1497 on Drugs and Therapeutics 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
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IN THIS ISSUE
ISSUE
1433
Volume 56
Published by The Medical Letter, Inc • A Nonprofi t Organization
ISSUE No
1497
on Drugs and Therapeutics
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
Trang 2
77
on Drugs and Therapeutics
Take CME Exams
ISSUE
1433
Volume 56
ISSUE No
1497 Spritam – A New Formulation of Levetiracetam for Epilepsy Two New Amphetamines for ADHD p 78p 80
Reslizumab (Cinqair) for Severe Eosinophilic Asthma p 81
Addendum: Doxycycline for Young Children? p 82
ALSO IN THIS ISSUE
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
A New Abuse-Deterrent
Opioid – Xtampza ER
▶
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 signifi cantly 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
Pronunciation Key
Xtampza : ex tamp’ zah
ABUSE-DETERRENT OPIOIDS — Five other abuse-
deterrent 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 diffi cult,
but it has not received FDA approval as an
abuse-deterrent 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 diffi cult, 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 diffi cult 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 capsules 1 Route Oral
Metabolism Hepatic mainly by CYP3A4 and to a lesser extent
by CYP2D6 Elimination Primarily in urine as metabolites
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.
Trang 3Oxycodone 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
diffi culty 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 third to
one-half 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
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 phar-macokinetic profi les of two extended-release oxycodone formu-lations 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 effi cacy 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.
Table 2 Some Abuse-Deterrent Opioid Formulations
Drug Abuse-Deterrent Mechanism Cost 1
Hydrocodone ER
Hysingla ER Resists crushing and breaking; $215.80
(Purdue) tablets form a viscous gel when
dissolved
Zohydro ER2 Contains excipients that form a 404.90
(Pernix) viscous gel when capsules
are crushed or dissolved Morphine ER/ Contains sequestered opioid
naltrexone antagonist, which is released if
Embeda (Pfi zer) capsules are crushed or dissolved 178.50
Oxycodone ER
OxyContin Resists crushing and breaking; 188.80
(Purdue) tablets form a viscous gel when
Xtampza ER Microspheres resist effects of 202.20
(Collegium) crushing and chewing; melted
or dissolved contents of capsules are diffi cult to inject
ER = extended-release
1 Approximate WAC for 30 days’ treatment at the recommended starting
dosage for patients who are not opioid tolerant WAC = wholesaler
acquisi-tion cost or manufacturer’s published price to wholesalers; WAC represents
a published catalogue or list price and may not represent an actual
trans-actional 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. 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
partial-onset, myoclonic, and primary generalized tonic-clonic 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 fi rst 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 Oral Formulation 250, 500, 750, 1000 mg tablets for oral suspension
Metabolism Not extensively metabolized Elimination Urine (66%)
1 The half-life in children is 5 hours.
CONCLUSION — Xtampza ER is the second
extended-release 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 ■
Trang 4Table 2 Levetiracetam for Epilepsy
Spritam (Aprecia) 250, 500, 750, 1000 mg tabs for oral susp 433.40
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 signifi cantly 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 diffi culties and
serious dermatological reactions, including
Stevens-Johnson syndrome and toxic epidermal necrolysis,
have been reported
PREGNANCY – Levetiracetam is classifi ed as
cate-gory 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 fi nd
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 le-vetiracetam following the administration of a single 1000-mg dose to healthy human volunteers under fasting and fed condi-tions 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, pla-cebo-controlled trial of levetiracetam as add-on therapy in pa-tients with refractory partial seizures European Levetiracetam Study Group Epilepsia 2000; 41:1179.
5 E Ben-Menachem and U Falter Effi cacy 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 ad-junctive 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.
Trang 5Two New Amphetamines for ADHD
▶
Two new extended-release amphetamine products
have been approved by the FDA for once-daily
treatment of attention-defi cit/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
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,
dextroampheta-mine, and lisdexamfetamine dimesylate, an oral
prodrug of dextroamphetamine, vary in duration
of action, but appear to be similar in effi cacy.1,2 All
stimulants used for treatment of ADHD are classifi ed
as Schedule II controlled substances by the DEA
Pronunciation Key
Adzenys : add zen’ iss Dyanavel : die an uh vel
Adzenys XR-ODT is the fi rst extended-release orally
disintegrating tablet formulation of amphetamine to
become available in the US It contains a 3:1 ratio of d-
to l-amphetamine in 50% immediate-release and 50% delayed-release particles Approval of Adzenys
XR-ODT 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
Dyanavel XR extended-release oral suspension contains
a 3.2:1 ratio of d- to l-amphetamine in a mixture of
imme-diate-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 set-ting, at 8 time points between 1 and 13 hours post-dose SKAMP-Combined scores improved signifi cantly more with
Dyanavel XR than with placebo at all time points.
