Contrave Extended-Release

1 INDICATIONS AND USAGE CONTRAVE is indicated in combination with a reduced-calorie diet and increased physical activity to reduce excess body weight and maintain weight reduction long term in adults with obesity or overweight in the presence of at least one weight-related comorbid condition. CONTRAVE is a combination of naltrexone, an opioid antagonist, and bupropion, an aminoketone antidepressant, indicated in combination with a reduced-calorie diet and increased physical activity to reduce excess body weight and maintain weight reduction long term in adults with obesity or overweight in the presence of at least one weight-related comorbid condition. ( 1 ) Limitations of Use: The effect of CONTRAVE on cardiovascular morbidity and mortality has not been established. ( 1 ) Coadministration with other naltrexone-containing products is not recommended. Coadministration with other bupropion-containing products is contraindicated. ( 1 , 4 ) Limitations of Use: The effect of CONTRAVE on cardiovascular morbidity and mortality has not been established. CONTRAVE contains naltrexone and bupropion. Coadministration with other naltrexone-containing products is not recommended. Coadministration with other bupropion-containing products is contraindicated.

2 DOSAGE AND ADMINISTRATION CONTRAVE dose escalation schedule ( 2.1 ): Morning Dose Evening Dose Week 1 1 tablet None Week 2 1 tablet 1 tablet Week 3 2 tablets 1 tablet Week 4 – Onward 2 tablets 2 tablets 2.1 Recommended Dosage Initiate and escalate the dosage of CONTRAVE according to the schedule in Table 1: Table 1. Dosage Initiation and Escalation Schedule for CONTRAVE Morning Dose Evening Dose Week 1 1 tablet None Week 2 1 tablet 1 tablet Week 3 2 tablets 1 tablet Week 4 – Onward 2 tablets 2 tablets A total daily dosage of 32 mg of naltrexone hydrochloride (HCl) and 360 mg bupropion HCl (two CONTRAVE 8 mg/90 mg tablets twice daily) is reached at the start of Week 4. CONTRAVE should be taken by mouth in the morning and in the evening. The tablets should not be cut, chewed, or crushed. Total daily doses greater than 32 mg/360 mg per day (two tablets twice daily) are not recommended. In clinical trials, CONTRAVE was administered with meals. However, CONTRAVE should not be taken with a high-fat meal because of a resulting significant increase in bupropion and naltrexone systemic exposure [see Warnings and Precautions (5.3) and Clinical Pharmacology (12.3) ] . Patients may develop elevated blood pressure or heart rate during CONTRAVE treatment; the risk may be greater during the initial three months of therapy [see Warnings and Precautions (5.6) ] . Because patients with hypertension may be at increased risk for developing blood pressure elevations, such patients should be monitored for this potential effect when initiating treatment with CONTRAVE. Response to therapy should be evaluated after 12 weeks at the maintenance dosage. If a patient has not lost at least 5% of baseline body weight, discontinue CONTRAVE, as it is unlikely that the patient will achieve and sustain clinically meaningful weight loss with continued treatment. 2.2 Dose Adjustment in Patients with Renal Impairment In patients with moderate or severe renal impairment, the maximum recommended daily dose for CONTRAVE is two tablets (one tablet each morning and evening). CONTRAVE is not recommended for use in patients with end-stage renal disease [see Use in Specific Population (8.6) and Clinical Pharmacology (12.3) ]. 2.3 Dose Adjustment in Patients with Hepatic Impairment In patients with moderate hepatic impairment, the maximum recommended daily maintenance dose of CONTRAVE is two tablets (one tablet each morning and evening). CONTRAVE is not recommended for use in patients with severe hepatic impairment [see Use in Specific Population (8.7) and Clinical Pharmacology (12.3) ]. 2.4 Switching a Patient To or From a Monoamine Oxidase Inhibitor (MAOI) Antidepressant At least 14 days should elapse between discontinuation of an MAOI intended to treat depression and initiation of therapy with CONTRAVE. Conversely, at least 14 days should be allowed after stopping CONTRAVE before starting an MAOI antidepressant [see Contraindications (4) and Drug Interactions (7.1) ] . 2.5 Concomitant Use with CYP2B6 Inhibitors During concomitant use with CYP2B6 inhibitors (e.g., ticlopidine or clopidogrel), the maximum recommended daily dose of CONTRAVE is two tablets (one tablet each morning and evening) [see Drug Interactions (7.4) and Clinical Pharmacology (12.3) ] .

