The medical letter on drugs and therapeutics june 8 2015

The Medical Letter

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on Drugs and Therapeutics
Objective Drug Reviews Since 1959
Volume 57

ISSUE
ISSUE
No.

1433
1470
Volume 56

June 8, 2015

IN THIS ISSUE

Drugs for Psoriasis ................................................................................................................p 81
Nivolumab (Opdivo) for Metastatic Melanoma and Metastatic NSCLC .............................p 85
Recombinant Human Parathyroid Hormone (Natpara) .......................................................p 87
Drugs for Psoriatic Arthritis ........................................................................................ online only

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The Medical Letter

®

on Drugs and Therapeutics
Objective Drug Reviews Since 1959

Volume 57

ISSUE

ISSUE No.

1433
1470
Volume 56

▶

June 8, 2015
Take CME Exams
ALSO IN THIS ISSUE

Nivolumab (Opdivo) for Metastatic Melanoma and Metastatic NSCLC .............................p 85
Recombinant Human Parathyroid Hormone (Natpara) .......................................................p 87
Drugs for Psoriatic Arthritis ........................................................................................ online only

Drugs for Psoriasis
Related article(s) since publication

Mild to moderate psoriasis is generally treated with
topical corticosteroids. Vitamin D analogs and tazarotene
are topical alternatives that can be used in combination
with topical corticosteroids. Phototherapy and systemic
therapy, including biologic agents, are recommended for
patients with moderate to severe disease.
Drugs for psoriatic arthritis are reviewed in a separate
article available at />TOPICAL THERAPY — Corticosteroids – Topical corticosteroids are widely used for treatment of psoriasis
both alone and in combination with phototherapy and
systemic therapy. Ointments are generally the most
effective. Foams and sprays can be applied to large
areas, but the alcohol base used in many of them may
cause burning in patients with sensitive skin.
Adverse Effects – Superpotent topical corticosteroids,
such as clobetasol propionate 0.05%, can induce
adrenal suppression when applied to large body

surface areas, but clinically significant adrenal
insufficiency is rare. Local cutaneous adverse
effects such as atrophy of the dermis and epidermis,
telangiectasias, and irreversible striae can occur when
these agents are used for prolonged periods of time or
under occlusion, when too much is applied, or when
corticosteroid-sensitive areas such as the face and
intertriginous regions are treated, but usually not when
they are applied to active psoriatic lesions.
Pregnancy – Topical corticosteroids with mild to
moderate potency appear to be safe for use during
pregnancy.1
Calcipotriene – The synthetic vitamin D3 analog
calcipotriene (Dovonex, Sorilux, and generics) is about

as effective as a mid-strength corticosteroid for topical
treatment of plaque psoriasis.2
Adverse Effects – Calcipotriene is generally well
tolerated, but burning and itching can occur. Hypercalcemia has been reported rarely.
Pregnancy – Calcipotriene is classified as category
C (fetotoxicity in animals; no adequate studies in
women) for use during pregnancy.
Calcipotriene/Betamethasone Dipropionate – This oncedaily combination ointment (Taclonex, and generics)
is more effective than either component alone for
treating plaque psoriasis and has been well tolerated.3
A suspension formulation that can be used on the scalp
(Taclonex Topical Suspension) is also applied once daily.
Calcitriol — A second vitamin D3 analog, calcitriol
(Vectical) is indicated for topical treatment of mild to
moderate plaque psoriasis in adults.4

Adverse Effects – Calcitriol causes less skin irritation
than calcipotriene.5 Skin discomfort, pruritus, and
erythema can occur, but are generally mild.
Pregnancy – Like calcipotriene, calcitriol is classified
as category C (fetotoxicity in animals; no adequate
studies in women) for use during pregnancy.
Tazarotene – An acetylenic retinoid, tazarotene
(Tazorac) has been effective for topical treatment
of psoriasis, and in some patients the therapeutic
effect may persist after treatment is stopped.6 Use of
tazarotene in combination with topical corticosteroids
may have a synergistic effect.7
Adverse Effects – Erythema, burning, pruritus,
peeling, and an increased risk of sunburn can occur
with tazarotene gel. The cream formulation is better
tolerated, but peeling may be more frequent.
81

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The Medical Letter

Vol. 57 (1470)

®

June 8, 2015

Table 1. Some Systemic Drugs for Psoriasis and/or Psoriatic Arthritis

Drug

Usual Adult Dosage

Cost1

Acitretin – Soriatane (Stiefel)2
Apremilast – Otezla (Celgene)2,4
Cyclosporine2 – generic
Neoral (Novartis)
Leflunomide6 – generic
Arava (Sanofi)
Methotrexate2 – generic
Sulfasalazine6 – generic
Azulfidine (Pfizer)
enteric coated – generic
Azulfidine EN-tabs
Biologics
Adalimumab – Humira (Abbvie)2,4
Certolizumab pegol – Cimzia (UCB)4
Etanercept – Enbrel (Amgen)2,4
Golimumab – Simponi (Centocor)4
Infliximab – Remicade (Janssen)2,4
Secukinumab – Cosentyx (Novartis)2
Ustekinumab – Stelara (Janssen)2,4

10-50 mg PO once/day3
30 mg PO bid5
2.5-4 mg/kg/day PO in 2 divided doses

$2778.40
5662.10
957.60
1091.80
182.30
3284.70
75.60
62.70
299.10
87.00
390.70

10-20 mg PO once/day
7.5-25 mg/week PO in a single dose or in 3 divided doses over 36 hours
2-3 g/day PO in divided doses

80 mg SC x 1,7 then 40 mg q2 weeks
400 mg SC at 0, 2, and 4 weeks, then 200 mg q2 weeks or 400 mg q4 weeks
50 mg SC twice/week x 12 weeks,7 then once/week
50 mg SC once/month
5 mg/kg IV at 0, 2, and 6 weeks, then q8 weeks
300 mg8 SC at 0, 1, 2, 3, and 4 weeks, then q4 weeks
45 mg10 SC at 0 and 4 weeks, then q12 weeks

9606.30
9129.90
9607.90
9821.50
5842.30
10,260.009

7661.20

1. Approximate WAC for 12 weeks’ treatment at the lowest usual adult maintenance dosage (cyclosporine and infliximab cost calculated for a patient weighing
80 kg). 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. May 5, 2015. Reprinted with permission by First Databank, Inc. All rights reserved.
©2015. www.fdbhealth.com/policies/drug-pricing-policy.
2. FDA-approved for treatment of psoriasis.
3. Some expert clinicians recommend not exceeding 25 mg/day to avoid adverse effects.
4. FDA-approved for treatment of psoriatic arthritis.
5. The recommended starting dose is 10 mg, which should be titrated over 5 days to 30 mg. The maintenance dosage is 30 mg bid, which should be reduced to
30 mg once/day in patients with severe renal impairment (CrCl <30 mL/min).
6. Not FDA-approved for treatment of psoriasis or psoriatic arthritis.
7. Starting dosage is only recommended for patients with psoriasis.
8. For some patients a dose of 150 mg may be acceptable.
9. A carton containing a 300-mg dose (two 150 mg/mL pens or syringes) costs the same as a carton containing a 150-mg dose (one 150 mg/mL pen or syringe).
10. Dose for psoriasis is 45 mg for patients weighing ≤100 kg, and 90 mg for those weighing >100 kg. Dose for psoriatic arthritis is 45 mg, except in patients
weighing >100 kg with coexistent moderate to severe psoriasis, for whom it is 90 mg.

Pregnancy – Systemic absorption is minimal, but the
drug is contraindicated during pregnancy.
PHOTOTHERAPY — UV phototherapy is used when
psoriasis is widespread or unresponsive to topical
agents. Narrow-band UVB is safer and more effective
than broad-band UVB and has largely replaced it. Oral
or topical psoralens combined with UVA radiation
(PUVA) is also effective for treating psoriasis, but it
increases the risk of skin cancer. Studies comparing
narrow-band UVB with oral or topical PUVA have
not shown that either one is consistently more
effective than the other for treatment of psoriasis.8

The excimer laser has been safe and effective for
localized disease and is FDA-approved for this
indication.9
Adverse Effects – Itching, burning, blistering, stinging,
dryness, and erythema can occur.
Pregnancy – Narrow-band UVB and the excimer laser
are safe for use during pregnancy.1
SYSTEMIC THERAPY — A variety of drugs, including
immunosuppressive agents, retinoids, and biologics,
are used for systemic treatment of psoriasis. The
biologics are the most expensive and appear to
be the most effective, but direct comparisons are
limited.10,11
82

Methotrexate – For control of moderate to severe
psoriasis refractory to topical treatments, low doses
of methotrexate (7.5-25 mg/week) are often used.
Adverse Effects – Nausea and vomiting are common
with methotrexate. Hepatotoxicity is the most
frequent serious adverse effect. Methotrexate is
immunosuppressive and should not be used in
patients with active infections. Methotrexate-induced
pneumonitis is rare, but can be fatal. Macrocytic
anemia, leukopenia, and thrombocytopenia can occur.
Liver function and blood counts should be monitored.
Decreased renal function and inadvertent overdosing
(daily rather than weekly) are common causes of
hematologic toxicity.
Pregnancy – Methotrexate is teratogenic and is

contraindicated during pregnancy; after stopping
it, men should wait at least 3 months and women
should wait one ovulatory cycle before attempting
to conceive.
Cyclosporine – Cyclosporine has been at least as
effective as methotrexate in treating moderate to
severe psoriasis.12,13
Adverse Effects – The doses of cyclosporine used
for psoriasis (2.5-4 mg/kg/day in 2 divided doses)
have generally been safe, but hypertension and


