The medical letter on drugs and therapeutics september 28 2015

The Medical Letter

®

on Drugs and Therapeutics
Objective Drug Reviews Since 1959
Volume 57

ISSUE
ISSUE
No.

1433
1478
Volume 56

September 28, 2015

IN THIS ISSUE

Flibanserin (Addyi) for Hypoactive Sexual Desire Disorder...............................................p 133
Naloxegol (Movantik) for Opioid-Induced Constipation ....................................................p 135
Racemic Amphetamine Sulfate (Evekeo) for ADHD ...........................................................p 137

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


Revised 10/20/15: See next page.

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
Objective Drug Reviews Since 1959

Volume 57

ISSUE

ISSUE No.

1433
1478

Volume 56

▶

September 28, 2015
Take CME Exams
ALSO IN THIS ISSUE

Naloxegol (Movantik) for Opioid-Induced Constipation ....................................................p 135
Racemic Amphetamine Sulfate (Evekeo) for ADHD ...........................................................p 137

Flibanserin (Addyi) for Hypoactive
Sexual Desire Disorder

The FDA has approved flibanserin (Addyi – Sprout) for
treatment of premenopausal women with acquired,
generalized hypoactive sexual desire disorder
(HSDD) not caused by another medical or psychiatric
condition, the effects of another drug, or relationship
difficulties. Flibanserin is the first drug to be approved
for treatment of HSDD. It is not approved for use
in men or postmenopausal women. Previous FDA
reviews of flibanserin in 2010 and 2013 did not result
in approval.
Pronunciation Key
Flibanserin: flib an' ser in
Addyi: add' ee

THE DISORDER — HSDD is defined as a deficiency
or lack of sexual thoughts or desire that causes

personal distress or interpersonal difficulty. It
is characterized as lifelong or acquired, and as
situational (related to a specific partner, situation,
or type of stimulation) or generalized. Estimates of
the prevalence of HSDD in women vary widely; one
study found that 14% of premenopausal women 2049 years old have HSDD.1
STANDARD TREATMENT — No drug has clearly
been shown to be effective in treating pre- or
postmenopausal women with HSDD, and none has
previously been approved for such use by the FDA.
Psychotherapy and cognitive behavioral therapy may
be helpful.2,3
MECHANISM OF ACTION — The mechanism of action
of flibanserin in treating HSDD is unknown. It is an
agonist at serotonin 5-HT1A receptors and an antagonist at 5-HT2A receptors. In animal models, the drug
decreases serotonin and increases norepinephrine
and dopamine levels in the prefrontal cortex.4

Table 1. Pharmacology
Formulation

100 mg tablets

Route

Oral

Tmax

0.8-1.8 hours

Metabolism

Hepatic; primarily by CYP3A4 and to a
lesser extent by CYP2C19

Elimination

Feces (51%); urine (44%)

Half-life (terminal)

11 hours

CLINICAL STUDIES — Three randomized, double-blind,
24-week trials compared flibanserin 100 mg/day
at bedtime to placebo in premenopausal women with
acquired, generalized HSDD of at least 6 months'
duration. The coprimary endpoints were changes from
baseline at week 24 in the number of satisfying sexual
events and the frequency and intensity of experiencing
sexual desire over the previous 4 weeks. Results are
summarized in Table 2.
Table 2. Some Flibanserin Clinical Trials
Mean Increase Mean Increase
in SSE/28 Days in Desire Score
at 24 Weeks
at 24 Weeks

Trial (n)

Treatment
Arms

DAISY1
(n=793)

Flibanserin
Placebo

1.94
1.1

8.55
6.8

VIOLET2
(n=585)

Flibanserin
Placebo

1.64
0.8

9.15
6.9

BEGONIA3
(n=1087)

Flibanserin
Placebo

2.54
1.5

1.04,6
0.7

SSE = satisfying sexual experiences
1. J Thorp et al. J Sex Med 2012; 9:793.
2. LR DeRogatis et al. J Sex Med 2012; 9:1074.
3. M Katz et al. J Sex Med 2013; 10:1807.
4. p <0.05 vs placebo.
5. Graded using the e-Diary Desire score (range 0-84), which sums daily
peak intensity of sexual desire over the previous 4 weeks.
6. Graded using the Desire Domain of the Female Sexual Function Index,
which measures frequency and intensity of sexual desire over the
previous 4 weeks with a score range of 1.2-6.0.

An FDA-conducted responder analysis asked women
in the 3 trials to assess their changes in sexual desire
and frequency of satisfying sexual events after 24
weeks. Those who found their condition was “very
much improved” or “much improved” were considered
133

Published by The Medical Letter, Inc. • A Nonprofit Organization

Revised 10/20/15: The price for flibanserin has been included in the Cost paragraph.

The Medical Letter

®

Vol. 57 (1478)

September 28, 2015

responders. The placebo-adjusted response rate with
flibanserin ranged from 10% to 13% for the desire
endpoint (NNT 7.7-10.0) and from 8% to 9% for the
satisfying sexual events endpoint (NNT 11.1-12.5).5

PREGNANCY — In animal studies of flibanserin,
fetal toxicity was observed only in the presence of
significant maternal toxicity. The drug has not been
studied in pregnant women.

