The risks of using Clomipramine hydrochloride capsules, USP in combination with other drugs have not been systematically evaluated. Given the primary CNS effects of Clomipramine hydrochloride capsules, USP, caution is advised in using it concomitantly with other CNS-active drugs (see Information for Patients). Clomipramine hydrochloride capsules, USP should not be used with MAO inhibitors (see CONTRAINDICATIONS).
Close supervision and careful adjustment of dosage are required when Clomipramine hydrochloride capsules, USP is administered with anticholinergic or sympathomimetic drugs.
Several tricyclic antidepressants have been reported to block the pharmacologic effects of guanethidine, clonidine, or similar agents, and such an effect may be anticipated with CMI because of its structural similarity to other tricyclic antidepressants.
The plasma concentration of CMI has been reported to be increased by the concomitant administration of haloperidol; plasma levels of several closely related tricyclic antidepressants have been reported to be increased by the concomitant administration of methylphenidate or hepatic enzyme inhibitors (e.g., cimetidine, fluoxetine) and decreased by the concomitant administration of hepatic enzyme inducers (e.g., barbiturates, phenytoin), and such an effect may be anticipated with CMI as well. Administration of CMI has been reported to increase the plasma levels of phenobarbital, if given concomitantly (see CLINICAL PHARMACOLOGY, Interactions).
Drugs Metabolized by P450 2D6 – The biochemical activity of the drug metabolizing isozyme cytochrome P450 2D6 (debrisoquin hydroxylase) is reduced in a subset of the Caucasian population (about 7% to 10% of Caucasians are so-called “poor metabolizers”); reliable estimates of the prevalence of reduced P450 2D6 isozyme activity among Asian, African and other populations are not yet available. Poor metabolizers have higher than expected plasma concentrations of tricyclic antidepressants (TCAs) when given usual doses. Depending on the fraction of drug metabolized by P450 2D6, the increase in plasma concentration may be small, or quite large (8 fold increase in plasma AUC of the TCA). In addition, certain drugs inhibit the activity of this isozyme and make normal metabolizers resemble poor metabolizers. An individual who is stable on a given dose of TCA may become abruptly toxic when given one of these inhibiting drugs as concomitant therapy. The drugs that inhibit cytochrome P450 2D6 include some that are not metabolized by the enzyme (quinidine; cimetidine) and many that are substrates for P450 2D6 (many other antidepressants, phenothiazines, and the Type 1C antiarrhythmics propafenone and flecainide). While all the selective serotonin reuptake inhibitors (SSRIs), e.g., fluoxetine, sertraline, paroxetine, and fluvoxamine, inhibit P450 2D6, they may vary in the extent of inhibition. Fluvoxamine has also been shown to inhibit P450 1A2, an isoform also involved in TCA metabolism. The extent to which SSRI-TCA interactions may pose clinical problems will depend on the degree of inhibition and the pharmacokinetics of the SSRI involved. Nevertheless, caution is indicated in the co-administration of TCAs with any of the SSRIs and also in switching from one class to the other. Of particular importance, sufficient time must elapse before initiating TCA treatment in a patient being withdrawn from fluoxetine, given the long half-life of the parent and active metabolite (at least 5 weeks may be necessary). Concomitant use of agents in the tricyclic antidepressant class (which includes Clomipramine hydrochloride) with drugs that can inhibit cytochrome P450 2D6 may require lower doses than usually prescribed for either the tricyclic antidepressant agent or the other drug. Furthermore, whenever one of these drugs is withdrawn from co-therapy, an increased dose of tricyclic antidepressant agent may be required. It is desirable to monitor TCA plasma levels whenever an agent of the tricyclic antidepressant class including Clomipramine hydrochloride capsules, USP is going to be co-administered with another drug known to be an inhibitor of P450 2D6 (and/or P450 1A2).
Because Clomipramine hydrochloride capsules, USP is highly bound to serum protein, the administration of Clomipramine hydrochloride to patients taking other drugs that are highly bound to protein (e.g., warfarin, digoxin) may cause an increase in plasma concentrations of these drugs, potentially resulting in adverse effects. Conversely, adverse effects may result from displacement of protein-bound Clomipramine hydrochloride capsules, USP by other highly bound drugs (see CLINICAL PHARMACOLOGY, Distribution).
Monoamine Oxidase Inhibitors (MAOIs)
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.
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 Clomipramine hydrochloride capsules, USP until delivery. Clomipramine hydrochloride capsules, USP should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
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.
Safety and effectiveness in the pediatric population other than pediatric patients with OCD have not been established (see BOX WARNING and WARNINGS, Clinical Worsening and Suicide Risk). Anyone considering the use of Clomipramine hydrochloride capsules, USP in a child or adolescent must balance the potential risks with the clinical need.
In a controlled clinical trial in children and adolescents (10 to 17 years of age), 46 outpatients received Clomipramine hydrochloride capsules, USP for up to 8 weeks. In addition, 150 adolescent patients have received Clomipramine hydrochloride capsules, USP 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 to 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 Clomipramine hydrochloride’s extended use in children and adolescents with OCD have not been systematically assessed. The evidence supporting the conclusion that Clomipramine hydrochloride capsules, USP 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 Clomipramine hydrochloride capsules, USP use on the growth, development, and maturation of children and adolescents. Although there is no evidence to suggest that Clomipramine Hydrochloride 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 Clomipramine hydrochloride capsules, USP in pediatric patients under the age of 10.
Clinical studies of Clomipramine hydrochloride capsules, USP 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 Clomipramine hydrochloride capsules, USP 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.
Clomipramine Hydrochloride has been associated with cases of clinically significant hyponatremia. Elderly patients may be at greater risk for this adverse reaction (see PRECAUTIONS, Hyponatremia ).
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