2.1 Important Recommendations Prior to Initiating and During Treatment with AUVELITY

Prior to initiating and during treatment with AUVELITY:

• assess blood pressure and monitor periodically during treatment [see Warnings and Precautions (5.3)].
• screen patients for a personal or family history of bipolar disorder, mania, or hypomania [see Warnings and Precautions (5.4)].
• screen patients to determine if they are receiving any other medications that contain bupropion or dextromethorphan [see Warnings and Precautions (5.2, 5.5, 5.8)].

2.2 Recommended Dosage for the Treatment of Major Depressive Disorder

The recommended starting dosage of AUVELITY (45 mg of dextromethorphan hydrobromide and 105 mg of bupropion hydrochloride) is one tablet once daily in the morning. After 3 days, increase to the maximum recommended dosage of one tablet twice daily, given at least 8 hours apart. Do not exceed two doses within the same day.

Administer AUVELITY orally with or without food [see Clinical Pharmacology (12.3)]. Swallow tablets whole, do not crush, divide, or chew.

2.3 Dosage Recommendations in Patients with Renal Impairment

The recommended dosage of AUVELITY for patients with moderate renal impairment (eGFR 30 to 59 mL/minute/1.73 m2) is one tablet once daily in the morning [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)].

2.4 Dosage Recommendations for Concomitant Use with Strong CYP2D6 Inhibitors

The recommended dosage of AUVELITY when co-administered with strong CYP2D6 inhibitors is one tablet once daily in the morning [see Drug Interactions (7.1), Clinical Pharmacology (12.3)].

2.5 Dosage Recommendations for Known CYP2D6 Poor Metabolizers (PMs)

The recommended dosage for patients known to be poor CYP2D6 metabolizers is one tablet once daily in the morning [see Use in Specific Populations (8.8), Clinical Pharmacology (12.3)].

2.6 Switching a Patient to or from a Monoamine Oxidase Inhibitor (MAOI) Antidepressant

At least 14 days must elapse between discontinuation of an MAOI intended to treat depression and initiation of therapy with AUVELITY. Conversely, at least 14 days must be allowed after stopping AUVELITY before starting an MAOI antidepressant [see Contraindications (4), Drug Interactions (7.1)].

5.1 Suicidal Thoughts and Behaviors in Adolescents and Young Adults

In pooled analyses of placebo-controlled trials of antidepressant drugs (SSRIs and other antidepressant classes) that included approximately 77,000 adult patients and 4,500 pediatric patients, the incidence of suicidal thoughts and behaviors in antidepressant-treated patients age 24 years and younger was greater than in placebo-treated patients. There was considerable variation in risk of suicidal thoughts and behaviors among drugs, but there was an increased risk identified in young patients for most drugs studied. There were differences in absolute risk of suicidal thoughts and behaviors across the different indications, with the highest incidence in patients with MDD. The drug-placebo differences in the number of cases of suicidal thoughts and behaviors per 1000 patients treated are provided in Table 1.

It is unknown whether the risk of suicidal thoughts and behaviors in children, adolescents, and young adults extends to longer-term use, i.e., beyond four months. However, there is substantial evidence from placebo-controlled maintenance studies in adults with MDD that antidepressants delay the recurrence of depression and that depression itself is a risk factor for suicidal thoughts and behaviors.

Monitor all antidepressant-treated patients for any indication for clinical worsening and emergence of suicidal thoughts and behaviors, especially during the initial few months of drug therapy, and at times of dosage changes. Counsel family members or caregivers of patients to monitor for changes in behavior and to alert the healthcare provider. Consider changing the therapeutic regimen, including possibly discontinuing AUVELITY, in patients whose depression is persistently worse, or who are experiencing emergent suicidal thoughts or behaviors.

5.2 Seizure

Bupropion, a component of AUVELITY, can cause seizure. The risk of seizure with bupropion is dose-related.

When a bupropion hydrochloride (HCl) sustained-release tablet was dosed up to 300 mg per day (approximately 1.5 times the maximum recommended daily dosage of AUVELITY), the incidence of seizure was approximately 0.1% (1/1,000) and increased to approximately 0.4% (4/1,000) at the maximum recommended dosage for the sustained-release tablet of 400 mg per day (approximately 2 times the maximum recommended daily dosage of AUVELITY).

