Pharmacological properties of the drug Clomipramine
Tricyclic antidepressant, non-selective monoamine reuptake inhibitor. Effectively eliminates symptoms of depression, including psychomotor retardation and anxiety. The therapeutic effect appears within the 1st week of treatment. Most of the side effects of clomipramine are due to its anticholinergic activity. Completely absorbed from the digestive tract after oral administration. The half-life is 21 hours (17–28 hours). Highly bound to plasma proteins (97.6%). Almost 2/3 of the administered dose is excreted in the urine in the form of water-soluble conjugates, about 1/3 in feces. Clomipramine is almost completely biotransformed in the liver, only 1–3% is excreted unchanged in the urine.
Indications for use of the drug Clomipramine
Endogenous, reactive, neurotic and organic depression, latent and involutional forms of depression, depressive states in schizophrenia and psychopathy, depressive syndrome in the elderly, chronic pain syndrome and chronic somatic diseases, depressive mood disorders of reactive, neurotic or psychopathic origin, including their somatic manifestations in childhood, obsessive-compulsive syndrome, phobias and panic states, cataplexy in narcolepsy, enuresis (in patients over 5 years of age, after excluding an organic cause of the disorder).
Use of the drug Clomipramine
Treatment and prevention of depression, obsessive-compulsive disorder and phobias in adults begins with the appointment of 25 mg 2-3 times a day for the first 2-3 days, after which the dose is gradually increased over 1 week, bringing it to 100-150 mg/day . The maintenance dose is usually 50–100 mg/day. For cataplexy (narcolepsy), 25–75 mg/day is usually prescribed. For chronic pain syndrome, a daily dose of 25–150 mg is prescribed in combination with analgesics (the dose of the latter, especially opioids, can be reduced in this case). Elderly patients are prescribed 12.5 mg/day, increasing the dose by 25–50 mg during the first 10 days of treatment until the optimal therapeutic dose is achieved. The average dose for children aged 5-7 years is 25 mg, 8-14 years old - 25-50 mg/day, over 14 years old - 50 mg/day according to the same regimen as for adults. 25–50 mg is administered intramuscularly, gradually increasing the dose to a maximum of 150 mg/day. In the case of severe, refractory depressive states, it is administered intravenously for 1.5–3 hours once a day, after diluting 50–75 mg of clomipramine in 250–500 ml of isotonic solution of sodium chloride or glucose. If the patient's condition improves, parenteral administration is continued for another 3–5 days, after which he is transferred to oral administration.
Side effects of the drug Clomipramine
Manifestations of anticholinergic action at the beginning of treatment are sedation, a feeling of dry mouth, tremor, dizziness, accommodation disturbances, orthostatic hypotension, urinary disorders, which disappear spontaneously or after a dose reduction. Allergic skin reactions are possible, requiring discontinuation of clomipramine. When using high doses, cardiac conduction disturbances, arrhythmia, insomnia, confusion, and anxiety may occur; very rarely - liver dysfunction, hyperthermia, convulsions.
Clomipramine
Clomipramine should be used with extreme caution in patients with epilepsy, as well as in the presence of other factors predisposing to the onset of seizures, for example, brain damage of any etiology, concomitant use of antipsychotic drugs, during periods of abstinence from alcohol or withdrawal of drugs with anticonvulsant properties (for example , benzodiazepines).
It is believed that the occurrence of seizures while taking Clomipramine depends on the dose of the drug. In this regard, the recommended daily dose of Clomipramine should not be exceeded.
with
extreme caution
to patients with cardiovascular diseases, primarily with cardiovascular insufficiency, intracardiac conduction disorders (for example, atrioventricular block I-III degrees) or arrhythmias. In such patients, as well as in elderly patients, it is necessary to regularly monitor blood pressure, cardiovascular function and ECG.
Because the drug has anticholinergic properties, it should be used with extreme caution in patients with a history of increased intraocular pressure, angle-closure glaucoma, or urinary retention (for example, due to prostate disease).
Caution is necessary when treating patients with severe liver disease with tricyclic antidepressants, as well as in patients with tumors of the adrenal medulla (for example, pheochromocytoma, neuroblastoma), since in this case these drugs can provoke the development of a hypertensive crisis.
Many patients with panic attacks experience increased anxiety when starting treatment with Clomipramine. This paradoxical increase in anxiety is most pronounced in the first days of therapy and usually subsides within two weeks.
