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- Anafranil's pharmacological properties Anafranil's pharmacodynamics Anafranil's therapeutic effect is believed to be mediated by its ability to inhibit the neuronal reuptake of noradrenaline and serotonin (5-HT), with the inhibition of serotonin reuptake being the most significant. Additionally, Anafranil exhibits a broader spectrum of pharmacological actions: alpha1-adrenolytic, anticholinergic, antihistamine, and antiserotonergic (blockade of 5-HT receptors). Anafranil acts on depressive syndromes, particularly on typical manifestations such as psychomotor retardation, depressed mood, and anxiety. The clinical effect usually appears after 2-3 weeks of treatment. Anafranil also has a specific effect on obsessive-compulsive disorder, which differs from its antidepressant effect. In chronic pain syndrome, whether or not caused by somatic disease, Anafranil's action is related to the improvement of nerve impulse transmission mediated by serotonin and noradrenaline. Anafranil's pharmacokinetics Anafranil absorption Clomipramine is completely absorbed from the gastrointestinal tract. Systemic bioavailability is approximately 50% and is associated with pronounced first-pass metabolism in the liver, leading to the formation of the active metabolite, N-desmethylclomipramine. Food intake does not significantly affect the bioavailability of clomipramine. A delay in absorption may occur, and consequently, the time to reach maximum plasma concentration may increase. In different patients, the steady-state plasma concentration of clomipramine after repeated oral administration of a constant dose varies significantly. With daily administration of 75mg/day, its steady-state concentration in serum ranges from 20 to 175mg/ml. The steady-state concentration of the active metabolite N-desmethylclomipramine is in a similar range. However, when 75mg of Anafranil is administered daily, this value is 40-85% higher compared to the concentration of clomipramine. Anafranil distribution Clomipramine binding to plasma proteins is 97.6%. The apparent volume of distribution is approximately 12-17 L/kg of body weight. The concentration of clomipramine in cerebrospinal fluid is about 2% of its level in plasma. Clomipramine passes into breast milk. The concentration is similar to the plasma concentration. Anafranil metabolism The main metabolic pathway of clomipramine is demethylation, leading to the formation of the active metabolite N-desmethylclomipramine. N-desmethylclomipramine can be formed by several P450 enzymes, mainly CYP3A4, CYP2C19, and CYP1A2. Clomipramine and N-desmethylclomipramine are hydroxylated to form 8-hydroxyclomipramine and 8-hydroxy-N-desmethylclomipramine. The activity of 8-hydroxymetabolites in vivo has not been determined. Clomipramine is also hydroxylated at position 2, and N-desmethylclomipramine can subsequently be demethylated to form didesmethylclomipramine. 2- and 8-hydroxymetabolites are excreted in urine as glucuronides. The elimination of the active components, clomipramine and N-desmethylclomipramine, by forming 2- and 8-hydroxyclomipramine, is catalyzed by CYP2D6. Anafranil elimination from blood The half-life of clomipramine is on average 21 hours (range 12-36 hours), and that of desmethylclomipramine is on average 36 hours. Approximately 2/3 of a single dose of clomipramine is excreted in urine as water-soluble conjugates, and approximately 1/3 of the dose is excreted in feces. Approximately 2% of the administered dose of clomipramine and approximately 0.5% of desmethylclomipramine are excreted unchanged in urine. Pharmacokinetics in specific patient groups In elderly individuals, compared to younger individuals, the concentration of clomipramine in serum is higher due to reduced intensity of clomipramine metabolism, regardless of the dose of Anafranil used. The effect of impaired kidney and liver function on clomipramine pharmacokinetics has not been studied. Anafranil indications Adults: Treatment of depressive states of various etiologies with various symptomatology: - Endogenous, reactive, neurotic, organic, masked, involutional forms of depression; - Depression in individuals with schizophrenia and psychopathy; - Depressive syndromes in the elderly; Depressive states caused by chronic pain syndrome or chronic somatic diseases; Depressive disorders of reactive, neurotic, or psychopathic nature; - Obsessive-compulsive syndromes; - Phobias and panic disorders (attacks); - Accompanying catalepsy associated with narcolepsy; - Chronic pain syndrome (idiopathic and neuropathic pain syndromes, specific pain syndrome in cancer). Children: - Obsessive-compulsive syndromes; - Nocturnal enuresis (only in patients over 6 years of age and after excluding organic causes of the disease). The use of Anafranil in children for depressive states of various etiologies (phobias, panic disorders, catalepsy associated with narcolepsy, chronic pain syndrome) has not yet been fully studied, therefore Anafranil is not used for these symptoms in children. Anafranil administration rules and dosages Adults: The dose of the drug is selected individually, taking into account the patient's condition. The goal of treatment is to achieve optimal effect with the lowest possible dose of the drug, as well as careful dose increase, especially in the elderly and adolescents who are more sensitive to Anafranil compared to patients in the intermediate age group. To prevent QT interval prolongation and serotonergic toxicity, it is recommended to prescribe Anafranil at recommended doses, and in case of need for high doses, special caution is required, especially if the patient is taking other drugs that prolong the QT interval. Depression, obsessive-compulsive syndrome, and phobias Treatment is initiated by administering 1 tablet containing 25mg clomipramine, 2-3 times a day. Then, during the first week of treatment, the dose of the drug is gradually increased, for example, by 25mg every few days (depending on tolerance), until a daily dose of 4-6 tablets of 25mg is reached. In severe cases, the daily dose can be increased to a maximum dose of 250mg. After significant improvement is achieved, a maintenance dose of 2-4 tablets of 25mg is selected. Panic disorders, agoraphobia Treatment is initiated with a dose of 10mg clomipramine per day, possibly in combination with benzodiazepine drugs. Then, depending on the patient's tolerance, the dose is increased until the desired effect is achieved; after that, benzodiazepine drugs are gradually withdrawn. The daily dose for different patients varies significantly in the range of 25-100mg. If necessary, it can be increased to 150mg. It is recommended to continue treatment for at least 6 months, during which the maintenance dose of the drug is gradually reduced. Catalepsy associated with narcolepsy, daily dose is 25-75mg. Chronic pain syndrome Dose is selected individually (10-150mg per day), taking into account the concomitant use of analgesics (and the possibility of reducing their use). Elderly individuals Treatment is initiated with a dose of 10mg per day. Then, the daily dose is increased to an optimal level of 30-50mg, and maintained at this level until the end of treatment. Anafranil - children and adolescents Obsessive-compulsive syndrome: Initial dose - 25mg per day, increased according to an individual schedule to 