The risk of seizures is also related to patient factors, clinical situations, and concomitant medications that lower the seizure threshold. Consider these risks before initiating treatment with AUVELITY. AUVELITY is contraindicated in patients with a seizure disorder, current or prior diagnosis of anorexia nervosa or bulimia, or undergoing abrupt discontinuation of alcohol, benzodiazepines, barbiturates, and antiepileptic drugs [see Contraindications (4), Drug Interactions (7.1)]. The following conditions can also increase the risk of seizure: severe head injury; arteriovenous malformation; CNS tumor or CNS infection; severe stroke; concomitant use of other medications that lower the seizure threshold (e.g., other bupropion products, antipsychotics, tricyclic antidepressants, theophylline, and systemic corticosteroids); metabolic disorders (e.g., hypoglycemia, hyponatremia, severe hepatic impairment, and hypoxia); use of illicit drugs (e.g., cocaine); or abuse or misuse of prescription drugs such as CNS stimulants. Additional predisposing conditions include diabetes mellitus treated with oral hypoglycemic drugs or insulin; use of anorectic drugs; and excessive use of alcohol, benzodiazepines, sedative/hypnotics, or opiates.

Because the risk of seizure with bupropion is dose-related, screen patients for use of other bupropion-containing products prior to initiating AUVELITY [see Dosage and Administration (2.1)]. If concomitant use of AUVELITY with other bupropion-containing products is clinically warranted, inform patients of the risk. Discontinue AUVELITY and do not restart treatment if the patient experiences a seizure.

5.3 Increased Blood Pressure and Hypertension

AUVELITY contains bupropion, which can cause elevated blood pressure and hypertension. The risk of hypertension is increased if AUVELITY is used concomitantly with MAOIs or other drugs that increase dopaminergic or noradrenergic activity [see Contraindications (4), Drug Interactions (7.1)].

Data from a comparative trial of a sustained-release tablet formulation of bupropion HCl, nicotine transdermal system (NTS), the combination of sustained-release bupropion plus NTS, and placebo as an aid to smoking cessation suggest a higher incidence of hypertension in patients treated with the combination of sustained-release bupropion and NTS. In this trial, 6.1% of subjects treated with the combination of sustained-release bupropion and NTS had hypertension compared with 2.5%, 1.6%, and 3.1% of subjects treated with sustained-release bupropion, NTS, and placebo, respectively. The majority of these subjects had evidence of pre-existing hypertension. Three subjects (1.2%) treated with the combination of sustained-release bupropion and NTS and 1 subject (0.4%) treated with NTS had study medication discontinued due to hypertension compared with none of the subjects treated with sustained-release bupropion or placebo. Monitor blood pressure in patients who receive the combination of bupropion and nicotine replacement.

In a clinical trial of an immediate-release bupropion tablet formulation in MDD subjects with stable congestive heart failure (N=36), bupropion was associated with an exacerbation of pre-existing hypertension in 2 subjects, leading to discontinuation of bupropion treatment. There are no controlled trials assessing the safety of bupropion in patients with a recent history of myocardial infarction or unstable cardiac disease.

Assess blood pressure prior to initiating treatment, and periodically monitor blood pressure during treatment with AUVELITY [see Dosage and Administration (2.1)].

5.4 Activation of Mania or Hypomania

Antidepressant treatment can precipitate a manic, mixed, or hypomanic manic episode. The risk appears to be increased in patients with bipolar disorder or who have risk factors for bipolar disorder. Prior to initiating AUVELITY, screen patients for a history of bipolar disorder and the presence of risk factors for bipolar disorder (e.g., family history of bipolar disorder, suicide, or depression) [see Dosage and Administration (2.1)]. AUVELITY is not approved for use in treating bipolar depression.

5.5 Psychosis and Other Neuropsychiatric Reactions

AUVELITY contains bupropion. Depressed patients treated with bupropion have had a variety of neuropsychiatric signs and symptoms, including delusions, hallucinations, psychosis, concentration disturbance, paranoia, and confusion. Some of these patients had a diagnosis of bipolar disorder. In some cases, these symptoms abated upon dose reduction and/or withdrawal of treatment.

AUVELITY contains dextromethorphan. Dextromethorphan overdose can cause toxic psychosis, stupor, coma, and hyperexcitability [see Overdosage (10)].

Because the risks of neuropsychiatric reactions are dose-related, screen patients for use of other bupropion- or dextromethorphan-containing products prior to initiating AUVELITY. If concomitant use of AUVELITY with other bupropion- or dextromethorphan-containing products is clinically warranted, monitor patients for neuropsychiatric reactions [see Dosage and Administration (2.1)] and instruct patients to contact a healthcare provider if such reactions occur.

