The medical letter on drugs and therapeutics june 22 2015

The Medical Letter

®

on Drugs and Therapeutics
Adapted for Canada

Objective Drug Reviews Since 1959
Volume 57

ISSUE
ISSUE
No.

1433
1471
Volume 56

June 22, 2015
IN THIS ISSUE

Liraglutide (Saxenda) for Weight Loss .................................................................................p 89
Which PPI? .............................................................................................................................p 91
Droxidopa (Northera) for Neurogenic Orthostatic Hypotension .........................................p 92
Bellafill for Acne Scars.......................................................................................................... p 93
In Brief: Ketoacidosis with SGLT2 Inhibitors ...................................................................... p 94
Addendum: Nivolumab (Opdivo) for Metastatic Melanoma and Metastatic NSCLC ........ p 94

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The Medical Letter

®

on Drugs and Therapeutics
Objective Drug Reviews Since 1959

Volume 57

ISSUE

ISSUE No.

1433
1471
Volume 56

▶

June 22, 2015
Take CME Exams
ALSO IN THIS ISSUE

Which PPI? .............................................................................................................................p 91
Droxidopa (Northera) for Neurogenic Orthostatic Hypotension .........................................p 92
Bellafill for Acne Scars...........................................................................................................p 93
In Brief: Ketoacidosis with SGLT2 Inhibitors ........................................................................p 94
Addendum: Nivolumab (Opdivo) for Metastatic Melanoma and Metastatic NSCLC .........p 94

Liraglutide (Saxenda) for
Weight Loss

The injectable glucagon-like peptide-1 (GLP-1)
receptor agonist liraglutide, previously approved by the
FDA for treatment of type 2 diabetes as Victoza,1 has
now also been approved at a higher dose as Saxenda
(Novo Nordisk) for chronic weight management
in adults with a BMI ≥30, or a BMI ≥27 with a
weight-related comorbidity such as hypertension,
dyslipidemia, or diabetes.
Pronunciation Key
Liraglutide: lir” a gloo’ tide
Saxenda: sax end ah

DRUGS FOR WEIGHT LOSS – Pharmacologic treatment
of obesity has been limited by modest efficacy, adverse
effects, low adherence rates, and regain of weight with
drug cessation.2 Drugs approved by the FDA for longterm treatment of obesity are listed in Table 2 on page 90.
Phentermine/topiramate ER (Qsymia) is the most
effective drug available to date for weight loss.
Lorcaserin (Belviq) is only modestly effective, but is
generally well tolerated.3 The lipase inhibitor orlistat
(Xenical, Alli) is also modestly effective, but it can
cause unpleasant adverse effects such as flatulence
with discharge, oily spotting, and fecal urgency. The
fixed-dose combination (Contrave) of bupropion
(Wellbutrin SR, Zyban, and others) and naltrexone
(ReVia, and others) has been effective, but nausea is
common, and serious neuropsychiatric reactions have
been reported.4
MECHANISM OF ACTION — Liraglutide decreases
caloric intake. The exact mechanism is unknown;
delayed gastric emptying and agonist effects on GLP-1

receptors in areas of the brain involved in appetite
regulation have been implicated.
CLINICAL STUDIES – Table 1 summarizes the results
of some randomized trials of liraglutide for weight loss
in overweight or obese adults.
Table 1. Liraglutide Clinical Trials1
Mean
Weight
Loss (%)

% of Patients
with Weight
Loss ≥5%

Study Design
Drug Regimen
Patients with Diabetes
RA DeFronzo et al.2,3 Liraglutide 3 mg
5.9%
49.9%
56 weeks (n=846)
Liraglutide 1.8 mg4 4.6%
35.6%
Placebo
2.0%
13.8%
Patients without Diabetes
X Pi-Sunyer et al.5
Liraglutide 3 mg
8.0%
63.2%
56 weeks (n=3731) Placebo
2.6%
27.1%
Patients without Diabetes after ≥5% Initial Weight Loss6
TA Wadden et al.7
Liraglutide 3 mg
6.2%8
50.5%8

56 weeks (n=422)
Placebo
0.2%8
21.8%8

1. In addition to diet and exercise in adults with a BMI ≥30 or a BMI ≥27 with a
weight-related comorbidity.
2. RA DeFronzo et al. Effects of liraglutide 3.0 mg and 1.8 mg on body weight
and cardiometabolic risk factors in overweight and obese adults with type
2 diabetes mellitus (T2DM): the SCALE Diabetes randomized, double-blind,
placebo-controlled, 56-week trial. The Endocrine Society’s 96th annual
meeting and expo, Chicago, June 21-24, 2014. Poster SAT-0930.
3. Effect of liraglutide on body weight in overweight or obese subjects with
type 2 diabetes: SCALE Diabetes. Available at . Accessed June 11, 2015.
4. FDA-approved as a titration dose, but not for maintenance.
5. X Pi-Sunyer et al. N Engl J Med 2015; 373:11.
6. Patients were first treated with a low-calorie diet and lost ≥5% of initial
body weight in 4-12 weeks during the run-in phase.
7. TA Wadden et al. Int J Obes (Lond) 2013; 37:1443.
8. Weight loss observed after randomization.

