Dosage & Administration
CONTRAVE dose escalation schedule :
| Morning Dose | Evening Dose | |
|---|---|---|
| Week 1 | 1 tablet | None |
| Week 2 | 1 tablet | 1 tablet |
| Week 3 | 2 tablets | 1 tablet |
| Week 4 – Onward | 2 tablets | 2 tablets |
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Contrave Prescribing Information
SUICIDALITY AND ANTIDEPRESSANT DRUGS
CONTRAVE® is not approved for use in the treatment of major depressive disorder or other psychiatric disorders. CONTRAVE contains bupropion, the same active ingredient as some antidepressant medications (including, but not limited to, WELLBUTRIN, WELLBUTRIN SR, WELLBUTRIN XL, and APLENZIN). Antidepressants increased the risk of suicidal thoughts and behavior in children, adolescents, and young adults in short-term trials. These trials did not show an increase in the risk of suicidal thoughts and behavior with antidepressant use in subjects over age 24; there was a reduction in risk with antidepressant use in subjects aged 65 and older. In patients of all ages who are started on CONTRAVE, monitor closely for worsening, and for the emergence of suicidal thoughts and behaviors. Advise families and caregivers of the need for close observation and communication with the prescriber. CONTRAVE is not approved for use in pediatric patients [see Warnings and Precautions (5.1), Use in Specific Populations (8.4)].
CONTRAVE is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of:
- 30 kg/m2 or greater (obese) or
- 27 kg/m2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia).
Limitations of Use:
- The effect of CONTRAVE on cardiovascular morbidity and mortality has not been established.
- The safety and effectiveness of CONTRAVE in combination with other products intended for weight loss, including prescription drugs, over-the-counter drugs, and herbal preparations, have not been established.
Recommended Dosing
CONTRAVE dosing should be escalated according to the following schedule:
| Morning Dose | Evening Dose | |
|---|---|---|
| Week 1 | 1 tablet | None |
| Week 2 | 1 tablet | 1 tablet |
| Week 3 | 2 tablets | 1 tablet |
| Week 4 – Onward | 2 tablets | 2 tablets |
A total daily dosage of 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
Dose Adjustment in Patients with Renal Impairment
In patients with moderate or severe renal impairment, the maximum recommended daily dose for CONTRAVE is two tablets (one tablet each morning and evening). CONTRAVE is not recommended for use in patients with end-stage renal disease [see Use in Specific Population (8.6) and Clinical Pharmacology (12.3)].
Dose Adjustment in Patients with Hepatic Impairment
In patients with moderate hepatic impairment, the maximum recommended daily maintenance dose of CONTRAVE is two tablets (one tablet each morning and evening). CONTRAVE is not recommended for use in patients with severe hepatic impairment [see Use in Specific Population (8.7) and Clinical Pharmacology (12.3)].
Switching a Patient To or From a Monoamine Oxidase Inhibitor (MAOI) Antidepressant
At least 14 days should elapse between discontinuation of an MAOI intended to treat depression and initiation of therapy with CONTRAVE. Conversely, at least 14 days should be allowed after stopping CONTRAVE before starting an MAOI antidepressant [see Contraindications (4) and Drug Interactions (7.1)].
Concomitant Use with CYP2B6 Inhibitors
During concomitant use with CYP2B6 inhibitors (e.g., ticlopidine or clopidogrel), the maximum recommended daily dose of CONTRAVE is two tablets (one tablet each morning and evening) [see Drug Interactions (7.4) and Clinical Pharmacology (12.3)].
CONTRAVE extended-release tablets: 8 mg/90 mg are blue, round, bi-convex, film-coated, and debossed with "NB-890" on one side.
Pregnancy
Risk Summary
Weight loss offers no benefit to a pregnant patient and may cause fetal harm. When a pregnancy is recognized, advise the pregnant patient of the risk to the fetus, and discontinue CONTRAVE (see Clinical Considerations). Available pharmacovigilance data and data from clinical trials with the individual components of CONTRAVE use in pregnant patients have not demonstrated a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes.
Bupropion
Data from epidemiological studies of pregnant patients exposed to bupropion in the first trimester have not identified an increased risk of congenital malformations overall (see Data). When bupropion was administered to pregnant rats during organogenesis, there was no evidence of fetal malformations at doses up to approximately 20 times the maximum recommended human dose (MRHD) of 360 mg/day. When given to pregnant rabbits during organogenesis, non-dose–related increases in incidence of fetal malformations, and skeletal variations were observed at doses approximately twice the MRHD and greater. Decreased fetal weights were seen at doses 5 times the MRHD and greater (see Data).
Naltrexone
Limited case report data of pregnant patients exposed to naltrexone in the first trimester have not identified an increased risk of congenital malformations overall. Daily oral administration of naltrexone during the period of organogenesis has been shown to increase the incidence of early fetal loss in rats and rabbits at doses ≥ 15 times and ≥ 60 times the MRHD of 32 mg/day, respectively. There was no evidence of fetal malformations in rats and rabbits at doses up to approximately 100 and 200 times the MHRD, respectively. (see Data).
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.
Clinical Considerations
Disease-associated maternal and/or embryo/fetal risk
Appropriate weight gain based on pre-pregnancy weight is currently recommended for all pregnant patients, including those who are already overweight or obese, due to the obligatory weight gain that occurs in maternal tissues during pregnancy.
Data
Human Data
In clinical studies, 21 (0.7%) of 3,024 women became pregnant while taking CONTRAVE: 11 carried to term and gave birth to a healthy infant, three had elective abortions, four had spontaneous abortions, and the outcome of three pregnancies were unknown.
Data from the international bupropion Pregnancy Registry (675 first trimester exposures) and a retrospective cohort study using the United Healthcare database (1,213 first trimester exposures) did not show an increased risk for malformations overall.
No increased risk for cardiovascular malformations overall has been observed after bupropion exposure during the first trimester. The prospectively observed rate of cardiovascular malformations in pregnancies with exposure to bupropion in the first trimester from the international Pregnancy Registry was 1.3% (9 cardiovascular malformations out of 675 first-trimester maternal bupropion exposures), which is similar to the background rate of cardiovascular malformations (approximately 1%). Data from the United Healthcare database and a case-control study (6,853 infants with cardiovascular malformations and 5,763 with non-cardiovascular malformations) from the National Birth Defects Prevention Study (NBDPS) did not show an increased risk for cardiovascular malformations overall after bupropion exposure during the first trimester.
Study findings on bupropion exposure during the first trimester and risk for left ventricular outflow tract obstruction (LVOTO) are inconsistent and do not allow conclusions regarding a possible association. The United Healthcare database lacked sufficient power to evaluate this 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/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.
Lactation
Risk Summary
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.
Data
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.
Pediatric Use
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.
Geriatric Use
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.
Renal Impairment
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)].
Hepatic Impairment
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 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)]