The medical letter on drugs and therapeutics april 11 2016

The Medical Letter

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on Drugs and Therapeutics

Volume 58

ISSUE
ISSUE
No.

1433
1492
Volume 56

April 11, 2016

IN THIS ISSUE

Which Oral Anticoagulant for Atrial Fibrillation?................................................................ p 45
Buprenorphine Buccal Film (Belbuca) for Chronic Pain .................................................... p 47
Calcipotriene/Betamethasone Foam (Enstilar) for Psoriasis ............................................ p 48
Dichlorphenamide (Keveyis) for Periodic Paralysis ........................................................... p 50

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The Medical Letter

®

on Drugs and Therapeutics

Volume 58

April 11, 2016
Take CME Exams

ISSUE

ISSUE No.

1433

1492
Volume 56

▶

ALSO IN THIS ISSUE

Buprenorphine Buccal Film (Belbuca) for Chronic Pain .................................................... p 47
Calcipotriene/Betamethasone Foam (Enstilar) for Psoriasis ............................................ p 48
Dichlorphenamide (Keveyis) for Periodic Paralysis ........................................................... p 50

Which Oral Anticoagulant for Atrial
Fibrillation?
Related article(s) since publication

Direct-to-consumer advertisements continue to
urge patients who take warfarin (Coumadin, and
others) for atrial fibrillation to ask their doctors
about the benefits of one or another of the newer
oral anticoagulants.
WARFARIN — In patients with nonvalvular atrial
fibrillation, warfarin reduces the risk of thromboembolic stroke by about 60%.1 If necessary, vitamin K,
prothrombin complex concentrate, or fresh frozen

plasma can reverse its anticoagulant effect.2
Drawbacks of warfarin include unpredictability and
variability in dosage requirements, dietary restrictions,
interactions with many other drugs, and the need for
close monitoring to keep the international normalized
ratio (INR) in the therapeutic range (2-3).

DIRECT ORAL ANTICOAGULANTS — The direct
thrombin inhibitor dabigatran etexilate (Pradaxa)
and the direct factor Xa inhibitors apixaban (Eliquis),
edoxaban (Savaysa), and rivaroxaban (Xarelto) do not
require routine monitoring of coagulation times and
they have fewer drug interactions than warfarin.

Table 1. Oral Anticoagulants for Atrial Fibrillation
Drug

Usual Dosage

Comments

Cost1

Apixaban2 – Eliquis (BMS)

5 mg bid3

Interacts with inhibitors and inducers of CYP3A4
and P-gp4

$333.60

Edoxaban2 – Savaysa (Daiichi Sankyo)

60 mg once/d5

Should not be used in patients with a CrCl >95 mL/min;

avoid use with the P-gp inducer rifampin

291.30

Rivaroxaban2 – Xarelto (Janssen)

20 mg once/d6

Should be taken with the evening meal; interacts
with inhibitors and inducers of CYP3A4 and P-gp7

333.30

Direct Thrombin Inhibitor
Dabigatran etexilate2 – Pradaxa
(Boehringer Ingelheim)

150 mg bid8

Must be dispensed and stored in the original container
(once the bottle is opened, use within 4 months); tablets
should not be broken, crushed, or chewed; dyspepsia is
common; interacts with inhibitors and inducers of P-gp9;
reversal agent available; dialyzable

333.60

Vitamin K Antagonist
Warfarin – generic
Coumadin (BMS)

2-10 mg once/d10

Interacts with many other drugs; has dietary restrictions;
INR monitoring required; reversal agents available

8.50
58.80

Direct Factor Xa Inhibitors

P-gp = P-glycoprotein; INR = international normalized ratio
1. Approximate WAC for 30 days’ treatment at the lowest usual 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. March 5, 2016. Reprinted with permission by First Databank, Inc. All rights reserved. ©2016. www.fdbhealth.com/policies/drug-pricing-policy.
2. FDA-approved for use in patients with nonvalvular atrial fibrillation.
3. Dosage is 2.5 mg bid for patients with ≥2 of the following: age ≥80 years, weight ≤60 kg, serum creatinine ≥1.5 mg/dL.
4. In patients taking strong inhibitors of both CYP3A4 and P-gp, reduce the dosage of apixaban by 50% to a minimum of 2.5 mg bid; avoid coadministration in
patients already taking 2.5 mg bid. Avoid use with strong inducers of both CYP3A4 and P-glycoprotein.
5. Dosage is 30 mg once/d for patients with a CrCl 15-50 mL/min. Not recommended for use in patients with a CrCl <15 mL/min.
6. Dosage is 15 mg once/d for patients with a CrCl 15-50 mL/min. Not recommended for use in patients with a CrCl <15 mL/min.
7. Avoid use with combined P-gp and strong CYP3A4 inhibitors or inducers.
8. The American College of Chest Physicians and Health Canada do not recommend use for atrial fibrillation in patients with a CrCl <30 mL/min. The US labeling
recommends a dosage of 75 mg twice daily in patients with a CrCl 15-30 mL/min; this dose is based on pharmacokinetic modeling and has not been studied
in clinical trials.
9. Avoid use with P-gp inducers. The dose should be reduced to 75 mg bid during coadministration with dronedarone or systemic ketoconazole in patients with a
CrCl 30-50 mL/min. Avoid use with P-gp inhibitors in patients with a CrCl 15-30 mL/min.
10. Should be coadministered with a parenteral anticoagulant for ≥5 days and until the INR is in the therapeutic range (2-3) for ≥24 hours.

