Mefloquine tablets 250mg, No. 10

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. Given that the sensitivity of the pathogen can vary over time and depending on the geographical area, it is recommended to follow the guidance of national and international guidelines. Prevention of malaria in persons traveling to malaria-prone regions, especially to regions with a high risk of infection with P. falciparum strains resistant to other antimalarial drugs. Emergency therapy (self-help): Self-administration as an emergency treatment for suspected malaria if urgent medical attention is not possible.

Inside. The dose, the regimen of use and the duration of therapy are determined individually, depending on the indications, clinical situation, age and body weight of the patient.

Active ingredient: mefloquine hydrochloride -274.09 mg,

which corresponds to the content of mefloquine base 250 mg

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.

Hypersensitivity to mefloquine or drugs close to it (quinine, quinidine). Concomitant use with halofantrine, taking halofantrine after therapy with mefloquine within 15 weeks after discontinuation of the latter. Concomitant use with ketoconazole, taking ketoconazole after mefloquine therapy within 15 weeks after the latter is discontinued. Prophylactic use for active depression and severe mental disorders, seizures (including a history). Children under 3 months of age or weighing less than 5 kg (experience of use is limited).

With care: liver failure, epilepsy, mental illness, heart disease, age over 65 years. In combination with quinine and quinidine.

The tablets are white or almost white, round, biconvex, with a line on one side.

Ingredients :

Active ingredient: mefloquine hydrochloride -274.09 mg,

which corresponds to the content of mefloquine base 250 mg

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.

Pharmaco-therapeutic group: Antimalarial agent

Pharmachologic effect:

Antimalarial 4-methanolquinoline derivative. Mefloquine acts on asexual intracellular erythrocyte forms of human malaria pathogens Plasmodium falciparum, Plasmodium vivax, on circulating schizonts Plasmodium malariae and Plasmodium ovale. Inactive against the hepatic stages of parasites. Effective against malaria pathogens resistant to other antimalarial drugs, such as chloroquine, proguanil, pyrimethamine, and pyrimethamine / sulfonamide combinations. P. falciparum may develop resistance to mefloquine mainly in Southeast Asia. In some regions, cross-resistance has been reported between mefloquine and halofantrine, mefloquine and quinine.

National expert organizations should be consulted for up-to-date information on resistance in different geographic regions.

Pharmacokinetics

After oral administration, mefloquine is well absorbed from the gastrointestinal tract. Eating food significantly speeds up the speed and increases the degree of absorption by 40%. The average time to reach Cmax of mefloquine after a single dose is 17 hours (6-24 hours). Cmax in plasma in ?g / L is approximately equal to the accepted dose in mg (for example, a single dose of 1000 mg gives a Cmax of about 1000 ?g / L). After taking 250 mg once a week, the equilibrium Cmax in plasma, equal to 1000-2000 ?g / l, is reached after 7-10 weeks. To achieve 95% effectiveness of prophylaxis, a blood concentration of mefloquine of 620 ng / ml is required.

The Vd of mefloquine is 20 l / kg, which indicates its penetration into many tissues. It accumulates in erythrocytes, inside which there are malaria parasites, at concentrations approximately twice the plasma concentration. Penetrates through the placenta and into breast milk. Excretion in breast milk appears to be minimal. Communication with plasma proteins - 98%.

Metabolism of mefloquine is mainly carried out in the liver with the participation of cytochrome P450. In in vitro and in vivo studies, it was shown that mefloquine is metabolized mainly by the CYP3A4 isoenzyme with the formation of 2 metabolites: the main metabolite - 2,8-bis-trifluoromethyl-4-quinoline carboxylic acid and alcohol. The main metabolite is inactive against P. falciparum, appears in plasma 2-4 hours after a single oral intake of mefloquine, its Cmax in plasma is 50% higher than that of mefloquine and is reached after 2 weeks. Thereafter, the decrease in plasma concentrations of the main metabolite and mefloquine occurs at the same rate. The AUC of the main metabolite is 3-5 times higher than that of the parent mefloquine. Another metabolite, alcohol, is present in very small amounts.

The average T1 / 2 of mefloquine is 3 weeks (from 2 to 4 weeks), does not change during long-term antimalarial prophylaxis. It is excreted in the form of metabolic products mainly with bile and feces. The total clearance, most of which is hepatic, is 30 ml / min. Excretion of unchanged mefloquine and its main metabolite by the kidneys is about 9% and 4%, respectively. Other metabolites are not found 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. Given that the sensitivity of the pathogen can vary over time and depending on the geographical area, it is recommended to follow the guidance of national and international guidelines. Prevention of malaria in persons traveling to malaria-prone regions, especially to regions with a high risk of infection with P. falciparum strains resistant to other antimalarial drugs. Emergency therapy (self-help): Self-administration as an emergency treatment for suspected malaria if urgent medical attention is not possible.

Dosage regimen

Inside. The dose, the regimen of use and the duration of therapy are determined individually, depending on the indications, clinical situation, age and body weight of the patient.

Side effect

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

From the side of metabolism: often - anorexia.

From the side of the psyche: very often - sleep disturbances (insomnia, nightmares); often - agitation, anxiety, 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, self-harm-risk behaviors such as suicidal 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 paresthesias, tremors, ataxia), convulsions; infrequently - encephalopathy.

From the side of the organ of vision: often - visual impairment; the frequency is unknown - blurred vision, cataracts, retinal lesions and neuropathy of the optic nerve with the possibility of delayed manifestation, both during and after the end of therapy.

On the part of the organ of hearing and labyrinthine disorders: very often - vergygo, often - hearing impairment, vestibular disorders, including ringing in the ears.

From the side of the cardiovascular system: often - tachycardia, palpitations, bradycardia, arrhythmia, extrasystoles, other transient cardiac conduction disorders; circulatory disorders (decrease, increase in blood pressure, hot flashes); infrequently: AV block.

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

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

From the liver and biliary tract: the frequency is unknown - liver dysfunction associated with the use of mefloquine (from an asymptomatic transient increase in the activity of granaminases to liver failure).

Skin and subcutaneous tissue disorders: often - skin rash, exanthema, erythema, urticaria, pruritus, alopecia, hyperhidrosis; infrequently - erythema multiforme, Stevens-Johnson syndrome.

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

On the part of laboratory parameters: often - a transient increase in the activity of transaminases.

General reactions: often - swelling, chest pain, weakness, feeling unwell, fatigue, chills, fever.

Contraindications for use

Hypersensitivity to mefloquine or drugs close to it (quinine, quinidine). Concomitant use with halofantrine, taking halofantrine after therapy with mefloquine within 15 weeks after discontinuation of the latter. Concomitant use with ketoconazole, taking ketoconazole after mefloquine therapy within 15 weeks after the latter is discontinued. Prophylactic use for active depression and severe mental disorders, seizures (including a history). Children under 3 months of age or weighing less than 5 kg (experience of use is limited).

With care: liver failure, epilepsy, mental illness, heart disease, age over 65 years. In combination with quinine and quinidine.

Application during pregnancy and lactation

If you need to use mefloquine during pregnancy and during breastfeeding, you should refer to the 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 they use reliable contraception for the entire duration of mefloquine intake and for 3 months after taking its last dose. But when pregnancy occurs against the background of chemoprophylaxis of malaria with mefloquine, there are no indications for termination of pregnancy.

The activity of small amounts of mefloquine passed into breast milk is unknown. In breastfed children whose mothers took mefloquine, no adverse reactions were noted.

In experimental studies, when using mefloquine 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, the experience of clinical use of mefloquine did not reveal any embryotoxic or teratogenic effects in it.

Application for violations of liver function

It should be used with caution in patients with hepatic impairment.

Application for impaired renal function

Use with caution in patients with impaired renal function.

Application in children

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

Use in elderly patients

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

special instructions

Mefloquine may increase the risk of seizures in people with epilepsy. Such patients can be prescribed mefloquine only for the purpose of treatment and in the presence of absolute indications for its use.

After taking quinine or quinidine, you can take mefloquine no earlier than 12 hours later.

In patients with impaired liver function, slow elimination of mefloquine is possible, which can lead to an increase in plasma concentrations of the latter 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 required. The safety profile of mefloquine in prophylactic use is characterized by the predominance of neuropsychiatric reactions, such as: anxiety, depression, anxiety or confusion. If these adverse events occur, mefloquine therapy should be discontinued and another drug should be prescribed. Due to the prolonged T1 / 2 of mefloquine, adverse reactions can develop or persist up to several weeks after the 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,that have been observed for several months or more after stopping mefloquine.

If visual impairment occurs, you should contact 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 the prevention of malaria depends on the resistance of P. falciparum to it in a particular region.

The release of drugs into the environment should be minimized. Disposal of mefloquine preparations with waste water or with household waste is not allowed. Whenever possible, special systems should be used for the disposal of drugs.

Influence on the ability to drive vehicles and control mechanisms

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

Drug interactions

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

Halofantrine usesimultaneously with mefloquine, as well as within 15 weeks after the last dose taken, leads to a significant lengthening of the QTc interval. The simultaneous administration of mefloquine and ketoconazole increases plasma concentrations of mefloquine and its T1 / 2. The administration of ketoconazole concomitantly with mefloquine, as well as within 15 weeks after the last dose of mefloquine, may lead to a prolongation of the QTc interval. There is no clinically significant QTc prolongation with mefloquine alone. Concomitant use of other drugs that affect cardiac conduction (antiarrhythmics, beta-blockers, slow calcium channel blockers, antihistamines, in particular histamine H1 receptor blockers, tricyclic antidepressants and phenothiazines) can theoretically also play a role in lengthening the QTc interval.The effect of the simultaneous use of mefloquine and the above drugs on cardiac function has not been conclusively established.

Mefloquine reduces the effectiveness of anticonvulsants (valproic acid, carbamazepine, phenobarbital, or phenytoin) by decreasing their plasma concentrations. It is necessary to control the concentration of drugs in plasma. In some cases, it may be necessary to adjust the dose of anticonvulsants.

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

No other drug interactions with mefloquine are known. But persons receiving other drugs, in particular, anticoagulants or hypoglycemic agents , must undergo medical supervision before leaving for an endemic region.

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

There is evidence that the simultaneous administration of ketoconazole, a strong inhibitor of the isoenzyme CYP3A4, and mefloquine led to an increase in plasma concentrations of the latter and its T1 / 2.

Long-term use of rifampicin, a potent inducer of the isoenzyme CYP3A4, led to a decrease in the plasma concentration of mefloquine and its T1 / 2.

Mefloquine is a P-glycoprotein inhibitor according to in vitro studies. Therefore, it is impossible to exclude the possibility of drug interaction of mefloquine with drugs that are substrates of P-glycoprotein or that have the ability to change the expression of this transporter. The clinical significance of this interaction is currently unknown.

Storage conditions

In a dry place at a temperature not exceeding 30 ? C. (in a sealed package)

Keep out of the reach of children.

Shelf life

3 years.

Do not use after the expiration date printed on the package.

Conditions of dispensing from pharmacies

On prescription.