The medical letter on drugs and therapeutics november 7 2016

1507 Drugs for Menopausal Symptoms ...p 142 Eteplirsen Exondys 51 for Duchenne Muscular Dystrophy ...p 145 ALSO IN THIS ISSUE Metformin for Prediabetes ▶ The oral biguanide metformin Glu

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IN THIS ISSUE

ISSUE

1433

Volume 56

Published by The Medical Letter, Inc • A Nonprofi t Organization

ISSUE No

1507

on Drugs and Therapeutics

Metformin for Prediabetes p 141

Drugs for Menopausal Symptoms p 142

Eteplirsen (Exondys 51) for Duchenne Muscular Dystrophy p 145

141

on Drugs and Therapeutics

Take CME Exams

ISSUE

1433

Volume 56

ISSUE No

1507 Drugs for Menopausal Symptoms p 142

Eteplirsen (Exondys 51) for Duchenne Muscular Dystrophy p 145

ALSO IN THIS ISSUE

Metformin for Prediabetes

▶

The oral biguanide metformin (Glucophage, and

others) is generally the drug of choice for initial

treatment of type 2 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

post-load glucose 140-199 mg/dL, or A1C 5.7-6.4%),

especially in those who are <60 years old, have

a BMI >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 <60 years old or with a

BMI ≥35 kg/m2

When the 3-year DPP trial ended, the intensive

lifestyle intervention group was offered

semi-annual counseling and the metformin group could

continue to take the drug During a follow-up of 15

years, the average annual incidence of diabetes,

compared to placebo, was 27% lower in patients

originally randomized to lifestyle intervention and

18% lower in those randomized to metformin.3

ADVERSE EFFECTS — No significant safety issues

have been detected with long-term use of metformin The drug can cause adverse gastrointestinal effects such as metallic taste, nausea, diarrhea, and abdominal pain, which usually decrease over time and can often be avoided by starting with a low dose.4 Metformin can cause weight loss, which is usually considered to be a benefit Hypoglycemia

is rare to nonexistent with metformin monotherapy Decreases in hemoglobin and hematocrit levels have occurred during the first year of treatment Vitamin B12 deficiency has been reported.5 Lactic acidosis

is a rare complication that can occur in patients with severe renal impairment or hepatic failure

CONCLUSION — In patients with elevated fasting

and post-load plasma glucose concentrations, long-term metformin monotherapy can delay or possibly prevent the onset of diabetes Lifestyle intervention, which has been more effective than metformin in clinical trials, is preferred and should

be tried first ■

1 American Diabetes Association Professional Practice Committee for the standards of medical care in diabetes -

2016 Diabetes Care 2016; 39(suppl 1):s107.

2 WC Knowler et al Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin N Engl J Med 2002; 346:393.

3 Diabetes Prevention Program Research Group Long-term effects of lifestyle intervention or metformin on diabetes development and microvascular complications over 15-year follow-up: the Diabetes Prevention Program Outcomes Study Lancet Diabetes Endocrinol 2015; 3:866.

4 Diabetes Prevention Program Research Group Long-term safety, tolerability, and weight loss associated with metformin

in the Diabetes Prevention Program Outcomes Study Diabetes Care 2012; 35:731.

5 VR Aroda et al Long-term metformin use and vitamin B12 defi ciency in the Diabetes Prevention Program Outcomes Study J Clin Endocrinol Metab 2016; 101:1754.

Drugs for Menopausal Symptoms

▶

The primary symptoms of menopause are

genitourinary and vasomotor A thin, dry vaginal lining

and thin urethral mucosa can cause vaginal and vulvar

burning and irritation, pain during intercourse, and an

increased risk of urinary tract infections Vasomotor

symptoms (“hot flashes”) cause daytime discomfort

and night sweats that may disrupt sleep

HORMONE THERAPY — Hormone therapy is the

most effective treatment for menopausal vasomotor

symptoms and the genitourinary syndrome of

menopause (GSM).1,2

Estrogen – For women with GSM without vasomotor

symptoms, low-dose vaginal estrogen products are

preferred All intravaginal formulations (see Table 1)

are similarly effective for treatment of vulvovaginal

atrophy Because systemic absorption is low, vaginal

estrogens generally do not relieve vasomotor

symptoms, but they have a lower incidence of systemic

adverse effects than oral estrogens The vaginal ring

Femring is an exception; it has signifi cant systemic

absorption and can also be used for treatment of

vasomotor symptoms

Oral, transdermal (gel, spray, and patch), and vaginal

formulations of estrogen are approved by the FDA

for treatment of menopausal vasomotor symptoms

(see Table 2) Systemic estrogen is the most effective

treatment for menopausal vasomotor symptoms; it

decreases hot flashes by 50-100% within 4 weeks.3

Transdermal estrogens are probably as effective as oral estrogens in treating menopausal vasomotor symptoms and observational data suggest that they may be less likely than standard-dose oral formulations to cause venous thromboembolism, but comparative randomized trials are lacking.4

