The medical letter on drugs and therapeutics april 13 2015

The Medical Letter

®

on Drugs and Therapeutics
Objective Drug Reviews Since 1959
Volume 57

ISSUE
ISSUE
No.

1433
1466
Volume 56

April 13, 2015

IN THIS ISSUE

Ivermectin Cream (Soolantra) for Rosacea ................................................................. p 51
Advice for Travelers ................................................................................................... p 52
In Brief: Severe Bradycardia with Sofosbuvir and Amiodarone ................................... p 58

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The Medical Letter

®

on Drugs and Therapeutics
Objective Drug Reviews Since 1959
Volume 57

ISSUE

ISSUE No.

1433
1466
Volume 56

▶

April 13, 2015
Take CME Exams
ALSO IN THIS ISSUE

Advice for Travelers ...............................................................................................................p 52
In Brief: Severe Bradycardia with Sofosbuvir and Amiodarone ...........................................p 58

Ivermectin Cream (Soolantra) for
Rosacea

The FDA has approved a 1% cream formulation
of the antiparasitic drug ivermectin (Soolantra –
Galderma) for topical treatment of inflammatory
lesions of rosacea. Ivermectin is available in the US
in tablets (Stromectol, and generics) for treatment of
onchocerciasis and other worm infestations and as a
0.5% lotion (Sklice) for treatment of head lice.
Pronunciation Key
Ivermectin: eye" ver mek' tin
Soolantra: soo lahn' tra

MECHANISM OF ACTION — The mechanism of
action of ivermectin in rosacea is unknown. The
drug has antiparasitic activity and possibly an antiinflammatory effect, and Demodex mites have been
implicated in the pathogenesis of the inflammatory
facial eruptions that characterize the disease.1
Table 1. Pharmacology
Drug class

Antiparasitic drug

Formulation

1% cream in 30, 45, and 60 g tubes

Route

Topical

Tmax

10 hours

Half-life (terminal)

~6.5 days

Metabolism

Primarily by CYP3A4

Excretion

Not characterized

TREATMENT OF ROSACEA — Rosacea is a common,
chronic inflammatory facial eruption of unknown
cause characterized by erythema, telangiectasias, and
recurrent, progressive crops of acneiform papules and

pustules, usually on the central part of the face.
Topical antibacterial drugs such as metronidazole
(Metrocream, and others) and azelaic acid (Finacea)
are generally tried first, sometimes in combination

with oral antimicrobials, such as low-dose doxycycline, which can produce a more rapid response.
Topical retinoids are used for patients who do not
respond to topical antimicrobials. The oral retinoid
isotretinoin is generally reserved for patients with
severe inflammatory nodulocystic disease. A topical
gel formulation of the alpha2 agonist brimonidine
(Mirvaso) appears to be somewhat effective in
reducing facial erythema in patients with rosacea, but
it has no effect on the papulopustular component of
the disease.2 Light and laser therapies can decrease
the severity of telangiectasias and erythema.
CLINICAL STUDIES — FDA approval of ivermectin
cream for treatment of rosacea was based on two 12week, randomized, double-blind trials that compared
once-daily application of ivermectin cream with its
vehicle alone in a total of 1371 patients with moderate
to severe papulopustular rosacea. In both trials,
complete or almost complete clearing of lesions
occurred in significantly more patients treated with
ivermectin (38.4% and 40.1%) than with the vehicle
alone (11.6% and 18.8%). Ivermectin reduced the
number of inflammatory lesions from baseline by
76% and 75%, compared to reductions of 50% with the
vehicle alone in both trials.3
Two 40-week extensions of these trials found that the
percentages of patients with complete or almost complete

clearing of lesions increased to 71.1% and 76% in the two
studies with continued use of ivermectin cream.4
A 16-week randomized trial in 962 patients with
moderate to severe papulopustular rosacea found that
ivermectin 1% cream once daily was significantly more
effective than metronidazole 0.75% cream twice daily
in reducing the number of inflammatory lesions from
baseline (83.0% vs. 73.7%) and in clearing or almost
clearing the lesions (84.9% vs. 75.4%).5
51

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The Medical Letter

Vol. 57 (1466)

®

▶

Table 2. Some Topical Drugs for Rosacea
Drug
Metronidazole –
generic
Metrocream
(Galderma)
Metrolotion
Metrogel

Some
Formulations

Usual Dosage1

Cost2

Apply once/d
0.75% gel, cream,
lotion; 1% gel
0.75% cream

$151.80

3

517.40

0.75% lotion
0.75%, 1% gel

594.70
311.404

Azelaic acid –
Finacea
(Bayer)

15% gel

Apply bid

255.00

Ivermectin –
Soolantra
(Galderma)

1% cream

Apply once/d

275.00

1. A pea-sized amount should be applied in a thin layer to each affected area
of the face.
2. Approximate WAC for the smallest size metered-dose pump or tube available. WAC = wholesaler acquisition cost, or manufacturer’s published price
to wholesalers; WAC represents a published catalogue or list price and may
not represent actual transactional prices. Source: AnalySource® Monthly.
March 5, 2015. Reprinted with permission by First Databank, Inc. All rights
reserved. ©2015. www.fdbhealth.com/policies/drug-pricing-policy.
3. Cost of a 45-g tube of 0.75% cream.
4. Cost of a 55-g metered-dose pump of 1% gel.

