Source: Health Products Regulatory Authority (IE) Revision Year: 2021 Publisher: zr pharma& GmbH, Hietzinger Hauptstrasse 37, 1130 Vienna, Austria
Pharmacotherapeutic group: Tricyclic antidepressant
ATC code: N06AA04
The pharmacological action includes alpha-adrenolytic, anticholinergic, anti-histaminic and 5-HT receptor blocking properties. The main property displayed by the compound is its ability to inhibit the neuronal re-uptake of noradrenaline and 5-HT. Inhibition of the latter is the dominant component.
The active substance is completely absorbed following oral administration and intramuscular injection.
The systemic bioavailability of unchanged clomipramine is reduced by 50% by hepatic “first-pass” metabolism to desmethylclomipramine (an active metabolite).
Following single dose administration 25 mg coated tablet and 75 mg sustained release tablet, the mean maximum plasma concentration (Cmax) of clomipramine were 63.37 ± 12.71 ng/mL (Tmax 4.83 ± 0.39 hr) and 32.55 ± 8.10 (Tmax 9.00 ± 1.81 hr), respectively. The dose of 75 mg Anafranil daily produces steady state concentrations of clomipramine ranging from about 20 to 175 ng/ml. The steady state plasma concentrations of the active metabolite N-desmethylclomipramine follow a similar pattern, but are 40-85% higher than those of clomipramine.
Clomipramine is 97.6% bound to plasma proteins. Clomipramine is extensively distributed throughout the body with the apparent volume of distribution of about 12-17 L/kg bodyweight. Concentrations in cerebrospinal fluid are about 2% of the plasma concentration. Clomipramine passes into maternal milk in concentrations similar to those in plasma and crosses the placenta.
The primary route of clomipramine metabolism is demethylation to form the active metabolite, N‑desmethylclomipramine. N-desmethylclomipramine can be formed by several P450 enzymes, primary CYP3A4, CYP2C19, and CYP1A2. Clomipramine and N-desmethylclomipramine are hydroxylated to form 8-hydroxyclomipramine or 8-hydroxy-N-desmethylclomipramine. Clomipramine is also hydroxylated at the 2-position and N-desmethylclomipramine can be further demethylated to form didesmethylclomipramine. The 2- and 8-hydroxy metabolites are excreted primarily as glucuronides in the urine. Elimination of the active components, clomipramine and N-desmethylclomipramine, by formation of 2- and 8-hydroxy clomipramine is catalysed by CYP2D6.
Oral clomipramine is eliminated from the blood with a mean half-life of 21 hours (range 12-36 h), and desmethylclomipramine with a half-life of 36 hours.
About two-thirds of a single dose of clomipramine is excreted in the form of water-soluble conjugates in the urine, and approximately one-third in the faeces. The quantity of unchanged clomipramine and desmethylclomipramine excreted in the urine amounts toabout 2% and 0.5% of the administered dose respectively.
Food has no significant impact on the pharmacokinetics of clomipramine. A slight delay in the onset of absorption may be observed with the administration of Anafranil with food.
The drug follows dose-proportionate pharmacokinetics over a dose range of 25 to 150 mg.
In elderly patients, clomipramine has relatively low clearance in comparison to younger adult patients. It is reported to reach a therapeutic steady state at doses lower than that reported for middle-aged patients. Clomipramine should be used with caution in elderly patients.
There are no specific reports describing the pharmacokinetic of the drug in patients with renal impairment. Although the drug is excreted as inactive metabolites in the urine and faeces, the accumulation of inactive metabolites may subsequently result in the accumulation of the parent drug and its active metabolite. In moderate and severe renal impairment, it is recommended to monitor the patient during the treatment.
Clomipramine is extensively metabolized in the liver by CYP2D6, CYP3A4, CYP2C19 and CYP1A2, hepatic impairment may impact on its pharmacokinetics. In patients with liver impairment, clomipramine should be administered with caution.
Although the impact of ethnic sensitivity and race on the pharmacokinetics of clomipramine has not been studied extensively, the metabolism of clomipramine and its active metabolite is governed by genetic factors leading to poor and extensive metabolism of the drug and its metabolite. The metabolism of clomipramine in Caucasians population may not be extrapolated to Asians, in particular, Japanese and Chinese because of the pronounced differences of metabolism of clomipramine between these two ethnic groups.
Sustained release of clomipramine from Anafranil sustained release formulation provides a smoother pharmacokinetic profile by maintaining therapeutic plasma concentrations over 24 hours. Maximum mean plasma concentrations are reached within about 9 hours post-dose. Following administration of 75 mg clomipramine as sustained release formulation, observed Cmax is half the maximum concentration levels reached after administration of 25 mg tablets three times a day. Nevertheless, the total exposure remains unchanged. Following multiple administration of sustained release formulation, Cmin and Cmax levels attained at steady state are within the therapeutic range. Sustained-release tablets are bioequivalent with coated tablets and capsules.
Phospholipidosis and testicular changes, commonly associated with tricyclic compounds, have been observed with clomipramine hydrochloride at doses ≥10-fold greater than the maximum recommended human daily dose (MRHD).
No adverse effects on reproductive performance, including male and female fertility, were observed in rats at oral doses up to 24 mg/kg.
No teratogenic effects were detected in mice, rats, and rabbits at doses up to 100, 50, and 60 mg/kg, respectively.
Various in vitro and in vivo mutagenicity tests were performed and did not reveal any mutagenic activity of clomipramine hydrochloride.
There was no evidence of carcinogenicity in mice and rats after 104 weeks of treatment with clomipramine hydrochloride.
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