Adult: Initially, 10 mg daily, may be increased gradually to 30-150 mg daily if necessary. Maintenance dose: 30-50 mg daily. Severe cases: Up to Max 250 mg daily, then may be adjusted to maintenance dose of 50-100 mg daily once distinct improvement is observed. All doses may be given as a single dose at bedtime or in divided doses throughout the day. Elderly: Initially, 10 mg daily, may be increased cautiously to 30-75 mg daily which should be achieved after approx 10 days.
Oral Obsessive compulsive disorder, Phobias
Adult: Initially, 25 mg daily, may be increased gradually to 100-150 mg daily which should be achieved over 2 weeks according to the severity of condition. Elderly: Initially, 10 mg daily.
Oral Adjunct for cataplexy associated with narcolepsy
Adult: Initially, 10 mg daily, may be increased gradually to 10-75 mg daily until satisfactory response occurs. Control of cataplexy should be achieved within 24 hours of reaching the optimal dose. Elderly: Dose reduction may be required.
Special Patient Group
Patients sensitive to TCAs for treatment of obsessive compulsive disorder and phobias: Initially, 10 mg daily.
Pharmacogenomics:
Clomipramine is metabolised primarily by CYP2C19 isoenzyme via demethylation to form its active desmethylclomipramine metabolite, and by CYP2D6 isoenzyme via hydroxylation into its less active hydroxyclomipramine metabolites.
CYP2D6 and CYP2C19 polymorphisms may affect the pharmacokinetic response, clinical efficacy, and safety of clomipramine. Individuals with reduced CYP2D6 enzyme activity, known as CYP2D6 poor metabolisers, may experience either a small increase or an 8-fold increase in clomipramine plasma concentrations, and an increased risk of adverse effects (e.g. anticholinergic, CNS, cardiac effects). CYP2D6 and CYP2C19 allele frequencies may considerably vary among individuals of different ethnic backgrounds. CYP2D6*10 is common in Asians while CYP2D6*17 is common in Sub-Saharan African ancestry but has a considerably lower prevalence in Caucasians of European ancestry. Available studies indicate that approx 7-10% of Caucasians are CYP2D6 poor metabolisers while reliable estimates of the prevalence among Asian, African and other populations are not yet available. CYP2C19*3 has an allele frequency of approx 15% in Asians but has low prevalence among most ethnic groups.
Genetic testing for CYP2D6 and CYP2C19 may serve as a guide to help clinicians optimise treatment initiation of clomipramine. Therapeutic drug monitoring and monitoring of plasma concentrations may also be utilised during dose adjustments.
CYP2D6 ultrarapid metabolisers
Carriers of more than 2 copies of functional alleles e.g. *1/*1xN, *1/*2xN: Increased metabolism causing lower clomipramine plasma concentrations and higher cardiotoxic hydroxy metabolite plasma concentrations, resulting to increased risk of pharmacotherapy failure and cardiotoxic adverse effects as compared to normal metabolisers.
Avoid use and consider alternative drugs not metabolised by CYP2D6 (e.g. citalopram, sertraline). 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 with 1-2 activity score e.g. *1/*1, *1/*2, *2/*2, *1/*9, *1/*41, *41/*41, *1/*4, *1/*5: Initiate therapy with recommended starting dose. No dosage adjustment needed.
CYP2D6 intermediate metabolisers
Carriers of 1 decreased and 1 no function allele e.g. *4/*41, *5/*9, *4/*10: Reduced metabolism causing higher clomipramine plasma concentrations resulting in an increased risk of adverse effects as compared to normal metabolisers.
Consider initiating therapy with 25% dose reduction of the recommended starting dose. 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: Greatly reduced metabolism causing higher clomipramine plasma concentrations resulting to increased risk of adverse effects as compared to normal metabolisers.
Avoid use and consider alternative drugs not metabolised by CYP2D6 (e.g. citalopram, sertraline). Consider reducing by 50% the recommended starting dose if TCA use is necessary. Dose adjustments may be guided by therapeutic drug monitoring.
CYP2C19 ultrarapid metabolisers
Carriers of 2 increased function alleles e.g. *17/*17: Increased metabolism of tertiary amines to secondary amines which may affect clomipramine response or adverse effects as compared to normal metabolisers.
Avoid tertiary amine 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 rapid metabolisers
Carriers of 1 normal and 1 increased function allele e.g. *1,*17: Increased metabolism of tertiary amines to secondary amines which may affect clomipramine response or adverse effects as compared to normal metabolisers.
Avoid tertiary amine 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: Initiate therapy with recommended starting dose. No dosage adjustment needed.
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: Reduced metabolism of tertiary amines as compared to normal metabolisers.
Initiate therapy with recommended starting dose. No dosage adjustment needed.
CYP2C19 poor metabolisers
Carriers of 2 no function alleles e.g. *2/*2, *2/*3, *3/*3: Greatly reduced metabolism of tertiary amines to secondary amines which may affect clomipramine response and adverse effects.
