Source: http://rxdruglabels.com/lib/rx/rx-meds/granisetron-hydrochloride-25/
Timestamp: 2013-05-18 11:02:06
Document Index: 766532068

Matched Legal Cases: ['§ 72', '§ 64', '§ 41', '§ 77', '§ 48', '§ 53', '§ 35', '§ 50', '§ 33']

Granisetron Hydrochloride – Roxane Laboratories, Inc: Prescription Medication…
Prescription Drug Information: Granisetron Hydrochloride
By Roxane Laboratories, Inc | Last revised: 1 November 2012
GRANISETRON HYDROCHLORIDE- granisetron hydrochloride tabletRoxane Laboratories, Inc Rx only DESCRIPTIONGranisetron Hydrochloride Tablets USP 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 molecular formula is C18 H24 N4 O•HCl, while its chemical structure is:
(click image for full-size original) Granisetron hydrochloride is a white to off-white solid that is readily soluble in water and normal saline at 20ºC.
Tablets for Oral AdministrationEach white, round, biconvex, Granisetron Hydrochloride Tablet USP contains 1.12 mg granisetron hydrochloride equivalent to granisetron, 1 mg. Inactive ingredients are: hypromellose, lactose (anhydrous), magnesium stearate, microcrystalline cellulose, and sodium starch glycolate.
CLINICAL PHARMACOLOGYGranisetron 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.
Pharmacokinetics In healthy volunteers and adult cancer patients undergoing chemotherapy, administration of granisetron tablets produced mean pharmacokinetic data shown in Table 1. Table 1: Pharmacokinetic Parameters (Median [range]) Following Granisetron Hydrochloride Tablets USP * 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 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
N.D.* N.D.† 0.52
Volunteers single 1 mg dose (N=39) 3.63
3.94 [1.89 to 39.4]
Absorption When 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.
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 tablets have not been studied. However, after intravenous infusion of granisetron, 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 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 granisetron injection.
Hepatically Impaired Patients A pharmacokinetic study with intravenous 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.
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 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 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 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 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 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 Response † 61 70‡ 81‡§ 72‡ No Vomiting 66 77‡ 88‡ 79‡ No Nausea 48 57 63‡ 54 Results from a second double-blind, randomized trial evaluating granisetron tablets 2 mg once a day and 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 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 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 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 Hydrochloride Tablets USP 1 mg twice a day (N=354) % Granisetron Hydrochloride Tablets USP 2 mg once a day (N=343) % Prochlorperazine † 10 mg twice daily (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 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 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.
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