Source: FDA, National Drug Code (US) Revision Year: 2022
CONTRAVE is contraindicated in
Anaphylactoid/anaphylactic reactions and Stevens-Johnson syndrome have been reported with bupropion [see Warnings and Precautions (5.6)].
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.
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:
| Age Range | Drug-Placebo Difference in Number of Cases of Suicidality per 1,000 Patients Treated |
|---|---|
| Increases Compared to Placebo | |
| <18 | 14 additional cases |
| 18 to 24 | 5 additional cases |
| Decreases Compared to Placebo | |
| 25 to 64 | 1 fewer case |
| ≥65 | 6 fewer cases |
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 adverse events have been reported in patients taking bupropion for smoking cessation. These postmarketing reports have included changes in mood (including depression and mania), psychosis, hallucinations, paranoia, delusions, homicidal ideation, aggression, hostility, agitation, anxiety, and panic, as well as suicidal ideation, suicide attempt, and completed suicide [see Warnings and Precautions (5.1)]. 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 CONTRAVE 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.
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:
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:
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.
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.
The following adverse reactions are discussed in other sections of the labeling:
Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
CONTRAVE was evaluated for safety in five double-blind placebo controlled trials in 4,754 overweight or obese patients (3,239 patients treated with CONTRAVE and 1,515 patients treated with placebo) for a treatment period up to 56 weeks. The majority of patients were treated with CONTRAVE 32 mg/360 mg total daily dose. In addition, some patients were treated with other combination daily doses including naltrexone up to 50 mg and bupropion up to 400 mg. All subjects received study drug in addition to diet and exercise counseling. One trial (N=793) evaluated patients participating in an intensive behavioral modification program and another trial (N=505) evaluated patients with type 2 diabetes. In these randomized, placebo-controlled trials, 2,545 patients received CONTRAVE 32 mg/360 mg for a mean treatment duration of 36 weeks (median, 56 weeks). Baseline patient characteristics included a mean age of 46 years, 82% women, 78% white, 25% with hypertension, 13% with type 2 diabetes, 56% with dyslipidemia, 25% with BMI greater than 40 kg/m 2, and less than 2% with coronary artery disease. Dosing was initiated and increased weekly to reach the maintenance dose within 4 weeks.
In CONTRAVE clinical trials, 24% of subjects receiving CONTRAVE and 12% of subjects receiving placebo discontinued treatment because of an adverse event. The most frequent adverse reactions leading to discontinuation with CONTRAVE were nausea (6.3%), headache (1.7%) and vomiting (1.1%).
Adverse reactions that were reported by greater than or equal to 2% of patients, and were more frequently reported by patients treated with CONTRAVE compared to placebo, are summarized in Table 3.
Table 3. Adverse Reactions Reported by Obese or Overweight Patients With an Incidence () of at Least 2 Among Patients Treated with CONTRAVE and More Common than with Placebo:
| Adverse Reaction | CONTRAVE 32 mg/360 mg N=2545 % | Placebo N=1515 % |
|---|---|---|
| Nausea | 32.5 | 6.7 |
| Constipation | 19.2 | 7.2 |
| Headache | 17.6 | 10.4 |
| Vomiting | 10.7 | 2.9 |
| Dizziness | 9.9 | 3.4 |
| Insomnia | 9.2 | 5.9 |
| Dry mouth | 8.1 | 2.3 |
| Diarrhea | 7.1 | 5.2 |
| Anxiety | 4.2 | 2.8 |
| Hot flush | 4.2 | 1.2 |
| Fatigue | 4.0 | 3.4 |
| Tremor | 4.0 | 0.7 |
| Upper abdominal pain | 3.5 | 1.3 |
| Viral gastroenteritis | 3.5 | 2.6 |
| Influenza | 3.4 | 3.2 |
| Tinnitus | 3.3 | 0.6 |
| Urinary tract infection | 3.3 | 2.8 |
| Hypertension | 3.2 | 2.2 |
| Abdominal pain | 2.8 | 1.4 |
| Hyperhidrosis | 2.6 | 0.6 |
| Irritability | 2.6 | 1.8 |
| Blood pressure increased | 2.4 | 1.5 |
| Dysgeusia | 2.4 | 0.7 |
| Rash | 2.4 | 2.0 |
| Muscle strain | 2.2 | 1.7 |
| Palpitations | 2.1 | 0.9 |
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
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).
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.
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. The observed increase in serum creatinine may be the result of OCT2 inhibition [see Clinical Pharmacology (12.3)].
The following adverse reactions have been identified during post approval use of CONTRAVE. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
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.
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 Cmax 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)].
Coadministration of CONTRAVE with digoxin may decrease plasma digoxin levels. Monitor plasma digoxin levels in patients treated concomitantly with CONTRAVE and digoxin [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.
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)].
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.
