VA Class:AP101
Mefloquine, a 4-quinolinemethanol derivative and quinine analog, is an antimalarial agent.1,2,3,7,161
Mefloquine is used for prevention of malaria caused by Plasmodium falciparum or P. vivax .1,2,50,51,54,62,63,64,105,115,121,130,134 Mefloquine also is used for the treatment of uncomplicated malaria caused by mefloquine-susceptible P. falciparum or P. vivax .1,2,134,143,144
Mefloquine is used for prevention or chemoprophylaxis of malaria caused by P falciparum (including chloroquine-resistant P. falciparum ) or P. vivax .1,2,50,51,54,62,63,64,105,115,121,130,134 Mefloquine has been designated an orphan drug by the US Food and Drug Administration (FDA) for prevention of P. falciparum malaria resistant to chloroquine or other antimalarials.56
The risk of acquiring malaria varies substantially from traveler to traveler and from region to region (even within a single country) because of differences in the intensity of malaria transmission within the various regions and the season, itinerary, duration, and type of travel.115,121 Malaria transmission occurs in large areas of Africa, Central and South America, parts of the Caribbean, Asia (including South Asia, Southeast Asia, and the Middle East), Eastern Europe, and the South Pacific.115 Although mosquito avoidance and protective measures against mosquito bites alone may be sufficient in areas where malaria occurs only sporadically and the risk for infection is considered low in travelers, malaria prevention in other areas involves chemoprophylaxis in addition to the usual mosquito avoidance and protective measures.115 Mosquito avoidance measures are important since no drug is 100% effective in preventing malaria.115,121 The choice of antimalarial for chemoprophylaxis depends on the traveler's risk of acquiring malaria in the area(s) visited, the risk of exposure to drug-resistant P. falciparum , other medical conditions (e.g., pregnancy), cost, and potential adverse effects.115,121,134
Although chloroquine has historically been considered the drug of choice for prevention of malaria in travelers to areas where chloroquine-resistant P. falciparum malaria has not been reported,121,134 chloroquine-resistant P. falciparum has now been confirmed in all areas with P. falciparum malaria, except the Caribbean, Central America west of the Panama Canal, and some countries in the Middle East.115 The US Centers for Disease Control and Prevention (CDC) and other experts state that options for prevention of malaria in travelers to malarious areas with chloroquine-susceptible P. falciparum include chloroquine (or hydroxychloroquine), the fixed combination of atovaquone and proguanil hydrochloride (atovaquone/proguanil), doxycycline, or mefloquine;115,121,134 primaquine phosphate may be an option in some cases (especially for travelers to areas with a high incidence of P. vivax malaria), provided the individual is not glucose-6-phosphate dehydrogenase (G-6-PD) deficient.115,121,134 Although travelers on long-term trips may prefer the convenience of the once-weekly regimen of chloroquine (or hydroxychloroquine), short-term travelers may prefer the shorter once-daily regimens of atovaquone/proguanil or primaquine.115 In addition, atovaquone/proguanil, doxycycline, or primaquine is a good choice for last-minute travelers since chemoprophylaxis with these drugs is started 1-2 days before travel whereas chloroquine, hydroxychloroquine, or mefloquine chemoprophylaxis must be started 1-2 weeks before travel.115
For prevention of malaria in individuals traveling to malarious areas where chloroquine-resistant P. falciparum has been reported, the CDC and other experts recommend atovaquone/proguanil, doxycycline, or mefloquine.50,51,54,55,61,62,105,113,115,121,134
For prevention of malaria in individuals traveling to malarious areas where mefloquine resistance has been confirmed (e.g., areas bordering Thailand and Burma [Myanmar] or Thailand and Cambodia, western provinces of Cambodia, eastern states of Burma on the border between Burma and China, along the borders of Laos and Burma, the adjacent parts of the Thailand-Cambodia border, southern Vietnam), the CDC and other experts recommend atovaquone/proguanil or doxycycline.115,121
Because malaria infection in pregnant women can be severe and can increase the risk of adverse pregnancy outcomes (e.g., prematurity, abortion, stillbirth) and since no drug is 100% effective in preventing malaria, women who are pregnant or likely to become pregnant should avoid travel to areas where malaria transmission is possible.115 Use of a chemoprophylaxis regimen is essential for pregnant women who cannot avoid travel to areas with malaria.115 Although chloroquine can be used for prevention of malaria in pregnant women traveling to areas where chloroquine-resistant P. falciparum malaria has not been reported, the CDC states that mefloquine is the drug of choice for prevention of malaria in women who are pregnant, or likely to become pregnant, if exposure to chloroquine-resistant P. falciparum is unavoidable.115 (See Pregnancy under Cautions: Pregnancy, Fertility, and Lactation.)
Because mefloquine is active only against the asexual erythrocytic forms of Plasmodium (not exoerythrocytic stages), it cannot prevent delayed primary attacks or relapse of P. ovale or P. vivax malaria and cannot provide a radical cure in malaria caused by these species.1,2,34,115 Therefore, terminal prophylaxis with a 14-day regimen of primaquine phosphate may be indicated in addition to mefloquine prophylaxis if travelers were exposed in areas where P. ovale or P. vivax is endemic.1,2,34,64,115 (See Primaquine Phosphate 8:30.08.)
Travelers to countries with malaria should be instructed to seek prompt medical attention as soon as possible if they develop symptoms of malaria (e.g., fever with influenza-like symptoms such as chills, headache, myalgias, malaise) while traveling or after return (especially during the first 2 months).115,121 Malaria symptoms can develop as early as 7 days after initial exposure or can appear months after departure from a malarious area, after chemoprophylaxis is discontinued.115 Travelers should understand that malaria can be effectively treated early in the course of the disease, but that delays before initiation of therapy can have serious or even fatal consequences.115
Information on the risk of malaria transmission in specific countries, information on mosquito avoidance measures, recommendations regarding whether chemoprophylaxis of malaria is indicated, and information on the choice of antimalarials for prevention of malaria is available from the CDC at [Web] and [Web].115
Results of clinical studies and clinical experience have demonstrated that mefloquine 250 mg once weekly for 6 to longer than 24 weeks provides total or near total (more than 90% efficacy) protection against mefloquine-susceptible falciparum or vivax malaria in adults not previously exposed to infection with the parasite (nonimmune population).2,50,54,63,64,113,128,130 Clinical experience indicates that long-term prophylaxis with mefloquine is effective and usually well tolerated, although serious adverse effects have been reported rarely.50,64,113,115,138 The dosage regimen appears to be an important consideration in providing adequate protection; administration of mefloquine 250 mg once weekly is substantially more effective in preventing the development of malarial infection than administration of mefloquine 250 mg once every 2 weeks.2,50,51
Presumptive Self-treatment of Malaria
Travelers who elect not to take chemoprophylaxis for prevention of malaria and travelers who require or choose to use a chemoprophylaxis regimen that may not have optimal efficacy (e.g., chloroquine prophylaxis in areas with chloroquine-resistant P. falciparum ) are at increased risk of acquiring malaria and may need prompt treatment.115 In addition, some travelers who are taking effective prophylaxis but who will be in very remote areas may decide, in consultation with their health-care provider, to take along an appropriate antimalarial that can be used for presumptive self-treatment if necessary.115,134
The antimalarial regimen provided for presumptive self-treatment should be different than the regimen that the traveler is using for prophylaxis.134 Travelers should be advised to initiate self-treatment promptly in the event of an influenza-like illness (e.g., fever, chills) if professional medical care is not readily available.115,134 Use of presumptive self-treatment is only a temporary measure and these travelers should be advised to seek medical advice as soon as possible.115
For presumptive self-treatment of malaria in travelers, the CDC and other experts recommend atovaquone/proguanil or the fixed combination of artemether and lumefantrine (artemether/lumefantrine).105,115,134 Mefloquine is not included in current CDC recommendations for presumptive self-treatment of malaria.115
Treatment of Uncomplicated Malaria
Mefloquine is used for the treatment of uncomplicated malaria caused by mefloquine-susceptible P. falciparum (including chloroquine-resistant P. falciparum ) or P. vivax .1,2,134,143,144 Mefloquine has been designated an orphan drug by the FDA for the treatment of malaria caused by P. falciparum or P. vivax .56
For the treatment of uncomplicated malaria caused by chloroquine-resistant P. falciparum or the treatment of uncomplicated malaria when the plasmodial species has not been identified, the CDC recommends atovaquone/proguanil, artemether/lumefantrine, or a regimen that includes quinine sulfate in conjunction with doxycycline, tetracycline, or clindamycin.143,144 Mefloquine is another option for treatment in these patients;143,144 however, because mefloquine used in treatment dosages has been associated with rare, but serious, adverse effects (e.g., potentially severe neuropsychiatric reactions), the CDC recommends that it be used only when other recommended treatment regimens cannot be used.143 In addition, because of concerns related to resistance, mefloquine is not recommended for the treatment of malaria acquired in Southeast Asia.144
For the treatment of uncomplicated malaria caused by chloroquine-susceptible P. falciparum , P. malariae , or P. knowlesi or the treatment of uncomplicated malaria when the plasmodial species has not been identified and the infection was acquired in areas where chloroquine resistance has not been reported, the CDC recommends chloroquine (or hydroxychloroquine).143,144 Alternatively, the CDC states that any of the regimens recommended for the treatment of uncomplicated chloroquine-resistant P. falciparum malaria may be used if preferred, more readily available, or more convenient.143,144
For the treatment of uncomplicated malaria caused by chloroquine-resistant P. vivax , the CDC recommends a regimen of quinine sulfate and doxycycline (or tetracycline) given in conjunction with primaquine, atovaquone/proguanil given in conjunction with primaquine, or mefloquine given in conjunction with primaquine.143,144 Because quinine sulfate, doxycycline (or tetracycline), atovaquone/proguanil, and mefloquine are active only against the asexual erythrocytic forms of Plasmodium (not exoerythrocytic stages), a 14-day regimen of primaquine is indicated to prevent delayed primary attacks or relapse and provide a radical cure whenever any of these drugs is used for treatment of P. vivax or P. ovale malaria.1,2,34,115,143,144 (See Primaquine Phosphate 8:30.08.)
Pediatric patients with uncomplicated malaria generally can receive the same treatment regimens recommended for adults using age- and weight-appropriate drugs and dosages.143,144 For the treatment of uncomplicated chloroquine-resistant P. falciparum in children younger than 8 years of age, the CDC recommends atovaquone/proguanil or artemether/lumefantrine; mefloquine can be considered if no other options are available.144 For the treatment of chloroquine-resistant P. vivax malaria in children younger than 8 years of age who should not receive tetracyclines, the CDC recommends mefloquine given in conjunction with primaquine.143,144 Alternatively, if mefloquine is not available or not tolerated and if potential benefits outweigh risks, atovaquone/proguanil or artemether/lumefantrine can be used for treatment of chloroquine-resistant P. vivax in this age group.143,144
Pregnant women with uncomplicated malaria caused by P. malariae , P. vivax , P. ovale , or chloroquine-susceptible P. falciparum should receive prompt treatment with chloroquine (or hydroxychloroquine).143 The CDC recommends that pregnant women with uncomplicated malaria caused by chloroquine-resistant P. falciparum receive prompt treatment with either mefloquine or a regimen of quinine sulfate and clindamycin;143 mefloquine is recommended for those with uncomplicated malaria caused by chloroquine-resistant P. vivax .143 (See Pregnancy under Cautions: Pregnancy, Fertility, and Lactation.) Alternatively, atovaquone/proguanil or artemether/lumefantrine can be considered for the treatment of uncomplicated malaria caused by chloroquine-resistant P. falciparum in pregnant women when other treatment options are not available or not tolerated and if potential benefits outweigh risks.143 Pregnant women with P. vivax or P. ovale malaria should be maintained on chloroquine prophylaxis for the duration of the pregnancy and should receive primaquine after delivery to provide a radical cure.143,144
Patients with severe malaria require aggressive antimalarial treatment with a parenteral regimen of IV quinidine gluconate in conjunction with doxycycline, tetracycline, or clindamycin initiated as soon as possible after the diagnosis.143,144 (See Uses: Malaria, in Quinidine 24:04.04.04.)
