Action And Clinical Pharmacology: Mefloquine acts on the asexual intraerythrocytic forms of the human malaria parasites: P. falciparum, P. vivax, P. malariae and P. ovale.
Mefloquine is also effective against malaria parasites resistant to other antimalarials such as chloroquine, proguanil, pyrimethamine and pyrimethamine-sulfonamide combinations.
Resistance to P. falciparum to mefloquine has been reported, mainly in parts of South-East Asia. Cross-resistance between mefloquine and halofantrine has been observed.
Pharmacokinetics: Absorption: The absolute oral bioavailabilty of mefloquine has not been determined since an i.v. formulation is not available. The bioavailability of the tablet formulation compared with an oral solution was over 85%. The presence of food significantly enhances the rate and extent of absorption, leading to about a 40% increase in bioavailability. Plasma concentrations peak 6 to 24 hours (median, about 17 hours) after a single dose of mefloquine. Maximum plasma concentrations in g/L are roughly equivalent to the dose in mg (for example, a single 1 000 mg dose produces a maximum concentration of about 1 000 g/L). At a dose of 250 mg once weekly, maximum steady-state plasma concentrations of 1 000 to 2 000 g/L are reached after 7 to 10 weeks.
Distribution: In healthy adults, the apparent volume of distribution is approximately 20 L/kg, indicating extensive tissue distribution. Mefloquine may accumulate in parasitized erythrocytes at an erythrocyte-to-plasma concentration ratio of about 2. Protein binding is about 98%. clinical experience suggests a minimal suppressive plasma concentration of mefloquine in the order of 600 g/L.
Mefloquine crosses the placenta (see Warnings, Pregnancy). Excretion into breast milk appears to be minimal (see Precautions, Lactation).
Metabolism: Two metabolites have been identified in humans. The main metabolite, 2-8-bis-trifluoromethyl-4-quinoline carboxylic acid, is inactive against P. falciparum. In a study in healthy volunteers, the carboxylic acid metabolite appeared in plasma 2 to 4 hours after a single oral dose of mefloquine. Maximum plasma concentrations, which were about 50% higher than those of mefloquine, were reached after 2 weeks. Thereafter, plasma levels of the main metabolite and mefloquine declined at a similar rate. The area under the plasma concentration-time curve (AUC) of the main metabolite was 3 to 5 times larger than that of the parent drug.
The other metabolite, an alcohol, was present in only minute amounts.
Elimination: In 15 studies in healthy adults, the mean elimination half-life of mefloquine varied between 2 and 4 weeks, with an average of about 3 weeks. Total clearance, which is essentially hepatic, is in the order of 30 mL/min. There is evidence that mefloquine is excreted mainly in the bile and feces. In volunteers, urinary excretion of unchanged mefloquine and its main metabolite accounted for about 9% and 4% of the dose, respectively. Concentrations of their metabolites could not be measured in the urine.
During long-term prophylaxis, the elimination half-life of mefloquine remains unchanged.
Indications And Clinical Uses: Prophylaxis: For the prophylaxis of P. falciparum and P. vivax malaria infections, including prophylaxis of chloroquine-resistant strains of P. falciparum.
Treatment of Acute Malaria Infections: For the treatment of mild to moderate acute malaria caused by mefloquine-susceptible strains of P. falciparum (both chloroquine-susceptible and resistant strains) or by P. vivax.
Note: In case of life-threatening, serious or overwhelming malaria infections due to P. falciparum, patients should be treated with an i.v. antimalarial drug. Following completion of i.v. treatment, mefloquine may be given orally to complete the course of therapy.
Patients with acute P. vivax malaria, treated with mefloquine, are at high risk of relapse because mefloquine does not eliminate exoerythrocytic (hepatic phase) parasites. To avoid relapse, after initial treatment of the acute infection with mefloquine, patients should subsequently be treated with an 8-aminoquinoline (e.g., primaquine).
There are insufficient clinical data to document the effect of mefloquine in malaria caused by P. ovale or P. malariae.
Contra-Indications: In patients with a known hypersensitivity to mefloquine or related compounds, e.g., quinine, quinidine, chloroquine.
Patients with a history of psychiatric disturbances (including depression) or convulsions should not be prescribed mefloquine prophylactically since mefloquine may precipitate these conditions.
