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CarBAMazepine

Pronunciation

Pronunciation

(kar ba MAZ e peen)

Index Terms

  • CBZ
  • SPD417

Dosage Forms

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

Brand Names: U.S.

  • Carbatrol
  • Epitol
  • Equetro
  • TEGretol
  • TEGretol-XR

Pharmacologic Category

  • Anticonvulsant, Miscellaneous

Pharmacology

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

Absorption

Slowly from the GI tract

Distribution

Vd: Neonates: 1.5 L/kg; Children: 1.9 L/kg; Adults: 0.59 to 2 L/kg; carbamazepine and its active epoxide metabolite distribute into breast milk

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

Excretion

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

Time to Peak

Unpredictable:

Immediate release: Suspension: Multiple doses: 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

Half-Life Elimination

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: 8 to 14 hours; Adults: 12 to 17 hours

Epoxide metabolite: Initial: 34 ± 9 hours

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%

Special Populations: Hepatic Function Impairment

Patients with hepatic impairment may experience elevated concentrations when switching from oral to IV carbamazepine administration (in comparison to patients with normal hepatic function).

Use: Labeled Indications

Bipolar 1 disorder (Equetro only): Treatment of acute manic or mixed episodes associated with bipolar 1 disorder

Epilepsy: Treatment of partial seizures with complex symptomatology (psychomotor, temporal lobe), generalized tonic-clonic seizures (grand mal), or mixed seizure patterns

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

Trigeminal or glossopharyngeal neuralgia (oral only): Treatment of pain associated with trigeminal or glossopharyngeal neuralgia

Off Label Uses

Neuropsychiatric symptoms of dementia

Data from older, small, short-term, controlled trials and a meta-analysis suggest carbamazepine may benefit those experiencing neuropsychiatric symptoms of dementia (also referred to as behavioral and psychological symptoms of dementia [BPSD]), specifically those patients with agitation, aggression or hostility symptoms [Ballard 2009], [Cooney 1996], [Olin 2001], [Tariot 1998]. Additional data may be necessary to further define the role of carbamazepine in the treatment of this condition.

Restless legs syndrome

Data from older controlled trials suggest carbamazepine may be beneficial for the treatment of restless legs syndrome (RLS). Additional data are necessary to further define the role of carbamazepine in this condition. Based on American Academy of Sleep Medicine guidelines, carbamazepine may be used to treat RLS, although the level of evidence is low and benefits are closely balanced with potential adverse effects.

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 or boceprevir; concomitant use of 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

Dosing: Adult

Dosage must be adjusted according to patient's response and serum concentrations. When converting from an immediate-release formulation to an extended-release formulation, the same total daily mg dose of carbamazepine should be administered, divided into twice daily dosing. Avoid abrupt withdrawal.

Epilepsy:

IV:

Note: IV carbamazepine is a replacement therapy for oral carbamazepine; therapy should generally be initiated with oral formulation. Convert back to oral therapy at previous total daily oral dose as soon as clinically appropriate. Use longer than 7 days is not recommended.

Total daily IV dose should be equivalent to 70% of previous total daily oral dose; divide total daily IV dose into 4 infusions (every 6 hours) over 30 minutes.

Oral:

Initial: 400 mg/day in 2 divided doses or 4 divided doses (oral suspension only); increase by up to 200 mg/day at weekly intervals using a twice daily regimen of extended-release capsule or tablet, or a 3 to 4 times/day regimen of other formulations until optimal response and therapeutic levels are achieved; usual dose: 800 to 1,200 mg/day.

Maximum recommended dose: 1,600 mg/day.

Trigeminal or glossopharyngeal neuralgia: Oral: Initial: 200 mg/day in a single dose (extended-release capsule), 2 divided doses (tablet forms) or 4 divided doses (oral suspension), gradually increasing in increments of 200 mg/day as needed. Administer extended-release capsule in 2 divided doses if total daily dose exceeds 200 mg.

Maintenance: Usual: 400 to 800 mg daily in 2 divided doses or 4 divided doses (oral suspension only); maximum dose: 1,200 mg/day.

Bipolar disorder: Equetro: Oral: Initial: 400 mg/day in 2 divided doses; may adjust by 200 mg/day increments; maximum dose: 1,600 mg/day.

