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Carbamazepine

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

Medically reviewed by Drugs.com. Last updated on Nov 12, 2018.

Warning

    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.114 189 191 192 193 194 195 213 214

  • 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.114 189 191 194

  • Strong association demonstrated 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.114 182 185 189 191 192 194 195 207 208 (See Pharmacogenomics of Carbamazepine-induced Cutaneous Reactions under Cautions.) The HLA-B*1502 allele is found almost exclusively in patients with ancestry across broad areas of Asia.114 182 189 191 207

  • Screen patients with ancestry in genetically at-risk populations for presence of HLA-B*1502 prior to initiating carbamazepine therapy.114 189 191 194 195 (See Pharmacogenetic Testing under Dosage and Administration.) Patients who test positive for the allele should not receive carbamazepine therapy unless benefits clearly outweigh risks.114 182 189

    Hematologic Effects
  • Aplastic anemia and agranulocytosis reported.114

  • Risk 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

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, including pain of diabetic neuropathy.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, 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).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

  • 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 http://www.aedpregnancyregistry.org.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

Interactions for Carbamazepine

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

Drug, Food, or Test

Interaction

Comments

Acetaminophen

Carbamazepine may induce metabolism of and decrease plasma concentrations of acetaminophen114

Plasma concentration monitoring or dosage adjustment of acetaminophen may be necessary114

Acetazolamide

Possible increased plasma carbamazepine concentrations114

Closely monitor plasma concentrations of carbamazepine and adjust dosage accordingly114

Albendazole

Carbamazepine may induce metabolism of and decrease plasma concentrations of albendazole114

Plasma concentration monitoring or dosage adjustment of albendazole may be necessary114

Alcohol

Risk of additive CNS depression (e.g., sedation)114

Use with caution114

Alprazolam

Substantially increased oral clearance and decreased elimination half-life of alprazolam234

Plasma concentration monitoring or dosage adjustment of alprazolam may be necessary114

Anticoagulants (e.g., apixaban, dabigatran, edoxaban, rivaroxaban, warfarin)

Warfarin: Carbamazepine may induce metabolism of and decrease plasma concentrations of warfarin 114

Apixaban, dabigatran, edoxaban, rivaroxaban: Possible decreased plasma concentrations and reduced efficacy of the anticoagulant114

Warfarin: Closely monitor patient and adjust dosage of warfarin as necessary114

Apixaban, dabigatran, edoxaban, rivaroxaban: Some manufacturers recommend that concomitant use be avoided114

Anticonvulsants

Felbamate, fosphenytoin, methsuximide, phenobarbital, phenytoin, primidone: Possible decreased plasma carbamazepine concentrations114 190

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

Clonazepam, eslicarbazepine, ethosuximide, lamotrigine, methsuximide, oxcarbazepine, phenytoin, tiagabine, topiramate, valproate, zonisamide: Carbamazepine may induce metabolism of and decrease plasma concentrations of these anticonvulsants114 190

Felbamate: Interaction is complex and resultant changes may be unpredictable114 162 163 164 165 166 167 168

Primidone: Carbamazepine may inhibit metabolism of and increase plasma concentrations of primidone190

Lacosamide: No substantial pharmacokinetic interaction observed232

Brivaracetam: Modest decrease in peak plasma concentrations and systemic exposure of brivaracetam; systemic exposure of carbamazepine not substantially altered, but exposure to its active metabolite markedly increased233

Levetiracetam: No effect on plasma carbamazepine concentrations231

Alterations in thyroid function reported with combination anticonvulsant therapy114 179

Felbamate, fosphenytoin, methsuximide, phenobarbital, phenytoin, primidone: Closely monitor plasma concentrations of carbamazepine and adjust dosage accordingly114 190

Clonazepam, eslicarbazepine, ethosuximide, lamotrigine, methsuximide, oxcarbazepine, phenytoin, tiagabine, topiramate, valproate, zonisamide: Plasma concentration monitoring or dosage adjustment of these concomitantly administered anticonvulsants may be necessary114

Phenytoin: Because interaction can result in either increased or decreased concentrations of phenytoin, closely monitor plasma phenytoin concentrations190

Primidone: Dosage reduction of primidone may be necessary when initiating carbamazepine therapy190