Progestin – Endometrial hyperplasia has been

reported in >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

Recommendations for Treatment of Menopausal Symptoms

▶ Estrogen is the most effective treatment for menopausal vasomotor symptoms and the genitourinary syndrome of menopause.

▶ Systemic estrogen formulations are preferred for treatment

of menopausal vasomotor symptoms Women with an intact uterus who take a systemic estrogen should also take a progestin

▶ Low-dose vaginal estrogen products are preferred for women with only genitourinary symptoms Addition of a progestin is generally not necessary.

▶ Nonhormonal therapies such as antidepressants and vaginal moisturizers and lubricants may be helpful in women who are unable or unwilling to take estrogen.

Table 1 Some Vaginal Estrogen Products for Vulvovaginal Atrophy 1

Vaginal Rings

Estring (Pfi zer) 2 mg/ring (0.0075 mg estradiol/d) 0.0075 mg/d 3 $339.80

Femring (Allergan)4 0.05, 0.1 mg estradiol/d 0.05-0.1 mg/d 3 387.70

Vaginal Tablet

Vagifem (Novo Nordisk) 0.01 mg estradiol tabs 5 0.01 mg once/d x 14 d, 723.20

Vaginal Creams

Estrace (Allergan) 0.1% cream (0.1 mg estradiol/gram) 2-4 g/d x 1-2 wks, 263.80 7

then 1-2 g/d x 1-2 wks 6

Premarin (Pfi zer) 0.625 mg conjugated estrogens/gram 0.5-2 g/d x 21 d followed 315.60 8

by 7 d off, or 0.5 g twice/wk

1 Low-dose vaginal estrogen products are preferred for women with only genitourinary symptoms Recommended doses of Estring and Vagifem and the 0.5-gram 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).

2 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.

3 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.

4 Femring has signifi cant systemic absorption and can also be used to treat vasomotor symptoms; the labeling recommends addition of a progestin.

5 Supplied as single-use, disposable applicators containing one estradiol tablet.

6 1 gram one to three times each week can be used after vaginal mucosa has been restored.

7 Cost of one 42.5-gram tube.

8 Cost of one 30-gram tube.

9 Available generically as Yuvafem (Amneal).

Table 2 Some Drugs for Menopausal Vasomotor Symptoms

Oral Estrogens 2

Conjugated estrogens – Premarin (Pfi zer)3 0.3, 0.45, 0.625, 0.9, 1.25 mg tabs 0.3-0.625 mg PO once/d $142.50 Estradiol 4 – Estrace (Allergan)3 0.5, 1, 2 mg tabs 1-2 mg PO once/d 130.50

Esterifi ed estrogen – Menest (Monarch)3 0.3, 0.625, 1.25, 2.5 mg tabs 1.25 mg PO once/d 79.70

Oral Estrogen-Progestin Combinations

Conjugated estrogens/medroxyprogesterone – 0.3/1.5 mg, 0.45/1.5 mg, 0.3/1.5-0.625/5 mg 174.80

Prempro (Pfi zer)3,5 0.625/2.5 mg, 0.625/5 mg tabs PO once/d

Estradiol/drospirenone – Angeliq (Bayer)6 0.5/0.25 mg, 1/0.5 mg tabs 0.5/0.25-1/0.5 mg PO once/d 143.10 Estradiol/norethindrone 4 – Activella (Gemini)6 0.5/0.1 mg, 1/0.5 mg tabs 0.5/0.1-1/0.5 mg PO once/d 216.15 Ethinyl estradiol/norethindrone 4 – Femhrt (Allergan) 2.5 mcg/0.5 mg 2.5 mcg/0.5 mg-5 mcg/1 mg 140.80

