Peak Plasma Concentration</span> <br/> <span class="Bold">(ng/mL)</span> <br/> </td><td align="center" class="Rrule" valign="top"><span class="Bold">Terminal Phase Plasma Half-Life</span> <br/> <span class="Bold">(h)</span> <br/> </td><td align="center" class="Rrule" valign="middle"><span class="Bold">Total </span> <br/> <span class="Bold">      Clearance       </span> <br/> <span class="Bold">(L/h/kg)</span> <br/> </td><td align="center" class="Rrule" valign="top"><span class="Bold">Volume of Distribution</span> <br/> <span class="Bold">(L/kg)</span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top"><span class="Bold">  Cancer Patients       </span><span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top"><span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top"></td><td align="center" class="Rrule" valign="middle"><span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top"></td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">     Mean <br/>     Range<span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">63.8<span class="Sup">*</span> <br/>18 to 176<span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">8.95<span class="Sup">*</span> <br/>0.9 to 31.1<span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">0.38<span class="Sup">*</span> <br/>0.14 to 1.54<span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">3.07<span class="Sup">*</span> <br/>0.85 to 10.4<span class="Bold"></span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top"><span class="Bold">  Volunteers</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><td align="center" class="Rrule" valign="top"> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">     21 to 42 years<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><td align="center" class="Rrule" valign="top"> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">     Mean <br/>     Range<br/> </td><td align="center" class="Rrule" valign="top">64.3<span class="Sup">†</span> <br/> 11.2 to 182<br/> </td><td align="center" class="Rrule" valign="top">4.91<span class="Sup">†</span> <br/>0.88 to 15.2<br/> </td><td align="center" class="Rrule" valign="top">0.79<span class="Sup">†</span> <br/>0.2 to 2.56<br/> </td><td align="center" class="Rrule" valign="top">3.04<span class="Sup">†</span> <br/>1.68 to 6.13<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">     65 to 81 years <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><td align="center" class="Rrule" valign="top"> <br/> </td> </tr> <tr class="Last"> <td class="Lrule Rrule" valign="top">     Mean <br/>     Range<span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">57<span class="Sup">†</span> <br/>14.6 to 153<span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">7.69<span class="Sup">†</span> <br/>2.65 to 17.7<span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">0.44<span class="Sup">†</span> <br/>0.17 to 1.06<span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">3.97<span class="Sup">†</span> <br/>1.75 to 7.01<span class="Bold"></span> <br/> </td> </tr> </tbody> </table></div>

Distribution Plasma protein binding is approximately 65% and granisetron distributes freely between plasma and red blood cells. Metabolism Granisetron metabolism involves N-demethylation and aromatic ring oxidation followed by conjugation. In vitro liver microsomal studies show that granisetron’s major route of metabolism is inhibited by ketoconazole, suggestive of metabolism mediated by the cytochrome P-450 3A subfamily. Animal studies suggest that some of the metabolites may also have 5-HT3 receptor antagonist activity. Elimination   Clearance is predominantly by hepatic metabolism. In normal volunteers, approximately 12% of the administered dose is eliminated unchanged in the urine in 48 hours. The remainder of the dose is excreted as metabolites, 49% in the urine, and 34% in the feces. Subpopulations Gender There was high inter- and intra-subject variability noted in these studies. No difference in mean AUC was found between males and females, although males had a higher Cmax generally. Elderly The ranges of the pharmacokinetic parameters in elderly volunteers (mean age 71 years), given a single 40 mcg/kg intravenous dose of granisetron hydrochloride injection, were generally similar to those in younger healthy volunteers; mean values were lower for clearance and longer for half-life in the elderly patients (see Table 3). Pediatric Patients A pharmacokinetic study in pediatric cancer patients (2 to 16 years of age), given a single 40 mcg/kg intravenous dose of granisetron hydrochloride injection, showed that volume of distribution and total clearance increased with age. No relationship with age was observed for peak plasma concentration or terminal phase plasma half-life. When volume of distribution and total clearance are adjusted for body weight, the pharmacokinetics of granisetron are similar in pediatric and adult cancer patients. Renal Failure Patients Total clearance of granisetron was not affected in patients with severe renal failure who received a single 40 mcg/kg intravenous dose of granisetron hydrochloride injection. Hepatically Impaired Patients A pharmacokinetic study in patients with hepatic impairment due to neoplastic liver involvement showed that total clearance was approximately halved compared to patients without hepatic impairment. Given the wide variability in pharmacokinetic parameters noted in patients, dosage adjustment in patients with hepatic functional impairment is not necessary. Postoperative Nausea and Vomiting In adult patients (age range, 18 to 64 years) recovering from elective surgery and receiving general balanced anesthesia, mean pharmacokinetic data obtained from a single 1 mg dose of granisetron hydrochloride injection administered intravenously over 30 seconds are shown in Table 4.

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="100%"> <caption> <span>Table 4 Pharmacokinetic Parameters in 16 Adult Surgical Patients Following a Single Intravenous 1 mg Dose of Granisetron Hydrochloride Injection     </span> </caption> <colgroup> <col width="12.98%"/> <col width="36.68%"/> <col width="24.06%"/> <col width="26.28%"/> </colgroup> <tbody class="Headless"> <tr class="Botrule First"> <td align="center" class="Lrule Rrule" valign="top"> <br/> </td><td align="center" class="Rrule" valign="top"><span class="Bold">Terminal Phase </span> <br/> <span class="Bold">Plasma Half-Life (h)</span> <br/> </td><td align="center" class="Rrule" valign="top"><span class="Bold">Total Clearance</span> <br/> <span class="Bold">(L/h/kg)</span> <br/> </td><td align="center" class="Rrule" valign="top"><span class="Bold">Volume of Distribution</span> <br/> <span class="Bold">(L/kg)</span> <br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top">Mean<br/> </td><td align="center" class="Rrule" valign="top">8.63<br/> </td><td align="center" class="Rrule" valign="top">0.28<br/> </td><td align="center" class="Rrule" valign="top">2.42<br/> </td> </tr> <tr class="Last"> <td align="center" class="Lrule Rrule" valign="top">Range<br/> </td><td align="center" class="Rrule" valign="top">1.77 to 17.73<br/> </td><td align="center" class="Rrule" valign="top">0.07 to 0.71<br/> </td><td align="center" class="Rrule" valign="top">0.71 to 4.13<br/> </td> </tr> </tbody> </table></div>

The pharmacokinetics of granisetron in patients undergoing surgery were similar to those seen in cancer patients undergoing chemotherapy.

In a 24-month carcinogenicity study, rats were treated orally with granisetron 1, 5 or 50 mg/kg/day (6, 30 or 300 mg/m2/day). The 50 mg/kg/day dose was reduced to 25 mg/kg/day (150 mg/m2/day) during week 59 due to toxicity. For a 50 kg person of average height (1.46 m2 body surface area), these doses represent 16, 81 and 405 times the recommended clinical dose (0.37 mg/m2, iv) on a body surface area basis. There was a statistically significant increase in the incidence of hepatocellular carcinomas and adenomas in males treated with 5 mg/kg/day (30 mg/m2/day, 81 times the recommended human dose based on body surface area) and above, and in females treated with 25 mg/kg/day (150 mg/m2/day, 405 times the recommended human dose based on body surface area). No increase in liver tumors was observed at a dose of 1 mg/kg/day (6 mg/m2/day, 16 times the recommended human dose based on body surface area) in males and 5 mg/kg/day (30 mg/m2/day, 81 times the recommended human dose based on body surface area) in females. In a 12-month oral toxicity study, treatment with granisetron 100 mg/kg/day (600 mg/m2/day, 1622 times the recommended human dose based on body surface area) produced hepatocellular adenomas in male and female rats while no such tumors were found in the control rats. A 24-month mouse carcinogenicity study of granisetron did not show a statistically significant increase in tumor incidence, but the study was not conclusive. Because of the tumor findings in rat studies, granisetron hydrochloride injection should be prescribed only at the dose and for the indication recommended [see Indications and Usage (1) and Dosage and Administration (2)]. Granisetron was not mutagenic in an in vitro Ames test and mouse lymphoma cell forward mutation assay, and in vivo mouse micronucleus test and in vitro and ex vivo rat hepatocyte UDS assays. It, however, produced a significant increase in UDS in HeLa cells in vitro and a significant increased incidence of cells with polyploidy in an in vitro human lymphocyte chromosomal aberration test. Granisetron at subcutaneous doses up to 6 mg/kg/day (36 mg/m2/day, 97 times the recommended human dose based on body surface area) was found to have no effect on fertility and reproductive performance of male and female rats.

Single-Day Chemotherapy Cisplatin-Based Chemotherapy In a double-blind, placebo-controlled study in 28 cancer patients, granisetron hydrochloride injection, administered as a single intravenous infusion of 40 mcg/kg, was significantly more effective than placebo in preventing nausea and vomiting induced by cisplatin chemotherapy (see Table 5).

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="829.92"> <caption> <span>Table 5 Prevention of Chemotherapy-Induced Nausea and Vomiting — Single-Day Cisplatin Therapy<span class="Sup">1</span></span> </caption> <colgroup> <col width="31.7307692307692%"/> <col width="29.8076923076923%"/> <col width="20.1923076923077%"/> <col width="18.2692307692308%"/> </colgroup> <tfoot> <tr class="First Last"> <td colspan="4"><span class="Sup">1 </span>Cisplatin administration began within 10 minutes of granisetron hydrochloride injection infusion and continued for 1.5 to 3 hours. Mean cisplatin dose was 86 mg/m<span class="Sup">2 </span>in the granisetron hydrochloride injection group and 80 mg/m<span class="Sup">2 </span>in the placebo group.<br/> <span class="Sup"></span><span class="Sup">2</span> No vomiting and no moderate or severe nausea. <br/> </td> </tr> </tfoot> <tbody class="Headless"> <tr class="Botrule First"> <td class="Lrule Rrule" valign="top"> <br/> </td><td align="center" class="Rrule" valign="top"><span class="Bold">Granisetron Hydrochloride Injection</span><span class="Bold"></span> <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">P-Value </span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  Number of Patients<br/> </td><td align="center" class="Rrule" valign="top">14<span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="middle">14<span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="middle"></td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  Response Over 24 Hours<br/> </td><td align="center" class="Rrule" valign="top"><span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="middle"></td><td align="center" class="Rrule" valign="middle"><span class="Bold"></span> <br/> </td> </tr> <tr class="Last"> <td class="Lrule Rrule" valign="top">  Complete Response<span class="Sup">2</span> <br/>  No Vomiting<br/>  No More Than Mild Nausea<br/> </td><td align="center" class="Rrule" valign="top">93%<br/>93%<br/>93%<br/> </td><td align="center" class="Rrule" valign="top">7%<br/>14%<br/>7%<br/> </td><td align="center" class="Rrule" valign="top">&lt; 0.001<br/>&lt; 0.001<br/>&lt; 0.001<br/> </td> </tr> </tbody> </table></div>

Granisetron hydrochloride injection was also evaluated in a randomized dose response study of cancer patients receiving cisplatin ≥ 75 mg/m2. Additional chemotherapeutic agents included: anthracyclines, carboplatin, cytostatic antibiotics, folic acid derivatives, methylhydrazine, nitrogen mustard analogs, podophyllotoxin derivatives, pyrimidine analogs, and vinca alkaloids. Granisetron hydrochloride injection doses of 10 and 40 mcg/kg were superior to 2 mcg/kg in preventing cisplatin-induced nausea and vomiting, but 40 mcg/kg was not significantly superior to 10 mcg/kg (see Table 6).