Assistance with diagnosis or treatment of malaria is available by contacting the CDC Malaria Hotline at 770-488-7788 or 855-856-4713 from 9:00 a.m. to 5:00 p.m. Eastern Standard Time or the CDC Emergency Operation Center at 770-488-7100 after hours and on weekends and holidays.143,144
Response rates of 90-100% have been reported in clinical studies in children and adults with mefloquine-susceptible P. falciparum malaria following administration of a single dose of mefloquine hydrochloride 750-1500 mg or 15-25 mg/kg.2,128,129 In these studies, mefloquine treatment was associated with parasite clearance within 41-94 hours, resolution of fever within 28-67 hours, and improvement in other signs of malaria infection such as splenomegaly and hepatomegaly; the incidence of recrudescence was low (less than 8%).2 In areas of Thailand where multiple-drug resistant plasmodium are endemic, mefloquine dosages of 25 mg/kg have been associated with better clinical and parasitologic responses compared with dosages of 15 mg/kg.2,68,69 Retreatment with mefloquine has been associated with a high failure rate (44% by day 42) and increased incidence of adverse CNS effects.69,70,128
Mefloquine has been used in conjunction with artesunate (not commercially available in the US as single entity or in fixed combination with mefloquine) for the treatment of uncomplicated P. falciparum malaria in areas where malaria is endemic.71,72,128,148,149,161 Artemisinin-based combination therapy (ACT), including artesunate and mefloquine, has been highly effective for the treatment of malaria148,149,161 and is recommended by the World Health Organization (WHO) for treatment of uncomplicated P. falciparum malaria in countries where the disease is endemic.161 Such regimens reduce malaria transmission in these areas and may delay or prevent emergence of resistance to the drugs contained in the combination regimen.148,149,161
Because falciparum malaria is the most prevalent form of malaria, data on efficacy of mefloquine in nonfalciparum malaria are limited.1,2,67 While efficacy of mefloquine in the treatment of malaria caused by P. vivax has been established,1,2,67 limited clinical data in patients with malaria caused by P. malariae or P. ovale indicate that mefloquine also is effective in these types of malaria.1,2,128
Mefloquine hydrochloride is administered orally with ample water (at least 8 oz [240 mL] of water for an adult).1
The drug should not be administered on an empty stomach.1
If a patient receiving mefloquine for the treatment of malaria vomits within 30 minutes after receiving a dose of the drug, another full dose should be administered as a replacement; if a patient vomits within 30-60 minutes after receiving a dose, 50% of the dose should be administered as a replacement.1 If vomiting recurs, the patient should be monitored closely and alternative malaria treatment considered if improvement is not observed within a reasonable period of time.1
For administration in children and others who are unable to swallow tablets, mefloquine hydrochloride tablets may be crushed and mixed with a small amount of liquid (e.g., water, milk, other beverage).1,129
When mefloquine hydrochloride doses less than 125 mg (less than one-half of a 250-mg tablet) are indicated for pediatric patients, gelatin capsules containing the calculated pediatric dosage should be prepared extemporaneously by a pharmacist using a crushed tablet.115,134
A mefloquine hydrochloride medication guide has been developed to help individuals understand the risks of malaria, risks and benefits of taking mefloquine to prevent malaria, and the rare but potentially serious adverse effects associated with use of the drug.1 As required by law, a copy of the mefloquine medication guide must be supplied to patients each time mefloquine is dispensed for prevention of malaria;1 an information wallet card also is supplied to the patient when the drug is dispensed.1
In the US, dosage of mefloquine hydrochloride is expressed in terms of the salt.1 Each 250-mg tablet of mefloquine hydrochloride commercially available in the US is equivalent to 228 mg of mefloquine base.1 Other formulations (e.g., 275-mg mefloquine hydrochloride tablets containing 250 mg of the base) may be available in other countries.134,161
Dosage of mefloquine hydrochloride in children is based on body weight.1
Mefloquine hydrochloride prophylaxis should be initiated 1-2 weeks prior to entering a malarious area and continued during and for 4 weeks after leaving the area.1,105,115,121,134 The CDC recommends that mefloquine prophylaxis be initiated at least 2 weeks before travel.115 Some clinicians state that it may be advisable to initiate mefloquine prophylaxis 3-4 weeks prior to travel to ensure that the drug or combination of drugs (in individuals receiving other drugs) is well tolerated and to allow ample time to change to another antimalarial if necessary.1,105,115,134
Because mefloquine cannot prevent delayed primary attacks or relapse of Plasmodium ovale or P. vivax malaria and cannot provide a radical cure in malaria caused by these species, terminal prophylaxis with primaquine phosphate may be indicated if exposure to malaria occurred in areas where P. ovale or P. vivax is endemic.115 Primaquine terminal prophylaxis should be given during the final 2 weeks of mefloquine prophylaxis or, if that is not feasible, it should be given for 14 days after primary prophylaxis is discontinued.115 (See Primaquine Phosphate 8:30.08.)
For prevention or chemoprophylaxis of malaria in adults, the recommended dosage of mefloquine hydrochloride is 250 mg once weekly given on the same day each week, preferably after the main meal.1,115,121,134
For prevention or chemoprophylaxis of malaria in pediatric patients weighing 45 kg or less, the recommended dosage of mefloquine hydrochloride is approximately 5 mg/kg once weekly given on the same day each week, preferably after the main meal.1
For prevention or chemoprophylaxis of malaria, children weighing more than 19 kg up to 30 kg should receive mefloquine hydrochloride in a dosage of 125 mg (one-half of a 250-mg tablet) once weekly; children weighing more than 30 kg up to 45 kg should receive 187.5 mg (three-fourths of a 250-mg tablet) once weekly; and children weighing more than 45 kg should receive the usual adult dosage (250 mg once weekly).1,115,121
Although only limited data are available regarding use of mefloquine hydrochloride in children weighing less than 20 kg (especially those weighing less than 5 kg),1,121 the US Centers for Disease Control and Prevention (CDC) and other experts state that those weighing 9 kg or less can receive a dosage of 5 mg/kg (extemporaneously prepared and dispensed by a pharmacist) once weekly and those weighing more than 9 kg up to 19 kg may receive 62.5 mg (one-fourth of a tablet; extemporaneously prepared and dispensed by a pharmacist) once weekly for prevention or chemoprophylaxis of malaria.115,121 (See Dosage and Administration: Administration.)
Treatment of Uncomplicated Malaria
If a patient with malaria does not respond to mefloquine treatment within 48-72 hours, an alternative antimalarial should be given; mefloquine should not be used for retreatment.1
Because mefloquine cannot prevent relapse of P. ovale or P. vivax malaria, a 14-day regimen of primaquine is indicated to provide a radical cure whenever mefloquine is used for the treatment of malaria caused by these species.134,143,144 (See Primaquine Phosphate 8:30.08.)
For the treatment of uncomplicated malaria caused by mefloquine-susceptible P. falciparum or P. vivax , the manufacturer recommends that adults receive 1250 mg of mefloquine hydrochloride (five 250-mg tablets) given as a single dose.1 The CDC and other experts recommend that adults receive a 2-dose regimen of mefloquine hydrochloride that involves an initial 750-mg oral dose (three 250-mg tablets) followed by a 500-mg oral dose (two 250-mg tablets) given 6-12 hours after the initial dose (total dose of 1250 mg).134,144
For the treatment of uncomplicated malaria caused by mefloquine-susceptible P. falciparum , the manufacturer recommends that children receive mefloquine hydrochloride in a dosage of 20-25 mg/kg and states that dividing the dosage into 2 doses given 6-8 hours apart may reduce the incidence and severity of adverse effects.1 The CDC and other experts recommend that children receive a 2-dose regimen of mefloquine hydrochloride that involves an initial dose of 15 mg/kg followed by 10 mg/kg given 6-12 hours after the initial dose (total dose of 25 mg/kg).134,144
Pediatric dosage should not exceed the usual adult dosage (1250 mg).1,144 Only limited data are available regarding use of mefloquine hydrochloride in children weighing less than 20 kg (especially those weighing less than 5 kg).1,121
Dosage in Renal and Hepatic Impairment
The manufacturer makes no specific recommendations regarding the need for dosage adjustment in individuals with renal impairment.1 When mefloquine is used for malaria prophylaxis, limited data indicate that dosage adjustment is not necessary in individuals undergoing hemodialysis.1,49
The manufacturer makes no specific recommendations regarding the need for dosage adjustment in individuals with hepatic impairment.1 Pharmacokinetic data indicate that elimination of mefloquine may be prolonged and plasma concentrations may be increased in patients with impaired hepatic function.1 (See Other Precautions and Contraindications under Cautions: Precautions and Contraindications.)
Although results of clinical studies and extensive clinical experience indicate that mefloquine generally is well tolerated, serious adverse effects have been reported rarely.1,2,50,61,74,75,76,103,113,129,130,131,132,138 Unlike primaquine phosphate, hemolytic anemia does not occur if mefloquine is administered to patients with glucose-6-phosphate dehydrogenase (G-6-PD) deficiency.1 In addition, mefloquine does not appear to share the phototoxic potential of certain other 4-quinolinemethanol derivatives.30,52
The most frequently reported adverse effects of mefloquine are nausea, vomiting, loose stools or diarrhea, abdominal pain, dizziness or vertigo, loss of balance, and neuropsychiatric events such as headache, somnolence, and sleep disorders (insomnia, abnormal dreams).1,2,50,51,61,63,76,113,138 Occasionally, more severe neuropsychiatric disorders have been reported.1 Adverse effects may occur shortly after mefloquine is initiated and some effects (e.g., dizziness or vertigo, tinnitus and hearing impairment, loss of balance, neuropsychiatric effects) may persist for several months or years following discontinuance of the drug and may be permanent in some cases.1 (See Cautions: Nervous System Effects.)
During postmarketing surveillance, adverse effects reported when mefloquine was used for prophylaxis of malaria were similar to those reported when the drug was used for the treatment of malaria.1 In one study in US Peace Corps volunteers in sub-Saharan Africa, adverse effects were reported in 44% of individuals who received mefloquine for less than 4 months and in 19% of those who received the drug for longer than 1 year.2,50 In this study, less than 1% of individuals discontinued mefloquine prophylaxis because of adverse effects.50
The most frequently reported adverse nervous system effects associated with mefloquine include dizziness,1,2,50,51,54,61,63,64,68,69,75,76,77,78,98,101,103 headache,1,2,61,62,63,64,75,77,103 and insomnia.1,2,50,51,54,61,63,64,75,76,77,101 The incidence of dizziness is dose-related, occurring more frequently in patients receiving mefloquine dosages of 25 mg/kg than in those receiving 15 mg/kg.69,74,76 Dizziness has been reported in about 40% of children receiving mefloquine for the treatment of acute malaria.1,129 Other adverse nervous system effects include abnormal dreams,1,50,51,61,64,70 altered consciousness,70,76 forgetfulness,1 motor and sensory neuropathy,1 seizures,1,18,62,64,74,78,84,85,88,113 vertigo,1,62,103 and tinnitus and hearing impairment.1 Some of these adverse nervous system effects (e.g., dizziness or vertigo, tinnitus and hearing impairment, loss of balance) may occur shortly after mefloquine is initiated and have been reported to continue for months or years after mefloquine was discontinued and may be permanent in some cases.1 (See Precautions and Contraindications Related to Nervous System Effects under Cautions: Precautions and Contraindications.)