ADVERSE EFFECTS — Burning and irritation of the skin
occurred in ≤1% of patients treated with ivermectin
cream in clinical trials. No systemic effects of the drug
were reported.
Pregnancy – Based on studies with large doses of oral

ivermectin in animals, Soolantra has been classified
as category C (evidence of toxicity in animals, no
adequate studies in women) for use during pregnancy.
DOSAGE AND ADMINISTRATION — A pea-sized
amount of ivermectin cream should be applied in a
thin layer to each affected area of the face (forehead,
nose, chin, and each cheek) once daily.
CONCLUSION — Ivermectin 1% cream (Soolantra)
appears to be effective for treatment of papulopustular
rosacea, with minimal adverse effects. ■
1. M Brown et al. Severe Demodex folliculorum-associated oculocutaneous rosacea in a girl successfully treated with ivermectin. JAMA Dermatol 2014; 150:61.
2. Brimonidine gel (Mirvaso) for rosacea. Med Lett Drugs Ther
2013; 55:82.
3. L Stein Gold et al. Efficacy and safety of ivermectin 1% cream
in treatment of papulopustular rosacea: results of two randomized, double-blind, vehicle-controlled pivotal studies. J Drugs
Dermatol 2014; 13:316.
4. L Stein Gold et al. Long-term safety of ivermectin 1% cream vs
azelaic acid 15% gel in treating inflammatory lesions of rosacea: results of two 40-week controlled, investigator-blinded
trials. J Drugs Dermatol 2014; 13:1380.
5. A Taieb et al. Superiority of ivermectin 1% cream over metronidazole 0.75% cream in treating inflammatory lesions of
rosacea: a randomized, investigator-blinded trial. Br J Dermatol
2014 Sept 16 (epub).

52

April 13, 2015

Advice for Travelers
Related article(s) since publication

Patients planning to travel to other countries often
ask for information about prevention of diarrhea,
malaria, and other travel-related conditions. Vaccines
recommended for travelers based on their destination,
length of stay, and planned activities were reviewed in
a previous issue.1
TRAVELERS’ DIARRHEA
The most common cause of travelers’ diarrhea,
usually a self-limited illness lasting several days,
is infection with noninvasive strains of Escherichia
coli. Infections with other types of bacteria such as
Campylobacter jejuni, Shigella spp., and Salmonella
spp., viruses, and parasites are less common. In
recent years, norovirus has become a more frequent
cause of diarrhea in travelers; according to one
study, norovirus infection was detected in 16% of
US travelers returning from Mexico with diarrhea.2
Travelers to areas where hygiene is poor should avoid
raw vegetables, fruit they have not peeled themselves,
unpasteurized dairy products, cooked food not served
steaming hot (dry foods such as bread are usually
safe), and tap water, including ice.
TREATMENT — For mild diarrhea without fever or
bloody stools, loperamide (Imodium, and others), an
over-the-counter synthetic opioid (4-mg loading dose,
then 2 mg orally after each loose stool to a maximum
of 8 mg/d for adults), often relieves symptoms in <24
hours, but some patients complain of constipation
after taking it. Addition of loperamide to an appropriate
antibiotic can shorten the duration of illness.3

Loperamide is not recommended for use in children <2
years old.
If diarrhea is moderate to severe, associated with
high fever or bloody stools, or extremely disruptive
of travel plans, self-treatment with a fluoroquinolone
such as ciprofloxacin is usually recommended (see
Table 1).4 Fluoroquinolones are not recommended
for use in children or pregnant women. Azithromycin
is an effective alternative and is the drug of choice
for travelers to areas with a high prevalence of
fluoroquinolone-resistant C. jejuni, such as South and
Southeast Asia.5,6 It can also be used in patients who
do not respond to a fluoroquinolone within 48 hours.
Rifaximin, a nonabsorbed oral antibiotic, appears to
be similar in efficacy to ciprofloxacin for treatment of
diarrhea due to noninvasive E. coli, with fewer adverse
effects.7 It should not be used for invasive infections


The Medical Letter

®

Table 1. Some Antimicrobial Drugs for Treatment of
Travelers' Diarrhea
Drug

Adult Dosage

Azithromycin1 –

Zithromax* (Pfizer)
Ciprofloxacin3 –
Cipro* (Bayer)

500 mg once/d x 1-3d or
1000 mg once2
500 mg once/d or bid4 or 750 mg
once/d x 1-3d

extended-release1
Cipro XR*
Levofloxacin1,3 – Levaquin*
(Ortho-McNeil)

500 or 1000 mg once/d x 1-3d
500 mg once/d x 1-3d

Rifaximin – Xifaxan (Salix)5

200 mg tid x 3d

*Also available generically
1. Not FDA-approved for treatment of travelers' diarrhea.
2. Use of a single 1000-mg dose of azithromycin has been associated with a
high incidence of adverse effects, particularly nausea. Pediatric dosage is
10 mg/kg/d x 3 days.
3. Not recommended for use in children or pregnant women.
4. FDA-approved dosage for treatment of infectious diarrhea is 500 mg bid.
5. FDA-approved for treatment of travelers’ diarrhea caused by noninvasive
strains of E. coli in travelers ≥12 years of age.

associated with fever or blood in the stool or for those
caused by C. jejuni, Salmonella spp., or Shigella spp.
Packets of oral rehydration salts (Ceralyte, ORS, and
others) mixed in potable water can prevent and treat
dehydration. They are available from suppliers of
travel-related products and some pharmacies in the
US, and from pharmacies overseas.
PROPHYLAXIS — Travel medicine experts generally
do not recommend antibiotic prophylaxis for travelers’
diarrhea because of concerns about adverse effects
and development of resistance. Some travelers,
however, such as persons with immunocompromising
conditions, poorly-controlled diabetes, or chronic renal
failure, or those with time-dependent activities who
cannot risk the temporary incapacitation associated
with diarrhea, might benefit from prophylaxis.
In such patients, ciprofloxacin 500 mg or levofloxacin
500 mg can be given once daily during travel (not
exceeding 2-3 weeks) and for 2 days after return.
Azithromycin 250 mg once daily is an alternative. It
is preferred over a fluoroquinolone for travel to areas
with a high rate of fluoroquinolone-resistant C. jejuni,
such as South and Southeast Asia. Rifaximin (200 mg
once or twice daily) appears to be effective in preventing
travelers’ diarrhea. In a recent study, it reduced the
incidence by 48%, compared to placebo, in travelers
going to South and Southeast Asia for 6-28 days.8
Bismuth subsalicylate (Pepto-Bismol, and others), 2
tablets (524 mg) 4 times a day taken for the duration

of travel, can prevent diarrhea in travelers, but it is less
effective than antibiotics and can cause the tongue and
stools to turn black. It is not recommended for children
<3 years old.

