α-2-Piperidyl-2,8-bis(trifluormethyl)chinolin-4-methanol

Pharmaceuticals

Pharmaceuticals -> Antiparasitic products, insecticides and repellents -> Antiprotozoals

Breast Feeding; Lactation; Milk, Human; Anti-infective Agents; Antimalarials; Antiparasitic Agents; Antiprotozoal Agents

Antimalarial medicines > For chemoprevention

250-254

174-176 °C

White or slightly yellow crystalline powder; odorless; mp 259-260 °C (decomposes). Exhibits polymorphism. Freely soluble in methanol; soluble in ethanol, ethyl acetate; very slightly soluble in water. UV max (methanol): 222, 283, 304, 318 (epsilon 46700, 6600, 4000, 3100) /Hydrochloride salt/

Warning

H302: Harmful if swallowed [Warning Acute toxicity, oral]

P264, P270, P301+P317, P330, and P501 (click each P-code to see the statement)

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, incl mefloquine hydrochloride, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Mefloquine hydrochloride/

Karbwang J, White NJ; Clinical Pharmacokinetics of Mefloquine. Clin Pharmacokinet 19 (4): 264-79 (1990). A review of the pharmacokinetics of mefloquine (WR-142490) is presented, including the history and pharmacology of the drug, analytical methods, formulation, toxicology, efficacy, single and multiple dose pharmacokinetics, metabolism, absorption and disposition in patients with Falciparum malaria, drug interactions of mefloquine hydrochloride in a combination dosage form with both sulfadoxine and pyrimethamine (Fansimef).

Panisko DM, Keystone JS; Treatment of Malaria--1990; Drugs 39 (Feb): 160-89 (1990). A review of the treatment of malaria is presented, including the chemistry, pharmacokinetics, mechanisms of action, resistance, and toxicity of quinine, quinidine, chloroquine, amodiaquine, pyrimethamine, sulfonamides, mefloquine, sesquiterpene lactones, tetracyclines, and primaquine. The distribution of malaria and patterns of resistance are examined and the therapy of chloroquine resistant malaria in particular is considered. Adult and pediatric dosage schedules of commonly used agents for the treatment of chloroquine resistant malaria are listed. Management of complications of infection with severe malaria is also discussed.

Mefloquine hydrochloride is photolabile, and tablets of the drug should be stored at 25 °C but may be exposed to 15-30 °C.

Keep container tightly closed in a dry and well-ventilated place. /Mefloquine hydrochloride/

Control of environmental exposure: Do not let product enter drains. /Mefloquine hydrochloride/

Personal precautions, protective equipment and emergency procedures: Use personal protective equipment. Avoid dust formation. Avoid breathing vapors, mist or gas. Ensure adequate ventilation. Avoid breathing dust. Environmental precautions: Do not let product enter drains. Methods and materials for containment and cleaning up: Pick up and arrange disposal without creating dust. Sweep up and shovel. Keep in suitable, closed containers for disposal. /Mefloquine hydrochloride/

SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.

Product: Offer surplus and non-recyclable solutions to a licensed disposal company. Contaminated packaging: Dispose of as unused product. /Mefloquine hydrochloride/

Handle in accordance with good industrial hygiene and safety practice. Wash hands before breaks and at the end of workday. /Mefloquine hydrochloride/

Avoid contact with skin and eyes. Avoid formation of dust and aerosols. Provide appropriate exhaust ventilation at places where dust is formed. ... /Mefloquine hydrochloride/

Gloves must be inspected prior to use. Use proper glove removal technique (without touching glove's outer surface) to avoid skin contact with this product. Dispose of contaminated gloves after use in accordance with applicable laws and good laboratory practices. Wash and dry hands. /Mefloquine hydrochloride/

SRP: Local exhaust ventilation should be applied wherever there is an incidence of point source emissions or dispersion of regulated contaminants in the work area. Ventilation control of the contaminant as close to its point of generation is both the most economical and safest method to minimize personnel exposure to airborne contaminants. Ensure that the local ventilation moves the contaminant away from the worker.