Severe neuropsychiatric disorders have been reported occasionally with mefloquine,1,63,78,86 including sensory and motor neuropathies (paresthesia, tremor, ataxia),1 agitation or restlessness,1 anxiety,1 depression,1 mood changes,1 panic attacks,1 impaired memory,1 confusion,1 hallucinations,1 aggression,1 psychotic or paranoid reactions,1 and encephalopathy.1 Suicidal ideation and suicide have been reported in patients receiving mefloquine.1,74
Other serious adverse neurologic and psychiatric effects reported in patients receiving mefloquine include depressive or bipolar (manic-depressive) reactions,74,80,113 psychotic reactions,61,62,74,78,79,81,82,87,89 acute brain syndrome,74,83 central anticholinergic syndrome,90 and toxic encephalopathy.1,74 Serious CNS effects during mefloquine therapy have been reported in about 1:1200 Asians and 1:200 Caucasians or Africans; serious CNS effects have been reported in about 1:10,000 of those receiving mefloquine prophylaxis.75
While the precise mechanism of serious neurologic and psychiatric reactions has not been determined,74,75,113 risk factors for these adverse CNS effects may include dosage, concomitant drug use, history of a CNS event, and severity of the malaria infection.74,75,125 Analysis of data compiled by an international database indicates that serious adverse effects are associated with higher mefloquine dosages than are nonserious effects, averaging 1637 and 1085 mg, respectively; however, the relationship between these adverse effects and plasma mefloquine concentrations has not been established.2,74,75
In addition to dose-related adverse CNS effects, concomitant administration of other antimalarials or severity of malarial infection may contribute to the incidence and severity of neuropsychiatric effects in patients receiving mefloquine.75,125 Limited evidence indicates that concomitant administration of quinine sulfate or chloroquine may increase the severity of mefloquine-associated CNS effects.75 However, adverse CNS effects observed in patients receiving another antimalarial agent (e.g., quinine sulfate) concomitantly may reflect severity of the illness and greater cerebral pathology associated with severe disease rather than drug-related adverse effects.75
Patients with epilepsy or a history of seizures who have received mefloquine prophylaxis appear to be at increased risk of this adverse effect,1 although seizures have occurred in those without such a history.2,64,74,75,78,128 Of 26 reports of seizure in patients receiving mefloquine prophylaxis, 7 occurred after the first dose, 11 patients recovered within 2 days of drug discontinuance, and most patients recovered within several days to 1 month.74 Of 9 patients who continued mefloquine after the initial seizure episode, 7 experienced a subsequent episode of seizures.74
Serious depression or bipolar (manic-depressive) reactions characterized by suicidal ideation, mania, and/or panic; depression accompanied by agitation, anxiety, and restlessness; and depression with psychotic features (e.g., hallucinations and delusions) have occurred in patients receiving mefloquine prophylaxis.74 Of 12 such cases, 5 had a personal or family history of depression or other psychiatric disorder.74,78 However, 3 individuals with no history of psychiatric disorder attempted suicide.74 Neuropsychiatric manifestations usually were apparent at about 9.5 days (range: 1-17 days), and generally became more intense (but did not take longer to resolve) in patients who continued mefloquine prophylaxis after the first manifestation.74 Serious psychotic reactions with typical features such as hallucinations, delusions, or paranoia also have occurred with mefloquine prophylaxis.74 These reactions have been accompanied by additional manifestations such as depression, aggression, anxiety, agitation, or suicidal ideation in some patients.1,74 In some patients, initial manifestations developed between day 1 and day 120, the recovery period ranged from 5 days to 7 months, and those who continued mefloquine after the initial manifestations did not experience more intense symptoms or delayed recovery.74
Fatigue/weakness,1,50,51,64,68,77 malaise,1 myoclonus,64 irritability,61,64 paresthesia,2,77,91 and asthenia1 also have been reported in patients receiving mefloquine. Toxic encephalopathy was reported in at least one patient receiving prophylaxis with the drug; however, a causal relationship between encephalopathy and mefloquine has not been established.1,74
A post-malaria neurologic syndrome (PMNS) has occurred infrequently in patients receiving mefloquine.125,128 Neuropsychiatric manifestations of this syndrome commonly include acute confusional state or acute psychosis; many patients also exhibit generalized seizures with or without acute confusional state.125 In one study, manifestations of the syndrome developed within a median of 78 hours (range: 11 hours to 22.4 days) after completion of antimalarial therapy, persisted for a median of 60 hours, and resolved without sequelae.125 While many patients also were receiving other antimalarials, the development of PMNS appeared to be associated with mefloquine use.125 A relationship between plasma mefloquine concentrations and any particular neuropsychiatric effect could not be shown.125
Adverse GI effects,54,61,78 including nausea,1,2,50,51,62,63,64,67,68,69,77,101,103 vomiting,1,2,18,68,69,76,77,100,101,103,129 diarrhea,1,2,50,51,62,64,68,69,76,77,100,101 abdominal pain,1,2,62,64,100,101,103 dyspepsia,1 and loss of appetite,1,68,69,77,103 occur frequently in patients receiving mefloquine.1,2 Vomiting has been reported in 3% of individuals receiving mefloquine for malaria prophylaxis.1 Nausea and vomiting have occurred in 10 and 20%, respectively, of children receiving the drug for the treatment of acute malaria,1 and children 6 years of age or younger experience early vomiting (within 1 hour of drug administration) more frequently than patients 7-50 years of age.18,68,70,76 Vomiting and diarrhea shortly after drug administration are associated with reduced oral bioavailability of mefloquine and with treatment failure.2,76,129
Mefloquine is a myocardial depressant and, while the effect of the drug on the compromised cardiovascular system has not been evaluated, transitory and clinically important silent ECG alterations have been reported in patients receiving the drug.1,2 Bradycardia1,2,76,94 has been reported in up to 50% of patients receiving mefloquine dosages of 750-1250 mg; these rhythm changes generally resolved within 42 days.2,94 Extrasystoles,1,2 reversible sinus arrhythmia,2,94,100 first-degree atrioventricular (AV) block,1 and other transient cardiac conduction alterations1,2,94,98 also have been reported. Prolongation of the corrected QT (QTc) interval and abnormal T waves have been reported.1 (See Other Precautions and Contraindications under Cautions: Precautions and Contraindications.)
Hypertension,1 hypotension,1 flushing,1 syncope,1 chest pain,1 tachycardia,1 palpitations,1,62,77,98 and irregular pulse1 have been reported in patients receiving mefloquine. Cardiopulmonary arrest,1 pericarditis,2 cardiovascular collapse,2 and myocardial infarction2 have been reported rarely.1,2
Rash,1,2,64,95,96 pruritus,1,2,63,96,103 exanthema,1 erythema,1 alopecia,1,2 telogen effluvium (loss of resting hair),1 or urticaria1,2,68,76 has occurred in patients receiving mefloquine. Serious cutaneous reactions, including Stevens-Johnson syndrome,1,2,93,99 erythema multiforme,1,2 and cutaneous vasculitis,97 have been reported rarely.1,2
Visual disturbances have been reported infrequently with mefloquine.1,50,63,64,77,103 Because certain other quinoline derivatives have exhibited phototoxic effects,30,52 the possibility that mefloquine could share this potential and possibly manifest as ocular toxicity should be considered.1,30,52 (See Other Precautions and Contraindications under Cautions: Precautions and Contraindications.)
Although ocular toxicity attributable to mefloquine has not been documented in patients receiving the drug to date,1,52 additional long-term experience is needed to elucidate whether such a relationship exists.52 Long-term studies (2 years) in rats using mefloquine dosages up to 30 mg/kg daily have revealed evidence of dose-related ocular lesions.1,52 Ocular lesions (i.e., retinal degeneration, retinal edema, lens opacity) were observed in both eyes of all surviving rats fed mefloquine 30 mg/kg daily; similar but less severe lesions were observed in 80% of female and 22% of male rats fed mefloquine 12.5 mg/kg daily, and corneal lesions only were observed in 9% of rats fed 5 mg/kg daily.1
Muscle weakness,1 muscle cramps,1 myalgia,1 arthralgia,1 fever,1 sweating,1 chills,1 and mouth ulcers63,78 have been reported with mefloquine. In addition, cholestasis,2 increased bilirubin,2 hepatitis,2 dyspnea,1,2 and allergic or interstitial pneumonitis2 have occurred rarely in patients receiving mefloquine.
Agranulocytosis1 and aplastic anemia1,92 have been reported in patients receiving mefloquine.1 Laboratory abnormalities observed in patients with acute malaria and possibly attributable to mefloquine include decreased hematocrit,1 transient elevation in transaminase values,1 leukopenia,1 and thrombocytopenia.1 Laboratory abnormalities observed occasionally in individuals indigenous to malaria-endemic areas receiving mefloquine prophylaxis include transient elevations in transaminase values,1 leukocytosis,1 and thrombocytopenia.1
Precautions and Contraindications
Mefloquine is contraindicated in patients hypersensitive to the drug, structurally related drugs (e.g., quinine, quinidine), or any ingredient in the formulation.1
Mefloquine is contraindicated for prevention or chemoprophylaxis of malaria in individuals with active depression, recent history of depression, generalized anxiety disorder, psychosis, schizophrenia, or other major psychiatric disorders.1 (See Precautions and Contraindications Related to Nervous System Effects under Cautions: Precautions and Contraindications.)
Mefloquine is contraindicated in individuals with a history of seizures.1 (See Precautions and Contraindications Related to Nervous System Effects under Cautions: Precautions and Contraindications.)
Precautions and Contraindications Related to Nervous System Effects
Patients receiving mefloquine should be advised that dizziness or vertigo, loss of balance, tinnitus, and other central or peripheral nervous system effects have occurred in patients receiving mefloquine and that such effects may persist for months or years after the drug is discontinued and may be permanent in some cases.1 If such symptoms occur, patients should be cautioned to avoid activities requiring alertness and fine motor coordination (e.g., driving, piloting aircraft, operating machinery, deep-sea diving).1 (See Cautions: Nervous System Effects.)
Patients receiving mefloquine should be advised that neuropsychiatric manifestations ranging from severe anxiety, paranoia, and depression to hallucinations and psychotic behavior have occurred in patients receiving mefloquine and that these manifestations may occur shortly after mefloquine is initiated and can persist for months or years after the drug has been discontinued.1 Neuropsychiatric manifestations such as acute anxiety, depression, restlessness, or confusion occurring in a patient receiving mefloquine prophylaxis suggest a risk for more serious psychiatric events or adverse neurologic effects.1
Mefloquine should not be used for prevention or chemoprophylaxis of malaria in any individual with active depression, a recent history of depression, generalized anxiety disorder, psychosis, schizophrenia, or other major psychiatric disorders1 and should be used with caution in individuals with a previous history of depression.1
Neuropsychiatric effects can occur in adults or children and may be particularly difficult to identify in children.1 Patients receiving mefloquine for prolonged periods should be periodically evaluated for neuropsychiatric effects.1 Vigilance is required to monitor for such manifestations, especially in nonverbal children.1
Patients receiving mefloquine for malaria prevention should be advised to discontinue the drug and contact their clinician if neurologic effects (e.g., dizziness or vertigo, loss of balance) or neuropsychiatric manifestations (e.g., acute anxiety, depression, restlessness or confusion, suicidal ideation) occur.1 An alternative antimalarial should be substituted.1
Because mefloquine may increase the risk of seizures in patients with epilepsy, such patients should not receive mefloquine for prevention or chemoprophylaxis of malaria and should receive the drug for treatment of malaria only if there are compelling medical reasons for its use.1
Selection and Use of Antimalarials
Oral antimalarials, including mefloquine, should not be used for initial treatment of severe malaria.1,143 In the event of life-threatening, serious, or overwhelming malaria, aggressive treatment with a parenteral antimalarial regimen is necessary.1,143,144 (See Treatment of Uncomplicated Malaria under Uses: Malaria.)
Mefloquine should not be used for treatment of malaria in patients who received the drug for chemoprophylaxis of malaria.1
Because of the increased incidence of adverse effects and high failure rate, mefloquine should not be used for retreatment in patients who did not respond to or were previously treated with the drug.1,69,70
Concomitant or sequential use of mefloquine and some other antimalarials (e.g., chloroquine, quinine, quinidine, halofantrine [not commercially available in the US]) or certain other drugs (e.g., ketoconazole) may increase the risk of potentially fatal prolongation of the QTc interval and/or may increase the risk for seizures.1,135,147 (See Drug Interactions.)
Other Precautions and Contraindications
The manufacturer states that the benefits of mefloquine should be weighed against the risks of adverse effects in patients with cardiac disease;1 some experts state that mefloquine should not be used in patients with cardiac conduction abnormalities.105,115,128,134 (See Cautions: Cardiovascular Effects.)
Ophthalmologic examinations should be performed periodically in patients receiving mefloquine for prolonged periods.1 Although retinal abnormalities reported with long-term use of chloroquine have not been observed in individuals receiving mefloquine, dose-related ocular lesions (i.e., retinal degeneration, retinal edema, lenticular opacity) have been observed in rats receiving mefloquine in long-term feeding studies.1 (See Cautions: Ocular Effects.)
Liver function should be evaluated periodically in patients receiving mefloquine for prolonged periods.1 The elimination of mefloquine may be prolonged and plasma concentrations increased in patients with hepatic impairment, resulting in an increased risk of adverse effects. 1
Safety and efficacy of mefloquine for the treatment of malaria in children younger than 6 months of age have not been established.1 Only limited data are available regarding use of mefloquine for prevention or treatment of malaria in children weighing less than 20 kg (especially those weighing less than 5 kg).1,121
Children of any age can contract malaria, and the indications for prophylaxis and treatment of malaria in children are the same as those for adults.22,100,101,102,105,113,128,129 Because of the risks associated with malaria infection in children younger than 6 weeks of age or weighing less than 5 kg, some experts recommend that parents of such infants be advised not to travel to countries with endemic malaria.105
The US Centers for Disease Control and Prevention (CDC) states that mefloquine may be considered for prevention or chemoprophylaxis of malaria in infants and children of any age, depending on the risk of exposure to drug-resistant Plasmodium .115
Use of mefloquine for the treatment of acute uncomplicated malaria caused by P. falciparum in children is supported by evidence from adequate and well-controlled studies in adults and published open-label and comparative studies in children younger than 16 years of age.1,100,101,102
While mefloquine generally is well tolerated in children, those 6 years of age or younger experience early vomiting (within 1 hour of drug administration) more frequently than individuals 7-50 years of age.18,68,70,76 Early vomiting has been cited as a possible cause of treatment failure in some children.1 If a replacement dose is not tolerated (see Dosage and Administration: Administration), the child should be monitored closely and alternative malarial treatment considered if the child does not improve within a reasonable period of time. 1
While clinical studies of mefloquine did not include sufficient numbers of patients 65 years of age and older to determine whether geriatric patients respond differently than younger patients, other clinical experience has not revealed age-related differences in response.1
Because mefloquine therapy is associated with ECG abnormalities, the greater frequency of cardiac disease observed in the elderly should be considered and the benefit of mefloquine therapy should be weighed against the possibility of adverse cardiac effects in geriatric individuals.1
Mutagenicity and Carcinogenicity
Mefloquine was not mutagenic in several assays (with and without prior metabolic activation) including the microbial (Ames) test, host-mediated assay in mice, fluctuation tests, and mouse micronucleus assay.1
No evidence of carcinogenic potential was observed in rats or mice fed mefloquine dosages up to 30 mg/kg daily for 2 years.1,30
Pregnancy, Fertility, and Lactation
The manufacturer states that mefloquine should be used during pregnancy only when clearly needed and that women of childbearing potential should be advised to use effective contraceptive measures while receiving mefloquine and for up to 3 months after the last dose of the drug.1
The CDC and American Academy of Pediatrics (AAP) state that mefloquine is the drug of choice for prevention of malaria in women who are pregnant, or likely to become pregnant, if exposure to chloroquine-resistant P. falciparum is unavoidable.105,115 In addition, the CDC states that mefloquine is a drug of choice for the treatment of uncomplicated malaria caused by chloroquine-resistant P. falciparum or chloroquine-resistant P. vivax in pregnant women.143,144 (See Uses: Malaria.)
