The medical letter on drugs and therapeutics july 21 2014

The Medical Letter

®

on Drugs and Therapeutics
Objective Drug Reviews Since 1959
Volume 56

ISSUE
ISSUE
No.

1433
1447
Volume 56

July 21, 2014

IN THIS ISSUE

In Brief: Generic Celecoxib ......................................................................................... p 61
Extended-Release Oxycodone and Acetaminophen (Xartemis XR).............................. p 61
Oral Propanolol (Hemangeol) for Infantile Hemangiomas ........................................... p 61
Ceritinib (Zykadia) for Non-Small Cell Lung Cancer .................................................... p 62
A Responsive Neurostimulator Device (RNS System) for Epilepsy .............................. p 63
In Brief: Esomeprazole Strontium............................................................................... p 64
In Brief: Low-Dose Indomethacin (Tivorbex) .............................................................. p 64

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The Medical Letter

®

on Drugs and Therapeutics
Objective Drug Reviews Since 1959
Volume 56

ISSUE

ISSUE No.

1433

1447
Volume 56

July 21, 2014
Take CME Exams
ALSO IN THIS ISSUE

Oral Propranolol (Hemangeol) for Infantile Hemangioma ........................................... p 61
Ceritinib (Zykadia) for Non-Small Cell Lung Cancer .................................................... p 62
A Responsive Neurostimulator Device (RNS System) for Epilepsy .............................. p 63
In Brief: Esomeprazole Strontium............................................................................... p 64
In Brief: Low-Dose Indomethacin (Tivorbex) for Pain ................................................. p 64

▶

IN BRIEF

Generic Celecoxib
The FDA has authorized two manufacturers (Teva,
Mylan) to market generic formulations of celecoxib
(Celebrex – Pfizer), the only COX-2 selective inhibitor
remaining on the US market. Celecoxib is less likely
than nonselective NSAIDs to cause gastric ulcers
or other GI toxicity,1 and unlike traditional NSAIDs, it
does not have an antiplatelet effect.
Celecoxib is much less COX-2 selective than rofecoxib
(Vioxx), which was removed from the US market because of an increased risk of cardiovascular events.
One analysis of randomized clinical trials that included a total of about 26,000 patients taking celecoxib
found no evidence of an increased risk of cardiovascular thrombotic events compared to nonselective
NSAIDs or placebo.2 A review of controlled observational studies found an increased cardiovascular risk

with celecoxib (RR 1.17) that was similar to the risk
with ibuprofen (RR 1.18) and slightly higher than the
risk with naproxen (RR 1.09).3 All NSAIDs can cause
renal toxicity, especially in the elderly.4 ■
1. PL McCormack. Celecoxib: a review of its use for symptomatic
relief in the treatment of osteoarthritis, rheumatoid arthritis and
ankylosing spondylitis. Drugs 2011; 71:2457.
2. WB White et al. Risk of cardiovascular events in patients receiving celecoxib: a meta-analysis of randomized clinical trials. Am
J Cardiol 2007; 99:91.
3. P McGettigan and D Henry. Cardiovascular risk with non-steroidal
anti-inflammatory drugs: systematic review of population-based
controlled observational studies. PLoS Med 2011; 8:e1001098.
4. RL Barkin et al. Should nonsteroidal anti-inflammatory drugs
(NSAIDs) be prescribed to the older adult? Drugs Aging 2010;
27:775.

Extended-Release Oxycodone and
Acetaminophen (Xartemis XR)

