Mefloquine (Tablets) Instructions for Use

Marketing Authorization Holder

Pharmazashchita SPC, FSUE FMBA of Russia (Russia)

ATC Code

P01BC02 (Mefloquine)

Active Substance

Mefloquine (Rec.INN WHO registered)

Dosage Form

Mefloquine

Tablets 250 mg: 8, 10, or 40 pcs.

Dosage Form, Packaging, and Composition

Tablets are white or almost white, round, biconvex, with a score on one side.

Excipients: microcrystalline cellulose – 193.41 mg, povidone K-25 – 25 mg, crospovidone – 2.5 mg, magnesium stearate – 2.5 mg, colloidal silicon dioxide – 2.5 mg.

4 pcs. – blister packs (2) – cardboard packs.
10 pcs. – blister packs (1) – cardboard packs.
10 pcs. – blister packs (4) – cardboard packs.

Clinical-Pharmacological Group

Antimalarial drug

Pharmacotherapeutic Group

Antiprotozoal agents; antimalarial agents; methanolquinolines

Pharmacological Action

Antimalarial agent, a derivative of 4-methanolquinoline. Mefloquine acts on the asexual intracellulare erythrocytic forms of human malaria pathogens Plasmodium falciparum, Plasmodium vivax, on the circulating schizonts of Plasmodium malariae and Plasmodium ovale. It is not active against the hepatic stages of the parasites. It is effective against malaria pathogens resistant to other antimalarial drugs, for example, chloroquine, proguanil, pyrimethamine and the combination of pyrimethamine with sulfonamides. For P. falciparum, the development of resistance to mefloquine is possible, mainly in Southeast Asia. In some regions, cross-resistance between mefloquine and halofantrine, mefloquine and quinine has been noted.

To obtain up-to-date information on resistance in different geographical regions, it is necessary to consult with national expert organizations.

Pharmacokinetics

After oral administration, Mefloquine is well absorbed from the gastrointestinal tract. Food intake significantly accelerates the rate and increases the extent of absorption by 40 %. The average time to reach C_max of mefloquine after a single dose is 17 hours (6-24 hours). C_max in plasma in µg/l is approximately equal to the dose taken in mg (for example, a single dose of 1000 mg gives a C_max of about 1000 µg/l). After taking 250 mg once a week, the equilibrium C_max in plasma, equal to 1000-2000 µg/l, is reached after 7-10 weeks. To achieve 95% prophylactic efficacy, a mefloquine blood concentration of 620 ng/ml is required.

The V_d of mefloquine is 20 l/kg, indicating its penetration into many tissues. It accumulates in erythrocytes, inside which malaria parasites are located, in concentrations approximately twice the plasma concentrations. It penetrates the placenta and into breast milk. Excretion in breast milk appears to be minimal. Plasma protein binding is 98 %.

Mefloquine metabolism occurs mostly in the liver with the participation of cytochrome P450. In vitro and in vivo studies have shown that Mefloquine is metabolized mainly by the isoenzyme CYP3A4 to form 2 metabolites: the main metabolite – 2,8-bis-trifluoromethyl-4-quinoline carboxylic acid and an alcohol. The main metabolite is inactive against P. falciparum, appears in plasma 2-4 hours after a single oral dose of mefloquine, its C_max in plasma is 50 % higher than that of mefloquine and is reached after 2 weeks. After this, the decrease in concentrations of the main metabolite and mefloquine in plasma occurs at the same rate. The AUC of the main metabolite is 3-5 times higher than the same indicator for the original mefloquine. The other metabolite, the alcohol, is present in very small quantities.

The average T_1/2 of mefloquine is 3 weeks (from 2 to 4 weeks), does not change during long-term antimalarial prophylaxis. It is excreted as metabolites mainly with bile and feces. The total clearance, most of which is hepatic, is 30 ml/min. The excretion of unchanged mefloquine and its main metabolite by the kidneys is about 9% and 4%, respectively. Other metabolites are not detected in urine.

In acute malaria, changes in pharmacokinetic parameters may be observed.

Indications

Treatment of mild and moderate forms of malaria caused by strains of P. falciparum resistant to other antimalarial drugs, P. vivax and malaria of mixed etiology. Considering that the sensitivity of the pathogen may vary over time and depending on the geographical area, it is recommended to follow the instructions of national and international guidelines. Prophylaxis of malaria in persons traveling to malaria-endemic regions, especially regions with a high risk of infection with strains of P. falciparum resistant to other antimalarial drugs. Emergency therapy (self-help): self-administration as emergency therapy for suspected malaria if it is not possible to obtain urgent medical care.

ICD codes

Dosage Regimen

Administer orally with at least 240 mL (8 oz) of water and with food to improve absorption and reduce gastrointestinal adverse effects.

For treatment of acute malaria in adults, administer a single dose of 1250 mg (five 250 mg tablets). For children, base the dose on body weight: administer 20-25 mg/kg as a single dose. Do not exceed the total adult dose of 1250 mg.

