Contrave

Contrave is a pharmaceutical drug that is a sustained release combination of Bupropion and Naltrexone approved in the United States of America for the treatment of Obesity for those with a body mass index ≥30 kg/m2 or ≥27 kg/m2 with one or more risk factors or comorbidities such as diabetes mellitus, dyslipidemia, sleep apnea, metabolic syndrome or hypertension.

Dosing of Contrave
The recommended daily dose of Contrave is two 8 mg naltrexone/90 mg bupropion (8/90) tablets taken twice daily for a total daily dose of 32 mg naltrexone/360 mg bupropion (32/360). However, the dosage is gradually increased over the course of 4 weeks starting with one tablet taken daily for the first week, followed by the addition of another tablet each day during each subsequent week, until the total daily maintenance dose of two tablets twice a day (32/360) is reached at the start of Week 4.

The Contrave clinical development program
The Contrave clinical development program was conducted in the framework of the requirements set forth in the 2007 FDA Guidance on developing products for weight management, with respect to appropriate patient exposure and study duration, and inclusion of patients with various comorbidities.

According to the guidance, demonstration of efficacy after 1 year of treatment can be achieved by meeting either of the following co-primary endpoints:


 * The difference in mean weight loss between the active treatment group and placebo is at least 5% and the difference is statistically significant.


 * The proportion of patients who lose ≥5% of their baseline body weight in the active treatment group is at least 35%, is approximately double the proportion in the placebo group, and the difference between the active and placebo groups is statistically significant.

All four Phase 3 studies showed statistically significant improvement in each co-primary endpoint relative to placebo. Contrave met the second benchmark for weight loss efficacy in three of the four studies. Achieving 5% weight loss is not only an FDA guidance efficacy benchmark, but this degree of weight loss is known to confer significant cardiometabolic benefit. Similarly, the Contrave trials demonstrated beneficial effects on prespecified weight-related cardiometabolic parameters, including:


 * waist circumference,
 * triglycerides, HDL-cholesterol,
 * high-sensitivity C-reactive protein(hs-CRP),
 * glycemic control (fasting glucose, fasting insulin, homeostasis model assessment of insulin resistance [HOMA-IR], and, in patients with diabetes, hemoglobin A1c [HbA1c]),
 * quality of life and control of eating.

Background for development of Contrave
Contrave (generally referred to as “NB”), is a novel combination product for the treatment of obesity, is composed of bupropion (a relatively weak inhibitor of the neuronal uptake of norepinephrine [NE] and dopamine [DA]) combined with naltrexone (a mu-opioid receptor antagonist).

Mechanism of Action of Contrave
Bupropion has been shown to stimulate hypothalamic pro-opiomelanocortin (POMC) neurons that release alpha-melanocyte stimulating hormone (α-MSH) which, in turn, binds to melanocortin 4 (MC4) receptors. The binding of α-MSH to MC4 receptors initiates a cascade of actions that results in weight loss via reduced energy intake and increased energy expenditure (Cowley et al., 1999). When α-MSH is released, POMC neurons simultaneously release β-endorphin, an endogenous agonist of the mu-opioid receptor that mediates a negative feedback loop on POMC neurons leading to a decrease in the release of α-MSH (Cowley et al., 2001; Ibrahim et al., 2003; Kelly et al., 1990; Loose and Kelly, 1990). Blocking this inhibitory feedback loop with naltrexone is proposed to facilitate a more potent and longer-lasting activation of POMC neurons, thereby amplifying effects on energy balance. As a result, co-administration of bupropion and naltrexone produces a substantially greater effect on the POMC firing rate than either compound administered alone, suggesting that the drugs act synergistically.

Contrave (NB) Clinical Development Program
The Contrave clinical development program comprised 23 completed trials, including 15 Phase 1, four Phase 2, and four pivotal Phase 3 studies. These 23 studies allowed for a thorough assessment of the safety, efficacy and pharmacokinetics (PK) of Contrave. Across the Phase 2 and Phase 3 studies, a total of 3475 patients were exposed to Contrave for a total of 2313 patient-years of exposure. Of the 3475 patients, nearly one-half (1661 patients; 47.8%) received Contrave for at least one year.

The 15 Phase 1 studies were conducted as part of the formulation development and clinical pharmacology programs. A number of these studies utilized crossover designs which accommodated multiple objectives (e.g., establishing both the effect of food on the PK of Contrave as well as investigating potential DDIs).

Contrave Phase 3 Efficacy Test Results
All four studies in the Contrave Phase 3 program demonstrated statistically significant and clinically meaningful weight loss following up to 56 weeks of treatment with Contrave. The average percent weight loss from baseline observed with Contrave treatment across the four studies corresponded to between approximately 5 and 9 kg(11 to 22 pounds).

