GRANISETRON: 2,547 Adverse Event Reports & Safety Profile

Granisetron Hydrochloride Injection, USP is a serotonin-3 (5-HT 3 ) 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 empirical formula is C 18 H 24 N 4 O•HCl, while its chemical structure is: Granisetron hydrochloride, USP Granisetron hydrochloride, USP is a white to off-white solid that is readily soluble in water and normal saline at 20ºC.

Granisetron Hydrochloride

Injection, USP is a clear, colorless, sterile, nonpyrogenic, aqueous solution for intravenous administration. Granisetron hydrochloride injection, USP 1 mg per mL is available in a 4 mL multiple-dose vial.

Each

1 mL contains granisetron hydrochloride, USP 1.12 mg; equivalent to granisetron, 1 mg; sodium chloride, 9 mg; citric acid anhydrous, 2 mg; methyl paraben, 1.8 mg; and propyl paraben, 0.2 mg as preservatives. Water for injection, q.s.; Sodium hydroxide and/or hydrochloric acid may be added to adjust the pH.The solution’s pH ranges from 4 to 6.

Granisetron Hydrochloride

Injection, USP 1 mg per mL is available in a 1 mL single-dose vial.

Granisetron Hydrochloride

Injection, USP 0.1 mg per mL is available in a 1 mL single-dose vial. 0.1 mg per mL: Each 1 mL contains granisetron hydrochloride USP, 0.112 mg equivalent to granisetron, 0.1 mg; sodium chloride, 9 mg; and citric acid, 2 mg. Contains no preservative. Sodium hydroxide and/or hydrochloric acid may be added to adjust the pH. 1 mg per mL: Each 1 mL contains granisetron hydrochloride USP, 1.12 mg equivalent to granisetron, 1 mg; sodium chloride, 9 mg; and citric acid, 2 mg. Contains no preservative. Sodium hydroxide and/or hydrochloric acid may be added to adjust the pH. chemical structure

AND USAGE Granisetron Hydrochloride Injection, USP is a serotonin-3 (5-HT 3 ) receptor antagonist indicated for: 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, USP is recommended even where the incidence of postoperative nausea and/or vomiting is low.

Granisetron Hydrochloride

Injection, USP is a serotonin-3 (5-HT 3 ) receptor antagonist indicated for: Prevention of nausea and/or vomiting associated with initial and repeat courses of emetogenic cancer therapy, including high-dose cisplatin. ( 1 ) Prevention and treatment of postoperative nausea and vomiting in adults. ( 1 )

AND ADMINISTRATION Administration ( 2.1 ): For subcutaneous injection only. Intended for administration by a healthcare provider. Administer in skin of the back of the upper arm or in the skin of the abdomen at least 1 inch away from the umbilicus. Do not administer anywhere the skin is burned, hardened, inflamed, swollen, or otherwise compromised. Due to the viscosity, administration requires a slow, sustained injection over 20 to 30 seconds.

Recommended

Dosage ( 2.2 ): The recommended dosage in adults is 10 mg administered as a single subcutaneous injection at least 30 minutes before the start of emetogenic chemotherapy on Day 1. Do not administer SUSTOL more frequently than once every 7 days. See full prescribing information for recommended dosage of concomitant dexamethasone.

Renal

Impairment ( 2.3 ): In patients with moderate renal impairment (Clcr 30-59 mL/min), administer SUSTOL not more frequently than once every 14 days. Avoid SUSTOL in patients with severe renal impairment (CLcr < 30 mL/min).

2.1 Important Administration Instructions For subcutaneous injection only. SUSTOL is intended for administration by a health care provider. SUSTOL is supplied as a refrigerated kit consisting of a single-dose, pre-filled, sterile syringe, a special thin walled 18 Ga 5/8&quot; administration needle, two syringe warming pouches, and a Point Lok ® needle protection device. See the SUSTOL Instructions for Use included in the kit for complete administration instructions with illustrations. Do not substitute non-kit components for any of the components from the kit for administration. Preparation At least 60 minutes prior to administration, remove the SUSTOL kit from refrigeration. Unpack the kit to allow the SUSTOL syringe and all other contents to warm to room temperature. Activate one of the syringe warming pouches, and wrap the SUSTOL syringe in the warming pouch for 5 to 6 minutes to warm SUSTOL to body temperature. Prior to administration, inspect the SUSTOL syringe visually for particulate matter and discoloration. Note that the syringe is amber colored glass. SUSTOL should not be administered if particulate matter or discoloration is observed, the tip cap is missing or has been tampered with, or if the Luer fitting is missing or dislodged.

