Melipramin^® (Tablets) Instructions for Use

Marketing Authorization Holder

Egis Pharmaceuticals PLC (Hungary)

ATC Code

N06AA02 (Imipramine)

Active Substance

Imipramine (Rec.INN registered by WHO)

Dosage Form

Melipramin®

Film-coated tablets, 25 mg: 50 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets red-brown in color, round, biconvex, with a matte surface, without or almost without odor.

Excipients: magnesium stearate – 1.5 mg, crospovidone – 3 mg, talc – 3 mg, povidone (K-25) – 7 mg, lactose monohydrate – 110.5 mg; coating (hypromellose – 2.61 mg, magnesium stearate – 0.24 mg, iron oxide red dye (C.I.77491, E172) – 0.68 mg, iron oxide black dye (C.I.77499, E172) – 0.12 mg, dimethicone (E-1049 39%) – 0.35 mg).

50 pcs. – dark glass bottles with first-opening control and a bellows cushion (1) – cardboard packs.

Clinical-Pharmacological Group

Antidepressant

Pharmacotherapeutic Group

Antidepressant

Pharmacological Action

An antidepressant from the group of tricyclic compounds.

The antidepressant effect is associated with the stimulation of adrenergic and serotonergic mechanisms in the brain due to the inhibition of neuronal reuptake of neurotransmitters. It inhibits the reuptake of norepinephrine and serotonin equally. It has a sedative, anticholinergic, and antihistamine effect. It possesses analgesic activity (of central origin). It has an antidiuretic effect (in nocturnal enuresis), which is apparently associated with anticholinergic activity, as well as with central blockade of serotonin uptake.

Pharmacokinetics

When taken orally, Imipramine is well absorbed from the gastrointestinal tract. Bioavailability is 29-77%. T_1/2 in blood plasma is reached 1-2 hours after oral administration and 30-60 minutes after intramuscular administration.

Plasma protein binding is 76-95%. Imipramine is rapidly distributed in tissues and easily penetrates the blood-brain barrier. It selectively accumulates in the brain, kidneys, and liver.

It is intensively metabolized in the liver. The ratio between desmethylimipramine – a metabolite with pronounced antidepressant activity – and imipramine in blood plasma is approximately 1.5:15.

Within 24 hours, up to 40% of the imipramine dose is excreted in the urine as inactive metabolites, 1-2% – unchanged. About 20% is excreted in the bile. T_1/2 varies from 4 to 24 hours (9-20 hours).

Indications

Depressions and depressive states of various etiologies, accompanied by motor and ideational retardation. Nocturnal enuresis in children. As part of combination therapy in patients with chronic pain syndromes.

ICD codes

Dosage Regimen

Set individually. For adults when taken orally – 25-50 mg 3-4 times/day; intramuscularly – up to 100 mg/day in divided doses.

For children when taken orally at the age of 6-12 years – 10-30 mg/day in 2 divided doses; over 12 years – 25-50 mg/day in divided doses, if necessary and taking into account tolerability, the dose can be gradually increased. The treatment regimen is set individually.

For nocturnal enuresis, depending on age – 25-75 mg once/day 1 hour before bedtime.

Maximum doses when taken orally for outpatients – up to 200 mg/day, in hospital settings – up to 300 mg/day; for elderly patients – 100 mg/day; for children – 100 mg/day.

Adverse Reactions

From the central nervous system tremor, nervousness, motor restlessness; when used in high doses, sleep disturbances, severe fear, confusion are possible; rarely – tinnitus, seizures.

From the cardiovascular system tachycardia, arterial hypotension, dizziness due to orthostatic hypotension; when used in high doses – arrhythmias.

Allergic reactions rarely – skin rash, itching, photosensitization, swelling of the face and tongue, eosinophilia.

From metabolism decrease in serum protein content.

From the liver rarely – cholestatic jaundice.

From the endocrine system rarely – breast enlargement, galactorrhea.

From the hematopoietic system in isolated cases – agranulocytosis.

Effects due to anticholinergic action dry mucous membranes, accommodation disturbances, eye pain, constipation, urination disorders are possible.

Contraindications

Impaired function of hematopoietic organs, liver and/or kidneys, heart failure, acute period of myocardial infarction, angle-closure glaucoma, bladder atony, benign prostatic hyperplasia, first trimester of pregnancy, lactation, hypersensitivity to imipramine and other tricyclic antidepressants, dibenzazepine derivatives.

Use in Pregnancy and Lactation

Contraindicated in the first trimester of pregnancy, during lactation.

Should not be used in the second and third trimesters of pregnancy, except in cases of extreme necessity. Adequate and strictly controlled studies of the safety of imipramine use in humans during pregnancy have not been conducted, but there are clinical data on congenital malformations associated with the use of imipramine.

Use in Hepatic Impairment

Contraindicated in impaired liver function.

Use in Renal Impairment

Contraindicated in impaired kidney function.

Pediatric Use

For the treatment of nocturnal enuresis in children, imipramine hydrochloride is indicated (but not pamoate). Not recommended for oral administration to children under 6 years of age, for intramuscular administration – to children under 12 years of age.

Special Precautions

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

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

Tricyclic antidepressants should not be used in combination with quinidine-like antiarrhythmic drugs.

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

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 imipramine use requires special caution.

During treatment, alcohol consumption should be avoided.

For the treatment of nocturnal enuresis in children, imipramine hydrochloride is indicated (but not pamoate). Not recommended for oral administration to children under 6 years of age, for intramuscular administration – to children under 12 years of age.

Effect on ability to drive vehicles and operate machinery

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

Drug Interactions

When used simultaneously with drugs that have a depressant effect on the central nervous system, with ethanol, a significant enhancement of the depressant effect on the central nervous system, on respiratory function, and an enhancement of the hypotensive effect are possible.

When used simultaneously with MAO inhibitors, the risk of developing agitation, convulsions, blood pressure fluctuations, hyperthermia, and coma significantly increases.

When used simultaneously with anticholinergic agents, an additive anticholinergic effect is observed.

When used simultaneously with thyroid hormone preparations, adrenergic effects are enhanced, due to an increase in the sensitivity of adrenoreceptors under the influence of thyroid drugs and inhibition of inactivation (transport into adrenergic axons) of norepinephrine under the influence of imipramine, which can cause tachyarrhythmia and the development of angina attacks.

When used simultaneously with adrenomimetics (epinephrine, norepinephrine, mesaton), the risk of tachycardia, arrhythmia, and arterial hypertension increases due to inhibition of catecholamine inactivation by imipramine.

When used simultaneously with barbiturates, a decrease in the concentration of imipramine in blood plasma is possible.

When used simultaneously with clonidine, the antihypertensive effect of clonidine decreases, which is possibly due to inhibition of its binding to presynaptic α-adrenoreceptors.

When used simultaneously with paroxetine, sertraline, the concentration of imipramine in blood plasma increases, due to inhibition of the CYP2D6 isoenzyme under the influence of paroxetine or sertraline.

When used simultaneously with ritonavir, there is a possibility of an increase in the concentration of imipramine in blood plasma; with phenytoin – an increase in the concentration of phenytoin in blood plasma is possible; with quinidine – an increase in the concentration of imipramine in blood plasma is possible, due to a decrease in its excretion from the body. This is apparently related to the inhibition of imipramine metabolism under the influence of quinidine.

When used simultaneously with cimetidine, the metabolism of imipramine slows down, its concentration in blood plasma increases, and toxic effects develop.

When used simultaneously with estrogens, a disturbance in the metabolism of imipramine is possible.

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.