Obesity Medications

PRESCRIPTION
WEIGHT-LOSS MEDICATION
Najla Lakkis, MD, MPH
Oct 6, 2012

Epidemy of Obesity
Lebanon: the prevalence of overweight and obesity
in the adults aged ≥ 20 years reached 37.0% and
11.0% respectively in 2009 compared to 37.0% and
7.3% in 1997.
U.S. population: 1/3 of adults are overweight and
another 1/3 are already obese.
Nasreddine L. et al. BMC Public Health 2012, 12:798

Epidemy of Obesity in Lebanon by Age/Gender
Nasreddine L. et al. BMC Public Health 2012, 12:798

Excessive Body Weight
Physical & Psychologic Complications
Hypertension
Dyslipidemia
Type 2 diabetes mellitus
Heart disease
Stroke
Certain types of cancer (endometrial, breast, prostate, colon)
Gallbladder disease
Sleep apnea and other respiratory problems
Reduced fertility
Osteoarthritis
Increase in all-cause mortality
Emotional distress
Discrimination
Social stigmatization
http://www.aafp.org/afp/2001/0601/p2185.html

PRESCRIPTION WEIGHT LOSS MEDICATIONS
They are indicated, as per the FDA, as
an adjunct to
a reduced-calorie diet & exercise for
chronic weight management with
initial BMI ≥ 27 kg/m 2
with at least 1 weight-related
comorbid condition
(eg, HTN, DM, dyslipidemia).

REMEMBER -SERIES OF FDA REJECTIONS
Weight loss drugs in general have not had a great track record for safety.
.
Fenfluramine+Phentermine combination and Dexfenfluramine were
withdrawn from the market in 1997 due to heart valve damage…
Rimonabant was formally rejected by the FDA in 2007(risk of serious
psychiatric problems and even suicide).
Sibutramine was also pulled from pharmacy shelves in 2010 due to
concerns about heart problems (↑cardiovx events & strokes).
The FDA also formally rejected:
Lorcaserin from Arena Pharmaceuticals in October 2010.
Phentermine + Topiramate ER (Qnexa) from Vivus in October 2010.
Bupropion+ Naltrexone (Contrave) from Orexigen Therapeutics in Feb 2011.
The FDA asked the maker of Contrave, to check for heart attack or
other cardiovascular risks by conducting a “randomized, double-blind,
placebo-controlled trial .
.

LORCASERIN
HYDROCHLORIDE
marketed as Belviq (BEL-VEEK) in the US
made by Arena Pharmaceuticals
Rejected by the FDA in October 2010 (because of concerns of an increased
CARDIOVX risk of heart disease and stroke among users)
Approved by the FDA in June 2012

LORCASERIN: Mechanism of Action
It is a SELECTIVE serotonin 2C (5-HT2C) receptor
agonist— It activates brain receptors for serotonin, a
neurotransmitter that triggers feelings of satiety and
satisfaction.
At dosages intended for weight loss, it does not
significantly turn on different serotonin switches
responsible for the effects of hallucinogens (such
as LSD) and addictive drugs of abuse.
Higher doses may trigger these switches.
Fryhofer S. Sep 2012. http://www.medscape.com/viewarticle/770264
Astrup A. & Pedersen S. Jun 2012. http://www.medscape.com/viewarticle/766467.

LORCASERIN: Dosage Forms & Strengths
Belviq 10-mg tablets Once to BID ± food.
It will become available in the US by early 2013.
It has a potential for abuse... It will be a controlled
substance…
http://www.rxlist.com/belviq-drug/indications-dosage.htm

LORCASERIN: Dose Adjustment
Renal impairment
Mild (CrCl 30-60 mL/min): No dosage adjustment required
Moderate (CrCl 15-30 mL/min): Use caution
Severe (CrCl 9): Use caution

CHILD-PUGH SCORE
The score employs five clinical measures of liver disease. Each measure is
scored 1-3, with 3 indicating most severe derangement.

LORCASERIN: How Well Does It Work?
One should expect at least 5% body weight loss
overall. If this result isn't evident after taking it for
3 months, the patient should stop the drug.
Clinical trials have shown that Lorcaserin produces
about 4 kg of weight loss over a 1-year period
compared with placebo, with some sustained weight
loss benefit after 2 years of treatment.
Thus, the weight loss seen with Lorcaserin is slightly
greater than that seen with Orlistat, which provides 2-
3 kg of placebo-subtracted weight loss.
Fryhofer S. Sep 2012. http://www.medscape.com/viewarticle/770264
Astrup A. & Pedersen S. Jun 2012. http://www.medscape.com/viewarticle/766467
Fidler MC, et al. J Clin Endocrinol Metab. 2011;96:3067-3077

LORCASERIN in persons with Type 2 DM
It improves glycemic control (A1c ↓ by 1%) in
addition to facilitating weight loss (5%).
It has modestly beneficial effects on Lipids & BP.
Symptomatic hypoglycemia occurred in 7.4% of
patients on Lorcaserin twice daily, 10.5% on
Lorcaserin once daily, and 6.3% on Placebo.
In this clinical trial, all patients were concomitantly
using a sulfonylurea (±metformin). Lorcaserin has
not been studied in patients taking Insulin.
Astrup A. & Pedersen S. Jun 2012. http://www.medscape.com/viewarticle/766467
O'Neil PM, et al. Obesity. 2012. doi: 10.1038/oby.2012.66.

LORCASERIN: Limitations of Use -1-
The safety and efficacy of coadministration of Lorcaserin
with other products intended for weight loss including
prescription drugs (e.g., Phentermine), OTDs, and herbal
preparations have not been established.
The effect of Lorcaserin on cardiovx morbidity&mortality
has not been established.
N.B. Preliminary data suggest that 5HT2B receptors may be
overexpressed in CHF…
The FDA is requiring 6 postmarketing studies, including a
long-term cardiovx trial to evaluate risk for heart attack and
stroke.
http://www.rxlist.com/belviq-drug.htm
Astrup A. & Pedersen S. Jun 2012. http://www.medscape.com/viewarticle/766467

LORCASERIN: Limitations of Use -2-
Risk of Serotonin Syndrome or Neuroleptic Malignant Syndrome
(NMS)-like reactions if combined with:
1. Serotonergic medications, including:
SSRIs & SNRIs
2. Drugs that may affect the serotonergic neurotransmitter systems
Triptans,
MAOIs
TCAs
Lithium
Bupropion
Tramadol
Tryptophan
St. John's Wort
Antipsychotics or other dopamine antagonists….
http://www.rxlist.com/belviq-drug.htm

LORCASERIN: Limitations of Use -3-
Lorcaserin should be used with caution in men who
have conditions that might predispose them to
priapism (e.g., sickle cell anemia, multiple myeloma, or
leukemia), or in men with anatomical deformation of
the penis (e.g., angulation, cavernosal fibrosis, or
Peyronie's disease).
There is limited experience with the combination of
Lorcaserin & medication for erectile dysfunction (e.g.,
phosphodiesterase 5 inhibitors). Therefore, the
combination with these medications should be used
with caution.
http://www.rxlist.com/belviq-drug.htm

LORCASERIN: Contra-Indications
Pregnancy & ?Breastfeeding
Children < 18year old (not studied yet)
Patient with Severe Renal Failure.
Patients on Serotonergic Medications.
Patients with CHF or hemodynamically-significant
VHD.
Patient who have conditions that might
predispose them to priapism.
http://www.rxlist.com/belviq-drug/overdosage-contraindications.htm

Lorcaserin: Adverse Effects-common
>10% % C % P
Headache 16.8 10.1
URTI 13.7 12.3
Nasopharyngitis 13.0 12.0
1-10% % %
Dizziness 8.5 3.8
Nausea 8.3 5.3
Fatigue 7.2 3.6
Diarrhea 6.5 5.6
UTI 6.5 5.4
Back pain 6.3 5.6
Constipation 5.8 3.9
Dry mouth 5.3 2.3
Vomiting 3.8 2.6
Rash 2.1 1.8
Musculoskeletal pain 2.0 1.4
http://www.rxlist.com/belviq-drug/side-effects-interactions.htm

Lorcaserin: Adverse Effects-others
Cognitive Impairment such memory problems and
attention disturbance (1.9% c versus 0.5% p )
Psychiatric Problems such as euphoria, hallucination,
and dissociation (0.2% c versus

