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Canadian Recommendations for the Prevention and Treatment of Malaria Among International Travellers

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8. Drugs for the Prevention and Treatment of Malaria

Travellers should be reminded that antimalarials, like all drugs, have the potential to cause adverse effects. These drugs should be prescribed after an individual risk assessment (as outlined in Chapter 2) to ensure that only those travellers truly at risk of malaria infection receive antimalarial chemoprophylaxis. Any drugs taken for chemoprophylaxis should be used in conjunction with personal protective measures to prevent mosquito bites (see Chapter 2). Most people using antimalarial chemoprophylaxis will have no or only minor adverse reactions, which can be minimized by careful adherence to dosing guidelines, precautions and contraindications. If there are concerns as to the ability of the traveller to tolerate a particular antimalarial regimen and if time permits, malaria prophylaxis may be initiated several weeks before travel in order to assess drug tolerance.

In light of the increasing prevalence of counterfeit medications in some countries and the potentially serious consequences of inadequate antimalarial prophylaxis or treatment, travellers should be advised to purchase their antimalarial medications prior to departure from Canada whenever possible (see Chapter 5, Counterfeit Drugs).

This chapter reviews the drugs (in alphabetical order) used for the prevention (chemoprophylaxis) and treatment of malaria. This information is not designed to be comprehensive. It is important to note that product recommendations are subject to change, and therefore providers should consult up-to-date information, including recent drug monographs, for any updates, particularly with respect to compatibility, adverse reactions, contraindications and precautions. Further details and discussion on recommendations concerning the use of these drugs for chemoprophylaxis and treatment can be found in Chapter 3 and in this chapter, respectively. Table 5 provides information on the base/salt equivalents of selected antimalarial drugs, and Table 6 summarizes information, including doses, for the antimalarial drugs routinely used in Canada. Figure 2 depicts the malaria lifecycle and the sites of action of recommended chemoprophylactic drugs.

This chapter reviews the drugs (in alphabetical order) used for the prevention (chemoprophylaxis) and treatment of malaria. This information is not designed to be comprehensive. It is important to note that product recommendations are subject to change, and therefore providers should consult up-to-date information, including recent drug monographs, for any updates, particularly with respect to compatibility, adverse reactions, contraindications and precautions. Further details and discussion on recommendations concerning the use of these drugs for chemoprophylaxis and treatment can be found in Chapter 3 and in this chapter, respectively.

Table 5 provides information on the base/salt equivalents of selected antimalarial drugs, and Table 6 summarizes information, including doses, for the antimalarial drugs routinely used in Canada.

Figure 2 depicts the malaria lifecycle and the sites of action of recommended chemoprophylactic drugs.

Figure 2: Malaria life cycle and primary areas of drug activity (modified from the U.S. Centers for Disease Control and Prevention DPDx site)

Figure 2, Text Equivalent

The malaria parasite life cycle involves two hosts. During a blood meal, a malaria-infected female anopheline mosquito inoculates sporozoites into the human host (1). Sporozoites infect liver cells (2) and mature into schizonts (3), which rupture and release merozoites (4). In P. vivax and P. ovale, a dormant stage (hypnozoites) can persist in the liver and cause relapses by invading the bloodstream weeks or even years later. After this initial replication in the liver (exo-erythrocytic schizogony A), the parasites undergo asexual multiplication in the erythrocytes (erythrocytic schizogony B). Merozoites infect red blood cells (5). The ring stage trophozoites mature into schizonts, which rupture releasing merozoites (6). Some parasites differentiate into sexual erythrocytic stages (gametocytes) (7). Blood stage parasites are responsible for the clinical manifestations of the disease.

Agents used for causal chemoprophylaxis include atovaquone/proguanil and primaquine. These drugs act at the liver stage of the malaria life cycle, prevent blood-stage infection, and need only be taken for 1 week after leaving a malaria-endemic area. Agents used for suppressive chemoprophylaxis (including mefloquine, chloroquine, doxycycline) act at the erythrocytic (asexual) stage of the malaria life cycle, and hence need to be taken for 4 weeks after departure from a malaria-endemic area.

Artemisinin and Derivatives

These are endoperoxide-containing natural antimalarials from sweet wormwood (Artemisia annua). Artemisinin (qinghaosu) derivatives, including artesunate, artemether, arteether and dihydroartesinin, are available in oral, parenteral and suppository formulations. They are all metabolized to a biologically active metabolite, dihydroartemisinin, and exert their antiparasitic effects on the younger, ring-forming parasites. They thereby decrease the numbers of late parasite forms that can obstruct the microvasculature of the host. All artemisinin preparations have been studied and used for treatment only. They are not recommended for prophylaxis because of their short half-life.

Artemisinin and its derivatives produce rapid clearance of parasitemia and rapid resolution of symptoms. They reduce parasite numbers by a factor of approximately 10,000 in each asexual cycle, which is more than other current antimalarials (which reduce parasite numbers 100- to 1000- fold per cycle)(199). The artemisinin derivatives act rapidly against drug-resistant P Falciparum strains but have high recrudescence rates (about 10% to 50%) when used as monotherapy for fewer than 5 days. Studies have examined longer durations of therapy (7 days) and combinations of artemisinin derivatives with mefloquine, lumefantrine, amodiaquine or tetracycline/doxycycline to prevent recrudescence. In Thailand, treatment with oral artesunate (over 3 to 5 days) combined with mefloquine (15 to 25 mg/kg) was more effective than mefloquine or artesunate alone. Combination therapy results in > 90% cure rates of primary and recrudescent P.Falciparum infections.

Coartemether (Riamet® in Europe, Coartem® in Africa) is a combination of artemether and lumefantrine that is currently licensed in some European countries and the U.S. and is becoming widely distributed in Africa for the treatment of malaria. A six-dose regimen of artemether-lumefantrine appears more effective than antima-larial regimens not containing artemisinin derivatives(200). Available data suggest that mefloquine plus artesunate is as effective and possibly superior to artemetherlumefantrine(201). Combinations of artesunate and mefloquine appear to be the most active drug regimens for treatment of multidrug-resistant Falciparum malaria in Southeast Asia(202).

Randomised trials comparing parenteral artesunate and quinine in patients from East Asia with severe malaria show clear evidence of benefit with artesunate. In the largest multi-centre trial, which enrolled 1,461 patients (including 202 children < 15 years), mortality was reduced by 35% compared with the quinine group(126).

Artemisinin-based combination treatments are now accepted as the best current treatment for uncomplicated Falciparum malaria(126). Parenteral artesunate is recommended by the WHO as the treatment of first choice for severe or complicated malaria(126). Artemisinin and its derivatives are available and increasingly used in Southeast Asia and Africa, and parenteral artesunate is now available in Canada and can be obtained from the CMN (see Appendix V).

