Clomipramine Hydrochloride (Page 5 of 7)

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.

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).

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).

Metabolism and Nutrition Disorders

Hyponatremia.

Endocrine Disorders

Syndrome of inappropriate antidiuretic hormone secretion (SIADH).

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