In another double-blind trial, 333 premenopausal
women with HSDD who had responded to 24 weeks
of treatment with flibanserin were randomized to
continue taking the active drug or to switch to placebo
for an additional 24 weeks. The frequency of satisfying
sexual events declined significantly less in women
taking flibanserin than in those switched to placebo
(-1.4 vs -2.3 events/4 weeks). The authors speculate
that the decline in sexually satisfying events in the

flibanserin-continued group could have been due to a
negative placebo effect.6

DRUG INTERACTIONS — Use of flibanserin with other
CNS depressants, such as opioids or hypnotics, could
increase the risk of CNS depression.

ADVERSE EFFECTS — In clinical trials, 21% of premenopausal women with HSDD taking flibanserin and 8% of
those taking placebo experienced symptoms of CNS
depression such as somnolence, sedation, and fatigue.
Other adverse effects occurring in ≥2% of women taking
the drug and more frequently than with placebo included
dizziness, nausea, insomnia, and dry mouth. Adverse effects led to discontinuation in 13% of women taking the
active drug and in 6% of those taking placebo.
Severe hypotension and syncope have been reported
in patients taking flibanserin. Use of alcohol
increases this risk and is contraindicated; the labeling
recommends that healthcare providers assess the
likelihood of abstention from alcohol before prescribing the drug. In an unpublished study (summarized in
the package insert), among 23 mostly male subjects
given 0.4 mg/kg of alcohol (the equivalent of two
5-ounce glasses of wine in a 70-kg person) with 100 mg
of flibanserin, 4 (all males) experienced hypotension
(-28 to -54 mmHg systolic; -24 to -46 diastolic) and/or
syncope requiring therapeutic intervention.
Hepatic impairment increases exposure to flibanserin,
increasing the risk of hypotension, syncope, and CNS
depression. The drug is contraindicated in women
with any degree of hepatic impairment.
In clinical trials, 6 of 3973 patients taking flibanserin

developed appendicitis, compared to none taking
placebo; a cause-and-effect relationship has not been
established.
In a 2-year study in rodents, a small dose-related
increase in malignant mammary tumors was observed
in female mice receiving 3-10 times the recommended
dose of flibanserin. Cancer rates were not increased in
male mice or in rats.
134

Concurrent use of strong or moderate CYP3A4
inhibitors, such as clarithromycin or fluconazole, significantly increases exposure to flibanserin and is
contraindicated. The drug should not be taken within
2 days before treatment with a strong or moderate
CYP3A4 inhibitor (if possible), or within 2 weeks
after treatment with one. Women taking a strong
CYP2C19 inhibitor, such as fluvoxamine, or multiple
weak CYP3A4 inhibitors, such as oral contraceptives
or cimetidine, concurrently with flibanserin should
be counseled about the possibility of an increased
risk of hypotension, syncope, and CNS depression.
Concurrent use of CYP3A4 inducers, such as rifampin,
significantly reduces flibanserin exposure and is not
recommended.7 Flibanserin increases exposure to
the P-glycoprotein substrate digoxin and the CYP3A4
substrate simvastatin.
DOSAGE, ADMINISTRATION, AND COST — The
recommended dosage of flibanserin is 100 mg taken
once daily at bedtime. Taking the drug during waking
hours increases the risk of injury related to hypotension,

syncope, and CNS depression. If a dose is missed, it
should be skipped. The drug should be discontinued
after 8 weeks if symptoms of HSDD do not improve.
According to the manufacturer, the wholesale acquisition
cost of a 30-tablet bottle of flibanserin is $800.
As part of a Risk Evaluation and Mitigation Strategy
(REMS) program, the FDA requires healthcare providers
to receive training and certification before prescribing
or dispensing flibanserin. Prescriber counseling about
the risk of alcohol consumption must be documented.
CONCLUSION — Flibanserin (Addyi) is the first drug
approved by the FDA for treatment of hypoactive
sexual desire disorder in women. About 10% more
premenopausal women who took flibanserin reported
"much" or "very much" improvement in their condition,
compared to those who took placebo. The drug must
be taken every day, and it can cause hypotension,
syncope, and CNS depression. Consumption of alcohol
during treatment with flibanserin increases the risk of
these effects and is contraindicated. Flibanserin is
likely to interact with many other drugs, and its longterm safety is unknown. ■


The Medical Letter

®

1. SR Leiblum et al. Hypoactive sexual desire disorder in postmenopausal women: US results from the Women’s International Study
of Health and Sexuality (WISHeS). Menopause 2006; 13:46.
2. Drugs for female sexual dysfunction. Med Lett Drugs Ther

2010; 52:100.
3. S Frühauf et al. Efficacy of psychological interventions for sexual dysfunction: a systematic review and meta-analysis. Arch
Sex Behav 2013; 42:915.
4. SM Stahl et al. Multifunctional pharmacology of flibanserin:
possible mechanism of therapeutic action in hypoactive sexual
desire disorder. J Sex Med 2011; 8:15.
5. FDA Summary Review for Regulatory Action. Available at:
www.accessdata.fda.gov/drugsatfda_docs/nda/2015/022526
Orig1s000SumR.pdf.
6. ER Goldfischer et al. Continued efficacy and safety of flibanserin in premenopausal women with hypoactive sexual desire
disorder (HSDD): results from a randomized withdrawal trial. J
Sex Med 2011; 8:3160.
7. Inhibitors and inducers of CYP enzymes and P-glycoprotein.
Med Lett Drugs Ther 2013; 55:e44.