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®

nephrotoxicity can occur. Cyclosporine can also
cause GI disturbances, infection, hirsutism, pruritus,
headache, paresthesias, hypertriglyceridemia, and
musculoskeletal or joint pain. It increases the risk of
skin malignancies in patients previously treated with
PUVA and interacts with many other drugs.
Pregnancy – Cyclosporine appears to be relatively safe
for use during pregnancy, but has been associated
with low birth weight and prematurity.1
Acitretin – Use of acitretin, an oral retinoid, in doses
of 25-50 mg/day can reduce the area and severity of
psoriasis, but with significant hepatic and mucocutaneous toxicity.6 Some expert clinicians recommend
using lower doses (10-25 mg/day) to avoid adverse
effects. Synergism has been reported when acitretin

was combined with UVB radiation or with PUVA.8
Adverse Effects – Like other systemic retinoids,
acitretin frequently causes cheilitis, hair loss, dry skin,
and desquamation. Increases in aminotransferase
levels occur in about one-third of patients; levels
usually return to normal even when treatment is
continued, but symptomatic retinoid hepatitis can
occur and rarely progresses to cirrhosis. Decreased
HDL cholesterol, hypertriglyceridemia, skeletal hyperostosis, conjunctivitis, corneal erosions and opacities,
iritis, and decreased visual acuity can also occur.
Pregnancy – Acitretin is a long-lasting teratogen;
patients should not become pregnant or donate blood
while taking the drug and for at least 3 years after
stopping it.
Phosphodiesterase Type-4 Inhibitor – Apremilast is
approved by the FDA for treatment of adults with
moderate to severe plaque psoriasis who are
candidates for phototherapy or systemic therapy.
In two unpublished, randomized, double-blind trials
(summarized in the package insert) in a total of 1257
adults with moderate to severe plaque psoriasis,
PASI 75 responses (≥75% improvement in Psoriasis
Area and Severity Index scores) occurred after 16
weeks in 33% and 29% of patients taking apremilast
versus 5% and 6% of those taking placebo.
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. Apremilast can

increase the risk of depression. Loss of 5-10% of body
weight has been reported.

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June 8, 2015

Pregnancy – Apremilast is classified as category
C (fetotoxicity in animals; no adequate studies in
women) for use during pregnancy.
BIOLOGIC AGENTS — In patients who have an inadequate response to monotherapy, combining a biologic
agent with traditional systemic therapy or phototherapy
may improve outcomes, but data are limited and the
long-term safety of such combinations is unknown.14
Switching from one biologic agent to another when the
response to the first one is inadequate has been effective
in some patients.15 All of the biologics are classified
as category B (no evidence of toxicity in animals, no
adequate studies in women) for use during pregnancy.
TNF Inhibitors – Three TNF inhibitors, etanercept,
infliximab, and adalimumab are approved for
treatment of psoriasis. One review of randomized,
double-blind, placebo-controlled trials compared their
efficacy for treatment of moderate to severe psoriasis;
the average percentages of patients achieving a PASI
75 response within a 12-week period with infliximab,
adalimumab, and etanercept were 78.6%, 70.5%, and
48.1%, respectively.16
Adverse Effects – Serious infections, including bacterial infections (particularly pneumonitis and cellulitis),
histoplasmosis, and reactivation of tuberculosis and

hepatitis B virus, have been reported with all the TNF
inhibitors, particularly in the first 2-7 months of treatment.17 These drugs should not be given to patients
with active localized or chronic infections. Screening
for exposure to tuberculosis is recommended before
starting anti-TNF therapy and annually thereafter.
Lymphoma and other malignancies have been reported
in patients with rheumatoid arthritis receiving these
drugs, but a cause-and-effect relationship has not
been established. They generally should not be used
in patients with a recent malignancy. Exacerbations
and new onset of heart failure, pancytopenia, and
demyelinating disorders such as multiple sclerosis
have been reported.18 Anti-TNF drugs have been
associated with development of autoantibodies and the
induction of a lupus-like syndrome. A review of clinical
studies found that autoantibodies reduced the efficacy
of infliximab and adalimumab, but not of etanercept.19
IL-12/23 Antagonist – Ustekinumab is a human
monoclonal antibody against interleukins 12 and 23.20
In a randomized, double-blind trial in 1230 adults
with moderate to severe psoriasis, PASI 75 responses
occurred in 66.7% of patients receiving ustekinumab
45 mg, in 75.7% of those receiving ustekinumab
90 mg, and in 3.7% receiving placebo.21 A randomized
83


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trial comparing ustekinumab (45 or 90 mg at weeks
0 and 4) with etanercept (50 mg twice weekly) in 903
patients with moderate to severe psoriasis found that
more patients treated with ustekinumab achieved
a PASI 75 response at week 12 (67.5% and 73.8% vs
56.8%).22 Ustekinumab has been effective in patients
with an inadequate response to methotrexate.23
Adverse Effects – Ustekinumab has been associated
with serious infections (especially tuberculosis),
malignancies, hypersensitivity reactions, and reversible posterior leukoencephalopathy. Screening for
tuberculosis is recommended before treatment.
Autoantibodies have developed; whether they reduce
treatment response remains to be determined.19
IL-17A Inhibitor – Secukinumab, an injectable human
interleukin-17A antagonist, is approved by the FDA
for treatment of moderate to severe plaque psoriasis
in adults who are candidates for systemic therapy or
phototherapy.24 In four double-blind trials in adults with
moderate to severe plaque psoriasis, secukinumab
150 mg or 300 mg was significantly more effective
than placebo after 12 weeks of treatment in achieving
a PASI 75 response (67-87% vs 0-5%). Both doses
of secukinumab were also superior to etanercept
(44%), which was included in one study as an active
control.25-27 Secukinumab was more effective than
ustekinumab for treatment of moderate to severe
psoriasis in an unpublished, randomized, double-blind
trial (PASI 90 response at week 16: 79.0% vs 57.6%).28
Adverse Effects – The most common adverse effects

of secukinumab in clinical trials were nasopharyngitis,
diarrhea, and upper respiratory infection. Serious
infections occurred in 1.2% of patients treated with
the drug. Patients should be screened for tuberculosis
before starting therapy. Crohn’s disease exacerbations,
urticaria, and anaphylaxis have been reported with
secukinumab.
INVESTIGATIONAL DRUG — Tofacitinib (Xeljanz), an
oral Janus kinase (JAK) inhibitor approved for use
in rheumatoid arthritis,29 has also been effective in
clinical trials in patients with psoriasis.30 ■
1. MB Hoffman et al. Psoriasis during pregnancy: characteristics
and important management recommendations. Expert Rev Clin
Immunol 2015; 11:709.
2. Calcipotriene for psoriasis. Med Lett Drugs Ther 1994; 36:70.
3. A betamethasone-calcipotriene combination for psoriasis. Med
Lett Drugs Ther 2006; 48:55.
4. Calcitriol (Vectical) for mild to moderate plaque psoriasis. Med
Lett Drugs Ther 2009; 51:70.
5. W Abramovits. Calcitriol 3 microg/g ointment: an effective and
safe addition to the armamentarium in topical psoriasis therapy. J Drugs Dermatol 2009; 8(8 Suppl):s17.

84

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June 8, 2015

6. Two new retinoids for psoriasis. Med Lett Drugs Ther 1997; 39:105.
7. A Menter et al. Guidelines of care for the management of psoriasis and psoriatic arthritis. Section 3. Guidelines of care for the

management and treatment of psoriasis with topical therapies.
J Am Acad Dermatol 2009; 60:643.
8. X Chen et al. Narrow-band ultraviolet B phototherapy versus broadband ultraviolet B or psoralen-ultraviolet A photochemotherapy for
psoriasis. Cochrane Database Syst Rev 2013; 10:CD009481.
9. MB Totonchy and MW Chiu. UV-based therapy. Dermatol Clin
2014; 32:399.
10. S Lee et al. Biologic and nonbiologic systemic agents and phototherapy for treatment of chronic plaque psoriasis [Internet].
AHRQ Comparative Effectiveness Reviews 2012 Nov. Report
No.12(13)-EHC144-EF.
11. J Schmitt et al. Efficacy and safety of systemic treatments for
moderate-to-severe psoriasis: meta-analysis of randomized
controlled trials. Br J Dermatol 2014; 170:274.
12. VM Heydendael et al. Methotrexate versus cyclosporine in
moderate-to-severe chronic plaque psoriasis. N Engl J Med
2003; 349:658.
13. I Flyström et al. Methotrexate vs. ciclosporin in psoriasis: effectiveness, quality of life and safety. A randomized controlled
trial. Br J Dermatol 2008; 158;116.
14. JC Cather and JJ Crowley. Use of biologic agents in combination with other therapies for the treatment of psoriasis. Am J
Clin Dermatol 2014; 15:467.
15. P Sator et al. Adalimumab in the treatment of moderate-to-severe chronic plaque psoriasis in patients switching from other
biologics. J Eur Acad Dermatol Venereol 2015 February 9 (epub).
16. IH Kim et al. Comparative efficacy of biologics in psoriasis: a
review. Am J Clin Dermatol 2012; 13:365.
17. RE Kalb et al. Risk of serious infection with biologic and systemic treatment of psoriasis: results from the psoriasis longitudinal assessment and regiatryy (PSOLAR). JAMA Dermatol
2015 May 13 (epub).
18. AL Semble et al. Safety and tolerability of tumor necrosis
factor- inhibitors in psoriasis: a narrative review. Am J Clin
Dermatol 2014; 15:37.
19. L Hsu et al. Antidrug antibodies in psoriasis: a systematic review. Br J Dermatol 2014; 170:261.
20. Ustekinumab (Stelara) for psoriasis. Med Lett Drugs Ther 2010;

