Brand names: Carbatrol, Carnexiv, Epitol Equetro, TEGretol
Drug class: Anticonvulsants, Miscellaneous
VA class: CN400
CAS number: 298-46-4

Medically reviewed by Drugs.com on Nov 4, 2024. Written by ASHP.

Introduction

Anticonvulsant; also an antimanic agent and specific analgesic for trigeminal neuralgia.^{114 190 191}

Uses for Carbamazepine

Seizure Disorders

Monotherapy or adjunctive therapy (i.e., in combination with other anticonvulsants) 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 a}

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

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}

Neuropathic Pain

Symptomatic treatment of pain associated with true trigeminal neuralgia.¹¹⁴

Beneficial results also reported in glossopharyngeal neuralgia.¹¹⁴

Symptomatic treatment of chronic pain arising from other peripheral neuropathic syndromes^{† [off-label]}, including pain of diabetic neuropathy^{† [off-label]}.^a

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

Bipolar Disorder

Treatment of acute manic or mixed episodes in patients with bipolar I disorder.^{178 190 215 216 217}

American Psychiatric Association (APA) considers carbamazepine an alternative treatment option for patients who do not respond adequately to first-line drugs (e.g., lithium, valproate, antipsychotic agents [e.g., olanzapine]).¹⁷⁸

Schizophrenia

Symptomatic management of the acute phase of schizophrenia^{† [off-label]}, 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

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

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)^{† [off-label]}.^a

Treatment of alcohol withdrawal syndrome^{† [off-label]}.^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

• Therapeutic drug monitoring may be useful for optimizing dosage, minimizing toxicity and adverse effects, and verifying drug compliance.^{114 150 190 191}

• Withdraw gradually in patients with seizure disorders to minimize potential for increased seizure frequency and status epilepticus.^{114 190 191} (See Discontinuance of Therapy under Cautions.)

• Closely monitor for marked changes in behavior that could indicate emergence or worsening of suicidal thoughts or behavior or depression.^{114 196 198 212} (See Suicidality Risk under Cautions.)

Pharmacogenetic Testing

• Pharmacogenetic testing for the variant HLA-B*1502 allele is recommended in patients who may be at increased risk of carbamazepine-induced SJS and TEN.^{114 185 186} (See Boxed Warning.)

• Prior to initiating carbamazepine therapy, screen patients in genetically at-risk populations for HLA-B*1502.^{114 150 185 189 191 192 194 195 207}

• High-resolution HLA-B*1502 typing recommended; the test is considered positive if 1 or 2 copies of HLA-B*1502 are detected and negative if no copies are detected.^{114 182}

• Do not initiate therapy in HLA-B*1502-positive patients unless benefits clearly outweigh risks.^{114 182 189 191}

• Also may consider genetic testing for presence of HLA-A*3101, another variant allele associated with a wider range of carbamazepine hypersensitivity reactions.¹¹⁴

• Because of limitations, HLA genotyping must not substitute for appropriate clinical vigilance and patient management.^{114 182 189 190 191}

• Many HLA-B*1502- and HLA-A*3101-positive patients treated with carbamazepine will never develop SJS, TEN, or other hypersensitivity reactions, and such reactions may develop infrequently in HLA-B*1502- and HLA-A*3101-negative patients of any ethnicity.^{114 189 190 191}

• For additional information and guidance on how to interpret and apply results of HLA-B*1502 and HLA-A*3101 testing, consult the Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for HLA genotype and use of carbamazepine and oxcarbazepine.¹⁸²

Administration

Usually administered orally; however, an IV preparation is available for temporary (i.e., ≤7 days) use in adults with seizure disorders when oral administration not feasible.^{114 150 180 190 191}

Oral Administration

Administer orally as conventional tablets, chewable tablets, extended-release tablets, extended-release capsules, or oral suspension.^{114 180 190 191}

Extended-release Capsules

Administer orally (usually twice daily) without regard to meals.^{190 191} Swallow extended-release capsules whole or administer by opening capsule and sprinkling contents over food (e.g., teaspoonful of applesauce).^{190 191} Do not crush or chew extended-release capsules or their contents.^{190 191}

Conventional and Chewable Tablets

Administer orally 2–4 times daily with meals.^{114 180}

Extended-release Tablets

Administer orally (usually 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 or 4 times daily with meals.¹¹⁴ Shake well before administration.¹¹⁴

Do not administer simultaneously with other liquid medications and diluents.^{114 176} (See Compatibility under Stability.)

