Contraveextended-Release

Contraveextended-Release is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of:

• 30 kg/m² or greater (obese) or
• 27 kg/m² or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia).

Limitations Of Use

• The effect of Contraveextended-Release on cardiovascular morbidity and mortality has not been established.
• The safety and effectiveness of Contraveextended-Release in combination with other products intended for weight loss, including prescription drugs, over-the-counter drugs, and herbal preparations, have not been established.

Recommended Dosing

Contraveextended-Release dosing should be escalated according to the following schedule:

A total daily dosage of two Contraveextended-Release 8 mg/90 mg tablets twice daily (32 mg/360 mg) is reached at the start of Week 4.

Contraveextended-Release 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, Contraveextended-Release was administered with meals. However, Contraveextended-Release should not be taken with a high-fat meal because of a resulting significant increase in bupropion and naltrexone systemic exposure.

Patients may develop elevated blood pressure or heart rate during Contraveextended-Release treatment; the risk may be greater during the initial three months of therapy. 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 Contraveextended-Release.

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 Contraveextended-Release, as it is unlikely that the patient will achieve and sustain clinically meaningful weight loss with continued treatment.

BMI is calculated by dividing weight (in kg) by height (in meters) squared. A BMI chart for determining BMI based on height and weight is provided in Table 1.

Table 1: BMI Conversion Chart

Dose Adjustment In Patients With Renal Impairment

In patients with moderate or severe renal impairment, the maximum recommended daily dose for Contraveextended-Release is two tablets (one tablet each morning and evening). Contraveextended-Release is not recommended for use in patients with end-stage renal disease. There is a lack of adequate information to guide dosing in patients with mild renal impairment.

Dose Adjustment In Patients With Hepatic Impairment

In patients with hepatic impairment, the maximum recommended daily dose of Contraveextended-Release is one tablet in the morning.

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 Contraveextended-Release. Conversely, at least 14 days should be allowed after stopping Contraveextended-Release before starting an MAOI antidepressant.

Concomitant Use With CYP2B6 Inhibitors

During concomitant use with CYP2B6 inhibitors (e.g., ticlopidine or clopidogrel), the maximum recommended daily dose of Contraveextended-Release is two tablets (one tablet each morning and evening).

Contraveextended-Release is contraindicated in

• Uncontrolled hypertension
• Seizure disorder or a history of seizures
• Use of other bupropion-containing products (including, but not limited to, WELLBUTRIN, WELLBUTRIN SR, WELLBUTRIN XL, and APLENZIN)
• Bulimia or anorexia nervosa, which increase the risk for seizure
• Chronic opioid or opiate agonist (e.g., methadone) or partial agonists (e.g., buprenorphine) use, or acute opiate withdrawal
• Patients undergoing an abrupt discontinuation of alcohol, benzodiazepines, barbiturates, and antiepileptic drugs
• Concomitant administration of monoamine oxidase inhibitors (MAOI). At least 14 days should elapse between discontinuation of MAOI and initiation of treatment with Contraveextended-Release. There is an increased risk of hypertensive reactions when Contraveextended-Release is used concomitantly with MAOIs. Starting Contraveextended-Release in a patient treated with reversible MAOIs such as linezolid or intravenous methylene blue is also contraindicated
• Known allergy to bupropion, naltrexone or any other component of Contraveextended-Release. Anaphylactoid/anaphylactic reactions and Stevens-Johnson syndrome have been reported with bupropion
• Pregnancy

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Suicidal Behavior And Ideation

Contraveextended-Release 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 Contraveextended-Release.

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 Contraveextended-Release for the treatment of obesity in adult patients, no suicides or suicide attempts were reported in studies up to 56 weeks duration with Contraveextended-Release (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 Contraveextended-Release.

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.

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 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 2.

Table 2: Risk Differences in the Number of Suicidality Cases by Age Group in the Pooled Placebo-Controlled Trials of Antidepressants in Pediatric and Adult Subjects

No suicides occurred in any of the antidepressant pediatric trials. There were suicides in the adult antidepressant 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 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. This warning applies to Contraveextended-Release because one of its components, bupropion, is a member of an antidepressant class.

