MEFLOQUINE

When chemoprophylaxis with mefloquine fails, physicians should carefully evaluate which antimalarial to use for therapy. 5. Chemoprophylaxis For malaria prophylaxis the stated dose of mefloquine should be given once weekly, always on the same day.

e. first intake 10 days before departure and 2nd intake 3 days before departure). Subsequent doses should be taken once a week (on a fixed day). Treatment should be continued for 4 weeks after leaving a malarious area (minimum treatment period 6 weeks).

The maximum recommended duration of administration of mefloquine is 12 months. The recommended chemoprophylactic dose of mefloquine is approximately 5 mg/kg bodyweight once weekly.

The following dosage schedule is given as a guide:

Dosage Adults and children of more than 45 kg bodyweight 1 tablet Children and adults weighing less than 45 kg 5 – 19 kg ¼ tablet 20 – 30 kg ½ tablet 31 – 45 kg ¾ tablet The tablets should be swallowed whole preferably after a meal with plenty of liquid.

Curative treatment The recommended total therapeutic dose of mefloquine is 20 – 25 mg/kg. 5 – 3 kg 1 tablet / 10 – 12 kg 20 – 30 kg 2 – 3 tablets > 30 – 45 kg 3 – 4 tablets > 45 – 60 kg 4 – 5 tablets > 60 kg ** 6 tablets * Experience with mefloquine in infants less than 3 months old or weighing less than 5 kg is limited.

** There is no specific experience with total dosages of more than 6 tablets in very heavy patients. g. 3 + 1, 3 + 2 or 3 + 2 + 1 tablets) taken 6 – 8 hours apart. A second full dose should be given to patients who vomit less than 30 minutes after receiving the drug.

If vomiting occurs 30 – 60 minutes after a dose, an additional half-dose should be given. If a full treatment course with mefloquine does not lead to improvement within 48 – 72 hours, alternative treatments should be considered. Mefloquine can be given for severe acute malaria after an initial course of intravenous quinine lasting at least 2 – 3 days.

5). Artemisinin combination therapy (ACT) is recommended as the standard of care for treatment of P. falciparum malaria, regardless of region of acquisition. Mefloquine is a recommended partner molecule for inclusion in ACT. Elderly No specific adaptation of the usual adult dosage is required for elderly patients.

a) Summary of safety profile At the doses given for acute malaria, adverse reactions to mefloquine may not be distinguishable from symptoms of the disease itself. In chemoprophylaxis, the safety profile of mefloquine is characterised by a predominance of neuropsychiatric adverse reactions.

Adverse reactions may also occur after discontinuation of the drug. The most common adverse reactions to mefloquine chemoprophylaxis are nausea, vomiting and dizziness. Nausea and vomiting are generally mild and may decrease with prolonged use, in spite of increasing plasma drug levels.

g. depression, dizziness or vertigo and loss of balance) may persist for months or longer, even after discontinuation of the drug. b) Tabulated list of adverse reactions In the table below, an overview of adverse reactions is presented, based on post-marketing data and a double-blind, randomised study including 483 patients on mefloquine (Overbosch et al, 2001).

The frequencies presented in this table are based on the double-blind randomised study. Adverse reactions are listed according to MedRA system organ class and frequency category.

Frequency categories are defined using the following convention:

Very common (≥1/10) Common (≥1/100, <1/10) Uncommon (≥1/1,000, <1/100) Rare (≥1/10,000, <1/1,000) Very rare (<1/10,000) Not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

g. delusional disorder, depersonalization, mania, and schizophrenia/schizophreniform disorder, paranoia, panic attacks, confusional state, hallucinations, aggression, agitation, restlessness, mood swings, disturbance in attention Nervous system disorders a), b , c) Common Dizziness, headache Not known Encephalopathy, cranial nerve paralysis, convulsions, amnesia (sometimes long lasting for more than 3 months), syncope, speech disorder, memory impairment, balance disorder, gait disturbance, peripheral motor neuropathy (including paraesthesia, tremor and ataxia), ), peripheral sensory neuropathy, somnolence Eye disorders c) Common Visual impairment Not known Cataract, retinal disorders and optic neuropathy which may occur with latency during or after treatment, vision blurred Ear and labyrinth disorders Common Vertigo Not known Vestibular disorders including tinnitus, partial deafness (sometimes prolonged), hearing impaired, hyperacusis Cardiac disorders c) Not known AV block, tachycardia, palpitation, bradycardia, irregular heart rate, extrasystoles, other transient conduction disorder Vascular disorders Not known Cardiovascular disorders (hypotension, hypertension, flushing) Respiratory, thoracic and mediastinal disorders c) Not known Pneumonia, pneumonitis of possible allergic etiology, dyspnoea Gastrointestinal disorders Common Nausea, diarrhoea, abdominal pain, vomiting Not known Pancreatitis, dyspepsia Hepatobiliary disorders c) Not known Hepatic failure, hepatitis, jaundice, asymptomatic transient transaminase (ALT, AST, GGT) increased Skin and subcutaneous tissue disorders Common Pruritus Not known Stevens-Johnson syndrome, erythema multiforme, rash, erythema, urticaria, alopecia, hyperhidrosis Musculoskeletal and Connective Tissue Disorders Not known Muscular weakness, muscle spasms, myalgia, arthralgia General disorders and administration site disorders Not known Oedema, chest pain, asthenia, malaise, fatigue, chills, pyrexia Renal and urinary disorder Not known Renal failure acute, nephritis, blood creatinine increased a) Occasionally it has been reported that these symptoms persist for a long time after mefloquine is discontinued.

Neuropsychiatric Adverse Reactions Mefloquine may induce psychiatric symptoms such as anxiety disorders, paranoia, depression, hallucinations and psychosis. 8). 8) have been reported. Patients on malaria chemoprophylaxis with mefloquine should be informed that if these reactions or changes to their mental state occur during mefloquine use, to stop taking mefloquine and seek medical advice immediately so that mefloquine can be replaced by alternative malaria prevention medication.

Adverse reactions may also occur after discontinuation of the drug. g. depression, dizziness or vertigo and loss of balance) may persist for months or longer, even after discontinuation of the drug. 3). 8).

Cardiac toxicity:

Mefloquine should be taken with caution in patients suffering from cardiac conduction disorders, since transient cardiac conduction alterations have been observed during curative and preventative use. g. quinine, quinidine and chloroquine) may produce electrocardiographic abnormalities.

Due to the risk of a potentially fatal prolongation of the QTc interval, halofantrine must not be used during mefloquine chemoprophylaxis or treatment of malaria, or within 15 weeks after the last dose of mefloquine. 2). Patients should be advised to consult a doctor, if signs of arrhythmia or palpitations occur during chemoprophylaxis with mefloquine.

These symptoms might, in rare cases, precede severe cardiologic side effects.

Seizure disorders:

In patients with epilepsy, mefloquine may increase the risk of convulsions. e. 5). g. valproic acid, carbamazepine, phenobarbital or phenytoin) may reduce seizure control by lowering the plasma levels of anticonvulsant. Therefore, patients concurrently taking anti-seizure medication, including valproic acid, carbamazepine, phenobarbital and phenytoin, and mefloquine should have the blood level of their anti-seizure medication monitored and the dosage adjusted as necessary.

g. quinine, quinidine), or to any of the excipients contained in the formulation. 5). 5). - in patients with a history of Blackwater fever, a complication of falciparum malaria with massive intravascular haemolysis causing haemoglobinuria.

8). - Prophylactic use in patients with severe impairment of liver function should be regarded for the time being as a contraindication as no experience has been gained in such patients.