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

Possible increased plasma carbamazepine concentrations114 211

Itraconazole, voriconazole: Carbamazepine may induce metabolism of and decrease plasma concentrations of the antifungal114 210

Closely monitor carbamazepine concentrations and adjust dosage accordingly114

Itraconazole, voriconazole: Dosage increase of itraconazole may be necessary; manufacturer of voriconazole states concomitant use contraindicated114 210

Antimalarial agents

Quinine: Possible increased plasma concentrations of carbamazepine190

Chloroquine and mefloquine: May antagonize activity of carbamazepine190

Quinine: If used concomitantly, dosage reduction of carbamazepine may be necessary190

Antimycobacterials (e.g., isoniazid, rifampin)

Isoniazid: Possible increased plasma carbamazepine concentrations114

Rifampin: Possible decreased plasma carbamazepine concentrations114

May increase isoniazid-induced hepatotoxicity114

Closely monitor plasma concentrations of carbamazepine and adjust dosage accordingly114

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

Aripiprazole, clozapine, olanzapine, paliperidone, risperidone, ziprasidone: Carbamazepine may induce metabolism of and decrease plasma concentrations of these antipsychotic agents; reduced efficacy of the antipsychotic may occur114 152 153 155 156 225 226 227 235

Haloperidol: Substantially decreased plasma concentrations and efficacy of haloperidol114 159

Clozapine: Neuroleptic malignant syndrome reported rarely with concomitant use; possible increased risk of adverse hematologic effects177 184

Olanzapine: Possible increased plasma carbamazepine concentrations114

Loxapine, quetiapine: Can inhibit epoxide hydrolase activity and increase plasma concentrations of CBZ-E114

Aripiprazole, olanzapine, paliperidone, risperidone, ziprasidone: Plasma concentration monitoring or dosage adjustment of the antipsychotic agent may be necessary114

Aripiprazole: If carbamazepine is added to aripiprazole therapy, double aripiprazole dosage and make additional increases based on clinical evaluation; if carbamazepine is withdrawn from combination therapy, reduce aripiprazole dosage accordingly114

Haloperidol: Carefully monitor patients for loss of antipsychotic efficacy and adjust haloperidol dosage accordingly; consider possibility of haloperidol toxicity after carbamazepine discontinuance151 152 157

Clozapine: Concomitant use not recommended;177 if used concomitantly, plasma concentration monitoring or dosage adjustment of clozapine may be necessary114 183

Loxapine, quetiapine, olanzapine: Monitor plasma concentrations of carbamazepine and adjust dosage accordingly114

Antiretrovirals, HIV nonnucleoside reverse transcriptase inhibitors (NNRTIs)

Delavirdine: Possible decreased plasma concentrations of delavirdine (by 90%) and loss of virologic response; plasma concentrations of carbamazepine may be increased150 190

Efavirenz: Possible decreased plasma concentrations of efavirenz and loss of virologic response; plasma concentrations of carbamazepine may be reduced, but exposure to CBZ-E not substantially altered150 190 219

Some manufacturers state concomitant use with NNRTIs contraindicated150 191

Antiretrovirals, HIV protease inhibitors (PIs)

Concomitant use with PIs that inhibit CYP3A4 may increase plasma concentrations of carbamazepine114

Carbamazepine can induce metabolism of and decrease plasma concentrations of PIs114

Closely monitor plasma concentrations of carbamazepine and adjust dosage accordingly114

Plasma concentration monitoring or dosage adjustment of the PI may be necessary114

Aprepitant

Possible increased plasma concentrations of carbamazepine114

Carbamazepine may induce metabolism of and decrease plasma concentrations of aprepitant114

Closely monitor plasma concentrations of carbamazepine and adjust dosage accordingly114

Plasma concentration monitoring or dosage adjustment of aprepitant may be necessary114

Buprenorphine

Carbamazepine may induce metabolism of and decrease plasma concentrations of buprenorphine114

Plasma concentration monitoring or dosage adjustment of buprenorphine may be necessary114

Bupropion

Carbamazepine may induce metabolism of and decrease plasma concentrations of bupropion114 220

Plasma concentration monitoring or dosage adjustment of bupropion may be necessary114

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

Diltiazem, verapamil: Possible increased carbamazepine concentrations and increased toxicity101 102 103 114 190

