...p 89p 91 Droxidopa Northera for Neurogenic Orthostatic Hypotension ...p 92 Bellafi ll for Acne Scars ...p 93 In Brief: Ketoacidosis with SGLT2 Inhibitors ...p 94 Addendum: Nivolumab O
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IN THIS ISSUE
ISSUE
1433
Volume 56
Published by The Medical Letter, Inc • A Nonprofi t Organization
ISSUE No
1471 Liraglutide (Saxenda) for Weight Loss Which PPI? p 89p 91
Droxidopa (Northera) for Neurogenic Orthostatic Hypotension p 92
Bellafi ll for Acne Scars p 93
In Brief: Ketoacidosis with SGLT2 Inhibitors .p 94
Addendum: Nivolumab (Opdivo) for Metastatic Melanoma and Metastatic NSCLC p 94
on Drugs and Therapeutics
Adapted for Canada Objective Drug Reviews Since 1959
Trang 289
on Drugs and Therapeutics
Objective Drug Reviews Since 1959
Take CME Exams
ISSUE
1433
Volume 56
ISSUE No
1471
ALSO IN THIS ISSUE Which PPI? p 91
Droxidopa (Northera) for Neurogenic Orthostatic Hypotension p 92
Bellafi ll 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 effi cacy, adverse
effects, low adherence rates, and regain of weight with
drug cessation.2 Drugs approved by the FDA for
long-term 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
fi xed-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
Table 1 Liraglutide Clinical Trials 1
Mean % of Patients
Study Design Drug Regimen Loss (%) Loss ≥5% Patients with Diabetes
RA DeFronzo et al 2,3 Liraglutide 3 mg 5.9% 49.9%
56 weeks (n=846) Liraglutide 1.8 mg 4 4.6% 35.6%
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 Loss 6
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 https://clinicaltrials.gov Ac-cessed 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 fi rst 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.
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
ADVERSE EFFECTS – Common adverse effects of
liraglutide include nausea, diarrhea, constipation, vom-iting, 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
Trang 3neuropsychiatric 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
benefi cial 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 fi ve 18 mg/3 mL
pre-fi lled multi-dose pens that deliver doses of 0.6,
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
ad-junct 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
Table 2 Some FDA-Approved Drugs for Long-Term Treatment of Obesity 1
Some Available Usual Mean Drug Formulations Adult Dosage Weight Loss 2 Cost 3
Sympathomimetic Amine/Antiepileptic Combination
Phentermine/topiramate ER – Qsymia (Vivus) 7.5/46, 15/92 mg ER caps 4 7.5/46-15/92 mg once/d 4.1-10.7 kg 5-7 $170.70
Lipase Inhibitor
Orlistat – Xenical (Genentech) 120 mg caps 120 mg tid 2.5-3.4 kg 8 512.10
Serotonin Receptor Agonist
Lorcaserin – Belviq (Eisai) 10 mg tabs 10 mg bid 2.9-3.6 kg 10-12 199.50
Opioid Antagonist/Antidepressant Combination
Naltrexone/bupropion – Contrave 8/90 mg ER tabs 16/180 mg bid 3.7-5.2 kg 7,13-15 199.50 (Orexigen/Takeda)
GLP-1 Receptor Agonist
Liraglutide – Saxenda (Novo Nordisk) 18 mg/3 mL prefi lled pen 16 3 mg SC once/d 5.8-5.9 kg 17,18 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 modifi cations 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 modifi cation: 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.
Trang 4Which 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
be-come 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
DRUG INTERACTIONS – Omeprazole and
esomep-razole 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
Table 1 Oral Proton Pump Inhibitors
Drug Some Available Formulations Usual Adult Dosage 1,2 Cost 3
Dexlansoprazole – Dexilant (Takeda) 30, 60 mg DR caps 30-60 mg once/d $222.10 Esomeprazole magnesium – generic 20, 40 mg DR caps 20-40 mg once/d 204.50
Nexium 24HR (OTC) (Pfi zer) 22.3 mg DR caps 5 16.40 6
Lansoprazole – generic 15, 30 mg DR caps 15-30 mg once/d 64.60
Prevacid 24HR (OTC)7 (Novartis) 15 mg DR caps 17.80 6
Omeprazole – generic 10, 20, 40 mg DR caps 20-40 mg once/d 16.30
Prilosec (AstraZeneca) 10, 20, 40 mg DR caps 4 218.70
Omeprazole/sodium bicarbonate 8 – generic 20, 40 mg packets for susp 9 ; 20-40 mg once/d 344.70
Zegerid (Salix) 20 mg/1.1 g, 40 mg/1.1 g caps 10 383.40
Pantoprazole – generic 20, 40 mg DR tabs 40 mg once/d 6.40
Rabeprazole – generic 20 mg DR tabs 20 mg once/d 52.40
Aciphex Sprinkle (Eisai) 5, 10 mg DR sprinkle caps 11 699.80
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 fi rst 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.
(Plavix, and generics) to its active form Whether
concurrent use of clopidogrel and omeprazole or esomeprazole results in clinically signifi cant 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 ■
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 clopido-grel-proton pump inhibitors interaction World J Gastrointest Pharmacol Ther 2015; 6:17.
Trang 5Droxidopa (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 defi ciency, or nondiabetic
autonomic neuropathy This is the fi rst 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
neuro-degenerative 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 modifi cations
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,
double-blind, 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
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
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 signifi cant 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 signifi cantly 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 classifi ed as category C
(fetal and maternal toxicity in animals; no adequate studies in women) for use during pregnancy
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%)
Trang 6DRUG 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
rec-ommended 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
Parkin-son’s disease (nOH306B) Mov Disord 2015; 30:646.
3 H Kaufmann et al Droxidopa for neurogenic orthostatic
hypo-tension: a randomized, placebo-controlled, phase 3 trial
Neu-rology 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
man-ufacturer’s published price to wholesalers; WAC represents a
published catalogue or list price and may not represent an
ac-tual 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.
Bellafi ll (Suneva), a dermal fi ller 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 fi ller approved in the US for correction of facial acne scars
MECHANISM OF ACTION — Bellafi ll 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 long-term structural support
A CLINICAL STUDY — Approval of Bellafi ll 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 Bellafi ll 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 Bellafi ll
and in 33% of those treated with saline Response rates were maintained through 12 months.1
ADVERSE EFFECTS — Swelling, redness, pain,
bruis-ing, lumps/bumps, itchbruis-ing, and discoloration at the treatment site can occur, but usually resolve within
7 days Bellafi ll should not be used in patients with
bleeding disorders or in those with known suscepti-bility to keloid formation or hypertrophic scarring
As with other long-acting dermal fi llers, 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 fi llers into facial blood vessels.3
DOSAGE, ADMINISTRATION, AND COST — Bellafi ll 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 Bellafi ll 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
Bellafi ll for Acne Scars
▶
Trang 7IN BRIEF
Ketoacidosis with SGLT2 Inhibitors
The FDA has warned that use of an SGLT2
(sodium-glucose co-transporter 2) inhibitor for treatment of
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 identifi ed in some patients.1 ■
View our detailed online table: SGLT-2 Inhibitors
1 FDA drug safety communication: FDA warns that SGLT2
inhibi-tors 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.
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
supporting the effi cacy 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
NONSQUAMOUS NSCLC – In an open-label trial
(avail-able 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 re-ceive nivolumab or docetaxel until disease progression or unacceptable toxicity occurred Nivolumab signifi cantly 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 signifi cantly 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 mono-therapy 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-squa-mous cell (non-SQ) non-small cell lung cancer (NSCLC) J Clin On-col 2015; 33 (suppl; abstr LBA109) Available at: abstracts.asco org/156/AbstView_156_154634.html Accessed June 11, 2015.
1 J Karnik et al A double-blind, randomized, multicenter,
con-trolled trial of suspended polymethylmethacrylate
micro-spheres for the correction of atrophic facial acne scars J Am
Acad Dermatol 2014; 71:77.
2 SM Daines and EF Williams Complications associated with
in-jectable soft-tissue fi llers: a 5-year retrospective review JAMA
Facial Plast Surg 2013; 15:226
3 FDA Unintentional injection of soft tissue fi ller into blood
vessels in the face: FDA safety communication Available at:
http://www.fda.gov/MedicalDevices/Safety/AlertsandNotices/
ucm448255.htm Accessed June 11, 2015.
4 Cost according to the manufacturer.
CONCLUSION — Bellafi ll appears to be cosmetically
effective in improving moderate to severe atrophic
facial acne scars Its safety remains to be established;
as with other dermal fi llers, granulomas can appear
days to years after injection, and serious injuries have
occurred from unintentional injection of dermal fi llers
into facial blood vessels ■
Trang 8Questions start on next page
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1 Review the effi cacy and safety of liraglutide (Saxenda) for chronic weight management.
2 Discuss the comparative effi cacy and tolerability of proton pump inhibitors.
3 Review the effi cacy and safety of droxidopa (Northera) for neurogenic orthostatic hypotension.
4 Discuss the FDA warning about the risk of ketoacidosis in patients taking SGLT2 inhibitors.
5 Review the new data supporting the effi cacy of nivolumab (Opdivo) for treatment of metastatic melanoma and NSCLC
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Trang 9The Medical Letter ®
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DO NOT FAX OR MAIL THIS EXAM
To take CME exams and earn credit, go to:
medicalletter.org/CMEstatus 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
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
Bellafi ll for Acne Scars
8 In the double-blind trial on which the approval of Bellafi ll 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
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 fi rst 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
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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