▶

Naloxegol (Movantik) for OpioidInduced Constipation

The FDA has approved naloxegol (Movantik –
AstraZeneca), a pegylated derivative of the opioid
antagonist naloxone, for oral treatment of opioidinduced constipation in adults with chronic noncancer
pain. It is the only oral opioid antagonist approved for
this indication in the US.
Pronunciation Key
Naloxegol: nal ox’ ee gol
Movantik: mo van' tic

Vol. 57 (1478)

September 28, 2015

inhibition of water and electrolyte secretion, and
increased rectal sphincter tone.5 Naloxegol is a
peripheral mu-opioid receptor antagonist. Pegylation
reduces the ability of naloxegol to cross the bloodbrain barrier and makes it a substrate of the efflux
transporter P-glycoprotein; these properties are
thought to minimize its interference with opioid
analgesic effects in the CNS.
Table 1. Pharmacology
Class
Formulation
Route
Tmax
Metabolism
Elimination
Half-life

Peripherally-acting mu-opioid receptor
antagonist
12.5, 25 mg tablets
Oral
<2 hours
Primarily by CYP3A
Feces (68%); urine (16%)
6-11 hours

CLINICAL STUDIES — FDA approval of naloxegol
was based on two identically designed 12-week
trials in 652 and 700 patients with opioid-induced

constipation who had been taking a stable dose of
an oral opioid for noncancer pain.6 Patients were
randomized to once-daily treatment with naloxegol
12.5 or 25 mg or placebo. Response was defined as
≥3 spontaneous bowel movements (SBMs) per week
for 12 weeks and an increase from baseline of at least
1 SBM per week for ≥9 of the 12 weeks and ≥3 of the
final 4 weeks of the trial. Regular laxative use was
prohibited during the trials.

STANDARD TREATMENT — Laxatives and stool
softeners are commonly used, often in combination,
for initial treatment of opioid-induced constipation,
but their efficacy is limited. Methylnaltrexone
(Relistor), a subcutaneously injected opioid antagonist, and lubiprostone (Amitiza), an oral chloride
channel activator, are effective in increasing the
frequency of bowel movements in patients with
opioid-induced constipation and are FDA-approved
for such use.1-3 Alvimopan (Entereg), an oral muopioid receptor antagonist, has also been shown
to be effective in patients with opioid-induced
constipation, but it is approved only for short-term
in-hospital treatment of postoperative ileus because
of a possible risk of myocardial infarction with longterm use.4

Significantly more patients responded to naloxegol
25 mg than to placebo in both trials (44% and 40%,
respectively, vs 29%). The response rate with the
12.5-mg dose was significantly higher than with
placebo in the first trial, but not in the second (41%
and 35% vs 29%). Prespecified subgroup analyses of

patients who met criteria for an inadequate response
to laxatives before randomization found that their
response rates (a secondary endpoint) were similar
to those of the overall study population (43% and
49% with naloxegol 12.5 and 25 mg, respectively,
vs 29% with placebo in the first trial, and 47% with
naloxegol 25 mg vs 31% with placebo in the second).
Median times to first post-dose SBM (another
secondary endpoint) in the two studies were 6 and
12 hours with naloxegol 25 mg, compared to 36 and
37 hours with placebo.

MECHANISM OF ACTION — Opioids exert their
analgesic effect by stimulating mu receptors in the
central nervous system (CNS), but they also stimulate
peripheral mu receptors in the gastrointestinal (GI)
tract, leading to decreased muscle contractility,

ADVERSE EFFECTS — The adverse effects of
naloxegol are dose-related; the most common have
been GI-related, including abdominal pain, diarrhea,
nausea, flatulence, and vomiting. Patients who were
receiving methadone as their analgesic had a higher
135


The Medical Letter

®

Vol. 57 (1478)

September 28, 2015

Table 2. FDA-Approved Drugs for Opioid-Induced Constipation
Drug

Formulations

Usual Adult Dosage

Response Rate
(Active Drug vs Placebo)1

Cost2

Mu-Opioid Receptor Antagonists
Naloxegol – Movantik
(AstraZeneca)

12.5, 25 mg tabs

25 mg PO once daily3

35-44% vs 29%

$249.60

Methylnaltrexone – Relistor
(Salix/Valeant)

8 mg/0.4 mL single-use syringes,
12 mg/0.6 mL single-use vials,
syringes

12 mg SC once daily4

59% vs 38%

2161.80

8, 24 mcg caps

24 mcg PO bid5

27% vs 19%

314.50

Chloride Channel Activator
Lubiprostone – Amitiza
(Sucampo/Takeda)

1. In pivotal clinical trials with a primary endpoint that consisted of having ≥3 SBMs per week during a 4-week treatment period (methylnaltrexone), that included
having ≥3 SBMs per week for at least 9 of 12 treatment weeks (lubiprostone), or that included having ≥3 SBMs per week during a 12-week treatment period
(naloxegol), as summarized in the package insert for each drug.
2. Approximate WAC for 30 days’ treatment. 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. September 5, 2015. Reprinted with permission by
First Databank, Inc. All rights reserved. ©2015. www.fdbhealth.com/policies/drug-pricing-policy.
3. Patients who cannot tolerate the higher dose can take 12.5 mg once daily. Tablets should be taken in the morning at least 1 hour before or 2 hours after a meal.

