Anafranil (Clomipramine Hcl)

ANAFRANIL®

Novartis Pharmaceuticals

Clomipramine HCl

Antidepressant – Antiobsessional

Action And Clinical Pharmacology: Clomipramine is a tricyclic agent with both antidepressant and antiobsessional properties. Like other tricyclics, clomipramine inhibits norepinephrine and serotonin uptake into central nerve terminals, possibly by blocking the membrane-pump of neurons, thereby increasing the concentration of transmitter monoamines at receptor sites. Clomipramine is presumed to influence depression and obsessive and compulsive behavior through its effects on serotonergic neurotransmission. The actual neurochemical mechanism is unknown, but clomipramine’s capacity to inhibit serotonin reuptake is thought to be important. Clomipramine appears to have a mild sedative effect which may be helpful in alleviating the anxiety component often accompanying depression.

As with other tricyclic compounds, clomipramine possesses anticholinergic properties which are responsible for certain side effects. It also has weak antihistamine and antiserotonin properties, lowers the convulsive threshold, potentiates the effect of norepinephrine and other drugs acting on the CNS, has a quinidine-like effect on the heart and may impair cardiac conduction.

The action of clomipramine on the human EEG is one of desynchronization. Clomipramine causes a persistent increase in the frequency of shifts into stage I sleep and produces marked reduction or suppression of rapid eye movement sleep (REM or paradoxical sleep). Partial recovery occurs within 3 to 4 weeks as does a rebound after drug withdrawal which appears to last approximately the same time. In normal human volunteers tricyclic antidepressants tend to produce a sedative effect accompanied by atropine-like symptoms and may produce some difficulty in concentrating and thinking.

Pharmacokinetics: Clomipramine is rapidly and completely absorbed after oral administration in humans. Peak plasma levels are usually reached 2 hours after dosage but much individual variation occurs. The plasma half-life after a single oral dose is approximately 21 hours. After 28 days of oral administration to patients in a daily dosage of 75 mg, plasma concentrations of clomipramine ranged from 17 to 70 ng/mL (mean=35.7 ng/mL). The concentration of the active metabolite, desmethylclomipramine, was about twice as high.

The binding of clomipramine to serum proteins is very high at 96 to 97% and is practically concentration-independent within the therapeutic range. Clomipramine has a volume of distribution of approximately 12 L/kg.

Clomipramine is extensively metabolized in the body with hydroxylation, demethylation and N-oxidation being the quantitatively more important routes of metabolism.

Owing to the lower clearance of clomipramine in plasma, elderly patients require lower doses of clomipramine than patients in younger age groups.

As expected, the metabolites of clomipramine are quite similar to those of imipramine, all retaining the benzazepine structure. Two-thirds of clomipramine is excreted as water-soluble conjugates in the urine and approximately one-third in the feces. After a 25 mg radiolabeled dose of clomipramine in 2 subjects, the urinary recoveries of clomipramine and desmethylclomipramine were about 2% and 0.5% of the total radioactivity, respectively.

Indications And Clinical Uses: For the treatment of depression. Clomipramine also appears to have a mild sedative effect which may be helpful in alleviating the anxiety component often accompanying depression.

For the treatment of obsessions and compulsions in patients with obsessive compulsive disorder (OCD). The obsessions and compulsions must cause marked distress, be time-consuming, or significantly interfere with social or occupational functioning.

The effectiveness of clomipramine for long-term use (e.g., for more than 10 weeks) has not been systematically evaluated in placebo-controlled trials. The physician who elects to use clomipramine for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient.

Contra-Indications: Patients who have known or suspected hypersensitivity to the drug or its excipients, or have known or suspected hypersensitivity to tricyclic antidepressants belonging to the dibenzazepine group.

Clomipramine should not be given in conjunction with or within 14 days before or after treatment with a MAO inhibitor (see Drug Interactions). The concomitant treatment with selective, reversible MAO-A inhibitors, such as moclobemide, is also contraindicated. Hypertensive crises, hyperactivity, hyperpyrexia, spasticity, severe convulsions or coma, and death have been reported in patients receiving such combinations.

It is contraindicated during the acute recovery phase following myocardial infarction and in the presence of acute congestive heart failure.

Clomipramine is contraindicated in patients with existing liver or kidney damage and should not be administered to patients with a history of blood dyscrasias.

