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 a capsule 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 have not been determined.
Interactions
Coadministration of haloperidol with clomipramine increases plasma concentrations of clomipramine. Coadministration of clomipramine with phenobarbital increases plasma concentrations of phenobarbital (see PRECAUTIONS: Drug Interactions). Younger subjects (18 to 40 years of age) tolerated clomipramine better and had significantly lower steady-state plasma concentrations, compared with subjects over 65 years of age. Children under 15 years of age had significantly lower plasma concentration/dose ratios, compared with adults. Plasma concentrations of clomipramine were significantly lower in smokers than in nonsmokers.
ANIMAL TOXICOLOGY
Phospholipidosis and testicular changes, commonly associated with tricyclic compounds, have been observed with clomipramine. In chronic rat studies, changes related to clomipramine consisted of systemic phospholipidosis, alterations in the testes (atrophy, mineralization) and secondary changes in the other tissues. In addition cardiac thrombosis and dermatitis/keratitis were observed in rats treated for 2 years at doses which were 24 and 10 times the maximum recommended human daily dose (MRHD), respectively, on a mg/kg basis, and 4 and 1.5 times the MRHD, respectively, on a mg/m2 basis.
Mylan Pharmaceuticals Inc.
Morgantown, WV 26505
JANUARY 2006
CLOM:R11
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