Vol. 57 (1466)

April 13, 2015
INSECT BITES

To minimize insect bites, travelers should wear lightcolored, long-sleeved shirts, pants, and socks and
covered shoes. They should sleep in air-conditioned
or screened areas and use insecticide-impregnated
bed nets. Mosquitoes that transmit malaria are most
active between dusk and dawn; those that transmit
dengue and chikungunya fever bite during the day,
particularly during early morning and late afternoon.9
DEET — The most effective topical insect repellent is N,
N-diethyl-m-toluamide (DEET). Applied on exposed skin,
DEET repels mosquitoes, as well as ticks, chiggers, fleas,
gnats, and some flies. DEET is available in formulations
of 5-100%, but increasing the concentration above 50%
has not been shown to improve efficacy. Travel medicine
experts prefer concentrations of 20-35%.
According to the CDC, DEET is safe for use in children
and infants >2 months old, but the American Academy
of Pediatrics recommends use of formulations
containing no more than 30% in children. One study
found that applying DEET regularly during the second
and third trimesters of pregnancy did not result in any

adverse effects on the fetus.10
DEET has been shown to decrease the effectiveness
of sunscreens when it is applied after the sunscreen;
nevertheless, sunscreen should be applied first
because it may increase the absorption of DEET when
DEET is applied first.11
PICARIDIN — Picaridin, which appears to be better
tolerated on the skin than DEET, is used against
flies, mosquitoes, chiggers, and ticks. It is available
in concentrations of 5-20%. The 20% formulation
(Natrapel 8 Hour; GoReady, and others) has been
shown to repel mosquitoes for up to 8 hours.12-14
OTHERS — IR3535 (Skin So Soft Bug Guard Plus
Expedition, SkinSmart, and others) and oil of lemon
eucalyptus (Repel, Off! Botanicals, and others) have
also been shown to prevent mosquito bites.15
PYRETHROIDS — Permethrin (Duranon, Permanone,
and others), a synthetic pyrethroid insecticide
available in liquid and spray forms, can be used on
clothing, mosquito nets, tents, and sleeping bags
for protection against mosquitoes and ticks. After
application to clothing, it remains active for several
weeks through multiple launderings. The combination
of DEET on exposed skin and permethrin on clothing
provides increased protection. Use of pyrethroidimpregnated mosquito nets while sleeping is helpful.
53


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®

Long-lasting insecticide-treated nets are available
that maintain effective levels of insecticide for at
least 3 years.
MALARIA
No drug is 100% effective for prevention of malaria;
travelers should be told to use protective measures
against mosquito bites in addition to medication.16
Travelers to malarious areas should be reminded to
seek medical attention if they develop fever either
during their trip or within the year after their return
(especially during the first 2 months). Travelers to
developing countries, where counterfeit and poor
quality drugs are common, should obtain antimalarial
agents before travel. Countries with a risk of malaria
are listed in Table 2.
CHLOROQUINE-SENSITIVE MALARIA — Chloroquine
is generally the drug of choice for prevention of
malaria in the few areas that still have chloroquinesensitive malaria (see Table 2, footnotes 5 and 7).
Patients who cannot take chloroquine should take
atovaquone/proguanil, doxycycline, mefloquine or, in
some circumstances, primaquine in the same doses
used for chloroquine-resistant malaria (see Table 3).
CHLOROQUINE-RESISTANT MALARIA — Three drugs
with
similar
efficacy
(atovaquone/proguanil,
mefloquine, and doxycycline) are recommended for

prevention of malaria in US travelers to areas with
chloroquine resistance.
The fixed-dose combination of atovaquone and
proguanil taken once daily is generally the best
tolerated prophylactic,17 but it can cause headache,
GI disturbances, nightmares, insomnia, and mouth
ulcers, and it is expensive. Cases of Stevens-Johnson
syndrome and hepatitis have been reported. There
have been isolated case reports of treatment-related
resistance to atovaquone/proguanil in Plasmodium
falciparum, but acquisition of resistant disease in
travelers appears to be rare.18-20 The protective efficacy
of atovaquone/proguanil against Plasmodium vivax is
variable; it has ranged from 84% in Indonesian New
Guinea21 to 100% in Columbia.22
Mefloquine has the advantage of once-weekly dosing,
but it is contraindicated in patients with a history of
any psychiatric disorder (including severe anxiety and
depression), and also in those with a history of seizures or cardiac conduction abnormalities.23 Dizziness,
headache, insomnia, and disturbing dreams are the
most common CNS adverse effects. The drug appears
to be better tolerated in children, with a lower incidence
54

April 13, 2015

Vol. 57 (1466)

Table 2. Countries with a Risk of Malaria1
AFRICA

Angola
Benin
Botswana2
Burkina Faso
Burundi
Cameroon
Cape Verde3
Central African
Republic
Chad
Comoros
Côte d’Ivoire
Democratic
Republic of the
Congo
Djibouti
Equatorial Guinea
Eritrea2

Ethiopia2
Gabon
Gambia, The
Ghana
Guinea
Guinea-Bissau
Kenya2
Liberia
Madagascar
Malawi
Mali

Mauritania
Mayotte
Mozambique
Namibia
Niger
Nigeria

Republic of the
Congo
Rwanda
São Tomé
and Príncipe
Senegal
Sierra Leone
Somalia
South Africa2,4
Sudan
South Sudan
Swaziland
Tanzania
Togo
Uganda
Western Sahara
Zambia
Zimbabwe

AMERICAS
Belize2,5
Bolivia2
Brazil

Colombia2
Dominican
Republic2,5
Ecuador2

French Guiana2
Guatemala2,5
Guyana
Haiti5
Honduras2,5
Mexico5
Nicaragua5

Panama2
Paraguay2,5,6
Peru2
Suriname
Venezuela2

ASIA
Afghanistan
Bangladesh2
Bhutan2
Burma (Myanmar)2,8
Cambodia2,8
China2,7,8
India
Indonesia2
Iran2

Korea, North5
Korea, South2,5
Laos2,8
Malaysia2
Myanmar (Burma)2,8
Nepal2
Pakistan
Philippines2
Saudi Arabia2

Tajikistan
Thailand2,8
Timor-Leste
(East Timor)
Turkey2,5
Vietnam2,8
Yemen

OCEANIA
Papua New Guinea

Solomon Islands

Vanuatu

1. Only includes countries for which prophylaxis is recommended.
Regional variation in risk may exist within a country. Updated detailed
information is available at www.cdc.gov/malaria/travelers/country_
table/a.html and medical personnel can call the CDC Malaria Hotline at
770-488-7788.