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 anxiety, 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 Contraveextended-Release should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose.

Neuropsychiatric Adverse Events And Suicide Risk In Smoking Cessation Treatment

Contraveextended-Release is not approved for smoking cessation treatment, but 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. 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 Contraveextended-Release 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. 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.

Depression, suicide, attempted suicide and suicidal ideation have been reported in the postmarketing experience with naltrexone used in the treatment of opioid dependence. No causal relationship has been demonstrated.

Seizures

Bupropion, a component of Contraveextended-Release, can cause seizures. The risk of seizure is dose-related. The incidence of seizure in patients receiving Contraveextended-Release in clinical trials was approximately 0.1% vs 0% on placebo. Contraveextended-Release should be discontinued and not restarted in patients who experience a seizure while being treated with Contraveextended-Release.

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 Contraveextended-Release. Contraveextended-Release 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. Caution should be used when prescribing Contraveextended-Release to patients with predisposing factors that may increase the risk of seizure including:

• history of head trauma or prior seizure, severe stroke, arteriovenous malformation, central nervous system tumor or infection, or metabolic disorders (e.g., hypoglycemia, hyponatremia, severe hepatic impairment, and hypoxia)
• excessive use of alcohol or sedatives, addiction to cocaine or stimulants, or withdrawal from sedatives
• patients with diabetes treated with insulin and/or oral diabetic medications (sulfonylureas and meglitinides) that may cause hypoglycemia
• concomitant administration of medications that may lower the seizure threshold, including other bupropion products, antipsychotics, tricyclic antidepressants, theophylline, systemic steroids

Recommendations For Reducing The Risk of Seizure

Clinical experience with bupropion suggests that the risk of seizure may be minimized by adhering to the recommended dosing recommendations , in particular:

• the total daily dose of Contraveextended-Release does not exceed 360 mg of the bupropion component (i.e., four tablets per day)
• the daily dose is administered in divided doses (twice daily)
• the dose is escalated gradually
• no more than two tablets are taken at one time
• coadministration of Contraveextended-Release with high-fat meals is avoided
• if a dose is missed, a patient should wait until the next scheduled dose to resume the regular dosing schedule

Patients Receiving Opioid Analgesics

Vulnerability To Opioid Overdose

Contraveextended-Release should not be administered to patients receiving chronic opioids, due to the naltrexone component, which is an opioid receptor antagonist. If chronic opiate therapy is required, Contraveextended-Release treatment should be stopped. In patients requiring intermittent opiate treatment, Contraveextended-Release therapy should be temporarily discontinued and lower doses of opioids may be needed. Patients should be alerted that they may be more sensitive to opioids, even at lower doses, after Contraveextended-Release treatment is discontinued.

An attempt by a patient to overcome any naltrexone opioid blockade by administering large amounts of exogenous opioids is especially dangerous and may lead to a fatal overdose or life-threatening opioid intoxication (e.g., respiratory arrest, circulatory collapse). Patients should be told of the serious consequences of trying to overcome the opioid blockade.

Precipitated Opioid Withdrawal

The symptoms of spontaneous opioid withdrawal, which are associated with the discontinuation of opioid in a dependent individual, are uncomfortable, but they are not generally believed to be severe or necessitate hospitalization. However, when withdrawal is precipitated abruptly, the resulting withdrawal syndrome can be severe enough to require hospitalization. To prevent occurrence of either precipitated withdrawal in patients dependent on opioids or exacerbation of a pre-existing subclinical withdrawal symptoms, opioid-dependent patients, including those being treated for alcohol dependence, should be opioid-free (including tramadol) before starting Contraveextended-Release treatment. An opioid-free interval of a minimum of 7 to 10 days is recommended for patients previously dependent on short-acting opioids, and those patients transitioning from buprenorphine or methadone may need as long as two weeks. Patients should be made aware of the risks associated with precipitated withdrawal and encouraged to give an accurate account of last opioid use.

