HM Medical Clinic

Guidelines for malaria prevention in travellers from the united kingdom

4 - Chemoprophylaxis 4.1Principles. 33 Chloroquine plus proguanil Atovaquone plus proguanil 4.3Dosage tables. 4.4Country tables. 4.5Popular destinations. 4.6Emergency Standby

4. Chemoprophylaxis Given the possibility of antimalarials purchased in the tropics being fake24, travellersshould obtain the medication required for their chemoprophylaxis from a reputablesource in the UK before they travel. ACMP also advises against purchasing antimalarialdrugs over the internet. Causal prophylaxis Causal prophylaxis is directed against the liver stage of the malaria parasite, whichtakes approximately 7 days to develop (see life cycle in figure1). Successful drugactivity at this stage prevents the parasite from progressing to infect red blood cells. Causal prophylactics need to be given for approximately 7 days after infection25, soACMP recommends that they are continued for 7 days after leaving a malarious area(see table 3 of drug regimens in chapter 4). It is important not to confuse liver-stage schizonts with hypnozoites. All 4 species ofhuman malaria have liver-stage schizonts but only Plasmodium vivax and P. ovale havethe hypnozoite stage, against which causal prophylaxis is NOT effective. Suppressive prophylaxis prophylactic drugs currently advised byACMP, acts against the hypnozoite stage Suppressive prophylaxis is directed of P. vivax or P. ovale. against the red blood cell stages of themalaria parasite and thus needs to be Primaquine is active against hypnozoites taken for several weeks to prevent (present only in P.vivax and P.ovale) and also has causal prophylactic activityagainst the liver stage schizonts of all Therefore, suppressive prophylactic drugs 4 malaria parasites of humans27.
should be continued for 4 weeks after Primaquine is occasionally used for leaving a malarious area (see drug terminal prophylaxis (also known as regimens in table 3, Chapter 4).
presumptive anti-relapse therapy) toeradicate hypnozoites of P.vivax and Prophylaxis against hypnozoites P.ovale. However, the routine use ofprimaquine for prophylaxis is not Plasmodium vivax and P. ovale have a recommended by ACMP. Practitioners dormant stage called the "hypnozoite".
considering the use of primaquine as a The hypnozoite remains dormant for prophylactic agent should consult an months and then "wakes up" to develop expert centre (see Chapter 9).
into a liver schizont. The dormanthypnozoite explains why attacks of vivax Primaquine is an oxidant drug and can or ovale malaria can occur long after the lead to haemolysis in G6PD-deficient end of chemoprophylaxis. This is not due to drug failure as none of the

Hispaniola (Haiti & the DominicanRepublic). Prophylaxis with chloroquine as The British National Formulary (BNF) a single agent is therefore rarely contains full listings of drug actions, appropriate (see tables 7-12). It remains dosages, side effects, interactions and effective against most P. vivax, all P. ovale contraindications summarised here and and virtually all P. malariae. should be consulted as required whenrecommending malaria chemoprophylaxis.
Chapter 6 of this book also provides The main side effects are gastrointestinal details of contraindications for different disturbances and headache. Convulsions medical conditions such as pregnancy are recorded. Chloroquine may cause and renal impairment.
itching in persons of African descent. NOTE: All adverse events of medication,
including attacks of malaria, should bereported. Members of the public and Drugs: Amiodarone (increased risk of healthcare professionals can report any ventricular arrhythmias); ciclosporin suspected side effects from malaria (increased risk of toxicity); digoxin medicines via the Yellow Card Scheme on (possibly increases plasma concentration the Medicines and Healthcare products of digoxin); mefloquine (increased risk of Regulatory Agency (MHRA) website.
convulsions); moxifloxacin (increased risk of ventricular arrhythmias; avoidconcomitant use). These drugs are not listed in order ofpreference.