Starting dosage for patients with a CrCl <60 mL/min is 12.5 mg once daily.
4. Dosage for noncancer pain. For patients with advanced illness, the drug should be given every other day at a dose of 8 mg SC for patients weighing 38 to <62
kg, 12 mg SC for those weighing 62-114 kg, or 0.15 mg/kg SC for those weighing <38 kg or >114 kg. In patients with a CrCl <30 mL/min, the dose should be
reduced by one-half.
5. Taken with food and water. The recommended starting dosage is 16 mcg bid for patients with moderate hepatic impairment and 8 mcg bid for those with
severe hepatic impairment.

rate of GI adverse effects than those receiving other
opioids. GI perforation has been reported with use
of methylnaltrexone; naloxegol is contraindicated in
patients with GI obstruction or at increased risk of
recurrent obstruction. Possible opioid withdrawal
(defined as ≥3 adverse effects potentially related
to opioid withdrawal, such as hyperhidrosis, chills,
anxiety, or irritability, occurring on the same day and
not all GI-related) occurred in 3% of patients taking
naloxegol 25 mg and in 1% of patients taking 12.5 mg,
compared to <1% of those taking placebo.
In a 52-week, open-label safety and tolerability
study, 804 patients with opioid-induced constipation
were randomized to treatment with naloxegol 25 mg
or usual care with a laxative regimen. GI adverse
effects and headache occurred more frequently with
naloxegol than with usual care. Rates were similar
to those observed in the 12-week efficacy studies.
No drug-related cases of bowel perforation, opioid
withdrawal, or major cardiovascular adverse events
were reported, and pain scores and mean daily opioid
doses were stable throughout the study in patients
treated with naloxegol.7

PREGNANCY — Naloxegol is classified as category
C for use during pregnancy. There are no adequate
studies in pregnant women. No adverse effects were
observed in pregnant animals given very high doses of
the drug. Use of naloxegol in women who are pregnant
or breastfeeding could precipitate opioid withdrawal
in the fetus or infant because of an immature bloodbrain barrier.
136

DRUG INTERACTIONS — Coadministration of
naloxegol and the strong CYP3A4 inhibitor
ketoconazole resulted in a 12.85-fold increase in
naloxegol exposure. Such increases could result
in opioid withdrawal; concomitant use of naloxegol
with any strong CYP3A4 inhibitor is contraindicated.
Concurrent administration of the moderate CYP3A4
inhibitor diltiazem increased serum concentrations
of naloxegol about 3-fold; the dosage of naloxegol
should be reduced to 12.5 mg daily if it must be
taken with a moderate CYP3A4 inhibitor. Patients
taking naloxegol should avoid consuming grapefruit
or grapefruit juice, which inhibit CYP3A4. Strong
CYP3A4 inducers such as rifampin can significantly
lower serum concentrations of naloxegol and
possibly reduce its efficacy.8
Taking naloxegol with another opioid antagonist
should be avoided because of possible additive effects
and an increased risk of opioid withdrawal.
DOSAGE AND ADMINISTRATION — All maintenance
laxatives should be stopped before initiating

treatment with naloxegol, but can be restarted after
3 days if symptoms persist. The recommended
dosage of naloxegol is 25 mg once daily in the
morning at least 1 hour before or 2 hours after
a meal; the daily dose can be reduced to 12.5
mg in patients who cannot tolerate the higher
dose. The starting dosage for patients with a CrCl
<60 mL/min is 12.5 mg once daily. Naloxegol tablets
should be swallowed whole and should not be
crushed or chewed.


The Medical Letter

®

CONCLUSION — Naloxegol (Movantik) is the first
oral mu-opioid receptor antagonist to be approved
for treatment of opioid-induced constipation. It may
be more effective than lubiprostone (Amitiza) and
is cheaper and more convenient to administer than
methylnaltrexone (Relistor), the other drugs approved
for this indication, but no direct comparisons are
available. It has not been studied in patients taking
opioids for cancer pain. Laxatives and stool softeners
should generally be tried first. ■
1. Methylnaltrexone (Relistor) for opioid-induced constipation.
Med Lett Drugs Ther 2008; 50:63.
2. Lubiprostone (Amitiza) for opioid-induced constipation. Med
Lett Drugs Ther 2013; 55:47.

