The medical letter on drugs and therapeutics jun 20 2016

The Medical Letter

®

on Drugs and Therapeutics

Volume 58

ISSUE
ISSUE
No.

1433
1497
Volume 56

June 20, 2016

IN THIS ISSUE

A New Abuse-Deterrent Opioid — Xtampza ER .................................................................. p 77
Spritam – A New Formulation of Levetiracetam for Epilepsy ........................................... p 78
Two New Amphetamines for ADHD..................................................................................... p 80
Reslizumab (Cinqair) for Severe Eosinophilic Asthma ...................................................... p 81
Addendum: Doxycycline for Young Children? .................................................................... p 82

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The Medical Letter

®

on Drugs and Therapeutics

Volume 58

June 20, 2016
Take CME Exams

ISSUE

ISSUE No.

1433
1497
Volume 56

▶

ALSO IN THIS ISSUE

Spritam – A New Formulation of Levetiracetam for Epilepsy ........................................... p 78
Two New Amphetamines for ADHD..................................................................................... p 80
Reslizumab (Cinqair) for Severe Eosinophilic Asthma ...................................................... p 81
Addendum: Doxycycline for Young Children? .................................................................... p 82

A New Abuse-Deterrent
Opioid – Xtampza ER

The FDA has approved Xtampza ER (Collegium),
a new extended-release, abuse-deterrent capsule
formulation of oxycodone, for management of pain
severe enough to require daily, around-the-clock,
long-term opioid treatment and for which alternative
treatment options are inadequate.
Pronunciation Key
Xtampza : ex tamp’ zah

ABUSE-DETERRENT OPIOIDS — Five other abusedeterrent opioid formulations were approved
earlier, three as single-drug products and two in
combinations with opioid antagonists.1 Two of
these products, Morphabond (morphine ER) and
Targiniq ER (oxycodone ER/naloxone), have not yet

been marketed. Zohydro ER (hydrocodone ER) was
reformulated in 2015 to make abuse more difficult,
but it has not received FDA approval as an abusedeterrent opioid. No studies are available comparing
the relative safety of these products.
No opioid formulation prevents consumption of a large
number of intact dosage units, the most common
method of abuse. Abuse-deterrent formulations have
one or more properties that make their intentional
nontherapeutic use more difficult, less attractive, or
less rewarding.
THE NEW FORMULATION — Xtampza ER is available
in capsules containing microspheres formulated with
oxycodone base and inactive ingredients that make
the formulation more difficult to manipulate for the
purpose of abuse. Each capsule contains 9, 13.5, 18,
27, or 36 mg of oxycodone (equivalent to 10, 15, 20,
30 or 40 mg of oxycodone HCl, respectively).
PHARMACOKINETICS — The oral bioavailability of
Xtampza ER is greater when taken with food (Cmax

Table 1. Pharmacology
Formulation

9, 13.5, 18, 27, 36 mg capsules1

Route

Oral

Tmax

4.5 hours2

Metabolism

Hepatic mainly by CYP3A4 and to a lesser extent
by CYP2D6

Elimination

Primarily in urine as metabolites

Half-life

5.6 hours3

1. Of oxycodone base. Equivalent to 10, 15, 20, 30, 40 mg of oxycodone HCl.
2. With food; 3 hours later than with immediate-release oxycodone.
3. With food; half-life of immediate-release oxycodone is 3.2 hours.

increased by 100-150% and AUC by 50-60% with
a high-fat meal). In one pharmacokinetic study,
crushing Xtampza ER capsules did not increase the
Cmax or the AUC of oxycodone compared to intact
capsules when both were taken with a high-fat meal.
Crushing the capsules also did not compromise the
extended-release properties of Xtampza ER, unlike
OxyContin abuse-deterrent tablets, which lost their
extended-release properties when crushed.2 In
another study, crushing and snorting Xtampza ER

capsules following a high-fat meal resulted in lower
peak serum concentrations of oxycodone than taking
intact capsules.3
CLINICAL STUDIES — A 12-week, randomized,
double-blind trial in 740 patients with moderate to
severe chronic low back pain compared Xtampza ER
with placebo. The maximum dose was 144 mg/day
(equivalent to 160 mg of oxycodone HCl). Patients
treated with the active drug had significantly lower
pain scores from week 2-12 than those who received
placebo.4
ADVERSE EFFECTS — Nausea, headache, constipation,
somnolence, pruritus, vomiting, and dizziness, all
typical opioid side effects, occurred commonly in the
clinical trial in patients treated with Xtampza ER.
PREGNANCY — As with other opioid analgesics,
prolonged use of Xtampza ER during pregnancy
can cause neonatal opioid withdrawal syndrome.
77