Increase In Blood Pressure And Heart Rate

Contraveextended-Release can cause an increase in systolic and/or diastolic blood pressure as well as an increase in resting heart rate. In clinical practice with other bupropion-containing products, hypertension, in some cases severe and requiring acute treatment, has been reported. The clinical significance of the increases in blood pressure and heart rate observed with Contraveextended-Release treatment is unclear, especially for patients with cardiac and cerebrovascular disease, since patients with a history of myocardial infarction or stroke in the previous 6 months, life-threatening arrhythmias, or congestive heart failure were excluded from Contraveextended-Release clinical trials. Blood pressure and pulse should be measured prior to starting therapy with Contraveextended-Release and should be monitored at regular intervals consistent with usual clinical practice, particularly among patients with controlled hypertension prior to treatment. Contraveextended-Release should not be given to patients with uncontrolled hypertension.

Among patients treated with Contraveextended-Release in placebo-controlled clinical trials, mean systolic and diastolic blood pressure was approximately 1 mmHg higher than baseline at Weeks 4 and 8, similar to baseline at Week 12, and approximately 1 mmHg below baseline between Weeks 24 and 56. In contrast, among patients treated with placebo, mean blood pressure was approximately 2 to 3 mmHg below baseline throughout the same time points, yielding statistically significant differences between the groups at every assessment during this period. The largest mean differences between the groups were observed during the first 12 weeks (treatment difference +1.8 to +2.4 mmHg systolic, all p < 0.001; +1.7 to +2.1 mmHg diastolic, all p < 0.001).

For heart rate, at both Weeks 4 and 8, mean heart rate was statistically significantly higher (2.1 bpm) in the Contraveextended-Release group compared with the placebo group; at Week 52, the difference between groups was +1.7 bpm (p < 0.001).

In an ambulatory blood pressure monitoring substudy of 182 patients, the mean change from baseline in systolic blood pressure after 52 weeks of treatment was -0.2 mmHg for the Contraveextended-Release group and -2.8 mmHg for the placebo group (treatment difference, +2.6 mmHg, p=0.08); the mean change in diastolic blood pressure was +0.8 mmHg for the Contraveextended-Release group and -2.1 mmHg for the placebo group (treatment difference, +2.9 mmHg, p=0.004).

A greater percentage of subjects had adverse reactions related to blood pressure or heart rate in the Contraveextended-Release group compared to the placebo group (6.3% vs 4.2%, respectively), primarily attributable to adverse reactions of Hypertension/Blood Pressure Increased (5.9% vs 4.0%, respectively). These events were observed in both patients with and without evidence of preexisting hypertension. In a trial that enrolled individuals with diabetes, 12.0% of patients in the Contraveextended-Release group and 6.5% in the placebo group had a blood pressure-related adverse reaction.

Allergic Reactions

Anaphylactoid/anaphylactic reactions characterized by symptoms such as pruritus, urticaria, angioedema, and dyspnea requiring medical treatment have been reported in clinical trials with bupropion. In addition, there have been rare spontaneous postmarketing reports of erythema multiforme, Stevens-Johnson syndrome, and anaphylactic shock associated with bupropion. Instruct patients to discontinue Contraveextended-Release and consult a healthcare provider if they develop an allergic or anaphylactoid/anaphylactic reaction (e.g., skin rash, pruritus, hives, chest pain, edema, or shortness of breath) during treatment.

Arthralgia, myalgia, fever with rash, and other symptoms suggestive of delayed hypersensitivity have been reported in association with bupropion. These symptoms may resemble serum sickness.

Hepatotoxicity

Cases of hepatitis and clinically significant liver dysfunction were observed in association with naltrexone exposure during naltrexone clinical trials and in postmarketing reports for patients using naltrexone. Transient, asymptomatic hepatic transaminase elevations were also observed. When patients presented with elevated transaminases, there were often other potential causative or contributory etiologies identified, including pre-existing alcoholic liver disease, hepatitis B and/or C infection, and concomitant usage of other potentially hepatotoxic drugs. Although clinically significant liver dysfunction is not typically recognized as a manifestation of opioid withdrawal, opioid withdrawal that is precipitated abruptly may lead to systemic sequelae, including acute liver injury.