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="823.27"> <caption> <span>Table 6 Prevention of Chemotherapy-Induced Nausea and Vomiting — Single-Day High-Dose Cisplatin Therapy<span class="Sup">1</span></span> </caption> <colgroup> <col width="39.7415185783522%"/> <col width="12.6009693053312%"/> <col width="14.5395799676898%"/> <col width="11.7932148626817%"/> <col width="11.6316639741519%"/> <col width="9.69305331179321%"/> </colgroup> <tfoot> <tr class="First Last"> <td colspan="6"><span class="Sup">1</span> Cisplatin administration began within 10 minutes of granisetron hydrochloride injection infusion and continued for 2.6 hours (mean). Mean cisplatin doses were 96 to 99 mg/m<span class="Sup">2</span>. <br/> <span class="Sup">2</span> No vomiting and no moderate or severe nausea. <br/> </td> </tr> </tfoot> <tbody class="Headless"> <tr class="Botrule First"> <td class="Lrule Rrule" rowspan="2" valign="top"> <br/> <span class="Bold"></span></td><td align="center" class="Rrule" colspan="3" valign="top"><span class="Bold"> Granisetron Hydrochloride Injection</span><span class="Bold"></span> <br/> <span class="Bold"> (mcg/kg)</span> <br/> </td><td align="center" class="Rrule" colspan="2" valign="top"><span class="Bold">P-Value </span> <br/> <span class="Bold">(vs. 2 mcg/kg)</span> <br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top"><span class="Bold">2</span> <br/> </td><td align="center" class="Rrule" valign="top"><span class="Bold">10</span> <br/> </td><td align="center" class="Rrule" valign="top"><span class="Bold">40</span> <br/> </td><td align="center" class="Rrule" valign="top"><span class="Bold">10</span> <br/> </td><td align="center" class="Rrule" valign="top"><span class="Bold">40</span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  Number of Patients<span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">52<span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">52<span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">53<span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top"></td><td align="center" class="Rrule" valign="top"><span class="Bold"></span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  Response Over 24 Hours <span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top"><span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top"></td><td align="center" class="Rrule" valign="top"><span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top"></td><td align="center" class="Rrule" valign="top"><span class="Bold"></span> <br/> </td> </tr> <tr class="Last"> <td class="Lrule Rrule" valign="top">  Complete Response<span class="Sup">2</span> <br/>  No Vomiting <br/>  No More Than Mild Nausea<span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">31%<br/>38%<br/>58%<span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">62%<br/>65%<br/>75%<span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">68%<br/>74%<br/>79%<span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">&lt; 0.002<br/>&lt; 0.001<br/>NS<span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">&lt; 0.001<br/>&lt; 0.001<br/>0.007<span class="Bold"></span> <br/> </td> </tr> </tbody> </table></div>

Granisetron hydrochloride injection was also evaluated in a double-blind, randomized dose response study of 353 patients stratified for high (≥ 80 to 120 mg/m2) or low (50 to 79 mg/m2) cisplatin dose. Response rates of patients for both cisplatin strata are given in Table 7.

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="821.94"> <caption> <span>Table 7 Prevention of Chemotherapy-Induced Nausea and Vomiting — Single-Day High-Dose and Low-Dose Cisplatin Therapy<span class="Sup">1</span></span> </caption> <colgroup> <col width="35.9223300970874%"/> <col width="9.70873786407767%"/> <col width="8.7378640776699%"/> <col width="8.7378640776699%"/> <col width="9.70873786407767%"/> <col width="9.70873786407767%"/> <col width="8.7378640776699%"/> <col width="8.7378640776699%"/> </colgroup> <tfoot> <tr class="First Last"> <td colspan="8"><span class="Sup">1</span> Cisplatin administration began within 10 minutes of granisetron hydrochloride injection infusion and continued for 2 hours (mean). Mean cisplatin doses were 64 and 98 mg/m<span class="Sup">2</span> for low and high strata.<br/> <span class="Sup">2</span> No vomiting and no use of rescue antiemetic. <br/> </td> </tr> </tfoot> <tbody class="Headless"> <tr class="Botrule First"> <td class="Lrule Rrule" rowspan="2" valign="top"></td><td align="center" class="Rrule" colspan="4" valign="top"><span class="Bold"> Granisetron Hydrochloride Injection</span><span class="Bold"></span> <br/> <span class="Bold"> (mcg/kg)</span> <br/> </td><td align="center" class="Rrule" colspan="3" valign="middle"><span class="Bold">P-Value</span> <br/> <span class="Bold">(vs. 5 mcg/kg)</span> <br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top"><span class="Bold">5</span> <br/> </td><td align="center" class="Rrule" valign="top"><span class="Bold">10</span> <br/> </td><td align="center" class="Rrule" valign="top"><span class="Bold">20</span> <br/> </td><td align="center" class="Rrule" valign="top"><span class="Bold">40</span> <br/> </td><td align="center" class="Rrule" valign="top"><span class="Bold">10</span> <br/> </td><td align="center" class="Rrule" valign="top"><span class="Bold">20</span> <br/> </td><td align="center" class="Rrule" valign="top"><span class="Bold">40</span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top"><span class="Bold">  High-Dose Cisplatin</span> <br/> </td><td align="center" class="Rrule" valign="top"></td><td align="center" class="Rrule" valign="top"><span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top"></td><td align="center" class="Rrule" valign="top"><span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top"></td><td align="center" class="Rrule" valign="top"><span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top"></td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  Number of Patients<span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">40<span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">49<span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">48<span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">47<span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top"></td><td align="center" class="Rrule" valign="top"><span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top"></td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  Response Over 24 Hours<span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top"></td><td align="center" class="Rrule" valign="top"><span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top"></td><td align="center" class="Rrule" valign="top"><span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top"></td><td align="center" class="Rrule" valign="top"><span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top"></td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">     Complete Response<span class="Sup">2</span> <br/>     No Vomiting<br/>     No Nausea<span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">18%<br/>28%<br/>15%<span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">41%<br/>47%<br/>35%<span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">40%<br/>44%<br/>38%<span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">47%<br/>53%<br/>43%<span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">0.018<br/>NS<br/>0.036<span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">0.025<br/>NS<br/>0.019<span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">0.004<br/>0.016<br/>0.005<span class="Bold"></span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top"><span class="Bold">   Low-Dose Cisplatin</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><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><td align="center" class="Rrule" valign="top"> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  Number of Patients<span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">42<br/> </td><td align="center" class="Rrule" valign="top">41<br/> </td><td align="center" class="Rrule" valign="top">40<br/> </td><td align="center" class="Rrule" valign="top">46<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="Botrule"> <td class="Lrule Rrule" valign="top">  Response Over 24 Hours<span class="Bold"></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><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><td align="center" class="Rrule" valign="top"> <br/> </td> </tr> <tr class="Last"> <td class="Lrule Rrule" valign="top">     Complete Response<span class="Sup">2</span> <br/>     No Vomiting<br/>     No Nausea<span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">29%<br/>36%<br/>29%<span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">56%<br/>63%<br/>56%<span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">58%<br/>65%<br/>38%<span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">41%<br/>43%<br/>33%<span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">0.012<br/>0.012<br/>0.012<span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">0.009<br/>0.008<br/>NS<span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">NS<br/>NS<br/>NS<span class="Bold"></span> <br/> </td> </tr> </tbody> </table></div>

For both the low and high cisplatin strata, the 10, 20, and 40 mcg/kg doses were more effective than the 5 mcg/kg dose in preventing nausea and vomiting within 24 hours of chemotherapy administration. The 10 mcg/kg dose was at least as effective as the higher doses. Moderately Emetogenic Chemotherapy Granisetron hydrochloride injection, 40 mcg/kg, was compared with the combination of chlorpromazine (50 to 200 mg/24 hours) and dexamethasone (12 mg) in patients treated with moderately emetogenic chemotherapy, including primarily carboplatin > 300 mg/m2, cisplatin 20 to 50 mg/m2 and cyclophosphamide > 600 mg/m2. Granisetron hydrochloride injection was superior to the chlorpromazine regimen in preventing nausea and vomiting (see Table 8).

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="829.92"> <caption> <span>Table 8 Prevention of Chemotherapy-Induced Nausea and Vomiting—Single-Day Moderately Emetogenic Chemotherapy </span> </caption> <colgroup> <col width="31.7307692307692%"/> <col width="29.8076923076923%"/> <col width="23.0769230769231%"/> <col width="15.3846153846154%"/> </colgroup> <tfoot> <tr class="First Last"> <td colspan="4"><span class="Sup">1</span> Patients also received dexamethasone, 12 mg. <br/> <span class="Sup">2</span> No vomiting and no moderate or severe nausea. <br/> </td> </tr> </tfoot> <tbody class="Headless"> <tr class="Botrule First"> <td class="Lrule Rrule" valign="top"></td><td align="center" class="Rrule" valign="top"><span class="Bold"> Granisetron Hydrochloride Injection</span><span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="middle"><span class="Bold"> Chlorpromazine<span class="Sup">1 </span></span> <br/> </td><td align="center" class="Rrule" valign="middle"><span class="Bold">P-Value </span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  Number of Patients<span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">133<span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="middle">133<span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="middle"><span class="Bold"></span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  Response Over 24 Hours<span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top"><span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="middle"></td><td align="center" class="Rrule" valign="middle"><span class="Bold"></span> <br/> </td> </tr> <tr class="Last"> <td class="Lrule Rrule" valign="top">  Complete Response<span class="Sup">2</span> <br/>  No Vomiting<br/>  No More Than Mild Nausea<span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">68%<br/>73%<br/>77%<span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">47%<br/>53%<br/>59%<span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">&lt; 0.001<br/>&lt; 0.001<br/>&lt; 0.001<span class="Bold"></span> <br/> </td> </tr> </tbody> </table></div>

In other studies of moderately emetogenic chemotherapy, no significant difference in efficacy was found between granisetron hydrochloride doses of 40 mcg/kg and 160 mcg/kg. Repeat-Cycle Chemotherapy In an uncontrolled trial, 512 cancer patients received granisetron hydrochloride injection, 40 mcg/kg, prophylactically, for two cycles of chemotherapy, 224 patients received it for at least four cycles, and 108 patients received it for at least six cycles. Granisetron hydrochloride injection efficacy remained relatively constant over the first six repeat cycles, with complete response rates (no vomiting and no moderate or severe nausea in 24 hours) of 60% to 69%. No patients were studied for more than 15 cycles. Pediatric Studies A randomized double-blind study evaluated the 24-hour response of 80 pediatric cancer patients (age 2 to 16 years) to granisetron hydrochloride injection 10, 20 or 40 mcg/kg. Patients were treated with cisplatin ≥ 60 mg/m2, cytarabine ≥ 3 g/m2, cyclophosphamide ≥ 1 g/m2 or nitrogen mustard ≥ 6 mg/m2 (see Table 9).

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="821.94"> <caption> <span>Table 9 Prevention of Chemotherapy-Induced Nausea and Vomiting in Pediatric Patients </span> </caption> <colgroup> <col width="43.6893203883495%"/> <col width="22.3300970873786%"/> <col width="17.4757281553398%"/> <col width="16.504854368932%"/> </colgroup> <tfoot> <tr class="First Last"> <td colspan="4"><span class="Sup">1</span> No vomiting and no moderate or severe nausea. <br/> </td> </tr> </tfoot> <tbody class="Headless"> <tr class="Botrule First"> <td class="Lrule Rrule" rowspan="2" valign="top"> <br/> <span class="Bold"></span></td><td align="center" class="Rrule" colspan="3" valign="top"><span class="Bold"> Granisetron Hydrochloride Injection</span><span class="Bold"> Dose</span> <br/> <span class="Bold">(mcg/kg)</span> <br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top"><span class="Bold">10</span> <br/> </td><td align="center" class="Rrule" valign="top"><span class="Bold">20</span> <br/> </td><td align="center" class="Rrule" valign="top"><span class="Bold">40</span> <br/> </td> </tr> <tr class="Last"> <td class="Lrule Rrule" valign="top">  Number of Patients<br/>  Median Number of Vomiting Episodes<br/>  Complete Response Over 24 Hours<span class="Sup">1</span><span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">29<br/>2<br/>21%<span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">26<br/>3<br/>31%<span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">25<br/>1<br/>32%<span class="Bold"></span> <br/> </td> </tr> </tbody> </table></div>

A second pediatric study compared granisetron hydrochloride injection 20 mcg/kg to chlorpromazine plus dexamethasone in 88 patients treated with ifosfamide ≥ 3 g/m2/day for two or three days. Granisetron hydrochloride injection was administered on each day of ifosfamide treatment. At 24 hours, 22% of granisetron hydrochloride injection patients achieved complete response (no vomiting and no moderate or severe nausea in 24 hours) compared with 10% on the chlorpromazine regimen. The median number of vomiting episodes with granisetron hydrochloride injection was 1.5; with chlorpromazine it was 7.

Prevention of Postoperative Nausea and Vomiting The efficacy of granisetron hydrochloride injection for prevention of postoperative nausea and vomiting was evaluated in 868 patients, of which 833 were women, 35 men, 484 Caucasians, 348 Asians, 18 Blacks, 18 Other, with 61 patients 65 years or older. Granisetron hydrochloride injection was evaluated in two randomized, double-blind, placebo-controlled studies in patients who underwent elective gynecological surgery or cholecystectomy and received general anesthesia. Patients received a single intravenous dose of granisetron hydrochloride injection (0.1 mg, 1 mg or 3 mg) or placebo either 5 minutes before induction of anesthesia or immediately before reversal of anesthesia. The primary endpoint was the proportion of patients with no vomiting for 24 hours after surgery. Episodes of nausea and vomiting and use of rescue antiemetic therapy were recorded for 24 hours after surgery. In both studies, granisetron hydrochloride injection (1 mg) was more effective than placebo in preventing postoperative nausea and vomiting (see Table 10). No additional benefit was seen in patients who received the 3 mg dose.

