Carbamazepine

Pharmacologic Category

Anticonvulsant, Miscellaneous

Dosing: Adult

Note: Safety: Before prescribing carbamazepine, test for HLA-B*1502 allele in patients at increased risk of developing serious cutaneous adverse reactions (SCAR) (ie, those of Asian ancestry, including South Asian Indians). A negative HLA-B*1502 genetic test does not entirely rule out the possibility of SCAR, so patients should still be monitored for cutaneous reactions and other forms of hypersensitivity (Leckband 2013). Although other alleles (eg, HLA-A*3101, HLA-A*24:02) may also increase the risk of hypersensitivity in a broader range of ethnic groups, testing recommendations are not well established (Amstutz 2014; Schachter 2019a; Shi 2017). Therapeutic drug monitoring: May be useful, particularly in patients with seizure disorder; monitor more closely during the first few months of therapy because carbamazepine induces hepatic enzymes, thereby increasing its own metabolism, which may lead to a decrease in serum levels after ~2 to 3 months and require subsequent dosage adjustment(s). Dosage forms: Dosing recommendations are expressed as the total daily dose (ie, per 24 hours) unless stated otherwise. Total daily oral dose is given in 2 to 4 divided doses per day depending on the type of preparation. Available oral preparations include: Immediate release (suspension, tablet, chewable tablet) (usually dosed 2 to 4 times daily) and 12-hour extended release (dosed twice daily).

Bipolar disorder, hypomania and mild to moderate manic or mixed episodes (alternative agent) and bipolar major depression (alternative agent) (BAP [Goodwin 2016]; Shelton 2019):

Acute treatment (monotherapy): Oral: Initial: 100 to 400 mg/day; may increase dose based on response and tolerability in increments of 200 mg/day every 1 to 4 days; usual dose range: 600 mg/day to 1.2 g/day; maximum dose: 1.6 g/day (Stovall 2019; WFSBP [Grunze 2009]; manufacturer's labeling). Doses up to 1.8 g/day may be necessary in some patients for optimal response (Stoval 2019).

Maintenance (monotherapy) (off-label use): Oral: Continue dose that was used to achieve control of the acute episode (Peselow 2016).

Focal (partial) onset seizures and generalized onset seizures (monotherapy or adjunctivetherapy): Note: Avoid use in nonmotor (absence) seizures.

Oral: Initial 2 to 3 mg/kg/day (100 to 200 mg/day) or up to 400 mg/day (according to manufacturer's labeling), which may not be as well tolerated; may gradually increase dose based on seizure control, tolerability, and serum concentrations every ≥5 days in increments of ≤200 mg/day to a usual maintenance dose of ~10 mg/kg/day (800 mg/day to 1.2 g/day). After 2 to 3 months of treatment, serum concentrations may decrease due to hepatic enzyme autoinduction and dose may need to be further increased to 15 to 20 mg/kg/day; doses up to ~2 g/day may be needed in some patients for optimal effect (Schachter 2019a).

Neuropathic pain: Note: For use in trigeminal or glossopharyngeal neuralgia (Rosenquist 2019). May also be used in critically ill patients with neuropathic pain as a component of multimodal pain control (alternative agent) (Pandey 2005; SCCM [Devlin 2018]).

Oral: Initial: 200 to 400 mg/day, gradually increasing (eg, over several weeks) in increments of 200 mg/day as needed. Usual maintenance dose: 600 to 800 mg/day; maximum dose: 1.2 g/day (Bajwa 2019; manufacturer's labeling).

Discontinuation of therapy: In chronic therapy, withdraw gradually over 2 to 6 months to minimize the potential of increased seizure frequency (in patients with epilepsy) and other withdrawal symptoms (eg, dysphoria, hallucinations, headache, insomnia, tremor) unless safety concerns require more rapid withdrawal (Chen 2014; Medical Research Council Antiepileptic Drug Withdrawal Study Group 1991; Schachter 2019b). In patients discontinuing therapy for treatment of bipolar disorder, close monitoring for several weeks to months for reemergence of mania/hypomania is recommended (Post 2019).

* See Dosage and Administration in AHFS Essentials for additional information.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment: Adult

Note: In moderate to severe kidney dysfunction, serum 10,11-carbamazepine epoxide levels may be increased. Consider measuring serum 10,11-carbamazepine epoxide levels in instances where toxicity is suspected, but serum carbamazepine levels are within normal range (Tutor-Crespo 2008).

Mild to severe impairment: Initial: No dosage adjustment necessary (Anderson 2014). Subsequent dose adjustments should be based on patient response, tolerability, and serum concentrations.

Hemodialysis: Initial: No dosage adjustment necessary. Dose may be administered without regard to timing of dialysis on dialysis days (Lee 1980; expert opinion). Subsequent dose adjustments should be based on patient response, tolerability, and serum concentrations.

Peritoneal dialysis: Initial: No dosage adjustment necessary (Mora Rodríguez 2018). Subsequent dose adjustments should be based on patient response, tolerability, and serum concentrations.

CRRT: Initial: No dosage adjustment necessary (Mahmoud 2017). Subsequent dose adjustments should be based on patient response, tolerability, and serum concentrations.

Dosing: Hepatic Impairment: Adult

There are no dosage adjustments provided in the manufacturer's labeling. Use with caution and consider dose reduction; carbamazepine is metabolized primarily in the liver.

Dosing: Pediatric

Note: Prior to initiating carbamazepine therapy, test for HLA-B*15:02 allele in patients with increased risk for this genetic variant (eg, Han Chinese, Thai, Malaysian, Indian, or Vietnamese descent); this is associated with a significantly increased risk of Stevens-Johnson syndrome and/or toxic epidermal necrolysis; do NOT initiate in patients with a positive result (Amstutz 2014; Leckband 2013). Although testing recommendations are not well established, consider testing for HLA-A*31:01 and HLA-A*24:02 allele. These alleles are found in a broader range of ethnic groups and also increase the risk for hypersensitivity reactions (Leckband 2013; Shi 2017). A negative genetic test does not entirely rule out the possibility of a hypersensitivity or cutaneous reaction, and patients should be monitored throughout therapy.

Seizure disorder: Dosage must be adjusted according to patient's response and serum concentrations.

Oral:

Infants and Children <6 years:

Immediate-release formulations:

Tablets: Initial: 10 to 20 mg/kg/day in divided doses twice or 3 times daily; titrate at weekly intervals until optimal response; maintenance doses administered 3 or 4 times daily; maximum daily dose: 35 mg/kg/day.

Suspension: Initial: 10 to 20 mg/kg/day in divided doses 4 times daily; titrate at weekly intervals until optimal response; maintenance doses administered 3 or 4 times daily; maximum daily dose: 35 mg/kg/day.

Children ≥6 to 12 years:

Immediate-release formulations:

Tablets: Initial: 100 mg twice daily, titrate by up to 100 mg/day at weekly intervals. Usual maintenance dose range: 400 to 800 mg/day in 3 to 4 divided doses. Maximum daily dose: 1,000 mg/day.

Suspension: Initial: 50 mg 4 times daily, titrate by up to 100 mg/day at weekly intervals. Usual maintenance daily dose range: 400 to 800 mg/day in 3 to 4 divided doses. Maximum daily dose: 1,000 mg/day.

Extended-release formulations: Capsules, tablets: Initial: 100 mg twice daily, titrate by up to 100 mg/day at weekly intervals. Usual maintenance daily dose range: 400 to 800 mg/day in divided doses twice daily. Maximum daily dose: 1,000 mg/day.

Adolescents:

Immediate-release formulations:

Tablets: Initial: 200 mg twice daily, titrate by up to 200 mg/day increments at weekly intervals. Usual maintenance daily dose range: 800 to 1,200 mg/day in divided doses 3 or 4 times daily.

Suspension: Initial: 100 mg 4 times daily, titrate by up to 200 mg/day increments at weekly intervals. Usual maintenance daily dose range: 800 to 1,200 mg/day in divided doses 3 or 4 times daily.

Extended-release formulations: Capsule, tablet: Initial: 200 mg twice daily, titrate by up to 200 mg/day increments at weekly intervals. Usual maintenance daily dose range: 800 to 1,200 mg/day in divided doses twice daily.

Maximum daily doses:

Adolescents ≤15 years: 1,000 mg/day.

Adolescents >15 years: 1,200 mg/day.

Rectal: Limited data available: Infants, Children, and Adolescents: Maintenance dose: Administer the same total daily dose as small, diluted doses administered more frequently than the oral; dilute the oral suspension with an equal volume of water; if defecation occurs within the first 2 hours, repeat the dose (Graves 1987).

Dosing conversions: Close monitoring and possible dosage adjustment may be necessary during any dosage form conversions due to pharmacokinetics differences amongst immediate-release dosage forms (ie, suspension formulation produces higher peak concentrations compared to the tablet) and between the immediate- and extended-release formulations.

Conversion from immediate-release solid dosage form to suspension: Use the same daily dose and divide into 3 daily doses; monitor serum concentrations.

Conversion from immediate-release tablets to extended-release formulations: Use the same daily dose and divide into 2 daily doses; monitor serum concentrations.

Discontinuation of therapy: Discontinuation of treatment for epilepsy is dependent on several factors to minimize chance of seizure relapse. Favorable factors include: Childhood onset, normal EEG at time of discontinuation, idiopathic generalized epilepsy, low seizure frequency before and during treatment, seizure type, normal neurologic exam, and normal intellectual development. Withdrawal of therapy is typically evaluated if patient has been seizure free for 2 years. Abrupt discontinuation is not recommended. Gradual tapers have ranged from 6 weeks to 9 months. The slow discontinuation should be tailored to the patient's preference and needs. Other considerations include the drug pharmacokinetic properties, dosage at the start of withdrawal, dosage forms, and need for follow-up serum concentration monitoring (Beghi 2013; Specchio 2004; Strozzi 2015).

Dosing: Renal Impairment: Pediatric

Altered kidney function: Infants, Children, and Adolescents:

Note: Consider measuring serum 10,11-carbamazepine epoxide levels in instances where toxicity is suspected, but serum carbamazepine levels are within normal range. Based on experience in adult patients, serum 10,11-carbamazepine epoxide levels may be increased with moderate to severe kidney dysfunction; clearance of parent drug and the 10,11-carbamazepine epoxide metabolite are urine flow dependent (Tutor-Crespo 2008).

Mild to severe impairment: Initial: No dosage adjustment necessary. Monitor closely and adjust dose based on clinical response, tolerability (eg, adverse drug reactions), and serum concentrations of carbamazepine and its active metabolite (Anderson 2014).

Hemodialysis, intermittent: There are no dosing adjustments in the manufacturer's labeling; based on pharmacokinetic profile of carbamazepine (ie, lipophilicity, high protein binding, minimal renal clearance), no dose adjustments to initial doses necessary; monitor closely and adjust dose based on clinical response, tolerability, and serum concentrations (Mora Rodríguez 2018).

Peritoneal dialysis: Initial: There are no dosing adjustments in the manufacturer's labeling; based on pharmacokinetic profile of carbamazepine (ie, lipophilicity, high protein binding, minimal renal clearance), no dose adjustments to initial doses necessary; monitor closely and adjust dose based on clinical response, tolerability, and serum concentrations (Mora Rodríguez 2018).

Continuous renal replacement therapy (CRRT): There are no pediatric-specific recommendations for dosing in patients receiving CRRT; based on adult experience, dose adjustments should be based on clinical response, tolerability, and serum concentrations (Mahmoud 2017).

Dosing: Hepatic Impairment: Pediatric

Infants, Children, and Adolescents: There are no dosage adjustments provided in the manufacturer's labeling. Use with caution in hepatic impairment and consider dose reduction; metabolized primarily in the liver.

Calculations

• Creatinine Clearance by Cockcroft-Gault
• Creatinine Clearance by Cockcroft-Gault (SI units)
• Creatinine Clearance by Cockcroft-Gault with IBW
• Creatinine Clearance by Cockcroft-Gault with IBW (SI units)
• Creatinine Clearance by Jelliffe
• Creatinine Clearance by Sanaka
• Glomerular Filtration Rate by Abbreviated MDRD
• Glomerular Filtration Rate by Abbreviated MDRD (SI units)
• Glomerular Filtration Rate by MDRD
• Glomerular Filtration Rate by MDRD (IDMS-Traceable SCr)
• Glomerular Filtration Rate by MDRD (SI units)
• Glomerular Filtration Rate by Schwartz
• Glomerular Filtration Rate Estimate in African Americans by AASK Equation

Use: Labeled Indications

Bipolar disorder: Monotherapy in the acute treatment of hypomania and mild to moderate manic or mixed episodes associated with bipolar disorder

Focal (partial) onset seizures and generalized onset seizures: Monotherapy and adjunctive therapy in the treatment of patients with focal onset seizures and generalized onset seizures

Limitations of use: Carbamazepine is not indicated for the treatment of nonmotor (absence) seizures; it has been associated with increased frequency of generalized convulsions in these patients.

Neuropathic pain: Treatment of trigeminal or glossopharyngeal neuralgia

* See Uses in AHFS Essentials for additional information.

Use: Off-Label: Adult

Bipolar major depressionLevel of Evidence [C, G]

Data from a double-blind, randomized, placebo-controlled trial suggest that carbamazepine monotherapy may decrease time to response for patients with bipolar major depression ^Ref.

Based on the Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) guidelines for the management of patients with bipolar disorder, carbamazepine is recommended as an alternative to preferred agents for patients with bipolar major depression ^Ref.

Maintenance treatment for bipolar disorderLevel of Evidence [C, G]

Data from a randomized, controlled trial suggest that carbamazepine may prevent hospitalization caused by a mood episode in patients with bipolar disorder, particularly those with type II bipolar disorder ^Ref.

Based on the CANMAT and ISBD guidelines for the management of patients with bipolar disorder and the British Association for Psychopharmacology evidence-based guidelines for treating bipolar disorder, carbamazepine is recommended as an alternative to preferred agents for maintenance treatment of bipolar disorder ^Ref.

