N06AA04 - Clomipramine |
Propably not porphyrinogenic |
PNP |
Rationale
Clomipramine is not an inhibitor or an inducer of any major CYP enzymes.
Risk for gastrointestinal adverse events in the form of nausea, constipation, diarrhoea, fatigue, vomiting, abdominal disorders and decreased appetite motivates vigilance against insufficient intake of food, especially of carbohydrate.
Chemical description
Chlorinated imipramine (Chloro dibenzazepine propyl methylamine hydrochloride)
Therapeutic characteristics
Clomipramine is indicated for the treatment of depression, obsessional and phobic states and adjunctive treatment of cataplexy associated with narcolepsy.
Very common side effects that can be potentially porphyrinogenic through reduction in carbohydrate intake and that also can be confused with an acute porphyria attack are nausea, constipation and fatigue. Other common side effects are vomiting, abdominal disorders, diarrhoea, decreased appetite, headache, paraesthesia and muscle hypertonia.
Hepatic exposure
Probably significant.
Metabolism and pharmakokinetics
Clomipramine is metabolised by CYP3A4, CYP2C19, CYP2D6 and CYP1A2 (SPC). N-desmethylclomipramine is an active metabolite. Half-life eliminations of clomipramine and N-desmethylclomipramine are around 21 hours and 36 hours, respectively.
Clomipramine is a weak inhibitor of CYP2D6 in vivo (Isoherranen 2009 and SPC).
No drug-drug interactions with clomipramine as a perpetrator are observed (SPC), which indicate that clomipramine is not an inhibitor or inducer of any major CYP enzymes.
Personal communication
Andersson; patient inquiry: used without ill effects (n=1).
Published experience
Clomipramine is listed with conflicting experimental evidence of porphyrinogenicity and is therefore listed as unsafe for use in acute porphyria (Moore 1997).
IPNet drug reports
Uneventful use reported in 3 patients with acute porphyria.
References
- Scientific articles
- Isoherranen N, Hachad H, et al. Qualitative analysis of the role of metabolites in inhibitory drug-drug interactions: literature evaluation based on the metabolism and transport drug interaction database. Chem Res Toxicol. 2009 Feb;22(2):294-8. #1005
- Moore MR, Hift RJ. Drugs in the acute porphyrias--toxicogenetic diseases. Cell Mol Biol (Noisy-le-grand). 1997 Feb;43(1):89-94. PMID 9074793. #1110
- Polasek TM, Miners JO. Time-dependent inhibition of human drug metabolizing cytochromes P450 by tricyclic antidepressants. Br J Clin Pharmacol. 2008 Jan;65(1):87-97. PMID 17662092. #2709
- Summary of Product Characteristics
- Norwegian medicines agency. Summary of Product Characteristics (SPC). klomipramin. #2708
- The electronic Medicines Compendium (emc). Summary of Product Characteristics (SPC). Clomipramine. #2710
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