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The Medical Letter

Vol. 58 (1497)

®

Table 2. Some Abuse-Deterrent Opioid Formulations

Drug
Hydrocodone ER
Hysingla ER
(Purdue)
Zohydro ER2
(Pernix)
Morphine ER/
naltrexone
Embeda (Pfizer)
Oxycodone ER
OxyContin
(Purdue)
Xtampza ER
(Collegium)

Abuse-Deterrent Mechanism

Cost

1

$215.80
Resists crushing and breaking;
tablets form a viscous gel when
dissolved
Contains excipients that form a
404.90
viscous gel when capsules
are crushed or dissolved
Contains sequestered opioid

antagonist, which is released if
capsules are crushed or dissolved 178.50
Resists crushing and breaking;
tablets form a viscous gel when
dissolved
Microspheres resist effects of
crushing and chewing; melted
or dissolved contents of capsules
are difficult to inject

188.80
202.20

ER = extended-release
1. Approximate WAC for 30 days’ treatment at the recommended starting
dosage for patients who are not opioid tolerant. 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. June 5, 2016. Reprinted
with permission by First Databank, Inc. All rights reserved. ©2016. www.
fdbhealth.com/policies/drug-pricing-policy.
2. Not FDA-approved as having abuse-deterrent properties.

Oxycodone is excreted in breast milk and can cause
opioid effects in breastfed newborns.
DRUG INTERACTIONS — Oxycodone is metabolized
mainly by CYP3A4 and to a lesser extent by CYP2D6.
Administration of Xtampza ER concurrently with
drugs that inhibit CYP3A4 (or discontinuation of
CYP3A4 inducers) can increase serum concentrations
of oxycodone and could be fatal. Concurrent use of
CYP3A4 inducers could decrease oxycodone serum

concentrations and the analgesic effect of the drug.5
DOSAGE AND ADMINISTRATION — The recommended
starting dosage of Xtampza ER for opioid-naive
patients is 9 mg every 12 hours. The capsules must be
taken with food; patients should consume the same
amount of food with every dose in order to ensure
consistent plasma levels. For patients who have
difficulty swallowing the capsules, their contents can
be sprinkled on soft foods or into a cup, and then
given orally or through a gastrostomy or nasogastric
tube. The maximum daily dose of Xtampza ER is
288 mg (equivalent to 320 mg oxycodone HCl).
The package insert contains dosing instructions
for conversion from other oxycodone formulations
or other opioids. Patients with hepatic impairment
starting Xtampza ER should take one-third to onehalf the usual dosage; they should not take the drug
if the required dose is <9 mg. Patients should be
monitored for respiratory depression for 72 hours
after either starting treatment or increasing the dose.
78

June 20, 2016

CONCLUSION — Xtampza ER is the second extendedrelease abuse-deterrent formulation of oxycodone.
How it compares to the abuse-deterrent formulation
of OxyContin for prevention of misuse is unknown.
Whether use of abuse-deterrent opioid products
actually reduces overall opioid abuse remains to be
determined. ■
1. Abuse-deterrent opioid formulations. Med Lett Drugs Ther

2015; 57:119.
2. J Gudin et al. Comparing the effect of tampering on the oral pharmacokinetic profiles of two extended-release oxycodone formulations with abuse-deterrent properties. Pain Med 2015; 16:2142.
3. LR Webster et al. A randomized, double-blind, double-dummy
study to evaluate the intranasal human abuse potential and
pharmacokinetics of a novel extended-release abuse-deterrent
formulation of oxycodone. Pain Med 2016; 17:1112.
4. N Katz et al. A phase 3, multicenter, randomized, double-blind,
placebo-controlled, safety, tolerability, and efficacy study of
Xtampza ER in patients with moderate-to-severe chronic low
back pain. Pain 2015; 156:2458.
5. Inhibitors and inducers of CYP enzymes and P-glycoprotein.
Med Lett Drugs Ther 2016; 58:e46.

▶

Spritam – A New Formulation of
Levetiracetam for Epilepsy

The FDA has approved a rapidly disintegrating tablet
formulation of the antiepileptic drug levetiracetam
(Spritam – Aprecia) for adjunctive treatment of partialonset, myoclonic, and primary generalized tonicclonic seizures. Oral and intravenous formulations
of levetiracetam (Keppra, and generics) have been
available for years. Although approved by the FDA only
as adjunctive therapy, levetiracetam is commonly used
as monotherapy for partial-onset and generalized
seizures and may also be effective in treating absence
seizures and seizures of Lennox-Gastaut syndrome.1
Pronunciation Key
Levetiracetam : lee” ve tye ra’ se tam Spritam : spree’ tam

THE NEW FORMULATION – Spritam is the first drug
to be manufactured in the US using 3D printing
technology. During manufacturing, the 3D printer
dispenses powdered medication in layers and a liquid
binding agent that binds the layers together. Since
no compression forces are used to manufacture the
3D-printed tablet, it is solid but porous.
Table 1. Pharmacology
Route
Formulation
Tmax
Metabolism
Elimination
Half-life

Oral
250, 500, 750, 1000 mg tablets for oral suspension
~1 hour (fasting)
Not extensively metabolized
Urine (66%)
7 hours1

1. The half-life in children is 5 hours.


The Medical Letter

®

Vol. 58 (1497)

June 20, 2016

Table 2. Levetiracetam for Epilepsy
Drug

Available Formulations

Usual Adult Dosage1

Cost2

Immediate-release – Keppra (UCB)
generic
Spritam (Aprecia)

250, 500, 750, 1000 mg tabs; 100 mg/mL
soln; 500 mg/5 mL IV soln
250, 500, 750, 1000 mg tabs for oral susp

1000-3000 mg/day PO or IV
in 2 divided doses

$436.40
33.103
433.40

Extended-release – Keppra XR
generic

500, 750 mg ER tabs

1000-3000 mg PO once/d

395.60
44.50

ER = extended-release; soln = solution; susp = suspension
1. Dosage may need to be adjusted for renal impairment.
2. Approximate WAC for 30 days’ treatment with tablets at the lowest usual adult dosage. WAC = wholesaler acquisition cost, or manufacturer’s published price
to wholesalers; WAC represents published catalogue or list prices and may not represent an actual transactional price. Source: AnalySource® Monthly. June 5,
2016. Reprinted with permission by First Databank, Inc. All rights reserved. ©2016. www.fdbhealth.com/policies/drug-pricing-policy.
3. The cost for 300 mL of generic oral solution is $130.00.

The rate and extent of absorption of Spritam tablets are
equivalent to those of immediate-release levetiracetam
tablets. The average disintegration time of a Spritam
tablet when taken with a sip of water is 11 seconds
(range 2-27 seconds).2
CLINICAL STUDIES – FDA approval of Spritam
was based on the results of earlier clinical trials
with
immediate-release
levetiracetam
tablets
and pharmacokinetic studies that demonstrated
bioequivalence between the two formulations. In
randomized, double-blind, placebo-controlled trials
in patients with partial-onset, myoclonic, or primary
generalized tonic-clonic seizures, levetiracetam

reduced seizure frequency by 17-33% over placebo,
and a significantly higher percentage of patients who
took levetiracetam had a ≥50% reduction from baseline
in seizure frequency.3-8
ADVERSE EFFECTS – Dizziness, somnolence, and
weakness occur commonly with levetiracetam.
Behavioral changes such as aggression, agitation,
hostility, irritability, hyperexcitability, restlessness,
hallucinations, and psychosis have also occurred,
especially in children9 and in patients with underlying
psychiatric disorders. Coordination difficulties and
serious dermatological reactions, including StevensJohnson syndrome and toxic epidermal necrolysis,
have been reported.
PREGNANCY – Levetiracetam is classified as category C (developmental toxicity and teratogenicity
in rats and rabbits; no adequate studies in pregnant
women) for use during pregnancy. Levetiracetam is
excreted in breast milk and may cause serious adverse
effects in the nursing infant.
DOSAGE AND ADMINISTRATION – The recommended
starting dosage of Spritam is 500 mg twice daily in
adults and children ≥4 years old who weigh >40 kg;
the dosage can be increased by 500 mg twice daily
every 2 weeks, up to a maximum of 1500 mg twice
daily. For children ≥4 years old who weigh 20-40 kg,

the starting dosage is 250 mg twice daily; the dosage
can be increased by 250 mg twice daily every 2 weeks,
up to a maximum of 750 mg twice daily.
Spritam disintegrates when taken with a sip of liquid.
The patient should place the tablet on the tongue with

a dry hand, take a sip of liquid, and then swallow after
the tablet disintegrates. The tablets should not be
broken, chewed, or swallowed whole. Patients should
peel the blister foil off the package rather than push
the tablet through the foil. Spritam tablets can also
be dispersed in a small volume of liquid and taken
immediately.
CONCLUSION – Patients with epilepsy who have
trouble taking oral levetiracetam tablets may find
the new rapidly disintegrating formulation (Spritam)
easier to swallow. Generic levetiracetam oral solution
is a much cheaper alternative. ■
1. Drugs for epilepsy. Treat Guidel Med Lett 2013; 11:9.
2. S Boudriau et al. Randomized comparative bioavailability of a
novel three-dimensional printed fast-melt formulation of levetiracetam following the administration of a single 1000-mg
dose to healthy human volunteers under fasting and fed conditions. Drugs R D 2016; 16:229.
3. JJ Cereghino et al. Levetiracetam for partial seizures: results
of a double-blind, randomized clinical trial. Neurology 2000;
55:236.
4. SD Shorvon et al. Multicenter double-blind, randomized, placebo-controlled trial of levetiracetam as add-on therapy in patients with refractory partial seizures. European Levetiracetam
Study Group. Epilepsia 2000; 41:1179.
5. E Ben-Menachem and U Falter. Efficacy and tolerability of
levetiracetam 3000 mg/d in patients with refractory partial
seizures: a multicenter, double-blind, responder-selected
study evaluating monotherapy. European Levetiracetam Study
Group. Epilepsia 2000; 41:1276.
6. TA Glauser et al. Double-blind, placebo-controlled trial of adjunctive levetiracetam in pediatric partial seizures. Neurology
2006; 66:1654.
7. S Noachtar et al. Levetiracetam for the treatment of idiopathic
generalized epilepsy with myoclonic seizures. Neurology 2008;

70:607.
8. SF Berkovic et al. Placebo-controlled study of levetiracetam in
idiopathic generalized epilepsy. Neurology 2007; 69:1751.
9. E Halma et al. Behavioral side-effects of levetiracetam in
children with epilepsy: a systematic review. Seizure 2014;
23:685.

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Vol. 58 (1497)

®

Adzenys XR-ODT is the first extended-release orally
disintegrating tablet formulation of amphetamine to
become available in the US. It contains a 3:1 ratio of dto l-amphetamine in 50% immediate-release and 50%
delayed-release particles. Approval of Adzenys XRODT was based on pharmacokinetic studies that found
that the serum concentration/time curves of d- and
l-amphetamine with Adzenys XR-ODT were virtually
identical to those with Adderall XR.

Two New Amphetamines for ADHD

Two new extended-release amphetamine products
have been approved by the FDA for once-daily

treatment of attention-deficit/hyperactivity disorder
(ADHD) in patients ≥6 years old: Adzenys XR-ODT
(Neos Therapeutics), an orally distintegrating tablet,
and Dyanavel XR (Tris Pharma), an oral suspension.
Adzenys : add zen’ iss

June 20, 2016

Pronunciation Key
Dyanavel : die an uh vel

Dyanavel XR extended-release oral suspension contains
a 3.2:1 ratio of d- to l-amphetamine in a mixture of immediate-release and extended-release particles. Approval of
Dyanavel XR was based on the results of an unpublished
trial (summarized in the package insert) in 108 children
6-12 years old with ADHD who were titrated to an optimal
dose (max 20 mg/day) of the new suspension over 5 weeks,
followed by 1 week of treatment with either the active drug
or placebo. After the 1-week treatment period, the children
were evaluated using the SKAMP-Combined score, which
measures ADHD symptoms in a laboratory school setting, at 8 time points between 1 and 13 hours post-dose.
SKAMP-Combined scores improved significantly more with
Dyanavel XR than with placebo at all time points.

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. Racemic amphetamine

sulfate, mixed amphetamine salts, dextroamphetamine, and lisdexamfetamine dimesylate, an oral
prodrug of dextroamphetamine, vary in duration
of action, but appear to be similar in efficacy.1,2 All
stimulants used for treatment of ADHD are classified
as Schedule II controlled substances by the DEA.
Table 1. Some Amphetamines for ADHD
Drug

Pediatric Dosage1
Initial/Usual

Cost2

3.1, 6.3, 9.4, 12.5, 15.7, 18.8 mg ER ODT4,5 10-12 h

6.3 mg qAM/6.3-18.8 mg qAM6

$270.00

2.5 mg/mL ER susp7

13 h

2.5-5 mg qAM/2.5-20 mg qAM

59.00

5, 10 mg tabs

10 h8

5 mg qAM or bid9/2.5-5 mg bid

324.4010

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

4-6 h

5 mg qAM or bid9/10 mg bid

5, 10, 15, 20, 25, 30 mg ER caps

10-12 h

5-10 mg qAM/30 mg qAM

61.10
322.30
154.80
213.70

5, 10 mg tabs

4-6 h

5 mg qAM or bid9/10 mg bid

2.5, 5, 7.5, 10, 15, 20, 30 mg tabs
5, 10, 15 mg SR caps13

6-8 h

5 mg qAM or bid/15 mg qAM

10, 20, 30, 40, 50, 60, 70 mg caps11

13-14 h14

30 mg qAM/30-70 mg qAM

Some Available Formulations

Amphetamines
Amphetamine –
Adzenys XR-ODT
(Neos Therapeutics)
Dyanavel XR (Tris)
Racemic amphetamine sulfate –
Evekeo (Arbor)
Mixed amphetamine salts –
short-acting – generic
Adderall (Teva)
long-acting – generic
Adderall XR (Shire)
Dextroamphetamines3
Dextroamphetamine12 –
short-acting – generic
Dexedrine (Amedra)
Zenzedi (Arbor)

long-acting – generic
Dexedrine Spansule (Amedra)
Lisdexamfetamine dimesylate –
Vyvanse (Shire)

Duration
of Action

3

11

118.50
342.00
346.80
148.80
504.60
248.30

ER = extended-release; ODT = orally disintegrating tablets; susp = suspension; 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. June 5,
2016. Reprinted with permission by First Databank, Inc. All rights reserved. ©2016. www.fdbhealth.com/policies/drug-pricing-policy.
3. Taking the drug with gastrointestinal acidifying agents such as ascorbic acid or fruit juice decreases its absorption and use of alkalinizing agents such as sodium bicarbonate increases its absorption. Drugs that acidify the urine can increase amphetamine excretion and those that alkalinize the urine can decrease its excretion.
4. Equivalent to 5, 10, 15, 20, 25, and 30 mg strengths of Adderall XR.
5. The tablet should be placed on the tongue and swallowed after it disintegrates. It should not be crushed or chewed.
6. The maximum recommended daily dose is 18.8 mg for patients 6-12 years old and 12.5 mg for patients 13-17 years old.
7. 2.5 mg of amphetamine base is equivalent to 4 mg of mixed amphetamine salts products.
8. AC Childress et al. J Child Adolesc Psychopharmacol 2015; 25:402.

9. Initial dosage for children 3-5 years old is 2.5 mg once daily.
10. Cost for 5 mg bid.
11. The contents of the capsule may be sprinkled on a small amount of applesauce and given immediately.
12. FDA-approved only for use in children 3-16 years old (short-acting) or 6-16 years old (long-acting).
13. Must be swallowed whole, and not be crushed or chewed.
14. According to the manufacturer.

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ADVERSE EFFECTS ― Adverse effects of amphetamines in children with ADHD 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.
CONCLUSION — The two new amphetamine products,
Adzenys XR-ODT and Dyanavel XR, offer once-daily
alternatives for children with ADHD who are unable to
swallow tablets or capsules. ■
1. Drugs for ADHD. Med Lett Drugs Ther 2015; 57:37.
2. Racemic amphetamine sulfate (Evekeo) for ADHD. Med Lett

Drugs Ther 2015; 57:137.