Level of Evidence Definitions

Level of Evidence Scale

Clinical Practice Guidelines

Bipolar Disorder:

British Association for Psychopharmacology, “Evidence-based guidelines for treating bipolar disorder: Revised third edition recommendations from the British Association for Psychopharmacology,” June 2016

CANMAT/ISBD, "2018 Guidelines for the Management of Patients With Bipolar Disorder," March 2018

Critical Care:

ACCM/SCCM, "Clinical Practice Guidelines for the Management of Pain, Agitation, and Delirium in Adult Patients in the Intensive Care Unit,” January 2013

ACCM/SCCM, "Clinical Practice Guidelines for the Management of Pain, Agitation/Sedation, Delirium, Immobility, and Sleep Disruption in Adult Patients in the ICU,” September 2018

Drug-Induced Liver Injury:

American College of Gastroenterology (ACG), “2014 ACG Guideline for Idiosyncratic Drug-induced Liver Injury,” July 2014

Seizure Disorders:

American Academy of Neurology and American Epilepsy Society, “Practice guideline update summary: Efficacy and tolerability of the new antiepileptic drugs I: Treatment of new-onset epilepsy,” 2018

Therapeutic Drug Monitoring:

AGNP, “Consensus guidelines for therapeutic drug monitoring in neuropsychopharmacology: Update 2017,“ September 2017

Trigeminal Neuralgia:

European Academy of Neurology, “European Academy of Neurology Guideline on Trigeminal Neuralgia,” 2019

Administration: Oral

Chewable or immediate-release tablets: Administer with food

Suspension: Shake well before administration. Must be given on a 3 to 4 times/day schedule versus tablets, which can be given 2 to 4 times/day. Because a given dose of suspension will produce higher peak and lower trough levels than the same dose given as the tablet form, patients given the suspension should be started on lower doses given more frequently (same total daily dose) and increased slowly to avoid unwanted side effects. When carbamazepine suspension has been combined with chlorpromazine or thioridazine solutions, a precipitate forms, which may result in loss of effect. Therefore, it is recommended that the carbamazepine suspension dosage form not be administered at the same time with other liquid medicinal agents or diluents. Should be administered with meals.

Extended-release capsule (Carbatrol, Equetro): Consists of three different types of beads: immediate release, extended release, and enteric release. The bead types are combined in a ratio to allow twice daily dosing. May be opened and contents sprinkled over food such as a teaspoon of applesauce; may be administered with or without food; do not crush or chew capsule or beads inside capsule.

Extended-release tablet: Should be inspected for damage. Damaged extended-release tablets (without release portal) should not be administered. Should be administered with meals; swallow whole, do not crush or chew.

Administration: Pediatric

Oral:

Immediate release:

Chewable and conventional tablets: Administer with food 2 to 3 times daily.

Oral suspension: Shake well before use; administer with food 3 to 4 times daily. Since a dose of suspension will produce higher peak and lower trough levels than the same dose given as the tablet form, patients given the suspension should be started on lower doses given more frequently (same total daily dose) and increased slowly to avoid unwanted side effects. When carbamazepine suspension has been combined with chlorpromazine or thioridazine solutions, a precipitate forms which may result in loss of effect. Therefore, it is recommended that the carbamazepine suspension dosage form not be administered at the same time with other liquid medicinal agents or diluents.

Extended release:

Capsules (Carbatrol, Equetro): Consists of 3 different types of beads: Immediate release, extended release, and enteric release. The bead types are combined in a ratio to allow twice daily dosing. Capsules may be opened and contents sprinkled over food such as a teaspoon of applesauce; do not store medication/food mixture for later use; drink fluids after dose to make sure mixture is completely swallowed; may be administered with or without food; do not crush or chew.

Tablet (Tegretol-XR): Administer with food twice daily; examine XR tablets for cracks or chips or other damage; do not use damaged extended-release tablets without release portal. Swallow tablet whole; do not crush or chew.

Rectal: Dilute the oral suspension with an equal volume of water prior to administer; if defecation occurs within the first 2 hours, repeat the dose (Graves 1987).

Dietary Considerations

Folate and vitamin B: Carbamazepine use has been associated with low serum concentrations of folate, vitamin B₂ (riboflavin), B₆ (pyridoxine) and B₁₂ (cyanocobalamin), which may contribute to hyperhomocysteinemia. Hyperhomocysteinemia may contribute to cardiovascular disease, venous thromboembolic disease, dementia, neuropsychiatric symptoms, and poor seizure control. Some health care providers recommend administering folic acid, riboflavin, pyridoxine, and cyanocobalamin supplements in patients taking carbamazepine (Apeland 2003; Apeland 2008; Belcastro 2012; Bochyńska 2012).

Hazardous Drugs Handling Considerations

Hazardous agent (NIOSH 2016 [group 2]).

Use appropriate precautions for receiving, handling, administration, and disposal. Gloves (single) should be worn during receiving, unpacking, and placing in storage.

NIOSH recommends single gloving for administration of intact tablets or capsules. If manipulating tablets/capsules (eg, to prepare an oral suspension), NIOSH recommends double gloving, a protective gown, and preparation in a controlled device; if not prepared in a controlled device, respiratory and eye/face protection as well as ventilated engineering controls are recommended. NIOSH recommends double gloving, a protective gown, and (if there is a potential for vomit or spit up) eye/face protection for administration of an oral liquid/feeding tube administration (NIOSH 2016). Assess risk to determine appropriate containment strategy (USP-NF 2017).

Storage/Stability

Carbatrol, Equetro: Store at controlled room temperature (25°C [77°F]); excursions permitted to 15°C to 30°C (59°F to 86°F); protect from light and moisture.

Tegretol-XR: Store at controlled room temperature, 15°C to 30°C (59°F to 86°F); protect from moisture.

Tegretol tablets and chewable tablets: Store at ≤30°C (86°F); protect from light and moisture.

Tegretol suspension: Store at ≤30°C (86°F); shake well before using.

Extemporaneously Prepared

Note: Commercial oral suspension is available (20 mg/mL)

40 mg/mL Oral Suspension

A 40 mg/mL oral suspension may be made with tablets. Crush twenty 200 mg tablets in a mortar and reduce to a fine powder. Add small portions of Simple Syrup, NF and mix to a uniform paste; mix while adding the vehicle in incremental proportions to almost 100 mL; transfer to a calibrated bottle, rinse mortar with vehicle, and add sufficient quantity of vehicle to make 100 mL. Label "shake well" and "refrigerate". Stable for 90 days.

Nahata MC, Pai VB, and Hipple TF, Pediatric Drug Formulations, 5th ed, Cincinnati, OH: Harvey Whitney Books Co, 2004.

Medication Patient Education with HCAHPS Considerations

What is this drug used for?

• It is used to treat seizures.

• It is used to treat pain caused by a problem with a nerve in the face.

• It is used to treat bipolar problems.

• It may be given to you for other reasons. Talk with the doctor.

Frequently reported side effects of this drug

• Dizziness

• Fatigue

• Nausea

• Vomiting

• Dry mouth

• Loss of strength and energy

• Constipation

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Swelling in your throat

• Infection

• Aplastic anemia like fever, sore throat, mouth sores, infections, bruising, or purple skin splotches.

• Stevens-Johnson syndrome/toxic epidermal necrolysis like red, swollen, blistered, or peeling skin (with or without fever); red or irritated eyes; or sores in mouth, throat, nose, or eyes.

• Liver problems like dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin.

• Low sodium like headache, difficulty focusing, trouble with memory, confusion, weakness, seizures, or change in balance.

• Pancreatitis like severe abdominal pain, severe back pain, severe nausea, or vomiting.

• Kidney problems like unable to pass urine, blood in the urine, change in amount of urine passed, or weight gain.

• DVT like edema, warmth, numbness, change in color, or pain in the extremities.

• Neuroleptic malignant syndrome like fever, muscle cramps or stiffness, dizziness, severe headache, confusion, change in thinking, fast heartbeat, abnormal heartbeat, or sweating a lot.

• Depression like thoughts of suicide, anxiety, emotional instability, or confusion.

• Agitation

• Irritability

• Panic attacks

• Mood changes

• Heart problems like cough or shortness of breath that is new or worse, swelling of the ankles or legs, abnormal heartbeat, weight gain of more than five pounds in 24 hours, dizziness, or passing out.

• Seizures

• Change in speech

• Sensing things that seem real but are not

• Involuntary eye movements

• Slow heartbeat

• Vision changes

• Swollen glands

• Severe muscle pain

• Severe joint pain

• Abnormal movements

• Burning or numbness feeling

• Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.

Medication Safety Issues

Sound-alike/look-alike issues:

High alert medication:

Geriatric Patients: High-Risk Medication:

Medication Guide and/or Vaccine Information Statement (VIS)

An FDA-approved patient medication guide, which is available with the product information and as follows, must be dispensed with this medication:

Carbatrol: http://www.fda.gov/downloads/Drugs/DrugSafety/UCM241639.pdf

Equetro: http://www.fda.gov/downloads/Drugs/DrugSafety/UCM328348.pdf

TEGretol, TEGretol-XR: http://www.fda.gov/downloads/Drugs/DrugSafety/UCM246796.pdf

Contraindications

Hypersensitivity to carbamazepine, tricyclic antidepressants, or any component of the formulation; bone marrow depression; with or within 14 days of MAO inhibitor use; concomitant use of nefazodone, delavirdine, or other non-nucleoside reverse transcriptase inhibitors that are substrate of CYP3A4.

Canadian labeling: Additional contraindications (not in US labeling): Atrioventricular (AV) heart block; hepatic disease; history of hepatic porphyria (acute intermittent porphyria, variegate porphyria, porphyria cutanea tarda); serious blood disorder; concurrent use with itraconazole and voriconazole.

Warnings/Precautions

Concerns related to adverse effects:

• Blood dyscrasias: [US Boxed Warning]: The risk of developing anemia or agranulocytosis is increased during treatment. Complete pretreatment hematological testing should be obtained prior to use; monitor patient closely if white blood cells or platelet counts decrease during therapy; discontinue if significant bone marrow suppression occurs. A spectrum of hematologic effects has been reported with use (eg, agranulocytosis, aplastic anemia, neutropenia, leukopenia, thrombocytopenia, pancytopenia, and anemias); patients with a previous history of adverse hematologic reaction to any drug may be at increased risk. Early detection of hematologic change is important; advise patients of early signs and symptoms including fever, sore throat, mouth ulcers, infections, easy bruising, and petechial or purpuric hemorrhage.

• CNS depression: May cause CNS depression, which may impair physical or mental abilities; patients must be cautioned about performing tasks which require mental alertness (eg, operating machinery or driving).

• Dermatologic toxicity: [US Boxed Warning]: Severe and sometimes fatal dermatologic reactions, including toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS), may occur during therapy. The risk is increased in patients with the variant HLA-B*1502 allele, found most often in patients of Asian ancestry. Patients with an increased likelihood of carrying this allele should be screened prior to initiating therapy. Avoid use in patients testing positive for the allele; discontinue therapy in patients who have a serious dermatologic reaction. The risk of SJS or TEN may also be increased if carbamazepine is used in combination with other antiepileptic drugs associated with these reactions. Presence of the HLA-B*1502 allele has not been found to predict the risk of less serious dermatologic reactions such as anticonvulsant hypersensitivity syndrome or nonserious rash.

• Hepatotoxicity: Hepatotoxicity ranging from slight elevations in liver enzymes to rare hepatic failure has been reported and may occur concomitantly with other immunoallergenic syndromes such as multiorgan hypersensitivity (DRESS syndrome) and serious dermatologic reactions including SJS; monitor baseline and periodic liver function, particularly in patients with a history of liver disease; discontinue carbamazepine immediately in cases of aggravated liver dysfunction or active liver disease. In some cases, hepatic effects may progress despite discontinuation of carbamazepine. Rare cases of a hepatic failure and vanishing bile duct syndrome involving destruction and disappearance of the intrahepatic bile ducts have been reported. Clinical courses of vanishing bile duct syndrome have been variable ranging from fulminant to indolent.

• Hypersensitivity reactions: The risk of developing a hypersensitivity reaction may be increased in patients with the variant HLA-A*3101 allele. These hypersensitivity reactions include SJS/TEN, maculopapular eruptions, and drug reaction with eosinophilia and systemic symptoms (DRESS/multiorgan hypersensitivity). The HLA-A*3101 allele may occur more frequently in patients of African-American, Asian, European, Indian, Arabic, Latin American, and Native American ancestry. Hypersensitivity has also been reported in patients experiencing reactions to other anticonvulsants; the history of hypersensitivity reactions in the patient or their immediate family members should be reviewed. Approximately 25% to 30% of patients allergic to carbamazepine will also have reactions with oxcarbazepine. Also, rare cases of anaphylaxis and angioedema have been reported; may occur after first dose or subsequent doses. Discontinue therapy if symptoms occur. Do not rechallenge patients if such reactions occur; initiate alternative treatment.

• Hyponatremia: Hyponatremia may occur and is often caused by the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Risk of SIADH appears to be dose-related. Elderly or patients taking diuretics are at increased risk for hyponatremia. Consider discontinuing therapy in patients with symptomatic hyponatremia.

• Multiorgan hypersensitivity reactions: Potentially serious, sometimes fatal multiorgan hypersensitivity reactions (also known as drug reaction with eosinophilia and systemic symptoms [DRESS]) have been reported with some antiepileptic drugs; including carbamazepine; monitor for signs and symptoms of possible disparate manifestations associated with lymphatic, hepatic, renal, and/or hematologic organ systems; gradual discontinuation and conversion to alternate therapy may be required.

• Psychiatric effects: May activate latent psychosis and/or cause confusion or agitation; elderly patients may be at an increased risk for psychiatric effects.

• Renal toxicity: Renal toxicity has been reported; monitor renal function at baseline and periodically thereafter.