Manufacturers’ Warnings In Clinical States: Concomitant administration of mefloquine and quinine, quinidine, chloroquine, or drugs producing beta-adrenergic blockade may produce electrocardiographic abnormalities or cardiac arrest. Because of the danger of a potentially fatal prolongation of the QTc interval, halofantrine must not be given simultaneously with or subsequent to mefloquine. Concomitant administration of mefloquine, quinine, quinidine or chloroquine may increase the risk of convulsions (see Precautions, Drug Interactions).
In patients with epilepsy, mefloquine, especially when used in high doses, may increase the risk of convulsions. Therefore, in such patients, mefloquine should be used only for curative treatment and only if there are compelling medical reasons.
In patients with impaired liver function the elimination of mefloquine may be prolonged, leading to higher plasma levels.
Pregnancy: Mefloquine crosses the placenta. Administered at 5 to 20 times the therapeutic dose in man, mefloquine was teratogenic in mice and rats and embryotoxic in rabbits. The safety of mefloquine use during the first trimester has not been established. Available data indicate that mefloquine is safe and effective in pregnancy beyond 16 weeks. Women of childbearing potential should be advised to practise contraception during malaria prophylaxis with mefloquine and for 3 months after the last dose.
Pregnancy has no clinically relevant effect on the pharmacokinetics of mefloquine.
Precautions: General: Occupational Hazards: Caution should be exercised with regard to driving, piloting airplanes, operating machines, or any other activity requiring alertness and fine motor coordination, as dizziness, a disturbed sense of balance and other disorders of the central and peripheral nervous system have been reported during and up to 3 weeks after the use of mefloquine (see Adverse Effects). During prophylactic use, if signs of unexplained anxiety, depression, restlessness or confusion are noticed, these may be considered prodromal to a more serious event. In these cases, the drug must be discontinued.
Mefloquine should be taken with caution in patients suffering from cardiac conduction disorders. Parenteral studies in animals show that mefloquine, a myocardial depressant, possesses 20% of the antifibrillatory action of quinidine and produces 50% of the increase in the PR interval reported with quinine. The effect of mefloquine on the compromised cardiovascular system has not been evaluated. In patients with cardiac disease, the benefits of mefloquine therapy should be weighed against the possibility of adverse effects.
During clinical trials, this drug was not administered for longer than 1 year. If the drug is to be administered for a prolonged period, periodic evaluations including liver function tests should be performed, if feasible. Although retinal abnormalities seen in humans with long-term chloroquine use have not been observed with mefloquine use, long-term feeding of mefloquine to rats resulted in dose-related ocular lesions (retinal degeneration, retinal edema and lenticular opacity at 12.5 mg/kg/day and higher). Therefore, periodic ophthalmic examinations are recommended.
Drug Interactions: Drug-drug interactions with mefloquine have not been explored in detail.
Concomitant administration of mefloquine and quinine, quinidine, or chloroquine may produce electrocardiographic abnormalities. If quinine or quinidine are to be used in the initial treatment of severe malaria, mefloquine administration should be delayed for at least 12 hours after the final dose of either of these drugs. Caution should also be exercised with other drugs that alter cardiac conduction (e.g., antiarrhythmics, b-adrenergic blocking agents, calcium channel blockers, antihistamines or H1-blocking agents (astemizole, terfenadine), tricyclic antidepressants and phenothiazines) since they may contribute to a prolongation of the QTc interval.
There is evidence that the use of halofantrine after mefloquine causes a significant lengthening of the QTc interval. Clinically significant QTc interval prolongation has not been found with mefloquine alone.
A patient with previous myocardial infarction suffered a cardiopulmonary arrest 5 hours after taking mefloquine. Propranolol and chloroquine were also taken. That patient recovered fully.
Concomitant administration of mefloquine with quinine, quinidine or chloroquine may increase the risk of convulsions.
Patients taking mefloquine while taking valproic acid had loss of seizure control and lower than expected valproic acid blood levels. Therefore, patients concurrently taking antiseizure medication, including valproic acid, carbamazepine, phenobarbital, and phenytoin, and mefloquine should have the blood level of their antiseizure medication monitored and the dosage adjusted appropriately.
In clinical trials, the concomitant administration of sulfadoxine and pyrimethamine did not alter the adverse reaction profile.
When mefloquine is taken concurrently with oral live typhoid vaccines, attenuation of immunization cannot be excluded. Vaccinations with attenuated live bacteria should therefore be completed at least 3 days before the first dose of mefloquine.