3mg/kg or 100mg during the first 2 weeks. The dose can be increased over the next few weeks to 3mg/kg or 200mg. Nocturnal enuresis In children aged 6-8 years, the initial dose is 20-30mg; in children aged 9-12 years - 1-2 tablets of 25mg; in older children - 1-3 tablets of 25mg. Higher doses are indicated if there is no clinical effect after 1 week. Usually, the entire daily dose of the drug is administered once after dinner, but if involuntary urination occurs in the first half of the night, a portion of the dose is administered earlier (at 4 PM). Once the desired effect is achieved, treatment should be continued for 1-3 months, with gradual dose reduction. There is no experience with the use of Anafranil in children under 6 years of age. There is no confirmed information on the use of this drug for depressive states of various etiologies (phobias, panic attacks, narcolepsy with catalepsy, chronic pain syndrome). Therefore, the use of Anafranil in children under 6 years of age is not recommended. Anafranil side effects Observed adverse events are usually mild and transient and resolve with continued treatment or dose reduction of Anafranil. The occurrence of side effects is not always related to the level of the active substance in the plasma or its dose. Often, it is difficult to distinguish between manifestations of depression and adverse events such as general weakness, sleep disturbances, anxiety, constipation, dry mouth. In case of development of a serious side effect on the nervous system or mental status, the use of Anafranil is discontinued. Elderly individuals are particularly sensitive to changes in the nervous system, cardiovascular system, mental sphere, as well as to the anticholinergic effects of Anafranil. In the elderly, metabolism and elimination of the drug may be slowed down, which, even with average therapeutic doses, leads to an increase in drug concentration in plasma. The frequency of adverse reactions was evaluated as follows: "very common" - ≥10%, "common" - ≥1% to ≤10%, "uncommon" - ≥0.1% to ≤1%, "rare" - ≥0.01% to ≤0.1%, "very rare" - <0.01%. Psychiatric disorders: very common - drowsiness, general weakness, agitation, increased appetite; very common - confusion, disorientation, hallucinations (especially in the elderly and those with Parkinson's disease), agitation, excitability, sleep disturbances, manic states, aggression, memory impairment, depersonalization, worsening of depression, impaired concentration, insomnia, nightmares, yawning; sometimes activation of psychotic symptoms. Neurological disorders: very common - dizziness, tremor, headache, myoclonus; common - delirium, speech disorders, paresthesia, muscle weakness, increased muscle tone; uncommon - seizures, ataxia; very rare - changes in electroencephalogram, hyperpyrexia. Anticholinergic effects: very common - dry mouth, sweating, constipation, accommodation disorders, decreased visual acuity, urinary retention; common - hot flashes, mydriasis, very rare - glaucoma, urinary retention. Cardiovascular system: common - sinus tachycardia, palpitations, orthostatic hypotension, clinically insignificant ECG changes (e.g., ST segment or T wave) in patients without heart disease; uncommon - arrhythmia, increased blood pressure; very rare - conduction disturbances (e.g., QRS complex widening, QT interval prolongation, PQ interval changes, bundle branch block, torsades de pointes, especially in hypokalemic individuals). Gastrointestinal tract: very rare - nausea, common - vomiting, abdominal discomfort, diarrhea, anorexia. Hepatobiliary system: common - increased transaminases; very rare - hepatitis with or without jaundice. Dermatological reactions: common - allergic reactions (rash, urticaria), photosensitivity, itching; very rare - edema (local or generalized), hair loss. Urinary system: very common - urinary retention, very rare - urinary retention, fluid retention. Endocrine system and metabolism: very common - weight gain, libido and potency disorders; common - galactorrhea, breast enlargement; very rare - syndrome of inappropriate secretion of antidiuretic hormone. Immune system: very common - allergic alveolitis (pneumonitis) with or without eosinophilia, systemic anaphylactic/anaphylactoid reactions, including hypotension. Hematopoietic system: very rare - leukopenia, agranulocytosis, thrombocytopenia, eosinophilia, purpura. Sensory organs: common - taste disturbances, tinnitus. Anafranil - other Sudden withdrawal or rapid dose reduction of Anafranil may cause symptoms such as nausea, vomiting, abdominal pain, diarrhea, insomnia, headache, irritability, anxiety. Overdose: Symptoms and complaints of overdose after oral administration of Anafranil are similar to those of overdose caused by other antidepressants. The main complications are cardiac and neurological disorders. Accidental ingestion of the drug by children, regardless of the dose used, is considered a serious event that can be fatal. Complaints and symptoms Symptoms usually appear within 4 hours of drug intake and reach maximum severity after 24 hours. Due to delayed absorption (anticholinergic effect of the drug), partially prolonged elimination half-life, and enterohepatic recirculation of the active substance, the period of "danger zone" for the patient is 4-6 days. The following complaints and symptoms may occur: Central nervous system: drowsiness, stupor, coma, ataxia, agitation, excitability, exaggerated reflexes, muscle rigidity, choreoathetoid movements, seizures. In addition, symptoms related to serotonin syndrome may occur (e.g., hyperpyrexia, myoclonus, delirium, and coma). Cardiovascular system: hypotension, tachycardia, arrhythmia, prolonged QTc interval and arrhythmia with torsades de pointes, conduction disturbances, shock, heart failure; in very rare cases - cardiac arrest. In addition, respiratory depression, cyanosis, vomiting, fever, mydriasis, sweating, oliguria or anuria may occur. Treatment There is no specific antidote; treatment is mainly symptomatic and supportive. Anafranil contraindications Hypersensitivity to clomipramine or any other ingredient of the drug, cross-hypersensitivity to tricyclic antidepressants of the dibenzazepine group. Concomitant administration of MAO inhibitors, as well as within 14 days before or after their use. Concomitant use of selective reversible MAO-A inhibitors such as moclobemide is also contraindicated. Recent myocardial infarction, congenital long QT syndrome. Anafranil is not indicated in the following situations: - Acute intoxication with CNS depressants (analgesics, psychotropic and hypnotic drugs, as well as alcohol); - Acute urinary retention; - Acute delirium; - Untreated narrow-angle glaucoma; - Prostatic hypertrophy with urinary retention; - Pyloric stenosis; paralytic intestinal obstruction. Pregnancy and lactation The use of Anafranil during pregnancy has not been fully studied. Anafranil is not used during pregnancy, as a possible link between the use of tricyclic antidepressants and fetal developmental abnormalities has been reported in isolated cases, except when the expected benefit of maternal treatment outweighs the potential risk to the fetus. In newborns whose mothers used tricyclic antidepressants during pregnancy and before delivery, a withdrawal syndrome was observed in the first few days or hours, characterized by dyspnea, drowsiness, colic, irritability, hypotension