IV Administration

Administer by IV infusion over 30 minutes.¹⁵⁰ When converting from oral to IV therapy, administer corresponding total daily IV dosage (equivalent to 70% of the total daily oral dosage) in 4 equally divided 30-minute infusions at 6-hour intervals.¹⁵⁰

Bioequivalence demonstrated between oral carbamazepine and 30-minute IV infusions of the drug.¹⁹⁷ IV route intended for temporary use only; switch patients back to oral therapy (at the previously administered oral dose and frequency) as soon as clinically appropriate.¹⁵⁰ Use of IV carbamazepine for >7 days not recommended.¹⁵⁰

Prior to administration, dilute commercially available concentrate for injection with a compatible diluent (0.9% sodium chloride injection, lactated Ringer’s injection, or 5% dextrose injection).¹⁵⁰ Withdraw appropriate volume of concentrate for injection (based on prescribed dose) and dilute in 100 mL of diluent.¹⁵⁰ (See Storage under Stability.)

Vials are for single dose only; discard unused portions.¹⁵⁰

Dosage

Adjust dosage carefully according to individual requirements and response.^{114 180 191} Initiate with a low dosage and increase gradually .^{114 180 191} Once a therapeutic effect has been achieved, attempt to reduce dosage to minimum effective dosage.^{114 180 191}

When transferring patients from conventional, immediate-release formulations to extended-release capsules or tablets, administer same total daily dosage in 2 divided doses.^{114 190 191} Following the transition, closely monitor patients and adjust dosage as needed.^{190 191}

Because 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}

When transferring 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}

To achieve therapeutic plasma carbamazepine concentrations more rapidly in pediatric patients (in about 2 hours), some clinicians have administered a loading-dose regimen using the oral suspension.¹²⁴

Pediatric Patients

Seizure Disorders

When carbamazepine is added to an existing anticonvulsant regimen, introduce the drug gradually while maintaining or gradually decreasing dosage of other anticonvulsant(s); certain enzyme-inducing anticonvulsants (e.g., phenytoin) may require an increase in dosage.^{114 190 191} (See Specific Drugs, Foods, and Laboratory Tests under Interactions.)

Oral (tablets or oral suspension)

Children <6 years of age: Initially, 10–20 mg/kg daily in 2 or 3 divided doses (as chewable or conventional tablets) or 4 divided doses (as oral suspension).^{114 180} Increase dosage at weekly intervals to achieve optimal clinical response, which is generally achieved at maintenance dosages <35 mg/kg daily.^{114 180} If clinical response not achieved, determine whether plasma carbamazepine concentrations in therapeutic range.^{114 180} Safety of dosages >35 mg/kg in a 24-hour period not established.^{114 180}

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.^{114 180} Increase dosage at weekly intervals by increments of up to 100 mg daily using a twice-daily divided dosing regimen (if using extended-release tablets) or a 3- or 4-times-daily divided dosing regimen (if using conventional or chewable tablets or oral suspension) until optimal response obtained; do not exceed maximum dosage of 1 g daily.^{114 180} Once adequate seizure control is achieved, adjust dosage to minimum effective level, usually 400–800 mg daily.^{114 180}

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 100 mg 4 times daily as oral suspension.^{114 180 190 191} Increase dosage at weekly intervals by increments of up to 200 mg daily using a twice-daily divided dosing regimen (if using extended-release dosage forms) or a 3- or 4-times-daily divided dosing regimen (if using conventional or chewable tablets or oral suspension) until optimal response obtained; do not exceed maximum dosage of 1 or 1.2 g daily in children 12–15 or >15 years of age, respectively.^{114 180 190 191} Once adequate seizure control is achieved, adjust dosage to minimum effective level, usually 800 mg to 1.2 g daily.^{114 180 191}

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

Oral (extended-release capsules)

Children <12 years of age: Optimal clinical response generally achieved at dosages of <35 mg/kg daily.^{190 191} If satisfactory response not achieved, determine whether plasma carbamazepine concentrations in therapeutic range;¹⁹¹ safety of dosages >35 mg/kg in 24 hours not established.^{190 191}