45

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The Medical Letter

April 11, 2016

Vol. 58 (1492)

®

Table 2. Direct Oral Anticoagulants vs Warfarin
Stroke or
Systemic
Embolism1
Dabigatran3,4

RR 0.66*

Rivaroxaban5
Apixaban8

HR 0.886
HR 0.79*

Edoxaban9,10

HR 0.79*11

Hemorrhagic

Stroke

Ischemic Stroke
(or unspecified)

Intracranial
Bleeding

Major
Bleeding

INR in
Therapeutic
Range2

RR 0.26*
HR 0.59*

RR 0.76*

RR 0.40*
HR 0.67*

RR 0.93

64%

HR 0.51*
HR 0.54*

HR 0.92

HR 1.04
HR 0.69*

62%

HR 0.80*

65%

HR 0.94
HR 1.0012

HR 0.42*
HR 0.47*

55%7

INR = international normalized ratio; *statistically significant; RR = relative risk; HR = hazard ratio
1. The primary endpoint in all four trials.
2. Mean percentage of time in the therapeutic range (2-3).
3. SJ Connolly et al. N Engl J Med 2009; 361:1139.
4. Results for the 150-mg dose. A 110-mg dose was also studied, but was not approved by the FDA for treatment of atrial fibrillation.
5. MR Patel et al. N Engl J Med 2011; 365:883.
6. Statistically significant for noninferiority, but not superiority.
7. The device used to measure the INR was later found to be inaccurate in patients with certain conditions, such as acute and chronic inflammatory conditions
and low hematocrit. A post-hoc analysis of the results in these patients and those without the implicated conditions determined that the malfunction of the
device did not have a significant effect on the results (MR Patel and AS Helkamp. N Engl J Med 2016; 374:785).
8. CB Granger et al. N Engl J Med 2011; 365:981.

9. RP Giugliano et al. N Engl J Med 2013; 369:2093.
10. Results for the 60-mg dose. A 30-mg dose was also studied, but is not the usual recommended dose for treatment of atrial fibrillation.
11. About 50% of the edoxaban dose is renally eliminated. The HR was 1.87 in patients with a CrCl >95 mL/min and 0.53 in those with a CrCl >50 and ≤80 mL/min.
12. The HR in patients with CrCl >95 mL/min was 2.16.

Drawbacks of the direct oral anticoagulants include
absence of any method for monitoring the extent of
their anticoagulant effect, short half-lives that increase
the risk of thrombosis with missed doses, lack of data
on their use in patients with end-stage renal disease,
and higher drug costs.
Efficacy – In the pivotal clinical trials against warfarin
that led to their approval by the FDA, all of the direct oral
anticoagulants were at least noninferior to warfarin for
prevention of stroke or systemic embolism in patients
with atrial fibrillation. In patients taking warfarin, the
INR was in the therapeutic range only 55-65% of the
time.3-6 Edoxaban was less effective than warfarin for
prevention of stroke or systemic embolism in patients
with a CrCl >95 mL/min; it was more effective in those
with a CrCl between 50 and 80 mL/min.7
Bleeding – All of the direct oral anticoagulants had
significantly lower rates of intracranial bleeding
and hemorrhagic stroke than warfarin in the pivotal
clinical trials. Compared to warfarin, the rates of
major bleeding with dabigatran and rivaroxaban were
similar and the rates with apixaban and edoxaban
were significantly lower.
Reversibility – In 2015, the FDA approved idarucizumab
(Praxbind) for urgent reversal of the anticoagulant effect

of dabigatran.8 No specific antidote is available in the US
for the three direct factor Xa inhibitors, but in one study in
healthy volunteers, an investigational synthetic product
(andexanet alfa) reversed the anticoagulant effects of
apixaban and rivaroxaban within minutes.9 The results
of some studies suggest that the anticoagulant effects
of all of the direct oral anticoagulants may be reversed
by prothrombin complex concentrate.10
46