Vaccines: Chloroquine may suppress theantibody response to pre-exposure 4.2.1 Chloroquine intradermal human diploid cell rabiesvaccine28. This interaction is not seen when rabies vaccine is givenintramuscularly (the currently Chloroquine is concentrated in the recommended mode of vaccination in malaria parasite lysosome and is thought to act by interfering withmalaria pigment formation, causing Contraindications generation of a ferriprotoporphyrin IX-chloroquine complex which is highly Chloroquine prophylaxis may exacerbate toxic to the parasite.
psoriasis and myasthenia gravis. It iscontraindicated in those with a history Chloroquine-resistant falciparum malariais now reported from all WHO regionsexcept Central America north of thePanama Canal and the Island of

prophylaxis with proguanil as a singleagent is rarely appropriate (see country Chloroquine is highly toxic in overdosage, tables 7-12, chapter 4).
so should be stored out of the reach of children. In long term use, eye examinations every 6-12 months shouldbe considered at 6 years prophylactic The principal side effects of proguanil are usage, though the risk of retinopathy mild gastric intolerance and diarrhoea.
developing on prophylactic dosage is Mouth ulcers and stomatitis occur considered to be very low29. See also occasionally, particularly when combined long-term traveller section in chapter 7.
with chloroquine. Methods of administration Tablets contain 155 or 150 mg Drugs: May enhance the anticoagulant chloroquine base; syrup contains effect of warfarin. Absorption reduced chloroquine base 50 mg/5 ml (see by oral magnesium salts. Antifolate effect paediatric dosages in tables 4 and 5).
is increased when given with Adult dose 300 mg (2 tablets) weekly, starting one week before entering amalarious area, continuing throughout Vaccines: None reported the time in the area and for 4 weeksafter leaving the area.
Contraindications Allergy to proguanil Proguanil is converted to an active Renal impairment. Pregnancy (folate metabolite cycloguanil which inhibits the enzyme dihydrofolate reductase andinterferes with the synthesis of folic acid.
Methods of administration It acts as a suppressive and also as acausal prophylactic30. Proguanil itself 100mg tablets only. Adult dose 200 mg has a second mode of action, mediated daily, starting one week before entering a by the parent drug rather than its malarious area, continuing throughout metabolite, which produces synergy the time in the area and for 4 weeks with atovaquone (see atovaquone plus after leaving the area.
There are very few regions in the worldwhere the local Plasmodium falciparumstrains are fully sensitive to proguanil, so

4.2.3 Chloroquine plus proguanil proguanil, but not those takingchloroquine plus proguanil33 but there For side effects, interactions, is no evidence that mefloquine use contraindications and methods of increases the risk of first-time diagnosis administration, please see individual of depression34 and no association between mefloquine prescriptions andhospitalisation35. Overall, mefloquine ACMP does not recommend the use
remains an important prophylactic agent of chloroquine plus proguanil for
which is tolerated by the majority of travellers to sub-Saharan Africa.
travellers who take it36.
If no alternative is felt to be
appropriate, the matter should be
discussed with an expert centre
(see chapter 9).
Drugs: Mefloquine antagonises theanticonvulsant effect of antiepileptics and interacts with a number of cardiacdrugs. Contraindications Mefloquine's mode of action has notbeen determined, but is thought to be Mefloquine prophylaxis is contraindicated unrelated to that of chloroquine and not in those with a current or previous to involve an anti-folate action. It acts as history of depression, neuropsychiatric a suppressive prophylactic.
disorders or epilepsy; or withhypersensitivity to quinine. The protective efficacy of mefloquine isapproximately 90% in Africa31. At the Pregnancy; (see Chapter 6,special present time, significant resistance of groups) breast-feeding; (see Chapter 6, P. falciparum to mefloquine is a problem special groups) cardiac conduction only in some areas of south-East Asia32, disorders. Not recommended in infants but is reported sporadically from the under 3 months (5kg).
Amazon basin.
Can mefloquine be taken by those who plan to undertake underwaterdiving? Attention has focused onneuropsychiatric problems with If the individual tolerates mefloquine mefloquine prophylaxis. Increased prophylaxis, there is no evidence that moderate problems have been found they cannot physically perform especially in women using mefloquine underwater diving. However, it should be when compared with those receiving noted that some sub-aqua centres do not doxycycline, or atovaquone plus permit those taking mefloquine to dive.

Although mefloquine may be suitable for scuba divers who have taken andtolerated the drug before, or those able Doxycycline hydrochloride preparations to start taking it early to ensure that no have a low pH and may produce adverse events occur, it should usually be oesophagitis, especially if taken on an avoided: it lowers the seizure threshold empty stomach and/or just before lying (and may therefore add to the down. Rarely, doxycycline may cause complications of decompression or photosensitivity which is mostly mild and narcosis events) and some transient38. Doxycycline is a broad neuropsychiatric adverse events, though spectrum antibiotic and may predispose excessively rare, can be sudden in onset.
to vaginal candidiasis.
The UK Civil Aviation Authority advises Drugs: The metabolism of doxycycline is that mefloquine should not be accelerated by carbamazepine and administered to airline pilots, although phenytoin. At present, there are no data there is no evidence that mefloquine to support a change in the dose of impairs function.
doxycycline used for malaria prophylaxisin individuals taking one or more of Methods of administration these agents. Tetracyclines possiblyenhance the anticoagulant effect of Oral. 250mg tablets. Weekly dosage, coumarins (e.g. warfarin), and may starting 2-3 weeks before entering a increase plasma concentration of malarious area to assess tolerability, ciclosporin. It may temporarily reduce continuing throughout the time in the the contraceptive effect of oestrogens area and for 4 weeks after leaving the (see FAQs in Chapter 8). malarious area.
Vaccines: Possibly reduces the efficacy of 4.2.5 Doxycycline oral typhoid vaccine if givensimultaneously. Should be separated by Doxycycline is lipophilic and acts Contraindications intracellularly, binding to ribosomalmRNA and inhibiting protein synthesis. Children under 12 years of age.
It acts as a suppressive prophylactic.
Pregnancy and breast feeding. Allergy totetracyclines.
Doxycycline is of comparableprophylactic efficacy to mefloquine37.

hypnozoites). It acts as a causalprophylactic agent, so needs to be Hepatic impairment. Patients taking continued for only 7 days after leaving a potentially hepatotoxic drugs. Myasthenia malarial area40. It also has activity against gravis. Systemic lupus erythematosus.
the erythrocytic stages of malariaparasites and is useful for treatment. Methods of administration Capsules (50 or 100mg) or dispersible100mg tablets only (consult summary of Prophylactic efficacy against P. falciparum product characteristics pertaining to is in excess of 90%41-48. There is less individual products). Dose 100mg daily, published data on protection against starting 1 to 2 days before entering a P. vivax, but data available indicate that malarious area, continuing whilst there atovaquone-proguanil is effective in the and for 4 weeks after leaving.
prevention of primary attacks of vivaxmalaria44,49. However, like chloroquine- Precautions in use proguanil, mefloquine and doxycycline, itwill not protect against hypnozoite- The prescriber should warn against induced episodes of P.vivax (or P.ovale) excessive sun exposure (and advise on the correct use of sunscreen), the risk ofvaginal candidiasis and the risk of oesophagitis if taken on an emptystomach and/or lying down too soon The most frequent side-effects are after taking it. Doxycycline should be headache and gastrointestinal upsets. swallowed whole with plenty of fluidduring meals while sitting or standing. 4.2.6 Atovaquone plus proguanil For proguanil see proguanil section Drugs: Plasma concentration ofatovaquone is reduced by rifabutin and Atovaquone works by inhibiting electron rifampicin (possible therapeutic failure of transport in the mitochondrial atovaquone), tetracycline (clinical cytochrome b-c1 complex, causing significance of this is not known) and collapse in the mitochondrial membrane potential. This action is potentiated byproguanil and is not dependent upon Antiretrovirals: Atovaquone possibly conversion to its metabolite cycloguanil.
reduces plasma concentration of Indeed, the combination remains indinavir. Atovaquone possibly inhibits effective in cycloguanil-resistant metabolism of zidovudine (increased plasma concentration). prevents development of pre-erythrocytic (liver) schizonts (but not Vaccines: None reported.

Contraindications Pregnancy: The BNF states "Manufacturer Renal impairment (See also the renal advises avoid unless essential." ACMP impairment section in chapter 6), advises against the use of diarrhoea or vomiting (reduced atovaquone/proguanil for antimalarial absorption of atovaquone).
chemoprophylaxis in pregnancy.
Inadvertent conception when using Methods of administration atovaquone/proguanil is not anindication to consider termination of the Tablets containing proguanil 100 mg and pregnancy, as no evidence of harm has atovaquone 250 mg. Paediatric tablets emerged in data so far available.
containing proguanil 25 mg andatovaquone 62.5 mg. Adult dose one Atovaquone/proguanil should generally tablet daily starting 1 to 2 days before be avoided in breast feeding, but ACMP entering a malaria endemic area, advises that atovaquone/proguanil can continuing throughout the time there be used when breast-feeding if there is and for 1 week after leaving. Paediatric no suitable alternative antimalarial.
dosage given in table 6.
4.3 Dosage tables Areas of chloroquine resistant P. falciparum 1 tablet/capsule daily Atovaquone-proguanil 250 (atovaquone) plus 100(proguanil) Areas of little chloroquine resistance; poorly effective where extensiveresistance 2 tablets daily plus Areas without drug resistance vailable in capsule f he adult tablet.
eight, 0.375 dose w oguanil paediatric dosag or mefloquine at t The adult dose is necessar e calculation.
ANTIMALARIALS FOR CHILDREN e, mefloquine (0.25 dose, _ hat it can be used f e purpose of dosag her countries tablet str or mefloquine indicat cline is unsuitable f MEASURES (THERE IS OFTEN A HALF SIZE MEASURE AT THE OTHER END OF THE SPOON) (2.5 ml plus 5 ml) (2.5 ml plus2 x 5 ml) N.B. These dose-steps are not the same as for chloroquine tablets, which differ from the syrup in chloroquine content. Chloroquine syrup (Nivaquine ®) contains 50mg chloroquine base in 5ml.
* Chemists may dispense dosing syringes for child doses.
PROPORTION NUMBER 4.4 Country tables (most tourist ar eme South East onl emen (no risk in Adana and east of ther Uzbekistan (sporadic cases w risk except El Faiyum) estern Region.
dah and the high-altitude ystan (except South y suspicious sympt ypt (El Faiyum onl ypt (whole countr Afghanistan (belo Iran (rural SE pr Mecca or Medina cities, Azerbaijan (southern bor Georgia (some South East villages, reness of small risk of malaria; a er) but tablets not consider ear in Zambezi valle eas of Mpumalanga & Nor th East KwaZulu-Natal as far south as thern half of the countr Equatorial Guinea OPHYLAXIS IN SUB-SAHARAN ound in the south; rde (some risk on São y suspicious sympt including the Kruger National Park, negligible in Harar reness of small risk of malaria; a er) but tablets not consider and the city of Mumbai no risk in Kathmandu) OPHYLAXIS IN SOUTH w to no risk in Rajasthan; Andhra Pradesh including Hyderabad, w risk in Southern states of K y suspicious sympt Bhutan (southern districts onl Sri Lanka (risk nor Bangladesh (except Chittag reness of small risk of malaria; a er) but tablets not consider Risk high + resistance, take tablets: mefloquine OR doxycycline OR atovaquone proguanil recommended Risk variable, take tablets: Chloroquine plus proguanil recommended.
Risk low, awareness and bite prevention JAMMU & KASHMIR
NEW DELHI
KERA TAMILN
ANDAMAN & NICOBAR
Risk high + resistance, take tablets: mefloquine OR doxycycline OR atovaquone proguanil recommended Risk low, awareness and bite prevention Risk variable, take tablets: chloroquine plus proguanil recommended Risk low, awareness and bite prevention Cambodia (western provinces) Thailand (near mainland borders with Cambodia, Laos and Myanmar; low risk and bite avoidance only Chiang Rai and Kwai bridge) Myanmar (eastern part of Shan State) Cambodia (except no risk in Phnom Penh) China (only in Yunnan and Hainan; chloroquine in other remote areas of China) East Timor (= Timor-Leste) Papua (Irian Jaya) (part of Indonesia) Laos (except no risk in Vientiane)Lombok (part of Indonesia) Myanmar (formerly Burma [see above for Shan State])Malaysia East (Sabah only except Kota Kinabalu whereawareness and bite prevention advised)Vietnam (except areas listed below that are low risk) Indonesia (except Bali and cities where low risk; for Papua (Irian Jaya) and Lombok mefloquine or doxycycline or atovaquone-proguanil recommended) Philippines (rural below 600m; no risk in cities, nor Cebu, Bohol and Catanduanes) Malaysia West (peninsular) Inland forested areas (notCameron Highlands) and Malaysia East (inland forestedareas of Sarawak) Risk very low Bali (part of Indonesia) BruneiChina (main tourist areas including Yangtze cruises)Hong KongMalaysia East (except Sabah (see above) and Sarawak(chloroquine plus proguanil) Malaysia West (low risk including Cameron Highlandsexcept inland forested areas where chloroquine plus proguanil)North Korea (a few southern areas have limited risk)South Korea (limited risk in extreme Northwest)SingaporeThailand (prophylaxis only advised for areas listed above) Vietnam (see above for high risk areas; low risk in cities,coast between Ho Chi Minh and Hanoi, and the MekongRiver until close to the Cambodian border) See tables 3-6 for details of regimens *Awareness of small risk of malaria; avoid mosquito bites and seek medical attention for any suspicious symptoms (up to about a year later) but tablets not considered necessary.
