Clomipramine

Pharmacological properties

the therapeutic effect of clomipramine is due to its ability to inhibit the neuronal uptake of norepinephrine (na) and serotonin (5-nt), and the most important is the suppression of serotonin reuptake.

Clomipramine, in addition, is characterized by a wide range of other pharmacological actions: α₁-adrenolytic, anticholinergic, antihistamine and antiserotonergic (blockade of 5-HT receptors).

Clomipramine affects the depressive syndrome as a whole, including especially its typical manifestations, such as psychomotor inhibition, depressed mood, and anxiety. The clinical effect is usually observed after 2-3 weeks of treatment.

Clomipramine also has a specific effect in obsessive-compulsive disorders, which differs from its antidepressant effect.

The action of clomipramine in chronic pain syndromes, caused or not caused by somatic diseases, is associated with facilitating the transmission of a nerve impulse mediated by serotonin and norepinephrine.

Pharmacokinetics

Suction. Clomipramine is completely absorbed in the digestive tract. The systemic bioavailability of an unchanged drug is about 50%, this is due to a pronounced metabolism during the first passage through the liver, which leads to the formation of an active metabolite of N-desmethylclomipramine.

After taking a constant dose of the drug inside, the equilibrium concentrations of clomipramine in plasma in individual patients vary significantly. With daily use of the drug at a dose of 75 mg / day, the equilibrium plasma concentration is set in the range of 20-175 ng / ml.

The value of the equilibrium concentration of the active metabolite of N-desmethylclomipramine is in a similar range. However, when taking clomipramine at 75 mg / day, these values ​​are 40–85% higher than the concentration of clomipramine.

Distribution. The binding of clomipramine to plasma proteins reaches 97.6%. The distribution volume is about 12-17 l / kg body weight. The concentration of the drug in the CSF is about 2% of the level in blood plasma. Clomipramine passes into breast milk, where it is determined in concentrations close to those in blood plasma.

Metabolism. The main pathway of clomipramine metabolism is demethylation with the formation of the active metabolite of N-desmethylclomipramine. N-desmethylclomipramine can be formed by several P450 enzymes, mainly CYP 3A4, CYP 2C19 and CYP 1A2. Clomipramine and N-desmethylclomipramine are hydroxylated to form 8-hydroxyclomipramine or 8-hydroxy-N-desmethylclomipramine. The activity of 8-hydroxymetabolites has not been determined in vivo. Clomipramine is also hydroxylated at the 2nd position, and N-desmethylclomipramine can be further demethylated to form didesmethylclomipramine. 2- and 8-hydroxymetabolites are excreted as urinary glucuronides. Excretion of the active components of clomipramine and N-desmethylclomipramine, forming 2- and 8-hydroxyclomipramine, catalyzes CYP 2D6.

After oral administration of T_½ clomipramine from plasma is an average of 21 hours (range of vibration is 12–36 hours), and desmethylclomipramine is an average of 36 hours.

About ⅔ of a single dose of clomipramine is excreted in the form of water-soluble conjugates with urine and about ¹/₃ doses - with feces. Unchanged in the urine, about 2% of the dose of clomipramine taken and about 0.5% of desmethylclomipramine are excreted.

Pharmacokinetics in certain groups of patients. In elderly patients, regardless of the dose of clomipramine taken, due to a decrease in the metabolism of clomipramine, the plasma concentration is higher than in patients of a younger age. The effect of impaired liver and kidney function on the pharmacokinetics of clomipramine has not yet been studied.

Indications

Adults

Depressive conditions of various etiologies, the course of which is characterized by various symptoms:

• endogenous, reactive, neurotic, organic, disguised, involutional forms of depression;
• depression in patients with schizophrenia and psychopathy;
• depressive syndromes that occur in the elderly; depressive conditions due to chronic pain or chronic somatic diseases;
• depressive mood disorders of a reactive, neurotic or psychopathic nature;
• phobias and panic disorders (seizures);
• obsessive-compulsive disorders;
• cataplexy, which is accompanied by narcolepsy;
• chronic pain syndrome (specific pain syndrome with cancer, neuropathic and idiopathic pain syndromes).

There is still insufficient evidence of the safety and effectiveness of clofranil in the treatment of children with depressive conditions of various etiologies, phobias, panic disorders, cataplexy, which is accompanied by narcolepsy, and with chronic pain syndrome. Therefore, clofranil should not be used for these indications in children and adolescents under the age of 18 years.