3. W Siemens et al. Advances in pharmacotherapy for opioid-induced constipation – a systematic review. Expert Opin Pharmacother 2015; 16:515.
4. Alvimopan (Entereg) for postoperative ileus. Med Lett Drugs
Ther 2008; 50:93.
5. HC Bruner et al. Clinical utility of naloxegol in the treatment of
opioid-induced constipation. J Pain Res 2015; 8:289.
6. WD Chey et al. Naloxegol for opioid-induced constipation in patients with noncancer pain. N Engl J Med 2014; 370:2387.
7. L Webster et al. Randomised clinical trial: the long-term
safety and tolerability of naloxegol in patients with pain and
opioid-induced constipation. Aliment Pharmacol Ther 2014;
40:771.
8. Inhibitors and inducers of CYP enzymes and P-glycoprotein.
Med Lett Drugs Ther 2013; 55:e44.

▶

Racemic Amphetamine Sulfate
(Evekeo) for ADHD

The FDA has approved racemic amphetamine sulfate
(Evekeo – Arbor) for oral treatment of attention-deficit/
hyperactivity disorder (ADHD) in children ≥3 years old.
It was also approved for treatment of narcolepsy in
patients ≥6 years old and for short-term treatment of
obesity in patients ≥12 years old.
Pronunciation Key
Evekeo: eh vee' key oh

AMPHETAMINES FOR ADHD ― Amphetamines
generally have been as effective as methylphenidate
in decreasing overactivity, impulsivity, and inattention

in children with ADHD. Some children who have not
responded to methylphenidate may respond to an
amphetamine, and vice versa. Dextroamphetamine,
mixed amphetamine salts, and lisdexamfetamine
dimesylate, an oral prodrug of dextroamphetamine,
vary in their durations of action, but appear to be
similar in efficacy.1 All stimulants used for treatment
of ADHD are classified as schedule II controlled
substances by the DEA.

Vol. 57 (1478)

September 28, 2015

Table 1. Pharmacology
Formulation

5, 10 mg tablets

Route

Oral

Tmax

~ 3 hours

Elimination

Primarily in urine (amount varies with

urinary pH)

Half-life

9-14 hours

A CLINICAL STUDY ― The FDA did not require the
manufacturer of Evekeo to submit any new clinical
data to establish the efficacy and safety of the drug;
approval was based on earlier clinical trials with
racemic amphetamine.
In a randomized, double-blind, placebo-controlled
trial, 107 children 6-12 years old with ADHD were
titrated to an optimal dose of Evekeo twice daily
over 8 weeks, followed by crossover treatment for
1 week each with placebo and the active drug once
daily in the morning. After each 1-week treatment
period, the children were evaluated using the SKAMPTotal score, which measures ADHD symptoms in a
laboratory school setting, at 6 time points between
0.75 and 10 hours post-dose. SKAMP-Total scores
were significantly better with the active drug than
with placebo at each of the 6 time points. ADHD
symptoms, as measured by the ADHD Rating Scale-IV
questionnaire, also improved from baseline each week
through week 8.2
ADVERSE EFFECTS ― Data on the safety of
amphetamines in children <6 years old are limited. The
most common adverse effects of Evekeo in the trial
in children 6-12 years old were decreased appetite,
abdominal pain, irritability, and headache.

Adverse effects of stimulants generally include
anorexia, failure to gain weight, tachycardia,
irritability, insomnia, motor or vocal tics and, rarely,
priapism and peripheral vasculopathy. Stimulants
can slow growth; the effect on final adult height is
unclear. Some children, especially teenagers, say
that stimulants make them feel less spontaneous
and less comfortable in their social interactions.
Stimulants can induce or exacerbate symptoms
in patients with psychiatric disorders; these drugs
should be used with caution in patients with a
history of mania, psychosis, drug dependence, or
alcoholism.
Several large studies have found no evidence that
stimulants used to treat ADHD increase the risk of
serious cardiovascular events in children or adults.3-5
Patients with no history or clinical signs of heart disease
137


The Medical Letter

®

Vol. 57 (1478)

September 28, 2015

Table 2. Some Amphetamines for ADHD
Drug

Dextroamphetamine3,4
short-acting – generic
Dexedrine (Amedra)
Zenzedi (Arbor)
long-acting – generic
Dexedrine Spansule (Amedra)
Dextroamphetamine Prodrug3
Lisdexamfetamine dimesylate
Vyvanse (Shire)
Mixed Amphetamine Salts3
short-acting – generic
Adderall (Teva)
long-acting – generic
Adderall XR (Shire)
Racemic Amphetamine Sulfate3
Evekeo (Arbor)