52:7.
21. KA Papp et al. Efficacy and safety of ustekinumab, a human
interleukin-12/23 monoclonal antibody, in patients with psoriasis: 52-week results from a randomised, double-blind, placebocontrolled trial (PHOENIX 2). Lancet 2008; 371:1675.
22. CE Griffiths et al. Comparison of ustekinumab and etanercept
for moderate-to-severe psoriasis. N Engl J Med 2010; 362:118.
23. C Paul et al. Transition to ustekinumab in patients with moderateto-severe psoriasis and inadequate response to methotrexate: a
randomized clinical trial (TRANSIT). Br J Dermatol 2014; 170:425.
24. Secukinumab (Cosentyx) for psoriasis. Med Lett Drugs Ther
2015; 57:45.
25. A Blauvelt et al. Secukinumab administration by pre-filled syringe:
efficacy, safety and usability results from a randomized controlled
trial in psoriasis (FEATURE). Br J Dermatol 2015; 172:484.
26. C Paul et al. Efficacy, safety and usability of secukinumab administration by autoinjector/pen in psoriasis: a randomized, controlled
trial (JUNCTURE). J Eur Acad Dermatol Venereol 2015; 29:1082.
27. RG Langley et al. Secukinumab in plaque psoriasis – results of
two phase 3 trials. N Engl J Med 2014; 371:326.
28. D Thaci et al. Secukinumab is superior to ustekinumab in clearing skin of subjects with moderate to severe plaque psoriasis:
16 week results from the CLEAR study. Presented at American
Academy of Dermatology 73rd Annual Meeting. San Francisco,
CA, March 20, 2015.
29. Tofacitinib (Xeljanz) for rheumatoid arthritis. Med Lett Drugs
Ther 2013; 55:1.
30. A Chiricozzi et al. Tofacitinib for the treatment of moderate-tosevere psoriasis. Expert Rev Clin Immunol 2015; 11:443.


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Nivolumab (Opdivo) for Metastatic
Melanoma and Metastatic NSCLC
Note: An addendum to this article has been published

The FDA has approved nivolumab (Opdivo – BMS),
an IV programmed death receptor-1 (PD-1) blocking
antibody, for treatment of unresectable or metastatic
melanoma that has progressed following treatment
with ipilimumab (and a BRAF inhibitor in patients who
are BRAF V600 mutation positive) and for treatment
of metastatic squamous non-small cell lung cancer
(NSCLC) that has progressed on or after platinumbased chemotherapy. It is the second PD-1 inhibitor to
be marketed in the US after pembrolizumab (Keytruda),1
and the first to be approved for treatment of NSCLC.
Pronunciation Key
Nivolumab: ni voe' loo mab"
Opdivo: op dee' voe

STANDARD TREATMENT — Metastatic melanoma –
High-dose interleukin-2 (aldesleukin – Proleukin) has
produced responses in 15-20% of patients with
metastatic melanoma, but its use has been limited
by severe toxicity and cumbersome administration
requiring hospitalization for treatment. The antiCTLA4 monoclonal antibody ipilimumab (Yervoy)

June 8, 2015

has produced response rates similar to those
with high-dose interleukin-2, with 20-26% of
patients surviving beyond 3 years.2,3 Recently,
pembrolizumab has produced a higher response rate
and longer progression-free and overall survival than
ipilimumab.4 A panel of experts has recommended
that pembrolizumab should be considered a first-line
option for treatment of metastatic melanoma.5
Dabrafenib (Tafinlar), vemurafenib (Zelboraf), and
trametinib (Mekinist) are kinase inhibitors used for
treatment of metastatic melanoma with BRAF V600
mutations, which are found in about 50% of melanomas.6,7
Metastatic Squamous NSCLC – Patients with
metastatic squamous NSCLC and a good performance
status usually receive platinum doublet therapy (a twodrug regimen that includes a platinum derivative such
as cisplatin or carboplatin). For those with refractory
disease, erlotinib (Tarceva), docetaxel (Taxotere) with
or without ramucirumab (Cyramza), or gemcitabine
(Gemzar) may be used; median overall survival in
these patients is less than 1 year.8
MECHANISM OF ACTION — The programmed death
receptor-1 (PD-1) is an inhibitory receptor expressed

Table 1. Some Drugs for Metastatic Melanoma
Drug
Nivolumab –
Opdivo (BMS)

Class
Programmed death

receptor-1 (PD-1)
inhibitor

Indication1
Disease progression
after ipilimumab and,
if BRAF V600 mutation
positive, a BRAF inhibitor

Pembrolizumab –
Keytruda (Merck)

Programmed death
receptor-1 (PD-1)
inhibitor

Ipilimumab –
Yervoy (BMS)

Cytotoxic T-lymphocyteassociated antigen 4
(CTLA4) blocker

Dabrafenib –
Tafinlar (GSK)

BRAF kinase inhibitor

Disease progression
after ipilimumab and,
if BRAF V600 mutation

positive, a BRAF inhibitor
Melanoma regardless of
BRAF mutation status,
before or after other
therapies
Melanoma with BRAF
V600E mutation5,6

Vemurafenib –
Zelboraf (Genentech)
Trametinib –
Mekinist (GSK)

BRAF kinase inhibitor
MEK kinase inhibitor

Melanoma with BRAF
V600E mutation
Melanoma with BRAF
V600E or V600K
mutations6,10

Efficacy
OS rate (1 yr estimated):
72.9% vs 42.1% with
dacarbazine
PFS: 5.1 mos vs 2.2 mos
with dacarbazine3
OS rate (1 yr estimated):
68.4%

PFS: 4.1 mos4

Usual Dosage
3 mg/kg IV
q2 wks

Cost2
$20,143.20

2 mg/kg IV
q3 wks

25,896.00

OS rate (1 yr estimated):
58.2%
PFS: 2.8 mos4

3 mg/kg IV
q3 wks x 4
doses

131,213.20

PFS: 5.1 mos vs 2.7 mos
with dacarbazine7

150 mg PO
bid8

26,393.90

PFS: 5.3 mos vs 1.6 mos
with dacarbazine9
PFS: 4.8 mos vs 1.5 mos
with dacarbazine or
paclitaxel11

960 mg (4 tabs) 32,552.40
PO bid
2 mg PO once/d 30,214.00

OS = overall survival, PFS = progression-free survival
1. FDA-approved for use in patients with unresectable or metastatic melanoma.
2. Approximate WAC for 12 weeks' treatment for IV drugs and for 3 months' treatment for oral drugs for a patient weighing 70 kg. Cost of administration not
included. 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. May 5, 2015. Reprinted with permission by First Databank, Inc. All rights reserved.
©2015. www.fdbhealth.com/policies/drug-pricing-policy.
3. Efficacy data in previously untreated patients (C Robert et al. N Engl J Med 2015; 372:320).
4. C Robert et al. N Engl J Med 2015 April 19 (epub).
5. Not indicated for treatment of patients with wild-type BRAF (BRAF-negative) melanoma.
6. The combination of dabrafenib and trametinib is FDA-approved for treatment of BRAF V600E or V600K mutation-positive unresectable or metastatic melanoma.
7. A Hauschild et al. Lancet 2012; 380:358.
8. Taken at least 1 hour before or at least 2 hours after a meal.
9. PB Chapman et al. N Engl J Med 2011; 364:2507.
10. Trametinib monotherapy is not recomended for patients who have previously been treated with a BRAF inhibitor.
11. KT Flaherty et al. N Engl J Med 2012; 367:107.

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June 8, 2015

Table 2. Some Drugs for Squamous NSCLC that Progressed on or after Platinum-Based Therapy1
Drug

Class

Usual Dosage

Cost2

Nivolumab – Opdivo (BMS)

Programmed death receptor-1
(PD-1) inhibitor

3 mg/kg IV q2 wks

$20,143.20

Taxane

75 mg/m2 IV q3 wks

13,814.20

Ramucirumab – Cyramza (Lilly)

VEGF receptor 2 antagonist

10 mg/kg IV before docetaxel infusion q3 wks

28,560.00

Erlotinib – Tarceva (OSI)4

EGFR inhibitor

150 mg PO once/d

20,127.005

Cytidine analog

1000 mg/m IV on days 1, 8, and 15 q4 wks
OR 1250 mg/m2 IV on days 1 and 8 q3 wks

10,669.70
11,855.20

Docetaxel – Taxotere (Sanofi)
3

Gemcitabine – Gemzar (Lilly)

6

2

VEGF = vascular endothelial growth factor; EGFR = epidermal growth factor receptor
1. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) Non-Small Cell Lung Cancer. Version 6. 2015.
Available at www.nccn.org. Accessed May 28, 2015.
2. Approximate WAC for 12 weeks’ treatment at the usual dosage for a patient with weight of 70 kg or body surface area of 1.6 m2. Cost of administration
not included. 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. May 5, 2015. Reprinted with permission by First Databank, Inc. All rights
reserved. ©2015. www.fdbhealth.com/policies/drug-pricing-policy.
3. Used only in combination with docetaxel.
4. Proteomic testing is recommended in patients with NSCLC and wild-type EGFR or with unknown EGFR status. Patients with “poor” classification should not
receive erlotinib (V Gregorc et al. Lancet Oncol 2014; 15:713).
5. Cost of a 90-day supply.
6. Not FDA-approved for this indication.

