Dextromethorphan and bupropion

Strong CYP2D6 inhibitors: For patients with MDD or agitation associated with dementia due to Alzheimer’s disease, maximum recommended dosage is one tablet of 45 mg dextromethorphan hydrobromide/105 mg bupropion hydrochloride by mouth once daily in the morning. ( 2.5 , 7.1 ) Strong CYP2B6 inducers: Avoid use. ( 7.1 ) CYP2D6 Substrates: Increases the exposures of drugs that are substrates of CYP2D6. ( 7.1 ) Digoxin: May decrease plasma digoxin levels. Monitor digoxin levels. ( 7.1 ) Drugs that lower seizure threshold: Coadministration may increase risk of seizure. ( 7.1 ) Dopaminergic drugs: Central Nervous System (CNS) toxicity can occur with concomitant use.

( 7.1 ) Drug-laboratory test interactions: AUVELITY can cause false-positive urine test results for amphetamines. ( 7.2 )

7.1 Drugs Having Clinically Important Interactions with AUVELITY Table 4: Clinically Important Drug Interactions with AUVELITY Monoamine Oxidase Inhibitors (MAOIs) Clinical Impact Concomitant use of AUVELITY with MAOIs increases the risk of hypertensive crisis and serotonin syndrome. Intervention AUVELITY is contraindicated in patients taking MAOIs (including MAOIs such as linezolid or intravenous methylene blue) or in patients who have taken MAOIs within the preceding 14 days.

Allow at least 14 days after stopping AUVELITY before starting an MAOI [see Dosage and Administration ( 2.7 ), Contraindications ( 4 ), Warnings and Precautions ( 5.3 , 5.8 )] Serotonergic Drugs Clinical Impact Concomitant use of AUVELITY with other serotonergic drugs increases the risk of serotonin syndrome. Intervention Monitor for symptoms of serotonin syndrome when AUVELITY is used concomitantly with other drugs that may affect the serotonergic neurotransmitter systems. If serotonin syndrome occurs, consider discontinuation of AUVELITY and/or concomitant serotonergic drug [see Dosage and Administration ( 2.1 ), Warnings and Precautions ( 5.8 )] .

Drugs that Lower Seizure Threshold Clinical Impact AUVELITY contains bupropion which can cause seizure. Co-administration with other drugs that lower seizure threshold may increase risk of seizure. Intervention Use caution when administering AUVELITY concomitantly with drugs that lower the seizure threshold [see Warnings and Precautions ( 5.2 )] . Discontinue AUVELITY and do not restart treatment if the patient experiences a seizure. Strong Inhibitors of CYP2D6 Clinical Impact Concomitant use of AUVELITY with strong CYP2D6 inhibitors increases plasma concentrations of dextromethorphan.

Intervention Dosage adjustment is necessary when AUVELITY is co-administered with strong inhibitors of CYP2D6 [see Dosage and Administration ( 2.5 )] . Monitor patients for adverse reactions potentially attributable to dextromethorphan, such as somnolence and dizziness. Strong Inducers of CYP2B6 Clinical Impact Concomitant use of AUVELITY with strong CYP2B6 inducers decreases plasma concentrations of dextromethorphan and bupropion and may decrease efficacy of AUVELITY [see Clinical Pharmacology ( 12.3 )] . Intervention Avoid co-administration of AUVELITY with strong inducers of CYP2B6. Consider alternatives to strong CYP2B6 inducers if needed.

Drugs Metabolized by CYP2D6 Clinical Impact CYP2D6 Substrates Coadministration of AUVELITY with drugs that are metabolized by CYP2D6 can increase the exposures of drugs that are substrates of CYP2D6. Drugs that Require Metabolic Activation by CYP2D6 Drugs that require metabolic activation by CYP2D6 to be effective could have reduced efficacy when administered concomitantly with AUVELITY. Intervention CYP2D6 Substrates When used concomitantly with AUVELITY, it may be necessary to decrease the dose of CYP2D6 substrates, particularly for drugs with a narrow therapeutic index.

Drugs that Require Metabolic Activation by CYP2D6 Patients treated concomitantly with AUVELITY may require increased doses of drugs that require activation by CYP2D6 to be effective. Digoxin Clinical Impact Coadministration of AUVELITY with digoxin may decrease plasma digoxin levels. Intervention Monitor plasma digoxin levels in patients treated concomitantly with AUVELITY and digoxin [see Clinical Pharmacology ( 12.3 )] . Dopaminergic Drugs Clinical Impact CNS toxicity was reported when bupropion was co-administered with levodopa or amantadine. Adverse reactions include restlessness, agitation, tremor, ataxia, gait disturbance, vertigo, and dizziness.

Intervention Use caution when administering AUVELITY concomitantly with dopaminergic drugs. Alcohol Clinical Impact AUVELITY contains bupropion which can increase adverse neuropsychiatric events or reduce alcohol tolerance. Intervention Consumption of alcohol should be minimized or avoided during treatment with AUVELITY.

7.2 Drug-Laboratory Test Interactions False-positive urine immunoassay screening tests for amphetamines have been reported in patients taking bupropion. This is due to lack of specificity of some screening tests. False positive test results may result even following discontinuation of bupropion therapy. Confirmatory tests, such as gas chromatography/mass spectrometry, will distinguish bupropion from amphetamines.

7.1 Drugs Having Clinically Important Interactions with AUVELITY Table 4: Clinically Important Drug Interactions with AUVELITY Monoamine Oxidase Inhibitors (MAOIs) Clinical Impact Concomitant use of AUVELITY with MAOIs increases the risk of hypertensive crisis and serotonin syndrome. Intervention AUVELITY is contraindicated in patients taking MAOIs (including MAOIs such as linezolid or intravenous methylene blue) or in patients who have taken MAOIs within the preceding 14 days.

