The medical letter on drugs and therapeutics june 9 2014

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On Drugs and Therapeutics
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IN THIS ISSUE (starts on next page)

In Brief: A Naloxone Auto-Injector (Evzio) .................................................. p 45
Extended-Release Hydrocodone (Zohydro ER) for Pain ............................... p 45
Sublingual Immunotherapy for Allergic Rhinitis .......................................... p 47
In Brief: Lowering the Dose of Lunesta .......................................................... p 48

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The Medical Letter

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On Drugs and Therapeutics
Published by The Medical Letter, Inc. • 145 Huguenot Street, New Rochelle, NY 10801 • A Nonprofit Publication
Volume 56 (Issue 1444)
June 9, 2014

ALSO IN THIS ISSUE

Sublingual Immunotherapy for Allergic
Rhinitis .......................................................... p 47
In Brief: Lowering the Dose of Lunesta ..... p 48
IN BRIEF

A Naloxone Auto-Injector (Evzio)
A recent Medical Letter article reported renewed interest
in the intranasal administration (off-label) of the opioid
antagonist naloxone because of an increase in deaths
from opioid overdose in the US.1 Now the FDA has
approved a more practical alternative for emergency
treatment of life-threatening opioid overdose in adults
and children: a single-dose naloxone auto-injector
(Evzio – Kaleo) for intramuscular or subcutaneous use.
Evzio will be available in kits containing two prefilled 0.4mg auto-injectors with voice guidance and a “trainer”
device that also has voice guidance, but does not
contain medication or a needle. The manufacturer has
not published a price for Evzio to date, but news reports

indicate that each kit could cost hundreds of dollars,
compared to about $20 for a standard 0.4-mg injectable
dose of naloxone, which can be given intranasally.
1. Intranasal naloxone for treatment of opioid overdose. Med Lett
Drugs Ther 2014; 56:21.

Extended-Release Hydrocodone
(Zohydro ER) for Pain
The FDA has approved an extended-release oral formulation of the opioid agonist hydrocodone (Zohydro ER –
Zogenix) for management of pain severe enough to
require continuous, long-term therapy and for which
alternative treatment options are inadequate. Zohydro ER
is the first single-ingredient hydrocodone product to be
marketed in the US. Hydrocodone has been available for
years in combination with acetaminophen (Vicodin, and
others) or ibuprofen (Vicoprofen, and others).1
PHARMACOLOGY — Hydrocodone is a semisynthetic
opioid. It is metabolized primarily by CYP3A4-mediated

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N-demethylation to norhydrocodone and to a lesser
extent by CYP2D6-mediated O-demethylation to hydromorphone. Overall hydrocodone exposure is similar
after administration of Zohydro ER or comparable daily
doses of immediate-release hydrocodone combination
products, but peak concentrations are lower with Zohydro ER and it has a longer half-life. Steady state is
reached after 3 days of continuous use.
CLINICAL STUDY — In a clinical trial in opioid-tolerant
patients with moderate to severe chronic back pain,

those who had been successfully converted from their
current opioid to single-agent hydrocodone ER during
an initial open-label phase (n = 302) were randomized
to continue active treatment with fixed stable doses of
twice-daily hydrocodone ER (40-200 mg/day) or switch
to placebo in the double-blind phase. After 12 weeks, the
average daily pain intensity score increased significantly
more with placebo than with hydrocodone ER.2
ADVERSE EFFECTS — The most common adverse
effects of hydrocodone ER during the clinical trial were
constipation, nausea, somnolence, fatigue, headache,
dizziness, dry mouth, vomiting, and pruritus. Use of
hydrocodone, particularly at high doses, has rarely been
associated with sensorineural hearing loss.3 Overdosage
with any opioid can result in respiratory depression
and death. Crushing, chewing, snorting, or injecting
the contents of Zohydro ER capsules could result in
uncontrolled delivery of hydrocodone, possibly leading to
overdose and death.
Hydrocodone ER is classified as category C (teratogenic
effects in animals; no adequate human studies) for use
during pregnancy. Infants born to mothers who received
opioid therapy while pregnant may need treatment for
neonatal opioid withdrawal syndrome.
POTENTIAL FOR ABUSE — Hydrocodone is a
schedule II controlled substance. Combination pain
medications containing hydrocodone are currently
classified as schedule III, but the DEA, following an
FDA recommendation, has proposed reclassification

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45


Table 1. Some Extended-Release Oral Opioids
Drug
Hydrocodone
Zohydro ER (Zogenix)
Hydromorphone
Exalgo (Mallinckrodt)
Morphine
Avinza (Pfizer)
Kadian (Actavis)
generic
MS Contin (Purdue)
generic
Oxycodone
OxyContin (Purdue)
Oxymorphone
Opana ER (Endo)
generic

Formulations

Starting Dosage1

Duration
of Action

Cost2

10, 15, 20, 30, 40, 50 mg ER caps

10 mg q12h

12 hrs

$351.00

8, 12, 16, 32 mg ER tabs

Footnote 3

24 hrs

380.104

30, 45, 60, 75, 90, 120 mg ER caps
10, 20, 30, 40, 50, 60, 70, 80,
100, 130, 150, 200 mg ER caps
20, 30, 50, 60, 80, 100 mg ER caps
15, 30, 60, 100, 200 mg ER tabs

30 mg q24h
30 mg q24h

24 hrs
12-24 hrs

159.00
210.60

15 mg q12h

8-12 hrs

136.80
133.80
40.20

10, 15, 20, 30, 40, 60, 80 mg ER tabs

10 mg q12h

12 hrs

136.20

5, 7.5, 10, 15, 20, 30, 40 mg ER tabs

5 mg q12h

12 hrs

112.80
87.00

1. For patients who are not opioid tolerant. For patients switching from another opioid, starting dosage is based on previous opioid dosage. Long-acting formulations are
generally not recommended for opioid-naive patients.

2. Approximate wholesale acquisition cost (WAC) for 30 days’ treatment at the starting dosage. Source: Analy$ource® Monthly (Selected from FDB MedKnowledge™) May 5,
2014. Reprinted with permission by FDB, Inc. All rights reserved. ©2014. www.fdbhealth.com/policies/drug-pricing-policy. Actual retail prices may be higher.
3. Only recommended for patients who are opioid tolerant. Starting dosage determined by previous opioid dosage.
4. Cost for 30 8-mg ER tablets.

of these products to schedule II. The new single-entity,
extended-release capsule formulation is not tamperresistant and is expected to be associated with higher
levels of abuse than the combination products.4,5
As part of a Risk Evaluation and Mitigation Strategy
(REMS) program, the FDA has required that healthcare
providers receive training in use of extended-release
or long-acting opioids such as hydrocodone ER before
prescribing them.
DRUG INTERACTIONS — Taking hydrocodone ER
with a CYP3A4 inhibitor such as clarithromycin (Biaxin,
and generics) could result in increased plasma concentrations of the opioid.6 Mixed agonist/antagonist opioid
analgesics such as pentazocine (Talwin) or butorphanol (Stadol, and generics) could decrease the analgesic effect of hydrocodone ER and result in withdrawal
symptoms. Urinary retention and severe constipation,
possibly leading to paralytic ileus, could occur with
concurrent use of hydrocodone ER and an anticholinergic drug. Use of hydrocodone ER within 14 days of a
monoamine oxidase inhibitor is not recommended.
Coadministration of 40% alcohol resulted in a 2.4-fold
increase in peak concentrations of hydrocodone ER.
Taking hydrocodone ER with CNS depressants such
as alcohol, sedatives, or other opioids can increase
the risk of profound sedation, respiratory depression,
coma, and death.
DOSAGE AND ADMINISTRATION — Opioids have no
ceiling on their analgesic effect, except that imposed
by adverse effects. The recommended starting dosage

of Zohydro ER in opioid-naive or opioid non-tolerant
46

patients is 10 mg twice daily. The dosage can be increased by 10 mg twice daily as needed every 3-7 days
to achieve adequate pain relief. For patients switching
from another opioid, the dosage depends on the previous drug and its dose; conversion ratios for different
opioids are listed in the prescribing information. Zohydro ER capsules should be swallowed whole and
should not be broken, crushed, dissolved, or chewed.
To prevent withdrawal symptoms when discontinuing
therapy, the dose should be tapered gradually.
CONCLUSION — The new extended-release formulation
of hydrocodone (Zohydro ER) is the first singleentity form of the drug; it permits higher dosing than
immediate-release hydrocodone, which is only available
in combination with ibuprofen or acetaminophen. Like
other extended-release opioids, Zohydro ER is likely to
be abused, and the FDA has required special training for
prescribers. □
1. Drugs for pain. Treat Guidel Med Lett 2013; 11:31.
2. RL Rauck et al. Single-entity hydrocodone extended-release capsules in opioid-tolerant subjects with moderate-to-severe chronic
low back pain: a randomized double-blind, placebo-controlled
study. Pain Med 2014; Feb 12 (epub).
3. D Krashin et al. Extended-release hydrocodone – gift or curse? J
Pain Res 2013; 6:53.
4. FDA Background Material – NDA 202880. Zohydro ER (hydrocodone) for the management of moderate to severe chronic pain.
Meeting of the AADPAC, December 7, 2012. Available at www.fda.
gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/
Drugs/AnestheticAndAnalgesicDrugProductsAdvisoryCommittee/
ucm330683.pdf. Accessed May 29, 2014.
5. Y Olsen and JM Sharfstein. Chronic pain, addiction, and Zohydro.
New Engl J Med 2014; 370:2061.