5.6 Angle-Closure Glaucoma

The pupillary dilation that occurs following use of many antidepressant drugs including bupropion, a component of AUVELITY, may trigger an angle closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy. Avoid use of antidepressants, including AUVELITY, in patients with untreated anatomically narrow angles.

5.7 Dizziness

AUVELITY may cause dizziness [see Adverse Reactions (6.1)]. In controlled studies of AUVELITY, 14% of patients receiving AUVELITY and 6% of patients on placebo experienced dizziness. Take precautions to reduce the risk of falls, particularly for patients with motor impairment affecting gait or those with a history of falls. Caution patients about operating hazardous machinery, including motor vehicles, until they are reasonably certain that AUVELITY therapy does not affect them adversely.

5.8 Serotonin Syndrome

AUVELITY contains dextromethorphan. Concomitant use of AUVELITY with SSRIs or tricyclic antidepressants may cause serotonin syndrome, a potentially life-threatening condition with changes including altered mental status, hypertension, restlessness, myoclonus, hyperthermia, hyperreflexia, diaphoresis, shivering, and tremor [see Drug Interactions (7.1), Overdosage (10)].

The concomitant use of AUVELITY with MAOIs is contraindicated. In addition, do not initiate AUVELITY in a patient being treated with MAOIs such as linezolid or intravenous methylene blue. If it is necessary to initiate treatment with an MAOI such as linezolid or intravenous methylene blue in a patient taking AUVELITY discontinue AUVELITY before initiating treatment with the MAOI [see Contraindications (4), Drug Interactions (7)].

Prior to initiating AUVELITY, screen patients for use of other dextromethorphan-containing products [see Dosage and Administration (2.1)]. If concomitant use of AUVELITY with other serotonergic drugs is clinically warranted, inform patients of the increased risk for serotonin syndrome and monitor for symptoms. Discontinue AUVELITY and/or concomitant serotonergic drug immediately if the above symptoms occur, and initiate supportive symptomatic treatment.

5.9 Embryo-fetal Toxicity

Based on animal studies, AUVELITY may cause fetal harm when administered during pregnancy. In developmental toxicity studies in rats and rabbits, when a combination of dextromethorphan/quinidine was given to pregnant animals, fetal malformations (rabbits) and embryolethality were demonstrated in offspring. 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. The separate effect of dextromethorphan on developmental toxicity at the recommended clinical dose is unclear. Discontinue treatment in pregnant females and advise the patient about the potential risk to a fetus. Use alternative treatment for females who are planning to become pregnant [see Use in Specific Populations (8.1, 8.3)].

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

AUVELITY was evaluated for safety in a total of 1114 patients with MDD or another indication from four studies (two 6-week studies in MDD, one 6-week study in another indication, and one long-term study in MDD and another indication). One 6-week study in MDD employed placebo as a control arm. Two 6-week studies, one in MDD and one in another indication, employed bupropion as a control arm. In the patients treated with AUVELITY in the long-term study (n=876), 597 received at least 6 months of treatment, and 110 received at least 12 months of treatment.

The data below are based on the 6-week, placebo-controlled study in which either AUVELITY (n=162) or placebo (n=164) was administered twice daily to patients with MDD (Study 1). Demographics of the patients who participated in this study are summarized in Clinical Studies [see Clinical Studies (14)].

Adverse Reactions Leading to Discontinuation

In the 6-week placebo-controlled study, 4% of patients treated with AUVELITY and 0% of placebo-treated patients discontinued participation due to adverse reactions. The adverse reaction that led to study discontinuation in ≥1% of patients treated with AUVELITY was anxiety (2%).

Most Common Adverse Reactions

In the 6-week placebo-controlled clinical study, the most common (incidence ≥5% for AUVELITY and more than twice as frequently as placebo) adverse reactions were dizziness (16%), headache (8%), diarrhea (7%), somnolence (7%), dry mouth (6%), sexual dysfunction (6%), and hyperhidrosis (5%).

Table 2 shows the incidence of adverse reactions that occurred in ≥2% of patients treated with AUVELITY and more frequently than in patients treated with placebo in Study 1.

6.2 Postmarketing Experience

The following adverse reactions have been identified with the use of the individual components of AUVELITY, dextromethorphan and bupropion, during postmarketing use. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Dextromethorphan

Drowsiness, dizziness, nervousness or restlessness, nausea, vomiting, and stomach pain.

Bupropion

Body (General): Arthralgia, myalgia, and fever with rash and other symptoms suggestive of delayed hypersensitivity. These symptoms may resemble serum sickness.

Cardiovascular: Complete atrioventricular block, extrasystoles, hypotension, hypertension (in some cases severe), phlebitis, pulmonary embolism, and Brugada pattern/syndrome.

Digestive: Colitis, esophagitis, gastrointestinal hemorrhage, gum hemorrhage, hepatitis, intestinal perforation, pancreatitis, and stomach ulcer.

Endocrine: Hyperglycemia, hypoglycemia, hyponatremia, and syndrome of inappropriate antidiuretic hormone secretion.

Hemic and Lymphatic: Anemia, leukocytosis, leukopenia, lymphadenopathy, pancytopenia, and thrombocytopenia. Altered PT and/or INR, infrequently associated with hemorrhagic or thrombotic complications, were observed when bupropion was coadministered with warfarin.

Metabolic and Nutritional: Glycosuria.

Musculoskeletal: Muscle rigidity/fever/rhabdomyolysis and muscle weakness.

Nervous System: Abnormal electroencephalogram (EEG), aggression, agitation, akinesia, aphasia, coma, completed suicide, delirium, delusions, depression, dysarthria, euphoria, extrapyramidal syndrome (dyskinesia, dystonia, hypokinesia, parkinsonism), hallucinations, homicidal ideation, hostility, increased libido, manic reaction, neuralgia, neuropathy, panic, paranoid ideation, psychosis, restlessness, suicide ideation, suicide attempt, and unmasking tardive dyskinesia.

Respiratory: Pneumonia.

Skin and subcutaneous tissue disorders: Alopecia, angioedema, exfoliative dermatitis, hirsutism, Stevens-Johnson syndrome, acute generalized exanthematous pustulosis, and drug reaction with eosinophilia and systemic symptoms (DRESS).

Special Senses: Deafness, increased intraocular pressure, and mydriasis.

Urogenital: Abnormal ejaculation, cystitis, dyspareunia, dysuria, gynecomastia, menopause, painful erection, salpingitis, urinary incontinence, urinary retention, and vaginitis.

7.1 Drugs Having Clinically Important Interactions 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.

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 the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Clinical Considerations

Disease-Associated Maternal and/or Embryo/Fetal Risk

A prospective, longitudinal study followed 201 pregnant women with a history of major depressive disorder who were euthymic and taking antidepressants during pregnancy at the beginning of pregnancy. The women who discontinued antidepressants during pregnancy were more likely to experience a relapse of major depression than women who continued antidepressants. Consider the risks to the mother of untreated depression and potential effects on the fetus when discontinuing or changing treatment with antidepressant medications during pregnancy and postpartum.

Data

Human Data

Bupropion

Data from the international bupropion Pregnancy Registry (675 first trimester exposures) and a retrospective cohort study using the United Healthcare database (1,213 first trimester exposures) did not show an increased risk for malformations overall. The Registry was not designed or powered to evaluate specific defects but suggested a possible increase in cardiac malformations.

No increased risk for cardiovascular malformations overall has been observed after bupropion exposure during the first trimester. The prospectively observed rate of cardiovascular malformations in pregnancies with exposure to bupropion in the first trimester from the international bupropion Pregnancy Registry was 1.3% (9 cardiovascular malformations/675 first trimester maternal bupropion exposures), which is similar to the background rate of cardiovascular malformations (approximately 1%). Data from the United Healthcare database, which had a limited number of exposed cases with cardiovascular malformations, and a case-control study (11,700 infants with cardiovascular malformations and 20,093 infants with non-cardiovascular malformations) of self-reported antidepressant use, including bupropion (n=728), from the National Birth Defects Prevention Study (NBDPS) did not show an increased risk for cardiovascular malformations overall after bupropion exposure during the first trimester.

Study findings on bupropion exposure during the first trimester and risk for left ventricular outflow tract obstruction (LVOTO) or ventricular septal defect (VSD) are inconsistent and do not allow conclusions regarding a possible association. The United Healthcare database lacked sufficient power to evaluate the LVOTO association. NBDPS found slightly increased risk for LVOTO after partially accounting for underlying maternal conditions (n = 14; adjusted odds ratio [OR] = 1.18; 95% CI: 0.58, 2.43), and the Slone Epidemiology case control study did not find increased risk for LVOTO.

