Paroxetine Hydrochloride

PAROXETINE HYDROCHLORIDE — paroxetine hydrochloride tablet, film coated, extended release
Physicians Total Care, Inc.

Suicidality and Antidepressant Drugs

Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents and young adults in short-term studies of major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use of paroxetine or any other antidepressant in a child, adolescent or young adult must balance this risk with the clinical need. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction in risk with antidepressants compared to placebo in adults aged 65 and older. Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Patients of all ages who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. Paroxetine is not approved for use in pediatric patients. (See WARNINGS: Clinical Worsening and Suicide Risk, PRECAUTIONS: Information for Patients and PRECAUTIONS: Pediatric Use.)

DESCRIPTION

Paroxetine hydrochloride extended-release tablets are an orally administered psychotropic drug with a chemical structure unrelated to other selective serotonin reuptake inhibitors or to tricyclic, tetracyclic or other available antidepressant or antipanic agents. It is the hydrochloride salt of a phenylpiperidine compound identified chemically as (3S-trans)-3-[(1,3-benzodioxol-5-yloxy)methyl)]4-(4-fluorophenyl)-piperidine hydrochloride hemihydrate and has the molecular formula of C19 H20 FNO3 • HCl • ½ H2 O. The molecular weight is 374.8 (329.4 as free base). The structural formula of paroxetine hydrochloride is:

Structural Formula
(click image for full-size original)

Paroxetine hydrochloride (hemihydrate), USP is an odorless, white to almost white crystalline powder, having a melting point range of 120° to 138°C and a solubility of 5.4 mg/mL in water.

Each enteric film-coated, extended-release tablet contains paroxetine hydrochloride hemihydrate equivalent to 12.5 mg, 25 mg or 37.5 mg paroxetine. Inactive ingredients consist of colloidal silicon dioxide, hydroxypropyl cellulose, hypromellose, lactose monohydrate, magnesium stearate, methacrylic acid copolymer type C, microcrystalline cellulose, polydextrose, polyethylene glycol, polysorbate 80, sodium hydroxide, talc, titanium dioxide, triacetin and triethyl citrate. In addition, the 25 mg product contains the following coloring agents: D&C Red No. 30 Aluminum Lake, FD&C Blue No. 2 Aluminum Lake, FD&C Yellow No. 6 Aluminum Lake and the 37.5 mg product contains D&C Red No. 30 Aluminum Lake, FD&C Yellow No. 6 Aluminum Lake, lecithin and sodium alginate.

In addition, paroxetine hydrochloride extended-release tablets may also contain imprinting ink consisting of either black pigment and natural resin or black iron oxide and propylene glycol.

Paroxetine hydrochloride complies with USP Chromatographic Purity Test 1.

CLINICAL PHARMACOLOGY

Pharmacodynamics

The efficacy of paroxetine in the treatment of major depressive disorder, panic disorder, social anxiety disorder and premenstrual dysphoric disorder (PMDD) is presumed to be linked to potentiation of serotonergic activity in the central nervous system resulting from inhibition of neuronal reuptake of serotonin (5-hydroxy-tryptamine, 5-HT). Studies at clinically relevant doses in humans have demonstrated that paroxetine blocks the uptake of serotonin into human platelets. In vitro studies in animals also suggest that paroxetine is a potent and highly selective inhibitor of neuronal serotonin reuptake and has only very weak effects on norepinephrine and dopamine neuronal reuptake. In vitro radioligand binding studies indicate that paroxetine has little affinity for muscarinic, alpha1 -, alpha2 -, beta-adrenergic-, dopamine (D2 )-, 5-HT1 -, 5-HT2 — and histamine (H1 )-receptors; antagonism of muscarinic, histaminergic and alpha1 -adrenergic receptors has been associated with various anticholinergic, sedative and cardiovascular effects for other psychotropic drugs.

Because the relative potencies of paroxetine’s major metabolites are at most 1/50 of the parent compound, they are essentially inactive.

Pharmacokinetics

Paroxetine hydrochloride is completely absorbed after oral dosing of a solution of the hydrochloride salt. The elimination half-life is approximately 15 to 20 hours after a single dose of paroxetine hydrochloride extended-release tablets. Paroxetine is extensively metabolized and the metabolites are considered to be inactive. Nonlinearity in pharmacokinetics is observed with increasing doses. Paroxetine metabolism is mediated in part by CYP2D6 and the metabolites are primarily excreted in the urine and to some extent in the feces. Pharmacokinetic behavior of paroxetine has not been evaluated in subjects who are deficient in CYP2D6 (poor metabolizers).

Absorption and Distribution

Paroxetine hydrochloride is 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 hydrochloride extended-release tablets at four 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 hydrochloride extended-release tablets is not affected by food.

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 and Excretion

The mean elimination half-life of paroxetine was 15 to 20 hours throughout a range of single doses of paroxetine hydrochloride extended-release tablets (12.5 mg, 25 mg, 37.5 mg and 50 mg). During repeated administration of paroxetine hydrochloride extended-release tablets (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 hydrochloride extended-release tablets (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 one 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. In comparison to Cmin values after 20 mg daily, values after 40 mg daily were only about 2 to 3 times greater than doubled.

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 PRECAUTIONS: Drug Interactions: Drugs Metabolized by CYP2D6).

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.

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