Clomipramine Hydrochloride: Package Insert and Label Information (Page 2 of 5)

Screening Patients for Bipolar Disorder

A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that clomipramine hydrochloride is not approved for use in treating bipolar depression.

Serotonin Syndrome

The development of a potentially life-threatening serotonin syndrome has been reported with SNRIs and SSRIs, including clomipramine hydrochloride capsules, alone but particularly with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, and St. John’s Wort) and with drugs that impair metabolism of serotonin (in particular, MAOIs, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).

Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular changes (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Patients should be monitored for the emergence of serotonin syndrome.

The concomitant use of clomipramine hydrochloride capsules with MAOIs intended to treat psychiatric disorders is contraindicated. Clomipramine hydrochloride capsules should also not be started in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue. All reports with methylene blue that provided information on the route of administration involved intravenous administration in the dose range of 1 mg/kg to 8 mg/kg. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection) or at lower doses. There may be circumstances when it is necessary to initiate treatment with an MAOI such as linezolid or intravenous methylene blue in a patient taking clomipramine hydrochloride capsules. Clomipramine hydrochloride capsules should be discontinued before initiating treatment with the MAOI (see CONTRAINDICATIONS and DOSAGE AND ADMINISTRATION).

If concomitant use of clomipramine hydrochloride capsules with other serotonergic drugs, including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan, and St. John’s Wort is clinically warranted, patients should be made aware of a potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases.

Treatment with clomipramine hydrochloride capsules and any concomitant serotonergic agents should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated.

Angle-Closure Glaucoma

The pupillary dilation that occurs following use of many antidepressant drugs including clomipramine hydrochloride capsules may trigger an angle closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy.

Seizures

During premarket evaluation, seizure was identified as the most significant risk of clomipramine hydrochloride capsules use.

The observed cumulative incidence of seizures among patients exposed to clomipramine hydrochloride capsules at doses up to 300 mg/day was 0.64% at 90 days, 1.12% at 180 days, and 1.45% at 365 days. The cumulative rates correct the crude rate of 0.7% (25 of 3519 patients) for the variable duration of exposure in clinical trials.

Although dose appears to be a predictor of seizure, there is a confounding of dose and duration of exposure, making it difficult to assess independently the effect of either factor alone. The ability to predict the occurrence of seizures in subjects exposed to doses of CMI greater than 250 mg is limited, given that the plasma concentration of CMI may be dose-dependent and may vary among subjects given the same dose. Nevertheless, prescribers are advised to limit the daily dose to a maximum of 250 mg in adults and 3 mg/kg (or 200 mg) in children and adolescents (see DOSAGE AND ADMINISTRATION).

Caution should be used in administering clomipramine hydrochloride capsules 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 hydrochloride capsules had been administered with other epileptogenic agents; in others, the patients involved had possibly predisposing medical conditions. Thus a causal association between clomipramine hydrochloride capsules treatment and these fatalities has not been established.

Physicians should discuss with patients the risk of taking clomipramine hydrochloride capsules 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.

DRESS

Rare cases of drug rash with eosinophilia and systemic symptoms (DRESS) have been reported with the use of clomipramine. In the event of severe acute reactions such as DRESS, discontinue clomipramine therapy immediately and institute appropriate treatment.

PRECAUTIONS

General

Suicide

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

Mania/Hypomania

During premarketing testing of clomipramine hydrochloride capsules 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 capsules.

Hepatic Changes

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

Central Nervous System

More than 30 cases of hyperthermia have been recorded by nondomestic postmarketing surveillance systems. Most cases occurred when clomipramine hydrochloride capsules were used in combination with other drugs. When clomipramine hydrochloride capsules 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 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 capsules 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, compared with 1% of patients receiving placebo. In these studies, 28% of patients receiving clomipramine hydrochloride capsules 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 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 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 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 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, 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 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:

(1)

The risk of seizure (see WARNINGS);

(2)

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

(3)

Since clomipramine hydrochloride capsules may impair the mental and/or physical abilities required for the performance of complex tasks, and since clomipramine hydrochloride capsules are 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 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 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.