The medical letter on drugs and therapeutics march 16 2015

The Medical Letter

®

on Drugs and Therapeutics
Objective Drug Reviews Since 1959

Volume 57

ISSUE
ISSUE
No.

1433
1464
Volume 56

March 16, 2015

IN THIS ISSUE

Drugs for ADHD ......................................................................................................... p 37
VEGF Inhibitors for AMD and Diabetic Macular Edema ................................................ p 41
In Brief: Lisdexamfetamine (Vyvanse) for Binge Eating Disorder ................................ p 42

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The Medical Letter

®

on Drugs and Therapeutics
Objective Drug Reviews Since 1959

Volume 57

ISSUE

ISSUE No.

1433
1464
Volume 56

▶

March 16, 2015
Take CME exams
ALSO IN THIS ISSUE

VEGF Inhibitors for AMD and Diabetic Macular Edema.........................................................p 41
In Brief: Lisdexamfetamine (Vyvanse) for Binge Eating Disorder .......................................p 42

Drugs for ADHD
Related article(s) since publication

Attention-deficit/hyperactivity disorder (ADHD) is a
disruptive behavior disorder that has been diagnosed
in up to 10% of school-age children in the US, most
often in boys, and frequently persists into adulthood.1,2
A recent study in a large Danish cohort found that
ADHD was associated with increased mortality in
children, adolescents, and adults, mainly due to
accidents.3 Pharmacologic treatment of ADHD has
been reported to lower the risk of serious traffic
accidents and criminal behavior.4,5
The drugs approved by the FDA for treatment of ADHD
are listed in Table 1 on pages 38-39. None of these
agents (except for short-acting dextroamphetamine)
are approved for use in children <6 years old.
STIMULANTS
All of the stimulants used for treatment of ADHD are
classified as schedule II controlled substances by the

US Drug Enforcement Administration.
METHYLPHENIDATE — Methylphenidate has been
shown to be effective in reducing ADHD symptoms in
both children and adults.6,7
Short-Acting – Immediate-release methylphenidate
formulations are rapidly absorbed; effects on behavior
can be seen within 30 minutes of administration
and persist for 3-5 hours. Their short duration of
action usually requires mid-day dosing in school or
during after-school programs. Immediate-release
methylphenidate tablets are sometimes used in
addition to longer-acting formulations, either to
provide a boost early in the morning or to smooth
withdrawal in the late afternoon.

Recommendations for Treatment of ADHD

▶ Treatment of ADHD in school-age children or adults should

begin with an oral stimulant, either a methylphenidatebased formulation or an amphetamine.

▶ The choice of a drug should be based on its rapidity of
onset, duration of action, and effectiveness.

▶ Mixing short- and long-acting stimulants can be helpful
to achieve an immediate effect for early-morning school
classes or for reducing rebound irritability or overactivity,
especially in the evening.

▶ An extended-release alpha2-adrenergic agonist may be

helpful when used concurrently with a stimulant in patients
who cannot tolerate usual doses of the stimulant, particularly those with tics.

▶ Atomoxetine is an alternative for patients who cannot toler-

ate stimulants or for whom treatment with a controlled
substance is undesirable.

Intermediate-Acting – Extended-release methylphenidate formulations have a slower onset of action than
immediate-release methylphenidate and a duration
of action of up to 8 hours. These drugs may be
better tolerated by some children who are sensitive
to stimulant side effects, but they have been highly
variable in duration and efficacy, and are generally
viewed as less useful in practice than immediaterelease or long-acting methylphenidate formulations.
Long-Acting – Once-daily dosing with long-acting
methylphenidate preparations has become the
standard clinical practice. Concerta, which has a
longer duration of action than Metadate CD, Ritalin LA,
or their generic equivalents, has been as effective as
multiple doses of immediate-release methylphenidate
in reducing symptoms, but some Concerta generic
equivalents have been less effective.8,9
Transdermal methylphenidate (Daytrana) is probably as
effective as oral long-acting formulations of the drug,

37

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

The Medical Letter

Vol. 57 (1464)

®

March 16, 2015

Table 1. Some Drugs for ADHD
Drug

Some Available
Formulations

Stimulants
Dexmethylphenidate
generic
2.5, 5, 10 mg tabs
Focalin (Novartis)
extended-release – generic 5, 10, 15, 20, 30,
Focalin XR3,4
35, 40 mg ER caps5
Methylphenidate
short-acting
generic
5, 10, 20 mg tabs; 5 mg/
5 mL, 10 mg/5 mL soln
Ritalin (Novartis)

5, 10, 20 mg tabs
Methylin Chewable
2.5, 5, 10 mg tabs
Tablets (Mallinckrodt)
Methylin Oral Solution
5 mg/5 mL,
(Mallinckrodt)
10 mg/5 mL soln7
intermediate-acting
generic
10, 20 mg ER tabs8
Metadate ER (Upstate)
20 mg ER tabs8
long-acting
generic
10, 20, 30, 40,
Metadate CD9,10 (UCB)
50, 60 mg ER caps5
generic
20, 30, 40 mg ER caps5
Ritalin LA3,4,9 (Novartis)
10, 20, 30, 40 mg ER caps5
11,12
18, 27, 36, 54 mg ER tabs8
generic
Concerta12 (Janssen)
12.5, 18.75, 25, 37.5 cm2
Daytrana13 (Noven)
transdermal patch14
Quillivant XR15 (Pfizer)

25 mg/5 mL ER susp16

Duration
of Action

Pediatric Dosage1
Initial/Usual

Adult Dosage
Initial/Usual

5-6 h

2.5 mg bid/10 mg bid

5 mg bid/15 mg bid

12 h

5 mg qAM/10-20 mg qAM

10 mg qAM/30 mg qAM

3-5 h

5 mg bid or tid/10 mg tid

10 mg bid or tid/20 mg tid

Cost2

67.20
77.80
227.80
252.60

75.60
84.20
535.50
596.406

4-8 h

20 mg qAM/40 mg qAM

20 mg qAM/80 mg qAM

372.00
108.00

8-12 h

20 mg qAM/30 mg qAM

20 mg qAM/80 mg qAM

8-12 h

10-20 mg qAM/30 mg qAM

10-12 h

18 mg qAM/36 mg qAM

10-12 h

10 mg patch on 9 hrs,
off 15 hrs/30 mg patch
on 9 hrs, off 15 hrs
20 mg qAM/30-40 mg qAM

10-20 mg qAM/80 mg
qAM
18 or 36 mg qAM/72 mg
qAM
30 mg patch on 9 hrs, off
15 hrs/60 mg patch on
9 hrs, off 15 hrs
No data

135.00
206.60
130.20
212.70
208.40
265.10
251.00

12 h

192.90

ER = extended-release; 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. March 5,
2015. Reprinted with permission by First Databank, Inc. All rights reserved. ©2015. www.fdbhealth.com/policies/drug-pricing-policy.
3. Should not be taken with antacids or other drugs that decrease gastric acidity.
4. Contains 50% immediate-release beads and 50% enteric-coated, delayed-release beads.
5. The contents of the capsule may be sprinkled on a small amount of applesauce or ice cream to disguise the bitter taste and given immediately. Pharmacokinetics are identical whether the beads are swallowed whole inside a capsule or sprinkled on food.
6. Cost of one 10 mg/5 mL 500-mL bottle.
7. Available in bottles containing 500 mL.
8. Must be swallowed whole, not crushed or chewed.
9. Alcohol consumption may increase the rate of release of methylphenidate and should be avoided.
10. Contains 30% immediate-release and 70% delayed-release beads.
11. Some generic formulations (manufactured by Mallinckrodt and Kudco) may not be therapeutically equivalent to the brand name product. The generic
formulation that is manufactured by Janssen and marketed by Actavis is bioequivalent ( />12. Osmotic-release delivery system that contains 20% of the dose for immediate release and 80% sequestered inside the tablet for release over 6-7 hours.
13. FDA-approved only for use in children 6-17 years old.
14. The four patch sizes deliver 10, 15, 20, or 30 mg over 9 hours, respectively. Daytrana is supplied in sealed trays containing 10 or 30 patches in individual pouches.

but a 2-hour delay in its onset of action could be a major
disadvantage when getting children ready for school in
the morning. After application of the transdermal patch,
methylphenidate is steadily absorbed and reaches
peak serum concentrations after 7-9 hours. Peak
methylphenidate levels are higher with chronic doses
of the patch than with equivalent doses of Concerta.10
The duration of action for a 9-hour wear period is about
11.5 hours. Adverse effects such as anorexia, insomnia,

and tics have occurred more frequently with the patch
formulation than with oral formulations, which may be
related to the absence of first-pass metabolism, and
mild skin reactions are common.11 One advantage of
the patch formulation is that it can be removed early in
patients who have a problem with insomnia.
38

Quillivant XR is the first liquid formulation of
methylphenidate to be approved for once-daily use;
how it compares to other long-acting methylphenidate
products is unclear.12
AMPHETAMINES — 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 – The onset of action of  immediaterelease dextroamphetamine occurs within one hour
of ingestion, and its duration of action is 4-6 hours,
somewhat longer than that of methylphenidate.


The Medical Letter

Vol. 57 (1464)

®

March 16, 2015

Table 1. Some Drugs for ADHD (continued)
Drug
Stimulants (continued)
Dextroamphetamine3,17,18
short-acting – generic
Dexedrine (Amedra)
Zenzedi (Arbor)

Some Available
Formulations

Duration
of Action

5, 10 mg tabs; 5 mg/5 mL 4-6 h
soln
5, 10 mg tabs
2.5, 5, 7.5, 10, 15, 20,
30 mg tabs
5, 10, 15 mg SR caps8
6-8 h

long-acting – generic
Dexedrine Spansule (Amedra)
Mixed amphetamine salts3,17
short-acting – generic
5, 7.5, 10, 12.5,
Adderall (Teva)
15, 20, 30 mg tabs

long-acting – generic
5, 10, 15, 20, 25,
Adderall XR (Shire)
30 mg caps5
17
Lisdexamfetamine – Vyvanse 10, 20, 30, 40, 50, 60,
(Shire)
70 mg caps
Non-Stimulants
Guanfacine extended-release13
generic
1, 2, 3, 4 mg ER tabs8
Intuniv (Shire)
Clonidine extended-release13
generic
0.1 mg ER tabs8
Kapvay (Shionogi)

Atomoxetine – Strattera (Lilly) 10, 18, 25, 40,
60, 80, 100 mg caps

Pediatric Dosage1
Initial/Usual

5 mg qAM or bid19/10 mg bid

Adult Dosage
Initial/Usual

—

Cost2

142.30
342.00
318.00

5 mg qAM or bid/15 mg qAM

—

147.30
337.50

4-6 h

5 mg bid/10 mg bid

5 mg bid/15 mg bid

141.60
295.20
20 mg qAM/60 mg qAM
156.50
213.70
30 mg qAM/30-70 mg qAM 199.00

10-12 h

5-10 mg qAM/30 mg qAM

13-14 h20

30 mg qAM/30-70 mg qAM

8-24 h20

1 mg once daily/1-4 mg
once daily21

—

249.60
291.30

12 h20

0.1 mg once daily at bedtime/
0.1-0.4 mg once daily at
bedtime or divided bid22

—

114.00
157.50

24 h

0.5 mg/kg/d once daily or
divided bid/1.2 mg/kg/d

once daily or divided bid

40 mg once daily/80 mg
once daily or divided bid

302.7023

15. Contains 20% immediate-release and 80% extended-release drug particles.
16. Must be reconstituted before administration and is stable for up to 4 months. It is available in bottles containing 60, 120, 150, or 180 mL. Each bottle is
packaged with an adapter and dosing syringe.
17. Taking the drug with ascorbic acid or fruit juice decreases its absorption, while alkalinizing agents such as sodium bicarbonate increase its absorption.
Acidification of the urine increases amphetamine excretion.
18. FDA-approved only for use in children 3-16 years old (short-acting) or 6-16 years old (long-acting).
19. Initial dose for children 3-5 years old is 2.5 mg once daily.
20. According to the manufacturer.
21. Dosage can be increased in 1 mg/week increments to a maximum dose of 7 mg/day.
22. Up to 0.4 mg/day is FDA-approved but may be more likely to cause hypotension.
23. Cost of 40 mg capsules.

Twice-daily administration can extend the therapeutic
effect throughout the school day, but children may
dislike taking the second dose in school. Long-acting
formulations can be taken once daily.
Mixtures – Adderall and Adderall XR are mixtures of
amphetamine salts. Adderall XR, which contains both
immediate-release and extended-release beads, has
a 10-12 hour duration of action. There is no evidence
that mixed amphetamine salts offer any advantage
over methylphenidate or dextroamphetamine, but
some patients may respond to one and not to another.

Lisdexamfetamine – Lisdexamfetamine dimesylate
(Vyvanse) is an oral prodrug that is converted to
d-amphetamine and l-lysine by enzymatic hydrolysis.13
The duration of action of lisdexamfetamine is longer
than that of other amphetamine preparations, but its
efficacy appears to be similar.14,15
ADVERSE EFFECTS — The most common adverse
effects leading to discontinuation of treatment

with stimulants have been motor or vocal tics,
anorexia, insomnia, and tachycardia. Some children,
especially teenagers, say that stimulants make them
feel less spontaneous and less comfortable in their
social interactions. Tactile and visual hallucinations
can occur. Stimulants can slow growth; the effect
on final adult height is unclear. They should be
used with caution in patients with a history of
mania, psychosis, drug dependence, or alcoholism.
Stimulants rarely can cause priapism; boys and men
should be instructed to seek immediate medical
attention if it occurs.16
Despite some earlier concerns, several large studies
have found no evidence that stimulants used to treat
ADHD increase the risk of serious cardiovascular
events in children or adults.17-19 In the absence
of a history or clinical evidence of heart disease,
there is no need to require an electrocardiogram or
a consultation with a cardiologist before starting
treatment with a stimulant.20
39

The Medical Letter

®

NON-STIMULANTS
EXTENDED-RELEASE ALPHA2-AGONISTS — Two
alpha2-adrenergic agonists have been approved by
the FDA for treatment of ADHD in children 6-17 years
old. Neither is a stimulant or a controlled substance.
Originally approved for treatment of hypertension, both
have been used for years for treatment of ADHD, either
alone or concurrently with stimulants, particularly in
children with tics.
Guanfacine – The extended-release formulation of guanfacine (Intuniv, and generics), which has been approved
by the FDA both as monotherapy and as an adjunct to a
stimulant for treatment of ADHD, leads to higher serum
concentrations of the drug in children than it does in
adults. It has been shown to be modestly more effective
than placebo in producing improvement in ADHD rating
scales, but somnolence has been a problem, and bradycardia, hypotension, and syncope have occurred.21
Clonidine – The extended-release formulation of
clonidine (Kapvay, and generics) is FDA-approved
as monotherapy and as an adjunct to a stimulant
for treatment of ADHD. Children with ADHD treated
with Kapvay have shown statistically significant
improvements in ADHD rating scales, and children
treated with both a stimulant and clonidine have
shown significantly greater improvement than those

treated with a stimulant alone.22 Clonidine may be
more sedating than guanfacine.
ATOMOXETINE — A selective norepinephrine reuptake
inhibitor, atomoxetine (Strattera) is approved by
the FDA for treatment of ADHD in both children and
adults.23 It is neither a controlled substance nor a
stimulant.
Efficacy – Atomoxetine was less effective than
methylphenidate in reducing ADHD symptoms in a
large randomized, double-blind clinical trial.24 It has
been used for patients who have not responded to or
cannot tolerate stimulants, particularly children with
low weight and short stature, and those for whom use
of a controlled substance is unacceptable.
Adverse Effects – Somnolence, nausea, and vomiting
have occurred in children starting atomoxetine,
particularly when the dose is increased from initial to
maximum levels within a few days. Atomoxetine rarely
can cause priapism; this effect appears to be more
common with atomoxetine than with methylphenidate.
As with stimulants, boys and men taking the drug
should be instructed to seek medical attention
immediately if priapism occurs. ■
40

Vol. 57 (1464)

March 16, 2015

1. HM Feldman and MI Reiff. Clinical practice. Attention deficithyperactivity disorder in children and adolescents. N Engl J

