Suicide – Since depression is a commonly associated feature of OCD, the risk of suicide must be considered. Prescriptions for Clomipramine hydrochloride capsules, USP 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 Clomipramine hydrochloride capsules, USP 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 Clomipramine hydrochloride capsules, USP 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 Clomipramine hydrochloride. As with tricyclic antidepressants to which it is closely related, Clomipramine hydrochloride capsules, USP may precipitate an acute psychotic episode in patients with unrecognized schizophrenia.

Mania/Hypomania – During premarketing testing of Clomipramine hydrochloride capsules, USP 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 hydrochloride.

Hepatic Changes – During premarketing testing, Clomipramine hydrochloride capsules, USP 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 post marketing 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 Clomipramine hydrochloride capsules, USP there have been postmarketing reports of leukopenia, agranulocytosis, thrombocytopenia, anemia, and pancytopenia in association with Clomipramine hydrochloride capsules, USP use. As is the case with tricyclic antidepressants to which Clomipramine hydrochloride is closely related, leukocyte and differential blood counts should be obtained in patients who develop fever and sore throat during treatment with Clomipramine hydrochloride capsules, USP.

Central Nervous System – More than 30 cases of hyperthermia have been recorded by nondomestic postmarketing surveillance systems. Most cases occurred when Clomipramine hydrochloride capsules, USP was used in combination with other drugs. When Clomipramine hydrochloride capsules, USP 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 hydrochloride capsules, USP 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 Clomipramine Hydrochloride 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 Clomipramine hydrochloride capsules, USP, compared with 1% of patients receiving placebo. In these studies, 28% of patients receiving Clomipramine Hydrochloride 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 Clomipramine hydrochloride capsules, USP 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 Clomipramine hydrochloride capsules, USP 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 Clomipramine hydrochloride capsules, USP 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 hydrochloride capsules, USP should be used with caution in the following:

1.
    Hyperthyroid patients or patients receiving thyroid medication, because of the possibility of cardiac toxicity;
2.
    Patients with increased intraocular pressure, a history of narrow-angle glaucoma, or urinary retention, because of the anticholinergic properties of the drug;
3.
    Patients with tumors of the adrenal medulla (e.g., pheochromocytoma, neuroblastoma) in whom the drug may provoke hypertensive crises;
4.
    Patients with significantly impaired renal function.

Withdrawal Symptoms – A variety of withdrawal symptoms have been reported in association with abrupt discontinuation of Clomipramine hydrochloride capsules, USP, 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 hydrochloride capsules, USP 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).