Trigeminal Neuralgia

Tegretol is indicated in the treatment of the pain associated with true trigeminal neuralgia. Beneficial results have also been reported in glossopharyngeal neuralgia.

CONTRAINDICATIONS: Tegretol should not be used in patients with a history of previous bone marrow depression, hypersensitivity to the drug, or known sensitivity to any of the tricyclic compounds, such as amitriptyline, desipramine, imipramine, protriptyline, nortriptyline, etc. Likewise, on theoretical grounds its use with monoamine oxidase inhibitors is not recommended.

CLINICAL PHARMACOLOGY:

Mechanism of Action: It appears to act by reducing polysynaptic responses and blocking the post-tetanic potentiation in rats and mice. Tegretol greatly reduces or abolishes pain induced by stimulation of the infraorbital nerve in cats and rats. It depresses thalamic potential and bulbar and polysynaptic reflexes, including the linguomandibular reflex in cats. Tegretol is chemically unrelated to other anticonvulsants or other drugs used to control the pain of trigeminal neuralgia. The mechanism of action remains unknown. The principal metabolite of Tegretol, carbamazepine-10,11-epoxide, has anticonvulsant activity as demonstrated in several in vivo animal models of seizures.

Pharmacokinetics

Tegretol in blood is 76% bound to plasma proteins. Plasma levels of Tegretol are variable and may range from 0.5-25 µg/mL, with no apparent relationship to the daily intake of the drug. Usual adult therapeutic levels are between 4 and 12 µg/mL. Following chronic oral administration of Tegretol tablets, plasma levels peak at approximately 4-5 hours after administration of conventional. The CSF/serum ratio is 0.22, similar to the 24% unbound Tegretol in serum. Initial half-life values range from 25-65 hours, decreasing to 12-17 hours on repeated doses. Tegretol is metabolized in the liver. Cytochrome P450 3A4 was identified as the major isoform responsible for the formation of carbamazepine-10,11-epoxide from Tegretol.

WARNINGS: Patients with a history of adverse hematologic reaction to any drug may be particularly at risk. Severe dermatologic reactions, including toxic epidermal necrolysis (Lyell's syndrome) and Stevens-Johnson syndrome, have been reported with Tegretol. Tegretol has shown mild anticholinergic activity; therefore, patients with increased intraocular pressure should be closely observed during therapy. Because of the relationship of the drug to other tricyclic compounds, the possibility of activation of a latent psychosis and, in elderly patients, of confusion or agitation should be borne in mind.

PRECAUTIONS:

General: Tegretol should be used with caution in patients with a mixed seizure disorder that includes atypical absence seizures, since in these patients Tegretol has been associated with increased frequency of generalized convulsions.Therapy should be prescribed only after critical benefit-to-risk appraisal in patients with a history of cardiac, hepatic, or renal damage; adverse hematologic or hypersensitivity reaction to other drugs, including reactions to other anticonvulsants; or interrupted courses of therapy with Tegretol.

Information for Patients: Patients should be made aware of the early toxic signs and symptoms of a potential hematologic problem, as well as dermatologic, hypersensitivity or hepatic reactions. These symptoms may include, but are not limited to, fever, sore throat, rash, ulcers in the mouth, easy bruising, lymphadenopathy and petechial or purpuric hemorrhage, and in the case of liver reactions, anorexia, nausea/vomiting, or jaundice. Since dizziness and drowsiness may occur, patients should be cautioned about the hazards of operating machinery or automobiles or engaging in other potentially dangerous tasks.

Laboratory Tests: Complete pretreatment blood counts, including platelets and possibly reticulocytes and serum iron, should be obtained as a baseline. Baseline and periodic evaluations of liver function, particularly in patients with a history of liver disease, must be performed during treatment with this drug since liver damage may occur. Baseline and periodic eye examinations are recommended. Baseline and periodic complete urinalysis and BUN determinations are recommended.

Pregnancy: Pregnancy Category D. Carbamazepine can cause fetal harm when administered to a pregnant woman.

Nursing Mothers: Tegretol and its epoxide metabolite are transferred to breast milk. Because of the potential for serious adverse reactions in nursing infants from carbamazepine, a decision should be made whether to discontinue nursing or to discontinue the drug.

Pediatric Use: Substantial evidence of Tegretol's effectiveness for use in the management of children with epilepsy is as adults.

Drug Interactions:

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, loratadine, terfenadine, isoniazid, niacinamide, nicotinamide, propoxyphene, ketaconazole, itraconazole, verapamil, valproate.