Published data on use of mefloquine for prevention or treatment of malaria during pregnancy, including data from randomized controlled trials, intervention trials, prospective and retrospective cohort studies, and case series, have not shown an increased risk of teratogenic effects or adverse pregnancy outcomes compared to the background rate in the general population.1 These data include more than 700 exposures to mefloquine in the first trimester of pregnancy and over 2,000 exposures in the second and third trimesters.1 However, mefloquine was teratogenic in mice, rats, and rabbits when given in dosages that were similar to those used for the treatment of malaria (based on body surface area comparisons).1 CNS effects (e.g., exencephaly, hydrocephaly, partially missing medulla oblongata) and craniofacial malformations were observed in all 3 species.1 Mefloquine also was embryotoxic in mice and rabbits at these dosages.1
Adverse fetal or pregnancy outcomes were not indicated in a double-blind study and clinical experience that included women who received mefloquine during the second and third trimesters.102,103,104,113,115,136 In addition, the frequencies of spontaneous abortion and congenital malformations in 1133 women exposed to mefloquine during the first trimester of pregnancy (more than 95% received mefloquine for prophylaxis) were within expected background rates, and the abnormalities did not fit a specific pattern and would be difficult to attribute to a single pathogenic mechanism.113,126,136 Data from a study evaluating the relationship between use of mefloquine for the treatment of malaria during pregnancy and pregnancy outcome indicate that mefloquine exposure during pregnancy was not associated with an increased incidence of abortion, low birthweight, neurologic retardation, or congenital malformations; however, mefloquine exposure was associated with a greater risk of stillbirth than exposure to other antimalarials, including quinine.136
There was no evidence of deleterious effects on human spermatozoa in adult men who received mefloquine in a dosage of 250 mg once weekly for 22 weeks.1
Fertility studies in rats given mefloquine dosages of 5, 20, or 50 mg/kg daily have demonstrated adverse effects on fertility in males given 50 mg/kg daily and in females given 20 or 50 mg/kg daily.1 Histopathologic lesions were noted in the epididymides from male rats given mefloquine 20 or 50 mg/kg daily.1,30
Small amounts of mefloquine are distributed into breast milk.1,2,102,107 In one study in a limited number of women, approximately 3-4% of a single 250-mg mefloquine dose was distributed into breast milk.1,2,107 Following administration of a single 250-mg dose of the drug in one woman, mefloquine concentrations in breast milk at 4 and 56 days were 53 and 32 ng/mL, respectively.107
The manufacturer states that mefloquine should be used with caution in nursing women.1 Because the amount of mefloquine consumed by a nursing infant is likely to be small, some clinicians suggest that the risk to nursing infants of maternal use of prophylactic dosages of mefloquine is low.2,102,107,115,128 However, the amount of mefloquine present in breast milk is insufficient to provide adequate protection against malaria in the nursing infant and, if chemoprophylaxis is necessary, such infants should receive recommended dosages of an appropriate antimalarial.102,115,128
Interactions between mefloquine and many other drugs, including cardiac drugs, have not been systematically evaluated.1,2 When mefloquine is used for prevention or chemoprophylaxis of malaria in travelers, possible effects of mefloquine on other drugs these individuals are receiving (especially anticoagulants and antidiabetic agents) should be assessed prior to departure.1
Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes
Because mefloquine is metabolized by cytochrome P-450 (CYP) isoenzyme 3A4, concomitant use with drugs that inhibit or induce CYP3A4 may affect mefloquine pharmacokinetics.1 Concomitant use with CYP3A4 inhibitors may increase mefloquine concentrations and increase the potential for adverse effects associated with the drug.1 Concomitant use with CYP3A4 inducers may decrease mefloquine concentrations and potentially could decrease efficacy of the antimalarial.1 Therefore, mefloquine should be used with caution in patients receiving CYP3A4 inhibitors or inducers.1
Because mefloquine does not inhibit or induce CYP isoenzymes, drug interactions are not expected if mefloquine is used concomitantly with drugs that are substrates for CYP isoenzymes.1
Drugs Affecting the P-glycoprotein Transport System
Mefloquine is a substrate for and an inhibitor of P-glycoprotein.1 Although the clinical importance is not known, pharmacokinetic interactions are possible if mefloquine is used concomitantly with drugs that are substrates for or are known to modify expression of this transporter. 1
Drugs Affecting the QT Interval
Concomitant use with other drugs that alter cardiac conduction, including antiarrhythmic agents, β-adrenergic blocking agents, calcium-channel blocking agents, antihistamines, tricyclic antidepressants, and phenothiazines, may increase the risk of prolongation of the QT interval.1
Concomitant use of mefloquine and an anticonvulsant (e.g., valproic acid, carbamazepine, phenobarbital, phenytoin) may decrease plasma concentrations of the anticonvulsant resulting in reduced seizure control.1,2,74 The manufacturer states that mefloquine is contraindicated in patients with a history of seizures.1 (See Cautions: Precautions and Contraindications.) If mefloquine is used in an individual receiving an anticonvulsant, plasma concentrations of the anticonvulsant should be monitored and dosage adjusted as necessary.1
Concomitant use of mefloquine (single 500-mg dose) and ketoconazole (400 mg once daily for 10 days) in healthy adults increased the mean peak plasma concentration and area under the plasma concentration-time curve (AUC) of mefloquine by 64 and 79%, respectively, and increased the mean elimination half-life of mefloquine from 13.4 days to 18.7 days.1
Because of the risk of potentially fatal prolongation of the QTc interval, ketoconazole should not be used concomitantly with mefloquine or within 15 weeks after the last mefloquine dose.1
Administration of the fixed combination of artemether and lumefantrine (artemether/lumefantrine) 12 hours after mefloquine in healthy adults decreased the peak plasma concentration and AUC of lumefantrine compared with administration of artemether/lumefantrine alone;145,146 the pharmacokinetics of artemether and mefloquine were not affected.145,146 Because this pharmacokinetic interaction may occur as the result of reduced absorption of lumefantrine secondary to a mefloquine-induced decrease in bile production,145 patients who receive artemether/lumefantrine shortly after mefloquine should be monitored for decreased efficacy and encouraged to take artemether/lumefantrine with food.145
Chloroquine, Quinine, and Quinidine
Concomitant use of mefloquine and other related antimalarials (e.g., chloroquine, quinine, quinidine) may result in potentially serious ECG abnormalities, including prolonged QT interval corrected for rate (QTc), and may increase the risk for torsades de pointes or other serious ventricular arrhythmias.1,147 Concomitant use may also increase the risk of seizures.1,147
In healthy adults who received 750 mg of oral mefloquine 24 hours before receiving 600 mg of oral quinine sulfate, the AUC of mefloquine was increased by 22% compared with that observed in those who received mefloquine alone and the QTc interval was prolonged to a clinically important extent.147
Mefloquine should not be used concomitantly with quinine or quinidine134 and these drugs should be used sequentially with caution.134 Because mefloquine has a long terminal elimination half-life (see Pharmacokinetics: Elimination), quinine or quinidine therapy for treatment of severe malaria should be initiated with caution in patients who were receiving mefloquine for prophylaxis.134 If quinidine gluconate is being initiated for the treatment of severe malaria in a patient who received mefloquine within the preceding 12 hours, a loading dose of quinidine gluconate should not be used.144 (See Quinidine 24:04.04.04.) If quinine, quinidine, or chloroquine is used for initial treatment of severe malaria, mefloquine should not be administered for follow-up treatment until at least 12 hours after the last dose of any of these drugs.1
Use of halofantrine (not commercially available in the US) after mefloquine has resulted in potentially fatal prolongation of the QTc interval.1,112,135 Because of the risk of a potentially fatal prolongation of QTc interval, halofantrine should not be used concomitantly with mefloquine or within 15 weeks after the last mefloquine dose.1
Concomitant use of mefloquine (single 500-mg dose) and rifampin (600 mg once daily for 7 days) in healthy individuals decreased the mean peak plasma concentration and AUC of mefloquine by 19 and 68%, respectively, and decreased the mean elimination half-life of mefloquine by 63%.1,150
The manufacturer of mefloquine states that rifampin and mefloquine should be used concomitantly with caution.1 Some experts recommend that concomitant use of the drugs be avoided, if possible; these experts state that use of rifabutin (instead of rifampin) or use of an alternative antimalarial should be considered.155
Concomitant use of ritonavir (200 mg twice daily) and mefloquine decreased the AUC of ritonavir, but did not affect the pharmacokinetics of mefloquine.151,155
The effect of concomitant use of mefloquine and ritonavir-boosted human immunodeficiency virus (HIV) protease inhibitors (PIs) is unknown, and some experts recommend that mefloquine be used with caution in patients receiving PIs.155
Concomitant use of mefloquine and quinidine may result in potentially serious ECG abnormalities.1,2 (See Drug Interactions: Antimalarial Agents.)
