Lariam

General characteristics. Structure:

Active agent: мефлохин 250 mg (in the form of a meflokhin of a hydrochloride of 274.09 mg);

Excipients: half-oxameasures 3800, cellulose microcrystallic, lactoses monohydrate, starch corn, кросповидон, ammonium calcium алгинат, talc, magnesium stearate.

Pharmacological properties:

Лариам® affects sexless intracellular erythrocyte forms of causative agents of malaria of the person Plasmodium falciparum, Plasmodium vivax, the circulating schizonts of Plasmodium malariae and Plasmodium ovale. It is not active concerning hepatic stages of parasites. It is effective concerning the causative agents of malaria steady against other antimalarial drugs, for example, to chloroquine, proguanil, Pyrimethaminum and a combination of Pyrimethaminum with sulfonamides.
For P. falciparum development of resistance to a meflokhin, generally in Southeast Asia is possible. In some regions cross resistance between meflokhiny and galofantriny, meflokhiny and quinine is noted.
Drug does not cause the hemolysis connected with insufficiency glyukozo-6-fosfatdegidrogenaza.

Pharmacokinetics. Absorption. Absolute bioavailability of a meflokhin after intake was not estimated (there is no intravenous form of release). Bioavailability of the tableted form makes over 85% of that at solution reception inside. Meal significantly accelerates speed and increases extent of absorption by 40%. The average time of achievement of the maximum concentration of a meflokhin after one-time reception - 17 hours (6-24 hours). The maximum concentration in plasma in mkg/l are approximately equal to the accepted dose in mg (for example, one-time reception of 1000 mg gives the maximum concentration about 1000 mkg/l). After reception of 250 mg once a week the equilibrium maximum plasma concentration equal of 1000-2000 mkg/l, is reached in 7-10 weeks. Concentration of a meflokhin in blood, equal 620 ng/ml is necessary for achievement of 95% of efficiency of prevention.

Distribution. The volume of distribution of a meflokhin of 20 l/kg that indicates penetration of drug into many fabrics. Collects in erythrocytes in which there are malarial parasites, in concentration approximately twice exceeding plasma. Gets through a placenta and into breast milk. Removal with breast milk, apparently, minimum (see the section "Pregnancy and Period of Feeding by a Breast"). Communication of drug with proteins of plasma of 98%.

Metabolism. Metabolism of a meflokhin mostly is carried out in a liver with the participation of P450 cytochrome. In the researches in vitro and in vivo it was shown what мефлохин is metabolized generally by CYP3A4 isoenzyme with formation of 2 metabolites: the main metabolite - 2,8 - an encore - trifluoromethyl-4-quinolinic carboxyacid and alcohol. The main metabolite is inactive concerning P. falciparum, appears in plasma in 2-4 hours after one-time oral administration of drug, its maximum concentration in plasma for 50% exceed those a meflokhin and are reached in 2 weeks. After that decrease in concentration of the main metabolite and meflokhin in plasma happens to identical speed. The area under a curve "concentration time" of the main metabolite by 3-5 times exceeds a similar indicator for initial drug. Other metabolite, alcohol, is present at very small quantities.

Removal. The average elimination half-life of a meflokhin - 3 weeks (from 2 to 4 weeks), does not change when performing long antimalarial prevention. It is removed in the form of metabolism products preferential with bile and a stake. The general clearance most of which part is made by hepatic is equal to 30 ml/min. Removal of not changed meflokhin and its main metabolite with urine makes about 9% and 4%, respectively. Other metabolites in urine are not found.

Pharmacokinetics in special cases

Children and patients of senile age
The age does not influence pharmacokinetics of a meflokhin.

Renal failure
Pharmacokinetic researches at patients with a renal failure were not conducted as with kidneys very small amount of drug is removed. In a little significant quantities мефлохин and its main metabolite by means of a hemodialysis are not removed. Dose adjustment for patients on a hemodialysis is not required.

Liver failure
At patients with an abnormal liver function removal of a meflokhin can be slowed down owing to what concentration of drug in plasma increase.

Pregnancy does not exert clinically significant impact on pharmacokinetics of a meflokhin.

Race
Pharmacokinetic distinctions have very small clinical value in comparison with the immune status of the infected patient and sensitivity of the activator.

Indications to use:

Treatment of easy and medium-weight forms of the malaria caused by the strains of P. falciparum steady against other antimalarial drugs, P. vivax and malaria of the mixed etiology.
Prevention of malaria at the persons which are driving off to regions, dangerous on malaria, especially, to regions with high risk of infection with the strains of P. falciparum steady against other antimalarial drugs.
Emergency treatment (self-care): independent reception as emergency treatment at suspicion of malaria if it is not possible to receive urgent medical care.

Route of administration and doses:

Inside, after meal, washing down with a large amount of liquid (not less than 200 ml), in 2-3 receptions.
Meflokhin has bitter and slightly burning taste. It is necessary to swallow of tablets entirely. At appointment children or persons who cannot swallow a tablet entirely can pound and dissolve it in a small amount of water, milk or other drink.
Up to reception of a tablet it is not necessary to take out from the blister as they are sensitive to moisture.

Prevention

To adults and children with body weight more than 45 kg - 5 mg/kg (250 mg, 1 tablet) once a week. To adults and children with the body weight of 30-45 kg - 3/4 tablets; 20-30 kg - 1/2 tablets; 10-20 kg - 1/4 tablets and at the body weight of 5-10 kg – 1/8 tablets (an approximate part of a tablet at the rate of 5 mg/kg of body weight. Exact doses of drug for children with body weight less than 10 kg whenever possible have to prepare and be given by druggists).

Weekly doses of the drug Lariam® should be accepted always in the same day of the week. Drug it is necessary to accept the first time not less than one week prior to arrival in the region, endemic on malaria. If it is impossible, it is necessary to appoint the shock dose of drug consisting of a week dose of the drug Lariam® within 3 days in a row, and then to switch over dosing to the standard mode. To reduce risk of a disease of malaria after departure from the endemic region, prevention is continued within 4 weeks. If the patient accepts other medicines, it is desirable to begin prevention in 2-3 weeks prior to departure to be convinced of good tolerance of at the same time accepted drugs.

Treatment
The recommended total therapeutic dose of a meflokhin makes 20-25 mg/kg.

Body weight (kg)	Total dose	Distribution of a dose to receptions *
5-10 10-20 20-30 30-45 45-60 > 60	1/2 - 1 tablet 1-2 tablets 2-3 tablets 3-4 tablets 5 tablets 6 tablets	2 + 1 tablets 2 + 2 tablets 3 + 2 tablets 3 + 2 + 1 tablets

* Distribution of a total therapeutic dose to 2-3 receptions with an interval of 6-8 hours can reduce the frequency and severity of side effects.

Experience of use of the total doses exceeding 6 tablets at persons with excess body weight, no.

Dosing in special cases
For persons with reduced immunity, inhabitants of regions, endemic on malaria, there can be sufficient a smaller total dose.
If within 30 minutes after administration of drug the patient had a vomiting, it is necessary to accept a full dose of the drug Lariam® repeatedly. If vomiting arises in 30-60 minutes after reception, in addition appoint a half of a dose.
After treatment of the malaria caused by P. vivax for elimination of hepatic forms of plasmodiums prevention of a recurrence by means of the drugs which are derivatives 8 aminoquinolines is shown (for example, Primachinum).
If the full course of treatment by the drug Lariam® in 48-72 hours does not lead to improvement of a condition of the patient, it is necessary to resolve an issue of purpose of other means. If during the prevention which is carried out by means of the drug Lariam® malaria develops, the doctor has to think over carefully what drug to choose for therapy. About purpose of a galofantrin see the section "Interaction with Other Medicines".

At heavy acute malaria of Lariam® it is possible to appoint after an initial intravenous course of therapy quinine lasting not less than 2-3 days. The majority of the medicinal interactions leading to development of side reactions can be prevented if to accept Lariam® not less than in 12 hours after introduction of the last dose of quinine.
In regions with polyresistant causative agents of malaria there can be reasonable an initial treatment artemisininom or its derivatives which therapy by the drug Lariam® follows, whenever possible.

Independent emergency treatment

Initial dose of the drug Лариам® 15 of mg/kg. Thus, for patients with the body weight of 45 kg and more - 3 tablets (750 mg). If medical care continues to remain unavailable within 24 hours and there are no heavy side reactions, then in 6-8 hours it is possible to accept the second part of a total therapeutic dose (for patients with the body weight of 45 kg and more - 2 tablets, 500 mg). Patients with body weight more than 60 kg in 6-8 hours after repeated reception have to take one more pill.
For confirmation or an exception of the presumable diagnosis patients should recommend to see a doctor even if after independent treatment they feel completely recovered.

Features of use:

Лариам® can increase risk of spasms at patients with epilepsy. Therefore, such patients can appoint drug only for the purpose of treatment and in the presence of absolute indications to its use (see also section "Interaction with Other Medicines").
After reception of quinine or quinidine it is possible to accept мефлохин not earlier than in 12 hours.
At preventive appointment during the long time (administration of drug is undesirable more than 1 year) the periodic analysis of indicators of function of a liver and ophthalmologic inspection is necessary.
At development of alarm, a depression, concern or disturbance of consciousness at preventive use drug should be cancelled.
Experience of use of the drug Lariam® for children aged up to 3 months or with body weight less than 5 kg is limited.

Influence on ability to driving of vehicles and work with cars and mechanisms
During treatment it is necessary to abstain from driving of motor transport and occupations potentially dangerous types of activity demanding the increased concentration of attention and speed of psychomotor reactions.

Side effects:

In the doses appointed for treatment of acute malaria, Lariam® can give the side reactions similar to symptoms of a basic disease.
Frequency of the undesirable phenomena during prevention meflokhiny is comparable to that at use of other schemes of chemoprophylaxis. The profile of side effects of a meflokhin is characterized by dominance of reactions from the psychological sphere.
The most frequent side effects during prevention by the drug Lariam® are usually poorly expressed and can decrease at continuation of use of drug regardless of the increasing concentration of drug in plasma: nausea, vomiting, dizziness.

From the mental sphere: most often - sleep disorders (an insomniya, dreadful dreams); more rare – excitement, concern, alarm, a depression, emotional lability, the panic attacks, confusion of consciousness, a hallucination, aggression, psychotic or paranoid reactions. Exceptional cases of suicide thoughts are described, however, their connection with administration of drug not was is established.

From a nervous system: most often – dizziness, balance loss, a headache, drowsiness; more rare – faints, spasms, memory disturbance, touch and motor neuropathies (including paresthesias, a tremor and an ataxy), anorexia. Separate cases of encephalopathy are described.

From an organ of sight: infrequently – vision disorders.

From an acoustic organ and vestibular mechanism: most often – a rotatory vertigo (true); more rare – vestibular disturbances, noise or a ring in ears or the head, a hearing disorder.

From heart: infrequently - tachycardia, tachycardia, bradycardia, irregular heart rate, extrasystoles, other tranzitorny disturbances of cordial conductivity. Separate cases of AV blockade are described.

Vascular disorders: infrequently – circulatory disturbances (decrease or increase in the ABP, a hyperemia).

From a respiratory organs: infrequently – an asthma. Very exceptional cases of a pneumonitis, perhaps allergic etiology were observed.

From bodies of digestive tract: most often – nausea, vomiting, diarrhea, an abdominal pain; more rare – dyspepsia.

From skin and a hypodermic fatty tissue: infrequently – rash, a dieback, an erythema, urticaria, an itch, an alopecia, a hyperhidrosis. Separate cases of a mnogoformny exudative erythema and Stephens-Johnson's syndrome are described.

From skeletal and muscular system: infrequently – muscular weakness, spasms in muscles, a mialgiya, an arthralgia.

From an organism in general: infrequently – hypostasis, a stethalgia, an adynamy, an indisposition, fatigue, a fever, fever.

From laboratory indicators: tranzitorny increase in activity of transaminases, leukopenia or leukocytosis, thrombocytopenia.

As well as at use of the majority of medicines, at purpose of the drug Lariam® there is a probability of development of the reactions of hypersensitivity varying from insignificant skin reactions to an anaphylaxis.

The statistical analysis of frequency of the undesirable phenomena was not carried out.

Because of a big elimination half-life of a meflokhin side reactions can develop or remain up to several weeks after the last administration of drug.

At a small number of patients cases of a rotatory and not rotatory vertigo, and also the balance losses continuing within several months after the termination of administration of drug were described.

In the researches in vitro and in vivo it was shown that drug does not cause the hemolysis connected with insufficiency glyukozo-6-fosfatdegidrogenazy.

Interaction with other medicines:

The concomitant use of the drug Lariam® and quinine, quinidine and chloroquine can cause changes on an ECG and increase risk of development of spasms.

Use of a galofantrin along with the drug Lariam®, and also within 15 weeks after the last accepted dose of the drug Lariam® leads to essential lengthening of an interval of QTc (QT interval, korrigirovanny on heart rate, is calculated on a formula: QTc=QT/RR1/2, where RR – a period between the next teeth of R on the ECG equal to duration of a cardial cycle). The concomitant use of the drug Lariam® and ketokonazol increases concentration of a meflokhin in plasma and the period of its semi-removal. Purpose of a ketokonazol along with the drug Lariam®, and also within 15 weeks after the last accepted drug Lariam® dose, can lead to lengthening of an interval of QTc. At therapy only meflokhiny clinically significant lengthening of QTC does not happen. The concomitant use of other drugs influencing cordial conductivity (antiarrhytmic means, beta adrenoblockers, blockers of "slow" calcium channels, antihistamines, in particular blockers of H1-histamine, tricyclic antidepressants and fenotiazin) also theoretically can play a role in lengthening of an interval of QTC. Influence of simultaneous use of a meflokhin and above-mentioned drugs on cordial function is not finalized.

Reduces efficiency of anticonvulsant drugs (valproic acid, carbamazepine, phenobarbital or Phenytoinum), reducing their concentration in plasma. It is necessary to control concentration of drugs in plasma. In certain cases dose adjustment of anticonvulsant drugs can be required.

Лариам® can reduce an immunogenicity of peroral live typroid vaccines at a concomitant use therefore live attenuated vaccines it is necessary to complete vaccination not less than in 3 days prior to the first administration of drug of Lariam®.

Other medicinal interactions of the drug Lariam® are unknown. But the persons receiving other drugs, in particular, anticoagulants or hypoglycemic means before departure to the endemic region have to undergo medical control.

Other possible interactions

Meflokhin is not inhibitor or the inductor of P450 cytochrome. Therefore, it is possible to expect that metabolism of the drugs appointed along with meflokhiny will remain invariable. However, inhibitors or inductors of an isoenzyme CYP3A4 can change pharmacokinetics and metabolism of a meflokhin that can lead to increase or reduction of concentration of a meflokhin in plasma, respectively.

CYP3A4 isoenzyme inhibitors

The conducted research with participation of healthy volunteers showed that the concomitant use of a ketokonazol, strong inhibitor of an isoenzyme CYP3A4, and a meflokhin led to increase in concentration of the last in plasma and the period of its semi-removal.

CYP3A4 isoenzyme inductors

Prolonged use of rifampicin, the powerful inductor of an isoenzyme CYP3A4, led to reduction of concentration of a meflokhin in plasma and the period of its semi-removal.

Substrates and inhibitors of the R-glycoprotein

In the researches in vitro it was shown what мефлохин is substrate and inhibitor of the R-glycoprotein. Therefore it is impossible to exclude a possibility of medicinal interaction of a meflokhin with the drugs which are substrates of the R-glycoprotein or having ability to change an expression of this conveyor. The clinical importance of this interaction is currently unknown.

Contraindications:

Hypersensitivity to a meflokhin, any components of drug or medicines, close to it (quinine, quinidine).
Joint appointment with galofantriny, reception of a galofantrin after therapy meflokhiny within 15 weeks after cancellation of the last.
Joint appointment with ketokonazoly, reception of a ketokonazol after therapy meflokhiny within 15 weeks after cancellation of the last.
Depression, psychoses, schizophrenia, alarming states, spasms (including in the anamnesis).

With care

The liver failure, the feeding period a breast, epilepsy, mental diseases, age up to 6 months, body weight to 5 kg, heart diseases, age is more senior than 65 years. In a combination with quinine and quinidine.

Pregnancy and period of feeding by a breast
Category C drug (on FDA classification – U.S. Food and Drug Administration).

At purpose of a meflokhin in doses, at 5-20 times exceeding therapeutic for the person it had teratogenic effect at mice and rats and embriotoksichesky action at rabbits. However, experience of a clinical use of the drug Lariam® did not reveal at it any embriotoksichesky or teratogenic effects. Nevertheless, Lariam® should appoint in the first trimester of pregnancy only if the expected advantage for mother exceeds potential risk for a fruit. Women of reproductive age should appoint treatment only on condition of use of reliable contraception during the whole time of reception of a meflokhin and 3 months after its last dose. But at emergence of pregnancy against the background of chemoprophylaxis of malaria the drug Lariam® of indications to its interruption is not present.

Activity of the small amounts of a meflokhin getting to breast milk is unknown. At a lactation drug is appointed only if the expected advantage for mother does not exceed potential risk for the child. At children on breastfeeding whose mothers accepted Lariam® side reactions are noted.

Overdose:

Symptoms: see the section "Side effect", however, more expressed.
Treatment: in case of overdose the symptomatic and maintenance therapy is recommended. The specific antidote does not exist.

Storage conditions:

List B.
To store at a temperature not above 30 °C in the dry place.
To store in the place, unavailable to children.

Issue conditions:

According to the recipe

Packaging:

Tablets of 250 mg
On 4 tablets in the blister from a film of three-layered (OPA/Al/PVC) and aluminum foil.
2 blisters together with the application instruction place in a cardboard pack.