Mefloquine dosing

A 7-year-old Indian boy was diagnosed as having cerebral malaria and received quinine followed by mefloquine (dose not given) (500). He developed hallucinations and removed his clothes and danced. His symptoms resolved within 24 hours of stopping mefloquine. This case highlights the fact that mefloquine should not be given after quinine in cases of severe malaria. 

The broad picture is that mefloquine appears not to worsen the psychomotor effects of moderate amounts of alcohol. Just why an unusual toxic reaction developed in one individual is not known, although mefloquine alone can increase the risk of psychiatric events. It has been postulated that many of the adverse effects of mefloquine are associated with liver damage, and concurrent insults to the liver, such as from alcohol and dehydration, may be related to the development of severe or prolonged adverse reactions to mefloquine. In a review of 516 published case reports of mefloquine adverse effects, 11 cited alcohol as a possible contributing fac-tor. It was suggested that travellers taking mefloquine should avoid alcohol particularly within 24 hours of their weekly mefloquine dose. However, the manufacturers have not issued such a warning. More study is needed. 

The success of quinine inspired the search for other antimalarials. The greatest impetus for the development of synthetic dmgs came this century when the two World Wars intermpted the supply of cinchona bark to the combatants. A stmcturally related 4-quinolinemethanol is mefloquine (65, Lariam [51773-92-3]) which now serves as an effective alternative agent for chloroquine-resistant P. falciparum. This is a potent substance that requires less than one-tenth the dose of quinine to effect cures. There are some untoward side effects associated with this dmg such as gastrointestinal upset and dizziness, but they tend to be transient. Mefloquine is not recommended for use by those using beta-blockers, those whose job requires fine coordination and spatial discrimination, or those with a history of epilepsy or psychiatric disorders. A combination of mefloquine with Fansidar (a mixture of pyrimethamine and sulfadoxine) is known as Fansimef but its use is not recommended. Resistance to mefloquine has been reported even though the compound has not been in wide use. 

Quinacrine (49) is an acridine that was used extensively from the mid-1920s to the end of World War 11. It acts much like chloroquine and is reasonably effective. Because it causes the skin to turn yellow and, in high doses, causes yellow vision, the dmg is no longer in use as an antimalarial. Pyronaridine (77), a 1-azaacridine developed in China, appears to be effective against mefloquine-resistant, but not entirely against chloroquine-resistant, strains of P falciparum. 

The loading dose of quinidine should be omitted in those patients who have received quinine or mefloquine. 

Artesunate x 3 days + mefloquine has been used in several Asian countries for MDR falciparum malaria. Artesunate 4 mg/kg/day x 3 day and mefloquine 25 mg/kg single splitting into 2 dose 6-8 hours apart (15 mg/kg then 10 mg/kg). 

There is very limited evidence available on the effectiveness of the drugs in pregnant women. A possible increase in risk of stillbirth with the use of mefloquine in pregnancy has been reported. Standard adult dose of antimalarial drugs recommended for 2nd and 3rd trimester pregnancy did not cause harm or congenital abnormalities. Evidence on the safety of all recommended antimalarial drugs in the 1st trimester is still unclear. 

Non-falciparum malaria (like P. vivax) can still be treated with chloroquine although chloroquine resistant P. vivax has been reported from Irian Jaya and Papua New Guinea. In those areas treatment with mefloquine is recommended. To treat the liverstages an additional 2-3 weeks treatment with primaquine is given. It appears that tafenoquine (dosed once a week), a new 8-aminoquinoline, would be a better replacement for primaquine in preventing relapses in P. vivax malaria. 

III. Quinoline-methanol derivatives Mefloquine (MEFLOC) 15 mg/kg single dose (for treatment, maximum 1 g) 5 mg/kg, up to 250 mg per wk (for prophylaxis in areas with multidrug resistance)... 

Weekly dosing with mefloquine for chemoprophylaxis may cause nausea, vomiting, dizziness, sleep and behavioral disturbances, epigastric pain, diarrhea, abdominal pain, headache, rash, and dizziness. Neuropsychiatric toxicities have received a good deal of publicity, but despite frequent anecdotal reports of seizures and psychosis, a number of controlled studies have found the frequency of serious adverse effects from mefloquine to be no higher than that with other common antimalarial chemoprophylactic regimens. Leukocytosis, thrombocytopenia, and aminotransferase elevations have been reported. 

The latter adverse effects are more common with the higher dosages required for treatment. These effects may be lessened by administering the drug in two doses separated by 6-8 hours. The incidence of neuropsychiatric symptoms appears to be about ten times more common than with chemoprophylactic dosing, with widely varying frequencies of up to about 50% being reported. Serious neuropsychiatric toxicities (depression, confusion, acute psychosis, or seizures) have been reported in less than one in 1000 treatments, but some authorities believe that these toxicities are actually more common. Mefloquine can also alter cardiac conduction, and arrhythmias and bradycardia have been reported. 

