The medical letter on drugs and therapeutics march 14 2016

The Medical Letter

®

on Drugs and Therapeutics
Volume 58

ISSUE
ISSUE
No.

1433
1490
Volume 56

March 14, 2016

IN THIS ISSUE

Safety of Testosterone Replacement Therapy .................................................................... p 33
Zarxio – A Filgrastim Biosimilar .......................................................................................... p 34
Low-Dose Meloxicam (Vivlodex) for Osteoarthritis Pain ................................................... p 35
Isavuconazonium Sulfate (Cresemba) – A New Antifungal Drug ...................................... p 37

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The Medical Letter

®

on Drugs and Therapeutics

Volume 58

ISSUE

ISSUE No.

1433
1490
Volume 56

▶

March 14, 2016
ALSO IN THIS ISSUE

Zarxio – A Filgrastim Biosimilar .......................................................................................... p 34
Low-Dose Meloxicam (Vivlodex) for Osteoarthritis Pain ................................................... p 35
Isavuconazonium Sulfate (Cresemba) – A New Antifungal ............................................... p 37

Safety of Testosterone Replacement
Therapy

Three coordinated double-blind, placebo-controlled
clinical trials have evaluated the efficacy of one year of
testosterone replacement therapy in improving sexual
function, physical function, and vitality in a total of
790 men ≥65 years old with moderately low serum
testosterone concentrations and symptoms suggesting hypoandrogenism. Sexual function improved
modestly, and there appeared to be marginal benefits
in some areas of physical function and vitality as well.

The trials were not designed to evaluate the safety of
testosterone replacement therapy.1
ADVERSE EFFECTS — Testosterone administration
has been associated with development of acne,
gynecomastia, peripheral edema, and polycythemia.
Injections of testosterone undecanoate rarely have
caused pulmonary oil microembolism (POME) and
anaphylactic reactions. The main concern with

testosterone replacement therapy, however, has
been the possibility that it could increase the risk of
prostate cancer and cardiovascular disease.

Table 1. Some Testosterone Replacement Products
Drug
Injectable
Testosterone cypionate – generic
Depo-Testosterone (Pfizer)
Testosterone enanthate – generic
Delatestryl (Endo)
Testosterone undecanoate – Aveed
(Endo)
Transdermal
Androderm (Actavis)
Testosterone 1% gel packet –
generic3
AndroGel 1.62% (Abbvie)
Axiron (Lilly)
Testosterone 2% gel – generic
Fortesta (Endo)
Testosterone 1% gel – generic
Vogelxo (Upsher Smith)
Testim (Auxilium/Endo)
Intranasal
Natesto (Trimel/Endo)
Buccal
Striant (Auxilium/Endo)

Some Available Formulations

Usual Adult Dosage

Cost1

1, 10 mL vial (100 mg/mL, 200 mg/mL)2,7

50-400 mg IM
q2-4 wks
50-400 mg IM
q2-4 wks
750 mg IM at 0 and
4 wks, then q10 wks

$45.30
73.50
68.00
82.80
850.00

4 mg once nightly
50 mg once/d

471.30

5 mL vial (200 mg/mL)7
3 mL vial (250 mg/mL)

2, 4 mg/d patch
2.5 g gel packet (25 mg test.); 5 g gel packet (50 mg test.);

75 g MDP (12.5 mg test. in 1.25 g gel/act)
1.25 g gel packet (20.25 mg test.); 2.5 g gel packet
(40.5 mg test.); 75 g MDP (20.25 mg test. in 1.25 g gel/act)
90 mL MDP (30 mg test. in 1.5 mL soln/act)
60 g MDP (10 mg test. in 0.5 g gel/act)

40.5 mg once/d
60 mg once/d4
40 mg once/d

374.30
489.00
521.80
341.30
383.50
309.60
445.50
490.20

5 g tube of gel (50 mg test.); 5 g gel packet (50 mg test.)5;
88 g MDP (12.5 mg test. in 1.25 g gel/act)
5 g tube of gel (50 mg test.)

