The medical letter on drugs and therapeutics november 7 2016

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on Drugs and Therapeutics
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IN THIS ISSUE

Metformin for Prediabetes ..................................................................................................p 141
Drugs for Menopausal Symptoms ......................................................................................p 142
Eteplirsen (Exondys 51) for Duchenne Muscular Dystrophy .............................................p 145

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The Medical Letter

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on Drugs and Therapeutics

Volume 58

November 7, 2016
Take CME Exams

ISSUE

ISSUE No.

1433
1507
Volume 56

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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 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 postload 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 semiannual 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
deficiency in the Diabetes Prevention Program Outcomes
Study. J Clin Endocrinol Metab 2016; 101:1754.

141

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Drugs for Menopausal Symptoms

Recommendations for Treatment of 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 significant 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

November 7, 2016

▶

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.

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

Table 1. 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

2 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 7 d off, or 0.5 g twice/wk

263.807

0.625 mg conjugated estrogens/gram

315.608

1. 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).
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 significant 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).

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Table 2. 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, 2 mg tabs
0.3, 0.625, 1.25, 2.5 mg tabs
0.75, 1.5, 3 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, 1 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

1. 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.
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 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 <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
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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

somnolence.20 In one study, the benzodiazepine
receptor agonist eszopiclone (Lunesta, and generics)
improved sleep and mood in perimenopausal and early
postmenopausal women.21

Conjugated Estrogens/SERM – Duavee, a fixeddose 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 longterm use of Duavee remain to be determined.12

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

Bioidentical Hormone Therapy – Bioidentical
hormone therapy refers to compounded plantderived 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, placebocontrolled studies of antidepressants have found
some modest improvements in hot flashes compared
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
144

ALTERNATIVE THERAPIES — Complementary and
alternative therapies are widely used for management
of menopausal symptoms in postmenopausal women,
but well-established safety and efficacy 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 metaanalysis 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
purified pollen extract taken orally was significantly
more effective than placebo in relieving hot flashes.25
In a 1-year study in 351 symptomatic postmenopausal
women, black cohosh did not significantly 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 ■
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 Endocrinol 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 vulvovaginal atrophy in postmenopausal women: results from a pivotal
phase 3 study. Menopause 2010; 17:480.

The Medical Letter

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8. DJ Portman et al. Ospemifene, a novel selective estrogen receptor modulator for treating dyspareunia associated with
postmenopausal vulvar and vaginal atrophy. Menopause 2013;
20:623.
9. C Bondi et al. Pharmacokinetics, pharmacodynamics and clinical efficacy 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 endocrinology practice: an Endocrine Society Scientific Statement. J
Clin Endocrinol Metab 2016; 101:1318.
14. AM Gaudard et al. Bioidenical hormones for women with vasomotor symptoms. Cochrane Database Syst Rev 2016;
8:CD010407.
15. DL Barton et al. Phase III, placebo-controlled trial of three doses of citalopram for the treatment of hot flashes: NCCTG trial
N05C9. J Clin Oncol 2010; 28:3278.
16. EW Freeman et al. Efficacy of escitalopram for hot flashes in
healthy menopausal women: a randomized controlled trial.
JAMA 2011; 305:267.
17. L Speroff et al. Efficacy and tolerability of desvenlafaxine succinate treatment for menopausal vasomotor symptoms: a randomized 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-norepinephrine 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 controlled 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 lipid profile, bone mineral density, and symptoms in menopausal
women: a randomized, double-blind, wheat germ placebo-controlled clinical trial. J Clin Endocrinol Metab 2005; 90:1390.
24. M Ghazanfarpour et al. Effects of flaxseed and Hypericum perforatum on hot flash, vaginal atrophy and estrogen-dependent
cancers in menopausal women: a systematic review and metaanalysis. 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, parallel study. Climacteric 2005; 8:162.
26. SD Reed et al. Vaginal, endometrial, and reproductive hormone
findings: randomized, placebo-controlled trial of black cohosh,
multibotanical herbs, and dietary soy for vasomotor symptoms:
the Herbal Alternatives for Menopause (HALT) Study. Menopause 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.

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November 7, 2016

Eteplirsen (Exondys 51) for
Duchenne Muscular Dystrophy

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 first drug to be approved for
treatment of DMD.
Pronunciation Key
Eteplirsen: e tep’ lir sen
Exondys: ex on' dis

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
Table 1. Pharmacology
Class

Antisense oligonucleotide

Formulation

100 mg/2 mL, 500 mg/10 mL single-dose vials

Route

Intravenous

Metabolism

Not significant

Elimination

Renal (60-70%)

Half-life

3-4 hours

CLINICAL STUDIES — Approval of eteplirsen was
based on the the results of a clinical trial that used the
surrogate endpoint of dystrophin increase in skeletal
muscle. No correlation has been established between
dystrophin levels and clinical outcomes in eteplirsentreated patients with DMD.3
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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 significantly 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 first 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 benefit 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 benefits 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
146

Vol. 58 (1507)

November 7, 2016

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 first
drug to be approved for treatment of Duchenne
muscular dystrophy (DMD). It slightly increased
dystrophin levels in the muscle cells of patients with
specific mutations of the dystrophin gene that occur
in about 13% of DMD cases. Whether this extremely
expensive drug could provide any significant clinical
benefit or slow progression of the disease remains to
be determined. ■
1. A Aartsma-Rus et al. Theoretic applicability of antisensemediated 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). Available 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 Briefing Document. Peripheral and Central Nervous
System Drugs Advisory Committee Meeting. April 25,
2016. Eteplirsen. Available at: www.fda.gov/downloads/
AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/
PeripheralandCentralNervousSystemDrugsAdvisoryCommittee/UCM497063.pdf. Accessed October 27, 2016.
7. 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.
October 5, 2016. Reprinted with permission by First Databank,
Inc. All rights reserved. ©2016. www.fdbhealth.com/policies/
drug-pricing-policy.

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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Discuss the criteria defining prediabetes and the pharmacologic and nonpharmacologic options available for treatment of prediabetes.
Discuss the pharmacologic options available for treatment of menopausal symptoms and compare them based on their efficacy, dosage and administration, and
potential adverse effects.
Determine the most appropriate therapy given the clinical presentation of an individual patient with menopausal symptoms.
Review the efficacy 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)
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

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 specific
mutations of the dystrophin gene.
b. The manufacturer is required to conduct additional studies
evaluating its clinical benefits.
c. It has not been associated with serious adverse effects.
d. all of the above

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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