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Kytril (Granisetron Hydrochloride) - Description and Clinical Pharmacology


(granisetron hydrochloride)


KYTRIL Tablets and KYTRIL Oral Solution contain granisetron hydrochloride, 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 C18H24N4O•HCl, while its chemical structure is:

Granisetron hydrochloride is a white to off-white solid that is readily soluble in water and normal saline at 20°C.

Tablets for Oral Administration

Each white, triangular, biconvex, film-coated KYTRIL Tablet contains 1.12 mg granisetron hydrochloride equivalent to granisetron, 1 mg. Inactive ingredients are: hydroxypropyl methylcellulose, lactose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, sodium starch glycolate, and titanium dioxide.

Oral Solution

Each 10 mL of clear, orange-colored, orange-flavored KYTRIL Oral Solution contains 2.24 mg of granisetron hydrochloride equivalent to 2 mg granisetron. Inactive ingredients: citric acid anhydrous, FD&C Yellow No. 6, orange flavor, purified water, sodium benzoate, and sorbitol.


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 Tablets slowed colonic transit in normal volunteers. However, KYTRIL 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 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
Volume of Distribution
Total Clearance
N.D. Not determined.
Cancer Patients
1 mg bid, 7 days
[0.63 to 30.9]
N.D.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.0.52
[0.09 to 7.37]
single 1 mg dose
[0.27 to 9.14]
[0.96 to 19.9]
[1.89 to 39.4]
[0.11 to 24.6]

A 2 mg dose of KYTRIL Oral Solution is bioequivalent to the corresponding dose of KYTRIL Tablets (1 mg x 2) and may be used interchangeably.


When KYTRIL 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 Tablets have not been studied. However, after intravenous infusion of KYTRIL, 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.


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.

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 with intravenous KYTRIL 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 dose, dosage adjustment in patients with possible hepatic functional impairment is not necessary.

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.


Chemotherapy-Induced Nausea and Vomiting

KYTRIL 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 Tablets doses of 0.25 mg to 2 mg bid, 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 Post-ChemotherapyChemotherapy included oral and injectable cyclophosphamide, carboplatin, cisplatin (20 mg/m2 to 50 mg/m2), dacarbazine, doxorubicin, epirubicin.
Percentages of Patients
KYTRIL Tablet Dose
Efficacy Measures0.25 mg bid
0.5 mg bid
1 mg bid
2 mg bid
Complete ResponseNo vomiting, no moderate or severe nausea, no rescue medication.6170 1 81Statistically significant (P<0.01) vs. 0.5 mg bid.72
No Vomiting66778879
No Nausea48576354

1 Statistically significant (P<0.01) vs. 0.25 mg bid.

Results from a second double-blind, randomized trial evaluating KYTRIL Tablets 2 mg qd and KYTRIL Tablets 1 mg bid were compared to prochlorperazine 10 mg bid derived from a historical control. At 24 hours, there was no statistically significant difference in efficacy between the two KYTRIL Tablet regimens. Both regimens were statistically superior to the prochlorperazine control regimen (see Table 3).

Table 3 Prevention of Nausea and Vomiting 24 Hours Post-ChemotherapyModerately emetogenic chemotherapeutic agents included cisplatin (20 mg/m2 to 50 mg/m2), oral and intravenous cyclophosphamide, carboplatin, dacarbazine, doxorubicin.
Percentages of Patients
Efficacy MeasuresKYTRIL Tablets
1 mg bid
(n = 354)
KYTRIL Tablets
2 mg qd
(n = 343)
ProchlorperazineHistorical control from a previous double-blind KYTRIL trial.
10 mg bid
Complete ResponseNo vomiting, no moderate or severe nausea, no rescue medication.69 1 6441
No Vomiting827748
No Nausea515335
Total ControlNo vomiting, no nausea, no rescue medication.515033

1 Statistically significant (P<0.05) vs. prochlorperazine historical control.

Results from a KYTRIL Tablets 2 mg qd 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 Tablets 2 mg qd 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.

Cisplatin-Based Chemotherapy

The first double-blind trial compared KYTRIL 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 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 Tablets 2 mg qd alone treatment arm in a second double-blind, randomized trial, were compared to both KYTRIL Tablets 1 mg bid and placebo historical controls. The 24-hour results for KYTRIL Tablets 2 mg qd were: complete response (44%), no vomiting (58%), no nausea (46%), total control (40%). The efficacy of KYTRIL Tablets 2 mg qd was comparable to KYTRIL Tablets 1 mg bid 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 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 Tablets were given one hour before the first radiation fraction of each day.

Twenty-two percent (22%) of patients treated with KYTRIL 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 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 Tablets.

Fractionated Abdominal Radiation

The efficacy of KYTRIL Tablets, 2 mg daily, was evaluated in a double-blind, placebo-controlled randomized trial of 260 patients. KYTRIL 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 Tablets, compared to placebo, was statistically significant (P<0.0001) at 24 hours after radiation, irrespective of the radiation dose. KYTRIL 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 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 provided significantly greater protection from nausea and vomiting than placebo.

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