SUSTOL (Page 4 of 5)

12.2 Pharmacodynamics

Cardiac Electrophysiology

The effect of SUSTOL on QTc prolongation was evaluated in a double-blind randomized, four-way crossover, placebo and positive (moxifloxacin) controlled study in 51 adult male and female healthy subjects. At 2-fold the recommended dosage of SUSTOL, there was no significant effect on the QTcF interval.

In 142 cancer patients, 24-hour Holter monitoring and 12-lead ECGs were evaluated. QTcF greater than 450 msec were seen in a total of 20 (19%) patients administered SUSTOL and 9 (31%) patients administered intravenous palonosetron hydrochloride. In the SUSTOL group, one patient had a QTcF interval greater than 500 msec and 4 patients had a change from baseline QTcF greater than 60 msec.

12.3 Pharmacokinetics

Absorption

SUSTOL is an extended-release injection formulation of granisetron using a polymer-based drug delivery system. Following a single-dose administration in healthy subjects, granisetron is released from the polymer over an extended period of time and remains detectable in plasma for 7 days post-dose (Figure 1). A mean concentration of 3.5 ng/mL (range 0 to 14 ng/mL) was observed at 5 days post-dose [see Warnings and Precautions (5.3)].

Figure 1. Plasma Concentrations of Granisetron Over 7 Days after a Single Subcutaneous Injection of SUSTOL in Healthy Subjects
image of figure 1
(click image for full-size original)

The granisetron pharmacokinetic parameters following injection of SUSTOL were similar between the abdomen and upper arm injection sites as shown in Table 3.

Table 3. Granisetron Pharmacokinetic Parameters Following a Single 10 mg Subcutaneous Injection of SUSTOL in Healthy Subjects by Injection Site Location
Parameter *Injection Site Location
AbdomenN=113Upper ArmN=113
*
Values shown are mean ± SD, except for Tmax where median [range] are shown.
Cmax (ng/mL)9.8 ± 4.810.8 ± 4.6
Tmax (hours) [range]12 [1 to 144]11 [1 to 120]
AUCinf , ng.h/mL680 ± 362720 ± 366

In patients, peak plasma granisetron concentrations were delayed compared to healthy subjects with a median Tmax of approximately 24 hours.

Distribution

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

Metabolism

Published data suggests that granisetron is metabolized by CYP1A1 and CYP3A4. Granisetron metabolism involves N-demethylation and aromatic ring oxidation followed by conjugation.

Elimination

Metabolism: Following a single 10 mg subcutaneous injection of SUSTOL, the terminal elimination half-life of granisetron was approximately 24 hours and was comparable between healthy subjects and patients.

Granisetron clearance is predominantly by hepatic metabolism.

Excretion: Approximately 12% of a granisetron dose, following intravenous administration of granisetron hydrochloride, is eliminated unchanged in the urine in 48 hours. The remainder of the dose is excreted as metabolites, 49% in the urine and 34% in the feces.

Specific Populations

Age: Geriatric Population: In a pooled analysis of samples collected from 56 cancer patients in 3 clinical studies, the mean Cmax and mean AUC0-inf for granisetron following subcutaneous administration of a 10 mg dose of SUSTOL was 39% and 76% higher in patients 65 years of age and older than in patients less than 65 years of age. These pharmacokinetic differences are not considered clinically meaningful taking into consideration the small number of patients 65 years of age and older in the analysis (n = 16) and the high inter-patient variability.

Sex: In a pooled analysis of samples collected from 56 cancer patients in 3 clinical studies, the mean Cmax and mean AUC0-inf for granisetron following subcutaneous administration of a 10 mg dose of SUSTOL was 34% and 132% higher in males than in females. These pharmacokinetic differences are not considered meaningful taking into consideration the small number of males in the analysis (n = 13) and the high inter-patient variability.

Renal Impairment: The total clearance of granisetron was similar in patients with severe renal failure compared to patients with normal renal function following a single 40 mcg/kg intravenous dose of granisetron hydrochloride.

Breakdown products of the polymer vehicle in SUSTOL can be detected in urine of healthy subjects [see Clinical Pharmacology (12.5)]. There are no pharmacokinetic data regarding elimination of the polymer vehicle of SUSTOL in patients with renal impairment [see Dosage and Administration (2.3), Use in Specific Populations (8.6)].

Hepatic Impairment: The total clearance of granisetron was approximately 50% lower in patients with hepatic impairment (neoplastic liver disease) compared to patients with normal hepatic function following a single 40 mcg/kg intravenous dose of granisetron hydrochloride. The high inter-subject variability in the pharmacokinetic parameters of granisetron in patients with hepatic impairment limits the interpretation of these findings.