Patients should be warned of the risk of hepatic injury and advised to seek medical attention if they experience symptoms of acute hepatitis. Use of Contraveextended-Release should be discontinued in the event of symptoms and/or signs of acute hepatitis.

In Contraveextended-Release clinical trials, there were no cases of elevated transaminases greater than three times the upper limit of normal (ULN) in conjunction with an increase in bilirubin greater than two times ULN.

Activation Of Mania

Bupropion, a component of Contraveextended-Release, is a drug used for the treatment of depression. Antidepressant treatment can precipitate a manic, mixed, or hypomanic episode. The risk appears to be increased in patients with bipolar disorder or who have risk factors for bipolar disorder. Prior to initiating Contraveextended-Release, 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). Contraveextended-Release is not approved for use in treating bipolar depression. No activation of mania or hypomania was reported in the clinical trials evaluating effects of Contraveextended-Release in obese patients; however, patients receiving antidepressant medications and patients with a history of bipolar disorder or recent hospitalization because of psychiatric illness were excluded from Contraveextended-Release clinical trials.

Angle-Closure Glaucoma

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

Potential Risk Of Hypoglycemia In Patients With Type 2 Diabetes Mellitus On Antidiabetic Therapy

Weight loss may increase the risk of hypoglycemia in patients with type 2 diabetes mellitus treated with insulin and/or insulin secretagogues (e.g., sulfonylureas). Measurement of blood glucose levels prior to starting Contraveextended-Release and during Contraveextended-Release treatment is recommended in patients with type 2 diabetes. Decreases in medication doses for antidiabetic medications which are non-glucose-dependent should be considered to mitigate the risk of hypoglycemia. If a patient develops hypoglycemia after starting Contraveextended-Release, appropriate changes should be made to the antidiabetic drug regimen.

Patient Counseling Information

See FDA-Approved Patient Labeling (Medication Guide)

Patient information is printed at the end of this insert. This information and the instructions provided in the Medication Guide should be discussed with patients.

Patients should be advised to take Contraveextended-Release exactly as prescribed. Patients should be instructed to follow the dose escalation schedule and not to take more than the recommended dose of Contraveextended-Release.

Patients should be made aware that Contraveextended-Release contains the same active ingredient (bupropion) found in certain antidepressants and smoking cessation products (including, but not limited to, WELLBUTRIN, WELLBUTRIN SR, WELLBUTRIN XL, APLENZIN and ZYBAN) and that Contraveextended-Release should not be used in combination with any other medications that contain bupropion.

Patients should be advised that some patients have experienced 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 when attempting to quit smoking while taking bupropion. Instruct patients to discontinue Contraveextended-Release and contact a healthcare professional if they experience such symptoms.

Patients should be advised of the potential serious risks associated with the use of Contraveextended-Release, including suicidality, seizures, and increases in blood pressure or heart rate.

Patients should be advised to call their healthcare provider to report new or sudden changes in mood, behavior, thoughts, or feelings.

Patients should be advised that taking Contraveextended-Release can cause mild pupillary dilation, which in susceptible individuals, can lead to an episode of angle-closure glaucoma. Pre-existing glaucoma is almost always open-angle glaucoma because angle-closure glaucoma, when diagnosed, can be treated definitively with iridectomy. Open-angle glaucoma is not a risk factor for angle-closure glaucoma. Patients may wish to be examined to determine whether they are susceptible to angle closure, and have a prophylactic procedure (e.g., iridectomy), if they are susceptible.

Patients should be educated on the symptoms of hypersensitivity and to discontinue Contraveextended-Release if they have a severe allergic reaction to Contraveextended-Release.

Patients should be told that Contraveextended-Release should be discontinued and not restarted if they experience a seizure while on treatment.

Patients should be advised that the excessive use or abrupt discontinuation of alcohol, benzodiazepines, antiepileptic drugs, or sedatives/hypnotics can increase the risk of seizure. Patients should be advised to minimize or avoid use of alcohol.