 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, clonazepam, clozapine, dicumarol, doxycycline, ethosuximide, haloperidol, lamotrigine, methsuximide, oral and other hormonal contraceptives, phensuximide, phenytoin, theophylline, tiagabine, topiramate, valproate, warfarin.

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

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.

SIDE EFFECTS: The most severe adverse reactions have been observed in the hemopoietic system the skin, liver, and the cardiovascular system.

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

Skin: Pruritic and erythematous rashes, urticaria, toxic epidermal necrolysis (Lyell's syndrome), Stevens-Johnson syndrome, 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.

Liver: Abnormalities in liver function tests, cholestatic and hepatocellular jaundice, hepatitis; very rare cases of hepatic failure.  

OVERDOSAGE:

Acute Toxicity: Lowest known lethal dose: adults, 3.2 g, children 1.6 g. The first signs and symptoms appear after 1-3 hours. Neuromuscular disturbances are the most prominent. Cardiovascular disorders are generally milder, and severe cardiac complications occur only when very high doses (> 60 g) have been ingested. Irregular breathing, respiratory depression. Tachycardia, hypotension or hypertension, shock, conduction disorders. Impairment of consciousness ranging in severity to deep coma. Convulsions, especially in small children. Motor restlessness, muscular twitching, tremor, athetoid movements, opisthotonos, ataxia, drowsiness, dizziness, mydriasis, nystagmus, adiadochokinesia, ballism, psychomotor disturbances, dysmetria. Initial hyperreflexia, followed by hyporeflexia. Nausea, vomiting. Anuria or oliguria, urinary retention.

Treatment: The prompt elimination of the drug, which may be achieved by inducing vomiting, irrigating the stomach, and by taking appropriate steps to diminish absorption. There is no specific antidote. Elimination of the Drug: Induction of vomiting. Gastric lavage. Even when more than 4 hours have elapsed following ingestion of the drug, the stomach should be repeatedly irrigated, especially if the patient has also consumed alcohol. Measures to Reduce Absorption: Activated charcoal, laxatives. Measures to Accelerate Elimination: Forced diuresis. Dialysis is indicated only in severe poisoning associated with renal failure. Replacement transfusion is indicated in severe poisoning in small children.

Respiratory Depression: Keep the airways free; resort, if necessary, to endotracheal intubation, artificial respiration, and administration of oxygen. Hypotension, Shock:    Keep the patient's legs raised and administer a plasma expander. If blood pressure fails to rise despite measures taken to increase plasma volume, use of vasoactive substances should be considered. Convulsions: Diazepam or barbiturates.  

DOSAGE AND ADMINISTRATION:

Usual adult and adolescent dose

Anticonvulsant: Initial: Oral, 200 mg two times a day on the first day, the dosage being increased by up to 200 mg a day at weekly intervals until the best response is obtained. Maintenance: Oral, adjusted to the minimum effective dosage, usually 600 mg to 1.6 grams a day.

Antineuralgic: Initial: Oral, 100 mg two times a day on the first day, the dosage being increased by up to 200 mg a day, using increments of 100 mg every twelve hours only as needed until pain is relieved. Maintenance: Oral, 200 mg to 1.2 grams a day (average 400 to 800 mg a day) in divided doses.

Usual adult and adolescent prescribing limits

Anticonvulsant: Patients 12 to 15 years of age: Dosage should generally not exceed 1 gram a day.

Antineuralgic: Dosage should not exceed 1.2 grams a day.

Usual pediatric dose

Anticonvulsant: Children up to 6 years of age: Initial—Oral, 10 to 20 mg per kg of body weight a day in two or three divided doses, the dosage being increased by up to 100 mg a day at weekly intervals as needed and tolerated. Maintenance—Oral, adjusted to the minimum effective dosage, usually 250 to 350 mg a day, and generally not exceeding 400 mg or 35 mg per kg of body weight a day.

Children 6 to 12 years of age: Initial—Oral, 100 mg two times a day on the first day, the dosage being increased by 100 mg a day at weekly intervals until the best response is obtained. Maintenance—Oral, adjusted to the minimum effective dosage, usually 400 to 800 mg a day.

How Supplied: Each Pack of Ruz-Carbamazepine 200 mg tablets contains 100 tablets in 10 blisters.

storage: Do not store above 30°C. Protect from light and moisture. Dispense in tight, light-resistant container

Reference: PDR 2000, page 2052-55

                  USPDI Vol for Professional Health Care, 2004, Page 709-16

                  Martindale 2005, Page 353-8