Med 2014; 370:838.
2. ND Volkow and JM Swanson. Clinical practice: adult attention
deficit-hyperactivity disorder. N Engl J Med 2014; 2013;
369:1935.
3. S Dalsgaard et al. Mortality in children, adolescents, and adults
with attention deficit hyperactivity disorder: a nationwide cohort study. Lancet 2015 February 24 (epub).
4. Z Chang et al. Serious transport accidents in adults with attention-deficit/hyperactivity disorder and the effect of medication:
a population-based study. JAMA Psychiatry 2014; 71:319.
5. P Lichtenstein et al. Medication for attention deficit-hyperactivity disorder and criminality. N Engl J Med 2012; 367:2006.
6. L Greenhill et al. Efficacy and safety of immediate-release
methylphenidate treatment for preschoolers with ADHD. J Am
Acad Child Adolesc Psychiatry 2006; 45:1284.
7. T Epstein et al. Immediate-release methylphenidate for attention deficit hyperactivity disorder (ADHD) in adults. Cochrane
Database Syst Rev 2014 Sept 18; 9:CD005041.
8. WE Pelham et al. Once-a-day Concerta methylphenidate versus
three-times-daily methylphenidate in laboratory and natural
settings. Pediatrics 2001; 107:E105.
9. FDA. Methylphenidate hydrochloride extended release tablets
(generic Concerta) made by Mallinckrodt and Kudco. Available
at: Accessed March 5, 2015.
10. D Coghill et al. Long-acting methylphenidate formulations in
the treatment of attention-defecit/hyperactivity disorder: a systematic review of head-to-head studies. BMC Psychiatry 2013;
13:237.
11. Transdermal methylphenidate (Daytrana) for ADHD. Med Lett
Drugs Ther 2006; 48:49.
12. Quillivant XR – an extended-release oral suspension of methylphenidate. Med Lett Drugs Ther 2013; 55:10.
13. Lisdexamfetamine dimesylate (Vyvanse) for ADHD. Med Lett
Drugs Ther 2007; 49:58.
14. LA Adler et al. Double-blind, placebo-controlled study of the efficacy and safety of lisdexamfetamine dimesylate in adults with
attention-deficit/hyperactivity disorder. J Clin Psychiatry 2008;

69:1364.
15. D Elbe et al. Focus on lisdexamfetamine: a review of its use in
child and adolescent psychiatry. J Can Acad Child Adolesc Psychiatry 2010; 19:303.
16. LS Eiland et al. Priapism associated with the use of stimulant
medications and atomoxetine for attention-deficit/hyperactivity disorder in children. Ann Pharmacother 2014; 48:1350.
17. WO Cooper et al. ADHD drugs and serious cardiovascular events
in children and young adults. N Engl J Med 2011; 365:1896.
18. LA Habel et al. ADHD medications and risk of serious cardiovascular events in young and middle-aged adults. JAMA 2011;
306:2673.
19. H Schelleman et al. Cardiovascular events and death in children exposed and unexposed to ADHD agents. Pediatrics 2011;
127:1102.
20. SA Shahani et al. Attention deficit hyperactivity disorder
screening electrocardiograms: a community-based perspective. Pediatr Cardiol 2014; 35:485.
21. Guanfacine extended-release (Intuniv) for ADHD. Med Lett
Drugs Ther 2010; 52:82.
22. Another extended-release alpha2-agonist for ADHD. Med Lett
Drugs Ther 2011; 53:10.
23. Atomoxetine (Strattera) for ADHD. Med Lett Drugs Ther 2003;
45:11.
24. JH Newcorn et al. Atomoxetine and osmotically released methylphenidate for the treatment of attention deficit hyperactivity
disorder: acute comparison and differential response. Am J
Psychiatry 2008; 165:721.


The Medical Letter

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Vol. 57 (1464)

®

VEGF Inhibitors for AMD and
Diabetic Macular Edema

Vascular endothelial growth factor (VEGF) is a principal
mediator of neovascularization in wet age-related
macular degeneration (AMD) and diabetic macular
edema. It induces angiogenesis and increases vascular
permeability and inflammation. VEGF inhibitors reduce
leakage from blood vessels, prevent proliferation of
new abnormal vessels, decrease swelling of the retina,
and improve visual acuity in patients with neovascular
(wet) AMD and diabetic macular edema.1,2 These drugs
are given as periodic intravitreal injections with topical
anesthesia.
Pronunciation Key
Ranibizumab: ra" ni biz' ue mab
Lucentis: loo' sen tis
Bevacizumab: be" va siz' ue mab
Avastin: uh vas' tin
Aflibercept: a flib' er sept
Eylea: eye' lee uh
Pegaptanib: peg ap' ta nib
Macugen: mac' yoo gen

Ranibizumab (Lucentis – Genentech) is a recombinant,
humanized, monoclonal anti-VEGF antibody fragment.
It has been approved by the FDA for treatment of wet
AMD,3 diabetic macular edema, and macular edema

following retinal vein occlusion.
Bevacizumab (Avastin – Genentech) is the fulllength monoclonal antibody from which ranibizumab
is derived. It has been approved by the FDA for
intravenous treatment of various malignancies
and has been used off-label as an intravitreal
injection for treatment of wet AMD, diabetic macular
edema, and macular edema following retinal vein
occlusion. Divided into aliquots and repackaged by
compounding pharmacies, it costs much less than
ranibizumab, pegaptanib, or aflibercept, which are
all available in ready-to-use formulations, but the
repackaging process has introduced some safety

March 16, 2015

risks. Ranibizumab and bevacizumab appear to have
similar effects on visual acuity in patients with wet
AMD.4
Aflibercept (Eylea – Regeneron), a fusion protein, is
FDA-approved for treatment of wet AMD, diabetic
macular edema, and macular edema following retinal
vein occlusion. In 2 controlled trials in patients with
wet AMD, it appeared to be similar to ranibizumab
in effectiveness.5 A large 1-year study sponsored by
the NIH and conducted by the Diabetic Retinopathy
Clinical Research Network randomized 660 adults
with diabetic macular edema to intravitreal aflibercept
2 mg, bevacizumab 1.25 mg, or ranibizumab 0.3 mg
every 4 weeks. In patients with mild initial visual acuity
loss (visual acuity letter score 69-78), there were no

significant differences in mean visual acuity at 1
year between the 3 groups. In patients with a visual
acuity letter score <69, the mean improvement was
significantly better with aflibercept (18.9 letters) than
with ranibizumab (14.2) or bevacizumab (11.8).6
Pegaptanib sodium (Macugen – Valeant), a selective
VEGF inhibitor, is approved by the FDA only for
treatment of wet AMD. It appears to be less effective
than ranibizumab or bevacizumab.7
ADVERSE EFFECTS – The adverse effects of VEGF
inhibitors have been largely related to the injection
procedure rather than to the drug itself; they include
conjunctival hemorrhage, acute intraocular pressure
rise, traumatic cataract, uveitis, and retinal detachment,
all occurring in <2% of patients.8
Endophthalmitis – Intravitreal injection of VEGF
inhibitors carries a risk of intraocular infection or
endophthalmitis. The overall risk of endophthalmitis
with intravitreal injections of VEGF inhibitors appears
to be low,9 but repackaging of bevacizumab without

Table 1. Intravitreal VEGF Inhibitors
Neovascular
AMD Dosage

Drug

Formulations

DME Dosage

Aflibercept – Eylea (Regeneron)

2 mg/0.05 mL single-use vial

2 mg q4 wks x 3 doses, 2 mg q4 wks x 5 doses,
then 2 mg q8 wks
then 2 mg q8 wks

Pegaptanib2 – Macugen (Valeant)

0.3 mg/0.09 mL single-use syringe

0.3 mg q6 wks

—

Ranibizumab – Lucentis
(Genentech)

0.3 mg/0.05 mL, 0.5 mg/0.05 mL
single-use vials

0.5 mg q4 wks

0.3 mg q4 wks

Bevacizumab4 – Avastin (Genentech)

25 mg/mL; 4, 16 mL vials

1.25 mg q4 wks

1.25 mg q4 wks

Cost1
$1950.00
995.003
1200.00
50.005

AMD = Age-related macular degeneration; DME = Diabetic macular edema
1. Medicare allowable charges for one intravitreal injection for treatment of DME.
2. Not FDA-approved for treatment of DME.
3. Approximate WAC for one intravitreal injection for treatment of AMD (administration cost not included). WAC = wholesaler acquisition cost, or manufacturer’s
published price to wholesalers; WAC represents a published catalogue or list price and may not represent actual transactional prices. Source: AnalySource®
Monthly. March 5, 2015. Reprinted with permission by First Databank, Inc. All rights reserved. ©2015. www.fdbhealth.com/policies/drug-pricing-policy.
4. Not FDA-approved for treatment of AMD or DME.
5. Cost of a 4-mL single-use vial is $663.75. A compounding pharmacy can divide the vial into small aliquots. Actual retail prices may vary.

41


The Medical Letter

®

proper aseptic technique has led to endophthalmitis
and loss of vision in some patients.10,11
One retrospective review of patients who received a

total of 11,710 intravitreal injections of a VEGF inhibitor
found that clinically suspected endophthalmitis
occurred in 5 cases.12 In one trial in 1185 patients,
endophthalmitis developed in 0.7% of patients treated
with ranibizumab and in 1.2% of those treated with
bevacizumab.13 A retrospective case-control study
in 6154 VEGF-treated patients and an equal number
of matched controls with neovascular AMD found
that the incidence of endophthalmitis was 0.09% per
injection, and the total incidence was 0.62% in patients
treated with VEGF inhibitors and 0.10% in controls.14
Obtaining repackaged bevacizumab from facilities
registered with the FDA, which are required to comply
with good manufacturing practices, may help ensure
the quality of compounded preparations.15
CONCLUSION – Intravitreal injections of aflibercept
(Eylea) every 8 weeks, ranibizumab (Lucentis) every
4 weeks, and bevacizumab (Avastin - off label) every
4 weeks appear to be similarly effective in treating
neovascular (wet) age-related macular degeneration
(AMD) and, in patients with mild visual acuity loss,
probably diabetic macular edema as well. In patients
with diabetic macular edema and worse initial loss
of visual acuity, aflibercept was significantly more
effective than ranibizumab and bevacizumab in a large
clinical trial. Bevacizumab is not FDA-approved for
these indications and has to be compounded. ■
1. Drugs for some common eye disorders. Treat Guidel Med Lett
2012; 10:79.
2. LM Jampol et al. Revolution to a new standard treatment of diabetic macular edema. JAMA 2014; 311:2269.

3. Ranibizumab (Lucentis) for macular degeneration. Med Lett
Drugs Ther 2006; 48:85.
4. SD Solomon et al. Anti-vascular endothelial growth factor for
neovascular age-related macular degeneration. Cochrane Database Syst Rev 2014 Aug 29; 8:CD005139.
5. Aflibercept (Eylea) for age-related macular degeneration. Med
Lett Drugs Ther 2012; 54:9.
6. The Diabetic Retinopathy Clinical Research Network. Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema.
N Engl J Med 2015 Feb 18 (epub).
7. Pegaptanib sodium (Macugen) for macular degeneration. Med
Lett Drugs Ther 2005; 47:55.
8. L Moja et al. Systemic safety of bevacizumab versus ranibizumab for neovascular age-related macular degeneration. Cochrane Database Syst Rev 2014 Sept 15; 9:CD011230.
9. SG Schwartz and HW Flynn Jr. Endophthalmitis associated with
intravitreal anti-vascular endothelial growth factor injections.
Curr Ophthalmol Rep 2014; 2:1.
10. C Biagi et al. Comparative safety profiles of intravitreal bevacizumab, ranibizumab and pegaptanib: the analysis of the WHO
database of adverse drug reactions. Eur J Clin Pharmacol 2014;
70:1505.

42

Vol. 57 (1464)

March 16, 2015

11. BA Frost and MA Kainer. Safe preparation and administration
of intravitreal bevacizumab injections. N Engl J Med 2011;
365:2238.
12. H Tabandeh et al. Endophthalmitis associated with intravitreal
injections: office-based setting and operating room setting.
Retina 2014; 34:18.

13. CATT Research Group. Ranibizumab and bevacizumab for
treatment of neovascular age-related macular degeneration:
two-year results. Ophthalmology 2012; 119:1388.
14. S Day et al. Ocular complications after anti-vascular endothelial growth factor therapy in Medicare patients with age-related
macular degeneration. Am J Ophthalmol 2011; 152:266.
15. FDA. Compounding: compounding quality act. Available at http://
www.fda.gov/drugs/GuidanceComplianceRegulatoryInformation/PharmacyCompounding/default.htm. Accessed March 5,
2015.

IN BRIEF

Lisdexamfetamine (Vyvanse) for Binge
Eating Disorder
Lisdexamfetamine dimesylate (Vyvanse), a prodrug of
dextroamphetamine previously approved for treatment
of attention-deficit/hyperactivity disorder, has now been
approved for treatment of moderate-to-severe binge
eating disorder (recurrent episodes of compulsive overeating without purging) in adults.
FDA approval of lisdexamfetamine for this indication
was based on two unpublished, 12-week trials,
summarized in the package insert, that randomized
patients with moderate-to-severe binge eating disorder
to lisdexamfetamine 30 mg/day, which was titrated to
50 mg or, if needed, 70 mg, or to placebo. In both studies,
patients treated with the active drug had a significantly
greater reduction from baseline in binge days/week than
those treated with placebo. In the first study (n=374),
the placebo-subtracted difference was 1.35 binge days/
week. In the second study (n=350), the difference was
1.66 binge days/week.

The recommended dosage of lisdexamfetamine for
treatment of binge eating disorder is 30 mg/day, which
can be titrated in 20-mg increments per week to a
maximum of 70 mg/day. The cost of 30 days' treatment
is about $217.1
Patients with eating disorders have an increased risk
of overuse of stimulants for weight loss. The long-term
effectiveness and safety of lisdexamfetamine in this
population remain to be determined. ■
1. Approximate WAC. WAC = wholesaler acquisition cost or manufacturer’s published price to wholesalers; WAC represents a published
catalogue or list price and may not represent an actual transactional price. Source: AnalySource® Monthly. March 5, 2015. Reprinted
with permission by First Databank, Inc. All rights reserved. ©2015.
www.fdbhealth.com/policies/drug-pricing-policy.


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Issue 1464 Questions

(Correspond to questions #51-60 in Comprehensive Exam #72, available July 2015)
Drugs for ADHD
1. Immediate-release methylphenidate has a duration of action of:
a. 1-3 hours
b. 3-5 hours
c. 6-8 hours
d. 8-10 hours
2. Which of the following is true about Concerta?
a. It has been as effective as multiple doses of immediaterelease methylphenidate.
b. It has a longer duration of action than some other longacting methylphenidate products.
c. Some of its generic equivalents have been less effective than
Concerta itself.
d. all of the above.
3. The increased frequency of adverse effects with the transdermal
patch formulation of methylphenidate may be related to:
a. the size of the patch
b. rapid absorption of the drug
c. the absence of first-pass metabolism that occurs with oral
formulations
d. all of the above
4. The main problem with short-acting stimulants is that:
a. they are less effective than intermediate- or long-acting
formulations
b. they have a higher incidence of adverse effects than longeracting drugs

c. they generally require administration of a second dose during
school hours
d. all of the above
5. A 9-year-old boy with ADHD has not responded to maximum
doses of methylphenidate. His mother asks if he should take an
amphetamine instead. You could tell her that:
a. amphetamines are more effective than methylphenidate
b. patients who do not respond to methylphenidate generally do
not respond to an amphetamine
c. patients who do not respond to methylphenidate may
respond to an amphetamine and vice versa
d. amphetamines are not approved by the FDA for use in
school-age children

6. A concerned father going through a difficult divorce brings his
14-year-old son to your office and asks for your help in dealing
with his behavior. His school performance has deteriorated,
and his teachers say that he does not pay attention in class.
In addition, his parents have noticed that he has developed
facial grimaces, especially when he is upset. His father asks if a
stimulant could be helpful. You would have to tell him that:
a. stimulants can themselves cause tics or make them worse
b. stimulants are highly effective in treating tics
c. stimulants are not approved by the FDA for use in
adolescents
d. stimulants have no adverse effects and are always worth
trying in these situations
7. The main problem in using extended-release alpha2-agonists to
treat ADHD has been:
a. somnolence

b. hypertension
c. rash
d. nausea
8. Atomoxetine (Strattera) is:
a. a stimulant
b. a controlled substance
c. a selective serotonin reuptake inhibitor
d. a selective norepinephrine reuptake inhibitor
VEGF Inhibitors for AMD and Diabetic Macular Edema
9. In choosing between ranibizumab (Lucentis) and bevacizumab
(Avastin) for treatment of neovascular AMD, it would be fair to say
that:
a. ranibizumab has been significantly more effective
b. ranibizumab carries a greater risk of endophthalmitis
c. they appear to have similar effects on visual acuity
d. the risk of endophthalmitis is high with either one
10. In the clinical trial comparing aflibercept (Eylea), ranibizumab, and
bevacizumab for treatment of diabetic macular edema:
a. aflibercept was the most effective in patients with mild
visual acuity loss
b. aflibercept was the most effective in patients with more
severe initial visual acuity loss
c. bevacizumab was as effective as aflibercept in patients with
all degrees of visual acuity loss
d. ranibizumab was as effective as aflibercept in patients with
all degrees of visual acuity loss

ACPE UPN: Per Issue Exam: 0379-0000-15-464-H01-P; Release: March 16, 2015, Expire: March 16, 2016
Comprehensive Exam 72: 0379-0000-15-072-H01-P; Release: July 2015, Expire: July 2016
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; 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; 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
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VICE PRESIDENT AND PUBLISHER: Yosef Wissner-Levy
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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,
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