The medical letter on drugs and therapeutics april 28 2014

The Medical Letter

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On Drugs and Therapeutics
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IN THIS ISSUE (starts on next page)

Conjugated Estrogens/Bazedoxifene (Duavee) for Menopausal
Symptoms and Prevention of Osteoporosis................................................ p 33
Tasimelteon (Hetlioz) for Non-24-Hour Sleep-Wake Disorder ...................... p 34
In Brief: Enteric-Coated Aspirin as an Antiplatelet Drug ........................... p 36

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The Medical Letter

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On Drugs and Therapeutics
Published by The Medical Letter, Inc. • 145 Huguenot Street, New Rochelle, NY 10801 • A Nonprofit Publication
Volume 56 (Issue 1441)
April 28, 2014

ALSO IN THIS ISSUE

Tasimelteon (Hetlioz) for Non-24-Hour
Sleep-Wake Disorder ................................. p 34
In Brief: Enteric-Coated Aspirin as an
Antiplatelet Drug ....................................... p 36

Conjugated Estrogens/Bazedoxifene
(Duavee) for Menopausal Symptoms and
Prevention of Osteoporosis
The FDA has approved Duavee (Pfizer), a fixeddose combination of conjugated estrogens and the
new selective estrogen receptor modulator (SERM)
bazedoxifene, for treatment of moderate to severe
vasomotor symptoms and for prevention of osteoporosis
in postmenopausal women with an intact uterus.
Bazedoxifene is an estrogen agonist/antagonist with
estrogen-like effects on bone and antiestrogen effects
on the uterus. It is the second SERM to be approved
for prevention of osteoporosis; raloxifene (Evista, and
generics) has been available as a single agent for this

indication since 1997.
HORMONAL THERAPY — Systemic estrogen is the most
effective treatment for menopausal vasomotor symptoms;
it decreases hot flushes by 50-100% within 4 weeks.1
However, women with an intact uterus who take systemic
estrogen are advised to also take an oral progestin to
reduce the risk of developing endometrial hyperplasia
or adenocarcinoma, and progestins can cause irregular
vaginal bleeding, increases in breast density, and breast
pain. Moreover, the Women’s Health Initiative found that
women 50-79 years old who took conjugated equine
estrogens 0.625 mg plus medroxyprogesterone acetate
2.5 mg (Prempro) for >5 years were at increased risk for
coronary heart disease, stroke, venous thromboembolism,
and breast cancer.2,3 Estrogen alone, which was assigned
to women without a uterus, did not increase the risk of
coronary heart disease or (at 7 years) breast cancer.

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Conjugated estrogens with or without the progestin
reduced the incidence of fractures.
MECHANISM OF ACTION — In vitro and in vivo
studies have demonstrated that bazedoxifene inhibits
the stimulating effect of conjugated estrogens on
endometrial and breast tissue, but not the positive
effects on vasomotor symptoms, vulvovaginal atrophy,
or bone mineral density.4
Table 1. Pharmacology

Conjugated
Estrogens

Bazedoxifene

Drug class

Estrogens

Estrogen agonist/
antagonist

Route

Oral

Oral

Tmax

6.5 hrs (estrone)

2.5 hrs

Metabolism

Primarily hepatic,
partly by CYP3A4

Primarily glucuronidation

Elimination

Mainly in urine

Feces (~85%); urine (1%)

Half-life

17 hrs (estrone)

30 hrs

CLINICAL STUDIES — A 12-week, randomized, double-blind trial in 332 postmenopausal women 40-65
years old with an intact uterus and >7 moderate to
severe hot flushes daily compared conjugated estrogens 0.45 mg/bazedoxifene 20 mg and conjugated
estrogens 0.625 mg/bazedoxifene 20 mg to placebo.
By week 4, the active drugs had reduced the average
daily number of hot flushes by 5.9 per day, significantly
more than the 2.8-reduction with placebo, and also
had significantly reduced their severity. At week 12,
patients treated with the drug combinations still reported significantly fewer and less severe hot flushes than
those who were taking placebo.5
Two larger clinical trials evaluated the efficacy of conjugated estrogens/bazedoxifene in preventing postmenopausal osteoporosis. A 24-month, randomized,
double-blind trial in 3397 postmenopausal women
40-75 years old with an intact uterus compared various
doses of bazedoxifene combined with either 0.45 mg
or 0.625 mg of conjugated estrogens to placebo, using