Application

Adults

Hypokalemia must be eliminated before prescribing clofranil.

The dose of the drug is selected individually, taking into account the patients condition. The tactics of treatment is to achieve the optimal effect against the background of using low doses of the drug, as well as to carefully increase them, especially in elderly patients (over 65 years old) and adolescents who are more sensitive to clofranil than patients of other age groups.

After maintenance therapy, the optimal dose should be followed. In patients with a history of relapse of depression, maintenance therapy may be indicated for a long period, depending on the individual risk of relapse. The duration and need for further therapy should be periodically reviewed.

To prevent a possible prolongation of the Q – T interval and the appearance of serotonergic toxicity, the recommended doses of clofranil should not be exceeded. Any increase in the dose of clofranil requires caution in the case of the simultaneous use of other serotonergic drugs that extend the Q – T interval.

Abrupt withdrawal of therapy without medical grounds should be avoided, as this can lead to adverse reactions. If clofranil must be discontinued after prolonged therapy, the dose should be reduced gradually, and the patient should be closely monitored.

Depression, obsessive-compulsive syndromes and phobias. Treatment begins with the appointment of 1 tablet, coated, which contains 25 mg of clomipramine, 2-3 times a day. Then, during the 1st week of treatment, the dose of the drug is gradually increased, for example, by 25 mg every few days (depending on tolerability), until a daily dose of 4-6 tablets of 25 mg is reached. In severe cases, the daily dose can be increased to a maximum of 250 mg.

After achieving a pronounced improvement, a maintenance dose of the drug is selected, which is 2-4 tablets of 25 mg.

Panic disorders, agoraphobia. Treatment begins with 10 mg of clomipramine per day. Then, depending on the tolerance of clofranil, its dose is increased until the desired effect is achieved. The daily dose of clofranil required in these cases varies significantly among patients and ranges from 25–100 mg. If necessary, it can be increased to 150 mg. It is not recommended to stop treatment for 6 months, the maintenance dose during this period should be slowly reduced.

Cataplexy that accompanies narcolepsy. The daily dose of clofranil is 25–75 mg.

Chronic pain syndromes.The dose of clofranil should be selected individually, taking into account the concomitant use of analgesics (as well as taking into account the possibility of reducing their use).

Elderly patients (from 65 years). Elderly patients (from 65 years old) are generally more sensitive to clofranil than patients of other age groups. Therefore, such patients should be careful to increase the dose of clofranil. Treatment begins with the appointment of 10 mg / day. Then gradually, over about 10 days, the daily dose of the drug is increased to the optimal level of 30-50 mg, and keep it at this level until the end of treatment.

Obsessive-compulsive syndromes. Adolescents are more sensitive to clofranil than patients of other age groups. Therefore, such patients should be careful to increase the dose of clofranil. Clinical data on short-term therapy in adolescents and children over 10 years of age are limited.

The initial dose is 25 mg / day, individually increased to 3 mg / kg body weight or 100 mg during the first 2 weeks. The dose can be increased over the next few weeks to 3 mg / kg or 200 mg, depending on which dose is lower.

Contraindications

Hypersensitivity to clomipramine or any other components of the drug, cross-sensitivity to tricyclic antidepressants of the dibenzazepine group.

• Antiarrhythmic drugs, such as quinidine and propafenone, which are potent CYP 2D6 inhibitors, should not be given in combination with tricyclic antidepressants.
• The simultaneous use of MAO inhibitors, as well as a period of less than 14 days before and after their use. The simultaneous use of selective reversible MAO-A inhibitors (such as moclobemide) or non-selective reversible MAO inhibitors (such as linezolid) is also contraindicated.
• Recently suffered myocardial infarction.
• Congenital syndrome of an extended Q – T interval.
• Acute intoxication with CNS depressants (such as sleeping pills, analgesics or psychotropic drugs) or alcohol.
• Acute urinary retention.
• Sharp delirium.
• Untreated glaucoma.
• Hypertrophy of the prostate gland with a final urinary retention.
• Pyloric stenosis.
• Paralytic intestinal obstruction.

Side effects

Adverse events that occur, as a rule, are mild and transient, disappear during the continuation of treatment or after reducing the dose of clofranil. they are not always associated with the level of the drug’s active substance in the blood plasma or its dose. some undesirable effects, such as general weakness, sleep disturbance, anxiety, anxiety, constipation, and dry mouth, are often difficult to distinguish from manifestations of depression.

