Imipramine is a classic tricyclic antidepressant. Besides depression, it is used for nocturnal enuresis (bedwetting) in children and chronic neuropathic pain. It tends to cause more side effects than modern antidepressants.
Also known as: Tofranil
Terbinafine may increase imipramine levels through CYP2D6 inhibition, intensifying anticholinergic and cardiac effects.
Terbinafine inhibits CYP2D6; imipramine is a substrate of this pathway.
Anticholinergic symptoms; ECG if treatment is prolonged.
Palpitations, urinary retention, confusion.
Watch for anticholinergic toxicity (dry mouth, urinary retention, constipation) and ECG changes; adjust the dose if needed.
DailyMed — Terbinafine HCl (Lamisil, RLD) and Imipramine HCl labels — note: setid 67e634b1 validates an otic combination label used only to confirm the CYP2D6 pathway; the TCA interaction citation follows EMC-UK (Terbinafine SmPC, Drug Interactions, CYP2D6): https://www.medicines.org.uk/emc/product/3347
Fluoxetine markedly increases imipramine levels, with risk of toxicity (delirium, urinary retention, arrhythmias, seizures).
Fluoxetine is a potent CYP2D6 inhibitor, imipramine\u2019s main metabolic pathway.
ECG (QT, QRS), anticholinergic and neurological signs.
Marked dry mouth, urinary retention, palpitations, confusion, seizures.
Avoid the combination; if a therapeutic switch is needed, reduce the TCA dose by 25–50% and monitor ECG.
DailyMed — Tofranil (imipramine) label, Drug Interactions (CYP2D6 inhibitors): https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=649837df-147f-436c-9553-32ffecf4c6f1
Sertraline can increase imipramine and its active metabolite (desipramine) levels, with anticholinergic and cardiac toxicity risk.
Sertraline moderately inhibits CYP2D6, reducing imipramine-to-desipramine conversion and the clearance of both.
Anticholinergic symptoms; ECG during prolonged treatment.
Palpitations, marked dry mouth, severe constipation.
Consider TCA dose reduction and clinical/ECG monitoring.
DailyMed — Tofranil-PA (imipramine HCl) and Zoloft (sertraline) labels, Drug Interactions: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=4cf8d5c8-842b-4e7c-9a99-3f41ef8abbdb
Paroxetine, a potent CYP2D6 inhibitor, markedly increases imipramine levels with a high toxicity risk.
Potent CYP2D6 inhibition by paroxetine reduces imipramine clearance.
ECG, confusion, tremor, urinary retention.
Dry mouth, palpitations, delirium, seizures.
Avoid the combination; if necessary, markedly reduce the TCA dose and monitor ECG and neurological status.
DailyMed — Tofranil (imipramine) label; INFARMED Prontuário Terapêutico, imipramine entry (CYP2D6 interactions): https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=649837df-147f-436c-9553-32ffecf4c6f1
Cimetidine increases imipramine levels, potentially intensifying sedative and anticholinergic effects.
Cimetidine inhibits hepatic CYP enzymes involved in TCA metabolism.
Anticholinergic symptoms and sedation.
Drowsiness, dry mouth, urinary retention.
Consider TCA dose reduction; prefer antacids or a PPI if possible.
DailyMed — Tofranil (imipramine) label, documented cimetidine interaction: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=649837df-147f-436c-9553-32ffecf4c6f1
Atropine plus imipramine adds anticholinergic effects (dry mouth, constipation, urinary retention, tachycardia, confusion in the elderly).
Imipramine has potent anticholinergic activity that adds to that of atropine.
Anticholinergic signs, especially in the elderly.
Acute urinary retention, confusion, tachycardia.
Avoid the combination when possible; use minimum doses for the shortest time.
DailyMed — Tofranil (imipramine) label, additive anticholinergic effects: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=649837df-147f-436c-9553-32ffecf4c6f1
In mixed overdose with tricyclic antidepressants and benzodiazepines, flumazenil may precipitate potentially fatal seizures and arrhythmias.
