Clomipramine, tablets 25 mg ref. 30

Pharmacological action – antidepressant, thymoleptic, sedative, psychostimulant.

Stimulates catecholaminergic transmission in CNS (due to inhibition of neuronal reuptake of mediators, to a greater extent affects serotonin uptake). It has adrenoblocking (predominantly alpha₁), m-cholinolytic and antihistamine activity. The psychostimulant effect is less pronounced than that of imipramine, and the sedative effect is weaker than that of amitriptyline.

After a single oral dose of 50 mg, the T_max of clomipramine in the blood is 2-6 h (average 4.7 h) and its de-methylated metabolite is 4-24 h. After multiple oral doses of 150 mg/day, the C_ss of clomipramine in plasma is reached within 7-14 days and varies considerably from patient to patient. Binding to plasma proteins (predominantly to albumin) is 97.6%. Passes through the BBB, penetrates into breast milk.

Metabolized in the liver, mainly with the formation of the active metabolite – desmethylclomipramine. T_1/2 – 21 h. T_1/2 may be prolonged to 36 h in depressed patients. After intravenous and intravenous administration, the final T_1/2 of clomipramine averages 25 h (range of variation from 20 to 40 h) and 18 h, respectively. The kidneys excrete 2/3 as water-soluble compounds, approximately 1/3 via the intestine. About 2% of the accepted dose of clomipramine and about 0.5% of desmethylclomipramine are excreted unchanged in the urine, the rest are excreted as hydroxylated metabolites.

In elderly patients, regardless of the dose used, due to a decrease in the intensity of metabolism of clomipramine its plasma concentrations are higher than in younger patients. The effect of hepatic and renal dysfunction on clomipramine pharmacokinetics has not been studied.

Indications

Depressive states of various etiologies: Endogenous, reactive, neurotic, organic, larvic, involutionary forms of depression;

p> depression in psychopathy, schizophrenia;

Presenile and senile depression;

Depressive states due to chronic pain syndrome or chronic somatic illness; obsessive-compulsive disorder;

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phobias; panic disorder;

cataplexy accompanying narcolepsy;

nocturnal enuresis in children over 5 years and adolescents.

Active ingredient

Composition

How to take, the dosage

In adults, 25-50 mg 2-3 times daily; children, depending on age, 25-50 mg/day. In adults intravenous 25-100 mg/day, intravenous drip 50-75 mg 1 time/day.

Maximum doses: when given orally in adults on an outpatient basis – 250 mg/day, in hospital – 300 mg/day; children over 10 years of age – 3 mg/kg/day, but not more than 200 mg/day.

Interaction

In concomitant use with drugs with CNS depressant effect, a significant increase in CNS depressant effect, hypotensive effect, respiratory depression is possible.

Concomitant use with agents with anticholinergic activity may increase the anticholinergic effect.

Concomitant use of clomipramine may decrease or completely eliminate the antihypertensive effect of antiadrenergic agents affecting neuronal excitation transmission (guanethidine, betanidine, reserpine, clonidine and alpha-methyldopa).

Concomitant use with antipsychotics (neuroleptics) may increase the level of clomipramine in the blood plasma, decrease the seizure threshold and develop convulsions. Combination with thioridazine may lead to severe arrhythmias.

Possible decrease in clomipramine plasma concentrations due to induction of microsomal liver enzymes by barbiturates.

Concomitant use with MAO inhibitors may cause hypertensive crisis, hyperpyrexia, myoclonus, generalized convulsions, delirium, and coma.

Concomitant use of selective serotonin reuptake inhibitors (including fluoxetine and fluvoxamine) may increase the effect on the serotonin system. Fluoxetine and fluvoxamine may increase plasma concentrations of clomipramine with associated side effects.

Clomipramine may increase the cardiovascular effects of adreno- and sympathomimetic agents (epinephrine, norepinephrine, isoprenaline, ephedrine and phenylephrine), including when these agents are combined with local anesthetic agents.

In case of concomitant use with ademetionine there has been described a case of serotonin syndrome; with sodium valproate there has been described a case of increased plasma concentrations of clomipramine and its metabolite desmethylclomipramine.

There have been reports of increased plasma concentrations of clomipramine and its major metabolite (desmethylclomipramine) when used concomitantly with carbamazepine.

Concomitant use with paroxetine increases plasma concentrations of clomipramine its metabolite S-desmethylclomipramine, apparently due to inhibition of CYP2D6 isoenzyme.

Concomitant use with cimetidine may increase clomipramine plasma concentrations due to inhibition of microsomal liver enzymes by cimetidine.

A case of increased clomipramine plasma concentrations has been described due to inhibition of CYP3A3/4 isoenzymes by erythromycin.

In concomitant use with estrogens, clomipramine metabolism may be impaired.

The effects of ethanol may be increased, especially during the first few days of therapy with clomipramine.

Special Instructions

With caution, use in patients with low seizure threshold; with severe liver or kidney disease; during treatment with steroid hormones; in pheochromocytoma and neuroblastoma due to risk of hypertensive crisis; in hyperthyroidism; diabetes mellitus (dosage regimen of hypoglycemic drugs should be adjusted).

Before treatment it is necessary to control BP; during treatment it is recommended to control peripheral blood picture; during long-term therapy it is necessary to control heart and liver functions.

Clomipramine should not be used before 14 days after withdrawal of MAOI inhibitors, starting therapy at the lowest dose. Do not use concomitantly with sympathomimetic agents, including epinephrine, ephedrine, isoprenaline, norepinephrine, phenylephrine, phenylpropanolamine; with quinidine-like antiarrhythmic drugs. If clomipramine is used concomitantly with alprazolam or disulfiram, reduction of the dose of clomipramine is required.

Patients with suicidal tendencies during the initial period of treatment require continuous medical monitoring.

The use of electroshock with clomipramine is possible only under strict indications and close medical supervision.

If treatment is stopped abruptly, withdrawal symptoms may occur.

Do not drink alcohol during treatment.

It is not recommended for oral administration in children under 6 years of age, parenterally in children under 12 years of age.

Impact on driving and operating machinery

At the time of treatment, one must refrain from potentially hazardous activities requiring increased attention and quick psychomotor reactions.

Contraindications

Hypersensitivity (including to other dibenzazepine antidepressants), concomitant use of MAOI inhibitors and less than 14 days before and after their administration (including selective reversible MAO A inhibitors, such as moclobemide), recent myocardial infarction, congenital QT interval syndrome, children under 5 years of age, pregnancy, lactation.

Side effects

CNS disorders: common – dizziness, increased fatigue, tremor, headache, myoclonus, visual disturbances; rarely – disorders of taste, fever, mydriasis, disorientation, hallucinations (most likely in elderly patients and in Parkinson’s disease), anxiety, agitation, sleep disorders, mania, hypomania, aggressiveness, memory disorders, depersonalization, yawning, nightmares, increased depression, concentration disorders, delirium, speech disorders, paresthesia, muscle tone disorders, tinnitus, seizures, ataxia; In some cases, an increase in psychotic symptoms, glaucoma.

Cardiovascular system: rarely – postural hypotension, sinus tachycardia, ECG changes, palpitation, arrhythmias, increased BP; in single cases – EEG changes, cardiac conduction disorders.

The digestive system: frequently – nausea, dry mouth, constipation; rarely – vomiting, abdominal discomfort, diarrhea, anorexia, increased transaminase activity; in rare cases – hepatitis, jaundice.

Hematopoietic system: in single cases – leukopenia, agranulocytosis, thrombocytopenia, eosinophilia, thrombocytopenic purpura.

Metabolism disorders: often – increase of appetite, weight gain.

Endocrine system disorders: often – disorders of libido and potency, galactorrhea, breast enlargement; in some cases – syndrome of inadequate secretion of ADH, edema.

Dermatological reactions: rarely – photosensitization.

Allergic reactions: rare – skin rash, itching.

Others: often – increased sweating; in some cases – increase in body temperature.

Overdose

Symptoms: conduction disorders and arrhythmia, insomnia, confusion, intensification or development of phobia.

Treatment: gastric lavage, symptomatic and supportive therapy, in severe anticholinergic symptoms – administration of cholinesterase inhibitors.