Some Available Formulations

Duration
of Action

Pediatric Dosage1
Initial/Usual

Cost2

5, 10 mg tabs; 5 mg/5 mL soln
5, 10 mg tabs
2.5, 5, 7.5, 10, 15, 20, 30 mg tabs

5, 10, 15 mg SR caps6

4-6 h

5 mg qAM or bid5/10 mg bid

142.30
342.00
318.00
147.30
504.30

6-8 h

5 mg qAM or bid/15 mg qAM

10, 20, 30, 40, 50, 60, 70 mg caps7

13-14 h8

30 mg qAM/30-70 mg qAM

227.70

5, 7.5, 10, 12.5, 15, 20, 30 mg tabs

4-6 h

5 mg qAM or bid5/10 mg bid

5, 10, 15, 20, 25, 30 mg caps7

10-12 h

5-10 mg qAM/30 mg qAM

141.60
295.20
156.50
213.60

5, 10 mg tabs

10 h9

5 mg qAM or bid5/2.5-5 mg bid

297.60

SR = sustained release
1. Dosage for children ≥6 years old.
2. Approximate WAC for 30 days’ treatment with the lowest usual pediatric 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.
September 5, 2015. Reprinted with permission by First Databank, Inc. All rights reserved. ©2015. www.fdbhealth.com/policies/drug-pricing-policy.
3. Taking the drug with gastrointestinal acidifying agents such as ascorbic acid or fruit juice decrease its absorption and alkalinizing agents such as sodium bicarbonate
increase its absorption. Drugs that acidify the urine can increase amphetamine excretion and those that alkalinize the urine can decrease its excretion.
4. FDA-approved only for use in children 3-16 years old (short-acting) or 6-16 years old (long-acting).
5. Initial dose for children 3-5 years old is 2.5 mg once daily.
6. Must be swallowed whole, not crushed or chewed.
7. The contents of the capsule may be sprinkled on a small amount of applesauce or yogurt and given immediately. Pharmacokinetics are identical whether the

beads are swallowed whole inside a capsule or sprinkled on food.
8. According to the manufacturer.
9. AC Childress et al. J Child Adolesc Psychopharmacol 2015; 25:402.

do not need an electrocardiogram or consultation with a
cardiologist before starting treatment with a stimulant.6
PREGNANCY ― Evekeo has not been studied in
pregnant women. Dextroamphetamine is embryotoxic
and teratogenic in mice. Infants born to mothers taking
amphetamine while pregnant have an increased risk of
premature delivery and low birth weight, and may need
treatment for neonatal withdrawal syndrome.
DRUG INTERACTIONS ― Like other stimulants,
Evekeo should not be administered concurrently with
a monoamine oxidase inhibitor, or within 14 days of
stopping one. Drugs that acidify the urine can increase
amphetamine excretion and those that alkalinize the
urine can decrease its excretion. Taking the drug with
gastrointestinal acidifying agents such as ascorbic
acid or fruit juice can decrease its absorption and
alkalinizing agents such as sodium bicarbonate can
increase its absorption.
DOSAGE AND ADMINISTRATION ― Evekeo is
available in 5- and 10-mg tablets containing racemic
amphetamine sulfate. The recommended starting
dosage for treatment of ADHD is 2.5 mg once daily in
the morning for children 3-5 years old and 5 mg once
or twice daily for those ≥6 years old. Additional doses
can be given every 4-6 hours as needed. The dose
can be increased in weekly increments of 2.5 mg for

138

children 3-5 years old and 5 mg for those ≥6 years old.
Evekeo is contraindicated in patients with advanced
arteriosclerosis, symptomatic cardiovascular disease,
moderate to severe hypertension, or hyperthyroidism.
CONCLUSION ― Racemic amphetamine sulfate
(Evekeo) has not been shown to offer any advantage
over other stimulants available for treatment of ADHD
in children. ■
1. Drugs for ADHD. Med Lett Drugs Ther 2015; 57:37.
2. AC Childress et al. The efficacy and safety of Evekeo, racemic
amphetamine sulfate, for treatment of attention-deficit/hyperactivity disorder symptoms: a multicenter, dose-optimized,
double-blind, randomized, placebo-controlled crossover laboratory classroom study. J Child Adolesc Psychopharmacol
2015; 25:402.
3. WO Cooper et al. ADHD drugs and serious cardiovascular events
in children and young adults. N Engl J Med 2011; 365:1896.
4. LA Habel et al. ADHD medications and risk of serious cardiovascular events in young and middle-aged adults. JAMA 2011;
306:2673.
5. H Schelleman et al. Cardiovascular events and death in children exposed and unexposed to ADHD agents. Pediatrics 2011;
127:1102.
6. SA Shahani et al. Attention deficit hyperactivity disorder
screening electrocardiograms: a community-based perspective. Pediatr Cardiol 2014; 35:485.