▶

Reslizumab (Cinqair) for Severe
Eosinophilic Asthma

The FDA has approved reslizumab (Cinqair – Teva), a
humanized interleukin-5 (IL-5) antagonist monoclonal
antibody, for add-on maintenance treatment of severe
asthma in adults who have an eosinophilic phenotype.
It is the second IL-5 antagonist to be approved in the
US; mepolizumab (Nucala) was approved for the same
indication in 2015.1
Pronunciation Key
Reslizumab : res liz' ue mab
Cinqair: sink ayr'

EOSINOPHILIC PHENOTYPE — What constitutes an
eosinophilic phenotype is not well defined, but patients
with this phenotype generally have severe disease with
high eosinophil levels in blood and/or sputum despite
treatment with a corticosteroid.2
OTHER MONOCLONAL ANTIBODIES — In clinical trials,
mepolizumab reduced exacerbations and the need for
maintenance oral corticosteroids in patients with severe
asthma and high eosinophil counts. The recombinant
humanized anti-IgE monoclonal antibody omalizumab
(Xolair), which is FDA-approved for treatment of
patients with moderate to severe persistent allergic

asthma not well controlled on an inhaled corticosteroid,
may be effective in patients with allergic asthma who
have high blood eosinophil counts.3 No studies are
available directly comparing mepolizumab, reslizumab,
and omalizumab with each other.
MECHANISM OF ACTION — IL-5 is the major cytokine
responsible for the growth, differentiation, recruitment,

Vol. 58 (1497)

June 20, 2016

and activation of eosinophils. Reslizumab binds to IL-5,
blocking its binding to IL-5 receptors on the surface
of eosinophils, thereby reducing the production
and survival of eosinophils and decreasing airway
inflammation.
CLINICAL STUDIES — Approval of reslizumab was
based on the results of four randomized, double-blind,
placebo-controlled trials.
Two of the studies enrolled a total of 953 patients
12-75 years old with moderate to severe asthma
inadequately controlled on at least a medium-dose
inhaled corticosteroid who had blood eosinophil counts
of ≥400 cells/mcL and ≥1 exacerbation in the previous
year. Patients were randomized to receive reslizumab
3 mg/kg or placebo every 4 weeks for 1 year. Reslizumab
significantly reduced the frequency of clinically significant
asthma exacerbations, the primary endpoint, by 54%
compared to placebo. One or more asthma exacerbations

occurred in 32% of patients receiving reslizumab
compared to 50% of those receiving placebo. The mean
increase from baseline in forced expiratory volume in
1 second (FEV1) was also significantly greater among
patients treated with reslizumab (110 mL vs placebo).4
Among patients 12-17 years old included in the oneyear studies (n=25), the annual asthma exacerbation
rate in those treated with reslizumab was twice as
high as the rate in the placebo group (2.86 vs 1.37).
In the third study, 315 patients 12-75 years old with
asthma inadequately controlled on at least a mediumdose inhaled corticosteroid and blood eosinophil counts
of ≥400 cells/mcL were randomized to reslizumab
0.3 or 3 mg/kg or placebo once every 4 weeks for 16
weeks. The mean increase in FEV1 from baseline was
115 mL with the lower dose of reslizumab and 160
mL with the higher dose, compared to placebo; both
Table 1. Reslizumab and Mepolizumab
Formulation
Route
Metabolism
Half-life

Reslizumab (Cinqair)
100 mg/10 mL singleuse vials
IV

Mepolizumab (Nucala)
100 mg single-dose
vials
SC

Degradation by proteolytic enzymes
~24 days

Degradation by proteolytic enzymes
16-22 days

Dosage

3 mg/kg IV q4 wks

100 mg SC q4 wks

Approved ages

≥18 years

≥12 years

Cost1

$2,5052

$2,500

1. Approximate WAC for a single 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. June 5, 2016. Reprinted
with permission by First Databank, Inc. All rights reserved. ©2016. www.
fdbhealth.com/policies/drug-pricing-policy.
2. Cost for a 70-kg patient (3 vials).

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®

differences were statistically significant. Reslizumab
3 mg/kg significantly improved asthma quality of life.5
The fourth study included patients 18-65 years old with
asthma inadequately controlled on at least a mediumdose inhaled corticosteroid. An elevated blood eosinophil
count was not a requirement for study entry; 80% of the
492 enrolled patients had counts of <400 cells/mcL.
Patients were randomized to reslizumab 3 mg/kg or
placebo once every 4 weeks for 16 weeks. The mean
change from baseline in FEV1 with the active drug was
not significantly different from the change with placebo.
No association was observed between baseline blood
eosinophil counts and placebo-subtracted improvements
in FEV1 with reslizumab.6
ADVERSE EFFECTS — Adverse effects that occurred at a
higher rate with reslizumab than with placebo in clinical
trials included musculoskeletal adverse reactions on the
day of infusion (2.2% vs 1.5%), oropharyngeal pain (2.6% vs
2.2%), creatine phosphokinase (CPK) elevations (14% vs
9%), and myalgia (1.0% vs 0.5%). Serious adverse events
that occurred more often with reslizumab than with placebo
were anaphylaxis (0.3% vs 0%) and malignancy (0.6%
vs 0.3%). Antibodies to reslizumab developed in about 5%

of patients treated with the drug in clinical trials; they did
not appear to affect the clinical efficacy of the drug.
PREGNANCY — There are no adequate studies of
reslizumab in pregnant women. No teratogenic
or embryofetal effects were detected in mice and
rabbits given doses that produced exposures up to
6 and 17 times, respectively, those achieved with the
maximum recommended human dose. The passage
of monoclonal antibodies like reslizumab across the
placenta increases linearly as pregnancy progresses.
DOSAGE AND ADMINISTRATION — The recommended
dosage of reslizumab is 3 mg/kg infused intravenously
over 20-50 minutes once every 4 weeks. The drug should
be administered in a healthcare facility and patients
should be observed during the infusion and for a period
of time afterward. Anaphylaxis has occurred after the
second or later doses and during or within 20 minutes
of completing the infusion. Withdrawal symptoms could
occur if inhaled or systemic corticosteroids are stopped
abruptly when reslizumab therapy is started.
CONCLUSION — Reslizumab (Cinqair) administered
IV once every 4 weeks can reduce asthma
exacerbations and increase FEV1 in adults with severe
treatment-refractory asthma and elevated blood
eosinophil counts. How it compares in safety and
efficacy to mepolizumab (Nucala), which is injected
subcutaneously, remains to be determined. ■
82

Vol. 58 (1497)

June 20, 2016

1. Mepolizumab (Nucala) for severe eosinophilic asthma. Med
Lett Drugs Ther 2016; 58:11.
2. KF Chung et al. International ERS/ATS guidelines on definition,
evaluation and treatment of severe asthma. Eur Respir J 2014;
43:343.
3. W Busse et al. High eosinophil count: a potential biomarker for
assessing successful omalizumab treatment effects. J Allergy
Clin Immunol 2013; 132:485.
4. M Castro et al. Reslizumab for inadequately controlled asthma
with elevated blood eosinophil counts: results from two multicentre, parallel, double-blind, randomised, placebo-controlled,
phase 3 trials. Lancet Respir Med 2015; 3:355.
5. L Bjermer et al. Reslizumab for inadequately controlled asthma
with elevated blood eosinophil levels: a randomized phase 3
study. Chest 2016 April 4 (epub).
6. J Corren et al. Phase 3 study of reslizumab in patients with
poorly controlled asthma: effects across a broad range of eosinophil counts. Chest 2016 March 24 (epub).

Addendum: Doxycycline for Young Children?
A reader commenting on our Treatment of Lyme Disease
article (Med Lett Drugs Ther 2016; 58:57) objected to a
footnote in the table advising against use of doxycycline
in children <8 years old. This warning has been included
in the labeling of all tetracyclines since 1970 when it was
recognized, after decades of use, that these drugs caused
permanent staining and enamel hypoplasia of developing
teeth. The CDC recently stated that short courses of
doxycycline, which was first marketed in the US in 1967 and

