CONTRAVE

CONTRAVE dosing should be escalated according to the following schedule:

A total daily dosage of two CONTRAVE 8 mg/90 mg tablets twice daily (32 mg/360 mg) 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.

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

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. There is a lack of adequate information to guide dosing in patients with mild renal impairment [see Use in Specific Population (8.6) and Clinical Pharmacology (12.3)].

In patients with hepatic impairment, the maximum recommended daily dose of CONTRAVE is one tablet in the morning [see Use in Specific Population (8.7) and Clinical Pharmacology (12.3)].

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)].

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)].

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.

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.

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

CONTRAVE is not approved for smoking cessation treatment, but serious neuropsychiatric symptoms have been reported in patients taking bupropion for smoking cessation. These have included changes in mood (including depression and mania), psychosis, hallucinations, paranoia, delusions, homicidal ideation, hostility, agitation, aggression, anxiety, and panic, as well as suicidal ideation, suicide attempt, and completed suicide [see Warnings and Precautions (5.1)]. Observe patients for the occurrence of neuropsychiatric reactions. Instruct patients to contact a healthcare professional if such reactions occur.

In many of these cases, a causal relationship to bupropion treatment is not certain, because depressed mood can be a symptom of nicotine withdrawal. However, some of the cases occurred in patients taking bupropion who continued to smoke.

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.

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

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 CONTRAVE. CONTRAVE 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 CONTRAVE 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 [see Dosage and Administration (2)], in particular:

• the total daily dose of CONTRAVE 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 CONTRAVE with high-fat meals is avoided [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3)]
• if a dose is missed, a patient should wait until the next scheduled dose to resume the regular dosing schedule

Vulnerability to Opioid Overdose: CONTRAVE should not be administered to patients receiving chronic opioids, due to the naltrexone component, which is an opioid receptor antagonist [see Contraindications (4)]. If chronic opiate therapy is required, CONTRAVE treatment should be stopped. In patients requiring intermittent opiate treatment, CONTRAVE 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 CONTRAVE 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 CONTRAVE 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.

CONTRAVE 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 CONTRAVE 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 CONTRAVE clinical trials. Blood pressure and pulse should be measured prior to starting therapy with CONTRAVE and should be monitored at regular intervals consistent with usual clinical practice, particularly among patients with controlled hypertension prior to treatment [see Dosage and Administration (2.1)]. CONTRAVE should not be given to patients with uncontrolled hypertension [see Contraindications (4)].

Among patients treated with CONTRAVE 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 CONTRAVE 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 CONTRAVE 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 CONTRAVE 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 CONTRAVE 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 CONTRAVE group and 6.5% in the placebo group had a blood pressure-related adverse reaction.

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 CONTRAVE 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.

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 CONTRAVE should be discontinued in the event of symptoms and/or signs of acute hepatitis.

In CONTRAVE 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.

Bupropion, a component of CONTRAVE, 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 CONTRAVE, 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). CONTRAVE is not approved for use in treating bipolar depression. No activation of mania or hypomania was reported in the clinical trials evaluating effects of CONTRAVE 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 CONTRAVE clinical trials.

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

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 CONTRAVE and during CONTRAVE 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 CONTRAVE, appropriate changes should be made to the antidiabetic drug regimen.

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/m², 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.

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

Neurocognitive Adverse Reactions

Adverse reactions involving attention, dizziness, and syncope occurred more often in individuals randomized to CONTRAVE 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% CONTRAVE, 0.6% placebo). Adverse reactions involving dizziness and syncope were more common in patients treated with CONTRAVE (10.6%) than in placebo-treated patients (3.6%); dizziness accounted for almost all of these reported events (10.4% CONTRAVE, 3.4% placebo). Dizziness was the primary reason for discontinuation for 0.9% and 0.3% of patients in the CONTRAVE and placebo groups, respectively.

