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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.
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.
Following single and multiple oral doses, KYTRIL (granisetron) Tablets slowed colonic transit in normal volunteers. However, KYTRIL (granisetron) had no effect on oro-cecal transit time in normal volunteers when given as a single intravenous (IV) infusion of 50 mcg/kg or 200 mcg/kg.
In healthy volunteers and adult cancer patients undergoing chemotherapy, administration of KYTRIL (granisetron) Tablets produced mean pharmacokinetic data shown in Table 1.
Table 1 : Pharmacokinetic Parameters (Median [range]) Following
KYTRIL Tablets (granisetron hydrochloride)
|Peak Plasma Concentration
|Terminal Phase Plasma Half-Life (h)||Volume of Distribution (L/kg)||Total Clearance (L/h/kg)|
1 mg bid, 7 days (n=27)
[0.63 to 30.9]
[0.09 to 7.37]
single 1 mg dose (n=39)
[0.27 to 9.14]
[0.96 to 19.9]
[1.89 to 39.4]
[0.11 to 24.6]
|1 Not determined after oral administration;
following a single intravenous dose of 40 mcg/kg, terminal phase half-life
was determined to be 8.95 hours.
N.D. Not determined.
A 2 mg dose of KYTRIL (granisetron) Oral Solution is bioequivalent to the corresponding dose of KYTRIL (granisetron) Tablets (1 mg x 2) and may be used interchangeably.
When KYTRIL (granisetron) Tablets were administered with food, AUC was decreased by 5% and Cmax increased by 30% in non-fasted healthy volunteers who received a single dose of 10 mg.
Plasma protein binding is approximately 65% and granisetron distributes freely between plasma and red blood cells.
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.
Clearance is predominantly by hepatic metabolism. In normal volunteers, approximately 11% of the orally administered dose is eliminated unchanged in the urine in 48 hours. The remainder of the dose is excreted as metabolites, 48% in the urine and 38% in the feces.
The effects of gender on the pharmacokinetics of KYTRIL (granisetron) Tablets have not been studied. However, after intravenous infusion of KYTRIL (granisetron) , no difference in mean AUC was found between males and females, although males had a higher Cmax generally.
In elderly and pediatric patients and in patients with renal failure or hepatic impairment, the pharmacokinetics of granisetron was determined following administration of intravenous KYTRIL (granisetron) .
The ranges of the pharmacokinetic parameters in elderly volunteers (mean age 71 years), given a single 40 mcg/kg intravenous dose of KYTRIL (granisetron) Injection, were generally similar to those in younger healthy volunteers; mean values were lower for clearance and longer for half-life in the elderly.
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 (granisetron) Injection.
Hepatically Impaired Patients
A pharmacokinetic study with intravenous KYTRIL (granisetron) 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.
A pharmacokinetic study in pediatric cancer patients (2 to 16 years of age), given a single 40 mcg/kg intravenous dose of KYTRIL (granisetron) 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.
Chemotherapy-Induced Nausea and Vomiting
KYTRIL (granisetron) Tablets prevent nausea and vomiting associated with initial and repeat courses of emetogenic cancer therapy, as shown by 24-hour efficacy data from studies using both moderately- and highly-emetogenic chemotherapy.
Moderately Emetogenic Chemotherapy
The first trial compared KYTRIL (granisetron) Tablets doses of 0.25 mg to 2 mg twice a day, in 930 cancer patients receiving, principally, cyclophosphamide, carboplatin, and cisplatin (20 mg/m² to 50 mg/m²). Efficacy was based on complete response (ie, no vomiting, no moderate or severe nausea, no rescue medication), no vomiting, and no nausea. Table 2 summarizes the results of this study.
Table 2 : Prevention of Nausea and Vomiting 24 Hours PostChemotherapy1
|Percentages of Patients
KYTRIL Tablet Dose
|Efficacy Measures||0.25 mg
twice a day
twice a day
twice a day
twice a day
|1 Chemotherapy included oral and injectable cyclophosphamide,
carboplatin, cisplatin (20 mg/m² to 50 mg/m²), dacarbazine,
2 No vomiting, no moderate or severe nausea, no rescue medication.
*Statistically significant (P < 0.01) vs. 0.25 mg bid.
†Statistically significant (P < 0.01) vs. 0.5 mg bid.
Results from a second double-blind, randomized trial evaluating KYTRIL (granisetron) Tablets 2 mg once a day and KYTRIL (granisetron) Tablets 1 mg twice a day were compared to prochlorperazine 10 mg twice a day derived from a historical control. At 24 hours, there was no statistically significant difference in efficacy between the two KYTRIL (granisetron) Tablet regimens. Both regimens were statistically superior to the prochlorperazine control regimen (see Table 3).