or hypertension, tremor, or spastic phenomena. To avoid such a syndrome, Anafranil should be gradually withdrawn at least 7 weeks before the expected delivery. Use in children: There is no experience with the use of Anafranil in children under 6 years of age. There is no confirmed information on the use of this drug for depressive states of various etiologies (phobias, panic attacks, narcolepsy with catalepsy, chronic pain syndrome). Therefore, the use of Anafranil in children under 6 years of age is not recommended. Special instructions Peculiarities of use: Suicide risk: Suicidal behavior is a risk characteristic of severe depression and may persist until remission is achieved. In this regard, a combination of Anafranil and benzodiazepines or neuroleptics may be indicated at the beginning of treatment. It is known that compared to other tricyclic antidepressants, there are fewer fatal cases in Anafranil overdose. Psychiatric effects: At the beginning of Anafranil treatment, agitation increases in most patients with panic attacks. This paradoxical increase in agitation is more pronounced in the first days of therapy and usually subsides within two weeks. In individuals with schizophrenia, activation of psychosis is sometimes observed during treatment with tricyclic antidepressants. It is known that in individuals with bipolar affective disorder, manic or hypomanic states may occur during the depressive phase of treatment with tricyclic antidepressants. In such cases, it may be necessary to discontinue Anafranil or reduce the dose and prescribe antipsychotics. After the condition is managed, Anafranil treatment may be resumed at low doses if indicated. Other tricyclic antidepressants can provoke drug-induced psychoses in individuals predisposed to mental disorders and in the elderly, mainly at night. These disorders usually resolve within a few days after discontinuation of the drug. Effect on the cardiovascular system: Anafranil should be used with particular caution in individuals with cardiovascular diseases, primarily those with heart failure, conduction disturbances (e.g., atrioventricular block of I-III degree), or arrhythmias. In such patients, as well as in the elderly, regular monitoring of cardiovascular system function and ECG is necessary. At high therapeutic doses or therapeutic concentrations of clomipramine, as well as with concomitant administration with selective serotonin reuptake inhibitors or serotonin-norepinephrine reuptake inhibitors, there is a risk of QT interval prolongation. Therefore, concomitant administration of drugs that can cause clomipramine accumulation is not allowed. Also, concomitant administration of drugs that can prolong the QT interval is not recommended. The basis for these events is hypokalemia. Therefore, before administering Anafranil concomitantly with serotonin inhibitors, serotonin-norepinephrine inhibitors, or diuretics, it is necessary to determine potassium levels in the blood and correct any deficiency. It is recommended to measure blood pressure before starting Anafranil therapy, as a sharp drop in blood pressure may occur in individuals with orthostatic hypotension or labile vascular system. Serotonin syndrome: If other serotonergic drugs are administered concomitantly, due to the risk of developing serotonergic toxicity, it is recommended to use recommended doses and increase the dose cautiously. Serotonin syndrome, characterized by signs such as hyperpyrexia, myoclonus, agitation, seizures, delirium, and coma, can develop if clomipramine is administered concomitantly with selective serotonin reuptake inhibitors, or serotonin-norepinephrine reuptake inhibitors, tricyclic antidepressants, or lithium preparations. The washout period for fluoxetine is 2-3 weeks. This period should be observed before starting or after treatment with fluoxetine. Seizures: Tricyclic antidepressants are known to lower the seizure threshold, so Anafranil should be used with caution in individuals with epilepsy, as well as in the presence of other factors predisposing to seizure disorders, such as brain damage of any etiology, concomitant use of neuroleptics, alcohol withdrawal, and withdrawal of anticonvulsant drugs (e.g., benzodiazepines). It is believed that the occurrence of seizures during Anafranil use depends on the dose of the drug. Therefore, exceeding the daily dose of Anafranil is not recommended. Anticholinergic action: Since the drug has anticholinergic effects, it should be used with caution in patients with a history of increased intraocular pressure, narrow-angle glaucoma, and urinary retention (e.g., due to prostate disease). Due to the anticholinergic effects characteristic of tricyclic antidepressants, tear secretion may decrease, which can lead to damage to the corneal epithelium in individuals wearing contact lenses. Special patient groups: Caution should be exercised when treating patients with severe liver diseases, as well as with tumors of the adrenal medulla (e.g., pheochromocytoma, neuroblastoma), as these drugs may provoke hypertensive crisis. Caution should be exercised when treating patients with hyperthyroidism or using thyroid hormone preparations; there is a risk of cardiotoxic effects. Periodic monitoring of liver enzyme activity is recommended for patients with liver diseases. Anafranil should be used with caution in individuals with chronic constipation. Tricyclic antidepressants can cause paralytic intestinal obstruction, mainly in the elderly or when bed rest is observed. Cases of dental caries have been reported with long-term treatment with tricyclic antidepressants. Therefore, regular dental visits are recommended during long-term Anafranil therapy. Hypersensitivity reactions: There are reports of isolated cases of anaphylactic shock. Therefore, special caution is required during intravenous administration of Anafranil. Blood test changes: Although only isolated cases of changes in leukocyte count have been reported during Anafranil treatment, periodic examination of peripheral blood count is recommended, and attention should be paid to symptoms such as fever and sore throat, especially during the first few months of therapy or during prolonged use of the drug. Anesthesia: Before general or local anesthesia, the anesthesiologist should be informed that the patient is taking Anafranil. Other effects: In some patients taking neuroleptics along with Anafranil, hyperthermia and neuroleptic malignant syndrome have been observed. Drug withdrawal: Abrupt withdrawal of Anafranil may lead to adverse reactions. Lactose and sucrose content: Anafranil is not recommended for patients with galactose and fructose intolerance or severe lactase deficiency. Effect on ability to drive and operate machinery During the use of Anafranil, patients are warned that decreased visual acuity, drowsiness, and other CNS disorders may occur. In such cases, it is necessary to refrain from driving vehicles, operating machinery, and other activities that require increased attention and rapid reaction. Overdose In case of Anafranil overdose, especially in children, the patient should be hospitalized and kept under observation for at least 72 hours. If the patient is conscious, gastric lavage or induction of vomiting should be performed as soon as possible. If the patient is unconscious, tracheal intubation with a cuffed tube should be performed before