50 mg once/d

11 g MDP (5.5 mg test. in 0.122 g gel/act)

11 mg tid6

650.70

30 mg buccal tablet

30 mg bid

545.50

act = actuation; MDP = metered-dose pump; test. = testosterone
1. Approximate wholesale acquisition cost (WAC) for one 10-mL vial (100 mg/mL) of testosterone cypionate, one 5-mL vial of testosterone enanthate, one 3-mL
vial of Aveed, or a 30-day supply of transdermal, intranasal, or buccal formulations at the usual adult dosage. WAC = wholesaler acquisition cost or manufacturer’s published price to wholesalers; WAC represents a published catalogue or list price and may not represent an actual transactional price. Source:
AnalySource® Monthly. February 5, 2016. Reprinted with permission by First Databank, Inc. All rights reserved. ©2016. www.fdbhealth.com/policies/drugpricing-policy. Cost of administration is not included.
2. The 100 mg/mL formulation is only available in a 10-mL vial.
3. AndroGel 1%, the reference product for these formulations, is no longer manufactured.
4. Should be administered as 1 pump actuation (30 mg) to each axilla.
5. Tubes and packets are therapeutically equivalent to Testim.
6. Should be administered as 1 pump actuation (5.5 mg) in each nostril.
7. Vial should be discarded within 28 days after being opened or accessed (United States Pharmacopeia General Chapter 797).

33

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The Medical Letter

®

Prostate Cancer – Testosterone replacement
therapy has been associated with increases in serum
prostate-specific antigen (PSA) concentrations.

In the coordinated trials, which excluded men at
high risk for prostate cancer, a PSA increase of
≥1.0 ng/mL occurred in 23 men treated with
testosterone and 8 treated with placebo. Four men
developed prostate cancer during the trials or in
the subsequent year; three were in the testosterone
group. Large randomized controlled trials are lacking, but recent reviews have found no convincing
evidence that higher testosterone levels increase the
risk of prostate cancer.2,3
Cardiovascular Disease – Some studies have found
an association between testosterone replacement
therapy and cardiovascular events. In the coordinated
trials, 7 men in each treatment group had a major
cardiovascular event.
In an earlier 6-month randomized trial in 209 men ≥65
years old with a high prevalence of cardiac risk factors,
23 treated with testosterone gel had cardiovascularrelated adverse events, compared to 5 who received
placebo (HR 2.4; p=0.05).4 A meta-analysis of randomized, placebo-controlled trials also found an
increased risk of cardiovascular-related adverse
events in men treated with testosterone (OR 1.54;
95% CI 1.09-2.18); an analysis by funding source
found that the risk was greater in trials not sponsored
by the pharmaceutical industry (OR 2.06 vs 0.89).5
Other studies have not found an association between
testosterone replacement therapy and cardiovascular
risk, and some have found a reduced incidence of
myocardial infarction and mortality in men treated
with testosterone.6-8
CONCLUSION — The safety of testosterone replacement therapy remains unclear. There is no convincing
evidence to date that it increases the risk of prostate

cancer. Some studies have found an increased
incidence of cardiovascular events in men treated with
testosterone, but others have not. ■
1. PJ Snyder et al. Effects of testosterone treatment in older men.
N Engl J Med 2016; 374:611.
2. JE Michaud et al. Testosterone and prostate cancer: an evidence-based review of pathogenesis and oncologic risk. Ther
Adv Urol 2015; 7:378.
3. P Boyle et al. Endogenous and exogenous testosterone and the
risk of prostate cancer and increased prostate specific antigen
(PSA): a meta-analysis. BJU Int 2016 January 18 (epub).
4. S Basaria et al. Adverse events associated with testosterone
administration. N Engl J Med 2010; 363:109.

34

Vol. 58 (1490)

March 14, 2016

5. L Xu et al. Testosterone therapy and cardiovascular events
among men: a systematic review and meta-analysis of placebo-controlled randomized trials. BMC Med 2013; 11:108.
6. G Corona et al. Cardiovascular risk associated with testosterone-boosting medications: a systematic review and metaanalysis. Expert Opin Drug Saf 2014; 13:1327.
7. R Sharma et al. Normalization of testosterone level is associated with reduced incidence of myocardial infarction and mortality in men. Eur Heart J 2015; 36:2706.
8. A Morgentaler et al. Testosterone therapy and cardiovascular risk: advances and controversies. Mayo Clin Proc 2015;
90:224.

