The medical letter on drugs and therapeutics march 3 2014

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

In Brief: Testosterone and Cardiovascular Risk...........................................p 17
Riociguat (Adempas) for Pulmonary Hypertension.................................... p 17
Low-Dose Diclofenac (Zorvolex) for Pain.................................................... p 19

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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 1437)
March 3, 2014

ALSO IN THIS ISSUE

Low-Dose Diclofenac (Zorvolex)
for Pain ........................................................ p 19
IN BRIEF

Testosterone and Cardiovascular Risk
Prompted by the recent publication of 2 retrospective studies, the FDA has announced that it is investigating the risk
of stroke, heart attack, and death in men taking FDA-approved testosterone products.1
The first study examined the records of 8709 men with
low testosterone levels (<300 ng/dL) who underwent
coronary angiography between 2005 and 2011; 1223 of
these men started testosterone therapy after a median
of 531 days following coronary angiography. Three years
after coronary angiography, the Kaplan-Meier estimated
cumulative percentages of men who died or had a myocardial infarction (MI) or ischemic stroke were 26% of
those treated with testosterone and 20% of those who
were not treated with the hormone, a hazard ratio of 1.29
(95% CI 1.04-1.58; P=0.02).2
The second study compared the rate of nonfatal MI during the 90 days after filling a prescription with the rate
in the prior year in 56,000 men given a prescription for

testosterone and in 167,000 given a phosphodiesterase
type 5 inhibitor (sildenafil [Viagra] or tadalafil [Cialis]). In
the testosterone group as a whole, the post/pre-prescription rate ratio was 1.36, but in men >65 years old it was
2.19 and in younger men with a history of heart disease
it was 2.90. In men who received a prescription for sildenafil or tadalafil, the rate ratio was 1.08 for all ages, 1.15
for those >65 years old, and 1.40 for younger men with a
history of heart disease.3
A recent meta-analysis of randomized, placebo-controlled
trials of testosterone therapy also found an increased risk of
cardiovascular-related events in men treated with the hormone (odds ratio [OR] 1.54; 95% CI 1.09-2.18); an analysis
by funding source found that the risk was greater in trials not
funded by the pharmaceutical industry (OR 2.06 vs. 0.89).4

www.medicalletter.org
Take CME Exams

1. FDA Drug Safety Communication January 31, 2014: FDA evaluating risk of stroke, heart attack and death with FDA-approved
testosterone products. Available at www.fda.gov/drugs/drugsafety/ucm383904.htm. Accessed February 24, 2014.
2. R Vigen et al. Association of testosterone therapy with mortality,
myocardial infarction, and stroke in men with low testosterone
levels. JAMA 2013; 310:1829.
3. WD Finkle et al. Increased risk of non-fatal myocardial infarction
following testosterone therapy prescription in men. PLoS One
2014; 9:e85805.
4. L Xu et al. Testosterone therapy and cardiovascular events
among men: a systematic review and meta-analysis of placebocontrolled randomized trials. BMC Med 2013; 11:108.

Riociguat (Adempas) for Pulmonary
Hypertension
The FDA has approved the sGC stimulator riociguat

(rye” oh sig’ ue at; Adempas – Bayer) for oral treatment of pulmonary arterial hypertension (PAH) and
chronic thromboembolic pulmonary hypertension
(CTEPH) following surgery or when surgery is not an
option. It is the first drug to be approved for treatment
of CTEPH.
Table 1. Pharmacology
Drug class

Soluble guanylate cyclase (sGC) stimulator

Route

Oral

Formulation

0.5, 1, 1.5, 2, 2.5 mg tablets

Tmax

1.5 hrs

Metabolism

Primarily by CYP1A1, 3A, 2C8 and 2J2

Elimination

Feces (53%); urine (40%)

Elimination half-life

12 hrs (patients), 7 hrs (healthy subjects)

DRUGS FOR PAH — Current management of PAH
usually includes warfarin (Coumadin, and others) and
furosemide (Lasix, and generics). Oral drugs approved
for PAH include the phosphodiesterase type 5 (PDE5)
inhibitors sildenafil (Revatio, and generics) and tadalafil
(Adcirca), the endothelin receptor antagonists bosentan (Tracleer), ambrisentan (Letairis), and, most recently, macitentan (Opsumit), a nonselective endothelin receptor antagonist derived from bosentan.1 Patients with
more advanced disease can be treated with a systemic
prostacyclin (see Table 2).