A controlled clinical study was carried out in 20 subjects to investigate a potential interaction between mefloquine and alcohol. The blood alcohol concentrations attained in the patients taking mefloquine (0.3 to 0.5 mg/mL), did not impair coordinated psychomotor activities. A single case in the literature reports a transient severe psychiatric disturbance, suggesting an adverse reaction to mefloquine associated with a heavy ingestion of alcohol (600 mL of whisky).
Mefloquine is highly bound (98%) to plasma proteins.
Impairment of Fertility: Fertility studies with mefloquine in rats have demonstrated adverse effects on fertility in males at the high dose (50 mg/kg/day) and in females at the mid and high dose (20 and 50 mg/kg/day). Administration of 250 mg/week of mefloquine (base) to adult males for 22 weeks failed to reveal any deleterious effects on human spermatozoa.
Lactation: Based on a study in a few subjects, low concentrations (3 to 4%) of mefloquine were excreted in human milk following a dose equivalent to 250 mg of the free base. The amount of mefloquine excreted in the milk is of no prophylactic value to the infant. Caution should be exercised when mefloquine is administered to a nursing woman.
Children: Two studies were conducted to look at the effects of mefloquine on children living in endemic areas for P. falciparum. All children in these studies had at least a low level of parasitemia and 18 to 40% had significant parasitemia with or without mild malaria symptoms. When given 20 to 30 mg/kg of mefloquine as a single dose, nausea and vomiting occurred in approximately 10 to 20%, and dizziness was seen in approximately 40% of children. The incidence of adverse reactions was higher than that observed in adults.
Experience with mefloquine in infants less than 3 months old or weighing less than 5 kg is limited. No relevant age-related changes have been observed in the pharmacokinetics of mefloquine.
Geriatrics: No relevant age-related changes have been observed in the pharmacokinetics of mefloquine.
Renal Insufficiency: No pharmacokinetic studies have been performed in patients with renal insufficiency since only a small proportion of the drug is eliminated renally.
Other: Pharmacokinetic differences have been observed between various ethnic populations. In practice, however, these are of minor importance compared with host immune status and sensitivity of the parasite.
In vitro and in vivo studies showed no hemolysis associated with G-6-PD deficiency.
Adverse Reactions: Overall the most frequently reported adverse events are nausea, vomiting, dizziness or vertigo, loss of balance, headache, somnolence, sleep disorders (insomnia, abnormal dreams), loose stools or diarrhea, and abdominal pain.
At the doses used for treatment of acute malaria infections, the symptoms possibly attributable to drug administration cannot be distinguished from those symptoms usually attributable to the disease itself.
Among subjects who received mefloquine for prophylaxis of malaria, the most frequently observed adverse experiences are nausea, vomiting, headache and dizziness. These adverse events are generally mild and may decrease with prolonged use.
Less frequently reported adverse events include: Central and Peripheral Nervous System: sensory and motor neuropathies (including paresthesia), convulsions or seizures, visual disturbances, tinnitus and vestibular disorders, tremor, abnormal coordination, ataxia, emotional problems (anxiety, panic attacks, restlessness, depressive moods, aggression, agitation, psychotic or paranoid reactions), forgetfulness, confusion, hallucinations.
Note: In the literature, the incidence of serious neuropsychiatric adverse drug reactions (e.g., seizures, psychotic reactions) with mefloquine has been reported at 1/215 following treatment and 1/13 000 following prophylactic use.
Cardiovascular: circulatory disturbances (hypotension, hypertension, flushing, syncope), tachycardia or palpitations, bradycardia, irregular pulse, extrasystoles and other transient cardiac conduction alterations. Isolated cases of AV-block have been reported. Cardiopulmonary arrest was reported in one patient shortly after ingesting a single prophylactic dose of mefloquine while concomitantly using propranolol (see Warnings and Precautions).
Skin: rash, exanthema, erythema, urticaria, pruritus, hair loss. Isolated cases of erythema multiforme and Stevens-Johnson syndrome have been reported.
Musculoskeletal: muscle weakness, muscle cramps, myalgia, arthralgia.
General Symptoms: asthenia, malaise, fatigue, fever, chills, loss of appetite. Isolated cases of encephalopathy have been reported.
Adverse reactions to mefloquine may occur or persist up to several weeks after the last dose.
Laboratory Abnormalities: Decreased hematocrit, transient elevation of transaminases, leukopenia or leukocytosis, and thrombocytopenia.
