If adverse reactions are of such severity that the drug must be discontinued, the physician must be aware that abrupt discontinuation of any anticonvulsant drug in a responsive epileptic patient may lead to seizures or even status epilepticus with its life-threatening hazards.

The most severe adverse reactions have been observed in the hemopoietic system (see BOXED WARNING), the liver and 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 low dosage recommended.

The following additional adverse reactions have been reported:

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; very rare cases of hepatic failure.

Pancreatic: Pancreatitis.

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 Tegretol orally from 4-52 weeks at dosage levels of 50-400 mg/kg/day. Additionally, rats receiving Tegretol 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 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. Inappropriate antidiuretic hormone (ADH) secretion syndrome has been reported. Cases of frank water intoxication, with decreased serum sodium (hyponatremia) and confusion, have been reported in association with Tegretol use (see PRECAUTIONS, Laboratory Tests). Decreased levels of plasma calcium have been reported.

Other: Multi-organ hypersensitivity reactions occurring days to weeks or months after initiating treatment have been reported in rare cases. Signs or symptoms may include, but are not limited to fever, skin rashes, vasculitis, lymphadenopathy, disorders mimicking lymphoma, arthralgia, leukopenia, eosinophilia, hepato-splenomegaly and abnormal liver function tests. These signs and symptoms may occur in various combinations and not necessarily concurrently. Signs and symptoms may initially be mild. Various organs, including but not limited to, liver, skin, immune system, lungs, kidneys, pancreas, myocardium, and colon may be affected (see PRECAUTIONS, General and PRECAUTIONS, INFORMATION FOR PATIENTS).

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 Tegretol, nor is there evidence of psychological or physical dependence in humans.

There has been a report of a patient who passed an orange rubbery precipitate in his stool the day after ingesting Tegretol suspension immediately followed by Thorazine® solution. Subsequent testing has shown that mixing Tegretol suspension and chlorpromazine solution (both generic and brand name) as well as Tegretol suspension and liquid Mellaril® resulted in the occurrence of this precipitate. Because the extent to which this occurs with other liquid medications is not known, Tegretol suspension should not be administered simultaneously with other liquid medicinal agents or diluents. (see DOSAGE AND ADMINISTRATION).

Clinically meaningful drug interactions have occurred with concomitant medications and include, but are not limited to, the following:

Agents That May Affect Tegretol Plasma Levels

CYP 3A4 inhibitors inhibit Tegretol metabolism and can thus increase plasma carbamazepine levels. Drugs that have been shown, or would be expected, to increase plasma carbamazepine levels include

cimetidine, danazol, diltiazem, macrolides, erythromycin, troleandomycin, clarithromycin, fluoxetine, fluvoxamine, nefazodone, loratadine, terfenadine, isoniazid, niacinamide, nicotinamide, propoxyphene, azoles (e.g., ketaconazole, itraconazole, fluconazole), acetazolamide, verapamil, grapefruit juice, protease inhibitors, valproate.*

CYP 3A4 inducers can increase the rate of Tegretol metabolism. Drugs that have been shown, or that would be expected, to decrease plasma carbamazepine levels include

cisplatin, doxorubicin HCl, felbamate,^† rifampin, phenobarbital, phenytoin, primidone, methsuximide, theophylline.

When carbamazepine is given with drugs that can increase or decrease carbamazepine levels, close monitoring of carbamazepine levels is indicated and dosage adjustment may be required.

Effect of Tegretol on Plasma Levels of Concomitant Agents

Increased levels: clomipramine HCl, phenytoin, primidone

Tegretol induces hepatic CYP activity. Tegretol causes, or would be expected to cause, decreased levels of the following:

acetaminophen, alprazolam, dihydropyridine calcium channel blockers (e.g., felodipine), cyclosporine, corticosteroids (e.g., prednisolone, dexamethasone), clonazepam, clozapine, dicumarol, doxycycline, ethosuximide, haloperidol, itraconazole, lamotrigine, levothyroxine, methadone, methsuximide, midazolam, olanzapine, oral and other hormonal contraceptives, oxcarbazepine, phensuximide, phenytoin, praziquantel, protease inhibitors, risperidone, theophylline, tiagabine, topiramate, tramadol, tricyclic antidepressants (e.g., imipramine, amitriptyline, nortriptyline), valproate, warfarin,ziprasidone, zonisamide.

In concomitant use with Tegretol, dosage adjustment of the above agents may be necessary.

Concomitant administration of carbamazepine and lithium may increase the risk of neurotoxic side effects.

Co-administration of carbamazepine with nefazodone results in insufficient plasma concentrations of nefazodone and its active metabolite to achieve a therapeutic effect. Co-administration of carbamazepine with nefazodone is contraindicated. (See CONTRAINDICATIONS).

Alterations of thyroid function have been reported in combination therapy with other anticonvulsant medications.

Concomitant use of Tegretol with hormonal contraceptive products (e.g., oral, and levonorgestrel subdermal implant contraceptives) may render the contraceptives less effective because the plasma concentrations of the hormones may be decreased. Breakthrough bleeding and unintended pregnancies have been reported. Alternative or back-up methods of contraception should be considered.

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