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Active ingredients
Clomipramine
Release form
Pills
Composition
Clomipramine hydrochloride 25 mg
Pharmacological effect
Tricyclic antidepressant, norepinephrine and serotonin reuptake inhibitor. It is believed that the therapeutic effect of Anafranil is due to its ability to inhibit reverse neuronal uptake of norepinephrine (NA) and serotonin (5-HT), released into the synaptic cleft, the most important is the inhibition of serotonin reuptake. Anafranil, in addition, has a wide range of other pharmacological actions: alpha1-adrenolytic, anticholinergic, antihistamine and antiserotonergic (blockade of 5-HT receptors). Anafranil acts on the depressive syndrome in general, incl. especially its typical manifestations such as psychomotor inhibition, depressed mood and anxiety. The clinical effect is usually observed after 2-3 weeks of treatment. In addition, Anafranil has a specific (different from its anti-depressive effect) effect in obsessive-compulsive disorders. The action of Anafranil in chronic pain syndromes, both caused and not caused by somatic diseases, is probably connected with the relief of transmission of nerve impulses mediated by serotonin and noradrenaline.
Pharmacokinetics
Absorption: After oral administration, clomipramine is completely absorbed from the gastrointestinal tract. The systemic bioavailability of unchanged clomipramine is about 50%. This decrease in bioavailability is due to the effect of the first passage through the liver with the formation of the active metabolite N-desmethylclomipramine. Food intake does not significantly affect the bioavailability of clomipramine. Only a slight slowdown in its absorption and, consequently, an increase in the time it takes to reach Cmax in the blood plasma. Anafranil (coated pills) and Anafranil CP (long-acting coated pills) are bioequivalent. After taking the drug inside in a constant daily dose of Css clomipramine in the blood plasma varies greatly in different patients. With daily intake of the drug at a dose of 75 mg / day, Css clomipramine in plasma is set in the range from 20 to 175 ng / ml.The Css values of the active metabolite of N-desmethylclomipramine are 40–85% higher than the concentration of clomipramine. Distribution: The binding of clomipramine to plasma proteins is 97.6%. Apparent Vd is about 12-17 L / kg body weight. The concentration of clomipramine in the cerebrospinal fluid is about 2% of its plasma level. Clomipramine penetrates into breast milk, where it is determined in concentrations close to plasma concentrations. Metabolism: Clomipramine is metabolized mainly by demethylation to form the active metabolite N-desmethylclomipramine. Several cytochrome P450 isoenzymes are involved in this reaction, but mainly CYP3A4, CYP2C19 and CYP1A2. Clomipramine and N-desmethylclipramine are hydroxylated to 8-hydroxy-clipramine and 8-hydroxy-N-desmethyl-cyclomipramine. In vivo activity of 8-hydroxymetabolites is not determined. Clomipramine is also hydroxylated at position 2; N-desmethylclomipramine can be further demethylated to didesmethyl clomipramine. 2- and 8-hydroxy metabolites are excreted mainly in the form of glucuronides in the urine. The elimination of two active components, clomipramine and N-desmethylclomipramine by the formation of 2- and 8-hydroxyclomipramine, is catalyzed by CYP2D6. Excretion: About 2/3 of a single dose of clomipramine is excreted in the form of water-soluble conjugates with urine and approximately 1/3 of the dose with feces. In unchanged form, about 2% of the received dose of clomipramine and about 0.5% of desmethyl clomipramine are excreted in the urine. T1 / 2 of clomipramine plasma averages 21 hours (range of oscillations from 12 to 36 hours), and desmethyl clomipramine an average of 36 hours. Pharmacokinetics in special clinical situations In elderly patients, regardless of the dose of Anafranil, due to a decrease in metabolic rate plasma clomipramine concentrations are higher than in younger patients. Data on the effect of impaired liver and kidney function on the pharmacokinetic parameters of clomipramine have not yet been obtained.
Indications
Depression, obsessive-compulsive syndromes, phobias and obsessive fears, narcolepsy accompanied by catalepsy, chronic pain syndromes, nocturnal enuresis.