Follow us on Twitter

Like us on Facebook


The Medical Letter

®

Continuing Medical Education Program
medicalletter.org/cme-program
Earn Up To 52 Credits Per Year
Choose CME from The Medical Letter in the format that’s right for you!
▶ Comprehensive Exam – Available online or in print to Medical Letter subscribers, this 130 question exam enables you to earn 26 credits immediately
upon successful completion of the test. A score of 70% or greater is required to pass the exam. Our comprehensive exams allow you to test at your
own pace in the comfort of your home or office. Comprehensive exams are offered every January and July enabling you to earn up to 52 credits per
year. $49/exam.
▶ Free Individual Exams – Free to active subscribers of The Medical Letter. Answer 10 questions per issue and submit answers online. Earn 2 credits/exam.
A score of 70% or greater is required to pass the exam.
▶ Paid Individual Exams – Available to non-subscribers. Answer 10 questions per issue and submit answers online. Earn 2 credits/exam. $12/exam.
A score of 70% or greater is required to pass the exam.
ACCREDITATION INFORMATION:
ACCME: The Medical Letter is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The Medical
Letter designates this enduring material for a maximum of 2 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their
participation in the activity. This CME activity was planned and produced in accordance with the ACCME Essentials and Policies.
AAFP : This enduring material activity, The Medical Letter Continuing Medical Education Program, has been reviewed and is acceptable for up to 52 Prescribed credits by the
American Academy of Family Physicians. Term of approval begins January 1, 2015. Term of approval is for one year from this date. Each issue is approved for 2 Prescribed
credits. Credit may be claimed for one year from the date of each issue. Physicians should claim only the credit commensurate with the extent of their participation in the
activity.
ACPE: The Medical Letter is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. This exam is acceptable
for 2.0 hour(s) of knowledge-based continuing education credit (0.2 CEU).
The American Academy of Nurse Practitioners (AANP) and the American Academy of Physician Assistants (AAPA) accept AMA Category 1 credit for the Physician’s
Recognition Award from organizations accredited by the ACCME.
This activity, being ACCME (AMA) approved, is acceptable for Category 2-B credit by the American Osteopathic Association (AOA).
Physician Assistants: The National Commission on Certification of Physician Assistants (NCCPA) accepts AMA PRA Category 1 Credit(s)™ from organizations accredited by
ACCME. NCCPA also accepts AAFP Prescribed credits for recertification. The Medical Letter is accredited by both ACCME and AAFP.

Physicians in Canada: Members of The College of Family Physicians of Canada are eligible to receive Mainpro-M1 credits (equivalent to AAFP Prescribed credits) as per our
reciprocal agreement with the American Academy of Family Physicians.
MISSION:
The mission of The Medical Letter’s Continuing Medical Education Program is to support the professional development of healthcare providers including physicians, nurse
practitioners, pharmacists, and physician assistants by providing independent, unbiased drug information and prescribing recommendations that are free of industry influence.
The program content includes current information and unbiased reviews of FDA-approved and off-label uses of drugs, their mechanisms of action, clinical trials, dosage and
administration, adverse effects, and drug interactions. The Medical Letter delivers educational content in the form of self-study material.
The expected outcome of the CME program is to increase the participant’s ability to know, or apply knowledge into practice after assimilating, information presented in
materials contained in The Medical Letter.
The Medical Letter will strive to continually improve the CME program through periodic assessment of the program and activities. The Medical Letter aims to be a leader in
supporting the professional development of healthcare providers through Core Competencies by providing continuing medical education that is unbiased and free of industry
influence. The Medical Letter is supported solely by subscription fees and accepts no advertising, grants, or donations.
GOAL:
Through this program, The Medical Letter expects to provide the healthcare community with unbiased, reliable, and timely educational content that they will use to make
independent and informed therapeutic choices in their practice.
LEARNING OBJECTIVES:
Activity participants will read and assimilate unbiased reviews of FDA-approved and off-label uses of drugs and other treatment modalities. Activity participants will be
able to select and prescribe, or confirm the appropriateness of the prescribed usage of, the drugs and other therapeutic modalities discussed in The Medical Letter with
specific attention to clinical trials, pathophysiology, dosage and administration, drug metabolism and interactions, and patient 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 flibanserin (Addyi) for treatment of hypoactive sexual desire disorder in premenopausal women.
2.
Review the efficacy and safety of naloxegol (Movantik) for treatment of opioid-induced constipation.
3.
Review the efficacy and safety of racemic amphetamine sulfate (Evekeo) for treatment of ADHD in children.
Privacy and Confidentiality: The Medical Letter guarantees our firm commitment to your privacy. We do not sell any of your information. Secure server software (SSL) is used
for commerce transactions through VeriSign, Inc. No credit card information is stored.
IT Requirements: Windows XP/Vista/7/8, Mac OS X+; current versions of Microsoft IE, Mozilla Firefox, Google Chrome, Safari, or any other compatible web browser. Highspeed connection.

Have any questions? Call us at 800-211-2769 or 914-235-0500 or e-mail us at:

Questions start on next page


The Medical Letter

®

Online Continuing Medical Education
DO NOT FAX OR MAIL THIS EXAM
To take CME exams and earn credit, go to:

medicalletter.org/CMEstatus

Issue 1478 Questions
(Correspond to questions #61-70 in Comprehensive Exam #73, available January 2016)
Flibanserin (Addyi) for Hypoactive Sexual Desire Disorder
1. A recently divorced 66-year-old woman is in a new relationship,
but the absence of sexual desire has caused her some distress.
She has been taking Prozac since her divorce and wonders
if that could be responsible for her lack of interest in sex, but
she also feels less respect for this new man than she felt
for her husband of many years. Based on the FDA-approved
indications, she would not be a candidate for Addyi because:
a. she is not premenopausal
b. her lack of sexual desire appears to be situational
c. her lack of sexual desire could be caused by another drug
d. all of the above
2. In clinical trials, the absolute difference between the percentage

of women who responded to flibanserin and the percentage
who responded to placebo was about:
a. 10%
b. 20%
c. 40%
d. 60%
3. The risk of hypotension and syncope with flibanserin is
increased with concurrent use of:
a. rifampin
b. digoxin
c. alcohol
d. all of the above
4. Flibanserin should be taken:
a. as needed 45 minutes before sexual activity
b. as needed 2 hours before sexual activity
c. as needed 1-6 hours before sexual activity
d. once daily at bedtime
Naloxegol (Movantik) for Opioid-Induced Constipation
5. Naloxegol is:
a. pegylated naloxone
b. taken orally
c. a mu-opioid receptor antagonist
d. all of the above