CONCLUSION — The direct oral anticoagulants
dabigatran (Pradaxa), apixaban (Eliquis), edoxaban
(Savaysa), and rivaroxaban (Xarelto) have been at
least as effective as warfarin (Coumadin, and others)
in preventing stroke or systemic embolism in patients
with nonvalvular atrial fibrillation, and they appear
to be safer. Patients well controlled on warfarin (INR
stable in the therapeutic range) could stay on it. For all
others, one of the direct oral anticoagulants might be a
better choice. Head-to-head comparisons of the new
drugs are lacking. ■
1. RG Hart et al. Meta-analysis: antithrombotic therapy to prevent
stroke in patients who have nonvalvular atrial fibrillation. Ann
Int Med 2007; 146:857.
2. Kcentra: a 4-factor prothrombin complex concentrate for reversal of warfarin anticoagulation. Med Lett Drugs Ther 2013;
55:53.
3. SJ Connolly et al. Dabigatran versus warfarin in patients with
atrial fibrillation. N Engl J Med 2009; 361:1139.
4. MR Patel et al. Rivaroxaban versus warfarin in nonvalvular atrial
fibrillation. N Engl J Med 2011; 365:883.

5. CB Granger et al. Apixaban versus warfarin in patients with
atrial fibrillation. N Engl J Med 2011; 365:981.
6. RP Giugliano et al. Edoxaban versus warfarin in patients with
atrial fibrillation. N Engl J Med 2013; 369:2093.
7. FDA draft briefing document for the Cardiovascular and
Renal Drugs Advisory Committee. NDA 206316. October
30, 2014. Available at www.fda.gov/downloads/Advisory
Committees/CommitteesMeetingMaterials/Drugs/Cardio
vascularandRenalDrugsAdvisoryCommittee/UCM420704.
pdf. Accessed March 31, 2016.
8. Idarucizumab (Praxbind) – an antidote for dabigatran. Med Lett
Drugs Ther 2015; 57:157.
9. DM Siegal et al. Andexanet alfa for the reversal of factor Xa inhibitor activity. N Engl J Med 2015; 373:2413.
10. JS Kalus. Pharmacologic interventions for reversing the effects
of oral anticoagulants. Am J Health Syst Pharm 2013; 70 (Suppl
1):S12.


The Medical Letter

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®

Buprenorphine Buccal Film (Belbuca)
for Chronic Pain

Belbuca (Endo), a buccal formulation of the partial
opioid agonist buprenorphine, has been approved by the
FDA for management of pain severe enough to require

daily, around-the-clock, long-term opioid treatment.
Buprenorphine is also available as a transdermal patch
(Butrans) and in a parenteral formulation (Buprenex, and
generics) for treatment of pain. A sublingual formulation
of buprenorphine and buccal and sublingual formulations
containing buprenorphine and the opioid antagonist
naloxone are approved for use as alternatives to
methadone for treatment of opioid dependence.1,2
Pronunciation Key
Buprenorphine : bue" pre nor' feen
Belbuca : bel bue' kuh

MECHANISM OF ACTION — Buprenorphine binds with
high affinity to, and slowly dissociates from, the muopioid receptor. In the dosage range for which Belbuca
is approved, buprenorphine produces typical opioid
agonist effects. In higher doses, its agonist effects reach
a ceiling and it can act as an antagonist.3 Used alone,
it may be less likely to cause respiratory depression
than full opioid agonists such as fentanyl or morphine.4
Table 1. Pharmacology
Class

Partial mu-opioid agonist

Route

Buccal

Formulation

75, 150, 300, 450, 600, 750,
900 mcg buccal films

Tmax (single 300-mcg dose)

2.5-3.0 hours1

Metabolism

N-dealkylation, primarily by
CYP3A4, and glucuronidation

Elimination

Feces (69%); urine (30%)

Half-life

27.6 hours

1. Steady-state concentrations were achieved prior to the 6th dose.

CLINICAL STUDIES — Approval of Belbuca was based
on two double-blind, placebo-controlled trials in
patients with moderate to severe chronic low back
pain. Each trial included an 8-week open-label phase
in which patients were titrated to an effective and
tolerable analgesic dose of buprenorphine. Patients
who were successfully titrated were eligible to enter a
12-week, double-blind treatment phase in which they

were randomized to continue taking buprenorphine or
switch to placebo.
In one trial, 461 (out of 749) opioid-naive patients entered
the treatment phase after being successfully titrated to
an adequate analgesic dose. The increase in mean daily
pain intensity score from baseline to week 12, the primary endpoint, was significantly greater in patients who
were switched to placebo than in those who continued