Contraindications
Hypersensitivity to clomipramine and other components of the drug,crosstalk. Increased sensitivity to tricyclic antidepressants from the dibenzazepine group. Simultaneous use of MAO inhibitors, as well as a period of less than 14 days before and after their use. Simultaneous use of selective MAO inhibitors of type A of reversible action (such as moclobemide). lengthening the interval. Do not recommend the use of the drug during pregnancy and during breastfeeding. The drug is not recommended for use in children under 5 years of age.
Precautionary measures
From the side of the central nervous system and peripheral nervous system. Mental status: very often - drowsiness, fatigue, anxiety, increased appetite, often - confusion, disorientation, hallucinations (especially in elderly patients and in patients with Parkinson's disease), anxiety, agitation, sleep disorders, mania, hypomania condition, aggressiveness, memory impairment, depersonalization, increased depression, concentration disorders, insomnia, nightmares, yawning, sometimes - activation of symptoms of psychosis. Neurological status: very often - dizziness, tremor, headache, myoclonus, often - delirium, speech disorders, paresthesia, muscle weakness, increased muscle tone, sometimes - convulsions, ataxia, very rarely - changes in EEG, fever. Effects caused by anticholinergic activity: very often - dry mouth, excessive sweating, constipation, accommodation disturbances, blurred vision (eye shade), urination disturbances, often tides, mydriasis, very rarely - glaucoma, urinary retention. Since the cardiovascular system: often - sinus tachycardia, palpitations, orthostatic hypotension, clinically insignificant changes on the ECG (for example, ST interval or T wave) in patients without heart disease, sometimes arrhythmias, increased blood pressure, very rarely - intracardiac conductivity (for example, expansion of the QRS complex, lengthening of the QT interval, changes in the PQ interval, blockade of the bundle of the His bundle, bidirectional spindle-shaped ventricular tachycardia / ventricular arrhythmias such as pirouette /), especially in patients with hypokalemia).On the part of the digestive system: very often - nausea, often - vomiting, abdominal discomfort, diarrhea, anorexia, increased transaminase levels, very rarely - hepatitis with jaundice or without it. Dermatological reactions: often - allergic skin reactions (rash, urticaria), photosensitivity, itching, very rarely - edema (local or general), hair loss. On the part of the endocrine system and metabolism: very often - an increase in body weight, disorders of libido and potency, often - galactorrhea, an increase in the mammary glands, very rarely - an syndrome of inappropriate secretion of antidiuretic hormone. Hypersensitivity reactions: very rarely, allergic alveolitis (pneumonitis) with or without eosinophilia, systemic anaphylactic / anaphylactoid reactions, including hypotension. On the part of the hemopoietic system: very rarely - leukopenia, agranulocytosis, eosinophilia, thrombocytopenia, purpura. On the part of the senses: often - a violation of taste, tinnitus.
Use during pregnancy and lactation
Experience with Anafranil during pregnancy is limited. Since there are individual reports of a possible connection between taking tricyclic antidepressants and fetal developmental disorders, use of Anafranil during pregnancy should be avoided, unless the expected effect of treatment on the mother undoubtedly exceeds the potential risk to the fetus. In cases where tricyclic antidepressants were used during pregnancy until childbirth, newborns developed withdrawal syndrome during the first few hours or days, manifested by shortness of breath, drowsiness, colic, irritability, arterial hypotension or hypertension, tremors, spastic phenomena or convulsions. To avoid the development of this syndrome, Anafranil should be phased out whenever possible, at least 7 weeks before the expected birth. Since the active ingredient of the drug is excreted in breast milk, you should either stop breastfeeding or gradually cancel Anafranil.
Dosage and administration
Doses of the drug are selected individually, taking into account the patient's condition. The goal of treatment is to achieve an optimal effect with the use of the lowest possible doses of the drug, as well as to carefully increase them, especially in elderly patients and adolescents who are generally more sensitive to Anafranil CP than patients in intermediate age groups. The initial daily dose is 75 mg (25 mg 2-3 p / day)
Side effects
Reactions due to anticholinergic effects (drowsiness, fatigue, tremor, myoclonus, increased appetite, dry mouth, urinary disturbances, visual disturbances, glaucoma), weight gain, inadequate response to external stimuli, hallucinations, agitation, transaminase level in the blood, gastrointestinal disorders, activation of symptoms of psychosis, convulsions, ataxia, arrhythmias, hypertension, cardiac conduction disturbances, hepatitis, changes in the number of blood cells, allergic alveolitis, anaphylactically / Anafilaktoidnyereaktsii, hyperpyrexia.
