Drug: Contrave
CONTRAVE extended-release tablets contain naltrexone hydrochloride and bupropion hydrochloride. Naltrexone hydrochloride, USP, an opioid antagonist, is a synthetic congener of oxymorphone with no opioid agonist properties. Naltrexone differs in structure from oxymorphone in that the methyl group on the nitrogen atom is replaced by a cyclopropylmethyl group. Naltrexone hydrochloride is also related to the potent opioid antagonist, naloxone, or nallylnoroxymorphone. Naltrexone hydrochloride has the chemical name of morphinan-6-one, 17-(cyclopropylmethyl)4,5-epoxy-3,14-dihydroxy-, hydrochloride, (5α)-. The empirical formula is C20H23NO4•HCl and the molecular weight is 377.86. The structural formula is: Naltrexone hydrochloride is a white to yellowish, crystalline compound. It is soluble in water to the extent of about 100 mg/mL. Bupropion hydrochloride is an antidepressant of the aminoketone class. Bupropion hydrochloride closely resembles the structure of diethylpropion. It is designated as (±)-1-(3 chlorophenyl)-2-[(1,1-dimethylethyl)amino]-1-propranone hydrochloride. It is related to phenylethylamines. The empirical formula is C13H18ClNO•HCl and the molecular weight is 276.2. The structural formula is: Bupropion hydrochloride powder is white, crystalline, and highly soluble in water. CONTRAVE is available for oral administration as a round, bi-convex, film-coated, extended-release tablet. Each tablet has a trilayer core composed of two drug layers, containing the drug and excipients, separated by a more rapidly dissolving inert layer. Each tablet contains 8 mg of naltrexone hydrochloride and 90 mg of bupropion hydrochloride. Tablets are blue and are debossed with NB-890 on one side. Each tablet contains the following inactive ingredients: microcrystalline cellulose, hydroxypropyl cellulose, lactose anhydrous, L-cysteine hydrochloride, crospovidone, magnesium stearate, hypromellose, edetate disodium, lactose monohydrate, colloidal silicon dioxide, Opadry II Blue and FD&C Blue #2 aluminum lake. Last reviewed on RxList: 9/22/2014
This monograph has been modified to include the generic and brand name in many instances.
This monograph has been modified to include the generic and brand name in many instances.
Source: http://www.rxlist.com
The following adverse reactions are discussed in other sections of the labeling:
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 Other Adverse Reactions The following additional adverse reactions were reported in less than 2% of patients treated with CONTRAVE but with an incidence at least twice that of placebo: Cardiac Disorders: tachycardia, myocardial infarction Ear and Labyrinth Disorders: vertigo, motion sickness Gastrointestinal Disorders: lower abdominal pain, eructation, lip swelling, hematochezia, hernia General Disorders and Administration Site Conditions: feeling jittery, feeling abnormal, asthenia, thirst, feeling hot Hepatobiliary Disorders: cholecystitis Infections and Infestations: pneumonia, staphylococcal infection, kidney infection Investigations: increased blood creatinine, increased hepatic enzymes, decreased hematocrit Metabolism and Nutrition Disorders: dehydration Musculoskeletal and Connective Tissue Disorders: intervertebral disc protrusion, jaw pain Nervous System Disorders: disturbance in attention, lethargy, intention tremor, balance disorder, memory impairment, amnesia, mental impairment, presyncope Psychiatric Disorders: abnormal dreams, nervousness, dissociation (feeling spacey), tension, agitation, mood swings Renal and Urinary Disorders: micturition urgency Reproductive System and Breast Disorders: vaginal hemorrhage, irregular menstruation, erectile dysfunction, vulvovaginal dryness Skin and Subcutaneous Tissue Disorders: alopecia Psychiatric And Sleep Disorders In the one-year controlled trials of CONTRAVE, the proportion of patients reporting one or more adverse reactions related to psychiatric and sleep disorders was higher in the CONTRAVE 32/360 mg group than the placebo group (22.2% and 15.5%, respectively). These events were further