2. No malaria in major urban areas.
3. Limited to island of Saõ Tiago.
4. Limited to KwaZulu-Natal, Limpopo, and Mpumalanga provinces, and
Kruger National Park.
5. Chloroquine is the drug of choice for prophylaxis.
6. Limited to departments of Alto Paraná, Caaguazu, and Canediyú.
7. Chloroquine is recommended in Anhui, Guizhou, Henan and Hubei
provinces.
8. Mefloquine resistance has been reported in the malarious areas of
Thailand and along the borders between Cambodia, China, Laos, Burma,
and Thailand (Laos-Burma, Laos-Thailand, China-Burma, etc.) and in
southern Vietnam.

of CNS effects.24 If a patient develops psychological
or behavioral abnormalities such as depression,
restlessness, or confusion while taking mefloquine,
another drug should be substituted. Halofantrine (not
available in the US) or ketoconazole should not be taken
with mefloquine, or within 15 weeks of the last dose of
mefloquine, due to potentially fatal prolongation of the
QT interval. Quinine, quinidine, or chloroquine should
not be taken with mefloquine.
Doxycycline, which frequently causes GI disturbances
and can cause photosensitivity and vaginitis, is an


The Medical Letter

®

Vol. 57 (1466)

April 13, 2015

Table 3. Drugs of Choice for Prevention of Malaria1

Drug

Adult Dosage

All Plasmodium species in chloroquine-sensitive areas2,3
Chloroquine phosphate4,5
500 mg (300 mg base)
(Aralen, and others)
once/wk
All Plasmodium species in chloroquine-resistant areas2,3
Atovaquone/proguanil6
1 adult tablet (250 mg/
(Malarone, Malarone Pediatric,
100 mg) once/d6
and others)

Pediatric Dosage

Duration

5 mg/kg base (300 mg max)
once/wk

Start: 1-2 wks before travel

Stop: 4 wks after leaving
malarious zone

5-8 kg: ½ ped tab/d6
9-10 kg: ¾ ped tab/d6
11-20 kg: 1 ped tab/d6
21-30 kg: 2 ped tabs/d6
31-40 kg: 3 ped tabs/d6
>40 kg: 1 adult tab/d6
≥8 yrs: 2.2 mg/kg/d,
up to 100 mg/d

Start: 1-2d before travel
Stop: 1 wk after leaving
malarious zone7

Doxycycline8
(Vibramycin, and others)

100 mg once/d

Mefloquine9

250 mg once/wk10

≤9 kg: 5 mg/kg salt once/wk11
10-19 kg: ¼ tab once/wk11
20-30 kg: ½ tab once/wk
31-45 kg: ¾ tab once/wk
>45 kg: 1 tab once/wk

30 mg base once/d

0.5 mg/kg base once/d

Alternative:
Primaquine phosphate13,14

1.
2.

3.

4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.

Start: 1-2d before travel
Stop: 4 wks after leaving
malarious zone
Start: ≥2 wks before travel12
Stop: 4 wks after leaving

malarious zone

Start: 1-2d before travel
Stop: 1 wk after leaving
malarious zone

No drug guarantees protection against malaria. Travelers should be advised to seek medical attention if fever develops during travel or after they return. Insect
repellents, insecticide-impregnated bed nets, and proper clothing are important adjuncts for malaria prophylaxis.
Chloroquine-resistant P. falciparum occurs in all malarious areas except Central America (resistance occurs in Panama east of the Canal Zone), Mexico, Haiti, the
Dominican Republic, Paraguay, North and South Korea, most of rural China, and some countries in the Middle East (chloroquine resistance has been reported in
Yemen, Saudi Arabia, and Iran). P. vivax with decreased susceptibility to chloroquine is a significant problem in Papua New Guinea and Indonesia. There are also
reports of resistance from Burma (Myanmar), Vietnam, the Solomon Islands, Vanuatu, Turkey, Guyana, Brazil, Colombia, and Peru (JK Baird, Clin Microbiol Rev
2009; 22:508). Chloroquine-resistant P. malariae has been reported from Sumatra, Indonesia (JD Maguire et al, Lancet 2002; 360:58).
Primaquine is given for prevention of relapse after infection with P. vivax or P. ovale. In addition to primary prophylaxis, some experts also prescribe primaquine
phosphate 30 mg base/d (0.5 mg/kg base/d for children) for 14 days after departure from areas where these species are endemic (Presumptive Anti-Relapse
Therapy [PART], “terminal prophylaxis”). Since this is not always effective as prophylaxis, others prefer to rely on surveillance to detect cases when they occur,
particularly when exposure was limited or doubtful. See also footnote 12.
Alternatives for patients who are unable to take chloroquine include atovaquone/proguanil, mefloquine, doxycycline, or primaquine dosed as for chloroquineresistant areas.
Chloroquine should be taken with food to decrease gastrointestinal adverse effects. If chloroquine phosphate is not available, hydroxychloroquine sulfate is as
effective; 400 mg of hydroxychloroquine sulfate is equivalent to 500 mg of chloroquine phosphate.
Atovaquone/proguanil is available as a fixed-dose combination tablet: adult tablets (Malarone, and others; 250 mg atovaquone/100 mg proguanil) and pediatric
tablets (Malarone Pediatric, and others; 62.5 mg atovaquone/25 mg proguanil). To enhance absorption and reduce nausea and vomiting, it should be taken with
food or a milky drink. The drug should not be given to patients with severe renal impairment (creatinine clearance <30 mL/min).
The results of some preliminary studies suggest that shorter courses of atovaquone/proguanil are effective in preventing malaria (GA Deye et al. Clin Infect Dis
2012; 54:232; E Leshem et al. J Travel Med 2014; 21:82). Some travel medicine experts now recommend stopping atovaquone/proguanil 3 days after exposure.
Doxycycline should be taken with adequate water to avoid esophageal irritation. It can be taken with food to minimize gastrointestinal adverse effects. It should
not be used in children <8 years old.
Mefloquine can be given to patients taking beta blockers if they do not have an underlying arrhythmia; it should not be used in patients with conduction
abnormalities. Mefloquine should not be taken on an empty stomach; it should be taken with at least 8 oz. of water.
In the US, a 250-mg tablet of mefloquine contains 228 mg mefloquine base. Outside the US, each 275-mg tablet contains 250 mg base.

