The medical letter on drugs and therapeutics may 26 2014

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

Apremilast (Otezla) for Psoriatic Arthritis .................................................... p 41
Eslicarbazepine Acetate (Aptiom) for Epilepsy .............................................. p 42
Sorafenib (Nexavar) for Thyroid Cancer ....................................................... p 43
In Brief: Heptavalent Botulism Antitoxin ................................................... p 44

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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 1443)
May 26, 2014

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Take CME Exams

ALSO IN THIS ISSUE

Table 1. Pharmacology

Eslicarbazepine Acetate (Aptiom) for
Epilepsy........................................................ p 42
Sorafenib (Nexavar) for Thyroid Cancer ... p 43
In Brief: Heptavalent Botulism
Antitoxin ...................................................... p 44

Drug class

PDE4 inhibitor

Route

Oral

Formulation

10, 20, 30 mg tablets1

Apremilast (Otezla) for Psoriatic
Arthritis
Apremilast (Otezla – Celgene), an oral phosphodiesterase type-4 (PDE4) inhibitor, has been approved
by the FDA for treatment of active psoriatic arthritis in
adults. It is the first PDE4 inhibitor to be approved for this
indication.
STANDARD TREATMENT — Up to 40% of patients
with psoriasis develop psoriatic arthritis.1 Nonsteroidal
anti-inflammatory drugs (NSAIDs) may be tried first
for treatment of mild disease. The disease-modifying
antirheumatic drug (DMARD) methotrexate is generally
used for treatment of moderate to severe disease.
If there is minimal improvement after 12-16 weeks of
methotrexate treatment, a tumor necrosis factor (TNF)
inhibitor is often added or substituted.2 Ustekinumab
(Stelara), a human interleukin-12 and -23 antagonist,
has also been approved by the FDA for treatment of
active psoriatic arthritis; how it compares in efficacy to
TNF inhibitors remains to be determined.3
MECHANISM OF ACTION — PDE4 degrades cyclic
adenosine monophosphate (cAMP) into AMP. Apremilast
inhibits PDE4, resulting in downregulation of the
inflammatory response.
CLINICAL STUDIES — Approval of apremilast was
based on 3 randomized, double-blind, placebocontrolled trials in a total of 1493 adults with active

psoriatic arthritis refractory to treatment with DMARDs.
Only one of these trials has been published4; the others
are summarized in the package insert. After 16 weeks,

Tmax

~2.5 hours

Half-life (terminal)

6-9 hours

Metabolism

Primarily by CYP3A4, to a minor extent
by CYP1A2 and 2A6, then glucuronidation
and hydrolysis
Urine (58%); feces (39%)

Elimination

1. The 10- and 20-mg tablets are only available in a 2-week titration pack.

significantly higher percentages of patients achieved an
American College of Rheumatology (ACR20) response,
indicating >20% improvement from baseline in at least
5 of 7 measures of disease activity, with apremilast
30 mg twice daily (32-41%) than with placebo (18-19%).
In the published trial, which enrolled 504 patients,
31% of patients taking 20 mg of apremilast twice daily

and 40% of those taking 30 mg twice daily achieved
an ACR20 response at week 16, both significant
differences from placebo (19%).
The percentages of patients who achieved an ACR50
or ACR70 response in the 3 trials with apremilast were
not significantly different from placebo.
No studies are available directly comparing apremilast
with a TNF inhibitor. In cross-study comparisons,
response rates appear to be lower with apremilast.
In patients with moderate to severe plaque psoriasis
without arthritis (not an FDA-approved indication),
apremilast has improved symptoms and reduced
lesions significantly more than placebo.5-7
ADVERSE EFFECTS — The most common adverse
effects of apremilast in clinical trials were diarrhea,
nausea, and headache. These effects occurred most
frequently during the first two weeks of treatment and
tended to resolve with continued use of the drug. No
increased risk of malignancy or serious infection,
including reactivation of tuberculosis, has been reported
to date. Apremilast can increase the risk of depression.
Loss of 5-10% of body weight has been reported.

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41


Apremilast is classified as category C (developmental
toxicity in animals; no adequate human studies) for use

during pregnancy.
DRUG INTERACTIONS — Apremilast is metabolized
primarily by CYP3A4. Coadministration with the
strong CYP3A4 inducer rifampin reduced the area
under the plasma concentration-time curve (AUC) of
apremilast by 72%. Concomitant use of apremilast with
strong CYP450 enzyme inducers such as rifampin or
carbamazepine is not recommended.8
DOSAGE, ADMINISTRATION, AND COST — To
reduce gastrointestinal adverse effects, apremilast
should be titrated over 6 days from 10 mg twice daily
to a final recommended dosage of 30 mg twice daily.
The final dose should be reduced to 30 mg once daily
in patients with severe renal impairment (CrCl <30
mL/min). Patients should be monitored for worsening
depression and clinically significant weight loss. A 30day supply of apremilast costs $1875.9
CONCLUSION — Apremilast (Otezla), an oral
phosphodiesterase type-4 (PDE4) inhibitor, has
been effective in improving symptoms of psoriatic
arthritis refractory to treatment with disease-modifying
antirheumatic drugs (DMARDs). Gastrointestinal toxicity
may be troublesome. Response rates appear to be lower
than those with TNF inhibitors, but direct comparisons
are lacking.
1. PJ Mease and AW Armstrong. Managing patients with psoriatic
disease: the diagnosis and pharmacologic treatment of psoriatic
arthritis in patients with psoriasis. Drugs 2014; 74:423.
2. Drugs for acne, rosacea and psoriasis. Treat Guidel Med Lett
2013; 11:1.
3. Certolizumab pegol (Cimzia) and ustekinumab (Stelara) for

psoriatic arthritis. Med Lett Drugs Ther 2014; 56:9.
4. A Kavanaugh et al. Treatment of psoriatic arthritis in a phase 3
randomised, placebo-controlled trial with apremilast, an oral
phosphodiesterase 4 inhibitor. Ann Rheum Dis 2014; 73:1020.
5. K Papp et al. Efficacy of apremilast in the treatment of moderate
to severe psoriasis: a randomised controlled trial. Lancet 2012;
380:738.
6. KA Papp et al. Efficacy and safety of apremilast in subjects
with moderate to severe plaque psoriasis: results from a phase
II, multicenter, randomized, double-blind, placebo-controlled,
parallel-group, dose-comparison study. J Eur Acad Dermatol
Venereol 2013; 27:e376.
7. V Strand et al. Improvements in patient-reported outcomes
with apremilast, an oral phosphodiesterase 4 inhibitor, in the
treatment of moderate to severe psoriasis: results from a phase
IIb randomized, controlled study. Health Qual Life Outcomes 2013;
11:82.
8. Inhibitors and inducers of CYP enzymes and P-glycoprotein. Med
Lett Drugs Ther 2013; 55:e44.
9. Approximate wholesale acquisition cost (WAC). 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.

42

Eslicarbazepine Acetate (Aptiom) for
Epilepsy
Eslicarbazepine acetate (Aptiom – Sunovion) has been

approved by the FDA for adjunctive treatment of partialonset seizures in adults. New drugs for epilepsy are
often approved by the FDA initially only as adjunctive
treatment for partial seizures.1 Eslicarbazepine acetate
is a prodrug of eslicarbazepine, which is the S-isomer of
the active metabolite of oxcarbazepine. Oxcarbazepine
itself is similar to carbamazepine. Both oxcarbazepine
and carbamazepine are available generically.
Table 1. Pharmacology
Drug class

Antiepileptic

Route

Oral

Formulation

200, 400, 600, 800 mg tablets

Tmax

1-4 hrs

Half-life

13-20 hours in patients with epilepsy

Metabolism

Hydrolysis to eslicarbazepine, the major
active metabolite

Elimination

Urine

MECHANISM OF ACTION — As with oxcarbazepine
and carbamazepine, the antiepileptic activity of
eslicarbazepine is believed to be due to inhibition
of voltage-gated sodium channels, which reduces
membrane excitability.2
CLINICAL STUDIES — Approval of eslicarbazepine
acetate was based on the results of 3 randomized,
double-blind, placebo-controlled trials in more than
1100 patients >18 years old with refractory partial-onset
seizures. Two of these trials have been published,3,4
and the third is summarized in the package insert. At
12 weeks, the mean number of seizures per 28 days
was significantly lower with eslicarbazepine 800 mg/day
(in 2 of the 3 studies) and 1200 mg/day than with placebo.
ADVERSE EFFECTS — Dizziness, somnolence,
nausea, headache, diplopia, vomiting, fatigue,
vertigo, ataxia, blurred vision, tremor, asthenia,
rash, and dysarthria have occurred with use of
Table 2. Clinical Trials with Eslicarbazepine Acetate1
Placebo

800 mg

1200 mg

Study 1 (n = 270)
No. of seizures (mean)
per 28 days

6.6

5.0

4.3

Study 2 (n = 267)
No. of seizures (mean)
per 28 days

8.6

6.2

6.6

Study 3 (n = 596)
No. of seizures (mean)
per 28 days

7.9

6.5 (NS)

6.0

NS = Not statistically significant compared to placebo
1. Data from the manufacturer’s package insert. The FDA required some revisions
to the data from the published trials.

The Medical Letter • Volume 56 • Issue 1443 • May 26, 2014


eslicarbazepine acetate. The percentages of
patients who discontinued the drug as a result of an
adverse reaction were 14% with the 800-mg dose
and 25% with the 1200-mg dose, compared to 7%
with placebo.
Hyponatremia (which has been problematic with
oxcarbazepine), serious dermatologic reactions (including
Stevens-Johnson syndrome), DRESS syndrome
(eosinophilia and hepatic toxicity), angioedema, and
anaphylactic reactions have been reported with use of
eslicarbazepine acetate.
Eslicarbazepine acetate is classified as category C
(developmental toxicity in animals; no adequate human
studies) for use during pregnancy.
DRUG INTERACTIONS — Eslicarbazepine can
inhibit CYP2C19 and induce CYP3A4. It can
increase serum concentrations of drugs metabolized
by CYP2C19, such as clobazam and omeprazole,
and decrease serum concentrations of drugs
metabolized by CYP3A4, such as simvastatin and
oral contraceptives.5,6

Enzyme-inducing antiepileptic drugs such as phenytoin,
phenobarbital, and primidone can reduce serum
concentrations of eslicarbazepine.
Table 3. Eslicarbazepine Acetate and Oxcarbazepine
Drug
Eslicarbazepine
acetate – Aptiom
(Sunovion)

Available
Formulations

Usual Adult
Dosage

200, 400, 600,
800 mg tabs

800 mg once
daily

Oxcarbazepine – 150, 300, 600 mg
generic
tabs; 300 mg/5 mL
Trileptal (Novartis) susp
extended-release 150, 300, 600 mg
Oxtellar XR
ER tabs
(Supernus)