Increases in Serum Creatinine

In the one-year controlled trials of CONTRAVE, larger mean increases in serum creatinine from baseline to trial endpoint were observed in the CONTRAVE 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 CONTRAVE 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) C_max and IC50 value of bupropion and hydroxybupropion were well below 0.1 suggesting a drug-drug interaction between CONTRAVE 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 CONTRAVE and OCT2 due to threohydrobupropion and erythrohydrobupropion is possible.

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)].

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. 

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)].

Bupropion is primarily metabolized to hydroxybupropion by CYP2B6. Therefore, the potential exists for drug interactions between CONTRAVE 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. During concomitant use with CYP2B6 inhibitors (e.g., ticlopidine or clopidogrel), the CONTRAVE daily dose should not exceed two tablets (one tablet each morning and evening) [see Dosage and Administration (2.5) and Clinical Pharmacology (12.3)].

Inducers of CYP2B6: Ritonavir, Lopinavir, and Efavirenz: Concomitant treatment with these drugs can decrease bupropion and hydroxybupropion exposure and may reduce efficacy. Avoiding concomitant use with ritonavir, lopinavir, or efavirenz is recommended [see Clinical Pharmacology (12.3)].

Use extreme caution when coadministering CONTRAVE with other drugs that lower seizure threshold (e.g., antipsychotics, antidepressants, theophylline, or systemic corticosteroids). Use low initial doses and increase the dose gradually. Concomitant use of other bupropion-containing products is contraindicated [see Contraindications (4) and Warnings and Precautions (5.3)].

Bupropion, levodopa, and amantadine have dopamine agonist effects. CNS toxicity has been reported when bupropion was coadministered with levodopa or amantadine. Adverse reactions have included restlessness, agitation, tremor, ataxia, gait disturbance, vertigo, and dizziness. It is presumed that the toxicity results from cumulative dopamine agonist effects. Use caution and monitor for such adverse reactions when administering CONTRAVE concomitantly with these drugs.

In postmarketing experience, there have been rare reports of adverse neuropsychiatric events or reduced alcohol tolerance in patients who were drinking alcohol during treatment with bupropion. The consumption of alcohol during treatment with CONTRAVE should be minimized or avoided.

False-positive urine immunoassay screening tests for amphetamines have been reported in patients taking bupropion. This is due to lack of specificity of some screening tests. False-positive test results may result even following discontinuation of bupropion therapy. Confirmatory tests, such as gas chromatography/mass spectrometry, will distinguish bupropion from amphetamines.

In vitro, CONTRAVE constituents inhibited the renal organic cation transporter OCT2 to a clinically relevant level. The systemic concentrations of substrate drugs transported by OCT2 (such as amantadine, amiloride, cimetidine, dopamine, famotidine, memantine, metformin, pindolol, procainamide, ranitidine, varenicline, oxaliplatin) are likely to increase as a result of reduced renal clearance when coadministered with CONTRAVE. Coadministration of CONTRAVE with such drugs should be approached with caution and patients should be monitored for adverse effects.

Pregnancy Category X

Risk Summary

CONTRAVE is contraindicated during pregnancy, because weight loss offers no potential benefit to a pregnant woman and may result in fetal harm. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard of maternal weight loss to the fetus.

Clinical Considerations

A minimum weight gain, and no weight loss, is currently recommended for all pregnant women, including those who are already overweight or obese, due to the obligatory weight gain that occurs in maternal tissues during pregnancy.

Human Data

There are no adequate and well-controlled studies of CONTRAVE in pregnant women. 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 association; the NBDPS found increased risk for LVOTO (n = 10; adjusted odds ratio [OR] = 2.6; 95% CI: 1.2, 5.7), and the Slone Epidemiology case control study did not find increased risk for LVOTO.