Patients should be advised that if they previously used opioids, they may be more sensitive to lower doses of opioids and at risk of accidental overdose should they use opioids after Contraveextended-Release treatment is discontinued or temporarily interrupted.

Patients should be advised that because naltrexone, a component of Contraveextended-Release, can block the effects of opioids, they will not perceive any effect if they attempt to self-administer any opioid drug in small doses while on Contraveextended-Release. Further advise patients that the attempt to administer large doses of any opioid or to bypass the blockade while on Contraveextended-Release may lead to serious injury, coma, or death.

Patients should be off all opioids for a minimum of 7 to 10 days before starting Contraveextended-Release in order to avoid precipitation of withdrawal. Advise patients they should not take Contraveextended-Release if they have any symptoms of opioid withdrawal.

Patients should be advised to call their healthcare provider if they experience increased blood pressure or heart rate.

Patients should be advised to notify their healthcare provider if they are taking, or plan to take, any prescription or over-the-counter drugs. Concern is warranted because Contraveextended-Release and other drugs may affect each other's metabolism.

Patients should be advised to notify their healthcare provider if they become pregnant, intend to become pregnant, or are breastfeeding during therapy.

Patients with type 2 diabetes mellitus on antidiabetic therapy should be advised to monitor their blood glucose levels and report symptoms of hypoglycemia to their healthcare provider(s).

Patients should be advised to swallow Contraveextended-Release tablets whole so that the release rate is not altered. Do not chew, divide, or crush tablets.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Studies to evaluate carcinogenesis, mutagenesis, or impairment of fertility with the combined products in Contraveextended-Release have not been conducted. The following findings are from studies performed individually with naltrexone and bupropion. The potential carcinogenic, mutagenic and fertility effects of the metabolite 6-beta-naltrexol are unknown. Safety margins were estimated using body surface area exposure (mg/m²) based on a body weight of 100 kg.

In a two-year carcinogenicity study in rats with naltrexone, there were small increases in the numbers of testicular mesotheliomas in males and tumors of vascular origin in males and females. The incidence of mesothelioma in males given naltrexone at a dietary dose of 100 mg/kg/day (approximately 50 times the recommended therapeutic dose on a mg/m² basis for the naltrexone maintenance dose for Contraveextended-Release) was 6%, compared with a maximum historical incidence of 4%. The incidence of vascular tumors in males and females given dietary doses of 100 mg/kg/day was 4%, but only the incidence in females was increased compared with a maximum historical control incidence of 2%. There was no evidence of carcinogenicity in a two-year dietary study with naltrexone in male and female mice.

Lifetime carcinogenicity studies of bupropion were performed in rats and mice at doses up to 300 and 150 mg/kg/day, respectively. These doses are approximately 15 and 3 times the maximum recommended human dose (MRHD) of the bupropion component in Contraveextended-Release, 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 5 to 15 times the MRHD of the bupropion component in Contraveextended-Release 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.

There was limited evidence of a weak genotoxic effect of naltrexone in one gene mutation assay in a mammalian cell line, in the Drosophila recessive lethal assay, and in non-specific DNA repair tests with E. coli. However, no evidence of genotoxic potential was observed in a range of other in vitro tests, including assays for gene mutation in bacteria, yeast, or in a second mammalian cell line, a chromosomal aberration assay, and an assay for DNA damage in human cells. Naltrexone did not exhibit clastogenicity in an in vivo mouse micronucleus assay.

Bupropion produced a positive response (two to three times control mutation rate) in two of five strains in the Ames bacterial mutagenicity test and an increase in chromosomal aberrations in one of three in vivo rat bone marrow cytogenetic studies.

Naltrexone administered orally to rats caused a significant increase in pseudopregnancy and a decrease in pregnancy rates in rats at 100 mg/kg/day (approximately 50 times the MRHD of the naltrexone component in Contraveextended-Release on a mg/m² basis). There was no effect on male fertility at this dose level. The relevance of these observations to human fertility is not known.