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33


raloxifene 60 mg as an active comparator. At both 12
months and 24 months, 0.45 mg of conjugated estrogens combined with bazedoxifene 20 mg had increased
lumbar spine and total hip bone mineral density significantly more than placebo or raloxifene.6
The second clinical trial evaluating the efficacy of
the combination for prevention of osteoporosis was
a 12-month trial in 1843 postmenopausal women
40-65 years old with an intact uterus that compared
conjugated estrogens 0.45 mg/bazedoxifene 20 mg and
conjugated estrogens 0.625 mg/bazedoxifene 20 mg to
conjugated estrogens 0.45 mg/medroxyprogesterone
acetate 1.5 mg (Prempro), bazedoxifene 20 mg alone,
and placebo. The conjugated estrogens 0.45 mg/
bazedoxifene 20 mg combination increased lumbar
spine and total hip bone mineral density significantly
more than placebo. The increase in lumbar spine
bone mineral density at 12 months was significantly
greater with Prempro than with conjugated estrogens
0.45 mg/bazedoxifene 20 mg. The increase in total hip
bone mineral density was about the same with both
treatments.7
A randomized, placebo-controlled, 5-year trial found that
bazedoxifene 20 mg alone significantly decreased the
risk of vertebral fractures in postmenopausal women.8
Duavee was not approved by the FDA for treatment of
vulvovaginal atrophy or dyspareunia.
ADVERSE EFFECTS — In clinical trials of conjugated

estrogens/bazedoxifene, the combination did not cause
vaginal bleeding, increase breast density, or cause
breast pain. The effects of the new combination on the
endometrium were similar to those with placebo. The
incidence of breast cancer, endometrial cancer, ovarian
cancer, venous thromboembolism, stroke, myocardial
infarction, and death from any cause in clinical trials
was 0%, or close to it, with both conjugated estrogens/
bazedoxifene and placebo. The long-term risk of venous
thromboembolism and ischemic stroke with the new
combination remains to be determined.
DRUG INTERACTIONS — Estrogens are metabolized
partly by CYP3A4; concurrent administration of a CYP3A4
inhibitor or inducer could, respectively, increase or decrease serum concentrations of the hormone.9 Increases
in estrogen serum concentrations could increase the
risks associated with estrogen therapy, including venous
thromboembolism. Bazedoxifene is metabolized by uridine diphosphate glucuronosyltransferase (UGT) enzymes; UGT inducers such as rifampin could reduce
serum concentrations of bazedoxifene, increasing the
risk of endometrial hyperplasia.
34

DOSAGE AND COST — Each Duavee tablet contains
0.45 mg of conjugated estrogens and 20 mg of
bazedoxifene. The recommended dosage for treatment
of vasomotor symptoms or prevention of osteoporosis
is one tablet daily. Thirty Duavee tablets cost $111.40,
compared to $198.00 for 30 tablets of Evista (60 mg) and
$103.90 for 28 tablets of Prempro (0.45 mg/1.5 mg).10
CONCLUSION — The combination of conjugated
estrogens with the estrogen agonist/antagonist

bazedoxifene (Duavee) is effective for treatment of
menopausal vasomotor symptoms and prevention of
postmenopausal osteoporosis, without the short-term
adverse effects of estrogen/progestin combinations. Its
long-term safety is unknown; venous thromboembolism
and stroke could occur. □
1. Drugs for menopausal symptoms. Med Lett Drugs Ther 2012;
54:41.
2. JE Rossouw et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the
Women’s Health Initiative randomized controlled trial. JAMA 2002;
288:321.
3. JE Manson et al. Estrogen plus progestin and the risk of coronary
heart disease. N Engl J Med 2003; 349:523.
4. S Mirkin and BS Komm. Tissue-selective estrogen complexes for
postmenopausal women. Maturitas 2013; 76:213.
5. JV Pinkerton et al. Relief of vasomotor symptoms with the tissueselective estrogen complex containing bazedoxifene/conjugated estrogens: a randomized, controlled trial. Menopause 2009; 16:1116.
6. R Lindsay et al. Efficacy of tissue-selective estrogen complex of
bazedoxifene/conjugated estrogens for osteoporosis prevention in
at-risk postmenopausal women. Fertil Steril 2009; 92:1045.
7. JV Pinkerton et al. Effects of bazedoxifene/conjugated estrogens
on the endometrium and bone: a randomized trial. J Clin Endocrinol Metab 2014; 99:E189
8. SL Silverman et al. Sustained efficacy and safety of bazedoxifene
in preventing fractures in postmenopausal women with osteoporosis: results of a 5-year, randomized, placebo-controlled study.
Osteoporos Int 2012; 23:351.
9. Inhibitors and inducers of CYP enzymes and P-glycoprotein. Med
Lett Drugs Ther 2013; 55:e44.
10. Approximate wholesale acquisition cost (WAC). Source:
Analy$ource® Monthly (Selected from FDB MedKnowledge™)
April 5, 2014. Reprinted with permission by FDB, Inc. All rights
reserved. ©2014. www.fdbhealth.com/policies/drug-pricing-policy.