Drug Interaction Studies

Effect of Other Drugs on Granisetron

Granisetron is metabolized by the hepatic cytochrome P-450 drug-metabolizing enzymes CYP1A1 and CYP3A4. Inducers or inhibitors of CYP1A1 and CYP3A4 enzymes may affect the clearance and half-life of granisetron. In in vitro human microsomal studies, ketoconazole inhibited ring oxidation of granisetron. However, the potential for an in vivo pharmacokinetic interaction with ketoconazole is not known.

Phenobarbital: Administration of intravenous granisetron hydrochloride with phenobarbital, an enzyme inducer, resulted in a 25% increase in total plasma clearance of granisetron. The clinical significance of this interaction is not known.

Effect of Granisetron on Other Drugs

Granisetron does not induce or inhibit the cytochrome P-450 drug-metabolizing enzyme system in vitro. In addition, the in vitro activity of the cytochrome P-450 subfamily 3A4, which is involved in the metabolism of some narcotic analgesics, is not modified by granisetron.

12.5 Polymer Breakdown Products

In a metabolic fate study conducted in healthy subjects, breakdown products of the triethylene glycol poly(orthoester) polymer vehicle of the SUSTOL formulation including triethylene glycol (TEG), pentaerythritol (PE), and the oxidative metabolite of TEG, triethylene glycol monocarboxylic acid (TEG acid) were detected in urine with incomplete recovery by the end of study period (10 days). Accumulation of these metabolites in plasma was not noted. The recovery of the polymer load was incomplete in this study and could be due to insufficient sampling and assay sensitivity issues preventing detection of additional metabolites [see Dosage and Administration (2.3), Use in Specific Populations (8.6)].

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis and Impairment of Fertility

Long-term studies in animals with SUSTOL have not been performed to evaluate the carcinogenic potential of the polymer vehicle of SUSTOL. In a 24-month carcinogenicity study of granisetron hydrochloride, rats were treated orally with 1, 5 or 50 mg/kg/day. The 50 mg/kg/day dose was reduced to 25 mg/kg/day during week 59 due to toxicity. For a 60 kg person, the 1, 5, and 25 mg/kg/day doses represent approximately 7, 34 and 169 times, respectively, the maximum recommended human dose (MRHD) (10 mg granisetron/week, approximately 6.2 mg/m2 /week) of SUSTOL 10 mg/week, based on body surface area. There was a statistically significant increase in the incidence of hepatocellular carcinomas and adenomas in male rats treated with 5 mg/kg/day (approximately 34 times the MRHD of SUSTOL 10 mg/week, based on body surface area) and above, and in female rats treated with 25 mg/kg/day (approximately 169 times the MRHD of SUSTOL 10 mg/week, based on body surface area). No increase in liver tumors was observed at a dose of 1 mg/kg/day (approximately 7 times the MRHD of SUSTOL 10 mg/week, based on body surface area) in male rats and 5 mg/kg/day (approximately 34 times the MRHD of SUSTOL 10 mg/week, based on body surface area) in female rats.

In a 12-month oral toxicity study with granisetron hydrochloride, rats were treated at 100 mg/kg/day (approximately 677 times the MRHD of SUSTOL 10 mg/week, based on body surface area). This dose produced hepatocellular adenomas in male and female rats while no such tumors were found in the control rats. A 24-month mouse carcinogenicity study of granisetron did not show a statistically significant increase in tumor incidence, but the study was not conclusive. Because of the tumor findings in rat studies, SUSTOL should be prescribed only at the dose and for the indication recommended [see Indications and Usage (1), Dosage and Administration (2.2)].

Granisetron hydrochloride was not mutagenic in an in vitro Ames test and mouse lymphoma cell forward mutation assay, and in vivo mouse micronucleus test and in vitro and ex vivo rat hepatocyte unscheduled DNA synthesis (UDS) assays. However, granisetron hydrochloride was positive in a mouse lymphoma assay with metabolic activation and produced a significant increase in UDS in HeLa cells in vitro and a significant increased incidence of cells with polyploidy in an in vitro human lymphocyte chromosomal aberration test.

Neither SUSTOL nor the polymer vehicle for SUSTOL was mutagenic in the Ames test, mouse lymphoma assay, and the in vivo rat bone marrow micronucleus test.

Granisetron hydrochloride at subcutaneous doses up to 6 mg/kg/day (approximately 40 times the MRHD of SUSTOL 10 mg/week, based on body surface area), and oral doses up to 100 mg/kg/day (approximately 677 times the MRHD of SUSTOL 10 mg/week, based on body surface area) was found to have no effect on fertility and reproductive performance of male and female rats.

The polymer vehicle for SUSTOL at subcutaneous doses up to 0.295 g per day (approximately 45 times the amount of polymer vehicle present in the maximum recommended /weekly single human dose of SUSTOL, based on body surface area) was found to have no adverse effect on fertility and reproductive performance of male and female rats.

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