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Two New Drugs for Weight Loss .................................. p 69
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The Medical Letter
®
On Drugs and Therapeutics
Published by The Medical Letter, Inc. • 145 Huguenot Street, New Rochelle, NY 10801 • A Nonprofit Publication
Volume 54 (Issue 1398)
September 3, 2012
www.medicalletter.org
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Two New Drugs for Weight Loss
The FDA has approved one new drug and a new
combination of 2 old drugs as adjuncts to lifestyle
changes for chronic weight management. Lorcaserin
(lor-ca-SER-in; Belviq – Arena/Esai) is a selective
serotonin 2C receptor agonist. Qsymia (Vivus) is a
fixed-dose combination of the weight-loss drug phentermine and an extended-release (ER) formulation of
topiramate. The new products are approved for use in
obese patients (body mass index [BMI] of >30 kg/m2)
and for patients who are overweight (BMI >27 kg/m2)
and have one weight-related risk factor such as
hypertension, dyslipidemia or type 2 diabetes.
Neither drug is available yet. Qsymia is expected to be
marketed later this year. Belviq cannot be marketed until
the Drug Enforcement Administration determines its controlled substance scheduling.
OLDER DRUGS FOR WEIGHT LOSS1 — The lipase
inhibitor orlistat is modestly effective (patients have
lost 2.5-3.2 kg more than with placebo over 1-4
years), but it causes unpleasant adverse effects such
as flatulence with discharge, oily spotting and fecal
urgency.
The sympathomimetic amines, which are approved
by the FDA only for short-term use to initiate dietinduced weight loss, are all controlled substances;
Table 1. Some FDA-Approved Drugs for Treatment of Obesity1
Drug
Lorcaserin –
Belviq (Arena/Esai)
Phentermine/topiramate ER –
Qsymia (Vivus)
Cost2
Some Available Formulations
Usual Daily Dosage
10 mg tabs
10 mg bid
N.A.
7.5/46, 15/92 mg3
7.5/46-15/92 mg once
N.A.
120 mg caps
60 mg caps
120 mg tid
60 mg tid
50 mg tabs
25-50 mg once
to 50 mg tid
25 mg tid or
75 mg once
Lipase Inhibitor
Orlistat –
Xenical (Genentech)
Alli 4 (GSK)
$395.10
39.60
Sympathomimetic Amines
Benzphetamine – generic
Didrex (Pfizer)
Diethylpropion – generic
Phendimetrazine –
generic
Bontril PDM (Valeant)
extended-release – generic
Bontril SR (Valeant)
Phentermine –
generic
Adipex-P (Teva)
Suprenza (Akrimax)
25 mg, 75 mg ER tabs
35 mg tabs
31.20
188.10
19.80
105 mg ER caps
35 mg bid
to 70 mg tid
105 mg once
8.40
34.20
22.20
37.20
15, 30, 37.5 mg caps, 37.5 mg tabs
37.5 mg tabs
15, 30 mg ODT
15-37.5 mg once
37.5 mg once
15-30 mg once
21.00
62.40
45.00
N.A. = Not yet available. Lorcaserin will not be available for sale in the US until the Drug Enforcement Administration determines its controlled substance
scheduling designation. Phentermine/topiramate ER will be available later this year, according to the manufacturer. ODT = orally disintegrating tablets.
1. Weight loss drugs, including over-the-counter medications, are not recommended for use during pregnancy.
2. Cost of 30 days’ treatment with the lowest strength available based on wholesale acquisition cost (WAC). Source: PricePointRx™. Reprinted with permission by
FDB. All rights reserved. ©2012. http://www.firstdatabank.com/support/drug-pricing-policy.aspx. Accessed August 27, 2012. Actual retail prices may be
higher. Medicare does not cover obesity drugs.
3. Also available in 3.75/23 and 11.25/69 mg capsules which are intended for use only during titration.
4. Available over the counter.
FORWARDING OR COPYING IS A VIOLATION OF U.S. AND INTERNATIONAL COPYRIGHT LAWS
69
methamphetamine has a high abuse potential and
probably should not be used. All sympathomimetics
can increase heart rate, raise blood pressure, and
cause nervousness and insomnia.