Dihydropyridine calcium-channel blocking agents (e.g., felodipine): Carbamazepine may induce metabolism of and decrease plasma concentrations of the calcium-channel blocker114 190

Diltiazem, verapamil: Closely monitor plasma concentrations of carbamazepine and for manifestations of carbamazepine-induced toxicity; adjust dosage accordingly101 102 114

If verapamil is initiated in patients receiving carbamazepine, 40–50% reduction in carbamazepine dosage may be necessary; if verapamil is discontinued, increase carbamazepine dosage to avoid loss of seizure control101 102 114

Dihydropyridine calcium-channel blockers: Plasma concentration monitoring or dosage adjustment of the calcium-channel blocker may be necessary114 190

Cimetidine

Possible increased plasma carbamazepine concentrations 114

Closely monitor plasma concentrations of carbamazepine and adjust dosage accordingly114

Ciprofloxacin

Possible increased plasma carbamazepine concentrations114

Closely monitor plasma concentrations of carbamazepine and adjust dosage accordingly114

Cisplatin

Possible decreased plasma carbamazepine concentrations114

Closely monitor plasma concentrations of carbamazepine and adjust dosage accordingly114

Clomipramine

Possible increased plasma clomipramine concentrations190

Dosage reduction of clomipramine may be necessary when initiating carbamazepine190

Clonazepam

Carbamazepine may induce metabolism of and decrease plasma concentrations of clonazepam114

Plasma concentration monitoring or dosage adjustment of clonazepam may be necessary114

Corticosteroids (e.g., dexamethasone, prednisolone)

Carbamazepine may induce metabolism of and decrease plasma concentrations of corticosteroids114

Plasma concentration monitoring or dosage adjustment of the corticosteroid may be necessary114

Cyclophosphamide

Carbamazepine may increase rate of metabolism of cyclophosphamide prodrug to its active metabolite, resulting in possible toxicity114

Danazol

Possible increased plasma carbamazepine concentrations114

Closely monitor plasma concentrations of carbamazepine and adjust dosage accordingly114

Dantrolene

Possible increased plasma carbamazepine concentrations114

Closely monitor plasma concentrations of carbamazepine and adjust dosage accordingly114

Diuretics (e.g., hydrochlorothiazide, furosemide)

May increase risk of symptomatic hyponatremia150

Dolutegravir

Decreased peak plasma concentrations and systemic exposure of dolutegravir229

Increase in dolutegravir dosage recommended229

Doxorubicin

Possible decreased plasma carbamazepine concentrations114

Closely monitor plasma concentrations of carbamazepine and adjust dosage accordingly114

Doxycycline

Carbamazepine may induce metabolism of and decrease plasma concentrations of doxycycline114

Plasma concentration monitoring or dosage adjustment of doxycycline may be necessary114

Everolimus

Carbamazepine may induce metabolism of and decrease plasma concentrations of everolimus114

Plasma concentration monitoring or dosage adjustment of everolimus may be necessary114

Fexofenadine

Substantially decreased peak plasma concentrations and systemic exposure of fexofenadine observed230

Grapefruit juice

Substantially increased peak plasma concentrations, trough concentrations, and systemic exposure of carbamazepine observed114 236

Closely monitor plasma concentrations of carbamazepine and adjust dosage accordingly114

Hormonal contraceptives

Carbamazepine can induce metabolism of and decrease concentrations of hormonal contraceptives; breakthrough bleeding and unintended pregnancies reported114 221

Consider use of alternative or additional contraceptive methods during carbamazepine therapy114

Ibuprofen

Possible increased plasma carbamazepine concentrations114

Closely monitor plasma concentrations of carbamazepine and adjust dosage accordingly114

Imatinib

Carbamazepine may induce metabolism of and decrease plasma concentrations of imatinib114

Plasma concentration monitoring or dosage adjustment of imatinib may be necessary114

Immunosuppressive agents (e.g., cyclosporine, sirolimus, tacrolimus)

Cyclosporine, sirolimus, tacrolimus: Carbamazepine may induce metabolism of and decrease plasma concentrations of these immunosuppressive agents114

Plasma concentration monitoring or dosage adjustment of the immunosuppressive agent may be necessary114 150

Lapatinib

Carbamazepine may induce metabolism of and decrease plasma concentrations of lapatinib114 222