In patients with schizophrenia receiving tricyclic antidepressants, activation of psychosis is sometimes observed. It is known that patients with cyclic affective disorders taking tricyclic antidepressants may develop manic or hypomanic states during the depressive phase. In such cases, it may be necessary to reduce the dose of Clomipramine or discontinue it and prescribe an antipsychotic drug. After relief of these conditions, if indicated, treatment with Clomipramine in low doses can be resumed. Before starting clomipramine therapy, it is recommended to measure blood pressure, since patients with orthostatic hypotension or vascular lability may experience a sharp decrease in blood pressure.
Due to possible cardiotoxic effects, caution is required when treating patients with hyperthyroidism or patients receiving thyroid hormone medications.
In patients with liver disease, periodic monitoring of liver enzyme activity is recommended.
Although changes in white blood cell levels during treatment with Clomipramine have been reported only in isolated cases, periodic examination of peripheral blood composition and attention to symptoms such as fever and sore throat are recommended, especially in the first months of therapy or during prolonged use of the drug.
Clomipramine, like other tricyclic antidepressants, is prescribed in combination with electroconvulsive therapy only under close medical supervision.
In predisposed patients and elderly patients, tricyclic antidepressants can provoke the development of drug-induced psychoses, mainly at night. After discontinuation of the drug, these disorders disappear within a few days.
Severe depression is characterized by a risk of suicidal actions, which can persist until significant remission is achieved.
In this regard, at the beginning of treatment, a combination of Clomipramine with drugs from the benzodiazepine group or antipsychotic drugs may be indicated. There are reports that while taking Clomipramine, there is a lower number of deaths due to overdose than when taking other tricyclic antidepressants.
Caution is required when using Clomipramine in patients with chronic constipation. Tricyclic antidepressants can cause paralytic ileus, mainly in elderly patients or in patients who are forced to remain in bed.
Before performing general or local anesthesia, the anesthesiologist should be warned that the patient is taking Clomipramine.
An increase in dental caries has been reported with long-term treatment with tricyclic antidepressants. Therefore, in case of long-term therapy with Clomipramine, regular examination of the patient by a dentist is recommended.
Due to the anticholinergic action characteristic of tricyclic antidepressants, there may be a decrease in tear production and a relative increase in the amount of mucus in the tear fluid, which can lead to damage to the corneal epithelium in patients using contact lenses. Abrupt withdrawal of Clomipramine should be avoided, as this may lead to adverse reactions.
Special instructions for the use of Clomipramine
Treatment is carried out under strict medical supervision. At the beginning of therapy, it is recommended to perform tonometry to adjust the dose depending on the degree of blood pressure reduction. The risk of developing orthostatic reactions, tachycardia and conduction disturbances is higher in patients with diseases of the cardiovascular system. In elderly people, parenteral administration of clomipramine is possible only in the absence of pathological changes on the ECG. During treatment with clomipramine, you should not drive vehicles or perform work that requires a quick psychomotor reaction. You should refrain from drinking alcohol for the entire period of treatment. It is not recommended to prescribe clomipramine in the first trimester of pregnancy. Clomipramine passes into breast milk, so breastfeeding should be stopped during treatment.
Clomipramine, 25 mg, film-coated tablets, 30 pcs.
- Hypersensitivity to Clomipramine.
— Hypersensitivity (including to dibenzazepine derivatives)
— Acute poisoning with alcohol, sleeping pills, sedatives and other psychotropic drugs
- drugs, as well as analgesics and general anesthesia.
— Heart failure in the stage of decompensation.
— Acute and recovery period of myocardial infarction.
— Conduction disorders of the heart muscle.
— Severe arterial hypertension.
— Acute diseases of the liver and kidneys, with severe dysfunction/
— Blood diseases/
— Peptic ulcer of the stomach and duodenum in the acute stage/
- Prostate hypertrophy.
- Atony of the bladder.
— Pyloric stenosis, paralytic ileus/
- Simultaneous use of MAO inhibitors and 2 weeks before and after the use of inhibitors, including selective MAO-A inhibitors of reversible action (see “Interaction with other drugs”).
— Congenital syndrome of prolongation of the QT interval.
— Pregnancy, breastfeeding period.
- Children under 10 years old.