Clomipramine is contraindicated in patients with glaucoma, as the condition may be aggravated due to the atropine-like effects of the drug.

Manufacturers’ Warnings In Clinical States: Seizures: Tricyclic agents are known to lower the convulsive threshold and clomipramine should, therefore, be used with extreme caution in patients with a history of convulsive disorders and other predisposing factors, e.g., brain damage of varying etiology, concomitant use of neuroleptics, alcoholism and withdrawal from alcohol, and concomitant use with other drugs that lower the seizure threshold. It appears that the occurrence of seizures is dose dependent. Therefore, the recommended total daily doses should not be exceeded (see Dosage).

Concurrent administration of ECT and clomipramine may be hazardous and such treatment should be limited to patients for whom it is essential. Physicians should discuss with patients the risk of taking clomipramine while engaging in activities in which a sudden loss of consciousness could result in serious injury to the patient or others, e.g., the operation of complex machinery, driving, swimming, or climbing.

Cardiovascular: Tricyclic antidepressants, particularly in high doses, have been reported to produce sinus tachycardia, changes in conduction time and arrhythmias. A few instances of unexpected death have been reported in patients with cardiovascular disorders. Myocardial infarction and stroke have also been reported with drugs of this class. Therefore, clomipramine should be administered with extreme caution to patients with a history of cardiovascular disorders, especially those with cardiovascular insufficiency, conduction disorders (e.g., atrioventricular block grades I to III) or other arrhythmias, those with circulatory lability and elderly patients. Clomipramine also has a hypotensive action which may be detrimental in these circumstances. In such cases, treatment should be initiated at low doses with progressive increases only if required and tolerated, and the patients should be under close surveillance at all dosage levels. Monitoring of cardiac function and the ECG is indicated in such patients as well as in the elderly.

Use in Concomitant Illness: Caution should be observed in prescribing clomipramine in hyperthyroid patients or for patients receiving thyroid medication. Transient cardiac arrhythmias have occurred in rare instances in patients who have been receiving other tricyclic compounds concomitantly with thyroid medication.

Because of its anticholinergic properties, clomipramine should be used with caution in patients with increased intraocular pressure, narrow angle glaucoma or urinary retention, particularly in the presence of prostatic hypertrophy.

Tricyclic antidepressants may give rise to paralytic ileus, particularly in the elderly and in hospitalized patients. Therefore, appropriate measures should be taken if constipation occurs.

Caution is called for when employing clomipramine in patients with tumors of the adrenal medulla (e.g., pheochromocytoma, neuroblastoma) in whom the drug may provoke hypertensive crisis.

Clomipramine should be kept in a safe place, well out of the reach of children.

Pregnancy: The safety of use in pregnant women has not been established. Therefore, clomipramine should not be administered to women of childbearing potential, or during pregnancy, unless, in the opinion of the physician, the expected benefit to the patient outweighs the potential risk to the fetus. Withdrawal symptoms including tremors, dyspnea, lethargy, colic, irritability, hypotonia/hypertonia, convulsions, and respiratory depression have been reported in neonates whose mothers received tricyclic antidepressants during the third trimester of pregnancy. To avoid such symptoms, clomipramine should, if possible, be gradually withdrawn at least 7 weeks before the calculated date of confinement.

Lactation: Since clomipramine passes into breast milk, the drug should be gradually withdrawn or the infant weaned if the patient is breast-feeding.

Precautions: Suicide: The possibility of a suicide attempt is inherent in depression with or without obsessive compulsive disorder. These patients should be carefully supervised during treatment with clomipramine, and hospitalization or concomitant ECT may be required. To minimize the risk of an intentional overdose by a depressed patient, prescriptions for clomipramine should be written for the smallest possible quantity of the drug consistent with good patient management.

Psychosis, Mania-Hypomania, and other Neuropsychiatric Phenomena: In patients treated with tricyclic antidepressants, activation of latent schizophrenia or aggravation of existing psychotic manifestations in schizophrenic patients may occur. Patients with manic-depressive tendencies may experience hypomanic or manic shifts. Hyperactive or agitated patients may become over-stimulated. A reduction in dose or discontinuation of clomipramine should be considered under these circumstances.

In predisposed and elderly patients, tricyclic antidepressants may, particularly at night, provoke pharmacogenic (delirious) psychoses that disappear within a few days of withdrawing the drug.