Skin protection: Handle with gloves. /Mefloquine hydrochloride/

Eye/face protection: Safety glasses with side-shields conforming to EN166. Use equipment for eye protection tested and approved under appropriate government standards such as NIOSH (US) or EN 166(EU). /Mefloquine hydrochloride/

Respiratory protection: For nuisance exposures use type P95 (US) or type P1 (EU EN 143) particle respirator.For higher level protection use type OV/AG/P99 (US) or type ABEK-P2 (EU EN 143) respirator cartridges. Use respirators and components tested and approved under appropriate government standards such as NIOSH (US) or CEN (EU). /Mefloquine hydrochloride/

Body Protection: Complete suit protecting against chemicals. The type of protective equipment must be selected according to the concentration and amount of the dangerous substance at the specific workplace. /Mefloquine hydrochloride/

There is a possible increase in the risk of arrhythmias if mefloquine is given together with beta blockers, calcium channel blockers, amiodarone, pimozide, digoxin or antidepressants; there is also a possible increase in the risk of convulsions with chloroquine and quinine. Mefloquine concentrations are increased when given with ampicillin, tetracycline and metoclopramide. Caution should be observed with alcohol.

Concomitant administration of mefloquine and other related antimalarial compounds (e.g., quinine, quinidine and chloroquine) may produce electrocardiographic abnormalities and increase the risk of convulsions. If these drugs are to be used in the initial treatment of severe malaria, mefloquine administration should be delayed at least 12 hours after the last dose. Clinically significant QTc prolongation has not been found with mefloquine alone.

It has been shown in vitro that mefloquine is a substrate and an inhibitor of P-glycoprotein. Therefore, drug-drug interactions could also occur with drugs that are substrates or are known to modify the expression of this transporter. The clinical relevance of these interactions is not known to date.

Mefloquine does not inhibit or induce the CYP 450 enzyme system. Thus, concomitant administration of mefloquine hydrochloride tablets and substrates of the CYP 450 enzyme system is not expected to result in a drug interaction. However, mefloquine is metabolized by CYP3A4 and inhibitors of CYP3A4 may modify the pharmacokinetics/metabolism of mefloquine, leading to an increase in mefloquine plasma concentrations and potential risk of adverse reactions. Therefore, mefloquine hydrochloride tablets should be used with caution when administered concomitantly with CYP3A4 inhibitors. Similarly, inducers of CYP3A4 may modify the pharmacokinetics/metabolism of mefloquine, leading to a decrease in mefloquine plasma concentrations and potential reduction in efficacy of mefloquine hydrochloride tablets. Therefore, mefloquine hydrochloride tablets should also be used with caution when administered concomitantly with CYP3A4 inducers.

For more Interactions (Complete) data for MEFLOQUINE (17 total), please visit the HSDB record page.

Chronic therapy with mefloquine is associated with asymptomatic, transient serum enzyme elevations in up to 18% of patients. These elevations are usually mild and resolve without dose modifications. Despite widespread use, mefloquine has rarely been linked to clinically apparent acute liver injury and too few reports are available to characterize the clinical features of such injury. Instances of acute hepatocellular injury as well as cholestatic hepatitis have been linked to use of mefloquine. Allergic manifestations (rash, fever, eosinophilia) and autoantibody formation are rare.

