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Contrave: Unlocking the Brains Secrets to Weight Loss

Richard L. Lipman M.D.

www.richardlipmanmd.com

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Disclaimer

The reading of this book does not establish a doctor-patient relationship between the reader and

Dr Lipman. As discussed numerous times in this book, successful weight loss requires a personal

relationship with an understanding physician. This book does not substitute for professional or

medical advice. The author and the publisher specifically disclaim any liability, loss, or risk,

personal or otherwise that might be incurred, directly or indirectly, as a result of the use and

application of any of the contents of this book. All matters regarding your health and require the

medical consultation and supervision of a physician. The names and identifying characteristics of

the individuals referred to in anecdotes in this book have been changed to protect their identities.

About the Author

Richard L. Lipman M.D. a board certified internist and endocrinologist has treated more than

30,000 individuals with weight and metabolic disorders in his office in Miami, Florida. A

graduate of the University of Pittsburgh, he did his internal medicine training at the Universities

of Pittsburgh and Miami. Dr. Lipman was Assistant Chief of Endocrinology at the USAF

Hospital in San Antonio, Texas while in the Air Force. While in the Air Force, Dr. Lipman

authored 18 publications on metabolism. Dr. Lipman is a staff member of Larkin and Cedars

Hospital in Miami, a charter member of the American Association of Clinical Endocrinologists, a

member of the American Diabetes Association, and a member of the American Association of

Bariatric Physicians. He has recently authored ten books on metabolism and weight loss. All are

available on Amazon.com.

Copyright 2014 by Richard Lipman M.D. All Rights Reserved.

No part of this book may be reproduced by any mechanical, photographic or electronic process,

or in the form of phonographic recording, scanning or otherwise, except as permitted under

section 107 or 108 of the 1976 United States Copyright Act, without prior written permission of

the author.

Other Books by Richard Lipman M.D.

The One-Hundred Calorie Secret

New Pounds and Inches

Restaurants and Restaurants

La Dieta HCG

800-Calorie HCG Diet

Diet Buddies: A Weight Loss Plan for Families

Lose Weight with Belviq

Qsymia Weight Loss Plan

Table of Contents

Introduction

Chapter 1: Contrave: What It is and How Does It Work?

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Chapter 2: How Did Contrave Become Newest Weight Loss

Medication?

Chapter 3: How to Take Contrave and What to Expect

Introduction

The Contrave Weight Loss Plan is designed to help you get rid of that extra weight now

and forever. It is not for the individual that has 10 to 20 pounds to lose. It is for the 100

million Americans who have 30, 50, or 100 pounds or more to lose, who feel they have

tried everything and failed. It is for the millions more with diabetes and other medical

problems whose obesity has been impossible to reverse. Its also for the millions of dieters who have lost weight many times only to regain the weight a year or two latter. It

is for those 100, 000 or more Americans whose obesity is so threatening that they are

considering drastic actions such as gastric bypass surgery

This revolutionary weight loss plan combines a simple, easy-to-remember food plan with

the newly FDA approved weight loss drug Contrave. The food plan is easy. There are no

complicated food preparations. In fact, there are no recipes at all! There is no shopping

for unusual foods, theres no counting calories, carbohydrates, fat, protein, or points. By understanding what makes you hungry and what makes you full, you will eat normal food

and eliminate most of your hunger and cravings even before you take medication.

The second part of the weight loss plan is the use of Contrave. Contrave is a combination

of two generic drugs- buproprion (trade name Wellbutrin, on the market since 1985) and

Naltrexone (trade name Riva, on the market since 1995). These two medications have

little weight loss effects when used individually. However, when combined in an

extended release forms the two components act synergistically in the hypothalamus of the

brain to reduce hunger, stop cravings and actually increase metabolism. The two

components of Contrave have been used safely by millions of people for problems other

than weight loss.

The powerful forces that tell you when to eat and when not to eatforces that easily overwhelm the normal control mechanisms of overweight individualsare revealed in groundbreaking new research and outlined in this booklet.

