Carbamazepine

Pronunciation

Class: Anticonvulsants, Miscellaneous
VA Class: CN400
CAS Number: 298-46-4
Brands: Carbatrol, Epitol, Tegretol

Warning(s)

  • Serious Dermatologic Reactions and HLA-B*1502 Allele
  • Serious and sometimes fatal dermatologic reactions, including toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS), reported in patients receiving carbamazepine therapy.189 191 192 193 194 195 209 e f

  • Such reactions are estimated to occur in 1–6 per 10,000 new users of carbamazepine in countries with mainly Caucasian populations; however, risk in some Asian countries estimated to be approximately 10 times higher.189 191 194 209

  • Retrospective, case-control studies in patients of Asian ancestry have demonstrated a strong association between risk of developing SJS and TEN and presence of human leukocyte antigen (HLA)-B*1502, an inherited allelic variant of the HLA-B gene.189 191 192 194 195 207 208 209 The HLA-B*1502 allele is found almost exclusively in patients with ancestry across broad areas of Asia.189 191 209

  • Screen patients with ancestry in genetically at-risk populations for presence of HLA-B*1502 prior to initiating carbamazepine therapy.189 191 194 195 209 Patients testing positive for the allele should not receive carbamazepine therapy unless benefit clearly outweighs risk.189 191 209 (See Serious Dermatologic Reactions and HLA-B*1502 Allele under Cautions.)

  • Hematologic Effects
  • Aplastic anemia and agranulocytosis reported.114

  • Risk of aplastic anemia or agranulocytosis in patients receiving carbamazepine appears to be 5–8 times greater than that in general population, but overall risk of these reactions in untreated general population is low (about 6 or 2 cases per million population year for agranulocytosis or aplastic anemia, respectively).114

  • Transient or persistent minor hematologic changes (e.g., decreased leukocyte or platelet counts) are not uncommon, but, in most cases, have not progressed to more serious conditions (e.g., aplastic anemia, agranulocytosis).114

  • Determine baseline hematologic function before initiation of therapy; closely monitor patients exhibiting abnormalities during therapy.114 Most hematologic changes observed during periodic monitoring are unlikely to signal occurrence of aplastic anemia or agranulocytosis.114

  • Consider discontinuance if evidence of substantial bone marrow depression develops.114

REMS:

FDA approved a REMS for carbamazepine to ensure that the benefits of a drug outweigh the risks. The REMS may apply to one or more preparations of carbamazepine and consists of the following: medication guide. See the FDA REMS page () or the ASHP REMS Resource Center ().

Introduction

Anticonvulsant, specific analgesic for trigeminal neuralgia;114 structurally related to tricyclic antidepressants.a

Uses for Carbamazepine

Seizure Disorders

Prophylactic management of partial seizures with complex symptomatology (psychomotor or temporal lobe seizures), generalized tonic-clonic (grand mal) seizures, and mixed seizure patterns that include partial seizures with complex symptomatology, generalized tonic-clonic seizures, or other partial or generalized seizures.114

Greater improvement seen in patients with partial seizures with complex symptomatology than with other types of seizures.114

Response in patients with mixed seizures may be variable.a

Ineffective in management of absence (petit mal) seizures or myoclonic and akinetic seizures.114 a

May use concomitantly with other anticonvulsants (e.g., phenytoin, phenobarbital, primidone).114 a

Neuropathic Pain

Symptomatic treatment of pain associated with true trigeminal neuralgia.114

Slideshow: View Frightful (But Dead Serious) Drug Side Effects

Beneficial results also reported in glossopharyngeal neuralgia.114

Symptomatic treatment of chronic pain arising from other peripheral neuropathic syndromes, including pain of diabetic neuropathy.a

Not a simple analgesic; do not use for relief of trivial aches or pain.114

Schizophrenia

Symptomatic management of the acute phase of schizophrenia, as an adjunct to therapy with an antipsychotic agent in patients who fail to respond to an adequate trial of the antipsychotic agent alone.177

American Psychiatric Association (APA) states that, with the exception of schizophrenic patients whose illness has strong affective components, carbamazepine therapy alone (i.e., monotherapy rather than adjunctive therapy) has not been shown to be substantially effective in the long-term treatment of schizophrenia.177 177

Bipolar Disorder

Treatment and prevention (alone or in combination with other drugs [e.g., antipsychotic agents]) of acute manic or mixed episodes in patients with bipolar disorder; clinical study results are inconsistent.178

APA recommends to reserve for patients unable to tolerate or who have an inadequate therapeutic response to lithium and valproate (e.g., valproic acid, divalproex).178

Other Uses

Management of aggression (e.g., uncontrolled rage outbursts) and/or loss of control (dyscontrol) in patients with or without an underlying seizure disorder (e.g., as features of intermittent explosive disorder, conduct disorder, antisocial personality disorder, borderline personality disorder, dementia).a

Treatment of alcohol withdrawal syndrome.a

Relief of neurogenic pain and/or control of seizures in a variety of conditions including “lightning” pains of tabes dorsalis.a

Relief of pain and control of paroxysmal symptoms of multiple sclerosis, paroxysmal kinesigenic choreoathetosis, Klüver-Bucy syndrome, post-hypoxic action myoclonus, and acute idiopathic polyneuritis (Landry-Guillain-Barré syndrome).a

Relief of pain of posttraumatic paresthesia and relief of hemifacial spasm and dystonia in children.a

Carbamazepine Dosage and Administration

General

Monitoring of plasma concentrations has increased efficacy and safety of anticonvulsants; may be particularly useful if dramatic increase in seizure frequency occurs or for verification of compliance and may aid in determining cause of toxicity when more than one drug is used.114 May be desirable to monitor serum concentrations of concomitantly administered anticonvulsants and adjust dosages as necessary.a (See Interactions and see Plasma Concentrations under Pharmacokinetics.)