The FDA has approved a fixed-dose extended-release
formulation of oxycodone and acetaminophen
(Xartemis XR – Mallinckrodt) for oral treatment of
acute pain severe enough to require an opioid. Oxycodone is available in the US as a single entity in oral
immediate-release (Oxecta, and others) and extendedrelease (OxyContin) formulations. Immediate-release
oxycodone is also available in combination with aspirin (Percodan, and others), acetaminophen (Percocet,
and others), or ibuprofen (see Table 1).1
THE NEW FORMULATION — Xartemis XR tablets contain immediate- and extended-release layers designed
to release the active ingredients at a steady rate over
an extended period. Oxycodone plasma concentrations
reach a peak in 3-4 hours. Acetaminophen levels peak

in 0.75-1 hour. The elimination half-life is 4.5 hours for
oxycodone and 5.8 hours for acetaminophen. Steadystate concentrations of both drugs are achieved within
24 hours after the first dose.
A CLINICAL STUDY — Approval of extended-release
oxycodone/acetaminophen was based on the results
of a randomized, double-blind trial in 303 adults with
moderate to severe acute pain following bunionectomy. Patients received 2 tablets of the combination
or placebo every 12 hours for 48 hours. More patients
treated with the combination had a ≥30% reduction
in pain intensity scores within 2 hours after the first
dose (63.1% vs. 27.2% with placebo). The mean time
between a dose of the combination and first use of
59

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


The Medical Letter

July 21, 2014

Vol. 56 (1447)

®

Table 1. Some Oral Opioid Combinations
Drugs

Some Available Formulations

Usual Daily Dosage

Cost1

5/325, 7.5/325, 10/325 mg tabs
2.5/325, 5/325, 7.5/325, 10/325 mg tabs
5/300, 7.5/300, 10/300 mg tabs
5/325 mg tabs2

1 tab q6h

$57.70
419.70
593.10
14.00

7.5/325 mg tabs

2 tabs q12h

128.80

2.5/325, 5/325, 7.5/325, 10/325 mg tabs2
5/325, 7.5/325, 10/325 mg tabs2
5/300, 7.5/300, 10/300 mg tabs
5/300, 7.5/300, 10/300 mg tabs

1 tab q4-6h

17.90

113.70
101.00
374.30

5/400 mg tabs

1 tab q6h

2.5/200, 5/200, 7.5/200, 10/200 mg tabs
2.5/200, 5/200, 10/200 mg tabs
7.5/200 mg tabs

1 tab q4-6h3

Acetaminophen-Containing Combinations
Oxycodone/acetaminophen
generic
Percocet
Primlev
Roxicet
extended-release
Xartemis XR
Hydrocodone/acetaminophen
generic
Lortab
Vicodin
Xodol
Ibuprofen-Containing Combinations
Oxycodone/ibuprofen
generic

Hydrocodone/ibuprofen
generic
Reprexain
Vicoprofen

59.40
138.90
177.70
196.00

1. Approximate wholesale acquisition cost (WAC) for 14 days' treatment with the lowest usual daily dosage for tablets containing 7.5 mg of oxycodone or hydrocodone or for the closest available formulation. Source: Analy$ource® Monthly (Selected from FDB MedKnowledge™) July 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.
2. Also available as an oral solution.
3. Formulations containing 2.5 or 5 mg of hydrocodone may be taken as two tablets q4-6h.

rescue medication increased from 6.2 hours during
the first dosing interval to 9.6 hours during the last
dosing interval (between 36 and 48 hours).2
ADVERSE EFFECTS — In clinical studies with the
combination, the most common adverse effects were
nausea, dizziness, headache, vomiting, constipation,
and somnolence. Like other opioids, oxycodone can
cause confusion, pruritus, dry mouth and sweating,
and overdose could result in hypotension, respiratory
depression, cardiac arrest, and death. Acetaminophen
overdose can cause serious or fatal hepatotoxicity; the
total dose of acetaminophen from all sources should
not exceed 4 g/day.
The combination is classified as category C
(fetotoxicity with acetaminophen in animals; no

adequate human studies) for use during pregnancy.
Prolonged use of opioids during pregnancy can result
in neonatal withdrawal syndrome.
DEPENDENCE AND ABUSE — Like other oxycodone
combinations, Xartemis XR is classified as a schedule
II controlled substance. Dependence and abuse have
been reported with all oxycodone-containing products.
Increasing the dose of the combination when oxycodone tolerance develops could lead to acetaminophen
toxicity. Crushing the tablets and then chewing or
snorting them, or injecting a solution made from the
crushed formulation, could result in opioid overdose
and death. Oxecta and OxyContin are formulated to
deter abuse of the drug by injection or snorting.
60