6. Inhibitors and inducers of CYP enzymes and P-glycoprotein. Med
Lett Drugs Ther 2013; 55:e44.

The Medical Letter • Volume 56 • Issue 1444 • June 9, 2014


Sublingual Immunotherapy for Allergic
Rhinitis

season in the first year after stopping Grastek, but not in
the second year.7

The FDA has approved 3 allergen extracts for sublingual
administration as immunotherapy for allergic rhinitis
confirmed by a positive skin test or in vitro testing for
pollen-specific IgE antibodies: Oralair (Stallergenes
S.A./Greer) and Grastek (Merck) for grass polleninduced allergic rhinitis and Ragwitek (Merck) for short
ragweed pollen-induced allergic rhinitis.

ADVERSE EFFECTS — Local adverse effects are common after the first few doses (and sometimes after subsequent doses) with all 3 allergen extracts. These include
itching of the mouth, ear, and tongue, throat irritation, and
oropharyngeal edema. Anaphylaxis has occurred rarely;
auto-injectable epinephrine should be available. These
extracts should not be used in patients with unstable or
severe asthma or in those with active inflammatory oral
lesions or open areas after tooth loss or extraction.

ALLERGIC RHINITIS — Orally administered secondgeneration H1-antihistamines are the preferred first-line
therapy for relief of itching, sneezing, and rhinorrhea associated with mild to moderate allergic rhinitis. Intranasal
corticosteroids are the most effective drugs available for

prevention and relief of allergic rhinitis symptoms, including itching, sneezing, discharge, and congestion, and are
the drugs of choice for moderate to severe disease.1
Traditionally, allergen-specific immunotherapy for
allergic rhinitis has required subcutaneous injection
of gradually increasing doses of the relevant inducing
allergen such as tree, grass, or weed pollen. It can alter
the natural history of the disorder, and the benefits may
last for years after injections are discontinued, but its
use has been limited by the need for continued (usually
monthly) maintenance injections and concerns about
local or systemic adverse effects, including, rarely,
anaphylaxis. Sublingual allergen immunotherapy for
treatment of allergic rhinitis and allergic conjunctivitis
induced by airborne allergens has been used for years
in Europe.2
CLINICAL STUDIES — Randomized, double-blind,
placebo-controlled trials with Oralair and Grastek in both
adults and children and with Ragwitek in adults have
shown that all of these agents, started 3-4 months before and taken daily throughout the pollen season, can
reduce symptom scores and use of other medications by
20-40%.3-6 One 5-year study in adults found that taking
Grastek for 3 consecutive years reduced symptom scores
for 3 years; the effect was sustained during the allergy

Oralair and Grastek are classified as category B (no
evidence of risk in animals; no human studies) and
Ragwitek as category C (risk cannot be ruled out) for
use during pregnancy. Immunotherapy should not be
started during pregnancy.
DRUG INTERACTIONS — All 3 allergen-extract

sublingual tablets should be used with caution in
patients also taking a beta-adrenergic blocker, an
alpha-adrenergic blocker, an ergot alkaloid, a tricyclic
antidepressant, a monoamine oxidase inhibitor, or levothyroxine because these drugs can either potentiate
or inhibit the effect of epinephrine if it is needed to treat
an allergic reaction.
DOSAGE AND ADMINISTRATION — Sublingual
immunotherapy should begin at least 12 weeks (16
weeks for Oralair) before the start of the allergy
season and continue daily for the duration of the
season. The tablet should be placed under the tongue
for at least 1 minute. Patients should not eat or drink
while taking the tablet and for 5 minutes afterwards.
Because of the potential for anaphylaxis and
laryngopharyngeal edema, the first dose should be
administered in a healthcare setting and patients should
be observed for at least 30 minutes after the first dose;
subsequent doses can be taken at home, but patients
should have auto-injectable epinephrine available and
be trained in its use. The optimal duration of treatment
remains to be established.

