PRECAUTIONS

General

Suicide

Since depression is a commonly associated feature of OCD, the risk of suicide must be considered. Prescriptions for Anafranil should be written for the smallest quantity of capsules consistent with good patient management, in order to reduce the risk of overdose.

Cardiovascular Effects

Modest orthostatic decreases in blood pressure and modest tachycardia were each seen in approximately 20% of patients taking Anafranil in clinical trials; but patients were frequently asymptomatic. Among approximately 1400 patients treated with CMI in the premarketing experience who had ECGs, 1.5% developed abnormalities during treatment, compared with 3.1% of patients receiving active control drugs and 0.7% of patients receiving placebo. The most common ECG changes were PVCs, ST-T wave changes, and intraventricular conduction abnormalities. These changes were rarely associated with significant clinical symptoms. Nevertheless, caution is necessary in treating patients with known cardiovascular disease, and gradual dose titration is recommended.

Psychosis, Confusion, And Other Neuropsychiatric Phenomena

Patients treated with Anafranil 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, it is impossible to provide a precise estimate of the extent of risk imposed by treatment with Anafranil. As with tricyclic antidepressants to which it is closely related, Anafranil may precipitate an acute psychotic episode in patients with unrecognized schizophrenia.

Mania/Hypomania

During premarketing testing of Anafranil 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 Anafranil.

Hepatic Changes

During premarketing testing, Anafranil was occasionally associated with elevations in SGOT and SGPT (pooled incidence of approximately 1% and 3%, respectively) of potential clinical importance (i.e., values greater than 3 times the upper limit of normal). In the vast majority of instances, these enzyme increases were not associated with other clinical findings suggestive of hepatic injury; moreover, none were jaundiced. Rare reports of more severe liver injury, some fatal, have been recorded in foreign postmarketing experience. Caution is indicated in treating patients with known liver disease, and periodic monitoring of hepatic enzyme levels is recommended in such patients.

Hematologic Changes

Although no instances of severe hematologic toxicity were seen in the premarketing experience with Anafranil, there have been postmarketing reports of leukopenia, agranulocytosis, thrombocytopenia, anemia, and pancytopenia in association with Anafranil use. As is the case with tricyclic antidepressants to which Anafranil is closely related, leukocyte and differential blood counts should be obtained in patients who develop fever and sore throat during treatment with Anafranil.

Central Nervous System

More than 30 cases of hyperthermia have been recorded by nondomestic postmarketing surveillance systems. Most cases occurred when Anafranil was used in combination with other drugs. When Anafranil 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 Anafranil 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.

Hyponatremia

Hyponatremia has occurred as a result of treatment with clomipramine. In many cases, hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Elderly patients may be at greater risk of developing hyponatremia with a serotonergic antidepressant. Also, patients taking diuretics or who are otherwise volume-depleted can be at greater risk. Discontinuation of Anafranil in patients with symptomatic hyponatremia and appropriate medical intervention should be instituted. Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which can lead to falls. More severe and/or acute cases have included hallucination, syncope, seizure, coma, respiratory arrest, and death.

Weight Changes

In controlled studies of OCD, weight gain was reported in 18% of patients receiving Anafranil, compared with 1% of patients receiving placebo. In these studies, 28% of patients receiving Anafranil 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 Anafranil and 1% receiving placebo had weight losses of at least 7% of their initial body weight.

Electroconvulsive Therapy

As with closely related tricyclic antidepressants, concurrent administration of Anafranil with electroconvulsive therapy may increase the risks; such treatment should be limited to those patients for whom it is essential, since there is limited clinical experience.

Surgery

Prior to elective surgery with general anesthetics, therapy with Anafranil 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, Anafranil 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 Anafranil, 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 Anafranil 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 (see Drug Abuse And Dependence).

Information For Patients

Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with clomipramine hydrochloride and should counsel them in its appropriate use. A patient Medication Guide about “Antidepressant Medicines, Depression and other Serious Mental Illness, and Suicidal Thoughts or Actions” is available for clomipramine hydrochloride. The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document.

Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking clomipramine hydrochloride.

Clinical Worsening And Suicide Risk

Patients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down. Families and caregivers of patients should be advised to look for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient's prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient's presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication.