DRUG INTERACTIONS — Drugs that inhibit CYP3A4
may increase plasma concentrations of oxycodone
and CYP3A4 inducers can decrease them.3 Mixed
agonist/antagonist opioid analgesics, such as
butorphanol (Stadol, and generics), could decrease
the analgesic effect of oxycodone and possibly
precipitate withdrawal symptoms in opioiddependent patients. Urinary retention and severe
constipation could occur with concurrent use of an
anticholinergic drug. Xartemis XR should not be used
with (or within 14 days of stopping) a monoamine
oxidase inhibitor.
DOSAGE AND ADMINISTRATION — Xartemis XR is
available as extended-release tablets containing 7.5
mg of oxycodone and 325 mg of acetaminophen.
The recommended dosage is 2 tablets every 12

hours with or without food. The tablets can become
sticky when wet and may adhere to the wall of the
esophagus; they should be taken one at a time with
enough water to ensure complete swallowing. A
second dose may be taken, if needed, as soon as 8
hours after the initial dose, but subsequent doses
should be taken every 12 hours.
CONCLUSION — The new extended-release formulation of oxycodone and acetaminophen (Xartemis XR)
offers a twice-daily option for treatment of moderate
to severe acute pain. It might provide more stable
analgesia than immediate-release combinations, but
no comparative studies are available. ■


The Medical Letter

®

1. Drugs for pain. Treat Guidel Med Lett 2013; 11:31.
2. N Singla et al. A randomized, double-blind, placebo-controlled
study of the efficacy and safety of MNK-795, a dual-layer, biphasic, immediate-release and extended-release combination
analgesic for acute pain. Curr Med Res Opin 2014; 30:349.
3. Inhibitors and inducers of CYP enzymes and P-glycoprotein.
Med Lett Drugs Ther 2013; 55:e44.

▶

Oral Propranolol (Hemangeol) for
Infantile Hemangioma

The FDA has approved an oral solution of the
nonselective beta-adrenergic blocker propranolol
(Hemangeol – Pierre Fabre) for treatment of proliferating infantile hemangiomas.
INFANTILE HEMANGIOMAS — These benign
congenital vascular tumors eventually tend to regress
spontaneously, but early in life they can grow rapidly
and can ulcerate, bleed, cause disfigurement, interfere
with respiration or vision, and cause heart failure.
Complicated infantile hemangiomas have been
treated with systemic corticosteroids. Interferon alfa
and vincristine are alternatives.
BACKGROUND — In a report describing 11 children
with complicated infantile hemangiomas treated with
propranolol (the first child was being treated for an
associated condition), the color of the tumor changed
within 24 hours from intense red to purple and its
texture softened. Subsequently, the tumors continued
to regress until they were nearly flat, with residual
skin telangiectasias.1 This initial report was followed
by widespread off-label use of propranolol, a large
number of case reports, and a consensus conference.2
MECHANISM OF ACTION — How propranolol causes
regression of hemangiomas is unknown. Suggested
mechanisms include vasoconstriction, blocking
angiogenesis, and causing apoptosis of tumor
endothelial cells.
PHARMACOLOGY — Propranolol is rapidly absorbed
from the GI tract, but undergoes extensive first-pass
metabolism in the liver, and only about 25% of an oral
dose reaches the systemic circulation. Trace amounts

of the drug are excreted unchanged in urine. It has a
plasma half-life of 3-6 hours.
CLINICAL STUDIES — Only one randomized, doubleblind, placebo-controlled trial of propranolol use to
treat infantile hemangiomas has been published.
Among 39 children 11 weeks to 4 years old with facial
or other potentially disfiguring infantile hemangiomas, use of propranolol oral solution 2 mg/kg/day in

Vol. 56 (1447)