▶

Zarxio – A Filgrastim Biosimilar

The FDA has approved filgrastim-sndz (Zarxio –
Sandoz), a biosimilar of the recombinant human
granulocyte colony-stimulating factor filgrastim
(G-CSF; Neupogen), which has been available in the
US since 1991. Zarxio is the first biosimilar product to
be approved in the US; it has been available in Europe
as Zarzio since 2009.
Filgrastim : fil gra' stim

Pronunciation Key
Zarxio : zar' zee oh

BIOSIMILARS — The FDA defines a biosimilar as a
biologic product that is highly similar to an approved
biologic product (reference product) with no clinically
meaningful differences in safety, purity, or potency;
minor differences in clinically inactive components are
allowed. An approved biosimilar product must have
the same mechanism of action, route of administration,
dosage form, and strength as the reference product.
Biosimilars can only be approved for the indications
for which the reference product is approved; they
may be approved for fewer indications than the
reference product. A biosimilar that is approved as
an “interchangeable product” (see Table 1) can be
substituted by a pharmacist for the reference product.1
Table 1. FDA Criteria for Interchangeability of Biosimilars

▶ The biosimilar product can be expected to produce the same
clinical result as the reference product in any given patient.

▶ If the biosimilar product is administered more than once to an
individual, the risk in terms of safety or diminished efficacy of
alternating or switching between use of the biosimilar product
and the reference product is not greater than the risk of using
the reference product without such alternation or switch.

Zarxio was approved for all of the same indications
as the US-licensed reference product Neupogen (see
Table 2), but was not reviewed for interchangeability.
CLINICAL STUDIES — In a phase 1, randomized,
double-blind, two-way crossover trial in 28 healthy
subjects, no statistically significant pharmacokinetic


The Medical Letter

Vol. 58 (1490)

®

Table 2. Approved Indications for Neupogen and Zarxio

▶ Decrease the incidence of infection‚ as manifested by febrile
neutropenia‚ in patients with nonmyeloid malignancies receiving
myelosuppressive anticancer drugs associated with a significant
incidence of severe neutropenia with fever

▶ Reduce the time to neutrophil recovery and the duration of fever,
following induction or consolidation chemotherapy treatment of

patients with acute myeloid leukemia

▶ Reduce the duration of neutropenia and neutropeniarelated clinical sequelae‚ e.g.‚ febrile neutropenia, in patients
with nonmyeloid malignancies undergoing myeloablative
chemotherapy followed by bone marrow transplantation

▶ Mobilize autologous hematopoietic progenitor cells into the
peripheral blood for collection by leukapheresis

▶ Reduce the incidence and duration of sequelae of severe
neutropenia (e.g.‚ fever‚ infections‚ oropharyngeal ulcers) in
symptomatic patients with congenital neutropenia‚ cyclic
neutropenia‚ or idiopathic neutropenia

or pharmacodynamic differences were detected
between 10 mcg/kg doses of filgrastim-sndz and
Neupogen. The safety profiles of the two products
were also similar.2
In a double-blind noninferiority trial, 218 women
with breast cancer who were being treated with
myelosuppressive chemotherapy were randomized
to receive 5 mcg/kg/day of subcutaneous Zarxio
or Neupogen, or an alternating course of the two
drugs over six chemotherapy cycles. Doses were
administered from day 2 of each cycle until the absolute neutrophil count recovered or for a maximum of
14 days. The mean duration of severe neutropenia in
cycle 1, the primary endpoint, was similar with Zarxio
and Neupogen. Alternating between the two products
produced no clinically meaningful differences in
efficacy or safety.3

Table 3. Neupogen and Zarxio
Drug

Available Formulations

Cost1

Filgrastim –
300 mcg/0.5 mL, 480 mcg/0.8 mL
Neupogen (Amgen) prefilled syringe; 300 mcg/1 mL, $516.45
480 mcg/1.6 mL vial
Filgrastim-sndz –
Zarxio (Sandoz)

300 mcg/0.5 mL, 480 mcg/0.8 mL
prefilled syringe

438.98

1. Approximate WAC for one 480 mcg/0.8 mL prefilled syringe. 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. February 5,
2016. Reprinted with permission by First Databank, Inc. All rights reserved.
©2016. www.fdbhealth.com/policies/drug-pricing-policy.

ADVERSE EFFECTS — In clinical trials, there were no
significant differences in adverse effects between
Zarxio and Neupogen. The most common doseand cycle-related adverse effects of filgrastim have
been pyrexia, pain (including bone and chest pain),
rash, thrombocytopenia, nausea, fatigue, dizziness,

cough, and dyspnea.

