CONTRAVE is indicated in combination with a reduced-calorie diet and increased physical activity to reduce excess body weight and maintain weight reduction long term in adults with obesity or overweight in the presence of at least one weight-related comorbid condition. CONTRAVE is a combination of naltrexone, an opioid antagonist, and bupropion, an aminoketone antidepressant, indicated in combination with a reduced-calorie diet and increased physical activity to reduce excess body weight and maintain weight reduction long term in adults with obesity or overweight in the presence of at least one weight-related comorbid condition.
( 1 ) Limitations of Use: The effect of CONTRAVE on cardiovascular morbidity and mortality has not been established. ( 1 ) Coadministration with other naltrexone-containing products is not recommended. Coadministration with other bupropion-containing products is contraindicated. ( 1 , 4 ) Limitations of Use: The effect of CONTRAVE on cardiovascular morbidity and mortality has not been established. CONTRAVE contains naltrexone and bupropion.
Coadministration with other naltrexone-containing products is not recommended. Coadministration with other bupropion-containing products is contraindicated.
Contraindications
CONTRAVE is contraindicated in Uncontrolled hypertension [see Warnings and Precautions (5.5) ] Seizure disorder or a history of seizures [see Warnings and Precautions (5.3) ] Use of other bupropion-containing products (including, but not limited to, WELLBUTRIN, WELLBUTRIN SR, WELLBUTRIN XL, APLENZIN and ZYBAN) Bulimia or anorexia nervosa, which increase the risk for seizure [see Warnings and Precautions (5.3) ] Chronic opioid or opiate agonist (e.g., methadone) or partial agonists (e.g., buprenorphine) use, or acute opiate withdrawal [see Warnings and Precautions (5.4) and Drug Interactions (7.2) ] Patients undergoing an abrupt discontinuation of alcohol, benzodiazepines, barbiturates, and antiepileptic drugs [see Warnings and Precautions (5.3) and Drug Interactions (7.7) ] Concomitant administration of monoamine oxidase inhibitors (MAOI).
At least 14 days should elapse between discontinuation of MAOI and initiation of treatment with CONTRAVE. There is an increased risk of hypertensive reactions when CONTRAVE is used concomitantly with MAOIs. Starting CONTRAVE in a patient treated with reversible MAOIs such as linezolid or intravenous methylene blue is also contraindicated [see Dosage and Administration (2.4) , Drug Interactions (7.1) ] Known allergy to bupropion, naltrexone or any other component of CONTRAVE.
Anaphylactoid/anaphylactic reactions and Stevens-Johnson syndrome have been reported with bupropion [see Warnings and Precautions (5.6) ] Uncontrolled hypertension ( 4 ) Seizure disorders, anorexia nervosa or bulimia, or undergoing abrupt discontinuation of alcohol, benzodiazepines, barbiturates, and antiepileptic drugs ( 4 ) Use of other bupropion-containing products ( 4 ) Chronic opioid use ( 4 ) During or within 14 days of taking monoamine oxidase inhibitors (MAOI) ( 4 ) Known allergy to any of the ingredients in CONTRAVE ( 4 )
Suicidal Behavior and Ideation: Monitor for depression or suicidal thoughts. Discontinue CONTRAVE if symptoms develop. ( 5.1 ) Neuropsychiatric Adverse Events During Smoking Cessation: Postmarketing reports of serious or clinically significant neuropsychiatric adverse events have included changes in mood (including depression and mania), psychosis, hallucinations, paranoia, delusions, homicidal ideation, aggression, hostility, agitation, anxiety, and panic, as well as suicidal ideation, suicide attempt, and completed suicide.
Observe patients taking CONTRAVE for the occurrence of such symptoms and instruct them to discontinue CONTRAVE and contact a healthcare provider if they experience such adverse events. ( 5.2 ) Risk of seizure may be minimized by adhering to the recommended dosing schedule and avoiding coadministration with high-fat meal. ( 5.3 ) Increase in Blood Pressure and Heart Rate: Monitor blood pressure and heart rate in all patients, especially those with cardiac or cerebrovascular disease.
( 5.5 ) Hepatotoxicity: Cases of hepatitis and clinically significant liver dysfunction observed with naltrexone exposure. ( 5.7 ) Angle-closure glaucoma: Angle-closure glaucoma has occurred in patients with untreated anatomically narrow angles treated with antidepressants. ( 5.9 ) Use of Antidiabetic Medications: Weight loss may cause hypoglycemia. Monitor blood glucose. ( 5.10 )
5.1Suicidal Behavior and Ideation
CONTRAVE contains bupropion, a dopamine and norepinephrine re-uptake inhibitor that is similar to some drugs used for the treatment of depression; therefore, the following precautions pertaining to these products should be considered when treating patients with CONTRAVE. Patients with major depressive disorder, both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs.
Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. In placebo-controlled clinical trials with CONTRAVE for the treatment of obesity in adult patients, no suicides or suicide attempts were reported in studies up to 56 weeks duration with CONTRAVE (equivalent to bupropion doses of 360 mg/day).
In these same studies, suicidal ideation was reported by 3 (0.20%) of 1,515 patients treated with placebo compared with 1 (0.03%) of 3,239 treated with CONTRAVE. Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (selective serotonin re-uptake inhibitors [SSRIs] and others) show that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18 to 24) with major depressive disorder (MDD) and other psychiatric disorders.
Short-term clinical trials did not show an increase in the risk of suicidality with antidepressants compared with placebo in adults beyond age 24; there was a reduction with antidepressants compared with placebo in adults aged 65 and older. CONTRAVE is not approved for use in pediatric patients. The pooled analyses of placebo-controlled trials of antidepressant drugs in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of nine antidepressant drugs in over 4,400 patients.
The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of two months) of 11 antidepressant drugs in over 77,000 patients. There was 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.
5.2Neuropsychiatric Adverse Events and Suicide Risk in Smoking Cessation Treatment
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, a
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Interactions
MAOIs: Increased risk of hypertensive reactions can occur when used concomitantly. ( 7.1 ) Drugs Metabolized by CYP2D6: Bupropion inhibits CYP2D6 and can increase concentrations of antidepressants, (e.g., selective serotonin reuptake inhibitors and many tricyclics), antipsychotics (e.g., haloperidol, risperidone and thioridazine), beta-blockers (e.g., metoprolol) and Type 1C antiarrhythmics (e.g., propafenone and flecainide).
Consider dose reduction when using with CONTRAVE. ( 7.3 ) Digoxin: May decrease plasma digoxin levels. Monitor digoxin levels. ( 7.3 ) Concomitant Treatment with CYP2B6 Inhibitors (e.g., ticlopidine or clopidogrel) can increase bupropion exposure. Do not exceed one tablet twice daily when taken with CYP2B6 inhibitors. ( 2.5 , 7.4 ) CYP2B6 Inducers (e.g., ritonavir, lopinavir, efavirenz, carbamazepine, phenobarbital, and phenytoin) may reduce efficacy by reducing bupropion exposure, avoid concomitant use.
( 7.4 ) Drugs that Lower Seizure Threshold: Dose CONTRAVE with caution. ( 5.3 , 7.5 ) Dopaminergic Drugs (levodopa and amantadine): CNS toxicity can occur when used concomitantly with CONTRAVE. ( 7.6 ) Drug-Laboratory Test Interactions: CONTRAVE can cause false- positive urine test results for amphetamines. ( 7.8 )
7.1Monoamine Oxidase Inhibitors (MAOI)
Concomitant use of MAOIs and bupropion is contraindicated. Bupropion inhibits the re-uptake of dopamine and norepinephrine and can increase the risk for hypertensive reactions when used concomitantly with drugs that also inhibit the re-uptake of dopamine or norepinephrine, including MAOIs. Studies in animals demonstrate that the acute toxicity of bupropion is enhanced by the MAOI phenelzine. At least 14 days should elapse between discontinuation of an MAOI and initiation of treatment with CONTRAVE.
Conversely, at least 14 days should be allowed after stopping CONTRAVE before starting an MAOI [ see Contraindications (4) ] .
7.2Opioid Analgesics
Patients taking CONTRAVE may not fully benefit from treatment with opioid-containing medicines, such as cough and cold remedies, antidiarrheal preparations, and opioid analgesics. In patients requiring intermittent opiate treatment, CONTRAVE therapy should be temporarily discontinued, and opiate dose should not be increased above the standard dose. CONTRAVE may be used with caution after chronic opioid use has been stopped for 7 to 10 days in order to prevent precipitation of withdrawal [see Contraindications (4) and Warnings and Precautions (5.4) ] .
During CONTRAVE clinical studies, the use of concomitant opioid or opioid-like medications, including analgesics or antitussives, were excluded.
7.3Potential for
CONTRAVE to Affect Other Drugs Metabolized by CYP2D6 In a clinical study, CONTRAVE (32 mg naltrexone/360 mg bupropion) daily was coadministered with a 50 mg dose of metoprolol (a CYP2D6 substrate). CONTRAVE increased metoprolol AUC and C max by approximately 4- and 2-fold, respectively, relative to metoprolol alone. Similar clinical drug interactions resulting in increased pharmacokinetic exposure of CYP2D6 substrates have also been observed with bupropion as a single agent with desipramine or venlafaxine.
