clomipramine ANAFRANIL
Class: TCA/DihydrodibenzazepineFDA Indications: OCD
Off-Label Use: Treatment Resistant Depression, Depression, Anxiety, Cataplexy, Insomnia, Neuropathic Pain
Prescribing
Forms: 25, 50, 75mg tabletDose Range: 75-300 mg/day
Starting: 25 mg qd qhs, ↑ over 2 weeks to 100mg qd; max dose generally 250mg qd
Stopping: ↓ 50% x3 days, then ↓ another 50% x3 days, then D/C entirely.
Monitoring: Suggested plasma level 300-1000 nmol/L
Precautions
Contraindications: Concomitant use of MAOIs; patient s/p MI; coadministration of other QT-prolonging agents; h/o QT ↑ or arrhythmia; caution in patients with hypo-K+ or hypo-Mg2+Serious Side Effects: 5HT syndrome; ↓ QT↑, arrhythmias, tachycardia, orthostatic hypotension; dose-related seizure risk (0.7% @ doses ≥300mg)
Side Effects: anticholinergic side effects, weight gain, sexual dysfunction, sedation/somnolence
Pharmacokinetics
t½: 32 (17-37)° TMAX: 4.7°Substrate of: 2D6; 1A2, 3A4, 2C19, 2C9
Inhibits: 2D6, UGT; Induces: ∅
Active Metabolites: N-desmethylclomipramine (t½ 54-77°); NET >> SERT inhibition
DDIs
- - DO NOT CO-PRESCRIBE WITH MAOIs (need a 14-day washout period)
- - caution combining with other CNS depressants & anticholingerics
- - VPA may ↑ levels
- - 2D6 inhibitors can ↑ serum levels; 2D6 inducers can ↓ serum levels
Misc
- - considered to be the most powerful antidepressant ever made
- - exhibits nonlinear pharmacokinetics
- - OCD tx often requires doses ≥200mg
- - unique among TCAs, clomipramine exhibits preferential selectivity for 5HT reuptake however its 2° metabolite, N-desmethylclomipramine, is an NE reuptake inhibitor
Special Populations
Category C—A case-control study showed ∅ ↑ congenital malformations with 1st trimester use & a review (n=209) showed ∅ assoc with congenital malformations or developmental delay.
RID 2.8%
Avoid due to its anticholinergicity and high sedation, especially when combining with other CNS depressants and/or anticholingerics. Caution regarding orthostatic hypotension (fall risk!). Can impair cognition.
2019 BEE℞S Recommendation: Avoid. Highly anticholinergic, sedating, and cause orthostatic hypotension.
No dosage adjustment necessary.
All TCAs are hepatically metabolzed, highly protein bound and will accumulate, and associated with ↑ LFTs.
References
Applied Clinical Pharmacokinetics And Pharmacodynamics Of Psychopharmacological AgentsConcise Guide To Drug Interaction Principles For Medical Practice
Foye's Principles Of Medicinal Chemistry
Pharmacology For Women's Health
Drug Interactions In Psychiatry, 3rd Ed.
Antidepressant Use During Pregnancy
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