Adult: For outpatients: Initially, 75 mg daily given in 3 divided doses or as a single dose at bedtime; may gradually increase to 150-200 mg daily as necessary. Usual maintenance dose: 50-100 mg daily. For severe cases in hospitalised patients: Dose may be further increased to 100 mg tid until significant improvement is achieved. Usual maintenance dose: 100 mg daily. Individualise maintenance doses according to the patient's response and tolerability. Dosage recommendations may vary among individual products and between countries (refer to specific product guidelines). Elderly: Initially, 10 mg daily, may gradually increase to 30-50 mg daily. Alternatively, initial dose of 30-40 mg daily, may gradually increase to Max of 100 mg daily. Dosage recommendations may vary among individual products and between countries (refer to specific product guidelines).
Oral Nocturnal enuresis
Child: As temporary adjunctive therapy in patients who did not respond to other forms of management and after possible organic causes have been excluded: 6-7 years 25 mg daily; 8-11 years 25-50 mg daily; >11 years 50-75 mg daily. All doses are given at least 1 hour before bedtime. Dose of 2.5 mg/kg daily should not be exceeded. Max treatment duration (including gradual withdrawal): 3 months. Dosage and treatment duration recommendations may vary among individual products and between countries (refer to specific product guidelines).
Special Patient Group
Pharmacogenomics:
Imipramine is extensively metabolised in the liver mainly via demethylation by CYP2C19, CYP3A4, and CYP1A2 into desipramine (primary active metabolite); imipramine and desipramine are further metabolised via hydroxylation by CYP2D6 to form 2-hydroxyimipramine and 2-hydroxydesipramine.
CYP2C19 and CYP2D6 genes are highly polymorphic and may affect the pharmacokinetic response, clinical efficacy, and safety of imipramine. Genetic testing for CYP2C19 and CYP2D6 may be considered before treatment initiation to help guide dosage adjustments and prevent potential adverse effects.
Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline as of December 2016:
CYP2C19
Phenotype and Genotype
Implications
Recommendations
CYP2C19 ultrarapid metaboliser
Patients carrying 2 increased function alleles e.g. *17/*17
Increased tertiary amine metabolism as compared to normal metabolisers. Increased conversion of imipramine to desipramine may affect treatment response or adverse effects.
Avoid imipramine use and consider an alternative drug not mainly metabolised by CYP2C19 (e.g. desipramine, nortriptyline). If imipramine use is necessary, utilise therapeutic drug monitoring to guide dose adjustments.
CYP2C19 rapid metaboliser
Patients carrying 1 normal function allele and 1 increased function allele e.g. *1/*17
Increased tertiary amine metabolism as compared to normal metabolisers. Increased conversion of imipramine to desipramine may affect treatment response or adverse effects.
Avoid imipramine use and consider an alternative drug not mainly metabolised by CYP2C19 (e.g. desipramine, nortriptyline). If imipramine use is necessary, utilise therapeutic drug monitoring to guide dose adjustments.
CYP2C19 intermediate metaboliser
Patients carrying 1 normal function allele and 1 non-functional allele or 1 non-functional allele and 1 increased function allele e.g. *1/*2, *1/*3, *2/*17
Decreased imipramine metabolism as compared to normal metabolisers.
Initiate treatment with the recommended starting dose.
CYP2C19 poor metaboliser
Patients carrying 2 non-functional alleles e.g. *2/*2, *2/*3, *3/*3
Greatly decreased imipramine metabolism as compared to normal metabolisers. Decreased conversion of imipramine to desipramine may affect treatment response or adverse effects.
Avoid imipramine use and consider an alternative drug not mainly metabolised by CYP2C19 (e.g. desipramine, nortriptyline). If imipramine use is necessary, consider a 50% reduction of the recommended initial dose. Use therapeutic drug monitoring to guide dose adjustments.
CYP2D6
Phenotype and Genotype
Implications
Recommendations
CYP2D6 ultrarapid metaboliser (activity score of >2)
Patients carrying duplications of functional alleles e.g. (*1/*1)xN, (*1/*2)xN, (*2/*2)xN
Increased TCA metabolism to less active metabolites as compared to normal metabolisers. Lower plasma concentrations of active metabolites may increase the possibility of treatment failure.
Avoid the use of TCA and consider an alternative drug not metabolised by CYP2D6. If TCA use is necessary, consider adjusting to a higher target dose compared to normal metabolisers. Use therapeutic drug monitoring to guide dose adjustments.
CYP2D6 intermediate metaboliser (activity score of 0.5)
Patients carrying 1 decreased function and 1 non-functional allele e.g. *4/*41, *5/*9, *4/*10
Decreased TCA metabolism to less active metabolites as compared to normal metabolisers. Higher plasma concentrations of active metabolites may increase the risk of adverse effects.
Consider a 25% reduction of the recommended initial dose with therapeutic drug monitoring to guide dose adjustments.