The Slone Epidemiology Study found an increased risk for VSD following first trimester maternal bupropion exposure (n = 17; adjusted OR = 2.5; 95% CI: 1.3, 5.0) but did not find increased risk for any other cardiovascular malformations studied (including LVOTO as above). The NBDPS and United Healthcare database study did not find an association between first trimester maternal bupropion exposure and VSD.

For the findings of LVOTO and VSD, the studies were limited by the small number of exposed cases, inconsistent findings among studies, and the potential for chance findings from multiple comparisons in case control studies.

Animal Data

In studies conducted in pregnant mice, dextromethorphan-bupropion was administered orally during the period of organogenesis at doses of 0-0, 26-57, 34-75, and 68-150 mg/kg/day, respectively. Administration of dextromethorphan-bupropion did not affect body weight, weight gain, food consumption, or pregnancy at any dose level and did not produce gross pathologic findings or placental or fetal findings at any dose level. The no-effect level for reproductive organ findings in mice was 68-150 mg/kg in both sexes, which is approximately 3.7/3.5 times the MRHD for AUVELITY on a mg/m2 basis.

When dextromethorphan/quinidine was administered orally (0/0, 5/100, 15/100, and 50/100 mg/kg/day) to pregnant rats during the period of organogenesis, embryo-fetal deaths were observed at the highest dose tested and reduced skeletal ossification was observed at all doses. Oral administration to pregnant rabbits during organogenesis in two separate studies (0/0, 5/60, 15/60, and 30/60 mg/kg day; 0/0, 5/100, 15/100, and 50/100 mg/kg/day) resulted in an increased incidence of fetal malformations at all but the lowest dose tested.

When dextromethorphan/quinidine was orally administered to female rats during pregnancy and lactation in two separate studies (0/0, 5/100, 15/100, and 30/100 mg/kg/day; 0/0, 5/100, 15/100, and 50/100 mg/kg/day), pup survival and pup weight were decreased at all doses, and developmental delay was observed in offspring at the mid and high doses. A no-effect dose for adverse developmental effects was not identified.

When dextromethorphan/quinidine was orally administered (0/0, 5/50, 15/50, 25/50 mg/kg) to male and female rats on postnatal day (PND) 7, the highest dose resulted in neuronal death in brain (thalamus and medulla oblongata). PND 7 in rat corresponds to the third trimester of gestation through the first several months of life but may extend to approximately three years of age in humans.

In studies conducted in pregnant rats and rabbits, bupropion alone was administered orally during the period of organogenesis at doses of up to 450 and 150 mg/kg/day, respectively (approximately 21 and 14 times the MRHD, respectively, on a mg/m2 basis). There was no evidence of fetal malformations in rats. When given to pregnant rabbits during organogenesis, non-dose–related increases in incidence of fetal malformations and skeletal variations were observed at the lowest dose tested (25 mg/kg/day, approximately 2 times the MRHD on a mg/m2 basis) and greater. Decreased fetal weights were observed at doses of 50 mg/kg/day (approximately 5 times the MRHD on a mg/m2 basis) and greater. No maternal toxicity was evident at doses of 50 mg/kg/day or less. In a pre- and postnatal development study, bupropion administered orally to pregnant rats at doses of up to 150 mg/kg/day (approximately 7 times the MRHD on a mg/m2 basis) from embryonic implantation through lactation had no effect on pup growth or development.

8.2 Lactation

Risk Summary

Data from published literature report the presence of bupropion and its metabolites in human milk (see Data). There are no data on the effects of bupropion or its metabolites on milk production. Limited data from postmarketing reports of bupropion use in lactating patients have not identified a clear association of adverse reactions in the breastfed infant.

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 [see Use in Specific Populations (8.1)]. It is not known whether dextromethorphan is present in human milk. There are no data on the effects of dextromethorphan on the breastfed infant or the effects on milk production. Because of the potential for neurotoxicity, advise patients that breastfeeding is not recommended during treatment with AUVELITY and for 5 days following final dose.

Data

In a lactation study of 10 women, levels of orally dosed bupropion and its active metabolites were measured in expressed milk. The average daily infant exposure (assuming 150 mL/kg daily consumption) to bupropion and its active metabolites was 2% of the maternal weight-adjusted dose. Postmarketing reports have described seizures in breastfed infants. The relationship of bupropion exposure and these seizures is unclear.

8.3 Females and Males of Reproductive Potential

Based on animal studies, AUVELITY may cause fetal harm when administered during pregnancy [see Warnings and Precautions (5.9), Use in Specific Populations (8.1)]. However, the separate effect of dextromethorphan on developmental toxicity at the recommended clinical dose is unclear. Use alternative treatment for females who are planning to become pregnant.

