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Commonly Observed

The most commonly observed adverse events associated with the use of Anafranil 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 Anafranil 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 Anafranil in adult or pediatric placebo-controlled clinical trials. The frequencies were obtained from pooled data of clinical trials involving either adults receiving Anafranil (N=322) or placebo (N=319) or children treated with Anafranil (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)

Body System/ Adverse Event* Adults Children and Adolescents
Anafranil
(N=322)
Placebo
(N=319)
Anafranil
(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
*Events reported by at least 1% of Anafranil patients are included.

Other Events Observed During the Premarketing Evaluation of Anafranil

During clinical testing in the U.S., multiple doses of Anafranil 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 Anafranil who experienced an event of the type cited on at least one occasion while receiving Anafranil. 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 Anafranil, 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.

Drug Abuse And Dependence

Anafranil has not been systematically studied in animals or humans for its potential for abuse, tolerance, or physical dependence. While a variety of withdrawal symptoms have been described in association with Anafranil discontinuation (see PRECAUTIONS, Withdrawal Symptoms), there is no evidence for drug-seeking behavior, except for a single report of potential Anafranil abuse by a patient with a history of dependence on codeine, benzodiazepines, and multiple psychoactive drugs. The patient received Anafranil for depression and panic attacks and appeared to become dependent after hospital discharge.

Despite the lack of evidence suggesting an abuse liability for Anafranil in foreign marketing, it is not possible to predict the extent to which Anafranil might be misused or abused once marketed in the U.S. Consequently, physicians should carefully evaluate patients for a history of drug abuse and follow such patients closely.