ATTENTION
Monitor for serotonin syndrome or NMS-like reactions
Studies suggest possibility of regurgitant VHD (not likely), monitor if
patient has CHF
Advise patient to take caution when operating hazardous machinery .
Monitor for worsening of depression, suicidal thoughts or behavior, or
any other unusual changes in mood or behavior
Monitor for hypoglycemia with type 2 DM, if hypoglycemia occurs while
on therapy, adjust antidiabetic drug regimen
Caution in men with predisposed conditions to priapism (eg sickle cell
anemia, multiple myeloma, or leukemia) or anatomical deformation of
the penis
Caution with bradycardia or a history of heart block
May cause decrease in WBC count and other hematological changes,
consider periodic monitoring of CBC
Moderately elevates prolactin levels
May cause pulmonary hypertension (insufficient data)

PHENTERMINE HYDROCHLORIDE
+
TOPIRAMATE EXTENDED-RELEASE
marketed as Qsymia (kyoo-sim-EE-uh)
made by Vivus Pharmaceuticals
Rejected by the FDA in Oct 2010 (Qnexa) because it increased cardiovx risk
Approval by the FDA in Jul 2012 (Qsymia)

Phentermine+Topiramate ER
It is a combination of 2 currently approved drugs:
The sympathomimetic amine anorectic Phentermine, the
safer "phen" part of the infamously unsafe fen-phen diet
drug combo. It triggers↑ release of Norepinephrine ↑
Leptin in blood ↓ appetite
The seizure/migraine drug Topiramate, that causes weight
loss in several ways:
increasing feelings of fullness
making foods taste less appealing
increasing calorie burning.

PHEN/TPM ER: Dosage Forms & Strengths
Qsymia 3.75 mg/23mg (14 and 30 capsules),
Qsymia 7.5 mg/46 mg (30 capsules),
Qsymia 11.25 mg/69 mg (30 capsules),
Qsymia 15 mg/92 mg (30 capsules).
Start with 3.75 mg/23mg, and ↑ to the recommended dose
7.5 mg/46 mg after 14 days. Evaluate weight loss after 12
weeks before shifting to a higher dose…then 12 weeks…
The combination is taken once a day in the morning ± food.
Qsymia should become available by Sep 2012.
It will be sold only through "certified pharmacies “ because
women taking this medication must use birth control, and the
drug Phentermine has a known potential for abuse.

PHEN/TPM ER: Dose Adjustment
Renal impairment:
Mild (≥50 mL/min): No dose adjustment required
Moderate (30-49 mL/min) and severe (

PHEN/TPM ER: How Well Does It Work?
2 year-long clinical trials (n≈3700 patients) reported
6.7%-8.9% additional weight loss in patients taking
Qsymia compared with those taking the placebo.
After 3 months of treatment, one can expect at least:
3% weight loss on lower doses
5% weight loss on higher doses.
If not, the drug should be stopped, but gradually:
Discontinue Qsymia 15mg/92mg gradually by taking a dose
every other day for at least 1 week prior to stopping
treatment altogether, due to the possibility of precipitating a
seizure.
Gadde KM et.al. Lancet. 2011 Apr 16;377(9774):1341-52.

56-week Randomized Clinical Trial (EQUIP Trial)
in Severely Obese Patients BMI≥35
1.6%
5.1%
10.9%
p < 0.0001
Allisson D et.al. Obesity (Silver Spring). 2012 February; 20(2): 330–342.

56-week Randomized Clinical Trial (EQUIP Trial)
in Severely Obese Patients BMI≥35
The 15/92 group had significantly greater changes
relative to placebo for WC, SBP & DBP, FBS, TGs, T.
Cholesterol, LDL-C, & HDL-C.
Allisson D et.al. Obesity (Silver Spring). 2012 February; 20(2): 330–342.

PHEN/TPM ER: Limitations of Use
The safety and effectiveness of Qsymia in combination with
other products intended for weight loss, including
prescription and OTC drugs and herbal preparations have
not been established.
The effect of Qsymia on cardiovx morbidity&mortality has
not been established. The FDA is requiring Qsymia
manufacturer Vivus, Inc. to conduct 10 postmarketing studies,
including 1 long-term study specifically looking at cardiovx
events, including heart attack and stroke.
•Lauer MS. Lemons for obesity. Ann Intern Med. 2012,157:139-140.
•Adamson Fryhofer S.- http://www.medscape.com/viewarticle/770262?src=mp