July 21, 2014

3 divided doses, compared to placebo, resulted in significantly greater reductions in tumor volume (60% vs.
14%), color, and elevation after 6 months of treatment.3
FDA approval of Hemangeol was based on an
unpublished double-blind study, summarized in the
package insert, in 460 infants 35 days to 5 months
old with proliferating infantile hemangiomas. The
patients were randomized to 1.2 or 3.4 mg/kg/day of
propranolol in 2 divided doses for 3 or 6 months, or to
placebo. Complete or nearly complete resolution of the
hemangioma at 24 weeks, the primary endpoint, was
achieved in 61 of 101 infants (60%) on propranolol
3.4 mg/kg/day for 6 months and in 2 of 55 (4%) receiving
a placebo. The package insert does not mention the
complete resolution rates among patients who took
the lower dose or were only treated for 3 months.
ADVERSE EFFECTS — Hypoglycemia, presumably related to adrenergic blockade, has been the most serious
adverse effect of propranolol therapy for infantile hemangioma. Hypoglycemic seizures have been reported.
Infants with poor oral intake or concomitant infection
appear to be at greatest risk.2

Propranolol can cause bronchospasm; it is contraindicated in children with asthma. Hyperkalemia has been
reported with its use for infantile hemangioma, possibly
related to breakdown of the tumor cells. Bradycardia
and hypotension can occur, but generally have been
asymptomatic and infrequent. Sleep disturbances
and nightmares have been reported. In children with
PHACE syndrome, which is characterized by large facial
hemangiomas accompanied by arterial anomalies of
the head and neck, treatment with propranolol may increase the risk of stroke.4
No deaths have been reported with use of oral
propranolol to treat infantile hemangioma.
DRUG INTERACTIONS — Patients receiving propranolol
who are treated concurrently with corticosteroids
may be at increased risk for hypoglycemia because
of adrenal suppression. Propranolol is a substrate
of cytochrome P450 enzymes 2D6, 1A2, and 2C19
and of the efflux transporter P-glycoprotein (P-gp).
Inhibitors of CYP2D6, 1A2, or 2C19 may increase serum
concentrations of the drug; inducers of CYP1A2 or 2C19
may decrease them.5
DOSAGE AND COST — Hemangeol is formulated as an
oral solution containing 4.28 mg/mL of propranolol
hydrochloride. The manufacturer recommends starting
treatment in infants 5 weeks to 5 months of age with
doses of 0.15 mL/kg (0.6 mg/kg) twice daily at least 9
61


The Medical Letter

®

hours apart. The dose should be increased after one
week to 0.3 mL/kg (1.1 mg/kg) twice daily. After the
second week, the dosage should be increased to the
maintenance dosage of 0.4 mL/kg (1.7 mg/kg) twice
daily, which is given for 6 months. The dose should be
administered during or just after a feeding to minimize
the risk of hypoglycemia. The drug should not be given
to children who are not eating or are vomiting. A 120mL bottle of Hemangeol costs $375.00.6
CONCLUSION — Oral propranolol is safe and effective
for treatment of complicated infantile hemangiomas.
Hypoglycemia appears to be the most worrisome
adverse effect. ■
1. C Léauté-Labrèze et al. Propranolol for severe hemangiomas of
infancy. N Engl J Med 2008; 358:2649.
2. BA Drolet et al. Initiation and use of propranolol for infantile
hemangioma: report of a consensus conference. Pediatrics
2013; 131:128.
3. M Hogeling et al. A randomized controlled trial of propranolol
for infantile hemangiomas. Pediatrics 2011; 128:e259.
4. D Metry et al. Propranolol use in PHACE syndrome with cervical
and intracranial arterial anomalies: collective experience in 32
infants. Pediatr Dermatol 2013; 30:71.
5. Inhibitors and inducers of CYP enzymes and P-glycoprotein.
Med Lett Drugs Ther 2013; 55:e44.
6. Approximate wholesale acquisition cost (WAC). Source:
Analy$ource® Monthly (Selected from FDB MedKnowledge™)
July 5, 2014. Reprinted with permission by FDB, Inc. All rights
reserved. ©2014. www.fdbhealth.com/policies/drug-pricingpolicy. Actual retail price may be higher.