March 14, 2016

CONCLUSION — Filgrastim-sndz (Zarxio) is the first
product to be approved by the FDA as a biosimilar. It is
similar to filgrastim (Neupogen) in efficacy and safety,
and it costs less. ■
1. FDA Biosimilars Guidances. Available at: www.fda.gov/Drugs/
GuidanceComplianceRegulatoryInformation/Guidances/
ucm290967.htm. Accessed March 3, 2016.
2. F Sörgel et al. Comparability of biosimilar filgrastim with originator filgrastim: protein characterization, pharmacodynamics,
and pharmacokinetics. BioDrugs 2015; 29:123.
3. K Blackwell et al. Comparison of EP2006, a filgrastim biosimilar,
to the reference: a phase III, randomized, double-blind clinical
study in the prevention of severe neutropenia in patients with
breast cancer receiving myelosuppressive chemotherapy. Ann
Oncol 2015; 26:1948.

▶

Low-Dose Meloxicam (Vivlodex) for
Osteoarthritis Pain

The FDA has approved Vivlodex (Iroko), a low-dose
formulation of the nonsteroidal anti-inflammatory drug
meloxicam (Mobic, and generics), for management of
osteoarthritis pain. According to the manufacturer, the
new formulation aligns with stronger FDA warnings
about the cardiovascular risks of NSAIDs and the

recommendation to use the lowest possible doses of
these drugs.1
Pronunciation Key
Meloxicam : mel ox' i kam
Vivlodex : viv loe' dex

STANDARD TREATMENT — Acetaminophen is
generally the first-line pharmacologic treatment for
osteoarthritis pain. Full doses of NSAIDs are more
effective than full doses of acetaminophen, but
NSAIDs have many more adverse effects, especially
in elderly patients. Intra-articular injection of a
corticosteroid is a reasonable alternative. Opioids can
be used as a last resort for treatment of intractable
osteoarthritis pain.2
THE NEW FORMULATION — Vivlodex is available as
5- and 10-mg capsules; standard meloxicam tablets
contain 7.5 or 15 mg of the drug. Like Zorvolex
(diclofenac)3 and Tivorbex (indomethacin),4 two
other low-dose NSAIDs available from the same
manufacturer, Vivlodex is formulated as capsules
containing submicron particles.
Absorption of meloxicam occurs more rapidly with
the capsules than with standard tablets. In a study
comparing the new 10-mg capsules with 15-mg
tablets in fasting healthy adults, mean maximum
serum concentrations (Cmax) of meloxicam were
35

The Medical Letter

Vol. 58 (1490)

®

Table 1. Meloxicam Products
Meloxicam

Available
Formulations

generic
7.5, 15 mg tabs
Mobic (Boehringer
Ingelheim)
Vivlodex
(Iroko)

5, 10 mg caps

2

Usual Adult
Dosage

Cost1

7.5-15 mg
once/d

$2.30
208.60

5-10 mg
once/d

594.003

1. Approximate WAC for 30 days’ treatment with the lowest usual dosage.
WAC = wholesaler acquisition cost or manufacturer’s published price to
wholesalers; WAC represents a published catalogue or list price and may
not represent an actual transactional price. Source: AnalySource® Monthly.
February 5, 2016. Reprinted with permission by First Databank, Inc. All rights
reserved. ©2016. www.fdbhealth.com/policies/drug-pricing-policy.
2. Also available as a 7.5 mg/5 mL PO suspension.
3. The 5- and 10-mg strengths cost the same.

similar with the two formulations, but the median
time to reach peak serum concentrations (Tmax) was
shorter with the new formulation (2 vs 4 hours). Mean
systemic meloxicam exposure (AUC) was 33% lower
with the low-dose capsules.5 As with the standard
formulation, taking the new meloxicam capsules
with food decreases the rate but not the extent of
absorption (Tmax delayed by 3 hours, mean Cmax 22%
lower, no significant effect on AUC).
CLINICAL STUDIES — FDA approval of Vivlodex
was based on the results of a randomized,
double-blind trial in 403 patients ≥40 years old

with confirmed hip or knee osteoarthritis who
had experienced significant pain flares after
discontinuation of acetaminophen or an NSAID.
Patients were randomized to receive 5- or 10-mg
capsules of meloxicam or placebo once daily for 12
weeks. Both the 5- and 10-mg capsules reduced
pain significantly more than placebo and were
similar in efficacy.6
ADVERSE EFFECTS — In the 12-week clinical trial,
only a small percentage of patients reported adverse
effects; diarrhea, nausea, and abdominal discomfort
occurred in 2-3% of patients taking low-dose
meloxicam versus 0-1% of those taking placebo. No
serious adverse effects were reported.
Dyspepsia and GI ulceration, perforation, and bleeding can occur with all NSAIDs. Serious GI complications
may occur without warning. High doses, prolonged
use, previous peptic ulcer disease, concomitant use of
systemic corticosteroids or aspirin (even 81 mg/day),
excessive alcohol intake, and advanced age increase
the risk of these complications.
All NSAIDs inhibit renal prostaglandins, decrease
renal blood flow, cause fluid retention, and may cause

