Clinical Topic A-Z Clinical Speciality

Malaria prophylaxis

Malaria prophylaxis
D008288Malaria
D014195Travel
Q000517prevention & control
Infections and infestationsPreventative medicine
2012-02-01Last revised in February 2012

Malaria prophylaxis - Summary

Malaria is a tropical disease caused by infection of red blood cells by a protozoan parasite from the Plasmodium species, which is transmitted to humans following a bite from its vector, the Anopheles mosquito.

Four species of malarial parasite cause almost all malarial infections in humans.

Plasmodium falciparum causes most cases of malaria and is the most likely to result in severe illness or death.

Plasmodium vivax and Plasmodium ovale may cause relapsing malaria.

Plasmodium malariae is less commonly seen in the UK and may present with late recrudescences many years after the person has left an endemic area.

Prophylaxis used depends on the area to be visited, the age of the person, contraindications to specific drugs in people with co-morbidities, and patient preference.

Options for malaria prophylaxis will vary according to the area to be visited. Up to date information can be found on the National Travel Health Network and Centre (NaTHNaC) website.

Methods of preventing mosquito bites include:

Covering up with clothing when practical.

Applying DEET-based insect repellents to all exposed areas of the body.

Spraying insecticides in the bedroom before sleep to kill mosquitoes and covering beds with mosquito nets (preferably impregnated with insecticide).

Using air conditioning or ceiling fans where available to cool the room and reduce mosquito activity.

Chemoprophylaxis and measures to prevent mosquito bites do not eliminate the risk of contracting malaria (although they significantly reduce it). Therefore people travelling to an area where malaria is endemic should be advised when to suspect malaria, and to seek medical attention as soon as possible if malaria is suspected. Malaria presents:

Most commonly with fever and flu-like symptoms (general malaise, headache, myalgia) but may also present with diarrhoea, respiratory symptoms, or jaundice.

Seven or more days after entering a malaria endemic area (the incubation period).

Up to 1 year after leaving a malaria endemic area (although malaria usually develops within three months of exposure).

The following interventions are not recommended for the prevention of malaria:

Herbal remedies, homeopathy, electronic buzzers, vitamin B1, garlic, yeast spreads, tea tree oil, and bath oils.

Pyrimethamine and sulfadoxine (Fansidar®).

Insect repellents other than DEET (N,N–diethyl-m-toluamide), unless there is a known allergy to DEET.

Have I got the right topic?

1months3060monthsBoth

This CKS topic covers the management of a person travelling to areas endemic with malaria, and is based on national guidelines written by the Advisory Committee on Malaria Prevention in travellers from the UK, which are published by the Health Protection Agency [Chiodini et al, 2007].

This CKS topic does not cover the treatment of acute malaria or the management of other tropical diseases.

There are separate CKS topics on Immunizations - travel and Malaria.

The target audience for this CKS topic is healthcare professionals working within the NHS in the UK, and providing first contact or primary health care.

How up-to-date is this topic?

How up-to-date is this topic?

Changes

Last revised in February 2012

November 2013 — minor update. Text changed in prescribing information section for mefloquine in line with the updated Summary of Product Characteristics [ABPI Medicines Compendium, 2013eg].

May 2013 - minor update. Typographical errors corrected.

February 2012 — revised. A literature search was conducted in October 2011 to identify evidence-based guidelines, UK policy, systematic reviews, and key RCTs published since the last revision of the topic. No changes to clinical recommendations have been made. The topic has been restructured to improve clarity and navigation. Issued in March 2012.

Previous changes

October 2010 — topic structure revised to ensure consistency across CKS topics — no changes to clinical recommendations have been made.

October 2009 — minor update. Advice that antacids and chloroquine should be taken 4 hours apart has been added to the Prescribing information section. Issued in October 2009.

November 2008 — minor update. Black triangle removed from Malarone Paediatric®. Issued in December 2008.

March to July 2007 — converted from CKS guidance to CKS topic structure. The evidence-base has been reviewed in detail, and recommendations are more clearly justified and transparently linked to the supporting evidence.

October 2005 — minor technical update. Issued in November 2005.

April 2004 — reviewed, incorporating new Health Protection Agency (formerly the Public Health Laboratory Service) guidance on malaria prophylaxis. Validated in September 2004 and issued in November 2004.

November 2001 — reviewed, incorporating new Public Health Laboratory Service guidance on malaria prophylaxis. Validated in March 2002 and issued in April 2002.

October 1998 — written.

Update

New evidence

Evidence-based guidelines

Guidelines published since the last revision of this topic:

PHE (2013) Guidelines for malaria prevention in travellers from the UK. Public Health England. Health Protection Agency www.hpa.org.uk [Free Full-text]

HTAs (Health Technology Assessments)

No new HTAs since 1 October 2011.

Economic appraisals

No new economic appraisals relevant to England since 1 October 2011.

Systematic reviews and meta-analyses

No new systematic reviews or meta-analyses published since 1 October 2011.

Primary evidence

No new randomized controlled trials published in the major journals since 1 October 2011.

Observational studies published since the last revision of this topic:

Schlagenhauf, P., Blumentals, W.A., Suter, P., et al. (2012) Pregnancy and fetal outcomes after exposure to mefloquine in the pre- and periconception period and during pregnancy. Clinical Infectious Diseases 54(11), e124-e131. [Abstract] [Free Full-text]

New policies

No new national policies or guidelines since 1 October 2011.

New safety alerts

No new safety alerts since 1 October 2011.

Changes in product availability

No changes in product availability since 1 October 2011.

Goals and outcome measures

Goals

To support primary healthcare professionals:

To advise on preventing mosquito bites

To provide suitable drugs to prevent malaria

Background information

Definition

What is it?

Malaria is a tropical disease caused by infection of red blood cells by Plasmodium, a protozoan parasite which is transmitted to humans following a bite from its vector, the anopheles mosquito.

Four species of malarial parasite cause almost all malarial infections in humans [White, 2009].

Plasmodium falciparum causes most cases of malaria imported into the UK — this type of malaria has no dormant stage and is the most likely to result in severe illness or death.

Plasmodium vivax and Plasmodium ovale may cause relapsing malaria.

Plasmodium malariae is less commonly seen in the UK and may present with late recrudescences many years after the person has left an endemic area [Chiodini et al, 2007; Fairhurst and Wellems, 2009].

In Malaysia, the macaque monkey malarial parasite Plasmodium knowlesi causes significant morbidity and mortality in humans [Fairhurst and Wellems, 2009].

Mixed infections with more than one species are uncommon [Chiodini et al, 2007].

Cryptic malaria is a term used when malaria is diagnosed, but there is no travel history to identify a possible exposure. This is very rare and thought to be related to an inadequate travel history, late detection, importation of the mosquito to the UK, transmission via infected blood, or by an unknown mechanism [HPA, 2006a].

Lifecyle of the malarial parasite

What is the life cycle of the malarial parasite?

An infected female mosquito releases 8–100 sporozoites (the infecting agent) into the person's bloodstream in one bite.

Sporozoites are transported in the bloodstream and enter liver cells, where they multiply (asexually) to form a hepatic schizont which contains tens of thousands of merozoites.

In the case of Plasmodium falciparum this takes 5–7 days.

In P. vivax and P. ovale infection only, some sporozoites develop into hypnozoites, which are a dormant stage and may start multiplying up to a year or more after being acquired.

The hepatic schizont then matures and ruptures, and the merozoites are released back into the bloodstream.

Each merozoite can penetrate a red blood cell forming a red cell schizont, where it grows and divides over 48 hours (P. falciparum, P. vivax or P. ovale) to 72 hours (P. malariae).

The red blood cell schizonts mature and rupture synchronously releasing more merozoites into the bloodstream. These merozoites enter more red blood cells, rapidly bringing about the clinical symptoms of the disease.

Some of the merozoites do not divide, but form male and female gametocytes instead — these may persist in the circulation for several weeks and can mate (reproduce sexually) when taken up by the biting mosquito, thus completing the cycle.

[White, 2009]

Clinical features of malaria

What clinical features does malaria cause?

Malaria usually presents as a non-specific 'flu-like' illness, and should be suspected in anyone who has travelled to a malaria-endemic area within the past year, especially if in the previous 3 months, regardless of whether they have taken chemoprophylaxis [Chiodini et al, 2007; Lalloo et al, 2007].

The symptoms of uncomplicated malaria include:

Headache, muscular ache, vague abdominal discomfort, lassitude, and lethargy. Fever is also a defining symptom and sign.

Children are often irritable and lethargic, and gastrointestinal symptoms such as diarrhoea and vomiting are common. Less commonly they may present with respiratory symptoms or jaundice. Children may deteriorate over a short period of time.

People who have taken chemoprophylaxis may present atypically (for example with backache) and, like people with partial immunity (due to previous infection), may present later.

Plasmodium falciparum infection can progress to severe complicated malaria. The onset can be gradual or sudden and begin within hours or days of the first febrile symptoms of malaria.

The only physical sign of malarial infection is fever. However, the absence of fever in an ill person does not exclude the diagnosis of malaria.

The fever in most people has no specific pattern and may present 1–2 days after initial symptoms. Initially, the temperature rises resulting in shivering (a cold phase lasting 15–60 minutes) then sweating (a hot phase lasting 2–6 hours). If the infection becomes established, malarial symptoms can come in cycles (paroxysms), occurring every 2–3 days.

Signs of the complications of severe malaria may be present. See Complications.

Immunity

Is it possible to acquire immunity to malaria?

Disease-controlling immunity to malaria can develop with continual exposure to infection. This immunity prevents the development of symptomatic and severe disease, despite the presence of malarial parasites in the bloodstream. However, it does not clear all of the parasites from the bloodstream [Fairhurst and Wellems, 2009].

Immunity develops slowly during natural untreated infections [White, 2009].

Cross-strain protection is weak or negligible [White, 2009].

Disease-controlling immunity is believed to be short-lived without continual exposure to infection [Fairhurst and Wellems, 2009].

People from endemic countries who have lived in the UK for more than 2 months are at high risk of severe malaria if they return home.

This group of people are often unaware of the importance of malaria prophylaxis for themselves and their children [HPA, 2009].

Prevalence

How common is it?

In 2008, 1370 people with malaria in the UK were reported to the Malaria Reference Laboratory, and there were six deaths [HPA, 2009].

Over 70% (1087) of these cases were due to infection with Plasmodium falciparum.

Most P. falciparum infections were acquired in West Africa.

The most likely group of people to be affected were those visiting friends and family abroad, particularly in Nigeria and Ghana.

Where ethnicity had been recorded, 924 people with imported malaria were African or of African descent, 129 people were reported as white British, and 131 people were reported as south Asian or of south Asian descent.

Most of those from whom a history of prophylaxis use was obtained had either taken no prophylaxis (83% [668/809]) or had taken a drug for prophylaxis not recommended for their area of travel.

The greatest number of P. falciparum infections in the UK are contracted in West Africa, by people visiting relatives in that region [CDR, 2004]. This occurs because the naturally acquired immunity developed by residents in endemic malarial areas only lasts for a period of months after leaving that area and symptomatic malaria may return when these people have subsequent further exposure.

Prognosis

What is the prognosis?

In the UK in 2008, six people died from malaria [HPA, 2009]. Annual mortality tends to range from 5 to 15 deaths [HPA, 2006b].

The mortality rate of Plasmodium falciparum malaria (once contracted) is estimated to be 0.5–1% [Bradley and Bannister, 2003].

P. falciparum malaria can result in death within 24 hours from the onset of symptoms, due to cerebral malaria or acute renal failure [Gill and Beeching, 2004]. See the section on Complications for more information on the complications of severe malaria.

A child may become comatose without any preceding fever or other symptoms with P. falciparum malaria, resulting in death within a few hours.

Of those who die from malaria, 90% are children under the age of 5 years, and of these deaths, 90% take place in sub-Saharan Africa [Murray, 2006].

Malaria caused by P. vivax, P. ovale, and P. malariae all have very low mortality, and even if untreated a person may recover within a month. Nevertheless, symptoms may become life-threatening in pregnant women, children, or people with co-morbidities such as immunosuppression, diabetes, or renal impairment [Lalloo et al, 2007].

After having adequate treatment for malaria (and if there is no further exposure), it is extremely rare to get a relapse of symptoms [Chiodini et al, 2007].

Complications

What are the complications?

Complications of severe malaria include [WHO, 2006; Chiodini et al, 2007]:

Cerebral malaria, which can result in impaired consciousness, seizure, or coma (resulting in 80% of deaths from malaria).

Severe anaemia, jaundice, and hypoglycaemia.

Renal failure, including 'blackwater fever' (massive intravascular haemolysis with haemoglobinuria).

Shock (circulatory collapse).

Pulmonary oedema or acute respiratory distress syndrome.

Spontaneous bleeding/disseminated intravascular coagulation.

Complications are likely to be more severe in pregnant women and children.

Management

Management

Scenario: Preventing malaria in adults : covers advice for adults about:

Malaria risks, symptoms and what to do if symptoms of malaria develop.

The recommended chemoprophylaxis for the country to be visited taking into account contra-indications for individuals with co-morbid conditions.

Preventing mosquito bites.

When to provide emergency standby treatment.

Scenario: Preventing malaria in children : covers advice for parents about:

Malaria risks, symptoms and what to do if symptoms of malaria develop.

The recommended chemoprophylaxis for the country to be visited taking into account contra-indications for children with co-morbid conditions.

Preventing mosquito bites.

When to seek specialist advice about providing emergency standby treatment.

Scenario: Preventing malaria when pregnant/breastfeeding/planning pregnancy : covers advice for breastfeeding or pregnant women and women planning pregnancy about:

Malaria risks, symptoms and what to do if symptoms of malaria develop.

The recommended chemoprophylaxis for the country to be visited taking into account contra-indications for children with co-morbid conditions.

Preventing mosquito bites.

When to seek specialist advice about providing emergency standby treatment.

Scenario: Preventing malaria in adults

Scenario: Preventing malaria in adults

192months3060monthsBoth

Overview of adult management

How should I manage an adult intending to travel to a malaria endemic area?

For pregnant and breastfeeding women see Scenario: Preventing malaria when pregnant/breastfeeding/planning pregnancy.

For all other adults:

Provide advice about malaria including:

The risk of contracting malaria with and without chemoprophylaxis, and the risk of harm from malaria if contracted.

The symptoms of malaria.

What to do if illness develops 7 days or more after entering a malaria endemic area or within one year of returning from that area.

Decide what chemoprophylaxis to recommend based on the area to be visited, contraindications to specific drugs in people with co-morbidities, and patient preference.

Provide advice about preventing mosquito bites.

Consider the need to provide emergency 'standby' treatment for people travelling in areas where they cannot access medical facilities within 24 hours.

Determine whether travel immunizations are recommended — for further information see the CKS topic on Immunizations - travel.

Basis for recommendation

Basis for recommendation

These recommendations are based on the expert opinion of the Health Protection Agency published in Guidelines for Malaria Prevention in Travellers from the United Kingdom [Chiodini et al, 2007].

Advice about malaria

What advice should I give people considering travel to a malaria endemic area?

Advise people considering travel to an area where malaria is endemic:

That chemoprophylaxis and measures to prevent mosquito bites do not eliminate the risk of contracting malaria (although they significantly reduce it).

Who have previously lived in an area where malaria is endemic that any immunity to malaria that they may have previously had will have been lost within a few months of leaving. Ensure they understand that they are at increased risk of contracting malaria when they return to these areas if they do not use chemoprophylaxis.

Who do not have a spleen that, if they contract malaria, they are much more likely to develop severe malaria than people with a spleen. Ensure they understand this risk before they decide to travel.

Who have other co-morbidities such as chronic renal, respiratory or heart disease, that they are at increased risk of harm if they contract malaria. Ensure they understand this risk before they decide to travel. The increased risk of harm depends on the severity of their co-morbidity and occurs because:

Malaria may be more severe in people with chronic ill-health.

Malaria may precipitate a deterioration in their chronic condition.

Advise people travelling to an area where malaria is endemic:

When to suspect malaria. Malaria presents:

Most commonly with fever and flu-like symptoms (general malaise, headache, myalgia) but may also present with diarrhoea, respiratory symptoms, or jaundice.

Seven or more days after entering a malaria endemic area (the incubation period).

Up to 1 year after leaving a malaria endemic area (although malaria usually develops within three months of exposure).

What to do if malaria is suspected. They should:

Seek medical attention as soon as possible.

Start emergency standby treatment (if carried) if they are unable to access medical facilities within 24 hours.

Advise people that malaria chemoprophylaxis is not prescribable on an FP10 prescription.

Chloroquine and proguanil can be obtained over-the-counter from a pharmacist.

Mefloquine, doxycycline, and atovaquone with proguanil (Malarone®) are only available on private prescription.

Basis for recommendation

Basis for recommendation

These recommendations are based on the expert opinion of the Health Protection Agency published in Guidelines for Malaria Prevention in Travellers from the United Kingdom [Chiodini et al, 2007].

Information about not prescribing malaria chemoprophylaxis on an FP10 prescription comes from the Department of Health [DH, 1995].

Chemoprophylaxis

What chemoprophylaxis should I prescribe?

Look up the recommended treatment options for the area to be visited (including stop-overs) from either:

The National Travel Health Network and Centre (NaTHNaC) website. Select the country in the country information section and scroll down to the section on malaria. This information is free.

Or the Health Protection Scotland TRAVAX website. Registration is required to use this site. It is free to NHS users in Scotland and available by subscription elsewhere.

Exclude treatment options that are contraindicated for the individual— see Table 1. A list version of contraindications is available for people using mobile devices.

Check for interactions if the person is taking other drugs. See the electronic Medicines Compendium (eMC) or the British National Formulary (BNF) for up-to-date information.

Seek specialist advice if all recommended treatments for the area to be visited are contraindicated — see Table 2 for sources of specialist advice.

Discuss the advantages and disadvantages of the remaining treatment options and prescribe the preferred option — see Table 3. A list version of the advantages and disadvantages of different regimes is available for people using mobile devices.

Table 1 . Contraindications to anti-malaria chemoprophylaxis in adults.
Contraindicated drugs Drugs that are not contraindicated
Depression and other psychiatric disorders Mefloquine Malarone®†, doxycyline, chloroquine, and proguanil
Hepatic impairment Depends on severity of hepatic impairment: mefloquine contraindicated in severe hepatic impairment — seek specialist advice Depends on the severity of hepatic impairment — seek specialist advice
Renal impairment Depending on severity of renal impairment chloroquine, proguanil and malarone may be contraindicated or prescribable with a dose reduction — seek specialist advice Mefloquine and doxycycline
Epilepsy Mefloquine, chloroquine Malarone®†, proguanil, and doxycyline
† Combination of proguanil and atovaquone.
Data from: [ABPI Medicines Compendium, 2010ee, ABPI Medicines Compendium, 2011v, ABPI Medicines Compendium, 2011w, ABPI Medicines Compendium, 2011u; ABPI Medicines Compendium, 2013eg]
Table 2 . Sources of expert advice on preventing malaria.
Source Website address Comment
National Travel Health Network and Centre (NaTHNaC) www.nathnac.org Advice line: 0845 602 6712
Liverpool School of Tropical Medicine (LSTM) www.liv.ac.uk/lstm Can give pre-travel advice when NaTHNaC is unavailable. Telephone (0151) 7053100
Malaria Reference Laboratory (MRL) www.malaria-reference.co.uk Provides 'advice for healthcare professionals'
TRAVAX (Health Protection Scotland) www.travax.nhs.uk Registration is required to use the website or access telephone advice. This is free to NHS users in Scotland; there is a subscription charge for NHS users in other parts of the UK
Information sources recommended by the Advisory Committee on Malaria Prevention in UK travellers: [Chiodini et al, 2007]
Table 3 . Advantage and disadvantages of drug regimens used to prevent malaria in adults.
Drug regimen Advantages Disadvantages
Chloroquine and proguanil* Low cost Complicated dosing regimen may reduce compliance. Toxic in overdose, especially in children.
Mefloquine Convenient weekly dosing Adverse effects: mefloquine , if they occur, tend to persist for weeks to months because of the long half-life of the drug. Needs to be started 10 days before departure to ensure it is well tolerated before travelling.
Doxycycline Low cost Generally well tolerated Causes photosensitivity in 3% of people and predisposes to vaginal candidal infections.
Malarone®† Only requires dosing for 1 week after return Generally well tolerated Expensive.
* Chloroquine is rarely used alone. † Combination of proguanil and atovaquone.
Data adapted from: [Chiodini et al, 2007]

Drug contraindications

Contraindications to specific chemoprophylaxis in adults

For people with depression and other psychiatric disorders:

Contraindicated drugs — mefloquine.

Drugs that are not contraindicated — malarone®, doxycyline, chloroquine, and proguanil.

For people with hepatic impairment: contraindications to individual drugs depends on the degree of hepatic impairment — mefloquine is contraindicated in severe hepatic impairment — seek specialist advice as to what to prescribe.

For people with renal impairment:

Drugs that may be contraindicated or prescribable with a dose reduction, depending on the severity of the renal impairment — chloroquine, proguanil, and malarone®.

Drugs that are not contraindicated — mefloquine and doxycycline.

For people with epilepsy:

Drugs that are contraindicated — mefloquine and chloroquine.

Drugs that are not contraindicated — malarone®, proguanil and doxycyline.

Advantages/disadvantages of different regimes

Advantages and disadvantages of different regimes

Chloroquine and proguanil:

Advantages: low cost.

Disadvantages: complicated dosing regimen may reduce compliance and toxic in overdose, especially in children.

Mefloquine:

Advantages: convenient weekly dosing.

Disadvantages: adverse effects (most commonly disturbance of balance and dizziness), if they occur, tend to persist for weeks to months because of the long half-life of the drug. Needs to be started 10 days before departure to ensure it is well tolerated before travelling.

Doxycycline:

Advantages: low cost and generally well tolerated.

Disadvantages: causes photosensitivity in 3% of people and predisposes to vaginal candidal infections.

Malarone® (combination of proguanil and atovaquone):

Advantages: only requires dosing for 1 week after return and is generally well tolerated.

Disadvantages: expensive.

Basis for recommendation

Basis for recommendation

These recommendations are based on the expert opinion of the Health Protection Agency published in Guidelines for Malaria Prevention in Travellers from the United Kingdom [Chiodini et al, 2007].

Information about contraindications to malaria prophylaxis is consistent with that given in the Summary of Product Characteristics for:

Chloroquine [ABPI Medicines Compendium, 2011v].

Doxycycline [ABPI Medicines Compendium, 2011u].

Malarone® [ABPI Medicines Compendium, 2011w].

Mefloquine [ABPI Medicines Compendium, 2013eg].

Proguanil [ABPI Medicines Compendium, 2010ee].

Preventing mosquito bites

What advice should I give a person to prevent mosquito bites when travelling to areas endemic with malaria?

Advise the person to:

Cover up with clothing when practical. Consider spraying cotton clothing with insect repellents. Alternatively, impregnated clothing can be bought already prepared.

Apply DEET-based insect repellents to all exposed areas of the body, especially the feet, ankles, and legs whilst outdoors. Only recommend alternative insect repellents (that are less effective) if DEET cannot be tolerated (usually because of skin reactions).

Stronger preparations of DEET (highest strength 50%) provide longer protection and need less frequent applications.

Apply DEET after suncream as it can reduce the efficacy of sun block protection if applied first.

Spray insecticides in the bedroom before sleep to kill mosquitoes. An electrically heated device to vaporise a 'mat' (tablet) containing a synthetic pyrethroid can be used each night to provide further protection.

Cover beds with mosquito nets (preferably impregnated with insecticide).

Use air conditioning or ceiling fans where available to cool the room and reduce mosquito activity.

Basis for recommendation

Basis for recommendation

These recommendations are based on the expert opinion of the Health Protection Agency published in Guidelines for Malaria Prevention in Travellers from the United Kingdom [Chiodini et al, 2007].

The evidence for the use of DEET in trials is limited but experience has led to a consensus that it is beneficial as an insect repellent for malaria.

The evidence for insect repellents other than DEET suggest a lower efficacy than the higher DEET concentrations. Some are comparable to lower DEET concentrations, but appear to have a shorter duration of protection than DEET overall.

There is evidence that insecticide-impregnated nets reduce the transmission of malaria, improving both mortality and morbidity in people who use them, and on a wider community level. These benefits have been proven in people residing in malaria endemic areas, but may also be extrapolated to other groups of people such as travellers.

The recommendation that DEET should be applied after suncream is based on expert opinion [Montemarano et al, 1997].

It is particularly important to protect the ankles, which the mosquito appears to favour. One study found that spraying just the ankles with DEET gave a three-fold reduction in the number of mosquito bites [Govere et al, 2001].

When to prescribe 'standby' treatment

When should I prescribe emergency 'standby' treatment for people visiting malaria endemic areas?

Offer emergency standby treatment for people travelling to remote areas where medical facilities cannot be accessed within 24 hours:

Seven or more days after entering or passing through a malaria endemic area.

Up to 12 months after leaving a malaria endemic area.

Explain that emergency standby treatment is NOT a substitute for regular chemoprophylaxis. It is carried to treat malaria that develops despite the use of regular chemoprophylaxis.

Seek expert advice as to what emergency standby treatment to prescribe. In general, the standby treatment should have a different mechanism of action to the regular chemoprophylaxis regimen. For sources of expert advice see Table 1.

Advise people to start emergency standby treatment if:

They develop any symptoms of malaria:

Most commonly fever and flu-like symptoms (general malaise, headache, myalgia) but occasionally diarrhoea, respiratory symptoms, or jaundice.

Seven or more days after entering a malaria endemic area (the incubation period).

Up to 1 year after leaving a malaria endemic area (although malaria usually develops within 3 months of exposure).

AND, they are unable to access medical facilities within 24 hours.

Advise them to seek medical attentions as soon as possible after starting emergency standby treatment.

Table 1 . Sources of expert advice.
Source Website address Comment
National Travel Health Network and Centre (NaTHNaC) www.nathnac.org Advice line: 0845 602 6712
Liverpool School of Tropical Medicine (LSTM) www.liv.ac.uk/lstm Can give pre-travel advice when NaTHNaC is unavailable. Telephone (0151) 7053100
Malaria Reference Laboratory (MRL) www.malaria-reference.co.uk Provides 'advice for healthcare professionals'
TRAVAX (Health Protection Scotland) www.travax.nhs.uk Registration is required to use the website or access telephone advice. This is free to NHS users in Scotland; there is a subscription charge for NHS users in other parts of the UK.
Information sources recommended by the Advisory Committee on Malaria Prevention in UK travellers: [Chiodini et al, 2007]

Basis for recommendation

Basis for recommendation

These recommendations are based on the expert opinion of the Health Protection Agency published in Guidelines for Malaria Prevention in Travellers from the United Kingdom [Chiodini et al, 2007].

Measures not recommended for prevention

What measures are not recommended for preventing malaria?

The following interventions are not recommended for the prevention of malaria:

Herbal remedies, homeopathy, electronic buzzers, vitamin B1, garlic, yeast spreads, tea tree oil, and bath oils.

Pyrimethamine and sulfadoxine.

Pyrimethamine and sulfadoxine are usually combined in a product with the proprietary name of Fansidar®. It is sometimes useful in the treatment of malaria, but is not recommended for its prevention.

Insect repellents other than DEET (N,N–diethyl-m-toluamide), unless there is a known allergy to DEET.

These include lemon eucalyptus, picaridin (available as a 20% solution), and 3-ethylaminopropionate.

Oil of citronella is no longer allowed to be marketed in Europe as an active ingredient for the prevention of mosquito bites.

There are no effective vaccines available.

Basis for recommendation

Basis for recommendation

These recommendations are based on the expert opinion of the Health Protection Agency published in Guidelines for Malaria Prevention in Travellers from the United Kingdom [Chiodini et al, 2007] and reflect either a lack of evidence to support the use of these interventions, or evidence that they are ineffective.

