Clomipramine Hydrochloride: Package Insert and Label Information (Page 3 of 5)
Drug Interactions
The risks of using clomipramine hydrochloride capsules in combination with other drugs have not been systematically evaluated. Given the primary CNS effects of clomipramine hydrochloride capsules, caution is advised in using it concomitantly with other CNS-active drugs (see PRECAUTIONS: Information for Patients). Clomipramine hydrochloride capsules should not be used with MAO inhibitors (see CONTRAINDICATIONS).
Close supervision and careful adjustment of dosage are required when clomipramine hydrochloride capsules are 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: Pharmacokinetics: 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 capsules) 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 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 are highly bound to serum protein, the administration of clomipramine hydrochloride capsules 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 by other highly bound drugs (see CLINICAL PHARMACOLOGY: Pharmacokinetics: Distribution).
Monoamine Oxidase Inhibitors (MAOIs)
(See CONTRAINDICATIONS, WARNINGS and DOSAGE AND ADMINISTRATION.)
Serotonergic Drugs
(See CONTRAINDICATIONS, WARNINGS and DOSAGE AND ADMINISTRATION.)
Carcinogenesis, Mutagenesis, Impairment of Fertility
No evidence of carcinogenecity 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 clomipramine hydrochloride capsules until delivery. Clomipramine hydrochloride capsules should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Nursing Mothers
Clomipramine hydrochloride 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
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 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 for up to 8 weeks. In addition, 150 adolescent patients have received clomipramine hydrochloride capsules 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 capsule’s extended use in children and adolescents with OCD have not been systematically assessed. The evidence supporting the conclusion that clomipramine hydrochloride capsules are 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 use on the growth, development, and maturation of children and adolescents. Although there is no evidence to suggest that clomipramine hydrochloride capsules adversely affect 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 in pediatric patients under the age of 10.
Geriatric Use
Clinical studies of clomipramine hydrochloride capsules 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 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 capsules have been associated with cases of clinically significant hyponatremia. Elderly patients may be at greater risk for this adverse reaction (see PRECAUTIONS: Hyponatremia).
ADVERSE REACTIONS
Commonly Observed
The most commonly observed adverse events associated with the use of clomipramine hydrochloride capsules and not seen at an equivalent incidence among placebo-treated patients were gastrointestinal complaints, including dry mouth, constipation, nausea, dyspepsia, and anorexia; nervous system complaints, including somnolence, tremor, dizziness, nervousness, and myoclonus; genitourinary complaints, including changed libido, ejaculatory failure, impotence, and micturition disorder; and other miscellaneous complaints, including fatigue, sweating, increased appetite, weight gain, and visual changes.
Leading to Discontinuation of Treatment
Approximately 20% of 3616 patients who received clomipramine hydrochloride capsules in U.S. premarketing clinical trials discontinued treatment because of an adverse event. Approximately one-half of the patients who discontinued (9% of the total) had multiple complaints, none of which could be classified as primary. Where a primary reason for discontinuation could be identified, most patients discontinued because of nervous system complaints (5.4%), primarily somnolence. The second-most-frequent reason for discontinuation was digestive system complaints (1.3%), primarily vomiting and nausea.
There was no apparent relationship between the adverse events and elevated plasma drug concentrations.
Incidence in Controlled Clinical Trials
The following table enumerates adverse events that occurred at an incidence of 1% or greater among patients with OCD who received clomipramine hydrochloride capsules in adult or pediatric placebo-controlled clinical trials. The frequencies were obtained from pooled data of clinical trials involving either adults receiving clomipramine hydrochloride capsules (N = 322) or placebo (N = 319) or children treated with clomipramine hydrochloride capsules (N = 46) or placebo (N = 44). The prescriber should be aware that these figures cannot be used to predict the incidence of side effects in the course of usual medical practice, in which patient characteristics and other factors differ from those that prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators. The cited figures, however, provide the physician with a basis for estimating the relative contribution of drug and nondrug factors to the incidence of side effects in the populations studied.
