Bupropion Hydrochloride Er (Xl)

1.1 Major Depressive Disorder (MDD) Bupropion hydrochloride extended-release tablets (XL) are indicated for the treatment of major depressive disorder (MDD), as defined by the Diagnostic and Statistical Manual (DSM). The efficacy of the immediate-release formulation of bupropion was established in two 4-week controlled inpatient trials and one 6-week controlled outpatient trial of adult patients with MDD. The efficacy of the sustained-release formulation of bupropion in the maintenance treatment of MDD was established in a long-term (up to 44 weeks), placebo-controlled trial in patients who had responded to bupropion in an 8-week study of acute treatment [see CLINICAL STUDIES (14.1)].

1.2 Seasonal Affective Disorde (SAD) Bupropion hydrochloride extended-release tablets (XL) are indicated for the prevention of seasonal major depressive episodes in patients with a diagnosis of seasonal affective disorder (SAD). The efficacy of bupropion hydrochloride extended-release tablets (XL) in the prevention of seasonal major depressive episodes was established in 3 placebo-controlled trials in adult outpatients with a history of MDD with an autumn-winter seasonal pattern as defined in the DSM [see CLINICAL STUDIES (14.2)].

Bupropion Hydrochloride Extended-Release Tablets USP (XL), 150 mg of bupropion hydrochloride, are white to pale yellow, round biconvex tablet with imprinting “YH 102” on one side and plain on the other side. Bupropion Hydrochloride Extended-Release Tablets USP (XL), 300 mg of bupropion hydrochloride, are white to pale yellow, round biconvex tablet with imprinting “YH 101” on one side and plain on the other side.

Bupropion hydrochloride extended-release tablets (XL) are contraindicated in patients with seizure disorder. Bupropion hydrochloride extended-release tablets (XL) are contraindicated in patients with a current or prior diagnosis of bulimia or anorexia nervosa as a higher incidence of seizures was observed in such patients treated with bupropion hydrochloride extended-release tablets (XL) [see WARNINGS AND PRECAUTIONS (5.3)]. Bupropion hydrochloride extended-release tablets (XL) are contraindicated in patients undergoing abrupt discontinuation of alcohol, benzodiazepines, barbiturates, and antiepileptic drugs [see WARNINGS AND PRECAUTIONS (5.3) and DRUG INTERACTIONS (7.3)]. The use of MAOIs (intended to treat psychiatric disorders) concomitantly with bupropion hydrochloride extended-release tablets (XL) or within 14 days of discontinuing treatment with bupropion hydrochloride extended-release tablets (XL) is contraindicated. There is an increased risk of hypertensive reactions when bupropion hydrochloride extended-release tablets (XL) is used concomitantly with MAOIs. The use of bupropion hydrochloride extended-release tablets (XL) within 14 days of discontinuing treatment with an MAOI is also contraindicated. Starting bupropion hydrochloride extended-release tablets (XL) in a patient treated with reversible MAOIs such as linezolid or intravenous methylene blue is contraindicated [see DOSAGE AND ADMINISTRATION (2.9), WARNINGS AND PRECAUTIONS (5.4) and DRUG INTERACTIONS (7.6)]. Bupropion hydrochloride extended-release tablets (XL) are contraindicated in patients with known hypersensitivity to bupropion or other ingredients of bupropion hydrochloride extended-release tablets (XL). Anaphylactoid/anaphylactic reactions and Stevens-Johnson syndrome have been reported [see WARNINGS AND PRECAUTIONS (5.8)].