Symptoms And Treatment Of Overdose: Symptoms and Treatment: The following procedure is recommended in case of overdosage: Induce vomiting or perform gastric lavage, as appropriate. Monitor cardiac function (if possible by ECG) and neuropsychiatric status for at least 24 hours. Provide symptomatic and intensive supportive treatment as required, particularly for cardiovascular disturbances.
Dosage And Administration: Mefloquine should be taken with food, and with at least 240 mL of liquid. All dosage instructions relate to the mefloquine base. The tablets may be crushed and suspended in a small amount of water, milk or other beverage for administration to small children and other persons unable to swallow them whole.
Prophylaxis: The recommended prophylactic dose of mefloquine is approximately 5 mg/kg once weekly. The first dose should be taken at least 1 week before arrival in an endemic area. Weekly doses should always be taken on the same day of the week. To reduce the risk of malaria after leaving an endemic area, prophylaxis must be continued for 4 additional weeks.
If it is not possible to initiate therapy 1 week before arrival in an endemic area, data from the literature indicate that a loading dose of mefloquine can be given in order to rapidly achieve effective blood levels of the drug; in adults weighing over 45 kg this is 1 tablet (250 mg mefloquine) daily for 3 days, followed by 1 tablet weekly during exposure and for 4 weeks after leaving an endemic area.
The use of a loading dose may also permit an assessment of drug tolerance before travel and allows a change to a suitable alternative if required. Consideration may also be given to initiating mefloquine prophylaxis 2 to 3 weeks prior to departure in order to determine tolerance to mefloquine and allow time to substitute other antimalarials if required.
Adults and children weighing over 45 kg: In persons over 45 kg, the prophylactic dose is 250 mg of mefloquine (1 tablet) once weekly.
Children and adults weighing less than 45 kg: The weekly dose decreases in proportion to body weight: >30 to 45 kg: 3/4 tablet; >20 to 30 kg: 1/2 tablet; 5 to 20 kg: 1/4 tablet.
Experience with mefloquine in infants less than 3 months old or weighing less than 5 kg is limited. Children weighing between 5 and 10 kg will receive a higher prophylactic dose of mefloquine than the recommended 5 mg/kg; however the tablet cannot be accurately subdivided into less than 1/4 tablet.
When prophylaxis with mefloquine fails, physicians should carefully evaluate which antimalarial to use for therapy. Regarding the use of halofantrine, see Warnings and Precautions.
Treatment: The recommended total therapeutic dose of mefloquine for nonimmune patients is 20 to 25 mg/kg. A lower total dose of 15 mg/kg may suffice for partially immune individuals. Thus, nonimmunes weighing over 45 kg should receive a total of 1 250 to 1 500 mg mefloquine (5 to 6 tablets) while partially immune patients of the same weight should receive 750 to 1 000 mg (3 to 4 tablets.
A second full dose should be given to patiens who vomit less than 30 minutes after receiving the drug. If vomiting occurs 30 to 60 minutes after a dose, an additional half-dose should be given.
Patients with acute P. vivax malaria treated with mefloquine are at high risk of relapse because mefloquine does not eliminate exoerythrocytic (hepatic phase) parasites. To avoid relapse after initial treatment of the acute infection with mefloquine, patients should subsequently be treated with an 8-aminoquinoline (e.g., primaquine) in order to eliminate liver forms.
If a full treatment course with mefloquine does not lead to improvement within 48 to 72 hours, alternative treatments should be considered. When breakthrough malaria occurs during mefloquine prophylaxis, physicians should carefully evaluate which antimalarial to use for therapy. Regarding the use of halofantrine, see Warnings and Precautions.
Mefloquine can be given for servere acute malaria after an initial course of i.v. quinine lasting at least 2 to 3 days. Interactions leading to adverse events can largely be prevented by allowing an interval of at least 12 hours after the last dose of quinine.
Availability And Storage: Each cross-scored (both sides), white, cylindrical, biplane tablet with bevelled edges imprinted ROCHE with hexagon on one side, contains: mefloquine base 250 mg as mefloquine HCl. Nonmedicinal ingredients: ammonium-calcium alginate, cornstarch, crospovidone, lactose, magnesium stearate, microcrystalline cellulose, poloxamer and talc. Blister packs of 8. Store at 15 to 30°C. The tablets are sensitive to moisture and should remain in their blister until consumed. (Shown in Product Recognition Section)
LARIAM® Roche Mefloquine HCl Antimalarial Agent