by T-cells during long-term antigen exposure, such as
occurs in chronic viral infections or cancer.9 Nivolumab binds to the receptor, blocking the interaction
with its ligands and promoting antitumor immune
responses. In animal models, blockade of the PD-1
pathway has decreased tumor growth.
CLINICAL STUDIES — Melanoma – Approval of
nivolumab was based on an open-label trial in 405
patients with unresectable stage IIIC or IV melanoma
that had progressed after being previously treated with
ipilimumab (and a BRAF inhibitor in those who were
BRAF V600 mutation-positive) who were randomized to

receive nivolumab or chemotherapy (either dacarbazine,
or paclitaxel plus carboplatin) until disease progression
or unacceptable toxicity occurred. In a prespecified
interim analysis that included 167 patients followed for
at least 6 months (120 of whom had received nivolumab),
the objective response rate was 31.7% with nivolumab
and 10.6% with chemotherapy.10
In a double-blind trial, 418 adults with unresectable,
previously untreated stage III or IV melanoma without a
BRAF mutation were randomized to receive nivolumab or
dacarbazine until disease progression or unacceptable
toxicity occurred. Nivolumab improved overall survival,
the primary endpoint, by 58% compared to dacarbazine;
1-year survival rates were 72.9% with nivolumab
and 42.1% with dacarbazine. Median progressionfree survival was 5.1 months with nivolumab and 2.2
months with dacarbazine. Patients taking nivolumab
were more likely to have an objective response (40.0%
vs 13.9%) and a complete response (7.6% vs 1.0%).11
Another study compared dual therapy with nivolumab
and ipilimumab to ipilimumab alone in 142 patients
86

with previously untreated stage III or IV melanoma.
Combination therapy was significantly more likely to
induce an objective response than ipilimumab alone
among patients with BRAF wild-type tumors (61% vs
11%). Patients with BRAF mutation-positive tumors
were also more likely to have an objective response
with combination therapy (52% vs 10%). A complete
response occurred in 22% of patients receiving

combination therapy and in no patients receiving
monotherapy.12
NSCLC – In a single-arm trial, 117 patients with stage
IIIB or IV squamous NSCLC previously treated with at
least 2 systemic regimens including platinum doubletbased chemotherapy received nivolumab until disease
progression or unacceptable toxicity occurred. An
objective response occurred in 14.5% of patients.
Median overall survival was 8.2 months, and the
1-year survival rate was 40.8%.13
In an open-label study, 272 patients with metastatic
squamous NSCLC previously treated with one platinum
doublet-based regimen were randomized to receive
nivolumab or docetaxel until disease progression or
unacceptable toxicity occurred. A prespecified interim
analysis found that nivolumab significantly improved
overall survival, the primary endpoint, by 41% compared
to docetaxel (median 9.2 vs 6.0 months).14
ADVERSE EFFECTS – Immune-mediated adverse
effects, including pneumonitis, colitis, hepatitis,
nephritis, and thyroid dysfunction, have occurred in
patients taking nivolumab. Some reactions have been
severe, and fatal pneumonitis has been reported. Liver
enzyme elevations, hyponatremia, and hyperkalemia
are common and can be severe. In the single-arm


The Medical Letter

®

NSCLC trial, severe (grade 3/4) dyspnea, fatigue, and
musculoskeletal pain each occurred in ≥5% of patients.
Less serious adverse effects occurring in ≥20% of
patients have included cough, decreased appetite,
nausea, constipation, and rash.
In the study evaluating dual use of nivolumab and
ipilimumab for metastatic melanoma, 54% of patients
taking the two drugs experienced at least one grade
3/4 adverse effect, and 47% discontinued treatment
because of an adverse effect. Three treatment-related
fatalities occurred.12
PREGNANCY – Nivolumab has caused fetal harm in
animal studies. Women who could become pregnant
should use effective contraception while taking the
drug and for at least 5 months after stopping it.
DOSAGE AND ADMINISTRATION – Nivolumab solution
is available in 40 mg/4 mL and 100 mg/10 mL singleuse vials. The recommended dosage is 3 mg/kg infused
intravenously over 60 minutes every 2 weeks until
disease progression or unacceptable toxicity occurs.
CONCLUSION — Nivolumab (Opdivo), like pembrolizumab (Keytruda), appears to increase response
rates and survival more than ipilimumab (Yervoy) and
should be considered an option for first-line treatment
of metastatic melanoma. Nivolumab also improved
survival rates in patients with metastatic squamous
non-small cell lung cancer (NSCLC) refractory to
platinum doublet-based chemotherapy. ■
1. Pembrolizumab (Keytruda) for metastatic melanoma. Med Lett
Drugs Ther 2014; 56:e114.
2. Ipilimumab (Yervoy) for metastatic melanoma. Med Lett Drugs
Ther 2011; 53:51.

3. D Schadendorf et al. Pooled analysis of long-term survival data
from phase II and phase III trials of ipilimumab in unresectable
or metastatic melanoma. J Clin Oncol 2015 February 9 (epub).
4. C Robert et al. Pembrolizumab versus ipilimumab in advanced
melanoma. N Engl J Med 2015 April 19 (epub).
5. National Comprehensive Cancer Network. NCCN Clinical Practice
Guidelines in Oncology (NCCN Guidelines) Melanoma. Version 3.
2015. Available at www.nccn.org. Accessed May 28, 2015.
6. Vemurafenib (Zelboraf) for metastatic melanoma. Med Lett
Drugs Ther 2011; 53:77.
7. Dabrafenib (Tafinlar) and trametinib (Mekinist) for metastatic
melanoma. Med Lett Drugs Ther 2013; 55:62.
8. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) Non-Small Cell
Lung Cancer. Version 6. 2015. Available at www.nccn.org. Accessed May 28, 2015.
9. DM Pardoll. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 2012; 12:252.
10. JS Weber et al. Nivolumab versus chemotherapy in patients
with advanced melanoma who progressed after anti-CTLA-4
treatment (CheckMate 037): a randomised, controlled, openlabel, phase 3 trial. Lancet Oncol 2015; 16:375.
11. C Robert et al. Nivolumab in previously untreated melanoma
without BRAF mutation. N Engl J Med 2015; 372:320.

Vol. 57 (1470)

June 8, 2015

12. MA Postow et al. Nivolumab and ipilimumab versus ipilimumab
in untreated melanoma. N Engl J Med 2015; 372:2006.
13. NA Rizvi et al. Activity and safety of nivolumab, an anti-PD-1
immune checkpoint inhibitor, for patients with advanced, refractory squamous non-small-cell lung cancer (CheckMate
063): a phase 2, single-arm trial. Lancet Oncol 2015; 16:257.

14. J Brahmer et al. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med 2015; 373: 123.

▶

Recombinant Human Parathyroid
Hormone (Natpara)

The FDA has approved a subcutaneously injected
formulation of recombinant human parathyroid
hormone (Natpara – NPS) as an adjunct to calcium
and vitamin D to control hypocalcemia in adults
with hypoparathyroidism. Natpara is an 84-amino
acid single-chain polypeptide identical to native
parathyroid hormone. It is the first parathyroid hormone formulation to be approved for this indication.
Pronunciation Key
Natpara: nat pa' ruh

PARATHYROID HORMONE — Secreted in response
to low serum calcium, parathyroid hormone binds
to PTH-1 receptors both in bone, causing release of
calcium into blood, and in the kidneys, increasing
tubular reabsorption of calcium and conversion of
vitamin D to its most active form.1
TREATMENT OF HYPOPARATHYROIDISM — Hypocalcemia caused by hypoparathyroidism is usually
managed with oral calcium and vitamin D. Patients
typically require at least 1-2 g/day of elemental
calcium in ≥3 divided doses to maintain serum
calcium levels in the low-normal range, which is the
goal for patients with hypoparathyroidism. Calcium
carbonate is often used because it is inexpensive and

can reduce hyperphosphatemia by binding phosphate
in the gut, but it requires an acidic pH for absorption
and must be taken with food. Calcium citrate is an
option for patients with achlorhydria, such as the
elderly and those taking a proton pump inhibitor.
Calcitriol, a synthetic form of the active metabolite
of vitamin D3, is preferred over other vitamin D
formulations (vitamin D2 and D3) because it does not
require parathyroid hormone for activation and has a
rapid onset of action and a short half-life.
Low-sodium diets and thiazide diuretics can reduce
the risk of nephrolithiasis caused by hypercalciuria,
which often occurs when hypocalcemia is corrected in
patients with hypoparathyroidism.2
CLINICAL STUDY — In a 24-week, double-blind trial
(REPLACE), 134 patients with hypoparathyroidism were
randomized to receive subcutaneous recombinant
87


The Medical Letter

human parathyroid hormone or placebo once daily. The
primary composite endpoint (≥50% reduction in vitamin
D and calcium doses and maintenance of serum
calcium between the baseline value and the upper limit
of normal) was achieved in 53% of patients receiving
the active drug and in 2% of those receiving placebo.3
ADVERSE EFFECTS — Hypo- and hypercalcemia occur
commonly with use of recombinant human parathyroid

hormone. Other adverse effects occurring in ≥10% of
patients in the clinical trial and more frequently than
with placebo included paresthesia, hypoesthesia,
headache, nausea, diarrhea, vomiting, arthralgia, and
extremity pain.
Osteosarcoma has occurred in rats with parathyroid
hormone levels 3-71 times those occurring in humans
receiving 100 mcg daily. Because of this potential risk,
the package insert states that Natpara should only be
used in patients who cannot be well controlled with
calcium and active forms of vitamin D alone. As part
of a risk evaluation and mitigation strategy (REMS)
program, the FDA has required that prescribers
and pharmacies be certified before prescribing or
dispensing the drug, and that patients and prescribers
sign a form before starting treatment acknowledging
that the risk of osteosarcoma was discussed.
PREGNANCY — Natpara is classified as category C
(developmental effects and fetal death in animals; no
adequate studies in women) for use during pregnancy.
DRUG INTERACTIONS — Coadministration of the
bisphosphonate alendronate can reduce the effectiveness of Natpara and is not recommended; other
bisphosphonates may have a similar effect. Hypocalcemia could reduce the efficacy of digoxin, and
hypercalcemia caused by Natpara could increase the
risk of digitalis toxicity.
DOSAGE, ADMINISTRATION, AND COST — The starting
dosage of Natpara is 50 mcg injected subcutaneously
in alternating thighs once daily. Treatment should not
be started unless serum calcium is >7.5 mg/dL and the
25(OH) vitamin D level is within normal limits. Once therapy is started, the daily dose of active vitamin D should

be reduced by half. Serum calcium should be measured
every 3-7 days after starting treatment, and daily doses
of vitamin D and calcium should be adjusted according
to the recommendations in Table 1.
If serum calcium cannot be maintained above 8 mg/dL
without vitamin D and/or calcium supplementation, the
daily Natpara dose may be increased by 25 mcg every 4
weeks to a maximum of 100 mcg. If serum calcium is re88

Vol. 57 (1470)

®

June 8, 2015

Table 1. Active Vitamin D and Calcium Dose Adjustments
with Natpara
Serum Calcium1
>10.6 mg/dL
>9 and
≤10.6 mg/dL
≥8 and
≤9 mg/dL
<8 mg/dL
1.

2.

Adjust First

Adjust Second

Active Vitamin D
Decrease
or discontinue2
Decrease
or discontinue2

Calcium Supplement
Decrease

No change

No change or decrease
if active vitamin D
has been discontinued
No change

Increase

Increase

Corrected for serum albumin levels. Should be measured every 3-7 days
until levels are within lower half of normal range, active vitamin D has been
discontinued, and calcium supplementation is sufficient to meet daily
requirements.
Discontinue in patients receiving the lowest available dose.

peatedly above 9 mg/dL after active vitamin D has been
discontinued and calcium supplementation has been decreased to a dose sufficient to meet daily requirements,

the dose of Natpara should be decreased to 25 mcg/day.
Natpara powder is supplied in a glass cartridge and
must be reconstituted with the enclosed diluent in
the provided reusable mixing device before use. Each
cartridge contains 14 doses. Cartridges should be
refrigerated before and during use, and discarded 14
days after reconstitution. The drug is injected via a
reusable pen injector. A 47-step guide describes how
to prepare, mix, and administer the drug. Patients
starting treatment receive complimentary visits
from a nurse educator to help them reconstitute and
administer the first two doses. A 4-week supply of
Natpara costs $7916.70.4
CONCLUSION — Use of recombinant human parathyroid
hormone (Natpara) can decrease calcium and vitamin
D dosage requirements in patients with hypocalcemia
caused by hypoparathyroidism, but it is expensive and
administration may be difficult. Osteosarcoma has
occurred in animals treated with parathyroid hormone.
Treatment with Natpara should be restricted to patients
whose serum calcium levels cannot be controlled with
calcium and active vitamin D alone. ■
1. V De Sanctis et al. Hypoparathyroidism: from diagnosis to
treatment. Curr Opin Endocrinol Diabetes Obes 2012; 19:435.
2. D Shoback. Clinical practice. Hypoparathyroidism. N Engl J
Med 2008; 359:391.
3. M Mannstadt et al. Efficacy and safety of recombinant human
parathyroid hormone (1-84) in hypoparathyroidism (REPLACE):
a double-blind, placebo-controlled, randomised, phase 3 study.
Lancet Diabetes Endocrinol 2013; 1:275.

4. Approximate WAC. Cost of administration not included. 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. May 5, 2015. Reprinted with
permission by First Databank, Inc. All rights reserved. ©2015.
www.fdbhealth.com/policies/drug-pricing-policy.


The Medical Letter publications are protected by US and international copyright laws.
Forwarding, copying or any other distribution of this material is strictly prohibited.
For further information call: 800-211-2769

The Medical Letter

®

on Drugs and Therapeutics
Objective Drug Reviews Since 1959

Volume 57

ISSUE

ISSUE No.

1433
1470

June 8, 2015

ALSO IN THIS ISSUE

Drugs for Psoriatic Arthritis .........................................................................................online only

Volume 56

▶

Drugs for Psoriatic Arthritis
Related article(s) since publication

Psoriatic arthritis is a chronic inflammatory arthropathy that develops in up to 40% of patients with
psoriasis. Several guidelines for treatment of psoriatic
arthritis have been published.1-4
NSAIDs
Nonselective NSAIDs can improve symptoms in
patients with mild disease. The selective cyclooxygenase-2 (COX-2) inhibitor celecoxib (Celebrex,
and generics) may also be effective; one randomized,
double-blind, 12-week trial in patients with a
psoriatic arthritis flare found that ACR20 response
rates (20% improvement on the American College of
Rheumatology scale) with celecoxib 200 or 400 mg
daily were superior to those with placebo at week 2,
but there was no difference between the groups at
week 12.5
Adverse Effects – Worsening of skin disease has
been reported when NSAIDs were started in patients
with psoriatic arthritis. Nonselective NSAIDs can
interfere with platelet function and prolong bleeding
time. Dyspepsia and GI ulceration, perforation, and

bleeding can occur. Celecoxib does not affect platelets
significantly and is less likely than nonselective
NSAIDs to cause GI toxicity. All NSAIDs inhibit renal
prostaglandins, decrease renal blood flow, cause fluid
retention, and may cause hypertension and renal
failure in some patients. An increased risk of serious
cardiovascular events has been reported with some
NSAIDs; the risk appears to be highest with diclofenac
(Voltaren-XR, and others) and lowest with naproxen
(Aleve, and others).

Table 1. Choice of Drugs for Psoriatic Arthritis

▶ NSAIDs or intra-articular injections of corticosteroids
can relieve the symptoms of mild psoriatic arthritis.

▶ First-line treatment options for moderate to severe
disease include methotrexate, a TNF inhibitor, or a
combination of methotrexate and a TNF inhibitor.

▶ Ustekinumab

and apremilast are additional
alternatives, but they have had lower response rates
than TNF inhibitors; direct comparisons are lacking.

CORTICOSTEROIDS
When only a few joints are involved, intra-articular
injections of corticosteroids may provide symptomatic
relief. Low doses (5-10 mg/day) of systemic

corticosteroids have also been used.2
Adverse Effects – Corticosteroids can cause fluid
retention, increased risk of infection, osteoporosis,
osteonecrosis, cataracts, glaucoma, impaired skin
healing, acne, insomnia, mood disorders, Cushing’s
syndrome, hyperglycemia, and adrenal suppression.
DMARDs
In patients with rheumatoid arthritis, diseasemodifying anti-rheumatic drugs (DMARDs) can control
symptoms and have been shown to delay and possibly
stop progression of the disease. Although they have
not been shown to prevent progression of joint damage
in patients with psoriatic arthritis, they are generally
recommended for first-line treatment of moderate to
severe disease. DMARDs are not approved by the FDA
for use in psoriatic arthritis.
METHOTREXATE – Methotrexate is the most widely
used DMARD for treatment of psoriatic arthritis.
Observational studies have reported beneficial clinical

e88

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


The Medical Letter

Vol. 57 (1470)

®

June 8, 2015

Table 2. Some Systemic Drugs for Psoriasis and/or Psoriatic Arthritis
Drug

Usual Adult Dosage

Cost1

Acitretin – Soriatane (Stiefel)2
Apremilast – Otezla (Celgene)2,4
Cyclosporine2 – generic
Neoral (Novartis)
Leflunomide6 – generic
Arava (Sanofi)
Methotrexate2 – generic
Sulfasalazine6 – generic
Azulfidine (Pfizer)
enteric coated – generic
Azulfidine EN-tabs
Biologics
Adalimumab – Humira (Abbvie)2,4
Certolizumab pegol – Cimzia (UCB)4
Etanercept – Enbrel (Amgen)2,4
Golimumab – Simponi (Centocor)4
Infliximab – Remicade (Janssen)2,4
Secukinumab – Cosentyx (Novartis)2
Ustekinumab – Stelara (Janssen)2,4

10-50 mg PO once/day3

30 mg PO bid5
2.5-4 mg/kg/day PO in 2 divided doses

$2778.40
5662.10
957.60
1091.80
182.30
3284.70
75.60
62.70
299.10
87.00
390.70

10-20 mg PO once/day
7.5-25 mg/week PO in a single dose or in 3 divided doses over 36 hours
2-3 g/day PO in divided doses

80 mg SC x 1,7 then 40 mg q2 weeks
400 mg SC at 0, 2, and 4 weeks, then 200 mg q2 weeks or 400 mg q4 weeks
50 mg SC twice/week x 12 weeks,7 then once/week
50 mg SC once/month
5 mg/kg IV at 0, 2, and 6 weeks, then q8 weeks
300 mg8 SC at 0, 1, 2, 3, and 4 weeks, then q4 weeks
45 mg10 SC at 0 and 4 weeks, then q12 weeks