Closely monitor for marked changes in behavior that could indicate emergence or worsening of suicidal thoughts or behavior or depression.196 197 198 209 212 d (See Suicidality Risk under Cautions.)

Administration

Oral Administration

Extended-release Capsules

Administer orally twice daily without regard to meals.c Do not crush or chew extended-release capsules, but may open and sprinkle beads over food (e.g., a teaspoonful of applesauce).c

Conventional and Chewable Tablets

Administer chewable or conventional tablets orally 2-4 times daily with meals.114

Extended-release Tablets

Administer extended-release tablets orally twice daily with meals.114

Swallow extended-release tablets whole; do not crush or chew.114 Inspect visually for chips or cracks; do not use damaged tablets.114

Extended-release tablet coating is not absorbed and may be noticeable in stools.114

Suspension

Administer orally 3-4 times daily with meals.114 Shake well before administration.114

Do not administer simultaneously with other liquid preparations.176 (See Compatibility under Stability.)

NG Tube

To minimize loss of oral suspension because of adherence to PVC tubing, dilute with an equal volume of diluent (e.g., sterile water, 5% dextrose, 0.9% sodium chloride) prior to administration.126 Flush the tube with 100 mL of diluent after administration.126 Do not administer with other liquid preparations.176 (See Compatibility under Stability.)

Dosage

Initiate with a low dosage; adjust dosage carefully and slowly according to individual requirements and response.114 Do not discontinue abruptly due to risk of increased seizure frequency.114 b c

When adding to an existing anticonvulsant regimen, add gradually while dosage of other anticonvulsant(s) is maintained or gradually adjusted.114 (See Specific Drugs, Foods, and Laboratory Tests under Interactions.)

A given dose administered as oral suspension will produce higher peak plasma concentrations than when administered as tablets; initiate therapy with oral suspension with low, frequent doses and increase slowly to reduce risk of adverse effects (e.g., sedation).114 115 116 117 118

To achieve therapeutic serum carbamazepine concentrations more rapidly (in about 2 hours), some clinicians recommend a loading-dose regimen (as oral suspension), preferably in a setting where plasma concentrations and the patient can be monitored closely.124

When converting patients from oral tablets to oral suspension, divide total daily dosage administered as tablets into smaller, more frequent doses of suspension (e.g., transfer from twice-daily divided dosing of tablets to 3-times-daily divided dosing of suspension).114 115 116 118

When converting patients from conventional, immediate-release formulations to extended-release capsules or tablets, administer same total daily dosage in 2 divided doses.114 a c

Pediatric Patients

Seizure Disorders
Oral

Children <6 years of age: Initially, 10–20 mg/kg daily in 2–3 divided doses as chewable or conventional tablets or 4 divided doses as suspension.114 Increase dosage at weekly intervals to achieve optimal clinical response, which is generally achieved at maintenance dosages <35 mg/kg daily in 3 or 4 divided doses.114 If clinical response not achieved, obtain plasma carbamazepine concentrations to determine if in therapeutic range.114 Safety of dosages >35 mg/kg in a 24-hour period not established.114

Children 6–12 years of age: Initially, 100 mg twice daily as tablets (chewable, conventional, or extended-release) or 50 mg 4 times daily as oral suspension.114 b c Increase dosage at weekly intervals by up to 100 mg daily using a twice daily divided dosage regimen as extended-release tablets or a 3 or 4 times daily divided dosage regimen as conventional or chewable tablets or oral suspension until optimal response obtained, up to a maximum dosage of 1 g daily.114 b c When adequate seizure control is achieved, adjust dosage to minimum effective level, usually 400–800 mg daily.114 b c

Children <12 years of age taking a total daily dosage of an immediate release formulation ≥400 mg may be converted to the same total daily dosage of extended-release capsules using a twice daily regimen.c

If rapid attainment of therapeutic serum carbamazepine concentrations is desired, some clinicians recommend an initial loading dose (as oral suspension) of 10 mg/kg in children <12 years of age.124

Children >12 years of age: Initially, 200 mg twice daily as tablets (conventional, chewable, or extended-release) or extended-release capsules or 100 mg 4 times daily as oral suspension.114 b c Increase dosage at weekly intervals by up to 200 mg daily using a twice daily divided dosage regimen as extended-release tablets or a 3 or 4 times daily divided dosage regimen as conventional or chewable tablets or oral suspension until optimal response obtained, up to a maximum dosage of 1 or 1.2 g in children 12–15 or >15 years of age, respectively.114 b c When adequate seizure control is achieved, adjust dosage to minimum effective level, usually 800 mg to 1.2 g daily.114 b c

If rapid attainment of therapeutic serum carbamazepine concentrations is desired, some clinicians recommend an initial loading dose (as oral suspension) of 8 mg/kg in children ≥12 years of age.124

Bipolar Disorder
Oral

Although dosage not established, experts generally recommend administering at the same range in dosage and therapeutic plasma concentrations as in the management of seizure disorders.178

Children >12 years of age: Initially, 200–600 mg daily, given in 3–4 divided doses; titrate dosage upward according to patient response and tolerability.178

In hospitalized patients >12 years of age with acute mania, increase dosage as tolerated in 200-mg daily increments up to 800 mg to 1 g daily, with slower increases thereafter as indicated.178 Do not exceed 1.6 g daily.178

In less acutely ill outpatients >12 years of age, adjust dosage more slowly, since rapid increases may cause patients to develop adverse GI or nervous system effects.178 If such adverse effects occur, consider temporary dosage reductions.178 Once adverse effects resolve, increase dosage again more slowly.178

