Mefloquine is an antimalarial agent for oral administration.

It is a 4-quinolinemethanol derivative with the specific chemical name of (R*, S*)-(+)-α-2-piperidinyl-2, 8-bis (trifluoromethyl)-4-quinolinemethanol hydrochloride. It is a 2-aryl substituted chemical structural analog of quinine.

Mefloquine is an antimalarial agent that acts as a blood schizonticide. It is effective against all species of malaria (P. falciparum, P. vivax, P. malariae and P. ovale). Its exact mechanism of action is not known. Mefloquine is active against the erythrocytic stages of Plasmodium species. However, the drug has no effect against the exoerythrocytic (hepatic) stages of the parasite and mature gametocytes. Mefloquine is effective against malaria parasites resistant to chloroquine and other 4-aminoquinoline derivatives, proguanil, pyrimethamine and pyrimethamine-sulphonamide combinations.

Similar to chloroquine and quinine, mefloquine appears to interfere with the parasite's ability to metabolize and utilise erythrocyte hemoglobin. The antimalarial activity of mefloquine may depend on the ability of the drug to form hydrogen bonds with cellular constituents. Mefloquine binds to high-density lipoproteins in serum ,specifically polypeptide apo A and is delivered to the erythrocytes where it interacts with a specific erythrocyte membrane protein, stromatin and is then transferred to the intracellular parasite by a pathway used for exogenous phospholipids. Mefloquine may exert its antimalarial action by disrupting the membrane trafficking events involved in the uptake of phospholipids.

Cross resistance between mefloquine and halofantrine and cross-resistance between mefloquine and quinine have been observed in some regions.

In vitro and in vivo studies with mefloquine showed no haemolysis associated with glucose-6-phosphate dehydrogenase deficiency.

Mefloquine is slowly absorbed from the GI tract and appears to undergo little, if any first pass elimination. The presence of food significantly enhances the rate and extent of absorption, leading to about a 40% increase in bioavailability. Mefloquine may accumulate in parasitized erythrocytes. Protein binding is about 98%.

Mefloquine is widely distributed into body tissues and fluids.

Mefloquine is metabolised in the liver. Two metabolites have been identified in humans. The main metabolite, 2,8-bis-trifluoromethyl-4-quinoline carboxyclic acid is inactive in Plasmodium falciparum. The other metabolite, an alcohol, was present in minute quantities only.

The mean elimination half life of mefloquine varied between 2 and 4 weeks, with an average of about 3 weeks.

Mefloquine is excreted mainly in the bile and feces.

The pharmacokinetics of mefloquine may be altered in acute malaria.

The pharmacokinetics of mefloquine in patients with compromised renal and hepatic function have not been studied.

Treatment of acute malaria infections : Mefloquine is indicated for the treatment of mild to moderate acute malaria caused by mefloquine-susceptible strains of P. falciparum (both chloroquine-susceptible and resistant strains) or by Plasmodium vivax.

Prevention of Malaria : Mefloquine is indicated for the prophylaxis of P. falciparum and P. vivax malarial infections, including prophylaxis of chloroquine-resistant strains of P. falciparum.

Use of mefloquine is contraindicated in patients with a known hypersensitivity to mefloquine or related compounds (eg, quinine and quinidine). Mefloquine should not be prescribed for prophylaxis in patients with active depression, a recent history of depression, generalized anxiety disorder, psychosis, or schizophrenia or other major psychiatric disorders, or with a history of convulsions. The use of mefloquine is contraindicated in persons who have received treatment with mefloquine in the previous 4 weeks.

Patients with acute P. vivax malaria, treated with mefloquine, are at high risk of relapse because mefloquine does not eliminate exoerythrocytic (hepatic phase) parasites. To avoid relapse, after initial treatment of the acute infection with mefloquine, patients should subsequently be treated with an 8-aminoquinoline (eg, primaquine).

In case of life-threatening, serious or overwhelming malaria infections due to P. falciparum, patients should be treated with an intravenous antimalarial drug. Following completion of intravenous treatment, mefloquine may be given to complete the course of therapy.

Data on the use of halofantrine subsequent to administration of mefloquine suggest a significant, potentially fatal prolongation of the QTc interval of the ECG. Therefore, halofantrine must not be given simultaneously with or subsequent to mefloquine.

Mefloquine may cause psychiatric symptoms in a number of patients, ranging from anxiety, paranoia, and depression to hallucinations and psychotic behavior. On occasions, these symptoms have been reported to continue long after mefloquine has been stopped. Rare cases of suicidal ideation and suicide have been reported though no relationship to drug administration has been confirmed. Mefloquine should be used with caution in patients with a previous history of depression.

During prophylactic use, if psychiatric symptoms such as acute anxiety, depression, restlessness or confusion occur, these may be considered prodromal to a more serious event. In these cases, the drug must be discontinued and an alternative medication should be substituted.