Neuropathic pain, critically ill patients (off-label use): Oral: Initial: 50 to 100 mg twice daily in combination with IV opioids; Maintenance: 100 to 200 mg every 4 to 6 hours; maximum dose: 1,200 mg daily (Barr 2013).

Neuropsychiatric symptoms of dementia (off-label use): Oral: Initial: 100 mg once or twice daily; dose increased by 50 to 100 mg every 2 to 7 days to a maximum of 400 to 600 mg daily in 2 to 4 divided doses; treatment durations ranged from 6 to 8 weeks (Cooney 1996; Olin 2001; Tariot 1998). The modal dose reported in one trial was 300 mg/day with a mean serum carbamazepine level of 5.3 mcg/mL (Tariot 1998). Additional data may be necessary to further define the role of carbamazepine in the treatment of this condition.

Restless legs syndrome (off-label use): Oral: 100 to 600 mg daily for up to 5 weeks have been studied (Lundvall 1983; Telstad 1984). Doses of 100 to 300 mg at bedtime have been shown to reduce RLS attacks (Telstad 1984). Additional data is necessary to further define the role of carbamazepine in the treatment of this condition.

Dosing: Geriatric

Use with caution due to the potential for SIADH or hyponatremia (Beers Criteria [AGS 2015]). Refer to adult dosing.

Dosing: Pediatric

Dosage must be adjusted according to patient's response and serum concentrations. Children <12 years who receive ≥400 mg/day of carbamazepine may be converted to extended-release capsules (Carbatrol) using the same total daily dosage divided twice daily. Avoid abrupt withdrawal.

Epilepsy: Oral:

Children <6 years: Initial: 10 to 20 mg/kg/day in 2 or 3 divided doses (tablet forms) or 4 divided doses (oral suspension only); increase dose every week until optimal response and therapeutic levels are achieved; maximum recommended dose: 35 mg/kg/day.

Children 6 to 12 years: Initial: 200 mg/day in 2 divided doses (tablet forms) or 4 divided doses (oral suspension only); increase by up to 100 mg/day at weekly intervals using a twice daily regimen of extended-release tablets or 3 to 4 times daily regimen of other formulations until optimal response and therapeutic levels are achieved.

Maintenance: Usual: 400 to 800 mg/day; maximum recommended dose: 1,000 mg/day (all tablet forms and oral suspension) or 35 mg/kg/day (capsule forms).

Children >12 years: Refer to adult dosing.

Maximum recommended doses:

Children 12 to 15 years: 1,000 mg/day.

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

Dosing: Renal Impairment

IV: Adults:

CrCl ≥60 mL/minute: No dosage adjustment necessary; monitor closely.

CrCl 15 to 59 mL/minute: Avoid use.

CrCl <15 mL/minute: No dosage adjustment provided in manufacturer’s labeling (has not been studied).

Oral: There are no dosage adjustments provided in the manufacturer’s labeling; however, the following recommendations have been used by some clinicians:

Children and Adults:

GFR <10 mL/minute: Administer 75% of dose (Aronoff 2007)

Hemodialysis, peritoneal dialysis: Administer 75% of dose (postdialysis) (Aronoff 2007)

Continuous renal replacement therapy (CRRT):

Adults: No dosage adjustment recommended (Aronoff 2007)

Children: Administer 75% of dose (Aronoff 2007)

Dosing: Hepatic Impairment

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.

Reconstitution

Injection, solution: Dilute the single dose in 100 mL of NS, LR, or D5W. Mix gently.

Extemporaneously Prepared

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

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.

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.

IV: For IV use only. Administer IV over 30 minutes.

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).

Storage

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.

Carnexiv: Store intact vials at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). The prepared solution may be stored at 20°C to 25°C (68°F to 77°F) for up to 4 hours, or up to 24 hours at 2°C to 8°C (36°F to 46°F). Discard any unused product.

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.

