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General

The most severe adverse reactions previously observed with carbamazepine were reported in the hemopoietic system and skin (see BOXED WARNING) and in the cardiovascular system.

The most frequently observed adverse reactions, particularly during the initial phases of therapy, are dizziness, drowsiness, unsteadiness, nausea, and vomiting. To minimize the possibility of such reactions, therapy should be initiated at the lowest dosage recommended.

The most commonly observed adverse experiences (5% and at least twice placebo) seen in association with the use of EQUETRO® (400 to 1600 mg/day, dose adjusted in 200 mg daily increments in week 1 in Bipolar I Disorder in the double-blind, placebo-controlled trials of 3 weeks' duration) are included in Table 1 below:

Table 1: Most Common Adverse Events Reported in Double-Blind, Placebo-Controlled Trials (Incidence ≥ 5% and at Least Twice Placebo)

Adverse Events EQUETRO®
(N = 251)
Placebo
(N = 248)
DIZZINESS 44% 12%
SOMNOLENCE 32% 13%
NAUSEA 29% 10%
VOMITING 18% 3%
ATAXIA 15% 0%
PRURITUS 8% 2%
DRY MOUTH 8% 3%
AMBLYOPIA* 6% 2%
SPEECH DISORDER 6% 0%
* Reported as blurred vision

EQUETRO® and placebo-treated patients from two of the double-blind, placebo-controlled studies were enrolled in a 6-month open-label study. Table 2 below summarizes the most common adverse events with an incidence of 5% or more.

Table 2: Most Common Adverse Events Reported in Open-Label Trials (Incidence ≥ 5%)

Body as a Whole % events reported Nervous System % events reported
Headache 22% Dizziness 16%
Infection 12% Somnolence 12%
Pain 12% Amnesia^ 8%
Asthenia 8% Anxiety 7%
Accidental Injury 7% Depression* 7%
Chest Pain 5% Manic Depressive Reaction 7%
Back Pain 5% Ataxia 5%
Digestive Skin Appendages
Diarrhea 10% Rash 13%
Dyspepsia 10% Pruritus 5%
Nausea 10%    
Constipation 5%    
^ Amnesia includes poor memory, forgetful, and memory disturbance.
* Depression includes suicidal ideation.

Other significant adverse events seen in less than 5% of patients include: Suicide Attempt, Manic Reaction, Insomnia, Nervousness, Depersonalization and Extrapyramidal Symptoms, Infections (Fungal, Viral, Bacterial), Pharyngitis, Rhinitis, Sinusitis, Bronchitis, Urinary Tract Infection, Leukopenia and Lymphadenopathy, Liver Function Tests Abnormal, Edema, Peripheral Edema, Allergic Reaction, Photosensitivity Reaction, Alopecia, Diplopia, and Ear Pain.

The following additional adverse reactions were previously reported with carbamazepine:

Hemopoietic System: Aplastic anemia, agranulocytosis, pancytopenia, bone marrow depression, thrombocytopenia, leukopenia, leukocytosis, eosinophilia, acute intermittent porphyria.

Skin: Toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS) (see BOXED WARNING), pruritic and erythematous rashes, urticaria, photosensitivity reactions, alterations in skin pigmentation, exfoliative dermatitis, erythema multiforme and nodosum, purpura, aggravation of disseminated lupus erythematosus, alopecia, and diaphoresis. In certain cases, discontinuation of therapy may be necessary. Isolated cases of hirsutism have been reported, but a causal relationship is not clear.

Cardiovascular System: Congestive heart failure, edema, aggravation of hypertension, hypotension, syncope and collapse, aggravation of coronary artery disease, arrhythmias and AV block, thrombophlebitis, thromboembolism, and adenopathy or lymphadenopathy. Some of these cardiovascular complications have resulted in fatalities. Myocardial infarction has been associated with other tricyclic compounds.

Liver: Abnormalities in liver function tests, cholestatic and hepatocellular jaundice, hepatitis.

Respiratory System: Pulmonary hypersensitivity characterized by fever, dyspnea, pneumonitis, or pneumonia.

Genitourinary System: Urinary frequency, acute urinary retention, oliguria with elevated blood pressure, azotemia, renal failure, and impotence. Albuminuria, glycosuria, elevated BUN, and microscopic deposits in the urine have also been reported.

Testicular atrophy occurred in rats receiving carbamazepine orally from 4–52 weeks at dosage levels of 50–400 mg/kg/day. Additionally, rats receiving carbamazepine in the diet for 2 years at dosage levels of 25, 75, and 250 mg/kg/day had a dose-related incidence of testicular atrophy and aspermatogenesis. In dogs, it produced a brownish discoloration, presumably a metabolite, in the urinary bladder at dosage levels of 50 mg/kg/day and higher. Relevance of these findings to humans is unknown.

Nervous System: Dizziness, drowsiness, disturbances of coordination, confusion, headache, fatigue, blurred vision, visual hallucinations, transient diplopia, oculomotor disturbances, nystagmus, speech disturbances, abnormal involuntary movements, peripheral neuritis and paresthesias, depression with agitation, talkativeness, tinnitus, and hyperacusis.

There have been reports of associated paralysis and other symptoms of cerebral arterial insufficiency, but the exact relationship of these reactions to the drug has not been established.

Isolated cases of neuroleptic malignant syndrome have been reported with concomitant use of psychotropic drugs.

Digestive System: Nausea, vomiting, gastric distress and abdominal pain, diarrhea, constipation, anorexia,and dryness of the mouth and pharynx, including glossitis and stomatitis.

Eyes: Scattered punctate cortical lens opacities, as well as conjunctivitis, have been reported. Although a direct causal relationship has not been established, many phenothiazines and related drugs have been shown to cause eye changes.

Musculoskeletal System: Aching joints and muscles, and leg cramps.

Metabolism: Fever and chills and inappropriate antidiuretic hormone (ADH) secretion syndrome have been reported. Cases of frank water intoxication, with decreased serum sodium (hyponatremia) and confusion, have been reported in association with carbamazepine use (see PRECAUTIONS, Laboratory Tests). Decreased levels of plasma calcium have been reported.

Other: Isolated cases of a lupus erythematosus-like syndrome have been reported. There have been occasional reports of elevated levels of cholesterol, HDL cholesterol, and triglycerides in patients taking anticonvulsants.

A case of aseptic meningitis, accompanied by myoclonus and peripheral eosinophilia, has been reported in a patient taking carbamazepine in combination with other medications. The patient was successfully dechallenged, and the meningitis reappeared upon rechallenge with carbamazepine.

Drug Abuse And Dependence

No evidence of abuse potential has been associated with carbamazepine, nor is there evidence of psychological or physical dependence in humans.