The medical letter on drugs and therapeutics march 31 2014

The Medical Letter

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

Golimumab (Simponi) for Ulcerative Colitis ...................................................p 25
A Long-Acting Depot Formulation of Testosterone (Aveed)......................... p 26
In Brief: Otrexup – A Single-Use Auto-Injector Formulation
of Methotrexate................................................................................................ p 28

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The Medical Letter

®

On Drugs and Therapeutics
Published by The Medical Letter, Inc. • 145 Huguenot Street, New Rochelle, NY 10801 • A Nonprofit Publication
Volume 56 (Issue 1439)
March 31, 2014

www.medicalletter.org
Take CME Exams

ALSO IN THIS ISSUE

A Long-Acting Depot Formulation of
Testosterone (Aveed).................................... p 26
In Brief: Otrexup – A Single-Use AutoInjector Formulation of Methotrexate ..... p 28

Golimumab (Simponi) for Ulcerative
Colitis
The FDA has approved golimumab (Simponi – Janssen),
a fully human monoclonal antibody specific for tumor necrosis factor (TNF) alpha, for induction and maintenance
of remission in patients with moderate to severe ulcerative colitis who do not respond to or cannot tolerate other
therapies or who require continuous treatment with corticosteroids. Golimumab was approved earlier for treatment
of rheumatoid arthritis, psoriatic arthritis, and ankylosing
spondylitis.1 It is the third TNF inhibitor to be approved for
use in ulcerative colitis.2
TREATMENT OF ULCERATIVE COLITIS — For mild
to moderate ulcerative colitis, an aminosalicylate such

as mesalamine is generally the first drug tried for induction and maintenance of remission. Oral prednisone is

effective for inducing remission in patients who do not
respond to an aminosalicylate or have severe symptoms. Corticosteroids are used systemically only until
acute inflammation is under control, and then are tapered and discontinued. Rectal administration of aminosalicylates and corticosteroids can be effective for
treatment of distal disease.3
For moderate to severe disease, a thiopurine (mercaptopurine or azathioprine) is often used as a corticosteroid-sparing agent for maintenance of remission.
TNF inhibitors are effective for treatment of moderate to
severe ulcerative colitis not responding to aminosalicylates or thiopurines or requiring chronic corticosteroids.
Infliximab and adalimumab have been effective in moderate to severe ulcerative colitis that did not respond to
corticosteroids.4 Cyclosporine is an alternative for treatment of severe, steroid-refractory ulcerative colitis.
CLINICAL STUDIES — FDA approval of golimumab for
ulcerative colitis was based on a 6-week induction trial and
a 54-week maintenance trial in patients with moderate to
severe ulcerative colitis that had not responded to standard treatments. In the induction trial, 774 patients were
randomized to receive a single dose of golimumab 200
mg or 400 mg or placebo, each followed 2 weeks later by

Table 1. TNF Inhibitors for Ulcerative Colitis
Route of
Administration

Some
Formulations

Usual
Adult Dosage

Mouse and
human

Intravenous

100 mg vials

Induction: 5 mg/kg at
weeks 0, 2, and 6
Maintenance: 5 mg/kg
q8 weeks

Adalimumab – Humira
(Abbvie)

Human

Subcutaneous

40 mg syringes
and pen injectors

Induction: 160 mg at week 0,
then 80 mg at week 2
Maintenance: 40 mg q2
weeks starting at week 4

5005.20

Golimumab – Simponi
(Janssen)

Human

Subcutaneous

100 mg syringes
and auto-injectors

Induction: 200 mg at week 0,
then 100 mg at week 2
Maintenance: 100 mg
q4 weeks

6234.30

Drug

Source

Infliximab – Remicade
(Janssen)

Cost1
$3374.20

1. Approximate wholesale acquisition cost (WAC) for 8 weeks’ treatment of a 70-kg patient with the maintenance dosage. Source: Analy$ource®
Monthly (Selected from FDB MedKnowledge™) March 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. Costs associated with administration are not included.