Study findings on bupropion exposure during the first trimester and risk for ventricular septal defect (VSD) are inconsistent and do not allow conclusions regarding a possible association. The Slone Epidemiology Study found an increased risk for VSD following first trimester maternal bupropion exposure (n = 17; adjusted OR = 2.5; 95% CI: 1.3, 5.0) but did not find 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

Reproduction and developmental studies have not been conducted for the combined products naltrexone and bupropion in CONTRAVE. Safety margins were estimated using body surface area exposure (mg/m²) based on a body weight of 100 kg.

Separate studies with bupropion and naltrexone have been conducted in pregnant rats and rabbits.

Naltrexone administered orally has been shown to increase the incidence of early fetal loss in rats administered ≥30 mg/kg/day (180 mg/m²/day) and rabbits administered ≥60 mg/kg/day (720 mg/m²/day), doses at least 15 and 60 times, respectively, the maximum recommended human dose [MRHD] of the naltrexone component in CONTRAVE on a mg/m² basis. There was no evidence of teratogenicity when naltrexone was administered orally to rats and rabbits during the period of major organogenesis at doses up to 200 mg/kg/day (approximately 100 and 200 times the recommended therapeutic dose, respectively, on a mg/m² basis). Rats do not form appreciable quantities of the major human metabolite, 6-beta-naltrexol; therefore, the potential reproductive toxicity of the metabolite in rats is not known.

Bupropion was administered orally in studies conducted in rats and rabbits at doses up to 450 and 150 mg/kg/day, respectively (approximately 20 and 15 times the MRHD, respectively, of the bupropion component in CONTRAVE on a mg/m² basis), during the period of organogenesis. 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/kg/day, approximately 2 times the MRHD on a mg/m² basis) and greater. Decreased fetal weights were seen at 50 mg/kg and greater (approximately 5 times the MRHD of the bupropion component in CONTRAVE on a mg/m² basis). When rats were administered bupropion at oral doses of up to 300 mg/kg/day (approximately 15 times the MRHD of the bupropion component in CONTRAVE on a mg/m² basis) prior to mating and throughout pregnancy and lactation, there were no apparent adverse effects on offspring development.

The constituents and metabolites of CONTRAVE have been shown to be secreted in human milk. Transfer of naltrexone and 6-beta-naltrexol into human milk has been reported with oral naltrexone. Bupropion and its metabolites are also secreted in human milk. CONTRAVE is not recommended for nursing mothers.

The safety and effectiveness of CONTRAVE in pediatric patients below the age of 18 have not been established and the use of CONTRAVE is not recommended in pediatric patients.

Of the 3,239 subjects who participated in clinical trials with CONTRAVE, 62 (2%) were 65 years and older and none were 75 years and older. Clinical studies of CONTRAVE did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Older individuals may be more sensitive to the central nervous system adverse effects of CONTRAVE. Naltrexone and bupropion are known to be substantially excreted by the kidney, and the risk of adverse reactions to CONTRAVE may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. CONTRAVE should be used with caution in patients over 65 years of age.

A dedicated pharmacokinetic study has not been conducted for CONTRAVE in subjects with renal impairment. Based on information available for the individual constituents, systemic exposure is significantly higher for bupropion and metabolites (two- to three-fold), and naltrexone and their metabolites in subjects with moderate-to-severe renal impairment. Therefore, the maximum recommended daily maintenance dose for CONTRAVE is two tablets (one tablet each morning and evening) in patients with moderate or severe renal impairment. CONTRAVE is not recommended for use in patients with end-stage renal disease. There is a lack of adequate information to guide CONTRAVE dosing in patients with mild renal impairment [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)].

CONTRAVE has not been evaluated in subjects with hepatic impairment. Based on information available for the individual constituents, systemic exposure is significantly higher for bupropion and metabolites (two- to three-fold), and naltrexone and their metabolites (up to 10-fold higher) in subjects with moderate-to-severe hepatic impairment. Therefore, the maximum recommended daily dose of CONTRAVE is one tablet in the morning in patients with hepatic impairment [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3)].

