Granisetron Hydrochloride

GRANISETRON HYDROCHLORIDE- granisetron hydrochloride tablet, film coated
Bionpharma Inc.

DESCRIPTION

Granisetron hydrochloride tablets USP contain granisetron hydrochloride USP, 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:

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

Each white to off-white film coated triangular shaped biconvex tablet contains 1.12 mg granisetron hydrochloride USP equivalent to granisetron, 1 mg. Inactive ingredients are: microcrystalline cellulose, sodium starch glycolate, lactose monohydrate, hypromellose, magnesium stearate and opadry white.

The components of opadry white are hypromellose, titanium dioxide, polyethylene glycol 6000 and polysorbate 80.

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-HT_1A ; 5-HT_1B/C ; 5-HT₂ ; for α_1- , α_2- , or β-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, granisetron hydrochloride tablets slowed colonic transit in normal volunteers. However, granisetron hydrochloride 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 hydrochloride tablets produced mean pharmacokinetic data shown in Table 1.

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

	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 twice a day, 7 days(n=27)	5.99[0.63 to 30.9]	N.D.1	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]

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.

Absorption

When granisetron hydrochloride tablets were administered with food, AUC was decreased by 5% and C_max 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

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.

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.

Subpopulations

Gender

The effects of gender on the pharmacokinetics of granisetron hydrochloride tablets have not been studied. However, after intravenous infusion of granisetron hydrochloride, no difference in mean AUC was found between males and females, although males had a higher C_max 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, dosage adjustment in patients with 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 hydrochloride 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 hydrochloride 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 (i.e., 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-Chemotherapy¹

	Percentages of Patients Granisetron Hydrochloride Tablet Dose
Efficacy Measures	0.25 mg twice a day (n=229) %	0.5 mg twice a day (n=235) %	1 mg twice a day (n=233) %	2 mg twice a day (n=233) %
Complete Response2	61	70*	81*†	72*
No Vomiting	66	77*	88*	79*
No Nausea	48	57	63*	54

¹ Chemotherapy included oral and injectable cyclophosphamide, carboplatin, cisplatin (20 mg/m² to 50 mg/m²), dacarbazine, doxorubicin, epirubicin.

² No vomiting, no moderate or severe nausea, no rescue medication.

*Statistically significant (P<0.01) vs. 0.25 mg twice a day.

†Statistically significant (P<0.01) vs. 0.5 mg twice a day.

Results from a second double-blind, randomized trial evaluating granisetron hydrochloride tablets 2 mg once a day and granisetron hydrochloride 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 granisetron hydrochloride 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-Chemotherapy¹

	Percentages of Patients
Efficacy Measures	Granisetron Hydrochloride Tablets 1 mg twice a day (n = 354) %	Granisetron Hydrochloride Tablets 2 mg once a day (n = 343) %	Prochlorperazine2 10 mg twice daily (n=111) %
Complete Response3	69*	64*	41
No Vomiting	82*	77*	48
No Nausea	51*	53*	35
Total Control4	51*	50*	33

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 granisetron hydrochloride 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 granisetron hydrochloride tablets 2 mg daily alone treatment arm in a third double-blind, randomized trial, were compared to prochlorperazine (PCPZ), 10 mg twice a day, derived from a historical control. The 24 hour results for granisetron hydrochloride 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.

Cisplatin-Based Chemotherapy

The first double-blind trial compared granisetron hydrochloride tablets 1 mg twice a day, relative to placebo (historical control), in 119 cancer patients receiving high-dose cisplatin (mean dose 80 mg/m²). At 24 hours, granisetron hydrochloride tablets 1 mg twice a day 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 granisetron hydrochloride tablets 2 mg once a day alone treatment arm in a second double-blind, randomized trial, were compared to both granisetron hydrochloride tablets 1 mg twice a day and placebo historical controls. The 24 hour results for granisetron hydrochloride tablets 2 mg once a day were: complete response (44%), no vomiting (58%), no nausea (46%), total control (40%). The efficacy of granisetron hydrochloride tablets 2 mg once a day was comparable to granisetron hydrochloride 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.