The weight loss efficacy of Contrave was observed across all demographic and clinical characteristics evaluated, including patients with hypertension, dyslipidemia, a history of cardiovascular (CV) disease, type 2 diabetes, impaired fasting glucose, or history of depression at baseline.

Weight-Related Cardiometabolic Parameters with Contrave
Across the four Phase 3 studies, treatment with Contrave (and Contrave16 in Study Contrave-301) on average resulted in statistically significant and clinically meaningful improvements on multiple weight-related cardiometabolic parameters, including waist circumference, HDL-C, triglycerides, and hs-CRP, compared to placebo, as shown below in the plot of effect sizes.

Blood Pressure effects of Contrave
Across the four Phase 3 studies, the mean changes from baseline to endpoint in systolic blood pressure (SBP) in Contrave-treated patients were small (-1.3 to +0.6 mm Hg); similar mean changes from baseline to endpoint were observed in diastolic blood pressure (DBP; -1.4 to +0.4 mm Hg). placebo-treated patients generally displayed greater mean decreases from baseline in blood pressure (-3.9 to -0.5 mm Hg for SBP and -2.8 to +0.3 mm Hg for DBP) compared to Contrave-treated patients. In Contrave-treated patients, greater decreases in mean SBP and DBP were observed in those achieving ≥5% weight loss at Week 56 compared to those Contrave-treated patients who did not reduce weight by at least that amount. While placebo-treated patients had greater reductions in blood pressure when they achieved ≥5% weight loss, they were significantly less likely to achieve this degree of weight loss compared to Contrave-treated patients.

Glycemic Control with Contrave
Results from Study Contrave-304 indicate that the effects of Contrave therapy on weight are also associated with clinically significant improvements in glycemic control in obese patients with type 2 diabetes mellitus.


 * At Week 56, Contrave-treated patients experienced a significant reduction of -0.63% in HbA1c compared with a -0.14% reduction in placebo-treated patients (p<0.001). In addition, a higher proportion of Contrave-treated patients achieved HbA1c values <7% (44.1%) and <6.5% (21.0%) compared with placebo-treated patients (<7%: 26.3%, and <6.5%: 10.2%).


 * A lower proportion of Contrave-treated patients required the use of rescue medications (i.e., new antidiabetic medications added or existing medication doses increased) for glycemic control compared with placebo-treated patients (NB32: 22.3%; placebo: 35.2%; p<0.01).

As expected in obese and overweight patients losing clinically meaningful amounts of weight, in the three Phase 3 studies in patients without diabetes, greater improvements were observed in fasting glucose, fasting insulin, and HOMA-IR for Contrave-treated patients compared with placebo-treated patients.

Quality of Life with Contrave
In each of the four pivotal studies, the Impact of Weight on Quality of Life (IWQOL)-Lite questionnaire (Kolotkin et al., 2001) was a secondary endpoint to assess the effect of Contrave treatment on patients’ self-reported overall quality of life. weight loss following treatment with Contrave was associated with significant improvement in the IWQOL-Lite total score in 3 of the 4 Phase 3 studies (NB-301, Contrave-302 and Contrave-303). Improvements were also observed in various subscales, most consistently on the physical function and self-esteem subscales. Furthermore, Contrave-treated patients in those three studies were more than twice as likely to achieve a clinically meaningful improvement, based on ad hoc analyses as described by Crosby et al. 2004, in their IWQOL-Lite total score relative to placebo-treated patients (p<0.001).

Control of Eating with Contrave
The Control of Eating (COE) questionnaire revelased Contrave helps with decreasing hunger, increasing satiety, and increased ability to resist food cravings.

Side effects of Contrave
The most common side effects include but not limited to nausea, constipation, headache, vomiting, dizziness, trouble sleeping, dry mouth, and diarrhea.

Possible serious side effects of Contrave

 * If you have a seizure, stop taking Contrave, tell your healthcare provider right away, and do not take Contrave again.


 * If you take opioid medicines, there may be a risk of opioid overdose. You should get emergency medical help right away if you have trouble breathing; become drowsy with slowed breathing; have slow, shallow breathing; or feel faint, dizzy, or confused


 * Sudden opioid withdrawal can be severe and may require hospitalization


 * Stop taking Contrave and get medical help immediately if you have any of the following signs and symptoms of severe allergic reactions: rash, itching, hives, fever, swollen lymph glands, painful sores in your mouth or around your eyes, swelling of your lips or tongue, chest pain, or trouble breathing


 * Increases in blood pressure or heart rate may occur


 * Contrave can cause liver damage or hepatitis. Stop taking Contrave if you have any of the following symptoms of liver problems: stomach area pain lasting more than a few days, dark urine, yellowing of the whites of your eyes, or tiredness.


 * Manic episodes can occur. Contrave can cause some people who were manic or depressed in the past to become manic or depressed again


 * Contrave can cause visual problems (angle-closure glaucoma). Signs and symptoms may include: eye pain, changes in vision, swelling or redness in or around the eye. Talk with your doctor to find out if you are at risk and to get treatment to prevent it.


 * Increased risk of low blood sugar (hypoglycemia) in people with type 2 diabetes mellitus who also take medicines to treat their diabetes (such as insulin or sulfonylureas). You should check your blood sugar before you start and while taking Contrave.

Contra-indications for Contrave
Do not take Contrave if you have any of the following


 * have uncontrolled hypertension
 * have or have had seizures
 * use other medicines that contain bupropion such as WELLBUTRIN, WELLBUTRIN SR, WELLBUTRIN XL, and APLENZIN
 * have or have had an eating disorder called anorexia (eating very little) or bulimia (eating too much and vomiting to avoid gaining weight)
 * are dependent on opioid pain medicines or use medicines to help stop taking opioids such as methadone or buprenorphine, or are in opiate withdrawal
 * drink a lot of alcohol and abruptly stop drinking, or use medicines called sedatives (these make you sleepy), benzodiazepines, or anti-seizure medicines and you stop using them all of a sudden
 * are taking medicines called monoamine oxidase inhibitors (MAOIs). Ask your healthcare provider or pharmacist if you are not sure if you take an MAOI, including linezoid. Do not start Contrave until you have stopped taking your MAOI for at least 14 days.
 * are allergic to naltrexone HCl or bupropion HCl or any of the ingredients in Contrave. See the end of this Medication Guide for a complete list of ingredients in Contrave.
 * are pregnant or planning to become pregnant. Tell your healthcare provider right away if you become pregnant while taking Contrave.

Blackbox warning for Contrave
Contrave can cause serious side effects of suicidal thoughts or actions. One of the ingredients in Contrave is bupropion HCl. 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; depression; anxiety; feeling very agitated or restless; panic attacks; trouble sleeping (insomnia); 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.

While taking Contrave, you or your family members should pay close attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings and maintain communication with your healthcare provider. Contrave has not been studied in and is not approved for use in children under the age of 18.

FDA REMS Program for Contrave
Risk Evaluation and Mitigation Strategy (REMS). Orexigen is proposing a risk mitigation plan to address the potential serious risks of Contrave therapy. The foundation of this plan is a REMS reinforced through elements of the product launch program to facilitate the appropriate use of Contrave.

Early weight loss as a Predictor of Long-Term weight loss with Contrave
Analyses were conducted to evaluate whether earlier weight loss (Weeks 4-28) is predictive of a 5% or greater weight loss response at week 56. Based on receiver operating characteristic curves 5% weight loss from baseline at Week 16 showed 75 to 85% accuracy in the four Phase 3 trials in identifying 5% responders at Week 56 with fair balance between sensitivity and specificity. Additionally, in a pooled analysis of the four Phase 3 trials, among the Contrave subjects who achieved ≥5% weight loss at Week 56 based on LOCF, more than 85% reached the responder status by Week 16.

Key benefits with treatment with Contrave

 * Clinically meaningful weight loss was apparent early in treatment, and was greater than that observed with either naltrexone or bupropion alone. weight loss was on average sustained, and those patients who continued treatment through 56 weeks experienced the most substantial weight loss. The efficacy of Contrave was observed across all demographic and clinical subgroups evaluated, including patients with hypertension, dyslipidemia, history of cardiovascular disease, type 2 diabetes, impaired fasting glucose, or history of depression.


 * Significant effects of Contrave treatment were observed on a number of weight-related cardiometabolic parameters (e.g., waist circumference, triglycerides, HDL-cholesterol, and hs-CRP); HDL increases and triglyceride reductions were observed irrespective of history of dyslipidemia or treatment for this condition.


 * Patients with type 2 diabetes benefitted from weight loss, improvements in waist circumference, HDL and triglycerides, and clinically significant improvements in glycemic control (particularly decreased HbA1c). A lower proportion of Contrave-treated patients required adjustments to their antidiabetic medications due to poor glycemic control.


 * Greater proportions of Contrave-treated patients reported clinically meaningful improvements in weight-related quality of life compared with placebo, providing further evidence of the range of clinical benefits that can be derived from Contrave treatment.


 * Greater effects of Contrave treatment were observed on multiple items of the COE questionnaire.