FORWARDING OR COPYING IS A VIOLATION OF U.S. AND INTERNATIONAL COPYRIGHT LAWS

25


half the first dose. At 6 weeks, clinical response rates were
51.0% and 54.9% for the groups given 200 mg/100 mg
and 400 mg/200 mg, respectively, and 30.3% for those receiving placebo.5
The maintenance trial randomized 464 patients who
had responded to golimumab in the induction trial to 100
mg or 50 mg of golimumab or placebo every 4 weeks
for 52 weeks. The rates of maintained clinical response
were significantly higher with golimumab (49.7% with
100 mg, 47.0% with 50 mg) than with placebo (31.2%).6
These rates of response and maintained response are
similar to those reported earlier with infliximab and
adalimumab.7-11
ADVERSE EFFECTS — TNF inhibitors should not be
given to patients with active localized or chronic infections. Serious infections, including bacterial sepsis and
reactivation of tuberculosis and hepatitis B, have been
reported with all TNF inhibitors, especially during the first
2-7 months of treatment. In the 54-week maintenance
trial of golimumab, 4 patients were found to have tuberculosis during the study; all of these patients were taking
corticosteroids at the time of enrollment in the induction
trial. There were 3 deaths during the maintenance trial,
including one from disseminated tuberculosis and one
from sepsis. Tuberculin skin testing and chest radiography are recommended before starting anti-TNF therapy.
Lymphoma and other malignancies have been reported
with use of TNF inhibitors, but a cause-and-effect relationship has not been established. A meta-analysis of 22
clinical trials found that use of TNF inhibitors for up to one
year in patients with inflammatory bowel disease did not
result in an increased risk of malignancy.12 TNF inhibitors

generally should not be used in patients with a recent malignancy.
Concomitant use of TNF inhibitors with other biological
agents such as abatacept (Orencia) or anakinra (Kineret) further increases the risk of infection and is not
recommended. Patients being treated with TNF inhibitors should not receive live vaccines.
Exacerbations and new onset of heart failure have occurred during treatment with TNF inhibitors. These
agents have been associated with development of autoantibodies, including anti-nuclear antibodies and antidsDNA antibodies, and, rarely, with induction of a lupuslike syndrome. Pancytopenia and demyelinating disorders such as multiple sclerosis have also been reported.
CONCLUSION — Golimumab (Simponi) appears to
be effective for treatment of ulcerative colitis that has

26

not responded to other therapies or requires continuous treatment with corticosteroids. No clinical trials are
available comparing it to other TNF inhibitors that are
approved for the same indication and have been in use
longer. □
1. Golimumab (Simponi) for inflammatory arthritis. Med Lett Drugs
Ther 2009: 51:55.
2. Drugs for inflammatory bowel disease. Treat Guidel Med Lett 2012:
10:19.
3. Budesonide (Uceris) for ulcerative colitis. Med Lett Drugs Ther
2013; 55:23.
4. A Kornbluth et al. Ulcerative colitis practice guidelines in adults:
American College of Gastroenterology, Practice Parameters Committee. Am J Gastroenterol 2010; 105:501.
5. WJ Sandborn et al. Subcutaneous golimumab induces clinical response and remission in patients with moderate-to-severe ulcerative colitis. Gastroenterology 2014; 146:85.
6. WJ Sandborn et al. Subcutaneous golimumab maintains clinical
response in patients with moderate-to-severe ulcerative colitis.
Gastroenterology 2014; 146:96.
7. P Rutgeerts et al. Infliximab for induction and maintenance therapy
for ulcerative colitis. N Engl J Med 2005; 353:2462.
8. W Reinisch et al. Long-term infliximab maintenance therapy for ulcerative colitic; the ACT-1 and -2 extension studies. Inflamm Bowel