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="100%"> <caption> <span>Table 10 Prevention of Postoperative Nausea and Vomiting in Adult Patients    </span> </caption> <colgroup> <col width="22.14%"/> <col width="17.86%"/> <col width="20%"/> <col width="20%"/> <col width="20%"/> </colgroup> <tfoot> <tr class="First Last"> <td colspan="85">*P&lt;0.05<br/> **P&lt;0.001 versus placebo<br/> Note: No Vomiting = no vomiting and no use of rescue antiemetic therapy; No Nausea = no nausea and no use of rescue antiemetic therapy     </td> </tr> </tfoot> <tbody class="Headless"> <tr class="Botrule First"> <td align="center" class="Lrule Rrule" valign="middle"><span class="Bold">Study and Efficacy Endpoint</span> <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">Granisetron</span> <br/> <span class="Bold">Hydrochloride</span> <br/> <span class="Bold">Injection</span> <br/> <span class="Bold">0.1 mg</span> <br/> </td><td align="center" class="Rrule" valign="middle"><span class="Bold">Granisetron</span> <br/> <span class="Bold">Hydrochloride</span> <br/> <span class="Bold">Injection</span> <br/> <span class="Bold">1 mg</span> <br/> </td><td align="center" class="Rrule" valign="middle"><span class="Bold">Granisetron</span> <br/> <span class="Bold">Hydrochloride</span> <br/> <span class="Bold">Injection</span> <br/> <span class="Bold">3 mg</span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle"><span class="Bold">Study 1</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><td align="center" class="Rrule" valign="top"></td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle"><span class="Bold">Number of Patients</span> <br/> </td><td align="center" class="Rrule" valign="middle"><span class="Bold">133</span> <br/> </td><td align="center" class="Rrule" valign="middle"><span class="Bold">132</span> <br/> </td><td align="center" class="Rrule" valign="middle"><span class="Bold">134</span> <br/> </td><td align="center" class="Rrule" valign="middle"><span class="Bold">128</span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle"><span class="Bold">No Vomiting</span> <br/> </td><td align="center" class="Rrule" valign="middle"></td><td align="center" class="Rrule" valign="middle"></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">0 to 24 hours<span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="middle">34%<span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="middle">45%<span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="middle">63%**<span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="middle">62%**<span class="Bold"></span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">No Nausea<br/> </td><td align="center" class="Rrule" valign="middle"></td><td align="center" class="Rrule" valign="middle"></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">0 to 24 hours<br/> </td><td align="center" class="Rrule" valign="middle">22%<span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="middle">28%<span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="middle">50%**<span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="middle">42%**<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">No Nausea or Vomiting<br/> </td><td align="center" class="Rrule" valign="middle"></td><td align="center" class="Rrule" valign="middle"></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">0 to 24 hours<br/> </td><td align="center" class="Rrule" valign="middle">18%<span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="middle">27%<span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="middle">49%**<span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="middle">42%**<span class="Bold"></span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">No Use of Rescue Antiemetic Therapy<br/> </td><td align="center" class="Rrule" valign="middle"></td><td align="center" class="Rrule" valign="middle"></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">0 to 24 hours<br/> </td><td align="center" class="Rrule" valign="middle">60%<span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="middle">67%<span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="middle">75%*<span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="middle">77%*<span class="Bold"></span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle"><span class="Bold">Study 2</span> <br/> </td><td align="center" class="Rrule" valign="middle"> <br/> </td><td align="center" class="Rrule" valign="middle"> <br/> </td><td align="center" class="Rrule" valign="middle"> <br/> </td><td align="center" class="Rrule" valign="middle"> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle"><span class="Bold">Number of Patients</span> <br/> </td><td align="center" class="Rrule" valign="middle"><span class="Bold">117</span> <br/> </td><td align="center" class="Rrule" valign="middle"><span class="Bold">–</span> <br/> </td><td align="center" class="Rrule" valign="middle"><span class="Bold">110</span> <br/> </td><td align="center" class="Rrule" valign="middle"><span class="Bold">114</span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">No Vomiting<br/> </td><td align="center" class="Rrule" valign="middle"> <br/> </td><td align="center" class="Rrule" valign="middle"> <br/> </td><td align="center" class="Rrule" valign="middle"> <br/> </td><td align="center" class="Rrule" valign="middle"> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">0 to 24 hours<br/> </td><td align="center" class="Rrule" valign="middle">56%<br/> </td><td align="center" class="Rrule" valign="middle">–<br/> </td><td align="center" class="Rrule" valign="middle">77%**<br/> </td><td align="center" class="Rrule" valign="middle">75%*<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">No Nausea<br/> </td><td align="center" class="Rrule" valign="middle"> <br/> </td><td align="center" class="Rrule" valign="middle"> <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">0 to 24 hours<br/> </td><td align="center" class="Rrule" valign="middle">37%<br/> </td><td align="center" class="Rrule" valign="middle">–<br/> </td><td align="center" class="Rrule" valign="middle">59%**<br/> </td><td align="center" class="Rrule" valign="middle">56%*<br/> </td> </tr> </tbody> </table></div>

Gender/Race There were too few male and Black patients to adequately assess differences in effect in either population. Treatment of Postoperative Nausea and Vomiting The efficacy of granisetron hydrochloride injection for treatment of postoperative nausea and vomiting was evaluated in 844 patients, of which 731 were women, 113 men, 777 Caucasians, 6 Asians, 41 Blacks, 20 Other, with 107 patients 65 years or older. Granisetron hydrochloride injection was evaluated in two randomized, double-blind, placebo-controlled studies of adult surgical patients who received general anesthesia with no prophylactic antiemetic agent, and who experienced nausea or vomiting within 4 hours postoperatively. Patients received a single intravenous dose of granisetron hydrochloride injection (0.1 mg, 1 mg or 3 mg) or placebo after experiencing postoperative nausea or vomiting. Episodes of nausea and vomiting and use of rescue antiemetic therapy were recorded for 24 hours after administration of study medication. Granisetron hydrochloride injection was more effective than placebo in treating postoperative nausea and vomiting (see Table 11). No additional benefit was seen in patients who received the 3 mg dose.

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="100%"> <caption> <span>Table 11 Treatment of Postoperative Nausea and Vomiting in Adult Patients      </span> </caption> <colgroup> <col width="39.02%"/> <col width="15.24%"/> <col width="15.26%"/> <col width="15.22%"/> <col width="15.26%"/> </colgroup> <tfoot> <tr class="First Last"> <td colspan="150">*P&lt;0.05<br/> **P&lt;0.01<br/> ***P&lt;0.001 versus placebo<br/> 1 Protocol Specified Analysis: Patients who had vomiting prior to treatment<br/> Note: No vomiting = no vomiting and no use of rescue antiemetic therapy; No nausea = no nausea and no use of rescue antiemetic therapy     </td> </tr> </tfoot> <tbody class="Headless"> <tr class="Botrule First"> <td class="Lrule Rrule" valign="middle"><span class="Bold">Study and Efficacy Endpoint</span> <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">Granisetron</span> <br/> <span class="Bold">Hydrochloride</span> <br/> <span class="Bold">Injection</span><span class="Bold"></span> <br/> <span class="Bold">0.1 mg</span> <br/> </td><td align="center" class="Rrule" valign="middle"><span class="Bold">Granisetron</span> <br/> <span class="Bold">Hydrochloride</span> <br/> <span class="Bold">Injection</span><span class="Bold"></span> <br/> <span class="Bold">1 mg</span> <br/> </td><td align="center" class="Rrule" valign="middle"><span class="Bold">Granisetron</span> <br/> <span class="Bold">Hydrochloride</span> <br/> <span class="Bold">Injection</span><span class="Bold"></span> <br/> <span class="Bold">3 mg</span> <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"><span class="Bold">Study 3</span> <br/> </td><td align="justify" class="Rrule" valign="top"> <br/> </td><td align="justify" class="Rrule" valign="top"> <br/> </td><td align="justify" class="Rrule" valign="top"> <br/> </td><td align="justify" class="Rrule" valign="top"> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle"><span class="Bold">Number of Patients</span> <br/> </td><td align="center" class="Rrule" valign="middle"><span class="Bold">133</span> <br/> </td><td align="center" class="Rrule" valign="middle"><span class="Bold">128</span> <br/> </td><td align="center" class="Rrule" valign="middle"><span class="Bold">133</span> <br/> </td><td align="center" class="Rrule" valign="middle"><span class="Bold">125</span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">No Vomiting<br/> </td><td align="center" class="Rrule" valign="middle"> <br/> </td><td align="center" class="Rrule" valign="middle"> <br/> </td><td align="center" class="Rrule" valign="middle"> <br/> </td><td align="center" class="Rrule" valign="middle"> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">0 to 6 hours<br/> </td><td align="center" class="Rrule" valign="middle">26%<br/> </td><td align="center" class="Rrule" valign="middle">53%***<br/> </td><td align="center" class="Rrule" valign="middle">58%***<br/> </td><td align="center" class="Rrule" valign="middle">60%***<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">0 to 24 hours<br/> </td><td align="center" class="Rrule" valign="middle">20%<br/> </td><td align="center" class="Rrule" valign="middle">38%***<br/> </td><td align="center" class="Rrule" valign="middle">46%***<br/> </td><td align="center" class="Rrule" valign="middle">49%***<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">No Nausea<br/> </td><td align="center" class="Rrule" valign="middle"> <br/> </td><td align="center" class="Rrule" valign="middle"> <br/> </td><td align="center" class="Rrule" valign="middle"> <br/> </td><td align="center" class="Rrule" valign="middle"> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">0 to 6 hours<br/> </td><td align="center" class="Rrule" valign="middle">17%<br/> </td><td align="center" class="Rrule" valign="middle">40%***<br/> </td><td align="center" class="Rrule" valign="middle">41%***<br/> </td><td align="center" class="Rrule" valign="middle">42%***<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">0 to 24 hours<br/> </td><td align="center" class="Rrule" valign="middle">13%<br/> </td><td align="center" class="Rrule" valign="middle">27%**<br/> </td><td align="center" class="Rrule" valign="middle">30%**<br/> </td><td align="center" class="Rrule" valign="middle">37%***<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">No Use of Rescue Antiemetic Therapy<br/> </td><td align="center" class="Rrule" valign="middle"> <br/> </td><td align="center" class="Rrule" valign="middle"> <br/> </td><td align="center" class="Rrule" valign="middle"> <br/> </td><td align="center" class="Rrule" valign="middle"> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">0 to 6 hours<br/> </td><td align="center" class="Rrule" valign="middle">–<br/> </td><td align="center" class="Rrule" valign="middle">–<br/> </td><td align="center" class="Rrule" valign="middle">–<br/> </td><td align="center" class="Rrule" valign="middle">–<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">0 to 24 hours<br/> </td><td align="center" class="Rrule" valign="middle">33%<br/> </td><td align="center" class="Rrule" valign="middle">51%**<br/> </td><td align="center" class="Rrule" valign="middle">61%***<br/> </td><td align="center" class="Rrule" valign="middle">61%***<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle"><span class="Bold">Study 4</span> <br/> </td><td align="center" class="Rrule" valign="middle"> <br/> </td><td align="center" class="Rrule" valign="middle"> <br/> </td><td align="center" class="Rrule" valign="middle"> <br/> </td><td align="center" class="Rrule" valign="middle"> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle"><span class="Bold">Number of Patients (All Patients)</span> <br/> </td><td align="center" class="Rrule" valign="middle"><span class="Bold">162</span> <br/> </td><td align="center" class="Rrule" valign="middle"><span class="Bold">163</span> <br/> </td><td align="center" class="Rrule" valign="middle"><span class="Bold">–</span> <br/> </td><td align="center" class="Rrule" valign="middle"><span class="Bold">–</span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">No Vomiting<br/> </td><td align="center" class="Rrule" valign="middle"> <br/> </td><td align="center" class="Rrule" valign="middle"> <br/> </td><td align="center" class="Rrule" valign="middle"> <br/> </td><td align="center" class="Rrule" valign="middle"> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">0 to 6 hours<br/> </td><td align="center" class="Rrule" valign="middle">20%<br/> </td><td align="center" class="Rrule" valign="middle">32%*<br/> </td><td align="center" class="Rrule" valign="middle">–<br/> </td><td align="center" class="Rrule" valign="middle">–<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">0 to 24 hours<br/> </td><td align="center" class="Rrule" valign="middle">14%<br/> </td><td align="center" class="Rrule" valign="middle">23%*<br/> </td><td align="center" class="Rrule" valign="middle">–<br/> </td><td align="center" class="Rrule" valign="middle">–<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">No Nausea<br/> </td><td align="center" class="Rrule" valign="middle"> <br/> </td><td align="center" class="Rrule" valign="middle"> <br/> </td><td align="center" class="Rrule" valign="middle"> <br/> </td><td align="center" class="Rrule" valign="middle"> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">0 to 6 hours<br/> </td><td align="center" class="Rrule" valign="middle">13%<br/> </td><td align="center" class="Rrule" valign="middle">18%<br/> </td><td align="center" class="Rrule" valign="middle">–<br/> </td><td align="center" class="Rrule" valign="middle">–<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">0 to 24 hours<br/> </td><td align="center" class="Rrule" valign="middle">9%<br/> </td><td align="center" class="Rrule" valign="middle">14%<br/> </td><td align="center" class="Rrule" valign="middle">–<br/> </td><td align="center" class="Rrule" valign="middle">–<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">No Nausea or Vomiting<br/> </td><td align="center" class="Rrule" valign="middle"> <br/> </td><td align="center" class="Rrule" valign="middle"> <br/> </td><td align="center" class="Rrule" valign="middle"> <br/> </td><td align="center" class="Rrule" valign="middle"> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">0 to 6 hours<br/> </td><td align="center" class="Rrule" valign="middle">13%<br/> </td><td align="center" class="Rrule" valign="middle">18%<br/> </td><td align="center" class="Rrule" valign="middle">–<br/> </td><td align="center" class="Rrule" valign="middle">–<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">0 to 24 hours<br/> </td><td align="center" class="Rrule" valign="middle">9%<br/> </td><td align="center" class="Rrule" valign="middle">14%<br/> </td><td align="center" class="Rrule" valign="middle">–<br/> </td><td align="center" class="Rrule" valign="middle">–<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">No Use of Rescue Antiemetic Therapy<br/> </td><td align="center" class="Rrule" valign="middle"> <br/> </td><td align="center" class="Rrule" valign="middle"> <br/> </td><td align="center" class="Rrule" valign="middle"> <br/> </td><td align="center" class="Rrule" valign="middle"> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">0 to 6 hours<br/> </td><td align="center" class="Rrule" valign="middle">–<br/> </td><td align="center" class="Rrule" valign="middle">–<br/> </td><td align="center" class="Rrule" valign="middle">–<br/> </td><td align="center" class="Rrule" valign="middle">–<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">0 to 24 hours<br/> </td><td align="center" class="Rrule" valign="middle">24%<br/> </td><td align="center" class="Rrule" valign="middle">34%*<br/> </td><td align="center" class="Rrule" valign="middle">–<br/> </td><td align="center" class="Rrule" valign="middle"> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle"><span class="Bold">Number of Patients (Treated for Vomiting)<span class="Sup">1</span></span> <br/> </td><td align="center" class="Rrule" valign="middle">86<br/> </td><td align="center" class="Rrule" valign="middle">103<br/> </td><td align="center" class="Rrule" valign="middle">–<br/> </td><td align="center" class="Rrule" valign="middle">–<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">No Vomiting<span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="middle"> <br/> </td><td align="center" class="Rrule" valign="middle"></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">0 to 6 hours<br/> </td><td align="center" class="Rrule" valign="middle">21%<br/> </td><td align="center" class="Rrule" valign="middle">27%<span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="middle">–<span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="middle">–<span class="Bold"></span> <br/> </td> </tr> <tr class="Last"> <td class="Lrule Rrule" valign="middle">0 to 24 hours<br/> </td><td align="center" class="Rrule" valign="middle">14%<span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="middle">20%<span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="middle">–<span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="middle">–<span class="Bold"></span> <br/> </td> </tr> </tbody> </table></div>