Artemisinin and its derivatives have been used in over 1 million patients and are generally well tolerated(203). Neurological lesions involving the brainstem have been seen in rats, dogs and primates given repeated doses of artemisinin derivatives, in particular the lipid soluble derivatives. Such effects have not been observed with oral administration of any artemisinin derivative or with intravenous artesunate. Treatment of uncomplicated malaria with coartemether may be associated with hearing loss in some patients, possibly from synergy between potentially ototoxic agents in combination(204). To date, there have been two human cases of complete heart block associated with the use of artemisinins, but most volunteer and clinical studies have found no evidence of cardiac adverse effects. The safety of artemisinin derivatives in pregnancy has not been established. Based on a recent review, the limited data available suggest that artemisinins are effective and unlikely to cause foetal loss or abnormalities when used in late pregnancy(126, 205). It is important to note that none of these studies had adequate power to rule out rare serious adverse events, even in the second and third trimesters. There is currently not enough evidence to effectively assess the risk-benefit profile of artemisinin compounds for pregnant women, particularly for first trimester exposure(205). Although there is good evidence that therapy with artemisinin compounds is generally safe, questions about cumulative neurological toxicity of intramuscular preparations still require resolution. Additional studies to monitor subtle neurological changes and hearing loss are required, especially in patients undergoing repetitive treatment.

Oral artemisinin derivatives are not yet licensed or available in Canada but have been approved recently in the U.S by the Food and Drug Administration. There is concern that the quality of artemisinin derivatives available in developing countries may be questionable, as they may not be produced in accordance with the good manufacturing production standards required in North America, or they may be counterfeit(123). Orally administered artemisinin drug combinations, such as the combination artemisinin-lumefantrine (CoArtem®), are recommended by the WHO as the treatment of choice for uncomplicated Falciparum malaria. Such drugs would increase the treatment choices for oral therapy of Falciparum malaria in Canada, where atovaquone/ proguanil (Malarone®) is frequently used for chemoprophylaxis (and hence may be disqualified as a therapeutic choice), and the only other treatment choice, quinine in combination with a tetracycline, is often poorly tolerated. Furthermore, Canadians travelling (particularly for longer periods) to malariaendemic areas where these drugs are available cannot safely rely on local drugs, since counterfeit artemisinins are becoming a serious problem in many countries(123) (see Chapter 5, Counterfeit Drugs).

List of projects which provides the project name, the project lead and the current status.
Artemisinin and derivatives: evidence-based medicine recommendations EBM rating
Artemether in combination with lumefantrine (Riamet® in Europe, Coartem® in Africa and the U.S.) is widely distributed in Africa for the treatment of P. Falciparum malaria. A six-dose regimen of artemether-lumefantrine appears more effective than antimalarial regimens not containing artemisinin derivatives(200, 201). A I
Parenteral artesunate is recommended as the first-line treatment of severe or complicated P. Falciparum malaria. Parenteral administration of artesunate should be followed by a full course of oral combination therapy (artemisinin-based combination treatments, or quinine plus doxycycline or clindamycin)(126). A II
On the basis of their short half-life, artemisinin compounds should not be used for chemoprophylaxis. C III

Atovaquone/Proguanil (ATQ/PG)

Trade Name: Malarone®, Malarone® Pediatric: licensed in Canada for malaria hemoprophylaxis in adults and in children weighing 11 kg and above, and for treatment of uncomplicated malaria in adults and in children weighing 11 kg and above(206) (see Chapter 5 for dosage in children weighing between 5 and 11 kg). There are two formulations of Malarone® available: Malarone® tablets containing 250 mg of atovaquone and 100 mg proguanil hydrochloride, and Malarone® pediatric tablets, containing 62.5 mg atovaquone and 25 mg proguanil hydrochloride.

Mechanism of action

Atovaquone/proguanil is a fixed drug combination of atovaquone and proguanil in a single tablet. The two components are synergistic, inhibiting electron transport and collapsing mitochondrial membrane potential. Atovaquone/proguanil is effective as a causal (acting at the liver stage) as well as a suppressive (acting at the blood stage) prophylactic agent. Atovaquone/proguanil must be taken daily. Because of the causal effects, tovaquone/proguanil can be discontinued 1 week after departure from a malariaendemic area.

Indications and efficacy

For malaria chemoprophylaxis, atovaquone/ proguanil has equal efficacy (i.e., ~ 95%) to that of doxycycline and mefloquine against chloroquineresistant Falciparum malaria(207). It is also effective along the borders of Thailand, where chloroquine and mefloquine resistance is documented(75, 97). Daily atovaquone/proguanil can now be considered as firstline chemoprophylaxis for travellers to areas with multidrug-resistant Falciparum malaria (with attention to contraindi-cations and precautions)(75, 199, 207).

In clinical trials of treatment of acute, uncomplicated P. Falciparum malaria conducted in Southeast Asia, South America, and Africa, the efficacy of the combination of atovaquone/proguanil (dosed once daily for 3 days) has exceeded 95%(71). As well, published case reports have documented that it successfully treated multidrug-resistant malaria that had failed to respond to other therapies(208). Therefore, atovaquone/ proguanil, an effective and well-tolerated therapy, is considered first-line treatment of non-complicated P. Falciparum infection, including multidrug-resistant P. Falciparum(209). However, there have been sporadic documented cases of atovaquone/proguanil-resistant P. Falciparum malaria acquired in sub-Saharan Africa(210, 211, 212).

There is insufficient evidence at this time to recommend atovaquone/proguanil for the routine treatment of non-Falciparum malaria, although limited data suggest efficacy for the treatment of P. vivax malaria when atovaquone/proguanil is combined with primaquine (beginning immediately after the 3 days of treatment with atovaquone/proguanil)(213).

Adverse effects, contraindications and precautions

Compared with other standard antimalarial regimens, the atovaquone/proguanil combination for chemoprophylaxis has demonstrated excellent safety and tolerance(203). During treatment, the most frequent adverse events are those associated with the gastrointestinal tract: approximately 8% to 15% of adults and children experience nausea, vomiting, abdominal pain or diarrhea, and 5% to 10% develop transient, asymptomatic elevations in transaminase and amylase levels. Serious adverse events associated with atovaquone/proguanil, such as seizure, hepatitis and rash, are rare. Atovaquone has been associated with fever and rash in HIVinfected patients, requiring discontinuation of therapy, and has been shown to be teratogenic in rabbits but not in rat models (US Food and Drug Administration category C drug). Proguanil is well tolerated, and although oral aphthous ulcerations are not uncommon they are rarely severe enough to warrant discontinuing this medication. Proguanil may potentiate the anticoagulant effect of warfarin and similar anticoagulants (those metabolized by CYP 2C9) through possible interference with metabolic pathways(199).

Pregnancy, severe renal insufficiency (creatinine clearance < 30 mL/min) and hypersensitivity to either component is a contraindication to atovaquone/proguanil use.

List of projects which provides the project name, the project lead and the current status.
Malarone: evidence-based medicine recommendations EBM rating
Atovaquone/proguanil prophylaxis has equal efficacy (i.e., ~ 95%) to that of doxycycline and
mefloquine against chloroquine-resistant falciparum malaria(207, 208).
A I
Daily atovaquone/proguanil can now be considered as first-line chemoprophylaxis for travellers to
areas with multidrug-resistant falciparum malaria(75, 207).
A I
Atovaquone/proguanil is considered a first-line treatment for acute, uncomplicated P. falciparum
malaria from Southeast Asia, South America, and Africa with an efficacy of ~ 95%(208).
A I
There is insufficient evidence at this time to recommend atovaquone/proguanil for the routine
treatment of non-falciparum malaria((208, 213).
C III

Chloroquine (or Hydroxychloroquine)
Trade Name: Novo-Chloroquine (or Plaquenil®, Apo-Hydroxyquine, Gen-Hydroxychloroquine)

Mechanism of action

Chloroquine is a synthetic 4-aminoquinoline, which acts against the intra-erythrocytic stage of parasite development. It interferes with the digestion of hemoglobin within the red cell and leads to toxic metabolite formation within the food vacuole of the parasite.

Indications and efficacy

Chloroquine/hydroxychloroquine, taken once weekly, is effective for malaria prevention in travellers to areas with chloroquine-sensitive malaria(75). It remains the drug of choice for malaria chemoprophylaxis of travellers to areas with chloroquine-sensitive malaria and the drug of choice for the treatment of chloroquine-sensitive falciparum malaria, chloroquine sensitive P. vivax, as well as P. ovale and P. malariae infections(126, 213).

Chloroquine is suitable for people of all ages and for pregnant women. There is insufficient drug excreted in breast milk to protect a breast-feeding infant, and therefore nursing infants should be given chloroquine (adjusted for changing weight, see Table 6). Since overdoses are frequently fatal, instructions for childhood doses should be carefully followed, and the medication should be kept out of the reach of children.

Weekly chloroquine plus daily proguanil (Saverine®) is less efficacious than atovaquone/proguanil, doxycycline or mefloquine and is not routinely recommended for prevention of malaria in Canadian travellers to sub-Saharan Africa(77, 207).

Adverse effects, contraindications and precautions

Except for its bitter taste, chloroquine is usually well tolerated. Taking the drug with food may reduce other mild side effects, such as nausea and headache. Black-skinned people may experience generalized pruritus, which is not indicative of drug allergy. Transient, minor visual blurring may occur initially but should not be a reason to discontinue chloroquine. Retinal toxic effects, which may occur with long-term daily doses of chloroquine (> 100 g total dose) used in the treatment of other diseases, is extremely unlikely with chloroquine given as a weekly chemoprophylaxis. Chloroquine may worsen psoriasis and, rarely, is associated with seizures and psychosis. Therefore, chloroquine should not be used in individuals with a history of epilepsy or generalized psoriasis(72, 203). Concurrent use of chloroquine interferes with antibody response to intradermal human diploid cell rabies vaccine.

List of projects which provides the project name, the project lead and the current status.
Chloroquine: evidence-based medicine recommendations EBM rating
Chloroquine/hydroxychloroquine, taken once weekly, is effective for malaria prevention in travellers to areas with chloroquine-sensitive malaria(75). A I
Chloroquine is the drug of choice for the treatment of malarias caused by chloroquine-sensitive P. Falciparum and P. vivax and all P. ovale and P. malariae infections(126, 213). A I
Weekly prophylaxis with chloroquine plus daily proguanil (Saverine®) is less efficacious than atovaquone/proguanil, doxycycline or mefloquine and is not recommended for Africa(77, 207). E I
Chloroquine should not be used in individuals with a history of epilepsy or generalized psoriasis(72, 203). C III

Clindamycin
Trade Name: Dalacin C®, Apo-Clindamycin, Novo-Clindamycin

Mechanism of action

Clindamycin is an antimicrobial that inhibits the parasite apicoplast.

Indications and efficacy

Clindamycin is indicated only for the treatment of malaria and only in restricted circumstances.
Clindamycin, although less effective than doxycycline or atovaquone/proguanil, is used in combination with quinine for those unable to tolerate, or who have contraindications to, the use of first-line agents (e.g., pregnant women and young children).

Adverse effects, contraindications and precautions

The most frequent adverse events with clindamycin are diarrhea and rash. Clostridium difficile associated disease, including pseudomembranous colitis, has been reported.

List of projects which provides the project name, the project lead and the current status.
Clindamycin: evidence-based medicine recommendations EBM rating
Until artemisinin and its derivatives become readily available in North America, clindamycin combined with quinine is recommended as treatment of chloroquine- or mefloquine-resistant P. Falciparum malaria in pregnant women, children (< 8 years of age) and tetracycline intolerant adults(213). A I

Doxycycline
Trade Name: Vibra-Tabs™, Apo-Doxy, Doxycin, Novo-Doxylin, Nu-Doxycycline, ratio-Doxycycline

Mechanism of action

Doxycycline is an antimicrobial that inhibits parasite protein synthesis.

Indications and efficacy

Doxycycline is effective for the prevention and treatment of chloroquine-resistant P. Falciparum. It has been shown to have equivalent efficacy to that of atovaquone/proguanil and mefloquine for the prevention of chloroquine-resistant P. Falciparum(75). Doxycycline is an efficacious chemoprophylactic agent against mefloquine-sensitive and mefloquineresistant P. Falciparum malaria(75) but must be taken daily for it to work. The major reason for doxycycline failures is non-compliance with this daily regimen.

Adverse effects, contraindications and precautions

Doxycycline can cause gastrointestinal upset and, rarely, esophageal ulceration, which is less likely to occur if the drug is taken with food and large amounts of fluid. It should not be taken in the 30 minutes before lying down nor simultaneously with Pepto-bismol® or antacids. Because doxycycline is photosensitizing, it may make the skin burn more easily; use of a sunscreen that blocks ultraviolet A rays may reduce this problem. Doxycycline may also increase the risk of vaginal candidiasis; therefore, women should carry antifungal therapy for selftreatment of vaginal candidiasis. Although tetracyclines and other antibiotics have been cited as a cause of oral contraceptive failure, a controlled clinical trial failed to demonstrate any significant association(214). Concurrent use of doxycycline with barbiturates, carbamazapine or phenytoin may result in a 50% decrease in doxycycline serum concentration because of induction of hepatic microsomal enzyme activity and resulting reduction of the half-life of
doxycycline.

