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Kytril (granisetron hydrochloride) Injection is an antinauseant and antiemetic agent. 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:
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granisetron hydrochloride
Granisetron hydrochloride is a white to off-white solid that is readily soluble in water and normal saline at 20°C. Kytril Injection is a clear, colorless, sterile, nonpyrogenic, aqueous solution for intravenous administration.
Kytril is available in 1 mL single-dose and 4 mL multi-dose vials.
Single-Dose Vials: Each 1 mL of preservative-free aqueous solution contains 1.12 mg granisetron hydrochloride equivalent to granisetron, 1.0 mg and sodium chloride, 9.0 mg. The solution' pH ranges from 4.7 to 7.3.
Multi-Dose Vials: Each 1 mL contains 1.12 mg granisetron hydrochloride equivalent to granisetron, 1.0 mg; sodium chloride, 9 mg; citric acid, 2 mg; benzyl alcohol, 10 mg, as a preservative. The solution' pH ranges from 4.0 to 6.0.
Granisetron is a selective 5-hydroxytryptamine 3 (5-HT 3 ) receptor antagonist with little or no affinity for other serotonin receptors, including 5-HT 1 ; 5-HT 1A ; 5-HT 1B/C ; 5-HT 2 ; for alpha 1 -, alpha 2 - or beta-adrenoreceptors; for dopamine-D 2 ; or for histamine-H 1 ; benzodiazepine; picrotoxin, or opioid receptors.
Serotonin receptors of the 5-HT 3 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-HT 3 receptors. This evokes vagal afferent discharge, inducing vomiting. Animal studies demonstrate that, in binding to 5-HT 3 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.
Kytril 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.
In adult cancer patients undergoing chemotherapy and in volunteers, infusion of a single 40 mcg/kg dose of Kytril Injection produced the following mean pharmacokinetic data:
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There was high inter and intrasubject variability noted in these studies. No difference in mean AUC was found between males and females, although males had a higher C max generally.
Granisetron metabolism involves N-demethylation and aromatic ring oxidation followed by conjugation. Animal studies suggest that some of the metabolites may also have 5-HT 3 receptor antagonist activity.
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.
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.
Plasma protein binding is approximately 65% and granisetron distributes freely between plasma and red blood cells.
Elderly: The ranges of the pharmacokinetic parameters in elderly volunteers (mean age 71 years), given a single 40 mcg/kg intravenous dose of Kytril Injection, were generally similar to those in younger healthy volunteers; mean values were lower for clearance and longer for half-life in the elderly (see Table 1).
Pediatric Patients: A pharmacokinetic study in pediatric cancer patients (2 to 16 years of age), given a single 40 mcg/kg intravenous dose of Kytril 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 Kytril 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 and the good tolerance of doses well above the recommended 10 mcg/kg dose, dosage adjustment in patients with possible hepatic functional impairment is not necessary.
Kytril Injection has been shown to prevent nausea and vomiting associated with single-day and repeat cycle cancer chemotherapy.
Cisplatin-Based Chemotherapy: In a double-blind, placebo-controlled study in 28 cancer patients, Kytril 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 2.
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Kytril Injection was also evaluated in a randomized dose response study of cancer patients receiving cisplatin >/=75 mg/m 2 . Additional chemotherapeutic agents included: anthracyclines, carboplatin, cytostatic antibiotics, folic acid derivatives, methylhydrazine, nitrogen mustard analogs, podophyllotoxin derivatives, pyrimidine analogs and vinca alkaloids. Kytril 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 3.
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Kytril (granisetron hydrochloride) Injection was also evaluated in a double-blind, randomized dose response study of 353 patients stratified for high (>/=80 to 120 mg/m 2 ) or low (50 to 79 mg/m 2 ) cisplatin dose. Response rates of patients for both cisplatin strata are given in Table 4.
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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: Kytril 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/m 2 , cisplatin 20 to 50 mg/m 2 and cyclophosphamide >600 mg/m 2 . Kytril Injection was superior to the chlorpromazine regimen in preventing nausea and vomiting. See Table 5.
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In other studies of moderately emetogenic chemotherapy, no significant difference in efficacy was found between Kytril doses of 40 mcg/kg and 160 mcg/kg doses.
In an uncontrolled trial, 512 cancer patients received Kytril 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. Kytril 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.
A randomized double-blind study evaluated the 24-hour response of 80 pediatric cancer patients (age 2 to 16 years) to Kytril Injection 10, 20 or 40 mcg/kg. Patients were treated with cisplatin >/=60 mg/m 2 , cytarabine >/=3 g/m 2 , cyclophosphamide >/=1 g/m 2 or nitrogen mustard >/=6 mg/m 2 . See Table 6.