5.1 Suicidal Thoughts and Behaviors in Children, Adolescents, and Young Adults Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (Selective Serotonin Reuptake Inhibitors [SSRIs] and others) show that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18 to 24) with major depressive disorder (MDD) and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older. The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4,400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk differences (drug vs. placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1,000 patients treated) are provided in Table 1. Table 1: Risk Differences in the Number of Suicidality Cases by Age Group in the Pooled Placebo-Controlled Trials of Antidepressants in Pediatric and Adult Patients Age Range Drug-Placebo Difference in Number of Cases of Suicidality per 1,000 Patients Treated Increases Compared to Placebo <18 years 14 additional cases 18-24 years 5 additional cases Decreases Compared to Placebo 25-64 years 1 fewer case ≥65 years 6 fewer cases No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide. It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression. All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases [see BOXED WARNING and USE IN SPECIFIC POPULATIONS (8.4)]. The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality. Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient's presenting symptoms. Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to healthcare providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for bupropion hydrochloride extended-release tablets (XL) should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose.

5.2 Neuropsychiatric Adverse Events and Suicide Risk in Smoking Cessation Treatment Bupropion hydrochloride extended-release tablets (XL) are not approved for smoking cessation treatment; however, bupropion HCl sustained-release is approved for this use. Serious neuropsychiatric adverse events have been reported in patients taking bupropion for smoking cessation. These postmarketing reports have included changes in mood (including depression and mania), psychosis, hallucinations, paranoia, delusions, homicidal ideation, aggression, hostility, agitation, anxiety, and panic, as well as suicidal ideation, suicide attempt, and completed suicide [see Adverse Reactions ( 6.2)] . Some patients who stopped smoking may have been experiencing symptoms of nicotine withdrawal, including depressed mood. Depression, rarely including suicidal ideation, has been reported in smokers undergoing a smoking cessation attempt without medication. However, some of these adverse events occurred in patients taking bupropion who continued to smoke. Neuropsychiatric adverse events occurred in patients without and with pre-existing psychiatric disease; some patients experienced worsening of their psychiatric illnesses. Observe patients for the occurrence of neuropsychiatric adverse events. Advise patients and caregivers that the patient should stop taking bupropion hydrochloride extended-release tablets (XL) and contact a healthcare provider immediately if agitation, depressed mood, or changes in behavior or thinking that are not typical for the patient are observed, or if the patient develops suicidal ideation or suicidal behavior. The healthcare provider should evaluate the severity of the adverse events and the extent to which the patient is benefiting from treatment, and consider options including continued treatment under closer monitoring, or discontinuing treatment. In many postmarketing cases, resolution of symptoms after discontinuation of bupropion was reported. However, the symptoms persisted in some cases; therefore, ongoing monitoring and supportive care should be provided until symptoms resolve.

5.3 Seizure Bupropion hydrochloride extended-release tablets (XL) can cause seizure. The risk of seizure is dose-related. The dose should not exceed 300 mg once daily. Increase the dose gradually. Discontinue bupropion hydrochloride extended-release tablets (XL) and do not restart treatment if the patient experiences a seizure. The risk of seizures is also related to patient factors, clinical situations, and concomitant medications that lower the seizure threshold. […]

The following adverse reactions are discussed in greater detail in other sections of the labeling: Suicidal thoughts and behaviors in children, adolescents, and young adults [see WARNINGS AND PRECAUTIONS (5.1)] Neuropsychiatric adverse events and suicide risk in smoking cessation treatment [see WARNINGS AND PRECAUTIONS (5.2)] Seizure [see WARNINGS AND PRECAUTIONS (5.3)] Hypertension [see WARNINGS AND PRECAUTIONS (5.4)] Activation of mania or hypomania [see WARNINGS AND PRECAUTIONS (5.5)] Psychosis and other neuropsychiatric events [see WARNINGS AND PRECAUTIONS (5.6)] Angle-Closure Glaucoma [see WARNINGS AND PRECAUTIONS (5.7)] Hypersensitivity reactions [see WARNINGS AND PRECAUTIONS (5.8)]

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 practice. Commonly Observed Adverse Reactions in Controlled Clinical Trials of Sustained-Release Bupropion Hydrochloride Adverse reactions that occurred in at least 5% of patients treated with bupropion HCl sustained-release (300 mg and 400 mg per day) and at a rate at least twice the placebo rate are listed below. 300 mg/day of bupropion HCl sustained-release: anorexia, dry mouth, rash, sweating, tinnitus, and tremor. 400 mg/day of bupropion HCl sustained-release: abdominal pain, agitation, anxiety, dizziness, dry mouth, insomnia, myalgia, nausea, palpitation, pharyngitis, sweating, tinnitus, and urinary frequency. Bupropion hydrochloride extended-release tablets (XL) have been demonstrated to have similar bioavailability both to the immediate-release and sustained-release formulations of bupropion. The information included under this subsection and under subsection 6.2 is based primarily on data from controlled clinical trials with the sustained-release and extended-release formulations of bupropion hydrochloride. Major Depressive Disorder Adverse Reactions Leading to Discontinuation of Treatment with Bupropion HCl Immediate-Release, Bupropion HCl Sustained-Release, and Bupropion HCl Extended-Release in Major Depressive Disorder Trials. In placebo-controlled clinical trials with bupropion HCl sustained-release, 4%, 9%, and 11% of the placebo, 300 mg/day and 400 mg/day groups, respectively, discontinued treatment because of adverse reactions. The specific adverse reactions leading to discontinuation in at least 1% of the 300 mg/day or 400 mg/day groups and at a rate at least twice the placebo rate are listed in Table 2. Table 2: Treatment Discontinuation Due to Adverse Reactions in Placebo-Controlled Trials in MDD Adverse Reaction Term Placebo (n=385) Bupropion HCl Sustained- Release 300 mg/day (n=376) Bupropion HCl Sustained- Release 400 mg/day (n=114) Rash 0.0% 2.4% 0.9% Nausea 0.3% 0.8% 1.8% Agitation 0.3% 0.3% 1.8% Migraine 0.3% 0.0% 1.8% In clinical trials with bupropion HCl immediate-release, 10% of patients and volunteers discontinued due to an adverse reaction. Reactions resulting in discontinuation (in addition to those listed above for the sustained-release formulation) included vomiting, seizures, and sleep disturbances. Adverse Reactions Occurring at an Incidence of >1% in Patients Treated with Bupropion HCl Immediate-Release or Bupropion HCl Sustained-Release in MDD Table 3 summarizes the adverse reactions that occurred in placebo-controlled trials in patients treated with bupropion HCl sustained-release 300 mg/day and 400 mg/day. These include reactions that occurred in either the 300 mg or 400 mg group at an incidence of 1% or more and were more frequent than in the placebo group. Table 3: Adverse Reactions in Placebo-Controlled Trials in Patients with MDD Body System/Adverse Reaction Placebo (n=385) Bupropion HCl Sustained-Release 300 mg/day (n=376) Bupropion HCl Sustained-Release 400 mg/day (n=114) Body (General) Headache 23% 26% 25% Infection 6% 8% 9% Abdominal pain 2% 3% 9% Asthenia 2% 2% 4% Chest pain 1% 3% 4% Pain 2% 2% 3% Fever — 1% 2% Cardiovascular Palpitation 2% 2% 6% Flushing — 1% 4% Migraine 1% 1% 4% Hot flashes 1% 1% 3% Digestive Dry mouth 7% 17% 24% Nausea 8% 13% 18% Constipation 7% 10% 5% Diarrhea 6% 5% 7% Anorexia 2% 5% 3% Vomiting 2% 4% 2% Dysphagia 0% 0% 2% Musculoskeletal Myalgia 3% 2% 6% Arthralgia 1% 1% 4% Arthritis 0% 0% 2% Twitch — 1% 2% Nervous System Insomnia 6% 11% 16% Dizziness 5% 7% 11% Agitation 2% 3% 9% Anxiety 3% 5% 6% Tremor 1% 6% 3% Nervousness 3% 5% 3% Somnolence 2% 2% 3% Irritability 2% 3% 2% Memory decreased 1% — 3% Paresthesia 1% 1% 2% Central nervous system stimulation 1% 2% 1% Respiratory Pharyngitis 2% 3% 11% Pharyngitis 2% 3% 1% Increased cough 1% 1% 2% Skin Sweating 2% 6% 5% Rash 1% 5% 4% Pruritus 2% 2% 4% Urticaria 0% 2% 1% Special Senses Tinnitus 2% 6% 6% Taste perversion — 2% 4% Blurred vision or diplopia 2% 3% 2% Urogenital Urinary frequency 2% 2% 5% Urinary urgency 0% — 2% Vaginal hemorrhage* — 0% 2% Urinary tract infection —† 1% 0% *Incidence based on the number of female patients. †Hyphen denotes adverse reactions occurring in greater than 0 but less than 0.5% of patients. The following additional adverse reactions occurred in controlled trials of bupropion HCl immediate-release (300 to 600 mg per day) at an incidence of at least 1% more frequently than in the placebo group were: cardiac arrhythmia (5% vs. 4%), hypertension (4% vs. 2%), hypotension (3% vs. 2%), menstrual complaints (5% vs. 1%), akathisia (2% vs. 1%), impaired sleep quality (4% vs. 2%), sensory disturbance (4% vs. 3%), confusion (8% vs. 5%), decreased libido (3% vs. 2%), hostility (6% vs. 4%), auditory disturbance (5% vs. 3%), and gustatory disturbance (3% vs. 1%). Seasonal Affective Disorder In placebo-controlled clinical trials in SAD, 9% of patients treated with bupropion hydrochloride extended-release tablets (XL) and 5% of patients treated with placebo discontinued treatment because of adverse reactions. The adverse reactions leading to discontinuation in at least 1% of patients treated with bupropion and at a rate numerically greater than the placebo rate were insomnia (2% vs. <1%) and headache (1% vs. <1%). Table 4 summarizes the adverse reactions that occurred in patients treated with bupropion hydrochloride extended-release tablets (XL) for up to approximately 6 months in 3 placebo-controlled trials. These include reactions that occurred at an incidence of 2% or more and were more frequent than in the placebo group. Table 4: Adverse Reactions in Placebo-Controlled Trials in Patients with SAD System Organ Class/Preferred Term Placebo (n=511) Bupropion HCl Extended-Release (n=537) Gastrointestinal Disorder Dry mouth 15% 26% Nausea 8% 13% Constipation 2% 9% Flatulence 3% 6% Abdominal pain <1% 2% Nervous System Disorders Headache 26% 34% Dizziness 5% 6% Tremor <1% 3% Infections and Infestations Nasopharyngitis 12% 13% Upper respiratory tract infection 8% 9% Sinusitis 4% 5% Psychiatric Disorders Insomnia 13% 20% Anxiety 5% 7% Abnormal dreams 2% 3% Agitation <1% 2% Musculoskeletal and Connective Tissue Disorders Myalgia 2% 3% Pain in extremity 2% 3% Respiratory, Thoracic, and Mediastinal Disorders Cough 3% 4% General Disorders and Administration Site Conditions Feeling jittery 2% 3% Skin and Subcutaneous Tissue Disorders Rash 2% 3% Metabolism and Nutrition Disorders Decreased appetite 1% 4% Reproductive System and Breast Disorders Dysmenorrhea <1% 2% Ear and Labyrinth Disorders Tinnitus <1% 3% Vascular Disorders Hypertension 0% 2% Changes in Body Weight Table 5 presents the incidence of body weight changes (≥5 lbs) in the short-term MDD trials using bupropion HCl sustained-release. There was a dose-related decrease in body weight. […]

