The medical letter on drugs and therapeutics april 13 2015

1466 Ivermectin Cream Soolantra for Rosacea ...Advice for Travelers ...p 51p 52 In Brief: Severe Bradycardia with Sofosbuvir and Amiodarone ...p 58 The Medical Letter on Drugs and Therap

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IN THIS ISSUE

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Volume 56

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ISSUE No

1466 Ivermectin Cream (Soolantra) for Rosacea Advice for Travelers .p 51p 52

In Brief: Severe Bradycardia with Sofosbuvir and Amiodarone .p 58

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on Drugs and Therapeutics

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ISSUE No

1466 Advice for Travelers In Brief: Severe Bradycardia with Sofosbuvir and Amiodarone p 52p 58

Ivermectin Cream (Soolantra) for

Rosacea

▶

Pronunciation Key Ivermectin: eye" ver mek' tin Soolantra: soo lahn' tra

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.

with oral antimicrobials, such as low-dose doxy-cycline, 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 12-week, 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 signifi cantly 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 signifi cantly 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

Table 1 Pharmacology

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

Route Topical

Half-life (terminal) ~6.5 days

MECHANISM OF ACTION — The mechanism of

action of ivermectin in rosacea is unknown The

drug has antiparasitic activity and possibly an

anti-inflammatory effect, and Demodex mites have been

implicated in the pathogenesis of the inflammatory

facial eruptions that characterize the disease.1

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 fi rst, sometimes in combination

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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 effi cacy to ciprofloxacin for treatment of

diarrhea due to noninvasive E coli, with fewer adverse

effects.7 It should not be used for invasive infections

Advice for Travelers

▶

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 classifi ed

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

oculo-cutaneous rosacea in a girl successfully treated with

2 Brimonidine gel (Mirvaso) for rosacea Med Lett Drugs Ther

2013; 55:82.

3 L Stein Gold et al Effi cacy and safety of ivermectin 1% cream

in treatment of papulopustular rosacea: results of two

random-ized, 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

rosa-cea: 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

met-ronidazole 0.75% cream in treating inflammatory lesions of

rosacea: a randomized, investigator-blinded trial Br J Dermatol

2014 Sept 16 (epub).

Table 2 Some Topical Drugs for Rosacea

Some Drug Formulations Usual Dosage 1 Cost 2

lotion; 1% gel

(Galderma)

Soolantra

(Galderma)

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

avail-able 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.

Related article(s) since publication

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 benefi t 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

Table 1 Some Antimicrobial Drugs for Treatment of

Travelers' Diarrhea

Zithromax* (Pfi zer) 1000 mg once 2

Ciprofloxacin 3 –

Cipro* (Bayer) 500 mg once/d or bid 4 or 750 mg

once/d x 1-3d extended-release 1

Levofloxacin 1,3 – Levaquin* 500 mg once/d x 1-3d

(Ortho-McNeil)

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

INSECT BITES

To minimize insect bites, travelers should wear light-colored, 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 effi cacy 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 fi rst because it may increase the absorption of DEET when DEET is applied fi rst.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 pyrethroid-impregnated mosquito nets while sleeping is helpful

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

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 fi rst 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

chloroquine-sensitive 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

mefloquine, and doxycycline) are recommended for

prevention of malaria in US travelers to areas with

chloroquine resistance

The fi xed-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 effi cacy

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

seiz-ures 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

Republic of the Congo Rwanda São Tomé and Príncipe Senegal Sierra Leone Somalia South Africa 2,4 Sudan South Sudan Swaziland Tanzania Togo Uganda Western Sahara Zambia Zimbabwe Panama 2 Paraguay 2,5,6 Peru 2 Suriname Venezuela 2

Tajikistan Thailand 2,8 Timor-Leste (East Timor) Turkey 2,5 Vietnam 2,8 Yemen

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 Sã 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

AFRICA

Angola Benin Botswana 2 Burkina Faso Burundi Cameroon Cape Verde 3 Central African Republic Chad Comoros Cơte d’Ivoire Democratic Republic of the Congo Djibouti Equatorial Guinea Eritrea 2

Ethiopia 2 Gabon Gambia, The Ghana Guinea Guinea-Bissau Kenya 2 Liberia Madagascar Malawi Mali Mauritania Mayotte Mozambique Namibia Niger Nigeria

AMERICAS

Belize 2,5 Bolivia 2 Brazil Colombia 2 Dominican Republic 2,5 Ecuador 2

French Guiana 2 Guatemala 2,5 Guyana Haiti 5 Honduras 2,5 Mexico 5 Nicaragua 5

ASIA

Afghanistan Bangladesh 2 Bhutan 2 Burma (Myanmar) 2,8 Cambodia 2,8 China 2,7,8 India Indonesia 2 Iran 2

