The Medical Letter ® on Drugs and Therapeutics Volume 58 ISSUE ISSUE No 1433 1507 Volume 56 November 7, 2016 IN THIS ISSUE Metformin for Prediabetes p 141 Drugs for Menopausal Symptoms p 142 Eteplirsen (Exondys 51) for Duchenne Muscular Dystrophy .p 145 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 November 7, 2016 Take CME Exams ISSUE ISSUE No 1433 1507 Volume 56 ▶ ALSO IN THIS ISSUE Drugs for Menopausal Symptoms p 142 Eteplirsen (Exondys 51) for Duchenne Muscular Dystrophy .p 145 Metformin for Prediabetes The oral biguanide metformin (Glucophage, and others) is generally the drug of choice for initial treatment of type diabetes It has also been used to prevent or at least delay the onset of diabetes in patients considered to be at high risk for the disease Recent guidelines recommend considering use of metformin in patients with prediabetes (fasting plasma glucose 100-125 mg/dL, 2-hr postload glucose 140-199 mg/dL, or A1C 5.7-6.4%), especially in those who are 35 kg/m2, or have a history of gestational diabetes.1 Metformin has not been approved for such use by the FDA CLINICAL STUDIES — In the Diabetes Prevention Program (DPP) trial, 3234 nondiabetic adults with a BMI ≥24 kg/m2 (≥22 kg/m2 in Asian patients) and elevated fasting and post-load plasma glucose concentrations were randomized to receive intensive lifestyle intervention focusing on weight loss and exercise, metformin 850 mg twice daily, or placebo.2 After a mean follow-up of 2.8 years, the incidence of diabetes was reduced, compared to placebo, by 58% with intensive lifestyle intervention and by 31% with metformin Metformin was as effective as lifestyle intervention among patients 20% of women taking an unopposed systemic estrogen for more than one year; the risk is closely related to the dosage and duration of treatment Women with an intact uterus who take a systemic estrogen should also take an oral progestin to reduce the risk of endometrial hyperplasia or adenocarcinoma Adding a progestin does reduce the risk of endometrial hyperplasia and cancer, but it also has been associated with an increased risk of invasive breast cancer and thromboembolic events Although Table Some Vaginal Estrogen Products for Vulvovaginal Atrophy1 Drug Vaginal Rings Estring (Pfizer) Femring (Allergan)4 Vaginal Tablet Vagifem (Novo Nordisk) generic9 Vaginal Creams Estrace (Allergan) Premarin (Pfizer) Available Formulations Usual Daily Dosage Cost2 mg/ring (0.0075 mg estradiol/d) 0.05, 0.1 mg estradiol/d 0.0075 mg/d3 0.05-0.1 mg/d3 $339.80 387.70 0.01 mg estradiol tabs5 0.01 mg once/d x 14 d, then 0.01 mg twice/wk 723.20 659.50 0.1% cream (0.1 mg estradiol/gram) 2-4 g/d x 1-2 wks, then 1-2 g/d x 1-2 wks6 0.5-2 g/d x 21 d followed by d off, or 0.5 g twice/wk 263.807 0.625 mg conjugated estrogens/gram 315.608 Low-dose vaginal estrogen products are preferred for women with only genitourinary symptoms Recommended doses of Estring and Vagifem and the 0.5gram dose of Premarin are considered low doses Addition of a progestin is generally not necessary for low-dose vaginal estrogen products (CA Stuenkel et al J Clin Endocrinol Metab 2015; 100:3975; JE Manson et al 2014; 21:911) Approximate WAC for 90 days’ maintenance treatment with the lowest strength 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 October 5, 2016 Reprinted with permission by First Databank, Inc All rights reserved ©2016 www.fdbhealth.com/policies/drug-pricing-policy The ring should remain in place continuously for 90 days A new ring can be inserted, but the need for continued treatment should be reassessed at 3- or 6-month intervals Femring has significant systemic absorption and can also be used to treat vasomotor symptoms; the labeling recommends addition of a progestin Supplied as single-use, disposable applicators containing one estradiol tablet gram one to three times each week can be used after vaginal mucosa has been restored Cost of one 42.5-gram tube Cost of one 30-gram tube Available generically as Yuvafem (Amneal) 142 The Medical Letter Vol 58 (1507) ® November 7, 2016 Table Some Drugs for Menopausal Vasomotor Symptoms Drug Some Available Formulations Usual Daily Dosage Cost1 0.3, 0.45, 0.625, 0.9, 1.25 mg tabs 0.5, 1, mg tabs 0.3, 0.625, 1.25, 2.5 mg tabs 0.75, 1.5, mg tabs 0.3-0.625 mg PO once/d 1-2 mg PO