Avoid tertiary amine use and consider alternative drugs not metabolised by CYP2C19 (e.g. nortriptyline, desipramine), or consider reducing by 50% the recommended starting dose for tertiary amines. Dose adjustments may be guided by therapeutic drug monitoring.
Administration
Should be taken with food.
Contraindications
Acute recovery phase of MI, recent MI, history of QTc interval prolongation, narrow-angle glaucoma, urinary retention, mania. Severe hepatic impairment. Concomitant use with selective MAO-A inhibitors (e.g. moclobemide), linezolid, IV methylene blue; with or within 21 days of initiating or discontinuing treatment with MAOIs intended to treat psychiatric disorders.
Special Precautions
Patients with depressive disorder, bipolar disorder or other psychiatric disorders, epilepsy or conditions predisposing to seizures (e.g. brain damage, alcoholism), cerebrovascular disease, congenital long QT syndrome, history of CV disease including previous MI, stroke, tachycardia or conduction abnormalities, bleeding tendency, hyperthyroidism, hypovolaemia, hypokalaemia, tumours of adrenal medulla (e.g. phaeochromocytoma, neuroblastoma), decreased gastrointestinal motility, chronic constipation, paralytic ileus, prostatic hypertrophy, history of increased intraocular pressure or narrow-angle glaucoma, visual problems, xerostomia. Concomitant electroconvulsive therapy and elective surgery. Renal and hepatic impairment. Elderly. Pregnancy and lactation. CYP2D6 ultrarapid, intermediate, and poor metabolisers. CYP2C19 ultrarapid, rapid and poor metabolisers.
Adverse Reactions
Significant: Suicidal ideation and behaviour, activation of psychosis and hypomanic or manic episodes, seizures, QTc prolongation, torsades de pointes, anticholinergic effects (e.g. constipation, paralytic ileus, xerostomia, blurred vision, urinary retention), CNS depression, bone fractures, dental caries, mild pupillary dilation, orthostatic hypotension, hypertensive crises, male sexual dysfunction, syndrome of inappropriate antidiuretic hormone secretion (SIADH), hyponatraemia, weight gain, increased ALT/AST, withdrawal or discontinuation syndrome. Rarely, bone marrow suppression, drug rash with eosinophilia and systemic syndrome (DRESS). Blood and lymphatic system disorders: Leucopenia, agranulocytosis, thrombocytopenia. Cardiac disorders: Sinus tachycardia, palpitation, ECG changes (e.g. ST and T changes). Ear and labyrinth disorders: Tinnitus. Eye disorders: Accommodation disorder. Gastrointestinal disorders: Nausea, vomiting, diarrhoea, dyspepsia. General disorders and admin site conditions: Fatigue, oedema, hyperpyrexia. Investigations: Weight increased, blood sugar changes. Metabolism and nutrition disorders: Increased or decreased appetite. Musculoskeletal and connective tissue disorders: Muscle weakness, hypertonia, myalgia. Nervous system disorders: Dizziness, headache, somnolence, tremor, myoclonus, speech disorder, paraesthesia, dysgeusia, memory impairment, attention disturbance. Psychiatric disorders: Restlessness, confusional state, insomnia, delirium, aggression, anxiety, agitation, disorientation, hallucinations, nightmares. Renal and urinary disorders: Micturition disorder. Reproductive system and breast disorders: Erectile dysfunction, libido disorder, galactorrhoea, breast enlargement, orgasmic impotence in women, ejaculation failure. Respiratory, thoracic and mediastinal disorders: Yawning, pharyngitis, rhinitis, cough. Skin and subcutaneous tissue disorders: Hyperhidrosis, rash, pruritus, photosensitivity. Vascular disorders: Hot flush. Potentially Fatal: Serotonin syndrome. Rarely, severe hepatic injury.
This drug may cause drowsiness, somnolence, or blurred vision, if affected, do not drive or operate machinery. Avoid abrupt withdrawal.
Monitoring Parameters
Monitor blood pressure and pulse rate prior to and during treatment; ECG, cardiac status, serum Na levels, renal function and LFTs in at-risk patients periodically during treatment and as clinically indicated. Closely monitor for signs of serotonin syndrome, and suicidal ideation or unusual behaviour changes especially during initial months of treatment or at times of dose changes.
