Clomipramine Other names: Chlorimipramine Monochlorimipramine

There may be a risk of QTc prolongation and Torsades de Pointes. Concomitant administration of drugs that can prolong the QTc interval should be avoided. It is established that hypokalaemia is a risk-factor of QTc prolongation and Torsades de pointes. Therefore, hypokalaemia should be treated before initiating treatment with clomipramine.

Tricyclic antidepressants may potentiate the effects of alcohol and other central depressant substances (e.g. barbiturates, benzodiazepines, or general anaesthetics).

Concomitant administration of clomipramine with St. John’s wort during the treatment may decrease the plasma concentrations of clomipramine.

Clomipramine may potentiate the cardiovascular effects of adrenaline, ephedrine, isoprenaline, noradrenaline, phenylephrine, and phenylpropanolamine (e.g. as contained in local and general anaesthetic preparations and nasal decongestants).

Some tricyclic antidepressants may potentiate the anticoagulant effect of coumarin drugs, such as warfarin, and this may be through inhibition of their metabolism (CYP2C9). There is no evidence for the ability of clomipramine to inhibit the metabolism of anticoagulants, such as warfarin, however, careful monitoring of plasma prothrombin has been advised for this class of drug.

Tricyclic antidepressants may potentiate the effects of these drugs (e.g. phenothiazine, antiparkinsonian agents, antihistamines, atropine, biperiden) on the eye, central nervous system, bowel and bladder.

Serotonin syndrome, a potentially life-threatening condition can possibly occur when clomipramine is administered with serotonergic co-medications such as selective serotonin re-uptake inhibitors (SSRIs), serotonin and noradrenergic re-uptake inhibitors (SNRIs), tricyclic antidepressants, buprenorphine/opioids, or lithium. Symptoms of serotonin syndrome may include mental-status changes, autonomic instability, neuromuscular abnormalities, gastrointestinal symptoms, hyperpyrexia, myoclonus, agitation, seizures, delirium, and coma.

If concomitant treatment with other serotonergic agents is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases.

For fluoxetine, a washout period of two to three weeks is advised before and after treatment with fluoxetine.

Clomipramine is also an in vitro (Ki = 2.2µM) and in vivo inhibitor of CYP2D6 activity (sparteine oxidation) and therefore, may cause increased concentrations of co-administered compounds that are primarily cleared by CYP2D6 in extensive metabolizers.

Concomitant administration of CYP2D6 inhibitors may lead to an increase in concentration of both active components, up to ~3-fold in patients with desbrinoquine/sparteine extensive metabolizer phenotype, converting them to poor-metabolizer phenotype. Concomitant administration of CYP1A2, CYP2C19 and CYP3A4 inhibitors are expected to increase clomipramine concentrations and decrease N-desmethylclomipramine, thus not necessarily affecting the overall pharmacology.

CYP3A and CYP2C inducers such as rifampicin or anticonvulsants (e.g. barbiturates, carbamazepine, phenobarbital and phenytoin), may decrease clomipramine concentrations.

Clomipramine should be given with caution in patients with renal impairment.

Concomitant administration of clomipramine with grapefruit, grapefruit juice or cranberry juice may increase the plasma concentrations of clomipramine.

Clomipramine should be given with caution in patients with hepatic impairment.

Clomipramine may diminish or abolish the antihypertensive effects of guanethidine, betanidine, reserpine, clonidine and alpha-methyldopa. Patients requiring comedication for hypertension should therefore be given antihypertensives of a different type (e.g. vasodilators, or beta-blockers).

Concomitant administration of ion exchange resins such as cholestyramine or colestipol may reduce the plasma levels of clomipramine. Staggering the dosage of clomipramine and resins, such that the drug is administered at least 2 h before or 4-6 h after the administration of resins, is recommended.

No interaction between chronic oral contraceptive use (15 or 30 mg ethinyl estradiol daily) and clomipramine (25 mg daily) has been documented. Oestrogens are not known to be inhibitors of CYP2D6, the major enzyme involved in clomipramine clearance and therefore, no interaction is expected. Although in a few cases with high dose oestrogen (50 mg daily) and the tricyclic antidepressant imipramine, increased side effects and therapeutic response were noted, it is unclear as to the relevance of these cases to clomipramine and lower dose oestrogen regimens. Monitoring therapeutic response of tricyclic antidepressants at high dose oestrogen regimens (50 mg daily) is recommended and dose adjustments may be necessary.

Comedication of antipsychotics (e.g. phenothiazines) may result in increased plasma levels of tricyclic antidepressants, a lowered convulsion threshold and seizures. Combination with thioridazine may produce severe cardiac arrhythmias.

There may be a risk of QTc prolongation and Torsades de Pointes, particularly at supratherapeutic doses or supra-therapeutic plasma concentrations of clomipramine, as occur in the case of co‑medication with selective serotonin reuptake inhibitors (SSRIs) or serotonin and noradrenergic reuptake inhibitors (SNRIs). Therefore, concomitant administration of drugs that can cause accumulation of clomipramine should be avoided.

Co-administration with the histamine 2 (H₂) receptor antagonist, cimetidine (an inhibitor of several P450 enzymes, including CYP2D6 and CYP3A4), may increase plasma concentrations of tricyclic antidepressants, whose dosage should therefore be reduced.

Methylphenidate may also increase concentrations of tricyclic antidepressants by potentially inhibiting their metabolism, and a dose reduction of tricyclic antidepressant may be necessary.

Known inducers of CYP1A2 (e.g. nicotine/components in cigarette smoke), decrease plasma concentrations of tricyclic drugs. In cigarette smokers, clomipramine steady-state plasma concentrations were decreased 2-fold compared to non-smokers (no change in N‑desmethylclomipramine).

Concomitant administration of valproate with clomipramine may cause inhibition of CYP2C and/or UGT enzymes resulting in increased serum levels of clomipramine and desmethylclomipramine.

Oral antifungal, terbinafine. Co-administration of clomipramine with terbinafine, a strong inhibitor of CYP2D6, may result in increased exposure and accumulation of clomipramine and its N-demethylated metabolite. Therefore, dose adjustments of clomipramine may be necessary when co-administered with terbinafine.

Because of its anticholinergic properties, clomipramine should be used with caution in patients with a history of increased intra-ocular pressure, narrow angle glaucoma or urinary retention) e.g. diseases of the prostate).

Caution is called for when giving tricyclic antidepressants to patients with tumours of the adrenal medulla (e.g. phaeochromocytoma, neuroblastoma), in whom they may provoke hypertensive crises.

Caution is called for in patients with chronic constipation. Tricyclic antidepressants may cause paralytic ileus, particularly in the elderly and in bedridden patients.

Caution is indicated in patients with hyperthyroidism or during concomitant treatment with thyroid preparations since aggravation of unwanted cardiac effects may occur.

Before general or local anaesthesia, the anaesthetist should be aware that the patient has been receiving clomipramine and of the possible interactions.

Before initiating treatment it is advisable to check the patient’s blood pressure, because individuals with hypotension or a labile circulation may react to the drug with a fall in blood pressure.

Clomipramine should be administered with particular caution in patients with cardiovascular disorders, especially those with cardiovascular insufficiency, conduction disorders, (e.g. atrioventricular block grades I to III), or arrhythmias. Monitoring of cardiac function and the ECG is indicated in such patients.

Tricyclic antidepressants are known to lower the convulsion threshold and clomipramine should therefore be used with extreme caution in patients with epilepsy and other predisposing factors, e.g. brain damage of varying aetiology, concomitant use of neuroleptics, withdrawal from alcohol or drugs with anticonvulsive properties (e.g. benzodiazepines). It appears that the occurrence of seizures is dose dependent, therefore the recommended total daily dose of clomipramine should not be exceeded.

There is limited amount of data from the use of clomipramine in pregnant women that indicates a potential to harm the foetus or cause congenital malformation. Clomipramine should be used during pregnancy only if the potential benefit outweighs the potential risk to the foetus.

Neonates whose mothers had taken tricyclic antidepressants until delivery showed drug withdrawal symptoms, such as dyspnoea, lethargy, colic, irritability, hypotension or hypertension, and tremor/convulsions, during the first few hours or days. To avoid such symptoms, clomipramine should if possible be gradually withdrawn at least 7 weeks before the calculated date of confinement.

Since clomipramine passes into breast milk, it should be gradually withdrawn or the infant weaned if the patient is breast-feeding.

Women of child-bearing potential

There are no data supporting any special recommendations in women of child-bearing potential.

Fertility

No adverse effects on reproductive performance, including male and female fertility, were observed in rats at oral doses up to 24 mg/kg.

No teratogenic effects were detected in mice, rats, and rabbits at doses up to 100, 50, and 60 mg/kg, respectively.

Patients receiving clomipramine should be warned that blurred vision, and other nervous system and psychiatric related disorders such as somnolence, disturbance in attention, confusion, disorientation, aggravation of depression, delirium etc, have been observed. In the presence of such effects, patients should not drive or operate machinery or do anything else which may require alertness or quick actions.

Unwanted effects are usually mild and transient, disappearing under continued treatment or with a reduction in the dosage. They do not always correlate with plasma drug levels or dose. It is often difficult to distinguish certain undesirable effects from symptoms of depression such as fatigue, sleep disturbances, agitation, anxiety, constipation, and dry mouth.

If severe neurological or psychiatric reactions occur, clomipramine should be withdrawn.

Frequency estimates: Very common ≥10%, common ≥1% to <10%, uncommon ≥0.1% to <1%, rare ≥0.01% to <0.1%, very rare <0.01%. The ADRs listed below are based on clinical trials as well as post marketing reports.

Tabulated summary of adverse drug reactions:

Additional adverse drug reaction from port-marketing spontaneous reports

The following additional adverse drug reactions have been identified with clomipramine oral or IM/IV dosage forms based on post-marketing spontaneous reports. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency.

Nervous system disorders

Frequency not known: Serotonin syndrome, extrapyramidal symptoms (including akathisia and tardive dyskinesia)

Musculoskeletal and connective tissue disorders

Frequency not known: Rhabdomyolysis (as a complication of neuroleptic malignant syndrome)

Reproductive system and breast disorders

Frequency not known: Ejaculation failure, Ejaculation delayed

Investigations

Frequency not known: Blood prolactin increased

Bone fractures

Epidemiological studies, mainly in patients 50 years of age and older, show an increased risk of bone fractures in patients receiving SSRIs and TCAs. The mechanism leading to the risk is unknown.

Withdrawal symptoms

The following symptoms commonly occur after abrupt withdrawal or reduction of the dose: nausea, vomiting, abdominal pain, diarrhoea, insomnia, headache, nervousness, and anxiety.

Geriatric population

Elderly patients are particularly sensitive to anticholinergic, neurological, psychiatric or cardiovascular effects. Their ability to metabolise and eliminate drugs may be reduced, leading to a risk of elevated plasma concentrations at therapeutic doses.