once/d 1.25 mg PO once/d 0.75-6 mg PO once/d $142.50 130.50 79.70 12.30 0.3/1.5 mg, 0.45/1.5 mg, 0.625/2.5 mg, 0.625/5 mg tabs 0.5/0.25 mg, 1/0.5 mg tabs 0.5/0.1 mg, 1/0.5 mg tabs 2.5 mcg/0.5 mg 0.3/1.5-0.625/5 mg PO once/d 0.5/0.25-1/0.5 mg PO once/d 0.5/0.1-1/0.5 mg PO once/d 2.5 mcg/0.5 mg-5 mcg/1 mg PO once/d 174.80 0.025, 0.05, 0.075, 0.1 mg/d patch 0.025, 0.0375, 0.05, 0.06, 0.075, 0.1 mg/d patch 0.025, 0.0375, 0.05, 0.075, 0.1 mg/d patch 0.75 mg/actuation (14 or 32 doses/unit)7 0.25, 0.5, mg/packet 0.52 mg/actuation (30 doses/unit)9 1.53 mg/spray (56 sprays/unit) 0.05 mg/d patch twice/wk 0.025 mg/d patch once/wk 94.70 114.20 0.0375 mg/d patch twice/wk 0.75 mg topically once/d 0.25-1 mg topically once/d 0.52 mg topically once/d 1.53 mg topically once/d 121.30 114.508 87.00 92.80 112.3010 0.05, 0.1 mg/d vaginal ring 0.05-0.1 mg/d11 387.7012 Transdermal Estrogen-Progestin Combinations Estradiol/levonorgestrel – Climara Pro (Bayer) 0.045/0.015 mg/d patch 151.60 Estradiol/norethindrone – CombiPatch (Noven)3 0.05/0.14, 0.05/0.25 mg/d patch 0.045/0.015 mg/d patch once/wk 0.05/0.14-0.05/0.25 mg/d patch twice/wk13 Conjugated estrogens/bazedoxifene – Duavee (Pfizer) 0.45/20 mg tabs 0.45/20 mg PO once/d 149.90 Selective Estrogen Receptor Modulator Ospemifene – Osphena (Shionogi)14,15 60 mg PO once/d 176.70 7.5 mg PO once/d at hs 178.00 Oral Estrogens2 Conjugated estrogens – Premarin (Pfizer)3 Estradiol4 – Estrace (Allergan)3 Esterified estrogen – Menest (Monarch)3 Estropipate4 (Allergan)3 Oral Estrogen-Progestin Combinations Conjugated estrogens/medroxyprogesterone – Prempro (Pfizer)3,5 Estradiol/drospirenone – Angeliq (Bayer)6 Estradiol/norethindrone4 – Activella (Gemini)6 Ethinyl estradiol/norethindrone4 – Femhrt (Allergan) Transdermal Estrogens2 Estradiol patches4 – Alora (Allergan)3 Climara (Bayer)3 Vivelle-DOT (Noven)3 Estradiol gel – EstroGel (Ascend Therapeutics)3 Divigel (Vertical) Elestrin (Meda) Estradiol transdermal spray – Evamist (Perrigo) Vaginal Estrogen Estradiol intravaginal ring – Femring (Allergan)2,3 143.10 216.15 140.80 145.50 Conjugated Estrogens/Selective Estrogen Reuptake Modulator 60 mg tabs Selective Serotonin Reuptake Inhibitor Paroxetine mesylate – Brisdelle (Noven Therapeutics) 7.5 mg tabs Approximate WAC for 30 days' treatment at the lowest usual daily 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 October 5, 2016 Reprinted with permission by First Databank, Inc All rights reserved ©2016 www.fdbhealth.com/policies/drug-pricing-policy For women with an intact uterus, addition of a progestin is recommended Also FDA-approved for treatment of vulvar and vaginal atrophy associated with menopause Available generically Also available as Premphase which contains both combination tablets and estrogen alone The 1/0.5 mg tabs are also FDA-approved for treatment of vulvar and vaginal atrophy associated with menopause Each actuation delivers 1.25 g of gel, which contains 0.75 mg of estradiol Cost of one 50-g bottle Each metered dose delivers 0.87 g of gel, which contains 0.52 mg of estradiol 10 Cost of one 8.1-mL bottle 11 The ring should remain in place continuously for 90 days A new ring can be inserted, but the need for continued treatment should be reassessed at 3- or 6-month intervals 12 Cost of one ring 13 Can also be used in combination with an estradiol-only transdermal system that is worn for the first 14 days of a 28-day cycle and then CombiPatch replaced every 3-4 days for the remaining 14 days 14 FDA-approved only for treatment of moderate to severe dyspareunia 15 The label recommends considering addition of a progestin (see p 144) long-term data are lacking, addition of a progestin is generally not necessary in women with an intact uterus who are using a low-dose vaginal estrogen product.1,5 Selective Estrogen Receptor Modulator (SERM) – Ospemifene (Osphena), an oral estrogen agonist/ antagonist, is approved by the FDA for treatment of moderate to severe dyspareunia in postmenopausal women.6 It is the fourth estrogen agonist/antagonist to become available in the US, but it is the only one that has an agonist effect on the vaginal epithelium In postmenopausal women, ospemifene can reduce the severity of dyspareunia and improve other symptoms associated with GSM.7-9 Adverse effects include hot flashes (in