7.1 Potential for Other Drugs to Affect Bupropion Hydrochloride Extended-Release Tablets (XL) Bupropion is primarily metabolized to hydroxybupropion by CYP2B6. Therefore, the potential exists for drug interactions between bupropion hydrochloride extended-release tablets (XL) and drugs that are inhibitors or inducers of CYP2B6. Inhibitors of CYP2B6 Ticlopidine and Clopidogrel: Concomitant treatment with these drugs can increase bupropion exposures but decrease hydroxybupropion exposure. Based on clinical response, dosage adjustment of bupropion hydrochloride extended-release tablets (XL) may be necessary when coadministered with CYP2B6 inhibitors (e.g., ticlopidine or clopidogrel) [see CLINICAL PHARMACOLOGY (12.3)]. Inducers of CYP2B6 Ritonavir, Lopinavir, and Efavirenz: Concomitant treatment with these drugs can decrease bupropion and hydroxybupropion exposure. Dosage increase of bupropion hydrochloride extended-release tablets (XL) may be necessary when coadministered with ritonavir, lopinavir, or efavirenz but should not exceed the maximum recommended dose [see CLINICAL PHARMACOLOGY (12.3)]. Carbamazepine, Phenobarbital, Phenytoin: While not systemically studied, these drugs may induce metabolism of bupropion and may decrease bupropion exposure [see CLINICAL PHARMACOLOGY (12.3)] . If bupropion is used concomitantly with a CYP inducer, it may be necessary to increase the dose of bupropion, but the maximum recommended dose should not be exceeded.

