Clomipramine Hydrochloride

CLOMIPRAMINE HYDROCHLORIDE- clomipramine hydrochloride capsule
Upsher-Smith Laboratories, LLC

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 clomipramine hydrochloride 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. Clomipramine hydrochloride is not approved for use in pediatric patients except for patients with obsessive compulsive disorder (OCD) (see WARNINGS, Clinical Worsening and Suicide Risk ; PRECAUTIONS, Information for Patients ; and PRECAUTIONS, Pediatric Use ).

DESCRIPTION

Clomipramine hydrochloride capsules, USP is an antiobsessional drug that belongs to the class (dibenzazepine) of pharmacologic agents known as tricyclic antidepressants. Clomipramine hydrochloride is available as capsules of 25, 50, and 75 mg for oral administration.

Clomipramine hydrochloride, USP is 3-chloro-5-[3-(dimethylamino) propyl]-10,11-dihydro-5H -dibenz[b,f ]azepine monohydrochloride, and its structural formula is:

Chemical-Structure
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Clomipramine hydrochloride, USP is a white to off-white crystalline powder. It is freely soluble in water, in methanol, and in methylene chloride, and insoluble in ethyl ether and in hexane.

Each capsule contains 25 mg, 50 mg or 75 mg of clomipramine hydrochloride USP.

Inactive ingredients: magnesium stearate, pregelatinized starch, and silicone dioxide.

The capsule shells contain: D&C Yellow 10, FD&C Blue 1, FD&C Blue 2, FD&C Red 40, ferrous iron oxide, gelatin, pharmaceutical glaze, propylene glycol and titanium dioxide.

The 25 mg capsule shells also contain iron oxide red and iron oxide yellow. The 50 mg capsule shells also contain FD&C Blue 1. The 75 mg capsule shells also contain D&C Red 33 and D&C Yellow 10.

CLINICAL PHARMACOLOGY

Pharmacodynamics

Clomipramine is presumed to influence obsessive and compulsive behaviors through its effects on serotonergic neuronal transmission. The actual neurochemical mechanism is unknown, but clomipramine’s capacity to inhibit the reuptake of serotonin (5-HT) is thought to be important.

Pharmacokinetics

Absorption/Bioavailability

Clomipramine from clomipramine hydrochloride capsules is as bioavailable as clomipramine from a solution. The bioavailability of clomipramine from capsules is not significantly affected by food.

In a dose proportionality study involving multiple clomipramine doses, steady-state plasma concentrations (Css ) and area-under-plasma-concentration-time curves (AUC) of clomipramine and clomipramine’s major active metabolite, desmethylclomipramine, were not proportional to dose over the ranges evaluated, i.e., between 25 to 100 mg/day and between 25 to 150 mg/day, although Css and AUC are approximately linearly related to dose between 100 to 150 mg/day. The relationship between dose and clomipramine/desmethylclomipramine concentrations at higher daily doses has not been systematically assessed, but if there is significant dose dependency at doses above 150 mg/day, there is the potential for dramatically higher Css and AUC even for patients dosed within the recommended range. This may pose a potential risk to some patients (see WARNINGS and PRECAUTIONS, Drug Interactions).

After a single 50 mg oral dose, maximum plasma concentrations of clomipramine occur within 2 to 6 hours (mean, 4.7 hr) and range from 56 ng/mL to 154 ng/mL (mean, 92 ng/mL). After multiple daily doses of 150 mg of clomipramine hydrochloride, steady-state maximum plasma concentrations range from 94 ng/mL to 339 ng/mL (mean, 218 ng/mL) for clomipramine and from 134 ng/mL to 532 ng/mL (mean, 274 ng/mL) for desmethylclomipramine. Additional information from a rising dose study of doses up to 250 mg suggests that desmethylclomipramine may exhibit nonlinear pharmacokinetics over the usual dosing range. At a dose of clomipramine hydrochloride 200 mg, subjects who had a single blood sample taken approximately 9 to 22 hours, (median 16 hours), after the dose had plasma concentrations of up to 605 ng/mL for clomipramine, 781 ng/mL for desmethylclomipramine, and 1386 ng/mL for both.

Distribution

Clomipramine distributes into cerebrospinal fluid (CSF) and brain and into breast milk. Desmethylclomipramine also distributes into CSF, with a mean CSF/plasma ratio of 2.6. The protein binding of clomipramine is approximately 97%, principally to albumin, and is independent of clomipramine concentration. The interaction between clomipramine and other highly protein-bound drugs has not been fully evaluated, but may be important (see PRECAUTIONS, Drug Interactions).

Metabolism

Clomipramine is extensively biotransformed to desmethylclomipramine and other metabolites and their glucuronide conjugates. Desmethylclomipramine is pharmacologically active, but its effects on OCD behaviors are unknown. These metabolites are excreted in urine and feces, following biliary elimination. After a 25 mg radiolabeled dose of clomipramine in two subjects, 60% and 51%, respectively, of the dose were recovered in the urine and 32% and 24%, respectively, in feces. In the same study, the combined urinary recoveries of clomipramine and desmethylclomipramine were only about 0.8% to 1.3% of the dose administered. Clomipramine does not induce drug-metabolizing enzymes, as measured by antipyrine half-life.

Elimination

Evidence that the Css and AUC for clomipramine and desmethylclomipramine may increase disproportionately with increasing oral doses suggests that the metabolism of clomipramine and desmethylclomipramine may be capacity limited. This fact must be considered in assessing the estimates of the pharmacokinetic parameters presented below, as these were obtained in individuals exposed to doses of 150 mg. If the pharmacokinetics of clomipramine and desmethylclomipramine are nonlinear at doses above 150 mg, their elimination half-lives may be considerably lengthened at doses near the upper end of the recommended dosing range (i.e., 200 mg/day to 250 mg/day). Consequently, clomipramine and desmethylclomipramine may accumulate, and this accumulation may increase the incidence of any dose- or plasma-concentration-dependent adverse reactions, in particular seizures (see WARNINGS).

After a 150 mg dose, the half-life of clomipramine ranges from 19 hours to 37 hours (mean, 32 hr) and that of desmethylclomipramine ranges from 54 hours to 77 hours (mean, 69 hr). Steady-state levels after multiple dosing are typically reached within 7 to 14 days for clomipramine. Plasma concentrations of the metabolite exceed the parent drug on multiple dosing. After multiple dosing with 150 mg/day, the accumulation factor for clomipramine is approximately 2.5 and for desmethylclomipramine is 4.6. Importantly, it may take two weeks or longer to achieve this extent of accumulation at constant dosing because of the relatively long elimination half-lives of clomipramine and desmethylclomipramine (see DOSAGE AND ADMINISTRATION). The effects of hepatic and renal impairment on the disposition of clomipramine hydrochloride have not been determined.

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