Vol. 58 (1492)

April 11, 2016

taking buprenorphine (1.59 vs 0.94 points on a scale
of 0-10). Significantly more patients who continued
buprenorphine had a ≥30% reduction in pain score from
the start of titration to the end of the study compared to
those who were switched to placebo (63% vs 47%).5
In the other trial, which is unpublished but summarized in
the package insert, 491 (out of 810) opioid-experienced
patients entered the treatment phase after being
successfully titrated to an adequate analgesic dose. The
mean pain score after 12 weeks, the primary endpoint,
was significantly lower among patients who continued
taking buprenorphine. Significantly more patients who
continued buprenorphine had a ≥30% reduction in
pain scores compared to those who were switched to
placebo (64% vs 31%).
According to the package insert, a third study in
patients with chronic low back pain did not show a
statistically significant difference in pain reduction

between buprenorphine buccal film and placebo.
ADVERSE EFFECTS — The most common adverse
effects reported with use of buprenorphine buccal film
in clinical trials were nausea, constipation, vomiting,
headache, dizziness, and somnolence. QTc interval
prolongation and hepatotoxicity have occurred. Respiratory depression (particularly in elderly, cachectic, and
debilitated patients), severe hypotension, and physical
and psychological dependence can occur. Belbuca is
classified as a schedule III controlled substance.
PREGNANCY — Prolonged opioid use during pregnancy
can result in neonatal withdrawal syndrome. Opioids
administered immediately before labor can cross
the placenta and cause excess sedation, respiratory
depression, and other adverse effects in the newborn.
Excess sedation and respiratory depression may also
occur in infants exposed to buprenorphine in breast
milk, and withdrawal symptoms may occur when
breastfeeding is stopped or maternal buprenorphine
use is discontinued.
DRUG INTERACTIONS — Buprenorphine is metabolized
primarily by CYP3A4. Inhibitors of CYP3A4 can
increase plasma concentrations of buprenorphine
and inducers of CYP3A4 can decrease them.6
Additive effects can occur when buprenorphine is
used with other CNS depressant drugs; coma and
death have occurred in patients taking buprenorphine
and benzodiazepines concurrently. Mixed agonist/
antagonist and partial agonist opioid analgesics such
as butorphanol and pentazocine (Talwin) should not
be used with buprenorphine because they can reduce

its efficacy and/or precipitate withdrawal symptoms.
47


The Medical Letter

Vol. 58 (1492)

®

Table 2. Belbuca vs Butrans for Chronic Pain
Route

Belbuca
Buccal

Butrans

Initial dosage
(opioid-naive)

75 mcg once/d
or q12h

5 mcg/hr

Maximum dosage

900 mcg q12 hours

20 mcg/hr

Oral MSE of maximum daily dose

160 mg

80 mg

Cost1

$255.60

$204.50

Transdermal
(7-day patch)

MSE = morphine sulfate equivalent
1. Approximate WAC for 30 days’ treatment with Belbuca or 28 days' treatment with Butrans at the initial dosage in opioid-naive patients. 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.
March 5, 2016. Reprinted with permission by First Databank, Inc. All rights
reserved. ©2016. www.fdbhealth.com/policies/drug-pricing-policy.

Buprenorphine should not be taken concurrently with
other drugs that prolong the QT interval.7
DOSAGE AND ADMINISTRATION — For opioid-naive
patients, the starting dosage of Belbuca is 75 mcg
once daily or every 12 hours; after 4 days, the dosage
can be increased to 150 mcg every 12 hours. If