Gender/Race There were too few male and Black patients to adequately assess differences in effect in either population.

Granisetron hydrochloride injection USP, 1 mg/mL (free base), is supplied in 1 mL Single-Dose Vials and 4 mg/4 mL Multiple-Dose Vials. 1 mg (base) per mL:    Single-Dose Vials in a carton of 1                                                    NDC 55150-175-01 4 mg per 4 mL (1 mg (base)/mL):    Multiple-Dose Vials in a carton of 1                                               NDC 55150-176-04 Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. Discard unused portion for the single-dose vials. Once the multiple-dose vial is penetrated, its contents should be used within 30 days. Do not freeze. Protect from light. Retain in carton until time of use. The vial stopper is not made with natural rubber latex.

{ "type": "p", "children": [], "text": "Granisetron hydrochloride injection USP, 1 mg/mL (free base), is supplied in 1 mL Single-Dose Vials and 4 mg/4 mL Multiple-Dose Vials.\n\n 1 mg (base) per mL:\n\n    Single-Dose Vials in a carton of 1                                                    NDC 55150-175-01\n\n 4 mg per 4 mL (1 mg (base)/mL):\n\n    Multiple-Dose Vials in a carton of 1                                               NDC 55150-176-04\n\n Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].\n Discard unused portion for the single-dose vials.\n Once the multiple-dose vial is penetrated, its contents should be used within 30 days.\n\nDo not freeze. Protect from light. Retain in carton until time of use.\n\nThe vial stopper is not made with natural rubber latex." }

Advise patients of the possibility of serotonin syndrome with concomitant use of granisetron and another serotonergic agent such as medications to treat depression and migraines. Advise patients to seek immediate medical attention if the following symptoms occur: changes in mental status, autonomic instability, neuromuscular symptoms with or without gastrointestinal symptoms. Distributed by: Eugia US LLC 279 Princeton-Hightstown Rd.E. Windsor, NJ 08520 Manufactured by: Eugia Pharma Specialities Limited Hyderabad - 500032India

Rx only                     NDC 55150-175-01 Granisetron Hydrochloride Injection, USP 1 mg (base) per mL For Intravenous use only 1 mL Single-Dose Vial 

{ "type": "p", "children": [], "text": "\nRx only                     NDC 55150-175-01\n\nGranisetron Hydrochloride Injection, USP 1 mg (base) per mL For Intravenous use only 1 mL Single-Dose Vial \n\n\n" }

Rx only                    NDC 55150-175-01 Granisetron Hydrochloride Injection, USP 1 mg (base) per mL For Intravenous use only Sterile 1 mL Single-Dose Vial eugia

{ "type": "p", "children": [], "text": "\nRx only                    NDC 55150-175-01\n\nGranisetron Hydrochloride Injection, USP 1 mg (base) per mL For Intravenous use only Sterile 1 mL Single-Dose Vial eugia\n\n\n" }

Rx only               NDC 55150-176-04 Granisetron Hydrochloride Injection, USP 4 mg per 4 mL (1 mg (base)/mL) For Intravenous use only 4 mL Multiple-Dose Vial

{ "type": "p", "children": [], "text": "\nRx only               NDC 55150-176-04 Granisetron Hydrochloride Injection, USP 4 mg per 4 mL (1 mg (base)/mL) For Intravenous use only 4 mL Multiple-Dose Vial\n\n\n" }

Rx only                   NDC 55150-176-04 Granisetron Hydrochloride Injection, USP 4 mg per 4 mL (1 mg (base)/mL) For Intravenous use only Sterile 4 mL Multiple-Dose Vial eugia

{ "type": "p", "children": [], "text": "\nRx only                   NDC 55150-176-04\n\nGranisetron Hydrochloride Injection, USP 4 mg per 4 mL (1 mg (base)/mL) For Intravenous use only Sterile 4 mL Multiple-Dose Vial eugia\n\n\n" }

SANCUSO® is indicated for the prevention of nausea and vomiting in adults receiving moderately and/or highly emetogenic chemotherapy regimens of up to 5 consecutive days duration.

{ "type": "p", "children": [], "text": "SANCUSO® is indicated for the prevention of nausea and vomiting in adults receiving moderately and/or highly emetogenic chemotherapy regimens of up to 5 consecutive days duration.\n" }

The recommended dosage is a single transdermal system applied to the upper outer arm a minimum of 24 hours, up to a maximum of 48 hours, before chemotherapy. The transdermal system should be worn at minimum, 24 hours after chemotherapy is finished. The transdermal system can be worn for up to 7 days.

{ "type": "p", "children": [], "text": "The recommended dosage is a single transdermal system applied to the upper outer arm a minimum of 24 hours, up to a maximum of 48 hours, before chemotherapy. The transdermal system should be worn at minimum, 24 hours after chemotherapy is finished. The transdermal system can be worn for up to 7 days.\n" }

Application and Removal Instructions

{ "type": "p", "children": [], "text": "\nApplication and Removal Instructions\n" }

{ "type": "ul", "children": [ "Each transdermal system releases 3.1 mg of granisetron per 24 hours for up to 7 days.\n", "Each transdermal system is packed in a pouch and should be applied directly after the pouch has been opened.\n", "Only wear one transdermal system at any time.\n", "\nDo not cut the transdermal system.\n", "Open the pouch and apply the transdermal system to clean, dry, nearly hairless, intact healthy skin on the upper outer arm.\n", "Do not place SANCUSO transdermal system on skin that is red, irritated, or damaged.\n", "Do not apply a heat pad or heat lamp over or in vicinity of the transdermal system and avoid extended exposure to heat [see Warnings and Precautions (5.4)].\n", "Cover the application site of the transdermal system with clothing, if there is a risk of exposure to direct natural or artificial sunlight throughout the period of wear and for 10 days following its removal [see Warnings and Precautions (5.5)].\n", "After the transdermal system is applied, wash hands thoroughly.\n", "Remove the transdermal system by peeling off gently from the skin.\n", "Upon removal, fold the transdermal system in half with the sticky side together, and discard in the household trash in a manner that prevents accidental contact or ingestion by children, pets or others.\n", "SANCUSO contains granisetron. Do not use other granisetron-containing products with SANCUSO.\n" ], "text": "" }

Transdermal System: a 52 cm2 thin, translucent, rectangular-shaped transdermal system with rounded corners imprinted on one side with "Granisetron 3.1 mg/24 hours". The transdermal system releases 3.1 mg of granisetron per 24 hours for up to 7 days.

{ "type": "p", "children": [], "text": "Transdermal System: a 52 cm2 thin, translucent, rectangular-shaped transdermal system with rounded corners imprinted on one side with \"Granisetron 3.1 mg/24 hours\". The transdermal system releases 3.1 mg of granisetron per 24 hours for up to 7 days.\n" }

SANCUSO is contraindicated in patients with known hypersensitivity to granisetron or to any of the components of the transdermal system [see Description (11)].

{ "type": "p", "children": [], "text": "SANCUSO is contraindicated in patients with known hypersensitivity to granisetron or to any of the components of the transdermal system [see Description (11)].\n" }

SANCUSO may mask a progressive ileus and/or gastric distention. This should be particularly considered before use of SANCUSO in patients who have had recent abdominal surgery. Monitor for decreased bowel activity, particularly in patients with risk factors for gastrointestinal obstruction.

The development of serotonin syndrome has been reported with 5-HT3 receptor antagonists. Most reports have been associated with concomitant use of serotonergic drugs (e.g., selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), monoamine oxidase inhibitors, mirtazapine, fentanyl, lithium, tramadol, and intravenous methylene blue). Some of the reported cases were fatal. Serotonin syndrome occurring with overdose of another 5-HT3 receptor antagonist alone has also been reported. The majority of reports of serotonin syndrome related to 5-HT3 receptor antagonist use occurred in a post-anesthesia care unit or an infusion center.

Symptoms associated with serotonin syndrome may include the following combination of signs and symptoms: mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, with or without gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Patients should be monitored for the emergence of serotonin syndrome, especially with concomitant use of SANCUSO and other serotonergic drugs. If symptoms of serotonin syndrome occur, discontinue SANCUSO and initiate supportive treatment. Patients should be informed of the increased risk of serotonin syndrome, especially if SANCUSO is used concomitantly with other serotonergic drugs. [see Drug Interactions (7)].

In clinical trials with SANCUSO, application site reactions were reported that were generally mild in intensity and did not lead to discontinuation of use. The incidence of reactions was comparable with placebo.

If severe reactions, or a generalized skin reaction occur (e.g., allergic rash, including erythematous, macular, papular rash or pruritus), remove the SANCUSO transdermal system.

Prolonged exposure to heat results in increasing plasma concentrations of granisetron during the period of heat exposure [see Clinical Pharmacology (12.3)]. Do not apply a heat pad or heat lamp over or in the vicinity of the SANCUSO transdermal system and avoid extended exposure to heat [see Dosage and Administration (2)].

Granisetron may be affected by direct natural or artificial sunlight, including sunlamps. An in vitro study using Chinese hamster ovary cells suggests that granisetron has the potential for photogenotoxicity [see Nonclinical Toxicology (13.3)]. To avoid a potential skin reaction, advise patients to cover the application site of the transdermal system with clothing if there is a risk of exposure to direct natural or artificial sunlight throughout the period of wear and for 10 days following its removal.

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 SANCUSO was evaluated in a total of 404 patients undergoing chemotherapy who participated in two double-blind, comparator studies with transdermal system treatment durations of up to 7 days. The control groups included a total of 406 patients who received a daily dose of 2 mg oral granisetron, for 1 to 5 days.

Adverse reactions occurred in 9% (35/404) of patients receiving SANCUSO and 7% (29/406) of patients receiving oral granisetron. The most common adverse reaction was constipation that occurred in 5% of patients in the SANCUSO group and 3% of patients in the oral granisetron group.

Table 1 lists the adverse reactions that occurred in at least 3% of patients treated with SANCUSO or oral granisetron.

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 1: Incidence of Adverse Reactions in Double-Blind, Active Comparator Controlled Studies in Cancer Patients Receiving Chemotherapy (³ 3% in either group) </span> </caption> <col align="left" width="51.067%"/> <col align="left" width="25.533%"/> <col align="left" width="23.400%"/> <tbody class="Headless"> <tr class="First"> <td align="left" class="Lrule Rrule Toprule" valign="top"></td><td align="center" class="Rrule Toprule" valign="top"><span class="Bold">SANCUSO</span></td><td align="left" class="Rrule Toprule" valign="top"></td> </tr> <tr> <td align="left" class="Lrule Rrule" valign="top"></td><td align="center" class="Rrule" valign="top"><span class="Bold">Transdermal System</span></td><td align="center" class="Rrule" valign="top"><span class="Bold">Oral granisetron</span></td> </tr> <tr> <td align="left" class="Lrule Rrule" valign="top"><span class="Bold Italics">Body System</span></td><td align="center" class="Rrule" valign="top"><span class="Bold">N=404</span></td><td align="center" class="Rrule" valign="top"><span class="Bold">N=406</span></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">     <span class="Bold">Preferred Term</span></td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold">(%)</span></td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold">(%)</span></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">Gastrointestinal disorders </td><td align="center" class="Botrule Rrule" colspan="2" valign="top"></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">     Constipation </td><td align="center" class="Botrule Rrule" valign="top">5 </td><td align="center" class="Botrule Rrule" valign="top">3 </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">Nervous system disorders </td><td align="center" class="Botrule Rrule" colspan="2" valign="top"></td> </tr> <tr class="Last"> <td align="left" class="Botrule Lrule Rrule" valign="top">     Headache </td><td align="center" class="Botrule Rrule" valign="top">1 </td><td align="center" class="Botrule Rrule" valign="top">3 </td> </tr> </tbody> </table></div>

5-HT3 receptor antagonists, such as granisetron, may be associated with arrhythmias or ECG abnormalities. Three ECGs were performed on 588 patients in a randomized, parallel group, double-blind, double-dummy study: at baseline before treatment, the first day of chemotherapy, and 5 to 7 days after starting chemotherapy. QTcF prolongation greater than 450 milliseconds was seen in a total of 11 (1.9%) patients after receiving granisetron, 8 (2.7%) on oral granisetron, and 3 (1.1%) on the transdermal system. No new QTcF prolongation greater than 480 milliseconds was observed in any patient in this study. No arrhythmias were detected in this study.

Adverse reactions reported in clinical trials with other formulations of granisetron include the following:

Gastrointestinal: abdominal pain, diarrhea, constipation, elevation of ALT and AST levels, nausea and vomiting

Cardiovascular: hypertension, hypotension, angina pectoris, atrial fibrillation and syncope have been observed rarely

Central Nervous System: dizziness, insomnia, headache, anxiety, somnolence and asthenia

Hypersensitivity: rare cases of hypersensitivity reactions, sometimes severe (e.g. anaphylaxis, shortness of breath, hypotension, urticaria) have been reported

Other: fever; events often associated with chemotherapy have also been reported: leucopenia, decreased appetite, anemia, alopecia, thrombocytopenia.

The following adverse reactions have been identified during post approval use of SANCUSO. 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.

General Disorders and Administration Site Conditions: Application site reactions (pain, pruritus, erythema, rash, irritation, vesicles, burn, discoloration, urticaria) [see Warnings and Precautions (5.3)]; transdermal system non-adhesion.

Cardiac Disorders: bradycardia, chest pain, palpitations, sick sinus syndrome

Serotonin syndrome (including altered mental status, autonomic instability, and neuromuscular symptoms) has been described following the concomitant use of 5-HT3 receptor antagonists and other serotonergic drugs, including selective serotonin reuptake inhibitors (SSRIs) and serotonin and noradrenaline reuptake inhibitors (SNRIs). Monitor for the emergence of serotonin syndrome. If symptoms occur, discontinue SANCUSO and initiate supportive treatment [see Warnings and Precautions (5.4)].

There have been no definitive drug-drug interaction studies to examine pharmacokinetic or pharmacodynamic interaction with other drugs. However, in humans, granisetron hydrochloride injection has been safely administered with drugs representing benzodiazepines, neuroleptics and anti-ulcer medications commonly prescribed with antiemetic treatments. Granisetron hydrochloride injection also does not appear to interact with emetogenic cancer therapies. In agreement with these data, no clinically relevant drug interactions have been reported in clinical studies with SANCUSO.

Risk Summary

Available published data and postmarketing reports with granisetron use in pregnant women have not identified a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In a published ex vivo human placental perfusion model, no transplacental passage of granisetron was detected at a concentration (5 ng/mL) that mimics the plasma concentration achieved following transdermal application of SANCUSO. In animal reproduction studies, no adverse developmental effects were observed in pregnant rats and rabbits administered granisetron hydrochloride during organogenesis at intravenous doses up to 24 times and 16 times, respectively, the maximum recommended human dose delivered by the SANCUSO transdermal system, based on body surface area (see Data).

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 risks of major birth defects and miscarriage in clinically recognized pregnancies are 2-4% and 15-20%, respectively.

In animal reproduction studies, no adverse developmental effects were observed in pregnant rats and rabbits administered granisetron hydrochloride at intravenous doses up to 24 times and 16 times, respectively, the maximum recommended human dose delivered by the SANCUSO transdermal system, based on body surface area (see Data).

Data

Animal Data

Reproduction studies with granisetron hydrochloride have been performed in pregnant rats at intravenous doses up to 9 mg/kg/day (54 mg/m2/day, about 24 times the recommended human dose delivered by the SANCUSO transdermal system, based on body surface area) and oral doses up to 125 mg/kg/day (750 mg/m2/day, about 326 times the recommended human dose with SANCUSO based on body surface area). Reproduction studies have been performed in pregnant rabbits at intravenous doses up to 3 mg/kg/day (36 mg/m2/day, about 16 times the human dose with SANCUSO based on body surface area) and at oral doses up to 32 mg/kg/day (384 mg/m2/day, about 167 times the human dose with SANCUSO based on body surface area). These studies did not reveal any harm to the fetus due to granisetron.

Risk Summary

There are no data on the presence of granisetron in human milk, the effects on the breastfed child, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for SANCUSO and any potential adverse effects on the breastfed child from SANCUSO or from the underlying maternal condition.

Safety and effectiveness of SANCUSO have not been established in pediatric patients.

Clinical studies of SANCUSO did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, cautious treatment selection for an elderly patient is prudent because of the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Although no studies have been performed to investigate the pharmacokinetics of SANCUSO in patients with renal or hepatic impairment, pharmacokinetic information is available for intravenous granisetron [see Clinical Pharmacology (12.3)]. No dosage adjustment is recommended for renal or hepatic impairment.

There is no specific antidote for granisetron overdosage. In the case of overdosage, symptomatic treatment should be given.

{ "type": "p", "children": [], "text": "There is no specific antidote for granisetron overdosage. In the case of overdosage, symptomatic treatment should be given.\n" }

SANCUSO contains granisetron, which is a serotonin-3 (5-HT3) receptor antagonist. Chemically it is 1-methyl-N-[(1R,3r,5S)-9-methyl-9-azabicyclo[3.3.1]non-3-yl]-1H-indazole-3-carboxamide with a molecular weight of 312.4. Its empirical formula is C18H24N4O, while its chemical structure is:

{ "type": "p", "children": [], "text": "SANCUSO contains granisetron, which is a serotonin-3 (5-HT3) receptor antagonist. Chemically it is 1-methyl-N-[(1R,3r,5S)-9-methyl-9-azabicyclo[3.3.1]non-3-yl]-1H-indazole-3-carboxamide with a molecular weight of 312.4. Its empirical formula is C18H24N4O, while its chemical structure is:\n" }

Granisetron is a white to off-white solid that is insoluble in water. The inactive ingredients are acrylate-vinylacetate copolymer, polyester, titanium dioxide, polyamide resin and polyethylene wax. SANCUSO is a 52 cm2 thin, translucent, matrix-type transdermal system that is rectangular- shaped with rounded corners, consisting of a backing (polyester), the drug matrix (acrylate- vinylacetate copolymer) and a release liner (siliconized polyester).

{ "type": "p", "children": [], "text": "Granisetron is a white to off-white solid that is insoluble in water. The inactive ingredients are acrylate-vinylacetate copolymer, polyester, titanium dioxide, polyamide resin and polyethylene wax. SANCUSO is a 52 cm2 thin, translucent, matrix-type transdermal system that is rectangular- shaped with rounded corners, consisting of a backing (polyester), the drug matrix (acrylate- vinylacetate copolymer) and a release liner (siliconized polyester).\n" }

Granisetron is a selective 5-hydroxytryptamine3 (5-HT3) receptor antagonist with little or no affinity for other serotonin receptors, including 5-HT1, 5-HT1A, 5-HT1B/C, 5-HT2; for alpha1-, alpha2-, or beta-adrenoreceptors; for dopamine-D2; or for histamine-H1; benzodiazepine; picrotoxin or opioid receptors.

Serotonin receptors of the 5-HT3 type are located peripherally on vagal nerve terminals and centrally in the chemoreceptor trigger zone of the area postrema. During chemotherapy that induces vomiting, mucosal enterochromaffin cells release serotonin, which stimulates 5-HT3 receptors. This evokes vagal afferent discharge, inducing vomiting. Animal studies demonstrate that, in binding to 5-HT3 receptors, granisetron blocks serotonin stimulation and subsequent vomiting after emetogenic stimuli such as cisplatin. In the ferret animal model, a single granisetron injection prevented vomiting due to high-dose cisplatin or arrested vomiting within 5 to 30 seconds.

The effect of granisetron on QTc prolongation was evaluated in a randomized, single-blind, positive (moxifloxacin 400 mg) - and placebo controlled parallel study in healthy subjects. A total of 120 subjects were administered SANCUSO transdermal system (n=60) or intravenous granisetron (10 mcg/kg over 30 seconds; n=60). In a study with demonstrated ability to detect small effects, the upper bound of the 90% confidence interval for the largest placebo adjusted, baseline corrected QTc based on Fridericia correction method (QTcF) for SANCUSO was below 10 ms. This study suggests that SANCUSO does not have significant effects on QT prolongation.

No evidence of an effect on plasma prolactin or aldosterone concentrations has been found in studies using granisetron.

The effect on oro-cecal transit time following application of SANCUSO has not been studied. Granisetron hydrochloride injection exhibited no effect on oro-cecal transit time in healthy subjects given a single intravenous infusion of 50 mcg/kg or 200 mcg/kg. Single and multiple oral doses of granisetron hydrochloride slowed colonic transit in healthy subjects.

Absorption

Granisetron crosses intact skin into the systemic circulation by a passive diffusion process.

Following a 7-day application of SANCUSO transdermal system in 24 healthy subjects, high inter- subject variability in systemic exposure was observed. Maximal concentration was reached at approximately 48 hours (range: 24-168 hours) following application. Mean Cmax was 5 ng/mL (CV: 170%) and mean AUC0-168hr was 527 ng-hr/mL (CV: 173%).

Mean Plasma Concentration of Granisetron (mean ± SD)

Based on the measure of residual content of the transdermal system after removal, approximately 66% (SD: ± 10.9) of granisetron is delivered following transdermal system application for 7 days.

Following consecutive application of two SANCUSO transdermal systems, each for seven days, granisetron plasma concentrations were maintained over the study period with evidence of minimal accumulation. The mean plasma concentration at 24 hours after the second transdermal system application was 1.5-fold higher due to residual granisetron from the first transdermal system. As the plasma concentration increased after the second transdermal system application, the difference decreased and the mean plasma concentration at 48 hours was 1.3-fold higher after application of the second transdermal system compared to that after application of the first transdermal system.

In a study designed to assess the effect of heat on the transdermal delivery of granisetron from SANCUSO in healthy subjects, a heat pad generating an average temperature of 42°C (107.6°F) was applied over the transdermal system for 4 hours each day over the 5 day period of wear. The application of the heat pad was associated with an increase in plasma granisetron concentrations during the period of heat pad application. The elevated plasma concentration declined after removal of the heat pad. Mean Cmax with intermittent heat exposure was 6% higher than without heat. Mean partial AUCs over 6 hours with 4 hour of heat application (AUC0-6, AUC24-30, and AUC48-54) were 4.9, 1.4, and 1.1 fold higher, respectively, with heat pad than without heat pad [see Dosage and Administration (2), Warnings and Precautions (5.4)].