Doxycycline is contraindicated during pregnancy, in breast-feeding women and in children < 8 years of age. Although the long-term safety (> 3 months) of doxycycline has not been established, historically tetracycline derivatives have been used at lower doses over many years for skin disorders.

List of projects which provides the project name, the project lead and the current status.
Doxycycline: evidence-based medicine recommendations EBM rating
Doxycycline is equivalent in efficacy to mefloquine and atovaquone/proguanil for the prevention of chloroquine-resistant P. Falciparum and to atovaquone/proguanil for mefloquine-resistant P. Falciparum(75). A I
Travellers should be informed about the small doxycycline-associated risks of oesophageal ulceration, vaginal candidiasis and photosensitivity(75, 126). A I
Doxycycline is contraindicated during pregnancy, in breast-feeding women and in children < 8 years of age(75, 126). A I
Concurrent use of doxycycline with barbiturates, carbamazapine or phenytoin may result in a 50% decrease in doxycycline serum concentration(75, 126). A I

Mefloquine
Trade Name: Lariam®, Apo-Mefloquine

Mechanism of action

Mefloquine is a quinoline-methanol. It is a lipophylic drug that acts on the intraerythrocytic asexual stages of parasite development, inhibiting heme polymerization within the food vacuole.

Indications and efficacy

Mefloquine is an effective chemoprophylactic and therapeutic agent against drug-resistant P. Falciparum. In Canada, it is routinely recommended only for chemoprophylaxis because of a higher rate of adverse effects with treatment doses. It is one of the drugs of choice, along with atovaquone/ proguanil or doxycycline, for the prevention of malaria in travellers to chloroquine-resistant regions(75). However, treatment failures in excess of 50% with mefloquine are being reported in border areas between Cambodia, Myanmar and Thailand(75, 126, 199).

There is no evidence that toxic metabolites of mefloquine accumulate, and long-term use of
mefloquine (> 1 year) by Peace Corps volunteers in Africa was not associated with additional adverse effects(203). It is recommended, therefore, that the duration of mefloquine use not be arbitrarily restricted in individuals who tolerate this medication and are at risk of acquiring malaria.

For travellers who will be at immediate high risk of drug-resistant Falciparum malaria, consideration may be given to the use of a loading dose of mefloquine. If time permits, mefloquine should preferably be initiated up to 3 weeks before travel in order to assess tolerance and achieve higher blood levels before the traveller enters malaria-endemic areas. This strategy also allows the traveller time to contact the prescribing physician to arrange an alternative antimalarial. Alternatively, data from several trials indicate that mefloquine taken once daily for 3 days before travel followed by a once weekly dose is relatively well-tolerated and an effective way to rapidly achieve therapeutic blood levels (reaching steady state levels in 4 days compared with 7 to 9 weeks with standard weekly dosing of mefloquine)(143). In controlled studies, only about 2% to 3% of loading dose recipients discontinued mefloquine, and most of these did so during the first week.

Adverse effects

Mefloquine is generally well tolerated when used for chemoprophylaxis. Approximately 25% to 50% of travellers will experience side effects from either mefloquine or chloroquine; most of these are mild and self-limiting(215, 216). The most frequent minor side effects reported with mefloquine use are nausea, strange vivid dreams, dizziness, mood changes, insomnia, headache and diarrhea. Approximately 1% to 6% of mefloquine users may have to discontinue
prophylaxis because of adverse effects. Tens of millions of travellers have used mefloquine
prophylaxis, and severe reactions (seizure, psychosis) to this drug are rare (reported from 1 in 6,000 to 1 in 13,000 users). The great majority of mefloquine users (about 95%) have either no side effects or only mild and temporary ones. Occasionally, a traveller (in particular, women(69, 203)) will experience a less severe but still troublesome neuropsychological
reaction (e.g., anxiety, mood change) to mefloquine (1 in 250 to 500 users), requiring a change to an alternative drug. This can sometimes be prevented by splitting the weekly dose into one half of a tablet twice a week for the same total weekly. Adverse reactions are generally reversible, but on rare occasions neuropsychological complaints have persisted long after mefloquine has been stopped, and rare cases of suicidal ideation and suicide have been reported; no relation to drug administration has been confirmed with any of these rare adverse events.

CATMAT does not routinely recommend mefloquine for the treatment of malaria, because in treatment doses (25 mg base/kg) it is less well tolerated. Severe neuropsychiatric reactions are reported to be 10 to 60 times more frequent, occurring in 1/215 to 1/1,700 users of treatment doses of mefloquine(203).

Contraindications

These include known hypersensitivity or past severe reaction to mefloquine; history of serious psychiatric disorder (e.g., psychosis, severe depression, generalized anxiety disorder, schizophrenia or other major psychiatric disorders); and seizure disorder.

Precautions

Precautions for the use of mefloquine include use in children < 5 kg; use in those with occupations requiring fine coordination or activities in which vertigo may be life-threatening, such as flying an aircraft; concurrent use of chloroquine or quinine-like drugs (halofantrine and mefloquine should not be used concurrently, see section on halofantrine below); underlying cardiac conduction disturbances or arrhythmia; and first trimester of pregnancy.

When mefloquine is prescribed for prophylactic use, individuals should be advised that if they
experience psychiatric symptoms, such as acute anxiety, depression, restlessness or confusion, these may be prodromal to more serious adverse events. They should report these adverse events immediately, the drug should be discontinued, and an alternative medication should be substituted.

There have been concerns regarding the co-administration of mefloquine and agents known to alter cardiac conduction, including beta-blockers, calcium channel blockers, phenothiazines, non-sedating antihistamines and tricyclic antidepressants. However, at present these concerns remain theoretical, and the concurrent use of these agents is not contraindicated. A review of available data suggests that mefloquine may be used in people concurrently taking most
beta-blockers if they have no underlying conduction delays or cardiac arrhythmia. Co-administration of mefloquine and erythromycin or ketoconizole can lead to toxic levels of mefloquine. Insufficient mefloquine is excreted in breast milk to protect a nursing infant. Although the package insert recommends that mefloquine not be given to children weighing < 5 kg, it should be considered for children at high risk of acquiring chloroquineresistant
P. Falciparum malaria (see Chapter 4). There are no pharmacokinetic data upon which
to recommend a correct dose for children weighing < 15 kg. The WHO has suggested a chemosuppressive dose of 5 mg base/kg weekly for children weighing > 5 kg.