Drug Interactions

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. Avoid combination

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

Afatinib: CarBAMazepine may decrease the serum concentration of Afatinib. Management: Per US labeling: if requiring chronic use of carbamazepine, increase afatinib dose by 10 mg as tolerated; reduce to original afatinib dose 2-3 days after stopping carbamazepine. Per Canadian labeling: avoid combination if possible. Consider therapy modification

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

Alcohol (Ethyl): CNS Depressants may enhance the CNS depressant effect of Alcohol (Ethyl). Monitor therapy

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

Analgesics (Opioid): CNS Depressants may enhance the CNS depressant effect of Analgesics (Opioid). Management: Avoid concomitant use of opioid analgesics and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Consider therapy modification

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

Apixaban: CYP3A4 Inducers (Strong) may decrease the serum concentration of Apixaban. Avoid combination

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

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

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

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

Azelastine (Nasal): CNS Depressants may enhance the CNS depressant effect of Azelastine (Nasal). 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. Monitor therapy

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

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

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

Blonanserin: CNS Depressants may enhance the CNS depressant effect of Blonanserin. Consider therapy modification

Boceprevir: CarBAMazepine may decrease the serum concentration of Boceprevir. Avoid combination

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

Bosentan: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

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

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

Brimonidine (Topical): May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

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

Buprenorphine: CNS Depressants may enhance the CNS depressant effect of Buprenorphine. Management: Consider reduced doses of other CNS depressants, and avoiding such drugs in patients at high risk of buprenorphine overuse/self-injection. Initiate buprenorphine patches (Butrans brand) at 5 mcg/hr in adults when used with other CNS depressants. 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. Consider therapy modification

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

Canagliflozin: CarBAMazepine may decrease the serum concentration of Canagliflozin. Management: Consider increasing canagliflozin dose to 300 mg/day in patients with estimated GFR >60 mL/min/1.73 m2 who tolerate canagliflozin 100 mg/day and require greater glycemic control. Consider alternatives in patients with estimated GFR 45-60 mL/min/1.73 m2. Consider therapy modification

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

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

Cannabis: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

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

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

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

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

Chlorphenesin Carbamate: May enhance the adverse/toxic effect of CNS Depressants. Monitor therapy

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

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

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

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. 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. Monitor therapy

ClomiPRAMINE: CarBAMazepine may increase the serum concentration of ClomiPRAMINE. 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. Avoid combination

CNS Depressants: May enhance the adverse/toxic effect of other CNS Depressants. Monitor therapy

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

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

Conivaptan: May increase the serum concentration of CYP3A4 Substrates. Avoid combination

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

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

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

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

CycloSPORINE (Systemic): CarBAMazepine may decrease the serum concentration of CycloSPORINE (Systemic). Consider therapy modification

CYP2B6 Substrates: CYP2B6 Inducers (Moderate) may decrease the serum concentration of CYP2B6 Substrates. Monitor therapy

CYP2C8 Substrates: CYP2C8 Inducers (Strong) may increase the metabolism of CYP2C8 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

CYP2C9 Substrates: CYP2C9 Inducers (Strong) may increase the metabolism of CYP2C9 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

CYP3A4 Inhibitors (Moderate): May decrease the metabolism of CYP3A4 Substrates. Monitor therapy

CYP3A4 Inhibitors (Strong): May decrease the metabolism of CYP3A4 Substrates. Consider therapy modification

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

Dabigatran Etexilate: CarBAMazepine may decrease the serum concentration of Dabigatran Etexilate. Monitor therapy

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates. 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). Consider therapy modification

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

Danazol: May decrease the metabolism of CarBAMazepine. Monitor therapy

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

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

Dasabuvir: CYP2C8 Inducers (Strong) may decrease the serum concentration of Dasabuvir. 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. Consider therapy modification

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Avoid combination

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

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

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

Desmopressin: CarBAMazepine may enhance the adverse/toxic effect of Desmopressin. 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 steroid efficacy. Consider therapy modification

Diclofenac (Systemic): CYP2C9 Inducers (Strong) may decrease the serum concentration of Diclofenac (Systemic). Monitor therapy

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. Avoid combination

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

Dimethindene (Topical): May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Dipyrone: May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased 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. Consider therapy modification

Doxercalciferol: CYP3A4 Inducers (Strong) may increase serum concentrations of the active metabolite(s) of Doxercalciferol. 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. Consider therapy modification