6. Taking naloxegol with a strong CYP3A4 inhibitor:
a. reduces its efficacy
b. may reduce the risk of opioid withdrawal
c. could increase its serum concentrations and possibly
result in opioid withdrawal
d. reduces the risk of GI adverse effects

7. A 65-year-old woman taking oxycodone for chronic pain due to
a lower back injury has developed opioid-induced constipation.
She has been taking senna and lactulose with little response.
You are considering treating her with naloxegol. Which of the
following statements about naloxegol is true for this patient?
a. it is FDA-approved only for use in patients with chronic
cancer pain
b. it is not effective in patients with an inadequate response
to laxatives
c. she should take naloxegol and methylnaltrexone
concurrently for better efficacy
d. she should stop her laxatives before starting treatment
with naloxegol
Racemic Amphetamine Sulfate (Evekeo) for ADHD
8. Compared to methylphenidate for treatment of ADHD,
amphetamines generally have been:
a. as effective
b. less effective
c. more effective
d. more likely to cause adverse effects
9. Adverse effects of stimulants generally include:
a. failure to gain weight
b. insomnia
c. motor or vocal tics
d. all of the above
10. If once- or twice-daily administration of Evekeo does not
control symptoms, additional doses can be given:
a. once in any 24-hour period
b. 8-12 hours after the last dose
c. every 4-6 hours as needed

d. every 8 hours as needed

ACPE UPN: Per Issue Exam: 0379-0000-15-478-H01-P; Release: September 28, 2015, Expire: September 28, 2016
Comprehensive Exam 73: 0379-0000-16-073-H01-P; Release: January 2016, Expire: January 2017

EDITOR IN CHIEF: Mark Abramowicz, M.D.; EXECUTIVE EDITOR: Gianna Zuccotti, M.D., M.P.H., F.A.C.P., Harvard Medical School; EDITOR: Jean-Marie Pflomm, Pharm.D.;
ASSISTANT EDITORS, DRUG INFORMATION: Susan M. Daron, Pharm.D., Corinne Z. Morrison, Pharm.D., Michael P. Viscusi, Pharm.D.; CONSULTING EDITORS: Brinda M. Shah, Pharm.D.,
F. Peter Swanson, M.D; SENIOR ASSOCIATE EDITOR: Amy Faucard
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;
Eric J. Epstein, M.D., Albert Einstein College of Medicine; Jane P. Gagliardi, M.D., M.H.S., F.A.C.P., Duke University School of Medicine; David N. Juurlink, BPhm, M.D., Ph.D.,
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
University
MANAGING EDITOR: Susie Wong; ASSISTANT MANAGING EDITOR: Liz Donohue; EDITORIAL ASSISTANT: Cheryl Brown
EXECUTIVE DIRECTOR OF SALES: Gene Carbona; FULFILLMENT & SYSTEMS MANAGER: Cristine Romatowski; DIRECTOR OF MARKETING COMMUNICATIONS: Joanne F. Valentino;
VICE PRESIDENT AND PUBLISHER: Yosef Wissner-Levy
Founded in 1959 by
Arthur Kallet and Harold Aaron, M.D.
Copyright and Disclaimer: The Medical Letter, Inc. is an independent nonprofit organization that provides healthcare professionals with unbiased drug prescribing recommendations. The editorial
process used for its publications relies on a review of published and unpublished literature, with an emphasis on controlled clinical trials, and on the opinions of its consultants. The Medical Letter,
Inc. is supported solely by subscription fees and accepts no advertising, grants, or donations. No part of the material may be reproduced or transmitted by any process in whole or in part without
prior permission in writing. The editors do not warrant that all the material in this publication is accurate and complete in every respect. The editors shall not be held responsible for any damage
resulting from any error, inaccuracy, or omission.

Subscription Services
Address:
The Medical Letter, Inc.
145 Huguenot St. Ste. 312
New Rochelle, NY 10801-7537

www.medicalletter.org

Customer Service:
Call: 800-211-2769 or 914-235-0500
Fax: 914-632-1733
E-mail:

Permissions:
To reproduce any portion of this issue,
please e-mail your request to:


Copyright 2015. ISSN 1523-2859

Subscriptions (US):
1 year - $129; 2 years - $232;
3 years - $345. $65 per year
for students, interns, residents, and
fellows in the US and Canada.
Reprints - $12 each.

Site License Inquiries:
E-mail:
Call: 800-211-2769 ext. 315
Special rates available for bulk
subscriptions.
Get Connected: