The Medical Letter ® on Drugs and Therapeutics Volume 58 ISSUE ISSUE No 1433 1499 Volume 56 July 18, 2016 IN THIS ISSUE SGLT2 Inhibitors and Renal Function p 91 Onzetra Xsail — Sumatriptan Nasal Powder p 92 Buprenorphine Implants (Probuphine) for Opioid Dependence p 94 Brivaracetam (Briviact) for Epilepsy p 95 Asfotase Alfa (Strensiq) for Hypophosphatasia online only In Brief: Cabozantinib (Cabometyx) for Advanced Renal Cell Carcinoma online only 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 Volume 58 July 18, 2016 Take CME Exams ISSUE ISSUE No 1433 1499 Volume 56 ▶ ALSO IN THIS ISSUE Onzetra Xsail — Sumatriptan Nasal Powder p 92 Buprenorphine Implants (Probuphine) for Opioid Dependence p 94 Brivaracetam (Briviact) for Epilepsy p 95 Asfotase Alfa (Strensiq) for Hypophosphatasia online only In Brief: Cabozantinib (Cabometyx) for Advanced Renal Cell Carcinoma online only SGLT2 Inhibitors and Renal Function At the same time that the FDA announced it was strengthening existing warnings about the risk of acute kidney injury in patients with type diabetes treated with the sodium-glucose co-transporter (SGLT2) inhibitors canagliflozin (Invokana, and others) and dapagliflozin (Farxiga, and others),1 a study was published showing that the third SGLT2 inhibitor, empagliflozin (Jardiance, and others), slowed the progression of renal dysfunction in patients with type diabetes.2 SGLT2 INHIBITION — SGLT2, a membrane protein expressed mainly in the kidney, transports filtered glucose from the proximal renal tubule into tubular epithelial cells SGLT2 inhibitors decrease renal glucose and sodium reabsorption and increase urinary glucose excretion, resulting in lower blood glucose levels and a modest reduction in HbA1c These drugs also increase urinary sodium excretion, cause weight loss, and lower blood pressure View our detailed online table: SGLT-2 Inhibitors ADVERSE EFFECTS — SGLT2 inhibitors can cause genital mycotic infections, increases in LDL cholesterol, and ketoacidosis,3,4 and recently the FDA updated the canagliflozin label to warn about an increased risk of fracture.5 Warnings about increases in serum creatinine and decreases in eGFR have been included in the labels of all three SGLT2 inhibitors since their initial approval; elderly patients with hypovolemia or pre-existing renal dysfunction are at increased risk ACUTE KIDNEY INJURY — SGLT2 inhibitors have diuretic effects, and drugs that have diuretic effects could increase the risk of acute kidney injury From March 2013 to October 2015, 101 cases of acute kidney injury in patients taking canagliflozin (73 patients) or dapagliflozin (28 patients) FDA Recommendations to Reduce the Risk of Acute Kidney Injury with SGLT2 Inhibitors ▶ Before starting therapy, consider factors that may predispose patients to acute kidney injury, such as hypovolemia, chronic renal insufficiency, congestive heart failure, and concomitant medications (diuretics, ACE inhibitors, ARBs, NSAIDs) ▶ Evaluate renal function before starting treatment and periodically thereafter; adjustments should be made based on eGFR ▶ If acute kidney injury occurs, discontinue the SGLT2 inhibitor promptly and institute treatment ▶ Consider temporarily discontinuing the SGLT2 inhibitor in cases of reduced oral intake (such as acute illness or fasting) or fluid loss (such as gastrointestinal illness or excessive heat exposure) were reported to the FDA Most of the patients required hospitalization and some received dialysis In more than half the cases, acute kidney injury occurred within one month of starting the drug Among the 101 patients, 51 reported concomitant ACE inhibitor use, 26 reported concomitant diuretic use, and reported concomitant nonsteroidal anti-inflammatory drug (NSAID) use Some patients had a prior history of chronic kidney disease or were dehydrated or hypotensive at the time of the acute kidney injury In most cases, renal function improved after the drug was stopped EMPAGLIFLOZIN — The EMPA-REG OUTCOME trial, which found that empagliflozin reduced the risk of major adverse cardiovascular events in patients with type diabetes and established cardiovascular disease,6 also evaluated the long-term effects of the drug on renal function, a pre-specified component of the secondary microvascular outcome of that trial Over a median follow-up of 3.1 years, incident or worsening nephropathy occurred in 525 of 4124 patients (12.7%) in the empagliflozin group, compared to 388 of 2061 patients (18.8%) in the placebo group, a statistically significant difference Patients randomized 91 Published by The Medical Letter, Inc • A Nonprofit Organization The Medical Letter Table Dosage and Cost of SGLT2 Inhibitors Drug Available Formulations Usual Adult Dosage Canagliflozin – Invokana (Janssen) 100, 300 mg tabs 100-300 mg once/d2 Cost1 $391.70 Dapagliflozin – 5, 10 mg Farxiga (AstraZeneca) tabs 5-10 mg once/d3 391.70 Empagliflozin – 10, 25 mg Jardiance (Boehringer tabs Ingelheim/Lilly) 10-25 mg once/d4 391.70 Approximate WAC for 30 days’ treatment at 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 July 5, 2016 Reprinted with permission by First Databank, Inc All rights reserved ©2016 www.fdbhealth.com/policies/drug-pricing-policy Dosage adjustment and more frequent renal function monitoring are recommended in patients with an eGFR