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

Introduction

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

Uses for Carbamazepine

Seizure Disorders

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

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

Response in patients with mixed seizures may be variable.^a

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

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

Neuropathic Pain

Symptomatic treatment of pain associated with true trigeminal neuralgia.¹¹⁴

Beneficial results also reported in glossopharyngeal neuralgia.¹¹⁴

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

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

Schizophrenia

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

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

Bipolar Disorder

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

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

Other Uses

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

Treatment of alcohol withdrawal syndrome†.^a

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

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

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

Carbamazepine Dosage and Administration

General

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

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

Administration

Oral Administration

Extended-release Capsules

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

Conventional and Chewable Tablets

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

Extended-release Tablets

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

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

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

Suspension

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

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

NG Tube

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

Dosage

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

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

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

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

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

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

Pediatric Patients

Seizure Disorders

Oral

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

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

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

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

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

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

Bipolar Disorder†

Oral

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

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

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

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

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

Adults

Seizure Disorders

Oral

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

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

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

Neuropathic Pain

Trigeminal Neuralgia

Oral

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

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

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

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

Bipolar Disorder†

Oral

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

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

Titrate dosage upward according to patient response and tolerability.¹⁷⁸

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

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

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

Prescribing Limits

Pediatric Patients

Seizure Disorders

Oral

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

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

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

Adults

Seizure Disorders

Oral

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

Neuropathic Pain

Trigeminal Neuralgia

Oral

Maximum 1.2 g daily.¹¹⁴

Bipolar Disorder†

Oral

Maximum 1.6 g daily.¹⁷⁸

Cautions for Carbamazepine

Contraindications

• History of previous bone marrow depression.¹¹⁴

• Acute intermittent porphyria.¹¹⁴

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

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

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

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

Warnings/Precautions

Warnings

Serious Dermatologic Reactions and HLA-B*1502 Allele

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

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

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

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

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

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

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

Hematologic Effects

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

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

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

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

Suicidality Risk

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

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

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

Withdrawal Seizures

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

Cognitive/Neuropsychiatric Effects

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

Anticholinergic Effects

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

Fetal/Neonatal Morbidity and Mortality

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

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

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

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

Sensitivity Reactions

Dermatologic and Sensitivity Reactions

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

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

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

General Precautions

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

Possible Prescribing and Dispensing Errors

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

Nervous System Effects

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

Hepatic Effects

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

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

Laboratory Monitoring

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

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

Baseline and periodic complete urinalysis and BUN determinations recommended.¹¹⁴

Decreased values of thyroid function tests reported.¹¹⁴

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

Specific Populations

Pregnancy

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

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

Lactation

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

Pediatric Use

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

Geriatric Use

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

Hepatic Impairment

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

Renal Impairment

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

Common Adverse Effects

Dizziness, drowsiness, unsteadiness, nausea, vomiting.¹¹⁴

Interactions for Carbamazepine

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

Anticonvulsants

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

Alterations in thyroid function reported with combination anticonvulsant therapy.

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

Drugs Affecting Hepatic Microsomal Enzymes

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

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

Drugs Metabolized by Hepatic Microsomal Enzymes

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

Specific Drugs, Foods, and Laboratory Tests

Carbamazepine Pharmacokinetics

Absorption

Bioavailability

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

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

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

Food

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

Plasma Concentrations

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

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

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

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

Distribution

Extent

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

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

Plasma Protein Binding

75–90%.¹¹⁴

Elimination

Metabolism

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

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

Elimination Route

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

Half-life

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

Special Populations

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

Stability

Storage

Oral

Capsules

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

Tablets

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

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

Suspension

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

Compatibility

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

Oral

Suspension

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

Actions

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

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

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

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

Advice to Patients

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

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

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

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

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

• Importance of not abruptly discontinuing therapy.¹¹⁴

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

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

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

Preparations

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

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