9606.30
9129.90
9607.90

9821.50
5842.30
10,260.009
7661.20

1. Approximate WAC for 12 weeks’ treatment at the lowest usual adult maintenance dosage (cyclosporine and infliximab cost calculated for a patient weighing
80 kg). 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. May 5, 2015. Reprinted with permission by First Databank, Inc. All rights reserved.
©2015. www.fdbhealth.com/policies/drug-pricing-policy.
2. FDA-approved for treatment of psoriasis.
3. Some expert clinicians recommend not exceeding 25 mg/day to avoid adverse effects.
4. FDA-approved for treatment of psoriatic arthritis.
5. The recommended starting dose is 10 mg, which should be titrated over 5 days to 30 mg. The maintenance dosage is 30 mg bid, which should be reduced to
30 mg once/day in patients with severe renal impairment (CrCl <30 mL/min).
6. Not FDA-approved for treatment of psoriasis or psoriatic arthritis.
7. Starting dosage is only recommended for patients with psoriasis.
8. For some patients a dose of 150 mg may be acceptable.
9. A carton containing a 300-mg dose (two 150 mg/mL pens or syringes) costs the same as a carton containing a 150-mg dose (one 150 mg/mL pen or syringe).
10. Dose for psoriasis is 45 mg for patients weighing ≤100 kg, and 90 mg for those weighing >100 kg. Dose for psoriatic arthritis is 45 mg, except in patients
weighing >100 kg with coexistent moderate to severe psoriasis, for whom it is 90 mg.

effects, but evidence from controlled clinical trials
is limited.6 One randomized, double-blind, 6-month
trial in 221 patients with active psoriatic arthritis
found that physician and patient global assessment
scores improved significantly with methotrexate
(target dose 15 mg/week), but the drug did not have
a significant effect on ACR20 response rates, psoriatic
arthritis response criteria (PsARC), measures of joint
inflammation, or pain compared to placebo.7

Adverse Effects – Nausea and vomiting are common
with methotrexate. Hepatotoxicity is the most
frequent serious adverse effect. Methotrexate is
immunosuppressive and should not be used in
patients with active infections. Methotrexate-induced
pneumonitis is rare, but can be fatal. Macrocytic
anemia, leukopenia, and thrombocytopenia can occur.
Liver function and blood counts should be monitored.
Decreased renal function and inadvertent overdosing
(daily rather than weekly) are common causes of
hematologic toxicity.
Pregnancy – Methotrexate is teratogenic and is
contraindicated during pregnancy; after stopping
it, men should wait a minimum of 3 months and
women should wait at least one ovulatory cycle before
attempting to conceive.
e89

LEFLUNOMIDE – An oral inhibitor of pyrimidine synthesis, leflunomide is often used for treatment of psoriatic
arthritis in patients who have not responded to
methotrexate or cannot tolerate it. In a randomized,
double-blind, 24-week trial in 190 patients with active
psoriatic arthritis, the PsARC response rate was 59%
with leflunomide (100 mg/day loading dose for 3 days
followed by 20 mg/day) compared to 30% with placebo.8
An observational study in 514 patients with active
psoriatic arthritis treated with leflunomide found that 86%
achieved a PsARC response after 24 weeks of treatment.9
Adverse Effects – Diarrhea occurs frequently with
leflunomide. Reversible alopecia, rash, hypertension,

myelosuppression, and aminotransferase elevations
have also been reported. Anaphylaxis, StevensJohnson syndrome, weight loss, interstitial lung
disease, peripheral neuropathy, and leukocytoclastic
vasculitis have occurred rarely.
Pregnancy – Leflunomide is contraindicated for use
during pregnancy.
SULFASALAZINE – In clinical studies in patients with
psoriatic arthritis, sulfasalazine has produced modest
improvements in symptoms.10 The beneficial effects
may not become apparent for 2-3 months after starting treatment.


The Medical Letter

®

Adverse Effects – Sulfasalazine frequently causes GI
disturbances. Leukopenia, agranulocytosis, reversible
oligospermia, a lupus-like syndrome, and hepatotoxicity have been reported.
Pregnancy – Sulfasalazine is classified as category
B (no evidence of toxicity in animals; no adequate
studies in women) for use during pregnancy.
CYCLOSPORINE — Use of cyclosporine has resulted
in modest improvements in pain and other symptoms
in small, open-label studies in patients with psoriatic
arthritis.10 In a 12-month, randomized, double-blind,
placebo-controlled trial in psoriatic arthritis patients
with an incomplete response to methotrexate, addition
of cyclosporine (2.5-4 mg/kg/day) significantly reduced
signs of joint inflammation.11 It is recommended only

for short-term use (up to 12 months).
Adverse Effects – The doses of cyclosporine used
for psoriatic arthritis (2.5-4 mg/kg/day in 2 divided
doses) have generally been safe, but hypertension
and nephrotoxicity can occur. Cyclosporine can
also cause diarrhea, nausea, vomiting, infection,
hirsutism, gingival hyperplasia, pruritus, headache,
paresthesias, and hypertriglyceridemia. It increases
the risk of skin malignancies in patients previously
treated with psoralens combined with UVA radiation
(PUVA) and interacts with many other drugs.
Pregnancy – Cyclosporine appears to be relatively safe
for use during pregnancy, but has been associated
with low birth weight and prematurity.12
PDE4 INHIBITOR
APREMILAST — The oral phosphodiesterase type-4
(PDE4) inhibitor apremilast is approved by the FDA
for treatment of active psoriatic arthritis in adults.
In 3 randomized, double-blind, placebo-controlled
trials in a total of 1493 adults with active psoriatic
arthritis refractory to DMARDs, 32-41% of patients
taking apremilast 30 mg twice daily achieved an
ACR20 response after 16 weeks compared to 18-19%
of those taking placebo.13,14 Among patients in one
of the studies who continued taking apremilast, the
ACR20 response at week 52 was 54.6% with 30 mg
twice daily.15 No studies directly comparing apremilast
with a TNF inhibitor are available; in cross-study
comparisons, response rates appear to be lower with
apremilast, and there is no evidence that apremilast

retards joint damage.
Adverse Effects – The most common adverse effects
of apremilast in clinical trials were diarrhea, nausea,

Vol. 57 (1470)

June 8, 2015

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.
Pregnancy – Apremilast is classified as category
C (fetotoxicity in animals; no adequate studies in
women) for use during pregnancy.
BIOLOGIC AGENTS
TNF INHIBITORS – The five tumor necrosis factor
(TNF) inhibitors available in the US, adalimumab,
certolizumab pegol, etanercept, golimumab, and
infliximab, are approved by the FDA for treatment
of active psoriatic arthritis and they appear to be
the most effective treatment available to date for
this disease. They have been shown to reduce
joint disease activity, prevent structural damage,
and improve function. Some patients who have not
responded to one TNF inhibitor have responded
to another.16,17 A cohort analysis of patients with

bone erosions treated in a psoriatic arthritis
clinic found that progression of radiographic joint
damage occurred less frequently in patients being
treated with a TNF inhibitor than in those receiving
methotrexate after 1-2 years (59% vs 80%) and after
3-4 years (61% vs 88%).18
In clinical trials with adalimumab, etanercept, infliximab
and golimumab, ACR 20 response rates in patients
with psoriatic arthritis were 58%, 59%, 58%, and 51%,
respectively after 12-14 weeks of treatment.1 No headto-head comparisons of TNF inhibitors for treatment
of psoriatic arthritis are available, but an indirect
comparison meta-analysis of adalimumab, etanercept,
golimumab, and infliximab found no statistically
significant differences in efficacy between the drugs.19
Certolizumab pegol, the most recently approved
TNF inhibitor, appears to be similar in efficacy to
the others.20 A randomized, double-blind trial in 409
patients with active psoriatic arthritis found that
significantly more patients receiving certolizumab
pegol 200 mg SC every other week or 400 mg SC every
4 weeks had an ACR20 response at week 12 compared
to those treated with placebo (58% and 52% vs 24%).21
Adverse Effects – Serious infections, including bacterial infections (particularly pneumonitis and cellulitis),
histoplasmosis, and reactivation of tuberculosis and
hepatitis B virus have been reported with all the TNF
e90


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®

inhibitors, particularly in the first 2-7 months of treatment.22 These drugs should not be given to patients
with active localized or chronic infections. Screening
for exposure to tuberculosis is recommended before
starting anti-TNF therapy and annually thereafter.
Lymphoma and other malignancies have been reported
in patients with rheumatoid arthritis receiving these
drugs, but a cause-and-effect relationship has not
been established. They generally should not be used
in patients with a recent malignancy. Exacerbations
and new onset of heart failure, pancytopenia, and
demyelinating disorders such as multiple sclerosis
have been reported.23 Anti-TNF drugs have been
associated with development of autoantibodies and
the induction of a lupus-like syndrome. A review of
clinical studies found that autoantibodies reduced
the efficacy of infliximab and adalimumab, but not of
etanercept.24
Pregnancy – TNF inhibitors are classified as category
B (no evidence of toxicity in animals; no adequate
studies in women) for use during pregnancy.
IL-12/23 ANTAGONIST – The human interleukin-12
and -23 antagonist ustekinumab is FDA-approved
for treatment of psoriatic arthritis.20 A randomized,
double-blind trial in 615 patients with active psoriatic
arthritis found that 42% and 50% of patients treated
with ustekinumab 45 mg and 90 mg, respectively,
achieved an ACR20 response at week 24 compared
to 23% of those receiving placebo; responses were

maintained at week 52.25 Ustekinumab also slowed
radiographic progression, compared to placebo, for
up to 52 weeks.26 Response rates with ustekinumab
have been somewhat lower than with TNF inhibitors,
but direct compartisons are lacking.
Adverse Effects – Ustekinumab has been associated
with serious infections (especially tuberculosis),
malignancies, hypersensitivity reactions, and reversible posterior leukoencephalopathy. Screening for
tuberculosis is recommended before treatment.
Autoantibodies have developed; whether they reduce
treatment response remains to be determined.24
Pregnancy – Ustekinumab is classified as category
B (no evidence of toxicity in animals; no adequate
studies in women) for use during pregnancy.
INVESTIGATIONAL DRUG
SECUKINUMAB — The IL-17A inhibitor secukinumab
is under investigation for treatment of psoriatic
arthritis. In a small randomized, double-blind, 24week trial in 42 patients with psoriatic arthritis, ACR20
e91