gastric lavage to prevent aspiration; vomiting should not be induced in this case. These measures are recommended if more than 12 hours have passed since the overdose, as the anticholinergic effect of Anafranil can slow gastric emptying. Activated charcoal may be useful to slow down drug absorption. Treatment is based on modern intensive care methods with constant monitoring of cardiac function, blood gas levels, and electrolyte balance, as well as emergency measures if necessary, such as anticonvulsant therapy, artificial lung ventilation, and resuscitation methods. Since reports have emerged that physostigmine can cause severe bradycardia, asystole, and seizures, its use for treating Anafranil overdose is not recommended. Hemodialysis and peritoneal dialysis are not effective, as clomipramine concentrations in blood plasma are not high. Drug interactions Pharmacodynamic effects Concomitant administration of CYP2C19, CYP1A2, and CYP3A4 inhibitors may lead to increased clomipramine concentration and decreased N-desmethylclomipramine. - MAO inhibitors similar to moclobemide, which also potentiate CYP2D6 inhibitors in vivo, are not prescribed with clomipramine. - Antiarrhythmic drugs (such as quinidine and propafenone), which potentiate CYP2D6 inhibitors, are not used in combination with tricyclic antidepressants. - Selective serotonin reuptake inhibitors, which are CYP2D6 inhibitors, such as fluoxetine, paroxetine, or sertraline, and others, including CYP1A2 and CYP2C19 (e.g., fluvoxamine), may also increase clomipramine plasma concentrations, with corresponding adverse effects. With concomitant administration of fluvoxamine, clomipramine plasma levels increase 4-fold (N-desmethylclomipramine decreases 2-fold). - Concomitant treatment with neuroleptics (e.g., phenothiazines) may lead to increased plasma levels of tricyclic antidepressants, lowering the threshold for seizures and convulsions. Combination with thioridazine may lead to severe cardiac arrhythmias. - Use with terbinafine may lead to increased exposure to clomipramine and its metabolites. Therefore, the dose of Anafranil should be adjusted in case of concomitant administration. - Concomitant use with (H2)-receptor histamine antagonists, cimetidine (an inhibitor of several P450 enzymes, including CYP2D6 and CYP3A4), may increase plasma concentrations of tricyclic antidepressants, and therefore, their dose should be reduced. - The interaction between concomitant use of oral contraceptives (15 or 30mg ethinylestradiol daily) and Anafranil (25mg daily) has not been studied. Estrogens are not known to be inhibitors of CYP2D6 (the main enzyme involved in clomipramine clearance), and therefore, interaction is not expected. However, in some cases, with high doses of estrogen (50mg daily) and the tricyclic antidepressant imipramine, increased side effects and therapeutic responses were observed, but the connection of these cases with reduced doses of clomipramine and estrogen has not been established. It is recommended to monitor the therapeutic response to tricyclic antidepressants at high estrogen doses (50mg daily), and therefore, dose adjustment may be necessary. - Methylphenidate (e.g., Ritalin) may increase the concentration of tricyclic antidepressants by potentiating the inhibition of their metabolism, and it may be necessary to reduce the dose of tricyclic antidepressants. - Some tricyclic antidepressants can potentiate the anticoagulant effect of coumarins, such as warfarin, possibly by inhibiting their metabolism (CYP2C9). Evidence of clomipramine inhibiting the metabolism of anticoagulants, such as warfarin, has not been provided, however, monitoring of prothrombin in plasma is recommended for drugs in this class. - Concomitant administration of Anafranil with enzymes that induce cytochrome P450 (CYP3A4, CYP2C19, and/or CYP1A2) may lead to reduced efficacy of Anafranil and accelerated metabolism. - CYP3A and CYP2C inducers, such as rifampicin or anticonvulsants (e.g., barbiturates, carbamazepine, phenobarbital, and phenytoin), may reduce clomipramine concentrations. - Known inducers of CYP1A2 (e.g., nicotine/components of tobacco smoke) reduce plasma concentrations of tricyclic drugs. In smokers, clomipramine plasma concentration is 2 times lower than in non-smokers (no changes are observed for N-desmethylclomipramine). - Clomipramine inhibits CYP2D6 activity in vitro (Ki= 2.2μM) and in vivo (oxidation of sparteine), and therefore, may lead to increased concentrations of drugs administered concomitantly with it. Interactions with other drugs: Antiadrenergic drugs that act on sympathetic neuronal transmission. Anafranil may reduce or completely suppress the antihypertensive effect of guanethidine, betanidine, reserpine, clonidine, and alphamethyldopa. Therefore, in cases where hypertension treatment is required during Anafranil use, other types of medications (e.g., vasodilators or beta-blockers) should be used. Anticholinergic agents. Tricyclic antidepressants may enhance the anticholinergic effects of certain agents (e.g., phenothiazines, antiparkinsonian, antihistamine drugs, atropine, biperiden) on the eyes, CNS, gastrointestinal tract, and bladder. CNS depressants. Tricyclic antidepressants may enhance the effects of alcohol and other CNS depressants (e.g., barbiturates, benzodiazepines, or anesthetics). Diuretics may cause hypokalemia, which in turn increases the risk of QT interval prolongation. Hypokalemia should be treated before Anafranil administration. MAO inhibitors. Anafranil should not be administered for at least 2 weeks after discontinuation of MAO inhibitors (there is a risk of developing severe symptoms such as hypertensive crisis, hyperpyrexia, and serotonin syndrome combined with, for example, myoclonus, generalized seizures, delirium, and coma). The same rule should be followed when administering MAO inhibitors after Anafranil treatment. In any case, the initial dose of Anafranil or MAO inhibitors should be low, and the dose should be increased gradually, with constant monitoring of the drug's effect. Existing experience shows that Anafranil can be administered at least 24 hours after discontinuation of a reversible MAO-A inhibitor (e.g., moclobemide). However, if such a drug is administered after discontinuation of Anafranil, the interval should be at least 2 weeks. Selective serotonin reuptake inhibitors. Concomitant use of Anafranil with these agents may lead to enhanced effects on the serotonin system. Serotonergic agents. Serotonin syndrome may occur with the concomitant administration of clomipramine and serotonergic drugs such as selective serotonin reuptake inhibitors (SSRIs) and serotonin and norepinephrine reuptake inhibitors (SNaRIs), tricyclic antidepressants, or lithium. The washout period for fluoxetine is 2-3 weeks; this period should be observed before and after treatment with fluoxetine. Sympathomimetic agents. Anafranil may enhance the cardiovascular effects of adrenaline, noradrenaline, isoprenaline, ephedrine, and phenylephrine (even when these substances are included in local anesthetics). Anafranil storage conditions and expiry dates Store Anafranil out of reach of children. At room temperature. Protect from moisture. Expiry date 5 years Do not use Anafranil after the expiry date indicated on the packaging < EXP >. Anafranil dispensing rule Pharmaceutical product group II (prescription only).