Concomitant administration of mefloquine and quinine or quinidine may produce electrocardiographic abnormalities. Concomitant administration of mefloquine with quinine or chloroquine may increase the risk of convulsions.

General

Hypersensitivity reactions ranging from mild cutaneous events to anaphylaxis cannot be predicted.

In patients with epilepsy, mefloquine may increase the risk of convulsions. The drug should therefore be prescribed only for curative treatment in such patients and only if there are compelling medical reasons for its use.

Caution should be exercised with regard to activities requiring alertness and fine motor coordination such as driving, piloting aircraft, operating machinery, and deep-sea diving, as dizziness, a loss of balance, or other disorders of the central or peripheral nervous system have been reported during and following the use of mefloquine. These effects may occur after therapy is discontinued due to the long half-life of the drug. Mefloquine should be used with caution in patients with psychiatric disturbances because mefloquine use has been associated with emotional disturbances.

In patients with impaired liver function the elimination of mefloquine may be prolonged, leading to higher plasma levels.

This drug has been administered for longer than 1 year. If the drug is to be administered for a prolonged period, periodic evaluations including liver function tests should be performed. Although retinal abnormalities seen in humans with long-term chloroquine use have not been observed with mefloquine use, long term feeding of mefloquine to rats resulted in dose-related ocular lesions (retinal degeneration, retinal edema and lenticular opacity at 12.5mg/Kg/day and higher). Therefore periodic ophthalmic examinations are recommended.

Parenteral studies in animals show that mefloquine, a myocardial depressant, possesses 20% of the antifibrillatory action of quinidine and produces 50% of the increase in the PR interval reported with quinine. The effect of mefloquine on the compromised cardiovascular system has not been evaluated. However, transitory and clinically silent ECG alterations have been reported during the use of mefloquine. Alterations included sinus bradycardia, sinus arrhythmia, first degree AV-block, prolongation of the QTc interval and abnormal T waves. The benefits of mefloquine therapy should be weighed against the possibility of adverse effects in patients with cardiac disease.

Mefloquine should be used with caution in patients with renal impairment.

There is one report of cardiopulmonary arrest, with full recovery, in a patient who was taking a beta blocker (propranolol). The effects of mefloquine on the compromised cardiovascular system have not been evaluated. The benefits of mefloquine therapy should be weighed against the possibility of adverse effects in patients with cardiac disease.

Because of the danger of a potentially fatal prolongation of QTc interval, halofantrine must not be given simultaneously with or subsequent of mefloquine.

Concomitant administration of mefloquine and other related 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. There is evidence that the use of halofantrine after mefloquine causes a significant lengthening of the QTc interval. Clinically significant QTc prolongation has not been found with mefloquine alone.

This appears to be the only clinically relevant interaction of this kind with mefloquine, although theoretically, coadministration of other drugs known to alter cardiac conduction (e.g. anti-arrhythmic or beta-adrenergic blocking agents, calcium channel blockers, antihistamines or H1-blocking agents, tricyclic antidepressants and phenothiazines) might also contribute to a prolongation of the QTc interval. There are no data that conclusively establish whether the concomitant administration of mefloquine and the above listed agents has an affect on cardiac function.

In patients taking an anticonvulsant (e.g. valproic acid, carbamazepine, phenobarbital or phenytoin), the concomitant use of mefloquine may reduce seizure control by lowering the plasma levels of the anticonvulsant. Therefore, patients concurrently taking antiseizure medication and mefloquine should have the blood level of their antiseizures medication monitored and the dosage adjusted appropriately.

When mefloquine is taken concurrently with oral live typhoid vaccines, attenuation of immunization cannot be excluded. Vaccination with attenuated live bacteria should therefore be completed at least 3 days before the first dose of mefloquine.

Concomitant administration of metoclopramide may increase plasma concentrations of mefloquine.

No other drug interactions are known. Nevertheless, the effects of mefloquine on travelers receiving comedication, particularly diabetics or patients using anticoagulants should be checked before departure.

In clinical trials, the concomitant administration of sulfadoxine and pyrimethamine did not alter the adverse reaction profile.

The effects of mefloquine on travellers receiving co-medication, particularly those on anticoagulants or antidiabetics, should be checked before departure.

Clinical : At the doses used for treatment of acute malaria infections, the symptoms possibly attributable to drug administration cannot be distinguished from those symptoms usually attributable to the disease itself.

Among subjects who received mefloquine for prophylaxis of malaria, the most frequently observed adverse experience was vomiting (3%). Dizziness, syncope, extrasystoles and other complaints affecting less than 1% were also reported.

Among subjects who received mefloquine for treatment, the most frequently observed adverse experiences included: dizziness, myalgia, nausea, fever, headache, vomiting, chills, diarrhoea, skin rash, abdominal pain, fatigue, loss of appetite, and tinnitus. Those side effects occurring in less than 1% included bradycardia, hair loss, emotional problems, pruritus, asthenia, transient emotional disturbances and telogen effluvium (loss of resting hair). Seizures have also been reported.

Two serious adverse reactions were cardiopulmonary arrest in one patient shortly after ingesting a single prophylactic dose of mefloquine while subsequently using propranolol and encephalopathy of unknown etiology during prophylactic mefloquine administration. The relationship of encephalopathy to drug administration could not be clearly established.

Postmarketing : Postmarketing surveillance indicates that the same kind of adverse experiences are reported during prophylaxis, as well as acute treatment.

The most frequently reported adverse events are nausea, vomiting, loose stools or diarrhea, abdominal pain, dizziness or vertigo, loss of balance, and neuropsychiatric events such as headache, somnolence, and sleep disorders (insomnia, abnormal dreams). These are usually mild and may decrease despite continued use.

Occasionally, more severe neuropsychiatric disorders have been reported such as: sensory and motor neuropathies (including paresthesia, tremor and ataxia), convulsions, agitation or restlessness, anxiety, depression, mood changes, panic attacks, forgetfulness, confusion, hallucinations, aggression, psychotic or paranoid reactions and encephalopathy. Rare cases of suicidal ideation and suicide have been reported though no relationship to drug administration has been confirmed.

Other infrequent adverse events include: Cardiovascular disorders: circulatory disturbances (hypotension, hypertension, flushing, syncope), chest pain, tachycardia or palpitation, bradycardia, irregular pulse, extrasystoles, A-V block and other transient cardiac conduction alterations.

Skin disorders : rash, exanthema, urticaria, pruritus, edema, hair loss, erythema multiforme and Stevens-Johnson syndrome.

Musculoskeletal disorders : muscle weakness, muscle cramps, myalgia and arthralgia

Other symptoms : visual disturbances, vestibular disorders including tinnitus and hearing impairment, dyspnea, asthenia, malaise, fatigue, fever, sweating, chills, dyspepsia and loss of appetite.

Laboratory test abnormalities

The most frequently associated laboratory alterations, which could be possibly attributable to drug administration were decreased hematocrit, transient elevation of transaminases, leukopenia and thrombocytopenia. These alterations were observed in patients with acute malaria who received treatment doses of the drug and were attributed to the disease itself.

During prophylactic administration of mefloquine to indigenous populations in malaria-endemic areas, the following occasional alterations in laboratory values were observed: transient elevation of transaminases, leukocytosis or thrombocytopenia.

Because of the long half life of mefloquine, adverse reactions to mefloquine may occur or persist up to several weeks after the last dose.

Mefloquine should not be administered on an empty stomach. The bioavailability of mefloquine is improved if it is taken after food. In addition, mefloquine hydrochloride should be administered with ample water.

Treatment - The recommended dose is 15 mg or 25 mg of mefloquine base per kg. Administration of the drug as a split dose at an interval of 6-24 h substantially improves tolerability. The drug should be taken with ample amounts of water and preferably not just prior to sleeping.

Mefloquine can be given for severe acute malaria after an initial course of intravenous quinine lasting at least 2 - 3 days. Interactions leading to adverse events can largely be prevented by allowing an interval of at least 12 hours after the last dose of quinine.

In areas with multi-resistant malaria, initial treatment with artemisinin or a derivative, if available, followed by mefloquine is also an option. It reduces the risk of recrudescence.

There is no evidence that dose adjustment is necessary for patients with renal insufficiency. However, since clinical evidence in such patients is limited, caution should be exercised when using mefloquine in patients with impaired renal function.

If a patient receiving mefloquine for the treatment of malaria vomits within 30 minutes of receiving a dose of the drug, they should receive another dose; those who vomit within 30 - 60 minutes of receiving a dose should receive half the previously administered dose. If vomiting recurs, the patients should be monitored closely and alternative malaria treatment considered if improvement is not observed within a reasonable period of time.

Geriatrics - No specific adaptation of the usual adult dosage is required for elderly patients.

Chemoprophylaxis - The recommended dose is 5 mg of mefloquine base per kg weekly, giving an adult dose of 250 mg of base per week. It is recommended that, whenever possible, mefloquine chemoprophylaxis should be started 2-3 weeks before departure.

Cardiac, hepatic and neurological symptoms have been reported in a patient who inadvertently received 5.25g of mefloquine over 6 days. All symptoms disappeared rapidly when mefloquine was discontinued.

In cases of overdosage with mefloquine, the symptoms mentioned under adverse reactions may be more pronounced. The following procedure is recommended in case of overdosage: Induce vomiting or perform gastric lavage, as appropriate. Monitor cardiac function (if possible by ECG) and neuropsychiatric status for at least 24 hours. Provide symptomatic and intensive supportive treatment as required, particularly for cardiovascular disturbances. Treat vomiting or diarrhoea with standard fluid therapy.

Store in cool dry dark place.

Strip of 6 Tablets