analgesia is inadequate, the dosage can be increased
every 4 days in increments of 150 mcg twice daily;
the maximum approved dosage is 900 mcg every 12
hours. Dosages of Belbuca >900 mcg every 12 hours
can increase the risk of QTc interval prolongation and
are not recommended. For patients already taking an
opioid, the Belbuca package insert provides detailed
dosing instructions. The dosage should be reduced
in patients with oral mucositis because they may
absorb buprenorphine more rapidly.
CONCLUSION — Buprenorphine buccal film (Belbuca)
appears to be effective for treatment of moderate to
severe chronic pain. Head-to-head trials comparing
the buccal film with the buprenorphine transdermal
patch (Butrans) or other opioids are lacking. ■
1. Transdermal buprenorphine (Butrans) for chronic pain. Med
Lett Drugs Ther 2011; 53:31.
2. Bunavail: another buprenorphine/naloxone formulation for opioid dependence. Med Lett Drugs Ther 2015; 57:19.
3. Center for Substance Abuse Treatment. Clinical guidelines for
the use of buprenorphine in the treatment of opioid addiction.
Rockville (MD): Substance Abuse and Mental Health Services
Administration (US); 2004. (Treatment Improvement Protocol
[TIP] Series, No. 40) 2 Pharmacology. Available at: www.ncbi.
nlm.nih.gov/books/NBK64236. Accessed March 31, 2016.
4. J Pergolizzi et al. Current knowledge of buprenorphine and its
unique pharmacological profile. Pain Pract 2010; 10:428.
5. RL Rauck et al. Efficacy and tolerability of buccal buprenorphine
in opioid-naive patients with moderate to severe chronic low
back pain. Postgrad Med 2016; 128:1.
6. Inhibitors and inducers of CYP enzymes and P-glycoprotein.

Med Lett Drugs Ther 2016; 58:e46.
7. RL Woosley and KA Romero. QT drugs list. Available at: www.
crediblemeds.org. Accessed March 31, 2016.

48

▶

April 11, 2016

Calcipotriene/Betamethasone Foam
(Enstilar) for Psoriasis

The FDA has approved Enstilar (Leo), an aerosol
foam formulation of the synthetic vitamin D3 analog
calcipotriene and the high-potency corticosteroid
betamethasone dipropionate, for topical treatment
of plaque psoriasis in adults. Topical ointment and
suspension formulations of the same combination
have been available for many years.
Pronunciation Key
Calcipotriene : kal" si poe trye' een
Enstilar : en' stil ar
Betamethasone : bay" ta meth' a sone

STANDARD TREATMENT — Mild to moderate psoriasis
is generally treated with a topical corticosteroid. Vitamin
D3 analogs and the retinoid tazarotene (Tazorac) are
topical alternatives. When used alone, calcipotriene is
about as effective in treating psoriasis as a mediumpotency steroid. The combination of calcipotriene and

betamethasone is more effective and better tolerated
than either component alone.1,2 Phototherapy and
systemic therapy, including biologic agents, are options
for patients with moderate to severe disease.3
THE
NEW
FORMULATION
—
Calcipotriene/
betamethasone aerosol foam is available in a 60gram pressurized aluminum spray can containing 2
flammable propellants, dimethyl ether and butane. An
in vitro study found that steady-state levels of both
calcipotriene and betamethasone were significantly
higher in skin samples treated with the foam than in
those treated with the ointment.4
CLINICAL STUDIES — In a randomized, double-blind
trial (PSO-FAST) in 426 adults with mostly moderate
psoriasis of the trunk and/or limbs, significantly more
patients using calcipotriene/betamethasone foam
once daily for up to 4 weeks achieved the primary
endpoint of treatment success according to physician’s
global assessment (defined as clear or almost clear
with at least moderate disease at baseline or clear with
mild disease at baseline) compared to those using the
vehicle alone (53.3% vs 4.8%). The mean amount of
foam used per week was about 30 grams.5
An unpublished, randomized, double-blind trial
(available only as an abstract) compared 4 weeks of
treatment with calcipotriene/betamethasone foam to
its components in 302 patients with mostly moderate

psoriasis, including 66% with scalp involvement.
Treatment success on the trunk and limbs, the primary
endpoint, occurred significantly more often with the


The Medical Letter

Vol. 58 (1492)

®

Table 1. Some Calcipotriene and Betamethasone Products
Drug

Some Formulations

Betamethasone Dipropionate, Augmented (0.05%)
generic
15, 50 g cream
15, 45, 50 g ointment
30, 60 mL lotion
15, 50 g gel
Diprolene AF (Merck)
15, 50 g cream
Diprolene
15, 50 g ointment
30, 60 mL lotion
Calcipotriene (0.005%)
generic
60, 120 g cream

60, 120 g ointment
60 mL solution
Dovonex (Leo)
60, 120 g cream
Sorilux (GSK)
60, 120 g foam

Cost

1

$74.40
133.60
150.50
109.30
180.20
180.20
182.10
335.60
295.60
238.60
632.40
648.70

Calcipotriene/Betamethasone Dipropionate (0.005%/0.064%)
generic
60, 100 g ointment
644.30
Taclonex (Leo)
60, 100 g ointment