LORCASERIN (Belviq) — Activation of the serotonin
2C receptor, which is found mainly in the central
nervous system, is thought to suppress appetite and
is considered unlikely to cause the hallucinations,
cardiac valvulopathy, and pulmonary hypertension
that have been associated with activation of other
serotonin receptor subtypes.2
Table 2. Pharmacology
Drug class
Formulation
Route
Tmax
Selective serotonin 2C receptor agonist
10-mg tablets
Oral
1.5-2 hours
Half-life
11 hours
Metabolism
Extensively metabolised in the liver by
multiple enzymes to inactive metabolites
Execretion
Urine (92%), feces (2%)
Clinical Studies – Approval of lorcaserin was based
on 3 randomized double-blind trials in obese or overweight adults; the first-year results are listed in Table
3.3-5 In the first trial (BLOOM), patients who lost >5%
of their body weight after one year on lorcaserin were
randomized to continue the drug or switch to placebo
for a second year. By the end of the second year,
patients who continued on lorcaserin had regained
about 25% of the initial weight loss, and those who
took lorcaserin during the first year and placebo during year 2 had lost an average of only 1.2 kg more
than those who had taken placebo for both years.3
Table 3. Lorcaserin Clinical Trials
Mean
Weight Loss
(52 weeks)
% Patients
with >5%
Weight Loss
BLOOM3
(average baseline wt: 100 kg)
Lorcaserin 10 mg bid
(n=1538)
Placebo (n=1499)
5.8 kg
47.5%
2.2 kg
20.3%
The BLOOM-DM trial was conducted in patients with
type 2 diabetes who were also being treated with metformin, a sulfonylurea or both. HbA1c decreased by
0.9% with lorcaserin twice daily, by 1.0% with lorcaserin
once daily, and by 0.4% with placebo.5
Adverse Effects – Headache, nausea, and dizziness
were the most frequent adverse effects reported with
lorcaserin in clinical trials. The discontinuation rates
were 50%, 45% and 36% in the 3 studies. Cardiac
valvulopathy did not occur more frequently with lorcaserin than with placebo. Euphoria has been reported
with doses >40 mg.
Drug Interactions – Lorcaserin inhibits CYP2D6; it has
increased peak serum concentrations of dextromethorphan, a 2D6 substrate, by 76%. Serotonin syndrome
occurred in 2 patients during the clinical trials; one of
these patients was also taking dextromethorphan.
Dosage and Administration – The dosage of lorcaserin recommended by the manufacturer is 10 mg
twice daily. If the patient has not lost at least 5% of baseline weight by 12 weeks, the drug should be discontinued. Lorcaserin is contraindicated for use during
pregnancy.
PHENTERMINE/TOPIRAMATE (Qsymia) — Phentermine is a sympathomimetic amine that has been
available in the US for many years for short-term
(weeks) treatment of obesity. When it was used with
fenfluramine (“phen-fen”), the combination was associated with heart valve abnormalities; fenfluramine
has since been withdrawn from the market. There
have been only rare reports of valvular disease occurring in patients taking phentermine alone.
Topiramate (Topamax, and others) is approved for use
in epilepsy and migraine, but not for weight control. It
has produced significant weight loss in some clinical trials; the mechanism is unclear.
Clinical Studies – Approval of Qsymia was based on
two 56-week trials in which patients were randomized
to placebo or to one of 2 doses of phentermine/topiramate; the 1-year results are listed in Table 4.6,7
BLOSSOM4
(average baseline wt: 100 kg)
Lorcaserin
10 mg once daily (n=801)
4.7 kg
10 mg bid (n=1602)
5.8 kg
Placebo (n=1601)
2.9 kg
40.2%
47.2%
25.0%
BLOOM DM5
(average baseline wt: 102-106 kg)
Lorcaserin
10 mg once daily (n=95)
5.0 kg
10 mg bid (n=251)
4.7 kg
Placebo (n=248)
1.6 kg
In an extension of the CONQUER trial, patients who
volunteered to continue their study regimens for an
additional 52 weeks lost (in total after 2 years) an average of 9.3% (9.6 kg) and 10.5% (10.9 kg) of their body
weight, compared to a loss of 1.8% (2.1 kg) in the
placebo group.8
44.7%
37.5%
16.1%
Adverse Effects – Adverse effects that occurred in
>5% of patients taking phentermine/topiramate ER and
were significantly more frequent than with placebo
70
The Medical Letter • Volume 54 • Issue 1398 • September 3, 2012
Revised 8/30/12: The last sentence in the Drug Interactions paragraph has been changed.
included dry mouth, paresthesia, constipation, dysgeusia and, with the higher dose, insomnia. Cognitive difficulties affecting attention, concentration and memory
were reported. The discontinuation rate of the combination was about 40% in the one-year trials. Topiramate is
a carbonic anhydrase inhibitor; metabolic acidosis and
kidney stones can occur. Antiepileptic drugs, including
topiramate, have been reported to increase the risk of
suicidal ideation and behavior.