Coadministration of CONTRAVE with drugs that are metabolized by CYP2D6 isozyme including certain antidepressants (SSRIs and many tricyclics), antipsychotics (e.g., haloperidol, risperidone and thioridazine), beta-blockers (e.g., metoprolol) and Type 1C antiarrhythmics (e.g., propafenone and flecainide), should be approached with caution and should be initiated at the lower end of the dose range of the concomitant medication.
If CONTRAVE is added to the treatment regimen of a patient already receiving a drug metabolized by CYP2D6, the need to decrease the dose of the original medication should be considered, particularly for those concomitant medications with a narrow therapeutic index [see Clinical Pharmacology (12.3) ] . Digoxin Coadministration of CONTRAVE with digoxin may decrease plasma digoxin levels. Monitor plasma digoxin levels in patients treated concomitantly with CONTRAVE and digoxin [see Clinical Pharmacology (12.3) ] .
7.4Potential for Other Drugs to Affect
CONTRAVE 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) ] .
7.5Drugs That Lower Seizure Threshold
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) ].
7.6Dopaminergic Drugs (Levodopa and Amantadine)
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.
7.7Use with Alcohol
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.
7.8Drug-Laboratory Test Interactions
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.
Pregnancy and breastfeeding
8.1Pregnancy Risk Summary
Weight loss offers no benefit to a pregnant patient and may cause fetal harm. When a pregnancy is recognized, advise the pregnant patient of the risk to the fetus, and discontinue CONTRAVE ( see Clinical Considerations ). Available pharmacovigilance data and data from clinical trials with the individual components of CONTRAVE use in pregnant patients have not demonstrated a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes.
Bupropion Data from epidemiological studies of pregnant patients exposed to bupropion in the first trimester have not identified an increased risk of congenital malformations overall (see Data ). When bupropion was administered to pregnant rats during organogenesis, there was no evidence of fetal malformations at doses up to approximately 20 times the maximum recommended human dose (MRHD) of 360 mg/day. When given to pregnant rabbits during organogenesis, non-dose–related increases in incidence of fetal malformations, and skeletal variations were observed at doses approximately twice the MRHD and greater.
Decreased fetal weights were seen at doses 5 times the MRHD and greater (see Data ) . Naltrexone Limited case report data of pregnant patients exposed to naltrexone in the first trimester have not identified an increased risk of congenital malformations overall . Daily oral administration of naltrexone during the period of organogenesis has been shown to increase the incidence of early fetal loss in rats and rabbits at doses ≥ 15 times and ≥ 60 times the MRHD of 32 mg/day, respectively.
There was no evidence of fetal malformations in rats and rabbits at doses up to approximately 100 and 200 times the MHRD, respectively. (see Data ). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.
Clinical Considerations Disease-associated maternal and/or embryo/fetal risk Appropriate weight gain based on pre-pregnancy weight is currently recommended for all pregnant patients, including those who are already overweight or obese, due to the obligatory weight gain that occurs in maternal tissues during pregnancy. Data Human Data In clinical studies, 21 (0.7%) of 3,024 women became pregnant while taking CONTRAVE: 11 carried to term and gave birth to a healthy infant, three had elective abortions, four had spontaneous abortions, and the outcome of three pregnancies were unknown.
Data from the international bupropion Pregnancy Registry (675 first trimester exposures) and a retrospective cohort study using the United Healthcare database (1,213 first trimester exposures) did not show an increased risk for malformations overall. No increased risk for cardiovascular malformations overall has been observed after bupropion exposure during the first trimester. The prospectively observed rate of cardiovascular malformations in pregnancies with exposure to bupropion in the first trimester from the international Pregnancy Registry was 1.3% (9 cardiovascular malformations out of 675 first-trimester maternal bupropion exposures), which is similar to the background rate of cardiovascular malformations (approximately 1%).
Data from the United Healthcare database and a case-control study (6,853 infants with cardiovascular malformations and 5,763 with non-cardiovascular malformations) from the National Birth Defects Prevention Study (NBDPS) did not show an increased risk for cardiovascular malformations overall after bupropion exposure during the first trimester. Study findings on bupropion exposure during the first trimester and risk for left ventricular outflow tract obstruction (LVOTO) are inconsistent and do not allow conclusions regarding a possible association.
The United Healthcare database lacked sufficient power to evaluate this 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. Separate studies with bupropion and naltrexone have been conducted in pregnant rats and rabbits. Safety margins were estimated using body surface area exposure (mg/m 2 ) 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/m 2 basis) and to rabbits at oral doses ≥60 mg/kg/day (60 times the MHRD on a mg/m 2 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/m 2 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/m 2 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/m 2 basis) and greater. Decreased fetal weights were observed at doses of 50 mg/kg/day (approximately 5 times the MRHD on a mg/m 2 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/m 2 basis) from embryonic implantation through lactation had no effect on pup growth or development.
Adverse reactions
The following adverse reactions are discussed in other sections of the labeling: Suicidal Behavior and Ideation [see Boxed Warning , Warnings and Precautions (5.1) ] Neuropsychiatric Adverse Events [see Warnings and Precautions (5.2) ] Seizures [see Contraindications (4) , Warnings and Precautions (5.3) ] Increase in Blood Pressure and Heart Rate [see Warnings and Precautions (5.5) ] Allergic Reactions [see Warnings and Precautions (5.6) ] Angle-Closure Glaucoma [see Warnings and Precautions (5.9) ] Most common adverse reactions (greater than or equal to 5%): nausea, constipation, headache, vomiting, dizziness, insomnia, dry mouth and diarrhea.
( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Currax Pharmaceuticals LLC at 1-800-793-2145 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .
6.1Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. CONTRAVE was evaluated for safety in five double-blind placebo-controlled trials in 4,754 overweight or obese patients (3,239 patients treated with CONTRAVE and 1,515 patients treated with placebo) for a treatment period up to 56 weeks.
The majority of patients were treated with CONTRAVE 32 mg/360 mg total daily dose. In addition, some patients were treated with other combination daily doses including naltrexone up to 50 mg and bupropion up to 400 mg. All subjects received study drug in addition to diet and exercise counseling. One trial (N=793) evaluated patients participating in an intensive behavioral modification program and another trial (N= 505) evaluated patients with type 2 diabetes.
In these randomized, placebo-controlled trials, 2,545 patients received CONTRAVE 32 mg/360 mg for a mean treatment duration of 36 weeks (median, 56 weeks). Baseline patient characteristics included a mean age of 46 years, 82% women, 78% white, 25% with hypertension, 13% with type 2 diabetes, 56% with dyslipidemia, 25% with BMI greater than 40 kg/m 2 , and less than 2% with coronary artery disease. Dosing was initiated and increased weekly to reach the maintenance dose within 4 weeks.
In CONTRAVE clinical trials, 24% of subjects receiving CONTRAVE and 12% of subjects receiving placebo discontinued treatment because of an adverse event. The most frequent adverse reactions leading to discontinuation with CONTRAVE were nausea (6.3%), headache (1.7%) and vomiting (1.1%). Common Adverse Reactions Adverse reactions that were reported by greater than or equal to 2% of patients and were more frequently reported by patients treated with CONTRAVE compared to placebo, are summarized in Table 3 .
Table 3. Adverse Reactions Reported by Obese or Overweight Patients With an Incidence (%) of at Least 2% Among Patients Treated with CONTRAVE and More Common than with Placebo Adverse Reaction CONTRAVE 32 mg/360 mg N=2545 % Placebo N=1515 % Nausea 32.5
6.7 Constipation 19.2
7.2 Headache 17.6
10.4 Vomiting 10.7
2.9 Dizziness 9.9
3.4 Insomnia 9.2
5.9 Dry mouth 8.1
2.3 Diarrhea 7.1
5.2 Anxiety 4.2
2.8 Hot flush 4.2
1.2 Fatigue 4.0
3.4 Tremor 4.0
0.7 Upper abdominal pain 3.5
1.3 Viral gastroenteritis 3.5
2.6 Influenza 3.4
3.2 Tinnitus 3.3
0.6 Urinary tract infection 3.3
2.8 Hypertension 3.2
2.2 Abdominal pain 2.8
1.4 Hyperhidrosis 2.6
0.6 Irritability 2.6
1.8 Blood pressure increased 2.4
1.5 Dysgeusia 2.4
0.7 Rash 2.4
2.0 Muscle strain 2.2
1.7 Palpitations 2.1
0.9Other 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).
6.2Postmarketing Experience
The following adverse reactions have been identified during post approval use of CONTRAVE, naltrexone, or bupropion. 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. Loss of consciousness, malaise Brugada pattern/syndrome Drug reaction with eosinophilia and systemic symptoms (DRESS) Acute generalized exanthematous pustulosis (AGEP) Aseptic meningitis
Prognia shows this product information for reference and learning. It is not treatment advice and can lag behind the official text. Always check the current product information and local protocols before prescribing.
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) ] .