Occupational Hazards: Since clomipramine may produce sedation, particularly during the initial phase of therapy, patients should be cautioned about the danger of engaging in activities requiring mental alertness, judgement and physical coordination.

Cardiovascular: Before initiating treatment, it is advisable to check the patient’s blood pressure, because individuals with hypotension or a labile circulation may react to the drug with a fall in blood pressure. Regular measurements of blood pressure should be performed in susceptible patients. Postural hypotension may be controlled by reducing the dosage or administering circulatory stimulants.

ECG abnormalities have been observed in patients treated with clomipramine. The most common ECG changes were premature ventricular contractions (PVCs), ST-T wave changes, and abnormalities in intraventricular conduction. These changes were rarely associated with significant clinical symptoms. Nevertheless, caution is necessary when treating patients with heart disease, as well as elderly subjects. In these patients cardiac function should be monitored and ECG examinations performed during long-term therapy. Gradual dose titration is also recommended.

Hepatic Changes: Clomipramine has occasionally been associated with elevations in AST and ALT of potential clinical significance (e.g., values greater than 3 times the upper limit of normal). In the majority of cases, these enzyme elevations were not associated with other clinical findings suggestive of hepatic injury.

Isolated cases of obstructive jaundice have been reported. Caution is indicated in treating patients with known liver disease, and periodic monitoring of hepatic function is recommended in such patients.

Hematologic Changes: Isolated cases of bone marrow depression with agranulocytosis have been reported. Leukocyte and differential blood cell counts are recommended in patients receiving treatment with clomipramine over prolonged periods, and should be performed for patients who develop fever, an influenzal infection, or sore throat. In the event of an allergic skin reaction, clomipramine should be withdrawn.

CNS: More than 30 cases of hyperthermia have been recorded by nondomestic post-marketing surveillance systems. Most cases occurred when clomipramine was used in combination with other drugs. When clomipramine and a neuroleptic were used concomitantly, the cases were sometimes considered to be examples of a neuroleptic malignant syndrome.

Withdrawal Symptoms: A variety of withdrawal symptoms has been reported in association with abrupt discontinuation of clomipramine, including dizziness, nausea, vomiting, headache, malaise, sleep disturbance, hyperthermia and irritability. In addition, such patients may experience a worsening of psychiatric status. While the withdrawal effects of clomipramine have not been systematically evaluated in controlled trials, they are well known with closely related tricyclic antidepressants. It is recommended that the dosage be tapered gradually and the patient monitored carefully during discontinuation.

Metabolic Effects: Tricyclic antidepressants have been associated with porphyrinogenicity in susceptible patients.

Renal Function: It is also advisable to monitor renal function during long-term therapy with tricyclic antidepressants.

Dental Effects: Lengthy treatment with tricyclic antidepressants can lead to an increased incidence of dental caries.

Lacrimation: Decreased lacrimation and accumulation of mucoid secretions, due to the anticholinergic properties of tricyclic antidepressants, may cause damage to the corneal epithelium in patients with contact lenses.

Endocrine Effects: As with certain other psychotherapeutic drugs, clomipramine elevates prolactin levels. Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin dependent in vitro, a factor of potential importance if the prescription of clomipramine is contemplated in a patient with a previously detected breast cancer. Although disturbances such as galactorrhea, amenorrhea, gynecomastia, and impotence have been reported, the clinical significance of elevated serum prolactin levels is unknown for most patients. An increase in mammary neoplasms has been found in rodents after chronic administration of neuroleptic drugs. Neither clinical studies nor epidemiologic studies conducted to date, however, have shown an association between chronic administration of these drugs and mammary tumorigenesis: the available evidence is considered too limited to be conclusive at this time.

Children: As clomipramine has not been studied in patients under 10 years of age, specific recommendations for use in this age group cannot be provided. The long-term effects of clomipramine on childhood growth and development have not been determined.

Drug Interactions: Patients should be warned that, while taking clomipramine, their responses to alcoholic beverages, other CNS depressants (e.g., barbiturates, benzodiazepines or general anesthetics) or anticholinergic agents (e.g., atropine, antihistamines, biperiden, levodopa) may be exaggerated.