categorized into sleep disorders (13.8% CONTRAVE, 8.4% placebo), depression (6.3% CONTRAVE, 5.9% placebo), and anxiety (6.1% CONTRAVE, 4.4% placebo). Patients who were 65 years or older experienced more psychiatric and sleep disorder adverse reactions in the CONTRAVE group (28.6%) compared to placebo (6.3%), although the sample size in this subgroup was small (56 CONTRAVE, 32 placebo); the majority of these events were insomnia (10.7% CONTRAVE, 3.1% placebo) and depression (7.1% CONTRAVE, 3.1% placebo). Neurocognitive Adverse Reactions Adverse reactions involving attention, dizziness, and syncope occurred more often in individuals randomized to CONTRAVE 32/360 mg group compared to placebo (15.0% and 5.5%, respectively). The most common cognitive-related adverse reactions were attention disorders (2.5% CONTRAVE, 0.6% placebo). Adverse reactions involving dizziness and syncope were more common in patients treated with CONTRAVE (10.6%) than in placebo-treated patients (3.6%); dizziness accounted for almost all of these reported events (10.4% CONTRAVE, 3.4% placebo). Dizziness was the primary reason for discontinuation for 0.9% and 0.3% of patients in the CONTRAVE and placebo groups, respectively. Increases In Serum Creatinine In the one-year controlled trials of CONTRAVE, larger mean increases in serum creatinine from baseline to trial endpoint were observed in the CONTRAVE group compared with the placebo group (0.07 mg/dL and 0.01 mg/dL, respectively) as well as from baseline to the maximum value during follow-up (0.15 mg/dL and 0.07 mg/dL, respectively). Increases in serum creatinine that exceeded the upper limit of normal and were also greater than or equal to 50% higher than baseline occurred in 0.6% of subjects receiving CONTRAVE compared to 0.1% receiving placebo. An in vitro drug-drug interaction study demonstrated that bupropion and its metabolites inhibit organic cation transporter 2 (OCT2), which is involved in the tubular secretion of creatinine, suggesting that the observed increase in serum creatinine may be the result of OCT2 inhibition. Based on in vitro results and FDA guidance for Drug Interaction Studies, the ratios of the free (unbound) Cmax and IC50 value of bupropion and hydroxybupropion were well below 0.1 suggesting a drug-drug interaction between CONTRAVE and OCT2 substrate due to bupropion and hydroxybupropion is unlikely. The ratio for the threohydrobupropion and erythrohydrobupropion metabolite mixture was 0.29, suggesting a drug-drug interaction between CONTRAVE and OCT2 due to threohydrobupropion and erythrohydrobupropion is possible. Read the Contrave (naltrexone hcl and bupropion hcl extended-release tablets) Side Effects Center for a complete guide to possible side effectsLearn More »
- Suicidal Behavior and Ideation [see WARNINGS AND PRECAUTIONS]
- Neuropsychiatric Symptoms [see WARNINGS AND PRECAUTIONS]
- Seizures [see CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS]
- Increase in Blood Pressure and Heart Rate [see WARNINGS AND PRECAUTIONS]
- Allergic Reactions [see WARNINGS AND PRECAUTIONS]
- Angle-Closure Glaucoma [see WARNINGS AND PRECAUTIONS]
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 Other Adverse Reactions The following additional adverse reactions were reported in less than 2% of patients treated with CONTRAVE but with an incidence at least twice that of placebo: Cardiac Disorders: tachycardia, myocardial infarction Ear and Labyrinth Disorders: vertigo, motion sickness Gastrointestinal Disorders: lower abdominal pain, eructation, lip swelling, hematochezia, hernia General Disorders and Administration Site Conditions: feeling jittery, feeling abnormal, asthenia, thirst, feeling hot Hepatobiliary Disorders: cholecystitis Infections and Infestations: pneumonia, staphylococcal infection, kidney infection Investigations: increased blood creatinine, increased hepatic enzymes, decreased hematocrit Metabolism and Nutrition Disorders: dehydration Musculoskeletal and Connective Tissue Disorders: intervertebral disc protrusion, jaw pain Nervous System Disorders: disturbance in