Overdose
Symptoms that develop with an overdose of Anafranil are similar to those described with an overdose of other tricyclic antidepressants. The main complications are abnormalities in the activity of the heart and neurological disorders. In children, accidental intake of the drug at any dose inside should be regarded as a very serious and potentially fatal event. Symptoms usually appear within 4 hours after taking the drug and reach maximum severity after 24 hours. Due to delayed absorption (anticholinergic effect of the drug), a long half-life and hepatoenteric recirculation of the active substance, 4-6 days. From the side of the central nervous system: drowsiness, stupor, coma, ataxia, anxiety, agitation, increased reflexes, muscle rigidity, choreoathetoid movements, convulsions. In addition, there may be manifestations of serotonin syndrome (fever, myoclonus, delirium, coma). On the part of the cardiovascular system: marked reduction in blood pressure, tachycardia, prolongation of the QTc interval, arrhythmias (including ventricular arrhythmias such as pirouette), intracardiac conduction disorders, shock, heart failure in very rare cases, cardiac arrest. Other: respiratory depression, cyanosis, vomiting, fever, mydriasis, sweating, oliguria or anuria are possible. Treatment: there is no specific antidote, the treatment is mainly symptomatic and supportive. If an overdose of Anafranil is suspected, especially in children, the patient should be hospitalized and carefully observed for at least 72 hours.If the patient is conscious, it is necessary to wash the stomach or induce vomiting as soon as possible. If the patient is unconscious, tracheal intubation should be performed with a tube with a cuff before starting gastric lavage to prevent aspiration; vomiting in this case do not cause. These activities are recommended in the event that 12 hours have passed since the overdose and even more, because The anticholinergic effect of Anafranil may slow gastric emptying. To slow the absorption of the drug is useful the use of activated carbon. Treatment is based on the use of modern intensive care methods with continuous monitoring of cardiac function, gas composition and blood electrolytes, as well as the use of such urgent measures as anticonvulsant therapy, mechanical ventilation and resuscitation methods. Since it has been reported that physostigmine can cause severe bradycardia, asystole, and seizures, it is not recommended to use this drug to treat an overdose of Anafranil. Hemodialysis and peritoneal dialysis are not effective, because Plasma clomipramine concentrations are low.
Interaction with other drugs
Pharmacodynamic interaction: Anafranil can reduce or completely eliminate the antihypertensive effect of guanethidine, betanidin, reserpine, clonidine and alpha methyldopa. Therefore, in cases where the treatment of arterial hypertension is required simultaneously with the administration of Anafranil, drugs of other classes (for example, vasodilators or beta-blockers) should be used. Tricyclic antidepressants, including Anafranil may potentiate the action of anticholinergics (for example, phenothiazines, antiparkinsonian drugs, atropine, biperidine, antihistamines) on the organ of vision, central nervous system, intestines and bladder. Tricyclic antidepressants can enhance the effects of ethanol and other drugs that have a depressant effect on the central nervous system (for example, barbiturates, benzodiazepines, or narcosis drugs). Anafranil should not be administered for at least 2 weeks after discontinuation of MAO inhibitors due to the risk of developing such severe symptoms and conditions as hypertensive crisis, fever, and symptoms of serotonin syndrome: myoclonus, agitation, convulsions, delirium and coma. The same rule should be followed if the MAO inhibitor is administered after prior treatment with Anafranil.In any of these cases, the initial dose of Anafranil or MAO inhibitors should be low, they should be increased gradually, under constant control of the effects of the drug. Existing experience shows that Anafranil can be administered no earlier than 24 hours after discontinuation of MAO inhibitors of type A of reversible action (such as moclobemide). But, if an inhibitor of MAO type A is prescribed after discontinuation of Anafranil, the duration of the break should be at least 2 weeks. The combined use of Anafranil with selective serotonin reuptake inhibitors can lead to an increased effect on the serotonin system. With simultaneous use of Anafranil with selective serotonin reuptake inhibitors or serotonin and noradrenaline reuptake inhibitors (norepinephrine), tricyclic antidepressants and lithium drugs, serotonin syndrome may develop with symptoms such as fever, myoclonus, agitation, seizures, and exercise, symptoms such as fever, myoclonus, agitation, seizures, myelo-nous, arousal, seizures, myeloidus, zyroxia, serotonin syndrome If you need to prescribe fluoxetine, it is recommended to take a two-three-week break between using Anafranil and fluoxetine - to end the use of fluoxetine 2-3 weeks before starting treatment with Anafranil, or to appoint fluoxetine 2-3 weeks after the end of treatment with Anafranil. Anafranil may enhance the effect on the cardiovascular system of sympathomimetic