Herbal and homeopathic remedies are not recommended as they have not been studied in randomized controlled trials (RCTs). There is no scientific or clinical basis for the use of homeopathy, and the Advisory Committee on Malaria Prevention in UK Travellers (ACMP) actively discourages its use. The Faculty of Homeopathy does not promote the use of homeopathic remedies in the prevention of malaria and notes that they are unlikely to be acceptable to insurers [HPA, 2007].

Electronic buzzers have been promoted as being effective for repelling mosquitoes, but are completely ineffective, as confirmed by a recent Cochrane review [Enayati et al, 2007].

Insect repellent anecdotes: there are beliefs that ingesting vitamin B1, garlic, or savoury yeast spreads (e.g. Marmite) repels mosquitoes. However, there is no evidence that this is the case. Similarly, CKS found no evidence that applications of tea tree oils or bath oils to skin repel mosquitoes.

Insect repellents other than DEET have no advantages over DEET and are probably not as effective .

Lemon eucalyptus is reported as being equivalent to 15% DEET (a lower concentration than is usually recommended), but has a shorter duration of action and requires more frequent application.

Picardin has been reported as having similar repellent properties as DEET, but has been less studied. If it is considered, the 20% formulation should be used.

Oil of citronella provides only short-term protection and should not be used.

Pyrimethamine combined with sulfadoxine (Fansidar®) has been found to be effective in the prevention of malaria in one RCT [Stemberger et al, 1984], but resistance to it is now widespread and it is not usually recommended for prophylaxis [BNF 62, 2011].

Vaccines to prevent malaria are not currently available in the UK. However, there are studies in progress and they have been the subject of three Cochrane reviews with mixed results.

One systematic review found that the SPf66 vaccine was ineffective at preventing Plasmodium falciparum infection in Africa [Graves and Gelband, 2006c].

One systematic review of vaccines designed to prevent pre-erythrocytic malaria found that RTS,S vaccine yielded promising results [Graves and Gelband, 2006a].

One systematic review of vaccines designed to prevent blood-stage malaria found limited evidence that MSP/RESA (combination B) reduced the rate of clinical malaria, but the effect was strain specific [Graves and Gelband, 2006b].

Scenario: Preventing malaria in children

Scenario: Preventing malaria in children

1months191monthsBoth

Overview of child management

How should I manage a child travelling to a malaria endemic area?

Provide advice for parents about:

The particular risks of malaria for children.

The symptoms of malaria.

What to do if illness develops 7 days or more after entering a malaria endemic area or within one year of returning from that area.

If travel with a child to a malaria endemic area is considered necessary, emphasize the need for meticulous compliance with chemoprophylaxis and measures to reduce bites from mosquitoes, and:

Decide what chemoprophylaxis to recommend based on the area to be visited, contraindications to specific drugs for children, and patient preference.

Provide advice about preventing mosquito bites.

Seek specialist advice about emergency standby treatment for children travelling to remote areas where malaria is endemic and medical facilities cannot be accessed within a few hours.

Determine whether travel immunizations are recommended — for further information see CKS topic on Immunizations - travel.

Basis for recommendation

Basis for recommendation

These recommendations are based on the expert opinion of the Health Protection Agency published in Guidelines for Malaria Prevention in Travellers from the United Kingdom [Chiodini et al, 2007].

The Health Protection Agency provide advice about when to provide emergency standby treatment for adults but recommend that children avoid remote areas where medical facilities cannot be readily accessed.

CKS recognizes the possibility that some children will travel to these areas despite the increased risks involved. Under these circumstances CKS considers it to be good practice to discuss the provision of standby treatment with a specialist.

Advice to parents

What advice should I give parents considering travelling to malaria endemic areas with children?

Advise parents:

Of the particular risks for a child contracting malaria:

Chemoprophylaxis and measures to prevent mosquito bites do not eliminate the risk of contracting malaria (although they significantly reduce it).

Children are at particular risk of severe and fatal malaria.

The only way to completely avoid these risks is to avoid taking a child to an area where malaria is endemic.

If parents decide to travel with children despite the risks, advise them:

To avoid travel to areas where medical help is not readily available because children can become seriously ill within 6–12 hours of the first symptoms of malaria.

To comply meticulously with chemoprophylaxis and take particular care to protect the child against mosquito bites.

Ensure parents understand that children who have previously lived in a malaria endemic area may have had some immunity to malaria but this is lost within a few months of leaving. Children are therefore at increased risk of contracting malaria when they return to these areas if they do not use chemoprophylaxis.

When to suspect malaria. Malaria presents:

Most commonly with fever and flu-like symptoms (general malaise, headache, myalgia) but may also present with diarrhoea, respiratory symptoms, or jaundice.

Seven or more days after entering a malaria endemic area (the incubation period).

Up to 1 year after leaving a malaria endemic area (although malaria usually develops within three months of exposure).

What to do if malaria is suspected. They should:

Seek medical attention as soon as possible if a child becomes unwell with any symptoms of malaria, especially a febrile illness.

Start emergency standby treatment as soon as malaria is suspected (if this has been provided) if they are unable to access medical facilities within a few hours.

Advise people that malaria chemoprophylaxis is not prescribable on an FP10 prescription.

Chloroquine and proguanil can be obtained over-the-counter from a pharmacist.

Mefloquine, doxycycline, and atovaquone with proguanil (Malarone®) are only available on private prescription.

Basis for recommendation

Basis for recommendation

These recommendations are based on the expert opinion of the Health Protection Agency published in Guidelines for Malaria Prevention in Travellers from the United Kingdom [Chiodini et al, 2007].

Information about not prescribing malaria chemoprophylaxis on an FP10 prescription comes from the Department of Health [DH, 1995].

Chemoprophylaxis

Which chemoprophylaxis should I prescribe a child travelling to a malaria endemic area?

Look up the recommended chemoprophylaxis for the area to be visited (including stop-overs) from either:

The National Travel Health Network and Centre (NaTHNaC) website. Select the country in the country information section. This information is free.

Or the Health Protection Scotland TRAVAX website. Registration is required to use this site. It is free to NHS users in Scotland and by subscription elsewhere.

Exclude treatment options that are contraindicated for an individual — see Table 1. A list version of contraindications is available for people using mobile devices.

Check for interactions if the child is taking other drugs. See the electronic Medicines Compendium (eMC) or the British National Formulary (BNF) for up-to-date information.

Seek specialist advice if all recommended treatments for the area to be visited are contraindicated or a child has a co-morbidity other than epilepsy — see Table 2.

Discuss the advantages and disadvantages of the remaining treatment options and prescribe the preferred option — see Table 3. A list version of advantages and disadvantages of different regimes is available for people using mobile devices.

Provide practical advice about how to use drugs that are not available in paediatric formulations — for further information see the section on Prescribing for a young child or baby.

Table 1 . Contraindications to anti-malaria chemoprophylaxis in children.
Contraindicated drugs Drugs that are not contraindicated
Children Doxycline (children under 12 years of age) Chloroquine and proguanil Mefloquine (for children over 5 kg) Malarone®†(for children over 11 kg)
Children with epilepsy Mefloquine and chloroquine Doxycline (children under 12 years of age) Malarone®† and proguanil
† Combination of proguanil and atovaquone.
Data from: [ABPI Medicines Compendium, 2010ee, ABPI Medicines Compendium, 2011v, ABPI Medicines Compendium, 2011w, ABPI Medicines Compendium, 2011u; ABPI Medicines Compendium, 2013eg]
Table 2 . Sources of expert advice on preventing malaria.
Source Website address Comment
National Travel Health Network and Centre (NaTHNaC) www.nathnac.org Advice line: 0845 602 6712
Liverpool School of Tropical Medicine (LSTM) www.liv.ac.uk/lstm Can give pre-travel advice when NaTHNaC is unavailable. Telephone (0151) 7053100
Malaria Reference Laboratory (MRL) www.malaria-reference.co.uk Provides 'advice for healthcare professionals'
TRAVAX (Health Protection Scotland) www.travax.nhs.uk Registration is required to use the website or access telephone advice. This is free to NHS users in Scotland; there is a subscription charge for NHS users in other parts of the UK.
Information sources recommended by the Advisory Committee on Malaria Prevention in UK travellers: [Chiodini et al, 2007]
Table 3 . Advantage and disadvantages of drug regimens used to prevent malaria in children.
Drug regimen Advantages Disadvantages
Chloroquine and proguanil* Low cost Chloroquine is available as a sweetened solution. Complicated dosing regimen may reduce compliance. Chloroquine tablets are bitter-tasting and must be swallowed whole. Toxic in overdose, especially in children.
Mefloquine Convenient weekly dosing Only available as tablets, making child doses difficult. Adverse effects: mefloquine , if they occur, tend to persist for weeks to months because of the long half-life of the drug. Needs to be started 10 days before departure to ensure it is well tolerated before travelling.
Malarone®† Only requires dosing for 1 week after return Generally well tolerated Expensive.
* Chloroquine is rarely used alone. † Combination of proguanil and atovaquone.
Data adapted from: [Chiodini et al, 2007]

Drug contra-indications

Contraindications to specific chemoprophylaxis in children

For children:

Contraindicated drugs for children who are under 12 years of age — doxycycline.

Drugs that are not contraindicated — mefloquine (for children over 5 kg), malarone® (for children over 11 kg), chloroquine, and proguanil.

For children with epilepsy:

Contraindicated drugs — mefloquine and chloroquine, and doxycyline for children under 12 years of age.

Drugs that are not contraindicated — malarone® and proguanil.

Advantages/disadvantages of different regimes

Advantages and disadvantages of different drug regimes

Chloroquine and proguanil:

Advantages: low cost. Chloroquine is available as a sweetened solution.

Disadvantages: complicated dosing regimen may reduce compliance and toxic in overdose, especially in children. Chloroquine tablets are bitter-tasting and must be swallowed whole.

Mefloquine:

Advantages: convenient weekly dosing

Disadvantages: only available as tablets, making child doses difficult. Adverse effects (most commonly disturbance of balance and dizziness), if they occur, tend to persist for weeks to months because of the long half-life of the drug. Needs to be started 10 days before departure to ensure it is well tolerated before travelling.

Malarone® (combination of proguanil and atovaquone):

Advantages: only requires dosing for 1 week after return and is generally well tolerated.

Disadvantages: expensive.

Basis for recommendation

Basis for recommendation

These recommendations are based on the expert opinion of the Health Protection Agency published in Guidelines for Malaria Prevention in Travellers from the United Kingdom [Chiodini et al, 2007].

There is evidence from controlled trials that the rates of clinical malaria, severe anaemia, and hospital admissions are lower in children receiving antimalarial drugs compared with those receiving placebo. However, these trials have been exclusively conducted in children living in Africa in areas endemic with malaria rather than in children living in non-endemic areas visiting endemic areas [Meremikwu et al, 2008].

Information about contraindications to malaria prophylaxis is consistent with that given in the Summary of Product Characteristics for:

Chloroquine [ABPI Medicines Compendium, 2011v].

Doxycycline [ABPI Medicines Compendium, 2011u].

Malarone® [ABPI Medicines Compendium, 2011w].

Mefloquine [ABPI Medicines Compendium, 2013eg].

Proguanil [ABPI Medicines Compendium, 2010ee].

Preventing mosquito bites

What advice should I give to prevent mosquito bites when travelling to areas endemic with malaria?

Advise the following:

Cover up with clothing where practical. Consider spraying cotton clothing with insect repellents. Alternatively, impregnated clothing can be bought already prepared.

Apply DEET-based insect repellents to all exposed areas of the body, especially the feet, ankles, and legs whilst outdoors. Only recommend alternative insect repellents (that are less effective) if DEET can not be tolerated (usually because of skin reactions) or for babies of less than 2 months.

Reassure parents that DEET is considered safe in children.

Stronger preparations of DEET (highest strength 50%) provide longer protection and need less frequent applications.

Apply DEET after suncream as it can reduce the efficacy of sun block protection if applied first.

Spray insecticides in the bedroom before sleep to kill mosquitoes. An electrically heated device to vaporise a 'mat' (tablet) containing a synthetic pyrethroid can be used each night to provide further protection.

Cover beds with mosquito nets (preferably impregnated with insecticide).

Use air conditioning or ceiling fans where available to cool the room and reduce mosquito activity.

Basis for recommendation

Basis for recommendation

These recommendations are based on the expert opinion of the Health Protection Agency published in Guidelines for Malaria Prevention in Travellers from the United Kingdom [Chiodini et al, 2007].

The evidence for the use of DEET in trials is limited but experience has led to a consensus that it is beneficial as an insect repellent for malaria.

The evidence for insect repellents other than DEET suggest a lower efficacy than the higher DEET concentrations. Some are comparable to lower DEET concentrations, but appear to have a shorter duration of protection than DEET overall.

There is evidence that insecticide-impregnated nets reduce the transmission of malaria, improving both mortality and morbidity in people who use them, and on a wider community level. These benefits have been proven in people residing in malaria-endemic areas, but may also be extrapolated to other groups of people such as travellers.

It is particularly important to protect the ankles, which the mosquito appears to favour. One study found that spraying just the ankles with DEET gave a three-fold reduction in the number of mosquito bites by [Govere et al, 2001].

The recommendation that DEET should be applied after suncream is based on expert opinion [Montemarano et al, 1997].

When to prescribe standby treatment

When should I prescribe emergency 'standby' treatment for children visiting malaria endemic areas?

Advise parents about the particular risks of malaria for children.

If parents consider it necessary to take children into remote areas where malaria is endemic and where medical facilities can not be easily accessed, seek specialist advice about the appropriateness of prescribing emergency standby treatment and what to prescribe. For sources of expert advice see Table 1.

If advised to prescribe emergency standby treatment by a specialist advise the parents:

That emergency standby treatment is NOT a substitute for regular chemoprophylaxis. It is carried to treat malaria that develops despite the use of regular chemoprophylaxis.

To start emergency standby treatment if they are unable to access medical facilities within a few hours and the child develops any symptoms of malaria:

Most commonly fever and flu-like symptoms (general malaise, headache, myalgia) but occasionally diarrhoea, respiratory symptoms, or jaundice.

Seven or more days after entering an endemic malaria area (the incubation period).

Up to 1 year after leaving an endemic malaria area (although malaria usually develops within three months of exposure).

To seek medical attention as soon as possible after starting emergency standby treatment.

Table 1 . Sources of expert advice.
Source Website address Comment
National Travel Health Network and Centre (NaTHNaC) www.nathnac.org Advice line: 0845 602 6712
Liverpool School of Tropical Medicine (LSTM) www.liv.ac.uk/lstm Can give pre-travel advice when NaTHNaC is unavailable. Telephone (0151) 7053100
Malaria Reference Laboratory (MRL) www.malaria-reference.co.uk Provides 'advice for healthcare professionals'
TRAVAX (Health Protection Scotland) www.travax.nhs.uk Registration is required to use the website or access telephone advice. This is free to NHS users in Scotland; there is a subscription charge for NHS users in other parts of the UK.
Information sources recommended by the Advisory Committee on Malaria Prevention in UK travellers: [Chiodini et al, 2007]

Basis for recommendation

Basis for recommendation

The Health Protection Agency in Guidelines for Malaria Prevention in Travellers from the United Kingdom [Chiodini et al, 2007] provide advice about when to provide emergency standby treatment for adults but recommend that children avoid remote areas where medical facilities can not be readily accessed.

CKS recognizes the possibility that some children will travel to these areas despite the increased risks involved. Under these circumstances CKS considers it to be good practice to discuss the provision of standby treatment with a specialist.

Measures not recommended for prevention

What measures are not recommended for preventing malaria?

The following interventions are not recommended for the prevention of malaria:

Herbal remedies, homeopathy, electronic buzzers, vitamin B1, garlic, yeast spreads, tea tree oil, and bath oils.

Pyrimethamine and sulfadoxine.

Pyrimethamine and sulfadoxine are usually combined in a product with the proprietary name of Fansidar®. It is sometimes useful in the treatment of malaria, but is not recommended for its prevention.

Insect repellents other than DEET (N,N–diethyl-m-toluamide), unless there is a known allergy to DEET.

These include lemon eucalyptus, picaridin (available as a 20% solution), and 3-ethylaminopropionate.

Oil of citronella is no longer allowed to be marketed in Europe as an active ingredient for the prevention of mosquito bites.

There are no effective vaccines available.

Basis for recommendation

Basis for recommendation

These recommendations are based on the expert opinion of the Health Protection Agency published in Guidelines for Malaria Prevention in Travellers from the United Kingdom [Chiodini et al, 2007]. They reflect either a lack of evidence to support the use of these interventions, or evidence that they are ineffective.

Herbal and homeopathic remedies are not recommended as they have not been studied in randomized controlled trials (RCTs). There is no scientific or clinical basis for the use of homeopathy, and the Advisory Committee on Malaria Prevention in UK travellers (ACMP) actively discourages its use. The Faculty of Homeopathy does not promote the use of homeopathic remedies in the prevention of malaria and notes that they are unlikely to be acceptable to insurers [HPA, 2007].

Electronic buzzers have been promoted as being effective for repelling mosquitoes, but are completely ineffective, as confirmed by a recent Cochrane review [Enayati et al, 2007].

Insect repellent anecdotes: there are beliefs that ingesting vitamin B1, garlic, or savoury yeast spreads (e.g. Marmite) repels mosquitoes. However, there is no evidence that this is the case. Similarly, CKS found no evidence that applications of tea tree oils or bath oils to skin repel mosquitoes.

Insect repellents other than DEET have no advantages over DEET and are probably not as effective (see Insect repellents).

Lemon eucalyptus is reported as being equivalent to 15% DEET (a lower concentration than is usually recommended), but has a shorter duration of action and requires more frequent application.

Picardin has been reported as having similar repellent properties as DEET, but has been less studied. If it is considered, the 20% formulation should be used.

Oil of citronella provides only short-term protection and should not be used.

Pyrimethamine combined with sulfadoxine (Fansidar®) has been found to be effective in the prevention of malaria in one RCT [Stemberger et al, 1984], but resistance to it is now widespread and it is not usually recommended for prophylaxis [BNF 62, 2011].

Vaccines to prevent malaria are not currently available in the UK. However, there are studies in progress and they have been the subject of three Cochrane reviews with mixed results.

One systematic review found that the SPf66 vaccine was ineffective at preventing Plasmodium falciparum infection in Africa [Graves and Gelband, 2006c].

One systematic review of vaccines designed to prevent pre-erythrocytic malaria found that RTS,S vaccine yielded promising results [Graves and Gelband, 2006a].

One systematic review of vaccines designed to prevent blood-stage malaria found limited evidence that MSP/RESA (combination B) reduced the rate of clinical malaria, but the effect was strain specific [Graves and Gelband, 2006b].

Scenario: Preventing malaria when pregnant/breastfeeding/planning pregnancy

Scenario: Preventing malaria in pregnant or breastfeeding women, or women planning pregnancy

144months3060monthsBoth

Overview of management

How should I manage breastfeeding or pregnant women, or women planning pregnancy intending to travel to a malaria endemic area?

Provide advice to pregnant women about:

The particular risks of malaria during pregnancy.

The symptoms of malaria.

What to do if illness develops 7 days or more after entering a malaria endemic area or within one year of returning from that area.

If travel during pregnancy to a malaria endemic area is considered necessary, emphasize the need for meticulous compliance with chemoprophylaxis and measures to reduce bites from mosquitoes and:

Decide what chemoprophylaxis to recommend based on the area to be visited, contraindications to specific drugs in pregnancy or when breastfeeding, and patient preference.

Provide advice about preventing mosquito bites.

Seek specialist advice about emergency standby treatment for women who are pregnant or intend to become pregnant who plan to travel to remote areas where malaria is endemic and medical facilities cannot be accessed within a few hours.

Determine whether travel immunizations are recommended — for further information see the CKS topic on Immunizations - travel.

Basis for recommendation

Basis for recommendation

These recommendations are based on the expert opinion of the Health Protection Agency published in Guidelines for Malaria Prevention in Travellers from the United Kingdom [Chiodini et al, 2007].

The Health Protection Agency provide advice about when to provide emergency standby treatment for adults but recommend that pregnant women avoid remote areas where medical facilities can not be readily accessed.

CKS recognizes the possibility that some pregnant women will travel to these areas despite the increased risks involved. Under these circumstances CKS considers it to be good practice to discuss the provision of standby treatment with a specialist.

Advice to pregnant women

What advice should I give to women who are pregnant or planning pregnancy who are considering travel to areas endemic with malaria?

Advise pregnant women and women planning pregnancy that:

They are at increased risk of contracting malaria even when taking chemoprophylaxis because:

They are more likely to be bitten by mosquitoes.

They may not be able to take the most effective chemoprophylaxis for the area to be visited when these treatments are contraindicated in pregnancy.

Malaria tends to be more severe during pregnancy and they are at greater risk of complications including:

Severe haemolytic anaemia, hypoglycaemia, jaundice, renal failure, hyperpyrexia, and pulmonary oedema.

Miscarriage, premature delivery, maternal and/or neonatal death.

The only way to completely avoid these risks is to avoid travel to these areas when pregnant.

If a pregnant woman or a woman who is planning pregnancy decides to travel to these areas despite the risks, advise them:

To comply meticulously with chemoprophylaxis and take particular care to protect against insect bites.

Ensure women who have previously lived in malaria endemic areas understand that any immunity they may have had to malaria will have been lost within a few months of leaving these areas and they are at increased risk of contracting malaria when they return to these areas if they do not use chemoprophylaxis.

To avoid travel to areas where medical help is not readily available.

When to suspect malaria. Malaria presents:

Most commonly with fever and flu-like symptoms (general malaise, headache, myalgia) but may also present with diarrhoea, respiratory symptoms, or jaundice.

Seven or more days after entering a malaria endemic area (the incubation period).

Up to 1 year after leaving a malaria endemic area (although malaria usually develops within three months of exposure).

What to do if malaria is suspected. They should:

Seek medical attention as soon as possible if they become unwell with any symptoms of malaria, especially a febrile illness.

Start emergency standby treatment as soon as malaria is suspected (if this has been provided) if they are unable to access medical facilities within a few hours.

Explain that malaria chemoprophylaxis is not prescribable on an FP10 prescription.

Chloroquine and proguanil can be obtained over-the-counter from a pharmacist.

Mefloquine, doxycycline, and atovaquone with proguanil (Malarone®) are only available on private prescription.

Basis for recommendation

Basis for recommendation

These recommendations are based on the expert opinion of the Health Protection Agency published in Guidelines for Malaria Prevention in Travellers from the United Kingdom [Chiodini et al, 2007].

Information about not prescribing malaria chemoprophylaxis on an FP10 prescription comes from the Department of Health [DH, 1995].

Chemoprophylaxis

Which drugs are recommended in pregnant or breastfeeding women, or women planning pregnancy?

Look up the recommended chemoprophylaxis for the area to be visited (including stop-overs) from either:

The National Travel Health Network and Centre website (NaTHNaC). Select the country in the country information section. This information is free.

Or the Health Protection Scotland site TRAVAX website. Registration is required to use this site. It is free for NHS users in Scotland and by subscription elsewhere.

Exclude treatment options that are contraindicated in pregnancy or breastfeeding or women planning pregnancy — see Table 1. A list version of contraindications is available for people using mobile devices.

Check for interactions if the person is taking other drugs. See the electronic Medicines Compendium (eMC) or the British National Formulary (BNF) for up-to-date information.

Seek specialist advice if all recommended treatments for the area to be visited are contraindicated— see Table 2 for sources of specialist advice.

Discuss the advantages and disadvantages of the remaining treatment options and prescribe the preferred option — see Table 3. A list version of advantages and disadvantages of different regimes is available for people using mobile devices.

For women taking proguanil who are pregnant or planning pregnancy, prescribe folic acid 5 mg daily to take for as long as she is taking proguanil.

Table 1 . Contraindications to anti-malaria chemoprophylaxis in pregnant or breastfeeding women or women planning pregnancy.
Contraindicated drugs Drugs that are not contraindicated
Pregnancy and women planning pregnancy Mefloquine in first trimester Malarone®† and doxycycline Chloroquine and proguanil
Breastfeeding Doxycycline and malarone®†. Chloroquine, proguanil and mefloquine
† Combination of proguanil and atovaquone.
Data from: [ABPI Medicines Compendium, 2010ee, ABPI Medicines Compendium, 2011v, ABPI Medicines Compendium, 2011w, ABPI Medicines Compendium, 2011u; ABPI Medicines Compendium, 2013eg]
Table 2 . Sources of expert advice on preventing malaria.
Source Website address Comment
National Travel Health Network and Centre (NaTHNaC) www.nathnac.org Advice line: 0845 602 6712
Liverpool School of Tropical Medicine (LSTM) www.liv.ac.uk/lstm Can give pre-travel advice when NaTHNaC is unavailable. Telephone (0151) 7053100
Malaria Reference Laboratory (MRL) www.malaria-reference.co.uk Provides 'advice for healthcare professionals'
TRAVAX (Health Protection Scotland) www.travax.nhs.uk Registration is required to use the website or access telephone advice. This is free to NHS users in Scotland; there is a subscription charge for NHS users in other parts of the UK.
Information sources recommended by the Advisory Committee on Malaria Prevention in UK travellers: [Chiodini et al, 2007]
Table 3 . Advantages and disadvantages of drug regimens used to prevent malaria in pregnant or breastfeeding women or women planning pregnancy.
Drug regimen Advantages Disadvantages
Chloroquine and proguanil* Low cost Complicated dosing regimen may reduce compliance. Toxic in overdose, especially in children.
Mefloquine Convenient weekly dosing Adverse effects: mefloquine , if they occur, tend to persist for weeks to months because of the long half-life of the drug. Needs to be started 10 days before departure to ensure it is well tolerated before travelling.†
* Chloroquine is rarely used alone. † The Summary of Product Characteristics for mefloquine states it should not be used during pregnancy, especially in the first trimester, unless the expected benefit justifies the potential risk to the fetus.
Data adapted from: [Chiodini et al, 2007; ABPI Medicines Compendium, 2013eg]

Drug contraindications

Drug contraindications

For pregnant women:

Contraindicated drugs — mefloquine in first trimester, malarone®, and doxycycline.

Drugs that are not contraindicated — chloroquine and proguanil.

For breastfeeding women:

Contraindicated drugs — doxycycline, and malarone®.

Drugs that are not contraindicated — chloroquine, proguanil and mefloquine.

Advantages/disadvantages of different regimes

Advantages and disadvantages of the different regimes

Chloroquine and proguanil:

Advantages: low cost.

Disadvantages: complicated dosing regimen may reduce compliance and toxic in overdose, especially in children.

Mefloquine:

Advantages: convenient weekly dosing.

Disadvantages: Adverse effects (most commonly disturbance of balance and dizziness), if they occur, tend to persist for weeks to months because of the long half-life of the drug. Needs to be started 10 days before departure to ensure it is well tolerated before travelling.

Basis for recommendation

Basis for recommendation

These recommendations are based on the expert opinion of the Health Protection Agency published in Guidelines for Malaria Prevention in Travellers from the United Kingdom [Chiodini et al, 2007].

Pregnancy

There is evidence from randomized controlled trials (RCTs) that the use of antimalarial drugs (in pregnant women living in endemic areas) has beneficial outcomes in terms of preventing the development of malaria, preventing anaemia, preventing perinatal death, and increasing birthweight [Garner and Gulmezoglu, 2006].

Chloroquine and proguanil have been used in the prevention of malaria in pregnant women for many years and have a good safety record [Hughes et al, 2003c].

The main problem with chloroquine-proguanil is that it does not offer adequate protection against chloroquine-resistant Plasmodium falciparum.

However, even in resistant areas, chloroquine-proguanil will offer some protection, and is probably better than no prophylaxis at all.

Mefloquine is probably suitable for use in the second and third trimesters but should be avoided in the first trimester of pregnancy [Hughes et al, 2003c].

The evidence from several studies (including animal studies, observational studies, drug company databases, and one RCT) is conflicting, but the consensus amongst experts is that mefloquine is suitable for use in the second and third trimesters. Further data are being collected, but future large-scale RCTs on non-immune pregnant women are unlikely due to practical and ethical concerns.

The manufacturer's Summary of Product Characteristics advises that mefloquine should not be used during pregnancy, especially in the first trimester, unless the anticipated benefit outweighs the risk [ABPI Medicines Compendium, 2013eg].

Doxycycline is contraindicated in pregnancy.

Malarone® is not recommended because of a lack of safety data in pregnant women.

Breastfeeding

There is very little evidence on the safety of using antimalarial drugs in breastfeeding women. Based on expert opinion [Hughes et al, 2003c]:

Chloroquine and proguanil are considered safe to use in breastfeeding mothers.

Mefloquine is probably safe to use, as the dose the child receives in the milk is likely to be small compared to the standard prophylactic dose they will probably be taking anyway. The manufacturer's Summary of Product Characteristics does not recommend taking mefloquine during breastfeeding [ABPI Medicines Compendium, 2013eg].

Doxycycline is excreted in breast milk and therefore contraindicated.

Malarone ® is not recommended due to a lack of safety data.

Preventing mosquito bites

What advice should I give a pregnant or breastfeeding women to prevent mosquito bites when travelling to areas endemic with malaria?

Advise the following:

Cover up with clothing where practical. Consider spraying cotton clothing with insect repellents. Alternatively, impregnated clothing can be bought already prepared.

Apply DEET-based insect repellents to all exposed areas of the body, especially the feet, ankles and legs, whilst outdoors. Only recommend less effective alternative insect repellents if DEET can not be tolerated (usually because of skin reactions).

Stronger preparations of DEET (highest strength 50%) provide longer protection and need less frequent applications.

Apply DEET after suncream as it can reduce the efficacy of sun block protection if applied first.

Advise nursing mothers to wash repellents off their hands and breast skin before handling infants.

Spray insecticides in the bedroom before sleep to kill mosquitoes. An electrically heated device to vaporise a 'mat' (tablet) containing a synthetic pyrethroid can be used each night to provide further protection.

Cover beds with mosquito nets (preferably impregnated with insecticide).

Use air conditioning or ceiling fans where available to cool the room and reduce mosquito activity.

Basis for recommendation

Basis for recommendation

These recommendations are based on the expert opinion of the Health Protection Agency published in Guidelines for Malaria Prevention in Travellers from the United Kingdom [Chiodini et al, 2007].

The evidence for the use of DEET in trials is limited but experience has led to a consensus that it is beneficial as an insect repellent for malaria.

The evidence for insect repellents other than DEET suggest a lower efficacy than the higher DEET concentrations. Some are comparable to lower DEET concentrations, but appear to have a shorter duration of protection than DEET overall.

There is evidence that insecticide-impregnated nets reduce the transmission of malaria, improving both mortality and morbidity in people who use them, and on a wider community level. These benefits have been proven in people residing in malaria endemic areas, but may also be extrapolated to other groups of people such as travellers.

The recommendation that DEET should be applied after suncream is based on expert opinion [Montemarano et al, 1997].

It is particularly important to protect the ankles, which the mosquito appears to favour. One study found that spraying just the ankles with DEET gave a three-fold reduction in the number of mosquito bites by [Govere et al, 2001].

When to prescribe standby treatment

When should I prescribe emergency standby treatment for a woman who is pregnant or planning pregnancy who intends to travel to a malaria endemic area?

Advise pregnant women and women planning pregnancy about the particular risks of malaria for a pregnant woman.

If they consider it necessary to travel to remote areas where malaria is endemic and where medical facilities can not be easily accessed, seek specialist advice about the appropriateness of prescribing emergency standby treatment and what to prescribe. For sources of expert advice see Table 1.

If emergency standby treatment is advised by a specialist, advise the woman:

That emergency standby treatment is NOT a substitute for regular chemoprophylaxis. It is carried to treat malaria that develops despite the use of regular chemoprophylaxis.

To start emergency standby treatment if they are unable to access medical facilities within a few hours and they develop any symptoms of malaria:

Most commonly fever and flu-like symptoms (general malaise, headache, myalgia) but occasionally diarrhoea, respiratory symptoms, or jaundice.

Seven or more days after entering an endemic malaria area (the incubation period).

Up to 1 year after leaving an endemic malaria area (although malaria usually develops within three months of exposure).

To seek medical attention as soon as possible after starting emergency standby treatment.

Table 1 . Sources of expert advice.
Source Website address Comment
National Travel Health Network and Centre (NaTHNaC) www.nathnac.org Advice line: 0845 602 6712
Liverpool School of Tropical Medicine (LSTM) www.liv.ac.uk/lstm Can give pre-travel advice when NaTHNaC is unavailable. Telephone (0151) 7053100
Malaria Reference Laboratory (MRL) www.malaria-reference.co.uk Provides 'advice for healthcare professionals'
TRAVAX (Health Protection Scotland) www.travax.nhs.uk Registration is required to use the website or access telephone advice. This is free to NHS users in Scotland; there is a subscription charge for NHS users in other parts of the UK.
Information sources recommended by the Advisory Committee on Malaria Prevention in UK travellers: [Chiodini et al, 2007]

Basis for recommendation

Basis for recommendation

The Health Protection Agency in Guidelines for Malaria Prevention in Travellers from the United Kingdom [Chiodini et al, 2007] provide advice about when to provide emergency standby treatment for adults but recommend that pregnant women avoid remote areas where medical facilities cannot be readily accessed.

CKS recognizes the possibility that some pregnant women will travel to these areas despite the increased risks involved. Under these circumstances CKS considers it to be good practice to discuss the provision of standby treatment with a specialist.

Measures not recommended for prevention

What measures are not recommended for preventing malaria?

The following interventions are not recommended for the prevention of malaria:

Herbal remedies, homeopathy, electronic buzzers, vitamin B1, garlic, yeast spreads, tea tree oil, and bath oils.

Pyrimethamine and sulfadoxine.

Pyrimethamine and sulfadoxine are usually combined in a product with the proprietary name of Fansidar®. It is sometimes useful in the treatment of malaria, but is not recommended for its prevention.

Insect repellents other than DEET (N,N–diethyl-m-toluamide), unless there is a known allergy to DEET.

These include lemon eucalyptus, picaridin (available as a 20% solution), and 3-ethylaminopropionate.

Oil of citronella is no longer allowed to be marketed in Europe as an active ingredient for the prevention of mosquito bites.

There are no effective vaccines available.

Basis for recommendation

Basis for recommendation

These recommendations are based on the expert opinion of the Health Protection Agency published in Guidelines for Malaria Prevention in Travellers from the United Kingdom [Chiodini et al, 2007] and reflect either a lack of evidence to support the use of these interventions, or evidence that they are ineffective.

Herbal and homeopathic remedies are not recommended as they have not been studied in randomized controlled trials (RCTs). There is no scientific or clinical basis for the use of homeopathy, and the Advisory Committee on Malaria Prevention in UK Travellers (ACMP) actively discourages its use. The Faculty of Homeopathy does not promote the use of homeopathic remedies in the prevention of malaria and notes that they are unlikely to be acceptable to insurers [HPA, 2007].

Electronic buzzers have been promoted as being effective for repelling mosquitoes, but are completely ineffective, as confirmed by a recent Cochrane review [Enayati et al, 2007].

Insect repellent anecdotes: there are beliefs that ingesting vitamin B1, garlic, or savoury yeast spreads (e.g. Marmite) repels mosquitoes. However, there is no evidence that this is the case. Similarly, CKS found no evidence that applications of tea tree oils or bath oils to skin repel mosquitoes.

Insect repellents other than DEET have no advantages over DEET and are probably not as effective (see Insect repellents).

Lemon eucalyptus is reported as being equivalent to 15% DEET (a lower concentration than is usually recommended), but has a shorter duration of action and requires more frequent application.

Picardin has been reported as having similar repellent properties as DEET, but has been less studied. If it is considered, the 20% formulation should be used.

Oil of citronella provides only short-term protection and should not be used.

Pyrimethamine combined with sulfadoxine (Fansidar®) has been found to be effective in the prevention of malaria in one RCT [Stemberger et al, 1984], but resistance to it is now widespread and it is not usually recommended for prophylaxis [BNF 62, 2011].

Vaccines to prevent malaria are not currently available in the UK. However, there are studies in progress and they have been the subject of three Cochrane reviews with mixed results.

One systematic review found that the SPf66 vaccine was ineffective at preventing Plasmodium falciparum infection in Africa [Graves and Gelband, 2006c].

One systematic review of vaccines designed to prevent pre-erythrocytic malaria found that RTS,S vaccine yielded promising results [Graves and Gelband, 2006a].

One systematic review of vaccines designed to prevent blood-stage malaria found limited evidence that MSP/RESA (combination B) reduced the rate of clinical malaria, but the effect was strain specific [Graves and Gelband, 2006b].

Important aspects of prescribing information relevant to primary healthcare are covered in this section specifically for the drugs recommended in this CKS topic. For further information on contraindications, cautions, drug interactions, and adverse effects, see the electronic Medicines Compendium (eMC) (http://medicines.org.uk/emc), or the British National Formulary (BNF) (www.bnf.org).

Drug availability on the NHS

Are antimalarial drugs available on the NHS?

Malaria chemoprophylaxis is not prescribable on an FP10 prescription [DH, 1995].

Chloroquine and proguanil can be obtained over the counter from a pharmacist.

Mefloquine, doxycycline, and atovaquone with proguanil (Malarone®) are only available on private prescription.

Prescribing for young child or baby

What issues should I consider when prescribing in a young child or baby?

Before prescribing, advise the parents of the following [Chiodini et al, 2007]:

Compliance with chemoprophylaxis is essential in children, who have a worse prognosis than adults if they contract malaria. Stress that courses of antimalarial drugs must be completed.

For most children, dosing of antimalarial drugs should be supervised.

Some regimens are complicated, even for adults (for example chloroquine-proguanil).

Some medicines are bitter-tasting, and may put children off swallowing, or cause vomiting. Care should be taken to ensure the child actually swallows tablets.

Some antimalarial drugs are poisonous in overdose, and have a particularly narrow therapeutic index in children. In particular, chloroquine should be safely stored out of reach of a young child [Hughes et al, 2003].

In general, because of the narrow therapeutic index of antimalarial drugs, weight is a better guide than age for calculating the dose required in children over 6 months of age [Chiodini et al, 2007].

All of the antimalarial drugs recommended for adults can be used in children with the exception of doxycyline, which is contraindicated. However, there are some limitations on the availability of suitable paediatric formulations [Chiodini et al, 2007].

Chloroquine is available as a sweetened solution. Tablets may be used in older children but are are bitter-tasting.

Proguanil is only available as tablets. These can be broken and crumbled into food such as milk, jam, or honey.

Mefloquine is only available as tablets. These are scored and must be cut to achieve the correct dose.

Atovaquone-proguanil (Malarone®) is available as paediatric tablets for children weighing more than 11 kg. Malarone paediatric tablets should preferably be swallowed whole; if this is difficult for young children they may be crushed and mixed with food or a milky drink just before administration [ABPI Medicines Compendium, 2011c].

Chloroquine

Regimen

What dosing regimen of chloroquine should I prescribe?

Chloroquine alone is now rarely considered as adequate treatment for malaria-endemic countries; it is usually taken in combination with proguanil.

Chloroquine should be started 1 week before travel, and continued for 4 weeks after leaving the malaria-endemic area.

Chloroquine is usually taken as a single dose once a week, on the same day each week.

Chloroquine on its own and in combination with proguanil can be taken indefinitely for long-term prophylaxis.

Basis for recommendation

This information is based on UK malaria prevention guidelines from the Advisory Committee on Malaria Prevention in UK Travellers, the manufacturer's Summary of Product Characteristics, and the British National Formulary (BNF) [Chiodini et al, 2007; ABPI Medicines Compendium, 2011b; BNF 62, 2011].

Chloroquine is a suppressive prophylactic (it is directed against the red blood cell stages of the malaria parasite) it needs to be continued for several weeks after exposure to prevent infection [Chiodini et al, 2007].

Cautions and contraindications

Who should avoid taking chloroquine?

Chloroquine is contraindicated in:

People with a history of epilepsy (rarely, convulsions have been reported in people taking chloroquine).

People who are concomitantly taking amiodarone (there is an increased risk of ventricular arrhythmias).

In addition, chloroquine may exacerbate psoriasis and myasthenia gravis, and should be avoided if possible in people with these co-morbidities.

Renal disease: chloroquine is only partially excreted by the kidneys and reduction of the dose for prophylaxis is not required except in severe impairment.

Hepatic impairment: use with caution in people with moderate to severe hepatic impairment. Changes in liver function have been reported rarely (including hepatitis and abnormal liver function tests).

Basis for recommendation

This information is based on UK malaria prevention guidelines from the Advisory Committee on Malaria Prevention in UK Travellers, the manufacturer's Summary of Product Characteristics, and the British National Formulary (BNF) [Chiodini et al, 2007; ABPI Medicines Compendium, 2011b; BNF 62, 2011].

Interactions

What drug interactions should I be aware of with chloroquine?

Chloroquine can prolong the QT interval and should not be combined with other drugs that are known to cause QT prolongation.

Chloroquine should not be used in people concurrently taking:

Amiodarone — increased risk of arrhythmias.

Bupropion — possible increased risk of seizures.

Mefloquine — increased risk of convulsions.

Antacids may reduce the absorption of chloroquine. They should be taken at least 4 hours apart.

Chloroquine may also interact with:

Ciclosporin (increased plasma concentrations of ciclosporin, increasing the risk of toxicity).

Cimetidine (increased plasma concentrations of chloroquine, increasing risk of adverse effects).