has less affinity for calcium than other tetracyclines, have
not been shown to cause tooth staining.1 That statement
was prompted by the discovery that children <10 years old
have a disproportionately high fatality rate from rickettsial
diseases, particularly Rocky Mountain spotted fever, for
which doxycycline is the drug of choice and chloramphenicol
is the only proven alternative.
The main evidence supporting the CDC's statement was
a retrospective cohort study consisting of a record review
and dental examination of 271 children living on a Native
American reservation. No staining was detected in any of the
58 children who had been treated with doxycycline before
the age of 8 years or in any of the 213 children who had not
been exposed to the drug. Enamel hypoplasia was present in
4% of children in both cohorts.2
Lyme disease, unlike Rocky Mountain spotted fever, is
seldom fatal and can be treated with antibiotics other than
doxycycline. A single dose of doxycycline is recommended
for prophylaxis after a tick bite. Given the CDC’s statement
about its safety, it would seem reasonable to use doxycycline
for prophylaxis in all age groups. When longer treatment
courses (10, 14, or 28 days) are recommended for the various
clinical manifestations of Lyme disease in children <8 years
old, alternative antibiotics generally could be used instead. ■
1. HM Biggs et al. Diagnosis and management of tickborne rickettsial
diseases: Rocky Mountain spotted fever and other spotted fever
group Rickettsioses, Ehrlichioses, and Anaplasmosis – United
States. MMWR Recomm Rep 2016; 65:1.
2. SR Todd et al. No visible dental staining in children treated with
doxycycline for suspected Rocky Mountain spotted fever. J Pediatr 2015; 166:1246.

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Issue 1497 Questions
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A New Abuse-Deterrent Opioid – Xtampza ER
1. Which of the following contributes to the abuse-deterrent
properties of Xtampza ER?
a. addition of a sequestered opioid antagonist
b. inclusion of substances that irritate nasal mucosa if drug is
crushed and snorted
c. microsphere technology
d. subcutaneous depot delivery system
2. Xtampza ER capsules:
a. must be taken on an empty stomach
b. must be swallowed whole
c. can be opened and their contents administered through a
nasogastric tube
d. lose their extended-release properties when crushed
Spritam — A New Formulation of Levetiracetam for Epilepsy
3. A 6-year-old boy with partial-onset seizures is having difficulty
swallowing Keppra tablets. His mother recently saw an
advertisement for Spritam and asks if her son should be switched
to the new drug. You could tell his mother that:
a. the new drug is designed to disintegrate when taken with a
sip of liquid
b. her son may find Spritam easier to take than Keppra tablets
c. Spritam costs significantly more than generic levetiracetam
oral solution

d. all of the above
Two New Amphetamines for ADHD
4. Adzenys XR-ODT :
a. contains a 3.2:1 ratio of d- to l-amphetamine
b. contains a mixture of immediate-release and extendedrelease particles in an oral suspension
c. is administered once daily
d. all of the above
5. Dyanavel XR :
a. contains a 3.2:1 ratio of d- to l-amphetamine
b. improved SKAMP-Combined scores significantly more than
placebo between 1 and 13 hours post-dose
c. can cause irritability
d. all of the above

6. A 7-year-old boy with ADHD has not responded to maximum
doses of methylphenidate. His father asks if he should take an
amphetamine instead. You could tell his father that:
a. methylphenidate is more effective than amphetamines
b. children 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 FDA-approved for use in children <8
years old
7. Adverse effects of stimulants generally include:
a. failure to gain weight
b. tachycardia
c. insomnia
d. all of the above
Reslizumab (Cinqair) for Severe Eosinophilic Asthma

8. In clinical trials, use of reslizumab:
a. significantly reduced the frequency of asthma exacerbations
compared to placebo
b. increased FEV1 from baseline significantly more than
placebo
c. was associated with more asthma exacerbations compared
to placebo in patients 12-17 years old
d. all of the above
9. A concerning potential adverse effect of reslizumab is:
a. hepatotoxicity
b. anaphylaxis
c. neutropenia
d. fungal infection
Addendum: Doxycycline for Young Children?
10. According to the CDC, doxycycline should be used to treat
children <8 years old who have:
a. otitis media
b. community acquired pneumonia
c. Rocky Mountain spotted fever
d. acne

ACPE UPN: Per Issue Exam: 0379-0000-16-497-H01-P; Release: June 20, 2016, Expire: June 20, 2017
Comprehensive Exam 74: 0379-0000-16-074-H01-P; Release: July 2016, Expire: July 2017

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