CONTRAINDICATIONS
Clomipramine HCl is contraindicated in patients with a history of hypersensitivity to clomipramine
HCl 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 HCl is contraindicated during the acute recovery period after a myocardial infarction.
WARNINGS
Seizures
During premarket evaluation, seizure was identified as the most significant risk of clomipramine HCl
use.
The observed cumulative incidence of seizures among patients exposed to clomipramine HCl 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 HCl 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 HCl had been
administered with other epileptogenic agents; in others, the patients involved had possibly
predisposing medical conditions. Thus a causal association between clomipramine HCl 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).
PRECAUTIONS
General
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 Effects: Modest orthostatic decreases in blood pressure and modest tachycardia
were each seen in approximately 20% of patients taking clomipramine HCl 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 HCl 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 HCl. As with tricyclic antidepressants to
which it is closely related, clomipramine HCl may precipitate an acute psychotic episode in patients
with unrecognized schizophrenia.
Mania/Hypomania: During premarketing testing of clomipramine HCl 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 HCl.
Hepatic Changes: During premarketing testing, clomipramine HCl 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; 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 HCl, there have been postmarketing reports of
leukopenia, agranulocytosis, thrombocytopenia, anemia, and pancytopenia in association with
clomipramine HCl use. As is the case with tricyclic antidepressants to which clomipramine HCl is
closely related, leukocyte and differential blood counts should be obtained in patients who develop
fever and sore throat during treatment with clomipramine HCl.
Central Nervous System: More than 30 cases of hyperthermia have been recorded by
nondomestic postmarketing surveillance systems. Most cases occurred when clomipramine HCl
was used in combination with other drugs. When clomipramine HCl 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 HCl 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 HCl, compared with 1% of patients receiving placebo. In these studies, 28%
of patients receiving clomipramine HCl 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 domipramine HCl 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 HCl 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 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 HCl
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 HCl, 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 HCl 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
Physicians are advised to discuss the following issues with patients for whom they prescribe
clomipramine HCl:
(1) The risk of seizure (see WARNINGS);
(2) The relatively high incidence of sexual dysfunction among males (see Sexual Dysfunction
) ;
(3) Since clomipramine HCl may impair the mental and/or physical abilities required for the
performance of complex tasks and since clomipramine HCl 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 HCl 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.
Carcinogenesis, Mutagenesis, Impairment of Fertility
In a 2-year bioassay, no clear evidence of carcinogenicity was found in rats given doses 20 times
the maximum daily human dose. Three out of 235 treated rats had a rare tumor
(hemangioendothelioma); it is unknown if these neoplasms are compound related.
In reproduction studies, no effects on fertility were found in rats given doses approximately 5 times
the maximum daily human dose.
Pregnancy Category C
No teratogenic effects were observed in studies performed in rats and mice at doses up to 20 times
the maximum daily human dose. Slight nonspecific fetotoxic effects were seen in the offspring of
pregnant mice given doses 10 times the maximum daily human dose. Slight nonspecific
embryotoxicity was observed in rats given doses 5-10 times the maximum daily human dose.
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 HCl until delivery. Clomipramine HCl should be used during pregnancy only if the
potential benefit justifies the potential risk to the fetus.
Nursing Mothers
Clomipramine HCl 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
In a controlled clinical trial in children and adolescents (10-17 years of age), 46 outpatients received
clomipramine HCl for up to 8 weeks. In addition, 150 adolescent patients have received
clomipramine HCl in open-label protocols for periods of several months to several years. Of the 196
adolescents studies, 50 were 13 years of age or less and 146 were 14-17 years of age. While the
adverse reaction profile in this age group (see ADVERSE REACTIONS) is similar to that in adults,
it is unknown what, if any, effects long-term treatment with clomipramine HCl may have on the
growth and development of 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 HCl in children under the
age of 10.
Use in Elderly
Clomipramine HCl has not been systematically studied in older patients; but 152 patients at least 60
years of age participating in U.S. clinical trials received clomipramine HCl for periods of several
months to several years. No unusual age-related adverse events have been identified in this elderly
population, but these data are insufficient to rule out possible age-related differences, particularly in
elderly patients who have concomitant systemic illnesses or who are receiving other drugs
concomitantly.