Alprazolam 0.25 mg, Sertraline 25 mg (SR) Tablets

The exact mechanism of action of alprazolam is unknown. Benzodiazepines bind to gamma aminobutyric acid (GABA) receptors in the brain and enhance GABA-mediated synaptic inhibition; such actions may be responsible for the efficacy of alprazolam in anxiety disorder and panic disorder.

Absorption — Following oral administration, alprazolam is readily absorbed. The peak plasma concentration is reached about 1.5 to 2 hours after administration of alprazolam given with or without water. When taken with water, mean Tmax occurs about 15 minutes earlier than when taken without water with no change in Cmax or AUC. Plasma levels are proportional to the dose given; over the dose range of 0.5 mg to 3 mg, peak levels of 8 to 37 ng/mL are observed. The elimination half-life of alprazolam is approximately 12.5 hours (range 7.9 to 19.2 hours) after administration of alprazolam in healthy adults.

Food decreased the mean Cmax by about 25% and increased the mean Tmax by 2 hours from 2.2 hours to 4.4 hours after the ingestion of a high-fat meal. Food did not affect the extent of absorption (AUC) or the elimination half-life.

Distribution — In vitro, alprazolam is bound (80 percent) to human serum protein. Serum albumin accounts for the majority of the binding.

Metabolism/Elimination — Alprazolam is extensively metabolized in humans, primarily by cytochrome P450 3A4 (CYP3A4), to two major metabolites in the plasma: 4-hydroxyalprazolam and α-hydroxyalprazolam. A benzophenone derived from alprazolam is also found in humans. Their half-lives appear to be similar to that of alprazolam. The plasma concentrations of 4-hydroxyalprazolam and α-hydroxyalprazolam relative to unchanged alprazolam concentration were always less than 4%. The reported relative potencies in benzodiazepine receptor binding experiments and in animal models of induced seizure inhibition are 0.20 and 0.66, respectively, for 4-hydroxyalprazolam and α-hydroxyalprazolam. Such low concentrations and the lesser potencies of 4-hydroxyalprazolam and α-hydroxyalprazolam suggest that they are unlikely to contribute much to the pharmacological effects of alprazolam. The benzophenone metabolite is essentially inactive.

Alprazolam and its metabolites are excreted primarily in the urine.

Special Populations — Changes in the absorption, distribution, metabolism and excretion of benzodiazepines have been reported in a variety of disease states including alcoholism, impaired hepatic function and impaired renal function. Changes have also been demonstrated in geriatric patients. A mean half-life of alprazolam of 16.3 hours has been observed in healthy elderly subjects (range: 9.0 to 26.9 hours, n=16) compared to 11.0 hours (range: 6.3 to 15.8 hours, n=16) in healthy adult subjects. In patients with alcoholic liver disease, the half-life of alprazolam ranged between 5.8 and 65.3 hours (mean: 19.7 hours, n=17) as compared to between 6.3 and 26.9 hours (mean=11.4 hours, n=17) in healthy subjects. In an obese group of subjects, the half-life of alprazolam ranged between 9.9 and 40.4 hours (mean=21.8 hours, n=12) as compared to between 6.3 and 15.8 hours (mean=10.6 hours, n=12) in healthy subjects.

Because of its similarity to other benzodiazepines, it is assumed that alprazolam undergoes transplacental passage and that it is excreted in human milk.

Race — Maximal concentrations (Cmax) and half-life of alprazolam are approximately 15% and 25% higher in Asians compared to Caucasians.

Pediatrics — The pharmacokinetics of alprazolam in pediatric patients have not been studied.

Gender — Gender has no effect on the pharmacokinetics of alprazolam.

Cigarette Smoking — Alprazolam concentrations may be reduced by up to 50% in smokers compared to non-smokers.

Drug-Drug Interactions — Alprazolam is primarily eliminated by metabolism via cytochrome P450 3A (CYP3A). Most of the interactions that have been documented with alprazolam are with drugs that inhibit or induce CYP3A.