36

March 14, 2016

hypertension and renal failure in some patients,
particularly the elderly. Diminished renal function
or decreased effective intravascular volume due to

diuretic therapy, cirrhosis, or heart failure increases
the risk of NSAID-induced renal toxicity.
Use of NSAIDs has also been associated with an
increased risk of myocardial infarction and stroke,
sometimes occurring during the first few weeks of
treatment, in patients with and without risk factors
for cardiovascular disease. NSAIDs frequently cause
small elevations of hepatic transaminases; serious
hepatotoxicity is rare.
PREGNANCY — Use of NSAIDs in the third trimester
of pregnancy can cause premature closure of the fetal
ductus arteriosus. In animal studies, NSAIDs have
not been teratogenic, but they can delay parturition,
leading to an increased incidence of stillbirth.
DRUG INTERACTIONS — NSAIDs may decrease
the effectiveness of diuretics, beta-blockers, ACE
inhibitors, and some other antihypertensive drugs,
and may increase the toxicity of lithium and methotrexate. If taken with warfarin, they can increase
the INR. Concomitant use of NSAIDs with warfarin
or other anticoagulants is generally discouraged.
Patients taking aspirin for cardiovascular protection
should not take NSAIDs regularly (except for
celecoxib) because they can interfere with the
antiplatelet effect of aspirin.
CONCLUSION — Low-dose meloxicam (Vivlodex)
appears to be effective in relieving osteoarthritis
pain, but how it compares in efficacy and safety to
standard-dose meloxicam, which costs much less,
is unknown. NSAIDs can be dangerous, particularly
in elderly patients. Acetaminophen is preferred for

first-line treatment of osteoarthritis pain. ■
1. FDA Drug Safety Communication: FDA strengthens warnings
that non-aspirin nonsteroidal anti-inflammatory drugs
(NSAIDs) can cause heart attacks or strokes. July 9, 2015.
Available at: www.fda.gov/Drugs/DrugSafety/ucm451800.htm.
Accessed March 3, 2016.
2. Drugs for osteoarthritis. Med Lett Drugs Ther 2014; 56:80.
3. Low-dose diclofenac (Zorvolex) for pain. Med Lett Drugs Ther
2014; 56:19.
4. In brief: Low-dose indomethacin (Tivorbex) for pain. Med Lett
Drugs Ther 2014; 56:64.
5. A Hussaini et al. Pharmacokinetic properties of low-dose SoluMatrix meloxicam in healthy adults. Clin Rheumatol 2015 Dec 5
(epub).
6. R Altman et al. Efficacy and safety of low-dose SoluMatrix
meloxicam in the treatment of osteoarthritis pain: a 12-week,
phase 3 study. Curr Med Res Opin 2015; 31:2331.


The Medical Letter

▶

®

Isavuconazonium Sulfate
(Cresemba) – A New Antifungal

The FDA has approved isavuconazonium sulfate
(Cresemba – Astellas) for intravenous and oral treatment
of invasive aspergillosis and invasive mucormycosis

in adults. Isavuconazonium sulfate is a prodrug of
isavuconazole, a broad-spectrum triazole antifungal.
Pronunciation Key
Isavuconazonium : eye" sa vue koe" na zoe' nee um
Isavuconazole: eye" sa vue kon' a zole
Cresemba : cree sem' bah

STANDARD TREATMENT — Voriconazole (Vfend,
and generics) is the preferred treatment for invasive
aspergillosis. Some experts recommend addition
of an echinocandin (see Table 2), but the role of
combination therapy for initial treatment has not been
well established.1 A lipid formulation of amphotericin
B (AmBisome, Abelcet) is generally used in patients
who cannot tolerate voriconazole. Patients who do
not respond to monotherapy are usually treated with
an echinocandin in addition to voriconazole or a lipid
formulation of amphotericin B. Posaconazole (Noxafil)
has been used off-label as salvage therapy.
Invasive mucormycosis is generally treated with
a lipid formulation of amphotericin B and surgical
debridement. Posaconazole has been used off-label
for oral step-down therapy in patients who have
responded to amphotericin B and as salvage therapy.

