Clomipramine Hydrochloride (Page 5 of 7)

ADVERSE REACTIONS

Commonly Observed

The most commonly observed adverse events associated with the use of Clomipramine hydrochloride capsules, USP 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, USP 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, USP 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, USP (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.

Incidence of Treatment-Emergent Adverse Experience in Placebo-Controlled Clinical Trials (Percentage of Patients Reporting Event)
*
Events reported by at least 1% of Clomipramine hydrochloride capsules, USP 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 capsules, USP

During clinical testing in the U.S., multiple doses of Clomipramine hydrochloride capsules, USP were administered to approximately 3600 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 3525 individuals exposed to Clomipramine hydrochloride capsules, USP 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 capsules, USP, 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 1/1000 patients; rare events are those occurring in less than 1/1000 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 capsules, USP. 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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