Vol. 57 (1470)

June 8, 2015

responses following 2 doses of IV secukinumab
(10 mg/kg) given 3 weeks apart were greater than
those with placebo, but the differences were not
statistically significant. There were significant reductions in C-reactive protein, erythrocyte sedimentation
rate, and quality of life assessment scores in patients
receiving secukinumab.27

COMBINATION THERAPY
In patients with moderate to severe psoriatic arthritis
who have an inadequate response to a DMARD,
guidelines recommend addition of a TNF inhibitor.1,3,4
This combination may also be considered for initial
treatment. Whether combining a DMARD with a TNF
inhibitor improves response rates in patients with
psoriatic arthritis beyond those achieved by treatment
with a TNF inhibitor alone is controversial. In clinical
trials of TNF inhibitors that allowed concomitant use of
methotrexate, the combination did not appear to have
additive or synergistic effects.28,29 In a nonrandomized,
unblinded study in patients with severe psoriatic
arthritis that had responded inadequately to
methotrexate, the combination of cyclosporine and
adalimumab was more effective than either drug
alone.30 ■
1. A Gottlieb et al. Guidelines of care for the management of psoriasis and psoriatic arthritis: Section 2. Psoriatic arthritis: overview and guidelines of care for treatment with an emphasis on
the biologics. J Am Acad Dermatol 2008; 58:851.
2. A Menter et al. Guidelines of care for the management of psoriasis and psoriatic arthritis: section 6. Guidelines of care for
the treatment of psoriasis and psoriatic arthritis: case-based
presentations and evidence-based conclusions. J Am Acad
Dermatol 2011; 65:137.
3. CT Ritchlin et al. Treatment recommendations for psoriatic arthritis. Ann Rheum Dis 2009; 68:1387.
4. L Gossec et al. European League Against Rheumatism recommendations for the management of psoriatic arthritis with
pharmacological therapies. Ann Rheum Dis 2012; 71:4.
5. AJ Kivitz et al. A comparison of the efficacy and safety of celecoxib 200 mg and celecoxib 400 mg once daily in treating
the signs and symptoms of psoriatic arthritis. Semin Arthritis
Rheum 2007; 37:164.
6. P Mease. Methotrexate in psoriatic arthritis. Bull Hosp Jt Dis

(2013) 2013; 71 suppl 1:S41.
7. GH Kingsley et al. A randomized placebo-controlled trial of
methotrexate in psoriatic arthritis. Rheumatology (Oxford)
2012; 51:1368.
8. JP Kaltwasser et al. Efficacy and safety of leflunomide in the
treatment of psoriatic arthritis and psoriasis: a multinational,
double-blind, randomized, placebo-controlled clinical trial. Arthritis Rheum 2004; 50:1939.
9. F Behrens et al. Leflunomide in psoriatic arthritis: results from a
large European prospective observational study. Arthritis Care
Res (Hoboken) 2013; 65:464.
10. ER Soriano and NJ McHugh. Therapies for peripheral joint disease in psoriatic arthritis. A systematic review. J Rheumatol
2006; 33:1422.
11. AD Fraser et al. A randomised, double-blind, placebo controlled,


The Medical Letter

Vol. 57 (1470)

®

multicentre trial of combination therapy with methotrexate
plus ciclosporin in patients with active psoriatic arthritis. Ann
Rheum Dis 2005; 64:859.
12. MB Hoffman et al. Psoriasis during pregnancy: characteristics
and important management recommendations. Expert Rev Clin
Immunol 2015; 11:709.
13. Apremilast (Otezla) for psoriatic arthritis. Med Lett Drugs Ther
2014; 56:41.
14. 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.
15. A Kavanaugh et al. Longterm (52-week) results of a phase III
randomized, controlled trial of apremilast in patients with psoriatic arthritis. J Rheumatol 2015; 42:479.
16. R Goulabchand et al. Effect of tumor necrosis factor blockers
on radiographic progression of psoriatic arthritis: a systematic
review and meta-analysis of randomised controlled trials. Ann
Rheum Dis 2014; 73:414.
17. AS Soubrier et al. Treatment response, drug survival and safety
of anti-tumour necrosis factor  therapy in 193 patients with
psoriatic arthritis: a twelve-year “real life” experience. Joint
Bone Spine 2015; 82:31.
18. L Eder et al. Tumour necrosis factor  blockers are more effective than methotrexate in the inhibition of radiographic joint
damage progression among patients with psoriatic arthritis.
Ann Rheum Dis 2014; 73:1007.
19. K Thorlund et al. Anti-tumor necrosis factor (TNF) drugs for the
treatment of psoriatic arthritis: an indirect comparison metaanalysis. Biologics 2012; 6:417.
20. Certolizumab pegol (Cimzia) and ustekinumab (Stelara) for
psoriatic arthritis. Med Lett Drugs Ther 2014; 56:9.
21. PJ Mease et al. Effect of certolizumab pegol on signs and
symptoms in patients with psoriatic arthritis: 24-week results
of a phase 3 double-blind randomised placebo-controlled

June 8, 2015

study (RAPID-PsA). Ann Rheum Dis 2014; 73:48.
22. RE Kalb et al. Risk of serious infection with biologic and systemic treatment of psoriasis: results from the psoriasis longitudinal assessment and regiatryy (PSOLAR). JAMA Dermatol
2015 May 13 (epub).
23. AL Semble et al. Safety and tolerability of tumor necrosis

factor- inhibitors in psoriasis: a narrative review. Am J Clin
Dermatol 2014; 15:37.
24. L Hsu et al. Antidrug antibodies in psoriasis: a systematic review. Br J Dermatol 2014; 170:261.
25. IB McInnes et al. Efficacy and safety of ustekinumab in patients
with active psoriatic arthritis: 1 year results of the phase 3,
multicentre, double-blind, placebo-controlled PSUMMIT 1 trial.
Lancet 2013; 382:780.
26. A Kavanaugh et al. Ustekinumab, an anti-IL-12/23 p40 monoclonal antibody, inhibits radiographic progression in patients
with active psoriatic arthritis: results of an integrated analysis
of radiographic data from the phase 3, multicentre, randomised,
double-blind, placebo-controlled PSUMMIT-1 and PSUMMIT-2
trials. Ann Rheum Dis 2014; 73:1000.
27. IB McInnes et al. Efficacy and safety of secukinumab, a fully human anti-interleukin-17A monoclonal antibody, in patients with
moderate-to-severe psoriatic arthritis: a 24-week, randomized,
double-blind, placebo-controlled, phase II proof-of-concept
trial. Ann Rheum Dis 2014; 73:349.
28. M Daly et al. Combination systemic therapies in psoriatic arthritis. J Dermatolog Treat 2011; 22:276.
29. ML Felquer and ER Soriano. New treatment paradigms in psoriatic
arthritis: an update on new therapeutics approved by the U.S. Food
and Drug Administration. Curr Opin Rheumatol 2015; 27:99.
30. GN Karanikolas et al. Adalimumab or cyclosporine as monotherapy and in combination in severe psoriatic arthritis: results
from a prospective 12-month nonrandomized unblinded clinical trial. J Rheumatol 2011; 38:2466.

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; SENIOR ASSOCIATE EDITOR: Amy Faucard
CONTRIBUTING EDITORS: Carl W. Bazil, M.D., Ph.D., Columbia University College of Physicians and Surgeons; Vanessa K. Dalton, M.D., M.P.H., University of Michigan Medical
School; 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; Franco M. Muggia, M.D., New York University Medical Center; 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
MANAGING EDITOR: Susie Wong; ASSISTANT MANAGING EDITOR: Liz Donohue; EDITORIAL ASSISTANT: Cheryl Brown
EXECUTIVE DIRECTOR OF SALES: Gene Carbona; FULFILLMENT & SYSTEMS MANAGER: Cristine Romatowski; DIRECTOR OF MARKETING COMMUNICATIONS: Joanne F. Valentino;
VICE PRESIDENT AND PUBLISHER: Yosef Wissner-Levy
Founded in 1959 by
Arthur Kallet and Harold Aaron, M.D.
Copyright and Disclaimer: The Medical Letter, Inc. is an independent nonprofit organization that provides healthcare professionals with unbiased drug prescribing recommendations. The editorial
process used for its publications relies on a review of published and unpublished literature, with an emphasis on controlled clinical trials, and on the opinions of its consultants. The Medical Letter,
Inc. is supported solely by subscription fees and accepts no advertising, grants, or donations. No part of the material may be reproduced or transmitted by any process in whole or in part without
prior permission in writing. The editors do not warrant that all the material in this publication is accurate and complete in every respect. The editors shall not be held responsible for any damage
resulting from any error, inaccuracy, or omission.

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on Drugs and Therapeutics
Objective Drug Reviews Since 1959
Volume 57 (Issue 1471)

June 22, 2015
Take CME Exams

Addendum: Nivolumab (Opdivo) for Metastatic
Melanoma and Metastatic NSCLC
After our article on nivolumab (Opdivo – BMS) for treatment
of metastatic melanoma and metastatic squamous nonsmall cell lung cancer (NSCLC) was published in the most
recent issue of The Medical Letter (June 8, 2015),1 some
new data became available supporting the efficacy of the
drug in previously untreated melanoma and previously
treated nonsquamous NSCLC.
MELANOMA – In a double-blind trial, 945 patients with
previously untreated, unresectable stage III or IV melanoma
were randomized to receive ipilimumab, nivolumab, or
combination therapy with ipilimumab and nivolumab.
Progression-free survival, a primary endpoint, improved by
43% with nivolumab (median 6.9 months) and by 58% with
combination therapy (median 11.5 months), compared to
ipilimumab (median 2.9 months). In patients with tumors
that expressed the programmed death ligand 1 (PD-L1) on
≥5% of cells, median progression-free survival was similar in
the nivolumab and combination groups (both 14.0 months);
in those with tumors that expressed PD-L1 on <5% of cells,
it was 5.3 months with nivolumab alone and 11.2 months
with both drugs. Rates of complete or partial response were
19.0% with ipilimumab, 43.7% with nivolumab, and 57.6%
with combination therapy. At least one severe (grade 3-4)
drug-related adverse effect occurred in 27.3% of patients
receiving ipilimumab, 16.3% of those receiving nivolumab,
and 55.0% of those receiving both drugs.2

NONSQUAMOUS NSCLC – In an open-label trial (available only as an abstract), 582 patients with advanced
nonsquamous NSCLC that had progressed during or after
treatment with a platinum doublet-based regimen (and,
if appropriate, a kinase inhibitor) were randomized to receive nivolumab or docetaxel until disease progression or
unacceptable toxicity occurred. Nivolumab significantly
improved overall survival, the primary endpoint, by 27%
compared to docetaxel (median 12.2 vs 9.4 months).
Survival rates in the two groups were similar in patients
with tumors expressing PD-L1 on <1% of cells, but in
patients with tumors expressing PD-L1 on ≥1%, ≥5%, and
≥10% of cells, nivolumab improved overall survival by
41%, 57%, and 60%, respectively, compared to docetaxel.
Patients receiving nivolumab were significantly more likely
to have an objective response (19.2% vs 12.4%). Severe
(grade 3+) drug-related adverse effects occurred in 10.5%
of patients receiving nivolumab and in 53.7% of those
receiving docetaxel.3 ■
1. Nivolumab (Opdivo) for metastatic melanoma and metastatic
NSCLC. Med Lett Drugs Ther 2015; 57:85.
2. J Larkin et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med 2015 May 31
(epub).
3. L Paz-Ares et al. Phase III, randomized trial (CheckMate 057) of
nivolumab (NIVO) versus docetaxel (DOC) in advanced non-squamous cell (non-SQ) non-small cell lung cancer (NSCLC). J Clin Oncol 2015; 33 (suppl; abstr LBA109). Available at: abstracts.asco.
org/156/AbstView_156_154634.html. Accessed June 11, 2015.

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; SENIOR ASSOCIATE EDITOR: Amy Faucard
CONTRIBUTING EDITORS: Carl W. Bazil, M.D., Ph.D., Columbia University College of Physicians and Surgeons; Vanessa K. Dalton, M.D., M.P.H., University of Michigan Medical

School; 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; Franco M. Muggia, M.D., New York University Medical Center; 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
MANAGING EDITOR: Susie Wong; ASSISTANT MANAGING EDITOR: Liz Donohue; EDITORIAL ASSISTANT: Cheryl Brown
EXECUTIVE DIRECTOR OF SALES: Gene Carbona; FULFILLMENT & SYSTEMS MANAGER: Cristine Romatowski; DIRECTOR OF MARKETING COMMUNICATIONS: Joanne F. Valentino;
VICE PRESIDENT AND PUBLISHER: Yosef Wissner-Levy
Founded in 1959 by
Arthur Kallet and Harold Aaron, M.D.
Copyright and Disclaimer: The Medical Letter, Inc. is an independent nonprofit organization that provides healthcare professionals with unbiased drug prescribing recommendations. The editorial
process used for its publications relies on a review of published and unpublished literature, with an emphasis on controlled clinical trials, and on the opinions of its consultants. The Medical Letter,
Inc. is supported solely by subscription fees and accepts no advertising, grants, or donations. No part of the material may be reproduced or transmitted by any process in whole or in part without
prior permission in writing. The editors do not warrant that all the material in this publication is accurate and complete in every respect. The editors shall not be held responsible for any damage
resulting from any error, inaccuracy, or omission.

Subscription Services
Address:
The Medical Letter, Inc.
145 Huguenot St. Ste. 312
New Rochelle, NY 10801-7537
www.medicalletter.org

Customer Service:
Call: 800-211-2769 or 914-235-0500
Fax: 914-632-1733
E-mail:

Permissions:
To reproduce any portion of this issue,

please e-mail your request to:


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3 years - $279. $49 per year
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Explain the current approach to the management of psoriasis.
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Discuss the pharmacologic options available for treatment of psoriasis and compare them based on their efficacy, dosage and administration, and potential adverse
effects.
3.
Review the efficacy and safety of nivolumab (Opdivo) for treatment of metastatic melanoma and metastatic NSCLC.
4.
Review the efficacy and safety of recombinant human parathyroid hormone (Natpara) for use in patients with hypocalcemia due to hypoparathyroidism.
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Issue 1470 Questions

(Correspond to questions #111-120 in Comprehensive Exam #72, available July 2015)
Drugs for Psoriasis
1. For treatment of psoriasis, topical corticosteroids are:
a. contraindicated
b. never used alone
c. always used alone
d. used alone and in combination with phototherapy and
systemic therapy
2. Phototherapy for psoriasis can include:
a. narrow-band UVB radiation
b. PUVA
c. the excimer laser
d. all of the above
3. A 26-year-old woman with moderate psoriasis that has not
responded to topical therapy asks you what else is available for
her. You could tell her that:

a. methotrexate in low doses is often used
b. cyclosporine is less effective but safer than methotrexate
c. acitretin is effective and has no significant toxicity
d. all of the above
4. In randomized controlled trials, the average percentage of
patients with psoriasis who achieved PASI 75 responses after
12 weeks of treatment with infliximab was:
a. 48.1%
b. 70.5%
c. 78.6%
d. 87.0%
5. All of the biologic agents used for treatment of psoriasis have
been associated with an increased risk of:
a. melanoma
b. infection
c. depression
d. rheumatoid arthritis

7. Although not directly compared for treatment of metastatic
melanoma, nivolumab appears to be:
a. more effective than ipilimumab in improving response rates
b. less effective than ipilimumab in improving response rates
c. about as effective as ipilimumab
d. more toxic than ipilimumab
Recombinant Human Parathyroid Hormone (Natpara)
8. In patients with hypoparathyroidism, the preferred source of
vitamin D is:
a. ergocalciferol
b. an over-the-counter vitamin D3 supplement
c. calcitriol

d. food
9. A 45-year-old woman with hypoparathyroidism has maintained
a serum calcium level of 8.3 mg/dL while taking 1.5 g/d of
elemental calcium and active vitamin D. She asks about the
new parathyroid hormone injection. You could tell her that:
a. there is a concern that use of the hormone might be
associated with osteosarcoma
b. she is not a candidate for the hormone because she is well
maintained on calcium and vitamin D supplementation
c. paresthesia and hypoesthesia are common adverse
effects of the hormone
d. all of the above
10. In the REPLACE trial, about what percentage of patients
receiving recombinant human parathyroid hormone achieved
the primary endpoint of a ≥50% reduction in calcium and
vitamin D doses and maintenance of normal calcium levels?
a. 35%
b. 50%
c. 65%
d. 80%

Nivolumab (Opdivo) for Metastatic Melanoma and Metastatic NSCLC
6. Compared to dacarbazine in previously untreated patients with
metastatic melanoma without a BRAF mutation, nivolumab:
a. improved overall survival
b. improved 1-year survival rates
c. improved median progression-free survival
d. all of the above
ACPE UPN: Per Issue Exam: 0379-0000-15-470-H01-P; Release: June 8, 2015, Expire: June 8, 2016
Comprehensive Exam 72: 0379-0000-15-072-H01-P; Release: July 2015, Expire: July 2016

EDITOR IN CHIEF: Mark Abramowicz, M.D.; EXECUTIVE EDITOR: Gianna Zuccotti, M.D., M.P.H., F.A.C.P., Harvard Medical School; EDITOR: Jean-Marie Pflomm, Pharm.D.;
ASSISTANT EDITORS, DRUG INFORMATION: Susan M. Daron, Pharm.D., Corinne Z. Morrison, Pharm.D., Michael P. Viscusi, Pharm.D.; CONSULTING EDITORS: Brinda M. Shah, Pharm.D.,
F. Peter Swanson, M.D; SENIOR ASSOCIATE EDITOR: Amy Faucard
CONTRIBUTING EDITORS: Carl W. Bazil, M.D., Ph.D., Columbia University College of Physicians and Surgeons; Vanessa K. Dalton, M.D., M.P.H., University of Michigan Medical
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