CYP2D6 poor metaboliser (activity score of 0)
Patients carrying only non-functional alleles e.g. *4/*4, (*4/*4)xN, *3/*4, *5/*5, *5/*6
Greatly decreased TCA metabolism to less active metabolites as compared to normal metabolisers. Higher plasma concentrations of active metabolites may increase the risk of adverse effects.
Avoid the use of TCA and consider an alternative drug not metabolised by CYP2D6. If TCA use is necessary, consider a 50% reduction of the recommended initial dose. Use therapeutic drug monitoring to guide dose adjustments.
Royal Dutch Pharmacists Association - Pharmacogenetics Working Group (DPWG) Guideline as of November 2018:
CYP2C19
Phenotype and Genotype
Description
Recommendations
CYP2C19 ultrarapid metaboliser
Decreased plasma concentrations of imipramine, but not imipramine and desipramine plasma levels.
No dose adjustment is needed.
CYP2C19 intermediate metaboliser
Increased plasma concentrations of imipramine, but not imipramine and desipramine plasma levels.
No dose adjustment is needed.
CYP2C19 poor metaboliser
Increased plasma concentrations of imipramine and desipramine, resulting in increased risk of adverse effects.
Avoid imipramine or use 70% of the standard dose. Monitor adverse effects or the imipramine and desipramine plasma levels to determine the maintenance dose.
CYP2D6
Phenotype and Genotype
Description
Recommendations
CYP2D6 ultrarapid metaboliser
Decreased imipramine and desipramine plasma concentrations which may elevate the plasma concentrations of hydroxy metabolites (potentially cardiotoxic), resulting in increased risk of treatment failure and cardiotoxic adverse effects.
Use 1.7 times the standard dose. Monitor adverse effects or the imipramine and desipramine plasma levels to determine the maintenance dose. Avoid imipramine if a dose increase is not preferred due to the potentially cardiotoxic hydroxy metabolites.
CYP2D6 intermediate metaboliser
Increased imipramine and desipramine plasma concentrations, resulting in increased risk of adverse effects.
Use 70% of the standard dose. Monitor adverse effects or the imipramine and desipramine plasma levels to determine the maintenance dose.
CYP2D6 poor metaboliser
Increased imipramine and desipramine plasma concentrations, resulting in increased risk of adverse effects.
Use 30% of the standard dose. Monitor adverse effects or the imipramine and desipramine plasma levels to determine the maintenance dose.
Hepatic Impairment
Severe: Contraindicated.
Administration
Imipramine May be taken with or without food.
Contraindications
Acute recovery period following MI; any degree of heart block or cardiac arrhythmias; acute porphyria. Severe hepatic impairment. Concomitant use or within 14 days of discontinuing MAOIs.
Special Precautions
Patient with decreased gastrointestinal motility, chronic constipation, paralytic ileus, benign prostatic hyperplasia, urinary retention; xerostomia, increased IOP, angle-closure glaucoma, visual problems; CV disease (e.g. stroke, tachycardia, conduction abnormalities), risk factors for orthostatic hypotension (e.g. hypovolaemia, cerebrovascular disease), diabetes mellitus, alcohol use disorder; hyperthyroidism, tumours of the adrenal medulla (e.g. phaeochromocytoma, neuroblastoma), myasthenia gravis; seizure disorder and its risk factors (e.g. head trauma, brain damage), bipolar disorder, history of suicidal-related events or a significant degree of suicidal ideation. Patients undergoing surgery or electroconvulsive therapy. CYP2C19 ultrarapid, rapid and poor metabolisers. CYP2D6 ultrarapid, intermediate and poor metabolisers. Avoid abrupt withdrawal. Renal and mild to moderate hepatic impairment. Children and elderly. Pregnancy and lactation.
Adverse Reactions
Significant: Suicidal thinking and behaviour, worsening of psychosis, precipitation of hypomanic or manic episodes, CNS depression, lowers seizure threshold; anticholinergic effects (e.g. blurred vision, constipation, urinary retention, xerostomia), bone fractures, orthostatic hypotension, photosensitisation, mild pupillary dilation which may lead to narrow-angle glaucoma; exacerbation of myasthenia gravis; altered blood glucose regulation; hyponatraemia (especially in the elderly); withdrawal symptoms (particularly if abruptly discontinued). Rarely, bone marrow suppression. Cardiac disorders: Arrhythmias, sinus tachycardia, palpitations, conduction disorders (e.g. bundle branch block). Eye disorders: Visual accommodation disorders, decreased lacrimation. Gastrointestinal disorders: Nausea, vomiting. General disorders and administration site conditions: Fatigue. Investigations: Increased weight and LFTs; abnormal ECG (e.g. widening QRS complex, PR changes). Metabolism and nutrition disorders: Anorexia. Nervous system disorders: Dizziness, headache, drowsiness, tremor, paraesthesia. Psychiatric disorders: Agitation, anxiety, confusion, delirium, disorientation, hallucinations, restlessness, sleep disorder. Renal and urinary disorders: Micturition disorder. Reproductive system and breast disorders: Changes in libido. Skin and subcutaneous tissue disorders: Diaphoresis, rash, urticaria, alopecia. Vascular disorders: Hot flushes. Potentially Fatal: Serotonin syndrome.