For chemoprophylaxis in adults, administer 250 mg once weekly. Start prophylaxis 1-3 weeks before travel to an endemic area. Continue weekly doses throughout the stay and for 4 weeks after leaving the endemic area.

For chemoprophylaxis in children, base the dose on body weight: administer 5 mg/kg once weekly. Do not exceed the adult dose of 250 mg. For children weighing less than 5 kg, do not use mefloquine.

For emergency self-treatment (stand-by therapy), administer a single dose as for acute malaria treatment. Use only if medical care is unavailable within 24 hours. Seek professional medical evaluation immediately after self-administration.

Crush and mix tablets with water for patients unable to swallow whole tablets. Do not administer to patients with a history of convulsions or severe psychiatric disorders.

Monitor for neuropsychiatric adverse reactions during and after prophylaxis. Discontinue therapy if signs of psychosis, depression, anxiety, or confusion occur.

Adverse Reactions

From the hematopoietic system: often – thrombocytopenia; infrequently – leukopenia, leukocytosis; frequency unknown – agranulocytosis and aplastic anemia.

From the metabolism: often – anorexia.

From the psyche: very often – sleep disorders (insomnia, nightmares); often – agitation, restlessness, anxiety, depression, aggression, emotional lability, panic attacks, confusion, hallucinations, bipolar disorder, psychotic reactions including delusional disorder, depersonalization and mania, paranoia. Infrequently, these symptoms persisted for a long time after discontinuation of mefloquine. Cases of suicide, suicidal thoughts, behavior with risk of self-harm, for example, suicide attempts, have been reported.

From the nervous system: very often – dizziness, loss of balance, headache, drowsiness; often – fainting, memory impairment, sensory and motor neuropathies (including paresthesia, tremor, ataxia), convulsions; infrequently – encephalopathy.

From the organ of vision: often – visual disturbances; frequency unknown – blurred vision, cataract, retinal lesions and optic neuropathy with the possibility of delayed manifestation, both during and after the end of therapy.

From the hearing organ and labyrinthine disorders: very often – vertigo; often – hearing impairment, vestibular disorders including tinnitus.

From the cardiovascular system: often – tachycardia, palpitations, bradycardia, arrhythmia, extrasystoles, other transient cardiac conduction disorders; circulatory disorders (decreased, increased blood pressure, hot flashes); infrequently: AV block.

From the respiratory system: often – shortness of breath; very rarely – pneumonia, pneumonitis (possibly of allergic etiology).

From the digestive system: very often – nausea, diarrhea, abdominal pain, vomiting; often – dyspepsia.

From the liver and biliary tract frequency unknown – liver function disorders associated with the use of mefloquine (from asymptomatic transient increase in transaminase activity to liver failure).

Disorders of the skin and subcutaneous tissues often – skin rash, exanthema, erythema, urticaria, itching, alopecia, hyperhidrosis; infrequently – erythema multiforme, Stevens-Johnson syndrome.

From the musculoskeletal system often – muscle weakness, muscle cramps, myalgia, arthralgia.

From laboratory parameters often – transient increase in transaminase activity.

General reactions often – edema, chest pain, weakness, malaise, fatigue, chills, fever.

Contraindications

Hypersensitivity to mefloquine or related drugs (quinine, quinidine). Concomitant use with halofantrine, administration of halofantrine after mefloquine therapy within 15 weeks after discontinuation of the latter. Concomitant use with ketoconazole, administration of ketoconazole after mefloquine therapy within 15 weeks after discontinuation of the latter. Use for prophylactic purposes in active depression and severe mental disorders, convulsions (including history). Children under 3 months of age or with body weight less than 5 kg (experience of use is limited).

With caution hepatic insufficiency, epilepsy, mental illness, heart disease, age over 65 years. In combination with quinine and quinidine.

Use in Pregnancy and Lactation

If it is necessary to use mefloquine during pregnancy and breastfeeding, reference should be made to current international guidelines (for example, WHO).

The use of mefloquine in the first trimester of pregnancy is possible only if the expected benefit to the mother outweighs the potential risk to the fetus. Women of reproductive age should be prescribed treatment only if reliable contraception is used throughout the entire time of taking mefloquine and for 3 months after taking its last dose. However, if pregnancy occurs during malaria chemoprophylaxis with mefloquine, there are no indications for termination of pregnancy.

The activity of small amounts of mefloquine entering breast milk is unknown. No adverse reactions were noted in breastfed children whose mothers took Mefloquine.

In experimental studies, when mefloquine was used in doses 5-20 times higher than therapeutic for humans, it had a teratogenic effect in mice and rats and an embryotoxic effect in rabbits. However, clinical experience with mefloquine has not revealed any embryotoxic or teratogenic effects.

Use in Hepatic Impairment

Should be used with caution in patients with hepatic insufficiency.

Use in Renal Impairment

Use with caution in patients with impaired renal function.

Pediatric Use

Contraindicated for use in children under 3 years of age (experience of use is limited).

Geriatric Use

Should be used with caution in patients over 65 years of age.

Special Precautions

Mefloquine may increase the risk of seizures in patients with epilepsy. Such patients can be prescribed Mefloquine only for treatment and if there are absolute indications for its use.

After taking quinine or quinidine, Mefloquine can be taken no earlier than 12 hours later.

In patients with impaired liver function, delayed elimination of mefloquine is possible, which may lead to an increase in its plasma concentrations and an increased risk of adverse reactions.

With prophylactic use for a long time (taking mefloquine for more than 1 year is undesirable), periodic analysis of liver function indicators and an ophthalmological examination are necessary. The safety profile of mefloquine during prophylactic use is characterized by a predominance of neuropsychiatric reactions, such as: anxiety, depression, restlessness or confusion. If these adverse events occur, mefloquine therapy should be discontinued and another drug prescribed. Due to the long T_1/2 of mefloquine, adverse reactions may develop or persist for up to several weeks after its last dose. In a small number of patients, cases of psychoneurotic disorders (including depression, dizziness and vertigo, as well as loss of balance) have been described, which were observed for several months or more after discontinuation of mefloquine.

If visual disturbances occur, you should consult your doctor to consider the possibility of continuing treatment with mefloquine.

If symptoms of polyneuropathy develop, including pain, burning, tingling, numbness and/or weakness, treatment with mefloquine should be discontinued.

The choice of drug for malaria prophylaxis depends on the resistance of P. falciparum to it in a particular region.

The entry of medicinal products into the environment should be minimized. Disposal of mefloquine preparations via wastewater or together with household waste is not allowed. If possible, special systems for the disposal of medicinal products should be used.

Effect on ability to drive vehicles and operate machinery

During the treatment period, patients should avoid driving vehicles and other activities requiring high concentration and speed of psychomotor reactions.

Drug Interactions

Concomitant administration of mefloquine and quinine, quinidine and chloroquine may cause ECG changes and increase the risk of seizures.

Use of halofantrine simultaneously with mefloquine, as well as within 15 weeks after the last dose taken, leads to a significant prolongation of the QTc interval. Concomitant administration of mefloquine and ketoconazole increases plasma concentrations of mefloquine and its T_1/2. Prescription of ketoconazole simultaneously with mefloquine, as well as within 15 weeks after the last dose of mefloquine, may lead to prolongation of the QTc interval. During therapy with mefloquine alone, clinically significant QTc prolongation does not occur. Concomitant use of other drugs affecting cardiac conduction (antiarrhythmic drugs, beta-blockers, slow calcium channel blockers, antihistamines, in particular histamine H₁-receptor blockers, tricyclic antidepressants and phenothiazines) may also theoretically play a role in QTc interval prolongation. The effect of simultaneous use of mefloquine and the above-mentioned drugs on cardiac function has not been definitively established.

Mefloquine reduces the effectiveness of anticonvulsant drugs (valproic acid, carbamazepine, phenobarbital or phenytoin) by reducing their plasma concentrations. It is necessary to monitor the plasma concentrations of the drugs. In some cases, dose adjustment of anticonvulsant drugs may be required.

Mefloquine may reduce the immunogenicity of oral live typhoid vaccines when taken concomitantly, so vaccination with live attenuated vaccines should be completed at least 3 days before the first dose of mefloquine.

Other drug interactions of mefloquine are unknown. But persons taking other drugs, in particular, anticoagulants or hypoglycemic agents, should undergo medical monitoring before traveling to an endemic region.

Mefloquine is not an inhibitor or inducer of cytochrome P450. Consequently, the metabolism of drugs prescribed simultaneously with mefloquine can be expected to remain unchanged. However, inhibitors of the CYP3A4 isoenzyme may alter the pharmacokinetics and metabolism of mefloquine, which may lead to an increase in mefloquine plasma concentration and possible development of adverse reactions. In this regard, caution should be exercised when using mefloquine and inhibitors of the CYP3A4 isoenzyme concomitantly. Inducers of the CYP3A4 isoenzyme may also alter the pharmacokinetics and metabolism of mefloquine, which may lead to a decrease in mefloquine plasma concentrations.

There is evidence that concomitant administration of ketoconazole, a strong inhibitor of the CYP3A4 isoenzyme, and mefloquine led to an increase in plasma concentrations of the latter and its T_1/2.

Long-term use of rifampicin, a potent inducer of the CYP3A4 isoenzyme, led to a decrease in mefloquine plasma concentration and its T_1/2.

Mefloquine is an inhibitor of P-glycoprotein according to in vitro studies. Therefore, the possibility of drug interaction of mefloquine with drugs that are substrates of P-glycoprotein or have the ability to alter the expression of this transporter cannot be excluded. The clinical significance of this interaction is currently unknown.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.