For pediatric doses <½ tablet, it is advisable to have a pharmacist crush the tablet, estimate doses by weighing, and package them in gelatin capsules. There is
no data for use in children <5 kg, but based on dosages in other weight groups, a dose of 5 mg/kg can be used.
Most adverse events occur within 3 doses. Some Medical Letter reviewers favor starting mefloquine 3-4 weeks prior to travel and monitoring the patient for
adverse events; this allows time to change to an alternative regimen if mefloquine is not tolerated.
Patients should be screened for G-6-PD deficiency before treatment with primaquine. It should be taken with food to minimize nausea and abdominal pain.
Not FDA-approved for this indication.

inexpensive once-daily alternative. Doxycycline
should not be taken concurrently with antacids, oral
iron, or bismuth salts (including Pepto-Bismol).
A fourth drug, primaquine phosphate, is the most
effective drug for preventing P. vivax, and it is
recommended for prophylaxis in areas where P.
vivax is the predominant species. It is somewhat
less effective than other drugs against P. falciparum,
but it can be used when other prophylactic drugs are
not tolerated or are contraindicated.25 In addition to
primary prophylaxis, some experts also prescribe
primaquine for “terminal prophylaxis” after departure
from areas where P. vivax and Plasmodium ovale are
endemic (see Table 3, footnote 3).

Primaquine can cause hemolytic anemia, especially
in patients with glucose-6-phosphate dehydrogenase
(G-6-PD) deficiency, which is most common in African,
Asian, and Mediterranean peoples. Travelers should
be screened for G-6-PD deficiency before taking this
drug. Primaquine should be taken with food to reduce
GI adverse effects.
MEFLOQUINE-RESISTANT MALARIA — Doxycycline

or atovaquone/proguanil is recommended for prophylaxis against mefloquine-resistant malaria, which
occurs in the malarious areas of Thailand, in the areas
of Burma (Myanmar) and Cambodia that border on
Thailand, in the border areas between Burma and China
and between Laos and Burma, and in southern Vietnam.
55


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®

PREGNANCY — Malaria in pregnancy is particularly
serious for both mother and fetus; prophylaxis is
indicated if travel cannot be avoided. Chloroquine
has been used extensively and safely for prophylaxis
of chloroquine-sensitive malaria during pregnancy.
Mefloquine is classified as category B (no evidence of
risk in humans) for use during pregnancy; it has been
reported to be safe for prophylactic use during any
trimester of pregnancy.26 The safety of atovaquone/
proguanil in pregnancy has not been established,
and its use is generally not recommended. However,
case series that included women in all trimesters of
pregnancy who were treated with the combination
have not identified major birth defects,27,28 and
proguanil alone has been used in pregnancy without
evidence of toxicity. Doxycycline and primaquine are
contraindicated in pregnancy.
SOME OTHER INFECTIONS

DENGUE AND CHIKUNGUNYA — Dengue and
chikungunya fever29 are viral diseases transmitted by
mosquito bites that occur worldwide in tropical and
subtropical areas, including cities. Dengue outbreaks
have increased in recent years in South Asia, subSaharan Africa, and the Middle East.30 Before 2013,
outbreaks of chikungunya had been identified in
countries in Africa, Asia, Europe, and the Indian and
Pacific Oceans. Local transmission of chikungunya
fever in the Americas was first reported in December
2013 on the island of Saint Martin in the Caribbean,31
and has since been reported in most countries in
the Caribbean, in Central and South America, and
in the US (Florida). Prevention of mosquito bites
is the primary way to protect against dengue and
chikungunya virus infection.
LEPTOSPIROSIS — Leptospirosis, a bacterial disease
that occurs in many domestic and wild animals, is
endemic worldwide, but the highest incidence is in
tropical and subtropical areas, particularly after heavy
rainfall or flooding. Transmission to humans usually
occurs through contact with fresh water or damp
soil contaminated by the urine of infected animals.32
Travelers at increased risk, such as adventure travelers
and those who engage in recreational water activities,
should consider prophylaxis with doxycycline 200 mg
orally once a week, beginning 1-2 days before and
continuing throughout the period of exposure.
NON-INFECTIOUS RISKS OF TRAVEL
Many non-infectious risks are associated with travel.
Injuries, such as traffic accidents and drowning,

56

Vol. 57 (1466)

April 13, 2015

account for the majority of preventable travel-related
deaths.
ACUTE ALTITUDE ILLNESS — Rapid exposure to
altitudes >8,000 feet (2500 meters) may cause acute
mountain sickness (AMS), which can progress to highaltitude cerebral or pulmonary edema.33 Symptoms
include headache, malaise, nausea, anorexia, sleep
disturbance, and dizziness. Sleeping altitude appears
to be especially important in determining whether
symptoms develop.
The most effective preventive measure is preacclimatization at intermediate altitude (6000-9000
feet) for several days and gradual ascent to higher
elevations. If rapid ascent to an altitude >9100 feet
(2800 meters) cannot be avoided, acetazolamide, a
carbonic anhydrase inhibitor taken in a dosage of 125
mg twice daily (or 500 mg daily with the slow-release
formulation Diamox Sequels) beginning the day before
ascent and continuing at high altitude for 2 days or
longer, decreases the incidence and severity of AMS.34
The recommended dose for children is 2.5 mg/kg (max
125 mg) every 12 hours. Although acetazolamide, a
nonantibiotic sulfonamide, has little cross-reactivity
with sulfonamide antibiotics, hypersensitivity reactions
to acetazolamide are more likely to occur in those who
have had severe (life-threatening) allergic reactions to