Actual retail prices may be higher.

Tasimelteon (Hetlioz) for Non-24-Hour
Sleep-Wake Disorder
The FDA has approved the melatonin receptor agonist
tasimelteon (Hetlioz – Vanda) for treatment of non-24hour sleep-wake disorder (non-24), which is common
in totally blind persons. Tasimelteon is the first drug
approved for this indication and the second melatonin
receptor agonist approved for use in the US; ramelteon
(Rozerem) was approved earlier for treatment of
insomnia.1 Melatonin itself has not been approved by
the FDA for any indication; it is available in the US as a
dietary supplement and is promoted as a sleep aid.2

The Medical Letter • Volume 56 • Issue 1441 • April 28, 2014


NON-24 — The intrinsic period of circadian rhythms
is typically slightly longer than 24 hours. In sighted
persons, the light-dark cycle is the main signal that
resets the circadian timing system every 24 hours. In
totally blind persons, the absence of light permits the
circadian cycle to run longer than 24 hours, causing
disruption of nighttime sleep and increased daytime
sleepiness. Administration of exogenous melatonin
has been tried in the treatment of non-24, with some
success.3
MECHANISM OF ACTION — Melatonin acts on
two receptors in the suprachiasmatic nucleus of the
hypothalamus (MT1 and MT2) to affect both sleep

and circadian rhythms.4 How it does so is not fully
understood, but it may act as a physiological signal of
darkness; in sighted persons, melatonin is secreted
into the bloodstream during the night, and its secretion
is suppressed by light. The MT1 receptor appears to
be more important in sleep-related effects, and the
MT2 receptor may mediate the phase-shifting effects of
melatonin. Melatonin receptor agonists may have higher
binding affinities for these receptors than melatonin
itself. Ramelteon has a stronger affinity for MT1 and
tasimelteon has a stronger affinity for MT2 .
CLINICAL STUDIES — According to the manufacturer,
it can take weeks or months of daily use of tasimelteon
before the patient experiences any benefit. FDA
approval of the drug was based on 2 unpublished,
randomized, double-masked, placebo-controlled clinical
trials in totally blind adults with non-24. Tasimelteon
20 mg was administered one hour before bedtime at
the same time each night.
The SET (Safety and Efficacy of Tasimelteon) trial in
84 patients with non-24 compared tasimelteon and
placebo for 6 months. Significantly more tasimelteontreated patients (20% vs. 3%) achieved entrainment
(synchronization) of the circadian rhythm as measured
by urine levels of a melatonin metabolite. Mean total
nighttime sleep was 28 minutes longer and daytime
nap time was 27 minutes shorter in patients taking
tasimelteon than in patients taking placebo.5
In the RESET (Randomized Withdrawal Study of the
Efficacy and Safety of Tasimelteon) trial, 20 patients who
were entrained after a 3-month open-label run-in phase

were randomized to tasimelteon or placebo for 2 months.
Entrainment was maintained in 90% of tasimelteontreated patients compared to 20% of those in the placebo
group. Mean total nighttime sleep was 67 minutes longer
and daytime nap time was 59 minutes shorter in patients
taking tasimelteon than in patients taking placebo.6