Children >12 years of age: Initially, 200 mg twice daily.^{190 191 191} Increase dosage at weekly intervals by increments of up to 200 mg daily using a twice-daily divided dosing regimen until optimal response obtained; do not exceed maximum dosage of 1 or 1.2 g daily in children 12–15 or >15 years of age, respectively.^{190 191} Once adequate seizure control is achieved, adjust dosage to minimum effective level, usually 800 mg to 1.2 g daily.¹⁹¹

Bipolar Disorder†

Oral

Manufacturer states that efficacy and safety of carbamazepine in pediatric patients not established;¹⁹⁰ however, initial dosages of 200–600 mg daily, given in 3 or 4 divided doses, have been used in children >12 years of age.¹⁷⁸

In hospitalized patients with acute mania, some experts state that dosage may be increased as tolerated in 200-mg daily increments up to 800 mg to 1 g daily, with slower increases thereafter as indicated.¹⁷⁸

In less acutely ill outpatients, adjust dosage at a slower rate because rapid increases may increase risk of adverse GI or CNS effects.¹⁷⁸ If such adverse effects occur, consider temporary dosage reduction.¹⁷⁸ May increase dosage again more slowly once adverse effects resolve.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

When carbamazepine is added to an existing anticonvulsant regimen, introduce the drug gradually while maintaining or gradually decreasing dosage of other anticonvulsant(s); certain enzyme-inducing anticonvulsants (e.g., phenytoin) may require an increase in dosage.^{114 190 191} (See Specific Drugs, Foods, and Laboratory Tests under Interactions.)

Oral

Initially, 200 mg twice daily (as chewable, conventional, or extended-release tablets, or extended-release capsules) or 100 mg 4 times daily (as oral suspension).^{114 180 190 191}

Increase dosage by increments of up to 200 mg daily at weekly intervals using a twice-daily divided dosing regimen (if using extended-release dosage forms) or a 3- or 4-times-daily divided dosing regimen (if using conventional or chewable tablets or oral suspension) until optimal response obtained.^{114 180 190 191} Dosage generally should not exceed 1.2 g daily;¹¹⁴ however, some patients have required dosages up to 1.6 g daily.^{114 180 191}

Once adequate seizure control is achieved, adjust dosage to minimum effective level, usually 800 mg to 1.2 g daily.^{114 180 191}

IV

When oral therapy is temporarily not feasible, may administer by IV infusion in a total daily dosage equivalent to 70% of the total daily oral dosage; administer total daily IV dosage in 4 equally divided 30-minute IV infusions at 6-hour intervals (e.g., a patient receiving an oral dosage of 400 mg daily should receive a corresponding IV dosage of 280 mg daily, administered as 70 mg every 6 hours).¹⁵⁰

Neuropathic Pain

Trigeminal Neuralgia

Oral

Initially, 100 mg twice daily as tablets (conventional, chewable, or extended-release), 200 mg once daily as extended-release capsules, or 50 mg 4 times daily as oral suspension on the first day of therapy.^{114 180 190 191}

Increase dosage gradually by up to 200 mg daily using 100-mg increments every 12 hours for tablets or capsules, or 50-mg increments 4 times daily for the suspension until pain is relieved.^{114 180 190 191}

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 as much as 1.2 g daily.^{114 180 190 191} Manufacturers state that a dosage of 1.2 g daily should not be exceeded.^{114 180 190 191}

At least once every 3 months, make attempt to decrease dosage to minimum effective level or discontinue drug.^{114 180 190 191}

Bipolar Disorder

Oral

Initially, 200 mg twice daily (as extended-release capsules).¹⁹⁰ Increase dosage as tolerated by increments of 200 mg daily until optimal clinical response is achieved.^{178 190}

In hospitalized patients with acute mania, some experts state that dosage may be increased as tolerated in 200-mg daily increments up to 800 mg to 1 g daily, with slower increases thereafter as indicated.¹⁷⁸

In less acutely ill outpatients, adjust dosage at a slower rate because rapid increases may increase risk of adverse GI or CNS effects.¹⁷⁸ If such adverse effects occur, consider temporary dosage reduction.¹⁷⁸ May increase dosage again more slowly once adverse effects resolve.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

In general, do 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

Dosages >1.6 g daily not recommended.¹⁷⁸

Special Populations

Hepatic Impairment

When switching from oral to IV therapy in patients with hepatic impairment, increased plasma concentrations of carbamazepine may occur due to reduced first-pass metabolism; monitor plasma carbamazepine concentrations in such patients.¹⁵⁰ (See Absorption: Special Populations, under Pharmacokinetics.)