sulfonamide antibiotics.35
Dexamethasone (Decadron, and others) 2 mg every
6 hours or 4 mg every 12 hours has also been shown
to prevent AMS in adults. It is not recommended for
prophylaxis in children. Sustained-release nifedipine
(Procardia XL, and others) may be helpful for prevention
and treatment of pulmonary edema. The addition of
tadalafil (Cialis; Adcirca) to acetazolamide has been
shown to reduce the incidence of pulmonary edema.36
VENOUS THROMBOEMBOLISM — Prolonged immobilization, particularly during air travel, increases the
risk of venous thromboembolism (lower extremity
deep vein thrombosis [DVT] or pulmonary embolism)
in travelers. Those with risk factors for thrombosis
(past history of thrombosis, recent surgery, severe
obesity, active malignancy, pregnancy, estrogen
use, advanced age, limited mobility, thrombophilic
disorders, increased platelets) are at even higher risk.
Nevertheless, flight-related symptomatic pulmonary
embolism is rare.37
To minimize the risk, travelers taking long-distance
flights (>6 hours) should be advised to walk around
frequently, exercise calf muscles while sitting, and


The Medical Letter

®

drink extra fluids.38 Properly fitted light compression
stockings can decrease the risk of asymptomatic

DVT.39 Giving a single dose of a low-molecular-weight
heparin as prophylaxis to travelers at high risk reduced
the incidence of asymptomatic DVT in a clinical trial.40
JET LAG — Disturbance of body and environmental
rhythms resulting from rapidly crossing multiple time
zones gives rise to jet lag, which is characterized by
insomnia, daytime sleepiness, decreased quality
of sleep, diminished physical performance, loss of
concentration, irritability, and GI disturbances. It is
usually more severe after eastward travel.41
Shifting daily activities to correspond to the time
zone of the destination country before arrival along
with taking short naps, remaining well hydrated,
avoiding alcohol, and pursuing activities in sunlight
on arrival may be helpful. A program of appropriately
timed light exposure and avoidance in the new time
zone may adjust the “body clock” and reduce jet lag.42
The dietary supplement melatonin (0.5-5 mg started
30-60 minutes before bedtime on the first night of
travel and continued for 1-5 days after arrival) has
been reported to facilitate the shift of the sleep-wake
cycle and decrease symptoms in some patients.43
Taking the benzodiazepine receptor agonist
zolpidem (Ambien, and others) or the melatonin
receptor agonist ramelteon (Rozerem) on the first
night after eastward travel and continuing for 3-4
nights has helped improve sleep.44,45 A randomized,
double-blind study found that taking the stimulant
armodafinil (Nuvigil) in the morning for 3 days after
eastward travel through 6 time zones increased

daytime wakefulness.46
MOTION SICKNESS — Therapeutic options for
motion sickness are limited.47 A transdermal patch
of the prescription anticholinergic drug scopolamine
(Transderm Scop) placed behind the ear 6-8 hours
before exposure and changed, alternating ears,
every 3 days can prevent symptoms. Oral promethazine (Phenergan, and others) is a highly sedating
alternative. Over-the-counter antihistamines such as
dimenhydrinate (Dramamine, and others) or meclizine
(Bonine, and others) are less effective, but may be
helpful for milder symptoms.
SUNBURN — Use of sunscreens is generally recommended for adults and children older than 6 months
during any sun exposure that might burn unprotected
skin. UVB is mostly responsible for the erythema of
sunburn. Both UVA and UVB can cause photoaging and
skin cancer. For patients without pathologic photosen-

Vol. 57 (1466)

April 13, 2015

sitivity, a sunscreen with a Sun Protection Factor (SPF)
of 15-30 as customarily used should be about as effective as one with a higher SPF. For those who need added
protection, a broad-spectrum (both UVA and UVB protection), high-SPF sunscreen is preferred. When using
both sunscreen and insect repellent, the sunscreen
should be applied first.11 ■
1. Vaccines for travelers. Med Lett Drugs Ther 2014; 56:115.
2. NJ Ajami et al. Seroepidemiology of norovirus-associated travelers’ diarrhea. J Travel Med 2014; 21:6.
3. MS Riddle et al. Effect of adjunctive loperamide in combination
with antibiotics on treatment outcomes in traveler’s diarrhea:

a systematic review and meta-analysis. Clin Infect Dis 2008;
47:1007.
4. R Steffen et al. Traveler’s diarrhea: a clinical review. JAMA 2015;
313:71.
5. D Jain et al. Campylobacter species and drug resistance in a
north Indian rural community. Trans R Soc Trop Med Hyg 2005;
99:207.
6. DR Tribble et al. Traveler’s diarrhea in Thailand: randomized,
double-blind trial comparing single-dose and 3-day azithromycin-based regimens with a 3-day levofloxacin regimen. Clin
Infect Dis 2007; 44:338.
7. KS Hong and JS Kim. Rifaximin for the treatment of acute infectious diarrhea. Ther Adv Gastroenterol 2011; 4:227.
8. P Zanger et al. Effectiveness of rifaximin in prevention of diarrhoea in individuals travelling to south and southeast Asia:
a randomised, double-blind, placebo-controlled, phase 3 trial.
Lancet Infect Dis 2013; 13:946.
9. E Mirzaian et al. Mosquito-borne illnesses in travelers: a review
of risk and prevention. Pharmacotherapy 2010; 30:1031.
10. R McGready et al. Safety of the insect repellent N,N-diethylM-toluamide (DEET) in pregnancy. Am J Trop Med Hyg 2001;
65:285.
11. Sunscreens revisited. Med Lett Drugs Ther 2011; 53:17.
12. A Badolo et al. Evaluation of the sensitivity of Aedes aegypti
and Anopheles gambiae complex mosquitoes to two insect repellents: DEET and KBR 3023. Trop Med Int Health 2004; 9:330.
13. SP Frances et al. Laboratory and field evaluation of commercial
repellent formulations against mosquitoes (Diptera: Culcidae)
in Queensland, Australia. Aust J Entomol 2005; 44:431.
14. C Costantini et al. Field evaluation of the efficacy and persistence of insect repellents DEET, IR3535, and KBR 3023 against
Anopheles gambiae complex and other Afrotropical vector
mosquitoes. Trans R Soc Trop Med Hyg 2004; 98:644.
15. Insect repellents. Med Lett Drugs Ther 2012; 54:75.
16. DO Freedman. Clinical practice. Malaria prevention in shortterm travelers. N Engl J Med 2008; 359:603.
17. PJ van Genderen et al. The safety and tolerance of atovaquone/