List of projects which provides the project name, the project lead and the current status.
Mefloquine: evidence-based medicine recommendations EBM rating
It is one of the drugs of choice, along with atovaquone/proguanil or doxycycline, for the prevention of malaria in travellers to chloroquine-resistant regions(75). A I
Treatment failures in excess of 50% with mefloquine are being reported in border areas between Cambodia, Myanmar and Thailand(75). B II
Long-term use of mefloquine (> 1 year) in Africa is not associated with additional adverse effects, and its use should not be arbitrarily restricted in individuals who tolerate this medication(203). B II
The most frequent minor side effects reported with mefloquine use are nausea, strange vivid dreams, dizziness, mood changes, insomnia, headache and diarrhea. Approximately 1% to 6% of mefloquine users may have to discontinue prophylaxis because of adverse effects(215). B II
Mefloquine is not recommended as a treatment of malaria. Severe neuropsychiatric reactions are reported to occur in 1/215 to 1/1,700(203). E III
Mefloquine is contraindicated in individuals with known hypersensitivity, past severe reaction to mefloquine, a history of serious psychiatric disorder (e.g., psychosis, severe depression, generalized anxiety disorder, schizophrenia or other major psychiatric disorders), seizure disorder and cardiac conduction delays(75, 203). C1-E1

Primaquine
Trade Name: Primaquine (primaquine phosphate)

Mechanism of action

Primaquine is an 8-aminoquinoline antimalarial that is active against multiple life cycle stages of
the Plasmodia that infect humans; it has been used for over 50 years. Its mechanism of action is incompletely understood. However, primaquine has activity against the developing liver stages (causal effect), thereby preventing establishment of infection; against liver hypnozoites, preventing relapses in established P. vivax and P. ovale infections; against blood stages; and against gametocytes, thereby preventing transmission.

Indications and efficacy

Evidence is accumulating that primaquine is an effective chemoprophylactic agent for P. Falciparum malaria(216). Recent studies have shown efficacy in semi-immune and non-immune subjects, although data for travellers and for varied geographic regions are limited. Given at a dose of 0.5 mg/kg base per day (adult dose 30 mg base per day) for 11 to 50 weeks, primaquine had a protective efficacy of 85% to 93% against both P. Falciparum and P. vivax infections(217). Primaquine was well tolerated in people who were not G6PD deficient. Because of the causal effects of primaquine, it can be discontinued 1 week after departure from a malaria-endemic area. All travellers need to be evaluated for G6PD deficiency before primaquine is initiated. Although not a first-line chemoprophylactic agent, primaquine may be considered an alternative chemoprophylactic agent (with attention to contraindications and precautions) for those without G6PD deficiency when other regimens are either inappropriate
or contraindicated.

P. vivax and P. ovale parasites can persist in the liver and cause relapses for as long as 5 years after departure from a malaria-endemic area. Since most malarial areas of the world (except Haiti and the Dominican Republic) have at least one species of relapsing malaria, travellers to these areas have some risk of acquiring either P. vivax or P. ovale, although actual risk for an individual traveller is difficult to define. Primaquine decreases the risk of relapses by acting against the liver stages of P. vivax and P. ovale. Primaquine terminal prophylaxis is administered after the traveller has left a malaria-endemic area, usually during or after the last 2 weeks of chemoprophylaxis. Terminal prophylaxis with primaquine is generally indicated only for people who have had prolonged exposure in malaria-endemic regions (e.g., long-term travellers or expatriates)(74). None of the other currently recommended chemoprophylaxis
regimens will prevent relapses due to P. vivax and P. ovale.

In order to reduce the risk of relapse following the treatment of symptomatic P. vivax or P. ovale
infection, primaquine is indicated to provide "radical cure". Primaquine should be initiated for radical cure after chloroquine therapy has been completed and the acute febrile illness is over (about 1 to 2 weeks). P. vivax isolates with a decreased responsiveness to primaquine are well documented in Southeast Asia and, in particular, Papua New Guinea and Papua (Irian Jaya)(126). On the basis of increasing numbers of reports of resistance to primaquine at the standard dose of 0.25 mg/kg, the recommended dose for radical cure has been increased to 30 mg (0.5 mg/kg) of primaquine base daily for 14 days in Oceania and South-East Asia(126).

Adverse effects, contraindications and precautions

Primaquine is generally well tolerated but may cause nausea and abdominal pain, which can be decreased by taking the drug with food. More importantly, primaquine may cause methemoglobinemia and oxidant-induced hemolytic anemia, particularly among individuals with G6PD deficiency, which is more common in those of Mediterranean, African and Asian ethnic origin. As well, those receiving > 15 mg base/day have a greater risk of hemolysis. Therefore, all individuals should have their G6PD level measured before primaquine therapy is initiated.

Primaquine is contraindicated in patients with severe G6PD deficiencies. In mild variants of G6PD deficiency, primaquine has been used safely at a lower dose for radical cure to prevent P. vivax and P. ovale relapses (0.8 mg base/kg weekly; adult dose 45 mg base weekly for 8 weeks); however, this reduced dose is insufficient for chemoprophylactic activity. When used at prophylactic doses (0.5 mg base/kg daily) in children and men with normal G6PD activity, mean methemoglobin rates (5.8%) were below those associated with toxicity (> 10%). Patients should be advised to stop their medication and report to a physician immediately if jaundice, gray skin or abnormally dark or brown urine is noted.

Primaquine use is contraindicated in pregnancy. P. vivax or P. ovale infections occurring during
pregnancy should be treated with standard doses of chloroquine (Table 6). Relapses can be prevented by weekly chemoprophylaxis with choloroquine until after delivery, when primaquine can be safely used for mothers with normal G6PD levels. However, primaquine should only be used in nursing mothers if the infant has been tested and found not to be G6PD deficient.

List of projects which provides the project name, the project lead and the current status.
Primaquine: evidence-based medicine recommendations EBM rating
Primaquine (30 mg base daily) is an effective chemoprophylactic agent with a protective efficacy of 85% to 93% against both P. Falciparum and P. vivax infections; it is recommended when the first-line agents mefloquine, doxycycline and atovaquine/proguanil cannot be used or in the prophylaxis of P. vivax or P. ovale malaria, when there is no G6PD deficiency(216, 218). A I
Parenteral quinine is the alternative drug for the treatment of severe or complicated malaria when parenteral artesunate is not available(126). B I

Other Drugs Not Available Or Not Routinely Recommended in Canada (in alphabetical order)

It is important for travellers and providers to understand that the medical management of malaria in countries where the disease is endemic may differ significantly from management in Canada. In countries where malaria is endemic there may be a limited number of effective medications available for treatment; indeed, some of the drugs used may be ineffective in non-immune travellers or be associated with unacceptable adverse outcomes. As well, the level of health care available in some of these countries may put travellers at risk of other infectious diseases(145,146).