For decades, even centuries, lack of willpower has been misidentified as a psychological

weakness in most overweight individuals. We now know that, through no fault of their

own, obese individuals brains are actually biochemically different from those of thin people. Overweight individuals have too much of the regulatory hormones that are

ineffective or are not responding normally to those chemicals, and they end up eating the

wrong foods or simply too much food.

In the past decade, researchers have returned to older medications and have discovered

new answers to complex human health problems. The results of this research have just

begun to reach the publicand the first of a new class of miracle medical drugs for obesity is here now.

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You and your doctor are about to learn that there is a long-term solution to losing weight

and keeping it off. It is never about counting anything. It is about controlling hunger and

cravingsnot through willpower, but by using the power of your bodys own chemicals (mimicked by Contrave and other drugs to come) along with a simple, personalized food

plan designed to eliminate a few trigger foods causing weight gain to prevent hunger and

satisfy cravings.

For the millions of overweight individuals the Contrave Weight Loss Plan will be the

last diet book you will ever need. Follow along as more information is accumulated on

Contrave on my website at: www.richardlipmanmd.com

Who Can Take Medications for Weight Loss

To qualify for any of the medications for weight loss, the FDA states you must have a BMI of

27, with medical problems, or 30 or more without co-morbidities. The FDA defines co-

morbidities as a hypertension, high blood lipids, diabetes mellitus or a waistline above 105 cm.

Here is a BMI table to calculate your BMI:

You can also obtain your BMI from an on line calculator at this CDC web site:

http://nhlbisupport.com/bmi/bminojs.htm.

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Chapter 2: Contrave: What It is and How Does It Work?

How Contrave is Different from the Newer FDA Approved Weight Loss

Medications Qsymia and Belviq

The Food and Drug Administration authorized two completely new medicines in 2012-3:

Qsymia and Belviq. These have been the first new medications in the past 17 years.

These are the first two medications approved by the FDA for very long term use. The

Phentermine (the reason for the controlled drug classification) is the appetite reducer and

is comparable to the Phentermine in Adipex and Fastin, which have been in the

marketplace since the middle of the 1970s. The only difference is that the dosage in

Qsymia is or that found in the usual phentermine-alone medication. Topamax has

been available for two decades and is commonly used for seizures and headaches. So

Qsymia is not really new. It's two older, generic prescription drugs combined in a special

delivery method and having synergetic effect on weight loss.

While demonstrating effectiveness, Qsymias wide acceptance has been limited by the side effects of the two components and the fact that birth defects have been found in

women taking topiramate. Phentermine has been associated with blood pressure

elevations, increase in heart rate, anxiety as well as insomnia. Topiramate has opposite

side effects including depression, sleepiness and numbness in finger and toes. Birth

defects including cleft palate have been reported in women taking topiramate.

Belviq or Lorcaserin is the second new medication for weight loss. It is a SSRI

medication (Selective Serotonin Reuptake Inhibitor) similar to Prozac, Lexapro, and

Zoloft. Belviq works by altering specifically the 5-HT2C serotonin receptors in the

hypothalamic appetite centers of the brain. It is similar to the SSRI, medication

fenfluramine (from phen-fen frame of the late 1990s) in affecting the serotonin 2 C receptors. The major difference is that fenfluramine effected receptors in the heart, brain

and all over the body, while Belviqs action is confined only to the receptors in the hypothalamic appetite centers. No cardiac problems have been noted in subjects taking

Belviq over the past five years. The drawback with Belviq has been only moderate

weight loss of 5 to 8% of starting weight after a few months. Although this satisfies the

FDA requirements to establish efficacy and is clinically helpful for improvement in

cardiovascular risk factors including control of blood sugar in diabetics, lowering of

blood pressure and cholesterol, most dieters are not satisfied with this little weight loss (

5% of 200 lbs is only 10 lbs, which may take 3 or more months to achieve.) The high

cost of the drug is a further detriment to widespread use. (Belviq retails for $180.00 per

month after a discount of $75.00)

The underwhelming response of both physicians and overweight individuals to Qsymia

and Belviq has led the pharmaceutical industry to seek out new weight loss medications.

