The medical letter on drugs and therapeutics june 23 2014

The Medical Letter

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

Low-Dose Aspirin for Prevention of Preeclampsia ...................................... p 49
Luliconazole Cream (Luzu) for Tinea Infections .......................................... p 50
Tobramycin Inhalation Solution (Bethkis) for Cystic Fibrosis .................... p 51

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The Medical Letter

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On Drugs and Therapeutics
Published by The Medical Letter, Inc. • 145 Huguenot Street, New Rochelle, NY 10801 • A Nonprofit Publication
Volume 56 (Issue 1445)
June 23, 2014

ALSO IN THIS ISSUE

Luliconazole Cream (Luzu) for Tinea
Infections....................................................... p 50
Tobramycin Inhalation Solution (Bethkis)
for Cystic Fibrosis........................................ p 51

Low-Dose Aspirin for Prevention
of Preeclampsia
The American College of Obstetricians and Gynecologists (ACOG) and the US Preventive Services Task
Force (USPSTF) have recommended that women at
risk for preeclampsia take low-dose aspirin daily after
the first trimester.1,2
PREECLAMPSIA — Preeclampsia is a multisystem
disorder characterized by hypertension and proteinuria
that occurs after 20 weeks’ gestation and can result in
significant maternal and fetal morbidity and mortality.
In severe cases, the mother may have severe
headache, visual disturbances, thrombocytopenia,
renal insufficiency, and impaired liver function, with
an increased risk of seizures (eclampsia), pulmonary

edema, stroke, and death. In the fetus, preeclampsia can
cause intrauterine growth restriction, premature delivery,
and death. Delivery is the only definitive treatment.
A NEW REVIEW — An analysis of 21 randomized controlled trials and 2 observational studies in women at
high or average risk for preeclampsia found that daily
low-dose aspirin (50-150 mg/day) started as early as
the second trimester was associated with absolute risk
reductions of 2-5% for preeclampsia, 1-5% for intrauterine growth restriction, and 2-4% for preterm birth.
None of these reductions were statistically significant.3
RECOMMENDATIONS — ACOG recommends lowdose aspirin (60-80 mg/day) beginning in the late first
trimester for women with a history of early-onset preeclampsia and preterm delivery at <34 weeks’ gestation
or preeclampsia in more than one prior pregnancy.1

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The USPSTF has released a preliminary statement
recommending low-dose aspirin (81 mg/day) for
patients with ≥1 high-risk factors (prior preeclampsia,
multiple gestation pregnancy, chronic hypertension,
diabetes, kidney disease, or autoimmune disease)
or several moderate-risk factors (nulliparity, obesity,
family history of preeclampsia, African American
race, low socioeconomic status, age >35 years,
previous adverse pregnancy outcome, >10-year
interval between pregnancies, or mother who
was born with a low birth weight or was small for
gestational age).2
ADVERSE EFFECTS — Low-dose aspirin taken after
the first trimester has not been shown to increase the

risk of antepartum or postpartum bleeding in the mother
or the newborn infant. The largest available controlled
trial of low-dose aspirin in pregnancy found no increase
in bleeding and no effect on the development of the
infant up to age 18 months.4
CONCLUSION — The evidence that low-dose aspirin
(81 mg/day) taken after 12 weeks’ gestation reduces the
risk of preeclampsia in women at risk for this disorder
is limited, but use of low-dose aspirin for this indication
generally appears to be safe. □
1. The American College of Obstetricians and Gynecologists.
Hypertension in pregnancy. Available at: />Resources_And_Publications/Task_Force_and_Work_Group_
Reports/Hypertension_in_Pregnancy. Accessed June 16, 2014.
2. U.S. Preventive Services Task Force. Low-dose aspirin for
the prevention of morbidity and mortality from preeclampsia:
U.S. Preventive Services Task Force recommendation statement
draft. Available at: />uspstf14/asprpreg/asprpregdraftrec.htm. Accessed June 16, 2014.
3. JT Henderson et al. Low-dose aspirin for prevention of morbidity
and mortality from preeclampsia: a systematic evidence review
for the U.S. Preventive Services Task Force. Ann Intern Med
2014; 160:695.
4. CLASP (Collaborative Low-dose Aspirin Study in Pregnancy)
Collaborative Group. CLASP: a randomised trial of low-dose aspirin for the prevention and treatment of pre-eclampsia among
9364 pregnant women. Lancet 1994; 343:619.