If serious adverse reactions from the nervous system or mental status develop, clofranil should be discontinued.

Elderly patients are especially sensitive to changes in the nervous, cardiovascular system, mental sphere, as well as the anticholinergic effect of clofranil. Metabolism and elimination of drugs at this age can slow down, which leads to an increase in plasma concentration even when using average therapeutic doses.

The incidence of adverse reactions is estimated as follows: very often (1/10); often (from 1/100 to 1/10); infrequently (from 1/1000 to 1/100); rarely (from 1/10 000 to 1/1000), very rarely (1/10 000), including isolated cases.

Mental disorders: very often - dizziness, transient fatigue, anxiety, increased appetite; sometimes - confusion, disorientation, hallucinations (especially in elderly patients and patients with Parkinson’s disease), anxiety, agitation, sleep disturbance, manic state, hypomanic state, aggressiveness, memory impairment, depersonalization, increased depression, impaired concentration, insomnia , nightmares; infrequently - activation of symptoms of psychosis.

From the nervous system: very often - dizziness, tremor, headache, myoclonus; often - delirium, speech disorders, paresthesia, muscle weakness, increased muscle tone; infrequently - convulsions, ataxia; very rarely - changes in the EEG, hyperpyrexia, extrapyramidal symptoms (including dyskinesia), drug fever, antipsychotic malignant syndrome.

From the side of the heart: often - sinus tachycardia, palpitations, clinically insignificant changes on the ECG (for example, S-T interval or T wave) in patients without heart disease; infrequently - arrhythmias, increased blood pressure; very rarely - intracardiac conduction disturbances (for example, expansion of the QRS complex, increase in the Q – T interval, changes in the P – Q interval, blockade of the bundle of His bundle), bidirectional ventricular tachycardia, especially in patients with hypokalemia.

From the vascular system: often - orthostatic hypotension.

From the alimentary canal: very often - dry mouth, constipation; often nausea; infrequently - vomiting, abdominal discomfort, diarrhea, loss of appetite, loss of appetite, dysgeusia.

From the hepatobiliary system: often - increased levels of transaminases; very rarely - hepatitis with or without jaundice.

On the part of the skin and subcutaneous tissue: often - allergic dermatitis (rash, urticaria), photosensitivity, itching; very rarely - local reactions after intravenous injection (thrombophlebitis, lymphangitis, a feeling of heat and allergic skin reactions), edema (local or general), hair loss.

From the kidneys and urinary system: very rarely - urinary retention and fluid retention in the body.

From the reproductive system and mammary glands: often - a violation of libido and potency, erectile dysfunction; infrequently - galactorrhea, amenorrhea, breast enlargement.

From the endocrine system: very often - dry mouth, increased sweating, impaired urination; often - hot flashes, mydriasis; very rarely - syndrome of inadequate secretion of antidiuretic hormone.

From the side of metabolism and nutrition: very often - an increase in body weight.

On the part of the immune system: very rarely - allergic alveolitis (pneumonitis) with or without eosinophilia, systemic anaphylactic / anaphylactoid reactions, including hypotension.

On the part of the blood system and lymphatic system: very rarely - leukopenia, agranulocytosis, thrombocytopenia, eosinophilia, purpura.

From the side of the organ of vision: very often - violation of accommodation, blurred vision; very rarely - glaucoma.

On the part of the organ of hearing and the labyrinth: often - ringing in the ears.

Others: after a sudden cancellation or a rapid reduction in the dose of clofranil, the following symptoms sometimes occur: nausea, vomiting, abdominal pain, diarrhea, insomnia, headache, irritability, anxiety.

Side effects identified on the basis of spontaneous messages during post-marketing surveillance. Since the size of the population covered is unknown, the frequency of occurrence of these reactions cannot be reliably determined.

From the nervous system: serotonin syndrome, extrapyramidal symptoms (including akathisia and tardive dyskinesia).

From the musculoskeletal system: rhabdomyolysis (as a complication of malignant antipsychotic syndrome).

Study: hyperprolactinemia.

Epidemiological studies, conducted mainly with patients aged ≥50 years, indicated an increased risk of bone fractures in patients receiving selective serotonin reuptake inhibitors and tricyclic antidepressants. The mechanism that causes this risk is unknown.

special instructions

Suicide risk. depression is associated with an increased risk of suicidal thoughts, the possibility of self-harm and suicide.exacerbation of suicidal thoughts and suicidal behavior can be noted in patients receiving antidepressant therapy.