ADVERSE EFFECTS – Common adverse effects of
liraglutide include nausea, diarrhea, constipation, vomiting, hypoglycemia, headache, decreased appetite,
and dyspepsia. Acute pancreatitis and cholelithiasis,
acute renal failure and worsening of chronic renal
failure, increased heart rate, suicidal thoughts, and
89

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The Medical Letter

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June 22, 2015

Table 2. Some FDA-Approved Drugs for Long-Term Treatment of Obesity1
Drug
Sympathomimetic Amine/Antiepileptic Combination
Phentermine/topiramate ER – Qsymia (Vivus)
Lipase Inhibitor
Orlistat – Xenical (Genentech)
Alli9 (GSK)
Serotonin Receptor Agonist
Lorcaserin – Belviq (Eisai)
Opioid Antagonist/Antidepressant Combination
Naltrexone/bupropion – Contrave
(Orexigen/Takeda)
GLP-1 Receptor Agonist
Liraglutide – Saxenda (Novo Nordisk)

Some Available
Formulations

Usual
Adult Dosage

Mean
Weight Loss2

Cost3

7.5/46, 15/92 mg ER caps4

7.5/46-15/92 mg once/d

4.1-10.7 kg5-7

$170.70

120 mg caps
60 mg caps

120 mg tid
60 mg tid

2.5-3.4 kg8

512.10
44.00

10 mg tabs

10 mg bid

2.9-3.6 kg10-12

199.50

8/90 mg ER tabs

16/180 mg bid

3.7-5.2 kg7,13-15

199.50

18 mg/3 mL prefilled pen16

3 mg SC once/d

5.8-5.9 kg17,18

1068.30

ER = extended-release
1. Weight loss drugs, including over-the-counter medications, are not recommended for use during pregnancy.
2. Placebo-corrected weight loss above diet and lifestyle modifications alone after one year.
3. Approximate WAC for 30 days’ treatment with the lowest usual dosage. WAC = wholesaler acquisition cost or manufacturer’s published price to wholesalers;
WAC represents a published catalogue or list price and may not represent an actual transactional price. Source: AnalySource® Monthly. June 5, 2015. Reprinted
with permission by First Databank, Inc. All rights reserved. ©2015. www.fdbhealth.com/policies/drug-pricing-policy. Medicare does not cover weight loss drugs.
4. Also available in 3.75/23 mg and 11.25/69 mg capsules, which are intended for use only during titration.
5. DB Allison et al. Controlled-release phentermine/topiramate in severely obese adults: a randomized controlled trial (EQUIP). Obesity (Silver Spring) 2012; 20:330.
6. 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.
7. The range includes weight loss observed with titration and maintenance dosages.
8. SZ Yanovski and JA Yanovski. Long-term drug treatment for obesity: a systematic and clinical review. JAMA 2014; 311:74.

9. Available over the counter.
10. SR Smith et al. Multicenter, placebo-controlled trial of lorcaserin for weight management. N Engl J Med 2010; 363:245.
11. 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.
12. PM O’Neil et al. Randomized placebo-controlled clinical trial of lorcaserin for weight loss in type 2 diabetes mellitus: the BLOOM-DM study. Obesity (Silver
Spring) 2012; 20:1426.
13. FL Greenway et al. Effect of naltrexone plus bupropion on weight loss in overweight and obese adults (COR-I): a multicentre, randomised, double-blind,
placebo-controlled, phase 3 trial. Lancet 2010; 376:595.
14. CM Apovian et al. A randomized, phase 3 trial of naltrexone SR/bupropion SR on weight and obesity-related risk factors (COR-II). Obesity (Silver Spring) 2013; 21:935.
15. TA Wadden et al. Weight loss with naltrexone SR/bupropion SR combination therapy as an adjunct to behavior modification: the COR-BMOD trial. Obesity
(Silver Spring) 2011; 19:110.
16. Each pen can deliver doses of 0.6, 1.2, 1.8, 2.4, or 3 mg. Sold in packages containing 3 or 5 multi-dose pens.
17. A Astrup et al. Safety, tolerability and sustained weight loss over 2 years with the once-daily human GLP-1 analog, liraglutide. Int J Obes (Lond) 2012; 36:843.
18. TA Wadden et al. Weight maintenance and additional weight loss with liraglutide after low-calorie-diet-induced weight loss: the SCALE Maintenance
randomized study. Int J Obes (Lond) 2013; 37:1443.