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49

Luliconazole Cream (Luzu) for Tinea
Infections
The FDA has approved luliconazole (Luzu Cream, 1% –
Valeant) for treatment of tinea pedis, tinea cruris, and
tinea corporis infections.
DRUGS FOR TINEA PEDIS — Tinea pedis is the most
common form of tinea infection. It is generally treated
with a topical allylamine, benzylamine, or imidazole
antifungal for 4 weeks (see Table 1). Allylamines
are more active in vitro than imidazoles against the
dermatophytes that cause the disease, but cure rates
for allylamines, benzylamines, and imidazoles have
generally been similar. Cure rates have been lower
with tolnaftate, and nystatin is not effective. Relapse is
common with all of these drugs.
PHARMACOLOGY — Maximum plasma concentrations of luliconazole were low but measurable after topical application of about 3.5 grams of cream daily for 15
days in patients with moderate to severe tinea pedis
or tinea cruris and were about 8-fold higher in patients
treated for tinea cruris.

CLINICAL STUDIES — Luliconazole applied once
daily for 14 days was compared to its vehicle alone in 2
unpublished, randomized, double-blind trials (summarized
in the package insert) in a total of 423 patients with
culture-proven tinea pedis. Complete clearance (clinical
and mycological cure) at 4 weeks post-treatment (the
primary endpoint) occurred in the 2 studies in 26% and
14% of patients treated with the active drug compared
to 2% and 3% of those treated with the vehicle alone.
Mycological cure occurred in the 2 studies in 62% and

56% of patients treated with the active drug compared to
18% and 27% of those treated with the vehicle alone. In
one similar published trial, 11 of 41 patients (27%) treated
for 2 weeks with luliconazole and 2 of 22 (9%) treated
with the vehicle alone achieved complete clearance at 2
weeks post-treatment (the primary endpoint).1
A randomized, double-blind, controlled trial of luliconazole
once daily for 7 days in 256 patients with tinea cruris found
that 35 of 165 patients (21%) treated with the active drug
and 4 of 91 (4%) treated with the vehicle alone achieved
complete clearance at 21 days post-treatment. Mycological cure occurred in 78% of those treated with luliconazole
compared to 45% of those treated with the vehicle alone.2

Table 1. Some Topical Antifungals for Tinea Pedis Infection
Drug

Some Available
Formulations1

Usual Adult
Dosage2

Cream, gel
Cream
Cream, gel

once/d x 2-4 wks4
bid x 1-2 wks7

Cream

Cream

once/d x 4 wks
or bid x 1 wk

Cream, solution
Cream
Cream
Cream
Cream
Cream, powder spray, powder
Liquid spray, powder spray, powder
Liquid spray, powder spray, powder
Cream, lotion
Cream
Cream, solution

bid x 4 wks

Cost3

Allylamines
Naftifine – Naftin (Merz)
Terbinafine6 – generic
Lamisil AT6 (Novartis Consumer)

$294.105
5.30
7.20

Benzylamines
Butenafine – Mentax (Mylan)
Lotrimin Ultra6 (MSD Consumer)

90.10
7.10

Imidazoles
Clotrimazole6 – generic
Lotrimin AF 6 (MSD Consumer)
Econazole – generic
Ketoconazole – generic
Luliconazole – Luzu (Valeant)
Miconazole6 – generic
Lotrimin AF 6 (MSD Consumer)
Desenex 6 (Novartis Consumer)
Oxiconazole – Oxistat (PharmaDerm)
Sertaconazole – Ertaczo (Valeant)
Sulconazole – Exelderm (Ranbaxy)

once/d x 4 wks
once/d x 6 wks
once/d x 2 wks
bid x 4 wks

once/d or bid x 4 wks
bid x 4 wks
bid x 4 wks

1.80

8.60
13.90
41.70
380.008
2.06
5.40
4.30
315.90
351.708
136.50

Other
Ciclopirox – generic
Loprox (Valeant)
Tolnaftate – generic
Tinactin 6 (MSD Consumer)

Gel, cream, lotion
Gel
Cream, lotion, solution, powder, spray, gel
Cream, liquid spray, powder spray, powder

bid x 4 wks
bid x 4 wks

64.50
627.809
2.70
7.20

1. Other formulations may be available for other indications.
2. Dosing schedule may vary based on formulation.
3. Approximate wholesale acquisition cost (WAC) for the number of tubes of cream or gel or bottles of powder spray needed for one course of treatment at the lowest usual
dosage (about 0.5 g/application). Source: Analy$ource® Monthly (Selected from FDB MedKnowledge™) June 5, 2014. Reprinted with permission by FDB, Inc. All rights
reserved. ©2014. www.fdbhealth.com/policies/drug-pricing-policy. Actual retail prices may be higher.
4. Four weeks for the 1% cream or gel; 2 weeks for the 2% formulations. The 1% gel should be applied bid.
5. Cost of a 45-g tube of Naftin 2% cream.
6. Available without a prescription.
7. One week between the toes; 2 weeks on bottom or sides of foot.
8. Cost of 60 g.
9. Cost of 100 g.

50

The Medical Letter • Volume 56 • Issue 1445 • June 23, 2014


ADVERSE EFFECTS — Luliconazole was well tolerated
in the clinical trials; adverse effects were similar to those
reported with use of the vehicle alone. Mild application
site reactions occurred in a few patients. Safety trials
in animals found that luliconazole cream had minimal
potential for irritation and did not show a potential
for sensitization, phototoxicity, or photoallergenicity.
Luliconazole is classified as category C (embryofetal
toxicity in animals at high doses; no adequate human
studies) for use during pregnancy.
DOSAGE AND ADMINISTRATION — Luzu is available
in 30- and 60-gram tubes. For treatment of tinea pedis,
it should be applied to affected areas and to about

1 inch of the adjacent areas once daily for 2 weeks.

Tobramycin Inhalation Solution
(Bethkis) for Cystic Fibrosis
The FDA has approved another solution of the
aminoglycoside antibiotic tobramycin (Bethkis –
Chiesi/Cornerstone) for oral inhalation via a nebulizer
for management of cystic fibrosis (CF) patients with
Pseudomonas aeruginosa.
INHALED ANTIBIOTICS FOR CF — Inhaled antibiotics, which can achieve high concentrations in the lung
with minimal systemic side effects, are probably the
most effective therapy available for chronic P. aeruginosa infection in patients with CF.1 Tobramycin and
aztreonam (Cayston) are the only 2 antibiotics that are
FDA-approved for such use. Bethkis delivers the same
dose of tobramycin as an older formulation (Tobi, and
generics), but in a more concentrated solution. An
orally inhaled dry powder formulation of tobramycin
(Tobi Podhaler) was approved by the FDA in 2013. It
is more convenient to administer than the nebulizer
solution, which may improve patient adherence, but it
can cause more cough, dysphonia, and dysgeusia.2,3
Inhaled tobramycin is generally preferred over inhaled

Application instructions are the same for tinea cruris
and tinea corporis, but the recommended treatment
duration is one week.
CONCLUSION — Luliconazole (Luzu Cream, 1%) appears to be moderately effective for treatment of tinea
pedis and tinea cruris infections. There is no evidence
that it is more effective than other topical antifungals
that are available generically or over the counter at a

much lower cost. □
1. M Jarratt et al. Luliconazole for the treatment of interdigital tinea
pedis: A double-blind, vehicle-controlled study. Cutis 2013; 91:203.
2. TM Jones et al. A randomized, multicenter, double-blind, vehiclecontrolled study evaluating the efficacy and safety of luliconazole
cream 1% once daily for 7 days in patients aged >12 years with
tinea cruris. J Drugs Dermatol 2014; 13:32.

aztreonam because more long-term data are available
supporting its safety and efficacy.
CLINICAL STUDIES — In two unpublished doubleblind trials (summarized in the package insert), a total
of 306 CF patients with P. aeruginosa infection were
randomized to receive the new tobramycin inhalation
solution or placebo for 1 cycle (28 days on treatment
followed by 28 days off) in study 1 and for 3 cycles in
study 2. All patients had a baseline forced expiratory
volume in one second (FEV1) between 40% and 80%
of predicted normal. Patients who received tobramycin
inhalation solution had statistically significant increases in FEV1 in both studies: 16% vs. 5% with placebo in
study 1 and 7% vs. 1% in study 2.
In one published study, Bethkis was compared to
Tobi inhalation solution in a randomized, open-label,
non-inferiority trial in 324 CF patients >6 years old
with chronic P. aeruginosa infection. After 28 days
of treatment, FEV1 increased by 7.0% with the new
formulation and by 7.5% with Tobi ; adverse events
were similar with the two formulations. In a 48-week
extension phase, improvements in lung function were

Table 1. Inhaled Antibiotics for Cystic Fibrosis
Drug

Formulations

Route

Usual Dosage1
≥6 yrs: 300 mg bid
x 28 days
≥6 yrs: 300 mg bid3
x 28 days
≥6 yrs: 112 mg (4 caps)
bid3 x 28 days
≥7 yrs: 75 mg tid
x 28 days

Tobramycin – Bethkis
(Chiesi/Cornerstone)
Tobi (Novartis)
generic
Tobi Podhaler (Novartis)

300 mg/4 mL ampule

Inhalation via nebuliizer

300 mg/5 mL ampule

Inhalation via nebulizer

28 mg capsule

Aztreonam lysine – Cayston
(Gilead)

75 mg vial of lyophilized powder
and 1 mL ampule of diluent

Inhalation via dry powder
inhaler
Inhalation via nebulizer

Cost2
3

$5675.00
7337.70
5769.10
6676.90
6070.80

1. One cycle consists of 28 days on treatment followed by 28 days off treatment.
2. Approximate wholesale acquisition cost for one treatment cycle. Source: Analy$ource® Monthly (Selected from FDB MedKnowledge™) June 5, 2014. Reprinted with
permission by FDB, Inc. All rights reserved. ©2014. www.fdbhealth.com/policies/drug-pricing-policy. Actual retail prices may be higher.
3. Doses should be inhaled as close to 12 hours apart as possible and not less than 6 hours apart.

The Medical Letter • Volume 56 • Issue 1445 • June 23, 2014

51

maintained in patients who continued to take the new
formulation, and no new safety issues were reported.4
ADVERSE EFFECTS — In the controlled clinical trials,
adverse effects occurring in >3% of patients treated with
the new product and more often than with placebo included a decrease in FEV1, rales, dysphonia, wheezing,
and epistaxis. Bronchospasm can occur. Voice alteration
and tinnitus have been reported with use of the older
formulation of tobramycin inhalation solution. Systemic
aminoglycosides can be nephrotoxic and possibly ototoxic, but the low serum concentrations associated with
oral inhalation of tobramycin make these effects unlikely.
Aminoglycosides are classified as category D (positive
evidence of fetal harm) for use during pregnancy. Whether
inhalation of tobramycin could harm a fetus is unknown.
USE WITH AZITHROMYCIN — Concomitant use of
oral azithromycin may antagonize the therapeutic effect
of inhaled tobramycin.5
DOSAGE AND ADMINISTRATION — The contents of
one 300 mg/4 mL ampule of tobramycin solution should
be inhaled by mouth via a nebulizer twice daily. The
doses should be taken as close to 12 hours apart as
possible, and not less than 6 hours apart.
Bethkis should be administered using the hand-held
PARI LC PLUS reusable nebulizer with a PARI Vios air
compressor over a period of about 15 minutes. Each cycle consists of 28 days on treatment followed by 28 days
off. Bethkis is supplied in cartons of 7 or 14 foil pouches,
each containing 4 single-use 300 mg/4 mL ampules,
which should be refrigerated and protected from light.
CONCLUSION — A new, more concentrated tobramycin
inhalation solution (Bethkis) for cystic fibrosis patients
with Pseudomonas aeruginosa appears to be similar in

efficacy and safety to the older tobramycin nebulizer solution (Tobi). How it compares to tobramycin inhalation
powder (Tobi Podhaler) or aztreonam inhalation solution
(Cayston) for this indication remains to be determined. □
1. L Máiz et al. Inhaled antibiotics for the treatment of chronic bronchopulmonary Pseudomonas aeruginosa infection in cystic fibrosis: systematic review of randomised controlled trials. Expert Opin
Pharmacother 2013; 14:1135.
2. Tobramycin inhalation powder (Tobi Podhaler) for cystic fibrosis.
Med Lett Drugs Ther 2013; 55:51.
3. MJ Harrison et al. Inhaled versus nebulised tobramycin: a real world
comparison in adult cystic fibrosis (CF). J Cyst Fibros 2014 May 9
(epub).
4. H Mazurek et al. Long-term efficacy and safety of aerosolized tobramycin 300 mg/4 ml in cystic fibrosis. Pediatr Pulmonol 2014 Jan 24 (epub).
5. JA Nick et al. Azithromycin may antagonize inhaled tobramycin
when targeting Pseudomonas aeruginosa in cystic fibrosis. Ann
Am Thorac Soc 2014; 11:342.

52

Coming Soon in The Medical Letter:
Treatment of Atrial Fibrillation
In Brief: Esomeprazole Strontium
Ceritinib (Zykadia) for Non-Small Cell Lung Cancer
RNS Stimulator Device for Epilepsy
Dalbavancin (Dalvance) for Skin and Skin Structure Infections
Propanolol (Hemangeol) for Infantile Hemangiomas
Oxycodone/Acetaminophen (Xartemis XR) for Pain