Amodiaquine is a 4-aminoquinoline that was first introduced as an alternative to chloroquine. Resistance to this drug has followed the path of chloroquine resistance. Bone marrow toxicity and hepatotoxicity have been noted when it is used for malaria prophylaxis. Amodiaquine is not recommended for malaria chemoprophylaxis.

Azithromycin (Zithromax™) is a macrolide antimicrobial that inhibits the parasite apicoplast. Azithromycin has been shown to not be very effective in the prevention of P. alciparum malaria. Studies performed to date indicate that azithromycin is less effective than atovaquone/proguanil, doxycycline, mefloquine or primaquine. There is insufficient evidence to recommend azithromycin as an alternative antimalarial except under circumstances in which other, more effective and safer, medications are not available or are contraindicated.

Azithromycin is considered to be safe in pregnancy and for children, and is available in suspension. However, in view of the serious consequences of malaria in pregnancy and in young children, use of this suboptimal antimalarial would not routinely be recommended.

Halofantrine is a phenanthrene methanol derivative related to mefloquine and quinine. It is available only in an oral formulation, which is limited by variable bio-availability. Halofantrine is not licensed in Canada and has been withdrawn from the world market because of concerns about cardiotoxicity. It does remain widely available in the tropics, and travellers should be made aware of the danger of this drug. The WHO has reported cardiac deaths associated with the use of halofantrine and no longer recommends its use.

Piperaquine is a bisquinoline antimalarial drug that was first synthesised in the 1960s and used extensively in China for malaria prophylaxis and treatment for about 20 years. With the development of piperaquine resistant strains of P. Falciparum and the emergence of the artemisinin derivatives, its use declined during the 1980s. However, in the 1990s piperaquine
was rediscovered by Chinese scientists as one of a number of compounds suitable for combination with an artemisinin derivative. Recent Indochinese studies have confirmed the excellent clinical efficacy of piperaquine-DHA combinations (28-day cure rates > 95%) and have demonstrated that currently recommended regimens are not associated with significant adverse effects. The pharmacokinetic properties of piperaquine have also been characterized recently, revealing that it is a highly lipid-soluble drug with a large volume of distribution at steady state, long elimination half-life and a clearance that is markedly higher in children than in adults. The tolerability, efficacy, pharmacokinetic profile and low cost of piperaquine make it a promising partner drug for use as part of artemisinin-based combination treatments(150).

Proguanil should not be used as a single agent for chemoprophylaxis(219). Proguanil is well tolerated. Although oral aphthous ulcerations are not uncommon, they are rarely severe enough to warrant discontinuing this medication. Proguanil is considered safe during
pregnancy and breast-feeding, but insufficient drug is excreted in the milk to protect a nursing infant.

Pyrimethamine alone (Daraprim®) is not recommended for malaria chemoprophylaxis because of widespread drug resistance in Asia and Africa and evidence of some resistance in Haiti(219, 220).

Pyrimethamine-sulfadoxine (Fansidar®) is a fixed drug combination antimetabolite that inhibits parasite folate synthesis. Historically, this drug has been used for treatment, including self-treatment, of P. Falciparum, but increasing resistance means it has limited utility for the treatment of P. Falciparum and is no longer recommended. Resistance has been reported in the Amazon Basin, Southeast Asia, and increasingly throughout Africa.

Pyrimethamine-sulfadoxine is not recommended by CATMAT, CDC or WHO for chemoprophylaxis because of the life-threatening complication of Stevens-Johnson syndrome and toxic epidermal necrolysis.

Pyronaridine is a benzonaphthyridine synthesized in China in 1970, which has been used for the treatment of P. vivax and P. Falciparum for more than 20 years and has been shown to be effective in the treatment of Falciparum malaria in children in Cameroon. It has more gastrointestinal side effects than chloroquine. Pyronaridine has been used in combination with the artemisinin derivatives in the treatment of Falciparum malaria(221).

Savarine: Weekly chloroquine plus daily proguanil (Saverine®) is less efficacious than atovaquone/ proguanil, doxycycline or mefloquine and is not routinely recommended for prevention of malaria in Canadian travellers(77, 214, 222, 223). Tafenoquine is a long-acting, 8-aminoquinoline with a half-life measured in weeks rather than hours. Initial research has shown efficacy with weekly chemoprophylaxis and evidence of causal prophylaxis. Studies
are ongoing in semi- and non-immune individuals. In the future, tafenoquine may provide another option for chemoprophylaxis in those without G6PD deficiency(224, 225).

Tafenoquine is a long-acting, 8-aminoquinoline with a half-life measured in weeks rather than hours. Initial research has shown efficacy with weekly chemoprophylaxis and evidence of causal prophylaxis. Studies are ongoing in semi- and non-immune individuals. In the future, tafenoquine may provide another option for chemoprophylaxis in those without G6PD deficiency(224, 225).

List of projects which provides the project name, the project lead and the current status.
Evidence-based medicine EBM rating
Azithromycin has been shown to not be very effective in the prevention of P. Falciparum malaria(226). E II
Amodiaquine is not recommended for malaria chemoprophylaxis because if its established risks of fatal hepatic or bone marrow toxicity(203, 216, 227). D III
Halofantrine has been associated with cardiac toxicity and should not be used as an antimalarial(203, 216). Travellers should be forewarned, as it may still be available in some countries. D III
Piperaquine tolerability, efficacy, pharmacokinetic profile and low cost make it a promising partner drug for use as part of an artemisinin-based combination treatment(228). B II
Pyrimethamine alone (Daraprim®) is not recommended for malaria hemoprophylaxis because of widespread antifolate drug resistance(219). D III
Proguanil should not be used as a single agent for chemoprophylaxis because of widespread drug resistance(229). D III
Pyrimethamine-sulfadoxine (Fansidar®) is not recommended for chemoprophylaxis because of the life-threatening complication of Stevens-Johnson syndrome and toxic epidermal necrolysis(203, 229). E III
Pyronaridine has received insufficient study to recommend its use for the treatment of malaria in non-immune travellers. D III
Savarine is less effective than mefloquine, doxycycline and atovaquone/proguanil and is not routinely recommended for malaria prophylaxis(77, 220, 223). EII
Tafenoquine shows promise for future use as a long duration chemoprophylactic in those without G6PD deficiency(224, 225). B II

