Carbatrol Drug Information

Monitoring of blood levels has increased the efficacy and safety of anticonvulsants (see PRECAUTIONS, Laboratory Tests ). Dosage should be adjusted to the needs of the individual patients. A low initial daily dosage with gradual increase is advised. As soon as adequate control is achieved, the dosage may be reduced very gradually to the minimum effective level.

Carbatrol may be taken with or without food. Carbatrol capsules may be swallowed whole or may be opened and all the beads sprinkled on a teaspoon of soft food such as applesauce. Make sure all of the food and medicine mixture is swallowed.

Do not crush or chew Carbatrol capsules or the sprinkled beads. Carbatrol is an extended-release formulation for twice a day administration. When converting patients from immediate release carbamazepine to Carbatrol extended-release capsules, the same total daily mg dose of carbamazepine should be administered.

Following conversion to Carbatrol, patients should be closely monitored for seizure control. Depending on the therapeutic response after conversion, the total daily dose may need to be adjusted within the recommended dosing instructions. Epilepsy (see INDICATIONS AND USAGE ) Adults and children over 12 years of age.

Initial: 200 mg twice daily. Increase at weekly intervals by adding up to 200 mg/day until the optimal response is obtained. Dosage generally should not exceed 1000 mg per day in children 12-15 years of age, and 1200 mg daily in patients above 15 years of age.

Doses up to 1600 mg daily have been used in adults. Maintenance: Adjust dosage to the minimum effective level, usually 800-1200 mg daily. Children under 12 years of age: Children taking total daily dosages of immediate-release carbamazepine of 400 mg or greater may be converted to the same total daily dosage of Carbatrol extended-release capsules, using a twice daily regimen.

Ordinarily, optimal clinical response is achieved at daily doses below 35 mg/kg. If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the therapeutic range. No recommendation regarding the safety of Carbatrol for use at doses above 35 mg/kg/24 hours can be made.

Combination Therapy: Carbatrol may be used alone or with other anticonvulsants. When added to existing anticonvulsant therapy, the drug should be added gradually while the other anticonvulsants are maintained or gradually decreased, except phenytoin, which may have to be increased (see PRECAUTIONS, Drug Interactions ). Trigeminal Neuralgia (see INDICATIONS AND USAGE ) Initial: On the first day, start with one 200 mg capsule. This daily dose may be increased by up to 200 mg/day every 12 hours only as needed to achieve freedom from pain.

Do not exceed 1200 mg daily. Maintenance: Control of pain can be maintained in most patients with 400-800 mg daily. However, some patients may be maintained on as little as 200 mg daily, while others may require as much as 1200 mg daily.

At least once every 3 months throughout the treatment period, attempts should be made to reduce the dose to the minimum effective level or even to discontinue the drug.

• General: 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 patient with epilepsy may lead to seizures or even status epilepticus with its life-threatening hazards. The most severe adverse reactions previously observed with carbamazepine were reported in the hemopoietic system and skin (see BOXED WARNING ), 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 lowest dosage recommended. 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 ), Acute Generalized Exanthematous Pustulosis (AGEP), pruritic and erythematous rashes, urticaria, photosensitivity reactions, alterations in skin pigmentation, exfoliative dermatitis, erythema multiforme and nodosum, purpura, aggravation of disseminated lupus erythematosus, alopecia, diaphoresis, onychomadesis and hirsutism. In certain cases, discontinuation of therapy may be necessary.
• 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.
• Immune system disorders: Hypogammaglobulinemia. Liver: Abnormalities in liver function tests, cholestatic and hepatocellular jaundice, hepatitis, and 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. There have been rare reports of impaired male fertility and/or abnormal spermatogenesis. 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: Bone loss, aching joints and muscles, and leg cramps.
• Metabolism: Fever and chills, decreased levels of plasma calcium leading to osteoporosis, and hyperammonemia 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 Interactions Clinically meaningful drug interactions have occurred with concomitant medications and include, but are not limited to the following: Agents Highly Bound to Plasma Protein: Carbamazepine is not highly bound to plasma proteins; therefore, administration of Carbatrol to a patient taking another drug that is highly protein bound should not cause increased free concentrations of the other drug. Agents that Inhibit Cytochrome P450 Isoenzymes and/or Epoxide Hydrolase: Carbamazepine is metabolized mainly by cytochrome P450 (CYP) 3A4 to the active carbamazepine 10,11-epoxide, which is further metabolized to the trans-diol by epoxide hydrolase. Therefore, the potential exists for interaction between carbamazepine and any agent that inhibits CYP3A4 and/or epoxide hydrolase.