▶

Ceritinib (Zykadia) for Non-Small
Cell Lung Cancer

Ceritinib (Zykadia – Novartis), an oral tyrosine
kinase inhibitor, has received accelerated approval
from the FDA for treatment of patients with anaplastic lymphoma kinase (ALK)-positive metastatic
non-small cell lung cancer (NSCLC) who have
progressed on or are intolerant to crizotinib (Xalkori).
It is the second tyrosine kinase inhibitor to be approved
for ALK-positive metastatic NSCLC; crizotinib was the
first.1 Translocations of the ALK gene are found in
about 5% of lung cancers2; they occur predominantly
in nonsmokers with adenocarcinoma.
Table 1. Pharmacology
Drug class

ALK tyrosine kinase inhibitor

Route

Oral

Formulation

150 mg capsules

Tmax

4-6 hours

Half-life

41 hours

Metabolism

Primarily by CYP3A

Elimination

Feces (~92%); urine (~1%)

62

Vol. 56 (1447)

July 21, 2014

MECHANISM OF ACTION — Translocations of ALK,
a receptor tyrosine kinase, result in expression
of oncogenic fusion proteins, which increase cell
proliferation. Ceritinib inhibits ALK and other receptor
tyrosine kinases.
CLINICAL STUDIES — A single-arm, open-label trial,
summarized in the package insert, in 163 patients with
metastatic ALK-positive NSCLC who had progressed
on or were intolerant to crizotinib found that 41.1%

of patients taking ceritinib 750 mg/day had a partial
response and 2.5% had a complete response. The
median duration of response was 7.1 months.
Single-arm trials of ceritinib in treatment-naive ALKpositive NSCLC patients and trials comparing it to
chemotherapy in treatment-naive and previouslytreated patients are ongoing.
ADVERSE EFFECTS — According to the manufacturer,
diarrhea, nausea, vomiting, or abdominal pain
occurred in 96% of patients (including severe cases
in 14%) treated with ceritinib in the clinical trial,
resulting in dose reductions in 38% of patients.
Elevated transaminases, fatigue, decreased appetite,
and constipation were also common. Ceritinib can
cause hepatotoxicity, bradycardia, hyperglycemia, and
prolongation of the QT interval. Severe, sometimes
fatal, pneumonitis has been reported.
DRUG INTERACTIONS — Ceritinib is a substrate
of CYP3A4 and P-glycoprotein. Inhibitors of 3A4
can increase serum concentrations of ceritinib and
inducers of 3A4 can decrease them.3 Concurrent use
of ceritinib with strong CYP3A inhibitors or inducers is
not recommended. Ceritinib itself may inhibit CYP3A
and CYP2C9.
DOSAGE, ADMINISTRATION, AND COST — The
recommended dosage of ceritinib is 750 mg
(5 capsules) once daily taken at least 2 hours before
or after a meal. Treatment should be continued until
disease progression or toxicity occurs. The labeling
specifies a number of dosage adjustments when
adverse effects occur. The dose of ceritinib should be
reduced by about one-third if concurrent use of a strong

CYP3A inhibitor is needed. A 30-day supply of Zykadia
costs about $13,500.4
CONCLUSION — Ceritinib (Zykadia), an oral tyrosine
kinase inhibitor, has produced a partial response in
patients with metastatic anaplastic lymphoma kinase
(ALK)-positive non-small cell lung cancer who have
progressed on or are intolerant to crizotinib (Xalkori).
Ceritinib can cause severe gastrointestinal adverse


The Medical Letter

®

effects, and it is expensive. The effectiveness of
ceritinib on progression-free and overall survival
remains to be determined. ■
1. Crizotinib (Xalkori) for non-small cell lung cancer. Med Lett
Drugs Ther 2012; 54:11.
2. AT Shaw et al. Ceritinib in ALK-rearranged non-small-cell lung
cancer. N Engl J Med 2014; 370: 1189.
3. Inhibitors and inducers of CYP enzymes and P-glycoprotein.
Med Lett Drugs Ther 2013; 55:e44.
4. Approximate wholesale acquisition cost (WAC). Source:
Analy$ource® Monthly (Selected from FDB Medknowledge™)
July 5, 2014. Reprinted with permission by FDB, Inc. All rights
reserved. ©2014. www.fdbhealth.com/policies/drug-pricingpolicy. Actual retail price may be higher.