drugs (adrenaline, norepinephrine, isoprenaline, ephedrine and phenylephrine), incl. and when these substances form part of local anesthetics. Pharmacokinetic interaction: The active substance of the drug Anafranil - clomipramine is mainly excreted as metabolites. The main metabolic pathway is demethylation to the active metabolite of N-desmethylclomipramine, followed by hydroxylation and conjugation of N-desmethylclomipramine with clomipramine. Several isoenzymes of cytochrome P450, mainly CYP3A4, CYP2C19 and CYP1A2, are involved in demethylation. The elimination of both active components is carried out by hydroxylation, which is catalyzed by CYP2D6. Co-administration with inhibitors of the CYP2D6 isoenzyme can lead to an increase in the concentrations of both active components up to threefold in individuals with the phenotype of the rapid metabolizer of debrisoquine / sparteine.At the same time, in these patients the metabolism decreases to the level characteristic of persons with a weak metabolizing phenotype. It is assumed that co-administration with inhibitors of isoenzymes CYP1A2, CYP2C19 and CYP3A4 may lead to an increase in the concentration of clomipramine and a decrease in the concentration of N-dezmetilklomipramin. MAO inhibitors (for example, moclobemide) are contraindicated when taking clomipamine, because in vivo, they are potent inhibitors of CYP2D6. Antiarrhythmic drugs (such as quinidine and propafenone) should not be used in conjunction with tricyclic antidepressants, since they are strong inhibitors of CYP2D6. Selective serotonin reuptake inhibitors (such as fluoxetine, paroxetine or sertraline) inhibit CYP2D6, other drugs of this group (for example fluvoxamine) also inhibit CYP1A2, CYP2C19, which can lead to an increase in plasma clomipramine concentration and the development of corresponding undesirable effects. A 4-fold increase in the equilibrium concentration of clomipramine was observed when taken together with fluvoxamine (the concentration of N-desmethyl clomipramine decreased by 2 times). The combined use of neuroleptics (for example, phenothiazines) can lead to an increase in plasma concentrations of tricyclic antidepressants, a decrease in seizure threshold, and the appearance of convulsions. Combination with thioridazine can lead to the development of severe cardiac arrhythmias. Combined use of histamine H2 receptors with cimetidine (which is an inhibitor of some of the cytochrome P450 isoenzymes, including CYP2D6 and CYP3A4) with the blocker can lead to an increase in plasma concentrations of tricyclic antidepressants, therefore, a lower dose of the latter is required. There is no data confirming the interaction between Anafranil (at a dose of 25 mg / day) and oral contraceptives (15 or 30 mg of ethinyl estradiol / day) while constantly taking the latter. There is no evidence that estrogens are inhibitors of CYP2D6 - the main isoenzyme involved in the elimination of clomipramine, so there is no reason to expect their interaction. Although with the simultaneous use of tricyclic antidepressant imipramine and estrogen in high doses (50 mg / day) in some cases it was reported that the side effects were aggravated and the therapeutic effect of the antidepressant increased. It is not known whether this data is significant with respect to the simultaneous use of clomipramine and estrogen in low doses.With the combined use of tricyclic antidepressants and estrogens in high doses (50 mg / day), monitoring of the therapeutic action of antidepressants and, if necessary, correction of the dosage regimen is recommended. Methylphenidate may increase the concentration of tricyclic antidepressants, possibly by suppressing their metabolism. With the joint use of these drugs may increase the concentration of tricyclic antidepressants in the blood plasma, it may be necessary to reduce the dose of the latter. Some tricyclic antidepressants may enhance the anticoagulant action of coumarins (eg, warfarin), possibly by inhibiting their metabolism (CYP2C9). There is no data proving the ability of clomipramine to inhibit the metabolism of anticoagulants (warfarin). However, when using this class of drugs, monitoring plasma prothrombin concentration is recommended. The combined use of Anafranil with cytochrome P450 inducer drugs, especially CYP3A4, CYP2C19 and / or CYP1A2, can lead to an increase in metabolism and reduce the effectiveness of Anafranil. Combined use of Anafranil with CYP3A and CYP2C inducer drugs, such as rifampicin or anticonvulsant drugs (such as barbiturates, carbamazepine, phenobarbital, and phenytoin), can lead to a decrease in plasma clomipramine concentration. Known inducers of CYP1A2 (for example nicotine / other components of cigarette smoke) reduce the concentration of tricyclic antidepressants in the blood plasma. The equilibrium concentration of clomipramine in persons smoking cigarettes is 2 times lower than in non-smokers (the concentration of N-desmethyl clomipramine has not changed). Clomipramine, both in vivo and in vitro, inhibits the activity of CYP2D6 (oxidation of sparteine). Thus, clomipramine can increase the concentrations of concurrently used drugs, which are metabolized mainly with the participation of CYP2D6, in individuals with the phenotype of a strong metabolizer.