Clofranil should not be used to treat depression in children and adolescents under the age of 18 years. In studies of the effectiveness of treating depression in this age group, the therapeutic efficacy of tricyclic antidepressants has not been demonstrated.

Published data from studies of selective serotonin reuptake inhibitors and similar drugs indicate an increased risk of suicidal behavior in the treatment of depression in children, adolescents, and young people (under 25 years old). A similar effect cannot be ruled out for other antidepressants (including clofranil) for which no relevant data are available.

Thus, in patients receiving antidepressants, careful monitoring of signs of worsening depression, in particular suicidal behavior and / or akathisia (internal anxiety, psychomotor agitation), is necessary, mainly at the beginning of therapy and when the dose is changed. In addition, patients need constant monitoring at the end of treatment, since similar symptoms can occur when treatment is canceled or in the initial phase of relapse.

In addition to depressive states, psychiatric diseases can also be associated with an increased risk of suicidal behavior, therefore, the same requirements should be observed when treating antidepressants.

The patient’s relatives and caregivers should be advised that they should be cautious about the development of other symptoms of psychiatric illness (see ADVERSE EFFECTS) and suicidality, and immediately inform the doctor who provides the patient with medical care.

Antidepressant care is not a complete substitute for hospitalization, which is necessary if the patient poses a threat to himself. The doctor should prescribe the minimum available dose of the drug, especially at the beginning of therapy, in order to avoid the risk of a similar situation.

Regarding the risk of fatal overdose, fewer fatal cases have been reported with Clofranil treatment than with other tricyclic antidepressants. To reduce the risk of overdose, the lowest possible dose of clofranil should be prescribed to achieve the optimal patient treatment effect.

Psychiatric effects. In many patients with panic attacks, anxiety intensifies at the beginning of treatment with clofranil. This paradoxical increase in anxiety is most pronounced in the early days of therapy and usually decreases within 2 weeks.

In patients with schizophrenia receiving tricyclic antidepressants, psychosis is sometimes observed to be activated. As a result of the activation effect of tricyclic antidepressants, it is possible to increase anxiety, internal anxiety and arousal in patients with agitation or concomitant schizophrenic symptoms.

It is known that in patients with cyclic affective disorders taking tricyclic antidepressants, manic or hypomanic conditions may develop during the depressive phase. In such cases, it may be necessary to reduce the dose of Clofranil or its cancellation and the appointment of an antipsychotic. After stopping these conditions, if there are indications, treatment with clofranil in low doses can be restored.

In patients prone to mental disorders and elderly people, tricyclic antidepressants can provoke the development of pharmacogenic psychosis (delirium), mainly at night. After discontinuation of the drug, these disorders disappear within a few days.

Cramps.It is known that tricyclic antidepressants lower the threshold for convulsive readiness, therefore, clofranil should be prescribed with extreme caution to patients with epilepsy, as well as in the presence of other factors causing the occurrence of convulsive syndrome, for example, with brain damage of any etiology, the simultaneous use of antipsychotics, during the period of refusal from alcohol or withdrawal of drugs with anticonvulsant properties (e.g. benzodiazepines). It is believed that the occurrence of seizures while taking clofranil depends on the dose of the drug. In this regard, the recommended daily dose of clofranil should be exceeded.

Clofranil, like other tricyclic antidepressants, is prescribed in combination with electroconvulsive therapy only with careful medical supervision.

Anticholinergic effects. Since the drug has anticholinergic properties, it should be prescribed with caution to patients who have a history of increased intraocular pressure, angle-closure glaucoma or urinary retention (for example, due to diseases of the prostate gland).

Due to the anticholinergic action inherent in tricyclic antidepressants, a decrease in tear production and a relative increase in the amount of mucus in the tear fluid are possible, which can lead to damage to the corneal epithelium in patients using contact lenses.

Serotonin syndrome. Due to the risk of serotonergic toxicity, it is necessary to adhere to the recommended doses and increase the dose with caution if another serotonergic drug is prescribed at the same time. Serotonin syndrome with symptoms such as hyperpyrexia, myoclonus, agitation, epileptic seizures, delirium and coma may occur if clomipramine is used concurrently with serotonergic drugs, such as selective serotonin reuptake inhibitors, serotonin reuptake inhibitors, and noradrena drugs lithium, tryptans, L-tryptophan, tramadol, fentanyl or sibutramine. It is recommended that 2-3 weeks before and after treatment with fluoxetine do not use clomipramine.