attention, lethargy, intention tremor, balance disorder, memory impairment, amnesia, mental impairment, presyncope Psychiatric Disorders: abnormal dreams, nervousness, dissociation (feeling spacey), tension, agitation, mood swings Renal and Urinary Disorders: micturition urgency Reproductive System and Breast Disorders: vaginal hemorrhage, irregular menstruation, erectile dysfunction, vulvovaginal dryness Skin and Subcutaneous Tissue Disorders: alopecia Psychiatric And Sleep Disorders In the one-year controlled trials of CONTRAVE, the proportion of patients reporting one or more adverse reactions related to psychiatric and sleep disorders was higher in the CONTRAVE 32/360 mg group than the placebo group (22.2% and 15.5%, respectively). These events were further categorized into sleep disorders (13.8% CONTRAVE, 8.4% placebo), depression (6.3% CONTRAVE, 5.9% placebo), and anxiety (6.1% CONTRAVE, 4.4% placebo). Patients who were 65 years or older experienced more psychiatric and sleep disorder adverse reactions in the CONTRAVE group (28.6%) compared to placebo (6.3%), although the sample size in this subgroup was small (56 CONTRAVE, 32 placebo); the majority of these events were insomnia (10.7% CONTRAVE, 3.1% placebo) and depression (7.1% CONTRAVE, 3.1% placebo). Neurocognitive Adverse Reactions Adverse reactions involving attention, dizziness, and syncope occurred more often in individuals randomized to CONTRAVE 32/360 mg group compared to placebo (15.0% and 5.5%, respectively). The most common cognitive-related adverse reactions were attention disorders (2.5% CONTRAVE, 0.6% placebo). Adverse reactions involving dizziness and syncope were more common in patients treated with CONTRAVE (10.6%) than in placebo-treated patients (3.6%); dizziness accounted for almost all of these reported events (10.4% CONTRAVE, 3.4% placebo). Dizziness was the primary reason for discontinuation for 0.9% and 0.3% of patients in the CONTRAVE and placebo groups, respectively. Increases In Serum Creatinine In the one-year controlled trials of CONTRAVE, larger mean increases in serum creatinine from baseline to trial endpoint were observed in the CONTRAVE group compared with the placebo group (0.07 mg/dL and 0.01 mg/dL, respectively) as well as from baseline to the maximum value during follow-up (0.15 mg/dL and 0.07 mg/dL, respectively). Increases in serum creatinine that exceeded the upper limit of normal and were also greater than or equal to 50% higher than baseline occurred in 0.6% of subjects receiving CONTRAVE compared to 0.1% receiving placebo. An in vitro drug-drug interaction study demonstrated that bupropion and its metabolites inhibit organic cation transporter 2 (OCT2), which is involved in the tubular secretion of creatinine, suggesting that the observed increase in serum creatinine may be the result of OCT2 inhibition. Based on in vitro results and FDA guidance for Drug Interaction Studies, the ratios of the free (unbound) Cmax and IC50 value of bupropion and hydroxybupropion were well below 0.1 suggesting a drug-drug interaction between CONTRAVE and OCT2 substrate due to bupropion and hydroxybupropion is unlikely. The ratio for the threohydrobupropion and erythrohydrobupropion metabolite mixture was 0.29, suggesting a drug-drug interaction between CONTRAVE and OCT2 due to threohydrobupropion and erythrohydrobupropion is possible. Read the Contrave (naltrexone hcl and bupropion hcl extended-release tablets) Side Effects Center for a complete guide to possible side effectsLearn More »
Source: http://www.rxlist.com
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 and CLINICAL PHARMACOLOGY]. 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]. 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
Weight (lb) 125 130 135 140 145 150 155 160 165 170 175 180 185 190 195 200 205 210 215 220 225 (kg) 56. 8 59. 1 61. 4 63. 6 65. 9 68. 2 70. 5 72. 7 75. 0 77. 3 79. 5 81. 8 84. 1 86. 4 88. 6 90. 9 93. 2 95. 5 97. 7 100. 0 102. 3 Height (in) (cm) 58 147. 3 26 27 28 29 30 31 32 34 35 36 37 38 39 40 41 42 43 44 45 46 47 59 149. 9 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 43 44 45 46 60 152. 4 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 61 154. 9 24 25 26 27 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 62 157. 5 23 24 25 26 27 27 28 29 30 31 32 33 34 35 36 37 38 38 39 40 41 63 160. 0 22 23 24 25 26 27 28 28 29 30 31 32 33 34 35 36 36 37 38 39 40 64 162. 6 22 22 23 24 25 26 27 28 28 29 30 31 32 33 34 34 35 36 37 38 39 65 165. 1 21 22 23 23 24 25 26 27 28 28 29 30 31 32 33 33 34 35 36 37 38 66 167. 6 20 21 22 23 23 24 25 26 27 27 28 29 30 31 32 32 33 34 35 36 36 67 170. 2 20 20 21 22 23 24 24 25 26 27 27 28 29 30 31 31 32 33 34 35 35 68 172. 7 19 20 21 21 22 23 24 24 25 26 27 27 28 29 30 30 31 32 33 34 34 69 175. 3 18 19 20 21 21 22 23 24 24 25 26 27 27 28 29 30 30 31 32 33 33 70 177. 8 18 19 19 20 21 22 22 23 24 24 25 26 27 27 28 29 29 30 31 32 32 71 180. 3 17 18 19 20 20 21 22 22 23 24 24 25 26 27 27 28 29 29 30 31 31 72 182. 9 17 18 18 19 20 20 21 22 22 23 24 24 25 26 27 27 28 29 29 30 31 73 185. 4 17 17 18 19 19 20 20 21 22 22 23 24 24 25 26 26 27 28 28 29 30 74 188. 0 16 17 17 18 19 19 20 21 21 22 23 23 24 24 25 26 26 27 28 28 29 75 190. 5 16 16 17 18 18 19 19 20 21 21 22 23 23 24 24 25 26 26 27 28 28 76 193. 0 15 16 16 17 18 18 19 20 20 21 21 22 23 23 24 24 25 26 26 27 27 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. There is a lack of adequate information to guide dosing in patients with mild renal impairment [see Use in Specific Population and CLINICAL PHARMACOLOGY]. Dose Adjustment In Patients With Hepatic Impairment In patients with hepatic impairment, the maximum recommended daily dose of CONTRAVE is one tablet in the morning [see Use in Specific Population and CLINICAL PHARMACOLOGY]. 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 and DRUG INTERACTIONS]. 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 and CLINICAL PHARMACOLOGY].
Weight (lb) 125 130 135 140 145 150 155 160 165 170 175 180 185 190 195 200 205 210 215 220 225 (kg) 56. 8 59. 1 61. 4 63. 6 65. 9 68. 2 70. 5 72. 7 75. 0 77. 3 79. 5 81. 8 84. 1 86. 4 88. 6 90. 9 93. 2 95. 5 97. 7 100. 0 102. 3 Height (in) (cm) 58 147. 3 26 27 28 29 30 31 32 34 35 36 37 38 39 40 41 42 43 44 45 46 47 59 149. 9 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 43 44 45 46 60 152. 4 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 61 154. 9 24 25 26 27 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 62 157. 5 23 24 25 26 27 27 28 29 30 31 32 33 34 35 36 37 38 38 39 40 41 63 160. 0 22 23 24 25 26 27 28 28 29 30 31 32 33 34 35 36 36 37 38 39 40 64 162. 6 22 22 23 24 25 26 27 28 28 29 30 31 32 33 34 34 35 36 37 38 39 65 165. 1 21 22 23 23 24 25 26 27 28 28 29 30 31 32 33 33 34 35 36 37 38 66 167. 6 20 21 22 23 23 24 25 26 27 27 28 29 30 31 32 32 33 34 35 36 36 67 170. 2 20 20 21 22 23 24 24 25 26 27 27 28 29 30 31 31 32 33 34 35 35 68 172. 7 19 20 21 21 22 23 24 24 25 26 27 27 28 29 30 30 31 32 33 34 34 69 175. 3 18 19 20 21 21 22 23 24 24 25 26 27 27 28 29 30 30 31 32 33 33 70 177. 8 18 19 19 20 21 22 22 23 24 24 25 26 27 27 28 29 29 30 31 32 32 71 180. 3 17 18 19 20 20 21 22 22 23 24 24 25 26 27 27 28 29 29 30 31 31 72 182. 9 17 18 18 19 20 20 21 22 22 23 24 24 25 26 27 27 28 29 29 30 31 73 185. 4 17 17 18 19 19 20 20 21 22 22 23 24 24 25 26 26 27 28 28 29 30 74 188. 0 16 17 17 18 19 19 20 21 21 22 23 23 24 24 25 26 26 27 28 28 29 75 190. 5 16 16 17 18 18 19 19 20 21 21 22 23 23 24 24 25 26 26 27 28 28 76 193. 0 15 16 16 17 18 18 19 20 20 21 21 22 23 23 24 24 25 26 26 27 27 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. There is a lack of adequate information to guide dosing in patients with mild renal impairment [see Use in Specific Population and CLINICAL PHARMACOLOGY]. Dose Adjustment In Patients With Hepatic Impairment In patients with hepatic impairment, the maximum recommended daily dose of CONTRAVE is one tablet in the morning [see Use in Specific Population and CLINICAL PHARMACOLOGY]. 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 and DRUG INTERACTIONS]. 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 and CLINICAL PHARMACOLOGY].
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Monoamine 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]. Opioid 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 and WARNINGS AND PRECAUTIONS]. During CONTRAVE clinical studies, the use of concomitant opioid or opioid-like medications, including analgesics or antitussives, were excluded. Potential 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 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]. Potential 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 and CLINICAL PHARMACOLOGY]. 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]. Drugs 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 bupropioncontaining products is contraindicated [see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS]. Dopaminergic 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. Use 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. Drug-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. Drug-Transporter Interactions In vitro, CONTRAVE constituents inhibited the renal organic cation transporter OCT2 to a clinically relevant level. The systemic concentrations of substrate drugs transported by OCT2 (such as amantadine, amiloride, cimetidine, dopamine, famotidine, memantine, metformin, pindolol, procainamide, ranitidine, varenicline, oxaliplatin) are likely to increase as a result of reduced renal clearance when coadministered with CONTRAVE. Coadministration of CONTRAVE with such drugs should be approached with caution and patients should be monitored for adverse effects. Drug Abuse And Dependence Abuse Humans CONTRAVE (naltrexone HCl and bupropion HCl) has not been systematically studied in humans for its potential for abuse, tolerance, or physical dependence. However, in outpatient clinical studies of up to 56 weeks in duration, there was no evidence of euphoric drug intoxication, physical dependence, diversion, or abuse. There was no evidence of an abstinence syndrome following abrupt or tapered drug discontinuation after 56 weeks of double-blind, placebo-controlled, randomized treatment. Naltrexone is a pure opioid antagonist. It does not lead to physical or psychological dependence. Tolerance to the opioid antagonistic effect is not known to occur. Controlled clinical trials of bupropion (immediate-release formulation) conducted in normal volunteers, in subjects with a history of multiple drug abuse, and in depressed subjects showed some increase in motor activity and agitation/excitement. In a population of individuals experienced with drugs of abuse, a single dose of 400 mg of bupropion produced mild amphetamine-like activity as compared with placebo on the Morphine-Benzedrine Subscale of the Addiction Research Center Inventories (ARCI) and a score intermediate between placebo and amphetamine on the Liking Scale of the ARCI. These scales measure general feelings of euphoria and drug desirability. Findings in clinical trials, however, are not known to reliably predict the abuse potential of drugs. Nonetheless, evidence from single-dose studies does suggest that the recommended daily dosage of bupropion when administered in divided doses is not likely to be significantly reinforcing to amphetamine or CNS stimulant abusers. Animals Studies in rodents and primates have shown that bupropion exhibits some pharmacologic actions common to psychostimulants. In rodents, it has been shown to increase locomotor activity, elicit a mild stereotyped behavioral response, and increased rates of responding in several schedule-controlled behavior paradigms. In primate models assessing the positive reinforcing effects of psychoactive drugs, bupropion was self-administered intravenously. In rats, bupropion produced amphetamine-like and cocaine-like discriminative stimulus effects in drug discrimination paradigms used to characterize the subjective effects of psychoactive drugs. Last reviewed on RxList: 9/22/2014
This monograph has been modified to include the generic and brand name in many instances.
This monograph has been modified to include the generic and brand name in many instances.
Source: http://www.rxlist.com
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).
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CONTRAVE is contraindicated in
This monograph has been modified to include the generic and brand name in many instances.
- Uncontrolled hypertension [see WARNINGS AND PRECAUTIONS]
- Seizure disorder or a history of seizures [see WARNINGS AND PRECAUTIONS]
- Use of other bupropion-containing products (including, but not limited to, WELLBUTRIN, WELLBUTRIN SR, WELLBUTRIN XL, and APLENZIN)
- Bulimia or anorexia nervosa, which increase the risk for seizure [see WARNINGS AND PRECAUTIONS]
- Chronic opioid or opiate agonist (e.g., methadone) or partial agonists (e.g., buprenorphine) use, or acute opiate withdrawal [see WARNINGS AND PRECAUTIONS and DRUG INTERACTIONS]
- Patients undergoing an abrupt discontinuation of alcohol, benzodiazepines, barbiturates, and antiepileptic drugs [see WARNINGS AND PRECAUTIONS and DRUG INTERACTIONS]
- 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, DRUG INTERACTIONS]
- 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]
- Pregnancy [see Use In Specific Populations]
This monograph has been modified to include the generic and brand name in many instances.
Source: http://www.rxlist.com
Human Experience There is no clinical experience with overdosage with CONTRAVE. The maximum daily dose of CONTRAVE administered in clinical trials contained 50 mg naltrexone and 400 mg bupropion. The most serious clinical implications of CONTRAVE overdose are likely those related to overdose of bupropion. Overdoses of up to 30 grams or more of bupropion (equivalent of up to 83 times the recommended daily dose of CONTRAVE 32 mg/360 mg) have been reported. Seizure was reported in approximately one third of all cases. Other serious reactions reported with overdoses of bupropion alone included hallucinations, loss of consciousness, sinus tachycardia, and ECG changes such as conduction disturbances (including QRS prolongation) or arrhythmias. Fever, muscle rigidity, rhabdomyolysis, hypotension, stupor, coma, and respiratory failure have been reported mainly when bupropion was part of multiple drug overdoses. Although most patients recovered without sequelae, deaths associated with overdoses of bupropion alone have been reported in patients ingesting large doses of the drug. Multiple uncontrolled seizures, bradycardia, cardiac failure, and cardiac arrest prior to death were reported in these patients. There is limited experience with overdose of naltrexone monotherapy in humans. In one study, subjects who received 800 mg naltrexone daily (equivalent to 25 times the recommended daily dose of CONTRAVE 32 mg/360 mg) for up to one week showed no evidence of toxicity. Animal Experience In the mouse, rat, and guinea pig, the oral LD50s for naltrexone were 1,100 to 1,550 mg/kg; 1,450 mg/kg; and 1,490 mg/kg; respectively. High doses of naltrexone (generally greater than or equal to 1,000 mg/kg) produced salivation, depression/reduced activity, tremors, and convulsions. Mortality in animals due to high-dose naltrexone administration usually was due to clonic-tonic convulsions and/or respiratory failure. Overdosage Management If over-exposure occurs, call your poison control center at 1-800-222-1222. There are no known antidotes for CONTRAVE. In case of an overdose, provide supportive care, including close medical supervision and monitoring. Consider the possibility of multiple drug overdose. Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm and vital signs. Induction of emesis is not recommended.
Source: http://www.rxlist.com
Dosage Forms And Strengths CONTRAVE extended-release tri-layer tablets, 8 mg/90 mg, are blue, round, bi-convex, film-coated, and debossed with “NB-890” on one side. Storage And Handling CONTRAVE 8 mg/90 mg (naltrexone HCl 8 mg and bupropion HCl 90 mg) extended-release, tri-layer tablets are blue, round, bi-convex, film-coated tablets debossed with “NB-890” on one side. CONTRAVE tablets are available as follows: NDC 64764-890-99 Bottles of 120 tablets Storage Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Distributed by: Takeda Pharmaceuticals America, Inc., Deerfield, IL 60015 Manufactured for: Orexigen Therapeutics, Inc., La Jolla, CA 92037. Approved: 2014 Last reviewed on RxList: 9/22/2014
This monograph has been modified to include the generic and brand name in many instances.
This monograph has been modified to include the generic and brand name in many instances.
Source: http://www.rxlist.com
Suicidal 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. 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. Neuropsychiatric Symptoms And Suicide Risk In Smoking Cessation Treatment CONTRAVE is not approved for smoking cessation treatment, but serious neuropsychiatric symptoms have been reported in patients taking bupropion for smoking cessation. These have included changes in mood (including depression and mania), psychosis, hallucinations, paranoia, delusions, homicidal ideation, hostility, agitation, aggression, anxiety, and panic, as well as suicidal ideation, suicide attempt, and completed suicide [see Suicidal Behavior and Ideation]. Observe patients for the occurrence of neuropsychiatric reactions. Instruct patients to contact a healthcare professional if such reactions occur. In many of these cases, a causal relationship to bupropion treatment is not certain, because depressed mood can be a symptom of nicotine withdrawal. However, some of the cases occurred in patients taking bupropion who continued to smoke. Depression, suicide, attempted suicide and suicidal ideation have been reported in the postmarketing experience with naltrexone used in the treatment of opioid dependence. No causal relationship has been demonstrated. Seizures 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:
This monograph has been modified to include the generic and brand name in many instances.
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. Neuropsychiatric Symptoms And Suicide Risk In Smoking Cessation Treatment CONTRAVE is not approved for smoking cessation treatment, but serious neuropsychiatric symptoms have been reported in patients taking bupropion for smoking cessation. These have included changes in mood (including depression and mania), psychosis, hallucinations, paranoia, delusions, homicidal ideation, hostility, agitation, aggression, anxiety, and panic, as well as suicidal ideation, suicide attempt, and completed suicide [see Suicidal Behavior and Ideation]. Observe patients for the occurrence of neuropsychiatric reactions. Instruct patients to contact a healthcare professional if such reactions occur. In many of these cases, a causal relationship to bupropion treatment is not certain, because depressed mood can be a symptom of nicotine withdrawal. However, some of the cases occurred in patients taking bupropion who continued to smoke. Depression, suicide, attempted suicide and suicidal ideation have been reported in the postmarketing experience with naltrexone used in the treatment of opioid dependence. No causal relationship has been demonstrated. Seizures Bupropion, a component of CONTRAVE, can cause seizures. The risk of seizure is dose-related. The incidence of seizure in patients receiving CONTRAVE in clinical trials was approximately 0.1% vs 0% on placebo. CONTRAVE should be discontinued and not restarted in patients who experience a seizure while being treated with CONTRAVE. The risk of seizures is also related to patient factors, clinical situations, and concomitant medications that lower the seizure threshold. Consider these risks before initiating treatment with CONTRAVE. CONTRAVE is contraindicated in patients with a seizure disorder, current or prior diagnosis of anorexia nervosa or bulimia, or undergoing abrupt discontinuation of alcohol, benzodiazepines, barbiturates, and antiepileptic drugs. Caution should be used when prescribing CONTRAVE to patients with predisposing factors that may increase the risk of seizure including:
- history of head trauma or prior seizure, severe stroke, arteriovenous malformation, central nervous system tumor or infection, or metabolic disorders (e.g., hypoglycemia, hyponatremia, severe hepatic impairment, and hypoxia)
- excessive use of alcohol or sedatives, addiction to cocaine or stimulants, or withdrawal from sedatives
- patients with diabetes treated with insulin and/or oral diabetic medications (sulfonylureas and meglitinides) that may cause hypoglycemia
- concomitant administration of medications that may lower the seizure threshold, including other bupropion products, antipsychotics, tricyclic antidepressants, theophylline, systemic steroids
- the total daily dose of CONTRAVE does not exceed 360 mg of the bupropion component (i.e., four tablets per day)
- the daily dose is administered in divided doses (twice daily)
- the dose is escalated gradually
- no more than two tablets are taken at one time
- coadministration of CONTRAVE with high-fat meals is avoided [see DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY]
- if a dose is missed, a patient should wait until the next scheduled dose to resume the regular dosing schedule
This monograph has been modified to include the generic and brand name in many instances.
Source: http://www.rxlist.com
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