Flumazenil removes the protective benzodiazepine effect on a seizure threshold already lowered by the tricyclic (sodium channel blockade, antimuscarinic and proconvulsant effects); the overlap precipitates seizures and ventricular arrhythmias — a situation formally excluded from flumazenil use.
ECG (QRS width), blood gases, electrolytes, neurological status, monitored cardiac rhythm.
QRS widening, seizures, ventricular arrhythmias, coma.
Do not give flumazenil when mixed tricyclic overdose is suspected; sedate with benzodiazepines, treat tricyclic cardiotoxicity with sodium bicarbonate and contact the poison centre.
Flumazenil Injection USP (Pfizer) label — use excluded in mixed overdose/patients at seizure risk: https://labeling.pfizer.com/ShowLabeling.aspx?id=684; INFARMED Prontuário Terapêutico (11th ed., 2012), Imipramine entry (tricyclic cardiovascular and convulsive toxicity).
Alcohol potentiates sedation and may worsen CNS effects and the seizure risk of tricyclics.
Avoid alcohol, especially at treatment start and with high doses.
Prontuário (tricyclics — alcohol); EMC-UK imipramine SmPC 4.4/4.5.
Tricyclics prolong QT and can cause arrhythmias — contraindicated with pre-existing long QT.
Baseline ECG (cardiac patients, elderly, high doses); watch for QRS widening in overdose.
Site monograph (imipramine — baseline ECG); Prontuário (tricyclics — arrhythmias).
Tricyclic anticholinergic activity precipitates angle-closure glaucoma attacks.
Exclude angle-closure glaucoma before starting.
Prontuário/site monograph (imipramine — angle-closure glaucoma).
Tricyclics are contraindicated in recent myocardial infarction recovery — arrhythmogenicity.
Prefer alternatives (SSRIs) in cardiac patients.
Prontuário/EMC-UK — imipramine SmPC 4.3 (recent MI).
Tricyclics lower the seizure threshold.
Maintain antiepileptics; titrate slowly.
Prontuário (tricyclics — seizure threshold).
Annex 1 records "avoid unless potential clinical benefits outweigh risks" (factor CM). TCAs have long experience without a major teratogenicity signal; risk in the 3rd trimester: neonatal withdrawal/anticholinergic symptoms (jitteriness, urinary retention).
Use only if necessary (enuresis, depression without alternative), at the lowest effective dose; monitor neonatal symptoms if used in the 3rd trimester.
Annex 2 refers to "Antidepressants (tricyclics and related)": present in milk at variable levels; avoidance or infant monitoring for sedation is recommended. TCAs have lower milk levels than SSRIs — individualised clinical decision.
Prontuário Terapêutico INFARMED — Annex 1: "Imipramine — avoid unless potential clinical benefits outweigh risks" (l. 40528); Annex 2: Antidepressants (l. 42741). EMC-UK (MHRA) — Imipramine SmPC (Tofranil).
Clinical and educational support tool. The information does not replace a medical prescription or the opinion of a qualified healthcare professional.
Prototype tricyclic antidepressant: effective but with a narrow therapeutic index and severe cardiac toxicity in overdose; current use reserved for specific indications (enuresis, neuropathic pain, resistant depression).
Inhibits serotonin and noradrenaline reuptake (SERT/NET transporters), increasing monoaminergic neurotransmission; antidepressant effects take 2–4 weeks (receptor desensitisation). M1, H1, alpha-1 antagonism explains dry mouth, sedation and hypotension; cardiac sodium channel blockade (phase 0) explains overdose cardiotoxicity and QT/QRS prolongation.
Good oral absorption (~75–95%), but significant first pass (bioavailability 30–75%); peak 1–2 h; high lipophilia, large volume of distribution (10–15 L/kg) and ~90% protein binding.
Hepatic N-demethylation (CYP2C19, CYP1A2, CYP3A4) to desipramine (more noradrenergic active metabolite); ring hydroxylation by CYP2D6 (important polymorphism — slow metabolisers accumulate). Glucuronidation and renal excretion.
6–20 h (imipramine); desipramine 14–25 h — allows 1–2×/day dosing, but prolongs overdose recovery.
Medicines from the same therapeutic group (ATC classification) or the same pharmacological class.