Carefully
Clomipramine should be used with extreme caution in patients with epilepsy, as well as in the presence of other factors predisposing to the onset of seizures, for example, brain damage of any etiology, concomitant use of antipsychotic drugs, during periods of abstinence from alcohol or withdrawal of drugs with anticonvulsant properties (for example , benzodiazepines).
It is believed that the occurrence of seizures while taking Clomipramine depends on the dose of the drug. In this regard, the recommended daily dose of Clomipramine should not be exceeded.
Clomipramine should be prescribed with extreme caution to patients with cardiovascular diseases, especially cardiovascular failure, intracardiac conduction disorders (for example, atrioventricular block I-III degrees) or arrhythmias. In such patients, as well as in elderly patients, it is necessary to regularly monitor blood pressure, cardiovascular function and ECG.
Because the drug has anticholinergic properties, it should be used with extreme caution in patients with a history of increased intraocular pressure, angle-closure glaucoma, or urinary retention (for example, due to prostate disease).
Caution is necessary when treating patients with severe liver disease with tricyclic antidepressants, as well as in patients with tumors of the adrenal medulla (for example, pheochromocytoma, neuroblastoma), since in this case these drugs can provoke the development of a hypertensive crisis.
Many patients with panic attacks experience increased anxiety when starting treatment with Clomipramine. This paradoxical increase in anxiety is most pronounced in the first days of therapy and usually subsides within two weeks.
In patients with schizophrenia receiving tricyclic antidepressants, activation of psychosis is sometimes observed. It is known that patients with cyclic affective disorders taking tricyclic antidepressants may develop manic or hypomanic states during the depressive phase. In such cases, it may be necessary to reduce the dose of Clomipramine or discontinue it and prescribe an antipsychotic drug. After relief of these conditions, if indicated, treatment with Clomipramine in low doses can be resumed.
Before starting clomipramine therapy, it is recommended to measure blood pressure, since patients with orthostatic hypotension or vascular lability may experience a sharp decrease in blood pressure.
Due to possible cardiotoxic effects, caution is required when treating patients with hyperthyroidism or patients receiving thyroid hormone medications.
In patients with liver disease, periodic monitoring of liver enzyme activity is recommended.
Although changes in white blood cell levels during treatment with Clomipramine have been reported only in isolated cases, periodic examination of peripheral blood composition and attention to symptoms such as fever and sore throat are recommended, especially in the first months of therapy or during prolonged use of the drug.
Clomipramine, like other tricyclic antidepressants, is prescribed in combination with electroconvulsive therapy only under close medical supervision.
In predisposed patients and elderly patients, tricyclic antidepressants can provoke the development of drug-induced psychoses, mainly at night. After discontinuation of the drug, these disorders disappear within a few days. Severe depression is characterized by a risk of suicidal actions, which can persist until significant remission is achieved.
In this regard, at the beginning of treatment, a combination of Clomipramine with drugs from the benzodiazepine group or antipsychotic drugs may be indicated. There are reports that while taking Clomipramine, there is a lower number of deaths due to overdose than when taking other tricyclic antidepressants.
Caution is required when using Clomipramine in patients with chronic constipation. Tricyclic antidepressants can cause paralytic ileus, mainly in elderly patients or in patients who are forced to remain in bed.
Before performing general or local anesthesia, the anesthesiologist should be warned that the patient is taking Clomipramine.
An increase in dental caries has been reported with long-term treatment with tricyclic antidepressants. Therefore, in case of long-term therapy with Clomipramine, regular examination of the patient by a dentist is recommended.
Due to the anticholinergic action characteristic of tricyclic antidepressants, there may be a decrease in tear production and a relative increase in the amount of mucus in the tear fluid, which can lead to damage to the corneal epithelium in patients using contact lenses.
Abrupt withdrawal of Clomipramine should be avoided, as this may lead to adverse reactions.
Drug interactions Clomipramine
Concomitant use of clomipramine with MAO inhibitors is contraindicated; the interval between their administration should be at least 2 weeks. The combination of clomipramine with antipsychotics, hypnotics and anxiolytics is possible subject to mandatory monitoring of the level of clomipramine in the blood serum. Clomipramine can weaken or completely eliminate the hypotensive effect of antiadrenergic drugs (for example, guanethidine), potentiate the effect of adrenaline and norepinephrine on the cardiovascular system, the effects of alcohol and anxiolytics, anticholinergic drugs. Inhibitors of microsomal liver enzymes enhance the effect of clomipramine. Special drugs for the treatment of alcoholism (disulfiram) increase the concentration of tricyclic antidepressants in the blood.
List of pharmacies where you can buy Clomipramine:
- Moscow
- Saint Petersburg
Clomipramine amp. (d/iv and intramuscular injection) 12.5 mg/ml 2 ml No. 10 Pharmzaschita/Russia
Contraindicated drug interactions MAO inhibitors (linezolid furazolidone, etc.). Clomipramine should not be used for at least 2 weeks after discontinuation of MAO inhibitors due to the risk of developing conditions such as hypertensive crisis, fever, and symptoms of serotonin syndrome: myoclonus, agitation, convulsions, delirium and coma. The same rule should be followed if a MAO inhibitor is used after previous treatment with clomipramine. In any of these cases, the initial doses of clomipramine or MAO inhibitors should be low and increased gradually, with constant monitoring of the drug's effects.
Current experience shows that clomipramine can be prescribed no earlier than 24 hours after discontinuation of reversible MAO-A inhibitors such as moclobemide. But if a reversible MAO-A inhibitor is used after discontinuation of the drug Clomipramine, the duration of the break should be at least 2 weeks. Linezolid (which is a non-selective, reversible MAO inhibitor) should not be used concomitantly with clomipramine.
Medicines not recommended for simultaneous use
Antiarrhythmic drugs (for example, quinidine and propafenone) should not be used concomitantly with tricyclic antidepressants, as they are potent inhibitors of the CYP2D6 isoenzyme.
Diuretic drugs. Diuretics may cause hypokalemia, which in turn increases the risk of QTc prolongation and varicose veins. Correction of hypokalemia should be carried out before starting drug therapy. It may be necessary to correct other fluid and electrolyte imbalances, such as hypomagnesemia, before starting drug therapy.
Selective serotonin reuptake inhibitors (such as fluoxetine, paroxetine or sertraline) inhibit the CYP2D6 isoenzyme; other drugs in this group (for example, fluvoxamine) also inhibit the CYP1A2, CYP2C19 isoenzymes, which can lead to an increase in the concentration of clomipramine in the blood plasma and the development of corresponding undesirable effects. A 4-fold increase in the equilibrium concentration of clomipramine was observed when taken simultaneously with fluvoxamine (the concentration of N-desmethylclomipramine decreased by 2 times).
With simultaneous use of clomipramine with selective serotonin reuptake inhibitors or serotonin and norepinephrine reuptake inhibitors, tricyclic antidepressants and lithium preparations, the development of serotonin syndrome is possible. If it is necessary to use fluoxetine, it is recommended to take a two- to three-week break between the use of clomipramine and fluoxetine - stop using fluoxetine 2-3 weeks before starting clomipramine therapy or start fluoxetine therapy 2-3 weeks after finishing clomipramine treatment.
Concomitant use of Clomipramine with selective serotonin reuptake inhibitors may lead to increased effects on the serotonin system.
Possible drug interactions
Drug interactions that enhance the therapeutic effects of Clomipramine
Concomitant use with inhibitors of the CYP2D6 isoenzyme can lead to an increase in the concentrations of both active components by up to three times in individuals with the phenotype of a rapid metabolizer of debrisoquine/sparteine. At the same time, in these patients, metabolism decreases to a level characteristic of individuals with a poor metabolizer phenotype.
It is assumed that co-administration with inhibitors of the isoenzymes CYP1A2, CYP2C19 and CYP3A4 may lead to an increase in the concentration of clomipramine and a decrease in the concentration of N-desmethylclomipramine, which generally does not affect the pharmacological parameters.
With simultaneous use of the drug Clomipramine with the antifungal drug terbinafine (a potent inhibitor of the CYP2D6 isoenzyme) in oral form, an increase in exposure and accumulation of clomipramine, as well as its N-demethylated metabolite, is possible. When clomipramine is used together with terbinafine, a dose adjustment of clomipramine is required.
Concomitant use with the H2-histamine receptor blocker cimetidine (which is an inhibitor of some cytochrome P450 isoenzymes, including CYP2D6 and CYP3A4) may lead to an increase in plasma concentrations of tricyclic antidepressants, which requires a reduction in the dose of the latter.
There is no data confirming the interaction between clomipramine (at a dose of 25 mg per day) and oral contraceptives (15 or 30 mcg ethinyl estradiol per day) when taken continuously. There is no evidence that estrogens are inhibitors of the CYP2D6 isoenzyme, the main isoenzyme involved in the elimination of clomipramine, so there is no reason to expect their interaction. Although with the simultaneous use of the tricyclic antidepressant imipramine and estrogens in high doses (50 mcg per day), in some cases, worsening side effects and an increase in the therapeutic effect of the antidepressant have been reported. It is unknown whether these data are significant with respect to the concomitant use of clomipramine and low-dose estrogens. With the simultaneous use of tricyclic antidepressants and estrogens in high doses (50 mcg per day), it is recommended to monitor the therapeutic effect of antidepressants and, if necessary, adjust the dosage regimen.
Concomitant use of antipsychotics (for example, phenothiazine derivatives) may lead to increased plasma concentrations of tricyclic antidepressants, a decrease in the seizure threshold and the occurrence of seizures. Combination with thioridazine can lead to the development of severe heart rhythm disturbances.
Methylphenidate may increase plasma concentrations of tricyclic antidepressants, possibly by inhibiting their metabolism. In this case, it may be necessary to reduce the dose of the latter.
With simultaneous use of valproic acid and clomipramine, inhibition of the CYP2C isoenzyme and/or uridyl diphosphate glucuronyl transferase is possible, which can lead to increased concentrations of clomipramine and desmethylclomipramine in the blood plasma.
Drug interactions that reduce the therapeutic effects of Clomipramine
The simultaneous use of clomipramine with inducers of the CYP3A and CYP2C isoenzymes, such as rifampicin or anticonvulsants (for example, barbiturates (phenobarbital), carbamazepine and phenytoin, which are inducers of cytochrome P450 isoenzymes, namely CYP3A4 CYP2C19), may lead to an acceleration of metabolism, a decrease in concentration clomipramine in plasma and a decrease in the effectiveness of the drug Clomipramine.
Inducers of the CYP1A2 isoenzyme (for example, nicotine/other components of cigarette smoke) reduce the concentrations of drugs with a tricyclic structure in the blood plasma. The steady-state concentration of clomipramine in patients who smoke cigarettes is 2 times lower than that in non-smokers (the concentration of N-desmethylclomipramine did not change).
With the simultaneous use of ion exchange resins (for example, cholestyramine or colestipol), a decrease in the concentration of clomipramine in the blood serum is possible. It is recommended to use clomipramine at least 2 hours before and 4-6 hours after applying resins.
St. John's wort may result in decreased plasma concentrations of clomipramine when administered concomitantly.
Drug interactions that do not affect the drug Clomipramine
Tricyclic antidepressants can potentiate the effect of drugs that have an anticholinergic effect (for example, phenothiazine derivatives, antiparkinsonian drugs, atropine, biperiden, H1 histamine receptor blockers) on the organ of vision, the central nervous system, intestines and bladder. In addition, with the simultaneous use of the above drugs, there is a risk of developing hyperthermia.
Clomipramine may reduce or completely eliminate the antihypertensive effects of guanethidine, betanidine, reserpine, clonidine and methyldopa. Therefore, in cases where treatment of arterial hypertension is required simultaneously with clomipramine, drugs of other classes (for example, vasodilators or beta-blockers) should be used.
Tricyclic antidepressants can enhance the effect of ethanol and other drugs that have a depressant effect on the central nervous system (for example, barbiturates, benzodiazepines or anesthetics).
Clomipramine may enhance the cardiovascular effects of epinephrine, norepinephrine, isoprenaline, ephedrine and phenylephrine (including when these substances are part of local anesthetics).
Some tricyclic antidepressants may enhance the anticoagulant effect of coumarin derivatives (eg, warfarin), possibly by inhibiting their metabolism (CYP2C9 isoenzyme). There is no data proving the ability of clomipramine to inhibit the metabolism of anticoagulants (warfarin). However, when using this class of drugs, monitoring the concentration of prothrombin in the blood plasma is recommended.
In addition, clomipramine is an in vitro and in vivo inhibitor of the activity of the CYP2D6 isoenzyme (sparteine oxidation). Thus, clomipramine may increase the concentrations of concomitantly used drugs that are metabolized primarily through the CYP2D6 isoenzyme.
Incompatibility: a solution of the drug Clomipramine with a solution of diclofenac.