| ||||
| Adults | Children and Adolescents | |||
| Body System/ Adverse Event * | Clomipramine HydrochlorideCapsules(N = 322) | Placebo
(N = 319) | Clomipramine HydrochlorideCapsules(N = 46) | Placebo
(N = 44) |
| Nervous System | ||||
| Somnolence | 54 | 16 | 46 | 11 |
| Tremor | 54 | 2 | 33 | 2 |
| Dizziness | 54 | 14 | 41 | 14 |
| Headache | 52 | 41 | 28 | 34 |
| Insomnia | 25 | 15 | 11 | 7 |
| Libido change | 21 | 3 | – | – |
| Nervousness | 18 | 2 | 4 | 2 |
| Myoclonus | 13 | – | 2 | – |
| Increased appetite | 11 | 2 | – | 2 |
| Paresthesia | 9 | 3 | 2 | 2 |
| Memory impairment | 9 | 1 | 7 | 2 |
| Anxiety | 9 | 4 | 2 | – |
| Twitching | 7 | 1 | 4 | 5 |
| Impaired concentration | 5 | 2 | – | – |
| Depression | 5 | 1 | – | – |
| Hypertonia | 4 | 1 | 2 | – |
| Sleep disorder | 4 | – | 9 | 5 |
| Psychosomatic disorder | 3 | – | – | – |
| Yawning | 3 | – | – | – |
| Confusion | 3 | – | 2 | – |
| Speech disorder | 3 | – | – | – |
| Abnormal dreaming | 3 | – | – | 2 |
| Agitation | 3 | – | – | – |
| Migraine | 3 | – | – | – |
| Depersonalization | 2 | – | 2 | – |
| Irritability | 2 | 2 | 2 | – |
| Emotional lability | 2 | – | – | 2 |
| Panic reaction | 1 | – | 2 | – |
| Aggressive reaction | – | – | 2 | – |
| Paresis | – | – | 2 | – |
| Skin and Appendages | ||||
| Increased sweating | 29 | 3 | 9 | – |
| Rash | 8 | 1 | 4 | 2 |
| Pruritus | 6 | – | 2 | 2 |
| Dermatitis | 2 | – | – | 2 |
| Acne | 2 | 2 | – | 5 |
| Dry skin | 2 | – | – | 5 |
| Urticaria | 1 | – | – | – |
| Abnormal skin odor | – | – | 2 | – |
| Digestive System | ||||
| Dry mouth | 84 | 17 | 63 | 16 |
| Constipation | 47 | 11 | 22 | 9 |
| Nausea | 33 | 14 | 9 | 11 |
| Dyspepsia | 22 | 10 | 13 | 2 |
| Diarrhea | 13 | 9 | 7 | 5 |
| Anorexia | 12 | – | 22 | 2 |
| Abdominal pain | 11 | 9 | 13 | 16 |
| Vomiting | 7 | 2 | 7 | – |
| Flatulence | 6 | 3 | – | 2 |
| Tooth disorder | 5 | – | – | – |
| Gastrointestinal disorder | 2 | – | – | 2 |
| Dysphagia | 2 | – | – | – |
| Esophagitis | 1 | – | – | – |
| Eructation | – | – | 2 | 2 |
| Ulcerative stomatitis | – | – | 2 | – |
| Body as a Whole | ||||
| Fatigue | 39 | 18 | 35 | 9 |
| Weight increase | 18 | 1 | 2 | – |
| Flushing | 8 | – | 7 | – |
| Hot flushes | 5 | – | 2 | – |
| Chest pain | 4 | 4 | 7 | – |
| Fever | 4 | – | 2 | 7 |
| Allergy | 3 | 3 | 7 | 5 |
| Pain | 3 | 2 | 4 | 2 |
| Local edema | 2 | 4 | – | – |
| Chills | 2 | 1 | – | – |
| Weight decrease | – | – | 7 | – |
| Otitis media | – | – | 4 | 5 |
| Asthenia | – | – | 2 | – |
| Halitosis | – | – | 2 | – |
| Cardiovascular System | ||||
| Postural hypotension | 6 | – | 4 | – |
| Palpitation | 4 | 2 | 4 | – |
| Tachycardia | 4 | – | 2 | – |
| Syncope | – | – | 2 | – |
| Respiratory System | ||||
| Pharyngitis | 14 | 9 | – | 5 |
| Rhinitis | 12 | 10 | 7 | 9 |
| Sinusitis | 6 | 4 | 2 | 5 |
| Coughing | 6 | 6 | 4 | 5 |
| Bronchospasm | 2 | – | 7 | 2 |
| Epistaxis | 2 | – | – | 2 |
| Dyspnea | – | – | 2 | – |
| Laryngitis | – | 1 | 2 | – |
| Urogenital System | ||||
| Male and Female Patients Combined | ||||
| Micturition disorder | 14 | 2 | 4 | 2 |
| Urinary tract infection | 6 | 1 | – | – |
| Micturition frequency | 5 | 3 | – | – |
| Urinary retention | 2 | – | 7 | – |
| Dysuria | 2 | 2 | – | – |
| Cystitis | 2 | – | – | – |
| Female Patients Only | (N = 182) | (N = 167) | (N = 10) | (N = 21) |
| Dysmenorrhea | 12 | 14 | 10 | 10 |
| Lactation (nonpuerperal) | 4 | – | – | – |
| Menstrual disorder | 4 | 2 | – | – |
| Vaginitis | 2 | – | – | – |
| Leukorrhea | 2 | – | – | – |
| Breast enlargement | 2 | – | – | – |
| Breast pain | 1 | – | – | – |
| Amenorrhea | 1 | – | – | – |
| Male Patients Only | (N = 140) | (N = 152) | (N = 36) | (N = 23) |
| Ejaculation failure | 42 | 2 | 6 | – |
| Impotence | 20 | 3 | – | – |
| Special Senses | ||||
| Abnormal vision | 18 | 4 | 7 | 2 |
| Taste perversion | 8 | – | 4 | – |
| Tinnitus | 6 | – | 4 | – |
| Abnormal lacrimation | 3 | 2 | – | – |
| Mydriasis | 2 | – | – | – |
| Conjunctivitis | 1 | – | – | – |
| Anisocoria | – | – | 2 | – |
| Blepharospasm | – | – | 2 | – |
| Ocular allergy | – | – | 2 | – |
| Vestibular disorder | – | – | 2 | 2 |
| Musculoskeletal | ||||
| Myalgia | 13 | 9 | – | – |
| Back pain | 6 | 6 | – | – |
| Arthralgia | 3 | 5 | – | – |
| Muscle weakness | 1 | – | 2 | – |
| Hemic and Lymphatic | ||||
| Purpura | 3 | – | – | – |
| Anemia | – | – | 2 | 2 |
| Metabolic and Nutritional | ||||
| Thirst | 2 | 2 | – | 2 |
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