Agents that are CYP3A4 inhibitors that have been found, or are expected, to increase plasma levels of Carbatrol include, for example, the following: Acetazolamide, aprepitant, azole antifungals (e.g., ketoconazole, itraconazole, fluconazole, voriconazole), cimetidine, ciprofloxacin, clarithromycin, dalfopristin, danazol, dantrolene, delavirdine, diltiazem, erythromycin, fluoxetine, fluvoxamine, grapefruit juice, ibuprofen, isoniazid, loratadine, macrolides, nefazodone, niacinamide, nicotinamide, olanzapine, omeprazole, oxybutynin, protease inhibitors, propoxyphene, quinine, quinupristin, ticlopidine, troleandomycin, valproate, verapamil, zileuton. Human microsomal epoxide hydrolase has been identified as the enzyme responsible for the formation of the 10,11-transdiol derivative from carbamazepine-10,11 epoxide. Coadministration of inhibitors of human microsomal epoxide hydrolase may result in increased carbamazepine-10,11 epoxide plasma concentrations.

Accordingly, the dosage of Carbatrol should be adjusted and/or the plasma levels monitored when used concomitantly with loxapine, quetiapine, or valproic acid. Thus, if a patient has been titrated to a stable dosage of Carbatrol, and then begins a course of treatment with one of these CYP3A4 or epoxide hydrolase inhibitors, it is reasonable to expect that a dose reduction for Carbatrol may be necessary. Agents that Induce Cytochrome P450 Isoenzymes: Carbamazepine is metabolized by CYP3A4. Therefore, the potential exists for interaction between carbamazepine and any agent that induces CYP3A4. Agents that are CYP inducers that have been found, or are expected, to decrease plasma levels of Carbatrol include, for example, the following: Aminophylline, cisplatin, doxorubicin HCL, felbamate, fosphenytoin, methsuximide, phenobarbital, phenytoin, primidone, rifampin and theophylline.

Phenytoin plasma levels have also been reported to increase and decrease in the presence of carbamazepine, see below. Thus, if a patient has been titrated to a stable dosage on Carbatrol, and then begins a course of treatment with one of these CYP3A4 inducers, it is reasonable to expect that a dose increase for Carbatrol may be necessary. Agents with Decreased Levels in the Presence of Carbamazepine due to Induction of Cytochrome P450 Enzymes: Carbamazepine is a potent inducer of hepatic CYP3A4 and is also known to be an inducer of CYP1A2, 2B6, 2C9/19 and may therefore reduce plasma concentrations of co-medications mainly metabolized by CYP 1A2, 2B6, 2C9/19 and 3A4, through induction of their metabolism.

When used concomitantly with Carbatrol, monitoring of concentrations or dosage adjustment of these agents may be necessary: When carbamazepine is added to aripiprazole, the aripiprazole dose should be doubled. Additional dose increases should be based on clinical evaluation. If carbamazepine is later withdrawn, the aripiprazole dose should be reduced.

When carbamazepine is used with tacrolimus, monitoring of tacrolimus blood concentrations and appropriate dosage adjustments are recommended. The use of concomitant strong CYP3A4 inducers such as carbamazepine should be avoided with temsirolimus. If patients must be coadministered carbamazepine with temsirolimus, an adjustment of temsirolimus dosage should be considered.

The use of carbamazepine with lapatinib should generally be avoided. If carbamazepine is started in a patient already taking lapatinib, the dose of lapatinib should be gradually titrated up. If carbamazepine is discontinued, the lapatinib dose should be reduced.

Concomitant use of carbamazepine with nefazodone results in plasma concentrations of nefazodone and its active metabolite insufficient to achieve a therapeutic effect. Coadministration of carbamazepine with nefazodone is contraindicated (see CONTRAINDICATIONS ). Monitor concentrations of valproate when Carbatrol is introduced or withdrawn in patients using valproic acid. In addition, Carbatrol causes, or would be expected to cause, decreased levels of, for example, the following drugs, for which monitoring of concentrations or dosage adjustment may be necessary: Acetaminophen, albendazole, alprazolam, aprepitant, buprenorphine, apixaban, bupropion, buspirone, citalopram, clobazam, clonazepam, clozapine, corticosteroids (e.g. prednisolone, dexamethasone), cyclosporin, dabigatran, delavirdine, desipramine, diazepam, dicumarol, dihydropyridine calcium channel blockers (e.g., felodipine), doxycycline, edoxaban, eslicarbazepine, ethosuximide, everolimus, felbamate, haloperidol, imatinib, itraconazole, lamotrigine, levothyroxine, lorazepam, methadone, methsuximide, midazolam, mirtazapine, nefazodone, nortriptyline, olanzapine, oral and other hormonal contraceptives, oxcarbazepine, paliperidone, phenytoin, praziquantel, protease inhibitors, quetiapine, risperidone, rivaroxaban, sertraline, sirolimus, tadalafil, theophylline, tiagabine, topiramate, tramadol, triazolam, trazodone, tricyclic antidepressants (e.g., imipramine, amitriptyline, nortriptyline), valproate, warfarin, ziprasidone, and zonisamide.