895.80
60, 100 g suspension
831.00
Enstilar (Leo)
60 g foam
831.00
1. Approximate WAC for 60 g or 60 mL of calcipotriene or calcipotriene/betamethasone dipropionate or for 50 g or 60 mL of betamethasone dipropionate. 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.
March 5, 2016. Reprinted with permission by First Databank, Inc. All rights
reserved. ©2016. www.fdbhealth.com/policies/drug-pricing-policy.

combination than with calcipotriene or betamethasone
alone (45% vs 14.9% and 30.7%, respectively).
Treatment success on the scalp occurred significantly
more often with calcipotriene/betamethasone than
with calcipotriene but not betamethasone (53% vs
35.6% and 47.5%, respectively).6
Foam vs Ointment — A 4-week, randomized trial in
adults with mostly moderate psoriasis of the trunk and
limbs compared calcipotriene/betamethasone foam
with an ointment formulation. Treatment success at
4 weeks, the primary endpoint, occurred in 54.6% of
patients using the foam and in 43.0% of those using
the ointment, a significant difference. The foam was
superior to the ointment as early as week 2.7
ADVERSE EFFECTS — Calcipotriene is generally
well tolerated, but burning and itching can occur.
Hypercalcemia has been reported rarely. Animal data
suggest that exposure to ultraviolet radiation while

using topical calcipotriene may increase the risk of skin
tumor development; the manufacturer recommends
limiting or avoiding use of phototherapy in patients
being treated with calcipotriene.
Topical corticosteroids such as betamethasone can induce adrenal suppression when applied to large body
surface areas. Local cutaneous adverse effects such as
dermal and epidermal atrophy, telangiectasias, and irreversible striae can occur.
An open-label study in 37 patients with moderate to
severe psoriasis found that use of calcipotriene/beta-

April 11, 2016

methasone foam once daily for 4 weeks did not result
in clinically relevant hypothalamic-pituitary-adrenal
(HPA) axis suppression or affect calcium homeostasis.8
PREGNANCY — The calcipotriene/betamethasone
combination is classified as category C (fetotoxicity in
animals with calcipotriene; teratogenicity in animals
with betamethasone; no adequate studies in women)
for use during pregnancy.
DOSAGE AND ADMINISTRATION — Enstilar foam
should be applied to affected areas once daily for up
to 4 weeks. It should not be used on the face, groin, or
axillae, or under occlusion. A maximum of 60 grams
of foam should be used every 4 days. Exposure of
Enstilar-treated skin to natural or artificial sunlight or
phototherapy may cause degradation of calcipotriene;
applying the foam at night might minimize this effect.
CONCLUSION — Enstilar, an aerosol foam formulation
of the vitamin D3 analog calcipotriene and the highpotency corticosteroid betamethasone dipropionate,

provides another option for topical treatment of
psoriasis. Some patients may find the foam more
convenient to apply and more cosmetically acceptable
than an ointment, and it might be somewhat more
effective. For treatment of scalp psoriasis, Enstilar
has not been shown to be more effective than topical
betamethasone alone. All calcipotriene/betamethasone
combination products are expensive. ■
1. PL McCormack. Calcipotriol/betamethasone dipropionate: a
review of its use in the treatment of psoriasis vulgaris of the
trunk, limbs and scalp. Drugs 2011; 71:709.
2. A Mason et al. Topical treatments for chronic plaque psoriasis:
an abridged Cochrane systematic review. J Am Acad Dermatol
2013; 69:799.
3. Drugs for psoriasis. Med Lett Drugs Ther 2015; 57:81.
4. L Hollesen Basse et al. Enhanced in vitro skin penetration and
antipsoriatic effect of fixed combination calcipotriol plus betamethasone dipropionate in an innovative foam vehicle. J Invest
Dermatol 2014; 134 (suppl 2): S33, abstract 192.
5. C Leonardi et al. Efficacy and safety of calcipotriene plus betamethasone dipropionate aerosol foam in patients with psoriasis vulgaris – a randomized phase III study (PSO-FAST). J
Drugs Dermatol 2015; 14:1468.
6. M Lebwohl et al. A novel aerosol foam formulation of calcipotriene (Cal) 0.005% plus betamethasone dipropionate (BD) 0.064%
is more efficacious than Cal and BD foam alone in treating psoriasis vulgaris: a randomized, double-blind, multicenter, threearm, phase II study. Presented at the 73rd Annual Meeting of the
American Academy of Dermatology, San Francisco, March 2024, 2015. Abstract 1670. Available at: www.aad.org/eposters/
view/Abstract.aspx?id=1670. Accessed March 31, 2016.
7. J Koo et al. Superior efficacy of calcipotriene and betamethasone dipropionate aerosol foam versus ointment in patients
with psoriasis vulgaris – a randomized phase II study. J Dermatolog Treat 2016; 27:120.
8. V Taraska et al. A novel aerosol foam formulation of calcipotriol
and betamethasone has no impact on HPA axis and calcium
homeostasis in patients with extensive psoriasis vulgaris. J
Cutan Med Surg 2016: 20:44.

