The medical letter on drugs and therapeutics september 28 2015

1478 on Drugs and Therapeutics Objective Drug Reviews Since 1959 Flibanserin Addyi for Hypoactive Sexual Desire Disorder ...p 133 Naloxegol Movantik for Opioid-Induced Constipation ...p

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IN THIS ISSUE

ISSUE

1433

Volume 56

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

ISSUE No

1478

on Drugs and Therapeutics Objective Drug Reviews Since 1959

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

133

on Drugs and Therapeutics Objective Drug Reviews Since 1959

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ISSUE

1433

Volume 56

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1478 Naloxegol (Movantik) for Opioid-Induced Constipation p 135

Racemic Amphetamine Sulfate (Evekeo) for ADHD p 137

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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

diffi culties Flibanserin is the fi rst 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

Flibanserin (Addyi) for Hypoactive

Sexual Desire Disorder

▶

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

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

20-49 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

antago-nist at 5-HT2A receptors In animal models, the drug

decreases serotonin and increases norepinephrine

and dopamine levels in the pre frontal cortex.4

Table 1 Pharmacology

Formulation 100 mg tablets

Metabolism Hepatic; primarily by CYP3A4 and to a

lesser extent by CYP2C19 Elimination Feces (51%); urine (44%) Half-life (terminal) 11 hours

Table 2 Some Flibanserin Clinical Trials

Mean Increase Mean Increase Treatment in SSE/28 Days in Desire Score Trial (n) Arms at 24 Weeks at 24 Weeks

DAISY 1 Flibanserin 1.9 4 8.5 5 (n=793) Placebo 1.1 6.8 VIOLET 2 Flibanserin 1.6 4 9.1 5

(n=585) Placebo 0.8 6.9 BEGONIA 3 Flibanserin 2.5 4 1.0 4,6

(n=1087) Placebo 1.5 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

Revised 10/20/15: See next page.

The Medical Letter ® Vol 57 (1478) September 28, 2015

PREGNANCY — In animal studies of flibanserin,

fetal toxicity was observed only in the presence of signifi cant maternal toxicity The drug has not been studied in pregnant women

DRUG INTERACTIONS — Use of flibanserin with other

CNS depressants, such as opioids or hypnotics, could increase the risk of CNS depression

Concurrent use of strong or moderate CYP3A4 inhibitors, such as clarithromycin or fluconazole, sig-nifi cantly 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, signifi cantly 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 certifi cation before prescribing

or dispensing flibanserin Prescriber counseling about the risk of alcohol consumption must be documented

CONCLUSION — Flibanserin (Addyi) is the fi rst 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 long-term safety is unknown ■

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

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 signifi cantly 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

ADVERSE EFFECTS — In clinical trials, 21% of

premeno-pausal 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

ef-fects 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

prescrib-ing 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

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

The Medical Letter ® Vol 57 (1478) September 28, 2015

1 SR Leiblum et al Hypoactive sexual desire disorder in

postmeno-pausal 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 Effi cacy of psychological interventions for

sex-ual 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 Goldfi scher et al Continued effi cacy and safety of

fliban-serin 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.

Table 1 Pharmacology

Class Peripherally-acting mu-opioid receptor

antagonist Formulation 12.5, 25 mg tablets Route Oral

Tmax <2 hours Metabolism Primarily by CYP3A Elimination Feces (68%); urine (16%)

Naloxegol (Movantik) for

Opioid-Induced Constipation

▶

Pronunciation Key Naloxegol: nal ox’ ee gol Movantik: mo van' tic

The FDA has approved naloxegol (Movantik –

AstraZeneca), a pegylated derivative of the opioid

antagonist naloxone, for oral treatment of

opioid-induced constipation in adults with chronic noncancer

pain It is the only oral opioid antagonist approved for

this indication in the US

STANDARD TREATMENT — Laxatives and stool

softeners are commonly used, often in combination,

for initial treatment of opioid-induced constipation,

but their effi cacy is limited Methylnaltrexone

(Relistor), a subcutaneously injected opioid

antag-onist, 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

mu-opioid 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

long-term use.4

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,

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 defi ned 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

fi nal 4 weeks of the trial Regular laxative use was prohibited during the trials

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

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

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 blood-brain 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

The Medical Letter ® Vol 57 (1478) September 28, 2015

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 signifi cantly lower serum concentrations of naloxegol and possibly reduce its effi cacy.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

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

(defi ned 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 effi cacy 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 classifi ed 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

blood-brain barrier

Table 2 FDA-Approved Drugs for Opioid-Induced Constipation

Drug Formulations Usual Adult Dosage (Active Drug vs Placebo) 1 Cost 2

Mu-Opioid Receptor Antagonists

Naloxegol – Movantik 12.5, 25 mg tabs 25 mg PO once daily 3 35-44% vs 29% $249.60

(AstraZeneca)

Methylnaltrexone – Relistor 8 mg/0.4 mL single-use syringes, 12 mg SC once daily 4 59% vs 38% 2161.80

(Salix/Valeant) 12 mg/0.6 mL single-use vials,

syringes

Chloride Channel Activator

Lubiprostone – Amitiza 8, 24 mcg caps 24 mcg PO bid 5 27% vs 19% 314.50

(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.

The Medical Letter ® Vol 57 (1478) September 28, 2015

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-in-duced constipation – a systematic review Expert Opin

Phar-macother 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

pa-tients 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.

CONCLUSION — Naloxegol (Movantik) is the fi rst

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 fi rst ■

Racemic Amphetamine Sulfate

(Evekeo) for ADHD

▶

The FDA has approved racemic amphetamine sulfate

(Evekeo – Arbor) for oral treatment of attention-defi cit/

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

A CLINICAL STUDY ― The FDA did not require the

manufacturer of Evekeo to submit any new clinical

data to establish the effi cacy 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 SKAMP-Total 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 signifi cantly 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 fi nal 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

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 effi cacy.1 All stimulants used for treatment

of ADHD are classifi ed as schedule II controlled

substances by the DEA

Table 1 Pharmacology

Formulation 5, 10 mg tablets

Elimination Primarily in urine (amount varies with

urinary pH)

The Medical Letter ® Vol 57 (1478) September 28, 2015

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 effi cacy and safety of Evekeo, racemic amphetamine sulfate, for treatment of attention-defi cit/hy-peractivity disorder symptoms: a multicenter, dose-optimized, double-blind, randomized, placebo-controlled crossover labo-ratory 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 cardio-vascular events in young and middle-aged adults JAMA 2011; 306:2673

5 H Schelleman et al Cardiovascular events and death in chil-dren exposed and unexposed to ADHD agents Pediatrics 2011; 127:1102

6 SA Shahani et al Attention defi cit hyperactivity disorder screening electrocardiograms: a community-based perspec-tive Pediatr Cardiol 2014; 35:485.

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 Follow us on Twitter Like us on Facebook

Table 2 Some Amphetamines for ADHD

Dextroamphetamine 3,4

short-acting – generic 5, 10 mg tabs; 5 mg/5 mL soln 4-6 h 5 mg qAM or bid 5 /10 mg bid 142.30

long-acting – generic 5, 10, 15 mg SR caps 6 6-8 h 5 mg qAM or bid/15 mg qAM 147.30

Dextroamphetamine Prodrug 3

Lisdexamfetamine dimesylate 10, 20, 30, 40, 50, 60, 70 mg caps 7 13-14 h 8 30 mg qAM/30-70 mg qAM 227.70

Mixed Amphetamine Salts 3

short-acting – generic 5, 7.5, 10, 12.5, 15, 20, 30 mg tabs 4-6 h 5 mg qAM or bid 5 /10 mg bid 141.60

long-acting – generic 5, 10, 15, 20, 25, 30 mg caps 7 10-12 h 5-10 mg qAM/30 mg qAM 156.50

Racemic Amphetamine Sulfate 3

Evekeo (Arbor) 5, 10 mg tabs 10 h 9 5 mg qAM or bid 5 /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.

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Upon completion of this program, the participant will be able to:

1 Review the effi cacy and safety of flibanserin (Addyi) for treatment of hypoactive sexual desire disorder in premenopausal women.

2 Review the effi cacy and safety of naloxegol (Movantik) for treatment of opioid-induced constipation.

3 Review the effi cacy and safety of racemic amphetamine sulfate (Evekeo) for treatment of ADHD in children.

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Issue 1478 Questions

(Correspond to questions #61-70 in Comprehensive Exam #73, available January 2016)

6 Taking naloxegol with a strong CYP3A4 inhibitor:

a reduces its effi cacy

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 effi cacy

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

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

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 nonprofi t 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.

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