Distribution

Plasma protein binding is approximately 65%. Granisetron distributes freely between plasma and red blood cells.

Elimination

Metabolism

Granisetron metabolism involves N-demethylation and aromatic ring oxidation followed by conjugation. In vitro liver microsomal studies show that granisetron's major route of metabolism is inhibited by ketoconazole, suggestive of metabolism mediated by the cytochrome P-450 3A subfamily. Animal studies suggest that some of the metabolites may also have 5-HT3 receptor antagonist activity.

Excretion

Clearance is predominantly by hepatic metabolism. Based on a study with intravenous injection, approximately 12% of the dose is excreted unchanged in the urine of healthy subjects in 48 hours. The remainder of the dose is excreted as metabolites, 49% in the urine, and 34% in the feces.

Use in Specific Populations

Geriatric Patients

Following application of SANCUSO transdermal system in healthy subjects, mean AUC0-z, Cmax, and Cavg were 17%, 15%, and 16% higher, respectively in male and female elderly subjects (≥ 65 years) compared to younger subjects (aged 18-45 years inclusive). These pharmacokinetic parameters were largely overlapped between the two age groups with high variability (CV: >50%).

Following a single 40 mcg/kg intravenous dose of granisetron hydrochloride in elderly subjects (mean age 71 years), lower clearance and longer half-life were observed compared to younger healthy subjects.

Male and Female Patients

There is evidence to suggest that female subjects had higher granisetron concentrations than males following transdermal system application. However, no statistically significant difference in clinical efficacy outcome was observed between males and females.

Racial or Ethnic Groups

The pharmacokinetic profile of granisetron from SANCUSO was assessed in healthy Japanese males. Following the application of a single 6-day SANCUSO 52 cm2 transdermal system, in healthy male Japanese subjects, mean Cmax, AUC(0-144), and AUC(0-∞) values were 5.02 ng/mL (CV: 66%), 492 ng.hr/mL (CV: 72%), and 562 ng.hr/mL (CV: 60%), respectively, and a median tmax value was 48 hours.

Patients with Renal Impairment

Total clearance of granisetron was not affected in patients with severe renal failure who received a single 40 mcg/kg intravenous dose of granisetron hydrochloride.

Patients with Hepatic Impairment

In patients with hepatic impairment due to neoplastic liver involvement, total plasma clearance following a single 40 mcg/kg intravenous dose of granisetron hydrochloride was approximately halved compared to patients without hepatic impairment. Given the wide variability in pharmacokinetic parameters of granisetron and the good tolerance of doses well above the recommended dose, dose adjustment in patients with hepatic functional impairment is not necessary.

Body Mass Index

In a clinical study designed to assess granisetron exposure from SANCUSO in subjects with differing levels of body fat, using body mass index (BMI) as a surrogate measure for subcutaneous fat, no significant differences were seen in the plasma pharmacokinetics of SANCUSO in male and female subjects with low BMI [<19.5 kg/m2 (males), <18.5 kg/m2 (females)] and high BMI (30.0 to 39.9 kg/m2 inclusive) compared to a control group (BMI 20.0 to 24.9 kg/m2 inclusive).

Drug Interaction Studies

Because granisetron is metabolized by hepatic cytochrome P-450 drug-metabolizing enzymes (CYP1A1 and CYP3A4), inducers or inhibitors of these enzymes may change the clearance and hence, the half-life of granisetron. In addition, the activity of the cytochrome P-450 subfamily 3A4 (involved in the metabolism of some of the main narcotic analgesic agents) is not modified by granisetron hydrochloride in vitro. In in vitro human microsomal studies, ketoconazole inhibited ring oxidation of granisetron hydrochloride. However, the clinical significance of in vivo pharmacokinetic interactions with ketoconazole is not known. In a human pharmacokinetic study, hepatic enzyme induction with phenobarbital resulted in a 25% increase in total plasma clearance of intravenous granisetron hydrochloride. The clinical significance of this change is not known.

In a 24-month carcinogenicity study, rats were treated orally with granisetron 1, 5 or 50 mg/kg/day (6, 30 or 300 mg/m2/day). The 50 mg/kg/day dose was reduced to 25 mg/kg/day (150 mg/m2/day) during week 59 due to toxicity. For a 50 kg person of average height (1.46 m2 body surface area), these doses represent about 2.6, 13, and 65 times the recommended clinical dose (3.1 mg/day, 2.3 mg/m2/day, delivered by the SANCUSO transdermal system, on a body surface area basis). There was a statistically significant increase in the incidence of hepatocellular carcinomas and adenomas in males treated with 5 mg/kg/day (30 mg/m2/day, about 13 times the recommended human dose with SANCUSO, on a body surface area basis) and above, and in females treated with 25 mg/kg/day (150 mg/m2/day, about 65 times the recommended human dose with SANCUSO, on a body surface area basis). No increase in liver tumors was observed at a dose of 1 mg/kg/day (6 mg/m2/day, about 2.6 times the recommended human dose with SANCUSO, on a body surface area basis) in males and 5 mg/kg/day (30 mg/m2/day, about 13 times the recommended human dose with SANCUSO, on a body surface area basis) in females.

In a 12-month oral toxicity study, treatment with granisetron 100 mg/kg/day (600 mg/m2/day, about 261 times the recommended human dose with SANCUSO, on a body surface area basis) produced hepatocellular adenomas in male and female rats while no such tumors were found in the control rats. A 24-month mouse carcinogenicity study of granisetron did not show a statistically significant increase in tumor incidence, but the study was not conclusive.

Because of the tumor findings in rat studies, SANCUSO should be prescribed only at the dose and for the indication recommended [see Indications and Usage (1), Dosage and Administration (2)].

Granisetron was not mutagenic in an in vitro Ames test and mouse lymphoma cell forward mutation assay, and in vivo mouse micronucleus test and in vitro and ex vivo rat hepatocyte UDS assays. It, however, produced a significant increase in UDS in HeLa cells in vitro and a significant increased incidence of cells with polyploidy in an in vitro human lymphocyte chromosomal aberration test.

Granisetron at subcutaneous doses up to 6 mg/kg/day (36 mg/m2/day, about 16 times the recommended human dose of SANCUSO, on a body surface area basis), and oral doses up to 100 mg/kg/day (600 mg/m2/day, about 261 times the recommended human dose of SANCUSO, on a body surface area basis) was found to have no effect on fertility and reproductive performance of male and female rats.

When tested for potential photogenotoxicity in vitro in a Chinese hamster ovary (CHO) cell line, at 200 and 300 mcg/mL, granisetron increased the percentage of cells with chromosomal aberration following photoirradiation [see Warnings and Precautions (5.5)].

Granisetron was not phototoxic when tested in vitro in a mouse fibroblast cell line. When tested in vivo in guinea-pigs, SANCUSO transdermal system did not show any potential for photoirritation or photosensitivity. No phototoxicity studies have been performed in humans.

The effectiveness of SANCUSO in the prevention of chemotherapy-induced nausea and vomiting (CINV) was evaluated in a randomized, parallel group, double-blind, double-dummy study conducted in the U.S. and abroad. The study compared the efficacy, tolerability and safety of SANCUSO transdermal system with that of 2 mg oral granisetron once daily in the prevention of nausea and vomiting in a total of 641 patients receiving multi-day chemotherapy.

{ "type": "p", "children": [], "text": "The effectiveness of SANCUSO in the prevention of chemotherapy-induced nausea and vomiting (CINV) was evaluated in a randomized, parallel group, double-blind, double-dummy study conducted in the U.S. and abroad. The study compared the efficacy, tolerability and safety of SANCUSO transdermal system with that of 2 mg oral granisetron once daily in the prevention of nausea and vomiting in a total of 641 patients receiving multi-day chemotherapy.\n" }

The population randomized into the trial included 48% males and 52% females aged 16 to 86 years receiving moderately emetogenic (ME) or highly emetogenic (HE) multi-day chemotherapy. Seventy-eight (78%) of patients were White, 12% Asian, 10% Hispanic/Latino and 0% Black.

{ "type": "p", "children": [], "text": "The population randomized into the trial included 48% males and 52% females aged 16 to 86 years receiving moderately emetogenic (ME) or highly emetogenic (HE) multi-day chemotherapy. Seventy-eight (78%) of patients were White, 12% Asian, 10% Hispanic/Latino and 0% Black.\n" }

SANCUSO was applied 24 to 48 hours before the first dose of chemotherapy and kept in place for 7 days. Oral granisetron was administered daily for the duration of the chemotherapy regimen, 1hour before each dose of chemotherapy. Efficacy was assessed from the first administration until 24 hours after the start of the last day's administration of the chemotherapy regimen.

{ "type": "p", "children": [], "text": "SANCUSO was applied 24 to 48 hours before the first dose of chemotherapy and kept in place for 7 days. Oral granisetron was administered daily for the duration of the chemotherapy regimen, 1hour before each dose of chemotherapy. Efficacy was assessed from the first administration until 24 hours after the start of the last day's administration of the chemotherapy regimen.\n" }

The primary endpoint of the trial was the proportion of patients achieving no vomiting and/or retching, no more than mild nausea and no rescue medication from the first administration until 24 hours after the start of the last day's administration of multi-day chemotherapy. Using this definition, the effect of SANCUSO was established in 60.2% of patients in the SANCUSO arm and 64.8% of patients receiving oral granisetron (difference -4.89%; 95% confidence interval – 12.91% to +3.13%).

{ "type": "p", "children": [], "text": "The primary endpoint of the trial was the proportion of patients achieving no vomiting and/or retching, no more than mild nausea and no rescue medication from the first administration until 24 hours after the start of the last day's administration of multi-day chemotherapy. Using this definition, the effect of SANCUSO was established in 60.2% of patients in the SANCUSO arm and 64.8% of patients receiving oral granisetron (difference -4.89%; 95% confidence interval – 12.91% to +3.13%).\n" }

An assessment of transdermal system adhesion in 621 patients receiving either active or placebo transdermal system showed that less than 1% of transdermal systems became detached over the course of the 7 day period of transdermal system application.

{ "type": "p", "children": [], "text": "An assessment of transdermal system adhesion in 621 patients receiving either active or placebo transdermal system showed that less than 1% of transdermal systems became detached over the course of the 7 day period of transdermal system application.\n" }

SANCUSO (granisetron transdermal system) is a 52 cm2 thin, translucent, rectangular-shaped transdermal system with rounded corners imprinted on one side with "Granisetron 3.1 mg/24 hours". The transdermal system releases 3.1 mg of granisetron per 24 hours for up to 7 days.

{ "type": "p", "children": [], "text": "SANCUSO (granisetron transdermal system) is a 52 cm2 thin, translucent, rectangular-shaped transdermal system with rounded corners imprinted on one side with \"Granisetron 3.1 mg/24 hours\". The transdermal system releases 3.1 mg of granisetron per 24 hours for up to 7 days.\n" }

Each SANCUSO transdermal system is packaged in a separate sealed foil-lined plastic pouch supplied in packages of 1 (NDC 66220-637-31) transdermal system.

{ "type": "p", "children": [], "text": "Each SANCUSO transdermal system is packaged in a separate sealed foil-lined plastic pouch supplied in packages of 1 (NDC 66220-637-31) transdermal system.\n" }

Store at 20°-25°C (68°-77°F); excursions permitted between 15°-30°C (59°-86°F). [see USP Controlled Room Temperature].

{ "type": "p", "children": [], "text": "Store at 20°-25°C (68°-77°F); excursions permitted between 15°-30°C (59°-86°F). [see USP Controlled Room Temperature].\n" }

SANCUSO should be stored in the original packaging.

{ "type": "p", "children": [], "text": "SANCUSO should be stored in the original packaging.\n" }

Progressive Ileus and Gastric Distention

Advise the patient to report new or worsening constipation to their healthcare provider and seek immediate medical care if symptoms of an ileus (pain or swelling in their abdomen) occur [see Warnings and Precautions (5.1)].

Serotonin Syndrome

Advise the patient of the possibility of serotonin syndrome with concomitant use of SANCUSO and another serotonergic agent such as medications to treat depression and migraines. Advise the patient to seek immediate medical attention if the following symptoms occur: changes in mental status, autonomic instability, neuromuscular symptoms, with or without gastrointestinal symptoms [see Warnings and Precautions (5.2)].

Skin Reactions

Instruct the patient remove the transdermal system if they have a severe skin reaction, or a generalized skin reaction (e.g. allergic rash, including erythematous, macular, papular rash or pruritus) [see Warnings and Precautions (5.3)].

