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 Important Copyright Message FORWARDING OR COPYING IS A VIOLATION OF U.S AND INTERNATIONAL COPYRIGHT LAWS The Medical Letter, Inc publications are protected by U.S and international copyright laws Forwarding, copying or any distribution of this material is prohibited Sharing a password with a non-subscriber or otherwise making the contents of this site available to third parties is strictly prohibited By accessing and reading the attached content I agree to comply with U.S and international copyright laws and these terms and conditions of The Medical Letter, Inc For further information click: Subscriptions, Site Licenses, Reprints or call customer service at: 800-211-2769 Published by The Medical Letter, Inc • A Nonprofit Organization The Medical Letter publications are protected by US and international copyright laws Forwarding, copying or any other distribution of this material is strictly prohibited For further information call: 800-211-2769 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 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 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 summarizes the results of some randomized trials of liraglutide for weight loss in overweight or obese adults Table 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 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 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 mg 6.2%8 50.5%8 56 weeks (n=422) Placebo 0.2%8 21.8%8 In addition to diet and exercise in adults with a BMI ≥30 or a BMI ≥27 with a weight-related comorbidity 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 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 Effect of liraglutide on body weight in overweight or obese subjects with type diabetes: SCALE Diabetes Available at https://clinicaltrials.gov Accessed June 11, 2015 FDA-approved as a titration dose, but not for maintenance X Pi-Sunyer et al N Engl J Med 2015; 373:11 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 TA Wadden et al Int J Obes (Lond) 2013; 37:1443 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 Published by The Medical Letter, Inc • A Nonprofit Organization The Medical Letter Vol 57 (1471) ® June 22, 2015 Table 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 mg SC once/d 5.8-5.9 kg17,18 1068.30 ER = extended-release Weight loss drugs, including over-the-counter medications, are not recommended for use during pregnancy Placebo-corrected weight loss above diet and lifestyle modifications alone after one year 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 Also available in 3.75/23 mg and 11.25/69 mg capsules, which are intended for use only during titration DB Allison et al Controlled-release phentermine/topiramate in severely obese adults: a randomized controlled trial (EQUIP) Obesity (Silver Spring) 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 trial Lancet 2011; 377:1341 The range includes weight loss observed with titration and maintenance dosages SZ Yanovski and JA Yanovski Long-term drug treatment for obesity: a systematic and clinical review JAMA 2014; 311:74 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 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 trial Lancet 2010; 376:595 14 CM Apovian et al A randomized, phase 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 mg Sold in packages containing or multi-dose pens 17 A Astrup et al Safety, tolerability and sustained weight loss over 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 (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 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 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 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 ■ Liraglutide (Victoza) for type diabetes Med Lett Drugs Ther 2010; 52:25 Diet, drugs, and surgery for weight loss Med Lett Drugs Ther 2015; 57:21 Two drugs for weight loss Med Lett Drugs Ther 2012; 54:69 Contrave – a combination of bupropion and naltrexone for weight loss Med Lett Drugs Ther 2014; 56:112 The Medical Letter ▶ 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 Drugs for peptic ulcer disease and GERD Treat Guidel Med Lett 2014; 12:25 PO Katz et al Guidelines for the diagnosis and management of gastroesophageal reflux disease Am J Gastroenterol 2013; 108:308 LB Gerson Proton pump inhibitors and potential interactions with clopidogrel: an update Curr Gastroenterol Rep 2013; 15:329 SD Bouziana and K Tziomalos Clinical relevance of clopidogrel-proton pump inhibitors interaction World J Gastrointest Pharmacol Ther 2015; 6:17 Table 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 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 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 hour before a meal Dexlansoprazole (Dexilant) can be taken with or without food 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 Also available in delayed-release powder or granules for suspension Equivalent to 20 mg of esomeprazole Cost for 28 tablets or capsules Also available generically Immediate-release formulation that contains sodium bicarbonate as a buffer; it should be used with caution in patients on a low-sodium diet 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 The Medical Letter ▶ ® 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 92 Vol 57 (1471) June 22, 2015 Table 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 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 The Medical Letter ® 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 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 ■ MJ Berger and K Kimpinski A practical guide to the treatment of neurogenic orthostatic hypotension Can J Neurol Sci 2014; 41:156 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 H Kaufmann et al Droxidopa for neurogenic orthostatic hypotension: a randomized, placebo-controlled, phase trial Neurology 2014; 83:328 I Biaggioni et al Randomized withdrawal study of patients with symptomatic neurogenic orthostatic hypotension responsive to droxidopa Hypertension 2015; 65:101 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) ▶ 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 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 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 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 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 The Medical Letter ® 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 ■ 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 SM Daines and EF Williams Complications associated with injectable soft-tissue fillers: a 5-year retrospective review JAMA Facial Plast Surg 2013; 15:226 FDA Unintentional injection of soft tissue filler into blood vessels in the face: FDA safety communication Available at: http://www.fda.gov/MedicalDevices/Safety/AlertsandNotices/ ucm448255.htm Accessed June 11, 2015 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 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 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 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 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 diabetes, and in some patients glucose levels were