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17


Table 2. Some Drugs for Pulmonary Arterial Hypertension
Drug

Route

Some Formulations

Usual Adult Dosage

Cost1

0.5, 1, 1.5, 2, 2.5 mg tabs

1-2.5 mg tid

$7500.00

Soluble Guanylate Cyclase (sGC) Stimulator
Riociguat – Adempas (Bayer)

Oral

Endothelin Receptor Antagonists
Nonselective
Macitentan – Opsumit (Actelion)

Oral

10 mg tabs

10 mg once/day

6840.00

Bosentan – Tracleer
(Actelion)

Oral

62.5, 125 mg tabs

62.5 mg bid (for 4 wks)

then 125 mg bid

7050.00

Oral

5, 10 mg tabs

5-10 mg once/day

6893.30

Oral

20 mg tabs
20 mg tabs

20 mg tid

239.40
2102.84

Oral

20 mg tabs

40 mg once/day

1899.00

Iloprost – Ventavis (Actelion)

Inhalation

10 and 20 mcg ampules

2.5-5 mcg/inhalation 6-9 times/day

Epoprostenol – generic
Flolan (Gilead)
Veletri (Actelion)

Continuous IV
infusion

0.5 and 1.5 mg in 17 mL
single-use vials
0.5 and 1.5 mg in 10 mL
single-use vials

20-40 ng/kg/min4

1145.545
1850.745
1849.925

Continuous SC or IV
infusion
Inhalation

1, 2.5, 5, 10 mg/mL
multi-dose vials
1.74 mg/2.9 mL ampules8

40-160 ng/kg/min7

7132.955

Selective
Ambrisentan – Letairis (Gilead)

Phosphodiesterase 5 (PDE5) Inhibitors
Sildenafil – generic

Revatio2 (Pfizer)
Tadalafil – Adcirca (Eli Lilly)
Prostacyclins

Treprostinil6 –
Remodulin (United Therapeutics)
Tyvaso (United Therapeutics)

9 breaths (54 mcg) qid

15,210.003

13,018.009

1. Approximate wholesale acquisition cost (WAC) for 30 days’ treatment at the lowest usual dosage. Source: Analy$ource® Monthly (Selected from FDB MedKnowledge™)
February 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.

Ancillary costs will substantially increase the cost of non-oral drugs.
2. Also available in an IV formulation for patients on oral sildenafil who are temporarily unable to take oral medication. Also approved in a powder for oral suspension.
3. Cost of 180 ampules of either strength.
4. Initial dosage recommended is 2 ng/kg/min with subsequent increases of 2 ng/kg/min every 15 minutes or longer as tolerated. Dosage requirements tend to increase over
time. Average dosage after 6 months is about 20-40 ng/kg/min.
5. Cost for a 70-kg patient.
6. The FDA recently approved an extended-release oral formulation of treprostinil (Orenitram) that will be available soon.
7. Initial dosage recommended is 1.25 ng/kg/min, or half if poorly tolerated, with subsequent increases of 1.25 ng/kg/min weekly for the first 4 weeks, then 2.5 ng/kg/min
weekly thereafter. Average dosage after 9 months is about 60 ng/kg/min.
8. Initial dosage is 3 breaths (18 mcg) 4 times daily, or 1-2 breaths if poorly tolerated then increasing to 3 breaths. The dosage should be increased by an additional 3 breaths
at 1-2 week intervals as tolerated. The target and maximum dosage is 9 breaths (54 mcg) 4 times daily.
9. Cost of 7 foil pouches containing 4 ampules each.

TREATMENT OF CTEPH — In CTEPH, residual
thromboemboli obstruct pulmonary arteries, leading to
an increase in pulmonary vascular resistance and subsequently to progressive pulmonary hypertension and
right heart failure. The treatment of choice is pulmonary endarterectomy, which can be curative but is not
an option in many patients because of distal occlusion
or comorbidities. About 10% of patients who undergo
surgery continue to experience pulmonary hypertension.2 Drugs for PAH have been used off-label to treat
patients with CTEPH.3
MECHANISM OF ACTION — Riociguat is a soluble
guanylate cyclase (sGC) stimulator. sGC binds to
nitric oxide (NO), forming an enzyme that promotes
synthesis of the signaling molecule cyclic guanosine
monophosphate (cGMP). Pulmonary hypertension
is associated with impaired synthesis of NO and insufficient stimulation of the NO-sGC-cGMP pathway.
Riociguat acts both by directly stimulating sGC inde-