When tricyclic antidepressants are given in combination with anticholinergics or neuroleptics with an anticholinergic action, hyperexcitation states or delirium may occur, as well as attacks of glaucoma.

Tricyclic antidepressants should not be employed in combination with antiarrhythmic agents of the quinidine type (see Warnings, Cardiovascular).

Since clomipramine may diminish or abolish the antihypertensive effects of guanethidine, bethanidine, clonidine, reserpine, or alpha-methyldopa, patients requiring concomitant treatment for hypertension should be given antihypertensives of a different type (e.g., diuretics, vasodilators, beta-blockers).

Clomipramine may potentiate the cardiovascular effects of norepinephrine or epinephrine, amphetamine, as well as nasal drops and local anesthetics containing sympathomimetics (e.g., isoprenaline, ephedrine, phenylephrine).

Fluoxetine, fluvoxamine and other selective serotonin reuptake inhibitors (SSRIs) may increase the activity and plasma concentrations of tricyclic antidepressants with corresponding adverse effects.

Caution should be exercised if clomipramine is administered together with cimetidine or methylphenidate since these drugs have been shown to inhibit the metabolism of several tricyclic antidepressants. Clinically significant increases in plasma levels of clomipramine may occur, necessitating a dosage reduction.

Substances which activate the hepatic mono-oxygenase enzyme system (e.g., barbiturates, carbamazepine, phenytoin, nicotine and oral contraceptives) may lower plasma concentrations of tricyclic antidepressants and so reduce their antidepressive effects. In addition, clomipramine may increase plasma levels of phenytoin and carbamazepine, therefore, it may be necessary to adjust the dosage of these drugs.

Clomipramine should not be administered for a period of at least 14 days after the discontinuation of treatment with MAO inhibitors due to the potential for severe interactions (see Contraindications). The same caution should also be observed when administering an MAO inhibitor after previous treatment with clomipramine.

Clomipramine should be discontinued prior to elective surgery for as long as is clinically feasible, since little is known about the interaction with general anesthetics.

Concomitant treatment with neuroleptic agents (e.g., phenothiazines and butyrophenones) may result in increased plasma concentrations of clomipramine, a lowered convulsion threshold and seizures. Combination with thioridazine may produce cardiac arrhythmias. No such effects are known to occur in combination with diazepam but it might be necessary to lower the dosage of clomipramine if administered concomitantly with alprazolam or disulfiram.

Tricyclic antidepressants may potentiate the anticoagulant effect of coumarin drugs by inhibiting hepatic metabolism of these drugs. Careful monitoring of plasma prothrombin is therefore advised.

If administered concomitantly with estrogens, the dose of clomipramine should be reduced since steroid hormones inhibit the metabolism of clomipramine.

Teratology: No teratogenic effects were observed in rats and mice at doses up to 20 times the maximum daily human dose. Slight nonspecific fetotoxic effects were seen in the offspring of pregnant mice given doses 10 times the maximum daily human dose. Slight nonspecific embryotoxicity was observed in rats given doses 5 to 10 times the maximum daily human dose.

Animal Toxicology: As with tricyclic compounds, clomipramine has been associated with changes in testicular and lung tissue in long-term animal toxicology studies. In 1- and 2-year studies in rats, a dose 4 times the maximum daily human dose was associated with phospholipidosis in the lungs and changes in the testes (atrophy, aspermatogenesis, and calcification). In a 1-year toxicity study in dogs, testicular atrophy was detected in animals receiving 10 times the maximum recommended daily human dose.

Adverse Reactions: The most commonly observed adverse events associated with the use of clomipramine and not seen at an equivalent incidence among placebo-treated patients were gastrointestinal complaints, including dry mouth, constipation, nausea, dyspepsia, and anorexia; nervous system complaints, including somnolence, tremor, dizziness, nervousness and myoclonus; genitourinary complaints including changed libido, ejaculatory failure, impotence and micturition disorder; and other miscellaneous complaints, including fatigue, sweating, increased appetite, weight gain, and visual changes.

If severe neurological or psychiatric reactions occur, clomipramine should be withdrawn.

Elderly patients are particularly susceptible to anticholinergic, psychiatric, neurological and cardiovascular effects.