At first thought to occur only after therapeutic doses of mefloquine, it is now clear that neuropsychiatric reactions... 

A 42-year-old man with no previous psychiatric history suddenly developed visual symptoms after the third dose (total dose 750 mg) of prophylactic mefloquine (501). The symptoms consisted of an impression of focusing on two different planes and of perceiving his surroundings as very far from him. They were associated with slurred speech and altered comprehension. They occurred daily, lasting up to an hour, for 6 months. He had previously taken a course of mefloquine for 7 weeks without any adverse events. 

A 52-year-old woman with no psychiatric history developed anxiety, paranoia, visual hallucinations, confusion, and depressive symptoms after 3 doses of prophylactic mefloquine (250 mg/week) (502). She had previously taken mefloquine prophylaxis intermittently for 4 years with no adverse events. 

A 48-year-old woman developed anxiety, tremor, depression, dry mouth, nausea, and marked weight loss (503). Physical examination, electrocardiography, chest X-ray, CT scan, and laboratory investigations were unremarkable. The Hamilton D score was 44 for 17 items. She had taken mefloquine 250 mg/week for 8 weeks for malaria prophylaxis, and after 2 weeks had started to feel unwell, with dysphoria, depression, and weakness. She was given fluoxetine 20 mg/day and alprazolam 1.5 mg/day. Her condition continued to deteriorate. The dose of fluoxetine was increased to 40 mg/day and flunitrazepam was added. She was later instead given milnacipran, a serotonin and noradrenaline reuptake... 

ANTI EPILEPTICS 1. ANTIMALARIALS -chloroquine, mefloquine 2. ANTIDEPRESSANTS-MAOIs, SSRIs, TCAs 3. ANTIPSYCHOTICS t risk of seizures These drugs lower seizure threshold Care with co-administration. Watch for t fit frequency warn patient of this risk when starting these drugs and take suitable precautions. Consider increasing dose of antiepileptic... 

BUPROPION 1. ANTIBIOTICS - fluoroquinolones 2. ANTICANCER AND IMMUNO-MODULATING DRUGS-corticosteroids, interferons 3. ANTIDEPRESSANTS-TCAs 4. ANTIMALARIALS - chloroquine, mefloquine 5. ANTIPSYCHOTICS 6. BRONCHODILATORS -theophylline 7. CNS STIMULANTS 8. PARASYMPATHOMIMETICS T risk of seizures. This risk is marked in elderly people, in patients with a history of seizures, with addiction to opiates/cocaine/ stimulants, and in diabetics treated with oral hypoglycaemics or insulin Bupropion is associated with a dose-related risk of seizures. These drugs, which lower seizure threshold, are individually epileptogenic. Additive effects occur when combined Extreme caution. The dose of bupropion should not exceed 4S0 mg/day (or 150 mg/day in patients with severe hepatic cirrhosis)... 

MEFLOQUINE ANTI EPILEPTICS 1 efficacy of antiepileptics Mefloquine can l seizure threshold Care with co-administration T dose of antiepileptic if T incidence of fits... 

The loading dose shovild not be given if the patient has received quinine, quinidine or mefloquine in the previous 24 h see also warnings about halofantrine (below). 

Artesunate is a water-soluble hemisuccinate derivative, available in parenteral and oral formulations. The parenteral drug is dispensed as powdered artesunic acid. Neutral aqueous solutions are unstable. Artesunate is effective by the intravenous, intramuscular, and oral routes in a dose of 10 mg/kg given for 5-7 days. The combination with mefloquine is very effective even against highly multi-resistant strains of Plasmodium falciparum, the combination must be given for at least 3 days. 

The artemisinin derivatives are limited by an unacceptable incidence of recrudescence with monotherapy, and they therefore need to be used in combination. A summary of prospective trials that looked specifically for adverse effects showed that artemisinins alone are very well tolerated (10). The same study showed no evidence of adverse interactions of artesunate with mefloquine, with an incidence of adverse effects similar to that expected from malaria and mefloquine (25 mg/kg) together. Reducing doses of mefloquine increases recrudescence rates to unacceptable levels (11). Combinations of artemisinins with quinine, co-trimoxazole, and doxycycUne are well tolerated. 

A large trial of the first fixed-dose combination of an artemisinin derivative likely to be licensed (artemether + benflumetol) had disappointing relapse rates compared with mefloquine monotherapy (6). In the 126 patients who took artemether + benflumetol there were no adverse effects attributed to drug treatment. However, less than 70% of patients were cured at 28 days. Benflumetol may be more effective at higher concentrations (12) but toxicity studies are lacking. 

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