- Active
- clomipramine
What is it?
Anafranil's pharmacological properties Anafranil's pharmacodynamics Anafranil's therapeutic effect is believed to be mediated by its ability to inhibit the neuronal reuptake of noradrenaline and serotonin (5-HT), with the inhibition of serotonin reuptake being the most significant. Additionally, Anafranil exhibits a broader spectrum of pharmacological actions: alpha1-adrenolytic, anticholinergic, antihistamine, and antiserotonergic (blockade of 5-HT receptors). Anafranil acts on depressive syndromes, particularly on typical manifestations such as psychomotor retardation, depressed mood, and anxiety. The clinical effect usually appears after 2-3 weeks of treatment. Anafranil also has a specific effect on obsessive-compulsive disorder, which differs from its antidepressant effect. In chronic pain syndrome, whether or not caused by somatic disease, Anafranil's action is related to the improvement of nerve impulse transmission mediated by serotonin and noradrenaline. Anafranil's pharmacokinetics Anafranil absorption Clomipramine is completely absorbed from the gastrointestinal tract. Systemic bioavailability is approximately 50% and is associated with pronounced first-pass metabolism in the liver, leading to the formation of the active metabolite, N-desmethylclomipramine. Food intake does not significantly affect the bioavailability of clomipramine. A delay in absorption may occur, and consequently, the time to reach maximum plasma concentration may increase. In different patients, the steady-state plasma concentration of clomipramine after repeated oral administration of a constant dose varies significantly. With daily administration of 75mg/day, its steady-state concentration in serum ranges from 20 to 175mg/ml. The steady-state concentration of the active metabolite N-desmethylclomipramine is in a similar range. However, when 75mg of Anafranil is administered daily, this value is 40-85% higher compared to the concentration of clomipramine. Anafranil distribution Clomipramine binding to plasma proteins is 97.6%. The apparent volume of distribution is approximately 12-17 L/kg of body weight. The concentration of clomipramine in cerebrospinal fluid is about 2% of its level in plasma. Clomipramine passes into breast milk. The concentration is similar to the plasma concentration. Anafranil metabolism The main metabolic pathway of clomipramine is demethylation, leading to the formation of the active metabolite N-desmethylclomipramine. N-desmethylclomipramine can be formed by several P450 enzymes, mainly CYP3A4, CYP2C19, and CYP1A2. Clomipramine and N-desmethylclomipramine are hydroxylated to form 8-hydroxyclomipramine and 8-hydroxy-N-desmethylclomipramine. The activity of 8-hydroxymetabolites in vivo has not been determined. Clomipramine is also hydroxylated at position 2, and N-desmethylclomipramine can subsequently be demethylated to form didesmethylclomipramine. 2- and 8-hydroxymetabolites are excreted in urine as glucuronides. The elimination of the active components, clomipramine and N-desmethylclomipramine, by forming 2- and 8-hydroxyclomipramine, is catalyzed by CYP2D6. Anafranil elimination from blood The half-life of clomipramine is on average 21 hours (range 12-36 hours), and that of desmethylclomipramine is on average 36 hours. Approximately 2/3 of a single dose of clomipramine is excreted in urine as water-soluble conjugates, and approximately 1/3 of the dose is excreted in feces. Approximately 2% of the administered dose of clomipramine and approximately 0.5% of desmethylclomipramine are excreted unchanged in urine. Pharmacokinetics in specific patient groups In elderly individuals, compared to younger individuals, the concentration of clomipramine in serum is higher due to reduced intensity of clomipramine metabolism, regardless of the dose of Anafranil used. The effect of impaired kidney and liver function on clomipramine pharmacokinetics has not been studied. Anafranil indications Adults: Treatment of depressive states of various etiologies with various symptomatology: - Endogenous, reactive, neurotic, organic, masked, involutional forms of depression; - Depression in individuals with schizophrenia and psychopathy; - Depressive syndromes in the elderly; Depressive states caused by chronic pain syndrome or chronic somatic diseases; Depressive disorders of reactive, neurotic, or psychopathic nature; - Obsessive-compulsive syndromes; - Phobias and panic disorders (attacks); - Accompanying catalepsy associated with narcolepsy; - Chronic pain syndrome (idiopathic and neuropathic pain syndromes, specific pain syndrome in cancer). Children: - Obsessive-compulsive syndromes; - Nocturnal enuresis (only in patients over 6 years of age and after excluding organic causes of the disease). The use of Anafranil in children for depressive states of various etiologies (phobias, panic disorders, catalepsy associated with narcolepsy, chronic pain syndrome) has not yet been fully studied, therefore Anafranil is not used for these symptoms in children. Anafranil administration rules and dosages Adults: The dose of the drug is selected individually, taking into account the patient's condition. The goal of treatment is to achieve optimal effect with the lowest possible dose of the drug, as well as careful dose increase, especially in the elderly and adolescents who are more sensitive to Anafranil compared to patients in the intermediate age group. To prevent QT interval prolongation and serotonergic toxicity, it is recommended to prescribe Anafranil at recommended doses, and in case of need for high doses, special caution is required, especially if the patient is taking other drugs that prolong the QT interval. Depression, obsessive-compulsive syndrome, and phobias Treatment is initiated by administering 1 tablet containing 25mg clomipramine, 2-3 times a day. Then, during the first week of treatment, the dose of the drug is gradually increased, for example, by 25mg every few days (depending on tolerance), until a daily dose of 4-6 tablets of 25mg is reached. In severe cases, the daily dose can be increased to a maximum dose of 250mg. After significant improvement is achieved, a maintenance dose of 2-4 tablets of 25mg is selected. Panic disorders, agoraphobia Treatment is initiated with a dose of 10mg clomipramine per day, possibly in combination with benzodiazepine drugs. Then, depending on the patient's tolerance, the dose is increased until the desired effect is achieved; after that, benzodiazepine drugs are gradually withdrawn. The daily dose for different patients varies significantly in the range of 25-100mg. If necessary, it can be increased to 150mg. It is recommended to continue treatment for at least 6 months, during which the maintenance dose of the drug is gradually reduced. Catalepsy associated with narcolepsy, daily dose is 25-75mg. Chronic pain syndrome Dose is selected individually (10-150mg per day), taking into account the concomitant use of analgesics (and the possibility of reducing their use). Elderly individuals Treatment is initiated with a dose of 10mg per day. Then, the daily dose is increased to an optimal level of 30-50mg, and maintained at this level until the end of treatment. Anafranil - children and adolescents Obsessive-compulsive syndrome: Initial dose - 25mg per day, increased according to an individual schedule to 3mg/kg or 100mg during the first 2 weeks. The dose can be increased over the next few weeks to 3mg/kg or 200mg. Nocturnal enuresis In children aged 6-8 years, the initial dose is 20-30mg; in children aged 9-12 years - 1-2 tablets of 25mg; in older children - 1-3 tablets of 25mg. Higher doses are indicated if there is no clinical effect after 1 week. Usually, the entire daily dose of the drug is administered once after dinner, but if involuntary urination occurs in the first half of the night, a portion of the dose is administered earlier (at 4 PM). Once the desired effect is achieved, treatment should be continued for 1-3 months, with gradual dose reduction. There is no experience with the use of Anafranil in children under 6 years of age. There is no confirmed information on the use of this drug for depressive states of various etiologies (phobias, panic attacks, narcolepsy with catalepsy, chronic pain syndrome). Therefore, the use of Anafranil in children under 6 years of age is not recommended. Anafranil side effects Observed adverse events are usually mild and transient and resolve with continued treatment or dose reduction of Anafranil. The occurrence of side effects is not always related to the level of the active substance in the plasma or its dose. Often, it is difficult to distinguish between manifestations of depression and adverse events such as general weakness, sleep disturbances, anxiety, constipation, dry mouth. In case of development of a serious side effect on the nervous system or mental status, the use of Anafranil is discontinued. Elderly individuals are particularly sensitive to changes in the nervous system, cardiovascular system, mental sphere, as well as to the anticholinergic effects of Anafranil. In the elderly, metabolism and elimination of the drug may be slowed down, which, even with average therapeutic doses, leads to an increase in drug concentration in plasma. The frequency of adverse reactions was evaluated as follows: "very common" - ≥10%, "common" - ≥1% to ≤10%, "uncommon" - ≥0.1% to ≤1%, "rare" - ≥0.01% to ≤0.1%, "very rare" - <0.01%. Psychiatric disorders: very common - drowsiness, general weakness, agitation, increased appetite; very common - confusion, disorientation, hallucinations (especially in the elderly and those with Parkinson's disease), agitation, excitability, sleep disturbances, manic states, aggression, memory impairment, depersonalization, worsening of depression, impaired concentration, insomnia, nightmares, yawning; sometimes activation of psychotic symptoms. Neurological disorders: very common - dizziness, tremor, headache, myoclonus; common - delirium, speech disorders, paresthesia, muscle weakness, increased muscle tone; uncommon - seizures, ataxia; very rare - changes in electroencephalogram, hyperpyrexia. Anticholinergic effects: very common - dry mouth, sweating, constipation, accommodation disorders, decreased visual acuity, urinary retention; common - hot flashes, mydriasis, very rare - glaucoma, urinary retention. Cardiovascular system: common - sinus tachycardia, palpitations, orthostatic hypotension, clinically insignificant ECG changes (e.g., ST segment or T wave) in patients without heart disease; uncommon - arrhythmia, increased blood pressure; very rare - conduction disturbances (e.g., QRS complex widening, QT interval prolongation, PQ interval changes, bundle branch block, torsades de pointes, especially in hypokalemic individuals). Gastrointestinal tract: very rare - nausea, common - vomiting, abdominal discomfort, diarrhea, anorexia. Hepatobiliary system: common - increased transaminases; very rare - hepatitis with or without jaundice. Dermatological reactions: common - allergic reactions (rash, urticaria), photosensitivity, itching; very rare - edema (local or generalized), hair loss. Urinary system: very common - urinary retention, very rare - urinary retention, fluid retention. Endocrine system and metabolism: very common - weight gain, libido and potency disorders; common - galactorrhea, breast enlargement; very rare - syndrome of inappropriate secretion of antidiuretic hormone. Immune system: very common - allergic alveolitis (pneumonitis) with or without eosinophilia, systemic anaphylactic/anaphylactoid reactions, including hypotension. Hematopoietic system: very rare - leukopenia, agranulocytosis, thrombocytopenia, eosinophilia, purpura. Sensory organs: common - taste disturbances, tinnitus. Anafranil - other Sudden withdrawal or rapid dose reduction of Anafranil may cause symptoms such as nausea, vomiting, abdominal pain, diarrhea, insomnia, headache, irritability, anxiety. Overdose: Symptoms and complaints of overdose after oral administration of Anafranil are similar to those of overdose caused by other antidepressants. The main complications are cardiac and neurological disorders. Accidental ingestion of the drug by children, regardless of the dose used, is considered a serious event that can be fatal. Complaints and symptoms Symptoms usually appear within 4 hours of drug intake and reach maximum severity after 24 hours. Due to delayed absorption (anticholinergic effect of the drug), partially prolonged elimination half-life, and enterohepatic recirculation of the active substance, the period of "danger zone" for the patient is 4-6 days. The following complaints and symptoms may occur: Central nervous system: drowsiness, stupor, coma, ataxia, agitation, excitability, exaggerated reflexes, muscle rigidity, choreoathetoid movements, seizures. In addition, symptoms related to serotonin syndrome may occur (e.g., hyperpyrexia, myoclonus, delirium, and coma). Cardiovascular system: hypotension, tachycardia, arrhythmia, prolonged QTc interval and arrhythmia with torsades de pointes, conduction disturbances, shock, heart failure; in very rare cases - cardiac arrest. In addition, respiratory depression, cyanosis, vomiting, fever, mydriasis, sweating, oliguria or anuria may occur. Treatment There is no specific antidote; treatment is mainly symptomatic and supportive. Anafranil contraindications Hypersensitivity to clomipramine or any other ingredient of the drug, cross-hypersensitivity to tricyclic antidepressants of the dibenzazepine group. Concomitant administration of MAO inhibitors, as well as within 14 days before or after their use. Concomitant use of selective reversible MAO-A inhibitors such as moclobemide is also contraindicated. Recent myocardial infarction, congenital long QT syndrome. Anafranil is not indicated in the following situations: - Acute intoxication with CNS depressants (analgesics, psychotropic and hypnotic drugs, as well as alcohol); - Acute urinary retention; - Acute delirium; - Untreated narrow-angle glaucoma; - Prostatic hypertrophy with urinary retention; - Pyloric stenosis; paralytic intestinal obstruction. Pregnancy and lactation The use of Anafranil during pregnancy has not been fully studied. Anafranil is not used during pregnancy, as a possible link between the use of tricyclic antidepressants and fetal developmental abnormalities has been reported in isolated cases, except when the expected benefit of maternal treatment outweighs the potential risk to the fetus. In newborns whose mothers used tricyclic antidepressants during pregnancy and before delivery, a withdrawal syndrome was observed in the first few days or hours, characterized by dyspnea, drowsiness, colic, irritability, hypotension or hypertension, tremor, or spastic phenomena. To avoid such a syndrome, Anafranil should be gradually withdrawn at least 7 weeks before the expected delivery. Use in children: There is no experience with the use of Anafranil in children under 6 years of age. There is no confirmed information on the use of this drug for depressive states of various etiologies (phobias, panic attacks, narcolepsy with catalepsy, chronic pain syndrome). Therefore, the use of Anafranil in children under 6 years of age is not recommended. Special instructions Peculiarities of use: Suicide risk: Suicidal behavior is a risk characteristic of severe depression and may persist until remission is achieved. In this regard, a combination of Anafranil and benzodiazepines or neuroleptics may be indicated at the beginning of treatment. It is known that compared to other tricyclic antidepressants, there are fewer fatal cases in Anafranil overdose. Psychiatric effects: At the beginning of Anafranil treatment, agitation increases in most patients with panic attacks. This paradoxical increase in agitation is more pronounced in the first days of therapy and usually subsides within two weeks. In individuals with schizophrenia, activation of psychosis is sometimes observed during treatment with tricyclic antidepressants. It is known that in individuals with bipolar affective disorder, manic or hypomanic states may occur during the depressive phase of treatment with tricyclic antidepressants. In such cases, it may be necessary to discontinue Anafranil or reduce the dose and prescribe antipsychotics. After the condition is managed, Anafranil treatment may be resumed at low doses if indicated. Other tricyclic antidepressants can provoke drug-induced psychoses in individuals predisposed to mental disorders and in the elderly, mainly at night. These disorders usually resolve within a few days after discontinuation of the drug. Effect on the cardiovascular system: Anafranil should be used with particular caution in individuals with cardiovascular diseases, primarily those with heart failure, conduction disturbances (e.g., atrioventricular block of I-III degree), or arrhythmias. In such patients, as well as in the elderly, regular monitoring of cardiovascular system function and ECG is necessary. At high therapeutic doses or therapeutic concentrations of clomipramine, as well as with concomitant administration with selective serotonin reuptake inhibitors or serotonin-norepinephrine reuptake inhibitors, there is a risk of QT interval prolongation. Therefore, concomitant administration of drugs that can cause clomipramine accumulation is not allowed. Also, concomitant administration of drugs that can prolong the QT interval is not recommended. The basis for these events is hypokalemia. Therefore, before administering Anafranil concomitantly with serotonin inhibitors, serotonin-norepinephrine inhibitors, or diuretics, it is necessary to determine potassium levels in the blood and correct any deficiency. It is recommended to measure blood pressure before starting Anafranil therapy, as a sharp drop in blood pressure may occur in individuals with orthostatic hypotension or labile vascular system. Serotonin syndrome: If other serotonergic drugs are administered concomitantly, due to the risk of developing serotonergic toxicity, it is recommended to use recommended doses and increase the dose cautiously. Serotonin syndrome, characterized by signs such as hyperpyrexia, myoclonus, agitation, seizures, delirium, and coma, can develop if clomipramine is administered concomitantly with selective serotonin reuptake inhibitors, or serotonin-norepinephrine reuptake inhibitors, tricyclic antidepressants, or lithium preparations. The washout period for fluoxetine is 2-3 weeks. This period should be observed before starting or after treatment with fluoxetine. Seizures: Tricyclic antidepressants are known to lower the seizure threshold, so Anafranil should be used with caution in individuals with epilepsy, as well as in the presence of other factors predisposing to seizure disorders, such as brain damage of any etiology, concomitant use of neuroleptics, alcohol withdrawal, and withdrawal of anticonvulsant drugs (e.g., benzodiazepines). It is believed that the occurrence of seizures during Anafranil use depends on the dose of the drug. Therefore, exceeding the daily dose of Anafranil is not recommended. Anticholinergic action: Since the drug has anticholinergic effects, it should be used with caution in patients with a history of increased intraocular pressure, narrow-angle glaucoma, and urinary retention (e.g., due to prostate disease). Due to the anticholinergic effects characteristic of tricyclic antidepressants, tear secretion may decrease, which can lead to damage to the corneal epithelium in individuals wearing contact lenses. Special patient groups: Caution should be exercised when treating patients with severe liver diseases, as well as with tumors of the adrenal medulla (e.g., pheochromocytoma, neuroblastoma), as these drugs may provoke hypertensive crisis. Caution should be exercised when treating patients with hyperthyroidism or using thyroid hormone preparations; there is a risk of cardiotoxic effects. Periodic monitoring of liver enzyme activity is recommended for patients with liver diseases. Anafranil should be used with caution in individuals with chronic constipation. Tricyclic antidepressants can cause paralytic intestinal obstruction, mainly in the elderly or when bed rest is observed. Cases of dental caries have been reported with long-term treatment with tricyclic antidepressants. Therefore, regular dental visits are recommended during long-term Anafranil therapy. Hypersensitivity reactions: There are reports of isolated cases of anaphylactic shock. Therefore, special caution is required during intravenous administration of Anafranil. Blood test changes: Although only isolated cases of changes in leukocyte count have been reported during Anafranil treatment, periodic examination of peripheral blood count is recommended, and attention should be paid to symptoms such as fever and sore throat, especially during the first few months of therapy or during prolonged use of the drug. Anesthesia: Before general or local anesthesia, the anesthesiologist should be informed that the patient is taking Anafranil. Other effects: In some patients taking neuroleptics along with Anafranil, hyperthermia and neuroleptic malignant syndrome have been observed. Drug withdrawal: Abrupt withdrawal of Anafranil may lead to adverse reactions. Lactose and sucrose content: Anafranil is not recommended for patients with galactose and fructose intolerance or severe lactase deficiency. Effect on ability to drive and operate machinery During the use of Anafranil, patients are warned that decreased visual acuity, drowsiness, and other CNS disorders may occur. In such cases, it is necessary to refrain from driving vehicles, operating machinery, and other activities that require increased attention and rapid reaction. Overdose In case of Anafranil overdose, especially in children, the patient should be hospitalized and kept under observation for at least 72 hours. If the patient is conscious, gastric lavage or induction of vomiting should be performed as soon as possible. If the patient is unconscious, tracheal intubation with a cuffed tube should be performed before gastric