Key safety findings with treatment with Contrave

 * The use of Contrave was generally well-tolerated, with the frequency and distribution of safety findings being consistent with the established profiles for naltrexone and bupropion.


 * Common side effects such as nausea and vomiting tended to occur early in treatment (during the dose-escalation phase), were mostly mild to moderate in severity, and were generally self-limiting.


 * The incidence of treatment-emergent serious side effects overall was low; the vast majority of SAEs in Contrave-treated patients were considered unrelated to study drug.


 * Initiation of treatment with Contrave was associated with transient increases from baseline of approximately 1 mm Hg in mean blood pressure, followed by small reductions below baseline. These increases are consistent with the known hemodynamic effects of bupropion and were attenuated by weight loss in patients who responded to therapy, although mean blood pressure reductions with Contrave were always less than that observed with comparable placebo patients. The small elevations in heart rate seen with Contrave treatment (compared with decreases with placebo) are also consistent with known bupropion effects.


 * The hemodynamic effects of Contrave are due to bupropion. Bupropion has been extensively prescribed since its original approval more than 20 years ago, and has a long history of safe use even in populations considered at risk for CV disease.


 * The incidence of major cardiovascular events (cardiovascular death, myocardial infarction and cerebrovascular accident) and revascularization procedures were low and comparable between Contrave- and placebo-treated patients, although the number of events is too low to draw firm conclusions.


 * Seizures occurred infrequently at a rate that is consistent with that observed for the lowest approved dose of bupropion SR.


 * Treatment with Contrave in the target patient population does not appear to be associated with an increased risk for depression or suicidality.


 * No hepatotoxicity was observed with long-term Contrave treatment.


 * Clinical laboratory evaluations were generally unremarkable, and values outside of normal ranges tended to be sporadic and unrelated to dose.


 * Neither bupropion nor naltrexone has historically been associated with prolongation of QTc intervals, and review of QT, QTc and the other ECG parameters in patients during long-term Contrave treatment revealed no noteworthy findings.

According to the FDA advisory committee, the benefits of Contrave outweigh the risks given the clinically meaningful weight loss and improvement in multiple markers of cardiometabolic risk and patient-reported quality of life. These benefits in aggregate are expected to be greater in general clinical practice, as proposed labeling would lead to discontinuation of treatment for patients not experiencing at least a 5% decrease from baseline in body weight. Benefits are observed across a range of overweight and obese patient subgroups and in various treatment settings. Of note, the population of patients receiving currently approved bupropion-containing therapies has important similarities to patients enrolled in the Contrave clinical program, as well as the population of patients who receive currently marketed obesity pharmacotherapy. In addition, clinical experience and investigation in relevant patient populations, including those with cardiovascular risk factors or established cardiovascular disease, have not identified specific safety signals for clinical cardiovascular events.

Overall, the Contrave safety profile is well-understood, with known risks that are predictable and manageable via appropriate risk mitigation approaches. Orexigen is developing a plan for additional clinical studies to assess:
 * 1) prescription utilization patterns,
 * 2) physician and patient adherence to labeling, and
 * 3) the impact of Contrave on cardiovascular outcomes.

Scale Down Program for Contrave
The manufacturer of Contrave has a personalized weight management support program for people taking Contrave. It is a weight management support program created by Harvard-trained researchers, at no cost for as long as you’re taking Contrave per your doctor's instructions. According to the manufacturer, the Scale Down program engages people on their weight management journey and is administered through a third party company with all membership fees paid for by the manufacturer as long as a patient is taking Contrave.

Cost of Contrave
Contrave is priced well with estimated monthly cost without insurance of $75.00 for the first two months to go down to $60.00 thereafter. For those with insurance coverage, the cost is a maximum of $55.00 which will go down to a maximum of $45.00 per month after two months. This compares very well with an estimated cost of the other new weight loss drugs approved in 2011, Belviq and Qsymia that cost about $6 or $7 a day, or about $180 to $210 a month.

Doctors that offer Contrave
While many doctors might offer Contrave, the parent company of WikiMD, W8MD medical weight loss centers of America announced it will offer Contrave at all of it's locations for eligible patients.

Comparison of Contrave with Belviq and Qsymia
From an efficacy perspective, Qsymia with Phentermine and Topiramate is a bit more effective with expected weight loss of about 9% but Contrave that gives about 5% weight loss does a bit better than Belviq(3-4.5%). However, from a pricing point of view, Contrave does extremely well and is relatively safe.

Contrave Distributor
Contrave is distributed in the United States by Takeda Pharmaceuticals America, Inc. located in Deerfield, Illinois and is Manufactured by Orexigen Therapeutics, Inc. of La Jolla, California. CONTRAVE® is a trademark of Orexigen Therapeutics, Inc.