Overdosage
Symptoms: Drowsiness, stupor, ataxia, restlessness, agitation, enhanced reflexes, muscular rigidity, athetoid or choreoathetoid movements, convulsions, serotonin syndrome (e.g. hypertensive crisis, hyperpyrexia, myoclonus, delirium, coma); mydriasis, sweating, fever, vomiting, oliguria, cyanosis, respiratory depression; hypotension, tachycardia, QTc prolongation, arrhythmia including torsades de pointes, conduction disorders, shock, heart failure. Rarely, cardiac arrest. Management: Symptomatic and supportive treatment. For overdoses for up to 12 hours or longer, may administer activated charcoal to reduce absorption, perform gastric lavage or induce vomiting as soon as possible if the patient is alert. Secure airway with cuffed endotracheal tube prior to lavage without inducing emesis if patient is unconscious. For respiratory failure, conduct intubation, and artificial respiration. For CV symptoms, place the patient in an appropriate position and give plasma expander, dopamine or dobutamine via IV drip in severe hypotension. Correct low K levels or acidosis and consider cardiac pacemaker implantation. Keep all patients with ECG abnormalities under close observation for at least 48 hours to check for relapse. For torsades de pointes, discontinue drug therapy and correct hypoxia, electrolyte abnormalities and acid-base disturbances. May administer 2 g (20 mL of 10% solution) Mg sulfate IV over 30-120 seconds, repeated twice at 5-15 minutes intervals if necessary, for persistent torsades de pointes. Alternatively, may abolish arrhythmia by atrial and ventricular pacing or isoprenaline infusion to achieve 90-110 bpm heart rate if previous measures fail. For convulsions, administer IV diazepam or other anticonvulsants like phenobarbitone or paraldehyde, but these agents may exacerbate existing respiratory failure, hypotension or coma.
Drug Interactions
Increased risk of ventricular arrhythmias with pimozide, thioridazine, levacetylmethadol; adverse cardiac effects with thyroid preparations; arrhythmias or hypotension with anaesthetics; severe postural hypotension with altretamine. Increased risk of bleeding with anticoagulants, salicylic acid derivatives, NSAIDs, antirheumatic agents. May potentiate CNS depressant effects of barbiturates, benzodiazepines, opioid analgesics, general anaesthetics. May increase plasma concentrations with antipsychotics, protease inhibitors, terbinafine, cimetidine, valproate, methylphenidate, diltiazem, verapamil. Increased risk of convulsions with tramadol, phenothiazines, neuroleptics. May decrease plasma levels with rifampicin, barbiturates, carbamazepine, phenobarbital, phenytoin, nicotine, colestipol, cholestyramine. May potentiate anticholinergic effects of antiparkinsonian agents (e.g. biperiden, entacapone, selegiline), antihistamines, atropine. May diminish or abolish antihypertensive effects of guanethidine, betanidine, reserpine, clonidine, methyldopa. May potentiate CV effects of adrenaline, ephedrine, isoprenaline, noradrenaline, phenylephrine, phenylpropanolamine. May enhance muscle relaxant effect of baclofen. Potentially Fatal: Increased risk of serotonin syndrome with MAOIs for treatment of psychiatric disorders (e.g. moclobemide), linezolid, IV methylene blue, and other serotonergic agents (e.g. SSRIs, serotonin-norepinephrine reuptake inhibitors, triptans, fentanyl, lithium, tramadol, buspirone). Increased risk of QTc prolongation and torsades de pointes with diuretics, antiarrhythmics (e.g. quinidine, disopyramide, procainamide, amiodarone, sotalol), other TCAs (e.g. amitriptyline, maprotiline), certain antipsychotics (e.g. lithium, phenothiazines, pimozide), certain antihistamines (e.g. terfenadine), quinine, pentamidine.
Food Interaction
Increased risk of serotonin syndrome with St. John’s wort and tryptophan. Enhanced CNS depressant effects with alcohol. May increase plasma concentrations with grapefruit, grapefruit juice, or cranberry juice.
Lab Interference
May cause false-positive results with urine detection of methadone.
Action
Description: Mechanism of Action: Clomipramine, a dibenzazepine-derivative tricyclic antidepressant, inhibits the neuronal reuptake of serotonin (5-HT) and norepinephrine released in the presynaptic neuronal membrane. It also has α1-adrenolytic, anticholinergic, antihistaminic, and anti-serotonergic (5-HT-receptor blocking) properties. Onset: 1-2 weeks. Max effect: 8-12 weeks. Duration: 1-2 days. Pharmacokinetics: Absorption: Rapidly absorbed from the gastrointestinal tract. Time to peak plasma concentration: Approx 2-6 hours. Distribution: Widely distributed into the body including CSF and brain. Crosses placenta and enters breast milk. Volume of distribution: Approx 12-17 L/kg. Plasma protein binding: 97%, mainly to albumin. Metabolism: Undergoes extensive first-pass metabolism in the liver mainly via N-demethylation to form desmethylclomipramine (active metabolite), and via hydroxylation and N-oxidation to form hydroxyclomipramine and clomipramine N-oxide metabolites. Excretion: Mainly via urine (50-60%; 0.8-1.3% as unchanged drug and active metabolite); faeces (24-32%). Elimination half-life: Approx 19-37 hours (clomipramine); approx 54-77 hours (desmethylclomipramine).
Chemical Structure
Clomipramine Source: National Center for Biotechnology Information. PubChem Database. Clomipramine, CID=2801, https://pubchem.ncbi.nlm.nih.gov/compound/Clomipramine (accessed on Jan. 21, 2020)
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