IDENTIFICATION AND USE: Mefloquine is a white or slightly yellow crystalline powder that is formulated into tablets. Mefloquine is an antimalarial agent which acts as a blood schizonticide. It is used for the prevention and treatment of malaria caused by strains of Plasmodium falciparum or P. vivax. HUMAN EXPOSURE AND TOXICITY: Overdosage of mefloquine produces manifestations that are similar to the adverse reactions reported with the drug. 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). Since seizures may also occur at therapeutic doses, mefloquine is contraindicated in patients with a history of seizures. Mefloquine has also been associated with neuropsychiatric manifestations: anxiety, paranoia, depression, hallucinations and psychotic behavior. These manifestations may continue long after mefloquine has been discontinued. These neuropsychiatric effects have been reported both after overdose and at therapeutic doses. To minimize the chance of these adverse effects, use of mefloquine for prophylaxis is contraindicated in patients with active depression, a recent history of depression, generalized anxiety disorder, psychosis, schizophrenia or other major psychiatric disorders. There is also evidence that the use of halofantrine during mefloqune therapy and within 15 weeks of the last dose of mefloquine increases the risk of a potential fatal prolongation of the corrected QT interval (QTc). This risk may also be increased following co-administration with ketoconazole. Clinically significant QTc interval prolongation has not been reported with mefloquine monotherapy. Several studies in pregnant women have shown no increase in the risk of teratogenic effects or adverse pregnancy outcomes following mefloquine treatment or prophylaxis during pregnancy. The WHO concluded however, that treatment with mefloquine should be undertaken cautiously during the first 12-14 weeks of gestation. ANIMAL STUDIES: While two year studies in mice and rats failed to show an increase in tumors, mefloquine did produce toxic effects. In one such study, rats were administered mefloquine in the diet at 0, 5, 12.5 or 30 mg/kg/day for 2 years. In the high dose group the weight gain of both sexes was significantly depressed and the incidence of spontaneous death was increased. Males had decreased testicle size and paralysis of hind limbs, while females showed increased vaginal hemorrhage, cystic ovaries and distended uteri filled with fluid. Elevated liver enzymes and blood urea nitrogen levels occurred for both sexes. At study completion, both sexes showed lesions in eye, lung, kidney, reproductive organs, skeletal muscle, spleen and lymph node. Retinal degeneration, opacity of the lens and/or retinal edema occurred at both the mid and high dose group. (Severity was greater in females). Mild lesions of reproductive organs and bile duct hyperplasia were seen in the mid dose group. Males had lesions in the epididymis and prostate; epithelial vacuolization of epididymis, foamy macrophages in lungs and skeletal muscle degeneration were observed in both sexes of the low dose group. The potential for mefloquine to cause neurological effects were investigated in 7-week-old female rats given a single oral dose of the drug. Potential mefloquine-induced neurological effects were monitored using a standard functional observational battery, automated open field tests, automated spontaneous activity monitoring, a beam traverse task, and histopathology. Mefloquine induced dose-related changes in endpoints associated with spontaneous activity and impairment of motor function and caused degeneration of specific brain stem nuclei (nucleus gracilis). Increased spontaneous motor activity was observed only during the rats' normal sleeping phase, suggesting a correlate to mefloquine-induced sleep disorders. Mefloquine was also shown to be teratogenic in mice, rats and rabbits. In one study, rats were administered mefloquine at doses up to 100 mg/kg/day by intragastric intubation. In the high dose group, rats grew slower and consumed less feed than controls. Fetuses had reduced body weight, reduced crown-rump length, increased incidence of externally visible soft tissue and skeletal defects; domes craniums occurred at a high rate, high incidence of hydrocephalus; malformed interparietals, incompletely ossified supra occipitals, and incompletely ossified skull bones were also observed. In a similar study in the mouse, mefloquine at doses of 100 and 200 mg/kg/day resulted in decreased body weight and a high incidence of cleft palate in fetuses. Mefloquine was also shown to impair fertility in both male and female rats. Mefloquine was not found to be mutagenic in the following tests: Ames Test, Fluctuation Test, Host (Mouse) Mediated Assay, Micronucleus Test, Induction of Point Mutations, Yeast Treat and Plate Test.

/HUMAN EXPOSURE STUDIES/ Cardiotoxicity has become a major concern during treatment with antimalarial drugs. Lengthening of the QTc and severe cardiac arrhythmia have been observed ... The purpose of this prospective study was to evaluate whether antimalarial agents alter dispersion of the QTc and ventricular repolarization dynamicity. Sixty patients with uncomplicated falciparum malaria were randomly allocated in four groups of 15 patients and treated with quinine, mefloquine, artemether, or halofantrine at recommended doses. Patients in treatment groups were compared with a group including 15 healthy controls with no history of malaria and/or febrile illness within the last month. QTc dispersion was measured on surface electrocardiograms. Repolarization dynamicity was analyzed from Holter recordings, which allow automatic beat-to-beat measurement of QT and RR intervals. Plasma drug concentration was determined by reversed-phase high-performance liquid chromatography. No change in QTc dispersion was observed after treatment with quinine, mefloquine, or artemether. ... Mefloquine and artemether did not alter ventricular repolarization. Quinine induced a significant decrease in QT/RR slope of the same order of magnitude as those previously observed with quinidine. ...

/SIGNS AND SYMPTOMS/ Mefloquine in therapeutic use or overdose may cause headache, dizziness, vertigo, insomnia, visual and auditory hallucinations, panic attacks, severe depression, psychosis, confusion, and seizures. Neuropsychiatric side effects generally resolve within a few days after withdrawal of mefloquine and with supportive pharmacotherapy, but occasionally symptoms persist for several weeks.

/SIGNS AND SYMPTOMS/ Overdosage of mefloquine would be expected to produce manifestations that are principally extensions of the adverse reactions reported with the drug. 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).

/SIGNS AND SYMPTOMS/ Halofantrine should not be administered with mefloquine or within 15 weeks of the last dose of mefloquine due to the risk of a potential fatal prolongation of the QTc interval.

For more Human Toxicity Excerpts (Complete) data for MEFLOQUINE (21 total), please visit the HSDB record page.

Drug-Induced Liver Injury Severity and Toxicity (DILIst)

mefloquine

DILI Positive

Oral

DOI:10.1016/j.drudis.2019.09.022

/LABORATORY ANIMALS: Acute Exposure/ The intrinsic action of mefloquine on the cardiovascular system was examined in mouse and dog studies. Overall, mefloquine elicited dose-related hypotension. In the dog, a dose of 2.5 to 40 mg/kg given intravenously over a two minute period resulted in hypotension. An IV bolus administration of doses ranging from 1 to 30 mg/kg induced transient hypotension.

/LABORATORY ANIMALS: Acute Exposure/ Groups of two male and two female beagle dogs received oral administration of single doses of mefloquine suspended in methylcellulose:Tween 80:water at 0, 6, 13.5, 30 or 68 mg/kg. Occasional slight emesis occurred in one or two dogs. An increase in the SGPT values was also noted.

/LABORATORY ANIMALS: Acute Exposure/ Groups of two white swine received four oral doses of mefloquine at 0, 25 or 50 mg/kg during 44 hours of irradiation and ten oral doses at 0, 15 or 25 mg/kg during ten days of irradiation. Mefloquine did not elicit a phototoxic reaction in white swine. However, four doses of 50 mg/kg during 44 hours of irradiation produced incoordination, convulsions and death. There was no evidence of abnormal hematologic or biochemical blood values or gross microscopic lesions at 15 or 25 mg/kg for ten days.

/LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ The intrinsic action of mefloquine on the cardiovascular system was examined in mouse and dog studies. Overall, mefloquine elicited dose-related hypotension. In the mouse study, a lethal intraperitoneal dose of 100 mg/kg caused transient hypertension that was followed by progressive hypotension. Intravenous administration of doses ranging from 1 to 20 mg/kg resulted in sharp dose-related hypotension.

For more Non-Human Toxicity Excerpts (Complete) data for MEFLOQUINE (40 total), please visit the HSDB record page.

Mefloquine is contraindicated in patients with a history of seizures. Because mefloquine may increase the risk of seizures in patients with epilepsy, use of the drug in such patients should be limited to treatment of malaria and only if there are compelling medical reasons for its use.

Mefloquine has been associated with neuropsychiatric manifestations ranging from anxiety, paranoia, and depression to hallucinations and psychotic behavior; these manifestations occasionally have been reported to continue long after mefloquine has been discontinued. To minimize the chance of these adverse effects, use of mefloquine for prophylaxis is contraindicated in patients with active depression, a recent history of depression, generalized anxiety disorder, psychosis, or schizophrenia or other major psychiatric disorders. In addition, mefloquine should be used with caution in individuals with a previous history of depression. Neuropsychiatric manifestations such as acute anxiety, depression, restlessness, or confusion occurring in a patient receiving mefloquine prophylaxis may be considered prodromal for a serious psychiatric event, and the manufacturer states that mefloquine should be discontinued in these patients and an alternative drug substituted.

... The relationship between mefloquine antimalarial treatment and the outcome of pregnancy in Karen women living in an area along the western border of Thailand where multidrug-resistant Plasmodium falciparum infections are common /was investigated/. Of 3,587 pregnancies investigated, 208 (5.8%) were exposed to mefloquine, 656 (18.3%) to quinine only, and 909 (25.3%) to other antimalarials, and 2,470 (68.9%) had no documented malaria. There were 61 stillbirths and 313 abortions. Women who received mefloquine treatment during but not before pregnancy had a significantly greater risk of stillbirth than did women treated with quinine alone (odds ratio [OR], 4.72; 95% confidence interval [CI], 1.7-12.7), women exposed to other treatments (OR, 5.10; 95% CI, 2-13.1), and women who had no malaria (OR, 3.50; 95% CI, 1.6-7.6) (P < .01). This association remained after adjustment for all identified confounding factors. Mefloquine was not associated with abortion, low birth weight, neurological retardation, or congenital malformations. Mefloquine treatment during pregnancy was associated with an increased risk of stillbirth.

Emergency and supportive measures: Maintain an open airway and assist ventilation if necessary. Treat seizures, coma, hypotension, and methemoglobinemia if they occur. Treat massive hemolysis with blood transfusions if needed, and prevent hemoglobin deposition in the kidney tubules by alkaline diuresis ... continuously monitor the ECG for at least 6 to 8 hr. /Chloroquine and Other Aminoquinolines/

Treat cardiotoxicity as for quinidine poisoning with sodium bicarbonate. Potassium should be administered for severe hypokalemia but should be dosed with caution and with frequent serum potassium measurements, as hyperkalemia may exacerbate quinidine-like cardiotoxicity. If dopamine and norepinephrine are not effective, epinephrine infusion may be useful in treating hypotension via combined vasoconstrictor and inotropic actions ... . High-dose diazepam ... (given over 30 minutes after endotracheal intubation) has been reported to reduce mortality in animals and to relieve cardiotoxicity in human chloroquine poisonings. The mechanism of protection is unknown. /Chloroquine and Other Aminoquinolines/

Decontamination: Prehospital. Administer activated charcoal orally if conditions are appropriate. Perform gastric lavage for significant ingestions. Because of extensive tissue distribution, enhanced removal procedures are ineffective. /Chloroquine and Other Aminoquinolines/

/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/

For more Antidote and Emergency Treatment (Complete) data for MEFLOQUINE (7 total), please visit the HSDB record page.

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, incl mefloquine hydrochloride, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Mefloquine hydrochloride/

P - Antiparasitic products, insecticides and repellents

P01BC02

Sporozoites located in the salivary glands of mosquitoes infected with malaria parasites are introduced into the bloodstream of a human host during mosquito feeding. These sporozoites rapidly invade the liver, where they mature into liver-stage schizonts, rupturing and releasing 2,000 - 40,000 merozoites that invade red blood cells. Mefloquine is an antimalarial drug acting as a blood schizonticide, preventing and treating malaria.

The mechanism of action of mefloquine is not completely understood. Some studies suggest that mefloquine specifically targets the 80S ribosome of the Plasmodium falciparum, inhibiting protein synthesis and causing subsequent schizonticidal effects. There are other studies in the literature with limited in vitro data on mefloquine's mechanism of action.

Mefloquine, like chloroquine and quinine, is a blood schizonticidal agent and is active against the intraerythrocytic stages of parasite development. Similar to chloroquine and quinine, mefloquine appears to interfere with the parasite's ability to metabolize and utilize erythrocyte hemoglobin. 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. While the precise mechanism of action of mefloquine is unknown, it may involve mechanisms that differ from those proposed for chloroquine.

The effects of the antimalarial drug, mefloquine, on the uptake and release of Ca2+ by crude microsomes from dog brain were investigated using a spectrophotometric method. Mefloquine inhibited the inositol-1,4,5-phosphate (IP3)-induced Ca2+ release with an IC50 of 42 uM, but was a weaker inhibitor of the uptake of Ca2+ into the vesicles (IC50: 272 uM). These effects of mefloquine are in contrast to its actions on Ca2+ uptake and release by skeletal muscle microsomes, where its predominant effect was seen to be the inhibition of Ca2+ uptake into the vesicles. Mefloquine was found to be more potent than quinine as a specific inhibitor of Ca2+ release from IP3-sensitive stores in dog brain microsomes. The possibility of the drug affecting cellular IP3-linked signal transduction processes should be considered.

The terminal elimination half-life of mefloquine ranges from 0.9 - 13.8 days, according to one pharmacokinetic review. In various studies of healthy adults, the mean elimination half-life of mefloquine varied between 2 and 4 weeks, with a mean half-life of approximately 21 days.

In healthy volunteers ... mefloquine /was/ absorbed with a half-life of 1 to 4 hours ... and terminal elimination half-life from 13.8 to 40.9 days (median 20 days).

Half-life: Elimination - 13 to 33 days (median 20 days); may be shorter in seriously ill patients, such as patients with acute malaria.

The pharmacokinetics of mefloquine were studied in 10 healthy subjects and in 12 patients with severe acute Plasmodium falciparum malaria who received 750 mg oral mefloquine. Peak concn of mefloquine were achieved in both groups at 20-24 hr. The mean elimination half-life was 385 hr in normal subjects and was 493 hr in patients with malaria, a significant difference.

In several studies in healthy adults, the mean elimination half-life of mefloquine varied between 2 and 4 weeks, with an average of about 3 weeks.

For more Biological Half-Life (Complete) data for MEFLOQUINE (9 total), please visit the HSDB record page.

Mefloquine is heavily metabolized in the liver by the CYP3A4 enzyme. Two metabolites have been identified; the main metabolite, 2,8-bis-trifluoromethyl-4-quinoline carboxylic acid, which inactive against plasmodium falciparum. The second metabolite, an alcohol, is found in small quantities.

Biotransformation: Hepatic (partial); metabolized primarily to the carboxylic acid metabolite.

Mefloquine is extensively metabolized in the liver by the cytochrome P450 system. In vitro and in vivo studies strongly suggested that CYP3A4 is the major isoform involved. Two metabolites of mefloquine have been identified in humans. The main metabolite, 2,8-bis-trifluoromethyl-4-quinoline carboxylic acid, is inactive in Plasmodium falciparum. In a study in healthy volunteers, the carboxylic acid metabolite appeared in plasma 2 to 4 hours after a single oral dose. Maximum plasma concentrations of the metabolite, 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 minute quantities only.

TML814419R

MEFLOQUINE

Established Pharmacologic Class [EPC] - Antimalarial

Mefloquine is an Antimalarial.

Mefloquine is readily absorbed from the gastrointestinal tract; food significantly increases absorption and increases bioavailability by 40%. The bioavailability of tablets compared with the oral solution preparation of mefloquine is over 85%. Cmax is achieved in 6 to 24 hours in healthy volunteers after a single dose. Average blood concentrations range between 50 to 110 ng/ml/mg/kg. A weekly dose of 250 mg leads to steady-state plasma concentrations of 1000 to 2000 μg/L, after 7 to 10 weeks of administration.

Mefloquine is believed to be excreted in the bile and feces. In healthy volunteers who have achieved steady-state concentrations of mefloquine, the unchanged drug was excreted at 9% of the ingested dose, and excretion of its carboxylic metabolite under was measured at 4% of the ingested dose. Concentrations of other metabolites could not be determined.

The apparent volume of distribution is in healthy adults is about 20 L/kg with wide tissue distribution. Various estimates of the total apparent volume of distribution range from 13.3 to 40.9L/kg. Mefloquine can accumulate in erythrocytes that have been infected with malaria parasites.

The systemic clearance of mefloquine ranges from 0.022 to 0.073 L/h/kg, with an increased clearance during pregnancy. Prescribing information mentions a clearance rate of 30 mL/min.

Mefloquine is reasonably well absorbed from the gastrointestinal tract but there is marked interindividual variation in the time required to achieve peak plasma concentrations. ... Mefloquine undergoes enterohepatic recycling. It is approximately 98% bound to plasma proteins and is widely distributed throughout the body. The pharmacokinetics of mefloquine may be altered by malaria infection with reduced absorption and accelerated clearance. ... Mefloquine is excreted in small amounts in breast milk. It has a long elimination half-life of around 21 days, which is shortened in malaria to about 14 days, possibly because of interrupted enterohepatic cycling. Mefloquine is metabolized in the liver and excreted mainly in the bile and feces. Its pharmacokinetics show enantioselectivity after administration of the racemic mixture, with higher peak plasma concentrations and area under the curve values, and lower volume of distribution and total clearance of the SR enantiomer than its RS antipode.

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 6-24 hours (median, about 17 hours) after a single oral dose of mefloquine. Maximum plasma concentrations in ug/L are roughly equivalent to the dose in milligrams (for example, a single 1000 mg dose produces a maximum concentration of about 1000 ug/L). At a dose of 250 mg once weekly, maximum steady state plasma concentrations of 1000-2000 ug/L are reached after 7-10 weeks.

Antimalarials

MEDICATION

Use (kg; approx.) in Germany (2009): >100

Fansimef is a combination of mefloquine with Fansidar (pyrimethamine and sulfadoxine) /Mefloquine hydrochloride/

Table: Mefloquine Hydrochloride Preparations [Table#6364]