1

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?

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 comorbidities 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.

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.

6
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 intake
PYY 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

7
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

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 <1% had a history of cardiovascular disease. Approximately half of the
individuals in the studies completed the 56 weeks of treatment. Those subjects who
withdrew from the study did so because of side effects,- usually nausea and fatigue. Each
study was indicated by the initials NB (for Naltrexone-buproprion) and given a number.
Doses of Contrave were indicated by the amount of Naltrexone either 16 or 32 mg.
Phase 2 and 3 completed 3475 patients for a total of 2313 patient years. All patients
accepted in the studies had a BMI of >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
4.

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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

11
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 rerandomized 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<0.001).

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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

13
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

14
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

15
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.

16

"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."

17

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

18

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.