proguanil for the long-term prophylaxis of plasmodium falciparum malaria in non-immune travelers and expatriates [corrected]. J Travel Med 2007; 14:92.
18. N Wurtz et al. Early treatment failure during treatment of Plasmodium falciparum malaria with atovaquone-proguanil in the
Republic of Ivory Coast. Malaria J 2012; 11:146.
19. E Legrand et al. First case of emergence of atovaquone
resistance in Plasmodium falciparum during second-line
atovaquone-proguanil treatment in South America. Antimicrob
Agents Chemother 2007; 51:2280.
20. CT Happi et al. Confirmation of emergence of mutations associated with atovaquone-proguanil resistance in unexposed Plasmodium falciparum isolates from Africa. Malar J 2006; 5:82.
21. J Ling et al. Randomized, placebo-controlled trial of atovaquone/proguanil for the prevention of Plasmodium falciparum

57


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®

or Plasmodium vivax malaria among migrants to Papua, Indonesia. Clin Infect Dis 2002; 35:825.
22. J Soto et al. Randomized, double-blind, placebo-controlled
study of Malarone for malaria prophylaxis in non-immune Colombian soldiers. Am J Trop Med Hyg 2006; 75:430.
23. LH Chen et al. Controversies and misconceptions in malaria
chemoprophylaxis for travelers. JAMA 2007; 297:2251.
24. P Schlagenhauf et al. Use of mefloquine in children – a review
of dosage, pharmacokinetics and tolerability data. Malar J
2011; 10:292.
25. DR Hill et al. Primaquine: report from CDC expert meeting on
malaria chemoprophylaxis I. Am J Trop Med Hyg 2006; 75:402.
26. P Schlagenhauf et al. Pregnancy and fetal outcomes after exposure to mefloquine in the pre- and periconception period and
during pregnancy. Clin Infect Dis 2012; 54:e124.
27. MH Irvine et al. Prophylactic use of antimalarials during pregnancy. Can Fam Physician 2011; 57:1279.

28. B Pasternak and A Hviid. Atovaquone-proguanil use in early
pregnancy and the risk of birth defects. Arch Intern Med 2011;
171:259.
29. SC Weaver and M Lecuit. Chikungunya virus and the global
spread of a mosquito-borne disease. N Engl J Med 2015;
372:1231.
30. MG Guzman and E Harris. Dengue. Lancet 2015; 385:453.
31. M Fischer et al. Notes from the field: chikungunya virus spreads
in the Americas - Caribbean and South America, 2013-2014.
MMWR Morb Mortal Wkly Rep 2014; 63:500.
32. C van de Werve et al. Travel-related leptospirosis: a series of 15
imported cases. J Travel Med 2013; 20:228.
33. P Bartsch and ER Swenson. Clinical practice: Acute high-altitude illness. N Engl J Med 2013; 368:2294.
34. EV Low et al. Identifying the lowest effective dose of acetazolamide for the prophylaxis of acute mountain sickness: systematic review and meta-analysis. BMJ 2012; 345:e6779.
35. TE Kelly and PH Hackett. Acetazolamide and sulfonamide allergy: a not so simple story. High Alt Med Biol 2010: 11:319.
36. E Leshem et al. Tadalafil and acetazolamide versus acetazolamide for the prevention of severe high-altitude illness. J Travel
Med 2012; 19:308.
37. D Chandra et al. Meta-analysis: travel and risk for venous
thromboembolism. Ann Intern Med 2009; 151:180.
38. SR Kahn et al. Prevention of VTE in nonsurgical patients:
Antithrombotic therapy and prevention of thrombosis, 9th ed:
American College of Chest Physicians evidence-based clinical
practice guidelines. Chest 2012; 141:e195S.
39. M Clarke et al. Compression stockings for preventing deep vein
thrombosis in airline passengers. Cochrane Database Syst Rev
2006; (2):CD004002.
40. MR Cesarone et al. Venous thrombosis from air travel: the LONFLIT3 study–prevention with aspirin vs low-molecular-weight
heparin (LMWH) in high-risk subjects: a randomized trial. Angiology 2002; 53:1.
41. RL Sack. Clinical practice. Jet lag. N Engl J Med 2010; 362:440.
42. J Waterhouse et al. Jet lag: trends and coping strategies. Lancet 2007; 369:1117.

43. V Srinivasan et al. Jet lag, circadian rhythm sleep disturbances,
and depression: the role of melatonin and its analogs. Adv Ther
2010; 27:796.
44. AO Jamieson et al. Zolpidem reduces the sleep disturbance of
jet lag. Sleep Med 2001; 2:423.
45. PC Zee et al. Effects of ramelteon on insomnia symptoms induced by rapid, eastward travel. Sleep Med 2010; 11:525.
46. RP Rosenberg et al. A phase 3, double-blind, randomized, placebo-controlled study of armodafinil for excessive sleepiness
associated with jet lag disorder. Mayo Clin Proc 2010; 85:630.
47. JF Golding and MA Gresty. Motion sickness. Curr Opin Neurol
2005; 18:29.

