Clomipramine Hydrochloride (Page 3 of 7)

PRECAUTIONS

General

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).

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 Clomipramine hydrochloride capsules, USP:

(1) The risk of seizure ( see WARNINGS );
(2) The relatively high incidence of sexual dysfunction among males ( see Sexual Dysfunction );
(3) Since Clomipramine hydrochloride capsules, USP may impair the mental and/or physical abilities required for the performance of complex tasks, and since Clomipramine hydrochloride capsules, USP is associated with a risk of seizures, patients should be cautioned about the performance of complex and hazardous tasks ( see WARNINGS );
(4) Patients should be cautioned about using alcohol, barbiturates, or other CNS depressants concurrently, since Clomipramine hydrochloride capsules, USP may exaggerate their response to these drugs;
(5) Patients should notify their physician if they become pregnant or intend to become pregnant during therapy;
(6) Patients should notify their physician if they are breast-feeding.

Patients should be advised that taking Clomipramine hydrochloride capsules, USP can cause mild pupillary dilation, which in susceptible individuals, can lead to an episode of angle-closure glaucoma. Pre‑ existing glaucoma is almost always open-angle 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.

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