• Suicidal ideation: Pooled analysis of trials involving various antiepileptics (regardless of indication) showed an increased risk of suicidal thoughts/behavior (incidence rate: 0.43% treated patients compared to 0.24% of patients receiving placebo); risk observed as early as 1 week after initiation and continued through duration of trials (most trials ≤24 weeks). Monitor all patients for notable changes in behavior that might indicate suicidal thoughts or depression; notify healthcare provider immediately if symptoms occur.

Disease-related concerns:

• Anticholinergic sensitivity: Has mild anticholinergic activity; use with caution in patients with sensitivity to anticholinergic effects (urinary retention, increased intraocular pressure, constipation).

• Cardiovascular disease: May cause conduction abnormalities, including AV heart block; use caution in patients with underlying ECG abnormalities, preexisting cardiac damage, or patients who are at risk for conduction abnormalities. In a scientific statement from the American Heart Association, carbamazepine has been determined to be an agent that may exacerbate underlying myocardial dysfunction (magnitude: major) in patients with heart failure (AHA [Page 2016]).

• Hepatic impairment: Use with caution in patients with hepatic impairment; avoid use in patients with hepatic porphyria (eg, acute intermittent porphyria, variegate porphyria, porphyria cutanea tarda).

• Renal impairment: Use with caution in patients with renal impairment.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Asian ancestry: [US Boxed Warning]: Patients with an increased likelihood of carrying the HLA-B*1502 allele, such as those of Asian descent, should be screened for the variant HLA-B*1502 allele prior to initiating therapy. This genetic variant has been associated with a significantly increased risk of developing Stevens-Johnson syndrome and/or toxic epidermal necrolysis. Patients with a positive result should not be started on carbamazepine.

• Elderly: May activate latent psychosis, confusion, or agitation.

• Pediatric: Exacerbation of certain seizure types have been seen after initiation of therapy in children with mixed seizure disorders.

Dosage form specific issues:

• Sorbitol: The suspension may contain sorbitol; avoid use in patents with hereditary fructose intolerance.

• Suspension: Administration of the suspension will yield higher peak and lower trough serum levels than an equal dose of the tablet form; consider a lower starting dose given more frequently (same total daily dose) when using the suspension.

Other warnings/precautions:

• Appropriate use: Not effective in absence, myoclonic, or akinetic seizures; carbamazepine administration may increase the frequency of seizures in patients with these types of seizures.

• Withdrawal: Anticonvulsants should not be discontinued abruptly because of the possibility of increasing seizure frequency; therapy should be withdrawn gradually to minimize the potential of increased seizure frequency, unless safety concerns require a more rapid withdrawal.

* See Cautions in AHFS Essentials for additional information.

Geriatric Considerations

Elderly are more susceptible to carbamazepine-induced confusion and agitation, AV block, bradycardia, and syndrome of inappropriate antidiuretic hormone (SIADH).

Warnings: Additional Pediatric Considerations

Substitution of different carbamazepine products may result in changes in serum concentrations; closely monitor serum concentrations when a change in product is required.

Some dosage forms may contain propylene glycol; in neonates large amounts of propylene glycol delivered orally, intravenously (eg, >3,000 mg/day), or topically have been associated with potentially fatal toxicities which can include metabolic acidosis, seizures, renal failure, and CNS depression; toxicities have also been reported in children and adults including hyperosmolality, lactic acidosis, seizures and respiratory depression; use caution (AAP 1997; Shehab 2009).

Pregnancy Considerations

Carbamazepine and its active metabolite cross the placenta; concentrations are variable but correlate with maternal serum concentrations (Kacirova 2016).

Carbamazepine may be associated with teratogenic effects, including spina bifida, craniofacial defects, and cardiovascular malformations. Data from the International Registry of Antiepileptic Drugs and Pregnancy (EURAP) and the UK and Ireland Epilepsy Pregnancy Registers (UKEPR) note the risk of congenital malformations increases with higher doses (Campbell 2014; Tomson 2011). The risk of teratogenic effects is higher with anticonvulsant polytherapy than monotherapy. Developmental delays have also been observed following in utero exposure to carbamazepine (per manufacturer).

Due to pregnancy-induced physiologic changes, some pharmacokinetic properties of carbamazepine may be altered; however, available studies have slightly conflicting results (Deligiannidis 2014; Tomson 2013). Therapeutic drug monitoring of carbamazepine is recommended in pregnant women (Harden 2009; Hiemke 2018).

Carbamazepine is not recommended for the treatment of bipolar disorder in pregnancy (Larsen 2015).

Carbamazepine may decrease plasma concentrations of hormonal contraceptives; alternate or back-up methods of contraception should be considered. Carbamazepine may interfere with some pregnancy tests.

Patients exposed to carbamazepine during pregnancy are encouraged to enroll themselves into the North American Antiepileptic Drug (NAAED) Pregnancy Registry by calling 1-888-233-2334. Additional information is available at www.aedpregnancyregistry.org.

Breast-Feeding Considerations

Carbamazepine and its active epoxide metabolite are present in breast milk.

Carbamazepine can also be detected in the serum of breastfed infants (Wisner 1998). Respiratory depression, seizures, nausea, vomiting, diarrhea, and/or decreased feeding have been observed in some neonates exposed to carbamazepine and may represent a neonatal withdrawal syndrome

According to the manufacturer, the estimated dose of carbamazepine to a breastfeeding infant is ~2 to 5 mg/day (~1 to 2 mg/day for the metabolite). Milk concentrations have been reported to be 39.4% ± 19.3% of the maternal serum (Kaneko 1979) and have no correlation with maternal carbamazepine dose (Froescher 1984). Concentrations of carbamazepine and the metabolite in breast milk are influenced by maternal use of other medications which influence its metabolism (Kacirova 2011).

According to the manufacturer, the decision to continue or discontinue breastfeeding during therapy should take into account the risk of exposure to the infant and the benefits of treatment to the mother. The WHO considers carbamazepine to be compatible with breastfeeding; infants should be monitored for adverse events (WHO 2002). When used for the treatment of bipolar disorder, carbamazepine is considered acceptable for use in breastfeeding women (Larsen 2015).

Measuring carbamazepine concentrations in the serum of breastfeeding infants is not recommended; however, breastfeeding should be discontinued if adverse events are observed (ACOG 2008).

Lexicomp Pregnancy & Lactation, In-Depth

• CarBAMazepine

Briggs' Drugs in Pregnancy & Lactation

• Carbamazepine

Adverse Reactions

>10%:

Central nervous system: Dizziness (44%), drowsiness (32%), ataxia (15%)

Gastrointestinal: Nausea (29%), vomiting (18%)

1% to 10%:

Cardiovascular: Hypertension (3%)

Central nervous system: Speech disturbance (6%), abnormality in thinking (2%), paresthesia (2%), twitching (2%), vertigo (2%)

Dermatologic: Pruritus (8%), skin rash (7%)

Gastrointestinal: Constipation (10%), xerostomia (8%)

Neuromuscular & skeletal: Weakness (8%), tremor (3%)

Ophthalmic: Blurred vision (5% to 6%)

Frequency not defined:

Cardiovascular: Arterial insufficiency (cerebral artery), atrioventricular block, cardiac arrhythmia, cardiac failure, collapse, coronary artery disease (aggravation), edema, exacerbation of hypertension, hypotension, pulmonary embolism, syncope, thromboembolism, thrombophlebitis

Central nervous system: Agitation, chills, confusion, depression, fatigue, headache, hyperacusis, involuntary body movements, neuroleptic malignant syndrome, peripheral neuritis, talkativeness, unsteadiness, visual hallucination

Dermatologic: Acute generalized exanthematous pustulosis, alopecia, diaphoresis, dyschromia, erythema multiforme, erythema nodosum, erythematous rash, exfoliative dermatitis, maculopapular rash, onychomadesis, pruritic rash, skin photosensitivity, Stevens-Johnson syndrome, toxic epidermal necrolysis, urticaria

Endocrine & metabolic: Acute porphyria, albuminuria, decreased serum calcium, glycosuria, hirsutism, hyponatremia, porphyria cutanea tarda, porphyria (variegate), SIADH

Gastrointestinal: Abdominal pain, anorexia, diarrhea, gastric distress, glossitis, pancreatitis, stomatitis

Genitourinary: Acute urinary retention, azotemia, defective spermatogenesis, impotence, microscopic urine deposits, oliguria, reduced fertility (male), urinary frequency

Hematologic & oncologic: Adenopathy, agranulocytosis, aplastic anemia, bone marrow depression, eosinophilia, hypogammaglobulinemia, leukocytosis, leukopenia, lymphadenopathy, pancytopenia, purpura, thrombocytopenia

Hepatic: Abnormal hepatic function tests, cholestatic jaundice, hepatic failure, hepatitis, hepatocellular jaundice, increased liver enzymes

Hypersensitivity: Hypersensitivity reaction

Immunologic: DRESS syndrome

Neuromuscular & skeletal: Arthralgia, exacerbation of systemic lupus erythematosus, leg cramps, lupus-like syndrome, myalgia, osteoporosis

Ophthalmic: Conjunctivitis, diplopia, increased intraocular pressure, punctate cataract, nystagmus, oculomotor disturbance

Otic: Tinnitus

Renal: Increased blood urea nitrogen, renal failure

Respiratory: Dry throat, pulmonary hypersensitivity

Miscellaneous: Fever

<1%, postmarketing, and/or case reports: Anaphylaxis, angioedema, aseptic meningitis, decreased thyroid hormones, dysgeusia (Syed 2016), eyelid edema, glottis edema, hepatotoxicity (idiosyncratic: Chalasani 2014), intrahepatic cholestasis (vanishing bile duct syndrome), laryngeal edema, lip edema, suicidal tendencies

* See Cautions in AHFS Essentials for additional information.

Allergy and Idiosyncratic Reactions

• Aromatic Anticonvulsant Allergy/Hypersensitivity

Metabolism/Transport Effects

Substrate of CYP2C8 (minor), CYP3A4 (major); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential; Induces BCRP/ABCG2, CYP1A2 (weak), CYP2B6 (moderate), CYP2C9 (weak), CYP3A4 (strong), OATP1B1/1B3 (SLCO1B1/1B3), P-glycoprotein/ABCB1, UGT1A1

Drug Interactions Open Interactions

Abemaciclib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Abemaciclib. Risk X: Avoid combination

Abiraterone Acetate: CYP3A4 Inducers (Strong) may decrease the serum concentration of Abiraterone Acetate. Management: Avoid whenever possible. If such a combination cannot be avoided, increase abiraterone acetate dosing frequency from once daily to twice daily during concomitant use. Risk D: Consider therapy modification

Acalabrutinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Acalabrutinib. Management: Avoid co-administration of strong CYP3A inducers in patients taking acalabrutinib. If strong CYP3A inducers cannot be avoided, increase the dose of acalabrutinib to 200 mg twice daily. Risk D: Consider therapy modification

Acetaminophen: CarBAMazepine may increase the metabolism of Acetaminophen. This may 1) diminish the effect of acetaminophen; and 2) increase the risk of liver damage. Risk C: Monitor therapy

Adenosine: CarBAMazepine may enhance the adverse/toxic effect of Adenosine. Specifically, the risk of higher degree heart block may be increased. Management: Consider using a lower initial dose of adenosine in patients who are receiving carbamazepine. Risk D: Consider therapy modification

Afatinib: P-glycoprotein/ABCB1 Inducers may decrease the serum concentration of Afatinib. Management: Per US labeling: if requiring chronic use of P-gp inducers, increase afatinib dose by 10 mg as tolerated; reduce to original afatinib dose 2-3 days after stopping P-gp inducers. Per Canadian labeling: avoid combination if possible. Risk D: Consider therapy modification

Albendazole: CarBAMazepine may decrease serum concentrations of the active metabolite(s) of Albendazole. Risk C: Monitor therapy

Allopurinol: May increase the serum concentration of CarBAMazepine. Risk C: Monitor therapy

Alpelisib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Alpelisib. Risk X: Avoid combination

Antihepaciviral Combination Products: CYP3A4 Inducers (Strong) may decrease the serum concentration of Antihepaciviral Combination Products. Risk X: Avoid combination

Apalutamide: CYP3A4 Inducers (Strong) may decrease the serum concentration of Apalutamide. Risk C: Monitor therapy

Apixaban: Inducers of CYP3A4 (Strong) and P-glycoprotein may decrease the serum concentration of Apixaban. Risk X: Avoid combination

Apremilast: CYP3A4 Inducers (Strong) may decrease the serum concentration of Apremilast. Risk X: Avoid combination

Aprepitant: CYP3A4 Inducers (Strong) may decrease the serum concentration of Aprepitant. Risk X: Avoid combination

ARIPiprazole: CYP3A4 Inducers (Strong) may decrease the serum concentration of ARIPiprazole. Management: Double the oral aripiprazole dose and closely monitor. Reduce oral aripiprazole dose to 10-15 mg/day (for adults) if the inducer is discontinued. Avoid use of strong CYP3A4 inducers for more than 14 days with extended-release injectable aripiprazole. Risk D: Consider therapy modification

ARIPiprazole Lauroxil: CYP3A4 Inducers (Strong) may decrease serum concentrations of the active metabolite(s) of ARIPiprazole Lauroxil. Management: Patients taking the 441 mg dose of aripiprazole lauroxil increase their dose to 662 mg if used with a strong CYP3A4 inducer for more than 14 days. No dose adjustment is necessary for patients using the higher doses of aripiprazole lauroxil. Risk D: Consider therapy modification

Artemether: CYP3A4 Inducers (Strong) may decrease serum concentrations of the active metabolite(s) of Artemether. Specifically, dihydroartemisinin concentrations may be reduced. CYP3A4 Inducers (Strong) may decrease the serum concentration of Artemether. Risk X: Avoid combination

Asunaprevir: CYP3A4 Inducers (Strong) may decrease the serum concentration of Asunaprevir. Risk X: Avoid combination

Avapritinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Avapritinib. Risk X: Avoid combination

Axitinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Axitinib. Risk X: Avoid combination

Bazedoxifene: CarBAMazepine may decrease the serum concentration of Bazedoxifene. This may lead to loss of efficacy or, if bazedoxifene is combined with estrogen therapy, an increased risk of endometrial hyperplasia. Risk C: Monitor therapy