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A second pediatric study compared Kytril Injection 20 mcg/kg to chlorpromazine plus dexamethasone in 88 patients treated with ifosfamide >/=3 g/m 2 /day for two or three days. Kytril Injection was administered on each day of ifosfamide treatment. At 24 hours, 22% of Kytril 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 Kytril Injection was 1.5; with chlorpromazine it was 7.0.
Kytril (granisetron hydrochloride) Injection is indicated for the prevention of nausea and vomiting associated with initial and repeat courses of emetogenic cancer therapy, including high-dose cisplatin.
Kytril Injection is contraindicated in patients with known hypersensitivity to the drug or to any of its components.
Granisetron does not induce or inhibit the cytochrome P-450 drug-metabolizing enzyme system. There have been no definitive drug-drug interaction studies to examine pharmacokinetic or pharmacodynamic interaction with other drugs, but in humans, Kytril Injection has been safely administered with drugs representing benzodiazepines, neuroleptics and anti-ulcer medications commonly prescribed with antiemetic treatments. Kytril 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.
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 (1.46m 2 body surface area), these doses represent 16, 81 and 405 times the recommended clinical dose (0.37 mg/m 2 , i.v.) 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, 81 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, 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/m 2 /day, 16 times the recommended human dose based on body surface area) in males and 5 mg/kg/day (30 mg/m 2 /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/m 2 /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, Kytril (granisetron hydrochloride) Injection should be prescribed only at the dose and for the indication recommended (see , 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 subcutaneous doses up to 6 mg/kg/day (36 mg/m 2 /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.
Teratogenic Effects. Pregnancy Category B. Reproduction studies have been performed in pregnant rats at intravenous doses up to 9 mg/kg/day (54 mg/m 2 /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/m 2 /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 Kytril Injection is administered to a nursing woman.
See DOSAGE AND ADMINISTRATION for use in children 2 to 16 years of age. Safety and effectiveness in children under 2 years of age have not been established.
During clinical trials, 713 patients 65 years of age or older received Kytril (granisetron HCl) Injection. Effectiveness and safety were similar in patients of various ages.
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 7 gives the comparative frequencies of the five most commonly reported adverse events (>/=3%) in patients receiving Kytril Injection, in single-day chemotherapy trials. These patients received chemotherapy, primarily cisplatin, and intravenous fluids during the 24-hour period following Kytril Injection administration. Events were generally recorded over seven days post- Kytril Injection administration. In the absence of a placebo group, there is uncertainty as to how many of these events should be attributed to Kytril, except for headache, which was clearly more frequent than in comparison groups.
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In over 3,000 patients receiving Kytril Injection (2 to 160 mcg/kg) in single-day and multiple-day clinical trials with emetogenic cancer therapies, adverse events, other than those in Table 7, were observed; attribution of many of these events to Kytril 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 Kytril 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 nonsustained 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 Kytril Injection (8.6%) than with comparative drugs (3.4%, P <0.014), which usually included dexamethasone.
There is no specific antidote for Kytril (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.
The recommended dosage for Kytril Injection is 10 mcg/kg administered intravenously within 30 minutes before initiation of chemotherapy, and only on the day(s) chemotherapy is given. Kytril 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.
Pediatric Use: The recommended dose in children 2 to 16 years of age is 10 mcg/kg (see CLINICAL TRIALS ). Children under 2 years of age have not been studied.
Use in the Elderly, Renal Failure Patients or Hepatically Impaired Patients: No dosage adjustment is recommended. (See , .)
Kytril Injection, administered as a 5-minute infusion, should be diluted in 0.9% Sodium Chloride or 5% Dextrose to a total volume of 20 to 50 mL.
Intravenous infusion of Kytril Injection should be prepared at the time of administration. However, Kytril 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, Kytril 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.
Kytril (granisetron hydrochloride) Injection, 1 mg/mL (free base), is supplied in 1 mL Single-Use Vials and 4 mL Multi-Dose Vials.
NDC 0029-4149-01 (package of 1 Single-Dose Vial)
NDC 0029-4152-01 (package of 1 Multi-Dose Vial)
Store single-dose vials and multi-dose vials at 25°C (77°F); excursions permitted to 15-30°C (59-86°F).
Once the multi-dose vial is penetrated, its contents should be used within 30 days.
Do not freeze. Protect from light. only
KY:L11A
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