Clomipramine (Tablets, Solution) Instructions for Use

ATC Code

N06AA04 (Clomipramine)

Active Substance

Clomipramine (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Antidepressant

Pharmacotherapeutic Group

Psychoanaleptics; antidepressants; non-selective monoamine reuptake inhibitors

Pharmacological Action

An antidepressant from the group of tricyclic compounds. The drug’s action is associated with the stimulation of adrenergic and serotonergic mechanisms in the CNS due to the inhibition of neuronal reuptake of neurotransmitters. It has a greater effect on serotonin reuptake; this apparently determines its efficacy in the treatment of obsessive-compulsive disorders. The antidepressant effect occurs relatively quickly (during the first week of treatment). It has adrenoblocking (predominantly alpha₁), cholinoblocking, and antihistamine activity.

The psychostimulant effect of clomipramine is less pronounced than that of imipramine, and the sedative effect is weaker than that of amitriptyline.

Pharmacokinetics

After oral administration or intramuscular injection, it is absorbed quickly and completely. C_max in plasma is reached 1.5-4 hours after oral administration. Plasma protein binding is 97.6%. V_d is 12 L. It undergoes intensive metabolism with the formation of an active metabolite, desmethylclomipramine.

T_1/2 in the terminal phase is 21 hours. It is excreted in the urine as metabolites and unchanged substance, and through the intestines as metabolites.

Indications

Depressive states of various etiologies (including endogenous, reactive, neurotic, organic, masked, and involutional depressions); depressive syndrome in schizophrenia and personality disorders; presenile and senile depressions; depressive states in chronic pain syndrome and in chronic somatic diseases; depressive disorders of reactive, neurotic, and psychopathic nature, including their somatic equivalents in children; obsessive-compulsive syndromes (phobia), panic attacks, chronic pain syndrome (chronic pain in cancer patients, migraine, rheumatic diseases, atypical facial pain, postherpetic neuralgia, post-traumatic neuropathy, diabetic or other peripheral neuropathy), narcolepsy accompanied by cataplexy; headache; migraine prophylaxis.

ICD codes

Dosage Regimen

Administer orally to adults. Initiate therapy at 25-50 mg two to three times daily.

Adjust the dose gradually based on individual tolerance and therapeutic response. Increase the dose slowly to minimize adverse effects.

For obsessive-compulsive disorder and panic attacks, higher doses within the recommended range may be required.

For depression, the usual maintenance dose is 50-100 mg daily, administered in divided doses.

For chronic pain management, use lower doses, typically 10-150 mg daily.

For pediatric patients (children 6 years and older), initiate treatment at 25-50 mg per day. Titrate the dose cautiously. The daily dose may be administered as a single or divided dose.

For inpatient settings, under close supervision, doses may be increased more rapidly.

The maximum recommended daily dose for outpatients is 250 mg.

The maximum recommended daily dose for inpatients is 300 mg.

For children over 10 years, do not exceed 3 mg/kg/day or 200 mg/day, whichever is lower.

For intramuscular administration to adults, administer 25-100 mg per day in divided injections.

For intravenous infusion, administer 50-75 mg once daily. Dilute the solution and infuse slowly over 1.5-3 hours.

Do not administer parenterally to children under 12 years of age.

In elderly patients and those with hepatic or renal impairment, use lower initial doses and titrate more cautiously.

Monitor patients for suicidal ideation, especially during the initial weeks of therapy and following dose changes.

Avoid abrupt discontinuation. Taper the dose gradually to prevent withdrawal symptoms.

Adverse Reactions

From the CNS often – dizziness, increased fatigue, tremor, headache, myoclonus, visual disturbances; rarely – taste disturbances, feeling of heat, mydriasis, disorientation, hallucinations (most likely in elderly patients and in Parkinson’s disease), anxiety, agitation, sleep disorders, mania, hypomania, aggressiveness, memory impairment, depersonalization, yawning, nightmares, worsening of depression, impaired concentration, delirium, speech disorders, paresthesia, muscle tone disorders, tinnitus, convulsions, ataxia; in some cases – worsening of psychotic symptoms, glaucoma.

From the cardiovascular system rarely – postural hypotension, sinus tachycardia, ECG changes, palpitation, arrhythmias, increased blood pressure; in some cases – EEG changes, cardiac conduction disorders.

From the digestive system often – nausea, dry mouth, constipation; rarely – vomiting, abdominal discomfort, diarrhea, anorexia, increased transaminase activity; in some cases – hepatitis, jaundice.

From the hematopoietic system in some cases – leukopenia, agranulocytosis, thrombocytopenia, eosinophilia, thrombocytopenic purpura.

From metabolism often – increased appetite, weight gain.

From the endocrine system often – libido and potency disorders, galactorrhea, breast enlargement; in some cases – syndrome of inappropriate ADH secretion, edema.

Dermatological reactions rarely – photosensitivity.

Allergic reactions rarely – skin rash, itching.

Other often – increased sweating; in some cases – increased body temperature.

Contraindications

Recently suffered myocardial infarction, conduction system blockades of the myocardium, arrhythmias, mania, severe hepatic insufficiency, closed-angle glaucoma, urinary retention, first trimester of pregnancy, lactation, hypersensitivity to clomipramine and other tricyclic antidepressants from the group of dibenzazepine derivatives.

Use in Pregnancy and Lactation

Contraindicated for use in the first trimester of pregnancy. Should not be used in the second and third trimesters of pregnancy, except in cases of extreme necessity. Adequate and well-controlled studies of the safety of clomipramine use during human pregnancy have not been conducted.

Clomipramine is excreted in small amounts in breast milk, so if it is necessary to use during lactation, the issue of discontinuing breastfeeding should be decided.

Use in Hepatic Impairment

Contraindicated in severe hepatic insufficiency.

Use with caution in severe liver diseases.

Use in Renal Impairment

Use with caution in severe kidney diseases.

Pediatric Use

Not recommended for oral administration to children under 6 years of age, for parenteral administration to children under 12 years of age.

Special Precautions

Use with caution in patients with a lowered seizure threshold; in severe liver or kidney diseases; during treatment with steroid hormones; in pheochromocytoma and neuroblastoma due to the risk of hypertensive crisis; in hyperthyroidism; diabetes mellitus (correction of the dosing regimen of hypoglycemic drugs is required).

Before starting treatment, blood pressure control is necessary; during treatment, monitoring of the peripheral blood picture is recommended; during long-term therapy – monitoring of heart and liver functions.

Clomipramine can be used no earlier than 14 days after discontinuation of MAO inhibitors, starting therapy with the minimum dose. Should not be used simultaneously with sympathomimetic agents, including epinephrine, ephedrine, isoprenaline, norepinephrine, phenylephrine, phenylpropanolamine; with quinidine-like antiarrhythmic drugs. When clomipramine is used simultaneously with alprazolam or disulfiram, a reduction in the dose of clomipramine is required.

Patients with a tendency to suicide in the initial period of treatment require constant medical supervision.

The use of electroconvulsive therapy against the background of clomipramine use is possible only for strict indications and with careful medical supervision.

Sudden discontinuation of treatment may lead to the development of withdrawal syndrome.

During treatment, alcohol consumption should be avoided.

Not recommended for oral administration to children under 6 years of age, for parenteral administration to children under 12 years of age.

Effect on ability to drive vehicles and mechanisms

During treatment, one should refrain from potentially hazardous activities requiring increased attention and rapid psychomotor reactions.

Drug Interactions

With simultaneous use with drugs that have a depressant effect on the CNS, a significant enhancement of the depressant effect on the CNS, hypotensive action, and respiratory depression is possible.

With simultaneous use with agents possessing anticholinergic activity, an enhancement of the anticholinergic effect is possible.

With simultaneous use, Clomipramine may reduce or completely eliminate the antihypertensive effect of antiadrenergic agents affecting neuronal transmission (guanethidine, betanidine, reserpine, clonidine, and alpha-methyldopa).

With simultaneous use with antipsychotic agents (neuroleptics), an increase in the plasma level of clomipramine, a decrease in the seizure threshold, and the development of convulsions are possible. Combination with thioridazine may lead to the occurrence of severe arrhythmias.

A decrease in the concentration of clomipramine in plasma is possible due to the induction of liver microsomal enzymes under the influence of barbiturates.

With simultaneous use with MAO inhibitors, hypertensive crisis, hyperpyrexia, myoclonus, generalized convulsions, delirium, and coma are possible.

With simultaneous use of selective serotonin reuptake inhibitors (including fluoxetine and fluvoxamine), an enhancement of the effect on the serotonin system is possible. Fluoxetine and fluvoxamine may increase the concentration of clomipramine in plasma, which is accompanied by the development of corresponding side effects.

Clomipramine may enhance the effect on the cardiovascular system of adreno- and sympathomimetic agents (epinephrine, norepinephrine, isoprenaline, ephedrine, and phenylephrine), including when these substances are part of combinations with local anesthetics.

With simultaneous use with ademetionine, a case of serotonin syndrome development has been described; with sodium valproate – a case of increased plasma concentration of clomipramine and its metabolite desmethylclomipramine has been described.

There is a report of an increase in the plasma concentration of clomipramine and its main metabolite (desmethylclomipramine) with simultaneous use with carbamazepine.

With simultaneous use with paroxetine, the plasma concentration of clomipramine and its metabolite S-desmethylclomipramine increases, apparently due to inhibition of the CYP2D6 isoenzyme.

With simultaneous use with cimetidine, an increase in the plasma concentration of clomipramine is possible due to inhibition of liver microsomal enzymes under the influence of cimetidine.

A case of increased plasma concentration of clomipramine has been described, which is due to inhibition of CYP3A3/4 isoenzymes under the influence of erythromycin.

With simultaneous use with estrogens, a disturbance in the metabolism of clomipramine is possible.

An enhancement of the effect of ethanol is possible, especially during the first few days of clomipramine therapy.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.