Clomipramine Full Prescribing Information
Brand Name: Anafranil
Outside U.S., Brand Names also known as: Anafranil 25; Anafranil Retard; Anafranil SR; Clofranil; Clomifril; Clopress; Gromin; Placil
Anafranil patient information (in plain English)
Suicidality in Children and Adolescents — Antidepressants increased the risk of suicidal thinking and behavior (suicidality) in short-term studies in children and adolescents with major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use of Anafranil or any other antidepressant in a child or adolescent must balance this risk with the clinical need. Patients who are started on therapy should be observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. Anafranil is not approved for use in pediatric patients. Pooled analyses of short-term (4 to 16 weeks) placebo-controlled trials of 9 antidepressant drugs (SSRIs and others) in children and adolescents with major depressive disorder (MDD), obsessive compulsive disorder (OCD), or other psychiatric disorders (a total of 24 trials involving over 4400 patients) have revealed a greater risk of adverse events representing suicidal thinking or behavior (suicidality) during the first few months of treatment in those receiving antidepressants. The average risk of such events in patients receiving antidepressants was 4%, twice the placebo risk of 2%. No suicides occurred in these trials.
Clomipramine hydrochloride (Anafranil) is a tricyclic antidepressant used to treat depression and obsessive-compulsive disorder (OCD). It may also be used to treat other conditions as determined by your doctor.
Clomipramine (CMI) is presumed to influence obsessive and compulsive behaviors through its effects on serotonergic neuronal transmission. The actual neurochemical mechanism is unknown, but CMI's capacity to inhibit the reuptake of serotonin (5-HT) is thought to be important.
Clomipramine is indicated for the treatment of obsessions and compulsions in patients with Obsessive-Compulsive Disorder (OCD). The obsessions or compulsions must cause marked distress, be time-consuming, or significantly interfere with social or occupational functioning, in order to meet the DSM-III-R (circa 1989) diagnosis of OCD.
The effectiveness of clomipramine for long-term use (i.e. 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.
Clomipramine is contraindicated in patients with a history of hypersensitivity to clomipramine or other tricyclic antidepressants.
Clomipramine HCl should not be given in combination, or within 14 days before or after treatment, with a monoamine oxidase (MAO) inhibitor. Hyperpyretic crisis, seizures, coma, and death have been reported in patients receiving such combinations.
Clomipramine is contraindicated during the acute recovery period after a myocardial infarction.
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.
Seizure was identified as the most significant risk of clomipramine use.
Caution should be used in administering clomipramine to patients with a history of seizures or other predisposing factors. e.g., brain damage of varying etiology, alcoholism, and concomitant use with other drugs that lower the seizure threshold.
Rare reports of fatalities in association with seizures have been reported by foreign post-marketing surveillance, but not in U.S. clinical trials. In some of these cases, clomipramine had been administered with other epileptogenic agents: in others, the patients involved had possibly predisposing medical conditions. Thus a causal association between clomipramine treatment and these fatalities has not been established.
Physicians should discuss with patients the risk of taking clomipramine HCl while engaging in activities in which sudden loss of consciousness could result in serious injury to the patient or others, e.g., the operation of complex machinery, driving, swimming, climbing.
Suicide: Since depression is a commonly associated feature of OCD, the risk of suicide must be considered. Prescriptions for clomipramine HCl should be written for the smallest quantity of capsules consistent with good patient management, in order to reduce the risk of overdose.
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 disease, especially those who have a history of conduction disorders, those with circulatory lability and elderly patients. It 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.
Psychosis, Confusion, And Other Neuropsychiatric Phenomena: Patients treated with clomipramine have been reported to show a variety of neuropsychiatric signs and symptoms including delusions, hallucinations, psychotic episodes, confusion, and paranoia. Because of the uncontrolled nature of many of the studies, its is impossible to provide a precise estimate of the extent of risk imposed by treatment with clomipramine. As with tricyclic antidepressants to which it is closely related, clomipramine may precipitate an acute psychotic episode in patients with unrecognized schizophrenia.
Mania/Hypomania: During premarketing testing of clomipramine in patients with affective disorder, hypomania or mania was precipitated in several patients. Activation of mania or hypomania has also been reported in a small proportion of patients with affective disorder treated with marketed tricyclic antidepressants, which are closely related to clomipramine.
Central Nervous System: 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.
Sexual Dysfunction: The rate of sexual dysfunction in male patients with OCD who were treated with clomipramine in the premarketing experience was markedly increased compared with placebo controls (i.e., 42% experienced ejaculatory failure and 20% experienced impotence, compared with 2.0% and 2.6% respectively, in the placebo group). Approximately 85% of males with sexual dysfunction chose to continue treatment.
Weight Changes: In controlled studies of OCD, weight gain was reported in 18% of patients receiving clomipramine, compared with 1% of patients receiving placebo. In these studies, 28% of patients receiving clomipramine had a weight gain of at least 7% of their initial body weight, compared with 4% of patients receiving placebo. Several patients had weight gains in excess of 25% of their initial body weight. Conversely, 5% of patients receiving placebo had weight losses of at least 7% of their initial body weight.
Surgery: Prior to elective surgery with general anesthetics, therapy with clomipramine HCl should be discontinued for as long as is clinically feasible, and the anesthetist should be advised.
Use in Concomitant Illness: As with closely related tricyclic antidepressants, clomipramine should be used with caution in the following:
- Hyperthyroid patients or patients receiving thyroid medication, because of the possibility of cardiac toxicity;
- Patients with increased intraocular pressure, a history of narrow-angle glaucoma, or urinary retention, because of the anticholinergic properties of the drug;
- Patients with tumors of the adrenal medulla (e.g., pheochromocytoma, neuroblastoma) in whom the drug may provoke hypertensive crises;
- Patients with significantly impaired renal function.
Withdrawal Symptoms: A variety of withdrawal symptoms have 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, and it is recommended that the dosage be tapered gradually and the patient monitored carefully during discontinuation
Information for Patients:
Physicians are advised to discuss the following issues with patients for whom they prescribe clomipramine:
- The risk of seizure
- The relatively high incidence of sexual dysfunction among males
- Since clomipramine HCl may impair the mental and/or physical abilities required for the performance of complex and hazardous tasks and since clomipramine HCl is associated with a risk of seizures, patients should be cautioned about the performance of complex and hazardous tasks
- Patients should be cautioned about using alcohol, barbiturates, or other CNS depressants concurrently, since clomipramine HCl may exaggerate their response to these drugs;
- Patients should notify their physician if they become pregnant or intend to become pregnant during therapy;
- Patients should notify their physician if they are breast-feeding.
Use in Pregnancy
There are no adequate or well-controlled studies in pregnant women. Withdrawal symptoms, including jitteriness, tremor, and seizures, have been reported in neonates whose mothers had taken clomipramine until delivery. Clomipramine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Use in Children
The safety and effectiveness in children below the age of 10 have not been established. Therefore, specific recommendations cannot be made for the use of clomipramine in children under the age of 10.
Use in Elderly
No unusual age-related adverse events have been identified in this elderly population, but the data is insufficient to rule out possible age-related differences, particularly in elderly patients who have concomitant systemic illnesses or who are receiving other drugs concomitantly.
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, biperiden, levodopa) may be exaggerated. When tricyclic antidepressants are given in combinations 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 anti-arrhythmic agents of the quinidine type.
Clomipramine should not be used with MAO inhibitors.
Since clomipramine may diminish or abolish the antihypertensive effects of guanethidine, clonidine, reserpine, methyldopa, patients requiring concomitant treatment for hypertension should be given antihypertensives of a different type (e.g. diuretics, beta-blockers).
Clomipramine should be discontinued prior to elective surgery, for as long as clinically feasible, since little is known about the interaction between clomipramine and general anesthetics.
If administered concomitantly with estrogens, the dose of clomipramine should be reduced since steroid hormones inhibit the metabolism of clomipramine.
Because clomipramine is highly bound to serum proteins, the administration of clomipramine to patients taking other drugs that are highly bound to protein (i.e. warfarin, digoxin) may cause an increase in plasma concentrations of these drugs, potentially resulting in adverse effects. Conversely, adverse reactions may result from the displacement of protein bound clomipramine by other highly bound drugs.
BEFORE USING THIS MEDICINE: INFORM YOUR DOCTOR OR PHARMACIST of all prescription and over-the-counter medicine that you are taking. This includes carbamazepine, cimetidine, dicumarol, clonidine, mibefradil, paroxetine, tramadol, other medicines for depression or emotional disorders, and medicines for seizures. Inform your doctor of any other medical conditions including heart conditions, allergies, pregnancy, or breast-feeding.
The most commonly observed adverse events associated with the use of clomipramine HCl 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.
The following list of adverse reactions have also been observed with clomipramine. These are listed in order of decreasing frequency.
Neurological: Extrapyramidal effects such as ataxia, also headache, delirium, speech disorders, muscle weakness, muscle hypertonia, tinnitus, paresthesias of the extremities, convulsions, EEG changes, hyperpyrexia. Peripheral neuropathy has been reported with other tricyclic antidepressants.
Cardiovascular: Hypotension, particularly orthostatic hypotension with associated vertigo, sinus tachycardia, palpitations. A quinidine-like effect and other reversible ECG changes in patients with normal cardiac status (such as flattening or inversion of T-waves, depressed S-T segments). Arrhythmias, hypertension, conduction disorders (e.g. widening of QRS complex, PQ changes, bundle-branch block), syncope.
Behavioral: Drowsiness, fatigue, restlessness, confusion accompanied by disorientation (particularly in geriatric patients and patients suffering from Parkinson's disease), anxiety states, agitation, sleep disturbances, insomnia, nightmares, aggravated depression, hypomania or manic episodes, disturbed concentration, visual hallucinations, impaired memory, aggressiveness, yawning, depersonalization, activation of latent psychosis, delusions.
Hematologic: Leukopenia, agranulocytosis, thrombocytopenia, eosinophilia and purpura. One case of pancytopenia has been reported.
Gastrointestinal: Vomiting, abdominal pain, diarrhea, taste perversion, elevated transaminases, obstructive jaundice, hepatitis with or without jaundice.
Endocrine: Weight loss, breast enlargement and galactorrhea in the female, inappropriate antidiuretic hormone (ADH) secretion syndrome, gynecomastia in the male, changes in blood sugar levels, increase in prolactin levels, menstrual irregularity.
Allergic: Allergic skin reactions (skin rash, urticaria), photosensitization, pruritus, edema, drug fever.
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.
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.
Signs and symptoms vary in severity depending upon factors such as the amount of drug absorbed, the age of the patient, and the time elapsed since drug ingestion. Blood and urine levels of clomipramine may not reflect the severity of poisoning: they have chiefly a qualitative rather than quantitative value, and they are unreliable indicators in the clinical management of the patient. The first signs and symptoms of poisoning with tricyclic antidepressants are generally severe anticholinergic reactions. CNS abnormalities may include drowsiness, stupor, coma, ataxia, restlessness, agitation, delirium, severe perspiration, hyperactive reflexes, muscle rigidity, athetoid and choreiform movement, and convulsions. Cardiac abnormalities may include arrhythmia, tachycardia, ECG evidence of impaired conduction, and signs of congestive heart failure, and in very rare cases, cardiac arrest. Respiratory depression, cyanosis, hypotension, shock, vomiting, hyperpyrexia, mydriasis, oliguria or anuria, and diaphoresis may also be present.
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.
In the alert patient, the stomach should be emptied promptly by lavage. In the obtunded patient, the airway should be secured with a cuffed endotracheal tube before beginning lavage (do not induce emesis). Instillation of activated charcoal slurry may help reduce absorption of CMI.
External stimulation should be minimized to reduce the tendency for convulsions. If anticonvulsants are necessary, diazepam and phenytoin may be useful. Adequate respiratory exchange should be maintained, including intubation and artificial respiration, if necessary. Respiratory stimulants should not be used.
In severe hypotension or shock, the patient should be placed in an appropriate position and given a plasma expander, and, if necessary, a vasopressor agent by intravenous drip. The use of corticosteroids in shock is controversial and may be contraindicated in case of overdosage with tricyclic antidepressants. Digitalis may increase conduction abnormalities and further irritate an already sensitized myocardium. If congestive heart failure necessitates rapid digitalization, particular care must be exercised. Hyperpyrexia should be controlled by whatever external means are available, including ice packs and cooling sponge baths, if necessary. Hemodialysis, peritoneal dialysis, exchange transfusions, and forced diuresis have generally been reported as ineffective because of the rapid fixation of clomipramine in tissues.
The slow intravenous administration of physostigmine salicylate has been used as a last resort to reverse severe CNS anticholinergic manifestations of overdosage with tricyclic antidepressants; however, it should not be used routinely, since it may induce seizures and cholinergic crises.
After you start taking this medicine, several weeks may pass before you feel the full benefit.
HOW TO USE THIS MEDICINE:
Follow the directions for using this medicine provided by your doctor.
- Take this medicine with food to prevent upset stomach.
- Store this medicine at room temperature, away from heat and light.
- Continue to take this medicine even if you feel better.
- Do not miss any doses. If you miss a dose of this medicine, take it as soon as possible. If it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not take 2 doses at once. If you take 1 dose daily at bedtime, do not take the missed dose the next morning.
Additional Information:: If your symptoms do not improve after taking this medicine for 4 weeks, inform your doctor. Do not share this medicine with others for whom it was not prescribed. Do not use this medicine for other health conditions. Keep this medicine out of the reach of children.
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 served with meals to reduce gastrointestinal side-effects.
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.
Adults-Initial Dosage: 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.
Children & Adolescents-Initial Dosage: As with adults, the starting dose is 25 mg daily and should be gradually increased (also given in divided doses with meals to reduce gastrointestinal side effects) during the first 2 weeks, as tolerated, up to a daily maximum of 3 mg/kg or 100 mg, whichever is smaller. Thereafter, the dosage may be increased gradually over the next several weeks up to a daily maximum of 3 mg/kg or 200 mg, whichever is smaller. As with adults, after titration, the total daily dose may be given once daily at bedtime to minimize daytime sedation.
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/Continuation Treatment (Adults, Children, and Adolescents): While there are no systematic studies that answer the question of how long to continue clomipramine, OCD is a chronic condition and it is reasonable to consider continuation for a responding patient. Although the efficacy of clomipramine after 10 weeks has not been documented in controlled trials, patients have been continued in therapy under double-blind conditions for up to 1 year without loss of benefit. However, dosage adjustments should be made to maintain the patient on the lowest effective dosage, and patients should be periodically reassessed to determine the need for treatment. During maintenance, the total daily dose may be given once daily at bedtime.
IF YOU WILL BE USING THIS MEDICINE FOR AN EXTENDED PERIOD OF TIME, be sure to obtain necessary refills before your supply runs out.
Tablets:: Anafranil is available as capsules of 10, 25, 50, and 75 mg for oral administration.
Anafranil patient information (in plain English)
The information in this monograph is not intended to cover all possible uses, directions, precautions, drug interactions or adverse effects. This information is generalized and is not intended as specific medical advice. If you have questions about the medicines you are taking or would like more information, check with your doctor, pharmacist, or nurse. Last updated 1/05.
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