special instructions
It is known that tricyclic antidepressants reduce the threshold of convulsive readiness, therefore Anafranil should be used with extreme caution in patients with epilepsy, as well as in the presence of other factors predisposing to the onset of convulsive syndrome, such as brain damage of any etiology, while using neuroleptic drugs during the failure from alcohol or discontinuation of drugs with anticonvulsant properties (for example, benzodiazepines).It is believed that the occurrence of seizures while taking Anafranil depends on the dose of the drug. Therefore, one should not exceed the recommended daily dose of Anafranil. With special care, Anafranil should be prescribed to patients with cardiovascular diseases, especially with cardiovascular insufficiency, impaired intracardiac conduction (for example, AV-blockade I-III degree) or arrhythmias. In such patients, as well as in elderly patients, it is necessary to regularly monitor the performance of the heart and ECG. Before starting treatment with Anafranil, it is recommended to measure blood pressure, since patients with orthostatic hypotension or cardiovascular lability may experience a sharp decrease in blood pressure. Since 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 diseases). Due to the anticholinergic action characteristic of tricyclic antidepressants, it is possible to reduce tearing and accumulation of mucous secretions, which can lead to damage to the cornea epithelium in patients using contact lenses. Caution is needed in the treatment of tricyclic antidepressants in patients with severe liver diseases, as well as in patients with adrenal medulla tumors (for example, pheochromocytoma, neuroblastoma), since in this case these drugs can provoke the development of hypertensive crisis. It is known that patients with cyclic affective disorders who take tricyclic antidepressants may develop manic or hypomaniac states during the depressive phase. In such cases, it may be necessary to reduce the dose of Anafranil or to cancel it and to prescribe antipsychotic therapy. After stopping these conditions, if there are indications, treatment with low-dose Anafranil can be resumed. In predisposed and elderly patients, tricyclic antidepressants can provoke the development of delirious psychosis, mainly at night.After drug withdrawal, these disorders disappear within a few days. Care must be taken when treating patients suffering from hyperthyroidism or receiving thyroid hormone preparations that may have a cardiotoxic effect. Although changes in the level of leukocytes during the period of treatment with Anafranil were reported only in some cases, periodic examination of the composition of peripheral blood and attention to symptoms such as fever and sore throat, especially during the first months of therapy or with prolonged use of the drug, are recommended. Caution is needed when using Anafranil in patients with chronic constipation. Tricyclic antidepressants can cause paralytic intestinal obstruction, mainly in elderly patients or in patients forced to adhere to bed rest. When using Anafranil in doses higher than the average therapeutic, or if the concentration of clomipramine in plasma exceeds the average therapeutic, there is a risk of prolonged QTc interval and the occurrence of bidirectional fusiform ventricular tachycardia (ventricular arrhythmias like pirouette). This is observed in the case of co-administration with selective serotonin reuptake inhibitors or serotonin and noradrenaline reuptake inhibitors. In this regard, it is necessary to avoid co-administration of clomipramine and drugs that cause its cumulation. It is also necessary to avoid co-administration with drugs that cause prolongation of the QTc interval. The use of diuretics can lead to the development of hypokalemia. It has been established that hypokalemia is a risk factor for prolongation of the QTc interval and the occurrence of bidirectional spindle-shaped ventricular tachycardia (ventricular arrhythmias such as pirouette). Therefore, hypokalemia should be eliminated before starting treatment with Anafranil. Anafranil should be prescribed with caution simultaneously with selective serotonin reuptake inhibitors or serotonin and noradrenaline reuptake inhibitors, as well as with diuretics. Due to the risk of serotonin toxicity, the recommended doses should be followed and the dose should be increased with caution if Anafranil is used simultaneously with serotonergic drugs.With the simultaneous use of Anafranil with serotonergic