7.2 Potential for Bupropion Hydrochloride Extended-Release Tablets (XL) to Affect Other Drugs Drugs Metabolized by CYP2D6 Bupropion and its metabolites (erythrohydrobupropion, threohydrobupropion, hydroxybupropion) are CYP2D6 inhibitors. Therefore, coadministration of bupropion hydrochloride extended-release tablets (XL) with drugs that are metabolized by CYP2D6 can increase the exposures of drugs that are substrates of CYP2D6. Such drugs include certain antidepressants (e.g., venlafaxine, nortriptyline, imipramine, desipramine, paroxetine, fluoxetine, and sertraline), antipsychotics (e.g., haloperidol, risperidone, and thioridazine), beta-blockers (e.g., metoprolol), and Type 1C antiarrhythmics (e.g., propafenone, and flecainide). When used concomitantly with bupropion hydrochloride extended-release tablets (XL), it may be necessary to decrease the dose of these CYP2D6 substrates, particularly for drugs with a narrow therapeutic index. Drugs that require metabolic activation by CYP2D6 to be effective (e.g., tamoxifen), theoretically could have reduced efficacy when administered concomitantly with inhibitors of CYP2D6 such as bupropion. Patients treated concomitantly with bupropion hydrochloride extended-release tablets (XL) and such drugs may require increased doses of the drug [see CLINICAL PHARMACOLOGY (12.3)].

7.3 Drugs That Lower Seizure Threshold Use extreme caution when coadministering bupropion hydrochloride extended-release tablets (XL) with other drugs that lower the seizure threshold (e.g., other bupropion products, antipsychotics, antidepressants, theophylline, or systemic corticosteroids). Use low initial doses of bupropion hydrochloride extended-release tablets (XL) and increase the dose gradually [see WARNINGS AND PRECAUTIONS (5.3)].

7.4 Dopaminergic Drugs (Levodopa and Amantadine) Bupropion, levodopa, and amantadine have dopamine agonist effects. CNS toxicity has been reported when bupropion was coadministered with levodopa or amantadine. Adverse reactions have included restlessness, agitation, tremor, ataxia, gait disturbance, vertigo, and dizziness. It is presumed that the toxicity results from cumulative dopamine agonist effects. Use caution when administering bupropion hydrochloride extended-release tablets (XL) concomitantly with these drugs.

7.5 Use with Alcohol In postmarketing experience, there have been rare reports of adverse neuropsychiatric events or reduced alcohol tolerance in patients who were drinking alcohol during treatment with bupropion hydrochloride extended-release tablets (XL). The consumption of alcohol during treatment with bupropion hydrochloride extended-release tablets (XL) should be minimized or avoided. 7.6 MAO Inhibitors Bupropion inhibits the reuptake of dopamine and norepinephrine. Concomitant use of MAOIs and bupropion is contraindicated because there is an increased risk of hypertensive reactions if bupropion is used concomitantly with MAOIs. Studies in animals demonstrate that the acute toxicity of bupropion is enhanced by the MAO inhibitor phenelzine. At least 14 days should elapse between discontinuation of an MAOI intended to treat depression and initiation of treatment with bupropion hydrochloride extended-release tablets (XL). Conversely, at least 14 days should be allowed after stopping bupropion hydrochloride extended-release tablets (XL) before starting an MAOI antidepressant [see Dosage and Administration ( 2.8, 2.9) and CONTRAINDICATIONS (4)].

7.7 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 during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for Antidepressants at 1-844-405-6185 or visiting online at https://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/antidepressants/. Risk Summary 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 ( see Clinical Considerations). When bupropion was administered to pregnant rats during organogenesis, there was no evidence of fetal malformations at doses up to approximately 10 times the maximum recommended human dose (MRHD) of 450 mg/day. When given to pregnant rabbits during organogenesis, non-dose-related increases in incidence of fetal malformations and skeletal variations were observed at doses approximately equal to the MRHD and greater. Decreased fetal weights were seen at doses twice the MRHD and greater ( see Animal Data). The estimated background risk for major birth defects and miscarriage are unknown for the indicated population. All pregnancies have a background rate 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 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 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 has a limited number of exposed cases with cardiovascular malformations, and a case-controlled study (6,853 infants with cardiovascular malformations and 5,753 with non- cardiovascular malformations) 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 left ventricular outflow tract obstruction (LVOTO) are inconsistent and do not allow conclusions regarding possible association. The United Healthcare database lacked sufficient power to evaluate this association; the NBDPS found increased risk for LVOTO (n=10; adjusted odds ratio (OR)=2.6; 95% CI: 1.2, 5.7), and the Slone Epidemiology case control study did not find increased risk for LVOTO. Study findings on bupropion exposure during the first trimester and risk for ventricular septal defect (VSD) are inconsistent and do not allow conclusions regarding a possible association. 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 an 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 rats and rabbits, bupropion was administered orally during the period of organogenesis at doses of up to 450 and 150 mg/kg/day, respectively (approximately 10 and 6 times the MRHD, respectively, on a mg/m 2 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 equal to the MRHD on a mg/m 2 basis) and greater. Decreased fetal weights were observed at doses of 50 mg/kg/day (approximately 2 times the MRHD on a mg/m 2 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 3 times the MRHD on a mg/m 2 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 have not identified a clear association of adverse reactions in the breastfed infant. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for bupropion hydrochloride extended-release tablets (XL) and any potential adverse effects on the breastfed child from bupropion hydrochloride extended-release tablets (XL) or from the underlying maternal condition. Data In a lactation study of ten 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.

8.4 Pediatric Use Safety and effectiveness in the pediatric population have not been established. When considering the use of bupropion hydrochloride extended-release tablets (XL) in a child or adolescent, balance the potential risks with the clinical need [see BOXED WARNING and WARNINGS AND PRECAUTIONS (5.1)].

8.5 Geriatric Use Of the approximately 6,000 patients who participated in clinical trials with bupropion hydrochloride sustained-release tablets (depression and smoking cessation studies), 275 were ≥65 years old and 47 were ≥75 years old. In addition, several hundred patients ≥65 years of age participated in clinical trials using the immediate-release formulation of bupropion hydrochloride (depression studies). No overall differences in safety or effectiveness were observed between these subjects and younger subjects. […]