Dis 2012; 18:201.
9. W Reinisch et al. Adalimumab for induction of clinical remission
in moderately to severely active ulcerative colitis: results of a randomised controlled trial. Gut 2011; 60:780.
10. W Reinisch et al. 52-week efficacy of adalimumab in patients with moderately to severely active ulcerative colitis who failed corticosteroids
and/or immunosuppressants. Inflamm Bowel Dis 2013; 19:1700.
11. WJ Sandborn et al. Adalimumab induces and maintains clinical
remission in patients with moderate-to-severe ulcerative colitis.
Gastroenterology 2012; 142:257.
12. CJ Williams et al. Systematic review with meta-analysis: malignancies with anti-tumour necrosis factor- therapy in inflammatory
bowel disease. Aliment Pharmacol Ther 2014; 39:447.

A Long-Acting Depot Formulation of
Testosterone (Aveed)
The FDA has approved testosterone undecanoate (Aveed –
Endo), an injectable depot formulation, for use in men
with hypogonadism who require testosterone replacement
therapy.
HYPOGONADISM — Failure of the testes to produce
adequate amounts of testosterone can lead to loss
of energy, decreased libido, erectile dysfunction, decreased axillary and pubic hair, loss of muscle mass,
anemia, and osteoporosis. Testosterone serum concentrations decrease by about 1-2% per year after
age 40. The normal range (usually 300-1000 ng/dL) is
based on serum concentrations in young men. Older
men with signs and symptoms of hypogonadism may
have levels <200 ng/dL.
DOSAGE AND PHARMACOKINETICS — Each 3-mL
vial of Aveed contains testosterone undecanoate 250
mg/mL in a mixture of 1500 mg of benzyl benzoate and

The Medical Letter • Volume 56 • Issue 1439 • March 31, 2014

Table 1. Some Testosterone Replacement Products
Formulations

Usual Dosage Cost1

Testosterone
enanthate –
generic
Delatestryl (Endo)

5 mL vial
(200 mg/mL)

50-400 mg
IM every
2-4 wks

Testosterone
cypionate –
generic
Depo-Testosterone
(Pfizer)

10 mL vial
(100 mg/mL)
1, 10 mL vial
(200 mg/mL)

50-400 mg
IM every
2-4 wks

Testosterone
undecanoate
Aveed (Endo)

3 mL vial
(250 mg/mL)

750 mg IM
825.002
at 0 and 4
wks, then q10 wks

Androderm
(Actavis)

2, 4 mg/d
patch

4 mg once
nightly

374.10

Androgel 1%
(Abbvie)

2.5 g gel packet
(25 mg test.)
5 g gel packet
(50 mg test.)
88 g MDP
(12.5 mg test. in
1.25 g gel/act.)

50 mg
once/d

389.40

Drugs
Injectable

$68.00
82.80

49.30
73.50

Transdermal

Androgel 1.62%
(Abbvie)

1.25 g gel packet 40.5 mg
(20.25 mg test.)
once/d

2.5 g gel packet
(40.5 mg test.)
88 g MDP
(20.25 mg test.
in 1.25 g gel/act.)

389.40

Axiron (Lilly)

90 mL MDP
60 mg once/d
(30 mg test. in
1.5 mL soln/act.)

393.10

Fortesta (Endo)

60 g MDP
(10 mg test.
in 0.5 g gel/act.)

40 mg once/d

355.10

5 g tube of gel
(50 mg test.)

50 mg once/d

382.80

30 mg buccal
tablet

30 mg bid

431.30

Testim (Auxilium)
Buccal
Striant (Auxilium)

act. = actuation; MDP = metered-dose pump; test. = testosterone
1. Approximate wholesale acquisition cost (WAC) for one 5-mL vial of testosterone
enanthate, one 10-mL vial (100 mg/mL) of testosterone cypionate, one 3-mL
vial of Aveed, or a 30-day supply of transdermal or buccal formulations at the
usual dosage. Source: Analy$ource® Monthly (Selected from FDB MedKnowledge™) March 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. Cost of administration is not included.
2. WAC according to the manufacturer.

885 mg of refined castor oil. The recommended dosage
is 750 mg injected intramuscularly at 0 and 4 weeks,
and then every 10 weeks thereafter. After one 750-mg
injection, serum testosterone levels peak in a median of
7 days and then slowly decline. Steady state is reached
after the third injection.

CLINICAL STUDIES — Many small studies in young
hypogonadal men have shown that androgen replacement increases libido, improves mood and erectile function, and increases bone formation, muscle mass, and
strength. In older men with low or low-normal testoster-

one concentrations, the effects of testosterone treatment
are less clear. It has been reported to increase libido,
improve mood, and increase bone density, and it may
also increase muscle mass and strength, but much less
so than in younger men. FDA approval of testosterone
treatment for hypogonadism is based on testosterone
serum concentrations.
An unpublished 84-week trial of testosterone undecanoate therapy in 130 hypogonadal men (mean
age 54 years), summarized in the package insert,
found that 94% of those who participated in the study
through week 24 maintained average serum testosterone concentrations in the normal range after the third
injection of the drug. The average maximum testosterone concentration at steady state was 891 ng/dL and
the average minimum was 324 ng/dL. The percentage
of patients with maximum concentrations >1500 ng/dL
was 7.7%.
A prospective uncontrolled trial in 1438 men with below-normal serum testosterone concentrations treated with up to 5 testosterone undecanoate injections
(formulations available outside the US) over a period
of 9-12 months found that mental and psychosexual
function improved markedly, mean waist circumference decreased by 4 cm, and the incidence of moderate or severe erectile dysfunction decreased from
67% to 19%.1
ADVERSE EFFECTS — In clinical trials, the most common adverse effects of testosterone undecanoate injections were acne, injection site pain, and an increase in
prostate specific antigen levels above 4 ng/mL, all of which
occurred in about 5% of patients. Postmarketing surveillance of testosterone undecanoate products approved in
other countries found that some patients developed pulmonary oil microembolism (POME) reactions that have included cough, dyspnea, throat tightening, chest pain, dizziness, and syncope occurring during or immediately after
injection of the drug. Some of these episodes lasted several hours, and some required hospitalization. Life-threatening anaphylactic reactions have also been reported. As a
result, the US labeling includes a boxed warning requiring

that patients be observed for 30 minutes after injections
of Aveed, and use of the drug is restricted to healthcare
providers and settings certified through a Risk Evaluation
and Mitigation Strategy (REMS) program.
The recently published results of 2 large retrospective
studies have prompted the FDA to investigate the possibility of an increased risk of stroke, heart attack, and
death in men treated with testosterone replacement
products.2 An earlier randomized, placebo-controlled
trial in 209 men >65 years old with low serum testoster-

The Medical Letter • Volume 56 • Issue 1439 • March 31, 2014

27


one concentrations had found an increased incidence
of cardiovascular adverse events in those treated with
testosterone gel for 6 months (23 vs. 5 with placebo).3
CONCLUSION — The new long-acting depot formulation of testosterone undecanoate (Aveed) offers a
convenient schedule of administration of the hormone,
but at the risk of serious pulmonary oil microembolism
reactions and anaphylaxis.
1. M Zitzmann et al. IPASS: a study on the tolerability and effectiveness of injectable testosterone undecanoate for the treatment of
male hypogonadism in a worldwide sample of 1,438 men. J Sex
Med 2013; 10:579.
2. In brief: Testosterone and cardiovascular risk. Med Lett Drugs Ther
2014; 56:17.
3. S Basaria et al. Adverse events associated with testosterone administration. N Engl J Med 2010; 363:109.

IN BRIEF

Otrexup – A Single-Use Auto-Injector
Formulation of Methotrexate
The FDA has approved a new injectable formulation of
methotrexate (Otrexup – Antares) for use in rheumatoid arthritis and polyarticular juvenile idiopathic arthritis,
and for severe psoriasis in adults. On its web site (www.
otrexup.com), the manufacturer states: “Otrexup is the
first subcutaneous (SC) methotrexate (MTX) for selfadministration delivered once weekly by auto-injector.”
Methotrexate has been available as a once-weekly injection (IM or SC) for these indications for many years,1 but
not specifically for self-administration and not in a singledose auto-injector. Methotrexate is generally given orally,
but injectable formulations may be helpful for patients
who have adverse gastrointestinal effects from the oral
formulation or lose benefit over time because of poor absorption.
Otrexup auto-injectors are available in strengths of 10,
15, 20, and 25 mg of methotrexate per 0.4 mL. The usual dosage of methotrexate for patients with rheumatoid
arthritis ranges from 7.5 to 25 mg once weekly. Otrexup
should be administered SC in the abdomen or thigh.
Four 25-mg auto-injectors cost $548.00, compared to
$5.00 for a single 4-mL vial of generic methotrexate
containing 25 mg/mL.2 Nevertheless, some patients
with rheumatoid arthritis who find it difficult to draw up
methotrexate solution from a vial and inject it with a syringe may prefer Otrexup.

Coming Soon in The Medical Letter:
Anoro Ellipta: An Inhaled Umeclidinium/Vilanterol Combination
for COPD
Ibrutinib (Imbruvica) for Chronic Lymphocytic Leukemia
Sorafenib (Nexavar) for Thyroid Cancer
Coming Soon in Treatment Guidelines:
Drugs for Peptic Ulcer Disease and GERD

Drugs for Hypertension

The Medical Letter

®

On Drugs and Therapeutics
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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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1. Drugs for rheumatoid arthritis. Treat Guidel Med Lett 2012; 10:37.
2. Approximate wholesale acquisition cost (WAC). Source:
Analy$ource® Monthly (Selected from FDB MedKnowledge™)
March 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.

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The Medical Letter • Volume 56 • Issue 1439 • March 31, 2014


The Medical Letter

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Online Continuing Medical Education
To take CME exams and earn credit, go to:
medicalletter.org/CMEstatus

Issue 1439 Questions
(Correspond to questions #37-42 in
Comprehensive Exam #70, available July 2014)
Golimumab (Simponi) for Ulcerative Colitis
1.

Mild to moderate ulcerative colitis is generally treated first with:
a. prednisone
b. an aminosalicylate
c. a TNF inhibitor
d. a thiopurine

2.

In clinical induction trials, the rate of response to golimumab was about:
a. 30%
b. 50%
c. 70%
d. 90%

3.

Use of TNF inhibitors has been associated with:
a. reactivation of TB

b. reactivation of hepatitis B
c. heart failure
d. all of the above

A Long-Acting Depot Formulation of Testosterone (Aveed)
4.

A 64-year-old man complaining of fatigue, depression, and
erectile dysfunction asks if Aveed could relieve his symptoms.
You could tell him that:
a. FDA approval of the drug was based on its effect
on testosterone levels
b. injections of testosterone products similar to Aveed
have clearly been shown to improve mood and erectile
dysfunction in older men
c. there is no reason to believe Aveed could have any
adverse effects
d. all of the above

5.

After the first 2 doses, Aveed is injected every:
a. 4 weeks
b. 7 weeks
c. 10 weeks
d. 26 weeks

6.

Aveed contains testosterone mixed in:

a. saline
b. mineral oil
c. a liposome suspension
d. castor oil

ACPE UPN: Per Issue Exam: 0379-0000-14-439-H01-P; Release: March 31, 2014, Expire: March 31, 2015
Comprehensive Exam 70: 0379-0000-14-070-H01-P; Release: July 2014, Expire: July 2015

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