Table 5: Base/salt equivalents of selected antimalarial drugs
Drug Base (mg) Salt (mg)
a Not available in Canada. b Intramuscular preparation should not be used intravenously.
Chloroquine phosphate 155.0 250.0
Chloroquine phosphatea 100.0 136.0
Clindamycin hydrochloride 150.0 225.0
Mefloquine 250.0 274.0
Primiquine 15.0 26.3
Quinidine gluconate 5.0 8.0
7.5 12.0
10.0 16.0
15.0 24.0
Quinidine sulfateb 7.5 9.0
10.0 12.0
15.0 18.0
Quinine dihydrochloride 5.0 6.0
7.5 9.0
15.0 18.0
16.7 20.0
Quinine sulfate 250.0 300.0

Table 6: Drugs for the treatment and prevention of malaria
Drug, generic (trade) name Indication
ATOVAQUONE/ PROGUANIL (ATQ/PG) (Malarone®) (Malarone® Pediatric) Prevention and treatment of P. Falciparum
* Glucose-6-phosphate dehydrogenase
** Suggested mixing instructions: to make 120 mL solution of concentration 8.3 mg base/mL combine 60 mL Orasweet and 60 mL Oraplus with 6 x 200 mg tablets of crushed quinidine sulfate
Adult dosage Pediatric dosage Advantage Disadvantage Adverse effects
Adult tablet: 250 mg atovaquone plus 100 mg proguanil hydrochloride
Prevention: 1 tablet daily; start one day before entering malarial area and continue for 7 days after leaving malarial area

Treatment: 1000 mg atovaquone AND 400 mg proguanil (4 tablets) once daily x 3 days
Pediatric tablets 62.5 mg atovaquone plus 25 mg proguanil hydrochloride
Adult tablet: 250 mg atovaquone plus 100 mg proguanil hydrochloride
Prevention: start 1 day before entering malarial area and continue for 7 days after leaving area;
< 11 kg: see Chapter 4
11-20 kg: 1 pediatric tablet daily
> 20-30 kg: 2 pediatric tablets daily (as single dose)
> 30-40 kg: 3 pediatric tablets daily (as single dose)
> 40 kg: 1 adult tablet daily Treatment: 20 mg/kg atovaquone AND 8 mg/kg proguanil once daily x 3 days;
< 11 kg: see Chapter 4 (based on a pediatric tablet of 62.5 mg atovaquone/25 mg proguanil, the daily doses are 2 pediatric tablet for 5 to 8 kg, and 3 pediatric tablet for > 8
to 10 kg)
11-20 kg: 1 adult tablet daily
>20-30 kg: 2 adult tablets daily
>30-40 kg: 3 adult tablets daily
> 40 kg: 4 adult tablets daily
Causal prophylaxis - only have to continue for 7 days after exposure Daily dosing for prophylaxis Frequent:
Nausea, vomiting, abdominal pain, diarrhea, increased transaminases

Rare:
Seizures, rash, mouth ulcers, hepatitis
Drug, generic (trade) name Indication
ARTESUNATE Vial 110 mg powder and vial buffered diluent Treatment of severe and complicated malaria
Adult dosage Pediatric dosage Advantage Disadvantage Adverse effects
Treatment:
2.4 mg/kg at hours 0, 12, 24 and 48 with possible doses daily for total of 7 days if concurrent doxycycline, atovaquone/ proguanil of clindamycin are not tolerated
Treatment:
2.4 mg/kg at hours 0, 12, 24, 48 and 72 with possible doses daily for total of 7 days if concurrent doxycycline, atovaquone/proguanil of clindamycin are not tolerated
Faster response than parenteral quinine; no cardiovascular or hypoglycemic effects Requires concurrent therapy with second drug  
Drug, generic (trade) name Indication
CHLOROQUINE (Novo-Chloroquine) Tablet: 155 mg base Prevention and treatment in chloroquinesensitive P. Falciparum areas Treatment of P. vivax, P. ovale, P. malariae
Adult dosage Pediatric dosage Advantage Disadvantage Adverse effects
Prevention: 310 mg base once weekly;
start 1 week before entering malarial area and continue for 4 weeks after leaving area Treatment:
Loading dose of 620 mg base, followed by 310 mg base 6 hours later. This is followed by 310 mg base on each of the next 2 days for a total of 1.55 g base
Prevention: once weekly dose, start 1 week before entering malarial area and continue for 4 weeks after leaving area
< 15 kg: 5 mg base/kg
15-<20 kg: one half tablet (125mg
chloroquine diphosphate)
20-<25 kg: ¾ tablet (187.5mg)
25-<35 kg: 1 tablet (250 mg)
35-50 kg: 1½ tablets (375 mg)
> 50 kg: 2 tablets (500 mg)
Treatment: 25 mg base/kg total over 3
days: 10 mg base/kg on days one and
two, 5 mg base/kg on day 3
Long-term
safety data for
prophylaxis
Most areas now
report chloroquine
resistance
Frequent:
Pruritis in blackskinned
individuals, nausea, headache

Occasional: Skin eruptions, reversible corneal opacity

Rare: Nail and mucous membrane discoloration, partial alopecia, photophobia, nerve deafness, myopathy, retinopathy with daily use, blood dyscrasias, psychosis and seizures
Drug, generic (trade) name Indication
CLINDAMYCIN (Dalacin C®, Apo-Clindamycin, Novo-Clindamycin) Alternative treatment for P. Falciparum
with a second drug if standard therapy contraindicated
Adult dosage Pediatric dosage Advantage Disadvantage Adverse effects
Prevention:
no indication
Treatment oral:
300 mg base every
6 hrs for 7 days
Treatment IV:
10 mg/kg (loading
dose) IV followed
by 5 mg/kg every
8 hours for 7 days
until oral therapy is
tolerated.
NOTE: Should
only use if patient
is unable to take
doxycycline or
ATQ/PG
Prevention: no indication
Treatment oral: 5 mg base/kg every 6
hours for 7 days
Treatment IV: 10 mg/kg (loading
dose) IV followed by 5 mg/kg every 8
hours for 7 days until oral therapy is
tolerated.
NOTE: Should only use if patient is
unable to take doxycycline or ATVPG
Safe in
pregnancy and
young children
Lower efficacy
than atovaquone/
proguanil alone or
combination of
doxycycline plus
quinine
Frequent: Diarrhea,
rash

Occasional:
Pseudomembranous
colitis

Rare: Hepatotoxicity,
blood dyscrasias
Drug, generic (trade) name Indication
DOXYCYCLINE (Vibra-TabsTM, Apo-Doxy, Doxycin, Novo-Doxylin, Nu-Doxycycline, ratio-Doxycycline) Prevention and treatment of chloroquineresistant
P. Falciparum
Adult dosage Pediatric dosage Advantage Disadvantage Adverse effects
Prevention: 1 tablet
(100 mg) once
daily; start 1 day
before entering
malarial area and
continue for 4
weeks after leaving
area
Treatment: 1 tablet
(100 mg) twice
daily for 7 days
Prevention:
< 25 kg or < 8 yr: contraindicated
Start 1 day before entering malarial area and continue for 4 weeks after leaving area
2 mg base/kg once daily (max 100 mg daily)
25-35 kg: 50 mg daily
> 35 kg-50 kg: 75 mg daily
> 50 kg: 100 mg daily
Treatment:
< 25 kg or < 8 yr: contraindicated 2 mg base/kg twice daily (max. 200 mg daily)
25-35 kg: 50 mg twice daily
> 35-50 kg: 75 mg twice daily
> 50 kg: 100 mg twice daily for 7 days
Protection
against
leptospirosis
Daily dosing
required for
chemoprophylaxis
Frequent:
Gastrointestinal upset, vaginal candidiasis, photosensitivity

Occasional: Azotemia in renal diseases

Rare: Allergic reactions, blood dyscrasias, esophageal ulceration
Drug, generic (trade) name Indication
HYDROXYCHLOROQUINE (Plaquenil, Apo- Hydroxyquine, Gen- Hydroxychloroquine) Tablet: 155 mg base Prevention and treatment in chloroquinesensitive
P. Falciparum areas Treatment of P. vivax,
P. ovale, P. malariae
Adult dosage Pediatric dosage Advantage Disadvantage Adverse effects
Prevention: 310 mg base once weekly;
start 1 week before entering malarial area and continue for 4 weeks after leaving area
Treatment:
Loading dose of 620 mg base, followed by 310 mg base 6 hours later. This is followed by 310 mg base on each of the next 2 days for a total of 1.55 g base
Prevention: 5 mg base/kg once weekly; maximum 310 mg base weekly; start 1 week before entering malarial area and continue for 4 weeks after leaving area
Treatment: Total dose of 25 mg base/kg over 3 days: 10 mg base/kg (not to exceed 620 mg base) on days 1 and 2, 5 mg base/kg on day 3
Long-term
safety data for
prophylaxis
Most areas now
report chloroquine
resistance
Frequent:
Pruritis in blackskinned individuals, nausea, headache

Occasional:
Skin eruptions, reversible corneal opacity

Rare:
Nail and mucous membrane discoloration, partial alopecia, photophobia, nerve deafness, myopathy, retinopathy with daily use, blood dyscrasias, psychosis and seizures
Drug, generic (trade) name Indication
MEFLOQUINE (Lariam®, Apo- Mefloquine) Prevention of P. Falciparum
Adult dosage Pediatric dosage Advantage Disadvantage Adverse effects
Prevention:
Start at least 1 week (preferably 2-3 weeks) before departure and continue for 4 weeks after leaving malarial area Loading dose - see text 250 mg once weekly
Treatment: not routinely recommended, see text
Prevention: Start at least 1 week (preferably 2-3 weeks) before departure and continue for 4 weeks after leaving malarial area Loading dose - see see text 5 mg/kg once weekly < 5 kg: no data.
See Chapter 4
5-10 kg: 1/8 tablet
> 10-20 kg: ¼ tablet
> 20-30 kg: ½ tablet
> 30-45 kg: ¾ tablet
> 45 kg: 1 tablet

Treatment:
not routinely recommended, see text
Weekly dosing
Long-term
safety data
There have been occasional publicized cases of severe intolerance to mefloquine, which may result in increased concern. If mefloquine is the best choice but concern is expressed, consider either a loading dose or start 3 weeks before departure to test for tolerability - see Chapter 9 Frequent:
Dizziness, headache, sleep disorders, nightmares, nausea, vomiting, diarrhea

Occasional:
Sensory and motor neuropathies, seizures, abnormal coordination, confusion, hallucinations, forgetfulness, emotional problems, including anxiety, aggression, agitation, depression, mood changes, panic attacks, psychotic or paranoid reactions, restlessness

Rare:
Suicidal ideation and suicide (relation to drug administration not established)
Drug, generic (trade) name Indication
PRIMAQUINE (Primaquine phosphate) Prevention of chloroquineresistant P. Falciparum
Terminal prophylaxis for P. vivax and P. ovale
Radical cure for P. vivax and P. ovale infections
Adult dosage Pediatric dosage Advantage Disadvantage Adverse effects
Prevention:
Primary
prophylaxis 30 mg
base daily.
Start 1 day before entering malarial area and continue for 7 days after leaving area Terminal prophylaxis or radical cure: 30 mg base/day for 14 days
Prevention:
Primary prophylaxis 0.5 mg base/ kg daily.
Start 1 day before entering malarial area and continue for 7 days after leaving area
Terminal prophylaxis or radical cure:
0.5 mg base/kg daily for 14 days
Causal prophylaxis - only have to continue for 7 days after exposure Daily dosing Require G6PD* testing, see text Occasional:
GI upset, hemolysis in G6PD deficiency, methemoglobinemia
Drug, generic (trade) name Indication
QUINIDINE GLUCONATE/ SULFATE  
Adult dosage Pediatric dosage Advantage Disadvantage Adverse effects
Prevention:
no indication
Treatment:
see Table 4
Prevention: no indication
Treatment: see Table 4- 28 mg base/kg daily, divided q 8 hourly.**
  Parenteral therapy requires cardiac monitoring Frequent:
Vomiting, cramps, cinchonism (tinnitus, nausea, headache, blurred vision)

Occasional:
Widening of QRS complex, cardiac disturbance, fever, delirium, rashes

Rare: Acute hemolytic anemia
Drug, generic (trade) name Indication
QUININE DIHYDROCHLORIDE  
Adult dosage Pediatric dosage Advantage Disadvantage Adverse effects
Prevention:
no indication
Treatment:
See Table 4
Prevention: no indication
Treatment: See Table 4
    Frequent:
Cinchonism (tinnitus, nausea, headache, blurred vision), hypoglycemia

Occasional:
Cardiac conduction disturbances, hypersensitivity

Rare: Hemolysis
Drug, generic (trade) name Indication
QUININE SULPHATE (Novo-Quinine®,
Apo-Quinine, Quinine-Odan)
 
Adult dosage Pediatric dosage Advantage Disadvantage Adverse effects
Prevention:
no indication
Treatment oral:
500 mg base 3 times daily for 3-7 days (7 days for SE Asia) IV: See Table 4
Prevention: no indication
Treatment oral: 7.5 mg base/kg (max 500 mg base) 3 times daily for 3-7 days (7 days for SE Asia)
IV: See Table 4
    Similar to above

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