BCG (Intravesical): Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical). Risk X: Avoid combination

Bedaquiline: CYP3A4 Inducers (Strong) may decrease the serum concentration of Bedaquiline. Risk X: Avoid combination

Benperidol: CYP3A4 Inducers (Strong) may decrease the serum concentration of Benperidol. Risk C: Monitor therapy

Benzhydrocodone: CYP3A4 Inducers (Strong) may decrease the serum concentration of Benzhydrocodone. Specifically, the serum concentrations of hydrocodone may be reduced. Risk C: Monitor therapy

Betrixaban: P-glycoprotein/ABCB1 Inducers may decrease the serum concentration of Betrixaban. Risk X: Avoid combination

Bictegravir: CarBAMazepine may decrease the serum concentration of Bictegravir. Management: When possible consider using an alternative anticonvulsant with concurrent bictegravir, emtricitabine, and tenofovir alafenamide. If the combination must be used, monitor closely for evidence of reduced antiviral effectiveness. Risk D: Consider therapy modification

Bortezomib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Bortezomib. Risk X: Avoid combination

Bosentan: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Risk C: Monitor therapy

Bosutinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Bosutinib. Risk X: Avoid combination

Brentuximab Vedotin: CYP3A4 Inducers (Strong) may decrease the serum concentration of Brentuximab Vedotin. Specifically, concentrations of the active monomethyl auristatin E (MMAE) component may be decreased. Risk C: Monitor therapy

Brentuximab Vedotin: P-glycoprotein/ABCB1 Inducers may decrease the serum concentration of Brentuximab Vedotin. Specifically, concentrations of the active monomethyl auristatin E (MMAE) component may be decreased. Risk C: Monitor therapy

Brexpiprazole: CYP3A4 Inducers (Strong) may decrease the serum concentration of Brexpiprazole. Management: If brexpiprazole is used together with a strong CYP3A4 inducer, the brexpiprazole dose should gradually be doubled over the course of 1 to 2 weeks. Risk D: Consider therapy modification

Brigatinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Brigatinib. Risk X: Avoid combination

Brivaracetam: May increase serum concentrations of the active metabolite(s) of CarBAMazepine. CarBAMazepine may decrease the serum concentration of Brivaracetam. Risk C: Monitor therapy

Bromperidol: CarBAMazepine may decrease the serum concentration of Bromperidol. Risk C: Monitor therapy

Buprenorphine: CYP3A4 Inducers (Strong) may decrease the serum concentration of Buprenorphine. Risk C: Monitor therapy

BuPROPion: CYP2B6 Inducers (Moderate) may decrease the serum concentration of BuPROPion. Risk C: Monitor therapy

BusPIRone: CYP3A4 Inducers (Strong) may decrease the serum concentration of BusPIRone. Management: Consider alternatives to this combination. If coadministration of these agents is deemed necessary, monitor patients for reduced buspirone effects and increase buspirone doses as needed. Risk D: Consider therapy modification

Cabozantinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Cabozantinib. Management: Avoid use of strong CYP3A4 inducers with cabozantinib if possible. If combined, cabozantinib dose adjustments are recommended and vary based on the cabozantinib product used and the indication for use. See monograph for details. Risk D: Consider therapy modification

Calcifediol: CYP3A4 Inducers (Strong) may decrease the serum concentration of Calcifediol. Risk C: Monitor therapy

Calcium Channel Blockers (Dihydropyridine): CarBAMazepine may increase the metabolism of Calcium Channel Blockers (Dihydropyridine). Management: Consider calcium channel blocker (CCB) dose adjustments or alternative therapy in patients receiving concomitant carbamazepine. Nimodipine Canadian labeling contraindicates concurrent use with carbamazepine. Exceptions: Clevidipine. Risk D: Consider therapy modification

Calcium Channel Blockers (Nondihydropyridine): May increase the serum concentration of CarBAMazepine. CarBAMazepine may decrease the serum concentration of Calcium Channel Blockers (Nondihydropyridine). Management: Consider empiric reductions in carbamazepine dose with initiation of nondihydropyridine calcium channel blockers. Monitor for increased toxic effects of carbamazepine and reduced therapeutic effects of the calcium channel blocker. Risk D: Consider therapy modification

Cannabidiol: CYP3A4 Inducers (Strong) may decrease the serum concentration of Cannabidiol. Risk C: Monitor therapy

Cannabis: CYP3A4 Inducers (Strong) may decrease the serum concentration of Cannabis. More specifically, tetrahydrocannabinol and cannabidiol serum concentrations may be decreased. Risk C: Monitor therapy

Carbonic Anhydrase Inhibitors: May increase the serum concentration of CarBAMazepine. Exceptions: Brinzolamide; Dorzolamide. Risk C: Monitor therapy

Cariprazine: CYP3A4 Inducers (Strong) may decrease the serum concentration of Cariprazine. Risk X: Avoid combination

Caspofungin: Inducers of Drug Clearance may decrease the serum concentration of Caspofungin. Management: Consider using an increased caspofungin dose of 70 mg daily in adults (or 70 mg/m², up to a maximum of 70 mg, daily in pediatric patients) when coadministered with known inducers of drug clearance. Risk D: Consider therapy modification

Celiprolol: P-glycoprotein/ABCB1 Inducers may decrease the serum concentration of Celiprolol. Risk C: Monitor therapy

Cenobamate: May decrease the serum concentration of CarBAMazepine. Risk C: Monitor therapy

Ceritinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Ceritinib. Risk X: Avoid combination

Chloramphenicol (Ophthalmic): May enhance the adverse/toxic effect of Myelosuppressive Agents. Risk C: Monitor therapy

Chlormethiazole: CarBAMazepine may decrease the serum concentration of Chlormethiazole. Risk C: Monitor therapy

ChlorproPAMIDE: CYP3A4 Inducers (Strong) may decrease the serum concentration of ChlorproPAMIDE. Risk C: Monitor therapy

Cimetidine: May increase the serum concentration of CarBAMazepine. The serum carbamazepine concentration might return to normal within one week of starting cimetidine. Risk C: Monitor therapy

Ciprofloxacin (Systemic): May increase the serum concentration of CarBAMazepine. Risk C: Monitor therapy

Citalopram: CarBAMazepine may decrease the serum concentration of Citalopram. Risk C: Monitor therapy

Cladribine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Risk X: Avoid combination

Clarithromycin: CarBAMazepine may increase serum concentrations of the active metabolite(s) of Clarithromycin. Clarithromycin may increase the serum concentration of CarBAMazepine. CarBAMazepine may decrease the serum concentration of Clarithromycin. Management: Consider alternatives to this combination when possible. If combined, monitor for increased carbamazepine effects/toxicities and for reduced clarithromycin efficacy. Risk D: Consider therapy modification

Clindamycin (Systemic): CYP3A4 Inducers (Strong) may decrease the serum concentration of Clindamycin (Systemic). Refer to the specific clindamycin (systemic) - rifampin drug interaction monograph for information concerning that combination. Risk C: Monitor therapy

Clofazimine: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk C: Monitor therapy

ClomiPRAMINE: CarBAMazepine may decrease the serum concentration of ClomiPRAMINE. Risk C: Monitor therapy

CloZAPine: CarBAMazepine may enhance the myelosuppressive effect of CloZAPine. More specifically, the risk of bone marrow suppression with this combination may be increased due to the independent myelosuppressive effects of the drugs. CarBAMazepine may decrease the serum concentration of CloZAPine. Risk X: Avoid combination

Cobicistat: CarBAMazepine may decrease the serum concentration of Cobicistat. Risk X: Avoid combination

Cobimetinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Cobimetinib. Risk X: Avoid combination

Codeine: CYP3A4 Inducers (Strong) may decrease serum concentrations of the active metabolite(s) of Codeine. Risk C: Monitor therapy

Conivaptan: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination

Copanlisib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Copanlisib. Risk X: Avoid combination

Corticosteroids (Systemic): CYP3A4 Inducers (Strong) may decrease the serum concentration of Corticosteroids (Systemic). Exceptions: Hydrocortisone (Systemic); PrednisoLONE (Systemic); PredniSONE. Risk C: Monitor therapy

Crizotinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Crizotinib. Risk X: Avoid combination

CycloSPORINE (Systemic): CarBAMazepine may decrease the serum concentration of CycloSPORINE (Systemic). Management: Monitor frequently for decreased serum concentrations and therapeutic effects of cyclosporine if combined with carbamazepine. Increased cyclosporine doses will likely be needed to maintain adequate serum concentrations. Risk D: Consider therapy modification

CYP2B6 Substrates (High risk with Inducers): CYP2B6 Inducers (Moderate) may decrease the serum concentration of CYP2B6 Substrates (High risk with Inducers). Risk C: Monitor therapy

CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Risk C: Monitor therapy

CYP3A4 Inducers (Strong): May decrease the serum concentration of CarBAMazepine. Risk C: Monitor therapy

CYP3A4 Inhibitors (Moderate): May decrease the metabolism of CYP3A4 Substrates (High risk with Inhibitors). Risk C: Monitor therapy

CYP3A4 Inhibitors (Strong): May decrease the metabolism of CYP3A4 Substrates (High risk with Inhibitors). Risk D: Consider therapy modification

CYP3A4 Substrates (High risk with Inducers): CYP3A4 Inducers (Strong) may increase the metabolism of CYP3A4 Substrates (High risk with Inducers). Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Exceptions: Benzhydrocodone; Buprenorphine; CarBAMazepine; Etizolam; HYDROcodone; Mirtazapine; TraMADol; Zolpidem. Risk D: Consider therapy modification

Dabigatran Etexilate: P-glycoprotein/ABCB1 Inducers may decrease the serum concentration of Dabigatran Etexilate. Management: Avoid concurrent use of dabigatran with P-glycoprotein inducers whenever possible. Risk X: Avoid combination

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Risk D: Consider therapy modification

Daclatasvir: CYP3A4 Inducers (Strong) may decrease the serum concentration of Daclatasvir. Risk X: Avoid combination

Danazol: May decrease the metabolism of CarBAMazepine. Risk C: Monitor therapy

Darolutamide: Inducers of CYP3A4 (Strong) and P-glycoprotein may decrease the serum concentration of Darolutamide. Risk X: Avoid combination

Darunavir: May increase the serum concentration of CarBAMazepine. Risk C: Monitor therapy

Dasabuvir: CYP3A4 Inducers (Strong) may decrease the serum concentration of Dasabuvir. Risk X: Avoid combination

Dasatinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Dasatinib. Management: Avoid when possible. If such a combination cannot be avoided, consider increasing dasatinib dose and monitor clinical response and toxicity closely. Risk D: Consider therapy modification

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Risk C: Monitor therapy

Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Management: Avoid the concomitant use of deferiprone and myelosuppressive agents whenever possible. If this combination cannot be avoided, monitor the absolute neutrophil count more closely. Risk D: Consider therapy modification

Deflazacort: CYP3A4 Inducers (Strong) may decrease serum concentrations of the active metabolite(s) of Deflazacort. Risk X: Avoid combination

Delamanid: CYP3A4 Inducers (Strong) may decrease the serum concentration of Delamanid. Risk X: Avoid combination

Delavirdine: CarBAMazepine may decrease the serum concentration of Delavirdine. Risk X: Avoid combination

Desmopressin: CarBAMazepine may enhance the adverse/toxic effect of Desmopressin. Risk C: Monitor therapy

DexAMETHasone (Systemic): CYP3A4 Inducers (Strong) may decrease the serum concentration of DexAMETHasone (Systemic). Management: Consider dexamethasone dose increases in patients receiving strong CYP3A4 inducers and monitor closely for reduced dexamethasone efficacy. Consider avoiding this combination when treating life threatening conditions (ie, multiple myeloma). Risk D: Consider therapy modification

Dienogest: CYP3A4 Inducers (Strong) may decrease the serum concentration of Dienogest. Management: Avoid use of dienogest for contraception when using medications that induce CYP3A4 and for at least 28 days after discontinuation of a CYP3A4 inducer. An alternative form of contraception should be used during this time. Risk X: Avoid combination

Diethylstilbestrol: CYP3A4 Inducers (Strong) may decrease the serum concentration of Diethylstilbestrol. Risk C: Monitor therapy

Dipyrone: May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased Risk X: Avoid combination

Dolutegravir: CarBAMazepine may decrease the serum concentration of Dolutegravir. Management: Increase dolutegravir dose to 50 mg twice daily when used together with carbamazepine. Patients with known or suspected integrase strand inhibitor resistance should use an alternative to carbamazepine when possible. Risk D: Consider therapy modification

Doravirine: CYP3A4 Inducers (Strong) may decrease the serum concentration of Doravirine. Risk X: Avoid combination

Doxercalciferol: CYP3A4 Inducers (Strong) may increase serum concentrations of the active metabolite(s) of Doxercalciferol. Risk C: Monitor therapy

DOXOrubicin (Conventional): CYP3A4 Inducers (Strong) may decrease the serum concentration of DOXOrubicin (Conventional). Management: Seek alternatives to strong CYP3A4 inducers in patients treated with doxorubicin. One U.S. manufacturer (Pfizer Inc.) recommends that these combinations be avoided. Risk D: Consider therapy modification

DOXOrubicin (Conventional): P-glycoprotein/ABCB1 Inducers may decrease the serum concentration of DOXOrubicin (Conventional). Management: Seek alternatives to P-glycoprotein inducers in patients treated with doxorubicin whenever possible. One U.S. manufacturer (Pfizer Inc.) recommends that these combinations be avoided. Risk D: Consider therapy modification

Doxycycline: CarBAMazepine may decrease the serum concentration of Doxycycline. Risk D: Consider therapy modification

Dronabinol: CYP3A4 Inducers (Strong) may decrease the serum concentration of Dronabinol. Risk C: Monitor therapy

Dronedarone: CYP3A4 Inducers (Strong) may decrease the serum concentration of Dronedarone. Risk X: Avoid combination