Generally avoid concomitant use114

If carbamazepine is initiated in a patient receiving lapatinib, gradually increase dosage of lapatinib; if carbamazepine is withdrawn from therapy, decrease dosage of lapatinib114

Levothyroxine

Carbamazepine may induce metabolism of and decrease plasma concentrations of levothyroxine114

Plasma concentration monitoring or dosage adjustment of levothyroxine may be necessary114

Lithium

Increased risk of adverse neurologic effects 114

Loratadine

Possible increased plasma carbamazepine concentrations 114

Closely monitor plasma concentrations of carbamazepine and adjust dosage accordingly114

Macrolides (e.g., clarithromycin, erythromycin)

Possible increased plasma carbamazepine concentrations105 106 114

Closely monitor plasma concentrations of carbamazepine and adjust dosage accordingly;105 106 107 114 some clinicians suggest use of alternative to erythromycin107

MAO inhibitors

Possible serotonin syndrome114 150 190

Concomitant use contraindicated; allow ≥14 days to elapse between discontinuance of an MAO inhibitor and initiation of carbamazepine114 190

Methadone

Carbamazepine may induce metabolism of and decrease plasma concentrations of methadone114

Plasma concentration monitoring or dosage adjustment of methadone may be necessary114

Midazolam

Carbamazepine may induce metabolism of and decrease plasma concentrations of midazolam 114

Plasma concentration monitoring or dosage adjustment of midazolam may be necessary114

Mirtazapine

Carbamazepine may induce metabolism of and decrease plasma concentrations of mirtazapine191

Plasma concentration monitoring or dosage adjustment of mirtazapine may be necessary191

Nefazodone

Plasma concentrations of nefazodone and its active metabolite may decrease substantially, resulting in levels insufficient to achieve an antidepressant effect114 150 190

Concomitant use contraindicated114

Neuromuscular blocking agents, nondepolarizing (e.g., cisatracurium, pancuronium, rocuronium, vecuronium)

Cisatracurium, pancuronium, rocuronium, vecuronium: Resistance to these nondepolarizing neuromuscular blocking agents reported in patients receiving long-term carbamazepine therapy; not known whether the same effect occurs with other neuromuscular blocking agents114 239

Monitor closely for more rapid than normal recovery from neuromuscular blockade; higher dosages of the neuromuscular blocking agent may be required114

Niacinamide

Possible increased plasma carbamazepine concentrations 114

Closely monitor plasma concentrations of carbamazepine and adjust dosage accordingly114

Omeprazole

Increased plasma carbamazepine concentrations demonstrated114 237

Closely monitor plasma concentrations of carbamazepine and adjust dosage accordingly114

Oxybutynin

Possible increased plasma carbamazepine concentrations114

Closely monitor plasma concentrations of carbamazepine and adjust dosage accordingly114

Praziquantel

Carbamazepine may induce metabolism of and decrease plasma concentrations of praziquantel 114

Plasma concentration monitoring or dosage adjustment of praziquantel may be necessary114

Pregnancy tests

Carbamazepine may interfere with some pregnancy tests114

Propoxyphene

Possible increased plasma carbamazepine concentrations114

Closely monitor plasma concentrations of carbamazepine and adjust dosage accordingly114

Quinine

Possible increased plasma carbamazepine concentrations114

Closely monitor plasma concentrations of carbamazepine and adjust dosage accordingly114

Quinupristin/dalfopristin

Possible increased plasma carbamazepine concentrations114

Closely monitor plasma concentrations of carbamazepine and adjust dosage accordingly114

Selective serotonin-reuptake inhibitors (SSRIs)

Citalopram: Carbamazepine may induce metabolism of and decrease plasma concentrations of citalopram; citalopram does not appear to alter plasma concentrations of carbamazepine114 223

Sertraline: Carbamazepine may induce metabolism of and decrease plasma concentrations of sertraline114

Fluoxetine, fluvoxamine: Possible increased plasma concentrations of carbamazepine114 169 170 171 223

Citalopram, sertraline: Plasma concentration monitoring or dosage adjustment of the SSRI may be necessary114

Fluoxetine, fluvoxamine: Closely monitor plasma concentrations of carbamazepine and adjust dosage accordingly114 169 170 171

Simvastatin

Decreased peak plasma concentrations and systemic exposure of simvastatin and simvastatin acid observed224