5 WARNINGS AND PRECAUTIONS Suicidal Behavior and Ideation: Monitor for depression or suicidal thoughts. Discontinue CONTRAVE if symptoms develop. ( 5.1 ) Neuropsychiatric Adverse Events During Smoking Cessation: 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 taking CONTRAVE for the occurrence of such symptoms and instruct them to discontinue CONTRAVE and contact a healthcare provider if they experience such adverse events. ( 5.2 ) Risk of seizure may be minimized by adhering to the recommended dosing schedule and avoiding coadministration with high-fat meal. ( 5.3 ) Increase in Blood Pressure and Heart Rate: Monitor blood pressure and heart rate in all patients, especially those with cardiac or cerebrovascular disease. ( 5.5 ) Hepatotoxicity: Cases of hepatitis and clinically significant liver dysfunction observed with naltrexone exposure. ( 5.7 ) Angle-closure glaucoma: Angle-closure glaucoma has occurred in patients with untreated anatomically narrow angles treated with antidepressants. ( 5.9 ) Use of Antidiabetic Medications: Weight loss may cause hypoglycemia. Monitor blood glucose. ( 5.10 ) 5.1 Suicidal Behavior and Ideation CONTRAVE contains bupropion, a dopamine and norepinephrine re-uptake inhibitor that is similar to some drugs used for the treatment of depression; therefore, the following precautions pertaining to these products should be considered when treating patients with CONTRAVE. Patients with major depressive disorder, 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. In placebo-controlled clinical trials with CONTRAVE for the treatment of obesity in adult patients, no suicides or suicide attempts were reported in studies up to 56 weeks duration with CONTRAVE (equivalent to bupropion doses of 360 mg/day). In these same studies, suicidal ideation was reported by 3 (0.20%) of 1,515 patients treated with placebo compared with 1 (0.03%) of 3,239 treated with CONTRAVE. Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (selective serotonin re-uptake 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 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. CONTRAVE is not approved for use in pediatric patients. The pooled analyses of placebo-controlled trials of antidepressant drugs in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of nine 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 two months) of 11 antidepressant drugs in over 77,000 patients. There was conside…

4 CONTRAINDICATIONS CONTRAVE is contraindicated in Uncontrolled hypertension [see Warnings and Precautions (5.5) ] Seizure disorder or a history of seizures [see Warnings and Precautions (5.3) ] Use of other bupropion-containing products (including, but not limited to, WELLBUTRIN, WELLBUTRIN SR, WELLBUTRIN XL, APLENZIN and ZYBAN) Bulimia or anorexia nervosa, which increase the risk for seizure [see Warnings and Precautions (5.3) ] Chronic opioid or opiate agonist (e.g., methadone) or partial agonists (e.g., buprenorphine) use, or acute opiate withdrawal [see Warnings and Precautions (5.4) and Drug Interactions (7.2) ] Patients undergoing an abrupt discontinuation of alcohol, benzodiazepines, barbiturates, and antiepileptic drugs [see Warnings and Precautions (5.3) and Drug Interactions (7.7) ] Concomitant administration of monoamine oxidase inhibitors (MAOI). At least 14 days should elapse between discontinuation of MAOI and initiation of treatment with CONTRAVE. There is an increased risk of hypertensive reactions when CONTRAVE is used concomitantly with MAOIs. Starting CONTRAVE in a patient treated with reversible MAOIs such as linezolid or intravenous methylene blue is also contraindicated [see Dosage and Administration (2.4) , Drug Interactions (7.1) ] Known allergy to bupropion, naltrexone or any other component of CONTRAVE. Anaphylactoid/anaphylactic reactions and Stevens-Johnson syndrome have been reported with bupropion [see Warnings and Precautions (5.6) ] Uncontrolled hypertension ( 4 ) Seizure disorders, anorexia nervosa or bulimia, or undergoing abrupt discontinuation of alcohol, benzodiazepines, barbiturates, and antiepileptic drugs ( 4 ) Use of other bupropion-containing products ( 4 ) Chronic opioid use ( 4 ) During or within 14 days of taking monoamine oxidase inhibitors (MAOI) ( 4 ) Known allergy to any of the ingredients in CONTRAVE ( 4 )

7 DRUG INTERACTIONS MAOIs: Increased risk of hypertensive reactions can occur when used concomitantly. ( 7.1 ) Drugs Metabolized by CYP2D6: Bupropion inhibits CYP2D6 and can increase concentrations of antidepressants, (e.g., selective serotonin reuptake inhibitors and many tricyclics), antipsychotics (e.g., haloperidol, risperidone and thioridazine), beta-blockers (e.g., metoprolol) and Type 1C antiarrhythmics (e.g., propafenone and flecainide). Consider dose reduction when using with CONTRAVE. ( 7.3 ) Digoxin: May decrease plasma digoxin levels. Monitor digoxin levels. ( 7.3 ) Concomitant Treatment with CYP2B6 Inhibitors (e.g., ticlopidine or clopidogrel) can increase bupropion exposure. Do not exceed one tablet twice daily when taken with CYP2B6 inhibitors. ( 2.5 , 7.4 ) CYP2B6 Inducers (e.g., ritonavir, lopinavir, efavirenz, carbamazepine, phenobarbital, and phenytoin) may reduce efficacy by reducing bupropion exposure, avoid concomitant use. ( 7.4 ) Drugs that Lower Seizure Threshold: Dose CONTRAVE with caution. ( 5.3 , 7.5 ) Dopaminergic Drugs (levodopa and amantadine): CNS toxicity can occur when used concomitantly with CONTRAVE. ( 7.6 ) Drug-Laboratory Test Interactions: CONTRAVE can cause false- positive urine test results for amphetamines. ( 7.8 ) 7.1 Monoamine Oxidase Inhibitors (MAOI) Concomitant use of MAOIs and bupropion is contraindicated. Bupropion inhibits the re-uptake of dopamine and norepinephrine and can increase the risk for hypertensive reactions when used concomitantly with drugs that also inhibit the re-uptake of dopamine or norepinephrine, including MAOIs. Studies in animals demonstrate that the acute toxicity of bupropion is enhanced by the MAOI phenelzine. At least 14 days should elapse between discontinuation of an MAOI and initiation of treatment with CONTRAVE. Conversely, at least 14 days should be allowed after stopping CONTRAVE before starting an MAOI [ see Contraindications (4) ] . 7.2 Opioid Analgesics Patients taking CONTRAVE may not fully benefit from treatment with opioid-containing medicines, such as cough and cold remedies, antidiarrheal preparations, and opioid analgesics. In patients requiring intermittent opiate treatment, CONTRAVE therapy should be temporarily discontinued, and opiate dose should not be increased above the standard dose. CONTRAVE may be used with caution after chronic opioid use has been stopped for 7 to 10 days in order to prevent precipitation of withdrawal [see Contraindications (4) and Warnings and Precautions (5.4) ] . During CONTRAVE clinical studies, the use of concomitant opioid or opioid-like medications, including analgesics or antitussives, were excluded. 7.3 Potential for CONTRAVE to Affect Other Drugs Metabolized by CYP2D6 In a clinical study, CONTRAVE (32 mg naltrexone/360 mg bupropion) daily was coadministered with a 50 mg dose of metoprolol (a CYP2D6 substrate). CONTRAVE increased metoprolol AUC and C max by approximately 4- and 2-fold, respectively, relative to metoprolol alone. Similar clinical drug interactions resulting in increased pharmacokinetic exposure of CYP2D6 substrates have also been observed with bupropion as a single agent with desipramine or venlafaxine. Coadministration of CONTRAVE with drugs that are metabolized by CYP2D6 isozyme including certain antidepressants (SSRIs and many tricyclics), antipsychotics (e.g., haloperidol, risperidone and thioridazine), beta-blockers (e.g., metoprolol) and Type 1C antiarrhythmics (e.g., propafenone and flecainide), should be approached with caution and should be initiated at the lower end of the dose range of the concomitant medication. If CONTRAVE is added to the treatment regimen of a patient already receiving a drug metabolized by CYP2D6, the need to decrease the dose of the original medication should be considered, particularly for those concomitant medications with a narrow therapeutic index [see Clinical Pharmacology (12.3) ] . Digoxin Coadministration of CONTRAVE with digoxin may decrease pl…

8.1 Pregnancy Risk Summary Weight loss offers no benefit to a pregnant patient and may cause fetal harm. When a pregnancy is recognized, advise the pregnant patient of the risk to the fetus, and discontinue CONTRAVE ( see Clinical Considerations ). Available pharmacovigilance data and data from clinical trials with the individual components of CONTRAVE use in pregnant patients have not demonstrated a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. Bupropion Data from epidemiological studies of pregnant patients exposed to bupropion in the first trimester have not identified an increased risk of congenital malformations overall (see Data ). When bupropion was administered to pregnant rats during organogenesis, there was no evidence of fetal malformations at doses up to approximately 20 times the maximum recommended human dose (MRHD) of 360 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 twice the MRHD and greater. Decreased fetal weights were seen at doses 5 times the MRHD and greater (see Data ) . Naltrexone Limited case report data of pregnant patients exposed to naltrexone in the first trimester have not identified an increased risk of congenital malformations overall . Daily oral administration of naltrexone during the period of organogenesis has been shown to increase the incidence of early fetal loss in rats and rabbits at doses ≥ 15 times and ≥ 60 times the MRHD of 32 mg/day, respectively. There was no evidence of fetal malformations in rats and rabbits at doses up to approximately 100 and 200 times the MHRD, respectively. (see Data ). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Clinical Considerations Disease-associated maternal and/or embryo/fetal risk Appropriate weight gain based on pre-pregnancy weight is currently recommended for all pregnant patients, including those who are already overweight or obese, due to the obligatory weight gain that occurs in maternal tissues during pregnancy. Data Human Data In clinical studies, 21 (0.7%) of 3,024 women became pregnant while taking CONTRAVE: 11 carried to term and gave birth to a healthy infant, three had elective abortions, four had spontaneous abortions, and the outcome of three pregnancies were unknown. 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 out of 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 associ…

6 ADVERSE REACTIONS The following adverse reactions are discussed in other sections of the labeling: Suicidal Behavior and Ideation [see Boxed Warning , Warnings and Precautions (5.1) ] Neuropsychiatric Adverse Events [see Warnings and Precautions (5.2) ] Seizures [see Contraindications (4) , Warnings and Precautions (5.3) ] Increase in Blood Pressure and Heart Rate [see Warnings and Precautions (5.5) ] Allergic Reactions [see Warnings and Precautions (5.6) ] Angle-Closure Glaucoma [see Warnings and Precautions (5.9) ] Most common adverse reactions (greater than or equal to 5%): nausea, constipation, headache, vomiting, dizziness, insomnia, dry mouth and diarrhea. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Currax Pharmaceuticals LLC at 1-800-793-2145 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, the 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. CONTRAVE was evaluated for safety in five double-blind placebo-controlled trials in 4,754 overweight or obese patients (3,239 patients treated with CONTRAVE and 1,515 patients treated with placebo) for a treatment period up to 56 weeks. The majority of patients were treated with CONTRAVE 32 mg/360 mg total daily dose. In addition, some patients were treated with other combination daily doses including naltrexone up to 50 mg and bupropion up to 400 mg. All subjects received study drug in addition to diet and exercise counseling. One trial (N=793) evaluated patients participating in an intensive behavioral modification program and another trial (N= 505) evaluated patients with type 2 diabetes. In these randomized, placebo-controlled trials, 2,545 patients received CONTRAVE 32 mg/360 mg for a mean treatment duration of 36 weeks (median, 56 weeks). Baseline patient characteristics included a mean age of 46 years, 82% women, 78% white, 25% with hypertension, 13% with type 2 diabetes, 56% with dyslipidemia, 25% with BMI greater than 40 kg/m 2 , and less than 2% with coronary artery disease. Dosing was initiated and increased weekly to reach the maintenance dose within 4 weeks. In CONTRAVE clinical trials, 24% of subjects receiving CONTRAVE and 12% of subjects receiving placebo discontinued treatment because of an adverse event. The most frequent adverse reactions leading to discontinuation with CONTRAVE were nausea (6.3%), headache (1.7%) and vomiting (1.1%). Common Adverse Reactions Adverse reactions that were reported by greater than or equal to 2% of patients and were more frequently reported by patients treated with CONTRAVE compared to placebo, are summarized in Table 3 . Table 3. Adverse Reactions Reported by Obese or Overweight Patients With an Incidence (%) of at Least 2% Among Patients Treated with CONTRAVE and More Common than with Placebo Adverse Reaction CONTRAVE 32 mg/360 mg N=2545 % Placebo N=1515 % Nausea 32.5 6.7 Constipation 19.2 7.2 Headache 17.6 10.4 Vomiting 10.7 2.9 Dizziness 9.9 3.4 Insomnia 9.2 5.9 Dry mouth 8.1 2.3 Diarrhea 7.1 5.2 Anxiety 4.2 2.8 Hot flush 4.2 1.2 Fatigue 4.0 3.4 Tremor 4.0 0.7 Upper abdominal pain 3.5 1.3 Viral gastroenteritis 3.5 2.6 Influenza 3.4 3.2 Tinnitus 3.3 0.6 Urinary tract infection 3.3 2.8 Hypertension 3.2 2.2 Abdominal pain 2.8 1.4 Hyperhidrosis 2.6 0.6 Irritability 2.6 1.8 Blood pressure increased 2.4 1.5 Dysgeusia 2.4 0.7 Rash 2.4 2.0 Muscle strain 2.2 1.7 Palpitations 2.1 0.9 Other Adverse Reactions The following additional adverse reactions were reported in less than 2% of patients treated with CONTRAVE but with an incidence at least twice that of placebo: Cardiac Disorders: tachycardia, myocardial infarction Ear and Labyrinth Disorders: vertigo, motion sickness Gastrointestinal Disorders: lower abdominal pain, eructation, lip swelling, hematochezia, hernia General Disorder…