neuropsychiatric reactions have been reported in clinical
trials. Serious hypersensitivity reactions, including
angioedema and anaphylaxis, have occurred in patients
treated with liraglutide. Thyroid C-cell tumors have been
reported in rodents given liraglutide, and the FDA has
required a boxed warning about the risk of thyroid C-cell
tumors in the package insert. The drug is contraindicated
in patients with a personal or family history of medullary
thyroid carcinoma and in those with Multiple Endocrine
Neoplasia syndrome type 2 (MEN 2).
PREGNANCY – Saxenda is contraindicated (category
X) for use during pregnancy because weight loss is not
beneficial for pregnant women and may harm the fetus.
DRUG INTERACTIONS – Liraglutide delays gastric
emptying and may decrease the rate of absorption

of other drugs. For patients who are taking an insulin
secretagogue concurrently, the dose of the insulin
secretagogue should be reduced.
DOSAGE AND ADMINISTRATION – Saxenda is available
in packages containing either three or five 18 mg/3 mL
pre-filled multi-dose pens that deliver doses of 0.6,
90

1.2, 1.8, 2.4, or 3 mg. The starting dose for treatment
of obesity is 0.6 mg injected subcutaneously in the
abdomen, thigh, or upper arm once daily. The dose
is titrated in weekly increments of 0.6 mg up to the
recommended daily dosage of 3 mg once daily (the
recommended daily dose for diabetes is 1.8 mg). If
weight loss of ≥4% is not achieved within 16 weeks of
starting treatment, liraglutide should be discontinued.
CONCLUSION – Use of the glucagon-like peptide-1
(GLP-1) receptor agonist liraglutide (Saxenda) as an adjunct to diet and exercise resulted in placebo-corrected
weight loss of about 6 kg after one year. As with other
drugs approved for this indication, its effectiveness
may wane in the second year and thereafter. Liraglutide
must be injected daily, gastrointestinal adverse effects
are common, and it is expensive. ■
1. Liraglutide (Victoza) for type 2 diabetes. Med Lett Drugs Ther
2010; 52:25.
2. Diet, drugs, and surgery for weight loss. Med Lett Drugs Ther
2015; 57:21.
3. Two drugs for weight loss. Med Lett Drugs Ther 2012; 54:69.
4. Contrave – a combination of bupropion and naltrexone for
weight loss. Med Lett Drugs Ther 2014; 56:112.

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Vol. 57 (1471)

®

Which PPI?

An article published in the New York Times on May 1,
2015 listed the 10 drugs on which Medicare Part D
spent the most in 2013. The most costly ($2.53
billion) was the proton pump inhibitor (PPI) Nexium
(esomeprazole magnesium), which has recently become available generically.
EFFICACY AND TOLERABILITY – PPIs are effective
in relieving symptoms of gastroesophageal reflux
disease (GERD) and in healing erosive esophagitis
and peptic ulcers, and they are generally well
tolerated. There is no convincing evidence that any
one PPI is more effective or better tolerated than
any other.1,2

June 22, 2015

(Plavix, and generics) to its active form. Whether
concurrent use of clopidogrel and omeprazole or
esomeprazole results in clinically significant adverse

cardiovascular outcomes is not clear.3,4 Nevertheless,
in patients taking clopidogrel, it might be prudent to
use pantoprazole, dexlansoprazole, lansoprazole, or
rabeprazole instead.
CONCLUSION — All PPIs appear to be similarly
effective and well tolerated for treatment of peptic
ulcer disease and GERD. Most are available generically
and over the counter for a fraction of the cost of
Nexium or other expensive brand name products. ■

DRUG INTERACTIONS – Omeprazole and esomeprazole are inhibitors of CYP2C19 and can increase
serum concentrations of drugs metabolized by this
pathway, such as diazepam (Valium, and generics)
and phenytoin (Dilantin, and others). They can also
inhibit conversion of the antiplatelet drug clopidogrel

1. Drugs for peptic ulcer disease and GERD. Treat Guidel Med Lett
2014; 12:25.
2. PO Katz et al. Guidelines for the diagnosis and management
of gastroesophageal reflux disease. Am J Gastroenterol 2013;
108:308.
3. LB Gerson. Proton pump inhibitors and potential interactions
with clopidogrel: an update. Curr Gastroenterol Rep 2013;
15:329.
4. SD Bouziana and K  Tziomalos. Clinical relevance of  clopidogrel-proton pump  inhibitors interaction. World J Gastrointest
Pharmacol Ther 2015; 6:17.

Table 1. Oral Proton Pump Inhibitors
Drug

Some Available Formulations

Usual Adult Dosage1,2

Cost3
$222.10

Dexlansoprazole – Dexilant (Takeda)

30, 60 mg DR caps

30-60 mg once/d

Esomeprazole magnesium – generic
Nexium (AstraZeneca)
Nexium 24HR (OTC) (Pfizer)

20, 40 mg DR caps
20, 40 mg DR caps4
22.3 mg DR caps5

20-40 mg once/d

204.50
250.90
16.406

Lansoprazole – generic
Prevacid (Takeda)
Prevacid Solutab (Takeda)

Prevacid 24HR (OTC)7 (Novartis)

15, 30 mg DR caps

15-30 mg once/d

64.60
333.70
333.70
17.806

Omeprazole – generic
Prilosec (AstraZeneca)
Prilosec OTC 7 (AstraZeneca/P&G)

10, 20, 40 mg DR caps
10, 20, 40 mg DR caps4
20 mg DR tabs

20-40 mg once/d

16.30
218.70
16.806

Omeprazole/sodium bicarbonate8 – generic
Zegerid (Salix)
Zegerid OTC (Bayer)

20, 40 mg packets for susp9;

20 mg/1.1 g, 40 mg/1.1 g caps10
20 mg/1.1 g caps10

20-40 mg once/d

344.70
383.40
16.106

Pantoprazole – generic
Protonix (Pfizer)

20, 40 mg DR tabs
20, 40 mg DR tabs4

40 mg once/d

6.40
274.20

Rabeprazole – generic
Aciphex (Eisai)
Aciphex Sprinkle (Eisai)

20 mg DR tabs

20 mg once/d

52.40
419.70

699.80

15, 30 mg ODT
15 mg DR caps

5, 10 mg DR sprinkle caps11

DR = delayed-release; OTC = over the counter; ODT = orally disintegrating tablets
1. The lower end of the range is generally used for initial treatment of GERD. Higher or more frequent doses may be needed for patients with erosive
esophagitis, peptic ulcer disease, hypersecretory conditions such as Zollinger-Ellison syndrome, or for treatment of Helicobacter pylori infection.
2. PPIs are generally taken 30-60 minutes before the first meal of the day. Taking one before the evening meal or taking the drug twice daily may be more
effective for nocturnal acid control. PPIs should generally be swallowed whole and should not be crushed or chewed. Omeprazole/sodium bicarbonate
(Zegerid) should be taken on an empty stomach at least 1 hour before a meal. Dexlansoprazole (Dexilant) can be taken with or without food.
3. Approximate WAC for 30 days’ treatment with the lowest usual adult dosage. WAC = wholesaler acquisition cost or manufacturer’s published price to
wholesalers; WAC represents a published catalogue or list price and may not represent an actual transactional price. Source: AnalySource® Monthly. June 5,
2015. Reprinted with permission by First Databank, Inc. All rights reserved. ©2015. www.fdbhealth.com/policies/drug-pricing-policy.
4. Also available in delayed-release powder or granules for suspension.
5. Equivalent to 20 mg of esomeprazole.
6. Cost for 28 tablets or capsules.
7. Also available generically.
8. Immediate-release formulation that contains sodium bicarbonate as a buffer; it should be used with caution in patients on a low-sodium diet.
9. Each packet also contains 1680 mg of sodium bicarbonate.
10. Each capsule contains 1.1 g of sodium bicarbonate; therefore, two 20-mg caps are not equivalent to one 40-mg cap.
11. Contents of the capsule should be sprinkled on soft food or liquid and taken within 15 minutes.

91


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Droxidopa (Northera) for Neurogenic
Orthostatic Hypotension

The FDA has approved droxidopa (Northera –
Lundbeck) for oral treatment of adults with symptomatic
neurogenic orthostatic hypotension (NOH) caused
by primary autonomic failure (Parkinson's disease,
multiple system atrophy, or pure autonomic failure),
dopamine beta-hydroxylase deficiency, or nondiabetic
autonomic neuropathy. This is the first approval for
droxidopa in the US. It has been available in Japan for
use in NOH since 1989.
Pronunciation Key
Droxidopa: drox" i doe' pa
Northera: nor ther ah

THE DISORDER — NOH occurs in many neurodegenerative and metabolic diseases and is also
associated with aging. Lightheadedness and dizziness
are common symptoms, but weakness, fatigue, and
cognitive dysfunction also occur.
STANDARD TREATMENT — Lifestyle modifications
such as avoiding rapid changes in posture, increasing
fluid and salt intake, and wearing compression
stockings can be helpful, but pharmacotherapy may
be necessary for patients with persistent symptoms.
Midodrine, an alpha1-selective adrenergic agonist,

was approved earlier for treatment of severe
symptomatic orthostatic hypotension based on its
effectiveness in increasing standing blood pressure,
but symptomatic or functional improvement in
patients with NOH has not been documented.
Other drugs commonly used (off-label) to treat
symptomatic NOH include fludrocortisone and
pyridostigmine.1
MECHANISM OF ACTION — Droxidopa is a prodrug of
norephinephrine. Norepinephrine increases peripheral
vascular resistance.
CLINICAL STUDIES — Approval of droxidopa was
based on the results of a randomized, doubleblind, placebo-controlled trial in 171 patients with
symptomatic NOH associated with Parkinson’s
disease. After titration to an optimized dosage of
droxidopa and one week of maintenance treatment,
the mean patient-reported symptom score for
dizziness/lightheadedness decreased (from a
baseline of 5.1 on a scale of 0-10) by 2.3 points with
droxidopa compared to 1.3 points with placebo, a
statistically significant difference. About 40% of
patients taking droxidopa required the maximum
dosage (600 mg three times daily). The mean
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Vol. 57 (1471)

June 22, 2015

Table 1. Pharmacology

Class

Norepinephrine prodrug

Route

Oral

Formulation

100, 200, 300 mg capsules

Tmax

1-4 hrs (delayed by ~2 hrs with a high-fat meal)

Distribution

Crosses the blood-brain barrier

Metabolism

Via catecholamine system; by dopa
decarboxylase to norepinephrine, by COMT
to 3-OM-DOPS, and by DOPS aldolase to
protocatechualdehyde

Half-life

~2.5 hrs

Excretion

Urine (~75%)

increase in standing systolic blood pressure was
6.4 mm Hg with droxidopa compared to 0.7 mm Hg
with placebo. Symptom scores after 2, 4, and 8 weeks
of maintenance treatment were not significantly
different in the droxidopa and placebo groups, but
the patients taking droxidopa reported fewer falls.2
In an earlier multicenter trial, 162 patients with
symptomatic NOH who responded to droxidopa during
an initial dose-titration period were randomized, after
a 7-day washout period, to droxidopa or placebo for
a 7-day double-blind treatment period.3 The FDA
found some of the results implausible, and the results
for only 122 patients are summarized in the package
insert. The mean dizziness/lightheadedness score
for these patients decreased by only 0.7 points more
with droxidopa than with placebo, which was not a
statistically significant difference.
A withdrawal study randomized 101 patients with
NOH who had been titrated to an optimized dose of
droxidopa and treated for 1-3 weeks to continue
droxidopa or switch to placebo for 14 days. Mean
dizziness/lightheadedness scores increased in both
groups and were not significantly different from each
other at the end of the study.4
ADVERSE EFFECTS — In short-term clinical trials,

headache, dizziness, nausea, and hypertension
were reported in >5% of patients taking droxidopa
and with at least a 3% higher incidence than with
placebo. Droxidopa may cause or exacerbate supine
hypertension. Postmarketing reports in Japanese
patients taking droxidopa have described a
symptom complex resembling neuroleptic malignant
syndrome. Droxidopa may exacerbate existing
ischemic heart disease, arrhythmias, and congestive
heart failure.
PREGNANCY — Droxidopa is classified as category C
(fetal and maternal toxicity in animals; no adequate
studies in women) for use during pregnancy.


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DRUG INTERACTIONS — Concurrent administration
of droxidopa and other drugs that increase
blood pressure could increase the risk of supine
hypertension. Concomitant use of the peripheral
dopa decarboxylase inhibitor carbidopa, particularly
at high doses, could prevent conversion of droxidopa
to norepinephrine outside the CNS. In clinical trials,
concomitant administration of levodopa/carbidopa
decreased the clearance of droxidopa, but did not
increase the incidence of adverse effects.
DOSAGE, ADMINISTRATION, AND COST — The recommended starting dosage of droxidopa is 100 mg

three times daily (on arising in the morning, at midday,
and in the late afternoon at least 3 hours before
bedtime). The dose can be increased in increments
of 100 mg three times daily every 24-48 hours to
a maximum of 600 mg three times daily. The drug
should be administered consistently either with or
without food.
A boxed warning in the labeling states that supine
blood pressure should be monitored before starting
droxidopa and during treatment, particularly after
increasing the dose. Patients should be told to elevate
the head of the bed when resting or sleeping.
The cost of a 30-day supply of Northera ranges,
depending on the dose, from $1548 to $9291,
compared to about $272 for generic midodrine 10 mg
three times daily.5
CONCLUSION — Droxidopa (Northera) appears to
be only marginally effective for treatment of the
symptoms of neurogenic orthostatic hypotension, and
it is expensive. It may decrease the risk of falling in
some patients with Parkinson’s disease. ■
1. MJ Berger and K Kimpinski. A practical guide to the treatment
of neurogenic orthostatic hypotension. Can J Neurol Sci 2014;
41:156.
2. RA Hauser et al. Droxidopa for the short-term treatment of
symptomatic neurogenic orthostatic hypotension in Parkinson’s disease (nOH306B). Mov Disord 2015; 30:646.
3. H Kaufmann et al. Droxidopa for neurogenic orthostatic hypotension: a randomized, placebo-controlled, phase 3 trial. Neurology 2014; 83:328.
4. I Biaggioni et al. Randomized withdrawal study of patients with
symptomatic neurogenic orthostatic hypotension responsive
to droxidopa. Hypertension 2015; 65:101.