Maintenance dosages average about 1 g daily, but may range from 200 mg to 1.6 g daily in routine clinical practice.178

Adults

Seizure Disorders
Oral

Initially, 200 mg twice daily as tablets (chewable, conventional, or extended-release) or capsules or 100 mg 4 times daily as oral suspension.114 b c

Increase dosage by up to 200 mg daily at weekly intervals using a twice daily divided dosage regimen as extended-release tablets or capsules or a 3 or 4 times daily divided dosage regimen as conventional tablets or oral suspension until optimal response obtained, up to a maximum dosage of 1.2 g.114 b c In rare instances, dosages up to 1.6 g have been used.114

When adequate seizure control is achieved, adjust dosage to minimum effective level, usually 800 mg to 1.2 g daily.114 b c

Neuropathic Pain
Trigeminal Neuralgia
Oral

Initially, 100 mg twice daily as tablets (conventional or extended-release), 200 mg once daily as extended-release capsules, or 50 mg 4 times daily as suspension on the first day of therapy.114 b c

Increase dosage gradually by up to 200 mg daily using 200-mg increments for capsules, 100-mg increments every 12 hours for conventional or extended-release tablets, or 50-mg increments 4 times daily for the suspension until pain is relieved up to a total dosage of 1.2 g daily.114 b The dosage necessary to relieve pain may range from 200 mg to 1.2 g daily.114 b c

After pain control is achieved, maintenance dosage of 400–800 mg daily is usually adequate; some patients may require as little as 200 mg daily while others may require 1.2 g daily.114 b c

At least once every 3 months, make attempt to decrease dosage to minimum effective level or to discontinue.114

Bipolar Disorder
Oral

Dosage not established.178 Experts generally recommend the same range in dosage and therapeutic plasma concentrations as in the management of seizure disorders.178

Initially, 200–600 mg daily, given in 3–4 divided doses.178

Titrate dosage upward according to patient response and tolerability.178

In hospitalized patients with acute mania, increase dosage as tolerated in 200-mg daily increments up to 800 mg to 1 g daily, with slower increases thereafter as indicated.178 Do not exceed 1.6 g daily.178

In less acutely ill outpatients, adjust dosage more slowly, since rapid increases may cause patients to develop adverse GI or nervous system effects.178 If such adverse effects occur, consider temporary dosage reductions.178 Once adverse effects resolve, increase dosage again more slowly.178

Maintenance dosages average about 1 g daily, but may range from 200 mg to 1.6 g daily in routine clinical practice.178

Prescribing Limits

Pediatric Patients

Seizure Disorders
Oral

Children <6 years of age: Safety of dosages exceeding 35 mg/kg in a 24-hour period not established.114

Children 6–15 years of age: Generally should not exceed 1 g daily.114

Children >15 years of age: Generally should not exceed 1.2 g daily.114

Adults

Seizure Disorders
Oral

Generally should not exceed 1.2 g daily; however, some patients have required up to 1.6–2.4 g daily.114 a

Neuropathic Pain
Trigeminal Neuralgia
Oral

Maximum 1.2 g daily.114

Bipolar Disorder
Oral

Maximum 1.6 g daily.178

Cautions for Carbamazepine

Contraindications

  • History of previous bone marrow depression.114

  • Acute intermittent porphyria.114

  • Hypersensitivity to carbamazepine or demonstrated sensitivity to any tricyclic antidepressant (e.g., amitriptyline, desipramine, imipramine, nortriptyline, protriptyline).114

  • Current or recent (i.e., within 2 weeks) MAO inhibitor therapy.114 (See Specific Drugs, Foods, and Laboratory Tests under Interactions.)

  • Concomitant use of nefazodone.209 213 (See Specific Drugs, Foods, and Laboratory Tests under Interactions.)

    The manufacturer of voriconazole states that concomitant use of carbamazepine and voriconazole is contraindicated.210 (See Specific Drugs, Foods, and Laboratory Tests under Interactions.)

Warnings/Precautions

Warnings

Serious Dermatologic Reactions and HLA-B*1502 Allele

Serious and sometimes fatal dermatologic reactions, including toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS), reported.189 191 192 193 194 195 209 e f Estimated to occur in 1–6 per 10,000 new users of the drug in countries with mainly Caucasian populations; risk in some Asian countries is estimated to be approximately 10 times higher.189 191 194 209 (See Boxed Warning.) Discontinue carbamazepine at first sign of rash, unless rash is clearly not drug-related.189 191 209 If signs or symptoms suggest SJS or TEN, do not resume carbamazepine; consider alternative therapy.189 191 209

Strong association found between presence of human leukocyte antigen (HLA)-B*1502, an inherited allelic variant of the HLA-B gene, and risk of developing SJS and TEN in patients of Chinese ancestry receiving carbamazepine.189 191 192 194 195 209 HLA-B*1502 allele is found almost exclusively in patients with ancestry across broad areas of Asia (including Han Chinese, Filipinos, Malaysians, South Asian Indians, and Thais); however, marked variation exists in its prevalence among various Asian populations.189 191 207 209 The allele is largely absent in individuals not of Asian origin (e.g., Caucasians, African-Americans, Hispanics, Native Americans).189 191 193 195 209

HLA-B*1502 allele not found to predict risk of less severe dermatologic reactions associated with carbamazepine (e.g., multiple-organ hypersensitivity reactions, non-serious rash such as maculopapular eruption).189 191 192 193 209

FDA and manufacturers of carbamazepine recommend screening patients with ancestry in genetically at-risk populations for presence of the HLA-B*1502 allele prior to initiating carbamazepine therapy.189 191 194 195 209 Patients testing positive for the allele should not receive carbamazepine therapy unless the benefits clearly outweigh the risks.189 191 209 Patients testing negative for the allele are considered to have a low risk of developing SJS and TEN.189 191 209