Concomitant use of Carbatrol 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 with carbamazepine. Alternative or back-up methods of contraception should be considered.

Phenytoin has also been reported to increase in the presence of carbamazepine. Careful monitoring of phenytoin plasma levels following co-medication with carbamazepine is advised. Following co-administration of carbamazepine 400mg/day with trazodone 100mg to 300mg daily, carbamazepine reduced trough plasma concentrations of trazodone (as well as meta-chlorophenylpiperazine ) by 76 and 60% respectively, compared to precarbamazepine values.

Warfarin's anticoagulant effect can be reduced in the presence of carbamazepine. Concomitant use of carbamazepine with rivaroxaban, apixaban, dabigatran, and edoxaban (direct acting oral anticoagulants) is expected to result in decreased plasma concentrations of these anticoagulants that may be insufficient to achieve the intended therapeutic effect. In general, coadministration of carbamazepine with rivaroxaban, apixaban, dabigatran, and edoxaban should be avoided.

Thus, if a patient has been titrated to a stable dosage on one of the agents in this category, and then begins a course of treatment with Carbatrol, it is reasonable to expect that a dose increase for the concomitant agent may be necessary. Agents with Increased Levels in the Presence of Carbamazepine: Carbatrol increases the plasma levels of the following agents. Thus, if a patient has been titrated to a stable dosage on one of the agents in this category, and then begins a course of the treatment with Carbatrol, it is reasonable to expect that a dose decrease for the concomitant agent may be necessary.

Clomipramine HCl, Phenytoin, and Primidone Carbatrol can increase the concentrations of clomipramine, phenytoin, and primidone. If a patient has been titrated to a stable dosage on one of these agents in this category, and then begins treatment with Carbatrol, it may be necessary to decrease the dose of these drugs. Phenytoin has also been reported to decrease in the presence of carbamazepine.

Careful monitoring of phenytoin plasma levels following co-medication with carbamazepine is advised. Cyclophosphamide Cyclophosphamide is an inactive prodrug and is converted to its active metabolite in part by CYP3A. The rate of metabolism and the leukopenic activity of cyclophosphamide are reportedly increased by chronic co-administration of CYP3A4 inducers. There is a potential for increased cyclophosphamide toxicity when coadministered with carbamazepine.

Pharmacological/Pharmacodynamic Interactions with Carbamazepine: Delavirdine Coadministration of Carbatrol with delavirdine may lead to loss of virologic response and possible resistance to delavirdine or to the class of non-nucleoside reverse transcriptase inhibitors (see CONTRAINDICATIONS ). Lithium Concomitant administration of carbamazepine and lithium may increase the risk of neurotoxic side effects. Thyroid Effects with Other Anticonvulsant Medications Alterations of thyroid function have been reported in combination therapy with other anticonvulsant medications. Chloroquine and Mefloquine Anti-malarial drugs, such as chloroquine and mefloquine, may antagonize the activity of carbamazepine.

Thus if a patient has been titrated to a stable dosage on one of the agents in this category, and then begins a course of treatment with Carbatrol, it is reasonable to expect that a dose adjustment may be necessary. CNS Depressants The concomitant use of Carbatrol and other CNS depressants can increase the risk of respiratory depression, profound sedation, hypotension, and syncope. CNS depressants include: alcohol, opioid analgesics, benzodiazepines, tricyclic antidepressants, sedative/hypnotics, anticonvulsants, antipsychotics, antihistamines, anticholinergics, alpha and beta blockers, general anesthetics, muscle relaxants, and illicit CNS depressants.

Consider reducing the dose of CNS depressants or Carbatrol when using these drugs concomitantly. Because of its primary CNS effect, caution should be used when Carbatrol is taken with other centrally acting drugs and alcohol. Neuromuscular Blocking Agents Resistance to the neuromuscular blocking action of the nondepolarizing neuromuscular blocking agents pancuronium, vecuronium, rocuronium and cisatracurium has occurred in patients chronically administered carbamazepine.

Whether or not carbamazepine has the same effect on other nondepolarizing agents is unknown. Patients should be monitored closely for more rapid recovery from neuromuscular blockade than expected, and infusion rate requirements may be higher.

Usage in Pregnancy (See WARNINGS )

Pediatric Use Substantial evidence of carbamazepine effectiveness for use in the management of children with epilepsy (see INDICATIONS for specific seizure types) is derived from clinical investigations performed in adults and from studies in several in vitro systems which support the conclusion that the pathogenic mechanisms underlying seizure propagation are essentially identical in adults and children, and the mechanism of action of carbamazepine in treating seizures is essentially identical in adults and children. Taken as a whole, this information supports a conclusion that the generally acceptable therapeutic range of total carbamazepine in plasma (i.e., 4-12 μg/mL) is the same in children and adults. The evidence assembled was primarily obtained from short-term use of carbamazepine.