OPHYLAXIS IN OCEANIA Bolivia (Amazon basin area) Brazil (Amazon basin (i.e. ‘Legal Amazon' area, see map); elsewhere very low risk and no chemoprophylaxis) Colombia (most areas below 800m) Ecuador (Esmeraldas Province; see below French Guiana (especially border areas)Guyana (all interior regions, lesser risk at coast)Peru (Amazon basin area)Suriname (except Paramaribo and coast)Venezuela (all areas south of and includingthe Orinoco river; north of the riverchloroquine plus proguanil recommendedsee below)Amazon basin areas of Bolivia andVenezuela and Peru Bolivia (rural areas below 2500m) Ecuador (areas below 1500m; no malaria in Galapagos Islands nor Guayaquil) Panama (east of canal, canal zone itself no risk) Peru (Other rural areas East of the Andes Chloroquine and West of the Amazon Basin below Venezuela (north of the Orinoco river;Caracas free of malaria; south and includingOrinoco river, risk high see above) Risk variable Argentina (rural areas along northern borders only)Belize (rural except Belize district)Costa Rica (rural below 500m) Dominican Republic El Salvador (only Santa Ana province in west) Guatemala (below 1500m)HaitiHondurasMexico (in states of Oaxaca & Chiapas)NicaraguaPanama (west of canal, canal zone itself no risk)Paraguay (some rural areas) See tables 3-6 for details of regimens Consult table 12 and figure 7 for details of prophylaxis advised for individual countries.
Amazon Basin area where high risk and resistance present, tablets recommended: mefloquine OR doxycycline OR atovaquone/proguanil Tropic of Capricorn FALKLAND
Risk high + resistance, take tablets: mefloquine OR doxycycline OR atovaquone proguanil recommended Risk low, awareness and bite prevention Minas Ger
Rio de Janeiro
Rio de Janeiro
Rio Grande
4.5 Popular destinations POPULAR DESTINATION ACMP RECOMMENDED REGIMEN Doxycycline OR Mefloquine OR Atovaquone/Proganil Doxycycline OR Mefloquine OR Atovaquone/Proganil Galapagos Islands Awareness*, unless close to theCambodia border when Mefloquine OR Doxycycline OR Atovaquone/ Proguanil Turkey (south coast) Awareness* in tourist resorts, forAdana and the far eastern area:chloroqine.
* awareness of small risk of malaria; avoid mosquito bites and seek medical attention for any suspicious symptoms (up to about a year later) but tablets not considered necessary.
4.6 Emergency Standby Treatment treatment dose of the antimalarialshould be taken if vomiting occurs within Emergency standby treatment should 30 minutes of taking it (half-dose if be recommended for those taking vomiting occurs after 30–60 minutes)51.
chemoprophylaxis and visiting remoteareas where they are unlikely to be The agent used for emergency standby within 24 hours of medical attention. treatment should be different from thedrugs used for chemoprophylaxis, both It is intended for those travellers who to minimise drug toxicity and due to believe that they may have malaria and is concerns over drug resistance51.
not a replacement for chemoprophylaxis. Individuals for whom emergency standby It is particularly important that the treatment is advised must be provided individual traveller is sufficiently well with written instructions for its use. In briefed to be able to use standby particular, they must be informed about emergency treatment appropriately, symptoms suggesting possible malaria, so written instructions for its use are including fever of 38°C and above, required, not least because studies from indications for starting the standby outside the UK have reported standby treatment, how to take it, expected treatment often being used side-effects and the possibility of drug inappropriately50. Standby emergency treatment should ACMP recommended regimens for be started if it is impossible to consult a emergency standby treatment are given doctor and/or reach a diagnosis within in table 14.
24 hours of the onset of fever. Medical attention should be sought as (SP) is NOT recommended due to reports soon as possible for full assessment and of widespread resistance to this agent to exclude other serious causes of fever.
among P. falciparum strains. Halofantrine This is particularly important as many is no longer recommended due to illnesses other than malaria may present concerns over its association with sometimes fatal cardiac arrhythmias52.
The traveller should complete the ACMP advises against purchasing standby treatment course and antimalarial drugs over the internet.
recommence their antimalarialchemoprophylaxis 1 week after taking Antimalarials purchased in the tropics the first treatment dose, except in the may be fake24 and travellers should case of mefloquine prophylaxis, which obtain the medication required for should be resumed 1 week after the last their emergency standby treatment treatment dose if quinine was used for from a reputable source in the UK before standby treatment. Antipyretics should they travel.
be used to treat fever. A second full 4 tablets initially, followed by 5 further doses of 4 tablets each given at 8, 24, 36, 48 and 60 hours.
Total 24 tablets overa period of 60 hours Tablets should betaken with food toenhance drugabsorption.
4 tablets as a single dose on each of three Quinine 2 tablets 3 times a day for 3 days, accompanied by doxycycline twicedaily for 7 days 4 tablets on days 1 & 2, 2 tablets on day 3 155 mgchloroquine to very fewgeographicalareas Quinine 2 tablets 3 times a day for 5-7 (150 mgpreferred) Clindamycin 3 tablets (450 mg) 3 times aday for 5 days Chloroquine doses are given as the base. Quinine plus clindamycin (or chloroquine alone in the very few non-resistant areas) is the only regimen to be used in pregnancy.
Emergency Standby MedicationTraveller Information LeafletAvailable to download from the HPA website www.hpa.org.uk You have been advised to carry emergency standby antimalarial medicationwith you on your forthcoming trip. This leaflet provides you with advice onwhen and how to use it. Please keep it safely with your medication. If you aretravelling with a companion, please ask them to read this leaflet as they maybe able to assist you in following its advice in the event of your becoming ill.
Incubation period of malariaThe minimum period between being bitten by an infected mosquito anddeveloping symptoms of malaria is 8 days, so a febrile illness starting withinthe first week of your arrival in a malarious area is not likely to be due tomalaria.
Symptoms and signs of malariaMalaria usually begins with a fever. You may then feel cold, shivery, shaky andvery sweaty. Headache, feeling sick and vomiting are common with malariaand you are also likely to experience aching muscles. Some people developjaundice (yellowness of the whites of the eyes and the skin). It is notnecessary for all these symptoms to be present before suspecting malaria asfever alone may be present at first.
When to take your Emergency Standby MedicationIf you develop a fever of 38°C [100°F] or more, more than one week afterbeing in a malarious area, please seek medical attention straight away.
If you will not be able to get medical attention within 24 hours of yourfever starting, start your standby medication and set off to find andconsult a doctor.
How to take your Emergency Standby MedicationFirst, take medication (usually paracetamol) to lower your fever. If your feveris controlled, it makes it less likely that you will vomit your antimalarial drugs.
Then, without delay, take the first dose of your emergency standbyantimalarial medication.
If you do vomit and it is within 30 minutes of taking the antimalarial drugs,repeat the first dose of them (but do not repeat the paracetamol). If youvomit 30–60 minutes after taking the first dose of the antimalarial drugs,repeat the treatment, but take only HALF the first dose.
Continue the treatment as instructed for the particular drugs prescribed for you.
Please remember that this emergency standby medication has beenprescribed based on your particular medical history and should be taken only by you as it may not be suitable for others.
Once you have completed your emergency standby medication you shouldrestart your malaria prophylactic drug(s) one week after you took the firsttreatment dose of. emergency standby medication. If your preventivemedication consists of mefloquine and your standby treatment includedquinine, you should wait a week after completing the course of quininebefore you restart mefloquine.

Source: http://www.tropnet.net/fileadmin/Redakteure/PDF/British_recommendations/Malaria_prevent_incl_map_UK_.pdf