In a double-blind, placebo-controlled trial in 411
healthy persons with transient insomnia induced by
shifting their sleep-wake schedule, tasimelteon given
30 minutes before bedtime improved sleep.7
ADVERSE EFFECTS — In the 6-month clinical trial,
the most common adverse effects of tasimelteon were
headache (17%), elevated aminotransferases (10%), and
nightmares or unusual dreams (10%). Serum concentrations of tasimelteon are 2-fold higher in patients >65 years
old, which might increase the risk of adverse effects.
DRUG INTERACTIONS — Strong CYP1A2 and
CYP3A4 inhibitors can increase serum concentrations
of tasimelteon, and strong inducers such as rifampin
can reduce them.8 Tasimelteon should not be used with
strong CYP1A2 inhibitors or strong CYP3A4 inducers.
Smoking moderately induces CYP1A2, which may
reduce the efficacy of tasimelteon.
DOSAGE, ADMINISTRATION AND COST — The
recommended dosage of tasimelteon is one 20-mg
capsule taken without food before bedtime at the
same time each night. Tasimelteon should not be used
in patients with severe hepatic impairment. The cost of
30 capsules of Hetlioz is $7020.9
CONCLUSION — The melatonin receptor agonist
tasimelteon (Hetlioz) taken once each night, at the cost

of more than $200 per capsule, can improve non-24-hour
sleep-wake disorder (non-24) in totally blind patients.
How it compares with ramelteon (Rozerem), which costs
much less, or melatonin itself in treating non-24 or other
sleep disorders remains to be established. □
1. Ramelteon (Rozerem) for insomnia. Med Lett Drugs Ther 2005;
47:89.
2. Drugs for insomnia. Treat Guidel Med Lett 2012; 10:57.
3. RL Sack et al. Circadian rhythm sleep disorders: part II, advanced
sleep phase disorder, delayed sleep phase disorder, free-running
disorder, and irregular sleep-wake rhythm. An American Academy
of Sleep Medicine review. Sleep 2007; 30:1484.
4. SA Ferguson et al. Melatonin agonists and insomnia. Expert Rev
Neurother 2010; 10:305.
5. SW Lockley et al. Tasimelteon treatment entrains the circadian
clock and demonstrates a clinically meaningful benefit in totally
blind individuals with non-24-hour circadian rhythms. The Endocrine Society 95th annual meeting (ENDO), San Francisco, June
15-18, 2013. Poster SUN-134.
6. SW Lockley et al. RESET study demonstrates that tasimelteon maintains entrainment of melatonin and cortisol in totally blind individuals
with non-24-hour circadian rhythms. The Endocrine Society 95th annual
meeting (ENDO), San Francisco, June 15-18, 2013. Poster SUN-137.
7. SM Rajaratnam et al. Melatonin agonist tasimelteon (VEC-162)
for transient insomnia after sleep-time shift: two randomized controlled multicentre trials. Lancet 2009; 373:482.
8. Inhibitors and inducers of CYP enzymes and P-glycoprotein. Med
Lett Drugs Ther 2013; 55:e44.
9. Approximate wholesale acquisition cost (WAC). Source: Analy$ource®
Monthly (Selected from FDB MedKnowledge™) April 5, 2014. Reprinted
with permission by FDB, Inc. All rights reserved. ©2014. www.fdbhealth.
com/policies/drug-pricing-policy. Actual retail prices may be higher.

The Medical Letter • Volume 56 • Issue 1441 • April 28, 2014

35


IN BRIEF

Enteric-Coated Aspirin as an
Antiplatelet Drug
One of our readers has suggested that more attention
should have been paid to a study comparing the
antiplatelet effects of immediate-release and entericcoated aspirin that appeared in Circulation last
year.1 The safety benefits of enteric-coated aspirin
are unclear. It may protect against dyspepsia, but
not against major gastrointestinal bleeding, which is
thought to be mainly a systemic effect of prostaglandin
inhibition.
ANTIPLATELET EFFECTS OF ASPIRIN — Aspirin
irreversibly acetylates cyclooxygenase-1, blocking
thromboxane synthesis and inhibiting platelet
activation and aggregation for the life of the platelet
(5-7 days). Aspirin prophylaxis reduces the incidence
of myocardial infarction and/or death by 15-25% in
patients with coronary heart disease or ischemic
stroke, and in those undergoing angioplasty or a
coronary artery bypass graft. Aspirin can also prevent
myocardial infarction in asymptomatic men and
ischemic stroke in asymptomatic women, but the riskbenefit ratio is less favorable because the thrombotic
risk is lower and the benefit in preventing thrombosis
is offset by a small risk of gastrointestinal bleeding or

hemorrhagic stroke.2
THE STUDY — The effects of a single 325-mg dose
of immediate-release or enteric-coated aspirin on
platelet aggregation were assessed 4 or 8 hours postdose in 400 healthy volunteers. The rate of platelet
nonresponse (<60% inhibition of platelet aggregation)
to enteric-coated aspirin was 49% at 4 hours and 17%
at 8 hours; ex vivo addition of aspirin to the samples
reduced the rates of nonresponse to 12% and 0%,
respectively. The rate of nonresponse to immediaterelease aspirin was 0%.1
CONCLUSION — A study in healthy volunteers
(not patients with atherosclerosis) of the effect
of a single 325-mg dose of immediate-release or
enteric-coated aspirin (not the usual recommended
maintenance dose of 81 mg) on platelet response
(not cardiovascular events) has limited applicability
to clinical practice. Nevertheless, most patients who
take aspirin for prophylaxis might be well advised to
take regular aspirin.