18

pendently of NO, and by increasing the sensitivity of
sGC to NO.
CLINICAL STUDIES — PAH – In a 12-week, doubleblind trial (PATENT-1), 443 patients with symptomatic
PAH were randomized to individually adjusted dosages of riociguat capped at either 1.5 or 2.5 mg 3
times daily, or to placebo.4 At the end of the study,
the mean 6-minute walk distance was longer by 31
meters in the 1.5-mg group and by 30 meters in the
2.5-mg group, compared to a decrease of 6 meters in
the placebo group. Time to clinical worsening, a secondary endpoint, was also longer in patients treated
with riociguat.
CTEPH – A 16-week, double-blind trial (CHEST-1) in
261 patients with inoperable CTEPH or persistent or recurrent pulmonary hypertension despite surgery found
that riociguat titrated to a maximum of 2.5 mg 3 times
daily increased 6-minute walk distance by 39 meters,
compared to a decrease of 6 meters with placebo.5

The Medical Letter • Volume 56 • Issue 1437 • March 3, 2014


Extension Trials – In long-term extensions of both trials (PATENT-2 and CHEST-2), treatment was unblinded
after 8 weeks. Exploratory analyses at 12 weeks found
that patients taking riociguat increased their 6-minute
walk distance from the original baseline by 53 meters in
PATENT-2 and by 63 meters in CHEST-2.4,5
ADVERSE EFFECTS — Adverse effects of riociguat
(>5%) that occurred more frequently than with placebo
in clinical trials were headache, dyspepsia/gastritis,
dizziness, nausea, diarrhea, hypotension, vomiting,
anemia, gastroesophageal reflux, and constipation.

Hypotension occurred in 10% of patients taking riociguat compared to 4% of those taking placebo. Serious hemorrhagic events, including one fatal case, occurred in 2.4% of patients treated with the drug and in
none with placebo.
PREGNANCY — Riociguat is contraindicated for use
during pregnancy (category X). It is available for women
only through a restricted access program.
DRUG INTERACTIONS — Because of the risk of hypotension, riociguat is contraindicated for use with nitrates, nitric oxide donors (such as amyl nitrite), PDE5
inhibitors (such as sildenafil) and nonspecific PDE inhibitors (such as dipyridamole or theophylline).
Concomitant use of riociguat with strong CYP and Pglycoprotein/breast cancer resistance protein (P-gp/
BCRP) inhibitors (such as ketoconazole, itraconazole,
and ritonavir) can increase riociguat serum concentrations and the risk of hypotension.
Plasma concentrations of riociguat are reduced by 5060% in smokers compared to nonsmokers. Antacids
such as aluminum hydroxide/magnesium hydroxide reduce absorption of riociguat.
DOSAGE AND ADMINISTRATION — The recommended starting dosage of riociguat is 1 mg 3 times
daily. The dose can be increased by 0.5 mg every 2
weeks up to the maximum of 2.5 mg 3 times daily.
In patients who cannot tolerate the drug’s hypotensive
effects, or in those taking concomitant strong CYP and
P-gp/BCRP inhibitors, the starting dosage can be lowered to 0.5 mg 3 times daily. Riociguat dosages higher
than 2.5 mg 3 times daily may be considered for patients who smoke. Dosage reductions may be necessary for patients who stop smoking. Antacids should not
be taken within 1 hour of taking riociguat.
CONCLUSION — Riociguat (Adempas) can improve
exercise capacity in patients with pulmonary arterial

hypertension (PAH) and in those with chronic thromboembolic pulmonary hypertension (CTEPH). □
1. Macitentan (Opsumit) for pulmonary arterial hypertension. Med
Lett Drugs Ther 2014; 56:15.
2. J Pepke-Zaba et al. Chronic thromboembolic pulmonary hypertension (CTEPH): results from an international prospective registry.
Circulation 2011; 124:1973.
3. M Delcroix. Chronic post-embolic pulmonary hypertension: a new
target for medical therapies? Eur Respir Rev 2013; 22:258.

4. HA Ghofrani et al. Riociguat for the treatment of pulmonary arterial
hypertension. N Engl J Med 2013; 369:330.
5. HA Ghofrani et al. Riociguat for the treatment of chronic thromboembolic pulmonary hypertension. N Engl J Med 2013; 369:319.