Table 1. Sublingual Allergen Immunotherapy Extracts for Allergic Rhinitis
Product

Pollen

Formulations

Usual Dosage

Cost1

Oralair (Stallergenes
S.A/Greer)

Sweet vernal, orchard
perennial rye, timothy, and
Kentucky blue grass

100 IR (~3000 BAUs)
sublingual tabs
300 IR (~9000 BAUs)
sublingual tabs

10-17 years: 100 IR SL
on day 1, then 200 IR on
day 2, then 300 IR once/day
18-65 years: 300 IR once/day

$10.00

Grastek (Merck)

Timothy grass

2800 BAUs sublingual tabs

5-65 years: 1 tab SL
once/day

8.30

Ragwitek (Merck)

Short ragweed

12 Amb a 1-unit
sublingual tabs

18-65 years: 1 tab SL
once/day

8.30

IR = index of reactivity; BAUs = bioequivalent allergy units; SL = sublingually
1. Approximate wholesale acquisition cost (WAC) of one tablet. Source: Analy$ource® Monthly (Selected from FDB MedKnowledge™) May 5, 2014. Reprinted with
permission by FDB, Inc. All rights reserved. ©2014. www.fdbhealth.com/policies/drug-pricing-policy. Actual retail prices may be higher.

The Medical Letter • Volume 56 • Issue 1444 • June 9, 2014

47


CONCLUSION — Sublingual immunotherapy with
Oralair and Grastek for treatment of grass polleninduced allergic rhinitis and with Ragwitek for short
ragweed pollen-induced allergic rhinitis can reduce
the symptoms of allergic rhinitis. How sublingual
immunotherapy with pollens compares to subcutaneous
immunotherapy in efficacy and safety remains to be

established. Both are expensive; second-generation
H1-antihistamines and intranasal corticosteroids, both
available over the counter, are relatively inexpensive
options for symptom control. □
1. Drugs for allergic disorders. Treat Guidel Med Lett 2013; 11:43.
2. SY Lin et al. Sublingual immunotherapy for the treatment of allergic
rhinoconjunctivitis and asthma: a systematic review. JAMA 2013;
309:1278.
3. LS Cox et al. Clinical efficacy of 300IR 5-grass pollen sublingual
tablet in a US study: the importance of allergen-specific serum IgE.
J Allergy Clin Immunol 2012; 130:1327.
4. A Didier et al. Sustained 3-year efficacy of pre- and coseasonal
5-grass-pollen sublingual immunotherapy tablets in patients with
grass pollen-induced rhinoconjunctivitis. J Allergy Clin Immunol
2011; 128:559.
5. J Maloney et al. Efficacy and safety of grass sublingual immunotherapy tablet, MK-7243: a large randomized controlled trial. Ann
Allergy Asthma Immunol 2014; 112:146.
6. PS Creticos et al. Randomized controlled trial of a ragweed allergy
immunotherapy tablet in North American and European adults. J
Allergy Clin Immunol 2013; 131:1342.
7. SR Durham et al. SQ-standardized sublingual grass immunotherapy: confirmation of disease modification 2 years after 3 years
of treatment in a randomized trial. J Allergy Clin Immunol 2012;
129:717.

IN BRIEF

Lowering the Dose of Lunesta
The FDA has required the manufacturer of eszopiclone
(Lunesta – Sunovion), a benzodiazepine receptor
agonist approved for the treatment of insomnia, to

lower the current recommended starting dose to 1 mg
for both men and women because a new study found
that an evening dose of 3 mg can impair driving skills,
memory, and coordination for more than 11 hours.1
Eszopiclone’s half-life is longer than that of any other
drug in its class, which includes zolpidem (Ambien,
and generics) and zaleplon (Sonata, and generics).
All benzodiazepine receptor agonists may impair
performance the next morning, including driving.2
Anterograde amnesia and complex sleep-related
behaviors without conscious awareness may also
occur. Hallucinations have been reported. Like the
benzodiazepines, benzodiazepine receptor agonists
are schedule IV controlled substances; withdrawal,
dependence, and abuse can occur.
1. FDA Drug Safety Communication. FDA warns of next-day
impairment with sleep aid Lunesta (eszopiclone) and lowers
recommended dose. Available at www.fda.gov/Drugs/DrugSafety/
ucm397260.htm. Accessed May 29, 2014.
2. Drugs for insomnia. Treat Guidel Med Lett 2012; 10:57.