Allow at least 14 days after stopping AUVELITY before starting an MAOI [see Dosage and Administration ( 2.7 ), Contraindications ( 4 ), Warnings and Precautions ( 5.3 , 5.8 )] Serotonergic Drugs Clinical Impact Concomitant use of AUVELITY with other serotonergic drugs increases the risk of serotonin syndrome. Intervention Monitor for symptoms of serotonin syndrome when AUVELITY is used concomitantly with other drugs that may affect the serotonergic neurotransmitter systems. If serotonin syndrome occurs, consider discontinuation of AUVELITY and/or concomitant serotonergic drug [see Dosage and Administration ( 2.1 ), Warnings and Precautions ( 5.8 )] .

Drugs that Lower Seizure Threshold Clinical Impact AUVELITY contains bupropion which can cause seizure. Co-administration with other drugs that lower seizure threshold may increase risk of seizure. Intervention Use caution when administering AUVELITY concomitantly with drugs that lower the seizure threshold [see Warnings and Precautions ( 5.2 )] . Discontinue AUVELITY and do not restart treatment if the patient experiences a seizure. Strong Inhibitors of CYP2D6 Clinical Impact Concomitant use of AUVELITY with strong CYP2D6 inhibitors increases plasma concentrations of dextromethorphan.

Intervention Dosage adjustment is necessary when AUVELITY is co-administered with strong inhibitors of CYP2D6 [see Dosage and Administration ( 2.5 )] . Monitor patients for adverse reactions potentially attributable to dextromethorphan, such as somnolence and dizziness. Strong Inducers of CYP2B6 Clinical Impact Concomitant use of AUVELITY with strong CYP2B6 inducers decreases plasma concentrations of dextromethorphan and bupropion and may decrease efficacy of AUVELITY [see Clinical Pharmacology ( 12.3 )] . Intervention Avoid co-administration of AUVELITY with strong inducers of CYP2B6. Consider alternatives to strong CYP2B6 inducers if needed.

Drugs Metabolized by CYP2D6 Clinical Impact CYP2D6 Substrates Coadministration of AUVELITY with drugs that are metabolized by CYP2D6 can increase the exposures of drugs that are substrates of CYP2D6. Drugs that Require Metabolic Activation by CYP2D6 Drugs that require metabolic activation by CYP2D6 to be effective could have reduced efficacy when administered concomitantly with AUVELITY. Intervention CYP2D6 Substrates When used concomitantly with AUVELITY, it may be necessary to decrease the dose of CYP2D6 substrates, particularly for drugs with a narrow therapeutic index.

Drugs that Require Metabolic Activation by CYP2D6 Patients treated concomitantly with AUVELITY may require increased doses of drugs that require activation by CYP2D6 to be effective. Digoxin Clinical Impact Coadministration of AUVELITY with digoxin may decrease plasma digoxin levels. Intervention Monitor plasma digoxin levels in patients treated concomitantly with AUVELITY and digoxin [see Clinical Pharmacology ( 12.3 )] . Dopaminergic Drugs Clinical Impact CNS toxicity was reported when bupropion was co-administered with levodopa or amantadine. Adverse reactions include restlessness, agitation, tremor, ataxia, gait disturbance, vertigo, and dizziness.

Intervention Use caution when administering AUVELITY concomitantly with dopaminergic drugs. Alcohol Clinical Impact AUVELITY contains bupropion which can increase adverse neuropsychiatric events or reduce alcohol…

8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antidepressants, including AUVELITY, during pregnancy. Healthcare providers are encouraged to register patients by contacting the National Pregnancy Registry for Antidepressants at 1-866-961-2388 or online at: https://womensmentalhealth.org/research/pregnancyregistry/antidepressants/ . Risk Summary Based on animal studies, AUVELITY may cause fetal harm when administered during pregnancy. AUVELITY is not recommended during pregnancy.

If a female becomes pregnant while being treated with AUVELITY, discontinue treatment and counsel the patient about the potential risk to a fetus [see Warnings and Precautions ( 5.9 )] . In oral studies conducted in rats and rabbits, a combination of dextromethorphan/quinidine demonstrated developmental toxicity, including fetal malformations (rabbits) and embryolethality, when given to pregnant animals. When bupropion alone was administered to pregnant rats during organogenesis, there was no evidence of fetal malformations at doses up to approximately 21 times the maximum recommended human dose (MRHD) of 210 mg/day.

When bupropion alone was given to pregnant rabbits during organogenesis, non-dose–related increases in incidence of fetal malformations, and skeletal variations were observed at doses approximately 2 to 5 times the MRHD and greater. Decreased fetal weights were seen at bupropion doses approximately 5 times the MRHD and greater. Neurotoxicity findings were observed in juvenile rats treated with a combination of dextromethorphan/quinidine on postnatal day (PND) 7, which corresponds to the third trimester of gestation through the first few months of life and may extend through the first three years of life in humans.

Based on these findings, AUVELITY may cause fetal harm when administered to pregnant women (see Data ) . The available clinical data on the use of AUVELITY during pregnancy is insufficient to evaluate for a drug-associated risk of major birth malformations, miscarriage, or other adverse maternal or fetal outcomes. However, there are available data on one of the individual components of AUVELITY, bupropion. Data from epidemiological studies of pregnant women exposed to bupropion in the first trimester have not identified an increased risk of congenital malformations overall (see Data ) .

There are risks to the mother associated with untreated depression in pregnancy (see Clinical Considerations ) . The estimated background risk of major birth defects and miscarriage for…