Table 3 : Prevention of Nausea and Vomiting 24 Hours PostChemotherapy1
|Efficacy Measures||Percentages of Patients|
|KYTRIL (granisetron) Tablets
1 mg twice a day
(n = 354)
|KYTRIL (granisetron) Tablets
2 mg once a day
(n = 343)
10 mg twice daily (n=111)
|1 Moderately emetogenic chemotherapeutic agents
included cisplatin (20 mg/m² to 50 mg/m²), oral and intravenous
cyclophosphamide, carboplatin, dacarbazine, doxorubicin.
2 Historical control from a previous double-blind KYTRIL (granisetron) trial.
3 No vomiting, no moderate or severe nausea, no rescue medication.
4 No vomiting, no nausea, no rescue medication.
*Statistically significant (P < 0.05) vs. prochlorperazine historical control.
Results from a KYTRIL (granisetron) Tablets 2 mg daily alone treatment arm in a third double-blind, randomized trial, were compared to prochlorperazine (PCPZ), 10 mg bid, derived from a historical control. The 24-hour results for KYTRIL (granisetron) Tablets 2 mg daily were statistically superior to PCPZ for all efficacy parameters: complete response (58%), no vomiting (79%), no nausea (51%), total control (49%). The PCPZ rates are shown in Table 3.
The first double-blind trial compared KYTRIL (granisetron) Tablets 1 mg bid, relative to placebo (historical control), in 119 cancer patients receiving high-dose cisplatin (mean dose 80 mg/m²). At 24 hours, KYTRIL (granisetron) Tablets 1 mg bid was significantly (P < 0.001) superior to placebo (historical control) in all efficacy parameters: complete response (52%), no vomiting (56%) and no nausea (45%). The placebo rates were 7%, 14%, and 7%, respectively, for the three efficacy parameters.
Results from a KYTRIL (granisetron) Tablets 2 mg once a day alone treatment arm in a second double-blind, randomized trial, were compared to both KYTRIL (granisetron) Tablets 1 mg twice a day and placebo historical controls. The 24-hour results for KYTRIL (granisetron) Tablets 2 mg once a day were: complete response (44%), no vomiting (58%), no nausea (46%), total control (40%). The efficacy of KYTRIL (granisetron) Tablets 2 mg once a day was comparable to KYTRIL (granisetron) Tablets 1 mg twice a day and statistically superior to placebo. The placebo rates were 7%, 14%, 7%, and 7%, respectively, for the four parameters.
No controlled study comparing granisetron injection with the oral formulation to prevent chemotherapy-induced nausea and vomiting has been performed.
Radiation-Induced Nausea and Vomiting
Total Body Irradiation
In a double-blind randomized study, 18 patients receiving KYTRIL (granisetron) Tablets, 2 mg daily, experienced significantly greater antiemetic protection compared to patients in a historical negative control group who received conventional (non-5-HT3 antagonist) antiemetics. Total body irradiation consisted of 11 fractions of 120 cGy administered over 4 days, with three fractions on each of the first 3 days, and two fractions on the fourth day. KYTRIL (granisetron) Tablets were given one hour before the first radiation fraction of each day.
Twenty-two percent (22%) of patients treated with KYTRIL (granisetron) Tablets did not experience vomiting or receive rescue antiemetics over the entire 4-day dosing period, compared to 0% of patients in the historical negative control group (P < 0.01).
In addition, patients who received KYTRIL (granisetron) Tablets also experienced significantly fewer emetic episodes during the first day of radiation and over the 4-day treatment period, compared to patients in the historical negative control group. The median time to the first emetic episode was 36 hours for patients who received KYTRIL (granisetron) Tablets.
Fractionated Abdominal Radiation
The efficacy of KYTRIL (granisetron) Tablets, 2 mg daily, was evaluated in a double-blind, placebo-controlled randomized trial of 260 patients. KYTRIL (granisetron) Tablets were given 1 hour before radiation, composed of up to 20 daily fractions of 180 to 300 cGy each. The exceptions were patients with seminoma or those receiving whole abdomen irradiation who initially received 150 cGy per fraction. Radiation was administered to the upper abdomen with a field size of at least 100 cm².
The proportion of patients without emesis and those without nausea for KYTRIL (granisetron) Tablets, compared to placebo, was statistically significant (P < 0.0001) at 24 hours after radiation, irrespective of the radiation dose. KYTRIL (granisetron) was superior to placebo in patients receiving up to 10 daily fractions of radiation, but was not superior to placebo in patients receiving 20 fractions.
Patients treated with KYTRIL (granisetron) Tablets (n=134) had a significantly longer time to the first episode of vomiting (35 days vs. 9 days, P < 0.001) relative to those patients who received placebo (n=126), and a significantly longer time to the first episode of nausea (11 days vs. 1 day, P < 0.001). KYTRIL (granisetron) provided significantly greater protection from nausea and vomiting than placebo.
Last reviewed on RxList: 10/28/2009
This monograph has been modified to include the generic and brand name in many instances.
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