Data from FDA (Food and Drug Administration, USA) - Curated by EPG Health - Last updated 01 June 2018

Indication(s)

INDICATIONS AND USAGE Clomipramine hydrochloride capsules, USP are indicated for the treatment of obsessions and compulsions in patients with Obsessive-Compulsive Disorder (OCD). The obsessions or compulsions must cause marked distress, be time-consuming, or significantly interfere with social or occupational functioning, in order to meet the DSM-III-R (circa 1,989) diagnosis of OCD. Obsessions are recurrent, persistent ideas, thoughts, images, or impulses that are ego dystonic. Compulsions are repetitive, purposeful, and intentional behaviors performed in response to an obsession or in a stereotyped fashion, and are recognized by the person as excessive or unreasonable. The effectiveness of clomipramine hydrochloride for the treatment of OCD was demonstrated in multicenter, placebo-controlled, parallel-group studies, including two 10-week studies in adults and one 8-week study in children and adolescents 10 to 17 years of age. Patients in all studies had moderate-to-severe OCD (DSM-III), with mean baseline ratings on the Yale-Brown Obsessive Compulsive Scale (YBOCS) ranging from 26 to 28 and a mean baseline rating of 10 on the NIMH Clinical Global Obsessive Compulsive Scale (NIMH-OC). Patients taking CMI experienced a mean reduction of approximately 10 on the YBOCS, representing an average improvement on this scale of 35% to 42% among adults and 37% among children and adolescents. CMI-treated patients experienced a 3.5 unit decrement on the NIMH-OC. Patients on placebo showed no important clinical response on either scale. The maximum dose was 250 mg/day for most adults and 3 mg/kg/day (up to 200 mg) for all children and adolescents. The effectiveness of clomipramine hydrochloride for long-term use (i.e., for more than 10 weeks) has not been systematically evaluated in placebo-controlled trials. The physician who elects to use clomipramine hydrochloride for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient (see DOSAGE AND ADMINISTRATION ).