49


The Medical Letter

▶

®

Dichlorphenamide (Keveyis) for
Periodic Paralysis

Dichlorphenamide (Keveyis – Taro), an oral carbonic
anhydrase inhibitor, has been approved by the
FDA for treatment of primary hypokalemic and
hyperkalemic periodic paralysis and related variants.
Dichlorphenamide is the first drug to be approved in
the US for this indication. It was approved as Daranide
in 1958 for treatment of glaucoma, but had not been
marketed since 2002.
Pronunciation Key
Dichlorphenamide : dye" klor fen' a mide Keveyis : keh vay' iss

THE DISEASE — Periodic paralysis is a rare hereditary
disorder caused by sodium or calcium channel defects
in skeletal muscle. The disease is characterized by
episodes of muscle weakness, paralysis, and often
hypo- or hyperkalemia. Acetazolamide (Diamox, and
generics), another oral carbonic anhydrase inhibitor, has

been used off-label for treatment of periodic paralysis
for years; in an observational study, 34 of 74 patients
with hypokalemic periodic paralysis (46%) benefited
from acetazolamide therapy.1
MECHANISM OF ACTION — Carbonic anhydrase
inhibitors are thought to decrease the frequency and
severity of periodic paralysis attacks by opening
calcium-activated potassium channels on myocytes,
allowing for influx or efflux of potassium.2
CLINICAL STUDIES — In a randomized, doubleblind, 9-week trial in 44 adults with hypokalemic
periodic paralysis, the median weekly attack rate
was lower in patients taking dichlorphenamide than
in those taking placebo (0.3 vs 2.4). In a similar trial
in 21 adults with hyperkalemic periodic paralysis,
the median weekly attack rate was also lower with
dichlorphenamide (0.9 vs 4.8 with placebo), but the
difference was not statistically significant. None of
the patients taking the active drug in either trial had
acute worsening of disease.3
In a double-blind crossover trial, 42 adults with
hypokalemic periodic paralysis were treated with
dichlorphenamide and placebo for 9 weeks each,
with a 9-week washout period between treatments.
An intolerable increase in attack severity or frequency,
the primary endpoint, occurred during both treatment
periods in 2 patients, only during treatment with
dichlorphenamide in 2 patients, and only during
treatment with placebo in 11 patients. In a similar
trial, 31 adults with hyperkalemic periodic paralysis
experienced a mean of 2.3 fewer attacks per week with

dichlorphenamide than with placebo.4
50

Vol. 58 (1492)

April 11, 2016

ADVERSE EFFECTS — The most common adverse
effects of dichlorphenamide in clinical trials were paresthesia, cognitive disorder, confusion, and dysgeusia.
PREGNANCY — Dichlorphenamide is classified as
category C (teratogenic effects in animals; no adequate studies in women) for use during pregnancy.
DRUG INTERACTIONS — Like acetazolamide,
dichlorphenamide can increase salicylate levels in
patients taking aspirin and can cause hypokalemia
and metabolic acidosis. Concurrent use of high-dose
aspirin and dichlorphenamide has been associated
with serious adverse effects including anorexia,
tachypnea, and coma and is contraindicated. Lowdose aspirin should be used with caution in patients
taking dichlorphenamide. Taking dichorphenamide
with other drugs that can cause hypokalemia or
metabolic acidosis may increase the likelihood and/or
severity of these effects.
DOSAGE, ADMINISTRATION, AND COST — The recommended starting dosage of dichlorphenamide is 50 mg
(one tablet) twice daily. The dosage can be increased at
weekly intervals up to a maximum of 200 mg daily. Use of
dichlorphenamide in patients with hepatic insufficiency,
severe pulmonary disease, or a history of sulfonamide
allergy is contraindicated. Serum potassium and
bicarbonate levels should be measured periodically. The
cost of a 30-day supply of Keveyis (50 mg twice daily)