5. Approximate WAC. WAC = wholesaler acquisition cost or manufacturer’s published price to wholesalers; WAC represents a
published catalogue or list price and may not represent an actual transactional price. Source: AnalySource® Monthly. June
5, 2015. Reprinted with permission by First Databank, Inc. All
rights reserved. ©2015. www.fdbhealth.com/policies/drugpricing-policy.

Vol. 57 (1471)

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June 22, 2015

Bellafill for Acne Scars

Bellafill (Suneva), a dermal filler approved earlier for
correction of nasolabial folds, has now also been
approved by the FDA for correction of moderate to
severe, atrophic, distensible facial acne scars on the
cheek in adults ≥21 years old. It is the only dermal filler
approved in the US for correction of facial acne scars.
MECHANISM OF ACTION — Bellafill contains 80%
bovine collagen solution (including 0.3% lidocaine) and
20% non-resorbable polymethylmethacrylate (PMMA)
microspheres. The collagen adds volume below pitted
acne scars to lift them to the level of the surrounding
skin, while the PMMA microspheres, according to
the manufacturer, create a matrix that supports
endogenous collagen production and provides longterm structural support.

A CLINICAL STUDY — Approval of Bellafill for atrophic
facial acne scars was based on a double-blind trial in

147 patients with ≥4 moderate to severe atrophic facial
acne scars. Patients were randomized to an injection
with ArteFill (which was rebranded as Bellafill in 2014) or
saline, with a touch-up injection 4 weeks later if needed.
The primary endpoint, at least a 2-point improvement on
the 4-point Acne Scar Rating Scale in ≥50% of scars at 6
months, occurred in 64% of patients treated with Bellafill
and in 33% of those treated with saline. Response rates
were maintained through 12 months.1
ADVERSE EFFECTS — Swelling, redness, pain, bruising, lumps/bumps, itching, and discoloration at the
treatment site can occur, but usually resolve within
7 days. Bellafill should not be used in patients with
bleeding disorders or in those with known susceptibility to keloid formation or hypertrophic scarring.
As with other long-acting dermal fillers, granulomas
can appear days to years after injection.2 The FDA
recently warned that serious injuries including vision
impairment, blindness, stroke, and tissue necrosis can
occur from unintentional injection of dermal fillers into
facial blood vessels.3
DOSAGE, ADMINISTRATION, AND COST — Bellafill is
available in a sterile 0.8-mL single-use syringe with a
26-gauge needle. Skin allergy testing should be done
before administration of the drug. Bellafill should be
injected into the deep dermis or dermal/subdermal
junction. If the desired result is not achieved, one or
two touch-up injections can be given at least 2 weeks
apart. The safety of injecting more than 3.5 mL per
treatment site or more than 8.9 mL overall has not been
established. The cost of one syringe is about $350.4
93

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CONCLUSION — Bellafill appears to be cosmetically
effective in improving moderate to severe atrophic
facial acne scars. Its safety remains to be established;
as with other dermal fillers, granulomas can appear
days to years after injection, and serious injuries have
occurred from unintentional injection of dermal fillers
into facial blood vessels. ■
1. J Karnik et al. A double-blind, randomized, multicenter, controlled trial of suspended polymethylmethacrylate microspheres for the correction of atrophic facial acne scars. J Am
Acad Dermatol 2014; 71:77.
2. SM Daines and EF Williams. Complications associated with injectable soft-tissue fillers: a 5-year retrospective review. JAMA
Facial Plast Surg 2013; 15:226.
3. FDA. Unintentional injection of soft tissue filler into blood
vessels in the face: FDA safety communication. Available at:
/>ucm448255.htm. Accessed June 11, 2015.
4. Cost according to the manufacturer.

IN BRIEF

Ketoacidosis with SGLT2 Inhibitors
The FDA has warned that use of an SGLT2 (sodiumglucose co-transporter 2) inhibitor for treatment of
type 2 diabetes may lead to ketoacidosis.1 Three
SGLT2 inhibitors, canagliflozin (Invokana, Invokamet),
dapagliflozin (Farxiga, Xigduo XR), and empagliflozin
(Jardiance, Glyxambi), are approved for treatment of type

2 diabetes in the US. Between March 2013 and June 2014,
20 cases of ketoacidosis requiring emergency room visits
or hospitalization were reported in patients who had
recently started taking an SGLT2 inhibitor; the median
time to onset of symptoms after initiation of therapy was
2 weeks (range 1-175 days). SGLT2 inhibitors decrease
renal glucose reabsorption and increase urinary glucose
excretion, resulting in a reduction in blood glucose levels.
The mechanism by which these drugs could cause
ketoacidosis has not been established.
Diabetic ketoacidosis (DKA) occurs primarily in patients
with type 1 diabetes; it is characterized by elevated blood
glucose levels (usually ≥250 mg/dL), a high anion gap,
glucosuria, and ketonuria.2 Unlike typical cases of DKA,
most ketoacidosis cases associated with SGLT2 inhibitors
have occurred in patients with type 2 diabetes, and in
some patients glucose levels were <200 mg/dL. Only
half of the 20 cases were associated with a recognizable
DKA-precipitating factor, such as infection, reduced
caloric intake, or reduced insulin dose. Other factors that
may contribute to the development of high anion gap
metabolic acidosis, such as hypovolemia, hypoxemia,
reduced oral intake, acute renal impairment, and a history
of alcohol use, were identified in some patients.1 ■
View our detailed online table: SGLT-2 Inhibitors
1. FDA drug safety communication: FDA warns that SGLT2 inhibitors for diabetes may result in a serious condition of too much
acid in the blood. Available at: www.fda.gov/Drugs/DrugSafety/
ucm446845.htm. Accessed June 11, 2015.
2. AE Kitabchi et al. Hyperglycemic crises in adult patients with
diabetes. Diabetes Care 2009; 32:1335.

94

Vol. 57 (1471)

June 22, 2015

Addendum: Nivolumab (Opdivo) for Metastatic
Melanoma and Metastatic NSCLC
After our article on nivolumab (Opdivo – BMS) for
treatment of metastatic melanoma and metastatic
squamous non-small cell lung cancer (NSCLC) was
published in the most recent issue of The Medical
Letter (June 8, 2015),1 some new data became available
supporting the efficacy of the drug in previously untreated
melanoma and previously treated nonsquamous NSCLC.
MELANOMA – In a double-blind trial, 945 patients
with previously untreated, unresectable stage III or IV
melanoma were randomized to receive ipilimumab,
nivolumab, or combination therapy with ipilimumab and
nivolumab. Progression-free survival, a primary endpoint,
improved by 43% with nivolumab (median 6.9 months)
and by 58% with combination therapy (median 11.5
months), compared to ipilimumab (median 2.9 months).
In patients with tumors that expressed the programmed
death ligand 1 (PD-L1) on ≥5% of cells, median
progression-free survival was similar in the nivolumab
and combination groups (both 14.0 months); in those
with tumors that expressed PD-L1 on <5% of cells, it was
5.3 months with nivolumab alone and 11.2 months with

both drugs. Rates of complete or partial response were
19.0% with ipilimumab, 43.7% with nivolumab, and 57.6%
with combination therapy. At least one severe (grade
3-4) drug-related adverse effect occurred in 27.3% of
patients receiving ipilimumab, 16.3% of those receiving
nivolumab, and 55.0% of those receiving both drugs.2
NONSQUAMOUS NSCLC – In an open-label trial (available only as an abstract), 582 patients with advanced
nonsquamous NSCLC that had progressed during or after
treatment with a platinum doublet-based regimen (and,
if appropriate, a kinase inhibitor) were randomized to receive nivolumab or docetaxel until disease progression or
unacceptable toxicity occurred. Nivolumab significantly
improved overall survival, the primary endpoint, by 27%
compared to docetaxel (median 12.2 vs 9.4 months).
Survival rates in the two groups were similar in patients
with tumors expressing PD-L1 on <1% of cells, but in
patients with tumors expressing PD-L1 on ≥1%, ≥5%, and
≥10% of cells, nivolumab improved overall survival by
41%, 57%, and 60%, respectively, compared to docetaxel.
Patients receiving nivolumab were significantly more
likely to have an objective response (19.2% vs 12.4%).
Severe (grade 3+) drug-related adverse effects occurred
in 10.5% of patients receiving nivolumab and in 53.7% of
those receiving docetaxel.3 ■
1. Nivolumab (Opdivo) for metastatic melanoma and metastatic
NSCLC. Med Lett Drugs Ther 2015; 57:85.
2. J Larkin et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med 2015 May 31
(epub).
3. L Paz-Ares et al. Phase III, randomized trial (CheckMate 057) of
nivolumab (NIVO) versus docetaxel (DOC) in advanced non-squamous cell (non-SQ) non-small cell lung cancer (NSCLC). J Clin Oncol 2015; 33 (suppl; abstr LBA109). Available at: abstracts.asco.
org/156/AbstView_156_154634.html. Accessed June 11, 2015.

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4.
Discuss the FDA warning about the risk of ketoacidosis in patients taking SGLT2 inhibitors.
5.
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Issue 1471 Questions

(Correspond to questions #121-130 in Comprehensive Exam #72, available July 2015)
6. Droxidopa is a prodrug of:
a. levodopa
b. carbidopa
c. epinephrine

d. norepinephrine

Liraglutide (Saxenda) for Weight Loss
1. Liraglutide is administered:
a. orally
b. subcutaneously
c. intramuscularly
d. intravenously
2. Mean weight loss with the recommended dose of liraglutide for
chronic weight management has been about:
a. <2%
b. 2-4%
c. 6-8%
d. 8-10%
3. A 28-year-old woman in good health with a BMI of 27 asks you
if she should take Saxenda to lose weight. You could tell her
that:
a. the drug is not recommended for adults with a BMI
<30 unless they have a weight-related disease such as
diabetes
b. there are some concerns about its safety, particularly that
it may cause thyroid C-cell tumors
c. it costs more than any other drug approved by the FDA for
long-term weight loss
d. all of the above
Which PPI?
4. Compared to other PPIs, esomeprazole is:
a. more effective
b. better tolerated
c. less likely to interact with other drugs

d. none of the above
Droxidopa (Northera) for Neurogenic Orthostatic Hypotension
5. Droxidopa:
a. is the first drug to be approved in the US for treatment of
orthostatic hypotension
b. is a new drug
c. has been available in Japan for NOH since 1989
d. was associated with limb-shortening fetal deformities in
the UK

7. Droxidopa has been reported to:
a. reduce falls in patients with Parkinson’s disease
b. reduce relapses in patients with multiple sclerosis
c. exacerbate diabetes
d. all of the above
Bellafill for Acne Scars
8. In the double-blind trial on which the approval of Bellafill was
based, 64% of patients treated with the active drug achieved at
least a 2-point improvement on the Acne Scar Rating Scale in
≥50% of acne scars, the primary endpoint. What percentage of
those treated with saline achieved the primary endpoint?
a. 0%
b. 10%
c. 14%
d. 33%
In Brief: Ketoacidosis with SGLT2 Inhibitors
9. In the cases of ketoacidosis reported in patients taking an
SGLT2 inhibitor:
a. all patients had blood glucose levels >250 mg/dL
b. symptoms developed after a median of 2 weeks

c. all patients had type 1 diabetes
d. none of the above
Addendum: Nivolumab (Opdivo) for Metastatic Melanoma and
Metastatic NSCLC
10. In the trial in patients with previously untreated melanoma, the
combination of nivolumab and ipilimumab:
a. improved progression-free survival more than either drug
alone
b. was more likely to induce a complete or partial response
than either drug alone
c. was more toxic than either drug used alone
d. all of the above

ACPE UPN: Per Issue Exam: 0379-0000-15-471-H01-P; Release: June 22, 2015, Expire: June 22, 2016
Comprehensive Exam 72: 0379-0000-15-072-H01-P; Release: July 2015, Expire: July 2016

EDITOR IN CHIEF: Mark Abramowicz, M.D.; EXECUTIVE EDITOR: Gianna Zuccotti, M.D., M.P.H., F.A.C.P., Harvard Medical School; EDITOR: Jean-Marie Pflomm, Pharm.D.;
ASSISTANT EDITORS, DRUG INFORMATION: Susan M. Daron, Pharm.D., Corinne Z. Morrison, Pharm.D., Michael P. Viscusi, Pharm.D.; CONSULTING EDITORS: Brinda M. Shah, Pharm.D.,
F. Peter Swanson, M.D; SENIOR ASSOCIATE EDITOR: Amy Faucard
CONTRIBUTING EDITORS: Carl W. Bazil, M.D., Ph.D., Columbia University College of Physicians and Surgeons; Vanessa K. Dalton, M.D., M.P.H., University of Michigan Medical
School; Eric J. Epstein, M.D., Albert Einstein College of Medicine; Jane P. Gagliardi, M.D., M.H.S., F.A.C.P., Duke University School of Medicine; Jules Hirsch, M.D., Rockefeller
University; David N. Juurlink, BPhm, M.D., Ph.D., Sunnybrook Health Sciences Centre; Richard B. Kim, M.D., University of Western Ontario; Hans Meinertz, M.D., University Hospital,
Copenhagen; Franco M. Muggia, M.D., New York University Medical Center; Sandip K. Mukherjee, M.D., F.A.C.C., Yale School of Medicine; Dan M. Roden, M.D., Vanderbilt University
School of Medicine; Esperance A.K. Schaefer, M.D., M.P.H., Harvard Medical School; F. Estelle R. Simons, M.D., University of Manitoba; Neal H. Steigbigel, M.D., New York
University School of Medicine; Arthur M. F. Yee, M.D., Ph.D., F.A.C.R., Weill Medical College of Cornell University
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Arthur Kallet and Harold Aaron, M.D.

Copyright and Disclaimer: The Medical Letter, Inc. is an independent nonprofit organization that provides healthcare professionals with unbiased drug prescribing recommendations. The editorial
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