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

Doxylamine: May enhance the CNS depressant effect of CNS Depressants. Management: The manufacturer of Diclegis (doxylamine/pyridoxine), intended for use in pregnancy, specifically states that use with other CNS depressants is not recommended. Monitor therapy

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

Dronabinol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

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

Droperidol: May enhance the CNS depressant effect of CNS Depressants. Management: Consider dose reductions of droperidol or of other CNS agents (e.g., opioids, barbiturates) with concomitant use. Consider therapy modification

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

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

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

Enzalutamide: CYP2C8 Inducers (Strong) may decrease the serum concentration of Enzalutamide. 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. 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. 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. Consider therapy modification

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

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

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

Etizolam: CYP3A4 Inducers (Strong) may decrease the serum concentration of Etizolam. 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 these combinations cannot be avoided, monitor patients closely for diminished etoposide response. 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. Consider therapy modification

Etravirine: CarBAMazepine may decrease the serum concentration of Etravirine. Avoid combination

Everolimus: CYP3A4 Inducers (Strong) may decrease the serum concentration of Everolimus. Management: Avoid concurrent use of strong CYP3A4 inducers, but if strong CYP3A4 inducers cannot be avoided, consider gradually (in 5 mg increments) increasing the everolimus dose from 10 mg/day to 20 mg/day (adult doses). Avoid combination

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

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. Consider therapy modification

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

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

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

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

Flunitrazepam: CNS Depressants may enhance the CNS depressant effect of Flunitrazepam. Consider therapy modification

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

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

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. Consider therapy modification

Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates. 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. 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. Avoid combination

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

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

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

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

GuanFACINE: CYP3A4 Inducers (Strong) may decrease the serum concentration of GuanFACINE. Management: Increase the guanfacine dose by up to double when initiating concomitant therapy with strong CYP3A4 inducers. Increase guanfacine dose gradually over 1-2 weeks if strong CYP3A4 inducer therapy is just beginning. Consider therapy modification

Haloperidol: CarBAMazepine may increase the metabolism of Haloperidol. Consider therapy modification

HYDROcodone: CNS Depressants may enhance the CNS depressant effect of HYDROcodone. Management: Avoid concomitant use of hydrocodone and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Consider therapy modification

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

HydrOXYzine: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

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

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

Idelalisib: May increase the serum concentration of CYP3A4 Substrates. 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. 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. 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. 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. Avoid combination

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

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

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

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

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

Kava Kava: May enhance the adverse/toxic effect of CNS Depressants. Monitor therapy

Lacosamide: CarBAMazepine may enhance the AV-blocking effect of Lacosamide. CarBAMazepine may decrease the serum concentration of Lacosamide. Monitor therapy

LamoTRIgine: May enhance the adverse/toxic effect of CarBAMazepine. CarBAMazepine may increase the metabolism of LamoTRIgine. 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. Avoid combination

Ledipasvir: CarBAMazepine may decrease the serum concentration of Ledipasvir. Avoid combination

LevETIRAcetam: May enhance the adverse/toxic effect of CarBAMazepine. CarBAMazepine may decrease the serum concentration of LevETIRAcetam. 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. Consider therapy modification

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

Lofexidine: May enhance the CNS depressant effect of CNS Depressants. 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. Consider therapy modification

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

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

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

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

Magnesium Sulfate: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

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. Consider therapy modification

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

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. Consider therapy modification

Mebendazole: CarBAMazepine may decrease the serum concentration of Mebendazole. 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. Consider therapy modification

Methadone: CarBAMazepine may increase the metabolism of Methadone. Consider therapy modification

Methotrimeprazine: May enhance the CNS depressant effect of CNS Depressants. CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Management: Reduce adult dose of CNS depressant agents by 50% with initiation of concomitant methotrimeprazine therapy. Further CNS depressant dosage adjustments should be initiated only after clinically effective methotrimeprazine dose is established. Consider therapy modification

Methylfolate: May decrease the serum concentration of CarBAMazepine. 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. Consider therapy modification

MetyroSINE: CNS Depressants may enhance the sedative effect of MetyroSINE. Monitor therapy

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

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

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

Minocycline: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

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. Consider therapy modification