Humans

CONTRAVE (naltrexone HCl and bupropion HCl) has not been systematically studied in humans for its potential for abuse, tolerance, or physical dependence. However, in outpatient clinical studies of up to 56 weeks in duration, there was no evidence of euphoric drug intoxication, physical dependence, diversion, or abuse. There was no evidence of an abstinence syndrome following abrupt or tapered drug discontinuation after 56 weeks of double-blind, placebo-controlled, randomized treatment.

Naltrexone is a pure opioid antagonist. It does not lead to physical or psychological dependence. Tolerance to the opioid antagonistic effect is not known to occur.

Controlled clinical trials of bupropion (immediate-release formulation) conducted in normal volunteers, in subjects with a history of multiple drug abuse, and in depressed subjects showed some increase in motor activity and agitation/excitement. In a population of individuals experienced with drugs of abuse, a single dose of 400 mg of bupropion produced mild amphetamine-like activity as compared with placebo on the Morphine-Benzedrine Subscale of the Addiction Research Center Inventories (ARCI) and a score intermediate between placebo and amphetamine on the Liking Scale of the ARCI. These scales measure general feelings of euphoria and drug desirability.

Findings in clinical trials, however, are not known to reliably predict the abuse potential of drugs. Nonetheless, evidence from single-dose studies does suggest that the recommended daily dosage of bupropion when administered in divided doses is not likely to be significantly reinforcing to amphetamine or CNS stimulant abusers.

Animals

Studies in rodents and primates have shown that bupropion exhibits some pharmacologic actions common to psychostimulants. In rodents, it has been shown to increase locomotor activity, elicit a mild stereotyped behavioral response, and increased rates of responding in several schedule-controlled behavior paradigms. In primate models assessing the positive reinforcing effects of psychoactive drugs, bupropion was self-administered intravenously. In rats, bupropion produced amphetamine-like and cocaine-like discriminative stimulus effects in drug discrimination paradigms used to characterize the subjective effects of psychoactive drugs.

CONTRAVE has two components: naltrexone, an opioid antagonist, and bupropion, a relatively weak inhibitor of the neuronal reuptake of dopamine and norepinephrine. Nonclinical studies suggest that naltrexone and bupropion have effects on two separate areas of the brain involved in the regulation of food intake: the hypothalamus (appetite regulatory center) and the mesolimbic dopamine circuit (reward system). The exact neurochemical effects of CONTRAVE leading to weight loss are not fully understood.

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 CONTRAVE (two 8 mg naltrexone/90 mg bupropion tablets) to healthy subjects, mean peak naltrexone concentration (C_max) was 1.4 ng/mL, time to peak concentration (T_max) was 2 hours, and extent of exposure (AUC_0-inf) was 8.4 ng∙hr/mL.

Bupropion

Following single oral administration of CONTRAVE (two 8 mg naltrexone/90 mg bupropion tablets) to healthy subjects, mean peak bupropion concentration (C_max) was 168 ng/mL, time to peak concentration (T_max) was three hours, and extent of exposure (AUC_0-inf) was 1,607 ng∙hr/mL.

Food Effect on Absorption

When CONTRAVE was administered with a high-fat meal, the AUC and C_max for naltrexone increased 2.1-fold and 3.7-fold, respectively, and the AUC and C_max for bupropion increased 1.4-fold and 1.8-fold, respectively. At steady state, the food effect increased AUC and C_max for naltrexone by 1.7-fold and 1.9-fold, respectively, and increased AUC and C_max for bupropion by 1.1-fold and 1.3-fold, respectively. Thus, CONTRAVE 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 (V_ss/F) is 5,697 liters.