HLA-B*1502 allele prevalence rates provided in the prescribing information for carbamazepine may provide a rough guide for deciding which patients to screen; however, consider limitations of these figures (e.g., wide variability in rates even within ethnic groups, difficulty in ascertaining ethnic ancestry, likelihood of mixed ancestry).189 191 209 In determining the need to screen genetically at-risk patients currently receiving the drug, consider that >90% of carbamazepine-treated patients who will experience SJS or TEN develop this reaction within the first few months of therapy.189 191 209

HLA-B*1502 may be a risk factor for development of SJS and TEN in patients of Chinese ancestry receiving other anticonvulsants associated with these reactions (e.g., lamotrigine, fosphenytoin, phenytoin).189 191 192 207 209 (See Anticonvulsants under Interactions.) Consider avoidance of such drugs in HLA-B*1502-positive patients, when alternative therapies are otherwise equally acceptable.189 191 207 209

Screening for HLA-B*1502 allele must not substitute for appropriate clinical vigilance and patient management,189 191 209 since many HLA-B*1502-positive Asian patients treated with carbamazepine will never develop SJS or TEN, and such reactions may develop infrequently in HLA-B*1502-negative patients of any ethnicity.189 191 209

Hematologic Effects

For warnings regarding aplastic anemia and agranulocytosis, see Boxed Warning.

Pancytopenia, bone marrow depression, thrombocytopenia, leukopenia, leukocytosis, eosinophilia, and acute intermittent porphyria reported.114

Increased risk of hematologic effects in patients exhibiting baseline hematologic abnormalities, receiving other potentially myelotoxic drugs, or with a history of adverse hematologic reaction to any drug; monitor closely.109 114

Obtain baseline pretreatment CBC, including platelets and possibly reticulocytes and serum iron.114 If patient exhibits low or decreased leukocyte or platelet counts during therapy, monitor closely.114

Suicidality Risk

Increased risk of suicidality (suicidal ideation or behavior) observed in an analysis of suicidality reports from placebo-controlled studies involving 11 anticonvulsants, including carbamazepine, in patients with epilepsy, psychiatric disorders (e.g., bipolar disorder, depression, anxiety), and other conditions (e.g., migraine, neuropathic pain); risk in patients receiving anticonvulsants (0.43%) was approximately twice that in patients receiving placebo (0.24%).196 197 198 209 212 Increased suicidality risk was observed ≥1 week after initiation of anticonvulsant therapy and continued through 24 weeks.196 197 198 209 Risk was higher for patients with epilepsy compared with those receiving anticonvulsants for other conditions.196 197 198 209

Closely monitor all patients currently receiving or beginning anticonvulsant therapy for changes in behavior that may indicate emergence or worsening of suicidal thoughts or behavior or depression.196 197 198 209 212 Anxiety, agitation, hostility, hypomania, and mania may be precursors to emerging suicidality.196

Balance risk of suicidality with the risk of untreated illness.196 209 Epilepsy and other illnesses treated with anticonvulsants are themselves associated with morbidity and mortality and an increased risk of suicidality.209 212 If suicidal thoughts or behavior emerge during anticonvulsant therapy, consider whether these symptoms may be related to the illness itself.209 212 (See Advice to Patients.)

Withdrawal Seizures

Abrupt withdrawal may result in increased seizure frequency or status epilepticus; withdraw gradually and reduce dosage slowly.114

Cognitive/Neuropsychiatric Effects

Consider possibility of activation of latent psychosis, and in geriatric patients, confusion or agitation because of relationship to other tricyclic agents.114

Anticholinergic Effects

Due to mild anticholinergic activity, observe patients with increased intraocular pressure closely during therapy.114

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm; possible association between carbamazepine use during pregnancy and congenital malformations and developmental disorders (e.g., spina bifida, craniofacial defects, cardiovascular malformations, anomalies involving various body systems).114 172 173 174 175 If used during pregnancy or patient becomes pregnant, apprise of potential fetal hazard.114 Consider tests to detect fetal abnormalities using currently accepted procedures as part of routine prenatal care.114 a

Possible increased prevalence of teratogenic effects with use of combination anticonvulsant therapy; if therapy is continued in pregnant women, monotherapy is preferred.114

Neonatal seizures and respiratory depression reported with concomitant maternal use of carbamazepine and other anticonvulsants.114 Neonatal vomiting, diarrhea, and/or decreased feeding also reported; may represent neonatal withdrawal syndrome.114

Do not discontinue in pregnant women in whom anticonvulsant is administered to prevent major seizures due to strong possibility of precipitating status epilepticus with attendant hypoxia and threat to life.a 114 Risks of minor seizures to developing embryo or fetus unknown.114 a Consider risks and benefits of therapy in pregnant women.114 a

Sensitivity Reactions

Dermatologic and Sensitivity Reactions

For warnings regarding serious and sometimes fatal dermatologic reactions, including TEN and SJS, see Boxed Warning and see also Serious Dermatologic Reactions and HLA-B*1502 Allele under Cautions.