The following adverse reactions have also been reported with clomipramine or other tricyclic antidepressants. (Frequency estimates: Frequent: >10%; Occasional: >1-10%; Rare: >0.01-1%; Isolated cases:
Neurological: Occasional: headache, paresthesia (numbness, tingling sensation, symptoms suggestive of peripheral neuropathy), delirium, muscle hypertonia. Rare: epileptic seizures. Isolated cases: tinnitus, incoordination, ataxia, alterations in EEG patterns, extrapyramidal symptoms, speech disorders, weakness, hyperpyrexia.

Behavioral: Occasional: drowsiness, insomnia, confusional states with hallucinations (particularly in geriatric patients and patients suffering from Parkinson’s disease), anxiety, agitation, restlessness, nightmares, aggravated depression, hypomania, mania, decrease in memory, feeling of unreality, yawning. Rare: activation of latent psychosis. Isolated cases: aggressiveness.

Anticholinergic: Frequent: dry mouth and rarely associated sublingual adenitis, disturbances of visual accommodation, hot flushes. Occasional: dilation of the urinary tract. Isolated cases: mydriasis, glaucoma, paralytic ileus.

Cardiovascular: Frequent: hypotension, particularly orthostatic hypotension with associated vertigo, sinus tachycardia, ECG changes (including flattening or inversion of T wave, depressed S-T segments) in patients of normal cardiac status. Occasional: arrhythmia, disturbances in cardiac conduction (e.g., widening of QRS complex, PQ changes, bundle-branch block), palpitation, syncope. Isolated cases: hypertension, congestive heart failure, myocardial infarction, heart block, asystole, stroke, peripheral vasospastic reactions.

Hematologic: Isolated cases: agranulocytosis, eosinophilia, leukopenia, purpura and thrombocytopenia may occur as an idiosyncratic response. One case of pancytopenia has been reported.

Gastrointestinal: Occasional: vomiting, abdominal cramps. Rare: diarrhea, elevated transaminases. Isolated cases: bitter taste, stomatitis, epigastric distress, black tongue, dysphagia, increased salivation, hepatitis with or without jaundice.

Respiratory: Isolated cases: bronchospasm.

Endocrine: Isolated cases: gynecomastia in the male, breast enlargement and galactorrhea in the female, testicular swelling, elevation or depression of blood sugar levels, weight loss, inappropriate antidiuretic hormone (SIADH) secretion syndrome, increase in prolactin levels, menstrual irregularity.

Allergic or Toxic: Occasional: skin rash, urticaria. Isolated cases: petechiae, itching, photosensitization (avoid excessive exposure to sunlight), edema (general or of face and tongue), drug fever, obstructive jaundice, nasal congestion, alopecia, allergic alveolitis (pneumonia) with or without eosinophilia, systemic analphylactic/anaphylactoid reactions including hypotension.

Withdrawal Symptoms: Abrupt cessation of treatment with tricyclic antidepressants after prolonged administration may occasionally produce nausea, vomiting, abdominal pain, diarrhea, insomnia, nervousness, anxiety, headache and malaise. These symptoms are not indicative of addiction.

Symptoms And Treatment Of Overdose: Since children may be more sensitive than adults to acute overdosage with tricyclic antidepressants, and since fatalities in children have been reported, effort should be made to avoid potential overdose particularly in this age group.Symptoms: These may vary in severity depending on various factors such as the amount of drug absorbed, the interval between drug ingestion and start of treatment, and the age of the patient. Accidental ingestion in children should be regarded as serious and potentially fatal.

Symptoms generally appear within 4 hours of ingestion and reach maximum severity after 24 hours. Owing to delayed absorption (increased anticholinergic effect due to overdose), long half-life and enterohepatic recycling of the drug, the patient may be at risk for up to 4 to 6 days.

Symptoms may include drowsiness, stupor, ataxia, vomiting, cyanosis, restlessness, agitation, delirium, severe perspiration, hyperactive reflexes, muscle rigidity, athetoid and choreiform movements, and convulsions. Hyperpyrexia, mydriasis, bowel and bladder paralysis, and respiratory depression may occur.

Hypotension and initial hypertension may occur. However, the usual finding is increasing hypotension which may lead eventually to shock. Serious cardiovascular disturbances are frequently present, including tachycardia, cardiac arrhythmias (flutter, atriofibrillation, premature ventricular beats and ventricular tachycardia) as well as impaired myocardial conduction, atrioventricular and intraventricular block, ECG abnormalities (such as widened QRS complexes and marked S-T shifts), signs of congestive heart failure and cardiac arrest. Coma may ensue.

Treatment: Patients in whom overdosage is suspected should be admitted to hospital without delay. No specific antidote is available and treatment is essentially symptomatic and supportive.

Gastric lavage or aspiration should be performed promptly and is recommended up to 12 hours or even more after the overdose, since the anticholinergic effect of the drug may delay gastric emptying. Administration of activated charcoal may help to reduce absorption of the drug. As clomipramine is largely protein bound, forced diuresis, peritoneal dialysis and hemodialysis are unlikely to be of value.

Treatment should be designed to insure maintenance of the vital functions. An open airway should be maintained in comatose patients and assisted ventilation instituted, if necessary, but respiratory stimulants should not be used. Hyperpyrexia should be controlled by external measures, such as ice packs and cooling sponge baths. Acidosis may be treated by cautious administration of sodium bicarbonate. Adequate renal function should be maintained.

ECG monitoring in an intensive care unit is recommended in all patients, particularly in the presence of ECG abnormalities, and should be maintained for several days after the cardiac rhythm has returned to normal. Unexpected deaths attributed to cardiac arrhythmias have been reported several days following an apparent recovery from tricyclic antidepressant overdose. Correction of hypoxia and acidosis, if present, may be beneficial. Correction of metabolic acidosis and low potassium concentrations by means of bicarbonate i.v. and potassium substitution may also be effective for treatment of arrhythmias. If bradyarrhythmia or AV-block occur, consider temporary insertion of a cardiac pacemaker. Because of its effect on cardiac conduction, digitalis should be used only with caution. If rapid digitalization is required for the treatment of congestive heart failure, special care should be exercised in using the drug.

External stimulation should be minimized to reduce the tendency to convulsions. If convulsions occur, anticonvulsants (preferably i.v. diazepam) should be administered. Barbiturates may intensify respiratory depression, particularly in children, and aggravate hypotension and coma. Paraldehyde may be used in some children to counteract muscular hypertonus and convulsions with less likelihood of causing respiratory depression. If the patient fails to respond rapidly to anticonvulsants, artificial ventilation should be instituted. Prompt control of convulsions is essential since they aggravate hypoxia and acidosis and may thereby precipitate cardiac arrhythmias and arrest.

Shock should be treated with supportive measures, such as i.v. fluids, plasma expanders and oxygen. The use of corticosteroids in shock is controversial and may be contraindicated in tricyclic antidepressant overdose. Hypotension usually responds to elevation of the foot of the bed. Pressor agents (but not epinephrine) should be given cautiously, if indicated. In the event of reduced myocardial function, consider recourse to treatment with dopamine or dobutamine by i.v. drip.

Since it has been reported that physostigmine may cause severe bradycardia, asystole and seizures, its use is not recommended in cases of overdosage with clomipramine.

Deaths by deliberate or accidental overdosage have occurred with this class of drugs. Since the propensity for suicide is high in depressed patients, a suicide attempt by other means may occur during the recovery phase. The possibility of simultaneous ingestion of other drugs should also be considered.

Dosage And Administration: Dosage should be individualized according to the requirements of each patient. Treatment should be initiated at the lowest recommended dose and increased gradually, noting carefully the clinical response and any evidence of intolerance. During the initial dose titration phase, the total daily dose of clomipramine should be divided and administered with meals to reduce gastrointestinal side effects.

Owing to the long elimination half-lives of clomipramine and its active metabolite, desmethylclomipramine, steady-state plasma levels may not be achieved until 2 to 3 weeks after a dosage adjustment. It may thus be advisable to wait 2 to 3 weeks after the initial dose titration phase, before attempting further dosage adjustments. It should be kept in mind that a lag in therapeutic response usually occurs at the onset of therapy, lasting from several days to a few weeks. Increasing the dosage does not normally shorten this latent period and may increase the incidence of side effects.

Depression: Initial Dosage: Adults: Clomipramine therapy should be initiated at daily doses of 25 mg. Dosage may be increased by 25 mg increments, as tolerated, at 3- to 4-day intervals up to a total daily dose of 150 mg by the end of 2 weeks. Thereafter, the dose may be gradually increased over a period of several weeks to 200 mg. Doses in excess of 200 mg daily are not recommended for outpatients. Occasionally, in more severely depressed hospitalized patients, dosages up to 300 mg daily may be required.

Elderly and Debilitated Patients: In general, lower dosages are recommended for these patients. Initially, 20 to 30 mg daily in divided doses is suggested, with very gradual increments, depending on tolerance and response. Blood pressure and cardiac rhythm should be checked frequently, particularly in patients who have unstable cardiovascular function.

Maintenance Dosage: Dosage during maintenance therapy should be kept at the lowest effective level. To minimize daytime sedation during maintenance treatment, the total daily dosage may be given as a single dose at bedtime. Medication should be continued for the expected duration of the depressive episode in order to minimize the possibility of relapse following clinical improvement.

Obsessive Compulsive Disorders: Initial Dosage: Adults: Clomipramine therapy in adult obsessive compulsive patients should be initiated at daily doses of 25 mg. Dosage may be increased by 25 mg increments, as tolerated, at 3- to 4-day intervals up to a total daily dose of 100 or 150 mg by the end of 2 weeks. Thereafter, the dose may be gradually increased over a period of several weeks to 200 mg. Doses in excess of 200 mg/day are not generally recommended for outpatients. However, in the treatment of severe cases of Obsessive Compulsive Disorder, daily doses of up to 250 mg may be required.

Children and Adolescents: In children aged 10 to 17 years, an initial dose of 25 mg/day is recommended. Dosage may be increased by 25 mg increments, as tolerated, at 3- to 4-day intervals. By the end of 2 weeks, patients may be titrated up to 100 to 150 mg/day or 3 mg/kg, whichever is lower. Thereafter, the dose may be gradually increased to 200 mg or 3 mg/kg whichever is lower. A total daily dose above 200 mg should not be used in children or adolescents.

Elderly and Debilitated Patients: In general, lower dosages are recommended for these patients. Initially, 20 to 30 mg daily in divided doses is suggested, with very gradual increments, depending on tolerance and response. Blood pressure and cardiac rhythm should be checked frequently, particularly in patients who have unstable cardiovascular function.

Maintenance Dosage (Adults, Children, and Adolescents): Double blind extension phase studies of clomipramine therapy in patients with Obsessive Compulsive Disorder have followed patients for up to 52 weeks. Although placebo enrollment in these studies was inadequate to permit a controlled comparison, data suggest that clomipramine therapy can be continued for up to a year without loss of efficacy.

Dosage adjustments may be made during maintenance therapy with the objective of maintaining the patient at the lowest effective dose. To minimize daytime sedation during maintenance treatment, the total daily dosage may be given as a single dose at bedtime. If symptoms recur, the dosage should be increased until the symptoms are controlled. Patients should be reassessed periodically to determine the need for continued treatment. To avoid withdrawal symptoms upon discontinuation of therapy, a gradual decrease in dosage and careful patient monitoring are recommended.

Availability And Storage: 10 mg: Each cream-colored, triangular, sugar-coated tablet, contains: clomipramine HCl 10 mg. Nonmedicinal ingredients: cellulose compounds, cornstarch, gelatin, glycerin, iron oxide, lactose, magnesium stearate, polyethylene glycol, polyvinylpyrrolidone, sucrose, talc and titanium dioxide. Bottles of 100 and 500.

25 mg: Each cream-colored, round, biconvex, sugar-coated tablet, branded GEIGY on one side and FH on the other side in black, contains: clomipramine HCl 25 mg. Nonmedicinal ingredients: cellulose compounds, colloidal silicon dioxide, cornstarch, glycerin, iron oxide, lactose, magnesium stearate, polyethylene glycol, polyvinylpyrrolidone, stearic acid, sucrose, talc and titanium dioxide. Bottles of 100 and 500.

50 mg: Each white, round, beveled edge, film-coated tablet, engraved GEIGY on one side and LP on the other side, contains: clomipramine HCl 50 mg. Nonmedicinal ingredients: cellulose compounds, colloidal silicon dioxide, lactose, magnesium stearate, polysorbates, talc and titanium dioxide. Bottles of 100 and 500.

Protect from heat. Store between 2 and 30°C. Keep out of reach of children.

ANAFRANIL® Novartis Pharmaceuticals Clomipramine HCl Antidepressant – Antiobsessional

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