CONTRAVE EXTENDED-RELEASE- naltrexone hydrochloride and bupropion hydrochloride tablet, extended release

Country: United States

Language: English

Source: NLM (National Library of Medicine)

Active ingredient:

NALTREXONE HYDROCHLORIDE (UNII: Z6375YW9SF) (NALTREXONE - UNII:5S6W795CQM), BUPROPION HYDROCHLORIDE (UNII: ZG7E5POY8O) (BUPROPION - UNII:01ZG3TPX31)

Available from:

Nalpropion Pharmaceuticals LLC

INN (International Name):

NALTREXONE HYDROCHLORIDE

Composition:

NALTREXONE HYDROCHLORIDE 8 mg

Administration route:

ORAL

Prescription type:

PRESCRIPTION DRUG

Therapeutic indications:

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

Product summary:

CONTRAVE 8 mg/90 mg (naltrexone HCl 8 mg and bupropion HCl 90 mg) extended-release tablets are blue, round, bi-convex, film-coated tablets debossed with "NB-890" on one side. CONTRAVE tablets are available as follows: Storage Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].

Authorization status:

New Drug Application

Patient Information leaflet

EXTENDED RELEASE
Nalpropion Pharmaceuticals LLC
----------
This Medication Guide has been approved by the U.S. Food and Drug
Administration
Revised: 11/2023
MEDICATION GUIDE
CONTRAVE® (CON-trayv)
(naltrexone HCl and bupropion HCl) extended-release tablets
What is the most important information I should know about CONTRAVE?
CONTRAVE can cause serious side effects, including:
•
Suicidal thoughts or actions. One of the ingredients in CONTRAVE is
bupropion. Bupropion has
caused some people to have suicidal thoughts or actions or unusual
changes in behavior, whether
or not they are taking medicines used to treat depression.
Bupropion may increase suicidal thoughts or actions in some children,
teenagers, and young
adults within the first few months of treatment.
If you already have depression or other mental illnesses, taking
bupropion may cause it to get
worse, especially within the first few months of treatment.
Stop taking CONTRAVE and call a healthcare provider right away if you,
or your family
member, have any of the following symptoms, especially if they are
new, worse, or worry you:
•
thoughts about suicide or dying
•
attempts to commit suicide
•
new or worse depression
•
new or worse anxiety
•
feeling very agitated or restless
•
panic attacks
•
new or worse irritability
•
acting aggressive, being angry, or violent
•
acting on dangerous impulses
•
an extreme increase in activity and talking (mania)
•
other unusual changes in behavior or mood
•
trouble sleeping (insomnia)
While taking CONTRAVE, you or your family members should:
•
Pay close attention to any changes, especially sudden changes, in
mood, behaviors, thoughts,
or feelings. This is very important when you start taking CONTRAVE or
when your dose
changes.
•
Keep all follow-up visits with your healthcare provider as scheduled.
Call your healthcare
provider between visits as needed, especially if you have concerns
about symptoms.
CONTRAVE has not been studied in and is not approved for use in
children under the age of 18.
Wha

Summary of Product characteristics

CONTRAVE EXTENDED-RELEASE- NALTREXONE HYDROCHLORIDE AND BUPROPION
HYDROCHLORIDE TABLET, EXTENDED RELEASE
NALPROPION PHARMACEUTICALS LLC
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HIGHLIGHTS OF PRESCRIBING INFORMATION
THESE HIGHLIGHTS DO NOT INCLUDE ALL THE INFORMATION NEEDED TO USE
CONTRAVE SAFELY AND
EFFECTIVELY. SEE FULL PRESCRIBING INFORMATION FOR CONTRAVE.
CONTRAVE (NALTREXONE HYDROCHLORIDE AND BUPROPION HYDROCHLORIDE)
EXTENDED-RELEASE
TABLETS, FOR ORAL USE
INITIAL U.S. APPROVAL: 2014
WARNING: SUICIDAL THOUGHTS AND BEHAVIORS
_SEE FULL PRESCRIBING INFORMATION FOR COMPLETE BOXED WARNING_
INCREASED RISK OF SUICIDAL THINKING AND BEHAVIOR IN CHILDREN,
ADOLESCENTS, AND YOUNG
ADULTS TAKING ANTIDEPRESSANTS FOR MAJOR DEPRESSIVE DISORDER AND OTHER
PSYCHIATRIC
DISORDERS. (5.1)
MONITOR FOR WORSENING AND EMERGENCE OF SUICIDAL THOUGHTS AND
BEHAVIORS. (5.1)
CONTRAVE HAS NOT BEEN STUDIED IN PEDIATRIC PATIENTS. (5.1)
INDICATIONS AND USAGE
CONTRAVE is a combination of naltrexone, an opioid antagonist, and
bupropion, an aminoketone
antidepressant, 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/m or greater (obese) or
27 kg/m or greater (overweight) in the presence of at least one
weight-related comorbidity (e.g.,
hypertension, type 2 diabetes mellitus, or dyslipidemia). (1)
Limitations of Use:
The effect of CONTRAVE on cardiovascular morbidity and mortality has
not been established. (1)
The safety and effectiveness of CONTRAVE in combination with other
products intended for weight loss,
including prescription and over-the-counter drugs, and herbal
preparations, have not been established.
(1)
DOSAGE AND ADMINISTRATION
CONTRAVE dose escalation schedule (2.1):
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
DOSAGE FORMS AND STRENGTHS
Extended-Release Tablets: 8 mg naltrexone hydrochloride (HCl) /90 mg
bupropion HCl (3)
CONTRAINDICATIONS
Uncontrolled hyper