Mefloquine, tablets 250 mg 10 pcs

Mefloquine is active against asexual intracellular erythrocytic forms of human malaria pathogens Plasmodium falciparum Plasmodium vivax against circulating schizonts Plasmodium malariae and Plasmodium ovale.

He is not active against hepatic stages of the parasites.

It is effective against malaria pathogens resistant to other antimalarial drugs such as chloroquine proguanil pyrimethamine and combination of pyrimethamine and sulfonamides.

For P. falciparum, resistance to mefloquine may have developed mainly in Southeast Asia. Cross-resistance between mefloquine and halofantrine mefloquine and quinine has been noted in some regions. National expert organizations should be consulted for up-to-date information on resistance in different geographic regions.

The drug does not cause hemolysis associated with glucose-6-phosphate dehydrogenase deficiency.

Pharmacokinetics:

Absorption

The absolute bioavailability of mefloquine after oral administration was not assessed (no intravenous form of release). The bioavailability of the tablet form is over 85% of that of the oral solution. Food intake significantly accelerates the rate and increases the degree of absorption by 40%.

The average time to reach the maximum concentration of Mefloquine after a single dose is 17 hours (6-24 hours). Maximum plasma concentrations in µg/L are approximately equal to the dose taken in mg (e.g., a single dose of 1000 mg gives a maximum concentration of about 1000 µg/L).

After administration of 250 mg once weekly, an equilibrium maximum plasma concentration of 1000-2000 µg/L is reached after 7-10 weeks. A blood concentration of mefloquine equal to 620 ng/ml is required to achieve 95% efficacy of prophylaxis.

Distribution

The volume of distribution of mefloquine is 20 l/kg which indicates penetration of the drug into many tissues. It accumulates in erythrocytes with malaria parasites inside at concentrations approximately twice as high as plasma concentrations. It penetrates through the placenta and into the breast milk.

The excretion with the breast milk seems to be minimal (see section “Administration during pregnancy and breast-feeding”).

The drug’s binding to plasma proteins is 98%.

Metabolism

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 CYP3A4 isoenzyme to form 2 metabolites: the main metabolite – 28-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 administration of the drug; its maximum concentrations in plasma are 50% higher than those of Mefloquine and are reached after 2 weeks. After that, plasma concentrations of the main metabolite and mefloquine decrease at the same rate. The area under the curve “concentration-time” of the main metabolite is 3-5 times greater than that of the original drug.

The other metabolite alcohol is present in very small amounts.

Excretion

The average half-life of mefloquine is 3 weeks (2 to 4 weeks) unchanged by long-term antimalarial prophylaxis. It is excreted as metabolic products mainly with bile and feces. 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 the urine.

Pharmacokinetics in special cases

In acute malaria changes in pharmacokinetic parameters may be observed.

Children and elderly patients

Age has no effect on the pharmacokinetics of mefloquine.

Renal failure

Pharmacokinetic studies in patients with renal failure have not been conducted because very small amounts of the drug are excreted with the kidneys. Mefloquine and its main metabolite are not excreted in any significant quantities by hemodialysis. No dose adjustment is required for patients on hemodialysis.

Hepatic impairment

In patients with impaired hepatic function, excretion of mefloquine may be delayed and therefore plasma concentrations of the drug are increased. Pregnancy has no clinically significant effect on the pharmacokinetics of mefloquine.

Race

Pharmacokinetic differences have very little clinical significance compared to the immune status of the infected patient and the sensitivity of the pathogen.

Indications

Treatment of mild to moderate forms of malaria caused by strains of P. falciparum resistant to other antimalarial drugs P. vivax and malaria of mixed etiology.

As sensitivity of the pathogen may vary over time and from one geographic area to another, it is recommended that national and international guidelines be followed.

Prevention of malaria in people traveling to malaria risk regions, especially those at high risk of infection with strains of P. falciparum resistant to other antimalarial drugs.

Emergency therapy (self-help): self-administration as emergency therapy in case of suspected malaria if it is not possible to obtain emergency medical care.

Active ingredient

Mefloheen

Composition

Per tablet:

Active ingredient: mefloquine hydrochloride – 274.09 mg (in terms of base – 250.00 mg).

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

How to take, the dosage

Orally after a meal with plenty of fluid (at least 200 ml) in 2-3 times.

Mefloquine has a bitter and slightly burning taste. The tablets should be swallowed whole. When prescribed for children or people who cannot swallow the whole tablet, it may be crushed and dissolved in a small amount of water, milk or other drink.

Do not take the tablets out of the blister until taken, because they are sensitive to moisture.

Preventive therapy

The standard dosage regimen

Adults and children with a body weight of more than 45 kg: 5 mg/kg (250 mg 1 tablet) once a week.

Adults and children with a body weight of 30-45 kg – 3/4 of a tablet; 20-30 kg – 1/2 of a tablet; 10-20 kg – 1/4 of a tablet and if the body weight is 5-10 kg – 1/8 of a tablet (approx. 5 mg/kg of body weight).

The exact doses of the drug for children with a body weight of less than 10 kg should, if possible, be prepared and given by pharmacists.

The weekly doses of Mefloquine should always be taken on the same day of the week. The first dose should be taken at least one week before arrival in a malaria-endemic region.

Dosing in special cases

If the preventive drug is not started at least one week before arrival in a malaria endemic region, a loading dose of the drug equal to the weekly dose of Mefloquine taken daily for 3 days should be administered and then the standard dosing regimen should be switched.

The use of shock doses increases the likelihood of adverse events.

To reduce the risk of malaria after leaving an endemic region, prophylaxis is continued for an additional 4 weeks.

If the patient is taking other medications, it is best to start prophylaxis two to three weeks before departure to make sure the drugs taken at the same time are well tolerated (see section “Interaction with other medications”).

If malaria develops during prophylaxis with Mefloquine, the doctor should consider carefully which drug to choose for therapy. See the section on Interaction with other medicines for information about the use of halofantrine.

Treatment

The standard dosing regimen

The recommended total therapeutic dose of mefloquine is 20 to 25 mg/kg.

* Distributing the total therapeutic dose into 2-3 doses at 6-8 hour intervals can reduce the frequency and severity of side effects.

There is no experience with total doses greater than 6 pills in overweight subjects.

Dosage in special cases

Mefloquine is indicated for the treatment of uncomplicated malaria caused by P. falciparum. It is common practice to use combination therapy for uncomplicated P. falciparum malaria. Because the sensitivity of the pathogen may vary over time and depending on the geographic area, it is recommended that national and international guidelines be followed during therapy.

The lower total dose may be adequate for people who are partially immune against malaria, such as those in malaria-endemic regions.

If vomiting occurs within 30 minutes after taking the drug, the full dose of Mefloquine should be repeated. If vomiting occurs 30-60 minutes after ingestion, an additional half dose should be administered.

After treatment of malaria caused by R. vivax, prophylaxis of recurrences with drugs that are derivatives of 8-aminoquinoline (e.g. primaquine) is indicated to eliminate hepatic forms of plasmodia.

If a full course of treatment with Mefloquine after 48-72 hours does not result in improvement of the patient’s condition it is necessary to decide on the prescription of another drug. If during prophylaxis with the help of Mefloquine malaria develops, the doctor should consider carefully which drug to choose for therapy. See the section on Interaction with other medicines for more information on prescribing halofantrine.

In severe acute malaria, Mefloquine may be given after an initial course of intravenous quinine therapy of at least 2-3 days. Most of drug interactions leading to development of side effects can be prevented if Mefloquine is taken not less than 12 hours after the last dose of quinine.

In regions with multidrug-resistant malaria pathogens, initial treatment with artemisinin or its derivatives may be appropriate, followed by therapy with Mefloquine if possible.

Mefloquine self-administered emergency therapy

Mefloquine self-administered emergency therapy is used if it is not possible to obtain urgent medical care within 24 hours after the onset of symptoms.

The starting dose of Mefloquine is 15 mg/kg.

So for patients with a body weight of 45 kg or more, 3 tablets (750 mg). If medical help continues to be unavailable for 24 hours and there are no severe adverse reactions, after 6-8 hours the second part of the total therapeutic dose can be taken (for patients weighing 45 kg or more – 2 tablets of 500 mg).

Patients with a body weight of more than 60 kg should take another tablet 6-8 hours after the second dose. In order to confirm or exclude the presumptive diagnosis, patients should be advised to consult a physician even if they feel fully recovered after self-treatment.

Interaction

Simultaneous administration of Mefloquine and quinine quinidine and chloroquine may cause ECG changes and increase the risk of seizures (see section “Dosage and administration”).

The use of halofantrine concomitantly with Mefloquine and within 15 weeks of the last dose of Mefloquine leads to a significant prolongation of the QTc interval (QT interval corrected by heart rate is calculated by the formula:

QTc=QT/RR1/2 where

RR is the time interval between adjacent R waves on the ECG equal to the duration of the cardiac cycle (see section “Special Precautions”).

The concomitant administration of Mefloquine and ketoconazole increases plasma concentrations of Mefloquine and its half-life.

The simultaneous use of ketoconazole with Mefloquine and also within 15 weeks after the last dose of Mefloquine may increase QTc interval prolongation. No clinically significant QTc prolongation occurs with Mefloquine therapy alone.

The concomitant use of other drugs that affect cardiac conduction (antiarrhythmic agents beta-adrenoblockers “slow” calcium channel blockers antihistamines such as H1-histamine receptor blockers tricyclic antidepressants and phenothiazines) may also theoretically play a role in QTc interval prolongation. The effect of concomitant use of mefloquine and the above drugs on cardiac function has not been definitively established.

It reduces the effectiveness of anticonvulsants (valproic acid carbamazepine phenobarbital or phenytoin) by reducing their plasma concentrations. Plasma concentrations of the drugs should be monitored. In some cases it may be necessary to adjust the dose of anticonvulsants.

The drug Mefloquine may decrease immunogenicity of oral live typhoid vaccines if administered simultaneously, therefore vaccination with live attenuated vaccines should be completed at least 3 days before the first administration of Mefloquine.

Other drug interactions of Mefloquine are unknown. But people receiving other medications such as anticoagulants or hypoglycemic agents should be medically monitored before traveling to an endemic region.

Other possible interactions

Mefloquine is not an inhibitor or inducer of cytochrome P450. Consequently, we can expect that the metabolism of drugs prescribed concomitantly with Mefloquine remains unchanged.

The inducers of CYP3A4 isoenzyme may also modify the pharmacokinetics and metabolism of mefloquine which may decrease plasma concentrations of mefloquine.

CYP3A4 isoenzyme inhibitors

A study in healthy volunteers showed that concomitant administration of ketoconazole, a potent CYP3A4 isoenzyme inhibitor, and mefloquine resulted in increased plasma concentrations of the latter and its half-life.

CYP3A4 isoenzyme inducers

Long-term use of the potent CYP3A4 isoenzyme inducer rifampicin resulted in decreased plasma concentrations of mefloquine and its half-life.

P-glycoprotein substrates and inhibitors

Mefloquine is a P-glycoprotein inhibitor according to in vitro studies. Therefore, the possibility of drug interaction between mefloquine and drugs that are substrates of P-glycoprotein or have the ability to change the expression of this transporter cannot be excluded. The clinical significance of this interaction is currently unknown. In clinical studies, riganavir which is a potent inhibitor of P-glycoprotein and CYP3A4 had no effect on the pharmacokinetics of mefloquine in healthy volunteers.

Special Instructions

The drug Mefloquine may increase the risk of seizures in patients with epilepsy. Therefore, in these patients the drug should be prescribed only for the purpose of treatment and in the presence of absolute indications for its use (see also section “Interaction with other medicinal products”).

Mefloquine can be taken after taking quinine or quinidine for up to 12 hours.

In patients with hepatic impairment, there may be delayed excretion of mefloquine which may increase its plasma concentrations and increase the risk of adverse reactions.

In long-term prophylactic administration (use of the drug for more than 1 year is undesirable), periodic liver function tests and ophthalmologic examination are necessary.

The safety profile of Mefloquine in prophylactic use is characterized by the prevalence of neuropsychiatric reactions such as: anxiety depression anxiety or confusion. In case these adverse events occur, therapy with Mefloquine should be discontinued and another drug should be prescribed.

Because of the long half-life of Mefloquine, adverse reactions may develop or persist up to several weeks after the last drug administration. A small number of patients have described cases of psychoneurotic disorders (including depression dizziness and vertigo and loss of balance) that have been observed for several months or more after discontinuation of the drug and continue for several months after discontinuation.

In cases of visual disturbances including optic neuropathy and retinal damage (including maculopathy) have been reported with mefloquine. If visual impairment occurs, the attending physician should be consulted to consider the possibility of continuing treatment with Mefloquine.

In case of development of symptoms of polyneuropathy including pain, burning, tingling, numbness and/or weakness, treatment with the drug should be discontinued. The choice of the drug for malaria prophylaxis depends on the resistance of P. falciparum in a particular region (see section “Pharmacological action”).

In cases of agranulocytosis and aplastic anemia have been reported when using the drug (see section “Adverse effects”).

Please of the drug into the environment should be minimized. Mefloquine must not be disposed of with wastewater or with household waste. If possible, special systems for disposal of medications should be used.

Influence on the ability to drive vehicles and machines:
During treatment it is necessary to refrain from driving vehicles and engaging in potentially dangerous activities that require high concentration and quick psychomotor reactions.

Contraindications

Hypersensitivity to mefloquine to any component of the drug or to drugs close to it (quinine quinidine).

Combined use with halofantrine administration of halofantrine after therapy with mefloquine for 15 weeks after discontinuation of the latter.

Combined use with ketoconazole administration of ketoconazole after therapy with mefloquine for 15 weeks after discontinuation of the latter.

Preventive use for active depression and severe psychiatric disorders (including a history of seizures).

Children under 3 months of age or with a body weight of less than 5 kg (experience with the drug is limited).

Lactose intolerance glucose-galactose malabsorption deficiency (due to the presence of lactose in the drug).

With caution:

Hepatic failure epilepsy mental illness heart disease age over 65 years.

In combination with quinine and quinidine.

Side effects

The adverse reactions were classified according to organ system classes and absolute frequency of occurrence according to MedDRA.

The frequency of occurrence was determined as follows: Very common (>1/10) common (>1/100 and <1/10) infrequent (>1/1000 and <1/100) rare (>1/10000 and <1/1000) very rare (<1/10000) frequency unknown (it is impossible to determine frequency based on available data).

With regard to the long-term presence of the drug on the market, the data presented in the list of adverse reactions below represent the frequency of cases reported rather than the frequency of cases seen in controlled studies.

Disorders of the blood and lymphatic system

Often: thrombocytopenia.

Infrequent: leukopenia leukocytosis.

Frequent unknown: agranulocytosis and aplastic anemia.

Metabolic and nutritional disorders

Often: anorexia.

Mental disorders

Very common: sleep disorders (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 long after discontinuation of mefloquine.

Suicidal thoughts of suicidal behavior with risk of self-harm such as suicide attempts have been reported.

Nervous system disorders

Very common: dizziness loss of balance headache sleepiness.

Often: fainting memory impairment sensory and motor neuropathies (including paresthesias tremor ataxia) seizures.

Infrequent: encephalopathy.

Visual disorders

Often: visual disturbances.

Frequent unknown: blurred vision cataracts retinal lesions and optic neuropathy with possible delayed onset both during and after therapy.

Hearing and labyrinth disorders

Very common: vergigo.

Often: hearing impairment vestibular disorders including tinnitus.

Heart disorders

Often: tachycardia palpitations bradycardia arrhythmia extrasystoles other transient cardiac conduction disorders.

Infrequent: AV blockade.

Vascular disorders

Often: circulatory disorders (decreased increased blood pressure flushes).

Respiratory system disorders of the thorax and mediastinum

Often: dyspnea.

Very rarely: pneumonia pneumonitis (possibly of allergic etiology).

Gastrointestinal disorders

Very common: nausea diarrhea abdominal pain vomiting.

Often: dyspepsia.

Hepatic and biliary tract disorders

Frequent unknown: liver function abnormalities associated with the use of the drug (from asymptomatic transient increase in transaminase activity to hepatic failure).

Skin and subcutaneous tissue disorders

Often: skin rash exanthema erythema urticaria pruritus alopecia hyperhidrosis.

Infrequent: erythema multiforme Stevens-Johnson syndrome.

Muscular and connective tissue disorders

Often: muscle weakness muscle cramps myalgia arthralgia.

Laboratory and instrumental findings

Often: transient increase in transaminase activity.

General disorders and disorders at the site of administration

Often: swelling chest pain weakness malaise chills chills fever.

Overdose

Symptoms: see section “Side effects” but more pronounced.Treatment: in case of overdose, symptomatic and supportive therapy is recommended. There is no specific antidote.

Pregnancy use

Pregnancy

When Mefloquine was administered in doses 5-20 times higher than therapeutic for humans, it had teratogenic effects in mice and rats and embryotoxic effects in rabbits. However, the experience of clinical use of Mefloquine did not reveal any embryogenic or teratogenic effects. Nevertheless, Mefloquine should be administered in the first trimester of pregnancy only if the expected benefits to the mother exceed the potential risk to the fetus.

Women of reproductive age should be prescribed treatment only if reliable contraception is used for the duration of Mefloquine and 3 months after the last dose. But if pregnancy occurs against the background of chemoprophylaxis with Mefloquine, there are no indications for its termination.

When prescribing Mefloquine to pregnant women, refer to current international guidelines (e.g., WHO).

Breastfeeding period

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

When prescribing Mefloquine to breastfeeding mothers, refer to current international guidelines (e.g., WHO).