The emphasis has been on discovering medications with greater efficacy, less weight loss

plateaus and at the same time having less side effects and restrictions as the currently

available medications.

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Combinations of older generic medications with synergetic effects similar to Qsymia

seem to be favored by the FDA. This is common in diabetic and anti-hypertensive

medications where two or three medications, each with a different mode of action are

combined together. Synergism in medications is the combining of two different

chemicals, each one affecting the target organ along different pathways but producing

result greater than the sum of the individual components. In the case of Contrave greater

weight loss is achieved with the combination of medications than seen with each of the

individual components alone. This leads to increase efficacy with lower doses often

leading to less side effects.

Using the Qsymia model, researchers reviewed older, generic FDA approved medications

known to have influence on the craving and eating centers located in the hypothalamus of

the brain. The search led to two older medicationsbuproprion and Naltrexone.

Buproprion, a stimulator of norepinephrine and dopamine release (by actually blocking

the re-uptake of these chemical in the nerve synapse) has been on the market since 1985.

Used for depression, smoking cessation and seasonal affective disorder there has been

over 50 million users of this medication.

Naltrexone, a mu-opioid receptor antagonist has been available since 1984 as a treatment

for opioid and alcohol addiction under the name ReVia. Over 1 million patient exposures

have been observed with Naltrexone. Buproprion alone has shown a modest weight loss

effect, especially in depressed patients. Naltrexone alone has very little weight loss

potential.

Mechanisms of Action of Contrave (Buproprion and Naltrexone)

The hypothalamus is the command center within the brain for the integration of

numerous signals related to appetite and energy balance. As seen in this figure 1, the fat

deposits, satiety (fullness), and hunger signals are routed to the hypothalamus in the

brain. Body weight is controlled by balancing the signals that stimulate food intakePYY and Grehlin (in figure 1) and thus cause weight gain, against signals that produce

satiety and loss of body weight (Leptin and insulin).

In the hypothalamus nerve cells with similar function are joined in groups. The neurons

that release impulses that reduce hunger, cravings and increase metabolism are in green

POMC group. In contrast, the neurons in the purple group NPY act to increase appetite

and reduce energy expenditure. Impulses from these two groups project from the base of

the hypothalamus thru large areas of the brain. From a pharmacologic mechanism of

action, any drug that selectively increases the activity of POMC in the hypothalamus will

serve to reduce appetite. Figure 2 demonstrates how Buproprion acts by stimulating

POMC firing while Naltrexone reduces b-endorphins which normally function to limit

POMC firing. The end result is the buproprion effect in amplified by the stimulation of

POMC from the Naltrexone. Greater firing of the POMC neurons results in more

impulses limiting appetite and increase metabolism being propagated thru the brain. This

is synergism between the two components of Contrave. You can appreciate how

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complicated control of body weight becomes and how taking two drugs with different

mechanisms of actions that act together might be more effective than a single medication.

Figure 1

Figure 2

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Chapter 3: How Did Contrave Become the Newest Weight Loss

Medication?

About the Contrave Clinical Studies

Contrave was developed in accordance with current FDA guidelines. (Guidelines for

Industry: Developing Products for Weight Management February 2007). This consisted of 23 completed trials including 15 Phase I, four Phase 2, and four pivotal Phase 3

studies. The initial trials extended from April 2005 thru July 2010 and included 3475

participants. Additional trials, called the Light Studies were requested by the FDA

because of concerns of cardiovascular complications. They were started in 2012 and are

ongoing. An interim report of 8900 patients was released in November 2013 showing no

cardiovascular complications which led to FDA approval of Contrave in June 2014 and

its release to the public in October 2014.

Contrave Phase 1, 2 and 3 Studies

These 23 studies allowed for the complete assessment of the safety, efficacy and

pharmacokinetics of the two components of Contrave. Complete reviews of these studies

can be found at

http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drug

s/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM235672.pdf+Contrave&cl

ient=FDAgov&site=FDAgov&lr=&proxystylesheet=FDAgov&output=xml_no_dtd&ie=

UTF-8&access=p&oe=UTF-8

The majority of the trial subjects were middle-aged Caucasian women. Elderly

individuals (65 years) represented 2% of the total trial population. Approximately 25% of individuals had extreme obesity (40 kg/m2), 10% had diabetes, 10% had a history of depression and 27 with complications or > 30 without. Four phase

2 studies evaluated safety, efficacy, and tolerability. Studies compared different doses

and combinations. Safety and tolerability vs. efficacy were evaluated. One phase 2

studies evaluated patients with nicotine dependence and second one with major

depression.

The most important clinical studies were the four phase 3 studies that lasted for 56 weeks

each. One group received customary diet and exercise recommendations. Group 2

received intensive lifestyle modifications counseling. Contrave doses and titration rates

were varied in Group 3 and obese patients with type 2 diabetes were evaluated in group

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Contrave Dosages: Contrave 16 and Contrave 32

Phase 1 and 2 studies evaluated different doses and titration schedule of Contrave. Two

dose levels were finally established based on difference in Naltrexone doses. Contrave

16 consists of 4 grams of Naltrexone and 90mg of buproprion. The treatment dose is two

tablets twice a day for a total of 16 mg of Naltrexone and 360 mg of buproprion.

Contrave 32 consists of two tablets, each one with 8 mg of Naltrexone and 90 mg of

buproprion taken two in the morning and two at night. The total daily dose is 32 mg of

Naltrexone and 360 mg of buproprion.

Phase 3 Contrave Clinical Studies: These 3 studies are called COR 1, II, III and IV

and are reviewed: (More complete data for each group is in the appendix)

COR-I: Low- High Dose (NB-301): A trial designed to assess the safety, tolerability

and efficacy of Contrave 16 and Contrave 32 versus placebo in 1,742 obese patients.

Both treatment groups lost more weight than placebo. This trial incorporated a typical

diet and exercise regimen and was conducted at 34 US centers. 48% of Contrave 32

patients lost more than 5% of their starting weight compared to 16% of placebo.

*COR II-BMOD: Intense Life Style Changes (NB-302): This trial was conducted in

male and female subjects between 18 to 65 years of age with either uncomplicated

obesity or with obesity/overweight with controlled hypertension and/or dyslipidemia.

This was the study that would be as close to the average non study patient in terms of

exercise and diet. Intensive behavior modification (BMOD) was designed by consultants

from the National Institutes of Health. Average starting weight was 220 lbs in both

groups. A total of 793 subjects were randomized to receive Contrave 32 (n=591) or

placebo (n=202). Subjects also participated in an intense behavior modification program

that included dietary instructions, twenty-eight 90-minute group sessions, and prescribed

exercise.

Each participant attended 90 minute weekly sessions at which time different weight loss

issues were discussed. A balance low calorie diet was prescribed with 1200 calories per

day for those patients whose starting weight was 249 lbs or less and 1500-1800 for those

over 250 lbs.

Exercise was prescribed and consisted of mild to moderate brisk walking for 180 to 240

minutes per week.

In this study, more than 66% of patients taking 32 mg Contrave with intensive

behavior modification lost > 5% of starting weight compared to 42% for placebo.

As expected, intensive life style changes resulted in greater weight loss in Contrave

and non-Contrave patient groups than seen in COR-I.

Most of the weight loss was achieved at 24 weeks at which time 8.5% of Contrave 32

patients lose > 5% of starting weight compared to 5% for placebo. During the

remainder of the study to 56 weeks weight loss amounted to another 1% for

Contrave patients. Nearly three times as many patients lost > 15% of their starting

weight as compared to those taking placebo (31% vs. 10%). Using the average

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starting weight of 220 lbs one might expect a weight loss of 33 lbs. Again most of this

occurred within the first 16 weeks with 90% of this loss by the 24th

week of

medications.

COR III: High and Low Doses, Slow and Fast Titration of Doses (NB-303): COR III was conducted in male and female subjects between 18 to 65 years of age with

uncomplicated obesity or with obesity/overweight with controlled hypertension and/or

dyslipidemia. There were 495 subjects randomized to receive placebo and 1001

randomized to receive Contrave 32. Subjects assigned to Contrave 32 were randomized

within each study center (1:1 ratio) to two alternative dosage schedules for Naltrexone,

fast or slow. For subjects in the fast titration group, the initial daily dose of Naltrexone was 8 mg, which was increased by 8 mg each week until reaching 32 mg at week 4. For

subjects in the slow titration group, the initial daily dose of Naltrexone was 4 mg, which

was increased by 4 mg each week until reaching 16 mg at week 4. The dose was

increased to 32 mg at week 5. Subjects received ancillary therapy consisting of diet

instruction and advice on behavior modification and exercise. Study visits occurred every

4 weeks. Beginning at week 28 through week 44, subjects randomized to receive

Contrave 32 who failed to achieve or maintain a 5% reduction in body weight were re-

randomized to either continue treatment with CONTRAVE 32 or have their dose

increased to Naltrexone 48 mg / buproprion 360 mg (Contrave 48). 55% of Contrave 32

lost more than 5% of body weight compared to 17% in the placebo group.

Treatments with even high doses of NB 48 yield no further weight loss.

COR IV: Non Insulin Dependent Type 2 Diabetics (NB-304): A trial designed to

assess the safety, tolerability and efficacy of Contrave32 versus placebo in 505 obese

patients with type 2 diabetes with HbA1c > 7% and < 10%; not on injectable diabetes medications or inhaled insulin. The safety and efficacy of a total daily dose of NB32 was

compared to placebo. A total of 505 subjects were randomized to receive 32 (n=335) or

placebo (n=170). T Measures of HbA1c and other measures of glycemic control were

key secondary endpoints. This trial incorporated a typical diet and exercise regimen and

was conducted at 52 US centers. As expected patients with diabetes lost less weight

than those without diabetes on the same doses of Contrave. 44% of diabetic patients

taking Contrave 32 lost more than 5% of their baseline weight at week 56, vs. 18%

of diabetics on placebo.

Proportions of Subjects Losing More than 5- 10% of Starting Body Weight

The proportions of subjects who lost at least 5% of baseline body weight up to Week 56

(Week 28 for NB-303) are shown in figure 1. All Contrave 32 versus placebo group

comparisons were of statistical significance. Forty percent of subjects randomized to

NB16 in study NB-301and 48% of NB32 lost at least 5% of baseline body weight

compared with 16% of subjects randomized to placebo (p

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figure 1 % of Subjects Losing >5% of Starting Weight

A better measure of efficacy of weight loss with Contrave is to look at the percent of

patients who lost more than 10% of their starting weight and compared to placebo:

(NB 32 is same as Contrave 32)

Change in Metabolic Parameters with Contrave: Waist Circumference, Blood

Lipids, Blood Pressure, Glucose and Insulin

Changes in Waist Circumference

One of the most important measures of loss of body fat besides weight changes is the

reduction in circumference of the waist. In studies 301 and 302 at 56 weeks, Contrave

treated patients had mean reduction in waist circumference of 6.2 and 10.0 cm vs. 2.5 and

6.8 cm in the placebo group.

Changes in Metabolic Parameters with Contrave:

HDL: Changes in fasting HDL cholesterol were consistent across the four trials in that

the increase in HDL levels seen with Contrave were greater than placebo and reached

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statistical significance in all 4 trials. The mean treatment differences from placebo ranged

from 2.6 to 3.5 mg/dL.

TRIGLYCERIDES: The reduction in percentage from baseline was consistent across

the four trials in that the decrease in triglycerides levels with Contrave treated patients

was greater than placebo and reached statistical significance in all four trials. The

decrease in TG was from 7 to 17% in the Contrave treated patients vs. placebo which

ranged from 5 to 10%.

LDL: Subjects who received Contrave treatment showed small decreases from baseline

in fasting LDL cholesterol, which were not statistically different from placebo.

GLUCOSE AND INSULIN LEVELS: These parameters change from baseline to

endpoint in the three Phase 3 trials in obese subjects without diabetes mellitus (301, 302,

and 303). Improvements in fasting glucose from baseline were greater for the Contrave

group compared with placebo but were only statistically significant for the Contrave 32

dose in Trial 301. In NB-301, the mean difference from placebo was -1.9 mg/dL.

In COR 4-Contrave TYPE 2 DIABETES: Glycemic controlBaseline mean HbA1c values were similar between the treatment groups (7.97% Contrave 32 and 7.99%

placebo). At endpoint, subjects receiving Contrave 32 had statistically significantly

greater decreases from baseline in HbA1c (mean change -0.63% vs. - 0.14% for placebo.

In addition 44% of Contrave patients had their HBA1c below 7.0% compared to 26% in

the placebo group. Using a cut off of below 6.5%, the numbers were 20% vs. 10% for

placebo. There were few subjects in each group with either dose reductions in oral

hypoglycemic medication (1.3% placebo, 1.9% Contrave 32) or dose increases (1.3%

placebo; 3.0% NB32).

BLOOD PRESSURE AND PULSE: A greater percentage of subjects experienced

blood pressure and pulse elevation in the Contrave treatment groups as compared with

the placebo group (5.9% and 4.2%, respectively). No serious blood pressure and pulse

events were reported. Blood pressure-related issues were reported mostly by subjects

with a history of hypertension. Antihypertensive medication use at baseline, occasionally

led to treatment discontinuation. Actual mean blood pressure change was in the order of

+2.4 mm at week 24 and +1.5 at week 56. These are really minimal changes of little

clinical significance. These data suggest that blood pressure needs to be watched and

controlled in patients taking Contrave especially in those patients with pre-existing

hypertension.

There was a slight increase in pulse (approximately 1 beat per minute) in Contrave

patients compared to placebo patients, whose pulse was generally unchanged. There were

no meaningful treatment effects on ECGs or laboratory measures including liver function

tests.

Control of Eating (COE) Questionnaire

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The Control of Eating (COE) questionnaire is a 21-item self-report visual analog scale

designed to assess food cravings. A food craving was defined as a strong urge to eat a

particular food or drink. Subjects were instructed to read each question carefully and

place a mark at the point that best represented their experience over the preceding 7 days

using a 100-mm line with extremes of 0 (not at all) to 100 (extremely or very often or

after every one). Item 19 askedGenerally, how difficult has it been to control your eating? and Orexigen states that Item 19 represents a summary measure of the subjects perception of eating control. There were significant differences for the Contrave treated

patients as compared to placebo.

Interim Findings in the Light Study

The interim findings leading to FDA approval of Contrave were released in November

2013 consisting of 8900 patients followed for 56 weeks. These studies were designed to

mirror the population where Contrave would be used. Unlike the initial studies there were

equal men and women, 89% had diabetes mellitus and 2000 out of 8900 were clinically

depressed. Many were taking SSRI medications. The 1 year results showed similar

weight loss and no increase in cardiovascular complications.

Effects of Buproprion on Mood, Anxiety and Depression Related Eating

Obesity has been associated with a 25% increase in the odds of mood or anxiety disorder.

A combined anti- obesity and antidepressant benefit would be unique among the

available weight loss drugs. The Contrave trials employed a therapeutic dose of

buproprion, an antidepressant, but there was no evidence of any treatment effects on

depression and anxiety scores. The ability of this study to assess the effect of Contrave on

mood and depressive symptoms was limited because subjects with active psychiatric

disease were excluded from the study, and baseline scores were low. Treatment with

Contrave was not associated with increases in symptoms of depression or suicidal

ideation.

A pilot study was reported in 2013 where Contrave 32 was given to 25 female, obese

patients with depression. There was significant improvement in depression at 12 and 24

weeks with greater than a 50% reduction in depression. Mean weight loss after 24 weeks

was -9.2%. There was improvement in food cravings and general control of eating at 12

and 24 weeks.

Safety Profile of Contrave

The safety profile of Contrave was consistent with the safety profiles for Naltrexone and

buproprion. Contrave was not associated with any serious adverse events, and events

influencing tolerability (such as nausea) were typically reported early in the course of

treatment and were of mild to moderate severity and transient. There was a higher

attrition rate due to adverse events (such as nausea) with higher doses illustrating a

general decrease in Naltrexone tolerability with higher doses. There was no evidence of

increased adverse events with Contrave relative to placebo on vital signs, laboratory

measures, or ECG parameters. There were inconsistent effects on mean blood pressure

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and pulse rate observed across treatment groups. There was no evidence that the addition of Naltrexone worsened the effects of buproprion on blood pressure and pulse.

At week 56, mean blood pressure was only +1.5 from baseline for Contrave patients

compared to placebo patients, who tended to experience a slight decrease (approximately

2 mm Hg) from baseline. There was a slight increase in pulse (approximately 1 beat per

minute) in Contrave patients compared to placebo patients, whose pulse was generally

unchanged. There were no meaningful treatment effects on ECGs or laboratory measures

including liver function tests...

Across the entire COR program, seven serious adverse events were attributed by

investigators as possibly related to Contrave treatment. These include cholecystitis

(gallbladder inflammation) (2), seizure (2), palpitations (1), parenthesis (1) and vertigo

(1). Considering the number of treated patients these were rare.

Other Adverse Effects with Contrave

The most frequently observed treatment-emergent adverse events were nausea,

constipation and headache. Nausea was the leading adverse event resulting in

discontinuation; however, for the majority of patients experiencing nausea, it was mild to

moderate, transient and manageable.

h

Here are the adverse effects noted in the four Contrave phase 3 studies. Placebo adjusted

frequency varied from -2% for upper respiratory infection to 25% for nausea.

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"The data are remarkably consistent across the COR program, giving us greater

confidence that Contrave has the potential to help obese patients, even those with

diabetes, to initiate and sustain weight loss and improve their health ," said Dr. Ken

Fujioka, Lead Investigator, Director of Nutrition and Metabolic Research, Scripps Clinic.

"These results mark the beginning of an exciting new era in the treatment of the global

obesity epidemic where drug therapies may play an increasingly important role."

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Chapter 4: How to Take Contrave and What to Expect

Who Can Take Contrave?

To qualify to take any FDA approved prescription weight loss medication you must have a BMI

of 27, with medical problems, or 30 or more without co-morbidities. This applies to phentermine,

Belviq and Contrave. The FDA defines co-morbidities as a hypertension, high blood lipids,

diabetes mellitus or a waistline above 105 cm. Here is a BMI table to calculate your BMI:

You can also obtain your BMI from an on line calculator at this CDC web site:

http://nhlbisupport.com/bmi/bminojs.htm.

Once you have your BMI, you will need to see you physician for a prescription. Although

Contrave is not a controlled drug like the other weight loss medications, you will still need a

prescription from your doctor. Your doctor will need to select the best dosage for your individual

circumstances and follow you closely over the first month of titration.

Who Should Not Take CONTRAVE:

Have uncontrolled high blood pressure currently

History of current seizures or seizures in the past

Use other medicines that contain buproprion such as WELLBUTRIN,

WELLBUTRIN SR, WELLBUTRIN XL, and APLENZIN

History of anorexia or bulimia presently or in the past

Currently taking opioid pain medicines or use medicines to help stop taking

opioid such as methadone or buprenorphine, this means both street drugs and

prescription pain medications including tramadol, cough, cold or diarrhea

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medicines containing opioids. At least 7-10 days should be allowed between

stopping these drugs and starting Contrave.

Heavy alcohol consumption or suddenly stop drinking alcohol which might bring

on a seizure.

Have taken medicines called monoamine oxidase inhibitors (MAOIs), including

linezolid, within the last 14 days

Are allergic to Naltrexone HCl or buproprion HCl or any of the ingredients in

CONTRAVE

Are pregnant or planning to become pregnant. Tell your healthcare provider

right away if you become pregnant while taking CONTRAVE.

Thoughts of suicide: The buproprion component of Contrave has been associated

with suicidal thoughts or actions or changes in behavior. This is more pronounced

in teens and young adults. (Contrave is not for children),

How to Take Contrave and What to Expect

How Supplied:

Contrave is a combination of two extended release medications: buproprion and

Naltrexone. There are two combinations, a low dose of Contrave with 4mg of Naltrexone

and 90 mg of buproprion and a higher dose of 8 mg of Naltrexone and 90 mg of

buproprion. The difference is in the amount of Naltrexone. The dose is titrated slowly

over 3 weeks as indicated below. The full dose of two CONTRAVE 8/90 tablets twice a

day (32/360) 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. Doses

above 32/360 mg (4 tablets daily) are not recommended.

Treatment initiation and escalation with a lower dose of CONTRAVE 4/90 tablets may

be considered. If well tolerated, patients using CONTRAVE 4/90 tablets should switch to

CONTRAVE 8/90 tablets to have their daily dose increases to the recommended daily

dose of 32 mg Naltrexone and 360 mg buproprion. Here is the suggested titration of

Contrave:

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Patients that experience side effects with the Contrave 8/90 titration can switch to the

lower 4/90 and titrate upward with this dose. The daily maintenance dose would be 16

mg of Naltrexone and 360 mg of buproprion.

Remember, a lot of eating is social and habitual, so you must make some effort not to end

up with 3 pieces of pizza sitting in front of you. You must not pull up to the drive-thru at

McDonalds and order a #2 or #3 as usual, or go to Outback and order a 10 oz. steak with fries. Have one piece of pizza in front of you. Order the salad at the drive-thru and

chicken and veggies at Outback. You wont be hungry and you will be surprised how full you will quickly become. But you need to give the pill a chance to work. Remember it

takes about 20 minutes to feel full from eating just about anything.

The side effects of this dose are variable among individuals. Some people will notice a

dry mouth, others a little bit of anxiety. More will notice nausea. All of these are mild

symptoms and they usually disappear after the first week or two. I have treated

overweight people with medications for weight loss for over 40 years. I have seen

medications come and go. What I have observed is that there is no medication that is

effective for weight loss that will have absolutely NO side effects. Its just part of the trade-off. If you cannot tolerate any side effects, you should not be taking these

medications.

Here are the possible serious side effects of CONTRAVE from the Manufacturer:

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

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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

The most common side effects of CONTRAVE include nausea, constipation, headache,

vomiting, dizziness, trouble sleeping, dry mouth, and diarrhea.

Frequently Asked Questions About Contrave

Will Insurance Pay for Contrave?

I have had several insurance companies pay for part or all of a Contrave prescription.

You will have to have a BMI greater than 30, probably greater than 34 or 35 (morbid

obesity). Some companies will require the presence of co-morbidities. Some companies

require letters from your physicians, similar to gastric bypass requirements. Other

companies will not pay at all. Remember, Contrave is new, so be patient. Once insurance

companies learn about this great drug, things will change.

How Long Can I take Contrave?

The studies have gone on for 56 weeks and are still going. Once you arrive at 56 weeks,

the studies will have been going for 2 years. I tell my patients you should take the drug as

long as you need it and as long as you are losing weight. The manufacturer says not to

continue to take it after 12 weeks if you have not lost at least 12% of your body weight.