Mefloquine

Concomitant administration 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.

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

Due to limited data, mefloquine should be administered with caution in patients with renal impairment.

Concomitant administration of mefloquine and drugs known to lower the epileptogenic threshold (antidepressants such as tricyclic or selective serotonin reuptake inhibitors (SSRIs); bupropion; antipsychotics; tramadol; chloroquine or some antibiotics) may increase the risk of convulsions.

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

Patients taking mefloquine while on concomitant treatment with anticonvulsants (e.g. valproic acid, carbamazepine, phenobarbital or phenytoin), had loss of seizure control and lower than expected anticonvulsants blood level Therefore dosage adjustments of anti-seizure medication may be necessary in some cases.

Concomitant administration of mefloquine and drugs known to lower the epileptogenic threshold (antidepressants such as tricyclic or selective serotonin reuptake inhibitors (SSRIs); bupropion; antipsychotics; tramadol; chloroquine or some antibiotics) may increase the risk of convulsions.

Concomitant administration of mefloquine and other related compounds (e.g. quinine, quinidine and chloroquine) may produce electrocardiographic abnormalities.

In patients with epilepsy, mefloquine may increase the risk of convulsions. Therefore in such cases, mefloquine should be used only for curative treatment (i.e. not for stand-by therapy) and only if compelling reasons exist.

Mefloquine may induce psychiatric symptoms such as anxiety disorders, paranoia, depression, hallucinations and psychosis. Psychiatric symptoms such as insomnia, abnormal dreams/nightmares, acute anxiety, depression, restlessness or confusion have to be regarded as prodromal for a more serious event. Cases of suicide, suicidal thoughts and self-endangering behaviour such as attempted suicide 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. In a small number of patients it has been reported that neuropsychiatric reactions (e.g. depression, dizziness or vertigo and loss of balance) may persist for months or longer, even after discontinuation of the drug.

To minimise the risk for these adverse reactions, mefloquine must not be used for chemoprophylaxis in patients with active or a history of psychiatric disturbances such as depression, anxiety disorders, schizophrenia or other psychiatric disorders.

Pneumonitis of possible allergic etiology has been reported in patients receiving mefloquine. Patients who develop signs of dyspnoea, dry cough or fever etc. while receiving mefloquine should be advised to contact a doctor to undergo medical evaluation.

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.

Cases of polyneuropathy (based on neurological symptoms such as pain, burning, sensory disturbances or muscle weakness, alone or in combination) have been reported in patients receiving mefloquine.

Mefloquine should be discontinued in patients experiencing symptoms of neuropathy, including pain, burning, tingling, numbness, and/or weakness in order to prevent the development of an irreversible condition.

Mefloquine was teratogenic in mice and rats and embryotoxic in rabbits; however, large clinical experience with mefloquine as prophylactic treatment has not revealed an embryotoxic or teratogenic effect. Data from a limited number of exposed pregnancies indicate no adverse effects of mefloquine on pregnancy or on the health of the foetus/newborn child. To date, no other relevant epidemiological data are available.

Therefore:

• due to the seriousness of malaria during pregnancy, pregnant women or women who wish to become pregnant should be discouraged from travelling in endemic areas. Prophylactic treatment with mefloquine may be considered regardless the term of pregnancy but in the strict respect of the indications.
• use of mefloquine as curative treatment in pregnant women is limited to the treatment of acute uncomplicated malaria when quinine is contra-indicated or in case of Plasmodium falciparum resistance to quinine.

In case of unplanned pregnancy, malaria chemoprophylaxis with mefloquine is not considered as an indication for pregnancy termination. For use of mefloquine during pregnancy, current national and international guidelines should be consulted.

Mefloquine is secreted into the breast milk in small amounts, the activity of which is unknown. As a precautionary measure, mefloquine should be avoided in breast-feeding women. For use of mefloquine in nursing mothers current national and international guidelines should be consulted.

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, vertigo or a loss of balance, or other disorders of the central or peripheral nervous system and psychiatric disorders have been reported during and following the use of mefloquine. These effects may occur after therapy is discontinued. In a small number of patients, it has been reported that dizziness or vertigo and loss of balance may persist for months or longer, even after discontinuation of the drug.

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. In a small number of patients it has been reported that neuropsychiatric reactions (e.g. depression, dizziness or vertigo and loss of balance) may persist for months or longer, even after discontinuation of the drug.

b) List of adverse reactions

In the list 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 list 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.

Blood and Lymphatic System Disorders

Not known: Agranulocytosis, aplastic anaemia, leukopenia, leukocytosis, thrombocytopenia

Immune system disorders

Not known: Hypersensitivity from mild cutaneous events to anaphylaxis

Metabolism and nutrition disorders

Not known: Decreased appetite

Psychiatric disorders^a

Very common: Abnormal dreams, insomnia

Common: Depression, anxiety

Not known: Suicide, attempted suicide, suicidal ideation and self-endangering behavior, bipolar disorder, psychotic disorder including e.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

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

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

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

Not known: Pneumonia, pneumonitis of possible allergic etiology, dyspnoea

Gastrointestinal disorders

Common: Nausea, diarrhoea, abdominal pain, vomiting

Not known: Pancreatitis, dyspepsia

Hepatobiliary disorders

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.

c) Description of selected adverse reactions

Of the most common adverse reactions to mefloquine prophylaxis, nausea, vomiting and dizziness are generally mild and may decrease with prolonged use, in spite of increasing plasma drug levels.

Neuropsychiatric adverse reactions

If neuropsychiatric reactions or changes to the mental state occur during mefloquine chemoprophylaxis, the patient should be advised to stop taking mefloquine and seek medical advice immediately so that mefloquine can be replaced by alternative malaria prevention medication.

Studies in vitro and in vivo showed no haemolysis associated with G6PD deficiency.

Abnormal dreams/nightmares

Abnormal dreams and insomnia are very common adverse reactions with mefloquine, therefore their significance should be considered in the overall evaluation of patients reporting reactions or changes to their mental state with mefloquine.