PO once/d

Transdermal Estrogens 2

Estradiol patches 4 – Alora (Allergan)3 0.025, 0.05, 0.075, 0.1 mg/d patch 0.05 mg/d patch twice/wk 94.70

Climara (Bayer)3 0.025, 0.0375, 0.05, 0.06, 0.075, 0.025 mg/d patch once/wk 114.20

0.1 mg/d patch Vivelle-DOT (Noven)3 0.025, 0.0375, 0.05, 0.075, 0.1 mg/d patch 0.0375 mg/d patch twice/wk 121.30

Estradiol gel – EstroGel (Ascend Therapeutics)3 0.75 mg/actuation (14 or 32 doses/unit) 7 0.75 mg topically once/d 114.50 8

Elestrin (Meda) 0.52 mg/actuation (30 doses/unit) 9 0.52 mg topically once/d 92.80

Estradiol transdermal spray – Evamist (Perrigo) 1.53 mg/spray (56 sprays/unit) 1.53 mg topically once/d 112.30 10

Vaginal Estrogen

Estradiol intravaginal ring – Femring (Allergan)2,3 0.05, 0.1 mg/d vaginal ring 0.05-0.1 mg/d 11 387.70 12

Transdermal Estrogen-Progestin Combinations

Estradiol/levonorgestrel – Climara Pro (Bayer) 0.045/0.015 mg/d patch 0.045/0.015 mg/d patch 151.60

once/wk

Estradiol/norethindrone – CombiPatch (Noven)3 0.05/0.14, 0.05/0.25 mg/d patch 0.05/0.14-0.05/0.25 mg/d 145.50

patch twice/wk 13

Conjugated Estrogens/Selective Estrogen Reuptake Modulator

Conjugated estrogens/bazedoxifene – Duavee (Pfi zer) 0.45/20 mg tabs 0.45/20 mg PO once/d 149.90

Selective Estrogen Receptor Modulator

Selective Serotonin Reuptake Inhibitor

Paroxetine mesylate – Brisdelle (Noven Therapeutics) 7.5 mg tabs 7.5 mg PO once/d at hs 178.00

1 Approximate WAC for 30 days' treatment at the lowest usual daily dosage WAC = wholesaler acquisition cost or manufacturer's published price to wholesal-ers; 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.

2 For women with an intact uterus, addition of a progestin is recommended.

3 Also FDA-approved for treatment of vulvar and vaginal atrophy associated with menopause.

4 Available generically.

5 Also available as Premphase which contains both combination tablets and estrogen alone.

6 The 1/0.5 mg tabs are also FDA-approved for treatment of vulvar and vaginal atrophy associated with menopause

7 Each actuation delivers 1.25 g of gel, which contains 0.75 mg of estradiol.

8 Cost of one 50-g bottle.

9 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 fi rst 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 <10% of patients), vaginal discharge, muscle spasms, and hyperhidrosis It can also cause endometrial thickening and uterine polyps, but no cases of endometrial hyperplasia or carcinoma have been reported with use of ospemifene for up to 52 weeks.10 Postmenopausal women with an intact uterus

who can be followed closely for vaginal bleeding or

spotting and do not have risk factors for endometrial

cancer could take ospemifene without a progestin For

all others, a progestin should be considered.11

Conjugated Estrogens/SERM – Duavee, a

fixed-dose combination of conjugated estrogens and

the SERM bazedoxifene, is approved by the FDA

for treatment of moderate to severe vasomotor

symptoms in postmenopausal women with an

intact uterus and for prevention of osteoporosis

in postmenopausal women Bazedoxifene has

estrogen-like effects on bone and antiestrogen

effects on the uterus One study found that patients

taking the combination had significantly fewer and

less severe hot flashes than those taking placebo

In clinical trials, the combination has not been

associated with the adverse effects of estrogen/

progestin combinations The risks of venous

thromboembolism and ischemic stroke with

long-term use of Duavee remain to be delong-termined.12

Bioidentical Hormone Therapy – Bioidentical

hormone therapy refers to compounded

plant-derived hormones (most commonly estradiol, estrone,

estriol, progesterone, testosterone, and DHEA) that

are supposed to mimic endogenous hormones The

potency and purity of the compounded products can

vary, and there is no acceptable evidence that they are

effective or safe.13,14

NONHORMONAL THERAPY — Randomized,

placebo-controlled studies of antidepressants have found

some modest improvements in hot flashes com pared

to placebo.15-17 A low-dose formulation of the selective

serotonin reuptake inhibitor (SSRI) paroxetine

mesylate (Brisdelle) is the only nonhormonal therapy

approved by the FDA for treatment of moderate to

severe menopausal vasomotor symptoms It has

reduced the frequency and severity of hot flashes

compared to placebo, but it can cause headache,

lethargy, nausea, and vomiting No trials are available

directly comparing Brisdelle with other paroxetine

formulations that are available generically or with any

other antidepressant.18 In one study, the serotonin

and norepinephrine reuptake inhibitor (SNRI)