Increased Drug Exposure with Use of External Heat Sources

Advise the patient to avoid prolonged exposure to heat and not to apply a heat pad or heat lamp over or near the SANCUSO transdermal system and avoid extended exposure to heat [see Warnings and Precautions (5.4)].

Phototoxicity with Ultraviolet Light Exposure

Advise the patient to avoid direct sunlight or exposure to sunlamps and to cover the application site of the transdermal system with clothing, if there is a risk of exposure to sunlight or sunlamps throughout the period of wear and for 10 days following its removal [see Warnings and Precautions (5.5)].

Application and Removal Instructions

Instruct the patient on how to apply and remove the transdermal system:

Manufactured by: Kindeva Drug Delivery L.P.Northridge, CA 91324

Manufactured for: Cumberland Pharmaceuticals Inc.Nashville, TN 37203

US Patent Number 7608282SANCUSO® is a registered trademark of Cumberland Pharmaceuticals Inc.

<div class="scrollingtable"><table width="100%"> <col align="left" width="80.000%"/> <col align="left" width="20.000%"/> <tfoot> <tr class="First Last"> <td align="left" valign="top"> <p class="First Footnote">This Patient Information has been approved by the U.S. Food and Drug Administration </p> </td><td align="right" valign="top"> <p class="First Footnote">Revised: 07/2024 </p> </td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td align="center" class="Botrule Lrule Rrule Toprule" colspan="2" valign="top"><span class="Bold">Patient Information <br/>SANCUSO</span><span class="Bold"><span class="Sup">® </span></span><span class="Bold">[san-KOO-so] </span> <br/>(granisetron transdermal system) <br/>for transdermal use </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" colspan="2" valign="top"><span class="Bold">Important: For skin use only.</span></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" colspan="2" valign="top">Read the Patient Information that comes with SANCUSO before you start using it and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or your treatment. If you have any questions about SANCUSO, ask your healthcare provider. </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" colspan="2" valign="top"><span class="Bold">What is SANCUSO?</span> <br/>SANCUSO is a prescription medicine used to prevent nausea and vomiting in adults receiving anti-cancer (chemotherapy) treatment that causes moderate or severe vomiting.<br/>SANCUSO is a skin patch (transdermal system) that slowly releases the medicine into your bloodstream while you wear the transdermal system.<br/>It is not known if SANCUSO is safe and effective in children. </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" colspan="2" valign="top"><span class="Bold">Who should not use SANCUSO?</span> <br/>Do not use SANCUSO if you are allergic to granisetron or any of the ingredients in SANCUSO. See the end of this leaflet for a list of ingredients in SANCUSO. </td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="2" valign="top"><span class="Bold">What should I tell my healthcare provider before using SANCUSO? Before using SANCUSO, tell your healthcare provider about all of your medical conditions, including if you:</span> <br/> <ul class="Disc"> <li>have pain or swelling in your stomach area (abdomen). </li> <li>are pregnant. It is not known if SANCUSO will harm your unborn baby. Talk to your healthcare provider if you are pregnant or plan to become pregnant. </li> <li>are breastfeeding or plan to breastfeed. It is not known if SANCUSO passes into your breast milk. </li> </ul> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" colspan="2" valign="top"><span class="Bold">Tell your healthcare provider about all the medicines you take</span>, including prescription and over-the-counter medicines, vitamins and herbal supplements. Other medicines may affect how SANCUSO works. SANCUSO may also affect how other medicines work. SANCUSO contains granisetron. Do not take other granisetron containing products with SANCUSO.<br/>Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine. </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" colspan="2" valign="top"><span class="Bold">How should I use SANCUSO?</span> <br/> <ul class="Disc"> <li>Read the Instructions for Use that comes with SANCUSO transdermal system. </li> <li>Use SANCUSO exactly as your healthcare provider tells you to. </li> </ul> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" colspan="2" valign="top"><span class="Bold">What should I avoid while using SANCUSO?</span> <br/> <span class="Bold">Do not apply any heat source over or near the SANCUSO transdermal system.</span> <br/> <ul class="Disc"> <li>A heating pad or heat lamp should not be used where the transdermal system is applied. </li> <li>You should avoid long periods of exposure to heat because heat can increase the amount of SANCUSO in your blood. </li> <li> <span class="Bold">Avoid sunlight and artificial sunlight.</span> The medicine in SANCUSO may not work as well and may affect your skin if exposed to direct sunlight or artificial sunlight from sunlamps or tanning beds. </li> <li>Keep the transdermal system covered with clothing if you will be in direct sunlight or artificial sunlight. </li> <li>Keep the skin where SANCUSO was applied covered for another 10 days after the transdermal system is taken off to protect from exposure to direct sunlight or artificial sunlight. </li> </ul> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" colspan="2" valign="top"><span class="Bold">What are the possible side effects of SANCUSO?</span> <br/>SANCUSO may cause serious side effects, including:<br/> <ul class="Disc"> <li> <span class="Bold">Using SANCUSO may make it harder to identify certain stomach (abdomen) and bowel problems that are from other causes.</span> Tell your healthcare provider if you have any abdominal pain or swelling while using SANCUSO. </li> </ul> </td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="2" valign="top"> <ul class="Disc"> <li> <span class="Bold">Serotonin Syndrome.</span> A potentially life-threatening problem called serotonin syndrome can happen if you use SANCUSO with certain medicines. <span class="Bold">Call your healthcare provider or go to the nearest hospital emergency room right away</span> if you have any of the following signs and symptoms of serotonin syndrome:<div class="scrollingtable"><table class="Noautorules" width="100%"> <col align="left" width="52.600%"/> <col align="left" width="47.400%"/> <tbody class="Headless"> <tr> <td align="left" valign="top"> <ul class="Circle"> <li>agitation </li> <li>seeing or hearing things that are not real (hallucinations) </li> <li>confusion </li> <li>coma </li> <li>fast heart beat </li> <li>changes in blood pressure </li> <li>dizziness </li> </ul> </td><td align="left" valign="top"> <ul class="Circle"> <li>sweating </li> <li>flushing </li> <li>high body temperature (hyperthermia) </li> <li>shaking (tremors), stiff muscles, or muscle twitching </li> <li>loss of coordination </li> <li>seizures </li> <li>nausea, vomiting, diarrhea </li> </ul> </td> </tr> </tbody> </table></div> </li> <li> <span class="Bold">Skin reactions.</span> Skin reactions can happen at the transdermal system application site or outside the transdermal system application site. Tell your healthcare provider if you get any redness, rashes, bumps, blisters or itching at or near the transdermal system application site, and especially if they spread outside the place where the transdermal system was applied or if they appear outside the transdermal system application site. You may need to stop using SANCUSO. </li> </ul> </td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="2" valign="top"><span class="Bold">The most common side effects of SANCUSO include:</span> <br/> <ul class="Disc"> <li>constipation </li> </ul> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" colspan="2" valign="top">Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of SANCUSO. For more information, ask your healthcare provider or pharmacist.<br/>Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. </td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="2" valign="top"><span class="Bold">How should I store SANCUSO?</span> <br/> <ul class="Disc"> <li>Store SANCUSO at room temperature between 68°F to 77°F (20°C to 25°C). </li> <li>Keep SANCUSO in the original package it comes in. </li> </ul> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" colspan="2" valign="top"><span class="Bold">Keep SANCUSO out of the reach of children.</span></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" colspan="2" valign="top"><span class="Bold">General information about the safe and effective use of SANCUSO.</span> <br/>Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use SANCUSO for a condition for which it was not prescribed. Do not give SANCUSO to other people, even if they have the same symptoms that you have. It may harm them. This Patient Information leaflet summarizes the most important information about SANCUSO. You can ask your pharmacist or healthcare provider for information about SANCUSO that is written for health professionals. </td> </tr> <tr class="Last"> <td align="left" class="Botrule Lrule Rrule" colspan="2" valign="top">Manufactured by:<br/>Kindeva Drug Delivery L.P.<br/>Northridge, CA 91324<br/> <br/>Manufactured for:<br/>Cumberland Pharmaceuticals Inc.<br/>Nashville, TN 37203<br/>For more information, go to <span class="Underline">www.sancuso.com</span> or call 1-877-683-6110. </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table width=\"100%\">\n<col align=\"left\" width=\"80.000%\"/>\n<col align=\"left\" width=\"20.000%\"/>\n<tfoot>\n<tr class=\"First Last\">\n<td align=\"left\" valign=\"top\">\n<p class=\"First Footnote\">This Patient Information has been approved by the U.S. Food and Drug Administration\n</p>\n</td><td align=\"right\" valign=\"top\">\n<p class=\"First Footnote\">Revised: 07/2024\n</p>\n</td>\n</tr>\n</tfoot>\n<tbody class=\"Headless\">\n<tr class=\"First\">\n<td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" colspan=\"2\" valign=\"top\"><span class=\"Bold\">Patient Information <br/>SANCUSO</span><span class=\"Bold\"><span class=\"Sup\">®\n</span></span><span class=\"Bold\">[san-KOO-so]\n</span>\n<br/>(granisetron transdermal system) <br/>for transdermal use\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\"><span class=\"Bold\">Important: For skin use only.</span></td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\">Read the Patient Information that comes with SANCUSO before you start using it and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or your treatment. If you have any questions about SANCUSO, ask your healthcare provider.\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\"><span class=\"Bold\">What is SANCUSO?</span>\n<br/>SANCUSO is a prescription medicine used to prevent nausea and vomiting in adults receiving anti-cancer (chemotherapy) treatment that causes moderate or severe vomiting.<br/>SANCUSO is a skin patch (transdermal system) that slowly releases the medicine into your bloodstream while you wear the transdermal system.<br/>It is not known if SANCUSO is safe and effective in children.\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\"><span class=\"Bold\">Who should not use SANCUSO?</span>\n<br/>Do not use SANCUSO if you are allergic to granisetron or any of the ingredients in SANCUSO. See the end of this leaflet for a list of ingredients in SANCUSO.\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"2\" valign=\"top\"><span class=\"Bold\">What should I tell my healthcare provider before using SANCUSO? Before using SANCUSO, tell your healthcare provider about all of your medical conditions, including if you:</span>\n<br/>\n<ul class=\"Disc\">\n<li>have pain or swelling in your stomach area (abdomen).\n</li>\n<li>are pregnant. It is not known if SANCUSO will harm your unborn baby. Talk to your healthcare provider if you are pregnant or plan to become pregnant.\n</li>\n<li>are breastfeeding or plan to breastfeed. It is not known if SANCUSO passes into your breast milk.\n</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\"><span class=\"Bold\">Tell your healthcare provider about all the medicines you take</span>, including prescription and over-the-counter medicines, vitamins and herbal supplements. Other medicines may affect how SANCUSO works. SANCUSO may also affect how other medicines work. SANCUSO contains granisetron. Do not take other granisetron containing products with SANCUSO.<br/>Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine.\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\"><span class=\"Bold\">How should I use SANCUSO?</span>\n<br/>\n<ul class=\"Disc\">\n<li>Read the Instructions for Use that comes with SANCUSO transdermal system.\n</li>\n<li>Use SANCUSO exactly as your healthcare provider tells you to.\n</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\"><span class=\"Bold\">What should I avoid while using SANCUSO?</span>\n<br/>\n<span class=\"Bold\">Do not apply any heat source over or near the SANCUSO transdermal system.</span>\n<br/>\n<ul class=\"Disc\">\n<li>A heating pad or heat lamp should not be used where the transdermal system is applied.\n</li>\n<li>You should avoid long periods of exposure to heat because heat can increase the amount of SANCUSO in your blood.\n</li>\n<li>\n<span class=\"Bold\">Avoid sunlight and artificial sunlight.</span> The medicine in SANCUSO may not work as well and may affect your skin if exposed to direct sunlight or artificial sunlight from sunlamps or tanning beds.\n</li>\n<li>Keep the transdermal system covered with clothing if you will be in direct sunlight or artificial sunlight.\n</li>\n<li>Keep the skin where SANCUSO was applied covered for another 10 days after the transdermal system is taken off to protect from exposure to direct sunlight or artificial sunlight.\n</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\"><span class=\"Bold\">What are the possible side effects of SANCUSO?</span>\n<br/>SANCUSO may cause serious side effects, including:<br/>\n<ul class=\"Disc\">\n<li>\n<span class=\"Bold\">Using SANCUSO may make it harder to identify certain stomach (abdomen) and bowel problems that are from other causes.</span> Tell your healthcare provider if you have any abdominal pain or swelling while using SANCUSO.\n</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"2\" valign=\"top\">\n<ul class=\"Disc\">\n<li>\n<span class=\"Bold\">Serotonin Syndrome.</span> A potentially life-threatening problem called serotonin syndrome can happen if you use SANCUSO with certain medicines. <span class=\"Bold\">Call your healthcare provider or go to the nearest hospital emergency room right away</span> if you have any of the following signs and symptoms of serotonin syndrome:<div class=\"scrollingtable\"><table class=\"Noautorules\" width=\"100%\">\n<col align=\"left\" width=\"52.600%\"/>\n<col align=\"left\" width=\"47.400%\"/>\n<tbody class=\"Headless\">\n<tr>\n<td align=\"left\" valign=\"top\">\n<ul class=\"Circle\">\n<li>agitation\n</li>\n<li>seeing or hearing things that are not real (hallucinations)\n</li>\n<li>confusion\n</li>\n<li>coma\n</li>\n<li>fast heart beat\n</li>\n<li>changes in blood pressure\n</li>\n<li>dizziness\n</li>\n</ul>\n</td><td align=\"left\" valign=\"top\">\n<ul class=\"Circle\">\n<li>sweating\n</li>\n<li>flushing\n</li>\n<li>high body temperature (hyperthermia)\n</li>\n<li>shaking (tremors), stiff muscles, or muscle twitching\n</li>\n<li>loss of coordination\n</li>\n<li>seizures\n</li>\n<li>nausea, vomiting, diarrhea\n</li>\n</ul>\n</td>\n</tr>\n</tbody>\n</table></div>\n</li>\n<li>\n<span class=\"Bold\">Skin reactions.</span> Skin reactions can happen at the transdermal system application site or outside the transdermal system application site. Tell your healthcare provider if you get any redness, rashes, bumps, blisters or itching at or near the transdermal system application site, and especially if they spread outside the place where the transdermal system was applied or if they appear outside the transdermal system application site. You may need to stop using SANCUSO.\n</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"2\" valign=\"top\"><span class=\"Bold\">The most common side effects of SANCUSO include:</span>\n<br/>\n<ul class=\"Disc\">\n<li>constipation\n</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\">Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of SANCUSO. For more information, ask your healthcare provider or pharmacist.<br/>Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"2\" valign=\"top\"><span class=\"Bold\">How should I store SANCUSO?</span>\n<br/>\n<ul class=\"Disc\">\n<li>Store SANCUSO at room temperature between 68°F to 77°F (20°C to 25°C).\n</li>\n<li>Keep SANCUSO in the original package it comes in.\n</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\"><span class=\"Bold\">Keep SANCUSO out of the reach of children.</span></td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\"><span class=\"Bold\">General information about the safe and effective use of SANCUSO.</span>\n<br/>Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use SANCUSO for a condition for which it was not prescribed. Do not give SANCUSO to other people, even if they have the same symptoms that you have. It may harm them. This Patient Information leaflet summarizes the most important information about SANCUSO. You can ask your pharmacist or healthcare provider for information about SANCUSO that is written for health professionals.\n</td>\n</tr>\n<tr class=\"Last\">\n<td align=\"left\" class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\">Manufactured by:<br/>Kindeva Drug Delivery L.P.<br/>Northridge, CA 91324<br/>\n<br/>Manufactured for:<br/>Cumberland Pharmaceuticals Inc.<br/>Nashville, TN 37203<br/>For more information, go to <span class=\"Underline\">www.sancuso.com</span> or call 1-877-683-6110.\n</td>\n</tr>\n</tbody>\n</table></div>" }