Bupropion

Bupropion is 84% plasma protein bound. The mean apparent volume of distribution at steady state for bupropion (V_ss/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 CONTRAVE tablets to healthy subjects, mean elimination half-life (T_1/2) was approximately 5 hours for naltrexone. Following twice daily administration of CONTRAVE, 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 CONTRAVE tablets to healthy subjects, mean elimination half-life (T_½) was approximately 21 hours for bupropion. Following twice daily administration of CONTRAVE, metabolites of bupropion, and to a lesser extent unchanged bupropion, accumulate and reach steady-state concentrations in approximately one week.

Specific Populations

Gender

Pooled analysis of CONTRAVE data suggested no clinically meaningful differences in the pharmacokinetic parameters of bupropion or naltrexone based on gender.

Race

Pooled analysis of CONTRAVE data suggested no clinically meaningful differences in the pharmacokinetic parameters of bupropion or naltrexone based on race.

Elderly

The pharmacokinetics of CONTRAVE have not been evaluated in the geriatric population. The effects of age on the pharmacokinetics of naltrexone or bupropion and their metabolites have not been fully characterized. An exploration of steady-state bupropion concentrations from several depression efficacy studies involving patients dosed in a range of 300 to 750 mg/day, on a three times daily schedule, revealed no relationship between age (18 to 83 years) and plasma concentration of bupropion. A single-dose pharmacokinetic study demonstrated that the disposition of bupropion and its metabolites in elderly subjects was similar to that of younger subjects. These data suggest there is no prominent effect of age on bupropion concentration; however, another pharmacokinetic study, single and multiple dose, has suggested that the elderly are at increased risk for accumulation of bupropion and its metabolites [see Use in Specific Populations (8.5)].

Smokers

Pooled analysis of CONTRAVE data revealed no meaningful differences in the plasma concentrations of bupropion or naltrexone in smokers compared with nonsmokers. The effects of cigarette smoking on the pharmacokinetics of bupropion were studied in 34 healthy male and female volunteers; 17 were chronic cigarette smokers and 17 were nonsmokers. Following oral administration of a single 150 mg dose of bupropion, there was no statistically significant difference in C_max, half-life, T_max, AUC, or clearance of bupropion or its active metabolites between smokers and nonsmokers.

Hepatic Impairment

Pharmacokinetic data are not available with CONTRAVE in patients with hepatic impairment. The following information is available for individual constituents:

Naltrexone

An increase in naltrexone AUC of approximately 5- and 10-fold in patients with compensated and decompensated liver cirrhosis, respectively, compared with subjects with normal liver function, has been reported. These data also suggest that alterations in naltrexone bioavailability are related to liver disease severity.

Bupropion

The effect of hepatic impairment on the pharmacokinetics of bupropion was characterized in two single-dose trials, one trial in patients with alcoholic liver disease and a second trial in patients with mild-to-severe cirrhosis.

The first trial showed that the half-life of hydroxybupropion was significantly longer in eight patients with alcoholic liver disease than in eight healthy volunteers (32±14 hours vs 21±5 hours, respectively). Although not statistically significant, the AUCs for bupropion and hydroxybupropion were more variable and tended to be greater (by 53% to 57%) in patients with alcoholic liver disease. The differences in half-life for bupropion and the other metabolites in the two patient groups were minimal.

The second trial demonstrated no statistically significant differences in the pharmacokinetics of bupropion and its active metabolites in nine subjects with mild-to-moderate hepatic cirrhosis compared with eight healthy volunteers. However, more variability was observed in some of the pharmacokinetic parameters for bupropion (AUC, C_max, and T_max) and its active metabolites (t_½) in subjects with mild-to-moderate hepatic cirrhosis. In subjects with severe hepatic cirrhosis, significant alterations in the pharmacokinetics of bupropion and its metabolites were seen (Table 4).

The dose of CONTRAVE should be reduced in patients with hepatic impairment [see Dosage and Administration (2.3) and Use in Specific Populations (8.7)].