is $9828.00. A 30-day supply of generic acetazolamide
(250 mg twice daily) costs $154.70.5
CONCLUSION — The carbonic anhydrase inhibitor
dichlorphenamide (Keveyis) reduces the frequency
of primary hypokalemic or hyperkalemic periodic
paralysis attacks, with minimal adverse effects. How
it compares to acetazolamide (Diamox, and generics),
which has been used off-label for years and costs
much less, remains to be determined. ■
1. E Matthews et al. Acetazolamide efficacy in hypokalemic periodic paralysis and the predictive role of genotype. Neurology
2011; 77:1960.
2. D Tricarico et al. Carbonic anhydrase inhibitors ameliorate the
symptoms of hypokalaemic periodic paralysis in rats by opening the muscular Ca2+-activated-K+ channels. Neuromuscul
Disord 2006; 16:39.
3. VA Sansone et al. Randomized, placebo-controlled trials of dichlorphenamide in periodic paralysis. Neurology 2016 February
10 (epub).
4. R Tawil et al. Randomized trials of dichlorphenamide in the
periodic paralyses. Working Group on Periodic Paralysis. Ann
Neurol 2000; 47:46.
5. Approximate wholesale acquisition cost (WAC). 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. March 5, 2016. Reprinted with permission by First Databank, Inc. All rights reserved. ©2016. www.fdbhealth.com/policies/
drug-pricing-policy.


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Discuss the available options for anticoagulation in patients with nonvalvular atrial fibrillation.
2.
Review the efficacy and safety of buprenorphine buccal film (Belbuca) for management of chronic pain.
3.
Review the efficacy and safety of calcipotriene/betamethasone foam (Enstilar) for treatment of plaque psoriasis.
4.
Review the efficacy and safety of dichlorphenamide (Keveyis) for treatment of hypokalemic and hyperkalemic periodic paralysis.
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Issue 1492 Questions
(Correspond to questions #71-80 in Comprehensive Exam #74, available July 2016)
6. Belbuca has been shown to be more effective for chronic pain
than:
a. placebo
b. gabapentin
c. Butrans
d. all of the above

Which Oral Anticoagulant for Atrial Fibrillation?
1. Drawbacks of warfarin include:
a. variability in dosage requirements
b. need for close monitoring
c. many drug interactions

d. all of the above

7. Belbuca has been shown to be more effective than placebo for
treatment of:
a. osteoarthritis of the knee
b. polymyalgia rheumatica
c. chronic low back pain
d. all of the above

2. In clinical trials compared to warfarin, all of the direct oral
anticoagulants had significantly lower rates of:
a. GI bleeding
b. intracranial bleeding
c. ischemic stroke
d. all of the above
3. Drawbacks of the direct oral anticoagulants include:
a. lack of data on their use in end-stage renal disease
b. very long half-lives
c. need for regular monitoring of coagulation parameters
d. all of the above
4. A 41-year-old man with longstanding nonvalvular atrial
fibrillation and normal renal function has taken warfarin
uneventfully for many years with an INR that in recent years
has been stable in the therapeutic range. He has seen
advertisements on television extolling the benefits of the direct
oral anticoagulants, and he wonders if he should switch to one
of them. You could tell him that:
a. edoxaban is preferred for patients like him with normal
renal function
b. he would save money if he made the switch

c. the new drugs have more dietary restrictions
d. he could stay on warfarin
Buprenorphine Buccal Film (Belbuca) for Chronic Pain
5. Which of the following statements about buprenorphine is true?
a. in dosages of 75-1800 mcg per day, it has typical opioid
agonist effects
b. there is no ceiling for its agonist effects
c. it is more likely than morphine to cause respiratory
depression
d. it should not be used with strong CYP2D6 inhibitors

Calcipotriene/Betamethasone Foam (Enstilar) for Psoriasis
8. In clinical trials, approximately what percentage of patients
achieved treatment success with Enstilar?
a. 30%
b. 50%
c. 70%
d. 90%
9. A 29-year-old woman with psoriasis is in her second month of
pregnancy. She has been given a prescription for Enstilar by her
dermatologist, but has not filled it because she is concerned
about possible adverse effects on her baby. You could tell her
that:
a. in animal studies calcipotriene has had toxic effects on
the fetus
b. betamethasone has had teratogenic effects in animals
c. there are no adequate studies of the drug’s safety in
pregnant women
d. all of the above
Dichlorphenamide (Keveyis) for Periodic Paralysis

10. Dichlorphenamide is a:
a. potassium-sparing diuretic
b. mineralocorticoid
c. carbonic anhydrase inhibitor
d. bisphosphonate

ACPE UPN: Per Issue Exam: 0379-0000-16-492-H01-P; Release: April 11, 2016, Expire: April 11, 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.
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