Anafranil Side Effects

Generic name: clomipramine

Generic Name: Clomipramine

Please note - some side effects for Anafranil may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA at http://www.fda.gov/medwatch/ or 1-800-FDA-1088 (1-800-332-1088).

Side Effects of Anafranil - for the consumer

Anafranil

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome when using Anafranil:

Constipation; diarrhea; dizziness; drowsiness; dry mouth; headache; irritability; loss of appetite; nausea; nightmares; sweating; tiredness; upset stomach; vomiting; weakness; weight loss or gain.

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); blurred vision or other vision changes; changes in sex drive; chest pain; confusion; decreased sexual ability; fainting; fast, slow, or irregular heartbeat; fever; flushing; frequent or difficult urination; impulsive behavior or other unusual changes in behavior; mental or mood changes (eg, increased anxiety, mood swings, agitation, irritability, nervousness, restlessness); numbness or tingling of the skin; panic attacks; ringing in the ears; seizures; severe dizziness or drowsiness; sore throat; stomach pain; suicidal thinking or behavior; swelling of the testicles; tremor; trouble sleeping; trouble walking or keeping your balance; twitching of the face or tongue; uncontrolled movements or stiffness of arms and legs; unusual bleeding or bruising; worsening of depression; yellowing of the skin or eyes.

For the professional

Anafranil

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.

Other Events Observed During the Premarketing Evaluation of Anafranil

During clinical testing in the U.S., multiple doses of Anafranil® (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 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.

By body system

Nervous system side effects

Nervous system side effects including drowsiness, dizziness, sedation, and headache have been reported frequently. Anticholinergic effects have been reported frequently and include dry mouth, blurry vision, constipation, and urinary retention. Tremor, delirium, akathisia, a tardive dyskinesia- like syndrome, myoclonus, motor hyperactivity during sleep, sleep abnormalities, dystonic reactions, Tourettism, and seizures have also been reported.

Where a primary reason for discontinuation could be identified, most patients discontinued because of nervous system complaints (5.4%), primarily somnolence.

One study has suggested that sedation may occur in 87% of treated patients.

The manufacturer reports that the cumulative incidence of seizures during premarketing testing averaged 0.64% at 90 days and 1.45% at 365 days.

Nearly all selective serotonin reuptake inhibitors, mixed serotonin/norepinephrine reuptake inhibitors, and tricyclic antidepressants cause sleep abnormalities to some extent. These antidepressants have marked dose-dependent effects on rapid eye movement (REM) sleep, causing reductions in the overall amount of REM sleep over the night and delays the first entry into REM sleep (increased REM sleep onset latency (ROL)), both in healthy subjects and depressed patients. The antidepressants that increase serotonin function appear to have the greatest effect on REM sleep. The reduction in REM sleep is greatest early in treatment, but gradually returns towards baseline during long-term therapy; however, ROL remains long. Following discontinuation of therapy the amount of REM sleep tends to rebound. Some of these drugs (i.e., bupropion, mirtazapine, nefazodone, trazodone, trimipramine) appear to have a modest or minimal effect on REM sleep.

Cardiovascular side effects

Both antiarrhythmic and proarrhythmic effects have been reported in association with tricyclic therapy.

One study of the cardiovascular effects of clomipramine in 26 depressed patients suggested that clomipramine may produce variable and complex cardiac effects. The authors concluded that the drug is "generally well tolerated but it does present some degree of risk for the heart".

Caution should be exercised if clomipramine must be used in patients with cardiovascular disease.

Cardiovascular side effects that have been associated with the use of tricyclic antidepressants have included orthostatic hypotension, tachycardia, QRS widening, other conduction abnormalities, malignant arrhythmias, and malignant hypertension.

Psychiatric side effects

Psychiatric side effects with use of this drug have included mania and hallucinations. Suicidal ideation, paradoxical aggressiveness, and mental status changes have also been reported with use of clomipramine and other tricyclic antidepressants.

Gastrointestinal side effects

A study of 26,005 antidepressant users has reported 3.6 times more upper GI bleeding episodes with the use of SSRI's relative to the population who did not receive antidepressant medications. Upper gastrointestinal tract bleeding was observed in 2.3 times more frequently in patients receiving clomipramine.

Where a primary reason for discontinuation could be identified, the second most frequent reason for discontinuation was digestive system complaints (1.3%), primarily nausea and vomiting.

Gastrointestinal side effects have included nausea, vomiting, dry mouth, and constipation.

General side effects

General side effects including increased appetite and weight gain have been associated with the use of clomipramine.

Other side effects

In one retrospective chart review of 352 patients who were supervised during tapering and discontinuation from serotonin reuptake inhibitor therapy, dizziness, lethargy, paresthesia, nausea, vivid dreams, irritability, and lowered mood were the most common symptoms reported. Patients with at least on qualitatively new symptom were defined in the clomipramine group at a rate of 30.8%.

Other side effects including withdrawal reactions involving both rebound worsening of preexisting psychiatric conditions and physiologic symptoms have been reported. Abrupt discontinuation may result in symptoms of withdrawal (such as nausea, headache, malaise, irritability and generalized CNS stimulation). Specific physiologic withdrawal symptoms may include nervousness, anxiety, restlessness, akathisia, nausea, malaise, sweating, salivation and seizures. Tachycardia has also been reported.

Genitourinary side effects

Decreased nocturnal penile tumescence and delayed ejaculation have been reported.

One report has suggested that cyproheptadine may be beneficial in the treatment of clomipramine- induced anorgasmia.

Cases of spontaneous orgasm associated with yawning and clomipramine therapy have been reported.

Genitourinary side effects have been reported frequently and have included sexual dysfunction (involving anorgasmia, impotence and decreased libido). Urinary retention has also been reported.

Hematologic side effects

Hematologic side effects have been rare and have included agranulocytosis and pancytopenia.

Endocrine side effects

Endocrine side effects including hyponatremia (in association with the syndrome of inappropriate secretion of antidiuretic hormone) have been reported rarely. Hyperprolactinemia, galactorrhea and secondary amenorrhea have also been reported. A case of pancreatitis associated with clomipramine overdose has been reported.

Following the ingestion of 750 mg to 1,500 mg of clomipramine, a 48 year old female patient developed acute chemical pancreatitis and subsequent abdominal ileus. Serum lipase levels were elevated to 2,546 international units at one point, with a concomitant serum amylase of 112 international units. Two weeks after discontinuing clomipramine and resting the patient's gastrointestinal tract, the ileus and pancreatitis had resolved.

Hepatic side effects

Hepatic side effects have been rare and have included elevated liver function tests and drug-induced hepatitis.

Dermatologic side effects

Dermatologic side effects have included sweating (common) and drug eruptions, photosensitivity, and contact allergy (rare).

Other side effects

Other side effects including neuroleptic malignant syndrome have been reported. One case of neuroleptic malignant syndrome in association with clomipramine (20 mg/day) has been reported. Symptoms including sweating, pyrexia, muscle rigidity, and urinary incontinence resolved with 48 hours after discontinuation of clomipramine and recurred upon rechallenge.

Metabolic side effects

Metabolic side effects including dyslipidemia have been reported. Dyslipidemia (i.e., hypercholesterolemia, hypertriglyceridemia) was reported in a patient receiving clomipramine 150 mg daily. A case of clomipramine-induced diabetes has also been reported.

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