Vol. 58 (1490)

March 14, 2016

Table 2. Pharmacology of Isavuconazole

Class

Triazole antifungal

Formulation

186 mg capsules (100 mg isavuconazole);
372 mg single-use vials containing lyophilized
powder for reconstitution (200 mg isavuconazole)

Route

Oral or IV

Metabolism

Hepatic via CYP3A4 and 3A5, followed by UGT

Bioavailability

98%

Tmax

Oral: 2-3 hours

Half-life

IV : 130 hours

Elimination

Oral: Urine (<1%)

Voriconazole is not effective for treatment of
mucormycosis; invasive mucormycosis has occurred
with use of voriconazole for prophylaxis or treatment
of other fungal infections.2 Untreated invasive
mucormycosis is almost always fatal.
MECHANISM OF ACTION — Like other triazole antifungals, isavuconazole inhibits the synthesis of ergosterol,
an essential component of the fungal cell membrane.
SPECTRUM OF ACTIVITY — Isavuconazole is a
broad-spectrum triazole antifungal that has in vitro
activity against most Candida spp., Trichosporon
spp., Aspergillus spp., the Mucorales, Fusarium spp.,
Scedosporium spp., and dimorphic fungi.3
CLINICAL STUDIES — Approval of isavuconazonium
sulfate for treatment of invasive aspergillosis was
based on the results of a double-blind trial (SECURE)
in 516 patients with invasive fungal disease caused by

Table 1. Some Drugs for Treatment of Invasive Aspergillosis
Drug

Some Available Formulations

Usual Adult Dosage1

Cost2

Azoles
Isavuconazonium sulfate –
Cresemba (Astellas)

372 mg single-use vials;
186 mg caps

372 mg IV or PO q8h x 6 doses, then
372 mg once/d

$6678.003

Posaconazole – Noxafil4 (Merck)

300 mg/16.7 mL IV soln; 40 mg/mL
300 mg IV q12h x 2 doses, then
PO susp; 100 mg delayed-release tabs5 300 mg once/d

14,852.60

Voriconazole – generic
Vfend (Pfizer)

200 mg single-use vials; 40 mg/mL
PO susp; 50, 200 mg PO tabs

6 mg/kg IV q12h x 2 doses, then 4 mg/kg
q12h6

9570.30

11,696.50

Echinocandins
Anidulafungin – Eraxis4 (Pfizer)

50, 100 mg single-use vials

200 mg IV on day 1, then 100 mg once/d

5040.00

Caspofungin – Cancidas (Merck)

50, 70 mg single-use vials

70 mg IV on day 1, then 50 mg once/d7

9455.90

Micafungin – Mycamine4 (Astellas)

50, 100 mg single-use vials

100-150 mg IV once/d

5236.00

Amphotericin B lipid complex (ABLC) –
Abelcet (Sigma Tau)

100 mg/20 mL single-use vials

5 mg/kg IV once/d

18,130.00

Liposomal amphotericin B (L-AmB) –
AmBisome (Astellas)

50 mg single-use vials

3-5 mg/kg IV once/d

21,373.80

Amphotericin B Products

1. Dosage adjustment may be required for hepatic or renal impairment.
2. Approximate WAC for 4 weeks' treatment with the lowest recommended adult maintenance dosage for a 70-kg patient. 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. February 5, 2016. Reprinted with permission by First Databank, Inc. All rights reserved. ©2016. www.fdbhealth.com/policies/drugpricing-policy. Cost of admnistration is not included.
3. Cost for IV formulation. Cost for 4 weeks' treatment with PO isavuconazonium sulfate is $3920.00.
4. Not FDA-approved for treatment of aspergillosis.
5. Noxafil delayed-release tablets and oral suspension are not interchangeable.
6. Patients who are responding may be switched to oral voriconazole, but the optimal dosage has not been established.
7. Daily dose may be increased to 70 mg if response is inadequate.