A fertility study of bupropion in rats at doses up to 300 mg/kg/day (approximately 15 times the MRHD of the bupropion component in Contraveextended-Release on a mg/m² basis) revealed no evidence of impaired fertility.

The following adverse reactions are discussed in other sections of the labeling:

• Suicidal Behavior and Ideation
• Neuropsychiatric Adverse Events
• Seizures
• Increase in Blood Pressure and Heart Rate
• Allergic Reactions
• Angle-Closure Glaucoma

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.

Contraveextended-Release was evaluated for safety in five double-blind placebo controlled trials in 4,754 overweight or obese patients (3,239 patients treated with Contraveextended-Release and 1,515 patients treated with placebo) for a treatment period up to 56 weeks. The majority of patients were treated with Contraveextended-Release 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 Contraveextended-Release 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/m², and less than 2% with coronary artery disease. Dosing was initiated and increased weekly to reach the maintenance dose within 4 weeks.

In Contraveextended-Release clinical trials, 24% of subjects receiving Contraveextended-Release and 12% of subjects receiving placebo discontinued treatment because of an adverse event. The most frequent adverse reactions leading to discontinuation with Contraveextended-Release 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 Contraveextended-Release 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 Contraveextended-Release and More Common than with Placebo

Other Adverse Reactions

The following additional adverse reactions were reported in less than 2% of patients treated with Contraveextended-Release 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 Disorders and Administration Site Conditions: feeling jittery, feeling abnormal, asthenia, thirst, feeling hot

Hepatobiliary Disorders: cholecystitis

Infections and Infestations: pneumonia, staphylococcal infection, kidney infection

Investigations: increased blood creatinine, increased hepatic enzymes, decreased hematocrit

Metabolism and Nutrition Disorders: dehydration

Musculoskeletal and Connective Tissue Disorders: intervertebral disc protrusion, jaw pain

Nervous System Disorders: disturbance in attention, lethargy, intention tremor, balance disorder, memory impairment, amnesia, mental impairment, presyncope

Psychiatric Disorders: abnormal dreams, nervousness, dissociation (feeling spacey), tension, agitation, mood swings

Renal and Urinary Disorders: micturition urgency

Reproductive System and Breast Disorders: vaginal hemorrhage, irregular menstruation, erectile dysfunction, vulvovaginal dryness

Skin and Subcutaneous Tissue Disorders: alopecia

Psychiatric And Sleep Disorders

In the one-year controlled trials of Contraveextended-Release, the proportion of patients reporting one or more adverse reactions related to psychiatric and sleep disorders was higher in the Contraveextended-Release 32/360 mg group than the placebo group (22.2% and 15.5%, respectively). These events were further categorized into sleep disorders (13.8% Contraveextended-Release, 8.4% placebo), depression (6.3% Contraveextended-Release, 5.9% placebo), and anxiety (6.1% Contraveextended-Release, 4.4% placebo). Patients who were 65 years or older experienced more psychiatric and sleep disorder adverse reactions in the Contraveextended-Release group (28.6%) compared to placebo (6.3%), although the sample size in this subgroup was small (56 Contraveextended-Release, 32 placebo); the majority of these events were insomnia (10.7% Contraveextended-Release, 3.1% placebo) and depression (7.1% Contraveextended-Release, 3.1% placebo).

Neurocognitive Adverse Reactions

Adverse reactions involving attention, dizziness, and syncope occurred more often in individuals randomized to Contraveextended-Release 32/360 mg group compared to placebo (15.0% and 5.5%, respectively). The most common cognitive-related adverse reactions were attention disorders (2.5% Contraveextended-Release, 0.6% placebo). Adverse reactions involving dizziness and syncope were more common in patients treated with Contraveextended-Release (10.6%) than in placebo-treated patients (3.6%); dizziness accounted for almost all of these reported events (10.4% Contraveextended-Release, 3.4% placebo). Dizziness was the primary reason for discontinuation for 0.9% and 0.3% of patients in the Contraveextended-Release and placebo groups, respectively.

