Clonazepam 0.5 mg, Paroxetine Hcl 25 mg (ER) Tablets

The mechanism of action of paroxetine in the treatment of major depressive disorder (MDD), panic disorder (PD), social anxiety disorder (SAD), and premenstrual dysphoric disorder (PMDD) is unknown, but is presumed to be linked to potentiation of serotonergic activity in the central nervous system resulting from inhibition of neuronal reuptake of serotonin (5-HT).

Absorption — Tablets of Paroxetine HCL CR contain a degradable polymeric matrix designed to control the dissolution rate of paroxetine over a period of approximately 4 to 5 hours. In addition to controlling the rate of drug release in vivo, an enteric coat delays the start of drug release until tablets of Paroxetine HCL CR have left the stomach.

Paroxetine extended-release tablets are completely absorbed after oral dosing of a solution of the hydrochloride salt. In a study in which normal male and female subjects (n = 23) received single oral doses of Paroxetine HCL CR at 4 dosage strengths (12.5 mg, 25 mg, 37.5 mg, and 50 mg), paroxetine Cmax and AUC0-inf increased disproportionately with dose (as seen also with immediate‑release formulations). Mean Cmax and AUC0-inf values at these doses were 2, 5.5, 9, and 12.5 ng/mL, and 121, 261, 338, and 540 ng·hr. /mL, respectively. Tmax was observed typically between 6 and 10 hours post‑dose, reflecting a reduction in absorption rate compared with immediate‑release formulations. The bioavailability of 25 mg Paroxetine HCL CR is not affected by food.

Distribution — Paroxetine distributes throughout the body, including the CNS, with only 1% remaining in the plasma.

Approximately 95% and 93% of paroxetine is bound to plasma protein at 100 ng/mL and 400 ng/mL, respectively. Under clinical conditions, paroxetine concentrations would normally be less than 400 ng/mL. Paroxetine does not alter the in vitro protein binding of phenytoin or warfarin.

Metabolism — The mean elimination half-life of paroxetine was 15 to 20 hours throughout a range of single doses of Paroxetine HCL CR (12.5 mg, 25 mg, 37.5 mg, and 50 mg). During repeated administration of Paroxetine HCL CR (25 mg once daily), steady state was reached within 2 weeks (i.e., comparable to immediate‑release formulations). In a repeat‑dose study in which normal male and female subjects (n = 23) received Paroxetine HCL CR (25 mg daily), mean steady state Cmax, Cmin, and AUC0-24 values were 30 ng/mL, 20 ng/mL, and 550 ng·hr./mL, respectively.

Based on studies using immediate‑release formulations, steady‑state drug exposure based on AUC0-24 was several‑fold greater than would have been predicted from single‑dose data. The excess accumulation is a consequence of the fact that 1 of the enzymes that metabolizes paroxetine is readily saturable.

In steady‑state dose proportionality studies involving elderly and nonelderly patients, at doses of the immediate‑release formulation of 20 mg to 40 mg daily for the elderly and 20 mg to 50 mg daily for the nonelderly, some nonlinearity was observed in both populations, again reflecting a saturable metabolic pathway (Figure 3).

Paroxetine is extensively metabolized after oral administration. The principal metabolites are polar and conjugated products of oxidation and methylation, which are readily cleared. Conjugates with glucuronic acid and sulfate predominate, and major metabolites have been isolated and identified. Data indicate that the metabolites have no more than 1/50 the potency of the parent compound at inhibiting serotonin uptake. The metabolism of paroxetine is accomplished in part by CYP2D6. Saturation of this enzyme at clinical doses appears to account for the nonlinearity of paroxetine kinetics with increasing dose and increasing duration of treatment. The role of this enzyme in paroxetine metabolism also suggests potential drug‑drug interactions [see Drug Interactions (7.3)].

Excretion — Approximately 64% of a 30 mg oral solution dose of paroxetine was excreted in the urine with 2% as the parent compound and 62% as metabolites over a 10‑day post‑dosing period. About 36% was excreted in the feces (probably via the bile), mostly as metabolites and less than 1% as the parent compound over the 10‑day post‑dosing period.

The precise mechanism by which clonazepam exerts its anti-seizure and anti-panic effects is unknown, although it is believed to be related to its ability to enhance the activity of gamma aminobutyric acid (GABA), the major inhibitory neurotransmitter in the central nervous system.