The manufacturer states that there is the theoretical possibility that use of mefloquine with other drugs that alter cardiac conduction (e.g., antiarrhythmic agents, β-adrenergic blocking agents, calcium channel blocking agents, antihistamines, tricyclic antidepressants, phenothiazines) might result in prolongation of the QTc interval.1 Some clinicians state that mefloquine may be used concomitantly with β-adrenergic blocking agents provided the patient does not have an underlying arrhythmia.134 Cardiopulmonary arrest with full recovery was reported in one individual who received mefloquine and propranolol concomitantly.1
In vitro, mefloquine inhibits the growth of Salmonella typhi , including the Ty21a strain contained in oral typhoid vaccine.108,109,110 There is no evidence that concomitant administration of mefloquine interferes with the immune response elicited by oral Ty21a typhoid vaccine.111 However, because there is potential for interference with the antibody response to typhoid vaccine live oral, the US Public Health Service Advisory Committee on Immunization Practices (ACIP) and American Academy of Pediatrics (AAP) state that vaccination with oral live typhoid vaccine should be delayed for 24 hours after a dose of mefloquine.105,108 In addition, vaccination with oral live typhoid vaccine should be completed at least 3 days before initiating mefloquine prophylaxis. 1,2
Overdosage of mefloquine would be expected to produce more pronounced manifestations of the adverse reactions reported with the drug.1,2 Vertigo, hallucinations, dizziness, nausea, hypotension, tachycardia, and seizures occurred in 2 patients who ingested an overdosage of mefloquine (up to 5250 mg over 5 days).2
If acute mefloquine overdosage occurs, supportive and symptomatic treatment should be initiated and the patient observed closely.1 Cardiac function (preferably using ECG) and neuropsychiatric status should be monitored.1 There is no known antidote for mefloquine overdosage.1
Mefloquine and its main metabolite are not appreciably removed by hemodialysis.1 Hemodialysis and peritoneal dialysis are unlikely to remove substantial amounts of mefloquine from the body,49 and these procedures should not be relied on to enhance elimination of the drug.128
The exact mechanism of antimalarial action of mefloquine has not been established.1,2,3,7 Mefloquine is a blood schizonticidal agent used for suppression and treatment of malaria.1,2,3,7,11,34
The life cycle of malarial parasites involves a sexual reproductive phase which occurs in the mosquito and an asexual reproductive phase which occurs in the human host.2,3,11,34,62 Human infection begins when malarial sporozoites are injected into the bloodstream when a female mosquito bites an individual.2,3,11,34,62 Sporozoites infect liver cells and develop into schizonts, which release merozoites into the bloodstream.2,3,11,34,62 Merozoites invade erythrocytes and divide asexually to form blood schizonts.2,3,11,34,62 After invading an erythrocyte, the growing parasite consumes and degrades intracellular proteins, mainly hemoglobin; the parasite also alters the erythrocyte membrane by changing its transport properties, exposing surface antigens, and inserting new parasite-derived proteins.34 The erythrocyte becomes irregular in shape, more antigenic, and less deformable.2,3,11,34 As the schizont stage parasites complete maturation, they lyse the host erythrocyte, releasing the next generation of merozoites.2,3,11,34,62 Alternatively, some intraerythrocytic parasites differentiate into male and female gametocytes which are available to infect other susceptible mosquitoes.2,3,11,34,62 During the intrahepatic stage, Plasmodium ovale and P. vivax form dormant tissue schizonts (i.e., hypnozoites) which are associated with relapses of malaria.2,3,11,34,62
Mefloquine, like chloroquine and quinine, is a blood schizonticidal agent and is active against the intraerythrocytic stages of parasite development.1,2,3,4,11,62 Similar to chloroquine and quinine, mefloquine appears to interfere with the parasite's ability to metabolize and utilize erythrocyte hemoglobin.2,3,7,11 The antimalarial activity of mefloquine may depend on the ability of the drug to form hydrogen bonds with cellular constituents; results of structure-activity studies indicate that the orientation of the hydroxyl and amine groups with respect to each other in the mefloquine molecule may be essential for antimalarial activity.2,3,16 While the precise mechanism of action of mefloquine is unknown, it may involve mechanisms that differ from those proposed for chloroquine.2,3,7,11
Photoaffinity labeling has been used to identify proteins that interact specifically with mefloquine, and a pathway for accumulation of mefloquine in the malaria parasite has been proposed based on these studies.7,8 Results of photoaffinity studies indicate that mefloquine binds to high-density lipoproteins in serum, specifically polypeptide apo-A, and is delivered to the erythrocytes where it interacts with a specific erythrocyte membrane protein, stromatin, and is then transferred to the intracellular parasite by a pathway used for exogenous phospholipids.7,8,9 Erythrocytes infected with mature-stage malaria parasites accumulate phospholipids from exogenous sources.7,9 Although the molecular mechanism for internalization of exogenous phospholipids is unclear, uptake of exogenous phospholipid molecules appears to be protein-mediated.7,9 While the final target of mefloquine has not been fully characterized, 2 high-affinity mefloquine-binding proteins have been identified in several strains of P. falciparum .7,8 One or both of these proteins may play a role in phospholipid trafficking in malaria-infected erythrocytes.7,9 While further study is needed, mefloquine may exert its antimalarial action by disrupting the membrane trafficking events involved in the uptake of phospholipids.7 Studies are under way to further characterize the mefloquine-binding proteins and the pathway for accumulation of mefloquine within the parasite.7
Like chloroquine and quinine, mefloquine has greater inhibitory activity against the late ring and early trophozoite forms than against the younger ring stages or mature schizont forms.2,10,116,128 Although the clinical importance remains to be determined, quinine and mefloquine produce similar morphologic changes in the early erythrocytic ring stages of P. falciparum and P. vivax .11 The major ultrastructural abnormality produced by mefloquine in P. falciparum is swelling of the parasitic food vacuoles.2,11
Mefloquine is a racemic mixture of the 2 erythro enantiomers (dextrorotatory 11 R ,2' S and levorotatory 11 S ,2' R ).1,2,3,4,6 Potency of the dextro enantiomer of mefloquine against P. falciparum is greater than or equal to that of the levo enantiomer.2,53 The major metabolite (the 4-carboxylic acid derivative) of mefloquine appears to have essentially no activity against P. falciparum .6,12
Mefloquine is a myocardial depressant.1 While mefloquine has cardiovascular effects similar to those of quinidine and quinine, effects associated with mefloquine administration are substantially less pronounced than those associated with quinidine or quinine.1,128 Results of animal studies indicate that parenteral mefloquine possesses 20% of the antifibrillatory action of quinidine and produces 50% of the increase in the PR interval reported with quinine.1 Prolongation of the corrected QT (QTc) interval and abnormal T waves have been reported in patients receiving mefloquine.1 (See Cautions: Cardiovascular Effects.)
Mefloquine is a blood schizonticidal agent1,2,11 and is active against asexual erythrocytic forms of P. falciparum , P. malariae , P. ovale , and P. vivax , including some P. falciparum resistant to chloroquine.2,11,113 Mefloquine is not active against mature gametocytes or against intrahepatic stages of plasmodial development.2,11
Mefloquine is active in vitro against Entamoeba histolytica ,13 and Giardia lamblia .15 Mefloquine also is active in vitro against the larval and adult stages of Brugia patei and B. malayi .14
Resistance to mefloquine can be induced in plasmodia and occurs in areas where mefloquine is used.2,3,7,18,19,20,21,22,113,114,115,152,153 In addition, P. falciparum strains with in vitro resistance to mefloquine have been identified in areas before introduction of the drug (i.e., intrinsic resistance).2,7,23,25,26 The incidence of mefloquine-resistant P. falciparum varies geographically and has been reported predominately in areas in Southeast Asia where multidrug-resistant malaria occurs.1,115 Mefloquine-resistant P. falciparum has been confirmed in areas bordering Thailand and Burma (Myanmar) or Thailand and Cambodia, western provinces of Cambodia, eastern states of Burma on the border between Burma and China, along the borders of Laos and Burma, the adjacent parts of the Thailand-Cambodia border, and southern Vietnam.18,115
Cross-resistance between mefloquine and chloroquine has been reported in P. falciparum and P. vivax in vitro.152,153 Cross-resistance also has been reported between mefloquine and quinine.1 Cross-resistance between mefloquine and halofantrine (an antimalarial not commercially available in the US) has been documented in vitro in P. falciparum .2,24,135
The mechanism of resistance of P. falciparum to mefloquine has not been fully elucidated.2,3,7,11 Genes in the multidrug-resistant (MDR) family may play a role in the resistance of P. falciparum to mefloquine.2,3,7,27 Mefloquine resistance in clinical isolates of P. falciparum appears to correlate with amplification and overexpression of a gene in the MDR family, pfmdr1.3,7,11,27,28,29,119 In addition, selection for mefloquine resistance in vitro is associated with amplification and increased expression of the pfmdr1 gene.3,7,11,27,28,29,119
Mefloquine is a racemic mixture of 2 erythro enantiomers whose rates of release, absorption, transport, action, degradation, and elimination may differ.1,2,4,30,41,42,43,44 Changes in the pharmacokinetics of mefloquine as a result of age, ethnicity, pregnancy, and malarial illness occur, but do not affect dosing regimens.1,2,3,30,36,37,38,45,46 Mefloquine hydrochloride originally was available from the US Army as a tablet formulation that differs from the currently available US commercial formulation.30 Although the relative bioavailabilities of these formulations have not been determined in crossover studies,30 it has been suggested that the currently available formulation probably is better absorbed.30
In the Pharmacokinetics section, dosages and concentrations of mefloquine hydrochloride are expressed in terms of the base.
Mefloquine hydrochloride is slowly absorbed from the GI tract when administered as tablets and appears to undergo little, if any, first-pass elimination; limited data suggest that the drug is absorbed more rapidly and completely when administered as an aqueous suspension compared with tablets.2,30,31,35,36,37 Following administration of single oral mefloquine doses of 250-1250 mg in healthy individuals, peak mefloquine concentrations in blood or plasma are attained within 6-24 hours and appear to be proportional to dose.2,30,31,35,36,37,38,39,40,45 An absorption half-life (t½α) of 0.36-3.8 hours has been reported.1,30,31,35 A parenteral formulation of mefloquine hydrochloride is not available, precluding determination of absolute bioavailability of the drug;30 however, data from a study using radiolabeled drug indicate that the extent of oral absorption following oral administration of single doses as tablets is about 87-89% of that following administration as an oral suspension.2,30,40
Limited evidence indicates that bioavailability of mefloquine is greater when the drug is administered with food than when administered in the fasting state.2,3,49 Following administration of single oral mefloquine doses of 250, 500, 750, or 1000 mg in healthy non-Asian adults, peak blood or plasma concentrations averaged 286, 430, 587, or 966 ng/mL, respectively.2,30,31,35,37,38,39,40 There is some evidence that peak blood or plasma concentrations of mefloquine are substantially higher in Asians than in other ethnic groups.2,30,37,38 Following administration of single oral mefloquine doses of 500 or 750 mg in healthy Asian adults, peak plasma or blood concentrations averaged 1010 or 1401 ng/mL, respectively.2,37,38 The reason for this ethnic variation has not been determined, but may involve differences in the volume of distribution secondary to the relatively lower body fat in Asians or differences in the enterohepatic circulation of mefloquine in Asians.2,40
In healthy white adults receiving 250 mg of mefloquine once weekly (the recommended regimen for prophylaxis), peak plasma concentrations of the drug at steady-state averaged 1680 ng/mL and trough concentrations averaged 1120 ng/mL.4 In this study, peak plasma mefloquine concentrations following the first 250-mg dose averaged 520 ng/mL.4 If 250 mg of mefloquine is administered once weekly, steady-state concentrations are achieved within 8 weeks.47,48,49,54,55 In individuals receiving mefloquine 250 mg once weekly, plasma drug concentrations following administration of the second dose are approximately half of the concentration at steady-state.42
Analysis of clinical studies indicates that blood mefloquine concentrations of about 915 ng/mL are associated with 99% prophylactic antimalarial efficacy, concentrations of 620 ng/mL with 95% efficacy, and concentrations of 462 ng/mL with 90% efficacy.50,51 Mefloquine prophylaxis initiated in the currently recommended regimen 1 week prior to entering the malarious area results in plasma concentrations that have not reached steady-state and may not be fully protective at the time of first possible exposure to malaria; alternative regimens that result in steady-state concentrations at the time of first possible exposure to malaria may be preferred.4,50,51,54,128 Administration of mefloquine 250 mg daily for 3 days results in achievement of steady-state blood concentrations after the third dose.54,55
The pharmacokinetics of mefloquine are stereoselective.1,2,4,30,41,42,43,44 In several studies in healthy Caucasian and Thai adults, peak concentrations and area under the plasma concentration-time curve (AUC) of the levorotatory enantiomer have been substantially higher than values for the dextrorotatory enantiomer.2,4,30,41,42,43,44
Limited data indicate that GI absorption of mefloquine is not reduced substantially in patients with uncomplicated malaria relative to healthy adults, but GI absorption may be incomplete and unreliable in patients with complicated malaria and should not be relied on for cerebral malaria.30,118 Differences in other pharmacokinetic parameters (e.g., volume of distribution, clearance, elimination half-life) have been described for patients with uncomplicated malaria compared with healthy individuals.30,37,40 In several comparative studies in patients with malaria, peak plasma concentrations of mefloquine were higher in patients responding to antimalarial therapy compared with those who did not respond (recrudescent patients), and treatment failure has been associated with reduced bioavailability secondary to vomiting and/or diarrhea.2,36,37,46 In one study, peak blood concentrations and AUC of mefloquine in patients who vomited within 1 hour of receiving a 1250-mg dose of the drug were substantially lower than concentrations in patients who did not vomit or who vomited 3 hours after drug administration.2,36 Because of the high incidence of vomiting associated with administration of mefloquine 1250 mg as a single dose, the incidence of vomiting and pharmacokinetic values were evaluated in patients receiving mefloquine 1250 mg in a divided dosage (750 mg initial dose, followed by 500 mg in 6 hours).45 Results of this study indicate that administration of mefloquine 1250 mg in a divided dosage produces similar mefloquine blood concentrations and is associated with a lower incidence of vomiting compared with administration as a single dose.45 GI absorption of the drug does not appear to be altered substantially during pregnancy.30,104
Following oral administration of a single mefloquine dose of 20 mg/kg (as a suspension) in Thai children 5-12 years of age with uncomplicated falciparum malaria, peak plasma drug concentrations were achieved in 6.6-7.4 hours and averaged 3.66-3.89 mcg/mL.120 In Thai children 6-24 months of age with uncomplicated falciparum malaria, peak drug concentrations were achieved in 12.8 hours and averaged 3.32 mcg/mL following administration of a single oral dose of mefloquine 25 mg/kg (as a suspension).137
Mefloquine is widely distributed into body tissues and fluids.1,2,30,31,37,38,39,45,46,107 The drug has an apparent volume of distribution of 20 L/kg in healthy adults.1,2,31,37,38,39,45,46,49 However, the apparent volume of distribution may be contracted substantially in patients with malaria, including those with uncomplicated disease,30,40 and appears to be expanded during pregnancy.30,104 In healthy Caucasian and Thai adults, the apparent volume of distribution of the dextrorotatory enantiomer has been substantially higher than that reported for the levorotatory enantiomer.4,41 An apparent volume of distribution of mefloquine in Thai children with uncomplicated malaria 6-24 months of age or 5-12 years of age averaged 11.95 or 8.84 L/kg, respectively.120,137
Mefloquine appears to concentrate in erythrocytes to a greater extent than in plasma.1,2,7,8,30,31,33,41,44,122,123 Such concentration of the drug results from high-affinity binding to erythrocytic membranes.30,122,123 Results of one in vitro study showed an erythrocyte to plasma concentration ratio of about 2.1,31,49 In a study in patients with malaria, the erythrocyte to plasma ratios initially (parasitemia of 20%) and 3 days later (parasitemia of 2%) were 4.1 and 1.2, respectively.44 While the magnitude of mefloquine distribution into erythrocytes is sufficient to predict a high blood to plasma ratio and some evidence has shown whole blood concentrations to exceed those in plasma,30,31,33,40 other evidence has shown whole blood and plasma concentrations to be equivalent, indicating that either fluid is suitable for pharmacokinetic determinations.30,33,44,124 This apparent discrepancy may be secondary to the compensating effect of plasma protein binding.33 Whether distribution of mefloquine enantiomers into erythrocytes is stereoselective has not been established, but cannot be excluded.3,41,44 In one study, the concentration of the dextro enantiomer in erythrocytes was twice that in plasma, and the concentration of the levo enantiomer in erythrocytes was 75% of that in plasma.44
Mefloquine is distributed into the CNS.74,83 In a study in male Wistar rats, administration of oral mefloquine for 22 days at the equivalent human therapeutic plasma concentration resulted in CNS penetration with a 30- to 50-fold greater brain-to-plasma drug ratio up to 10 days after the final dose.1 CNS and blood mefloquine concentrations of 1162 and 6719 ng/mL, respectively, were reported in a 4-year old child receiving oral mefloquine 125 mg weekly.74 Following administration of mefloquine 1500 mg, CNS drug concentrations of 50 or 1162 ng/mL were detected in 2 patients with acute brain syndrome.83 However, because GI absorption of the drug may be incomplete and erratic in patients with severe malaria, oral mefloquine therapy should not be relied on for the treatment of CNS infections.128
Small amounts of mefloquine are distributed into breast milk.1,2,102,107 In one study in a limited number of women, about 3-4% of a single 250-mg dose of mefloquine was distributed in breast milk.1,2,107 Following administration of a single 250 mg dose of mefloquine in one woman, drug concentrations in breast milk were 53 and 32 ng/mL on day 4 and 56, respectively.107
Mefloquine is 98% bound to plasma proteins,1,2,3,30,31,33,44,45 and the extent of such binding appears to be similar in healthy adults and patients with malaria.30,40
The metabolic fate of mefloquine in humans has not been fully determined, but the drug is extensively metabolized in the liver by the cytochrome P-450 (CYP) isoenzyme system,1,2,3 probably by CYP3A4.1
Plasma concentrations of the principal metabolite, the 4-carboxylic acid derivative, exceed those of mefloquine.1,3,31,44 In one study in healthy men receiving mefloquine 250 mg weekly, the ratio of mean plasma 4-carboxylic acid metabolite concentration (1470-5550 ng/mL) to plasma mefloquine concentration (560-1250 ng/mL) at steady-state ranged from 2.3-8.6.47
Mefloquine and its metabolites are excreted in feces, with only small amounts (less than 13% combined) appearing in urine.1,2,3,42,48 Mefloquine is thought to undergo biliary excretion and extensive enterohepatic circulation,3,30 and some evidence suggests that enterohepatic circulation and fecal elimination may be increased in patients with malaria compared with those in healthy adults.30 Total clearance of the drug reportedly is about 30 mL/minute,1,31,39 but may be reduced in patients with uncomplicated or severe malaria.30,32,37,40
Mefloquine is slowly eliminated from the body.1,2,3,4,30,31,35,37,38,39,41,42,45,47 The terminal elimination half-life for mefloquine shows considerable interindividual variation, ranging from 13-33 days (mean: 21 days) in healthy adults, and about 10-15 days in patients with uncomplicated malarial infection.1,2,30,31,35,37,38,39,41,42,45,47 The faster elimination in patients with uncomplicated malaria relative to healthy individuals may result from decreased enterohepatic recirculation and resultant increased fecal elimination in such patients.30 In patients with severe malaria, the terminal elimination half-life has been reported to be longer than that in patients with uncomplicated disease, averaging about 20 days in those with severe disease.30,32,45 A terminal elimination half-life for mefloquine of 9.8-10.7 days has been reported in Thai children with uncomplicated malaria 6-24 months of age and 5-12 years of age.120,137 Terminal elimination half-lives for the levorotatory or dextrorotatory enantiomers of 14-22 or 7-8 days have been reported in healthy individuals.4,41,42 The terminal elimination half-life for the 4-carboxylic acid metabolite reportedly is about 20 days in healthy individuals.39
Although alterations in the pharmacokinetics of mefloquine have been documented in pregnant women (e.g., increased mefloquine clearance in late pregnancy),1,2,106 such changes are not considered clinically relevant.1
Mefloquine and its 4-carboxylic acid metabolite are not removed by hemodialysis.49
Mefloquine, a 4-quinolinemethanol derivative, is a synthetic antimalarial agent.1,2,3,7,161 Mefloquine is a 2-aryl substituted analog of quinine.1,2,7
Like quinine and chloroquine, mefloquine is one of several quinoline derivatives known to possess antimalarial activity.7 However, mefloquine and quinine are highly lipophilic, which is thought to contribute to pharmacologic differences between these quinolinemethanol derivatives and the less lipophilic chloroquine, an aminoquinoline derivative.7 Orientation of the hydroxyl and amine groups with respect to each other in the mefloquine molecule may be essential for its hydrogen binding and antimalarial activity.2,3,16,53 Mefloquine contains 2 asymmetric carbon atoms, and the drug is commercially available as a racemic mixture of the 2 erythro enantiomers (dextrorotatory 11 R ,2' S and levorotatory 11 S ,2' R ).1,2,3,4,6 Both enantiomers exhibit antimalarial activity against Plasmodium falciparum , but pharmacokinetic characteristics differ.1,2,4,6,12,30,41,42,43,44 For oral administration, mefloquine is commercially available as the hydrochloride salt.1
Mefloquine hydrochloride occurs as a white to almost white crystalline compound with a bitter taste.1,115 Mefloquine hydrochloride is slightly soluble in water.1 Because of the poor aqueous solubility of the drug, attempts at developing a parenteral formulation were abandoned.30
Mefloquine hydrochloride tablets should be stored at 20-25°C.1 The drug is photolabile52 and should be protected from light.161
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
---|---|---|---|---|
Oral | Tablets | 250 mg* | Mefloquine Hydrochloride Tablets (scored) |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
AHFS® Drug Information. © Copyright, 1959-2024, Selected Revisions March 5, 2014. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
1. Teva Pharmaceuticals. Mefloquine hydrochloride tablets prescribing information. Sellersville, Pa; 2013 Jun.
2. Palmer KJ, Holliday SM, Brogden RN. Mefloquine: a review of its antimalarial activity, pharmacokinetic properties and therapeutic efficacy. Drugs . 1993; 45:430-75. [PubMed 7682911]
3. Tracy JW, Webster LT Jr. Drugs used in the chemotherapy of protozoal infections: malaria. In: Hardman JG, Limbird LE, Molinoff PB et al, eds. Goodman and Gilman's the pharmacological basis of therapeutics. 9th ed. New York: McGraw-Hill; 1995:978-98..
4. Gimenez F, Pennie RA, Koren G et al. Stereoselective pharmacokinetics of mefloquine in healthy Caucasians after multiple doses. J Pharm Sci . 1994; 83:824-7. [PubMed 9120814]
5. Reber-Liske R. Note on the stability of mefloquine hydrochloride in aqueous solution. Bull World Health Organ . 1983; 61:525-7. [PubMedCentral][PubMed 6349842]
6. Basco LK, Gillotin C, Gimenez F et al. In vitro activity of the enantiomers of mefloquine, halofantrine and enpiroline against Plasmodium falciparum . Br J Clin Pharmacol . 1992; 33:517-20. [PubMedCentral][PubMed 1524966]
7. Foley M, Tilley L. Quinoline antimalarials: mechanisms of action and resistance. Int J Parasitol . 1997; 27:231-40. [PubMed 9088993]
8. Desneves J, Thorn G, Berman A et al. Photoaffinity labelling of mefloquine-binding proteins in human serum, uninfected erythrocytes and Plasmodium falciparum-infected erythrocytes. Mol Biochem Parasitol . 1996; 82:181-94. [PubMed 8946384]
9. Berman A, Shearing LN, Ng KF et al. Photoeffinity labeling of Plasmodium falciparum proteins involved in phospholipid transport. Mol Biochem Parasitol . 1994:67:235-43.
10. Geary TG, Divo AA, Jensen JB. Stage specific actions of antimalarial drugs on Plasmodium falciparum in culture. Am J Trop Med Hyg . 1989; 40:240-4. [PubMed 2648881]
11. Krogstad DJ. Plasmodium species (malaria). In: Mandell GL, Bennett JE, Dolin R eds. Mandell, Douglas and Bennett's principles and practice of infectious diseases. 4th ed. New York: Churchill Livingstone; 1995:2415-26.
12. Basco LK, Gillotin C, Gimenez F et al. Absence of antimalarial activity or interaction with mefloquine enantiomers in vitro of the main human metabolite of mefloquine. Trans R Soc Trop Med Hyg . 1991; 85:208-9. [PubMed 1887471]
13. Osisanya JOS. Comparative in vitro activity of mefloquine, diloxanide furoate and other conventionally used amoebicides against entamoeba histolytica. E Afr Med J . 1986; 63:263-8.
14. Walter RD, Wittich RM, Kuhlow F. Filaricidal effect of mefloquine on adults and microfilariae of Brugia patei and Brugia malayi. Trop Med Parsitol . 1987; 38:55-6.
15. Crouch AA, Seow WK, Thong YH. Effect of twenty-three chemotherapeutic agents on the adherence and growth of Giardia lamblia in vitro. Trans R Soc Trop Med Hyg . 1986; 80:893-6. [PubMed 3603639]
16. Karle JM, Karle IL. Crystal structure and molecular structure of mefloquine methylsulfonate monohydrate: implications for a malaria receptor. Antimicrob Agents Chemother . 1991; 35:2238-45. [PubMedCentral][PubMed 1803997]
18. Nosten F, ter Kuile F, Chongsuphajaisiddhi T et al. Mefloquine-resistant falciparum malaria on the Thai-Burmese border. Lancet . 1991; 337:1140-3. [PubMed 1674024]
19. Sowunmi A, Oduola AMJ, Salako LA et al. The relationship between the response of Plasmodium falciparum malaria to mefloquine in African children and its sensitivity in vitro . Trans R Soc Trop Med Hyg . 1992; 86:368-71. [PubMed 1440804]
20. Lambros C, Notsch JD. Plasmodium falciparum : mefloquine resistance produced in vitro . Bull World Health Organ . 1984; 62:433-7. [PubMedCentral][PubMed 6380785]
21. Oduola AMJ, Milhous WK, Weatherly NF et al. Plasmodium falciparum : induction of resistance to mefloquine in cloned strains by continuous drug exposure in vitro . Exp Parasitol . 1988; 67:354-60. [PubMed 3056740]
22. Nosten F, ter Kuile F, Chongsuphajaisiddhi T et al. Mefloquine pharmacokinetics and resistance in children with acute falciparum malaria. Br J Clin Pharmacol . 1991; 31:556-9. [PubMedCentral][PubMed 1888626]
23. White NJ. Mefloquine: in the prophylaxis and treatment of falciparum malaria. BMJ . 1994; 308:286-7. [PubMedCentral][PubMed 8124114]
24. Gay F, Bustos DG, Diquet B et al. Cross-resistance between mefloquine and halofantrine. Lancet . 1990; 336:1262. [PubMed 1978108]
25. Brasseur P, Kauamouo J, Druilhe P. Mefloquine-resistant malaria induced by inappropriate quinine regimens? J Infect Dis . 1991; 164:625-6. Letter. (IDIS 288700)
26. Edrissian GH, Ghorbani M, Afshar A et al. In vitro response of Plasmodium falciparum to mefloquine in south-eastern Iran. Trans R Soc Trop Med Hyg . 1987; 81:164-5. [PubMed 3328332]
27. Wilson CM, Serrano AE, Wasley A et al. Amplification of a gene related to mammalian mdr genes in drug-resistant Plasmodium falciparum . Science . 1989; 244:1184-6. [PubMed 2658061]
28. Wilson CM, Volkman SK, Thaithong S et al. Amplification of pfmdr 1 associated with mefloquine and halofantrine resistance in Plasmodium falciparum from Thailand. Mol Biochem Parasitol . 1993; 57:151-60. [PubMed 8426608]
29. Cowman AF, Galatis D, Thompson JK. Selection for mefloquine resistance in Plasmodium falciparum is linked to amplification of the pfmdr1 gene and cross-resistance to halofantrine and quinine. Proc Natl Acad Sci USA . 1994; 91:1143-7. [PubMedCentral][PubMed 8302844]
30. Karbwang J, White NJ. Clinical pharmacokinetics of mefloquine. Clin Pharmacokinet . 1990; 19:264-79. [PubMed 2208897]
31. Schwartz DE, Eckert G, Hartmann D et al. Single dose kinetics of mefloquine in man: plasma levels of the unchanged drug and of one of its metabolites. Chemotherapy . 1982; 28:70-84. [PubMed 6976886]
32. Parise ME (Division of Parasitic Diseases, US Centers for Disease Control and Prevention, Atlanta, GA). Personal communication; 2000 Sep 29.
33. Tajerzadeh H, Cutler DJ. Blood to plasma ratio of mefloquine: interpretation and pharmacokinetic implications. Biopharm Drug Disp . 1993; 14:87-91.
34. White NJ, Breman JG. Malaria and other diseases caused by red blood cell parasites. In: Fauci AS, Braunwald E, Isselbacher KJ, et al, eds. Harrison's principles of internal medicine. 14th ed. New York: McGraw-Hill; 1998:1180-9.
35. Desjardins RE, Pamplin CL III, von Bredow J et al. Kinetics of a new antimalarial, mefloquine. Clin Pharmacol Ther . 1979; 26:372-9. [PubMed 466930]
36. Karbwang J, Na Bangchang K, Bunnag D et al. Pharmacokinetics and pharmacodynamics of mefloquine in Thai patients with acute falciparum malaria. Bull World Health Organ . 1991; 69:207-12. [PubMedCentral][PubMed 1860148]
37. Karbwang J, Back DJ, Bunnag D et al. A comparison of the pharmacokinetics of mefloquine in healthy Thai volunteers and in Thai patients with falciparum malaria. Eur J Clin Pharmacol . 1988; 35:677-80. [PubMed 3069480]
38. Karbwang J, Bunnag D, Breckenridge AM et al. The pharmacokinetics of mefloquine when given alone or in combination with sulphadoxine and pyrimethamine in Thai male and female subjects. Eur J Clin Pharmacol . 1987; 32:173-7. [PubMed 3495440]
39. de Souza JM, Heizmann P, Schwartz DE. Single-dose kinetics of mefloquine in Brazilian male subjects. Bull World Health Organ . 1987; 65:353-6. [PubMedCentral][PubMed 3499250]
40. Looareesuwan S, White NJ, Warrell DA et al. Studies of mefloquine bioavailability and kinetics using a stable isotope technique: a comparison of Thai patients with falciparum malaria and healthy caucasian volunteers. Br J Clin Pharmacol . 1987; 24:37-42. [PubMedCentral][PubMed 3304385]
41. Martin C, Gimenez F, Bangchang KN et al. Whole blood concentrations of mefloquine enantiomers in healthy Thai volunteers. Eur J Clin Pharmacol . 1994; 47:85-7. [PubMed 7988631]
42. Hellgren U, Berggren-Palme I, Bergqvist Y et al. Enantioselective pharmacokinetics of mefloquine during long-term intake of the prophylactic dose. Br J Clin Pharmacol . 1997; 44:119-24. [PubMedCentral][PubMed 9278194]
43. Bourahla A, Martin C, Gimenez F et al. Stereoselective pharmacokinetics of mefloquine in young children. Eur J Clin Pharmacol . 1996; 50:241-4. [PubMed 8737767]
44. Hellgren U, Jastrebova J, Jerling M et al. Comparison between concentrations of racemic mefloquine, its separate enantiomers and the carboxylic acid metabolite in whole blood serum and plasma. Eur J Clin Pharmacol . 1996; 51:171-3. [PubMed 8911884]
45. Karbwang J, Na-Bangchang K. Clinical application of mefloquine pharmacokinetics in the treatment of P falciparum malaria. Fundam Clin Pharmacol . 1994; 8:491-502. [PubMed 7721226]
46. Boudreau EF, Fleckenstein L, Pang LW et al. Mefloquine kinetics in cured and recrudescent patients with acute falciparum malaria and in healthy volunteers. Clin Pharmacol Ther . 1990; 48:399-409. [PubMed 2225700]
47. Mimica I, Fry W, Eckert G et al. Multiple-dose kinetic study of mefloquine in healthy male volunteers. Chemotherapy . 1983; 29:184-7. [PubMed 6603336]
48. Schwartz DE, Eckert G, Ekue JMK. Urinary excretion of mefloquine and some of its metabolites in African volunteers at steady state. Chemotherapy . 1987; 33:305-8. [PubMed 3499298]
49. Crevoisier CA, Joseph I, Fischer M et al. Influence of hemodialysis on plasma concentration-time profiles of mefloquine in two patients with end-stage renal disease: a prophylactic drug monitoring study. Antimicrob Agents Chemother . 1995; 39:1892-5. [PubMedCentral][PubMed 7486943]
50. Lobel HO, Miani M, Eng T et al. Long-term malaria prophylaxis with weekly mefloquine. Lancet . 1993; 341:848-51. [PubMed 8096560]
51. Lobel HO, Bernard KW, Williams SL et al. Effectiveness and tolerance of long-term malaria prophylaxis with mefloquine: need for a better dosing regimen. JAMA . 1991; 265:361-4. [PubMed 1984534]
52. Tonnesen HH, Grislingaas AL. Photochemical stability of biologically active compounds. II. Photochemical decomposition of mefloquine in water. Int J Pharm . 1990; 60:157-62.
53. Karle JM, Olmeda R, Gerena L et al. Plasmodium falciparum : role of absolute stereochemistry in the antimalarial activity of synthetic amino alcohol antimalarial agents. Exp Parasitol . 1993; 76:345-51. [PubMed 8513873]
54. Wallace MR, Sharp TW, Smoak B et al. Malaria among United States troops in Somalia. Am J Med . 1996; 100:49-55. [PubMed 8579087]
55. Boudreau E, Schuster B, Sanchez J et al. Tolerability of prophylactic Lariam® regimens. Trop Med Parasitol . 1993; 44:257-65. [PubMed 8256107]
56. Food and Drug Administration. List of orphan designations and approvals. From FDA web site. [Web]
61. Wolfe MS. Protection of travelers. Clin Infect Dis . 1997; 25:177-84. [PubMed 9332506]
62. Wyler DJ. Malaria chemoprophylaxis for the traveler. N Engl J Med . 1993; 329:31-7. [PubMed 8505942]
63. Steffen R, Fuchs E, Schildknecht J et al. Mefloquine compared with other malaria chemoprophylactic regimens in tourists visiting East Africa. Lancet . 1993; 341:1299-303. [PubMed 8098447]
64. Hopperus Buma APCC, van Thiel PPAM, Lobel HO et al. Long-term malaria chemoprophylaxis with mefloquine in Dutch marines in Cambodia. J Infect Dis . 1996; 173:1506-9. [PubMed 8648231]
66. Day JH, Behrens RH. Delay in onset of malaria with mefloquine prophylaxis. Lancet . 1995; 345:398. [PubMed 7845154]
67. Dixon KE, Pitaktong U, Phintuyothin P. A clinical trial of mefloquine in the treatment of Plasmodium vivax malaria. Am J Trop Med Hyg . 1985; 34:435-7. [PubMed 3890575]
68. ter Kuile FO, Nosten F, Thieren M et al. High-dose mefloquine in the treatment of multidrug-resistant falciparum malaria. J Infect Dis . 1992; 166:1393-400. [PubMed 1431257]
69. Smithuis FM, van Woensel JBM, Nordlander E et al. Comparison of two mefloquine regimens for treatment of Plasmodium falciparum malaria on the northeastern Thai-Cambodian border. Antimicrob Agents Chemother . 1993; 37:1977-81. [PubMedCentral][PubMed 8239616]
70. White NJ. The treatment of malaria. N Engl J Med . 1996; 335:800-6. [PubMed 8703186]
71. Nosten F, Luxemburger C, ter Kuile FO et al. Treatment of multidrug-resistant Plasmodium falciparum malaria with 3-day artesunate-mefloquine combination. J Infect Dis . 1994; 170:971-7. [PubMed 7930743]
72. Looareesuwan S, Viravan C, Vanijanonta S et al. Randomised trial of artesunate and mefloquine alone and in sequence for acute uncomplicated falciparum malaria. Lancet . 1992; 339:821-4. [PubMed 1347854]
73. de Vries PJ, Dien TK. Clinical pharmacology and therapeutic potential of artemisinin and its derivatives in the treatment of malaria. Drugs . 1996; 52:818-36. [PubMed 8957153]
74. Bem JL, Kerr L, Stuerchler D. Mefloquine prophylaxis: an overview of spontaneous reports of severe psychiatric reactions and convulsions. J Trop Med Hyg . 1992; 95:167-79. [PubMed 1597872]
75. Phillips-Howard PA, ter Kuile FO. CNS adverse events associated with antimalarial agents: fact or fiction? Drug Saf . 1995; 12:370-83.
76. ter Kuile FO, Nosten F, Luxemburger C et al. Mefloquine treatment of acute falciparum malaria: a prospective study of non-serious adverse effects in 3673 patients. Bull World Health Organ . 1995; 73:631-42. [PubMedCentral][PubMed 8846489]
77. Schlagenhauf P, Steffen R, Lobel H et al. Mefloquine tolerability during chemoprophylaxis: focus on adverse event assessments, stereochemistry and compliance. Trop Med Int Health . 1996; 1:485-94. [PubMed 8765456]
78. Barrett PJ, Emmins PD, Clarke PD et al. Comparison of adverse events associated with use of mefloquine and combination of chloroquine and proguanil as antimalarial prophylaxis: postal and telephone survey of travellers. BMJ . 1996; 313:525-8. [PubMedCentral][PubMed 8789977]
79. Sowunmi A, Adio RA, Oduola AMJ et al. Acute psychosis after mefloquine: report of six cases. Trop Geograph Med . 1995; 47:179-80.
80. Caillon E, Schmitt L, Moron P. Acute depressive symptoms after mefloquine treatment. Am J Psychiatry . 1992; 149:712. [PubMed 1575269]
81. Björkman A. Acute psychosis following mefloquine prophylaxis. Lancet . 1989; II:865.
82. Stuiver PC, Ligthelm RJ, Goud TJLM. Acute psychosis after mefloquine. Lancet . 1989; II:282.
83. Rouveix B, Bricaire F, Michon C et al. Mefloquine and an acute brain syndrome. Ann Intern Med . 1989; 110:577-8. [PubMed 2784297]
84. Pous E, Gascón J, Obach J et al. Mefloquine-induced grand mal seizure during malaria chemoprophylaxis in a non-epileptic subject. Trans R Soc Trop Med Hyg . 1995; 89:434. [PubMed 7570889]
85. Ruff TA, Sherwen SJ, Donnan GA. Seizure associated with mefloquine for malaria prophylaxis. Med J Aust . 1994; 161:453. [PubMed 7935106]
86. Hennequin C, Bourée P, Bazin N et al. Severe psychiatric side effects observed during prophylaxis and treatment with mefloquine. Arch Intern Med . 1994; 154:2360-2. [PubMed 7944858]
87. Piening RB, Young SA. Mefloquine-induced psychosis. Ann Emerg Med . 1996; 27:792-3. [PubMed 8644976]
88. Singh K, Shanks GD, Wilde H. Seizures after mefloquine. Ann Intern Med . 1991; 114:994. [PubMed 2024874]
89. Croft AMJ, World MJ. Neuropsychiatric reactions with mefloquine chemoprophylaxis. Lancet . 1996; 347:326. [PubMed 8569381]
90. Speich R, Haller A. Central anticholinergic syndrome with the antimalarial drug mefloquine. N Engl J Med . 1994; 331:57-8. [PubMed 8202114]
91. Olson PE, Kennedy CA, Morte PD. Paresthesias and mefloquine prophylaxis. Ann Intern Med . 1992; 117:1058-9. [PubMed 1443980]
92. Stracher AR, Stoeckle MY, Giordano MF. Aplastic anemia during malarial prophylaxis with mefloquine. Clin Infect Dis . 1994; 18:263-4. [PubMed 8161647]
93. Van den Enden E, Van Gompel A, Colebunders R et al. Mefloquine-induced Stevens-Johnson syndrome. Lancet . 1991; 337:683. [PubMed 1672030]
94. Laothavorn P, Karbwang J, Na Bangchang K et al. Effect of mefloquine on electrocardiographic changes in uncomplicated falciparum malaria patients. Southeast Asian J Trop Med Pub Health . 1992; 23:51-4.