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

Nabilone: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

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

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

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

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

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

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

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

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

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

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

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

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

Ombitasvir, Paritaprevir, Ritonavir, and Dasabuvir: CYP2C8 Inducers (Strong) may decrease the serum concentration of Ombitasvir, Paritaprevir, Ritonavir, and Dasabuvir. Specifically, the serum concentrations of dasabuvir may decrease significantly. Avoid combination

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

Orphenadrine: CNS Depressants may enhance the CNS depressant effect of Orphenadrine. Avoid combination

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

OXcarbazepine: CarBAMazepine may decrease serum concentrations of the active metabolite(s) of OXcarbazepine. Specifically, concentrations of the major active 10-monohydroxy metabolite may be reduced. Management: Consider increasing the initial adult oxcarbazepine extended release tablet (Oxtellar XR) dose to 900 mg/day. No specific recommendations are available for other oxcarbazepine formulations. Consider therapy modification

Oxomemazine: May enhance the CNS depressant effect of CNS Depressants. Avoid combination

OxyCODONE: CNS Depressants may enhance the CNS depressant effect of OxyCODONE. Management: Avoid concomitant use of oxycodone and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Consider therapy modification

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

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

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

Paraldehyde: CNS Depressants may enhance the CNS depressant effect of Paraldehyde. Avoid combination

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

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. Consider therapy modification

Pimavanserin: CYP3A4 Inducers (Strong) may decrease the serum concentration of Pimavanserin. Monitor therapy

Piribedil: CNS Depressants may enhance the CNS depressant effect of Piribedil. Monitor therapy

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

Pramipexole: CNS Depressants may enhance the sedative effect of Pramipexole. Monitor therapy

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

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

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

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

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

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

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

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

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

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

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

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

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

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

RisperiDONE: CarBAMazepine may decrease the serum concentration of RisperiDONE. Management: Consider increasing the dose of risperidone (to no more than double the original dose) if carbamazepine is initiated/dose increased. Monitor for reduced therapeutic effects of risperidone. Consider therapy modification

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

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

ROPINIRole: CNS Depressants may enhance the sedative effect of ROPINIRole. Monitor therapy

Rotigotine: CNS Depressants may enhance the sedative effect of Rotigotine. Monitor therapy

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

Sarilumab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

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

Selective Serotonin Reuptake Inhibitors: CNS Depressants may enhance the adverse/toxic effect of Selective Serotonin Reuptake Inhibitors. Specifically, the risk of psychomotor impairment may be enhanced. Monitor therapy

Selexipag: CYP2C8 Inducers (Strong) may decrease serum concentrations of the active metabolite(s) of Selexipag. Monitor therapy

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

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

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

Sodium Oxybate: May enhance the CNS depressant effect of CNS Depressants. Management: Consider alternatives to combined use. When combined use is needed, consider minimizing doses of one or more drugs. Use of sodium oxybate with alcohol or sedative hypnotics is contraindicated. Consider therapy modification

Sofosbuvir: CarBAMazepine may decrease the serum concentration of Sofosbuvir. Avoid combination

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

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

St John's Wort: May decrease the serum concentration of CYP3A4 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

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

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

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

Suvorexant: CYP3A4 Inducers (Strong) may decrease the serum concentration of Suvorexant. Avoid combination

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. Consider therapy modification

Tapentadol: May enhance the CNS depressant effect of CNS Depressants. Management: Avoid concomitant use of tapentadol and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Consider therapy modification

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

Telaprevir: May increase the serum concentration of CarBAMazepine. CarBAMazepine may decrease the serum concentration of Telaprevir. 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. Consider therapy modification

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

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

Tetrahydrocannabinol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Thalidomide: CNS Depressants may enhance the CNS depressant effect of Thalidomide. 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. 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. Monitor therapy

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

Thyroid Products: CarBAMazepine may decrease the serum concentration of Thyroid Products. 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. 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. Avoid combination

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

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

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

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

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

Treprostinil: CYP2C8 Inducers (Strong) may decrease the serum concentration of Treprostinil. Monitor therapy

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

Trimeprazine: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

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

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

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

Valbenazine: CYP3A4 Inducers (Strong) may decrease the serum concentration of Valbenazine. 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. Monitor therapy