Cautions for Carbamazepine

Contraindications

• History of bone marrow depression.¹¹⁴

• Hypersensitivity to carbamazepine or 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.¹¹⁴ (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

Serious and sometimes fatal dermatologic reactions, including TEN and SJS, reported.^{114 189 191 192 193 194 195 213 214} Risk is higher in some Asian populations.^{114 189 191 194} (See Boxed Warning and also see Pharmacogenomics of Carbamazepine-induced Cutaneous Reactions under Cautions.)

Discontinue carbamazepine at first sign of rash, unless rash is clearly not drug related.^{114 189 191} If signs or symptoms suggest SJS or TEN, do not resume carbamazepine; consider alternative therapy.^{114 189 191}

Pharmacogenomics of Carbamazepine-induced Cutaneous Reactions

Retrospective, case-control studies in patients of Chinese ancestry demonstrated a strong association between risk of developing carbamazepine-induced SJS and TEN and presence of the HLA-B*1502 allele.^{114 182 185 189 191 192 194 195 207 208} (See Boxed Warning.)

Frequency of HLA-B*1502 is >15% in Hong Kong, Thailand, Malaysia, and parts of the Philippines compared with about 10% in Taiwan and 4% in North China.^{114 182 189 191 192 194} South Asians, including Indians, appear to have an intermediate prevalence (2–4%).^{114 189 191} HLA-B*1502 is present in <1% of Japanese and Korean populations and largely absent in individuals not of Asian origin (e.g., Caucasians, African-Americans, Hispanics, Native Americans).^{114 182 189 191 193 195}

HLA-A*3101 is another variant allele associated with a wider range of carbamazepine-induced hypersensitivity reactions.^{114 182 186} Retrospective, case-control studies demonstrated a moderate association between risk of hypersensitivity reactions (including multi-organ hypersensitivity, maculopapular exanthema, SJS, and TEN) and presence of HLA-A*3101 in patients receiving carbamazepine.^{114 182 186}

Frequency of HLA-A*3101 varies from >15% in patients with Japanese, Native American, South Indian, and some Arabic ancestry to ≤5–10% in patients with Chinese, Korean, European, Latin American, African-American, Thai, Taiwanese, and other Indian ancestry.¹¹⁴

Prior to initiating carbamazepine therapy, screen patients with ancestry in genetically at-risk populations for presence of HLA-B*1502.^{114 189 191 194 195} (See Pharmacogenetic Testing under Dosage and Administration.) HLA-B*1502-positive patients should not receive carbamazepine therapy unless benefits clearly outweigh risks.^{114 189 191} Patients who test negative are considered to have a low risk of developing SJS and TEN.^{114 189 191}

Consider risks versus benefits of therapy in patients who test positive for HLA-A*3101.^{114 182} Experts recommend that carbamazepine should not be used in treatment-naive, HLA-A*3101-positive patients if alternative therapies are available; however, may consider cautious use in HLA-A*3101-positive patients who have previously received the drug for >3 months without experiencing a cutaneous reaction.¹⁸²

Hematologic Effects

Aplastic anemia and agranulocytosis reported.¹¹⁴ (See Boxed Warning.) Although transient or persistent minor hematologic changes (e.g., decreased leukocyte or platelet counts) are not uncommon with carbamazepine, most cases have not progressed to more serious conditions (e.g., aplastic anemia, agranulocytosis).¹¹⁴

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.^{109 110 111 112 114 119 120} Consider discontinuance of therapy if any evidence of significant bone marrow depression develops.^{114 119}

Because acute attacks of porphyria have been reported, do not use carbamazepine in patients with a history of hepatic porphyria.^{114 190 191}

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%).^{114 196 198 212} Increased suicidality risk was observed as early as 1 week after initiation of anticonvulsant therapy and continued through 24 weeks.^{114 196 198} Risk was higher for patients with epilepsy compared with those receiving anticonvulsants for other conditions.^{114 196 198}

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.^{114 196 198 212}

Balance risk of suicidality with the risk of untreated illness.^{114 196} Epilepsy and other illnesses treated with anticonvulsants are themselves associated with morbidity and mortality and an increased risk of suicidality.^{114 212} If suicidal thoughts or behavior emerge during anticonvulsant therapy, consider whether these symptoms may be related to the illness itself.^{114 212} (See Advice to Patients.)