95. Shlim DR. Severe facial rash associated with mefloquine. JAMA . 1991; 266:2560. [PubMed 1834867]
96. Martin GJ, Malone JL, Ross EV. Exfoliative dermatitis during malarial prophylaxis with mefloquine. Clin Infect Dis . 1993; 16:341-2. [PubMed 8443327]
97. White AC Jr, Gard DA, Sessoms SL. Cutaneous vasculitis associated with mefloquine. Ann Intern Med . 1995; 123:894. [PubMed 7486482]
98. Richter J, Burbach G, Hellgren U et al. Aberrant atrioventricular conduction triggered by antimalarial prophylaxis with mefloquine. Lancet . 1997; 349:101-2. [PubMed 8996427]
99. McBride SR, Lawrence CM, Pape SA et al. Fatal toxic epidermal necrolysis associated with mefloquine antimalarial prophylaxis. Lancet . 1997; 349:101. [PubMed 8996426]
100. Chongsuphajaisiddhi T, Sabchareon A, Chantavanich P et al. A phase-III clinical trial of mefloquine in children with chloroquine-resistant falciparum malaria in Thailand. Bull World Health Organ . 1987; 65:223-6. [PubMedCentral][PubMed 3301042]
101. Sowunmi A, Oduola AMJ. Open comparison of mefloquine, mefloquine/sulfadoxine/pyrimethamine and chloroquine in acute uncomplicated falciparum malaria in children. Trans R Soc Trop Med Hyg . 1995; 89:303-5. [PubMed 7660443]
102. Marcy SM. Malaria prophylaxis in young children and pregnant women. Pediatr Infect Dis J . 1996; 15:101-2.
103. Nosten F, ter Kuile F, Maelankiri L et al. Mefloquine prophylaxis prevents malaria during pregnancy: a double-blind, placebo-controlled study. J Infect Dis . 1994; 169:595-603. [PubMed 8158032]
104. Na Bangchang K, Davis TME, Looareesuwan S et al. Mefloquine pharmacokinetics in pregnant women with acute falciparum malaria. Trans R Soc Trop Med Hyg . 1994; 88:321-3. [PubMed 7974678]
105. American Academy of Pediatrics. Red Book: 2012 Report of the Committee on Infectious Diseases. 29th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2012.
106. Nosten F, Karbwang J, White NJ et al. Mefloquine antimalarial prophylaxis in pregnancy: dose finding and pharmacokinetic study. Br J Clin Pharmacol . 1990; 30:79-85. [PubMedCentral][PubMed 2390434]
107. Edstein MD, Veenendaal JR, Hyslop R. Excretion of mefloquine in human breast milk. Chemotherapy . 1988; 34:165-9. [PubMed 3262044]
108. Centers for Disease Control Immunization Practices Advisory Committee (ACIP). Typhoid immunization: recommendations of the Immunization Practices Advisory Committee (ACIP). MMWR Recomm Rep . 1994; 43(RR-14):1-7. [Fulltext MMWR]
109. Horowitz H, Carbonaro CA. Inhibition of the Salmonella typhi oral vaccine strain, Ty21a, by mefloquine and chloroquine. J Infect Dis . 1992; 166:1462-4. [PubMed 1431270]
110. Brachman PS, Metchock B, Kozarsky PE. Effects of antimalarial chemoprophylactic agents on the viability of the Ty21a typhoid vaccine strain. Clin Infect Dis . 1992; 15:1057-8. [PubMed 1457647]
111. Kollaritsch H, Que JU, Kunz C et al. Safety and immunogenicity of live oral cholera and typhoid vaccines administered alone or in combination with antimalarial drugs, oral polio vaccine, or yellow fever vaccine. J Infect Dis . 1997; 175:871-5. [PubMed 9086143]
112. Nosten F, ter Kuile FO, Luxemburger C et al. Cardiac effects of antimalarial treatment with halofantrine. Lancet . 1993; 341:1054-6. [PubMed 8096959]
113. Lobel HO, Kozareky PE. Update on prevention of malaria for travelers. JAMA . 1997; 278:1767-71. [PubMed 9388154]
114. Shanks GD. The rise and fall of mefloquine as an antimalarial drug in South East Asia. Mil Med . 1984; 159:275-81.
115. Centers for Disease Control and Prevention. CDC health information for international travel, 2014. Atlanta, GA: US Department of Health and Human Services. Updates may be available at CDC website. [Web]
116. ter Kuile F, White NJ, Holloway P et al. Plasmodium falciparum: in vitro studies of the pharmacodynamic properties of drugs used for the treatment of severe malaria. Exp Parasitol . 1993; 76:85-95. [PubMed 8467901]
117. Davis TME, Dembo LG, Kaye-Eddie SA et al. Neurological, cardiovascular and metabolic effects of mefloquine in healthy volunteers: a double-blind, placebo-controlled trial. Br J Clin Pharmacol . 1996; 42:415-21. [PubMedCentral][PubMed 8904612]
118. Chanthavanich P, Looareesuwan S, White NJ et al. Intragastric mefloquine is absorbed rapidly in patients with cerebral malaria. Am J Trop Med Hyg . 1985; 34:1028-36. [PubMed 3879657]
119. Price R, Robinson G, Brockman A et al. Assessment of pfmdr 1 gene copy number by tandem competitive polymerase chain reaction. Mol Biochem Parasitol . 1997; 85:161-9. [PubMed 9106190]
120. Singhasivanon V, Chongsuphajaisiddhi T, Sabchareon A et al. Pharmacokinetic study of mefloquine in Thai children aged 5-12 years suffering from uncomplicated falciparum malaria treated with MSP or MSP plus primaquine. Eur J Drug Metab Pharmacokinet . 1994; 19:27-32. [PubMed 7957448]
121. . Advice for travelers. Treat Guidel Med Lett . 2012; 10:45-56. [PubMed 22777212]
122. Fitch CD, Chan RL, Chevli R. Chloroquine resistance in malaria: accessibility of drug receptors to mefloquine. Antimicrob Agents Chemother . 1979; 15:258-62. [PubMedCentral][PubMed 371544]
123. San George RC, Nagel RL, Fabry ME. On the mechanism for the red-cell accumulation of mefloquine, an antimalarial drug. Biochim Biophys Acta . 1984; 803:174-81. [PubMed 6608378]
124. Karbwang J, Looareesuwan S, Phillips RE et al. Plasma and whole blood mefloquine concentrations during treatment of chloroquine-resistant falciparum malaria with the combination mefloquine-sulphadoxine-pyrimethamine. Br J Clin Pharmacol . 1987; 23:477-81. [PubMedCentral][PubMed 3555581]
125. Mai NTH, Day NPJ, Chuong LV et al. Post-malaria neurological syndrome. Lancet . 1996; 348:917-21. [PubMed 8843810]
126. Smoak BL, Writer JV, Keep LW et al. The effects of inadvertent exposure of mefloquine chemoprophylaxis on pregnancy outcomes and infants of US army servicewomen. J Infect Dis . 1997; 176:831-3. [PubMed 9291347]
127. Wongsrichanalai C, Nguyen TD, Trieu NT et al. In vitro susceptibility of Plasmodium falciparum isolates in Vietnam to artemisinin derivatives and other antimalarials. Acta Tropica . 1997; 63:151-8. [PubMed 9088428]
128. Reviewers' comments (personal observations).
129. Luxemburger C, Price RN, Nosten F et al. Mefloquine in infants and young children. Ann Trop Pediatr . 1996; 16:281-6.
130. Ohrt C, Richie TL, Widjaja H et al. Mefloquine compared with doxycycline for the prophylaxis of malaria in Indonesian soldiers: a randomized, double-blind, placebo-controlled trial. Ann Intern Med . 1997; 126:963-72. [PubMed 9182474]
131. Croft AMJ, Clayton TC, World MJ. Side effects of mefloquine prophylaxis for malaria: an independent randomized controlled trial. Trans R Soc Trop Med Hyg . 1997; 91:199-203. [PubMed 9196769]
132. Vuurman EFPM, Muntjewerff ND, Uiterwijk MMC et al. Effects of mefloquine alone and with alcohol on psychomotor and driving performance. Eur J Clin Pharmacol . 1996; 50:475-82. [PubMed 8858275]
133. Steketee RW, Wirima JJ, Slutsker L et al. Malaria treatment and prevention in pregnancy: indications for use and adverse events associated with use of chloroquine or mefloquine. Am J Trop Med Hyg . 1996; 55:50-6. [PubMed 8702037]
134. Anon. Drugs for parasitic infections. Treat Guidel Med Lett . 2010; 8:e1-16. [Web]
135. SmithKline Beecham Pharmaceuticals. Halfan® (halofantrine hydrochloride) tablets prescribing information. Philadelphia, PA: 2001 Oct.
136. Nosten F, Vincenti M, Simpson J et al. The effects of mefloquine treatment in pregnancy. Clin Infect Dis . 1999; 28:808-15. [PubMed 10825043]
137. Singhasivanon V, Chongsuphajaisiddhi T, Sabcharoen A et al. Pharmacokinetics of mefloquine in children aged 6 to 24 months. Eur J Drug Metab Pharmacokinet . 1992; 17:275-9. [PubMed 1301357]
138. Peragallo MS, Sabatinelli G, Sarnicola G. Compliance and tolerability of mefloquine and chloroquine plus proguanil for long-term malaria chemoprophylaxis in groups at particular risk (the military). Trans R Soc Trop Med Hyg . 1999; 93:73-7. [PubMed 10492796]
139. Centers for Disease Control and Prevention. Malaria deaths following inappropriate malaria chemoprophylaxisUnited States, 2001. MMWR Morb Mortal Wkly Rep . 2001; 50:597-9. [PubMed 11476528]
140. Anon. Drug ruled out as cause of violence at Army base in N.C. Washington Post . 2002 Oct 31.
141. Anon. Ft. Bragg deaths tied to marital woes, stress: report says Army culture discourages military families from seeking help. Washington Post . 2002 Nov 8.
143. Centers for Disease Control and Prevention. CDC treatment guidelines: Treatment of malaria (guidelines for clinicians). 2013 Jul. From the CDC website. Accessed 2013 Sep 27. [Web]
144. Centers for Disease Control and Prevention. Guidelines for treatment of malaria in the United States (based on drugs currently available for use in the United States-updated July 1, 2013). From the CDC website. Accessed 2013 Sep 27. [Web]
145. Novartis Pharmaceuticals Corporation. Coartem® (artemether/lumefantrine) tablets prescribing information. East Hanover, NJ; 2013 Apr.
146. Lefèvre G, Bindschedler M, Ezzet F et al. Pharmacokinetic interaction trial between co-artemether and mefloquine. Eur J Pharm Sci . 2000; 10:141-51. [PubMed 10727880]
147. AR Scientific, Inc. Qualaquin® (quinine sulfate) capsules prescribing information. Philadelphia, PA; 2013 Apr.
148. Saha P, Guha SK, Das S et al. Comparative efficacies of artemisinin combination therapies in Plasmodium falciparum malaria and polymorphism of pfATPase6, pfcrt, pfdhfr, and pfdhps genes in tea gardens of Jalpaiguri District, India. Antimicrob Agents Chemother . 2012; 56:2511-7. [PubMedCentral][PubMed 22314538]
149. Santelli AC, Ribeiro I, Daher A et al. Effect of artesunate-mefloquine fixed-dose combination in malaria transmission in Amazon basin communities. Malar J . 2012; 11:286. [PubMedCentral][PubMed 22905900]
150. Ridtitid W, Wongnawa M, Mahatthanatrakul W et al. Effect of rifampin on plasma concentrations of mefloquine in healthy volunteers. J Pharm Pharmacol . 2000; 52:1265-9. [PubMed 11092571]
151. Khaliq Y, Gallicano K, Tisdale C et al. Pharmacokinetic interaction between mefloquine and ritonavir in healthy volunteers. Br J Clin Pharmacol . 2001; 51:591-600. [PubMedCentral][PubMed 11422019]
152. Chehuan YF, Costa MR, Costa JS et al. In vitro chloroquine resistance for Plasmodium vivax isolates from the Western Brazilian Amazon. Malar J . 2013; 12:226. [PubMedCentral][PubMed 23819884]
153. Zatra R, Lekana-douki JB, Lekoulou F et al. In vitro antimalarial susceptibility and molecular markers of drug resistance in Franceville, Gabon. BMC Infect Dis . 2012; 12:307. [PubMedCentral][PubMed 23153201]
155. Panel on Opportunistic Infections in HIV-infected Adults and Adolescents. Guidelines for prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: recommendations from the Centers for Disease Control and Prevention, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America (May 7, 2013). Updates may be available at HHS AIDS Information (AIDSinfo) website. [Web]
161. World Health Organization (WHO). Guidelines for the treatment of malaria. 2nd edition. Geneva, Switzerland: World Health Organization; 2010. Updates may be available at WHO website. [Web]