lavage to prevent aspiration; vomiting should not be induced in this case. These measures are recommended if more than 12 hours have passed since the overdose, as the anticholinergic effect of Anafranil can slow gastric emptying. Activated charcoal may be useful to slow down drug absorption. Treatment is based on modern intensive care methods with constant monitoring of cardiac function, blood gas levels, and electrolyte balance, as well as emergency measures if necessary, such as anticonvulsant therapy, artificial lung ventilation, and resuscitation methods. Since reports have emerged that physostigmine can cause severe bradycardia, asystole, and seizures, its use for treating Anafranil overdose is not recommended. Hemodialysis and peritoneal dialysis are not effective, as clomipramine concentrations in blood plasma are not high. Drug interactions Pharmacodynamic effects Concomitant administration of CYP2C19, CYP1A2, and CYP3A4 inhibitors may lead to increased clomipramine concentration and decreased N-desmethylclomipramine. - MAO inhibitors similar to moclobemide, which also potentiate CYP2D6 inhibitors in vivo, are not prescribed with clomipramine. - Antiarrhythmic drugs (such as quinidine and propafenone), which potentiate CYP2D6 inhibitors, are not used in combination with tricyclic antidepressants. - Selective serotonin reuptake inhibitors, which are CYP2D6 inhibitors, such as fluoxetine, paroxetine, or sertraline, and others, including CYP1A2 and CYP2C19 (e.g., fluvoxamine), may also increase clomipramine plasma concentrations, with corresponding adverse effects. With concomitant administration of fluvoxamine, clomipramine plasma levels increase 4-fold (N-desmethylclomipramine decreases 2-fold). - Concomitant treatment with neuroleptics (e.g., phenothiazines) may lead to increased plasma levels of tricyclic antidepressants, lowering the threshold for seizures and convulsions. Combination with thioridazine may lead to severe cardiac arrhythmias. - Use with terbinafine may lead to increased exposure to clomipramine and its metabolites. Therefore, the dose of Anafranil should be adjusted in case of concomitant administration. - Concomitant use with (H2)-receptor histamine antagonists, cimetidine (an inhibitor of several P450 enzymes, including CYP2D6 and CYP3A4), may increase plasma concentrations of tricyclic antidepressants, and therefore, their dose should be reduced. - The interaction between concomitant use of oral contraceptives (15 or 30mg ethinylestradiol daily) and Anafranil (25mg daily) has not been studied. Estrogens are not known to be inhibitors of CYP2D6 (the main enzyme involved in clomipramine clearance), and therefore, interaction is not expected. However, in some cases, with high doses of estrogen (50mg daily) and the tricyclic antidepressant imipramine, increased side effects and therapeutic responses were observed, but the connection of these cases with reduced doses of clomipramine and estrogen has not been established. It is recommended to monitor the therapeutic response to tricyclic antidepressants at high estrogen doses (50mg daily), and therefore, dose adjustment may be necessary. - Methylphenidate (e.g., Ritalin) may increase the concentration of tricyclic antidepressants by potentiating the inhibition of their metabolism, and it may be necessary to reduce the dose of tricyclic antidepressants. - Some tricyclic antidepressants can potentiate the anticoagulant effect of coumarins, such as warfarin, possibly by inhibiting their metabolism (CYP2C9). Evidence of clomipramine inhibiting the metabolism of anticoagulants, such as warfarin, has not been provided, however, monitoring of prothrombin in plasma is recommended for drugs in this class. - Concomitant administration of Anafranil with enzymes that induce cytochrome P450 (CYP3A4, CYP2C19, and/or CYP1A2) may lead to reduced efficacy of Anafranil and accelerated metabolism. - CYP3A and CYP2C inducers, such as rifampicin or anticonvulsants (e.g., barbiturates, carbamazepine, phenobarbital, and phenytoin), may reduce clomipramine concentrations. - Known inducers of CYP1A2 (e.g., nicotine/components of tobacco smoke) reduce plasma concentrations of tricyclic drugs. In smokers, clomipramine plasma concentration is 2 times lower than in non-smokers (no changes are observed for N-desmethylclomipramine). - Clomipramine inhibits CYP2D6 activity in vitro (Ki= 2.2μM) and in vivo (oxidation of sparteine), and therefore, may lead to increased concentrations of drugs administered concomitantly with it. Interactions with other drugs: Antiadrenergic drugs that act on sympathetic neuronal transmission. Anafranil may reduce or completely suppress the antihypertensive effect of guanethidine, betanidine, reserpine, clonidine, and alphamethyldopa. Therefore, in cases where hypertension treatment is required during Anafranil use, other types of medications (e.g., vasodilators or beta-blockers) should be used. Anticholinergic agents. Tricyclic antidepressants may enhance the anticholinergic effects of certain agents (e.g., phenothiazines, antiparkinsonian, antihistamine drugs, atropine, biperiden) on the eyes, CNS, gastrointestinal tract, and bladder. CNS depressants. Tricyclic antidepressants may enhance the effects of alcohol and other CNS depressants (e.g., barbiturates, benzodiazepines, or anesthetics). Diuretics may cause hypokalemia, which in turn increases the risk of QT interval prolongation. Hypokalemia should be treated before Anafranil administration. MAO inhibitors. Anafranil should not be administered for at least 2 weeks after discontinuation of MAO inhibitors (there is a risk of developing severe symptoms such as hypertensive crisis, hyperpyrexia, and serotonin syndrome combined with, for example, myoclonus, generalized seizures, delirium, and coma). The same rule should be followed when administering MAO inhibitors after Anafranil treatment. In any case, the initial dose of Anafranil or MAO inhibitors should be low, and the dose should be increased gradually, with constant monitoring of the drug's effect. Existing experience shows that Anafranil can be administered at least 24 hours after discontinuation of a reversible MAO-A inhibitor (e.g., moclobemide). However, if such a drug is administered after discontinuation of Anafranil, the interval should be at least 2 weeks. Selective serotonin reuptake inhibitors. Concomitant use of Anafranil with these agents may lead to enhanced effects on the serotonin system. Serotonergic agents. Serotonin syndrome may occur with the concomitant administration of clomipramine and serotonergic drugs such as selective serotonin reuptake inhibitors (SSRIs) and serotonin and norepinephrine reuptake inhibitors (SNaRIs), tricyclic antidepressants, or lithium. The washout period for fluoxetine is 2-3 weeks; this period should be observed before and after treatment with fluoxetine. Sympathomimetic agents. Anafranil may enhance the cardiovascular effects of adrenaline, noradrenaline, isoprenaline, ephedrine, and phenylephrine (even when these substances are included in local anesthetics). Anafranil storage conditions and expiry dates Store Anafranil out of reach of children. At room temperature. Protect from moisture. Expiry date 5 years Do not use Anafranil after the expiry date indicated on the packaging < EXP >. Anafranil dispensing rule Pharmaceutical product group II (prescription only).