Administration

Use standard aseptic technique when performing the injection. Administer SUSTOL as a single subcutaneous injection in the skin of the back of the upper arm or in the skin of the abdomen at least one inch away from the umbilicus. Avoid injecting SUSTOL anywhere the skin is burned, hardened, inflamed, swollen, or otherwise compromised [see Warnings and Precautions ( 5.1 )] . Topical anesthetic may be used at the injection site prior to administration of SUSTOL. Due to the viscosity of SUSTOL, the time required for injection is greater than most medications administered subcutaneously. SUSTOL requires a slow, sustained injection which may take up to 20 to 30 seconds . Pressing the plunger harder will NOT expel SUSTOL faster.

2.2 Recommended Dosage 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 NK 1 receptor antagonist, see the prescribing information of the NK 1 receptor antagonist for the recommended dexamethasone dosage.

2.3 Dosage Adjustment in Renal Impairment 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) <span class="opacity-50 text-xs">[see Use in Specific Populations ( 8.6 )]</span> .

SUSTOL is contraindicated in patients with hypersensitivity to granisetron, any of the components of SUSTOL, or to any of the other 5-HT 3 receptor antagonists [see Warnings and Precautions ( 5.3 ), Description ( 11 )] . Hypersensitivity to granisetron, any of the components of SUSTOL, or to any of the other 5-HT 3 receptor antagonists. ( 4 , 5.3 )

REACTIONS QT prolongation has been reported with granisetron hydrochloride [see Warnings and Precautions (5.2) and Drug Interactions (7) ] . Most common adverse reactions: Chemotherapy-induced nausea and vomiting (≥3%): Headache, and constipation ( 6.1 ) Postoperative nausea and vomiting (≥ 2%): Pain, headache, fever, abdominal pain and hepatic enzymes increased ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Fresenius Kabi USA, LLC at 1-800-551-7176 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience 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.

Table

1: Principal Adverse Reactions in Clinical Trials — Single-Day Chemotherapy Percent of Patients With Reaction Granisetron Hydrochloride Injection 40 mcg/kg (n=1,268)

Comparator

1 (n=422)

Headache Constipation

14% 3% 6% 3% 1 Metoclopramide/dexamethasone and phenothiazines/dexamethasone. 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.

Table

2: Adverse Reactions in Controlled Clinical Trials in Postoperative Nausea a nd Vomiting (Reported in ≥ 2% of Adults Receiving Granisetron Hydrochloride Injection 1 mg) Percent of Patients With Reaction Granisetron Hydrochloride Injection 1 mg (n=267) Placebo (n=266)

Pain

10.1

8.3 Headache 8.6

7.1 Fever 7.9

4.5 Abdominal Pain 6 6 Hepatic Enzymes Increased 5.6

4.1 Dizziness 4.1

3.4 Diarrhea 3.4

1.1 Flatulence 3 3 Dyspepsia 3

1.9 Oliguria 2.2

1.5 Coughing 2.2

1.1 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%).

6.2 Postmarketing Experience 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 <span class="opacity-50 text-xs">[see Warnings and Precautions (5.2) and Drug Interactions (7) ]</span>.

6.1 Clinical Trials Experience 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.

Table

1: Principal Adverse Reactions in Clinical Trials — Single-Day Chemotherapy Percent of Patients With Reaction Granisetron Hydrochloride Injection 40 mcg/kg (n=1,268)

Comparator

1 (n=422)

Headache Constipation

14% 3% 6% 3% 1 Metoclopramide/dexamethasone and phenothiazines/dexamethasone. 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.

Table

2: Adverse Reactions in Controlled Clinical Trials in Postoperative Nausea a nd Vomiting (Reported in ≥ 2% of Adults Receiving Granisetron Hydrochloride Injection 1 mg) Percent of Patients With Reaction Granisetron Hydrochloride Injection 1 mg (n=267) Placebo (n=266)

Pain

10.1

8.3 Headache 8.6

7.1 Fever 7.9

4.5 Abdominal Pain 6 6 Hepatic Enzymes Increased 5.6

4.1 Dizziness 4.1

3.4 Diarrhea 3.4

1.1 Flatulence 3 3 Dyspepsia 3

1.9 Oliguria 2.2

1.5 Coughing 2.2

1.1 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%).

6.2 Postmarketing Experience 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 <span class="opacity-50 text-xs">[see Warnings and Precautions (5.2) and Drug Interactions (7) ]</span>.