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

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

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

Velpatasvir: CYP2C8 Inducers (Strong) may decrease the serum concentration of Velpatasvir. Avoid combination

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

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

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

Vinflunine: CYP3A4 Inducers (Strong) may decrease the serum concentration of Vinflunine. 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. Warfarin dose adjustments will likely be required. Consider therapy modification

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

Voriconazole: CarBAMazepine may decrease the serum concentration of Voriconazole. 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. Consider therapy modification

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

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

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

Test Interactions

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

Adverse Reactions

>10%:

Central nervous system: Dizziness (oral: 44%; intravenous: 9%), drowsiness (oral: 32%; intravenous: 5%), ataxia (15%)

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

1% to 10%:

Cardiovascular: Hypertension (oral: 3%), atrial tachycardia (intravenous: <2%), inversion T wave on ECG (intravenous: <2%)

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

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

Endocrine & metabolic: Hyponatremia (intravenous: <2%)

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

Hematologic & oncologic: Anemia (intravenous: 7%)

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

Ophthalmic: Blurred vision (5% to 6%), diplopia (intravenous: 5%; oral: <1%)

Frequency not defined:

Cardiovascular: Atrioventricular block, cardiac arrhythmia, cardiac failure, coronary artery disease (aggravation), edema, hypotension, syncope, thromboembolism, thrombophlebitis

Central nervous system: Agitation, amnesia, chills, depression, fatigue, hallucination, headache, hyperacusis, neuroleptic malignant syndrome (NMS), peripheral neuritis, talkativeness

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

Endocrine & metabolic: Albuminuria, glycosuria, porphyria, SIADH

Gastrointestinal: Glossitis, pancreatitis, stomatitis

Genitourinary: Azotemia, impotence, microscopic urine deposits, oliguria, urinary frequency, urinary retention

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

Hepatic: Abnormal hepatic function tests, hepatitis, jaundice

Hypersensitivity: Hypersensitivity reaction, multi-organ hypersensitivity

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

Ophthalmic: Cataract, conjunctivitis, increased intraocular pressure

Renal: Increased blood urea nitrogen, renal failure

Respiratory: Dry throat, pneumonia, pulmonary hypersensitivity

Miscellaneous: Fever

<1%, postmarketing, and/or case reports: Abdominal pain, abnormal thyroid function test, aseptic meningitis, anorexia, confusion, decreased serum calcium, defective spermatogenesis, diarrhea, diplopia, dysgeusia (Syed 2016), gastric distress, hepatic failure, hepatotoxicity (idiosyncratic) (Chalasani 2014), hirsutism, increased liver enzymes, intrahepatic cholestasis, involuntary body movements, lupus-like syndrome, nystagmus, oculomotor disturbances, paralysis, reduced fertility (male), suicidal ideation, tinnitus

ALERT: U.S. Boxed Warning

Serious dermatologic reactions and HLA-B*1502 allele:

Serious and sometimes fatal dermatologic reactions, including toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome, have been reported during treatment with carbamazepine. These syndromes may be accompanied by mucous membrane ulcers, fever, or painful rash. These reactions are estimated to occur in 1 to 6 per 10,000 new users in countries with mainly white populations, but the risk in patients of Asian descent is estimated to be approximately 10 times higher. Studies in patients of Chinese ancestry have found a strong association between the risk of developing Stevens-Johnson syndrome/TEN and the presence of HLA-B*1502, an inherited allelic variant of the HLA-B gene. HLA-B*1502 is found almost exclusively in patients with ancestry across broad areas of Asia. Test for HLA-B*1502 prior to initiating treatment with carbamazepine in patients with an increased likelihood of carrying this allele. Avoid use of carbamazepine in patients testing positive for the allele unless the benefit clearly outweighs the risk. Discontinue carbamazepine if the patient is suspected of having a serious dermatologic reaction.

Aplastic anemia and agranulocytosis:

Aplastic anemia and agranulocytosis have been reported in association with the use of carbamazepine. Data from a population-based case-control study demonstrate that the risk of developing these reactions is 5 to 8 times greater than in the general population. However, the overall risk of these reactions in the untreated general population is low, approximately 6 patients per 1 million population per year for agranulocytosis and 2 patients per 1 million population per year for aplastic anemia.