Physicians are advised to discuss the following issues with patients for whom they prescribe Anafranil:

The risk of seizure (see WARNINGS );

); The relatively high incidence of sexual dysfunction among males (see Sexual Dysfunction );

); Since Anafranil may impair the mental and/or physical abilities required for the performance of complex tasks, and since Anafranil is associated with a risk of seizures, patients should be cautioned about the performance of complex and hazardous tasks (see WARNINGS );

); Patients should be cautioned about using alcohol, barbiturates, or other CNS depressants concurrently, since Anafranil 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.

Patients should be advised that taking Anafranil can cause mild pupillary dilation, which in susceptible individuals, can lead to an episode of angle-closure glaucoma. Pre-existing glaucoma is almost always openangle glaucoma because angle-closure glaucoma, when diagnosed, can be treated definitively with iridectomy. Open-angle glaucoma is not a risk factor for angle-closure glaucoma. Patients may wish to be examined to determine whether they are susceptible to angle closure, and have a prophylactic procedure (e.g., iridectomy), if they are susceptible.

Carcinogenesis, Mutagenesis, Impairment Of Fertility

No evidence of carcinogenicity was found in two 2-year bioassays in rats at doses up to 100 mg/kg, which is 24 and 4 times the maximum recommended human daily dose (MRHD) on a mg/kg and mg/m² basis, respectively, or in a 2-year bioassay in mice at doses up to 80 mg/kg, which is 20 and 1.5 times the MRHD on a mg/kg and mg/m² basis, respectively.

In reproduction studies, no effects on fertility were found in rats given up to 24 mg/kg, which is 6 times, and approximately equal to, the MRHD on a mg/kg and mg/m² basis, respectively.

Pregnancy Category C

No teratogenic effects were observed in studies performed in rats and mice at doses up to 100 mg/kg, which is 24 times the maximum recommended human daily dose (MRHD) on a mg/kg basis and 4 times (rats) and 2 times (mice) the MRHD on a mg/m² basis. Slight nonspecific embryo/fetotoxic effects were seen in the offspring of treated rats given 50 and 100 mg/kg and of treated mice given 100 mg/kg.

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 Anafranil until delivery. Anafranil should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing Mothers

Anafranil has been found in human milk. Because of the potential for adverse reactions, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

Safety and effectiveness in the pediatric population other than pediatric patients with OCD have not been established (see BOX WARNING and WARNINGS, Clinical Worsening and Suicide Risk). Anyone considering the use of Anafranil in a child or adolescent must balance the potential risks with the clinical need.

In a controlled clinical trial in children and adolescents (10 to 17 years of age), 46 outpatients received Anafranil for up to 8 weeks. In addition, 150 adolescent patients have received Anafranil in open-label protocols for periods of several months to several years. Of the 196 adolescents studied, 50 were 13 years of age or less and 146 were 14 to 17 years of age. The adverse reaction profile in this age group (see ADVERSE REACTIONS) is similar to that observed in adults.

The risks, if any, that may be associated with Anafranil's extended use in children and adolescents with OCD have not been systematically assessed. The evidence supporting the conclusion that Anafranil is safe for use in children and adolescents is derived from relatively short term clinical studies and from extrapolation of experience gained with adult patients. In particular, there are no studies that directly evaluate the effects of long term Anafranil use on the growth, development, and maturation of children and adolescents. Although there is no evidence to suggest that Anafranil adversely affects growth, development or maturation, the absence of such findings is not adequate to rule out a potential for such effects in chronic use.

The safety and effectiveness in pediatric patients below the age of 10 have not been established. Therefore, specific recommendations cannot be made for the use of Anafranil in pediatric patients under the age of 10.

Geriatric Use

Clinical studies of Anafranil did not include sufficient numbers of subjects age 65 and over to determine whether they respond differently from younger subjects; 152 patients at least 60 years of age participating in various U.S. clinical trials received Anafranil for periods of several months to several years. No unusual agerelated adverse events were identified in this population. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy.

Anafranil has been associated with cases of clinically significant hyponatremia. Elderly patients may be at greater risk for this adverse reaction (see PRECAUTIONS, Hyponatremia).