AND PRECAUTIONS Injection site reactions (ISRs), including infection, bleeding, pain, nodules, swelling and induration: Monitor for ISRs following SUSTOL injection. Inform patients that some ISRs may occur 2 weeks or more after SUSTOL administration. In patients receiving antiplatelet agents or anticoagulants, consider the increased risk of bruising or severe hematoma prior to the use of SUSTOL. ( 5.1 ) Gastrointestinal disorders: Monitor for constipation and consider optimizing patients' current bowel regimens used for managing preexisting constipation. Also monitor for decreased bowel activity, particularly in patients with risk factors for gastrointestinal obstruction. Instruct patients to seek immediate medical care if signs and symptoms of ileus occur. ( 5.2 ) Hypersensitivity reactions: Serious reactions have been reported and may occur up to 7 days or longer following SUSTOL administration and may have an extended course. If a reaction occurs, administer appropriate treatment and monitor until signs and symptoms resolve. ( 5.3 ) Serotonin syndrome: Reported with 5-HT receptor antagonists alone but particularly with concomitant use of serotonergic drugs. If such symptoms occur, discontinue SUSTOL and initiate supportive treatment. If concomitant use of SUSTOL with other serotonergic drugs is clinically warranted, patients should be made aware of a potential increased risk for serotonin syndrome. ( 5.4 , 7.1 )

5.1 Injection Site Reactions (ISRs)

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 Monitor patients for ISRs following SUSTOL injection. Some ISRs (infections, bruising, and hematoma) may occur up to 2 weeks or more after SUSTOL administration. In patients receiving antiplatelet agents or anticoagulants, consider the increased risk of bruising or severe hematoma prior to the use of SUSTOL. In patients with ongoing or unresolved ISRs, administer SUSTOL at a site away from areas affected by ISRs [see Dosage and Administration ( 2.1 )] .

5.2 Gastrointestinal Disorders 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-HT 3 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.

5.3 Hypersensitivity Reactions Hypersensitivity reactions, including anaphylaxis, have been reported in granisetron-treated patients who have exhibited hypersensitivity to other 5-HT 3 receptor antagonists <span class="opacity-50 text-xs">[see Contraindications ( 4 )]</span> . Avoid SUSTOL in patients who have had hypersensitivity reactions to other 5-HT 3 receptor antagonists <span class="opacity-50 text-xs">[see Contraindications ( 4 )]</span> . 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.

5.4 Serotonin Syndrome The development of serotonin syndrome has been reported with 5-HT 3 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-HT 3 receptor antagonist alone has also been reported. The majority of reports of serotonin syndrome related to 5-HT 3 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 <span class="opacity-50 text-xs">[see Drug Interactions ( 7.1 )]</span> .

PRECAUTIONS 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.

Drug Interactions

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, this 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-HT 3 receptor antagonists and other serotonergic drugs, including selective serotonin reuptake inhibitors (SSRIs) and serotonin and noradrenaline reuptake inhibitors (SNRIs) ( see WARNINGS ). Carcinogenesis, Mutagenesis, Impairment of Fertility In a 24 month carcinogenicity study, rats were treated orally with granisetron 1, 5 or 50 mg/kg/day (6, 30 or 300 mg/m 2 /day).

The

50 mg/kg/day dose was reduced to 25 mg/kg/day (150 mg/m 2 /day) during week 59 due to toxicity. For a 50 kg person of average height (1.46 m 2 body surface area), these doses represent 4, 20, and 101 times the recommended clinical dose (1.48 mg/m 2 , oral) 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/m 2 /day, 20 times the recommended human dose based on body surface area) and above, and in females treated with 25 mg/kg/day (150 mg/m 2 /day, 101 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/m 2 /day, 4 times the recommended human dose based on body surface area) in males and 5 mg/kg/day (30 mg/m 2 /day, 20 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/m 2 /day, 405 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 should be prescribed only at the dose and for the indication recommended (see INDICATIONS AND USAGE , and DOSAGE AND ADMINISTRATION ). Granisetron was not mutagenic in 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 oral doses up to 100 mg/kg/day (600 mg/m 2 /day, 405 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.

Pregnancy Teratogenic Effects Pregnancy

Category B . Reproduction studies have been performed in pregnant rats at oral doses up to 125 mg/kg/day (750 mg/m 2 /day, 507 times the recommended human dose based on body surface area) and pregnant rabbits at oral doses up to 32 mg/kg/day (378 mg/m 2 /day, 255 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.

Nursing

Mothers 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 is administered to a nursing woman.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

During clinical trials, 325 patients 65 years of age or older received granisetron hydrochloride tablets; 298 were 65 to 74 years of age, and 27 were 75 years of age or older. Efficacy and safety were maintained with increasing age.

INTERACTIONS 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-HT 3 receptor antagonists and other serotonergic drugs, including selective serotonin reuptake inhibitors (SSRIs) and serotonin and noradrenaline reuptake inhibitors (SNRIs) [see Warnings and Precautions (5.4) ] . Granisetron hydrochloride injection has been administered safely with benzodiazepines, neuroleptics, and anti-ulcer medications. ( 7 ) Does not appear to interact with emetogenic cancer chemotherapies. ( 7 ) Inducers or inhibitors of CYP450 enzymes may change the clearance and therefore the half-life of granisetron. ( 7 ) Coadministration of granisetron hydrochloride injection with drugs known to prolong the QT interval and/or are arrhythmogenic may result in clinical consequences. ( 7 )