Increases In Serum Creatinine

In the one-year controlled trials of Contraveextended-Release, larger mean increases in serum creatinine from baseline to trial endpoint were observed in the Contraveextended-Release group compared with the placebo group (0.07 mg/dL and 0.01 mg/dL, respectively) as well as from baseline to the maximum value during follow-up (0.15 mg/dL and 0.07 mg/dL, respectively). Increases in serum creatinine that exceeded the upper limit of normal and were also greater than or equal to 50% higher than baseline occurred in 0.6% of subjects receiving Contraveextended-Release compared to 0.1% receiving placebo. An in vitro drug-drug interaction study demonstrated that bupropion and its metabolites inhibit organic cation transporter 2 (OCT2), which is involved in the tubular secretion of creatinine, suggesting that the observed increase in serum creatinine may be the result of OCT2 inhibition.

Based on in vitro results and FDA guidance for Drug Interaction Studies, the ratios of the free (unbound) Cmax and IC50 value of bupropion and hydroxybupropion were well below 0.1 suggesting a drug-drug interaction between Contraveextended-Release and OCT2 substrate due to bupropion and hydroxybupropion is unlikely. The ratio for the threohydrobupropion and erythrohydrobupropion metabolite mixture was 0.29, suggesting a drug-drug interaction between Contraveextended-Release and OCT2 due to threohydrobupropion and erythrohydrobupropion is possible.

Postmarketing Experience

Additional adverse reactions have been identified during post approval use of Contraveextended-Release. Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

• Loss of consciousness, malaise

Human Experience

There is no clinical experience with overdosage with Contraveextended-Release. The maximum daily dose of Contraveextended-Release administered in clinical trials contained 50 mg naltrexone and 400 mg bupropion. The most serious clinical implications of Contraveextended-Release overdose are likely those related to overdose of bupropion.

Overdoses of up to 30 grams or more of bupropion (equivalent of up to 83 times the recommended daily dose of Contraveextended-Release 32 mg/360 mg) have been reported. Seizure was reported in approximately one third of all cases. Other serious reactions reported with overdoses of bupropion alone included hallucinations, loss of consciousness, sinus tachycardia, and ECG changes such as conduction disturbances (including QRS prolongation) or arrhythmias. Fever, muscle rigidity, rhabdomyolysis, hypotension, stupor, coma, and respiratory failure have been reported mainly when bupropion was part of multiple drug overdoses.

Although most patients recovered without sequelae, deaths associated with overdoses of bupropion alone have been reported in patients ingesting large doses of the drug. Multiple uncontrolled seizures, bradycardia, cardiac failure, and cardiac arrest prior to death were reported in these patients.

There is limited experience with overdose of naltrexone monotherapy in humans. In one study, subjects who received 800 mg naltrexone daily (equivalent to 25 times the recommended daily dose of Contraveextended-Release 32 mg/360 mg) for up to one week showed no evidence of toxicity.

Animal Experience

In the mouse, rat, and guinea pig, the oral LD50s for naltrexone were 1,100 to 1,550 mg/kg; 1,450 mg/kg; and 1,490 mg/kg; respectively. High doses of naltrexone (generally greater than or equal to 1,000 mg/kg) produced salivation, depression/reduced activity, tremors, and convulsions. Mortality in animals due to high-dose naltrexone administration usually was due to clonic-tonic convulsions and/or respiratory failure.

Overdosage Management

If over-exposure occurs, call your poison control center at 1-800-222-1222. There are no known antidotes for Contraveextended-Release. In case of an overdose, provide supportive care, including close medical supervision and monitoring. Consider the possibility of multiple drug overdose. Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm and vital signs. Induction of emesis is not recommended.

Combined, bupropion and naltrexone increased the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons in vitro, which are associated with regulation of appetite. The combination of bupropion and naltrexone also reduced food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, an area associated with regulation of reward pathways.

Absorption

Naltrexone

Following single oral administration of Contraveextended-Release (two 8 mg naltrexone/90 mg bupropion tablets) to healthy subjects, mean peak naltrexone concentration (Cmax) was 1.4 ng/mL, time to peak concentration (Tmax) was 2 hours, and extent of exposure (AUC0-inf) was 8.4 ng•hr/mL.

Bupropion

Following single oral administration of Contraveextended-Release (two 8 mg naltrexone/90 mg bupropion tablets) to healthy subjects, mean peak bupropion concentration (Cmax) was 168 ng/mL, time to peak concentration (Tmax) was three hours, and extent of exposure (AUC0-inf) was 1,607 ng•hr/mL.

Food Effect On Absorption

When Contraveextended-Release was administered with a high-fat meal, the AUC and Cmax for naltrexone increased 2.1-fold and 3.7-fold, respectively, and the AUC and Cmax for bupropion increased 1.4-fold and 1.8-fold, respectively. At steady state, the food effect increased AUC and Cmax for naltrexone by 1.7-fold and 1.9-fold, respectively, and increased AUC and Cmax for bupropion by 1.1-fold and 1.3-fold, respectively. Thus, Contraveextended-Release should not be taken with high-fat meals because of the resulting significant increases in bupropion and naltrexone systemic exposure.

Distribution

Naltrexone

Naltrexone is 21% plasma protein bound. The mean apparent volume of distribution at steady state for naltrexone (Vss/F) is 5,697 liters.

Bupropion

Bupropion is 84% plasma protein bound. The mean apparent volume of distribution at steady state for bupropion (Vss/F) is 880 liters.

Metabolism And Excretion

Naltrexone

The major metabolite of naltrexone is 6-beta-naltrexol. The activity of naltrexone is believed to be the result of both the parent and the 6-beta-naltrexol metabolite. Though less potent, 6-beta-naltrexol is eliminated more slowly and thus circulates at much higher concentrations than naltrexone. Naltrexone and 6-beta-naltrexol are not metabolized by cytochrome P450 enzymes and in vitro studies indicate that there is no potential for inhibition or induction of important isozymes.

Naltrexone and its metabolites are excreted primarily by the kidney (53% to 79% of the dose). Urinary excretion of unchanged naltrexone accounts for less than 2% of an oral dose. Urinary excretion of unchanged and conjugated 6-beta-naltrexol accounts for 43% of an oral dose. The renal clearance for naltrexone ranges from 30 to 127 mL/min, suggesting that renal elimination is primarily by glomerular filtration. The renal clearance for 6-beta-naltrexol ranges from 230 to 369 mL/min suggesting an additional renal tubular secretory mechanism. Fecal excretion is a minor elimination pathway.

Following single oral administration of Contraveextended-Release tablets to healthy subjects, mean elimination half-life (T½) was approximately 5 hours for naltrexone. Following twice daily administration of Contraveextended-Release, naltrexone did not accumulate and its kinetics appeared linear. However, in comparison to naltrexone, 6-beta-naltrexol accumulates to a larger extent (accumulation ratio ~3).

Bupropion

Bupropion is extensively metabolized with three active metabolites: hydroxybupropion, threohydrobupropion and erythrohydrobupropion. The metabolites have longer elimination half-lives than bupropion and accumulate to a greater extent. Following bupropion administration, more than 90% of the exposure is a result of metabolites. In vitro findings suggest that CYP2B6 is the principal isozyme involved in the formation of hydroxybupropion whereas cytochrome P450 isozymes are not involved in the formation of the other active metabolites. Bupropion and its metabolites inhibit CYP2D6. Plasma protein binding of hydroxybupropion is similar to that of bupropion (84%) whereas the other two metabolites have approximately half the binding.

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. The fraction of the oral dose of bupropion excreted unchanged was 0.5%, a finding consistent with the extensive metabolism of bupropion.

Following single oral administration of Contraveextended-Release tablets to healthy subjects, mean elimination half-life (T½) was approximately 21 hours for bupropion. Following twice daily administration of Contraveextended-Release, metabolites of bupropion, and to a lesser extent unchanged bupropion, accumulate and reach steady-state concentrations in approximately one week.