Mechanism of Action

Granisetron is a selective 5-hydroxytryptamine3 (5-HT₃) receptor antagonist with little or no affinity for other serotonin receptors, including 5-HT₁; 5-HT_1A; 5-HT_1B/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 enterochromaffm 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.

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.

Pharmacokinetics

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 KYTRIL Injection are shown in Table 3.

Table 3: Pharmacokinetic Parameters in Adult Cancer Patients Undergoing Chemotherapy and in Volunteers, Following a Single Intravenous 40 mcg/kg Dose of KYTRIL Injection

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 3 A 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 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 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 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, 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 KYTRIL Injection administered intravenously over 30 seconds are shown in Table 4.

Table 4: Pharmacokinetic Parameters in 16 Adult Surgical Patients Following a Single Intravenous 1 mg Dose of KYTRIL Injection

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

Clinical Studies

Chemotherapy-Induced Nausea and Vomiting

Single-Day 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 5).

Table 5: Prevention of Chemotherapy-Induced Nausea and Vomiting — Single-Day Cisplatin Therapy¹

KYTRIL 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. 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 6).

Table 6 Prevention of Chemotherapy-Induced Nausea and Vomiting — Single-Day High-Dose Cisplatin Therapy¹

KYTRIL 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.

Table 7: Prevention of Chemotherapy-Induced Nausea and Vomiting — Single-Day High-Dose and Low-Dose Cisplatin Therapy1

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/m², cisplatin 20 to 50 mg/m² and cyclophosphamide > 600 mg/m². KYTRIL Injection was superior to the chlorpromazine regimen in preventing nausea and vomiting (see Table 8).

Table 8: Prevention of Chemotherapy-Induced Nausea and Vomiting—Single-Day Moderately Emetogenic Chemotherapy

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.

Repeat-Cycle Chemotherapy

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.

Pediatric Studies

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/m², cytarabine ≥ 3 g/m², cyclophosphamide ≥ 1 g/m² or nitrogen mustard ≥ 6 mg/m² (see Table 9).

Table 9: Prevention of Chemotherapy-Induced Nausea and Vomiting in Pediatric Patients

A second pediatric study compared KYTRIL Injection 20 mcg/kg to chlorpromazine plus dexamethasone in 88 patients treated with ifosfamide ≥ 3 g/m²/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.

Postoperative Nausea and Vomiting

Prevention of Postoperative Nausea and Vomiting

The efficacy of KYTRIL 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. KYTRIL 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 KYTRIL 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, KYTRIL 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.

Table 10: Prevention of Postoperative Nausea and Vomiting in Adult Patients

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 KYTRIL 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. KYTRIL 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 KYTRIL 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. KYTRIL 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.

Table 11: Treatment of Postoperative Nausea and Vomiting in Adult Patients

Gender/Race

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

Last reviewed on RxList: 6/22/2011
This monograph has been modified to include the generic and brand name in many instances.