▶

A Responsive Neurostimulator
Device (RNS System) for Epilepsy

The FDA has approved the use of a responsive
neurostimulator device (RNS System – NeuroPace)
for adjunctive treatment of adults with partial-onset
seizures that are not controlled with ≥2 antiepileptic
drugs and who have frequent and disabling seizures
and no more than 2 epileptogenic foci.
TREATMENT OF EPILEPSY — Treatment of epilepsy
should begin with a single drug, gradually increasing
the dosage until seizures are controlled or adverse
effects become unacceptable. If seizures persist,
expert clinicians generally prescribe at least one
and sometimes a second alternative drug as monotherapy before considering use of two drugs at the
same time.1
About 30-40% of patients with epilepsy continue to have
seizures despite treatment with antiepileptic drugs or
have intolerable side effects.2 Vagus nerve stimulation,
which requires subcutaneous implantation of an electrical pulse generator in the left chest wall that is connected to an electrode wrapped around the left vagus
nerve in the neck, delivers pre-programmed impulses to
the brain through the vagus nerve. It has been used for
years with some success in patients refractory to treatment with antiepileptic drugs.3
THE NEW DEVICE — The RNS System consists of a
neurostimulator that is implanted in the skull under
the scalp and leads that are surgically implanted in the
brain near the seizure focus or foci. The neurostimulator is a programmable, battery-powered device that
continuously monitors brain electrical activity and
delivers electrical stimulation to the foci as needed to
prevent seizures. The device costs about $40,000, and

the average battery life is about 2-3.5 years.4

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July 21, 2014

A CLINICAL STUDY — Approval of the new device was
based on the results of a double-blind trial in 191 adults
with partial-onset seizures who had >3 seizures per
month, 1 or 2 epileptogenic regions, and were refractory
to treatment with ≥2 antiepileptic drugs. Patients were
randomized to responsive cortical stimulation with the
implanted neurostimulator or to sham neurostimulation (stimulation turned off) for 12 weeks. After the
initial 12 weeks, all patients received open-label active
responsive cortical neurostimulation for an additional
84 weeks.
During the initial 12 weeks, patients who received responsive cortical stimulation had a 38% reduction in
mean seizure frequency from baseline, the primary endpoint, compared to a 17% reduction among those who
had sham neurostimulation, a statistically significant
difference.5
A follow-up study found that neurostimulation with
the RNS System reduced mean seizure frequency by
44% after 1 year and by 53% at 2 years post-implant.6
ADVERSE EFFECTS — The most frequent adverse
effects reported during the clinical trial were
implant-site infections and premature battery depletion. Implant-site pain and headache are common in
the post-operative period. Intracranial hemorrhage can
also occur. During the 2-year follow-up study, adverse
effects included device lead damage, device lead division, and increased seizure frequency. Patients with
the device should avoid having an MRI, electroconvulsive therapy, transcranial magnetic stimulation, or diathermy procedures.

CONCLUSION — The responsive neurostimulator
device (RNS System) is effective in reducing seizure
frequency in adults with partial-onset seizures that
are not controlled with >2 antiepileptic drugs and who
have no more than 2 epileptogenic foci. Its long-term
effects are unknown. How use of this device compares
to vagus nerve stimulation for this indication remains to
be determined. ■
1. Drugs for epilepsy. Treat Guidel Med Lett 2013; 11:9.
2. JA French and TA Pedley. Clinical Practice. Initial management
of epilepsy. N Engl J Med 2008; 359:166.
3. RH Howland. Vagus nerve stimulation. Curr Behav Neurosci
Rep 2014; 1:64.
4. Cost according to the manufacturer.
5. MJ Morrell et al. Responsive cortical stimulation for the treatment of medically intractable partial epilepsy. Neurology 2011;
77:1295.
6. CN Heck et al. Two-year seizure reduction in adults with medically intractable partial onset epilepsy treated with responsive
neurostimulation: final results of the RNS System pivotal trial.
Epilepsia 2014; 55:432.

63


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Vol. 56 (1447)

®

July 21, 2014

IN BRIEF

IN BRIEF

Esomeprazole Strontium

Low-Dose Indomethacin (Tivorbex) for
Pain

The FDA has approved the proton pump inhibitor (PPI)
esomeprazole strontium for use in adults for the same
indications as esomeprazole magnesium (Nexium) :
treatment of gastroesophageal reflux disease (GERD),
prevention of NSAID-induced gastric ulcers, eradication of Helicobacter pylori, and treatment of pathological hypersecretory conditions. It was first marketed
in December 2013 as a branded drug (Esomeprazole
Strontium) and a month later as a generic drug.
Table 1. Oral Proton Pump Inhibitors
Drug

Usual Dosage1,2

Cost3

Dexlansoprazole – Dexilant
(Takeda)
Esomeprazole magnesium –
Nexium (AstraZeneca)
Nexium 24HR (OTC)
Esomeprazole strontium –

generic5
Esomeprazole Strontium (Amneal)5
Lansoprazole – generic
Prevacid (Takeda)
Prevacid 24HR (OTC)
Omeprazole8 – generic
Prilosec (AstraZeneca)
Prilosec OTC
Pantoprazole – generic
Protonix (Pfizer)
Rabeprazole – generic
Aciphex, Aciphex Sprinkle (Eisai)

30-60 mg once/d

$183.90

20-40 mg once/d
236.70
16.404
24.65-49.3 mg
once/d6
15-30 mg once/d
20-40 mg once/d
40 mg once/d
20 mg once/d

60.007
200.807
93.70

276.30
17.804
17.90
204.40
17.804
7.00
229.80
59.00
349.90

OTC = Over the counter
1. The lower end of the range is generally used for initial treatment of GERD.
Higher doses and bid dosing may be needed for patients with peptic ulcers,
hypersecretory states like Zollinger-Ellison Syndrome, or for treatment of H.
pylori infection.
2. PPIs are generally taken 30-60 minutes before the first meal of the day. Taking
one before the evening meal may be more effective for nocturnal acid control.
3. Approximate wholesale acquisition cost (WAC) for 30 days’ treatment with
the lowest usual dosage. Source: Analy$ource® Monthly (Selected from FDB
MedKnowledgeTM) July 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.
4. Cost of 28 tablets or capsules.
5. Branded and generic formulations are marketed by Amneal under the same
name.
6. Equivalent to 20-40 mg of esomeprazole.
7. Cost of 49.3-mg capsules. The 24.65-mg capsules are not yet available.
8. Also available in combination with sodium bicarbonate (Zegerid and Zegerid OTC).

Strontium is incorporated into bone. It is not recommended for use in children or during pregnancy

because of the absence of safety data in those populations. Use of esomeprazole strontium is not recommended for patients with severe renal impairment.
Esomeprazole strontium is the seventh PPI to become available as a single agent in the US. No new
clinical trials were required for its approval, which
was based on earlier clinical trials with esomeprazole magnesium. All of the PPIs appear to be equally
effective.1 ■
1. Drugs for peptic ulcer disease and GERD. Treat Guidel Med Lett
2014; 12:25.

64

The same pharmaceutical company (Iroko) that
recently marketed low-dose diclofenac (Zorvolex)
for treatment of mild to moderate acute pain1 has
now received approval from the FDA to market a lowdose oral formulation of indomethacin (Tivorbex) for
the same indication. Tivorbex is available in 20- and
40-mg capsules; conventional immediate-release
indomethacin capsules contain 25 mg and 50 mg of
the drug.
The rationale for this new product is the same as
the one offered for Zorvolex: the drug is formulated
as submicron particles that increase surface
area, leading to faster dissolution and absorption.
According to the package insert, the time to reach
peak serum concentrations (Tmax) was 1.67 hours
with a 40-mg capsule of Tivorbex, compared to
2.02 hours with a standard 50-mg capsule of
indomethacin.
The problem with Tivorbex is the same as the
problem with Zorvolex: there are no studies
comparing its efficacy to that of standard doses of

indomethacin or to any other NSAID. In addition,
indomethacin is generally considered one of the
most potent NSAIDs and one of those most likely to
cause GI bleeding, increase cardiovascular risk, and
damage the kidneys. There is no good reason to use
indomethacin in any dosage for treatment of mild to
moderate pain. ■
1. Low-dose diclofenac (Zorvolex) for pain. Med Lett Drugs Ther
2014; 56:19.

Coming Soon in The Medical Letter:
Drugs for Inflammatory Bowel Disease
Dalbavancin (Dalvance) for Skin and Skin Structure Infections
Sucroferric Oxyhydroxide (Velphoro) for Hyperphosphatemia
A Transcutaneous Electrical Nerve Stimulation Device
(Cefaly) for Migraine
Drugs for Osteoarthritis

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Issue 1447 Questions

(Correspond to questions #11-20 in Comprehensive Exam #71, available January 2015)
Generic Celecoxib

Ceritinib (Zykadia) for Non-Small Cell Lung Cancer

1. Celecoxib is less likely than nonselective NSAIDs to cause:
a. renal toxicity
b. GI toxicity
c. cardiovascular thrombotic events
d. all of the above

6. Ceritinib is FDA-approved for patients:
a. with metastatic non-small cell lung cancer
b. with the ALK translocation
c. who have not responded to crizotinib
d. all of the above

Extended-Release Oxycodone and Acetaminophen (Xartemis XR)

7. A 63-year-old man with metastatic non-small cell lung cancer
being treated with ceritinib complains of severe abdominal
pain. The most likely cause is:
a. bowel perforation
b. pancreatitis
c. ceritinib toxicity
d. peptic ulcer

2. Xartemis XR is approved by the FDA for use in patients with:
a. chronic pain
b. acute pain
c. acute pain severe enough to require an opioid
d. severe chronic pain
3. One apparent advantage of Xartemis XR over other oral opioid
combinations is:
a. fewer doses per day
b. less risk of abuse
c. less danger from overdosage
d. all of the above
Oral Propranolol (Hemangeol) for Infantile Hemangioma
4. Infantile hemangiomas can:

a. interfere with vision
b. interfere with respiration
c. cause heart failure
d. all of the above
5. The most serious adverse effect of propranolol therapy for
infantile hemangioma appears to be:
a. bradycardia
b. hypertension
c. hypoglycemia
d. hypokalemia

A Responsive Neurostimulator Device (RNS System) for Epilepsy
8. The neurostimulator in the RNS System is:
a. worn on a belt around the waist
b. implanted subcutaneously in the abdomen
c. implanted under the scalp
d. implanted in the brain
9. A 23-year-old woman with partial-onset seizures and 2
epileptogenic foci has been treated with carbamazepine, but
continues to have frequent, disabling seizures. She is not a
candidate for the RNS System because:
a. it has only been approved for use in children
b. she has not been treated with at least 2 antiepileptic drugs
c. she has more than one epileptic focus
d. all of the above
Esomeprazole Strontium
10. Esomeprazole strontium is:
a. approved by the FDA for adults for the same indications as
Nexium
b. available generically

c. not recommended for use in patients with severe renal
impairment
d. all of the above

ACPE UPN: Per Issue Exam: 0379-0000-14-447-H01-P; Release: July 21, 2014, Expire: July 21, 2015
Comprehensive Exam 71: 0379-0000-15-071-H01-P; Release: January 2015, Expire: January 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.,
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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
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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.,
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Copyright and Disclaimer: The Medical Letter, Inc. is an independent nonprofit organization that provides healthcare professionals with unbiased drug prescribing recommendations. The editorial
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