PHEN/TPM ER: Common Side Effects
4 Clinical Trials Experience
CNS: paresthesia*, headache*, dizziness*, dysgeusia, hypoesthesia,
disturbance in attention
Psychiatric: insomnia*, depression*, anxiety*
GI: constipation*, dry mouth*, nausea, diarrhea, dyspepsia,
heartburn
General: fatigue, irritability*
Eye Disorders: blurred vision*
Infections: URTI, nasopharyngitis, sinusitis, bronchitis, UTI,
gastroenteritis
Laboratory Abnormalities: ↓CO2 content; ↓K + ; ↑ Creat
Weight loss may ↑ the risk of hypoglycemia in patients with type 2 DM treated with
insulin and/or insulin secretagogues.
Weight loss may ↑ the risk of hypotension in patients on anti-hypertensive drugs.
http://www.rxlist.com/qsymia-drug-center.htm
http://www.fda.gov/downloads/Drugs/DrugSafety/UCM312590.pdf

Common Side Effects
Post-Marketing
Phentermine
Allergic: Urticaria
Cardiovx : ↑BP, Ischemic events
CNS: Euphoria, Psychosis, Tremor
Reproductive: Changes in libido, Impotence
Topiramate
Dermatologic: Bullous skin reactions (including erythema
multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis),
Pemphigus
Gastrointestinal: Pancreatitis
Hepatic: Hepatic failure (including fatalities), Hepatitis
Metabolic: Hyperammonemia Hypothermia
Ophthalmic: Maculopathy
http://www.rxlist.com/qsymia-drug-center.htm

DRUG-DRUG INTERACTION
MAOIs.
Carbonic Anhydrase Inhibitor (e.g., zonisamide, acetazolamide, or
dichlorphenamide).
OCPs: increased exposure to the progestin and lower exposure to the
estrogen irregular bleeding (spotting)
CNS Depressants (barbiturates, benzodiazepines, sleep medications)
including Alcohol: may potentiate CNS depression such as dizziness
or cognitive adverse reactions, or other centrally mediated effects of
these agents.
Non- K + Sparing Diuretics: ↓ K + (Monitor K + level).
Antiepileptic Drugs:
Carbamazepine or Phenytoin ↓ plasma concentrations of
topiramate by 40-48%
Valproic A. hyperammonemia ± encephalopathy.
hypothermia ± hyperammonemia

Warnings & Precautions
Fetal Toxicity (Topiramate in T1: Cleft Lips ± Palate).
↑ in HR, so HR monitoring is recommended.
Suicidal Behavior and Ideation (Topiramate)
Acute Myopia and Secondary Angle Closure Glaucoma
Mood and Sleep Disorders (++Avoid Alcohol intake)
Cognitive Impairment e.g., impairment of concentration,
difficulty with memory, and speech or language problems,
particularly word-finding difficulties).
Metabolic Acidosis
http://www.rxlist.com/qsymia-drug-center.htm

Contre-Indications
Hypersensitivity to sympathomimetic amines
Pregnancy or Planning for Pregnancy or no effective
Contraception method
Unstable heart disease or stroke
Glaucoma
Hyperthyroidism
Severe Liver Failure
Use of Phentermine is contraindicated during or within 14
days following MAOIs -- risk for hypertensive crisis
Use of Topiramate is contraindicated during Carbonic
Anhydrase Inhibitor due to risk of metabolic acidosis and
risk of kidney stone formation.
http://www.fda.gov/downloads/Drugs/DrugSafety/UCM312590.pdf

ORLISTAT
Modest weight loss
an average of 2.9 kg at 1 to 4 years
Little information on its effect on longer-term complications of
obesity
Rucker D et al. BMJ 2007, 335 (7631): 1194–99.
Wood S. Medscape News. Retrieved 26 April 2011.

ORLISTAT: Story with the FDA
1999: The FDA approved Orlistat capsules as a prescription
drug to treat obesity.
2007: The FDA approved Orlistat capsules (60mg) as
an OTC weight loss aid for overweight adults. Orlistat
capsules (120mg) remained a prescription drug for obesity
in the USA.
2010: new FDA safety information about cases of severe
liver injury with hepatocellular necrosis or acute hepatic
failure that have been reported rarely (n=13) with the use
of this medication (60mg and 120mg). Some of these cases
resulting in liver transplant (n=3) or death (n=2).
http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2007/ucm108839.htm

ORLISTAT: Mechanism of Action
It inhibits gastric and pancreatic lipases TGs from the
diet are not hydrolyzed into absorbable free fatty acids,
and are excreted undigested instead.
Only trace amounts are absorbed systemically.
It prevents approximately about 25% (60mg TID) to 30%
(120mg TID) of dietary fat from being . Higher
doses do not produce more potent effects.

ORLISTAT: Dosage Forms & Stengths
Orlistat 60mg (Alli -GSK) TID
Orlistat 120mg (Xenical -Roche) TID
with each main meal containing fat
(during or up to 1 hour after the meal)

ORLISTAT: How Well Does It Work?
The weight loss achieved with Orlistat varies. In 1-
year clinical trials:
35.5%-54.8% achieved 5% or greater decrease in BMI 16.4%-
24.8% achieved at least a 10% decrease in BMI
After Orlistat was stopped, a significant no. of subjects
regained up to 35% of the weight they had lost.
The incidence of T2DM in an obese population over
4 yrs is decreased with Orlistat (6.2%) compared to
placebo (9.0%). *
Long-term use of Orlistat also leads to a modest
reduction in BP. ** *Torgerson J et al. Diabetes Care 2004, 27 (1): 155–61.
**Siebenhofer A et al. Cochrane Database Syst Rev 2009, 8 (3): CD007654.

ORLISTAT: Common Side Effects
Clinical Trials Experience
High rates of GI side effects: oily stool / spotting,
passing gas with oily discharge, stool incontinence,
diarrhea, nausea/vomiting
↓ absorption of fat soluble vitamins (D, E, K) & betacarotene—better
to take supplements once a day at least
2 hrs before or after the administration of Orlistat, such
as at bedtime.
Rare cases of hypersensitivity: pruritus, rash, urticaria,
angioedema, bronchospasm and anaphylaxis. Very rare
cases of bullous eruption.
http://www.rxlist.com/xenical-drug.htm

ORLISTAT: Side Effects
Postmarketing Surveillance
↑ risk for severe liver injury.
↑ in transaminases & alk. Phosphatase.
↑ risk for gall stones.
↑ risk for the development of kidney stones
(oxalate-induced acute kidney injury).
↑ risk for acute kidney injuries.
↑ risk for acute Pancreatitis.
Wood S. Medscape News. Retrieved 26 April 2011
http://www.rxlist.com/xenical-drug.htm

ORLISTAT: Drug-Drug Interactions
It can impair absorption of:
Vit K: ↑ INR in patients on Orlistat & Warfarin.
Levothyroxine: administer it at least 4 hrs before Orlistat.
Cyclosporine: administer it 3 hrs after Orlistat.
Amiodarone.
http://www.rxlist.com/xenical-drug/indications-dosage.htm

ORLISTAT: Contre-indications
Pregnancy. It is not known if Orlistat passes into breast milk.
Hypersensitivity to Orlistat or to any of its components
Chronic Malabsorption Syndrome.
Gallbladder problem (cholestasis) or Reduced gallbladder function
(e.g. after cholecystectomy).
Impaired Liver Function.
Pancreatic Disease.
Kidney stones/problems (such as calcium oxalate kidney stones,
hyperoxaluria).
Organ Transplant.
Anorexia Nervosa/Bulimia.

BUPROPION+ NALTREXONE
marketed as Contrave
made by Orexigen Therapeutics

BUPROPION+ NALTREXONE
Both drugs have been on the market for about 25
yrs.
Bupropion, commonly prescribed to treat depression
and also approved to help people quit smoking,
curbs the appetite.
Naltrexone, an opioid blocker, approved to treat
opioid and alcohol addictions, amplifies the effect of
Bupropion on the appetite.
Most patients taking this combination in clinical
trials lost about 4.2-5.0% of their starting body
weight compared to those taking a placebo, which is
below the FDA standard of 5%.

BUPROPION+ NALTREXONE
Dec 7, 2012
An FDA advisory committee voted 13 to 7 to
recommend approval of Contrave.
But many of the FDA committee members
expressed concern about:
1. the drug's impact on cardiovascular health (↑BP)
2. The lack of data that give any clues about the
drug's safety or efficacy beyond the one-year mark
for a long-term health condition.

BUPROPION+ NALTREXONE
Feb. 1, 2011
The FDA has decided not to approve the weight loss
drug Contrave.
The FDA issued a response letter that asks Orexigen
Therapeutics, the maker of Contrave, to check for
heart attack or other cardiovascular risks by
conducting a “randomized, double-blind, placebocontrolled
trial.”