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Advisory information

contraindications
CONTRAINDICATIONS Clomipramine hydrochloride is contraindicated in patients with a history of hypersensitivity to clomipramine hydrochloride or other tricyclic antidepressants. Monoamine Oxidase Inhibitors (MAOIs) The use of MAOIs intended to treat psychiatric disorders with clomipramine hydrochloride or within 14 days of stopping treatment with clomipramine hydrochloride is contraindicated because of an increased risk of serotonin syndrome. The use of clomipramine hydrochloride within 14 days of stopping an MAOI intended to treat psychiatric disorders is also contraindicated (see WARNINGS and DOSAGE AND ADMINISTRATION ). Starting clomipramine hydrochloride in a patient who is being treated with linezolid or intravenous methylene blue is also contraindicated because of an increased risk of serotonin syndrome (see WARNINGS and DOSAGE AND ADMINISTRATION ). Myocardial Infarction Clomipramine hydrochloride is contraindicated during the acute recovery period after a myocardial infarction.
Special warnings and precautions
PRECAUTIONS General Suicide Since depression is a commonly associated feature of OCD, the risk of suicide must be considered. Prescriptions for clomipramine hydrochloride 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 in clinical trials; but patients were frequently asymptomatic. Among approximately 1,400 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 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. As with tricyclic antidepressants to which it is closely related, clomipramine hydrochloride may precipitate an acute psychotic episode in patients with unrecognized schizophrenia. Mania/Hypomania During premarketing testing of clomipramine hydrochloride 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. Hepatic Changes During premarketing testing, clomipramine hydrochloride 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 clomipramine hydrochloride, there have been postmarketing reports of leukopenia, agranulocytosis, thrombocytopenia, anemia, and pancytopenia in association with clomipramine hydrochloride use. As is the case with tricyclic antidepressants to which clomipramine hydrochloride is closely related, leukocyte and differential blood counts should be obtained in patients who develop fever and sore throat during treatment with clomipramine hydrochloride. Central Nervous System More than 30 cases of hyperthermia have been recorded by nondomestic postmarketing surveillance systems. Most cases occurred when clomipramine hydrochloride was used in combination with other drugs. When clomipramine hydrochloride 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 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 hydrochloride, compared with 1% of patients receiving placebo. In these studies, 28% of patients receiving clomipramine hydrochloride 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 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 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 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 should be used with caution in the following: Hyperthyroid patients or patients receiving thyroid medication, because of the possibility of cardiac toxicity; Patients with increased intraocular pressure, a history of narrow-angle glaucoma, or urinary retention, because of the anticholinergic properties of the drug; Patients with tumors of the adrenal medulla (e.g., pheochromocytoma, neuroblastoma) in whom the drug may provoke hypertensive crises; Patients with significantly impaired renal function. Withdrawal Symptoms A variety of withdrawal symptoms have been reported in association with abrupt discontinuation of clomipramine hydrochloride, 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 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: The risk of seizure (see WARNINGS ); The relatively high incidence of sexual dysfunction among males (see Sexual Dysfunction ); Since clomipramine hydrochloride may impair the mental and/or physical abilities required for the performance of complex tasks, and since clomipramine hydrochloride is associated with a risk of seizures, patients should be cautioned about the performance of complex and hazardous tasks (see WARNINGS ); Patients should be cautioned about using alcohol, barbiturates, or other CNS depressants concurrently, since clomipramine hydrochloride may exaggerate their response to these drugs; Patients should notify their physician if they become pregnant or intend to become pregnant during therapy; Patients should notify their physician if they are breast-feeding. Patients should be advised that taking clomipramine hydrochloride 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. Drug Interactions The risks of using clomipramine hydrochloride in combination with other drugs have not been systematically evaluated. Given the primary CNS effects of clomipramine hydrochloride, caution is advised in using it concomitantly with other CNS-active drugs (see Information for Patients ). Clomipramine hydrochloride should not be used with MAO inhibitors (see CONTRAINDICATIONS ). Close supervision and careful adjustment of dosage are required when clomipramine hydrochloride 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 is going to be co-administered with another drug known to be an inhibitor of P450 2D6 (and/or P450 1A2). Because clomipramine hydrochloride 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 by other highly bound drugs (see CLINICAL PHARMACOLOGY, 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 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/m2basis, 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 until delivery. Clomipramine hydrochloride 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 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 for up to 8 weeks. In addition, 150 adolescent patients have received clomipramine hydrochloride 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 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 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 in pediatric patients under the age of 10. Geriatric Use Clinical studies of clomipramine hydrochloride 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 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.
Adverse reactions
ADVERSE REACTIONS Commonly Observed The most commonly observed adverse events associated with the use of clomipramine hydrochloride 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 3,616 patients who received clomipramine hydrochloride 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 in adult or pediatric placebo- controlled clinical trials. The frequencies were obtained from pooled data of clinical trials involving either adults receiving clomipramine hydrochloride (N=322) or placebo (N=319) or children treated with clomipramine hydrochloride (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. *Events reported by at least 1% of clomipramine hydrochloride patients are included. Adults Children and Adolescents Body System/ Adverse Event* Clomipramine hydrochloride (N=322) Placebo (N=319) Clomipramine hydrochloride (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 Other Events Observed During the Premarketing Evaluation of Clomipramine Hydrochloride During clinical testing in the U.S., multiple doses of clomipramine hydrochloride were administered to approximately 3,600 subjects. Untoward events associated with this exposure were recorded by clinical investigators using terminology of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse events without first grouping similar types of untoward events into a smaller number of standardized event categories. In the tabulations that follow, a modified World Health Organization dictionary of terminology has been used to classify reported adverse events. The frequencies presented, therefore, represent the proportion of the 3,525 individuals exposed to clomipramine hydrochloride who experienced an event of the type cited on at least one occasion while receiving clomipramine hydrochloride. All events are included except those already listed in the previous table, those reported in terms so general as to be uninformative, and those in which an association with the drug was remote. It is important to emphasize that although the events reported occurred during treatment with clomipramine hydrochloride, they were not necessarily caused by it. Events are further categorized by body system and listed in order of decreasing frequency according to the following definitions: frequent adverse events are those occurring on one or more occasions in at least 1/100 patients; infrequent adverse events are those occurring in 1/100 to 1/1,000 patients; rare events are those occurring in less than 1/1,000 patients. Body as a Whole Infrequent - general edema, increased susceptibility to infection, malaise. Rare - dependent edema, withdrawal syndrome. Cardiovascular System Infrequent - abnormal ECG, arrhythmia, bradycardia, cardiac arrest, extrasystoles, pallor. Rare - aneurysm, atrial flutter, bundle branch block, cardiac failure, cerebral hemorrhage, heart block, myocardial infarction, myocardial ischemia, peripheral ischemia, thrombophlebitis, vasospasm, ventricular tachycardia. Digestive System Infrequent - abnormal hepatic function, blood in stool, colitis, duodenitis, gastric ulcer, gastritis, gastroesophageal reflux, gingivitis, glossitis, hemorrhoids, hepatitis, increased saliva, irritable bowel syndrome, peptic ulcer, rectal hemorrhage, tongue ulceration, tooth caries. Rare - cheilitis, chronic enteritis, discolored feces, gastric dilatation, gingival bleeding, hiccup, intestinal obstruction, oral/pharyngeal edema, paralytic ileus, salivary gland enlargement. Endocrine System Infrequent - hypothyroidism. Rare - goiter, gynecomastia, hyperthyroidism. Hemic and Lymphatic System Infrequent - lymphadenopathy. Rare - leukemoid reaction, lymphoma-like disorder, marrow depression. Metabolic and Nutritional Disorder Infrequent - dehydration, diabetes mellitus, gout, hypercholesterolemia, hyperglycemia, hyperuricemia, hypokalemia. Rare - fat intolerance, glycosuria. Musculoskeletal System Infrequent - arthrosis. Rare - dystonia, exostosis, lupus erythematosus rash, bruising, myopathy, myositis, polyarteritis nodosa, torticollis. Nervous System Frequent - abnormal thinking, vertigo. Infrequent - abnormal coordination, abnormal EEG, abnormal gait, apathy, ataxia, coma, convulsions, delirium, delusion, dyskinesia, dysphonia, encephalopathy, euphoria, extrapyramidal disorder, hallucinations, hostility, hyperkinesia, hypnagogic hallucinations, hypokinesia, leg cramps, manic reaction, neuralgia, paranoia, phobic disorder, psychosis, sensory disturbance, somnambulism, stimulation, suicidal ideation, suicide attempt, teeth- grinding. Rare - anticholinergic syndrome, aphasia, apraxia, catalepsy, cholinergic syndrome, choreoathetosis, generalized spasm, hemiparesis, hyperesthesia, hyperreflexia, hypoesthesia, illusion, impaired impulse control, indecisiveness, mutism, neuropathy, nystagmus, oculogyric crisis, oculomotor nerve paralysis, schizophrenic reaction, stupor, suicide. Respiratory System Infrequent - bronchitis, hyperventilation, increased sputum, pneumonia. Rare - cyanosis, hemoptysis, hypoventilation, laryngismus. Skin and Appendages Infrequent - alopecia, cellulitis, cyst, eczema, erythematous rash, genital pruritus, maculopapular rash, photosensitivity reaction, psoriasis, pustular rash, skin discoloration. Rare - chloasma, folliculitis, hypertrichosis, piloerection, seborrhea, skin hypertrophy, skin ulceration. Special Senses Infrequent - abnormal accommodation, deafness, diplopia, earache, eye pain, foreign body sensation, hyperacusis, parosmia, photophobia, scleritis, taste loss. Rare - blepharitis, chromatopsia, conjunctival hemorrhage, exophthalmos, glaucoma, keratitis, labyrinth disorder, night blindness, retinal disorder, strabismus, visual field defect. Urogenital System Infrequent - endometriosis, epididymitis, hematuria, nocturia, oliguria, ovarian cyst, perineal pain, polyuria, prostatic disorder, renal calculus, renal pain, urethral disorder, urinary incontinence, uterine hemorrhage, vaginal hemorrhage. Rare - albuminuria, anorgasmy, breast engorgement, breast fibroadenosis, cervical dysplasia, endometrial hyperplasia, premature ejaculation, pyelonephritis, pyuria, renal cyst, uterine inflammation, vulvar disorder. Postmarketing Experience The following adverse drug reaction has been reported during post-approval use of clomipramine hydrochloride. Because this reaction is reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate frequency. Eye Disorders Angle-closure glaucoma. Immune System Disorders Drug Rash with Eosinophilia and Systemic Symptoms (DRESS)