The Medical Letter

®

On Drugs and Therapeutics
EDITOR IN CHIEF: Mark Abramowicz, M.D.
EXECUTIVE EDITOR: Gianna Zuccotti, M.D., M.P.H., F.A.C.P., Harvard Medical School
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Jane P. Gagliardi, M.D., M.H.S., F.A.C.P Duke University School of Medicine
Jules Hirsch, M.D., Rockefeller University
David N. Juurlink, BPhm, M.D., Ph.D., Sunnybrook Health Sciences Centre
Richard B. Kim, M.D., University of Western Ontario
Hans Meinertz, M.D., University Hospital, Copenhagen
Sandip K. Mukherjee, M.D., F.A.C.C., Yale School of Medicine
Dan M. Roden, M.D., Vanderbilt University School of Medicine
Esperance A.K. Schaefer, M.D., M.P.H., Harvard Medical School
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The Medical Letter • Volume 56 • Issue 1445 • June 23, 2014


The Medical Letter

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Online Continuing Medical Education
To take CME exams and earn credit, go to:
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Issue 1445 Questions
(Correspond to questions #73-78 in
Comprehensive Exam #70, available July 2014)
Low-Dose Aspirin for Prevention of Preeclampsia
1.

Which of the following are considered high-risk factors for preeclampsia?
a. twins
b. diabetes

c. autoimmune disease
d. all of the above

2.

Taking low-dose aspirin daily throughout the second and third trimesters of
pregnancy has been shown to reduce the absolute risk of preeclampsia by
as much as:
a. 5%
b. 20%
c. 40%
d. 80%

Luliconazole Cream (Luzu) for Tinea Infections
3.

In the published trial, complete clearance of tinea pedis (clinical and
mycological cure) 2 weeks post-treatment with luliconazole occurred in
about what percentage of patients?
a. 25%
b. 40%
c. 60%
d. 75%

4.

A 20-year-old college basketball player with tinea pedis and no health
insurance has been given a sample tube and a prescription for Luzu cream
but is concerned about the cost. You could tell him that:
a. Luliconazole has been shown to be more effective than most

other topical products for treatment of tinea pedis.
b. Luliconazole is an imidazole antifungal, and this class of topical
antifungals has been shown to be more effective than any other,
but he could use a less expensive imidazole product.
c. Luliconazole has been shown in clinical trials to be more
effective than other imidazole antifungals.
d. Cure rates have generally been similar with all topical antifungals
used to treat tinea pedis, and there is no good reason to pay for
an expensive brand name product for this condition.

Tobramycin Inhalation Solution (Bethkis) for Cystic Fibrosis
5.

Compared to the older tobramycin inhalation solution (Tobi), Bethkis:
a. is easier to administer
b. is more concentrated
c. has been shown to be more effective in eradicating
Pseudomonas aeruginosa
d. all of the above

6.

Concomitant use of which of the following may antagonize the therapeutic
effect of inhaled tobramycin?
a. inhaled albuterol
b. oral aztreonam
c. oral azithromycin
d. an inhaled anticholinergic

ACPE UPN: Per Issue Exam: 0379-0000-14-445-H01-P; Release: June 23, 2014, Expire: June 23, 2015

Comprehensive Exam 70: 0379-0000-14-070-H01-P; Release: July 2014, Expire: July 2015

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GOAL:
Through this program, The Medical Letter expects to provide the healthcare community with unbiased, reliable, and
timely educational content that they will use to make independent and informed therapeutic choices in their practice.
LEARNING OBJECTIVES:
Activity participants will read and assimilate unbiased reviews of FDA-approved and off-label uses of drugs and
other treatment modalities. Activity participants will be able to select and prescribe, or confirm the appropriateness
of the prescribed usage of, the drugs and other therapeutic modalities discussed in The Medical Letter with specific
attention to clinical trials, pathophysiology, dosage and administration, drug metabolism and interactions, and patient
management. Activity participants will make independent and informed therapeutic choices in their practice.
Upon completion of this program, the participant will be able to:
1.
Explain the evidence supporting the use of low-dose aspirin for prevention of preeclampsia.
2.
Review the efficacy and safety of luliconazole cream (Luzu) for treatment of tinea infections.
3.
Review the efficacy and safety of tobramycin inhalation solution (Bethkis) for treatment of cystic fibrosis patients with
Pseudomonas aeruginosa and explain how it compares to other available inhaled antibiotics for this indication.
Privacy and Confidentiality: The Medical Letter guarantees our firm commitment to your privacy. We do not sell any
of your information. Secure server software (SSL) is used for commerce transactions through VeriSign, Inc. No credit
card information is stored.
IT Requirements: Windows XP/Vista/7/8, Mac OS X+; current versions of Microsoft IE, Mozilla Firefox, Google Chrome,
Safari or any other compatible Web browser. High-speed connection.
Have any questions? Call us at 800-211-2769 or 914-235-0500 or e-mail us at: