Adult: Ambulatory or outpatient: Initially, up to 75 mg daily in divided doses or as a single dose at bedtime, may gradually increase to 150-200 mg daily as necessary. Usual maintenance: 50-150 mg daily, individualised according to patient requirements. Severely depressed hospitalised patients: May be increased to 100 mg tid until distinct improvement is achieved then determine maintenance dose according to individual patient requirements. Usual maintenance: Approx 100 mg daily. Elderly: Initially, 10 mg daily, may gradually increase to 30-50 mg daily. Dosage recommendations for the elderly may vary among countries. Refer to individual product and country guidelines.
Oral Nocturnal enuresis
Child: 6-7 years 20-25 kg: 25 mg daily; 8-11 years 25-35 kg: 25-50 mg daily; >11 years 35-54 kg: 50-75 mg daily. Max: 75 mg daily. Doses are given just before bedtime. Max treatment duration: 3 months.
Special Patient Group
Pharmacogenomics:
CYP2D6 and CYP2C19 polymorphisms may affect the pharmacokinetic response, clinical efficacy, and safety of imipramine. Individuals with reduced CYP2D6 enzyme activity, known as CYP2D6 poor metabolisers, may experience an increase in imipramine plasma concentrations, and an increased risk of adverse effects (e.g. anticholinergic, CNS, cardiac effects). Available studies indicate that approx 7-10% of Caucasians are CYP2D6 poor metabolisers. CYP2C19*3 is more common among individuals of Asian ancestry.
Genetic testing for CYP2D6 and CYP2C19 may serve as a guide to help clinicians optimise treatment initiation of imipramine. Therapeutic drug monitoring and monitoring of plasma concentrations may also be utilised during dose adjustments.
Clinical Pharmacogenetics Implementation Consortium guideline (CPIC) for CYP2D6 and CYP2C19 Genotypes and Dosing of Tricyclic Antidepressants: 2016 Update
CYP2D6 phenotypes
CYP2D6 ultrarapid metabolisers
Carriers of more than 2 copies of functional alleles (e.g. *1/*1xN, *1/*2xN) with an activity score of >2.0 have increased metabolism of TCAs causing lower imipramine plasma concentrations resulting to increased risk of pharmacotherapy failure. Avoid use and consider alternative drugs not metabolised by CYP2D6. Consider titrating to a higher target dose if TCA use is necessary. Dose adjustments may be guided by therapeutic drug monitoring.
CYP2D6 normal metabolisers
Carriers of 2 normal function alleles, or 2 decreased function alleles, or 1 normal and no function allele, or 1 normal and decreased function allele, or combinations of duplicated alleles (e.g. *1/*1, *1/*2, *2/*2, *1/*9, *1/*41, *41/*41, *1/*4, *1/*5) with an activity score of 1.0-2.0 have normal metabolism of imipramine. Start treatment with the recommended initial dose.
CYP2D6 intermediate metabolisers
Carriers of 1 decreased and 1 no function allele (e.g. *4/*41, *5/*9, *4/*10) with an activity score of 0.5 have reduced metabolism of TCAs causing higher imipramine plasma concentrations resulting to increased risk of adverse effects. Consider reducing the recommended initial dose by 25%. Dose adjustments may be guided by therapeutic drug monitoring.
CYP2D6 poor metabolisers
Carriers of only no function alleles (e.g. *4/*4, *4/*4xN, *3/*4, *5/*5, *5/*6) with an activity score of 0 have greatly reduced metabolism of TCAs causing higher imipramine plasma concentrations resulting to increased risk of adverse effects. Avoid use and consider alternative drugs not metabolised by CYP2D6. Consider reducing the recommended initial dose by 50% if TCA use is necessary. Dose adjustments may be guided by therapeutic drug monitoring.
CYP2C19 phenotypes
CYP2C19 ultrarapid metabolisers and rapid metabolisers
Ultrarapid metabolisers are carriers of 2 increased function alleles (e.g. *17/*17) while rapid metabolisers are carriers of 1 normal and 1 increased function allele (e.g. *1/*17). These phenotypes and genotypes have increased metabolism of tertiary amines to secondary amines which may affect imipramine response or adverse effects. Avoid use and consider alternative drugs not metabolised by CYP2C19 (e.g. nortriptyline, desipramine). Dose adjustments may be guided by therapeutic drug monitoring if tertiary amine use is necessary.
CYP2C19 normal metabolisers
Carriers of 2 normal function alleles (e.g. *1/*1) have normal metabolism of tertiary amines. Start treatment with the recommended initial dose.
CYP2C19 intermediate metabolisers
Carriers of 1 normal and 1 no function allele, or 1 no function and 1 increased function allele (e.g. *1/*2, *1/*3, *2/*17) have reduced metabolism of tertiary amines. Start treatment with the recommended initial dose.
CYP2C19 poor metabolisers
Carriers of 2 no function alleles (e.g. *2/*2, *2/*3, *3/*3) have greatly reduced metabolism of tertiary amines to secondary amines which may affect imipramine response and adverse effects. Avoid use and consider alternative drugs not metabolised by CYP2C19 (e.g. nortriptyline, desipramine), or consider reducing the recommended initial dose by 50%. Dose adjustments may be guided by therapeutic drug monitoring.
Dutch Pharmacogenetics Working Group (DPWG) Guideline for Imipramine: November 2018 Update
CYP2D6 phenotypes
CYP2D6 poor metabolisers
Increased plasma concentrations of imipramine and the desipramine (active metabolite) resulting in increased risk of adverse effects. Use 30% of the standard dose and determine the maintenance dose by monitoring the effect and adverse effects or the plasma concentrations of imipramine and desipramine.
CYP2D6 intermediate metabolisers
Increased plasma concentrations of imipramine and desipramine resulting in increased risk of adverse effects. Use 70% of the standard dose and determine the maintenance dose by monitoring the effect and adverse effects or the plasma concentrations of imipramine and desipramine.
CYP2D6 ultrarapid metabolisers
Reduced plasma concentrations of imipramine and the desipramine and increased plasma concentrations of the potentially cardiotoxic hydroxy metabolites, resulting in risk of reduced efficacy and increased cardiotoxic adverse effects. Use 1.7 times the standard dose and determine the maintenance dose by monitoring the effect and adverse effects or the plasma concentrations of imipramine and desipramine. Avoid use if a dose increase is not possible due to the potentially cardiotoxic hydroxy metabolites. Consider alternative drugs that are not metabolised by CYP2D6 (e.g. citalopram, sertraline).
CYP2C19 phenotypes
CYP2C19 poor metabolisers
Increased plasma concentrations of imipramine + desipramine resulting in increased risk of adverse effects. Use 70% of the standard dose and determine the maintenance dose by monitoring the effect and adverse effects or the plasma concentrations of imipramine and desipramine; or avoid use. Consider the use of alternative drugs that are not metabolised by CYP2C19 (e.g. nortriptyline, fluvoxamine, mirtazapine).
CYP2C19 intermediate metabolisers
Increases imipramine plasma concentrations, but not imipramine + desipramine plasma concentrations, which directs efficacy and adverse effects. No dosage adjustment needed.
CYP2C19 ultrarapid metabolisers
Decreases imipramine plasma concentrations, but not imipramine + desipramine plasma concentrations, which directs efficacy and adverse effects. No dosage adjustment needed.
Hepatic Impairment
Severe: Contraindicated.
Administration
May be taken with or without food.
Contraindications
Recent MI, any degree of heart block or cardiac arrhythmias, narrow-angle glaucoma, urinary retention, mania, porphyria. Severe hepatic impairment. Children <6 years. Concomitant or within 14 days of MAOI use.
Special Precautions
Patient with decreased gastrointestinal motility, paralytic ileus, BPH, xerostomia, increased intraocular pressure, visual problems, diabetes mellitus, CV disease (e.g. stroke, tachycardia, conduction abnormalities), chronic constipation, hyperthyroidism, tumours of the adrenal medulla (e.g. phaeochromocytoma, neuroblastoma), risk factors for orthostatic hypotension (e.g. hypovolaemia, cerebrovascular or cardiovascular disease), alcohol use disorder, history of suicidal-related events, risk or history of seizure disorder (e.g. head trauma, brain damage, alcoholism). Smokers. Patients with CYP2D6 or CYP2C19 polymorphism. Patients undergoing electroconvulsive treatment or elective surgery. Avoid abrupt withdrawal. Hepatic and renal impairment. Children and elderly. Pregnancy and lactation.
Adverse Reactions
Significant: Anticholinergic effects (e.g. xerostomia, blurred vision, constipation, urinary retention), bone fractures, orthostatic hypotension, photosensitisation, mild pupillary dilation, hypomanic or manic episodes, bone marrow suppression. Cardiac disorders: Arrhythmias, sinus tachycardia, palpitations, conduction disorders (e.g. bundle branch block, widening of QRS complex, PR changes). Eye disorders: Decreased lacrimation, blurred vision, visual accommodation disorder. Gastrointestinal disorders: Nausea, vomiting, diarrhoea. General disorders and administration site conditions: Fatigue. Investigations: Increased weight, abnormal ECG and LFT. Metabolism and nutrition disorders: Anorexia. Nervous system disorders: Dizziness, headache, sedation, somnolence, tremor, paraesthesia. Psychiatric disorders: Anxiety, agitation, euphoria, confusion, delirium, disorientation, hallucinations, restlessness, sleep disorder. Renal and urinary disorders: Micturition disorder. Reproductive system and breast disorders: Libido disorder. Skin and subcutaneous tissue disorders: Hyperhidrosis, rash, urticaria. Vascular disorders: Hot flushes. Potentially Fatal: Suicidal ideation or behaviour, serotonin syndrome.