Sensitivity Reactions

Dermatologic and Sensitivity Reactions

For warnings regarding serious and sometimes fatal dermatologic reactions, including TEN and SJS, see Boxed Warning and also see Serious Dermatologic Reactions under Cautions.

Hypersensitivity Reactions

Possible cross-hypersensitivity between carbamazepine and other anticonvulsants including phenytoin, primidone, and phenobarbital.^{114 190 191} Approximately one-third of patients who demonstrated hypersensitivity reactions to carbamazepine may experience hypersensitivity reactions to oxcarbazepine.^{114 190 191} Obtain patient’s history of hypersensitivity.^{114 190 191} If previous reaction reported, carefully consider risks versus benefits of carbamazepine therapy; if used, carefully monitor patients for hypersensitivity.^{114 190 191}

Anaphylaxis and angioedema involving the larynx, glottis, lips, and eyelids reported rarely; can be fatal.¹¹⁴ If a serious hypersensitivity reaction develops, discontinue carbamazepine and initiate alternative therapy; do not rechallenge.¹¹⁴

Multi-organ Hypersensitivity

Multi-organ hypersensitivity (also known as drug reaction with eosinophilia and systemic symptoms [DRESS]) reported; can be fatal or life-threatening.^{114 190 191} Clinical presentation is variable but typically includes eosinophilia, fever, rash, lymphadenopathy, and/or facial swelling associated with other organ system involvement (e.g., hepatitis, nephritis, hematologic abnormalities, myocarditis, myositis).^{114 190 191}

If manifestations of multi-organ hypersensitivity occur, evaluate patient immediately.^{114 190 191} If an alternative cause cannot be identified, discontinue carbamazepine.^{114 190 191}

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

Discontinuance of Therapy

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

Cognitive/Neuropsychiatric Effects

Possible adverse neuropsychiatric effects include dizziness, vertigo, drowsiness, fatigue, ataxia, disturbances of coordination, confusion, headache, visual hallucinations, speech disturbances, and abnormal involuntary movements.^a Rarely, peripheral neuritis and paresthesia, depression with agitation, talkativeness, and tinnitus have occurred.^a (See Advice to Patients.)

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

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}

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}

Risk of Seizure Exacerbation

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.^{100 114}

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 a}

Obtain baseline and periodic evaluations of hepatic function, particularly in patients with a history of hepatic disease.^{114 190 191} Consider discontinuance in patients with evidence of liver disease based on clinical judgment; some manufacturers recommend immediate discontinuance if worsening liver dysfunction or active liver disease observed.^{114 190 191}

Monitoring

HLA-B*1502 genotyping is recommended in high-risk patients.^{114 150} (See Pharmacogenetic Testing under Dosage and Administration.)

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

Baseline and periodic complete urinalysis and BUN determinations recommended.¹¹⁴

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

Specific Populations

Pregnancy

May cause fetal harm.¹¹⁴ (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

North American Antiepileptic Drug (NAAED) Pregnancy Registry at 888-233-2334 (for patients) or [Web].¹¹⁴

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.¹¹⁴ Possible confusion or agitation; use with caution.¹¹⁴

Hepatic Impairment

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

The effect of hepatic impairment on carbamazepine pharmacokinetics not known.¹⁵⁰ (See Hepatic Impairment under Dosage and Administration.)

Renal Impairment

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

Manufacturer of carbamazepine injection states the drug generally should not be used in patients with moderate or severe renal impairment.¹⁵⁰

Common Adverse Effects

Dizziness, drowsiness, unsteadiness, nausea, vomiting.¹¹⁴

Drug Interactions

Metabolized by CYP3A4.¹¹⁴ Potent inducer of CYP3A4; also induces CYP1A2, 2B6, and 2C9/19.¹¹⁴

Induces P-glycoprotein (P-gp) and uridine diphosphate glucuronosyltransferase (UGT) 1A1.^{229 230}

Active metabolite (carbamazepine 10,11-epoxide [CBZ-E]) is metabolized by epoxide hydrolase.^{114 190}

Drugs Affecting Hepatic Microsomal Enzymes

CYP3A4 inhibitors: Potential increased plasma concentrations of carbamazepine and increased adverse effects of the drug.^{114 190} (See Specific Drugs, Foods, and Laboratory Tests under Interactions.)

CYP3A4 inducers: Potential decreased plasma concentrations of carbamazepine and reduced efficacy of the drug.^{114 190} (See Specific Drugs, Foods, and Laboratory Tests under Interactions.)

Drugs Metabolized by Hepatic Microsomal Enzymes

CYP3A4 substrates: Potential decreased plasma substrate concentrations.^{114 190} (See Specific Drugs, Foods, and Laboratory Tests under Interactions.)

Drugs Affected by P-gp Transport

P-gp substrates: Potential reduced plasma concentrations of substrate drug.²³⁰

Drugs Metabolized by UGT

UGT1A1 substrates: Potential reduced plasma concentrations of drugs metabolized by UGT1A1.²²⁹

Drugs Associated with SJS and TEN

Consider avoidance of other drugs associated with SJS and TEN in HLA-B*1502-positive patients when alternative therapies are available.^{114 189 191 192 207 208} (See Boxed Warning.)

Drugs that Inhibit Epoxide Hydrolase

Drugs that inhibit epoxide hydrolase can increase plasma concentrations of the active CBZ-E metabolite of carbamazepine.^{114 190}

Specific Drugs, Foods, and Laboratory Tests

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.^{114 180 191}

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 oral therapy may be required to achieve steady-state plasma concentrations.^a

Following IV administration at a dosage adjusted by the 70% oral-to-IV conversion factor, systemic exposure was comparable to that observed following oral administration.^{150 197} Pharmacokinetics of carbamazepine 10,11-epoxide (CBZ-E) were similar following oral and IV dosing.¹⁵⁰

Food

Rate but not extent of absorption increased following administration of carbamazepine extended-release capsules (400-mg single dose) with a high-fat meal.¹⁹¹

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

Special Populations

Patients with hepatic impairment may exhibit increased plasma concentrations when switching from oral to IV therapy because of a reduction in first-pass metabolism.¹⁵⁰

Distribution

Extent

Widely distributed throughout the body; detected in CSF, brain, duodenal fluids, bile, and saliva.¹¹⁴ 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 CBZ-E 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

In patients with mild renal impairment (Cl_cr 60–89 mL/minute), clearance of carbamazepine not altered; effects of moderate or severe renal impairment on carbamazepine pharmacokinetics not known.¹⁵⁰

Effects of hepatic impairment on carbamazepine pharmacokinetics not known.¹⁵⁰

Stability

Storage

Oral

Capsules

Extended-release capsules: Tight, light-resistant containers at 25°C (may be exposed to 15–30°C); protect from moisture.^{190 191}

Tablets

Conventional and chewable tablets: Tight containers at ≤30°C; protect from moisture.^{114 123 a} Protect chewable tablets from light.¹¹⁴

Extended-release tablets: Tight containers at 25°C (may be exposed to 15–30°C).^{114 a}

Suspension

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

Parenteral

Injection

20–25°C (may be exposed to 15–30°C).¹⁵⁰

Following dilution, may store prepared infusion solution for ≤4 hours at room temperature (20–25°C) or ≤24 hours at 2–8°C.¹⁵⁰

Compatibility

Oral

Suspension

Coadministration of carbamazepine suspension with certain liquid preparations (e.g., chlorpromazine, thioridazine) has resulted in a rubbery, orange precipitate.^{114 176} The extent to which this interaction occurs with other liquid preparations is not known.¹⁷⁶

Parenteral

Solution Compatibility

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 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 instructing patients to read the patient information (medication guide) before taking carbamazepine.^{114 212}

• 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 patients 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).^{114 196 198} 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).^{114 196}

• 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.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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

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