Multiple-organ hypersensitivity reactions occurring days to weeks or months after initiating therapy reported rarely.114 209 May initially be mild and may affect skin, liver, hematopoietic organs, lungs, kidneys, pancreas, myocardium, colon, immune and/or other systems.114 209 Lupus erythematosus reported.114 Consider discontinuance if any evidence of hypersensitivity develops.114 209

Possible hypersensitivity reactions in patients who previously experienced reaction to anticonvulsants (e.g., phenytoin, phenobarbital).114 209 Obtain history of hypersensitivity for patient and immediate family members; if previous reaction reported, use caution in prescribing carbamazepine.114 209 Approximately 25–30% of patients who demonstrated hypersensitivity reactions to carbamazepine may experience hypersensitivity reactions to oxcarbazepine.209

General Precautions

Obtain detailed history and physical examination before therapy initiation.114 Use only after critical benefit-risk appraisal in patients with history of cardiac, hepatic, or renal damage; cardiac conduction disturbance; adverse hematologic or hypersensitivity reaction to other drugs, including reactions to other anticonvulsants; or interrupted courses of carbamazepine therapy.114

Possible Prescribing and Dispensing Errors

Ensure accuracy of prescription; similarity in spelling between Tegretol or Tegretol-XR (trade names for carbamazepine) and Toprol-XL (metoprolol succinate, a β-adrenergic blocking agent) may result in errors.187 188 These medication errors have been associated with serious adverse events sometimes requiring hospitalization as a result of either lack of the intended medication (e.g., seizure recurrence, return of hallucinations, suicide attempt, hypertension recurrence) or exposure to the wrong drug (e.g., bradycardia in a patient erroneously receiving metoprolol).187 188

Nervous System Effects

Risk of increased frequency of generalized convulsions in patients with mixed seizure disorders that include atypical absence seizures; use with caution and consider possibility that worsening seizures after initiation may be drug induced.114 (See Suicidality Risk under Cautions.)

Hepatic Effects

Possible hepatic complications, including slight increases in hepatic enzymes, cholestatic and hepatocellular jaundice, hepatitis, and rarely, hepatic failure; hepatic effects may progress despite discontinuance in some cases.114

Obtain baseline and periodic evaluations of hepatic function, particularly in patients with a history of hepatic disease.114 Consider discontinuance if newly occurring or worsening clinical or laboratory evidence of hepatic impairment or damage or active liver disease.114

Laboratory Monitoring

For genetically at-risk patients (see Boxed Warning and see also Serious Dermatologic Reactions and HLA-B*1502 Allele under Cautions), high-resolution HLA-B*1502 typing is recommended.209 The test is positive if 1 or 2 HLA-B*1502 alleles are detected and negative if no HLA-B*1502 alleles are detected.209

Baseline and periodic eye examinations, including slit-lamp, funduscopy, and tonometry, recommended.114

Baseline and periodic complete urinalysis and BUN determinations recommended.114

Decreased values of thyroid function tests reported.114

Hyponatremia reported with carbamazepine either alone or in combination with other drugs.114

Specific Populations

Pregnancy

Category D.114 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

North American Antiepileptic Drug Pregnancy Registry at 888-233-2334 (for patients).209

Lactation

Carbamazepine and its active metabolite, carbamazepine 10,11-epoxide (CBZ-E), are distributed into milk.114 Discontinue nursing or the drug because of potential risk to nursing infant.114

Pediatric Use

Anticonvulsant efficacy in children is based on extrapolation of demonstrated efficacy in adults and in vitro studies that confirmed pathogenic mechanisms associated with seizure propagation and mechanism of carbamazepine action in treating seizures are essentially the same in adults and children.114 Safety data from long-term (>6 months) clinical studies in children are not available.114

Geriatric Use

Safety and efficacy not specifically studied in geriatric patients. Possible confusion or agitation in geriatric patients; use with caution.114

Hepatic Impairment

Use only after careful benefit-to-risk evaluation in patients with a history of hepatic damage.114

Renal Impairment

Use only after careful benefit-to-risk evaluation in patients with a history of renal damage.114

Common Adverse Effects

Dizziness, drowsiness, unsteadiness, nausea, vomiting.114

Interactions for Carbamazepine

Metabolized by CYP3A4.114 Induces CYP3A4; induces own metabolism.114

Anticonvulsants

The pharmacokinetics of carbamazepine or other anticonvulsants may be altered with concomitant use.114

Alterations in thyroid function reported with combination anticonvulsant therapy.

The HLA-B*1502 allele (found almost exclusively in patients with ancestry across broad areas of Asia) may be a risk factor for the development of SJS and TEN in patients of Asian ancestry who are receiving carbamazepine and some other anticonvulsants associated with these reactions (e.g., lamotrigine, fosphenytoin, phenytoin).189 191 192 207 208 209 Consider avoidance of these anticonvulsants and other drugs associated with SJS and TEN in HLA-B*1502-positive patients when alternative therapies are otherwise equally acceptable.189 191 207 209 (See Boxed Warning and see Serious Dermatologic Reactions and HLA-B*1502 Allele under Cautions.)

Drugs Affecting Hepatic Microsomal Enzymes

Inhibitors of CYP3A4: potential pharmacokinetic interaction (increased plasma carbamazepine concentrations).114

Inducers of CYP3A4: potential pharmacokinetic interaction (decreased plasma concentrations of carbamazepine).114

Drugs Metabolized by Hepatic Microsomal Enzymes

Substrates of CYP3A4: potential pharmacokinetic interaction (decreased plasma substrate concentrations).114

Specific Drugs, Foods, and Laboratory Tests

Drug, Food, or Test

Interaction

Comments

Acetaminophen

Decreased plasma acetaminophen concentrations shown or expected 114

Acetazolamide

Increased plasma carbamazepine concentrations shown or expected 114

Alcohol

Risk of additive CNS depression (e.g., sedation) with concomitant use209

Use with caution209

Alprazolam

Decreased plasma alprazolam concentrations shown or expected 114

Anticoagulants (e.g., dicumarol, warfarin)

Decreased plasma anticoagulant concentrations shown or expected 114

If must be used concomitantly, closely monitor patient and adjust dosage of both drugs as requireda

Antifungals, azoles (e.g., fluconazole, itraconazole, ketoconazole, voriconazole)