8.4 Pediatric Use

The safety and effectiveness of AUVELITY have not been established in pediatric patients.

AUVELITY contains bupropion. Antidepressants, including bupropion, increase the risk of suicidal thoughts and behaviors in pediatric patients [see Boxed Warning, Warning and Precautions (5.1)].

8.5 Geriatric Use

Clinical studies with AUVELITY did not include patients 65 years of age and older to determine whether they respond differently than younger adult patients.

8.6 Renal Impairment

Dosage adjustment of AUVELITY is recommended in patients with moderate renal impairment (eGFR 30 to 59 mL/minute/1.73 m2) [see Dosage and Administration (2.3), Clinical Pharmacology (12.3)]. The pharmacokinetics of AUVELITY have not been evaluated in patients with severe renal impairment. AUVELITY is not recommended in patients with severe renal impairment (eGFR 15 to 29 mL/minute/1.73 m2).

8.7 Hepatic Impairment

No dose adjustment of AUVELITY is recommended in patients with mild (Child-Pugh A) or moderate hepatic impairment (Child-Pugh B) [see Clinical Pharmacology (12.3)]. The pharmacokinetics of AUVELITY have not been evaluated in patients with severe hepatic impairment (Child-Pugh C). AUVELITY is not recommended in patients with severe hepatic impairment.

8.8 CYP2D6 Poor Metabolizers

Dosage adjustment is recommended in patients known to be poor CYP2D6 metabolizers because these patients have higher dextromethorphan concentrations than extensive/intermediate CYP2D6 metabolizers [see Dosage and Administration (2.5), Clinical Pharmacology (12.3)].

9.1 Controlled Substance

AUVELITY contains dextromethorphan and bupropion which are not controlled substances.

9.2 Abuse

Abuse is the intentional, non-therapeutic use of a drug, even once, for its desirable psychological or physiological effects.

AUVELITY has not been systematically studied in animals or humans for its potential for abuse, tolerance, or physical dependence. However, AUVELITY is a combination product containing dextromethorphan and bupropion, and cases of dextromethorphan abuse have been reported.

While clinical studies with AUVELITY did not reveal drug-seeking behavior, these observations were not systematic and it is not possible to predict on the basis of this experience the extent to which AUVELITY will be misused, diverted, and/or abused once marketed. Therefore, patients with a history of drug abuse should be observed closely for signs of AUVELITY misuse or abuse (e.g., development of tolerance, increases in dose, drug-seeking behavior).

AUVELITY is intended for oral use only. Seizures and/or cases of death have been reported when bupropion has been administered intranasally or by parenteral injection.

Dextromethorphan

Dextromethorphan has not been systematically studied in animals or humans for its potential for abuse, tolerance, or physical dependence. Cases of dextromethorphan abuse have been reported, predominantly in adolescents.

Bupropion

Controlled clinical trials conducted in normal volunteers, in subjects with a history of multiple drug abuse, and in depressed subjects showed some increase in motor activity and agitation/excitement, often typical of central stimulant activity.

In a population of individuals experienced with drugs of abuse, a single oral dose of 400 mg of bupropion (approximately 1.9 times the maximum recommended daily dosage of AUVELITY) produced mild amphetamine-like activity as compared with placebo on the Morphine-Benzedrine Subscale of the Addiction Research Center Inventories (ARCI) and a score intermediate between placebo and amphetamine on the Liking Scale of the ARCI. These scales measure general feelings of euphoria and drug liking which are often associated with abuse potential.

Findings in clinical trials, however, are not known to reliably predict the abuse potential of drugs. Nonetheless, evidence from single-dose studies does suggest that the recommended daily dosage of bupropion when administered in divided doses is not likely to be significantly reinforcing to people who abuse amphetamines or CNS stimulants. However, higher doses (which could not be tested because of the risk of seizure) might be modestly attractive to those who abuse CNS stimulant drugs.

12.1 Mechanism of Action

Dextromethorphan is an uncompetitive antagonist of the NMDA receptor (an ionotropic glutamate receptor) and a sigma-1 receptor agonist. The mechanism of dextromethorphan in the treatment of MDD is unclear.

The mechanism of action of bupropion in the treatment of MDD is unclear; however, it may be related to noradrenergic and/or dopaminergic mechanisms. Bupropion increases plasma levels of dextromethorphan by competitively inhibiting cytochrome P450 2D6, which catalyzes a major biotransformation pathway for dextromethorphan. Bupropion is a relatively weak inhibitor of the neuronal reuptake of norepinephrine and dopamine and does not inhibit monoamine oxidase or the reuptake of serotonin.

12.2 Pharmacodynamics

Cardiac Electrophysiology

At the maximum recommended dose, AUVELITY does not prolong the QT interval to any clinically relevant extent.

12.3 Pharmacokinetics

AUVELITY is a combination of dextromethorphan and bupropion. Bupropion inhibits the metabolism of dextromethorphan via CYP2D6. Dextromethorphan when co-administered with bupropion displays nonlinear pharmacokinetics at steady state, with greater than dose-proportional changes in AUC and Cmax for varying doses of dextromethorphan [60 to 120 mg (0.67-1.33 times the maximum recommended dose of AUVELITY)] and less than dose-proportional changes for varying doses of bupropion [150 to 300 mg (0.71-1.43 times the maximum recommended dose of AUVELITY)].

Steady state plasma concentrations of dextromethorphan and bupropion when given as AUVELITY are achieved within 8 days. The accumulation ratios for dextromethorphan at steady state when given as AUVELITY are 20 and 32, respectively based on Cmax and AUC0- 12, compared to 1.3 and 1.4, respectively, for dextromethorphan given without bupropion. The accumulation ratios for bupropion at steady state are 1.1 and 1.5, respectively based on Cmax and AUC0-12.

Absorption

The median Tmax of dextromethorphan and bupropion when given as AUVELITY was 3 hours and 2 hours, respectively.

The Cmax of the hydroxybupropion metabolite occurred approximately 3 hours post-dose and was approximately 14 times the peak level of bupropion and its AUC0-12 was about 19 times that of bupropion. The Cmax of the erythrohydroxybupropion and threohydroxybupropion metabolites occurred approximately 4 hours post-dose and were approximately equal to and 5 times that of bupropion, respectively. The AUC0-12 values were 1.2 and 7 times that of bupropion, respectively.

Effect of Food

AUVELITY can be taken with or without food. Dextromethorphan Cmax and AUC0-12 were unchanged and decreased by 14%, respectively, and bupropion Cmax and AUC0-12 were increased by 3% and 6%, respectively, when AUVELITY was administered with food.

Distribution

The plasma protein binding of dextromethorphan is approximately 60-70% and bupropion is 84%. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion; whereas, the extent of protein binding of the threohydroxybupropion metabolite is about half that seen with bupropion.

Elimination

Following 8 days of administration of AUVELITY in extensive metabolizers, the mean elimination half-life of dextromethorphan was increased approximately 3-fold to 22 hours, as compared to dextromethorphan given without bupropion.

The mean elimination half-life of dextromethorphan and bupropion was 22 hours and 15 hours, respectively. The apparent elimination half-life of hydroxybupropion, erythrohydroxybupropion and threohydroxybupropion metabolites were approximately 35, 44 and 33 hours, respectively.

Metabolism

Dextromethorphan is primarily metabolized by CYP2D6 to dextrorphan. Bupropion is extensively metabolized with three active metabolites: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydroxybupropion and erythrohydroxybupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydroxybupropion. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydroxybupropion and erythrohydroxybupropion are 5-fold less potent than bupropion.

Excretion

In CYP2D6 extensive metabolizers, approximately 37-52% of the orally administered dose of dextromethorphan is recovered in the urine. Less than 2% of the administered dose is excreted as unchanged parent drug in the urine. In CYP2D6 poor metabolizers, approximately 45-83% of the administered dose is recovered in the urine. Approximately 26% of the administered dose is excreted as unchanged parent drug in the urine.

Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. Only 0.5% of the oral dose was excreted as unchanged bupropion.

Specific Populations

Geriatric Patients

The pharmacokinetics of AUVELITY have not been studied in patients 65 years or older.

Pediatric Patients

The pharmacokinetics of AUVELITY in pediatric patients have not been studied.

Male and Female/ Racial or Ethnic Groups

No significant pharmacokinetic differences based on sex and race have been observed for AUVELITY.

Patients with Renal Impairment, Patients with Hepatic Impairment, and CYP2D6 Poor Metabolizers

The effects of renal impairment, hepatic impairment, and CYP2D6 poor metabolizer status on the exposure to AUVELITY are summarized in Figure 1 [see Dosage and Administration (2.3, 2.5)].

Figure 1 Effects of Renal Impairment, Hepatic Impairment, and CYP2D6 Poor Metabolizer Status on AUVELITY PK

Results are based on plasma concentrations of AUVELITY after 8 days of twice daily dosing. Data are GMRs and 90% CIs. Reference = matched healthy subjects for renal and hepatic impairment studies, and extensive or ultra-extensive CYP2D6 metabolizers. AUC = area under the plasma concentration-time curve from zero to 12 hours; BUP = bupropion; CI = confidence interval; Cmax = maximum plasma concentration; DM = dextromethorphan; GMRs = geometric mean ratios; PK = pharmacokinetics.

Drug Interaction Studies

In Vitro Assessment of Drug Interactions

The potential for dextromethorphan and bupropion to inhibit or induce cytochrome P450 in vitro were evaluated in human liver microsomes.

Bupropion and its metabolites (hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion) are inhibitors of CYP2D6. At therapeutically relevant concentrations dextromethorphan does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A4. Dextromethorphan does not cause induction of CYP1A2, CYP3A4, or CYP2B6.

Dextromethorphan is a substrate of the human P-gp transporter. Dextromethorphan does not inhibit transporters at therapeutically relevant concentrations.

In Vivo Assessment of Drug Interactions

The effects of other drugs on the exposure to AUVELITY are summarized in Figure 2 [see Dosage and Administration (2.4)].

Figure 2 Effects of Co-administered Compounds on AUVELITY PK

Results are based on steady state plasma concentrations of twice daily dosing of AUVELITY. Data are GMRs and 90% CIs. AUC = area under the plasma concentration-time curve from zero to 12 hours; BUP = bupropion; CI = confidence interval; Cmax = maximum plasma concentration; DM = dextromethorphan; GMRs = geometric mean ratios; PK = pharmacokinetics.

Digoxin

Literature data showed that digoxin exposure was decreased when a single oral dose of 0.5-mg digoxin was administered 24 hours after a single oral dose of extended-release 150 mg bupropion in healthy volunteers.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

In a 26-week carcinogenicity study in the Tg.rasH2 transgenic mouse, dextromethorphan at oral doses up to 100 mg/kg/day did not show any evidence of carcinogenic potential.

In a two-year carcinogenicity study in rats, dextromethorphan was administered at an oral dose of 50 mg/kg/day. No biologically significant tumor findings were observed. This dose is approximately 5.4 times the maximum recommended human dose (MRHD) of 90 mg/day on a mg/m2 basis.

Lifetime carcinogenicity studies were performed in rats and mice at bupropion doses up to 300 and 150 mg/kg/day, respectively. These doses are approximately 13.9 and 3.5 times the MRHD, respectively, on a mg/m2 basis. In the rat study there was an increase in nodular proliferative lesions of the liver at doses of 100 to 300 mg/kg/day (approximately 4.6 to 13.9 times the MRHD on a mg/m2 basis); lower doses were not tested. The question of whether or not such lesions may be precursors of neoplasms of the liver is currently unresolved. Similar liver lesions were not seen in the mouse study, and no increase in malignant tumors of the liver and other organs was seen in either study.

Mutagenesis

Dextromethorphan was negative in in vitro (bacterial reverse mutation, chromosomal aberration in human lymphocytes) and in vivo (mouse micronucleus) assays.

Bupropion produced a positive response (2 to 3 times control mutation rate) in 2 of 5 strains in the Ames bacterial mutagenicity assay. Bupropion produced an increase in chromosomal aberrations in 1 of 3 in vivo rat bone marrow cytogenetic studies.

Impairment of fertility

When dextromethorphan was co-administered with quinidine orally (0/0, 5/100, 15/100, and 50/100 mg/kg/day) to male and female rats prior to and during mating, and continuing to Day 7 of gestation in females, no effect on fertility was observed up to the highest dose tested.

There were no effects on male and female fertility when rats were administered oral doses of bupropion up to 300 mg/kg/day (approximately 14 times the MRHD on a mg/m2 basis) in females prior to mating and either through Day 13 of gestation or through lactation, and in males for 60 days prior to and through mating. However, doses of 200 mg/kg/day (approximately 9 times the MRHD on a mg/m2 basis) or greater, caused transient ataxia or behavioral changes in adult female rats. There were also no adverse effects on fertility, reproduction, or growth and development of male or female offspring.

The effects on fertility of administering dextromethorphan and bupropion in combination are not known at this time.