Granisetron Hydrochloride

GRANISETRON HYDROCHLORIDE — granisetron hydrochloride tablet
Ascend Laboratories, LLC

RX Only

DESCRIPTION

Granisetron HCL tablets 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 C18 H24 N4 O•HCl, while its chemical structure is:

structureGranisetron 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 Granisetron HCl Tablet contains 1.12 mg granisetron hydrochloride equivalent to granisetron, 1 mg. Inactive ingredients are: hyprmellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, sodium starch glycolate and titanium dioxide.

CLINICAL PHARMACOLOGY

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.

3 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, Granisetron HCl Tablets slowed colonic transit in normal volunteers. However, Granisetron HCl 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.

Pharmacokinetics

In healthy volunteers and adult cancer patients undergoing chemotherapy, administration of Granisetron HCl Tablets produced mean pharmacokinetic data shown in Table 1.

Table 1 Pharmacokinetic Parameters (Median [range]). Following Granisetron HCl Tablets

* Not determined after oral administration; following a single intravenous dose of 40 mcg/kg, terminal phase half-life was determined to be 8.95 hoursN.D. Not determined
Peak Plasma Concentration(ng/mL) Terminal Phase Plasma Half-Life(h) Volume of Distribution(L/kg) Total Clearance(L/h/kg)
Cancer Patients 1 mg bid, 7 days(n=27) 5.99[0.63 to 30.9] N.D.* N.D. 0.52[0.09 to 7.37]
Volunteers single 1 mg dose(n=39) 3.63[0.27 to 9.14] 6.23[0.96 to 19.9] 3.94[1.89 to 39.4] 0.41[0.11 to 24.6]

Absorption

When Granisetron hydrochloride 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.

Distribution

Plasma protein binding is approximately 65% and granisetron distributes freely between plasma and red blood cells.

Metabolism

3 receptor antagonist activity.

Elimination

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.

Subpopulation

Gender

The effects of gender on the pharmacokinetics of Granisetron HCl Tablets have not been studied. However, after intravenous infusion of Granisetron HCl, 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 granisetron hydrochloride.

Elderly

The ranges of the pharmacokinetic parameters in elderly volunteers (mean age 71 years), given a single 40 mcg/kg intravenous dose of granisetron hydrochloride 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 granisetron hydrochloride Injection.

Hepatically Impaired Patients: A pharmacokinetic study with intravenous granisetron hydrochloride 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 granisetron hydrochloride 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.

Clinical Trials

Chemotherapy-Induced Nausea and vomiting

Granisetron HCl 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 Granisetron HCl 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-Chemotherapy *
*
Chemotherapy included oral and injectable cyclophosphamide, carboplatin, cisplatin (20 mg/m2 to 50 mg/m2), dacarbazine, doxorubicin, epirubicin.
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.
Percentages of Patients Granisetron HCl Tablet Dose
Efficacy Measures 0.25 mg bid(n=229)% 0.5 mg bid(n=235)% 1 mg bid(n=233)% 2 mg bid(n=233)%
Complete Response 617081§72
No Vomiting66778879
No Nausea48576354

Results from a second double-blind, randomized trial evaluating Granisetron HCl Tablets 2 mg qd and Granisetron HCl 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 Granisetron HCl 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-Chemotherapy *
*
Moderately emetogenic chemotherapeutic agents included cisplatin (20 mg/m2 to 50 mg/m2), oral and intravenous cyclophosphamide, carboplatin, dacarbazine, doxorubicin.
Historical control from a previous double-blind granisetron hydrochloride trial.
No vomiting, no moderate or severe nausea, no rescue medication
§
Statistically significant (P<0.05) vs. prochlorperazine historical control.
No vomiting, no nausea, no rescue medication.
Percentages of Patients
Efficacy Measures Granisetron HCl tablets1 mg bid(n = 354)% Granisetron HCl tablets2 mg qd(n = 343)% Prochlorperazine 10 mg bid(n=111)%
Complete Response 69§ 64§41
No Vomiting 82§77§ 48
No Nausea 51§ 53§ 35
Total Control 51§ 50§ 33

Results from a Granisetron HCl 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 Granisetron HCl 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.

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