Weight loss offers no benefit to a pregnant patient and may cause fetal harm. When a pregnancy is recognized, advise the pregnant patient of the risk to the fetus, and discontinue CONTRAVE (see Clinical Considerations). Available pharmacovigilance data and data from clinical trials with the individual components of CONTRAVE use in pregnant patients have not demonstrated a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes.
Data from epidemiological studies of pregnant patients exposed to bupropion in the first trimester have not identified an increased risk of congenital malformations overall (see Data). When bupropion was administered to pregnant rats during organogenesis, there was no evidence of fetal malformations at doses up to approximately 20 times the maximum recommended human dose (MRHD) of 360 mg/day. When given to pregnant rabbits during organogenesis, non-dose–related increases in incidence of fetal malformations, and skeletal variations were observed at doses approximately twice the MRHD and greater. Decreased fetal weights were seen at doses 5 times the MRHD and greater (see Data).
Limited case report data of pregnant patients exposed to naltrexone in the first trimester have not identified an increased risk of congenital malformations overall. Daily oral administration of naltrexone during the period of organogenesis has been shown to increase the incidence of early fetal loss in rats and rabbits at doses ≥ 15 times and ≥ 60 times the MRHD of 32 mg/day, respectively. There was no evidence of fetal malformations in rats and rabbits at doses up to approximately 100 and 200 times the MHRD, respectively (see Data).
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.
Appropriate weight gain based on pre-pregnancy weight is currently recommended for all pregnant patients, including those who are already overweight or obese, due to the obligatory weight gain that occurs in maternal tissues during pregnancy.
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.
Reproduction and developmental studies have not been conducted for the combined products naltrexone and bupropion in CONTRAVE. Separate studies with bupropion and naltrexone have been conducted in pregnant rats and rabbits. Safety margins were estimated using body surface area exposure (mg/m²) based on a body weight of 100 kg.
Daily oral administration of naltrexone has been shown to increase the incidence of early fetal loss when given to rats at doses ≥30 mg/kg/day (15 times the MHRD on a mg/m² basis) and to rabbits at oral doses ≥60 mg/kg/day (60 times the MHRD on a mg/m² basis).
Daily oral administration of naltrexone to rats and rabbits during the period of organogenesis did not induce malformations at doses up to 200 mg/kg/day (approximately 100 and 200 times the MHRD, 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. In studies conducted in pregnant rats and rabbits, bupropion was administered orally during the period of organogenesis at doses of up to 450 and 150 mg/kg/day, respectively (approximately 20 and 14 times the MRHD, respectively, on a mg/m² basis). There was no evidence of fetal malformations in rats. When given to pregnant rabbits during organogenesis, non-dose-related increases in incidence of fetal malformations and skeletal variations were observed at the lowest dose tested (25 mg/kg/day, approximately 2 times the MRHD on a mg/m² basis) and greater. Decreased fetal weights were observed at doses of 50 mg/kg/day (approximately 5 times the MRHD on a mg/m² basis) and greater. No maternal toxicity was evident at doses of 50 mg/kg/day or less.
In a pre- and postnatal development study, bupropion administered orally to pregnant rats at doses of up to 150 mg/kg/day (approximately 7 times the MRHD on a mg/m² basis) from embryonic implantation through lactation had no effect on pup growth or development.
Data from published literature report the presence of bupropion and its metabolites in human milk. Limited data from postmarketing reports with bupropion use during lactation have not identified a clear association of adverse effects on a breastfed infant (see Data). Naltrexone and its major metabolite, 6β-naltrexol, are present in human milk. There are no data on bupropion, naltrexone, or their metabolites on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for CONTRAVE and any potential adverse effects on the breastfed infant from CONTRAVE or from the mother’s underlying condition.
In a lactation study of ten women, levels of orally dosed bupropion and its active metabolites were measured in expressed milk. The average daily infant exposure (assuming 150 mL/kg daily consumption) to bupropion and its active metabolites was 2% of the maternal weight-adjusted dose. Postmarketing reports have described seizures in breastfed infants. The relationship of bupropion exposure and these seizures is unclear.
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.
In a pharmacokinetic study conducted for CONTRAVE in subjects with renal impairment (mild, moderate and severe), exposure to naltrexone metabolite, 6-beta naltrexol, and bupropion metabolites, threohydrobupropion, and erythrohydrobupropion was increased. 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 [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)].
In a pharmacokinetic study conducted for CONTRAVE in subjects with hepatic impairment (mild, moderate, and severe), exposure to naltrexone, bupropion, and their metabolites were increased. Therefore, the maximum recommended daily maintenance dose of CONTRAVE is two tablets (one tablet each morning and evening) in patients with moderate hepatic impairment. CONTRAVE is not recommended for use in patients with severe hepatic impairment [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3)].
CONTRAVE 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.
The inhalation of crushed tablets or injection of dissolved bupropion has been reported. Seizures and/or cases of death have been reported when bupropion has been administered intranasally or by parenteral injection. CONTRAVE (naltrexone HCl and bupropion HCl) extended-release tablets are intended for oral use only.
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.
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