Instructions for Use SANCUSO® [san-KOO-so] (granisetron transdermal system) for transdermal use

{ "type": "p", "children": [], "text": "\nInstructions for Use SANCUSO®\n[san-KOO-so] (granisetron transdermal system) for transdermal use\n" }

Read this Instructions for Use before you start using SANCUSO transdermal system and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or treatment.

{ "type": "p", "children": [], "text": "Read this Instructions for Use before you start using SANCUSO transdermal system and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or treatment.\n" }

Important Information:

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

{ "type": "ul", "children": [ "SANCUSO is for skin use only (transdermal system).\n", "Avoid exposing the SANCUSO transdermal system application site to direct heat sources such as a heating pad or heat lamp.\n", "Avoid exposing the SANCUSO transdermal system to direct sunlight or artificial light such as a sunlamp or tanning bed.\n", "Keep the SANCUSO transdermal system covered with clothing if you will be in sunlight or artificial sunlight.\n", "Keep the skin where the SANCUSO transdermal system was applied covered for another 10 days after the SANCUSO transdermal system is taken off, to protect from exposure to direct sunlight or artificial sunlight.\n", "Skin reactions can happen at the SANCUSO transdermal system application site or outside the SANCUSO transdermal system application site. Tell your healthcare provider if you get any redness, rashes, bumps, blisters or itching at the SANCUSO transdermal system application site, and especially if they spread outside the place where the SANCUSO transdermal system was applied or if they appear outside the SANCUSO transdermal system application site. You may need to stop using the SANCUSO transdermal system.\n" ], "text": "" }

How should I store the SANCUSO transdermal system?

{ "type": "p", "children": [], "text": "\nHow should I store the SANCUSO transdermal system?\n" }

{ "type": "ul", "children": [ "Store the SANCUSO transdermal system at room temperature between 68°F to 77°F (20°C to 25°C).\n", "Keep the SANCUSO transdermal system in the original package it comes in.\n", "Do not open the package until you are ready to apply the SANCUSO transdermal system.\n" ], "text": "" }

Supplies:

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

{ "type": "ul", "children": [ "SANCUSO transdermal system\n", "surgical or medical adhesive tape (not included)\n" ], "text": "" }

When do I apply the SANCUSO transdermal system?

{ "type": "p", "children": [], "text": "\nWhen do I apply the SANCUSO transdermal system?\n" }

{ "type": "ul", "children": [ "Use the SANCUSO transdermal system exactly as your healthcare provider tells you to.\n", "Apply the SANCUSO transdermal system at least 1 day (24 hours) or up to 2 days (48 hours) before your scheduled anti-cancer (chemotherapy) treatment.\n", "Wear the SANCUSO transdermal system all the time during your chemotherapy treatment.\n", "Wait at least 1 day (24 hours) after your chemotherapy treatment is finished to remove the SANCUSO transdermal system.\n", "The SANCUSO transdermal system may be worn for up to 7 days.\n" ], "text": "" }

Where do I apply the SANCUSO transdermal system?

{ "type": "p", "children": [], "text": "\nWhere do I apply the SANCUSO transdermal system?\n" }

{ "type": "ul", "children": [ "SANCUSO transdermal system should only be applied to the outside of the upper arm.\n", "Apply the SANCUSO transdermal system to a clean, dry, nearly hairless, healthy area of skin on the outside part of your upper arm. If there is hair, do not shave. Instead, clip hair as close to the skin as possible.\n\n", "The area you choose should not be oily or recently shaved. The SANCUSO transdermal system should not be placed on skin that is red, irritated, or damaged (cut or scraped).\n", "\nDo not apply the SANCUSO transdermal system to areas that have been treated with creams, oils, lotions, powders or other skin products that could keep the SANCUSO transdermal system from sticking well to your skin.\n" ], "text": "" }

How do I apply the SANCUSO transdermal system?

{ "type": "p", "children": [], "text": "\nHow do I apply the SANCUSO transdermal system?\n" }

The SANCUSO transdermal system comes inside a pouch which is inside the carton.

{ "type": "p", "children": [], "text": "The SANCUSO transdermal system comes inside a pouch which is inside the carton.\n" }

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

What do I do if the SANCUSO transdermal system does not stick well?

{ "type": "p", "children": [], "text": "\nWhat do I do if the SANCUSO transdermal system does not stick well?\n" }

If the SANCUSO transdermal system does not stick well or the edges lift off the skin, you may apply pieces of surgical or medical adhesive tape on each lifted edge to keep the SANCUSO transdermal system in place. Only place pieces of the surgical or medical adhesive tape on the edges of the SANCUSO transdermal system. Do not completely cover the SANCUSO transdermal system with surgical or medical adhesive tape and do not wrap completely around your arm. If the SANCUSO transdermal system comes more than half off or it becomes damaged (e.g. rips), contact your healthcare provider.

{ "type": "p", "children": [], "text": "If the SANCUSO transdermal system does not stick well or the edges lift off the skin, you may apply pieces of surgical or medical adhesive tape on each lifted edge to keep the SANCUSO transdermal system in place. Only place pieces of the surgical or medical adhesive tape on the edges of the SANCUSO transdermal system. Do not completely cover the SANCUSO transdermal system with surgical or medical adhesive tape and do not wrap completely around your arm. If the SANCUSO transdermal system comes more than half off or it becomes damaged (e.g. rips), contact your healthcare provider.\n" }

Can I bathe or shower while wearing the SANCUSO transdermal system?

{ "type": "p", "children": [], "text": "\nCan I bathe or shower while wearing the SANCUSO transdermal system?\n" }

You can continue to shower and wash normally while wearing the SANCUSO transdermal system.

{ "type": "p", "children": [], "text": "You can continue to shower and wash normally while wearing the SANCUSO transdermal system.\n" }

It is not known how other activities, for example swimming, strenuous exercise or using a sauna or whirlpool, may affect the SANCUSO transdermal system. Avoid these activities while wearing the SANCUSO transdermal system.

{ "type": "p", "children": [], "text": "It is not known how other activities, for example swimming, strenuous exercise or using a sauna or whirlpool, may affect the SANCUSO transdermal system. Avoid these activities while wearing the SANCUSO transdermal system.\n" }

How do I remove and dispose of the SANCUSO transdermal system?

{ "type": "p", "children": [], "text": "\nHow do I remove and dispose of the SANCUSO transdermal system?\n" }

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

What are the ingredients in the SANCUSO transdermal system?

{ "type": "p", "children": [], "text": "\nWhat are the ingredients in the SANCUSO transdermal system?\n" }

Active ingredient: granisetron.

{ "type": "p", "children": [], "text": "Active ingredient: granisetron.\n" }

Inactive ingredients: acrylate-vinylacetate copolymer, polyester, titanium dioxide, polyamide resin and polyethylene wax. This Instructions for Use has been approved by the U.S. Food and Drug Administration.

{ "type": "p", "children": [], "text": "Inactive ingredients: acrylate-vinylacetate copolymer, polyester, titanium dioxide, polyamide resin and polyethylene wax. This Instructions for Use has been approved by the U.S. Food and Drug Administration.\n" }

Manufactured by: Kindeva Drug Delivery L.P.Northridge, CA 91324

{ "type": "p", "children": [], "text": "\nManufactured by:\nKindeva Drug Delivery L.P.Northridge, CA 91324\n" }

Manufactured for: Cumberland Pharmaceuticals Inc., Nashville, TN 37203

{ "type": "p", "children": [], "text": "\nManufactured for:\nCumberland Pharmaceuticals Inc., Nashville, TN 37203\n" }

Revised: 07/2024

{ "type": "p", "children": [], "text": "\nRevised: 07/2024\n" }

Principal Display Panel – 168 h Pouch Label

{ "type": "p", "children": [], "text": "\nPrincipal Display Panel – 168 h Pouch Label\n" }

Sancuso®

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

(Granisetron Transdermal System)

{ "type": "p", "children": [], "text": "(Granisetron Transdermal System)\n" }

3.1 mg/24 hours

{ "type": "p", "children": [], "text": "\n3.1 mg/24 hours\n" }

NDC 66220-637-31

{ "type": "p", "children": [], "text": "\nNDC 66220-637-31\n" }

7 day transdermal system

{ "type": "p", "children": [], "text": "7 day transdermal system\n" }

Each 52 cm2 transdermal systemcontains 34.3 mg of granisetron.

{ "type": "p", "children": [], "text": "Each 52 cm2 transdermal systemcontains 34.3 mg of granisetron.\n" }

For Transdermal Use Only.

{ "type": "p", "children": [], "text": "\nFor Transdermal Use Only.\n" }

Read patient information before use.Do not cut the transdermal system.Keep out of the reach of children.Store at 20° to 25°C (68° to 77°F).Keep pouch in outer carton.Rx Only

{ "type": "p", "children": [], "text": "Read patient information before use.Do not cut the transdermal system.Keep out of the reach of children.Store at 20° to 25°C (68° to 77°F).Keep pouch in outer carton.Rx Only\n" }

Includes 1 transdermal system

{ "type": "p", "children": [], "text": "Includes 1 transdermal system\n" }

Mfd. for:

{ "type": "p", "children": [], "text": "Mfd. for:\n" }

Cumberland Pharmaceuticals Inc.

{ "type": "p", "children": [], "text": "Cumberland Pharmaceuticals Inc.\n" }

Nashville, TN 37203

{ "type": "p", "children": [], "text": "Nashville, TN 37203\n" }

CUMBERLAND® PHARMACEUTICALS

{ "type": "p", "children": [], "text": "CUMBERLAND®\nPHARMACEUTICALS\n" }