Concomitant use of carbamazepine with azole antifungals that inhibit CYP3A4 has been shown, or would be expected, to increase plasma carbamazepine concentrations209 211

Fluconazole: Increased plasma carbamazepine concentrations and associated toxicity reported211

Itraconazole: Increased plasma carbamazepine concentrations shown or expected;209 decreased plasma itraconazole concentrations shown or expected 209

Voriconazole: Increased plasma carbamazepine concentrations shown or expected;209 substantially decreased plasma voriconazole concentrations expected210

Fluconazole: Monitoring of plasma carbamazepine concentrations has been recommended211

Voriconazole: The manufacturer of voriconazole states that concomitant use of carbamazepine and voriconazole is contraindicated210

Antineoplastic agents (e.g., cisplatin, doxorubicin)

Decreased carbamazepine concentrations shown or expected 114

Antipsychotic agents (e.g., aripiprazole, clozapine, haloperidol, risperidone, ziprasidone)

Decreased plasma concentrations of antipsychotic agent shown or expected, sometimes resulting in reductions in antipsychotic efficacy with reemergence of symptoms114 150 152 153 155 156 157 158 182 183

Neuroleptic malignant syndrome reported rarely with concomitant use184

Possible increased risk of adverse hematologic effects with clozapine177

Carefully monitor patients receiving carbamazepine and haloperidol concomitantly for loss of antipsychotic control and, if interaction suspected, adjust haloperidol dosage accordingly; consider possibility of haloperidol toxicity after carbamazepine discontinuance150 151 152 157

If carbamazepine is added to aripiprazole therapy, double aripiprazole dosage and make additional increases based on clinical evaluation; if carbamazepine is withdrawn from the combination therapy, reduce aripiprazole dosage accordingly182

Concomitant use with clozapine not recommended;177 185 186 if used concomitantly, consider that discontinuance of carbamazepine may result in increased plasma clozapine concentrations183 185 186

Antituberculosis agents (e.g., isoniazid, rifampin)

Increased plasma carbamazepine concentrations shown or expected with concomitant use of CYP3A4 inhibitors (e.g., isoniazid); conversely, decreased plasma carbamazepine concentrations shown or expected with concomitant use of CYP3A4 inducers (e.g., rifampin)114

Calcium-channel blocking agents (e.g., diltiazem, felodipine, verapamil)

Increased carbamazepine concentrations shown or expected with concomitant use of diltiazem or verapamil114

Decreased plasma concentrations of dihydropyridine calcium-channel blocking agents (e.g., felodipine) shown or expected114

If verapamil is initiated in patients receiving carbamazepine, 40–50% reduction in carbamazepine dosage may be necessary; monitor closely for manifestations of carbamazepine toxicity and for alterations in carbamazepine pharmacokinetics, adjusting dosage accordingly101 102 114

If verapamil is discontinued, increase carbamazepine dosage to avoid loss of seizure control101 102 114

Chlorpromazine

Rubbery, orange precipitate results when chlorpromazine oral solution is mixed with carbamazepine suspension;114 176 effect on bioavailability of either drug is not known176

In at least 1 patient, orange rubbery precipitate was passed in stool the day after ingestion of carbamazepine suspension immediately followed by chlorpromazine oral solution114

Do not administer carbamazepine suspension simultaneously with other liquid preparations114 176

Cimetidine

Increased plasma carbamazepine concentrations shown or expected 114

Clomipramine

Increased plasma clomipramine concentrations shown or expected 114

Clonazepam

Decreased plasma clonazepam concentrations shown or expected 114

Corticosteroids (e.g., dexamethasone, prednisolone)

Decreased plasma corticosteroid concentrations shown or expected 114

Cyclosporine

Decreased plasma cyclosporine concentrations shown or expected 114

Danazol

Increased plasma carbamazepine concentrations shown or expected 114

Doxycycline

Decreased plasma doxycycline concentrations shown or expected 114

Avoid concomitant administration if possible; if concomitant therapy necessary, administer doxycycline at 12-hour intervals and/or closely monitor serum doxycycline concentrationsa

Ethosuximide

Decreased plasma ethosuximide concentrations shown or expected 114

Felbamate

Decreased plasma carbamazepine concentrations and increased CBZ-E concentrations shown or expected;114 interaction is complex and resultant changes may be unpredictable114 162 163 164 165 166 167 168

Fluoxetine

Increased plasma carbamazepine and CBZ-E concentrations and toxicity114 169 170 171

Monitor patient and plasma concentrations of carbamazepine and its metabolite closely when fluoxetine is initiated or discontinued; adjust dosage accordingly169 170 171

Fluvoxamine

Increased plasma carbamazepine concentrations shown or expected 114

Grapefruit juice

Increased plasma carbamazepine concentrations shown or expected 114

HIV protease inhibitors

Increased plasma carbamazepine concentrations and decreased plasma protease inhibitor concentrations shown or expected 114

Hormonal contraceptives

Possible increased contraceptive metabolism resulting from induction of hepatic microsomal enzymes, resulting in decreased plasma concentrations of hormones;114 breakthrough bleeding and unintended pregnancies reported114

Consider use of a nonhormonal method of birth control during carbamazepine therapy114

Lamotrigine

Decreased plasma lamotrigine concentrations shown or expected114

Levothyroxine

Decreased plasma levothyroxine concentrations shown or expected114

Lithium

Increased risk of adverse neurologic effects 114

Macrolides (e.g., clarithromycin, erythromycin, troleandomycin)

Increased plasma carbamazepine concentrations shown or expected114

Monitor patients receiving carbamazepine and erythromycin concomitantly for evidence of carbamazepine toxicity; reduce carbamazepine dosage when necessary;105 106 107 some clinicians suggest use of alternative to erythromycin107