48

Coming Soon in The Medical Letter:
Tobramycin Inhalation Solution (Bethkis) for Cystic Fibrosis
A Transcutaneous Electrical Nerve Stimulation Device (Cefaly)
for Migraine
Luliconazole (Luzu) for Tinea Infections
Treatment of Atrial Fibrillation

The Medical Letter

®

On Drugs and Therapeutics
EDITOR IN CHIEF: Mark Abramowicz, M.D.
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Jane P. Gagliardi, M.D., M.H.S., F.A.C.P Duke University School of Medicine
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David N. Juurlink, BPhm, M.D., Ph.D., Sunnybrook Health Sciences Centre
Richard B. Kim, M.D., University of Western Ontario
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Sandip K. Mukherjee, M.D., F.A.C.C., Yale School of Medicine
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The Medical Letter • Volume 56 • Issue 1444 • June 9, 2014


The Medical Letter

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Online Continuing Medical Education
To take CME exams and earn credit, go to:
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Issue 1444 Questions
(Correspond to questions #67-72 in
Comprehensive Exam #70, available July 2014)
Extended-Release Hydrocodone (Zohydro ER) for Pain
1.

Compared to similar doses of immediate-release hydrocodone, Zohydro ER :
a. is more effective
b. causes fewer adverse effects
c. has a longer duration of action
d. none of the above

2.

A 55-year-old man with chronic back pain tells you that he has seen ads on
TV for Zohydro ER and asks if he could try it. He currently takes Vicodin as
needed for back pain but says that he usually only needs one or two tablets
a day to control his pain. He also takes the anticholinergic drug oxybutynin
for urinary incontinence. You could tell him that:
a. you would recommend a starting dose of 50 mg q12h
b. you have no concerns about Zohydro ER interacting with any of
his current medications
c. he could crush the Zohydro ER capsules if they are too large to
swallow
d. none of the above

3.

Zohydro ER :
a. is not affected by concurrent use of alcohol
b. is tamper-resistant
c. is more effective than other long-acting opioids for chronic pain
d. none of the above

Sublingual Immunotherapy for Allergic Rhinitis

4.

A mother asks you about the new products that she has heard about for
grass pollen allergy and wants to know if they would help her 9-year-old
daughter’s allergy symptoms. You could tell her that:
a. they need to be taken daily starting at least 12 weeks before
allergy season
b. after taking them for 1 year, they will prevent symptoms of grass
pollen allergy for life
c. unlike traditional allergen-specific immunotherapy that requires
subcutaneous injection, the new sublingual therapies do not
pose a risk for anaphylaxis
d. all of the above

5.

Adverse effects of the 3 new allergen extracts for sublingual administration
as immunotherapy for allergic rhinitis include:
a. itching of the mouth, ear, and tongue
b. throat irritation
c. oropharyngeal edema
d. all of the above

In Brief: Lowering the Dose of Lunesta
6.

The recommended starting dose of Lunesta is now:
a. 0.5 mg
b. 1 mg
c. 2 mg

d. 3 mg

ACPE UPN: Per Issue Exam: 0379-0000-14-444-H01-P; Release: June 9, 2014, Expire: June 9, 2015
Comprehensive Exam 70: 0379-0000-14-070-H01-P; Release: July 2014, Expire: July 2015

Over


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Through this program, The Medical Letter expects to provide the healthcare community with unbiased, reliable, and
timely educational content that they will use to make independent and informed therapeutic choices in their practice.
LEARNING OBJECTIVES:
Activity participants will read and assimilate unbiased reviews of FDA-approved and off-label uses of drugs and
other treatment modalities. Activity participants will be able to select and prescribe, or confirm the appropriateness
of the prescribed usage of, the drugs and other therapeutic modalities discussed in The Medical Letter with specific
attention to clinical trials, pathophysiology, dosage and administration, drug metabolism and interactions, and patient
management. Activity participants will make independent and informed therapeutic choices in their practice.
Upon completion of this program, the participant will be able to:
1.
Review the efficacy and safety of extended-release hydrocodone (Zohydro ER) for treatment of chronic pain.
2.
Review the efficacy and safety of sublingual immunotherapy for treatment of allergic rhinitis.
3.
Explain the new dosing recommendations for Lunesta and why the FDA recommended such a change.
Privacy and Confidentiality: The Medical Letter guarantees our firm commitment to your privacy. We do not sell any
of your information. Secure server software (SSL) is used for commerce transactions through VeriSign, Inc. No credit
card information is stored.
IT Requirements: Windows XP/Vista/7/8, Mac OS X+; current versions of Microsoft IE, Mozilla Firefox, Google Chrome,
Safari or any other compatible Web browser. High-speed connection.
Have any questions? Call us at 800-211-2769 or 914-235-0500 or e-mail us at: