Bupropion Hydrochloride SR

1 INDICATIONS AND USAGE Bupropion Hydrochloride Extended-Release Tablets (SR) are indicated as an aid to smoking cessation treatment. Bupropion Hydrochloride Extended-Release Tablets (SR) are an aminoketone agent indicated as an aid to smoking cessation treatment. ( 1 )

2 DOSAGE AND ADMINISTRATION Starting dose: 150 mg per day for first 3 days. ( 2.1 ) General: Increase dose gradually to reduce seizure risk. ( 2.1 , 5.3 ) Begin dosing one week before quit day. ( 2.1 ) After 3 days, increase the dose to 300 mg per day, given as 150 mg twice daily at an interval of at least 8 hours. ( 2.1 ) May be used with a nicotine transdermal system. ( 2.5 ) Moderate to severe hepatic impairment: 150 mg every other day. ( 2.6 , 8.7 ) Mild hepatic impairment: Consider reducing the dose and/or frequency of dosing. ( 2.6 , 8.7 ) Renal impairment: Consider reducing the dose and/or frequency. ( 2.7 , 8.6 ) 2.1 Usual Dosage Treatment with bupropion hydrochloride extended-release tablets (SR) should be initiated before the patient’s planned quit day, while the patient is still smoking , because it takes approximately 1 week of treatment to achieve steady-state blood levels of bupropion. The patient should set a “target quit date” within the first 2 weeks of treatment with bupropion hydrochloride extended-release tablets (SR). Dosing To minimize the risk of seizure: Begin dosing with one 150-mg tablet per day for 3 days. Increase dose to 300 mg per day given as one 150-mg tablet twice each day with an interval of at least 8 hours between each dose. Do not exceed 300 mg per day. Bupropion hydrochloride extended-release tablets (SR) should be swallowed whole and not crushed, divided, or chewed, as this may lead to an increased risk of adverse effects including seizures [see Warnings and Precautions ( 5.3 )] . Bupropion hydrochloride extended-release tablets (SR) may be taken with or without food [see Clinical Pharmacology ( 12.3 )] . 2.2 Duration of Treatment Treatment with bupropion hydrochloride extended-release tablets (SR) should be continued for 7 to 12 weeks. If the patient has not quit smoking after 7 to 12 weeks, it is unlikely that he or she will quit during that attempt so treatment with bupropion hydrochloride extended-release tablets (SR) should probably be discontinued and the treatment plan reassessed. The goal of therapy with bupropion hydrochloride extended-release tablets (SR) is complete abstinence. Discuss discontinuing treatment with bupropion hydrochloride extended-release tablets (SR) after 12 weeks if the patient feels ready but consider whether the patient may benefit from ongoing treatment. Patients who successfully quit after 12 weeks of treatment but do not feel ready to discontinue treatment should be considered for ongoing therapy with bupropion hydrochloride extended-release tablets (SR); longer treatment should be guided by the relative benefits and risks for individual patients. It is important that patients continue to receive counseling and support throughout treatment with bupropion hydrochloride extended-release tablets (SR) and for a period of time thereafter. 2.3 Individualization of Therapy Patients are more likely to quit smoking and remain abstinent if they are seen frequently and receive support from their physicians or other healthcare professionals. It is important to ensure that patients read the instructions provided to them and have their questions answered. Physicians should review the patient’s overall smoking cessation program that includes treatment with bupropion hydrochloride extended-release tablets (SR). Patients should be advised of the importance of participating in the behavioral interventions, counseling, and/or support services to be used in conjunction with bupropion hydrochloride extended-release tablets (SR) [see Medication Guide] . Patients who fail to quit smoking during an attempt may benefit from interventions to improve their chances for success on subsequent attempts. Patients who are unsuccessful should be evaluated to determine why they failed. A new quit attempt should be encouraged when factors that contributed to failure can be eliminated or reduced, and conditions are more favorable. 2.4 Maintenance Tobacco dependence is a chronic condition. S…

5 WARNINGS AND PRECAUTIONS Neuropsychiatric adverse events: Postmarketing reports of serious or clinically significant neuropsychiatric adverse events 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. Observe patients attempting to quit smoking with bupropion hydrochloride extended-release tablets (SR) for the occurrence of such symptoms and instruct them to discontinue bupropion hydrochloride extended-release tablets (SR) and contact a healthcare provider if they experience such adverse events. ( 5.2 ) Seizure risk: The risk is dose-related. Can minimize risk by gradually increasing the dose and limiting daily dose to 300 mg. Discontinue if seizure occurs. ( 4 , 5.3 , 7.3 ) Hypertension: Bupropion hydrochloride extended-release tablets (SR) can increase blood pressure. Monitor blood pressure before initiating treatment and periodically during treatment, especially if used with nicotine replacement. ( 5.4 ) Activation of mania/hypomania: Screen patients for bipolar disorder and monitor for these symptoms. ( 5.5 ) Psychosis and other neuropsychiatric reactions. Instruct patients to contact a healthcare professional if reactions occur. ( 5.6 ) Angle-closure glaucoma: Angle-closure glaucoma has occurred in patients with untreated anatomically narrow angles treated with antidepressants. ( 5.7 ) 5.1 Suicidal Thoughts and Behaviors in Children, Adolescents, and Young Adults Although bupropion hydrochloride extended-release tablets (SR) are not indicated for treatment of depression, it contains the same active ingredient as the antidepressant medications WELLBUTRIN ® , WELLBUTRIN SR ® , and WELLBUTRIN XL ® . Antidepressants increased the risk of suicidal thoughts and behavior in children, adolescents, and young adults in short-term trials. 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 MDD and other psychiatric disorders. Short-term clinical trials did not show an increase in the risk of suicidality with antidepressants compared with placebo in adults beyond age 24; there was a reduction with antidepressants compared with 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 subjects. 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 subjects. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger subjects 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 differe…

4 CONTRAINDICATIONS Bupropion Hydrochloride Extended-Release Tablets (SR) are contraindicated in patients with a seizure disorder. Bupropion Hydrochloride Extended-Release Tablets (SR) 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 the immediate-release formulation of bupropion [see Warnings and Precautions ( 5.3 )] . Bupropion Hydrochloride Extended-Release Tablets (SR) are contraindicated in patients undergoing abrupt discontinuation of alcohol, benzodiazepines, barbiturates, and antiepileptic drugs [see Warnings and Precautions ( 5.3 ), Drug Interactions ( 7.3 )] . The use of MAOIs (intended to treat psychiatric disorders) concomitantly with Bupropion Hydrochloride Extended-Release Tablets (SR) or within 14 days of discontinuing treatment with Bupropion Hydrochloride Extended-Release Tablets (SR) is contraindicated. There is an increased risk of hypertensive reactions when Bupropion Hydrochloride Extended-Release Tablets (SR) are used concomitantly with MAOIs. The use of Bupropion Hydrochloride Extended-Release Tablets (SR) within 14 days of discontinuing treatment with an MAOI is also contraindicated. Starting Bupropion Hydrochloride Extended-Release Tablets (SR) in a patient treated with reversible MAOIs such as linezolid or intravenous methylene blue is contraindicated [see Dosage and Administration ( 2.8 ), Warnings and Precautions ( 5.4 ), Drug Interactions ( 7.6 )] . Bupropion Hydrochloride Extended-Release Tablets (SR) are contraindicated in patients with a known hypersensitivity to bupropion or other ingredients of Bupropion Hydrochloride Extended-Release Tablets (SR). Anaphylactoid/anaphylactic reactions and Stevens-Johnson syndrome have been reported [see Warnings and Precautions ( 5.8 )] . Seizure disorder. ( 4 , 5.3 ) Current or prior diagnosis of bulimia or anorexia nervosa. ( 4 , 5.3 ) Abrupt discontinuation of alcohol, benzodiazepines, barbiturates, antiepileptic drugs. ( 4 , 5.3 ) Monoamine Oxidase Inhibitors (MAOIs): Do not use MAOIs intended to treat psychiatric disorders with Bupropion Hydrochloride Extended-Release Tablets (SR) or within 14 days of stopping treatment with Bupropion Hydrochloride Extended-Release Tablets (SR). Do not use Bupropion Hydrochloride Extended-Release Tablets (SR) within 14 days of stopping an MAOI intended to treat psychiatric disorders. In addition, do not start Bupropion Hydrochloride Extended-Release Tablets (SR) in a patient who is being treated with linezolid or intravenous methylene blue. ( 4 , 7.6 ) Known hypersensitivity to bupropion or other ingredients of Bupropion Hydrochloride Extended-Release Tablets (SR). ( 4 , 5.8 )