Duvelisib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Duvelisib. Risk X: Avoid combination

Edoxaban: CarBAMazepine may decrease the serum concentration of Edoxaban. Management: Combined use of carbamazepine and edoxaban should generally be avoided. Risk D: Consider therapy modification

Efavirenz: CarBAMazepine may decrease the serum concentration of Efavirenz. Efavirenz may decrease the serum concentration of CarBAMazepine. Risk X: Avoid combination

Elagolix: CYP3A4 Inducers (Strong) may decrease the serum concentration of Elagolix. Risk C: Monitor therapy

Elbasvir: CYP3A4 Inducers (Strong) may decrease the serum concentration of Elbasvir. Risk X: Avoid combination

Elexacaftor, Tezacaftor, and Ivacaftor: CYP3A4 Inducers (Strong) may decrease the serum concentration of Elexacaftor, Tezacaftor, and Ivacaftor. Risk X: Avoid combination

Eliglustat: CYP3A4 Inducers (Strong) may decrease the serum concentration of Eliglustat. Risk X: Avoid combination

Elvitegravir: CarBAMazepine may decrease the serum concentration of Elvitegravir. Risk X: Avoid combination

Encorafenib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Encorafenib. Risk X: Avoid combination

Enfortumab Vedotin: CYP3A4 Inducers (Strong) may decrease the serum concentration of Enfortumab Vedotin. Specifically, concentrations of the active monomethyl auristatin E (MMAE) component may be decreased. Risk C: Monitor therapy

Entrectinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Entrectinib. Risk X: Avoid combination

Enzalutamide: CYP3A4 Inducers (Strong) may decrease the serum concentration of Enzalutamide. Management: Consider using an alternative agent that has no or minimal CYP3A4 induction potential when possible. If this combination cannot be avoided, increase the dose of enzalutamide from 160 mg daily to 240 mg daily. Risk D: Consider therapy modification

Enzalutamide: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Concurrent use of enzalutamide with CYP3A4 substrates that have a narrow therapeutic index should be avoided. Use of enzalutamide and any other CYP3A4 substrate should be performed with caution and close monitoring. Risk D: Consider therapy modification

Eravacycline: CYP3A4 Inducers (Strong) may decrease the serum concentration of Eravacycline. Management: Increase the eravacycline dose to 1.5 mg/kg every 12 hours when combined with strong CYP3A4 inducers. Risk D: Consider therapy modification

Erdafitinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Erdafitinib. Risk X: Avoid combination

Erlotinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Erlotinib. Management: Avoid combination if possible. If combination must be used, increase erlotinib dose by 50 mg increments every 2 weeks as tolerated, to a maximum of 450 mg/day. Risk D: Consider therapy modification

Erythromycin (Systemic): May increase the serum concentration of CarBAMazepine. Management: Consider alternative antimicrobial therapy in combination with carbamazepine. If combined, monitor for increased carbamazepine effects/toxicities. Risk D: Consider therapy modification

Eslicarbazepine: CarBAMazepine may enhance the adverse/toxic effect of Eslicarbazepine. CarBAMazepine may decrease the serum concentration of Eslicarbazepine. Risk C: Monitor therapy

Estriol (Systemic): CYP3A4 Inducers (Strong) may decrease the serum concentration of Estriol (Systemic). Risk C: Monitor therapy

Estriol (Topical): CYP3A4 Inducers (Strong) may decrease the serum concentration of Estriol (Topical). Risk C: Monitor therapy

Estrogen Derivatives (Contraceptive): CarBAMazepine may diminish the therapeutic effect of Estrogen Derivatives (Contraceptive). Contraceptive failure is possible. Management: Use of a nonhormonal contraceptive is recommended. Risk D: Consider therapy modification

Etizolam: CYP3A4 Inducers (Strong) may decrease the serum concentration of Etizolam. Risk C: Monitor therapy

Etoposide: CYP3A4 Inducers (Strong) may decrease the serum concentration of Etoposide. Management: When possible, seek alternatives to strong CYP3A4-inducing medications in patients receiving etoposide. If combined, monitor patients closely for diminished etoposide response and need for etoposide dose increases. Risk D: Consider therapy modification

Etoposide Phosphate: CYP3A4 Inducers (Strong) may decrease the serum concentration of Etoposide Phosphate. Management: When possible, seek alternatives to strong CYP3A4-inducing medications in patients receiving etoposide phosphate. If these combinations cannot be avoided, monitor patients closely for diminished etoposide phosphate response. Risk D: Consider therapy modification

Etravirine: CYP3A4 Inducers (Strong) may decrease the serum concentration of Etravirine. Risk X: Avoid combination

Everolimus: CYP3A4 Inducers (Strong) may decrease the serum concentration of Everolimus. Management: Avoid concurrent use of strong CYP3A4 inducers if possible. If coadministration cannot be avoided, double the daily dose of everolimus using increments of 5 mg or less. Monitor everolimus serum concentrations closely when indicated. Risk D: Consider therapy modification

Evogliptin: CYP3A4 Inducers (Strong) may decrease the serum concentration of Evogliptin. Risk C: Monitor therapy

Exemestane: CYP3A4 Inducers (Strong) may decrease the serum concentration of Exemestane. Management: Exemestane U.S. product labeling recommends using an increased dose (50 mg/day) in patients receiving concurrent strong CYP3A4 inducers. The Canadian product labeling does not recommend a dose adjustment with concurrent use of strong CYP3A4 inducers. Risk D: Consider therapy modification

Ezogabine: CarBAMazepine may decrease the serum concentration of Ezogabine. Management: Consider increasing the ezogabine dose when adding carbamazepine. Monitor patients using the combination closely for evidence of adequate ezogabine therapy. Risk D: Consider therapy modification

Fedratinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Fedratinib. Risk X: Avoid combination

Felbamate: CarBAMazepine may decrease the serum concentration of Felbamate. Felbamate may decrease the serum concentration of CarBAMazepine. Management: In patients receiving carbamazepine, initiate felbamate at 1200 mg/day in divided doses 3-4 times daily while reducing carbamazepine dose by 20%. Monitor for reduced concentrations/effects of both drugs. Risk D: Consider therapy modification

FentaNYL: CYP3A4 Inducers (Strong) may decrease the serum concentration of FentaNYL. Risk C: Monitor therapy

Fingolimod: CarBAMazepine may decrease the serum concentration of Fingolimod. Risk C: Monitor therapy

Flibanserin: CYP3A4 Inducers (Strong) may decrease the serum concentration of Flibanserin. Risk X: Avoid combination

Fluconazole: May increase the serum concentration of CarBAMazepine. Risk C: Monitor therapy

Flunarizine: CarBAMazepine may decrease the serum concentration of Flunarizine. Risk C: Monitor therapy

FLUoxetine: May increase the serum concentration of CarBAMazepine. Risk C: Monitor therapy

FluvoxaMINE: May increase the serum concentration of CarBAMazepine. Risk C: Monitor therapy

Fosaprepitant: CYP3A4 Inducers (Strong) may decrease the serum concentration of Fosaprepitant. Specifically, CYP3A4 Inducers (Strong) may decrease serum concentrations of the active metabolite aprepitant. Risk X: Avoid combination

Fosnetupitant: CYP3A4 Inducers (Strong) may decrease serum concentrations of the active metabolite(s) of Fosnetupitant. Risk X: Avoid combination

Fosphenytoin: May decrease the serum concentration of CarBAMazepine. CarBAMazepine may decrease the serum concentration of Fosphenytoin. CarBAMazepine may increase the serum concentration of Fosphenytoin. Possibly by competitive inhibition at sites of metabolism. Risk D: Consider therapy modification

Fostamatinib: CYP3A4 Inducers (Strong) may decrease serum concentrations of the active metabolite(s) of Fostamatinib. Risk X: Avoid combination

Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination

Gefitinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Gefitinib. Management: In the absence of severe adverse reactions, increase gefitinib dose to 500 mg daily in patients receiving strong CYP3A4 inducers; resume 250 mg dose 7 days after discontinuation of the strong inducer. Carefully monitor clinical response. Risk D: Consider therapy modification

Gemigliptin: CYP3A4 Inducers (Strong) may decrease serum concentrations of the active metabolite(s) of Gemigliptin. CYP3A4 Inducers (Strong) may decrease the serum concentration of Gemigliptin. Risk X: Avoid combination

Gestrinone: CarBAMazepine may decrease the serum concentration of Gestrinone. Risk C: Monitor therapy

Gilteritinib: Inducers of CYP3A4 (Strong) and P-glycoprotein may decrease the serum concentration of Gilteritinib. Risk X: Avoid combination

Glasdegib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Glasdegib. Risk X: Avoid combination

Glecaprevir and Pibrentasvir: CarBAMazepine may decrease the serum concentration of Glecaprevir and Pibrentasvir. Risk X: Avoid combination

Grapefruit Juice: May increase the serum concentration of CarBAMazepine. Risk C: Monitor therapy

Grazoprevir: CYP3A4 Inducers (Strong) may decrease the serum concentration of Grazoprevir. Risk X: Avoid combination

GuanFACINE: CYP3A4 Inducers (Strong) may decrease the serum concentration of GuanFACINE. Management: Increase the guanfacine dose by up to double when initiating guanfacine in a patient taking a strong CYP3A4 inducer. Increase guanfacine dose gradually over 1 to 2 weeks if initiating strong CYP3A4 inducer therapy in a patient already taking guanfacine. Risk D: Consider therapy modification

Haloperidol: CarBAMazepine may decrease the serum concentration of Haloperidol. Risk C: Monitor therapy

HYDROcodone: CYP3A4 Inducers (Strong) may decrease the serum concentration of HYDROcodone. Risk C: Monitor therapy

Hydrocortisone (Systemic): CYP3A4 Inducers (Strong) may decrease the serum concentration of Hydrocortisone (Systemic). Risk C: Monitor therapy

Ibrutinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Ibrutinib. Risk X: Avoid combination

Idelalisib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Idelalisib. Risk X: Avoid combination

Idelalisib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination

Ifosfamide: CYP3A4 Inducers (Strong) may increase serum concentrations of the active metabolite(s) of Ifosfamide. CYP3A4 Inducers (Strong) may decrease serum concentrations of the active metabolite(s) of Ifosfamide. Risk C: Monitor therapy

Imatinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Imatinib. Management: Avoid concurrent use of imatinib with strong CYP3A4 inducers when possible. If such a combination must be used, increase imatinib dose by at least 50% and monitor the patient's clinical response closely. Risk D: Consider therapy modification

Irinotecan Products: CYP3A4 Inducers (Strong) may decrease serum concentrations of the active metabolite(s) of Irinotecan Products. Specifically, serum concentrations of SN-38 may be reduced. CYP3A4 Inducers (Strong) may decrease the serum concentration of Irinotecan Products. Risk X: Avoid combination

Isavuconazonium Sulfate: CYP3A4 Inducers (Strong) may decrease serum concentrations of the active metabolite(s) of Isavuconazonium Sulfate. Specifically, CYP3A4 Inducers (Strong) may decrease isavuconazole serum concentrations. Risk X: Avoid combination

Isoniazid: CarBAMazepine may enhance the hepatotoxic effect of Isoniazid. Isoniazid may increase the serum concentration of CarBAMazepine. Risk C: Monitor therapy

Istradefylline: CYP3A4 Inducers (Strong) may decrease the serum concentration of Istradefylline. Risk X: Avoid combination

Itraconazole: CYP3A4 Inducers (Strong) may decrease the serum concentration of Itraconazole. Risk X: Avoid combination

Ivabradine: CYP3A4 Inducers (Strong) may decrease the serum concentration of Ivabradine. Risk X: Avoid combination

Ivacaftor: CYP3A4 Inducers (Strong) may decrease the serum concentration of Ivacaftor. Risk X: Avoid combination

Ivosidenib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Ivosidenib. Risk X: Avoid combination

Ixabepilone: CYP3A4 Inducers (Strong) may decrease the serum concentration of Ixabepilone. Management: Avoid this combination whenever possible. If this combination must be used, a gradual increase in ixabepilone dose from 40 mg/m² to 60 mg/m² (given as a 4-hour infusion), as tolerated, should be considered. Risk D: Consider therapy modification

Ixazomib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Ixazomib. Risk X: Avoid combination

Lacosamide: Antiepileptic Agents (Sodium Channel Blockers) may enhance the adverse/toxic effect of Lacosamide. Specifically the risk for bradycardia, ventricular tachyarrhythmias, or a prolonged PR interval may be increased. Risk C: Monitor therapy

LamoTRIgine: May enhance the adverse/toxic effect of CarBAMazepine. CarBAMazepine may increase the metabolism of LamoTRIgine. Risk D: Consider therapy modification

Lapatinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Lapatinib. Management: If therapy overlap cannot be avoided, consider titrating lapatinib gradually from 1,250 mg/day up to 4,500 mg/day (HER2 positive metastatic breast cancer) or 1,500 mg/day up to 5,500 mg/day (hormone receptor/HER2 positive breast cancer) as tolerated. Risk X: Avoid combination

Larotrectinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Larotrectinib. Management: Avoid use of strong CYP3A4 inducers with larotrectinib. If this combination cannot be avoided, double the larotrectinib dose. Reduced to previous dose after stopping the inducer after a period of 3 to 5 times the inducer half-life. Risk D: Consider therapy modification

Ledipasvir: P-glycoprotein/ABCB1 Inducers may decrease the serum concentration of Ledipasvir. Risk X: Avoid combination

Lefamulin: CYP3A4 Inducers (Strong) may decrease the serum concentration of Lefamulin. Management: Avoid concomitant use of lefamulin with strong CYP3A4 inducers unless the benefits outweigh the risks. Risk D: Consider therapy modification

Lefamulin: P-glycoprotein/ABCB1 Inducers may decrease the serum concentration of Lefamulin. Management: Avoid concomitant use of lefamulin with P-glycoprotein/ABCB1 inducers unless the benefits outweigh the risks. Risk D: Consider therapy modification

