SYNDROS (Page 5 of 6)

12.3 Pharmacokinetics

Absorption

Dronabinol (delta-9-THC) is almost completely absorbed (90 to 95%) after a single oral dose. Due to the combined effects of first pass hepatic metabolism and high lipid solubility, only 10 to 20% of the administered dose reaches the systemic circulation. Relative bioavailability data from healthy male and female subjects suggest that a dose of 4.2 mg of SYNDROS provides comparable systemic exposure (Cmax and AUC) to a 5 mg dronabinol capsule, under fasted conditions [see Dosage and Administration (2.1)]. The concentrations of both dronabinol and its major active metabolite (11-hydroxy-delta-9-THC) peak at approximately 0.5 to 4 hours after oral dosing with SYNDROS and decline over several days. The mean inter- and intra-subject variability in dronabinol pharmacokinetics (Cmax and AUCinf ) was approximately 66% and 47% and 67% and 14%, respectively, following administration of SYNDROS to healthy subjects.

Table 1: Summary of Single-Dose Pharmacokinetic Parameters of Dronabinol After Replicated Oral Administration of SYNDROS (4.2 mg to Healthy Subjects under Fasted Conditions)

* Arithmetic mean ± standard deviation except Tmax for which the median [range] is reported

Parameter* Dronabinol
Cmax (ng/mL) 1.9 ± 1.3
Tmax (h) 1.0 [0.5 to 4.0]
AUC(inf) (ng.h/mL) 3.8 ± 1.8
t½ (h) 5.6 ± 2.7

Food Effect: The effect of food on the pharmacokinetics of SYNDROS was studied by concomitant dosing of SYNDROS with a high-fat (59 grams of fat, approximately 50% of total caloric content of the meal), high calorie meal (approximately 950 calories). An appreciable food effect was observed: food resulted in approximately a 2.5-fold increase in total exposure (AUCinf ) and approximately a 5 hour delay in median Tmax . Food also decreased Cmax by approximately 20% [see Dosage and Administration (2.2, 2.3)].

Distribution:

Dronabinol has an apparent volume of distribution of approximately 10 L/kg, because of its lipid solubility. The plasma protein binding of dronabinol and its metabolites is approximately 97% [see Drug Interactions (7.3)].

Elimination

The pharmacokinetics of dronabinol can be described using a two compartment model with an initial (alpha) half-life of about 5 hours and a terminal (beta) half-life of 25 to 36 hours. Values for clearance average about 0.2 L/kg-hr; but are highly variable due to the complexity of cannabinoid distribution.

Metabolism

Dronabinol undergoes extensive first-pass hepatic metabolism, primarily by hydroxylation, yielding both active and inactive metabolites. The major metabolite (11-hydroxy-delta-9-THC) is pharmacologically active. Published in vitro data indicate that CYP2C9 and CYP3A4 are the primary enzymes in the metabolism of dronabinol. CYP2C9 appears to be the enzyme responsible for the formation of the primary active metabolite [see Clinical Pharmacology (12.5)].

Excretion

Dronabinol and its biotransformation products are excreted in both feces and urine. Biliary excretion is the major route of excretion with about half of a radio-labeled oral dose being recovered from the feces within 72 hours as contrasted with 10 to 15% recovered from urine. Less than 5% of an oral dose is recovered unchanged in the feces.

Due to its re-distribution, dronabinol and its metabolites may be excreted for prolonged periods of time. Following single dose administration, dronabinol metabolites have been detected for more than 5 weeks in the urine and feces.

In a study of dronabinol capsules involving AIDS patients, urinary cannabinoid/creatinine concentration ratios were studied bi-weekly over a six week period. The urinary cannabinoid/creatinine ratio was closely correlated with dose. No increase in the cannabinoid/creatinine ratio was observed after the first two weeks of treatment, indicating that steady-state cannabinoid levels had been reached. This conclusion is consistent with predictions based on the observed terminal half-life of dronabinol.

Drug Interaction Studies

Formal drug-drug interaction studies have not been conducted with dronabinol.

The enzyme inhibition and induction potential of dronabinol and its active metabolite are not completely understood.

Published data showed an increase in the elimination half-life of pentobarbital by 4 hours when concomitantly dosed with dronabinol [see Warnings and Precautions (5.1)].

12.5 Pharmacogenomics

Published data indicate a 2- to 3-fold higher dronabinol exposure in individuals carrying genetic variants associated with diminished CYP2C9 function.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

The recommended dose ranges for SYNDROS in AIDS and cancer patients are designed to achieve the same systemic exposure ranges as with the recommended dose ranges for dronabinol capsules.

Therefore, the animal to human dose multiples for carcinogenicity studies, as shown below, are based on the MRHD (maximum recommended human dose) for dronabinol capsules in AIDS patients, instead of the MRHD for SYNDROS which is 15% lower. This approach for dose comparison between animals and humans is supported by the demonstrated difference in dronabinol bioavailability between SYNDROS and dronabinol capsules. The animal to human dose multiples for the fertility study in rats, as shown below, are based on the MRHD for dronabinol capsules in AIDS or cancer patients.

In 2-year carcinogenicity studies, there was no evidence of carcinogenicity in rats at doses up to 50 mg/kg/day dronabinol (approximately 20 times the MRHD for dronabinol capsules in AIDS patients on a body surface area basis) or in mice at doses up to 500 mg/kg/day (approximately 100 times the MRHD for dronabinol capsules in AIDS patients on a body surface area basis).

Dronabinol was not genotoxic in the Ames tests, the in vitro chromosomal aberration test in Chinese hamster ovary cells, and the in vivo mouse micronucleus test. However, dronabinol produced a weak positive response in a sister chromatid exchange test in Chinese hamster ovary cells.

In a long-term study (77 days) in rats, oral administration of dronabinol at doses of 30 to 150 mg/m2 , equivalent to 2 to 10 times the MRHD of 15 mg/m2 /day (dronabinol capsules) in AIDS patients or 0.3 to 1.5 times the MRHD of 90 mg/m2 /day (dronabinol capsules) in cancer patients, reduced ventral prostate, seminal vesicle and epididymal weights and caused a decrease in seminal fluid volume. Decreases in spermatogenesis, number of developing germ cells, and number of Leydig cells in the testis were also observed. However, sperm count, mating success and testosterone levels were not affected. The significance of these animal findings in humans is not known.

14 CLINICAL STUDIES

The effectiveness of SYNDROS has been established based on studies of dronabinol capsules for the treatment of anorexia associated with weight loss in patients with AIDS and nausea and vomiting associated with cancer chemotherapy in patients who have failed to respond adequately to conventional antiemetic treatments.

16 HOW SUPPLIED/STORAGE AND HANDLING

  • SYNDROS (dronabinol) oral solution, 5 mg/mL is a clear, pale yellow to brown solution. SYNDROS is supplied in a multi-dose, clear, amber-colored 30 mL glass bottle. It is closed with a 20 mm child-resistant, white polypropylene screw cap with a Teflon coated liner. The bottle is wrapped with a polyvinyl chloride body band to provide tamper evidence and packaged in a carton with an oral syringe, and a push-in bottle adapter.
    NDC 20482-335-30 (30 mL multi-dose bottle, an oral syringe and a push-in bottle adapter)
  • Store in a refrigerator between 2°C and 8°C (36°F and 46°F); excursions permitted up to 25°C (77°F). The opened bottle can be stored at 25°C (77°F). Discard unused portion 42 days after first opening [see USP Controlled Room Temperature].
  • Keep SYNDROS oral solution and the oral syringe in the supplied carton.

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