The safety of carbamazepine in children has been systematically studied up to 6 months. No longer term data from clinical trials is available.

Carbamazepine 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 and nortriptyline. Likewise, on theoretical grounds its use with monoamine oxidase inhibitors is not recommended. Before administration of carbamazepine, MAO inhibitors should be discontinued for a minimum of 14 days, or longer if the clinical situation permits.

Coadministration of carbamazepine and nefazodone may result in insufficient plasma concentrations of nefazodone and its active metabolite to achieve a therapeutic effect. Coadministration of carbamazepine with nefazodone is contraindicated. Coadministration of Carbatrol is contraindicated with delavirdine due to the potential for loss of virologic response and possible resistance to delavirdine or to the class of non-nucleoside reverse transcriptase inhibitors.

• Acute Toxicity Lowest known lethal dose: adults, >60 g (39-year-old man).
• Highest known doses survived: adults, 30 g (31-year-old woman); children, 10 g (6-year-old boy); small children, 5 g (3-year-old girl).
• Oral LD 50 in animals (mg/kg): mice, 1100-3750; rats, 3850-4025; rabbits, 1500-2680; guinea pigs, 920. Signs and Symptoms 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.
• Respiration: Irregular breathing, respiratory depression.
• Cardiovascular System: Tachycardia, hypotension or hypertension, shock, conduction disorders.
• Nervous System and Muscles: 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.
• Gastrointestinal Tract: Nausea, vomiting.
• Kidneys and Bladder: Anuria or oliguria, urinary retention.
• Laboratory Findings: Isolated instances of overdosage have included leukocytosis, reduced leukocyte count, glycosuria, and acetonuria. ECG may show dysrhythmias.
• Combined Poisoning: When alcohol, tricyclic antidepressants, barbiturates, or hydantoins are taken at the same time, the signs and symptoms of acute poisoning with carbamazepine may be aggravated or modified. Treatment For the most up to date information on management of carbamazepine overdose, please contact the poison center for your area by calling 1-800-222-1222. The prognosis in cases of carbamazepine poisoning is generally favorable. Of 5,645 cases of carbamazepine exposures reported to US poison centers in 2002, a total of 8 deaths (0.14% mortality rate) occurred. Over 39% of the cases reported to these poison centers were managed safely at home with conservative care. Successful management of large or intentional carbamazepine exposures requires implementation of supportive care, frequent monitoring of serum drug concentrations, as well as aggressive but appropriate gastric decontamination.
• Elimination of the Drug: The primary method for gastric decontamination of carbamazepine overdose is use of activated charcoal. For substantial recent ingestions, gastric lavage may also be considered. Administration of activated charcoal prior to hospital assessment has the potential to significantly reduce drug absorption. There is no specific antidote. In overdose, absorption of carbamazepine may be prolonged and delayed. More than one dose of activated charcoal may be beneficial in patients that have evidence of continued absorption (e.g., rising serum carbamazepine levels).
• Measures to Accelerate Elimination: The data on use of dialysis to enhance elimination in carbamazepine is scarce. Dialysis, particularly high flux or high efficiency hemodialysis, may be considered in patients with severe carbamazepine poisoning associated with renal failure or in cases of status epilepticus, or where there are rising serum drug levels and worsening clinical status despite appropriate supportive care and gastric decontamination. For severe cases of carbamazepine overdose unresponsive to other measures, charcoal hemoperfusion may be used to enhance drug clearance.
• 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.
• Warning: Diazepam or barbiturates may aggravate respiratory depression (especially in children), hypotension, and coma. However, barbiturates should not be used if drugs that inhibit monoamine oxidase have also been taken by the patient either in overdosage or in recent therapy (within 1 week).
• Surveillance: Respiration, cardiac function (ECG monitoring), blood pressure, body temperature, pupillary reflexes, and kidney and bladder function should be monitored for several days.
• Treatment of Blood Count Abnormalities: If evidence of significant bone marrow depression develops, the following recommendations are suggested: stop the drug, perform daily CBC, platelet, and reticulocyte counts, do a bone marrow aspiration and trephine biopsy immediately and repeat with sufficient frequency to monitor recovery.
• Special periodic studies might be helpful as follows: white cell and platelet antibodies, 59 Fe-ferrokinetic studies, peripheral blood cell typing, cytogenetic studies on marrow and peripheral blood, bone marrow culture studies for colony-forming units, hemoglobin electrophoresis for A2 and F hemoglobin, and serum folic acid and B 12 levels. A fully developed aplastic anemia will require appropriate, intensive monitoring and therapy, for which specialized consultation should be sought.