Coming Soon in The Medical Letter:
Avanafil (Stendra) for Erectile Dysfunction
Treatment of MRSA Skin and Soft-Tissue Infections
Coming Soon in Treatment Guidelines:
Drugs for Hypertension
Adult Immunizations

The Medical Letter

®

On Drugs and Therapeutics
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Jane P. Gagliardi, M.D., M.H.S., F.A.C.P Duke University School of Medicine
Jules Hirsch, M.D., Rockefeller University
David N. Juurlink, BPhm, M.D., Ph.D., Sunnybrook Health Sciences Centre
Richard B. Kim, M.D., University of Western Ontario
Hans Meinertz, M.D., University Hospital, Copenhagen
Sandip K. Mukherjee, M.D., F.A.C.C., Yale School of Medicine
Dan M. Roden, M.D., Vanderbilt University School of Medicine
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F. Estelle R. Simons, M.D., University of Manitoba
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1. T Grosser et al. Drug resistance and pseudoresistance: an unintended consequence of enteric coating aspirin. Circulation 2013;
127:377.
2. Antithrombotic drugs. Treat Guidel Med Lett 2011; 9:61.

36

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The Medical Letter • Volume 56 • Issue 1441 • April 28, 2014


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Issue 1441 Questions
(Correspond to questions #49-54 in

Comprehensive Exam #70, available July 2014)
Conjugated Estrogens/Bazedoxifene (Duavee) for Menopausal
Symptoms and Prevention of Osteoporosis
1.

Bazedoxifene has estrogen-like effects on:
a. bone
b. breast
c. uterus
d. all of the above

2.

In clinical trials, conjugated estrogens/bazedoxifene did not cause:
a. vaginal bleeding
b. an increase in breast density
c. breast pain
d. any of the above

Tasimelteon (Hetlioz) for Non-24-Hour Sleep-Wake Disorder
3.

In clinical trials in non-24 patients, the mean increase in nighttime
sleep with tasimelteon was about:
a. ½ to 1 hour
b. 2 hours
c. 3 hours
d. 4 hours

4.

A 42-year-old blind man with non-24 and no health insurance asks
you if he could use melatonin instead of Hetlioz to treat his sleep
disorder. You could tell him that:
a. melatonin has not been approved by the FDA
b. melatonin is available as a dietary supplement
c. whether melatonin would be as effective as tasimelteon
has not been established
d. all of the above

Enteric-Coated Aspirin as an Antiplatelet Drug
5.

A single dose of aspirin has an antiplatelet effect for:
a. 4-6 hours
b. 24 hours
c. 5-7 days
d. 30 days

6.

In the study of the effect of 325 mg of aspirin on platelets in healthy
volunteers, the rate of non-response to immediate-release (not entericcoated) aspirin was:
a. 0%
b. 10%
c. 30%
d. 50%

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Comprehensive Exam 70: 0379-0000-14-070-H01-P; Release: July 2014, Expire: July 2015

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management. Activity participants will make independent and informed therapeutic choices in their practice.
Upon completion of this program, the participant will be able to:
1. Review the efficacy and safety of the combination of conjugated estrogens and the estrogen agonist/antagonist bazedoxifene
(Duavee) for treatment of menopausal vasomotor symptoms and prevention of postmenopausal osteoporosis.
2. Review the efficacy and safety of tasimelteon (Hetlioz) for treatment of non-24-hour sleep-wake disorder.
3. Compare the antiplatelet effect of enteric-coated and regular aspirin.
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card information is stored.
IT Requirements: Windows 98/NT/2000/XP/Vista/7/8, Pentium+ processor, Mac OS X+ w/compatible processor;
Microsoft IE 6.0+, Mozilla Firefox 2.0+ or any other compatible Web browser. Dial-up/high-speed connection.
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