venlafaxine (Effexor XR, and generics) was about as

effective as low-dose oral estradiol in reducing the

frequency of menopausal vasomotor symptoms, but

venlafaxine can cause fatigue and small increases in

blood pressure.19

The anticonvulsant gabapentin has also been reported

to reduce hot flashes It can cause dizziness and

1 RJ Baber et al 2016 IMS recommendations on women’s midlife health and menopause hormone therapy Climacteric 2016; 19:109.

2 CA Stuenkel et al Treatment of symptoms of the menopause:

an Endocrine Society Clinical Practice Guideline J Clin Endocri-nol Metab 2015; 100:3975.

3 AH Maclennan et al Oral oestrogen and combined oestrogen/ progestogen therapy versus placebo for hot flushes Cochrane Database Syst Rev 2004; 4:CD002978.

4 Addendum: transdermal estrogen Med Lett Drugs Ther 2012; 54:56.

5 J Gandhi et al Genitourinary syndrome of menopause: an overview of clinical manifestations, pathophysiology, etiology, evaluation, and management Am J Obstet Gynecol 2016 July

26 (epub).

6 Ospemifene (Osphena) for dyspareunia Med Lett Drugs Ther 2013; 55:55

7 GA Bachmann et al Ospemifene effectively treats vulvovagi-nal atrophy in postmenopausal women: results from a pivotal phase 3 study Menopause 2010; 17:480.

somnolence.20 In one study, the benzodiazepine

receptor agonist eszopiclone (Lunesta, and generics)

improved sleep and mood in perimenopausal and early postmenopausal women.21

For treatment of GSM, nonhormonal vaginal moisturizers and lubricants are generally tried fi rst and are often used in combination with systemic or topical estrogens

ALTERNATIVE THERAPIES — Complementary and

alternative therapies are widely used for management

of menopausal symptoms in postmenopausal women, but well-established safety and effi cacy data are lacking

Phytoestrogens (isoflavones, coumestans, or lignans) are plant-derived nonsteroidal compounds that bind to estrogen receptors and have both estrogenic and antiestrogenic properties A meta-analysis found that ingesting soy-containing foods and soy extracts (both sources of isoflavones) was associated with a modest reduction in hot flashes and vaginal dryness.22 A meta-analysis of 9 trials found that flaxseed (a lignan) relieved vasomotor symptoms, but the results of studies have been mixed.23,24 In one randomized controlled trial, a purifi ed pollen extract taken orally was signifi cantly more effective than placebo in relieving hot flashes.25

In a 1-year study in 351 symptomatic postmenopausal women, black cohosh did not signifi cantly reduce vasomotor symptoms compared to placebo.26

Evening primrose oil, ginseng, dong quai, wild yam, red clover, and acupuncture have all been tried for treatment of vasomotor symptoms, but there is no acceptable evidence that any of them are effective.27 ■

Eteplirsen (Exondys 51) for

Duchenne Muscular Dystrophy

▶

Pronunciation Key Eteplirsen: e tep’ lir sen Exondys: ex on' dis

Eteplirsen (Exondys 51 – Sarepta), an antisense

oligonucleotide, has received accelerated approval from the FDA for treatment of Duchenne muscular dystrophy (DMD) in patients who have a mutation

of the dystrophin gene that is amenable to exon

51 skipping It is the fi rst drug to be approved for treatment of DMD

Table 1 Pharmacology

Class Antisense oligonucleotide Formulation 100 mg/2 mL, 500 mg/10 mL single-dose vials Route Intravenous

Metabolism Not signifi cant Elimination Renal (60-70%)

THE DISORDER — DMD is a progressive, X-linked,

recessive, neuromuscular disorder characterized by

a near-complete absence of the protein dystrophin in muscle cells Dystrophin is essential for maintenance

of myocyte integrity.1 About 1 in 3600 infant males has DMD Patients with DMD begin experiencing progressive muscle weakness and deterioration when they are 3-5 years old and usually become nonambulatory by their early teenage years Death almost always occurs before age 40 High-dose prednisone therapy (0.75 mg/kg/day) is commonly used to slow disease progression

MECHANISM OF ACTION — Eteplirsen is a synthetic

strand of nucleic acid that binds to exon 51 of the pre-messenger RNA sequence that encodes for dystrophin, resulting in exclusion ("skipping") of this exon during transcription In DMD patients with mutations amenable to exon 51 skipping (about 13%

of DMD cases), this allows formation of a truncated, partially functional dystrophin protein similar to that formed in Becker muscular dystrophy, a less severe disorder.2

8 DJ Portman et al Ospemifene, a novel selective estrogen

re-ceptor modulator for treating dyspareunia associated with

postmenopausal vulvar and vaginal atrophy Menopause 2013;

20:623.

9 C Bondi et al Pharmacokinetics, pharmacodynamics and

clini-cal effi cacy of ospemifene for the treatment of dyspareunia

and genitourinary syndrome of menopause Expert Opin Drug

Metab Toxicol 2016; 12:1233.

10 JA Simon et al One-year long-term safety extension study of

ospemifene for the treatment of vulvar and vaginal atrophy

in postmenopausal women with a uterus Menopause 2013;

20:418.

11 GD Constantine et al Endometrial safety of ospemifene: results

of the phase 2/3 clinical development program Menopause

2015; 22:36.

12 Conjugated estrogens/bazedoxifene (Duavee) for menopausal

symptoms and prevention of osteoporosis Med Lett Drugs

Ther 2014; 56:33.

13 N Santoro et al Compounded bioidentical hormones in

endo-crinology practice: an Endocrine Society Scientifi c Statement J

Clin Endocrinol Metab 2016; 101:1318.

14 AM Gaudard et al Bioidenical hormones for women with

va-somotor symptoms Cochrane Database Syst Rev 2016;

8:CD010407.

15 DL Barton et al Phase III, placebo-controlled trial of three

dos-es of citalopram for the treatment of hot flashdos-es: NCCTG trial

N05C9 J Clin Oncol 2010; 28:3278.

16 EW Freeman et al Effi cacy of escitalopram for hot flashes in

healthy menopausal women: a randomized controlled trial

JAMA 2011; 305:267.

17 L Speroff et al Effi cacy and tolerability of desvenlafaxine

suc-cinate treatment for menopausal vasomotor symptoms: a

ran-domized controlled trial Obstet Gynecol 2008; 111:77.

18 Paroxetine (Brisdelle) for hot flashes Med Lett Drugs Ther

2013; 55:85.

19 H Joffe et al Low-dose estradiol and the

serotonin-norepineph-rine reuptake inhibitor venlafaxine for vasomotor symptoms: a

randomized clinical trial JAMA Intern Med 2014; 174:1058.

20 KJ Pandya et al Gabapentin for hot flashes in 420 women with

breast cancer: a randomised double-blind placebo-controlled

trial Lancet 2005; 366:818.

21 CN Soares et al Eszopiclone in patients with insomnia during

perimenopause and early postmenopause: a randomized

con-trolled trial Obstet Gynecol 2006; 108:1402.

22 OH Franco et al Use of plant-based therapies and menopausal

symptoms: a systematic review and meta-analysis JAMA

2016; 315:2554.

23 S Dodin et al The effects of flaxseed dietary supplement on

lip-id profi le, bone mineral density, and symptoms in menopausal

women: a randomized, double-blind, wheat germ

placebo-con-trolled clinical trial J Clin Endocrinol Metab 2005; 90:1390.

24 M Ghazanfarpour et al Effects of flaxseed and Hypericum

per-foratum on hot flash, vaginal atrophy and estrogen-dependent

cancers in menopausal women: a systematic review and

meta-analysis Avicenna J Phytomed 2016; 6:273.

25 K Winther et al Femal, a herbal remedy made from pollen

extracts, reduces hot flushes and improves quality of life in

menopausal women: a randomized, placebo-controlled,

paral-lel study Climacteric 2005; 8:162.

26 SD Reed et al Vaginal, endometrial, and reproductive hormone

fi ndings: randomized, placebo-controlled trial of black cohosh,

multibotanical herbs, and dietary soy for vasomotor symptoms:

the Herbal Alternatives for Menopause (HALT) Study

Meno-pause 2008; 15:51.