Korea, North 5 Korea, South 2,5 Laos 2,8 Malaysia 2 Myanmar (Burma) 2,8 Nepal 2

Pakistan Philippines 2 Saudi Arabia 2

OCEANIA

Papua New Guinea

Table 2 Countries with a Risk of Malaria 1

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) defi ciency, which is most common in African, Asian, and Mediterranean peoples Travelers should

be screened for G-6-PD defi ciency 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 prophy-laxis 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

Table 3 Drugs of Choice for Prevention of Malaria 1

All Plasmodium species in chloroquine-sensitive areas2,3

malarious zone

All Plasmodium species in chloroquine-resistant areas2,3

21-30 kg: 2 ped tabs/d 6 31-40 kg: 3 ped tabs/d 6

>40 kg: 1 adult tab/d 6

malarious zone

31-45 kg: ¾ tab once/wk

>45 kg: 1 tab once/wk

Alternative:

Stop: 1 wk after leaving malarious zone

1 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

2 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 signifi cant 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).

3 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.

4 Alternatives for patients who are unable to take chloroquine include atovaquone/proguanil, mefloquine, doxycycline, or primaquine dosed as for chloroquine-resistant areas.

5 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.

6 Atovaquone/proguanil is available as a fi xed-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).

7 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.

8 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.

9 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.

10 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

11 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.

12 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.

13 Patients should be screened for G-6-PD defi ciency before treatment with primaquine It should be taken with food to minimize nausea and abdominal pain.

14 Not FDA-approved for this indication.

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,

sub-Saharan Africa, and the Middle East.30 Before 2013,

outbreaks of chikungunya had been identifi ed in

countries in Africa, Asia, Europe, and the Indian and

Pacifi c Oceans Local transmission of chikungunya

fever in the Americas was fi rst 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 traffi c accidents and drowning,

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 high-altitude 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 pre-acclimatization 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

tadalafi l (Cialis; Adcirca) to acetazolamide has been

shown to reduce the incidence of pulmonary edema.36

VENOUS THROMBOEMBOLISM — Prolonged

immobi-lization, 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

drink extra fluids.38 Properly fi tted 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 fi rst 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 fi rst

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

armodafi nil (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

prometha-zine (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

recom-mended 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-sitivity, a sunscreen with a Sun Protection Factor (SPF)

of 15-30 as customarily used should be about as effec-tive as one with a higher SPF For those who need added protection, a broad-spectrum (both UVA and UVB pro-tection), high-SPF sunscreen is preferred When using both sunscreen and insect repellent, the sunscreen should be applied fi rst.11 ■

1 Vaccines for travelers Med Lett Drugs Ther 2014; 56:115.

2 NJ Ajami et al Seroepidemiology of norovirus-associated trav-elers’ 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 azithro-mycin-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 infec-tious diarrhea Ther Adv Gastroenterol 2011; 4:227.

8 P Zanger et al Effectiveness of rifaximin in prevention of di-arrhoea 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-diethyl-M-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 re-pellents: DEET and KBR 3023 Trop Med Int Health 2004; 9:330.

13 SP Frances et al Laboratory and fi eld 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 effi cacy and persis-tence 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 short-term 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 falci-parum malaria in non-immune travelers and expatriates [cor-rected] J Travel Med 2007; 14:92.

18 N Wurtz et al Early treatment failure during treatment of Plas-modium 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 Confi rmation of emergence of mutations associ-ated with atovaquone-proguanil resistance in unexposed Plas-modium falciparum isolates from Africa Malar J 2006; 5:82.

21 J Ling et al Randomized, placebo-controlled trial of atova-quone/proguanil for the prevention of Plasmodium falciparum

or Plasmodium vivax malaria among migrants to Papua,

Indo-nesia 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

Co-lombian 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

ex-posure 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

preg-nancy 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 fi eld: 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-alti-tude illness N Engl J Med 2013; 368:2294.

34 EV Low et al Identifying the lowest effective dose of

acetazol-amide for the prophylaxis of acute mountain sickness:

system-atic review and meta-analysis BMJ 2012; 345:e6779.

35 TE Kelly and PH Hackett Acetazolamide and sulfonamide

al-lergy: a not so simple story High Alt Med Biol 2010: 11:319.

36 E Leshem et al Tadalafi l and acetazolamide versus

acetazol-amide 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, 9 th 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 LON-

FLIT3 study–prevention with aspirin vs low-molecular-weight

heparin (LMWH) in high-risk subjects: a randomized trial

Angi-ology 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

Lan-cet 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

in-duced by rapid, eastward travel Sleep Med 2010; 11:525

46 RP Rosenberg et al A phase 3, double-blind, randomized,

pla-cebo-controlled study of armodafi nil 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.

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 signifi cant 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 fi rst 48 hours Daily monitoring of heart rate, either at home or in an outpatient setting, should continue for at least the

fi rst 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 http://www.fda gov/Drugs/DrugSafety/ucm439484.htm Accessed April 2, 2015.

2 U Klotz Antiarrhythmics: elimination and dosage consid-erations in hepatic impairment Clin Pharmacokinet 2007; 46:985.

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