Compounds that are potent inhibitors of CYP3A would be expected to increase plasma alprazolam concentrations. Drug products that have been studied in vivo, along with their effect on increasing alprazolam AUC, are as follows: ketoconazole, 3.98 fold; itraconazole, 2.70 fold; nefazodone, 1.98 fold; fluvoxamine, 1.96 fold; and erythromycin, 1.61 fold [see Contraindications (4), Warnings and Precautions (5.8), and Drug Interactions (7)].

Sertraline potentiates serotonergic activity in the central nervous system through inhibition of neuronal reuptake of serotonin (5-HT).

Absorption — Following oral once-daily sertraline hydrochloride dosing over the range of 50 to 200 mg for 14 days, mean peak plasma concentrations (C max) of sertraline occurred between 4.5 to 8.4 hours post-dosing. The average terminal elimination half-life of plasma sertraline is about 26 hours. Consistent with the terminal elimination half-life, there is an approximately two-fold accumulation up to steady-state concentrations, which are achieved after one week of once-daily dosing. Linear dose-proportional pharmacokinetics were demonstrated in a single dose study in which the C maxand area under the plasma concentration time curve (AUC) of sertraline were proportional to dose over a range of 50 to 200 mg. The single dose bioavailability of sertraline hydrochloride tablets is approximately equal to an equivalent dose of sertraline oral solution. Administration with food causes a small increase in C maxand AUC.

Metabolism — Sertraline undergoes extensive first pass metabolism. The principal initial pathway of metabolism for sertraline is N-demethylation. N-desmethylsertraline has a plasma terminal elimination half-life of 62 to 104 hours. Both in vitrobiochemical and in vivopharmacological testing have shown N-desmethylsertraline to be substantially less active than sertraline. Both sertraline and N-desmethylsertraline undergo oxidative deamination and subsequent reduction, hydroxylation, and glucuronide conjugation. In a study of radiolabeled sertraline involving two healthy male subjects, sertraline accounted for less than 5% of the plasma radioactivity. About 40 to 45% of the administered radioactivity was recovered in urine in 9 days. Unchanged sertraline was not detectable in the urine. For the same period, about 40 to 45% of the administered radioactivity was accounted for in feces, including 12 to 14% unchanged sertraline.

Desmethylsertraline exhibits time-related, dose dependent increases in AUC (0-24-hour), C maxand C min,with about a 5- to 9-fold increase in these pharmacokinetic parameters between day 1 and day 14.

Protein Binding — In vitroprotein binding studies performed with radiolabeled 3H-sertraline showed that sertraline is highly bound to serum proteins (98%) in the range of 20 to 500 ng/mL. However, at up to 300 and 200 ng/mL concentrations, respectively, sertraline and N-desmethylsertraline did not alter the plasma protein binding of two other highly protein bound drugs, warfarin and propranolol.

Pediatric Patients — Sertraline pharmacokinetics were evaluated in a group of 61 pediatric patients (29 aged 6 to12 years, 32 aged 13 to 17 years) including both males (N=28) and females (N=33). Relative to the adults, pediatric patients aged 6 to12 years and 13 to 17 years showed about 22% lower AUC (0 to 24 hr) and C maxvalues when plasma concentration was adjusted for weight. The half-life was similar to that in adults, and no gender-associated differences were observed [See Dosage and Administration (2.1), Use in Specific Populations (8.4)] .

Geriatric Patients — Sertraline plasma clearance in a group of 16 (8 male, 8 female) elderly patients treated with 100 mg/day of sertraline hydrochloride for 14 days was approximately 40% lower than in a similarly studied group of younger (25 to 32 year old) individuals. Steady-state, therefore, was achieved after 2 to 3 weeks in older patients. The same study showed a decreased clearance of desmethylsertraline in older males, but not in older females [See Use in Specific Populations (8.5)] .