drugs, such as selective serotonin reuptake inhibitors, serotonin and noradrenaline reuptake inhibitors, tricyclic antidepressants or lithium drugs, serotonin syndrome may develop with symptoms such as fever, myoclonus, agitation, prophylaxis, prophylaxis, a physical therapy, a vessel, and a human being who develops serotonin syndrome with such symptoms as fever, myoclonus, agitation, and physical therapy. . If fluoxetine is prescribed, it is recommended to take a two-three-week break between the use of Anafranil and fluoxetine. Anxiety increases in many patients with panic disorders at the beginning of treatment with Anafranil. Such a 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 noted. In patients with liver diseases, periodic monitoring of liver enzyme activity is recommended. Anafranil, as well as other tricyclic antidepressants, is prescribed in combination with electroconvulsive therapy only with careful medical supervision. Severe depression is characterized by the risk of suicidal acts, which can persist until a reliable remission is achieved. In patients with depression, in both adults and children, there may be an increase in depression and / or suicidal behavior or other psychiatric symptoms, regardless of whether they receive antidepressant therapy or not. Antidepressants increased the risk of suicidal thoughts and suicidal behavior in short-term studies in children and adolescents with depression and other psychiatric diseases. All patients taking Anafranil according to any of the indications should be examined for deterioration of the clinical picture, suicidal behavior and other psychiatric symptoms, especially in the initial phase of therapy or when changing the dose of the drug. In such patients, the possibility of changing the treatment regimen, including the possible discontinuation of the drug, should be considered, especially if such changes are pronounced, suddenly appeared, or were not observed in the patients at baseline.Families and carers of patients (both children and adults) taking antidepressants for psychiatric or non-psychiatric reasons should be warned about the need to monitor patients because of the risk of other psychiatric symptoms, including and suicidal behavior, and immediately report such symptoms to the attending physicians. When prescribing Anafranil, the minimum number of pills should be indicated to reduce the risk of overdose. At the same time it is necessary to observe the adequate mode of therapy. There is evidence that, while taking Anafranil, there are fewer deaths due to overdose than with other tricyclic antidepressants. Before performing general or local anesthesia, the anesthesiologist should be warned that the patient is taking Anafranil. An increase in the incidence of dental caries was reported with prolonged treatment with tricyclic antidepressants. Therefore, in the case of long-term therapy with Anafranil, it is recommended that the patient be regularly examined by a dentist. The use of diuretics can lead to the development of hypokalemia, which increases the risk of prolonging the QTc interval and the occurrence of bidirectional fusiform ventricular tachycardia (such as pirouette). Before starting treatment with Anafranil, correction of hypokalemia should be carried out. Avoid abrupt cancellations of Anafranil, since This may lead to adverse reactions. If the decision is made to stop treatment, the drug should be discontinued gradually, as quickly as the clinical situation allows. It should be borne in mind that abrupt withdrawal of the drug may be accompanied by the development of certain symptoms. 25 mg coated pills contain lactose and sucrose. Patients with rare hereditary diseases, such as intolerance to galactose and fructose, severe lactase deficiency, sucrose-isomaltase deficiency or malabsorption of glucose-galactose, should not take Anafranil coated pills. It should be borne in mind that alcohol may exacerbate adverse events on the part of the central nervous system, such as blurred vision, drowsiness.Use in pediatrics The experience of using Anafranil in children under 5 years of age is not available; therefore, it is not recommended to use the drug in children of this age group. Influence on the ability to drive vehicles and control mechanisms Patients who have drowsiness and other disorders of the central nervous system (including blurred vision) against the background of Anafranil should not drive a car, operate machinery, or engage in other activities requiring increased attention and quick response.