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Dosing and administration
DOSAGE AND ADMINISTRATION The treatment regimens described below are based on those used in controlled clinical trials of clomipramine hydrochloride in 520 adults, and 91 children and adolescents with OCD. During initial titration, clomipramine hydrochloride should be given in divided doses with meals to reduce gastrointestinal side effects. The goal of this initial titration phase is to minimize side effects by permitting tolerance to side effects to develop or allowing the patient time to adapt if tolerance does not develop. Because both CMI and its active metabolite, DMI, have long elimination half-lives, the prescriber should take into consideration the fact that steady-state plasma levels may not be achieved until 2 to 3 weeks after dosage change (see CLINICAL PHARMACOLOGY ). Therefore, after initial titration, it may be appropriate to wait 2 to 3 weeks between further dosage adjustments. Initial Treatment/Dose Adjustment (Adults) Treatment with clomipramine hydrochloride should be initiated at a dosage of 25 mg daily and gradually increased, as tolerated, to approximately 100 mg during the first 2 weeks. During initial titration, clomipramine hydrochloride should be given in divided doses with meals to reduce gastrointestinal side effects. Thereafter, the dosage may be increased gradually over the next several weeks, up to a maximum of 250 mg daily. After titration, the total daily dose may be given once daily at bedtime to minimize daytime sedation. Initial Treatment/Dose Adjustment (Children and Adolescents) As with adults, the starting dose is 25 mg daily and should be gradually increased (also given in divided doses with meals to reduce gastrointestinal side effects) during the first 2 weeks, as tolerated, up to a daily maximum of 3 mg/kg or 100 mg, whichever is smaller. Thereafter, the dosage may be increased gradually over the next several weeks up to a daily maximum of 3 mg/kg or 200 mg, whichever is smaller (see PRECAUTIONS, Pediatric Use ). As with adults, after titration, the total daily dose may be given once daily at bedtime to minimize daytime sedation. Maintenance/Continuation Treatment (Adults, Children, and Adolescents) While there are no systematic studies that answer the question of how long to continue clomipramine hydrochloride, OCD is a chronic condition and it is reasonable to consider continuation for a responding patient. Although the efficacy of clomipramine hydrochloride after 10 weeks has not been documented in controlled trials, patients have been continued in therapy under double- blind conditions for up to 1 year without loss of benefit. However, dosage adjustments should be made to maintain the patient on the lowest effective dosage, and patients should be periodically reassessed to determine the need for treatment. During maintenance, the total daily dose may be given once daily at bedtime. Switching a Patient To or From a Monoamine Oxidase Inhibitor (MAOI) Intended to Treat Psychiatric Disorders At least 14 days should elapse between discontinuation of an MAOI intended to treat psychiatric disorders and initiation of therapy with clomipramine hydrochloride. Conversely, at least 14 days should be allowed after stopping clomipramine hydrochloride before starting an MAOI intended to treat psychiatric disorders (see CONTRAINDICATIONS ). Use of Clomipramine Hydrochloride With Other MAOIs, Such as Linezolid or Methylene Blue Do not start clomipramine hydrochloride in a patient who is being treated with linezolid or intravenous methylene blue because there is increased risk of serotonin syndrome. In a patient who requires more urgent treatment of a psychiatric condition, other interventions, including hospitalization, should be considered (see CONTRAINDICATIONS ). In some cases, a patient already receiving clomipramine hydrochloride therapy may require urgent treatment with linezolid or intravenous methylene blue. If acceptable alternatives to linezolid or intravenous methylene blue treatment are not available and the potential benefits of linezolid or intravenous methylene blue treatment are judged to outweigh the risks of serotonin syndrome in a particular patient, clomipramine hydrochloride should be stopped promptly, and linezolid or intravenous methylene blue can be administered. The patient should be monitored for symptoms of serotonin syndrome for two weeks or until 24 hours after the last dose of linezolid or intravenous methylene blue, whichever comes first. Therapy with clomipramine hydrochloride may be resumed 24 hours after the last dose of linezolid or intravenous methylene blue (see WARNINGS ). The risk of administering methylene blue by non-intravenous routes (such as oral tablets or by local injection) or in intravenous doses much lower than 1 mg/kg with clomipramine hydrochloride is unclear. The clinician should, nevertheless, be aware of the possibility of emergent symptoms of serotonin syndrome with such use (see WARNINGS ).
Pregnancy and lactation
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.