Low-Dose Diclofenac (Zorvolex) for Pain
The FDA has approved Zorvolex (Iroko), a low-dose
oral formulation of the relatively COX-2 selective NSAID
diclofenac, for treatment of mild-to-moderate acute pain
in adults.
Zorvolex is available as 18- and 35-mg capsules. Other oral formulations of diclofenac include immediaterelease, extended-release, and enteric-coated tablets
and capsules in strengths ranging from 25 to 100 mg.
Diclofenac is also available topically as a transdermal
patch (Flector), a gel (Voltaren Gel), and a solution
(Pennsaid).
THE NEW FORMULATION — Each capsule of Zorvolex
contains diclofenac as submicron particles. The reduction
in particle size increases surface area, leading to faster
dissolution and absorption of the drug. A single-dose
crossover study compared the new 35-mg formulation
of diclofenac to diclofenac potassium 50 mg in healthy
subjects. Taken without food, Tmax was about 1 hour for
both formulations; Cmax and AUC were about 26% and
23% lower, respectively, with the new formulation. Taking
Zorvolex with food delayed its Tmax by 2.32 hours and
reduced its Cmax by 60% and its AUC by 11%.
CLINICAL STUDIES — Approval of Zorvolex was
based on the results of a double-blind clinical trial in
428 patients with moderate-to-severe pain following
bunionectomy. Patients were randomized to diclofenac
18 mg or 35 mg 3 times daily, celecoxib 200 mg twice

daily after a 400-mg loading dose, or placebo. At 12
hours, pain intensity with diclofenac 18 and 35 mg was
reduced from baseline by 48% and 51%, respectively,
compared to 24% with placebo. At 24 hours, pain intensity was reduced by 69% and 73% versus 52%. All
of these differences from placebo were statistically significant. Compared with celecoxib, overall reductions in
pain intensity were greater with diclofenac 35 mg and
similar with diclofenac 18 mg.1

The Medical Letter • Volume 56 • Issue 1437 • March 3, 2014

19


In a randomized, double-blind trial in 305 patients with
osteoarthritis, diclofenac 35 mg three times daily for 12
weeks was significantly more effective than placebo
in relieving pain; twice-daily administration of the drug
was not significantly better than placebo.2
ADVERSE EFFECTS — NSAIDs frequently cause
small increases in aminotransferase activity; serious
hepatotoxicity is rare, but may occur more frequently
with diclofenac. An increased risk of serious cardiovascular events has been reported with some NSAIDs;
the risk appeared to be highest with diclofenac.3 In the
12-week osteoarthritis trial, no serious gastrointestinal,
cardiovascular, or renal adverse events were reported
with diclofenac 35 mg 3 times daily.4
DRUG INTERACTIONS — Diclofenac is metabolized
primarily by CYP2C9; co-administration with CYP2C9
inhibitors (such as fluconazole) may increase its serum
concentrations and toxicity.5 Like other NSAIDs, diclofenac may decrease the effectiveness of diuretics, beta

blockers, ACE inhibitors and some other antihypertensive drugs, may increase the toxicity of lithium, methotrexate, and cyclosporine, and may increase the risk of
gastrointestinal bleeding in patients taking warfarin.
DOSAGE, ADMINISTRATION, AND COST — The recommended dosage of Zorvolex is 18 mg or 35 mg three
times daily. It can be taken with or without food, but its
effectiveness may be reduced when taken with food. A
single Zorvolex capsule of either strength costs $2.50,
compared to about $0.70 for one 50-mg tablet of generic diclofenac potassium.6
CONCLUSION — NSAIDs can cause serious adverse
effects and should be used in the lowest effective dosage.
Zorvolex, a new low-dose oral formulation of diclofenac,
is more effective than placebo in relieving acute pain.
How it compares in efficacy or safety to oral immediaterelease diclofenac potassium, which is available generically, or to any other traditional NSAID, is unknown. □
1. A Gibofsky et al. Lower-dose diclofenac submicron particle capsules
provide early and sustained acute patient pain relief in a phase 3
study. Postgrad Med 2013; 125:130.
2. A Gibofsky et al. A phase 3 study of lower-dose diclofenac submicron
particle capsules demonstrates effective pain relief in patients with osteoarthritis. Osteoarthritis Cartilage 2013; 21(4) suppl:S267. Abs. 518.
3. Drugs for pain. Treat Guidel Med Lett 2013; 11:31.
4. C Young and MC Hochberg. Safety of lower-dose diclofenac submicron particle capsules dosed up to 12 weeks in patients with osteoarthritis. Arthritis Rheum 2013; 65(10) suppl:S915. Abs. 2149.
5. Inhibitors and inducers of CYP enzymes and P-glycoprotein. Med
Lett Drugs Ther 2013; 55:e44.
6. Approximate wholesale acquisition cost (WAC). Source: Analy$ource
Monthly (Selected from FDB MedKnowledge™) February 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.