Some experts recommend that concomitant use be avoided; if concomitant use is necessary, increase dosage of simvastatin224

Tadalafil

Carbamazepine may induce metabolism of and decrease plasma concentrations of tadalafil114

Plasma concentration monitoring or dosage adjustment of tadalafil may be necessary114

Temsirolimus

Carbamazepine can induce metabolism of and decrease plasma concentrations of temsirolimus114

Generally avoid concomitant therapy; if concomitant use is necessary, consider dosage adjustment of temsirolimus114

Theophylline

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

Closely monitor plasma concentrations of both drugs and adjust dosages accordingly114

Ticlopidine

Possible increased plasma carbamazepine concentrations114

Closely monitor plasma concentrations of carbamazepine and adjust dosage accordingly114

Tramadol

Carbamazepine may induce metabolism of and decrease plasma concentrations of tramadol114

Plasma concentration monitoring or dosage adjustment of tramadol may be necessary114

Trazodone

Decreased plasma concentrations of trazodone and active metabolite, m-chlorophenylpiperazine observed114 181

Possible increased plasma concentrations of carbamazepine114

Closely monitor patient and increase trazodone dosage if necessary114 181

Closely monitor plasma concentrations of carbamazepine and adjust dosage accordingly114

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

Carbamazepine may induce metabolism of and decrease plasma concentrations of tricyclic antidepressants114 238

Plasma concentration monitoring or dosage adjustment of the tricyclic antidepressant may be necessary114

Zileuton

Possible increased plasma carbamazepine concentrations191

Dosage reduction of carbamazepine may be necessary191

Zolpidem

Reduced bioavailability of zolpidem; however, clinical importance not known228

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 (Clcr 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

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

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

Compatible150

Dextrose 5% in water

Ringer’s injection, lactated

Sodium chloride 0.9%

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

carBAMazepine

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Capsules, extended-release

100 mg*

carBAMazepine Extended-release Capsules

Carbatrol

Shire

Equetro

Validus

200 mg*

carBAMazepine Extended-release Capsules

Carbatrol

Shire

Equetro

Validus

300 mg*

carBAMazepine Extended-release Capsules

Carbatrol

Shire

Equetro

Validus

Suspension

100 mg/5 mL*

carBAMazepine Suspension

TEGretol

Novartis

Tablets

200 mg*

carBAMazepine Tablets

Epitol (scored)

Teva

TEGretol (scored)

Novartis

Tablets, chewable

100 mg*

carBAMazepine Chewable Tablets

TEGretol (scored)

Novartis

200 mg*

carBAMazepine Chewable Tablets

Tablets, extended-release

100 mg*

carBAMazepine Extended-release Tablets

TEGretol-XR

Novartis

200 mg*

carBAMazepine Extended-release Tablets

TEGretol-XR

Novartis

400 mg*

carBAMazepine Extended-release Tablets

TEGretol-XR

Novartis

Parenteral

Concentrate, for injection, for IV infusion

10 mg/mL

Carnexiv

Lundbeck

AHFS DI Essentials™. © Copyright 2019, Selected Revisions November 12, 2018. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

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

References

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101. Macphee GJA, McInnes GT, Thompson GG et al. Verapamil potentiates carbamazepine neurotoxicity: a clinically important inhibitory interaction. Lancet. 1986; 1:700-3. http://www.ncbi.nlm.nih.gov/pubmed/2870222?dopt=AbstractPlus

102. Mangini RJ, ed. Drug interaction facts. St. Louis: JB Lippincott Co; 1986(Oct):135a.

103. Brodie MJ, Macphee GJA. Carbamazepine neurotoxicity precipitated by diltiazem. BMJ. 1986; 292:1170-1.

104. Mangini RJ, ed. Drug interaction facts. St. Louis: JB Lippincott Co; 1986(Oct):130a.

105. Ludden TM. Pharmacokinetic interactions of the macrolide antibiotics. Clin Pharmacokinet. 1985; 10:63-79. http://www.ncbi.nlm.nih.gov/pubmed/3882305?dopt=AbstractPlus

106. Hansten PD. Drug interactions. 5th ed. Philadelphia: Lea & Febiger; 1985:117.

107. Shinn AF, Shrewsbury RP. Evaluations of drug interactions. 3rd ed. St. Louis, MO: CV Mosby Company; 1985:221.

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110. Silverstein FS, Boxer L, Johnston MV. Hematological monitoring during therapy with carbamazepine in children. Ann Neurol. 1983; 13: 685-6.

111. Camfield C, Camfield P, Smith E et al. Asymptomatic children with epilepsy: little benefit from screening for anticonvulsant-induced liver, blood, or renal damage. Neurology. 1986; 36:838-41. http://www.ncbi.nlm.nih.gov/pubmed/3703292?dopt=AbstractPlus

112. Lott RS. Seizure disorders. In: Young LY, Koda-Kimble MA, eds. Applied therapeutics: the clinical use of drugs. 4th ed. Vancouver, WA: Applied Therapeutics, Inc.; 1988:1369-96.

113. The United States pharmacopeia, 22nd rev, and the national formulary, 17th ed. Rockville, MD: The United States Pharmacopeial Convention, Inc; 1992(Suppl 6):2807.

114. Novartis Pharmaceuticals. Tegretol (carbamazepine) chewable tablets, tablets, and suspension and Tegretol XR (carbamazepine) extended-release tablets prescribing information. East Hanover, NJ; 2018 Mar.

115. Hooper WD, King AR, Patterson M et al. Simultaneous plasma carbamazepine and carbamazepine-epoxide concentrations in pharmacokinetic and bioavailability studies. Ther Drug Monit. 1985; 7:36-40. http://www.ncbi.nlm.nih.gov/pubmed/3992620?dopt=AbstractPlus

116. Wada JA, Troupin AS, Friel P et al. Pharmacokinetic comparison of tablet and suspension dosage forms of carbamazepine. Epilepsia. 1978; 19:251-55. http://www.ncbi.nlm.nih.gov/pubmed/679894?dopt=AbstractPlus

117. Morselli PL, Monaco F, Gerna M et al. Bioavailability of two carbamazepine preparations during chronic administration to epileptic patients. Epilepsia. 1975; 16:759-64. http://www.ncbi.nlm.nih.gov/pubmed/1222752?dopt=AbstractPlus

118. Bloomer D, Dupuis LL, MacGregor D et al. Palatability and relative bioavailability of an extemporaneous carbamazepine oral suspension. Clin Pharm. 1987; 6:646-9. http://www.ncbi.nlm.nih.gov/pubmed/3691011?dopt=AbstractPlus

119. Kriegman AG (Ciba-Geigy Corporation, Summit, NJ): Personal communication; 1989 Mar.

120. Pisciotta AV. Carbamazepine: hematological toxicity. In: Woodbury DM, Penry JK, Pippenger CE, eds. Antiepileptic drugs. New York: Raven Press; 1982:533-41.

121. Pisciotta AV. Hematologic toxicity of carbamazepine. Adv Neurol. 1975; 11:355-68. http://www.ncbi.nlm.nih.gov/pubmed/1217569?dopt=AbstractPlus

122. Simon LT, Hsu B, Adornato BT. Carbamazepine-induced aseptic meningitis. Ann Int Med. 1990; 112:627-8. http://www.ncbi.nlm.nih.gov/pubmed/2327680?dopt=AbstractPlus

123. Anon. Safeguards needed for carbamazepine. FDA Drug Bull. 1990; (Apr):5.

124. Miles MV, Lawless ST, Tennison MB et al. Rapid loading of critically ill patients with carbamazepine suspension. Pediatrics. 1990; 86:263-6. http://www.ncbi.nlm.nih.gov/pubmed/2371100?dopt=AbstractPlus

125. Hilton E, Stroh EM. Aseptic meningitis associated with administration of carbamazepine. J Infect Dis. 1989; 159:363-4. http://www.ncbi.nlm.nih.gov/pubmed/2915162?dopt=AbstractPlus

126. Clark-Schmidt AL, Garnett WR, Lowe DR et al. Loss of carbamazepine suspension through nasogastric feeding tubes. Am J Hosp Pharm. 1990; 47:2034-7. http://www.ncbi.nlm.nih.gov/pubmed/2121028?dopt=AbstractPlus

127. Anon. Carbamazepine update. Lancet. 1989; 2:595-7. http://www.ncbi.nlm.nih.gov/pubmed/2570287?dopt=AbstractPlus

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