Cardiovascular effects. With extreme caution, clofranil should be prescribed to patients with cardiovascular diseases, especially cardiovascular insufficiency, intracardiac conduction disorders (for example, with AV block I-III degree) or arrhythmias. In such patients, as in elderly patients, it is necessary to regularly monitor indicators of the function of the cardiovascular system and ECG.

There may be a risk of an increase in the Q – T interval and the occurrence of atypical ventricular tachycardia when prescribing higher therapeutic doses of clomipramine, as well as in the case of combined administration with selective serotonin reuptake inhibitors or serotonin and norepinephrine reuptake inhibitors. Therefore, the simultaneous administration of drugs that can cause the accumulation of clomipramine should be avoided. You should also avoid the simultaneous administration of drugs that can extend the Q – T interval. The basis of these phenomena is hypokalemia. Therefore, before prescribing clofranil or clofranil in combination with serotonin inhibitors, serotonin-noradrenergic inhibitors or diuretics, it is necessary to determine the level of potassium in the blood plasma and, if it is reduced, it should be adjusted. The combined use of clofranil with selective serotonin reuptake inhibitors, serotonin and noradrenaline reuptake inhibitors, and diuretics requires caution.

Before starting Clofranil therapy, it is recommended to measure blood pressure, since in patients with orthostatic hypotension or vascular lability, a sharp decrease in blood pressure is possible.

Special patient groups.Caution should be exercised when treating patients with severe liver diseases as well as patients with tumors of the adrenal medulla (for example, pheochromocytoma, neuroblastoma) with tricyclic antidepressants, since in this case hypertensive crisis may develop.

Caution should be exercised in the treatment of patients with hyperthyroidism and patients receiving thyroid hormone preparations, since the anticholinergic effects of the tricyclic antidepressants of these drugs can exacerbate unwanted cardiac effects.

If necessary, in patients with kidney and liver diseases, constant monitoring is recommended both in terms of the level of liver enzymes and renal function, and in the concentration of the active substance and its metabolites in blood plasma.

Caution is needed when treating patients with chronic constipation with clofranil. Tricyclic antidepressants can cause paralytic intestinal obstruction, mainly in elderly patients or in patients who have to comply with bed rest.

Caries has been reported with prolonged treatment with tricyclic antidepressants. Therefore, in the case of prolonged therapy with clofranil, regular examination by a dentist is recommended.

There is no evidence of further safety for children and adolescents by height, puberty, and cognitive and behavioral development.

Hypersensitivity reactions. There have been isolated cases of anaphylactic shock. The introduction of clofranil requires caution.

Changes in blood counts. Although changes in leukocyte counts during treatment with clofranil have been reported only in individual cases, a periodic study of the composition of peripheral blood and attention to symptoms such as fever and sore throat are recommended, especially in the first months of therapy or with prolonged use of the drug. With a decrease in the number of neutrophils below normal, the drug should be discontinued.

Anesthesia. Before performing general or local anesthesia, an anesthetist should be advised that the patient is taking clofranil.

Other effects. Hyperthermia as a symptom of malignant antipsychotic syndrome was noted in several patients who received concomitant therapy with antipsychotic drugs with clofranil.

Drug withdrawal. Abrupt withdrawal of clofranil should be avoided, as this can lead to adverse reactions. If it is necessary to stop therapy, the dose should be reduced as quickly as possible, but always bear in mind that abrupt cancellation of therapy can lead to adverse reactions.

Lactose content. Patients with rare hereditary forms of galactose intolerance, acute lactose deficiency, glucose-galactose malabsorption should not use the drug.

Use during pregnancy and lactation. There is clear evidence of a risk to the human fetus, but this risk may prevail over the therapeutic benefits for the pregnant woman. Since there are separate reports of a possible connection between the administration of tricyclic antidepressants and impaired fetal development, clofranil should be avoided during pregnancy, unless the expected effect of the treatment for the pregnant woman undoubtedly exceeds the potential risk to the fetus.

Newborns whose mothers took tricyclic antidepressants before giving birth had symptoms such as respiratory disorders, lethargy, colic, increased irritability, hypotension or hypertension, trembling, convulsions and epileptic seizures during the first few hours or days after birth.

To avoid the development of this syndrome, clofranil should be withdrawn gradually approximately 7 weeks before the expected birth, according to clinical indications.

Since the active substance of the drug passes into breast milk, breast-feeding should be discontinued, or clofranil should be gradually withdrawn.