7 DRUG INTERACTIONS CYP2B6 inducers: Dose increase may be necessary if coadministered with CYP2B6 inducers (e.g., ritonavir, lopinavir, efavirenz, carbamazepine, phenobarbital and phenytoin) based on clinical response, but should not exceed the maximum recommended dose. ( 7.1 ) Drugs metabolized by CYP2D6: Bupropion inhibits CYP2D6 and can increase concentrations of: antidepressants (e.g., venlafaxine, nortriptyline, imipramine, desipramine, paroxetine, fluoxetine, sertraline), antipsychotics (e.g., haloperidol, risperidone, thioridazine), beta-blockers (e.g., metoprolol), and Type 1C antiarrhythmics (e.g., propafenone, flecainide). Consider dose reduction when using with bupropion. ( 7.2 ) Digoxin: May decrease plasma digoxin levels. Monitor digoxin levels. ( 7.2 ) Drugs that lower seizure threshold: Dose bupropion hydrochloride extended-release tablets (SR) with caution. ( 5.3 , 7.3 ) Dopaminergic drugs (levodopa and amantadine): Central nervous system (CNS) toxicity can occur when used concomitantly with bupropion hydrochloride extended-release tablets (SR). ( 7.4 ) MAOIs: Increased risk of hypertensive reactions can occur when used concomitantly with bupropion hydrochloride extended-release tablets (SR). ( 7.6 ) Drug-laboratory test interactions: Bupropion hydrochloride extended-release tablets (SR) can cause false-positive urine test results for amphetamines.( 7.8 ) 7.1 Potential for Other Drugs to Affect Bupropion Hydrochloride Extended-Release Tablets (SR) Bupropion is primarily metabolized to hydroxybupropion by CYP2B6. Therefore, the potential exists for drug interactions between bupropion hydrochloride extended-release tablets (SR) and drugs that are inhibitors or inducers of CYP2B6. Inhibitors of CYP2B6 Ticlopidine and Clopidogrel: Concomitant treatment with these drugs can increase bupropion exposure but decrease hydroxybupropion exposure. Based on clinical response, dosage adjustment of bupropion hydrochloride extended-release tablets (SR) 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 (SR) may be necessary when coadministered with ritonavir, lopinavir, or efavirenz [see Clinical Pharmacology ( 12.3 )] but should not exceed the maximum recommended dose. Carbamazepine, Phenobarbital, Phenytoin: While not systematically studied, these drugs may induce the 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 (SR) 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 (SR) 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, thioridazine), beta-blockers (e.g., metoprolol), and Type 1C antiarrhythmics (e.g., propafenone and flecainide). When used concomitantly with bupropion hydrochloride extended-release tablets (SR), 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…

8.1 Pregnancy Pregnancy Category C. Risk Summary Data from epidemiological studies of pregnant women exposed to bupropion in the first trimester indicate no increased risk of congenital malformations overall. All pregnancies, regardless of drug exposure, have a background rate of 2% to 4% for major malformations, and 15% to 20% for pregnancy loss. No clear evidence of teratogenic activity was found in reproductive developmental studies conducted in rats and rabbits; however, in rabbits, slightly increased incidences of fetal malformations and skeletal variations were observed at doses approximately 2 times the maximum recommended human dose (MRHD) and greater and decreased fetal weights were seen at doses three times the MRHD and greater. Bupropion hydrochloride extended-release tablets (SR) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Clinical Considerations Pregnant smokers should be encouraged to attempt cessation using educational and behavioral interventions before pharmacological approaches are used. 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. 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 and a case-control study (6,853 infants with cardiovascular malformations and 5,763 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 for left ventricular outflow tract obstruction (LVOTO) are inconsistent and do not allow conclusions regarding a possible association. The United Healthcare database lacked sufficient power to evaluate this association; the NBDPS found increased risk for LVOTO (n=10; adjusted 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 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 rats and rabbits, bupropion was administered orally during the period of organogenesis at doses of up to 450 and 150 mg per kg per day, respectively (approximately 15 and 10 times the MRHD respectively, on a mg per m 2 basis). No clear evidence of teratogenic activity was found in either species; however, in rabbits, slightly increased incidences of fetal malformations and skeletal variations were observed at the lowest dose tested (25 mg per kg per day, approximately 2 times the MRHD on a mg per…

8.3 Nursing Mothers Bupropion and its metabolites are present in human milk. 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 per kg daily consumption) to bupropion and its active metabolites was 2% of the maternal weight-adjusted dose. Exercise caution when bupropion hydrochloride extended-release tablets (SR) are administered to a nursing woman.