Digoxin (increased plasma digoxin levels, increasing the risk of toxicity).

Basis for recommendation

This information is based on UK malaria prevention guidelines from the Advisory Committee on Malaria Prevention in UK Travellers, the manufacturer's Summary of Product Characteristics, and the British National Formulary (BNF) [Chiodini et al, 2007; ABPI Medicines Compendium, 2011b; BNF 62, 2011].

Adverse effects: chloroquine

What are the adverse effects of chloroquine?

Chloroquine is very toxic in overdose — seek immediate advice from a Poison's centre if this occurs (see the CKS topic on Poisoning or overdose for more information).

Chloroquine is generally well tolerated at usual doses, with gastrointestinal adverse effects and headache being most commonly reported.

Rarely, seizures have been reported in people taking chloroquine; it should not be prescribed for people with epilepsy.

People of African descent may get a sensation of itching, which can be severe enough to prevent people continuing treatment. This is not mediated by histamine and is therefore unlikely to respond to antihistamines, although a sedating antihistamine at night may help sleep.

Irreversible retinal damage and corneal changes may develop during long term prophylaxis with chloroquine. As a precaution, the manufacturer recommends regular eye checks every 3–6 months in people taking chloroquine weekly for longer than 3 years.

Basis for recommendation

This information is based on UK malaria prevention guidelines from the Advisory Committee on Malaria Prevention in UK Travellers (ACMP), the manufacturer's Summary of Product Characteristics (SPC), and the British National Formulary (BNF) [Chiodini et al, 2007; ABPI Medicines Compendium, 2011b; BNF 62, 2011].

There is a lack of consensus regarding when a person should have eye checks on long term chloroquine. The SPC recommends eye checks every 3–6 months after 3 years of chloroquine prophylaxis, whilst the ACMP recommends annual eye checks after 6 years of chloroquine prophylaxis.

The recommendation to try a sedating antihistamine at night for itch due to chloroquine is a pragmatic one. CKS found no good quality studies on the management of this adverse effect.

Proguanil

Proguanil

Regimen

What dosing regimen of proguanil should I prescribe?

Proguanil is usually combined with Chloroquine, or atovaquone (in a combination product with the proprietary name of Malarone®).

The dosing schedule depends on whether proguanil is given alone or in combination:

When given alone, dosing should start 1 week before entering the endemic area and be continued 4 weeks after leaving the area.

When combined with chloroquine, dosing should start 1 week before entering the endemic area and be continued 4 weeks after leaving.

Malarone® is usually started 1 or 2 days before entering the endemic area and continued for 1 week after leaving.

Proguanil should be taken daily, at the same time each day

Proguanil on its own and in combination with chloroquine can be taken indefinitely for long-term prophylaxis.

Proguanil is a folate inhibitor, and pregnant women taking the drug should be prescribed a supplement of folic acid (5 mg per day) to take for as long as they are taking proguanil.

Basis for recommendation

This information is based on UK malaria prevention guidelines from the Advisory Committee on Malaria Prevention in UK Travellers (ACMP), the manufacturer's Summary of Product Characteristics, and the British National Formulary (BNF) [Chiodini et al, 2007; ABPI Medicines Compendium, 2010; BNF 62, 2011].

Because atovaquone is a causal prophylactic (it is directed against the liver stage of the malaria parasite, which takes approximately 7 days to develop) it only needs to be continued for 1 week after leaving the endemic area [Chiodini et al, 2007].

Cautions and contraindications

Who should avoid taking proguanil?

The dose of proguanil should be reduced in people with moderate or severe kidney disease (stages 3–5), as there is an increased risk of haematological toxicity.

eGFR 20–60 mL/minute/1.73 m2 — 100 mg once a day

eGFR 10–20 mL/minute/1.73 m2 — 50 mg on alternate days

eGFR less than 10 mL/minute/1.73 m2 — 50 mg once a week

Basis for recommendation

Recommendations for the dose of proguanil in people with renal impairment are from the British National Formulary (BNF) [BNF 62, 2011].

Interactions

What drug interactions should I be aware of with proguanil?

Warfarin: proguanil may enhance the anticoagulant effect of warfarin, although in practice problems are rarely seen.

Antacids may reduce the absorption of proguanil, so should be taken at least 2–3 hours apart.

Basis for recommendation

This information is taken from Stockley's Drug Interactions [Baxter, 2010].

There has been an isolated report of bleeding in a woman taking warfarin and proguanil concomitantly. Although rare, this should be considered in anyone with an enhanced response to warfarin.

Magnesium trisilicate reduces the bioavailability of proguanil by about two thirds. A similar effect is possible for other antacids.

Adverse effects: proguanil

What are the adverse effects of proguanil?

Proguanil is generally well tolerated. The most common adverse effects are mild gastrointestinal effects (nausea, diarrhoea, and constipation), which usually reduce with continued treatment.

Occasionally mouth ulcers and stomatitis have been reported with proguanil, particularly when combined with chloroquine.

Basis for recommendation

This information is based on UK malaria prevention guidelines from the Advisory Committee on Malaria Prevention in UK Travellers (ACMP), the manufacturer's Summary of Product Characteristics, and the British National Formulary (BNF) [Chiodini et al, 2007; ABPI Medicines Compendium, 2010; BNF 62, 2011].

Mefloquine

Regimen

What dosing regimen of mefloquine should I prescribe?

Mefloquine has the advantage of simple once-weekly dosing, which may improve compliance.

Mefloquine should be started 10 days before travel, to see if there are any adverse effects (which are most likely to present initially).

Advise the person to seek medical advice if adverse effects occur.

Mefloquine should be continued for 4 weeks after leaving the endemic area.

Mefloquine is licensed for use for up to 1 year (although it has been used for up to 3 years without significant problems).

Basis for recommendation

This information is based on based on UK malaria prevention guidelines from the Advisory Committee on Malaria Prevention in UK Travellers (ACMP), the British National Formulary (BNF), and the manufacturer's Summary of Product Characteristics [Chiodini et al, 2007; BNF 62, 2011; ABPI Medicines Compendium, 2013eg].

Mefloquine is a suppressive prophylactic (it acts against the red blood cell stages of the malaria parasite) and therefore needs to be taken for several weeks after exposure [Chiodini et al, 2007].

Cautions and contraindications

Who should avoid taking mefloquine?

Mefloquine is contraindicated in people with:

Active depression, a history of depression, generalised anxiety disorder, psychosis, suicide attempts and ideations, schizophrenia or other psychiatric disorders as it may precipitate these conditions.

A history of epilepsy or convulsions of any origin.

A history of Blackwater fever.

Severe hepatic impairment.

Cardiac conduction disorders (caution).

Mefloquine is not recommended for women in the first trimester of pregnancy (see the Scenario: Preventing malaria when pregnant/breastfeeding/planning pregnancy).

Advise women of childbearing potential who are taking mefloquine for prophylaxis against malaria to take reliable contraceptive precautions for the entire duration of prophylaxis therapy and for 3 months after the last dose of mefloquine.

Mefloquine is not recommended in infants under 3 months (or weighing less than 5 kg).

Diving — some sub-aqua centres do not permit people taking mefloquine to dive.

Basis for recommendation

This information is based on UK malaria prevention guidelines from the Advisory Committee on Malaria Prevention in UK Travellers (ACMP), the British National Formulary (BNF), and the manufacturer's Summary of Product Characteristics (SPC) [Chiodini et al, 2007; BNF 62, 2011; ABPI Medicines Compendium, 2013eg].

Mefloquine is a suppressive prophylactic (it acts against the red blood cell stages of the malaria parasite) and therefore needs to be taken for several weeks after exposure [Chiodini et al, 2007].

Mefloquine is metabolized in the liver, and there is limited clinical experience with mefloquine in this group of people. The SPC therefore advises that mefloquine is contraindicated for people with severe liver impairment [ABPI Medicines Compendium, 2013eg].

Although there is no evidence that a person who tolerates mefloquine is not physically able to dive, it lowers the seizure threshold and may therefore add to the complications of decompression or narcosis. In addition, although extremely rare, some neuropsychiatric adverse events can be sudden in onset [Chiodini et al, 2007]

Adverse effects: mefloquine

What are the adverse effects of mefloquine?

Common adverse effects include gastrointestinal irritation, headache, dizziness, and sleep disturbances.

Neuropsychiatric reactions (such as sensory and motor neuropathies, tremor, ataxia, anxiety, depression, panic attacks, agitation, hallucinations, psychosis, convulsions) are less frequent but potentially serious.

Advise the person to seek immediate medical advice if they experience these whilst taking mefloquine.

Mefloquine may cause dizziness and disturbed balance and fine co-ordination, which may occur for weeks to months after stopping mefloquine.

Basis for recommendation

This information is based on UK malaria prevention guidelines from the Advisory Committee on Malaria Prevention in UK Travellers (ACMP), the British National Formulary (BNF), and the manufacturer's Summary of Product Characteristics (SPC) [Chiodini et al, 2007; BNF 62, 2011; ABPI Medicines Compendium, 2013eg].

Although there is no evidence that a person who tolerates mefloquine is not physically able to dive, it lowers the seizure threshold and may therefore add to the complications of decompression or narcosis. In addition, although extremely rare, some neuropsychiatric adverse events can be sudden in onset [Chiodini et al, 2007].

Evidence from a Cochrane systematic review found that mefloquine users have worse total mood disturbance scores and experience more neuropsychiatric adverse outcomes than users of Malarone® or doxycycline. In addition, it found 22 case reports of deaths associated with the use of mefloquine at normal doses, including five reported suicides and no case reports of deaths associated with other drugs used for malaria chemoprophylaxis. This finding should be interpreted with caution because this is open to a significant risk of reporting bias.

Interactions

What drug interactions should I be aware of with mefloquine?

Amiodarone and ivabradine — increased risk of arrhythmias. Do not prescribe mefloquine concomitantly with amiodarone or ivabradine.

Beta-blockers, calcium-channel blockers, and digoxin — possible increased risk of bradycardia.

Chloroquine — increased risk of convulsions. Do not use concomitantly.

Bupropion — possible increased risk of seizures.

Anti-epileptic drugs (AEDs) — mefloquine antagonises the anticonvulsant effect of AEDs, potentially reducing seizure control. Mefloquine is not recommended for prophylaxis in people with epilepsy.

Basis for recommendation

This information is based on UK malaria prevention guidelines from the Advisory Committee on Malaria Prevention in UK Travellers (ACMP), the British National Formulary (BNF), and the manufacturer's Summary of Product Characteristics [Chiodini et al, 2007; BNF 62, 2011; ABPI Medicines Compendium, 2013eg].

Malarone® (proguanil plus atovaquone)

Malarone® (proguanil plus atovaquone)

Regimen

What dosing regimen of Malarone® should I prescribe?

Malarone® is a combination of proguanil with atovaquone.

Malarone® should be taken once a day with food.

Malarone® is usually started 1 or 2 days before entering the endemic area and continued for 1 week after leaving.

Proguanil is a folate inhibitor, and pregnant women taking the drug should be prescribed a supplement of folic acid (5 mg per day) to take for as long as they are taking Malarone®.

Malarone is licensed for use for up to 28 days, but can be used for up to 1 year with caution.

Basis for recommendation

This information is based on UK malaria prevention guidelines from the Advisory Committee on Malaria Prevention in UK Travellers (ACMP), the manufacturer's Summary of Product Characteristics, and the British National Formulary (BNF) [Chiodini et al, 2007; ABPI Medicines Compendium, 2011c; BNF 62, 2011].

Because atovaquone is a causal prophylactic (it is directed against the liver stage of the malaria parasite, which takes approximately 7 days to develop) it only needs to be continued for 1 week after leaving the endemic area [Chiodini et al, 2007].

Contraindications

Who should avoid taking Malarone®?

Renal impairment — do not use Malarone® for prophylaxis in people with severe renal impairment (eGFR less that 30 mL/min/1.73 m2).

Malarone® is not recommended in pregnancy (see the scenario Scenario: Preventing malaria when pregnant/breastfeeding/planning pregnancy).

Children — Malarone® should not be prescribed as malaria prophylaxis for children weighing less than 11 kg.

Basis for recommendation

This information is based on UK malaria prevention guidelines from the Advisory Committee on Malaria Prevention in UK Travellers (ACMP), the manufacturer's Summary of Product Characteristics, and the British National Formulary (BNF) [Chiodini et al, 2007; ABPI Medicines Compendium, 2011c; BNF 62, 2011].

Adverse effects: Malarone®

What are the adverse effects of proguanil and atovaquone?

Common adverse effects of Malarone® include headache and gastrointestinal intolerance (see also Adverse effects: proguanil).

Basis for recommendation

This information is based on UK malaria prevention guidelines from the Advisory Committee on Malaria Prevention in UK Travellers (ACMP), the manufacturer's Summary of Product Characteristics, and the British National Formulary (BNF) [Chiodini et al, 2007; ABPI Medicines Compendium, 2011c; BNF 62, 2011].

Interactions

What drug interactions should I be aware of with Malarone®?

Possible interactions with Malarone® are as for proguanil:

Warfarin: proguanil may enhance the anticoagulant effect of warfarin, although in practice problems are rarely seen.

Antacids may reduce the absorption of proguanil, so should be taken at least 2–3 hours apart.

Basis for recommendation

This information is taken from Stockley's Drug Interactions [Baxter, 2010].

There has been an isolated report of bleeding in a woman taking warfarin and proguanil concomitantly. Although rare, this should be considered in anyone with an enhanced response to warfarin.

Magnesium trisilicate reduces the bioavailability of proguanil by about two thirds. A similar effect is possible for other antacids.

Doxycycline

Regimen

What dosing regimen of doxycycline should I prescribe?

Treatment should be started 1–2 days before entering the malaria-endemic area, and continued for 4 weeks after leaving.

Doxycycline is taken once a day, at a dose of 100 mg.

Doxycycline can be used as prophylaxis for up to 2 years.

Basis for recommendation

This information is based on UK malaria prevention guidelines from the Advisory Committee on Malaria Prevention in UK Travellers and the British National Formulary (BNF) [Chiodini et al, 2007; BNF 62, 2011].

Cautions and contraindications

Who should avoid using doxycycline?

Doxycyline is contraindicated in pregnancy, during breastfeeding, or in children under 12 years of age (it is deposited in the teeth and bones of the unborn or developing child).

Advise women of childbearing age to take effective contraception for the duration of their doxycycline prophylaxis.

Doxycycline should be used with caution in people with:

Myasthenia gravis — doxycycline may cause muscle weakness.

Systemic lupus erythematosis — may be exacerbated by doxycycline.

Hepatic impairment: care should be taken when giving doxycycline to people with hepatic impairment or other potentially hepatotoxic drugs, as abnormal liver function has been reported rarely with tetracyclines.

Basis for recommendation

This information is based on UK malaria prevention guidelines from the Advisory Committee on Malaria Prevention in UK Travellers, the manufacturer's Summary of Product Characteristics, and the British National Formulary (BNF) [Chiodini et al, 2007; ABPI Medicines Compendium, 2011a; BNF 62, 2011].

Adverse effects: doxycycline

What are the adverse effects of doxycycline?

Photosensitivity may be a problem for travellers taking doxycycline, occurring in about 3% of people.

Photosensitivity appears as an exaggerated sunburn reaction, with erythema and swelling. Vesicles, blisters, and bullae may appear. Unlike heat rash, the reaction is limited to exposed areas of skin.

People should be warned about the effect, and given advice regarding minimizing exposure to the sun.

If a photosensitivity reaction occurs, treatment should be stopped and advice sought regarding alternative antimalarial prophylaxis.

Gastrointestinal disturbances are the most common adverse effects associated with doxycycline use, and the drug should be taken with food where possible.

Yeast infections (such as vulvovaginal candidiasis) may occur as a result of the broad-spectrum nature of tetracyclines.

Consider offering 'as required' treatment for vulvovaginal candidiasis if appropriate (e.g. clotrimazole pessaries and/or oral fluconazole).

Doxycycline can cause severe oesophagitis, presenting as a burning pain in the lower chest.

To counteract this, it is recommended that doxycycline is taken whilst standing upright, with plenty of water, and without chewing or breaking the capsules.

Benign intracranial hypertension is a rare but important adverse effect of doxycyline.

Advise the person that if they develop headache and visual disturbances, they should stop taking doxycycline immediately and seek medical advice.

Basis for recommendation

This information is based on UK malaria prevention guidelines from the Advisory Committee on Malaria Prevention in UK Travellers, the manufacturer's Summary of Product Characteristics, and the British National Formulary (BNF) [Chiodini et al, 2007; ABPI Medicines Compendium, 2011a; BNF 62, 2011].

Yeast infections result from the disruption of the normal mucocutaneous flora, and consequent colonization with species unaffected by the antibiotic (this may also be the mechanism for the gastrointestinal upset that occurs) [Brown and Shalita, 1998].

Interactions

What drug interactions should I be aware of with doxycycline?

For women taking oral hormonal contraception additional contraceptive precautions are not required during or after courses of doxycycline. However, women should be advised about the importance of correct contraceptive practice if they experience vomiting or diarrhoea.

The absorption of doxycycline may be reduced by antacids, and it is recommended that they are not taken at the same time of day.

Basis for recommendation

The recommendation regarding oral hormonal contraception is based on guidance from the Faculty of Sexual and Reproductive Healthcare (FSRH) Drug interactions with hormonal contraception [FSRH, 2011]. For further information, see the section on Antibiotics in the CKS topic on Contraception - assessment.

Other information is taken from the manufacturer's Summary of Product Characteristics, and the British National Formulary (BNF) [ABPI Medicines Compendium, 2011a; BNF 62, 2011].

Evidence

Evidence

Supporting evidence

Insect repellents

Evidence on insect repellents for the prevention of mosquito bites

The evidence for DEET (N,N–diethyl-m-toluamide) from trials is limited and based on small randomized controlled trials (RCTs) with non-clinical outcomes. Nevertheless, decades of experience of using DEET has led to a consensus that it is the most effective insect repellent for malaria prophylaxis. DEET can be used at a concentration of 50%. It can also be used in all stages of pregnancy, for breastfeeding women, and in children over the age of 2 months.

Trials have compared DEET with other insect repellents and shown DEET to have a longer duration of protection.

A trial involving 15 volunteers compared DEET (4 types of formulations up to 23.8% concentrations) with ethyl butylacetylaminopropionate, wrist bands impregnated with insect repellents, and a moisturiser with repellent properties. The results showed DEET to have an average duration of protection of around 5 hours, the ethyl butylacetylaminopropionate protected for about 23 minutes, and the others for less than 20 minutes [Fradin and Day, 2002].

In trials, the insect repellents IR3535 (ethyl butylacetylaminopropionate), IR3023 (picaridin), and lemon eucalyptus (p-methane 3,8 diol) have been proven to be well tolerated for mosquito-bite prevention in humans [Chiodini et al, 2007].

Trials have suggested that:

Picaridin (IR3023) has a similar effectiveness to DEET [Badolo et al, 2004; Costantini et al, 2004].

Lemon eucalyptus (p-methane 3,8 diol) appears to be comparable to 15% DEET concentrations [Govere et al, 2000].

A number of case series have reported systemic reactions with DEET. Fourteen case studies highlight adverse skin reactions resulting in contact urticaria and dermatitis. However, the general consensus is that DEET is suitable for use in anyone over 2 months of age [Croft, 2006].

Insecticide-impregnated nets

Evidence on insecticide-impregnated nets for preventing malaria

There is evidence from randomized controlled trials (RCTs) that mosquito nets reduce child mortality and clinical malaria in residents of malaria-endemic countries. Although, there is no trial evidence for the use of impregnated nets reducing malaria in travellers, it is reasonable to extrapolate the results to this group [Croft, 2006].

A Cochrane review identified 18 RCTs that investigated the efficacy of insecticide-impregnated nets in reducing various outcomes associated with malaria.

Two RCTs reported a relative risk reduction (RRR) of mild malaria episodes of 48% (95% CI 41 to 54%).

Three RCTs report a relative risk (RR) of child mortality of 0.83 (no confidence intervals reported) and a further RCT suggested an RR of 0.77 (no confidence intervals reported).

The review reported a summary risk difference of 5.6 deaths averted per 1000 children protected per year.

A 6-year follow-up study in Kenya showed that impregnated nets reduced childhood mortality, with an RR of 0.76 (P = 0.0001), by substantially reducing the transmission levels of malaria. There was no evidence of a shift of mortality from younger to older children, which might have suggested a delay rather than the nets having a preventative effect on mortality [Diallo et al, 2004].

A study carried out in Western Africa showed that impregnated nets not only reduced mortality and morbidity in the population using them, but also provided protection beyond the village to the wider community. This study suggested that the nets not only provide physical protection to users, but affect the mosquito-population-based transmission of malaria. Therefore, to maximize the public health impact in Africa, high usage of impregnated nets is important [Hawley et al, 2003].

Drugs for preventing malaria

Evidence on individual drugs for preventing malaria

The evidence from randomized controlled trials to support the use of drugs for the prevention of malaria in adults is limited because of the practical and ethical difficulties of designing trials, and for economic reasons (including historical use of some drugs).

Chloroquine

Chloroquine has not been studied extensively by randomized controlled trials (RCTs). It is an older drug, and the best evidence for its effectiveness comes from accumulated clinical knowledge gathered over many years of use. However, in recent years the malarial parasite Plasmodium falciparum has become increasingly resistant to the drug, meaning it is ineffective in many parts of the world and is now rarely appropriate for use as monotherapy.

Chloroquine is believed to work by concentrating in Plasmodium lysosomes, causing the production of a ferriprotoporphyrin IX-chloroquine complex, which is highly toxic to the malarial parasite [Chiodini et al, 2007]. It works as a suppressive prophylaxis (i.e. on the red blood cell stage), so must be taken for several weeks after exposure to the infection.

Chloroquine first came into use in 1945, and had been in use for several decades before high-quality RCTs were regularly used to assess the efficacy and safety of drugs. CKS could not find any trials that compared chloroquine with placebo. One RCT (n = 173) used chloroquine as an active comparator with sulfadoxine and pyrimethamine [Stemberger et al, 1984]. There were no clinically significant differences between the drugs.

The first case of chloroquine-resistant P. falciparum came to light in 1957, and since then the efficacy of chloroquine has been decreasing, so that it is now rarely suitable for use in monotherapy against P. falciparum [Wongsrichanalai et al, 2002]. However, in general, it is still effective against P. vivax, P. ovale, and P. malariae [Chiodini et al, 2007], and is often used in combination with proguanil; see Supporting evidence on Proguanil combined with chloroquine.

Mefloquine

Mefloquine has been shown to be effective at preventing malaria in one randomized controlled trial (RCT). It is recommended for most people who are travelling to areas where there may be chloroquine-resistant Plasmodium, although the person should be made aware that mefloquine may have adverse effects (a trial of mefloquine should be offered before travel).

Mefloquine is a suppressive anti-malarial drug with a mechanism of action that is not fully understood, but is thought to be different to chloroquine. At present the protective efficacy of mefloquine to Plasmodium falciparum is thought to be about 90% in Africa, and resistance is rare, being largely confined to areas of Southeast Asia and isolated cases in the Amazon [Chiodini et al, 2007].

A Cochrane review (search date: September 2002) identified 10 RCTs (n = 2750) that compared mefloquine with placebo or an active comparator [Croft and Garner, 2000]. The trials were described as being well-designed and of high methodological quality, using intention-to-treat analysis with low levels of loss to follow-up. Four RCTs were supported by the manufacturer of mefloquine. The results and conclusion were as follows:

Comparison with placebo: five trials compared mefloquine with placebo.

Only one trial assessed the effectiveness of mefloquine [Ohrt et al, 1997]. There were no cases of malaria in the mefloquine group (202 person-months) compared with 53 cases in the placebo group (109 person-months).

Four trials assessed withdrawal rates and, when results were combined in a meta-analysis, found they were higher in the mefloquine group (OR 3.56, 95% CI 1.67 to 7.60).

Comparison with another active regimen: six trials made this comparison.

Only one RCT measured the relative incidence of malaria with a different regimen (mefloquine compared with doxycycline), but the low sample size and number of negative outcomes were too low to draw firm conclusions on the superiority of either drug [Ohrt et al, 1997].

One study (comparing mefloquine with chloroquine combined with proguanil) used antibody markers as a surrogate outcome, but again numbers were too low to draw useful conclusions.

Four studies investigated the rate of non-adherence, and although rates with mefloquine tended to be higher, there were no statistical differences.

Also, see evidence on the relative safety and tolerability of mefloquine compared to malarone® and doxycycline.

Proguanil combined with chloroquine

There is limited evidence from randomized controlled trials (RCTs) that the combination of proguanil with chloroquine is effective in preventing malaria and is a relatively well tolerated option. However, resistance of Plasmodium to proguanil combined with chloroquine is increasing, making the combination unsuitable for many areas of the world.

Proguanil inhibits the synthesis of folic acid in Plasmodium, and acts as both a causal and suppressive prophylactic (i.e. it inhibits both liver and blood stages of infection). It was first introduced in 1948, and resistance to proguanil was reported a year later [Wongsrichanalai et al, 2002]. It is now almost never used as monotherapy, but is combined with either chloroquine, or atovaquone, with which it acts synergistically. For further information see Supporting evidence on Atovaquone combined with proguanil (Malarone®).

CKS was unable to find any systematic reviews investigating the effectiveness or safety of proguanil combined with chloroquine. However, the following RCTs were identified:

A relatively large RCT randomized 767 participants travelling from Scandinavia to East Africa to receive prophylaxis with proguanil-chloroquine, or chloroquine combined with sulfadoxine-pyrimethamine [Fogh et al, 1988].

The regimens were similarly effective in preventing malaria, with four people developing the infection with proguanil-chloroquine, compared with three in the other group.

Adverse effects were generally mild, but were more common in the chloroquine combined with sulfadoxine-pyrimethamine group (p = 0.043).

A relatively large RCT (n = 1421) compared two different proguanil-chloroquine combinations with proguanil alone in Dutch travellers. Confirmed prophylactic failure occurred in less than 1% of participants (12 people) and was highest for the proguanil monotherapy regimen [Wetsteyn and de Geus, 1993].

Proguanil-chloroquine was used as the active comparator with atovaquone-proguanil in an open-label RCT with 221 paediatric participants [Camus et al, 2004].

No children developed malaria.

Adverse effects were reported as being more common in the proguanil-chloroquine group, with two children stopping this regimen because of adverse effects.

Atovaquone combined with proguanil (Malarone®)

Atovaquone combined with proguanil is the most recent addition to the drug regimens used to prevent malaria, and has been shown to be well-tolerated and effective in numerous randomized controlled trials (RCTs). Currently resistance levels to the regimen are low, and it is estimated as having a protective rate of 90% against Plasmodium falciparum in sensitive areas.

Atovaquone inhibits the mitochondria of the malarial parasite, causing death. It works synergistically with proguanil, and the regimen can be considered as a causal prophylaxis, meaning that it only needs to be taken for a short duration after returning from malaria-endemic areas [Chiodini et al, 2007].

Atovaquone was introduced in 1996, and drug resistance was reported in the same year. However, malaria is still sensitive to it in most geographical areas [Wongsrichanalai et al, 2002].

CKS did not find any systematic reviews of atovaquone combined with proguanil, although it was the subject of a non-systematic review where it was found to be as effective as other regimens whilst being well tolerated [Marra et al, 2003]. The following individual RCTs have investigated the effectiveness of proguanil-atovaquone (many of these trials were not carried out in travellers, and participants were likely to have some pre-existing naturally acquired immunity to malaria).

A randomized placebo-controlled trial of children (n = 320) living in a hyperendemic area found that none of the children receiving the active agent had positive smears for malaria compared with 18% (25 out of 140) who tested positive in the placebo group. No differences in adverse effects were reported [Lell et al, 1998].

A double-blind RCT compared two doses of atovaquone-proguanil with placebo in volunteers living in Kenya (n = 192). None of the volunteers in the active group had positive smears for malaria, compared with 48% of those who received placebo [Shanks et al, 1998].

A double-blind placebo-controlled randomized trial in volunteers from Zambia (n = 274) reported a successful prophylaxis rate of 98% in the atovaquone-proguanil group compared with 63% in the control (p < 0.001). The active intervention was not associated with more adverse effects [Sukwa et al, 1999].

An RCT allocated European people travelling to malaria-endemic countries (n = 483) to receive atovaquone-proguanil or mefloquine. No participants returned with confirmed cases of malaria. However, mefloquine caused significantly more neuropsychiatric adverse effects than proguanil-atovaquone, and more people withdrew from the mefloquine group [Overbosch et al, 2001].

A double-blind RCT randomized migrants (n = 297) from a low-endemic malarial area to an area with high endemicity to receive atovaquone-proguanil or placebo. Overall, the active intervention gave 93% protection (95% CI 77 to 98%) compared with placebo [Ling et al, 2002].

An open-label RCT in non-immune paediatric travellers (n = 221) compared atovaquone-proguanil with proguanil-chloroquine. No children in either group developed malaria, but adverse effects were reported as being more common in the proguanil-chloroquine group, and two children stopped this regimen because of adverse effects [Camus et al, 2004].

Doxycycline

Doxycycline has been shown to be as effective as other regimens in two comparative randomized controlled trials (RCTs), and is still effective in many chloroquine-resistant areas. Its main drawback is that it is contraindicated in children and pregnant women, and has some unpleasant adverse effects.

Doxycycline works by binding to the ribosomes of the malarial parasite, preventing protein production. It is a suppressive antibiotic, meaning it must be taken for several weeks after exposure to falciparum [Chiodini et al, 2007].

CKS did not find any systematic reviews on the use of doxycycline for the prevention of malaria. However, it has been studied in comparative trials with mefloquine and azithromycin.

A double-blind RCT compared mefloquine, doxycycline, and placebo in Indonesian soldiers who had recently been posted to a chloroquine-resistant area [Ohrt et al, 1997].

In the placebo group, 53 of 69 soldiers developed malaria, equating to an attack rate of 5.8 cases per person-year (95% CI 4.3 to 7.7).

No cases were reported in the mefloquine group.

In the doxycycline group, only 1% (one developed malaria [out of 67]), giving doxycycline a protective efficacy of 99% (95% CI 94 to 100%).

Both drugs were well tolerated in the trial.

A double-blind RCT randomized people from Indonesia with limited immunity (n = 300) to receive azithromycin, doxycycline (the active comparator), or placebo [Taylor et al, 1999].

The incidence rates of infection with P. falciparum relative to placebo were 71.6% (95% CI 50.3 to 83.8%) for azithromycin and 98.0% (95% CI 88.0 to 99.9%) for doxycycline, showing doxycycline to be an effective prophylactic against this strain of malaria.

Both drugs were effective against P. vivax.

Relative safety/tolerability of malarone®, doxycycline and mefloquine

Relative safety/tolerability of malarone®, doxycycline, and mefloquine

A Cochrane review found limited evidence that mefloquine users have a worse total mood disturbance scores and experience more neuropsychiatric adverse outcomes than users of Malarone® or doxycycline. In addition it found 22 case reports of deaths associated with the use of mefloquine at normal dosages, including five reported suicides and no case reports of deaths associated with other drugs used for malaria chemoprophylaxis.

A Cochrane systematic review (search date: September 2009) identified eight randomized controlled trials (RCTs) with 4240 participants that compared the risk of adverse outcomes of Malarone®, mefloquine, and doxycycline in non-immune adults and children living in North America or Europe travelling to areas endemic with chloroquine-resistant Plasmodium falciparum for less than 3 months. The adverse outcomes of each drug was compared against each other, that is: Malarone® compared with doxycycline, Malarone® compared with mefloquine, and mefloquine compared with doxycycline. Adverse outcomes investigated included:

Any adverse effects and events.

Dermatological adverse effects and events.

Neuropsychiatric adverse effects and events.

Any serious adverse event.

Adverse outcomes of Malarone® compared with doxycycline: no significant difference in the risk of any adverse outcome was found in the one RCT that compared these interventions in 317 people.

Adverse outcomes of mefloquine compared with Malarone®: two RCTs (n = 1293) were identified. Results found a significantly greater risk of:

Any adverse effect with mefloquine compared with Malarone® (risk ratio [RR] 0.72, 95% CI 0.60 to 0.85).

Neuropsychiatric adverse effects with mefloquine compared with Malarone® (RR 0.49, 95% CI 0.38 to 0.63).

Neuropsychiatric adverse events with mefloquine compared with Malarone® (RR 0.86, 95% CI 0.75 to 0.99).

A reduced mood disturbance score with mefloquine compared with Malarone® (mean difference -7.20, 95% CI -10.79 to +3.61).

Adverse outcomes of mefloquine compared with doxycycline: two RCT's in 441 people found there was a significantly greater risk of neuropsychiatric adverse events with mefloquine compared with doxycycline (risk ratio 0.84, 95% CI 0.73 to 0.96).

Comment: the low number of participants meant that the studies were underpowered to detect potential differences in many of the relatively uncommon adverse outcomes examined.

In addition, the authors identified 22 case reports of deaths with mefloquine use, including 5 suicides. They did not identify any reports of other currently used anti-malarial drugs causing death. These findings should be interpreted with caution because this is open to significant risk of reporting bias and no causal basis has been established.

Preventing malaria in pregnancy

Evidence on drugs for preventing malaria in pregnant women

Pregnant women are at greater risk of developing malaria and are more likely to suffer a poor outcome once infected. Although the available trial evidence are limited to treatment of women living in malaria-endemic areas and cannot be accurately extrapolated, the results show a positive benefit of chemoprophylaxis, and treatment of travelling women should be considered essential. Chloroquine, proguanil, and mefloquine have a favourable benefit-to-harms ratio for pregnant women who are likely to be exposed to malaria.

A Cochrane review (search date: March 2006) identified 16 trials suitable for inclusion (n = 12,638) that investigated the effect of anti-malarial drugs on pregnant women and their babies [Garner and Gulmezoglu, 2006]. The trials were of variable quality in terms of randomization (not all were randomized), concealment of allocation, and blinding. Most trials were carried out in women who lived in areas endemic with malaria.

Effect on all mothers: two trials (n = 328) found that antimalarial drugs significantly reduced the risk of malaria in pregnant women compared with placebo or no drug (RR 0.53, 95% CI 0.33 to 0.86). Four trials (n = 2890) found that antimalarial drugs significantly reduce anaemia (RR 0.62, 95% CI 0.50 to 0.78).

Effect on mothers having their first or second baby: several trials found that antimalarial drugs significantly reduced the rates of severe antenatal anaemia, malaria infection, and perinatal death.

Effect on babies born to all mothers: there were no significant differences found in terms of perinatal death, preterm birth, or birthweight. However, it is possible that the included studies were underpowered to detect a difference.

Effect on babies born to mothers of one or two children: a meta-analysis of three trials showed that antimalarial drugs were associated with fewer perinatal deaths in this group. Babies born to women of low parity who used antimalarial drugs also had a significantly higher birthweight compared with those who did not (RR 0.57, 95% CI 0.46 to 0.72).

Head to head comparisons:

Proguanil compared with chloroquine: one trial (n = 223) found that proguanil was associated with significantly fewer episodes of fever and positive blood smear tests compared with chloroquine.

Sulfadoxine-pyrimethamine compared with chloroquine: two trials (n = 717) found that sulfadoxine-pyrimethamine was more effective than chloroquine at reducing malaria (as detected by blood smear). Low birthweight was also significantly reduced in the former group.

The authors concluded that chemoprophylaxis for pregnant women in endemic areas reduces the rate of malarial infection. In women of low parity, antimalarial drugs also have positive effects on birthweight and possibly also on perinatal death.

Although it is not possible to accurately extrapolate the magnitude of effect of prophylactic cover in pregnant travelling women, the available evidence supports chemoprophylaxis.

Pregnant women are at greater risk of contracting malaria and have worse outcomes, for both mother and child.

The available controlled trials in pregnant women support a positive effect. Future placebo-controlled trials in travelling pregnant women are unlikely due to ethical concerns.

Trials in non-pregnant travelling women and men also show that chemoprophylaxis is beneficial (see Drugs for preventing malaria).

Not all drugs are suitable for pregnant women. See Scenario: Preventing malaria when pregnant/breastfeeding/planning pregnancy for further information.

Preventing malaria in children

Evidence on drugs for preventing malaria in children

A Cochrane review found evidence that children taking regular antimalarial prophylaxis or intermittent treatment, were less likely to get malaria, severe anaemia, or be admitted to hospital, but there was no overall difference in the overall death rate when compared to children not receiving any treatment.

A Cochrane review (search date: September 2007, 21 randomized controlled trials [RCT's], n = 19,394) examined the risks of harm from malaria in children aged one month to six years, living in an area where malaria is endemic. The risk to children taking regular antimalarial prophylaxis or an intermittent full treatment course was compared to the risk to children taking placebo or no drug [Meremikwu et al, 2008]. The results were as follows:

Clinical malaria: 10 RCT's with 7037 participants found that prophylaxis and intermittent anti-malarial treatment, when analysed together, significantly reduced the risk of developing clinical malarial (risk ratio 0.53, 95% CI 0.38 to 0.74).

Severe anaemia:

Regular prophylaxis (one RCT with 415 participants) significantly reduced the risk of developing severe anaemia (risk ratio 0.48, 95% CI 0.34 to 0.67).

Intermittent treatment (eight RCT's with 5030 participants) was not shown to significantly reduce the risk of developing severe anaemia (risk ratio 0.76, 95% CI 0.57 to 1.02).

Admission to hospital: 6 RCT's with 3722 participants found that prophylaxis and intermittent anti-malarial treatment when analysed together significantly reduced the risk admission to hospital (risk ratio 0.64, 95% CI 0.49 to 0.82).

Death from any cause: 10 RCT's with 7369 participants found no significant difference in the risk of death in children given prophylaxis or intermittent anti-malarial treatment compared to children who did not receive any treatment.

It is not possible to accurately extrapolate the magnitude of effect of prophylactic cover in children travelling to endemic areas from the available studies. However, treatment is strongly recommended because:

Malaria is more severe in children with a high mortality rate.

The available controlled trials in children living in endemic areas support a positive effect. Future placebo-controlled trials in travelling children are very unlikely due to ethical concerns.

Trials in travelling adults also show that chemoprophylaxis is beneficial (see Drugs for preventing malaria). It is probably reasonable to extrapolate this data to children.

Not all antimalarial drugs are suitable for children. See the scenario Preventing malaria in children for more information.

Search strategy

Scope of search

A literature search was conducted for guidelines, systematic reviews and randomized controlled trials on primary care management of Malaria prophylaxis.

Search dates

2007 – October 2011.

Key search terms

Various combinations of searches were carried out. The terms listed below are the core search terms that were used for Medline and these were adapted for other databases. Further details are available on request.

exp Malaria/, prophylaxis.tw., prevention.tw.,

Table 1 . Key to search terms.
Search commands Explanation
/ indicates a MeSh subject heading with all subheadings selected
.tw indicates a search for a term in the title or abstract
exp indicates that the MeSH subject heading was exploded to include the narrower, more specific terms beneath it in the MeSH tree
$ indicates that the search term was truncated (e.g. wart$ searches for wart and warts)
Sources of guidelines

National Institute for Health and Care Excellence (NICE)

Scottish Intercollegiate Guidelines Network (SIGN)

NICE Evidence

National Guidelines Clearinghouse

New Zealand Guidelines Group

British Columbia Medical Association

Canadian Medical Association

Institute for Clinical Systems Improvement

Guidelines International Network

National Library of Guidelines

National Health and Medical Research Council (Australia)

Alberta Medical Association

University of Michigan Medical School

Michigan Quality Improvement Consortium

Royal College of Nursing

Singapore Ministry of Health

Royal Australian College of General Practitioners

Health Protection Agency

National Resource for Infection Control

CREST

World Health Organization

NHS Scotland National Patient Pathways

Agency for Healthcare Research and Quality

TRIP database

Patient UK Guideline links

UK Ambulance Service Clinical Practice Guidelines

RefHELP NHS Lothian Referral Guidelines

Medline (with guideline filter)

Driver and Vehicle Licensing Agency

Sources of systematic reviews and meta-analyses

The Cochrane Library :

Systematic reviews

Protocols

Database of Abstracts of Reviews of Effects

Medline (with systematic review filter)

EMBASE (with systematic review filter)

Sources of health technology assessments and economic appraisals

NIHR Health Technology Assessment programme

The Cochrane Library :

NHS Economic Evaluations

Health Technology Assessments

Canadian Agency for Drugs and Technologies in Health

International Network of Agencies for Health Technology Assessment

Sources of randomized controlled trials

The Cochrane Library :

Central Register of Controlled Trials

Medline (with randomized controlled trial filter)

EMBASE (with randomized controlled trial filter)

Sources of evidence based reviews and evidence summaries

Bandolier

Drug & Therapeutics Bulletin

MeReC

NPCi

BMJ Clinical Evidence

DynaMed

TRIP database

Central Services Agency COMPASS Therapeutic Notes

Sources of national policy

Department of Health

Health Management Information Consortium (HMIC)

Sources of medicines information

The following sources are used by CKS pharmacists and are not necessarily searched by CKS information specialists for all topics. Some of these resources are not freely available and require subscriptions to access content.

British National Formulary (BNF)

electronic Medicines Compendium (eMC)

European Medicines Agency (EMEA)

LactMed

Medicines and Healthcare products Regulatory Agency (MHRA)

REPROTOX

Scottish Medicines Consortium

Stockley's Drug Interactions

TERIS

TOXBASE

Micromedex

UK Medicines Information

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