Renal Impairment

A dedicated pharmacokinetic study has not been conducted for CONTRAVE in subjects with renal impairment. The following information is available for the individual constituents:

Naltrexone

Limited information is available for naltrexone in patients with moderate to severe renal impairment. In a study of seven patients with end-stage renal disease requiring dialysis, peak plasma concentrations of naltrexone were elevated at least 6-fold compared to healthy subjects.

Bupropion

Limited information is available for bupropion in patients with moderate to severe renal impairment. An inter-trial comparison between normal subjects and patients with end-stage renal failure demonstrated that the bupropion C_max and AUC values were comparable in the two groups, whereas the hydroxybupropion and threohydrobupropion metabolites had a 2.3- and 2.8-fold increase, respectively, in AUC for patients with end-stage renal failure. A second trial, comparing normal subjects and patients with moderate-to-severe renal impairment (GFR 30.9 ± 10.8 mL/min) showed that exposure after a single 150 mg dose of sustained-release bupropion was approximately 2-fold higher in patients with impaired renal function while levels of the hydroxybupropion and threo/erythrohydrobupropion (combined) metabolites were similar in the two groups. The elimination of bupropion and/or the major metabolites of bupropion may be reduced by impaired renal function.

The dose of CONTRAVE should be reduced in patients with moderate or severe renal impairment. CONTRAVE is not recommended for use in patients with end-stage renal disease [see Dosage and Administration (2.2) and Use in Specific Populations (8.6)].

Drug Interactions

In Vitro Assessment of Drug Interactions

At therapeutically relevant concentrations, naltrexone and 6-beta-naltrexol are not major inhibitors of CYP isoforms CYP1A2, CYP2B6, CYP2C8, CYP2E1, CYP2C9, CYP2C19, CYP2D6 or CYP3A4. Both naltrexone and 6-beta-naltrexol are not major inducers of CYP isoforms CYP1A2, CYP2B6, or CYP3A4.

Bupropion and its metabolites (hydroxybupropion, erythrohydrobupropion, threohydrobupropion) are inhibitors of CYP2D6.

In vitro studies suggest that paroxetine, sertraline, norfluoxetine, fluvoxamine, and nelfinavir inhibit the hydroxylation of bupropion.

Bupropion (IC₅₀ 9.3 mcM) and its metabolites, hydroxybupropion (IC₅₀ 82 mcM) and threohydrobupropion and erythrohydrobupropion (1:1 mixture; IC₅₀ 7.8 mcM), inhibited the renal organic transporter OCT2 to a clinically relevant level. The systemic concentrations of substrate drugs transported by OCT2 are likely to increase as a result of reduced renal clearance when coadministered with CONTRAVE.

Effects of Naltrexone/Bupropion on the Pharmacokinetics of Other Drugs

Drug interaction between CONTRAVE and CYP2D6 substrates (metoprolol) or other drugs (atorvastatin, glyburide, lisinopril, nifedipine, valsartan) has been evaluated. In addition, drug interaction between bupropion, a component of CONTRAVE, and CYP2D6 substrates (desipramine) or other drugs (citalopram, lamotrigine) has also been evaluated.

Effects of Other Drugs on the Pharmacokinetics of Naltrexone/Bupropion

Drug interactions between CYP2B6 inhibitors (ticlopidine, clopidogrel, prasugrel), CYP2B6 inducers (ritonavir, lopinavir) and bupropion (one of the CONTRAVE components), or between other drugs (atorvastatin, glyburide, metoprolol, lisinopril, nifedipine, valsartan) and CONTRAVE have been evaluated. While not systematically studied, carbamazepine, phenobarbital, or phenytoin may induce the metabolism of bupropion.

Studies to evaluate carcinogenesis, mutagenesis, or impairment of fertility with the combined products in CONTRAVE 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 CONTRAVE) 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 CONTRAVE, 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 CONTRAVE 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 CONTRAVE 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 CONTRAVE on a mg/m² basis) revealed no evidence of impaired fertility.