6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling: Suicidal thoughts and behaviors in adolescents and young adults [see Boxed Warning, W arnings 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 reactions [see Warnings and Precautions ( 5.6 )] Angle-closure glaucoma [see Warnings and Precautions ( 5.7 )] Hypersensitivity reactions [see Warnings and Precautions ( 5.8 )] Most common adverse reactions (incidence ≥5% and ≥1% more than placebo rate) are insomnia, rhinitis, dry mouth, dizziness, nervous disturbance, anxiety, nausea, constipation, and arthralgia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Epic Pharma, LLC at 1-888-374-2791 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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 with rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Adverse Reactions Leading to Discontinuation of Treatment Adverse reactions were sufficiently troublesome to cause discontinuation of treatment in 8% of the 706 subjects treated with bupropion hydrochloride extended-release tablets (SR) and 5% of the 313 patients treated with placebo. The more common events leading to discontinuation of treatment with bupropion hydrochloride extended-release tablets (SR) included nervous system disturbances (3.4%), primarily tremors, and skin disorders (2.4%), primarily rashes. Commonly Observed Adverse Reactions The most commonly observed adverse reactions consistently associated with the use of bupropion hydrochloride extended-release tablets (SR) were dry mouth and insomnia. The incidence of dry mouth and insomnia may be related to the dose of bupropion hydrochloride extended-release tablets (SR). The occurrence of these adverse reactions may be minimized by reducing the dose of bupropion hydrochloride extended-release tablets (SR). In addition, insomnia may be minimized by avoiding bedtime doses. Adverse reactions reported in the dose-response and comparator trials are presented in Table 2 and Table 3, respectively. Reported adverse reactions were classified using a COSTART-based dictionary. Table 2. Adverse Reactions Reported by at Least 1% of Subjects and at a Greater Frequency than Placebo in the Dose-Response Trial Adverse Reaction Bupropion Hydrochloride Extended-Release Tablets (SR) 100 to 300 mg/day ( n=461) % P lacebo ( n=150) % Body (General) Neck pain 2 <1 Allergic reaction 1 0 Cardiovascular Hot flashes 1 0 Hypertension 1 <1 Digestive Dry mouth 11 5 Increased appetite 2 <1 Anorexia 1 <1 Musculoskeletal Arthralgia 4 3 Myalgia 2 1 Nervous system Insomnia 31 21 Dizziness 8 7 Tremor 2 1 Somnolence 2 1 Thinking abnormality 1 0 Respiratory Bronchitis 2 0 Skin Pruritus 3 <1 Rash 3 <1 Dry skin 2 0 Urticaria 1 0 Special senses Taste perversion 2 <1 Table 3. Adverse Reactions Reported by at Least 1% of Subjects on Active Treatment and at a Greater Frequency than Placebo in the Comparator Trial Adverse Experience (COSTART Term) Bupropion Hydrochloride Extended-Release Tablets (SR) 300 mg/day ( n=243) % Nicotine Transdermal System (NTS) 21 mg/day (n=243) % Bupropion Hydrochloride Extended-Release Tablets (SR) and NTS (n=244) % Placebo (n=159) % Body Abdominal pain 3 4 1 1 Accidental injury 2 2 1 1 Chest pain <1 1 3 1 Neck pain 2 1 <1 0 Facial edema <1 0 1 0 Cardiovascular Hypertension 1 <1 2 0 Palpitations 2 0 1 0 Digestive Nausea 9 7 11 4 Dry mouth 10 4 9 4 Constipation 8 4 9 3 Diarrhea 4 4 3 1 Anorexia 3 1 5 1 Mouth ulcer 2 1 1 1 Thirst…