37

The Medical Letter

®

Aspergillus spp. or other filamentous fungi. Patients
were randomized to receive isavuconazonium sulfate
or voriconazole for a maximum of 84 days. The rate
of all-cause mortality through day 42 was similar with
the two drugs (19% with isavuconazonium vs 20% with
voriconazole). The overall response rates (complete
and partial) at the end of therapy were also similar in
both groups (35% vs 36%).4
A single-arm trial (VITAL) in a subset of 37 previously
treated or treatment-naive patients with proven or
probable invasive mucormycosis found that allcause mortality through day 84 was 43.2% with
isavuconazonium sulfate. A complete response at the
end of therapy was achieved in 14.3% of patients.5
According to the manufacturer, an unpublished, doubleblind, randomized trial (ACTIVE) in 440 patients with
candidemia and other invasive Candida infections did
not find isavuconazonium sulfate to be noninferior to
caspofungin (Cancidas); the overall response rate at
the end of IV therapy was 60.3% in the isavuconazole
group and 71.1% in the caspofungin group.
ADVERSE EFFECTS — Isavuconazonium sulfate is
generally well tolerated. The most common adverse
effects of the drug in clinical trials were nausea,
vomiting, diarrhea, headache, elevated hepatic
transaminases, hypokalemia, constipation, dyspnea,
cough, peripheral edema, and back pain. Hypotension,
chills, dizziness, paresthesia, and hypoesthesia have

been reported with IV administration.
In the invasive aspergillosis clinical trial, patients
treated with isavuconazonium sulfate had lower
incidences of hepatobiliary (9% vs 16%), eye (15% vs
27%), and skin or subcutaneous tissue (33% vs 42%)
adverse effects than those treated with voriconazole.
Drug-related adverse effects were reported in 109
patients (42%) receiving isavuconazonium and in 155
(60%) receiving voriconazole.4
Isavuconazole can shorten the QTc interval; the drug
is contraindicated in patients with familial short QT
syndrome.
PREGNANCY — Isavuconazonium sulfate is classified
as category C (perinatal mortality in rats and skeletal
abnormalities in rats and rabbits; no adequate studies
in pregnant women) for use during pregnancy.
DRUG INTERACTIONS — Isavuconazole is a substrate of
CYP3A4 and 3A5; coadministration with strong CYP3A4
inhibitors or inducers is contraindicated.6 It is also a
moderate inhibitor of CYP3A4 and mild inhibitor of the
38

Vol. 58 (1490)

March 14, 2016

Table 3. Some Advantages of Isavuconazonium Sulfate
vs Voriconazole1

▶ Once-daily dosing

▶ IV formulation can be used in patients with renal impairment
▶ No dosage adjustment for mild to moderate hepatic impairment
▶ Fewer CYP-mediated drug interactions
▶ Predictable pharmacokinetics
▶ Fewer serious adverse effects
▶ Active against Mucorales
1. NN Pettit and PL Carver. Ann Pharmacother 2015; 49:825; MH Miceli and
CA Kauffman. Clin Infect Dis 2015; 61:1558; MA Slavin and KA Thursky.
Lancet 2016, 387:726.

drug transporters P-glycoprotein (P-gp), organic cation
transporter 2 (OCT2), and breast cancer resistance
protein (BCRP). In vitro, it inhibits CYP2C8, 2C9, 2C19,
and 2D6 and induces CYP3A4, 2B6, 2C8, and 2C9; the
clinical significance of these effects is unknown.
DOSAGE AND ADMINISTRATION — The recommended
dosage of isavuconazonium sulfate for treatment of
invasive aspergillosis or mucormycosis is 372 mg
(IV or PO) every 8 hours for 6 doses, followed by 372
mg once daily. The injectable formulation should be
reconstituted, further diluted in 250 mL of diluent,
and administered over ≥1 hour through an in-line
filter to prevent an insoluble precipitate from forming
in the tubing or container. The capsules should
be swallowed whole and not be chewed, crushed,
dissolved, or opened. The capsules and the injectable
formulation are bioequivalent and can be used
interchangeably.
CONCLUSION — Isavuconazonium sulfate (Cresemba),
a prodrug of the triazole antifungal isavuconazole, was

noninferior to voriconazole (Vfend, and generics) in
one clinical trial for treatment of invasive aspergillosis,
and was less likely than voriconazole to cause hepatobiliary, ophthalmic, and cutaneous adverse effects. It
also appears to be effective for treatment of invasive
mucormycosis; how it compares to amphotericin B
(AmBisome, and others) or posaconazole (Noxafil) for
this indication remains to be determined. ■
1. KA Marr et al. Combination antifungal therapy for invasive aspergillosis: a randomized trial. Ann Intern Med 2015; 162:81.
2. Antifungal drugs. Treat Guidel Med Lett 2012; 10:61.
3. GR Thompson 3rd and NP Wiederhold. Isavuconazole: a comprehensive review of spectrum of activity of a new triazole. Mycopathologia 2010; 170:291.
4. JA Maertens et al. Isavuconazole versus voriconazole for primary treatment of invasive mould disease caused by Aspergillus and other filamentous fungi (SECURE): a phase 3, randomised-controlled, non-inferiority trial. Lancet 2016; 387:760.
5. FM Marty et al. Isavuconazole treatment for mucormycosis: a
single-arm open-label trial and case-control analysis. Lancet
Infect Dis 2016 (in press).
6. Inhibitors and inducers of CYP enzymes and P-glycoprotein.
Med Lett Drugs Ther 2013; 55:e44.


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Review the efficacy and safety of low-dose meloxicam (Vivlodex) for treatment of osteoarthritis pain.
4.
Review the efficacy and safety of isavuconazonium sulfate (Cresemba) for treatment of invasive aspergillosis and invasive mucormycosis.
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Issue 1490 Questions
(Correspond to questions #51-60 in Comprehensive Exam #74, available July 2016)
Safety of Testosterone Replacement Therapy
1. The double-blind, placebo-controlled clinical trials that evaluated
the efficacy of testosterone replacement therapy in men ≥65 years
old found that the hormone produced the greatest improvement in:
a. sexual function
b. physical function
c. vitality
d. mood
2. Studies of the association between testosterone replacement
therapy and cardiovascular risk have found:
a. an increase in risk
b. no significant change in risk
c. a decrease in risk
d. all of the above
Zarxio – A Filgrastim Biosimilar
3. A biosimilar must:
a. not have clinically meaningful differences in safety, purity, or
potency from the reference product
b. have the same mechanism of action as the reference product

c. have the same route of administration as the reference product
d. all of the above
4. Which of the following statements regarding Zarxio is true?
a. Zarxio is the second biosimilar filgrastim product to be
approved in the US
b. in one clinical trial, no significant pharmacokinetic differences
were detected between Zarxio and Neupogen
c. in one clinical trial, Zarxio increased the absolute neutrophil
count significantly more than Neupogen
d. Zarxio has been associated with more dose-related adverse
effects than Neupogen
Low-Dose Meloxicam (Vivlodex) for Osteoarthritis Pain
5. Which of the following statements regarding the new Vivlodex 10-mg
capsules is true ?
a. mean maximum serum concentrations are higher with the new
formulation than with 15-mg meloxicam tablets
b. median time to reach peak serum concentrations is shorter
with the new formulation than with 15-mg meloxicam tablets
c. the new low-dose formulation is more likely to cause
hepatotoxicity than the standard-dose formulation
d. all of the above

6. Adverse effects of Vivlodex include:
a. diarrhea
b. nausea
c. abdominal discomfort
d. all of the above
7. A 70-year-old woman with osteoarthritis pain controlled with
acetaminophen recently saw an advertisement for Vivlodex and
asks if she should switch to the new formulation. You should tell her

that:
a. acetaminophen is the preferred first-line treatment for
management of osteoarthritis pain
b. NSAIDs are not as effective as acetaminophen, especially in
the elderly
c. she should switch to Vivlodex because it causes fewer adverse
effects than acetaminophen
d. all of the above
Isavuconazonium Sulfate (Cresemba) – A New Antifungal
8. Invasive mucormycosis is usually treated with surgical debridement
and:
a. voriconazole
b. voriconazole plus an echinocandin
c. a lipid formulation of amphotericin B
d. an echinocandin
9. In the clinical trial for treatment of invasive aspergillosis,
isavuconazonium sulfate:
a. was significantly more effective than voriconazole in reducing
all-cause mortality through day 84 of treatment
b. caused less ophthalmic adverse effects than voriconazole
c. was associated with overall response rates that were
significantly higher than those achieved with voriconazole
d. all of the above
10. You are considering treating a 55-year-old woman who has invasive
aspergillosis and moderate renal dysfunction with IV voriconazole,
but the ID consult suggests IV isavuconazonium sulfate instead.
Which of the following statements about the two antifungals is true?
a. unlike IV voriconazole, IV isavuconazonium sulfate can be
used in patients with moderate renal impairment
b. isavuconazonium sulfate may have fewer drug interactions

than voriconazole
c. following a loading dose, isavuconazonium sulfate is dosed
once daily
d. all of the above

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Comprehensive Exam 74: 0379-0000-16-074-H01-P; Release: July 2016, Expire: July 2017

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