20

Coming Soon in The Medical Letter:
Golimumab (Simponi) for Ulcerative Colitis
Drugs for Gout
Tobramycin Inhalation (Bethkis) for Cystic Fibrosis

Coming Soon in Treatment Guidelines:
Drugs for Peptic Ulcer Disease and GERD
Drugs for Hypertension

The Medical Letter

®

On Drugs and Therapeutics
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., F. Peter Swanson, M.D.
CONTRIBUTING EDITORS:
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Eric J. Epstein, M.D., Albert Einstein College of Medicine
Jane P. Gagliardi, M.D., M.H.S., F.A.C.P Duke University School of Medicine
Jules Hirsch, M.D., Rockefeller University
David N. Juurlink, BPhm, M.D., Ph.D., Sunnybrook Health Sciences Centre
Richard B. Kim, M.D., University of Western Ontario
Hans Meinertz, M.D., University Hospital, 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., Weill Medical College of Cornell University

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The Medical Letter • Volume 56 • Issue 1437 • March 3, 2014


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Online Continuing Medical Education
To take CME exams and earn credit, go to:
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Issue 1437 Questions

(Correspond to questions #25-30 in
Comprehensive Exam #70, available July 2014)

Riociguat (Adempas) for Pulmonary Hypertension
1.

Which of the following are used to manage PAH?
a. warfarin
b. furosemide
c. sildenafil
d. all of the above

2.

Riociguat taken for 12 weeks increased the 6-minute walk distance from
baseline by about:
a. 10 meters
b. 30 meters
c. 50 meters
d. 70 meters

3.

In clinical trials, 10% of patients treated with riociguat experienced:
a. hypotension
b. hypertension
c. bradycardia
d. tachycardia

Low-Dose Diclofenac (Zorvolex) for Pain

4.

Compared to diclofenac potassium 50 mg, the AUC and Cmax of Zorvolex
35 mg were about:
a. 10% higher
b. 25% higher
c. 25% lower
d. 50% lower

5.

A 56-year-old woman with mild osteoarthritis of the knee treated fairly
successfully with acetaminophen has seen advertisements for Zorvolex and
asks if she could try it instead. She has had atrial fibrillation for 10 years, for
which she takes warfarin and a beta blocker. You could tell her that:
a. Zorvolex may be less convenient than acetaminophen because
taking it with food could decrease its effectiveness
b. diclofenac could increase the risk of gastrointestinal bleeding in
patients taking warfarin
c. diclofenac could decrease the effectiveness of the beta blocker
d. all of the above

6.

Compared to other NSAIDs, diclofenac is more likely to cause:
a. gastric ulcer
b. renal toxicity
c. serious hepatotoxicity
d. all of the above

ACPE UPN: Per Issue Exam: 0379-0000-14-437-H01-P; Release: March 3, 2014, Expire: March 3, 2015
Comprehensive Exam 70: 0379-0000-14-070-H01-P; Release: July 2014, Expire: July 2015

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activities. The Medical Letter aims to be a leader in supporting the professional development of healthcare professionals

through Core Competencies by providing continuing medical education that is unbiased and free of industry influence.
The Medical Letter is supported solely by subscription fees and accepts no advertising, grants, or donations.
GOAL:
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 riociquat (Adempas) for treatment of pulmonary arterial hypertension.
2. Review the efficacy and safety of a new lower-dose formulation of diclofenac (Zorvolex) for treatment of pain.
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 98/NT/2000/XP/Vista/7/8, Pentium+ processor, Mac OS X+ w/compatible processor;
Microsoft IE 6.0+, Mozilla Firefox 2.0+ or any other compatible Web browser. Dial-up/high-speed connection.
Have any questions? Call us at 800-211-2769 or 914-235-0500 or e-mail us at: