A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Anafranil Warnings, Precautions, Pregnancy, Nursing, Abuse - Clomipramine Hcl
Anafranil Warnings, Precautions, Pregnancy, Nursing, Abuse - Clomipramine Hcl
WARNINGS
Seizures
During premarket evaluation, seizure was identified as the most significant risk of Anafranil use.
The observed cumulative incidence of seizures among patients exposed to Anafranil 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 Anafranil 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, Anafranil had been administered with other epileptogenic agents; in others, the patients involved had possibly predisposing medical conditions. Thus a causal association between Anafranil treatment and these fatalities has not been established.
Physicians should discuss with patients the risk of taking Anafranil 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 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® (clomipramine hydrochloride capsules, USP) 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 non-domestic 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.
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:
(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: Avariety 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
Physicians are advised to discuss the following issues with patients for whom they prescribe Anafranil:
(1) The risk of seizure (see WARNINGS);
(2) The relatively high incidence of sexual dysfunction among males (see Sexual Dysfunction);
(3) 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);
(4) Patients should be cautioned about using alcohol, barbiturates, or other CNS depressants concurrently, since Anafranil 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
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® (clomipramine hydrochloride capsules, USP) 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 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 14-17 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 age-related 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.
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