CONCLUSION — Both lorcaserin (Belviq) and the
phentermine/topiramate ER combination (Qsymia)
taken as adjuncts to diet and exercise may be effective
in increasing weight loss in the first year of use, but
much less so in the second year. Qsymia appears to
be more effective than lorcaserin, but may cause more
troublesome adverse effects. 
1.
2.
Table 4. Qsymia Trials
Mean
Weight Loss
(56 weeks)
% Patients
with >5%
Weight Loss
3.
4.
EQUIP6
(average baseline wt: 115-118 kg)
Phentermine/topiramate ER
3.75/23 mg (n=241)
15/92 mg (n=512)
Placebo (n=514)
6.0 kg
12.6 kg
1.9 kg
CONQUER7
(average baseline wt: 103 kg)
Phentermine/topiramate ER
7.5/46 mg (n=498)
15/92 mg (n=995)
Placebo (n=994)
44.9%
66.7%
17.3%
5.
6.
8.1 kg
10.2 kg
1.4 kg
62%
70%
21%
Drug Interactions – Topiramate is a mild inducer of
CYP3A4 and a mild inhibitor of CYP2C19. Serum
potassium concentrations were lower in patients who
took both topiramate and hydrochlorothiazide than in
those who took either drug alone. Topiramate taken with
valproic acid has been associated with hyperammonemia, with and without encephalopathy. Serum concentrations of topiramate decreased about 40% when the
drug was taken with phenytoin or carbamazapine.
Phentermine is contraindicated while taking, and for 14
days after stopping, a monoamine oxidase (MAO)
inhibitor because of the risk of hypertensive crisis.
7.
8.
Diet, drugs and surgery for weight loss. Treat Guidel Med Lett
2011; 9:17.
KM Hurren and HD Berlie. Lorcaserin: an investigational serotonin 2C agonist for weight loss. Am J Health Syst Pharm
2011; 68:2029.
SR Smith et al. Multicenter, placebo-controlled trial of lorcaserin for weight management. N Engl J Med 2010; 363:245.
MC Fidler et al. A one-year randomized trial of lorcaserin for
weight loss in obese and overweight adults: the BLOSSOM
trial. J Clin Endocrinol Metab 2011; 96:3067.
PM O’Neill et al. Randomized placebo-controlled clinical trial of
lorcaserin for weight loss in type 2 diabetes mellitus: The
BLOOM-DM Study. Obesity 2012; 20:1426.
DB Allison et al Controlled-release phentermine/topiramate in
severely obese adults: a randomized controlled trial (EQUIP).
Obesity 2012; 20:330.
KM Gadde et al. Effects of low-dose, controlled-release, phentermine plus topiramate combination on weight and associated
comorbidities in overweight and obese adults (CONQUER): a randomised, placebo-controlled, phase 3 trial. Lancet 2011;
377:1341.
WT Garvey et al. Two-year sustained weight loss and metabolic
benefits with controlled-release phentermine/topiramate in obese
and overweight adults (SEQUEL): a randomized, placebo-controlled, phase 3 extension study. Am J Clin Nutr 2012; 95:297.
Pregnancy – Topiramate has been associated with a 2to 5-fold increased risk of oral clefts when taken in the
first trimester of pregnancy. Qsymia is contraindicated for
use during pregnancy and is available only through a
restricted access program (Qsymia REMS) designed to
prevent fetal exposure to the drug.
Dosage and Administration – Phentermine/topiramate ER is taken once daily, preferably in the morning to
prevent insomnia. The recommended dosage is 3.75/23
mg for 14 days followed by 7.5/46 mg. If a 3% weight
loss is not achieved after 12 weeks on the 7.5/46 mg
dose, the dosage may be increased to 11.25/69 mg for
14 days, and then to 15/92 mg. If the patient does not
achieve at least a 5% decrease in weight after 12 weeks
on the highest dose, the drug should be discontinued
gradually; abrupt withdrawal of topiramate can cause
seizures even in patients with no history of epilepsy.
The Medical Letter • Volume 54 • Issue 1398 • September 3, 2012
71
The Medical Letter®
On Drugs and Therapeutics
EDITOR IN CHIEF: Mark Abramowicz, M.D.
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The Medical Letter • Volume 54 • Issue 1398 • September 3, 2012