This drug may cause blurred vision and drowsiness, if affected, do not drive or operate machinery. Avoid excessive sunlight exposure.
Monitoring Parameters
Monitor blood pressure, pulse rate, blood glucose, CBC, weight and BMI; serum Na levels as clinically indicated in at-risk patients. Perform ECG at baseline and with dose increases (especially in the elderly, patients with CV disease or those receiving high doses). Closely monitor mental status and for signs of serotonin syndrome, infection, clinical worsening, suicidal ideation, and unusual changes in behaviour.
Overdosage
Symptoms: CNS effects (e.g. drowsiness, agitation, restlessness, stupor, ataxia, athetoid or choreiform movements, convulsions), CV effects (e.g. hypotension, tachycardia, arrhythmia, conduction disorders, heart failure), respiratory depression, cyanosis, vomiting, shock, fever, sweating, anuria, and oliguria. Management: Symptomatic and supportive treatment. Perform gastric lavage or induce vomiting if the patient is fully conscious. Administration of activated charcoal may reduce absorption. If the patient has impaired consciousness, secure the airway before employing gastric lavage; avoid inducing vomiting. For dysrhythmias, cautiously give IV Na bicarbonate to maintain serum pH between 7.45-7.55 or initiate hyperventilation (if pH response is inadequate). Intubation and artificial respiration may be considered for respiratory depression. Convulsions may be controlled with benzodiazepines (e.g. IV diazepam) or other anticonvulsants (e.g. phenobarbital, phenytoin). Continuously monitor cardiac function, blood gases, and electrolytes.
Drug Interactions
Increased risk of arrhythmias with agents that prolong QT interval (e.g. thioridazine). May enhance the CNS depressant effects of benzodiazepines, barbiturates, and general anaesthetics. May reduce the antihypertensive effects of methyldopa, clonidine, bethanidine, guanethidine, debrisoquine, and reserpine. May increase the risk of orthostatic hypotension with diuretics and altretamine. May enhance the anticholinergic effects of phenothiazine, antiparkinsonian agents (e.g. biperiden), antihistamines, and atropine. Neuroleptic agents, β-blockers (e.g. propranolol, labetalol), cimetidine, terbinafine, Ca channel blockers (e.g. verapamil, diltiazem), methylphenidate, and ritonavir may increase the plasma concentration of imipramine. May potentiate the CV effects of sympathomimetic agents (e.g. epinephrine, ephedrine, norepinephrine, phenylephrine) and the anticoagulant effect of coumarins, respectively. Increased metabolism resulting in reduced plasma levels and efficacy with hepatic enzyme inducers (e.g. barbiturates, carbamazepine, phenytoin, oral contraceptives, nicotine). Potentially Fatal: Increased risk of serotonin syndrome with MAOIs, serotonergic agents (e.g. SSRIs, SNRIs, lithium) and opioids (e.g. buprenorphine, tramadol).
Food Interaction
May increase the risk of serotonin syndrome with St. John's wort. May enhance the CNS depressant effects of alcohol.
Action
Description: Mechanism of Action: Imipramine is a dibenzazepine TCA with moderate antimuscarinic and lower sedating properties. The exact mechanism of activity is unknown; however, it is believed to inhibit the neuronal reuptake of serotonin and norepinephrine into presynaptic terminals, thereby increasing their synaptic concentration in the CNS. Additionally, receptor effects have been observed with imipramine, including desensitisation of adenyl cyclase and the downregulation of β-adrenergic and serotonin receptors. 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. Crosses the placenta and enters breast milk. Volume of distribution: Approx 10-20 L/kg. Plasma protein binding: 60-96%, mainly to α1-acid glycoproteins and lipoproteins and to a lesser extent to albumin. Metabolism: Extensively metabolised in the liver mainly via demethylation by CYP2C19, CYP3A4, and CYP1A2 into desipramine (primary active metabolite); imipramine and desipramine are further metabolised via hydroxylation by CYP2D6 to form 2-hydroxyimipramine and 2-hydroxydesipramine. Undergoes significant first-pass effect. Excretion: Via urine (80% as inactive metabolites); faeces (20% as inactive metabolites). Elimination half-life: 8-21 hours.
Chemical Structure
Imipramine Source: National Center for Biotechnology Information. PubChem Compound Summary for CID 3696, Imipramine. https://pubchem.ncbi.nlm.nih.gov/compound/Imipramine. Accessed May 27, 2025.
Storage
Store between 15-30°C. Protect from light and moisture.
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