Interactions

Drug Interactions The risks of using clomipramine hydrochloride in combination with other drugs have not been systematically evaluated. Given the primary CNS effects of clomipramine hydrochloride, caution is advised in using it concomitantly with other CNS-active drugs (see Information for Patients ). Clomipramine hydrochloride should not be used with MAO inhibitors (see CONTRAINDICATIONS ). Close supervision and careful adjustment of dosage are required when clomipramine hydrochloride 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 is going to be co-administered with another drug known to be an inhibitor of P450 2D6 (and/or P450 1A2). Because clomipramine hydrochloride 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 by other highly bound drugs (see CLINICAL PHARMACOLOGY, 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 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/m2basis, respectively.

More information

Category Value
Authorisation number ANDA208961
Agency product number 2LXW0L6GWJ
Orphan designation No
Product NDC 70710-1067,70710-1066,70710-1065
Date Last Revised 18-04-2018
Type HUMAN PRESCRIPTION DRUG
RXCUI 857305
Marketing authorisation holder Zydus Pharmaceuticals (USA) Inc.
Warnings Suicidality and Antidepressant Drugs Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use of clomipramine hydrochloride or any other antidepressant in a child, adolescent, or young adult must balance this risk with the clinical need. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction in risk with antidepressants compared to placebo in adults aged 65 and older. Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Patients of all ages who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. Clomipramine hydrochloride is not approved for use in pediatric patients except for patients with obsessive compulsive disorder (OCD) (see WARNINGS, Clinical Worsening and Suicide Risk; PRECAUTIONS, Information for Patients; and PRECAUTIONS, Pediatric Use).