58

Vol. 57 (1466)

April 13, 2015

IN BRIEF

Severe Bradycardia with Sofosbuvir
and Amiodarone
The FDA recently announced changes in the labeling
of the hepatitis C drugs Sovaldi (sofosbuvir) and
Harvoni (sofosbuvir/ledipasvir) to warn about a risk
of serious and potentially fatal bradycardia when
either drug is taken with the antiarrhythmic drug
amiodarone (Cordarone, and others).1 Symptomatic
bradycardia was reported following initiation
of treatment with Harvoni or with Sovaldi plus
simeprevir (Olysio) or the investigational antiviral

drug daclatasvir in 9 patients already taking
amiodarone; it occurred within 24 hours of starting
hepatitis C therapy in 6 patients and within 2-12
days in 3 others. One patient died of cardiac arrest
and 3 required pacemaker implantation. In 3 patients
who continued taking amiodarone, rechallenge
with Harvoni or Sovaldi resulted in recurrence
of symptomatic bradycardia. In another patient,
rechallenge 8 weeks after stopping amiodarone did
not result in bradycardia.
The mechanism of this effect is unknown. Factors
possibly contributing to the cardiac events include
concomitant beta blocker therapy (in 7 patients) and
preexisting cardiac and hepatic disease. Hepatic
impairment increases the risk of cardiac conduction
abnormalities and could increase adverse effects
of amiodarone, which is metabolized by the liver.2
Use of sofosbuvir without amiodarone has not been
associated with significant bradycardia.
The new labels warn that sofosbuvir and amiodarone
should not be taken concurrently. If concomitant
use is necessary, cardiac monitoring in an inpatient
setting is recommended for the first 48 hours. Daily
monitoring of heart rate, either at home or in an
outpatient setting, should continue for at least the
first 2 weeks of treatment. Amiodarone has a very
long half-life, and its effects may persist for weeks
to months after discontinuation. ■
1. FDA. FDA Drug Safety Communication: FDA warns of
serious slowing of the heart rate when antiarrhythmic drug

amiodarone is used with hepatitis C treatments containing
sofosbuvir Harvoni or Sovaldi in combination with another
direct acting antiviral drug. Available at .
gov/Drugs/DrugSafety/ucm439484.htm. Accessed .April 2,
2015.
2. U Klotz. Antiarrhythmics: elimination and dosage considerations in hepatic impairment. Clin Pharmacokinet 2007;
46:985.


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Review the efficacy and safety of topical ivermectin 1% cream (Soolantra) for treatment of inflammatory lesions of rosacea.
Review the recommendations for malaria prophylaxis, treatment of travelers' diarrhea, and other strategies to minimize the risk of travel-related illness for US travelers.
Discuss the new FDA label changes for Harvoni and Sovaldi as they relate to patients taking the antiarrhythmic drug amiodarone.

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Issue 1466 Questions

(Correspond to questions #71-80 in Comprehensive Exam #72, available July 2015)
Ivermectin Cream (Soolantra) for Rosacea
1. In 12-week trials, complete or almost complete clearing of
lesions occurred in approximately what percentage of patients
with moderate to severe papulopustular rosacea treated with
ivermectin cream?
a. 20%
b. 40%
c. 60%
d. 80%
2. In the 16-week trial comparing ivermectin cream with
metronidazole cream in patients with moderate to severe
papulopustular rosacea, the absolute difference between the
2 agents in the percentage of patients with clearing or almost
complete clearing of lesions was approximately:
a. 10%
b. 20%
c. 30%
d. 40%
Advice for Travelers
3. Which of the following would you recommended for selftreatment of moderate to severe travelers’ diarrhea in a 30-yearold woman who is traveling to Southeast Asia?
a. azithromycin
b. ciprofloxacin
c. levofloxacin
d. rifaximin
4. Rifaximin:
a. is the drug of choice for patients with travelers’ diarrhea
and bloody stool
b. is not effective for prophylaxis of travelers’ diarrhea
c. is as effective as ciprofloxacin for treatment of travelers’

diarrhea due to noninvasive Escherichia coli
d. is highly absorbed with significant systemic toxicity

6. Mefloquine would be an option for malaria prophylaxis in which
of the following patients:
a. a 42-year-old woman with depression traveling to Nigeria
b. a 30-year-old pregnant woman traveling to Brazil
c. a 50-year-old man with atrial fibrillation traveling to
southern Vietnam
d. a 12-year-old boy with epilepsy traveling to India
7. Mosquitoes that transmit malaria are most active:
a. in the morning
b. at midday
c. in the late afternoon
d. between dusk and dawn
8. The highest concentration of DEET recommended by the
American Academy of Pediatrics for use in children is:
a. 30%
b. 40%
c. 50%
d. they don’t recommend use of DEET in children
9. The most effective measure to prevent acute altitude illness is:
a. acetazolamide 500 mg q12h
b. dexamethasone 4 mg q6h
c. nifedipine 30 mg q12h
d. pre-acclimatization and gradual ascent
Severe Bradycardia with Sofosbuvir and Amiodarone
10. Which of the following factors may have contributed to the
severe bradycardia reported in patients taking Harvoni or
Sovaldi with amiodarone?

a. concurrent beta blocker therapy
b. underlying cardiac disease
c. underlying hepatic disease
d. all of the above

5. Which of the following is among the most effective drugs used
for prevention of chloroquine-resistant malaria and is generally
the best tolerated?
a. atovaquone/proguanil
b. mefloquine
c. doxycycline
d. primaquine phosphate
ACPE UPN: Per Issue Exam: 0379-0000-15-466-H01-P; Release: April 13, 2015 Expire: April 13, 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
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; Sandip K. Mukherjee, M.D., F.A.C.C., Yale School of Medicine; Dan M. Roden, M.D., Vanderbilt University School of Medicine; Esperance A.K. Schaefer, M.D., M.P.H.,
Harvard Medical School; F. Estelle R. Simons, M.D., University of Manitoba; Neal H. Steigbigel, M.D., New York University School of Medicine; Arthur M. F. Yee, M.D., Ph.D., F.A.C.R.,
Weill Medical College of Cornell University
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Copyright and Disclaimer: The Medical Letter, Inc. is an independent nonprofit organization that provides healthcare professionals with unbiased drug prescribing recommendations. The editorial

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