27 NAMS Nonhormonal management of menopause-associated

vasomotor symptoms: 2015 position statement of the North

American Menopause Society Menopause 2015; 22:1155.

based on the the results of a clinical trial that used the surrogate endpoint of dystrophin increase in skeletal

dystrophin levels and clinical outcomes in eteplirsen-treated patients with DMD.3

1 A Aartsma-Rus et al Theoretic applicability of antisense-mediated exon skipping for Duchenne muscular dystrophy mutations Hum Mutat 2009; 30:293.

2 F Muntoni et al Dystrophin and mutations: one gene, several proteins, multiple phenotypes Lancet Neurol 2003; 2:731.

3 FDA summary review Exondys 51 injection (eteplirsen) Avail-able at: www.accessdata.fda.gov/drugsatfda_docs/nda/2016/ 206488_summary%20review_Redacted.pdf Accessed October

27, 2016.

4 JR Mendell et al Eteplirsen for the treatment of Duchenne muscular dystrophy Ann Neurol 2013; 74:637.

5 JR Mendell et al Longitudinal effect of eteplirsen versus historical control on ambulation in Duchenne muscular dystrophy Ann Neurol 2016; 79:257.

6 FDA Briefi ng Document Peripheral and Central Nervous System Drugs Advisory Committee Meeting April 25,

2016 Eteplirsen Available at: www.fda.gov/downloads/ AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/ PeripheralandCentralNervousSystemDrugsAdvisoryCommit-tee/UCM497063.pdf Accessed October 27, 2016.

7 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 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.

In an unpublished, open-label trial (summarized in

the package insert), 13 patients with DMD received

eteplirsen 30 mg/kg once weekly for 48 weeks

Their mean dystrophin level at baseline, expressed

as a percentage of the level in healthy subjects,

was 0.16%; after 48 weeks it increased to 0.44%,

a statistically significant difference The median

increase was 0.1%

In a double-blind, 24-week trial, 12 boys 7-13 years old

were randomized to receive eteplirsen 30 or 50 mg/kg

or placebo once weekly At 24 weeks, the mean change

from baseline on the 6-minute walk test (6MWT)

was not signifi cantly different between the eteplirsen

and placebo groups.4

In an open-label extension of the 24-week trial,

patients who were taking eteplirsen continued to take

the same dosage and those who had taken placebo

were randomized to either 30 or 50 mg/kg of the

drug once weekly.5 A post-hoc analysis conducted

by the manufacturer at 48 weeks omitted 2 patients

taking eteplirsen who became nonambulatory soon

after enrollment; the remaining eteplirsen-treated

patients had better results on the 6MWT after 48

weeks of treatment than those who had taken

placebo for the fi rst 24 weeks before switching to

eteplirsen All patients who took eteplirsen for up

to 4 years during the extension trial experienced a

gradual decline in physical function, and there was

no evidence of a clinical benefi t in treated patients

compared to untreated matched historical controls.6

At 180 weeks, the mean dystrophin level was 0.93%

of that in healthy subjects

The effect of eteplirsen on dystrophin levels appears

to be dose-related The FDA is requiring that the

manufacturer conduct new clinical trials evaluating

the clinical benefi ts of eteplirsen at much higher doses

(e.g., 30 mg/kg/day)

ADVERSE EFFECTS — Adverse effects that occurred

at a ≥25% higher rate with eteplirsen than with

placebo in the 24-week clinical trial included

balance disorder, vomiting, and contact dermatitis

Transient erythema, facial flushing, and elevated

body temperature have occurred on infusion days

No serious adverse events occurred in patients who

received eteplirsen for about 3 years

DOSAGE, ADMINISTRATION, AND COST — The

recommended dosage of eteplirsen is 30 mg/kg once

weekly infused intravenously over 35-60 minutes

A 500-mg vial of Exondys 51 costs $8000 and a

100-mg vial costs $1600; one year’s treatment of a child weighing 25 kg would cost about $665,000.7

CONCLUSION — Eteplirsen (Exondys 51) is the fi rst

drug to be approved for treatment of Duchenne muscular dystrophy (DMD) It slightly increased dystrophin levels in the muscle cells of patients with specifi c mutations of the dystrophin gene that occur

in about 13% of DMD cases Whether this extremely expensive drug could provide any signifi cant clinical benefi t or slow progression of the disease remains to

be determined ■

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Coming Soon in The Medical Letter:

Drugs for Head Lice

Ustekinumab (Stelara) for Crohn's Disease

MiniMed 670G: A Hybrid Closed-Loop Insulin System

Lesinurad (Zurampic) for Gout

Ameluz for Actinic Keratosis

Drugs for Diabetes

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1 Discuss the criteria defi ning prediabetes and the pharmacologic and nonpharmacologic options available for treatment of prediabetes

2 Discuss the pharmacologic options available for treatment of menopausal symptoms and compare them based on their effi cacy, dosage and administration, and potential adverse effects.

3 Determine the most appropriate therapy given the clinical presentation of an individual patient with menopausal symptoms.

4 Review the effi cacy and safety of eteplirsen (Exondys 51) for treatment of Duchenne muscular dystrophy.

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Issue 1507 Questions

(Correspond to questions #91-100 in Comprehensive Exam #75, available January 2017)

6 You are planning to prescribe an oral estrogen for a 56-year-old woman with menopausal vasomotor symptoms and an intact uterus and are considering whether to add a progestin Which

of the following statements about use of these hormones in this patient is true?

a Taking an oral estrogen alone increases the risk of uterine cancer.

b Adding a progestin to oral estrogen decreases the risk of uterine cancer.

c Adding a progestin to oral estrogen may increase the risk

of invasive breast cancer.

d all of the above

7 Ospemifene can reduce:

a the frequency of hot flashes

b the severity of dyspareunia

c the risk of endometrial hyperplasia

d all of the above

8 The only nonhormonal drug approved by the FDA for treatment

of menopausal vasomotor symptoms is:

a venlafaxine

b paroxetine

c gabapentin

d eszopiclone

Eteplirsen (Exondys 51) for Duchenne Muscular Dystrophy

9 Approval of eteplirsen for treatment of Duchenne muscular dystrophy was based on a clinical trial showing that the drug:

a increased dystrophin levels in skeletal muscle

b delayed disease progression

c reduced mortality

d improved results on the 6-minute walk test

10 Which of the following statements about eteplirsen is true?

a It is only indicated for a subset of patients with specifi c mutations of the dystrophin gene.

b The manufacturer is required to conduct additional studies evaluating its clinical benefi ts.

c It has not been associated with serious adverse effects.

d all of the above

Metformin for Prediabetes

1 A patient is considered to have prediabetes if they have:

a a fasting plasma glucose 100-125 mg/dL

b a post-load glucose 140-199 mg/dL

c an A1C 5.7-6.4%

d any of the above

2 In the Diabetes Prevention Program trial, which of the following

was most effective in reducing the incidence of diabetes?

a intensive lifestyle intervention

b metformin

c placebo

d insulin

Drugs for Menopausal Symptoms

3 A thin, dry vaginal lining and thin urethral mucosa can cause:

a vaginal and vulvar burning and irritation

b pain during intercourse

c an increased risk of urinary tract infections

d all of the above

4 A 54-year-old woman with severe hot flashes asks for

advice about choosing treatment for menopausal vasomotor

symptoms You could tell her that:

a oral, transdermal, and vaginal formulations of estrogen are

all equally effective

b transdermal estrogens are probably as effective as oral

estrogens

c vaginal estrogen products are as effective as transdermal

estrogens

d Femring is not effective

5 A 61-year-old postmenopausal woman with an intact uterus

and a family history of breast cancer is complaining of vaginal

dryness and dyspareunia She does not have any vasomotor

symptoms The best treatment for this patient would be:

a an oral estrogen alone

b an oral estrogen plus a progestin

c a low-dose vaginal estrogen

d Femring

ACPE UPN: Per Issue Exam: 0379-0000-16-507-H01-P; Release: November 7, 2016, Expire: November 7, 2017 Comprehensive Exam 75: 0379-0000-17-075-H01-P; Release: January 2017, Expire: January 2018

PRESIDENT: Mark Abramowicz, M.D.; VICE PRESIDENT AND EXECUTIVE EDITOR: Gianna Zuccotti, M.D., M.P.H., F.A.C.P., Harvard Medical School; EDITOR IN CHIEF: Jean-Marie Pflomm,

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Pharm.D., F Peter Swanson, M.D

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;

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Sunnybrook Health Sciences Centre; Richard B Kim, M.D., University of Western Ontario; 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

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