Lefamulin (Intravenous): CYP3A4 Inducers (Strong) may decrease the serum concentration of Lefamulin (Intravenous). Management: Avoid concomitant use of lefamulin intravenous infusion with strong CYP3A4 inducers unless the benefits outweigh the risks. Risk D: Consider therapy modification

Lefamulin (Intravenous): P-glycoprotein/ABCB1 Inducers may decrease the serum concentration of Lefamulin (Intravenous). Management: Avoid concomitant use of lefamulin (intravenous) with P-glycoprotein/ABCB1 inducers unless the benefits outweigh the risks. Risk D: Consider therapy modification

Lemborexant: CYP3A4 Inducers (Strong) may decrease the serum concentration of Lemborexant. Risk X: Avoid combination

Letermovir: P-glycoprotein/ABCB1 Inducers may decrease the serum concentration of Letermovir. Risk X: Avoid combination

Letermovir: May increase the serum concentration of UGT1A1 Inducers. Risk X: Avoid combination

LevETIRAcetam: May enhance the adverse/toxic effect of CarBAMazepine. CarBAMazepine may decrease the serum concentration of LevETIRAcetam. Risk C: Monitor therapy

Levomethadone: CarBAMazepine may decrease the serum concentration of Levomethadone. Risk C: Monitor therapy

LinaGLIPtin: CYP3A4 Inducers (Strong) may decrease the serum concentration of LinaGLIPtin. Management: Strongly consider using an alternative to any strong CYP3A4 inducer in patients who are being treated with linagliptin. If this combination is used, monitor patients closely for evidence of reduced linagliptin effectiveness. Risk D: Consider therapy modification

LinaGLIPtin: P-glycoprotein/ABCB1 Inducers may decrease the serum concentration of LinaGLIPtin. Management: Strongly consider using an alternative to any P-glycoprotein inducer in patients who are being treated with linagliptin. If this combination is used, monitor patients closely for evidence of reduced linagliptin effectiveness. Risk D: Consider therapy modification

Lithium: CarBAMazepine may enhance the adverse/toxic effect of Lithium. Risk C: Monitor therapy

Lopinavir: CarBAMazepine may decrease the serum concentration of Lopinavir. Management: Increased doses of lopinavir may be necessary when using these agents in combination. Do not use a once daily lopinavir/ritonavir regimen together with carbamazepine. Increase monitoring of therapeutic response in all patients using this combination. Risk D: Consider therapy modification

Lorlatinib: CYP3A4 Inducers (Strong) may enhance the hepatotoxic effect of Lorlatinib. CYP3A4 Inducers (Strong) may decrease the serum concentration of Lorlatinib. Risk X: Avoid combination

Loxapine: May increase serum concentrations of the active metabolite(s) of CarBAMazepine. Risk C: Monitor therapy

Lumacaftor and Ivacaftor: CYP3A4 Inducers (Strong) may decrease the serum concentration of Lumacaftor and Ivacaftor. Specifically, the serum concentration of ivacaftor may be decreased. Risk X: Avoid combination

Lumateperone: CYP3A4 Inducers (Strong) may decrease the serum concentration of Lumateperone. Risk X: Avoid combination

Lumefantrine: CYP3A4 Inducers (Strong) may decrease the serum concentration of Lumefantrine. Risk X: Avoid combination

Lurasidone: CYP3A4 Inducers (Strong) may decrease the serum concentration of Lurasidone. Risk X: Avoid combination

Macimorelin: CYP3A4 Inducers (Strong) may decrease the serum concentration of Macimorelin. Risk X: Avoid combination

Macitentan: CYP3A4 Inducers (Strong) may decrease the serum concentration of Macitentan. Risk X: Avoid combination

Manidipine: CYP3A4 Inducers (Strong) may decrease the serum concentration of Manidipine. Management: Consider avoiding concomitant use of manidipine and strong CYP3A4 inducers. If combined, monitor closely for decreased manidipine effects and loss of efficacy. Increased manidipine doses may be required. Risk D: Consider therapy modification

Maraviroc: CYP3A4 Inducers (Strong) may decrease the serum concentration of Maraviroc. Management: Increase maraviroc adult dose to 600 mg twice daily when used with strong CYP3A4 inducers. This does not apply to patients also receiving strong CYP3A4 inhibitors. Do not use maraviroc with strong CYP3A4 inducers in patients with CrCl less than 30 mL/min. Risk D: Consider therapy modification

Mebendazole: CarBAMazepine may decrease the serum concentration of Mebendazole. Risk C: Monitor therapy

Mefloquine: May diminish the therapeutic effect of Anticonvulsants. Mefloquine may decrease the serum concentration of Anticonvulsants. Management: Mefloquine is contraindicated for malaria prophylaxis in persons with a history of convulsions. Monitor anticonvulsant concentrations and treatment response closely with concurrent use. Risk D: Consider therapy modification

Meperidine: CYP3A4 Inducers (Strong) may decrease the serum concentration of Meperidine. Risk C: Monitor therapy

Mesalamine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Risk C: Monitor therapy

Methadone: CarBAMazepine may decrease the serum concentration of Methadone. Risk C: Monitor therapy

Methylfolate: May decrease the serum concentration of CarBAMazepine. Risk C: Monitor therapy

MethylPREDNISolone: CYP3A4 Inducers (Strong) may decrease the serum concentration of MethylPREDNISolone. Management: Consider methylprednisolone dose increases in patients receiving strong CYP3A4 inducers and monitor closely for reduced steroid efficacy. Risk D: Consider therapy modification

Mianserin: May diminish the therapeutic effect of CarBAMazepine. CarBAMazepine may decrease the serum concentration of Mianserin. Risk C: Monitor therapy

Midostaurin: CYP3A4 Inducers (Strong) may decrease the serum concentration of Midostaurin. Risk X: Avoid combination

MiFEPRIStone: CYP3A4 Inducers (Strong) may decrease the serum concentration of MiFEPRIStone. Risk X: Avoid combination

Mirodenafil: CYP3A4 Inducers (Strong) may decrease the serum concentration of Mirodenafil. Management: Consider avoiding the concomitant use of mirodenafil and strong CYP3A4 inducers. If combined, monitor for decreased mirodenafil effects. Mirodenafil dose increases may be required to achieve desired effects. Risk D: Consider therapy modification

Mirtazapine: CYP3A4 Inducers (Strong) may decrease the serum concentration of Mirtazapine. Risk C: Monitor therapy

Mitotane: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Doses of CYP3A4 substrates may need to be adjusted substantially when used in patients being treated with mitotane. Risk D: Consider therapy modification

Monoamine Oxidase Inhibitors: CarBAMazepine may enhance the adverse/toxic effect of Monoamine Oxidase Inhibitors. Management: Avoid concurrent use of carbamazepine during, or within 14 days of discontinuing, treatment with a monoamine oxidase inhibitor. Risk X: Avoid combination

Naldemedine: CYP3A4 Inducers (Strong) may decrease the serum concentration of Naldemedine. Risk X: Avoid combination

Naloxegol: CYP3A4 Inducers (Strong) may decrease the serum concentration of Naloxegol. Risk X: Avoid combination

Nefazodone: May increase the serum concentration of CarBAMazepine. Also, concentrations of the active CarBAMazepine epoxide metabolite may be reduced. CarBAMazepine may decrease the serum concentration of Nefazodone. Concentrations of active Nefazodone metabolites may also be reduced. Risk X: Avoid combination

Neratinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Neratinib. Risk X: Avoid combination

Netupitant: CYP3A4 Inducers (Strong) may decrease the serum concentration of Netupitant. Risk X: Avoid combination

Neuromuscular-Blocking Agents (Nondepolarizing): CarBAMazepine may decrease the serum concentration of Neuromuscular-Blocking Agents (Nondepolarizing). Risk C: Monitor therapy

Nevirapine: CarBAMazepine may decrease the serum concentration of Nevirapine. Risk X: Avoid combination

NIFEdipine: CYP3A4 Inducers (Strong) may decrease the serum concentration of NIFEdipine. Risk X: Avoid combination

Nilotinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Nilotinib. Risk X: Avoid combination

NiMODipine: CYP3A4 Inducers (Strong) may decrease the serum concentration of NiMODipine. Risk X: Avoid combination

Nintedanib: Combined Inducers of CYP3A4 and P-glycoprotein may decrease the serum concentration of Nintedanib. Risk X: Avoid combination

Nisoldipine: CYP3A4 Inducers (Strong) may decrease the serum concentration of Nisoldipine. Risk X: Avoid combination

OLANZapine: CarBAMazepine may decrease the serum concentration of OLANZapine. Risk C: Monitor therapy

Olaparib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Olaparib. Risk X: Avoid combination

Orlistat: May decrease the serum concentration of Anticonvulsants. Risk C: Monitor therapy

Osimertinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Osimertinib. Risk D: Consider therapy modification

OXcarbazepine: CYP3A4 Inducers (Strong) may decrease the serum concentration of OXcarbazepine. Specifically, the concentrations of the 10-monohydroxy active metabolite of oxcarbazepine may be decreased. Risk C: Monitor therapy

Palbociclib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Palbociclib. Risk X: Avoid combination

Paliperidone: CarBAMazepine may decrease the serum concentration of Paliperidone. Risk C: Monitor therapy

Panobinostat: CYP3A4 Inducers (Strong) may decrease the serum concentration of Panobinostat. Risk X: Avoid combination

PAZOPanib: CYP3A4 Inducers (Strong) may decrease the serum concentration of PAZOPanib. Risk X: Avoid combination

Perampanel: CarBAMazepine may decrease the serum concentration of Perampanel. Management: Increase the perampanel starting dose to 4 mg/day when perampanel is used with carbamazepine. Patients receiving this combination should be followed closely for response, especially with any changes to carbamazepine therapy. Risk D: Consider therapy modification

Pexidartinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Pexidartinib. Risk X: Avoid combination

P-glycoprotein/ABCB1 Substrates: P-glycoprotein/ABCB1 Inducers may decrease the serum concentration of P-glycoprotein/ABCB1 Substrates. P-glycoprotein inducers may also further limit the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Exceptions: Betrixaban; Edoxaban. Risk C: Monitor therapy

Phenytoin: CarBAMazepine may decrease the serum concentration of Phenytoin. Phenytoin may decrease the serum concentration of CarBAMazepine. CarBAMazepine may increase the serum concentration of Phenytoin. Possibly by competitive inhibition at sites of metabolism. Risk D: Consider therapy modification

Pimavanserin: CYP3A4 Inducers (Strong) may decrease the serum concentration of Pimavanserin. Risk X: Avoid combination

Piperaquine: CYP3A4 Inducers (Strong) may decrease the serum concentration of Piperaquine. Risk X: Avoid combination

Pitolisant: CYP3A4 Inducers (Strong) may decrease the serum concentration of Pitolisant. Management: For patients who are stable on pitolisant doses of 8.9 mg or 17.8 mg/day and who are also taking a strong CYP3A4 inducer, increase the pitolisant dose over 7 days to double the original dose (ie, to either 17.8 mg/day or 35.6 mg/day, respectively). Risk D: Consider therapy modification

Polatuzumab Vedotin: CYP3A4 Inducers (Strong) may decrease the serum concentration of Polatuzumab Vedotin. Exposure to unconjugated MMAE, the cytotoxic small molecule component of polatuzumab vedotin, may be decreased. Risk C: Monitor therapy

PONATinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of PONATinib. Risk X: Avoid combination

Pravastatin: CarBAMazepine may decrease the serum concentration of Pravastatin. Risk C: Monitor therapy

Praziquantel: CYP3A4 Inducers (Strong) may decrease the serum concentration of Praziquantel. Management: Use of praziquantel with strong CYP3A4 inducers is contraindicated. Discontinue rifampin 4 weeks prior to initiation of praziquantel therapy. Rifampin may be resumed the day following praziquantel completion. Risk X: Avoid combination

PrednisoLONE (Systemic): CYP3A4 Inducers (Strong) may decrease the serum concentration of PrednisoLONE (Systemic). Risk C: Monitor therapy

PredniSONE: CYP3A4 Inducers (Strong) may decrease the serum concentration of PredniSONE. Risk C: Monitor therapy

Pretomanid: CYP3A4 Inducers (Strong) may decrease the serum concentration of Pretomanid. Risk X: Avoid combination

Progestins (Contraceptive): CarBAMazepine may diminish the therapeutic effect of Progestins (Contraceptive). Contraceptive failure is possible. Management: Use of alternative, nonhormonal contraceptives is recommended. Risk D: Consider therapy modification

Promazine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Risk C: Monitor therapy

Propacetamol: CarBAMazepine may increase the metabolism of Propacetamol. This may 1) diminish the desired effects of propacetamol; and 2) increase the risk of liver damage. Risk C: Monitor therapy

Propafenone: CYP3A4 Inducers (Strong) may decrease the serum concentration of Propafenone. Risk C: Monitor therapy

Protease Inhibitors: CarBAMazepine may increase the metabolism of Protease Inhibitors. Protease Inhibitors may decrease the metabolism of CarBAMazepine. Risk D: Consider therapy modification

QUEtiapine: May increase serum concentrations of the active metabolite(s) of CarBAMazepine. CarBAMazepine may decrease the serum concentration of QUEtiapine. Management: Quetiapine dose increases to as much as 5 times the regular dose may be required to maintain therapeutic benefit. Reduce the quetiapine dose back to the previous/regular dose within 7 to 14 days of discontinuing carbamazepine. Risk D: Consider therapy modification

QuiNINE: CarBAMazepine may decrease the serum concentration of QuiNINE. QuiNINE may increase the serum concentration of CarBAMazepine. Risk D: Consider therapy modification

Radotinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Radotinib. Management: Consider alternatives to this combination when possible as the risk of radotinib treatment failure may be increased. Risk D: Consider therapy modification

Ramelteon: CYP3A4 Inducers (Strong) may decrease the serum concentration of Ramelteon. Risk C: Monitor therapy

Ranolazine: CYP3A4 Inducers (Strong) may decrease the serum concentration of Ranolazine. Risk X: Avoid combination

Reboxetine: CYP3A4 Inducers (Strong) may decrease the serum concentration of Reboxetine. Risk C: Monitor therapy

Regorafenib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Regorafenib. Risk X: Avoid combination

Resveratrol: May increase the serum concentration of CarBAMazepine. Risk C: Monitor therapy

Ribociclib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Ribociclib. Risk X: Avoid combination

Rilpivirine: CarBAMazepine may decrease the serum concentration of Rilpivirine. Risk X: Avoid combination

RisperiDONE: CYP3A4 Inducers (Strong) may decrease the serum concentration of RisperiDONE. Management: Consider increasing the dose of oral risperidone (to no more than double the original dose) if a strong CYP3A4 inducer is initiated. For patients on IM risperidone, consider an increased IM dose or supplemental doses of oral risperidone. Risk D: Consider therapy modification

Rivaroxaban: CYP3A4 Inducers (Strong) may decrease the serum concentration of Rivaroxaban. Risk X: Avoid combination

Roflumilast: CYP3A4 Inducers (Strong) may decrease the serum concentration of Roflumilast. Management: Roflumilast U.S. prescribing information recommends against combining strong CYP3A4 inducers with roflumilast. The Canadian product monograph makes no such recommendation but notes that such agents may reduce roflumilast therapeutic effects. Risk X: Avoid combination

Rolapitant: CYP3A4 Inducers (Strong) may decrease the serum concentration of Rolapitant. Management: Avoid rolapitant use in patients requiring chronic administration of strong CYP3A4 inducers. Monitor for reduced rolapitant response and the need for alternative or additional antiemetic therapy even with shorter-term use of such inducers. Risk D: Consider therapy modification

RomiDEPsin: CYP3A4 Inducers (Strong) may decrease the serum concentration of RomiDEPsin. Risk X: Avoid combination

Rosuvastatin: CarBAMazepine may decrease the serum concentration of Rosuvastatin. Risk C: Monitor therapy

Rufinamide: May decrease the serum concentration of CarBAMazepine. CarBAMazepine may decrease the serum concentration of Rufinamide. Risk C: Monitor therapy

Ruxolitinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Ruxolitinib. Risk C: Monitor therapy

Sarilumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Risk C: Monitor therapy

SAXagliptin: CYP3A4 Inducers (Strong) may decrease the serum concentration of SAXagliptin. Risk C: Monitor therapy

Sertraline: CarBAMazepine may decrease the serum concentration of Sertraline. Risk C: Monitor therapy

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Risk C: Monitor therapy

Simeprevir: CYP3A4 Inducers (Strong) may decrease the serum concentration of Simeprevir. Risk X: Avoid combination

Sirolimus: CYP3A4 Inducers (Strong) may decrease the serum concentration of Sirolimus. Management: Avoid concomitant use of strong CYP3A4 inducers and sirolimus if possible. If combined, monitor for reduced serum sirolimus concentrations. Sirolimus dose increases will likely be necessary to prevent subtherapeutic sirolimus levels. Risk D: Consider therapy modification

Sofosbuvir: P-glycoprotein/ABCB1 Inducers may decrease the serum concentration of Sofosbuvir. Risk X: Avoid combination

Sonidegib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Sonidegib. Risk X: Avoid combination

SORAfenib: CYP3A4 Inducers (Strong) may decrease the serum concentration of SORAfenib. Risk X: Avoid combination

Stiripentol: May increase the serum concentration of CarBAMazepine. Risk X: Avoid combination

SUFentanil: CYP3A4 Inducers (Strong) may decrease the serum concentration of SUFentanil. Risk C: Monitor therapy

Sulthiame: CarBAMazepine may decrease the serum concentration of Sulthiame. Risk C: Monitor therapy

SUNItinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of SUNItinib. Management: Avoid when possible. If such a combination cannot be avoided, sunitinib dose increases are recommended, and vary by indication. See full monograph for details. Risk D: Consider therapy modification

Tadalafil: CYP3A4 Inducers (Strong) may decrease the serum concentration of Tadalafil. Management: Erectile dysfunction: monitor for decreased effectiveness - no standard dose adjustments recommended. Avoid use of tadalafil for pulmonary arterial hypertension in patients receiving a strong CYP3A4 inducer. Risk D: Consider therapy modification

Tamoxifen: CYP3A4 Inducers (Strong) may decrease serum concentrations of the active metabolite(s) of Tamoxifen. CYP3A4 Inducers (Strong) may decrease the serum concentration of Tamoxifen. Management: Consider alternatives to concomitant use of strong CYP3A4 inducers and tamoxifen. If the combination cannot be avoided, monitor for reduced therapeutic effects of tamoxifen. Risk D: Consider therapy modification

Tasimelteon: CYP3A4 Inducers (Strong) may decrease the serum concentration of Tasimelteon. Risk X: Avoid combination

Tazemetostat: CYP3A4 Inducers (Strong) may decrease the serum concentration of Tazemetostat. Risk X: Avoid combination

Telithromycin: CYP3A4 Inducers (Strong) may decrease the serum concentration of Telithromycin. Risk X: Avoid combination

Temsirolimus: CarBAMazepine may decrease the serum concentration of Temsirolimus. Concentrations of the active metabolite, sirolimus, are also likely to be decreased (and maybe to an even greater degree). Management: Temsirolimus prescribing information recommends against coadministration with strong CYP3A4 inducers such as carbamazepine; however, if concurrent therapy is necessary, an increase in temsirolimus adult dose to 50 mg/week should be considered. Risk D: Consider therapy modification

Tenofovir Alafenamide: CarBAMazepine may decrease the serum concentration of Tenofovir Alafenamide. Risk X: Avoid combination

Tetrahydrocannabinol: CYP3A4 Inducers (Strong) may decrease the serum concentration of Tetrahydrocannabinol. Risk C: Monitor therapy

Tetrahydrocannabinol and Cannabidiol: CYP3A4 Inducers (Strong) may decrease the serum concentration of Tetrahydrocannabinol and Cannabidiol. Risk C: Monitor therapy

Tezacaftor and Ivacaftor: CYP3A4 Inducers (Strong) may decrease the serum concentration of Tezacaftor and Ivacaftor. Risk X: Avoid combination

Theophylline Derivatives: CarBAMazepine may decrease the serum concentration of Theophylline Derivatives. Theophylline Derivatives may decrease the serum concentration of CarBAMazepine. Management: Seek alternatives to this combination when possible. If these agents are used together, monitor closely for decreased serum concentrations/therapeutic effects of both medications. Exceptions: Dyphylline. Risk D: Consider therapy modification

Thiazide and Thiazide-Like Diuretics: May enhance the adverse/toxic effect of CarBAMazepine. Specifically, there may be an increased risk for hyponatremia. Risk C: Monitor therapy

Thiotepa: CYP3A4 Inducers (Strong) may increase serum concentrations of the active metabolite(s) of Thiotepa. CYP3A4 Inducers (Strong) may decrease the serum concentration of Thiotepa. Management: Thiotepa prescribing information recommends avoiding concomitant use of thiotepa and strong CYP3A4 inducers. If concomitant use is unavoidable, monitor for adverse effects. Risk D: Consider therapy modification

Thiothixene: CarBAMazepine may decrease the serum concentration of Thiothixene. Risk C: Monitor therapy

Thyroid Products: CarBAMazepine may decrease the serum concentration of Thyroid Products. Risk C: Monitor therapy

TiaGABine: CYP3A4 Inducers (Strong) may decrease the serum concentration of TiaGABine. Management: Approximately 2-fold higher tiagabine doses and a more rapid dose titration will likely be required in patients concomitantly taking a strong CYP3A4 inducer. Risk D: Consider therapy modification

Ticagrelor: CYP3A4 Inducers (Strong) may decrease serum concentrations of the active metabolite(s) of Ticagrelor. CYP3A4 Inducers (Strong) may decrease the serum concentration of Ticagrelor. Risk X: Avoid combination

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Risk C: Monitor therapy

Tofacitinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Tofacitinib. Risk X: Avoid combination

Tolvaptan: CYP3A4 Inducers (Strong) may decrease the serum concentration of Tolvaptan. Management: If concurrent use is necessary, increased doses of tolvaptan (with close monitoring for toxicity and clinical response) may be needed. Risk X: Avoid combination

Topiramate: CarBAMazepine may decrease the serum concentration of Topiramate. Risk D: Consider therapy modification

Toremifene: CYP3A4 Inducers (Strong) may decrease the serum concentration of Toremifene. Risk X: Avoid combination

Trabectedin: CYP3A4 Inducers (Strong) may decrease the serum concentration of Trabectedin. Risk X: Avoid combination

TraMADol: May enhance the CNS depressant effect of CarBAMazepine. TraMADol may diminish the therapeutic effect of CarBAMazepine. CarBAMazepine may decrease the serum concentration of TraMADol. Risk X: Avoid combination

Tricyclic Antidepressants: CarBAMazepine may decrease the serum concentration of Tricyclic Antidepressants. Risk C: Monitor therapy

Tropisetron: CYP3A4 Inducers (Strong) may decrease the serum concentration of Tropisetron. Risk C: Monitor therapy

Ubrogepant: CYP3A4 Inducers (Strong) may decrease the serum concentration of Ubrogepant. Risk X: Avoid combination

Udenafil: CYP3A4 Inducers (Strong) may decrease the serum concentration of Udenafil. Risk C: Monitor therapy

Ulipristal: CYP3A4 Inducers (Strong) may decrease the serum concentration of Ulipristal. Risk X: Avoid combination

Upadacitinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Upadacitinib. Risk X: Avoid combination

Valbenazine: CYP3A4 Inducers (Strong) may decrease the serum concentration of Valbenazine. Risk X: Avoid combination

Valproate Products: May increase serum concentrations of the active metabolite(s) of CarBAMazepine. Parent carbamazepine concentrations may be increased, decreased, or unchanged. CarBAMazepine may decrease the serum concentration of Valproate Products. Risk C: Monitor therapy

Vandetanib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Vandetanib. Risk X: Avoid combination

Vecuronium: CarBAMazepine may decrease the serum concentration of Vecuronium. Risk C: Monitor therapy

Velpatasvir: CYP2B6 Inducers (Moderate) may decrease the serum concentration of Velpatasvir. Risk X: Avoid combination

Velpatasvir: CYP3A4 Inducers (Strong) may decrease the serum concentration of Velpatasvir. Risk X: Avoid combination

Velpatasvir: P-glycoprotein/ABCB1 Inducers may decrease the serum concentration of Velpatasvir. Risk X: Avoid combination

Vemurafenib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Vemurafenib. Management: Avoid concurrent use of vemurafenib with a strong CYP3A4 inducer and replace with another agent when possible. If a strong CYP3A4 inducer is indicated and unavoidable, the dose of vemurafenib may be increased by 240 mg (1 tablet) as tolerated. Risk D: Consider therapy modification

Venetoclax: CYP3A4 Inducers (Strong) may decrease the serum concentration of Venetoclax. Risk X: Avoid combination

Vilazodone: CYP3A4 Inducers (Strong) may decrease the serum concentration of Vilazodone. Management: Consider increasing vilazodone dose by as much as 2-fold (do not exceed 80 mg/day), based on response, in patients receiving strong CYP3A4 inducers for > 14 days. Reduce to the original vilazodone dose over 1-2 weeks after inducer discontinuation. Risk D: Consider therapy modification

VinCRIStine (Liposomal): CYP3A4 Inducers (Strong) may decrease the serum concentration of VinCRIStine (Liposomal). Risk X: Avoid combination

VinCRIStine (Liposomal): P-glycoprotein/ABCB1 Inducers may decrease the serum concentration of VinCRIStine (Liposomal). Risk X: Avoid combination

Vinflunine: CYP3A4 Inducers (Strong) may decrease the serum concentration of Vinflunine. Risk X: Avoid combination

Vitamin K Antagonists (eg, warfarin): CarBAMazepine may decrease the serum concentration of Vitamin K Antagonists. Management: Monitor for decreased INR and effects of vitamin K antagonists if carbamazepine is initiated/dose increased, or increased INR and effects if carbamazepine is discontinued/dose decreased. Vitamin K antagonist dose adjustments will likely be required. Risk D: Consider therapy modification

Vorapaxar: CYP3A4 Inducers (Strong) may decrease the serum concentration of Vorapaxar. Risk X: Avoid combination

Voriconazole: CarBAMazepine may decrease the serum concentration of Voriconazole. Risk X: Avoid combination

Vortioxetine: CYP3A4 Inducers (Strong) may decrease the serum concentration of Vortioxetine. Management: Consider increasing the vortioxetine dose to no more than 3 times the original dose when used with a strong drug metabolism inducer for more than 14 days. The vortioxetine dose should be returned to normal within 14 days of stopping the strong inducer. Risk D: Consider therapy modification

Voxelotor: CYP3A4 Inducers (Strong) may decrease the serum concentration of Voxelotor. Management: Avoid concomitant use of voxelotor and strong CYP3A4 inducers. If concomitant use is unavoidable, increase the voxelotor dose to 2,500 mg once daily. Risk D: Consider therapy modification

Voxilaprevir: CYP3A4 Inducers (Strong) may decrease the serum concentration of Voxilaprevir. Risk X: Avoid combination

Zaleplon: CYP3A4 Inducers (Strong) may decrease the serum concentration of Zaleplon. Management: Consider the use of an alternative hypnotic that is not metabolized by CYP3A4 in patients receiving strong CYP3A4 inducers. If zalephon is combined with a strong CYP3A4 inducer, monitor for decreased effectiveness of zaleplon. Risk D: Consider therapy modification

Zanubrutinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Zanubrutinib. Risk X: Avoid combination

Ziprasidone: CarBAMazepine may decrease the serum concentration of Ziprasidone. Risk C: Monitor therapy

Zolpidem: May enhance the CNS depressant effect of CarBAMazepine. CarBAMazepine may decrease the serum concentration of Zolpidem. Management: Monitor zolpidem response closely. Reduce the Intermezzo brand sublingual zolpidem dose to 1.75 mg for men who are also receiving carbamazepine. No such dose change is recommended for women. Risk C: Monitor therapy

Zuclopenthixol: CYP3A4 Inducers (Strong) may decrease the serum concentration of Zuclopenthixol. Risk C: Monitor therapy

Food Interactions

Carbamazepine serum levels may be increased if taken with food and/or grapefruit juice. Management: Monitor for increased toxic effects with concurrent ingestion of grapefruit juice. Maintain adequate hydration, unless instructed to restrict fluid intake.

Test Interactions

May cause false-positive serum TCA screen; may interact with some pregnancy tests

Gene Testing Required

• HLA-B - Carbamazepine

Gene Testing May Be Considered

• HLA-A - Carbamazepine

Genes of Interest

• Cytochrome P450 3A4
• Heat Shock Protein Family A (Hsp70) Member 1 Like
• RalA Binding Protein 1

Monitoring Parameters

Baseline and periodic: CBC with platelet count and differential, reticulocytes, serum iron, liver and renal function tests, urinalysis, BUN, serum sodium, ophthalmic exam including intraocular pressure.

As appropriate: Lipid panel, serum carbamazepine levels, thyroid function tests; pregnancy test; observe patient for excessive sedation, especially when instituting or increasing therapy; signs of rash; HLA-B*1502 and HLA-A*3101 genotype screening prior to therapy initiation in patients with ancestry in genetically at-risk populations; suicidality (eg, suicidal thoughts, depression, behavioral changes)

Reference Range

Timing of serum samples: Oral absorption is slow, peak levels occur 8 to 65 hours after ingestion of the first dose; the half-life ranges from 8 to 60 hours, therefore, steady-state is achieved in 2 to 5 days. Serum levels are particularly important during the first few weeks of therapy when autoinduction is occurring (Stoner 2007).

Timing of serum samples: Draw trough just before next dose (APA [Hirschfeld 2002])

Epilepsy: Therapeutic levels: 4 to 12 mcg/mL (SI: 17 to 51 micromole/L). The same goal range is applied for bipolar disorder, despite limited data on monitoring serum concentrations in this population (APA [Hirschfeld 2002]).

Toxic concentration: >15 mcg/mL; patients who require higher levels of 8 to 12 mcg/mL (SI: 34 to 51 micromole/L) should be watched closely. Side effects including CNS effects occur commonly at higher dosage levels. If other anticonvulsants are given therapeutic range is 4 to 8 mcg/mL.

Advanced Practitioners Physical Assessment/Monitoring

Obtain CBC with differential and platelet count, reticulocytes, serum iron, liver function tests, renal function tests, and urinalysis as baseline and periodically during therapy. Obtain an ophthalmic exam including intraocular pressure. Obtain lipid panel, serum carbamazepine levels, thyroid function tests, and serum sodium as clinically indicated. Test for HLA-B*1502 prior to initiating treatment with carbamazepine in patients of Asian descent with an increased likelihood of carrying this allele due to risk of serious dermatologic reactions. Assess other medicines patient may be taking; alternate therapy or dosage adjustments may be needed. Assess patient for excessive sedation, rash, and suicidal ideation. Assess for effectiveness of treatment.

Nursing Physical Assessment/Monitoring

Check ordered labs and report abnormalities. Observe and teach seizure/safety precautions. Monitor for and educate patient to report rash, mental and CNS changes, excessive sedation (especially when initiating or increasing therapy), suicidal ideation, and mood changes.

Dosage Forms: US

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Capsule Extended Release 12 Hour, Oral:

Carbatrol: 100 mg [contains fd&c blue #2 (indigotine)]

Carbatrol: 200 mg, 300 mg

Equetro: 100 mg, 200 mg, 300 mg [contains fd&c blue #2 (indigotine)]

Generic: 100 mg, 200 mg, 300 mg

Suspension, Oral:

TEGretol: 100 mg/5 mL (450 mL) [contains fd&c yellow #6 (sunset yellow), propylene glycol; citrus-vanilla flavor]

Generic: 100 mg/5 mL (450 mL)

Tablet, Oral:

Epitol: 200 mg [scored]

TEGretol: 200 mg [scored; contains fd&c red #40]

Generic: 200 mg

Tablet Chewable, Oral:

Generic: 100 mg

Tablet Extended Release 12 Hour, Oral:

TEGretol-XR: 100 mg, 200 mg, 400 mg

Generic: 100 mg, 200 mg, 400 mg

Dosage Forms: Canada

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Suspension, Oral:

TEGretol: 100 mg/5 mL (450 mL) [contains fd&c yellow #6 (sunset yellow), propylene glycol]

Generic: 100 mg/5 mL (450 mL)

Tablet, Oral:

TEGretol: 200 mg

Generic: 200 mg

Tablet Chewable, Oral:

TEGretol: 100 mg [DSC], 200 mg [DSC] [contains corn starch]

Generic: 100 mg, 200 mg

Tablet Extended Release 12 Hour, Oral:

TEGretol CR: 200 mg, 400 mg

Generic: 200 mg, 400 mg

Anatomic Therapeutic Chemical (ATC) Classification

• N03AF01

Generic Available (US)

Yes

Pricing: US

Capsule, 12-hour (carBAMazepine ER Oral)

100 mg (per each): $1.91 - $1.96

200 mg (per each): $1.91 - $1.96

300 mg (per each): $1.91 - $1.96

Capsule, 12-hour (Carbatrol Oral)

100 mg (per each): $2.13

200 mg (per each): $2.13

300 mg (per each): $2.13

Capsule, 12-hour (Equetro Oral)

100 mg (per each): $4.63

200 mg (per each): $5.23

300 mg (per each): $5.87

Chewable (carBAMazepine Oral)

100 mg (per each): $0.64 - $0.69

Suspension (carBAMazepine Oral)

100 mg/5 mL (per mL): $0.17 - $0.20

Suspension (TEGretol Oral)

100 mg/5 mL (per mL): $0.44

Tablet, 12-hour (carBAMazepine ER Oral)

100 mg (per each): $1.14

200 mg (per each): $2.08

400 mg (per each): $4.15

Tablet, 12-hour (TEGretol-XR Oral)

100 mg (per each): $1.63

200 mg (per each): $3.25

400 mg (per each): $6.49

Tablets (carBAMazepine Oral)

200 mg (per each): $1.12 - $1.68

Tablets (Epitol Oral)

200 mg (per each): $1.60

Tablets (TEGretol Oral)

200 mg (per each): $3.04

Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.

Mechanism of Action

In addition to anticonvulsant effects, carbamazepine has anticholinergic, antineuralgic, antidiuretic, muscle relaxant, antimanic, antidepressive, and antiarrhythmic properties; may depress activity in the nucleus ventralis of the thalamus or decrease synaptic transmission or decrease summation of temporal stimulation leading to neural discharge by limiting influx of sodium ions across cell membrane or other unknown mechanisms; stimulates the release of ADH and potentiates its action in promoting reabsorption of water; chemically related to tricyclic antidepressants

Pharmacodynamics/Kinetics

Absorption: Slowly from the GI tract

Distribution: V_d: Neonates: 1.52 ± 0.5 L/kg (Rey 1979); Children: 1.94 ± 0.8 L/kg (Rey 1979); Adults: 0.59 to 2 L/kg

Protein binding: Carbamazepine: 75% to 90%, bound to alpha₁-acid glycoprotein and nonspecific binding sites on albumin; may be decreased in newborns; Epoxide metabolite: 50%

Metabolism: Induces liver enzymes to increase metabolism and shorten half-life over time; metabolized in the liver by cytochrome P450 3A4 to active epoxide metabolite; epoxide metabolite is metabolized by epoxide hydrolase to the trans-diol metabolite; ratio of serum epoxide to carbamazepine concentrations may be higher in patients receiving polytherapy (vs monotherapy) and in infants (vs older children); boys may have faster carbamazepine clearances and may, therefore, require higher mg/kg/day doses of carbamazepine compared to girls of similar age and weight

Bioavailability: 75% to 85%; relative bioavailability of ER tablet to suspension: 89%

Half-life elimination: Note: Half-life is variable because of autoinduction which is usually complete 3 to 5 weeks after initiation of a fixed carbamazepine regimen.

Carbamazepine: Initial: 25 to 65 hours; Extended release: 35 to 40 hours; Multiple doses: Children and Adolescents: Mean range: 3.1 to 20.8 hours (Battino 1995); Adults: 12 to 17 hours

Epoxide metabolite: Initial: 34 ± 9 hours

Time to peak, serum: Unpredictable:

Immediate release: Multiple doses: Suspension: 1.5 hour; tablet: 4 to 5 hours

Extended release: Carbatrol, Equetro: 12 to 26 hours (single dose), 4 to 8 hours (multiple doses); Tegretol-XR: 3 to 12 hours

Excretion: Urine 72% (1% to 3% as unchanged drug); feces (28%)

Dental Use

Pain relief of trigeminal or glossopharyngeal neuralgia

* See Uses in AHFS Essentials for additional information.

Local Anesthetic/Vasoconstrictor Precautions

No information available to require special precautions

Effects on Dental Treatment

Key adverse event(s) related to dental treatment: Xerostomia (normal salivary flow resumes upon discontinuation). Rare occurrence of taste alteration, lip edema, laryngeal edema; glossitis and stomatitis has been reported but frequency not defined. Both hypertension and hypotension has been reported. Blood pressure monitoring is essential prior to dental treatment. Hypotension could predispose the patient to orthostatic hypotension.

Effects on Bleeding

A spectrum of hematologic effects has been reported including agranulocytosis, aplastic anemia, neutropenia and thrombocytopenia (see Warning/Precautions); detection of hematologic change to include symptoms of fever, sore throat, mouth ulcers and easy bruising would necessitate a medical consult prior to dental treatment.

Dental Usual Dosing

Trigeminal or glossopharyngeal neuralgia: Oral:

Adults: Initial: 200 mg/day in 2 divided doses (tablets, extended release tablets, or extended release capsules) or 4 divided doses (oral suspension) with food, gradually increasing in increments of 200 mg/day as needed

Maintenance: Usual: 400-800 mg daily in 2 divided doses (tablets, extended release tablets, or extended release capsules) or 4 divided doses (oral suspension); maximum dose: 1200 mg/day

Related Information

• Adverse Effects of Anticonvulsants
• Agents Approved for Bipolar Disorder
• Beers Criteria 2019: Potentially Inappropriate Medication Use in Older Adults ≥65 Years of Age
• Drugs With Actionable Pharmacogenomic Recommendations
• Narrow Therapeutic Index Drugs
• Oral Medications That Should Not Be Crushed or Altered
• Safe Handling of Hazardous Drugs

Index Terms

CBZ; SPD417

FDA Approval Date

March 11, 1968

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Brand Names: International

Actinerval (AR, PY); Anleptic 200 CR (LK); Apo-Carbamazepine (MY); Arbateg (EG); Arbil (GB); Azepal (HU); Bamgetol (ID); Brucarcer (MX); Calzepin (VN); Camapine (TW); Carazepin (AE, CY, IQ, IR, JO, KW, LY, OM, SA, SY, YE); Carbadac (BF, BJ, CI, ET, GH, GM, GN, KE, LR, MA, ML, MR, MU, MW, NE, NG, SC, SD, SL, SN, TN, TZ, UG, ZM, ZW); Carbagen (GB); Carbalex (EE, LV, UA); Carbam (EC); Carbamazepin-B (HU); Carbapex (EG); Carbapin (PE, UA); Carbastal (PH); Carbatec (SY); Carbatol (AE, BH, ET, IN, JO, TW); Carbatol CR (LK, SG); Carbazene (TH); Carbazina (MX); Carbilepp (PH); Carmapine (TH); Carmaz (BD, IN); Carmian (CL); Carmine (KR); Carpin (MX); Carzepin (HK, MY); Ceplep (BD); Convulax (AE, KW); Degranol (ZA); Elpenor (DE); Epazin (PH); Epicarb (ZW); Epilep (BD); Epilep CR (BD); Epileptol (KR); Epileptol CR (KR); Eposal Retard (CO); Espa-lepsin (DE); Finlepsin (BG, HU, LV, RO, UA); Fitzecalm (BH, QA); Hermolepsin (SE); Karbamazepin (DK); Lepsitol (ID); Mezacar SR (PH); Neugeron (MX); Neurolep (MX); Neurotol (FI); Neurotop (AT, BG, HU, LB); Sepibest (MX); Sirtal (DE); Stazepine (HU); Storilat (MT); Taver (MY, TR, VN); Tegol (TW); Tegral (PK); Tegrepin (PH); Tegretal (CL, DE); Tegretol (AE, AR, AU, BB, BD, BE, BF, BH, BJ, BM, BR, BS, BZ, CH, CI, CN, CO, CR, CY, CZ, DK, DO, EC, EE, EG, ES, ET, FI, FR, GB, GH, GM, GN, GR, GT, GY, HK, HN, HR, HU, ID, IE, IL, IQ, IR, IS, IT, JM, JO, JP, KE, KR, KW, LB, LK, LR, LT, LU, LY, MA, ML, MR, MT, MU, MW, MX, MY, NE, NG, NI, NL, NO, NZ, OM, PA, PE, PH, PK, PL, PT, PY, QA, RO, RU, SA, SC, SD, SE, SG, SI, SL, SN, SR, SV, SY, TH, TN, TR, TT, TW, TZ, UA, UG, UY, VE, YE, ZM, ZW); Tegretol CR (BE, CZ, EE, EG, HR, HU, IL, KR, LB, LU, LV, MT, NL, NZ, PE, QA, RO, SA, SG, SI, SK, TR, ZW); Tegretol Retard (FI); Tegretol-XR (BB); TegretolCR (BD); Temporol (HU, ZA); Teril (AU, IL, NZ); Teril-CR (IL); Timonil (DE, HU); Timonil Retard (CH, DE, IL); Timonol SR (KR); Torbarec (ZW); Trepina (MX); Trimonil Retard (NO); Vulsivan (CO); Zeptol CR (LK); Zigma CR (LK)

Last Updated 3/10/20