Children. There is no experience with clofranil in children.

The ability to influence the reaction rate when driving vehicles or other mechanisms. Patients who take clofranil should be warned that they may experience blurred vision, dizziness and other disorders of the central nervous system (see ADVERSE EFFECTS), and in such cases they should refuse to drive vehicles, work with machinery, as well as from other activities requiring increased attention. Patients should also be warned that these effects may increase with the use of other drugs and alcohol.

Interactions

Pharmacodynamic interaction

MAO inhibitors. Clofranil should not be prescribed less than 2 weeks after the withdrawal of MAO inhibitors (there is a risk of developing severe symptoms and conditions such as hypertensive crisis, hyperpyrexia, myoclonus, agitation, generalized convulsions, delirium and coma). The same rule should be followed if an MAO inhibitor is prescribed after prior treatment with clofranil. In any of these cases, the initial doses of clofranil or MAO inhibitors should be low, they should be increased gradually, under constant monitoring of the effects of the drug.

The existing risk indicates that clofranil can be used no earlier than 24 hours after the withdrawal of MAO-A reversible inhibitors, such as moclobemide. But if a similar drug is prescribed after discontinuation of clofranil, the duration of the break should be at least 2 weeks.

Since the linezolid antibiotic is a non-selective reversible MAO inhibitor, it should not be prescribed to patients who receive clomipramine.

Selective serotonin reuptake inhibitors. The use of clofranil in combination with these drugs can lead to increased effects on the serotonin system.

Serotonergic drugs. Serotonin syndrome can occur when clomipramine is used with serotonergic drugs, such as selective serotonin reuptake inhibitors and serotonin and norepinephrine reuptake inhibitors, tricyclic antidepressants or lithium salts. Before and after treatment with fluoxetine, it is recommended not to use clomipramine for 2-3 weeks.

Antiadrenergic drugs that affect neuronal transmission of arousal. Clofranil can reduce or completely eliminate the antihypertensive effect of guanethidine, betanidine, reserpine, clonidine, and alpha-methyldopa. Therefore, in cases where treatment with hypertension is necessary at the same time as taking clofranil, other types of drugs should be used (for example, vasodilators or β-adrenergic blockers).

Sympathomimetics. Clofranil can enhance the effect on the cardiovascular system of epinephrine, norepinephrine, isoprenaline, ephedrine and phenylephrine (including when these substances are part of local anesthetics).

Central nervous system depressants. Tricyclic antidepressants can enhance the effects of alcohol and other drugs that have a depressing effect on the central nervous system (for example, opiates, barbiturates, benzodiazepines, or general anesthetics).

Anticholinergics. Tricyclic antidepressants can enhance the anticholinergic effect of a number of drugs (for example, phenothiazines, antiparkinsonics, antihistamines, atropine, biperiden) on the organ of vision, central nervous system, intestines and bladder. There is a risk of hyperthermia.

Diuretics. The combined use of clofranil with diuretics can lead to hypokalemia, which, in turn, increases the risk of lengthening the Q-Tc interval and bidirectional ventricular tachycardia.Hypokalemia must be eliminated before prescribing clofranil.

Pharmacokinetic interaction. Clofranil (clomipramine) is excreted mainly through metabolism. The main metabolic pathway is demethylation with the formation of the active metabolite of N-desmethylclomipramine, followed by hydroxylation and subsequent conjugation of N-desmethylclomipramine and the initial drug substance. Several cytochromes P450 are involved in demethylation, mainly CYP 3A4, CYP 2C19 and CYP 1A2. Excretion of both active components occurs by hydroxylation, and this catalyzes CYP 2D6.

The simultaneous use of CYP 2D6 inhibitors can lead to an approximately 3-fold increase in the concentration of both active substances in patients with the phenotype of accelerated metabolism of debrisoquine / spartein, which turns their phenotype into a phenotype of slow metabolism. The combined use of inhibitors of CYP 1A2, CYP 2C19 and CYP 3A4 leads to an increase in the concentration of clomipramine and a decrease in the concentration of N-desmethylclomipramine, so this appointment does not necessarily affect the general pharmacology.

• MAO inhibitors, which are also powerful in vivo CYP 2D6 inhibitors, such as moclobemide, are contraindicated for concomitant use with clomipramine.
• Antiarrhythmic drugs (such as quinidine and propafenone), which are potent inhibitors of CYP 2D6, should not be used in conjunction with