Table 1 Some Amphetamines for ADHD
Amphetamine –
Adzenys XR-ODT 3.1, 6.3, 9.4, 12.5, 15.7, 18.8 mg ER ODT 4,5 10-12 h 6.3 mg qAM/6.3-18.8 mg qAM 6 $270.00 (Neos Therapeutics)
Racemic amphetamine sulfate –
Mixed amphetamine salts –
Dextroamphetamines 3
Dextroamphetamine 12 –
Lisdexamfetamine dimesylate –
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 bi-carbonate 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.
Trang 6
Reslizumab (Cinqair) for Severe
Eosinophilic Asthma
▶
Pronunciation Key
Reslizumab : res liz' ue mab Cinqair: sink ayr'
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
EOSINOPHILIC PHENOTYPE — What constitutes an
eosinophilic phenotype is not well defi ned, 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,
ADVERSE EFFECTS ― Adverse effects of
ampheta-mines in children with ADHD include anorexia, failure to
gain weight, tachycardia, irritability, insomnia, motor or
vocal tics and, rarely, priapism and peripheral
vasculo-pathy 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
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.
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 signifi cantly reduced the frequency of clinically signifi cant 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 signifi cantly greater among patients treated with reslizumab (110 mL vs placebo).4
Among patients 12-17 years old included in the one-year 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 medium-dose 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
Reslizumab (Cinqair) Mepolizumab (Nucala)
Formulation 100 mg/10 mL single- 100 mg single-dose
Metabolism Degradation by pro- Degradation by
teolytic enzymes teolytic enzymes
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 trans-actional 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).
Trang 7differences were statistically signifi cant Reslizumab
3 mg/kg signifi cantly improved asthma quality of life.5
The fourth study included patients 18-65 years old with
asthma inadequately controlled on at least a
medium-dose 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 signifi cantly 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 effi cacy 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
effi cacy to mepolizumab (Nucala), which is injected
subcutaneously, remains to be determined ■
1 Mepolizumab (Nucala) for severe eosinophilic asthma Med Lett Drugs Ther 2016; 58:11.
2 KF Chung et al International ERS/ATS guidelines on defi nition, 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 multi-centre, 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 eo-sinophil 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 fi rst marketed in the US in 1967 and has less affi nity 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 Pedi-atr 2015; 166:1246.
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Trang 8Questions start on next page
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1 Review the effi cacy and safety of the new extended-release, abuse-deterrent capsule formulation of oxycodone (Xtampza ER) for management of pain
2 Review the effi cacy and safety of the rapidly disintegrating tablet formulation of levetiracetam (Spritam) for adjunctive treatment of partial-onset, myoclonic, and primary
generalized tonic-clonic seizures.
3 Review the effi cacy and safety of the two new extended-release amphetamine products (Adzenys XR-ODT and Dyanavel XR) for treatment of attention-defi cit/
hyperactivity disorder in patients ≥6 years old.
4 Review the effi cacy and safety of the interleukin-5 antagonist monoclonal antibody reslizumab (Cinqair) for maintenance treatment of severe asthma in adults with an
eosinophilic phenotype.
5 Explain the basis for the CDC’s statement that short courses of doxycycline have not been shown to cause tooth staining.
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Trang 9The Medical Letter ®
Online Continuing Medical Education
DO NOT FAX OR MAIL THIS EXAM
To take CME exams and earn credit, go to:
medicalletter.org/CMEstatus Issue 1497 Questions
(Correspond to questions #121-130 in Comprehensive Exam #74, available July 2016)
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 signifi cantly reduced the frequency of asthma exacerbations compared to placebo
b increased FEV1 from baseline signifi cantly 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
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 diffi culty
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 fi nd Spritam easier to take than Keppra tablets
c Spritam costs signifi cantly 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
extended-release 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 signifi cantly more than
placebo between 1 and 13 hours post-dose
c can cause irritability
d all of the above
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
PRESIDENT: Mark Abramowicz, M.D.; VICE PRESIDENT AND EXECUTIVE EDITOR: Gianna Zuccotti, M.D., M.P.H., F.A.C.P., Harvard Medical School; EDITOR IN CHIEF: Jean-Marie Pflomm,
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Pharm.D., F Peter Swanson, M.D
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;
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