Although reports of transient or persistent decreased platelet or white blood cell counts (WBCs) are not uncommon in association with the use of carbamazepine, data are not available to accurately estimate their incidence or outcome. However, the vast majority of the cases of leukopenia have not progressed to the more serious conditions of aplastic anemia or agranulocytosis.

Because of the very low incidence of agranulocytosis and aplastic anemia, the vast majority of minor hematological changes observed while monitoring patients on carbamazepine are unlikely to signal the occurrence of either abnormality. Nonetheless, obtain complete pretreatment hematological testing as a baseline and monitor complete blood cell count periodically. If a patient in the course of treatment exhibits low or decreased white blood cell or platelet counts, monitor the patient closely. Consider discontinuation of the drug if any evidence of significant bone marrow depression develops.

Warnings/Precautions

Concerns related to adverse effects:

• Blood dyscrasias: [US Boxed Warning]: The risk of developing anemia or agranulocytosis is increased during treatment. Monitor CBC, platelets, and differential prior to and 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 (TENS) 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 TENS 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.

• 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. Avoid use of IV product in moderate or severe 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:

• Injection: Vials contain the excipient cyclodextrin (sulfobutylether beta-cyclodextrin), which may accumulate in patients with renal insufficiency, although the clinical significance of this finding is uncertain (Luke 2010).

• 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.

Monitoring Parameters

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

As appropriate: Lipid panel, serum carbamazepine levels, thyroid function tests, serum sodium; 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)

Pregnancy Risk Factor

D (product specific)

Pregnancy Considerations

Studies in pregnant women have demonstrated a risk to the fetus. Carbamazepine and its metabolites can be found in the fetus and may be associated with teratogenic effects, including spina bifida, craniofacial defects, cardiovascular malformations, and hypospadias. 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); however, socioeconomic factors, maternal and paternal IQ, and polytherapy may contribute to these findings. Pregnancy may cause small decreases of carbamazepine plasma concentrations in the second and third trimesters; monitoring should be considered. When used for the treatment of bipolar disorder, use of carbamazepine should be avoided during the first trimester of pregnancy if possible. The use of a single medication for the treatment of bipolar disorder or epilepsy in pregnancy is preferred. Carbamazepine may decrease plasma concentrations of hormonal contraceptives; breakthrough bleeding or unintended pregnancy may occur and alternate or back-up methods of contraception should be considered.

Patients exposed to carbamazepine during pregnancy are encouraged to enroll themselves into the AED Pregnancy Registry by calling 1-888-233-2334. Additional information is available at www.aedpregnancyregistry.org.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience fatigue, nausea, vomiting, dry mouth, loss of strength and energy, or constipation. Have patient report immediately to prescriber signs of infection, signs of aplastic anemia (fever, pharyngitis, mouth sores, infections, bruising, or purple skin splotches), signs of Stevens-Johnson syndrome/toxic epidermal necrolysis (red, swollen, blistered, or peeling skin [with or without fever]; red or irritated eyes; or sores in mouth, throat, nose, or eyes), signs of liver problems (dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or jaundice), signs of low sodium (headache, difficulty focusing, memory impairment, confusion, weakness, seizures, or change in balance), signs of pancreatitis (severe abdominal pain, severe back pain, severe nausea, or vomiting), signs of kidney problems (urinary retention, hematuria, change in amount of urine passed, or weight gain), signs of DVT (edema, warmth, numbness, change in color, or pain in the extremities), swollen glands, signs of neuroleptic malignant syndrome (fever, muscle cramps or stiffness, dizziness, severe headache, confusion, change in thinking, tachycardia, abnormal heartbeat, or sweating a lot), signs of depression (suicidal ideation, anxiety, emotional instability, or confusion), agitation, irritability, panic attacks, mood changes, abnormal heartbeat, seizures, change in speech, hallucinations, involuntary eye movements, severe dizziness, passing out, bradycardia, vision changes, shortness of breath, excessive weight gain, swelling of arms or legs, severe muscle pain, severe joint pain, abnormal movements, or burning or numbness feeling (HCAHPS).

• Educate patient about signs of a significant reaction (eg, 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. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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