MAO inhibitors

Possible serotonin syndrome114

Combined therapy contraindicated; observe a medication-free period of ≥14 days when transferring patients from MAO inhibitors to carbamazepine; initiate carbamazepine cautiously with gradual increases in dosage to obtain desired response114

Methadone

Decreased plasma methadone concentrations shown or expected 114

Methsuximide

Decreased plasma carbamazepine and methsuximide concentrations shown or expected 114

Midazolam

Decreased plasma midazolam concentrations shown or expected 114

Nefazodone

Substantially reduced (by 95%) plasma concentrations of nefazodone and its active metabolite, hydroxynefazodone, resulting in levels insufficient to achieve an antidepressant effect209 213

Concomitant use contraindicated209 213

Niacinamide

Increased plasma carbamazepine concentrations shown or expected 114

Phenobarbital

Decreased plasma carbamazepine concentrations shown or expected 114

Phenytoin

Decreased or increased plasma phenytoin concentrations shown or expected;114 carbamazepine may decrease the half-life of phenytoina 114

Decreased carbamazepine plasma concentrations shown or expected114

May be desirable to monitor serum concentrations of concomitantly administered anticonvulsants; make dosage adjustments as necessary114

Praziquantel

Decreased plasma praziquantel concentrations shown or expected 114

Pregnancy tests

Carbamazepine may interfere with some pregnancy tests114

Primidone

Decreased plasma carbamazepine concentrations and increased plasma primidone concentrations shown or expected 114

Propoxyphene

Increased plasma carbamazepine concentrations shown or expected 114

Theophylline

Carbamazepine and theophylline may induce each other’s metabolism, with resultant changes in elimination half-life and plasma concentrations114 159 160 161

If used concomitantly, monitor patient and plasma concentrations of the drugs; adjust dosage accordingly159

Thioridazine

Rubbery, orange precipitate results when liquid thioridazine preparations are mixed with carbamazepine suspension;114 176 effect on bioavailability of either drug is not known176

Do not administer carbamazepine suspension simultaneously with other liquid preparations114 176

Tiagabine

Decreased plasma tiagabine concentrations shown or expected 114

Topiramate

Decreased plasma topiramate concentrations shown or expected 114

Tramadol

Decreased plasma tramadol concentrations shown or expected 114

Trazodone

Decreased plasma concentrations of trazodone and an active metabolite, m-chlorophenylpiperazine180 181

If used concomitantly, monitor patient and increase trazodone dosage if necessary180 181

Tricyclic antidepressants (e.g., amitriptyline, imipramine, nortriptyline)

Decreased plasma tricyclic antidepressant concentrations shown or expected 114

Valproic acid

Valproic acid may affect both plasma carbamazepine and CBZ-E concentrations, but interaction is complex and resultant changes may be unpredictable114 162 163 164 165 166 167 168

Increased plasma CBZ-E concentrations and decreased plasma valproate concentrations shown or expected114

Effect of valproic acid on carbamazepine concentrations may depend principally on increases in plasma CBZ-E concentrations relative to parent drug (possibly secondary to inhibition of epoxide hydrolase activity) but other suggested mechanisms (e.g., displacement of carbamazepine from protein binding sites) may contribute to overall effect162 163 164 165 166 167 168

Consider importance of determining CBZ-E concentrations in patients exhibiting toxicity during concomitant use164 165 166 167 168

Zonisamide

Decreased plasma zonisamide concentrations shown or expected114

Carbamazepine Pharmacokinetics

Absorption

Bioavailability

Slowly absorbed from GI tract.a Following chronic oral administration of tablets, suspension, extended-release tablets, or extended-release capsules, peak plasma concentrations are reached in 4.5, 1.5, 3–12, or 4.1–7.7 hours, respectively.114 b c

Oral bioavailabilities of tablets and suspension reportedly are equivalent, although rate of absorption is faster for suspension.114 115 116 117 118 Bioavailability of extended-release tablets is reportedly 89% of that of suspension.114 a

2–4 days of therapy may be required to achieve steady-state plasma concentrations.114 a

Food

Rate but not extent of absorption increased following administration of carbamazepine extended-release capsules (400-mg single dose) with a high-fat meal.c

Plasma Concentrations

Optimal therapeutic plasma concentrations suitable for all patients not yet determined.114

For both anticonvulsant effects and relief of pain of trigeminal neuralgia, therapeutic plasma concentrations are usually 3–14 mcg/mL.a

Nystagmus frequently occurs with plasma concentrations >4 mcg/mL.a

Ataxia, dizziness, and anorexia often occur with plasma concentrations ≥10 mcg/mL.a

Distribution

Extent

Widely distributed throughout the body; detected in CSF, brain, duodenal fluids, bile, and saliva.114 Carbamazepine 10,11-epoxide (CBZ-E) also detected in CSF.114

Rapidly crosses placenta and accumulates in fetal tissues, with higher concentrations in liver and kidney than in brain and lungs.114 Carbamazepine and its epoxide metabolite are distributed into breast milk.114

Plasma Protein Binding

75–90%.114

Elimination

Metabolism

Metabolic fate not completely elucidated, but major metabolic pathway appears to be oxidation by CYP3A4 to form CBZ-E, which is almost completely metabolized to trans-10,11-dihydroxy-10,11-dihydrocarbamazepine.114 a CBZ-E has anticonvulsant activity in animals.114

Induces own metabolism; autoinduction is complete after 3–5 weeks of a fixed dosage regimen.114

Elimination Route

After oral administration, 72 and 28% recovered in urine and feces, respectively; only 1–3% excreted in urine unchanged.114

Half-life

25–65 hours initially; 12–17 hours with multiple dosing.114

Special Populations

In children <15 years of age, carbamazepine is more rapidly metabolized to CBZ-E than in adults.114 CBZ-E/CBZ ratio is inversely related to increasing age in children <15 years of age.114

Stability

Storage

Oral

Capsules

Tight, light-resistant containers at 15–25°C.c

Tablets

Store conventional and chewable tablets in tight, light-resistant containers at ≤30°C.114 a Keep in dry location, away from excessive moisture.123

Store extended-release tablets in tight, light-resistant containers, protected from moisture at 15–30°C.114 a

Suspension

Tight, light-resistant containers at ≤30°C; avoid freezing.113 114

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Oral

Suspension

Mixing with either chlorpromazine oral solution or with liquid thioridazine preparations results in a rubbery, orange precipitate; it is not known if bioavailability of either carbamazepine or the other drugs is decreased.114 176 Extent to which this interaction occurs with other liquid preparations is not known.176

Actions

  • Pharmacologic actions appear to be qualitatively similar to those of hydantoin-derivative anticonvulsants.a

  • Anticonvulsant activity principally involves limitation of seizure propagation by reduction of posttetanic potentiation (PTP) of synaptic transmission.114 a

  • Appears to provide relief of pain in trigeminal neuralgia by reducing synaptic transmission within the trigeminal nucleus; demonstrates only slight analgesic properties.a

  • Demonstrates sedative, anticholinergic, antidepressant, muscle relaxant, antiarrhythmic, antidiuretic, and neuromuscular transmission-inhibitory actions.a

Advice to Patients

  • Importance of providing copy of written patient information (medication guide) each time carbamazepine is dispensed.209 212

  • Importance of immediately reporting early manifestations of adverse hematologic, dermatologic, hypersensitivity, or hepatic reactions, such as fever, sore throat, infection, rash, mouth ulcers, easy bruising, lymphadenopathy, petechial or purpuric hemorrhage, anorexia, nausea/vomiting, or jaundice.114 Advise to report these manifestations even if mild in severity or occur after extended use.114

  • Risk of suicidality (anticonvulsants, including carbamazepine, may increase risk of suicidal thoughts or actions in about 1 in 500 people).196 197 198 209 d Importance of patients, family, and caregivers being alert to day-to-day changes in mood, behavior, and actions and immediately informing clinician of any new or worrisome behaviors (e.g., talking or thinking about wanting to hurt oneself or end one’s life, withdrawing from friends and family, becoming depressed or experiencing worsening of existing depression, becoming preoccupied with death and dying, giving away prized possessions).196 209

  • Risk of dizziness or drowsiness; avoid driving, operating machinery, or performing hazardous tasks until effects on individual are known.114

  • Importance of exercising caution regarding alcohol use because of possible additive sedative effects.114

  • Importance of not abruptly discontinuing therapy.114

  • Importance of women informing clinicians if they are or plan to become pregnant or to breast-feed; advise pregnant women of risk to fetus.114

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and herbal products.114

  • Importance of informing patients of other important precautionary information.114 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Carbamazepine

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Capsules, extended-release

100 mg

Carbatrol

Shire

200 mg

Carbatrol

Shire

300 mg

Carbatrol

Shire

Suspension

100 mg/5 mL

Carbamazepine Suspension

Tegretol

Novartis

Tablets

200 mg*

Epitol (scored)

Teva

Tegretol (scored)

Novartis

Tablets, chewable

100 mg*

Tegretol (scored)

Novartis

Tablets, extended-release

100 mg

Tegretol-XR

Novartis

200 mg

Tegretol-XR

Novartis

400 mg

Tegretol-XR

Novartis

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 02/2014. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

CarBAMazepine 100MG 12-hr Capsules (NOSTRUM LABORATORIES): 30/$52.99 or 90/$145.96

CarBAMazepine 100MG Chewable Tablets (TARO): 60/$14.99 or 120/$19.97

CarBAMazepine 100MG/5ML Suspension (TARO): 450/$67.95 or 1350/$178.71

CarBAMazepine 200MG 12-hr Capsules (NOSTRUM LABORATORIES): 30/$52.99 or 90/$145.96

CarBAMazepine 200MG 12-hr Tablets (TARO): 100/$86.65 or 300/$259.96

CarBAMazepine 200MG Tablets (TARO): 90/$14.99 or 270/$35.97

CarBAMazepine 300MG 12-hr Capsules (NOSTRUM LABORATORIES): 30/$52.99 or 90/$145.96

CarBAMazepine 400MG 12-hr Tablets (TARO): 100/$175.99 or 300/$499.95

Carbatrol 100MG 12-hr Capsules (SHIRE US INC.): 30/$65.99 or 90/$177.97

Carbatrol 200MG 12-hr Capsules (SHIRE US INC.): 60/$118.99 or 120/$225.96

Carbatrol 300MG 12-hr Capsules (SHIRE US INC.): 60/$115.99 or 180/$342.98

Equetro 300MG 12-hr Capsules (VALIDUS PHARMACEUTICALS): 60/$148.75 or 180/$427.87

TEGretol 100MG Chewable Tablets (NOVARTIS): 60/$45.99 or 180/$115.97

TEGretol 100MG/5ML Suspension (NOVARTIS): 450/$81.99 or 1350/$226.97

TEGretol 200MG Tablets (NOVARTIS): 30/$43.99 or 90/$109.97

TEGretol XR 100MG 12-hr Tablets (NOVARTIS): 30/$30.99 or 90/$64.97

TEGretol XR 200MG 12-hr Tablets (NOVARTIS): 30/$42.99 or 90/$107.97

TEGretol XR 400MG 12-hr Tablets (NOVARTIS): 30/$77.99 or 90/$216.97

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions October 27, 2011. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

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