This drug may cause blurred vision, dizziness and fatigue, if affected, do not drive or operate machinery. Avoid excessive exposure to sunlight.
Monitoring Parameters
Monitor CBC, blood pressure, pulse rate, serum Na (at-risk populations), blood glucose, weight, and BMI. Perform ECG at baseline and with dose increases (especially the elderly, patients with CV disease or those receiving high doses). Monitor closely for signs of serotonin syndrome and infection (e.g. fever, sore throat) and evaluate mental status, suicidal ideation, anxiety, social functioning, panic attacks or unusual changes in behaviour. Screen patients for possible risk for bipolar disorder prior to treatment initiation.
Overdosage
Symptoms: CNS effects (e.g. drowsiness, agitation, ataxia, restlessness, stupor, enhanced reflexes, muscle rigidity, athetoid, choreiform movements, convulsions), cardiac abnormalities (e.g. hypotension, tachycardia, arrhythmia, conduction disorders, heart failure), respiratory depression, cyanosis, vomiting, shock, fever, dry mouth, constipation, sweating, anuria, oliguria. Management: Symptomatic and supportive treatment. Obtain ECG and closely monitor for changes. Initiate gastric decontamination including large volume gastric lavage followed by activated charcoal. If patient has impaired consciousness, secure airway prior to lavage. Respiratory depression may necessitate intubation and artificial respiration. Plasma expander may be administered in severe hypotension. Convulsions may be controlled with benzodiazepines (e.g. diazepam) or other anticonvulsants (e.g. phenobarbital, phenytoin).
Drug Interactions
May reduce the antihypertensive effects of methyldopa, clonidine, bethanidine, guanethidine, debrisoquine, and reserpine. May potentiate the CV effects of sympathomimetic agents (e.g. epinephrine, ephedrine, phenylephrine). May potentiate the effects of CNS depressants (e.g. benzodiazepines, barbiturates, general anaesthetics), phenothiazine, antiparkinsonian agents (e.g. biperiden), antihistamines, atropine. May potentiate the anticoagulant effect of coumarins. May increase the serum concentrations of phenytoin or carbamazepine. SSRIs (e.g. fluoxetine, fluvoxamine, paroxetine), neuroleptic agents (e.g. phenothiazine), β-blockers (e.g. propranolol, labetalol), cimetidine, Ca channel blockers (e.g. verapamil, diltiazem), methylphenidate may increase the plasma concentration of imipramine. Drugs that activate the hepatic mono-oxygenase enzyme system (e.g. phenytoin, nicotine, oral contraceptives) may accelerate the metabolism thereby decrease plasma concentration and decreased efficacy of imipramine. Oral antifungals (e.g. terbinafine) may increase the exposure and accumulation of imipramine. QT-prolonging drugs (e.g. cisapride, thioridazine, cotrimoxazole) may induce tachycardia and Torsades de pointes. May increase the risk of postural hypotension with diuretics. Potentially Fatal: Increased risk of hypertensive crisis, hyperpyrexia, myoclonus, agitation, seizures, delirium, and coma with MAOIs (e.g. moclobemide).
Food Interaction
May enhance the CNS depressant effects of alcohol.
Action
Description: Mechanism of Action: Imipramine is a dibenzazepine TCA that is believed to increase the synaptic concentration of serotonin and norepinephrine in the CNS by inhibition of their reuptake into presynaptic terminals. Additional receptor effects have been found including desensitisation of adenyl cyclase, and down regulation of β-adrenergic and serotonin receptors. Onset: 4-8 weeks. Pharmacokinetics: Absorption: Well absorbed from the gastrointestinal tract. Bioavailability: 22-77%. Time to peak plasma concentration: 2-6 hours. Distribution: Widely distributed throughout the body. Crosses the blood-brain barrier and the placenta. Enters breast milk. Volume of distribution: Approx 10-20 L/kg. Plasma protein binding: 60-96% (mainly to α1-acid glycoproteins and lipoproteins; to a lesser extent to albumin). Metabolism: Metabolised in the liver via first-pass effect mainly by CYP2D6 to desipramine (primary active metabolite). Excretion: Via urine (80%, mainly as inactive metabolites and <5% as unchanged drug) and faeces (20%, as inactive metabolites). Elimination half-life: 8-21 hours.
Chemical Structure
Imipramine Source: National Center for Biotechnology Information. PubChem Database. Imipramine, CID=3696, https://pubchem.ncbi.nlm.nih.gov/compound/Imipramine (accessed on Jan. 21, 2020)
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