1200-2400 mg
divided bid
1200-2400 mg
once daily

Cost1

CONCLUSION — Eslicarbazepine acetate (Aptiom),
which is a prodrug for an active metabolite of
oxcarbazepine, is modestly effective for once-daily
adjunctive treatment of partial-onset seizures in
adults with epilepsy. Whether it offers any advantage
over oxcarbazepine, which costs less, remains to be
established.
1. Drugs for epilepsy. Treat Guidel Med Lett 2013; 11:9.
2. A Verrotti et al. Eslicarbazepine acetate: an update on efficacy and
safety in epilepsy. Epilepsy Res 2014; 108:1.
3. E Ben-Menachem et al. Eslicarbazepine acetate as adjunctive
therapy in adult patients with partial epilepsy. Epilepsy Res 2010;
89:278.
4. C Elger et al. Efficacy and safety of eslicarbazepine acetate
as adjunctive treatment in adults with refractory partial-onset
seizures: a randomized, double-blind, placebo-controlled, parallel
group phase III study. Epilepsia 2009; 50:454.
5. Inhibitors and inducers of CYP enzymes and P-glycoprotein. Med
Lett Drugs Ther 2013; 55:e44.
6. A Falcão et al. Effect of eslicarbazepine acetate on the
pharmacokinetics of a combined ethinylestradiol/levonorgestrel
oral contraceptive in healthy women. Epilepsy Res 2013; 105:368.

Sorafenib (Nexavar) for Thyroid Cancer
The FDA has approved the use of the oral multikinase
inhibitor sorafenib (Nexavar – Bayer) for treatment
of locally recurrent or metastatic, progressive,
differentiated thyroid cancer (papillary or follicular)
refractory to radioactive iodine treatment. Sorafenib
was approved earlier for treatment of advanced renal
cell and unresectable hepatocellular cancer.1

$599.40

114.60
551.30
495.00

1. Approximate wholesale acquisition cost (WAC) for 30 days’ treatment at the
lowest usual 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.

DOSAGE
AND
ADMINISTRATION
—
The
recommended starting dosage of eslicarbazepine
acetate is 400 mg once daily, which should be
increased after 1 week to 800 mg once daily, up to a
maximum dosage of 1200 mg/day. Patients with renal
impairment (CrCl <50 mL/min) should receive 200 mg

once daily for 2 weeks, then 400 mg once daily, up to
a maximum dosage of 600 mg/day.
Patients who have experienced a serious dermatologic
reaction while taking oxcarbazepine or carbamazepine
should not take eslicarbazepine acetate.

STANDARD TREATMENT — Surgery and radioactive
iodine are the preferred treatments for thyroid cancer.
When these fail, cytotoxic drugs have not been very
effective and kinase inhibitors including sorafenib have
been used. Two other kinase inhibitors, vandetanib
(Caprelsa) and cabozantinib (Cometriq), were
approved earlier for treatment of advanced medullary
thyroid cancer, which is relatively rare.2
CLINICAL STUDIES — A meta-analysis of 7 trials
in patients with radioiodine-refractory differentiated
thyroid cancer treated with sorafenib found that a partial
response occurred in 22% of patients and the disease
stabilized in 52% of patients. The median progressionfree survival was 12.4 months.3
A randomized, double-blind, placebo-controlled trial
(DECISION) in 417 patients with locally advanced or
metastatic, progressive, differentiated thyroid cancer
refractory to radioactive iodine found that median
progression-free survival, the primary endpoint, was
10.8 months with sorafenib and 5.8 months with
placebo, a statistically significant difference.4

The Medical Letter • Volume 56 • Issue 1443 • May 26, 2014

43

ADVERSE EFFECTS — The most common adverse
effects of sorafenib reported in the clinical trial were palmar-plantar erythrodysesthesia (76%), diarrhea (69%),
alopecia (67%), and rash or desquamation (50%).
Sorafenib can also cause severe liver injury, bleeding,
thromboembolism, and (rarely) gastrointestinal perforation, interfere with wound healing, increase the INR in
patients taking warfarin, and prolong the QT interval.
DOSAGE, ADMINISTRATION, AND COST — Nexavar is
available as 200-mg tablets. The recommended dosage is
400 mg twice daily taken at least 1 hour before or 2 hours
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. A 30-day supply of Nexavar costs $10,525.5
CONCLUSION — Sorafenib (Nexavar) is effective for
treatment of locally recurrent or metastatic, progressive,
differentiated thyroid cancer refractory to radioactive
iodine, at a cost of more than $125,000 per year.
1. Two new drugs for renal cell carcinoma. Med Lett Drugs Ther 2007;
49:18.
2. Vandetanib (Caprelsa) for medullary thyroid cancer. Med Lett
Drugs Ther 2012; 54:3.
3. CT Shen et al. Sorafenib in the treatment of radioiodine-refractory
differentiated thyroid cancer: a meta-analysis. Endocr Relat Cancer 2014; 21:253.
4. MS Brose et al. Sorafenib in radioactive iodine-refractory, locally advanced or metastatic differentiated thyroid cancer: a randomised, double-blind, phase 3 trial. Lancet 2014; April 23 (epub).
5. Approximate wholesale acquisition cost (WAC). Source:
Analy$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 price may be higher.

Coming Soon in The Medical Letter:
Sublingual Allergen Immunotherapy for Allergic Rhinitis
Tobramycin Inhalation Solution (Bethkis) for Cystic Fibrosis
A Naloxone Auto-Injector (Evzio)
Coming Soon in Treatment Guidelines:
Adult Immunization

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®

On Drugs and Therapeutics
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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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Esperance A.K. Schaefer, M.D., M.P.H., Harvard Medical School
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IN BRIEF

Heptavalent Botulism Antitoxin
The FDA has approved the use of an equine heptavalent
botulism antitoxin (BAT, Cangene Corporation).

The new antitoxin includes antibodies against all 7
botulinum neurotoxin types (A-G). A human-derived
antitoxin (BabyBIG) has been available for years for
infant botulism. The heptavalent product is now the
preferred antitoxin for adult botulism. It is a solution of
immunoglobulin fragments obtained from equine plasma
that has gone through several steps of purification and
viral inactivation. (The use of immunoglobulin fragments
reduces side effects compared to intact immunoglobulin.)
BAT is available from the CDC through state and local
health departments.

44

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The Medical Letter • Volume 56 • Issue 1443 • May 26, 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 1443 Questions
(Correspond to questions #61-66 in
Comprehensive Exam #70, available July 2014)
Apremilast (Otezla) for Psoriatic Arthritis
1.

The percentage of patients with active psoriatic arthritis achieving
an ACR20 response with apremilast has been about:
a. 30-40%
b. 50-60%
c. 60-70%
d. >70%

2.

Which of the following are among the most common side
effects of apremilast?
a. an increased risk of serious infection
b. rash
c. diarrhea
d. all of the above

Eslicarbazepine Acetate (Aptiom) for Epilepsy
3.

Eslicarbazepine is an active metabolite of:
a. carbamazepine
b. oxcarbazepine
c. neither
d. both

4.

A 23-year-old woman with poorly controlled partial-onset
seizures and no health insurance has heard that Aptiom is
the newest treatment for this disorder and would like to try it.

You could tell her that:
a. the drug would probably cost more than $500
per month
b. it would probably reduce the number of her
seizures by 50%
c. it has been shown to be superior to carbamazepine
and oxcarbazepine
d. all of the above

Sorafenib (Nexavar) for Thyroid Cancer
5.

The FDA has approved sorafenib for which of the following:
a. advanced renal cell cancer
b. unresectable hepatocellular cancer
c. locally recurrent or metastatic, progressive,
differentiated thyroid cancer
d. all of the above

6.

The most common adverse effect of sorafenib in patients with
thyroid cancer has been:
a. gastrointestinal perforation
b. bleeding
c. generalized rash or desquamation
d. palmar-plantar erythrodysesthesia

ACPE UPN: Per Issue Exam: 0379-0000-14-443-H01-P; Release: May 26, 2014, Expire: May 26, 2015
Comprehensive Exam 70: 0379-0000-14-070-H01-P; Release: July 2014, Expire: July 2015

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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 apremilast (Otezla) for treatment of psoriatic arthritis.
2. Review the efficacy and safety of eslicarbazepine acetate (Aptiom) for treatment of partial-onset seizures in adults.
3. Review the efficacy and safety of sorafenib (Nexavar) for treatment of thyroid cancer.
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: 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.
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