Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2019 Publisher: CHEPLAPHARM Arzneimittel GmbH, Ziegelhof 24, 17489, Greifswald, Germany
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 (see section 4.8). Cases of suicide, suicidal thoughts and self-endangering behaviour such as attempted suicide (see section 4.8) 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. 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 (see section 4.3).
Hypersensitivity reactions ranging from mild cutaneous events to anaphylaxis may occur (see section 4.8).
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.
Concomitant administration of mefloquine and other related compounds (e.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. Due to increased plasma concentrations and elimination half-life of mefloquine following co-administration with ketoconazole, the risk of QTc prolongation may also be expected if ketoconazole is taken during mefloquine chemoprophylaxis or treatment of malaria, or within 15 weeks after the last dose of mefloquine (see sections 4.5 and 5.2).
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.
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 (see sections 4.3 and 4.5).
Concomitant administration of mefloquine and anticonvulsants (e.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.
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 (see section 4.5).
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 (see section 4.8).
Any patient presenting with a visual disorder should be referred to a physician as certain conditions (such as retinal disorders or optic neuropathy) may require stopping treatment with mefloquine.
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.
Pneumonitis of possible allergic etiology has been reported in patients receiving mefloquine (see section 4.8). 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.
Cases of agranulocytosis and aplastic anaemia have been reported during mefloquine therapy (see section 4.8).
Inhibitors and Inducers of the isoenzyme CYP3A4 may modify the pharmacokinetics/metabolism of mefloquine, leading to an increase or decrease in mefloquine plasma concentrations (see section 4.5).
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 (see section 4.5).
During clinical trials, this drug was not administered for longer than one year. If the drug is to be administered for a prolonged period, periodic evaluations including liver function tests and periodic ophthalmic examinations should be performed.
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Geographical drug resistance patterns of P. falciparum occur and preferred choice of malaria chemoprophylaxis might be different from one area to another. Resistance of P. falciparum to mefloquine has been reported, predominantly in areas of multi-drug resistance in South-East Asia. Cross-resistance between mefloquine and halofantrine and cross-resistance between mefloquine and quinine have been observed in some regions. For current advice on geographical resistance patterns competent national expert centres should be consulted.
The possibility of hypoglycaemia in patients with congenital hyperinsulinaemic hypoglycaemia should be considered.
Experience with mefloquine in infants less than 3 months old or weighing less than 5 kg is limited.
Patients should not disregard the possibility that re-infection or recrudescence may occur after effective antimalarial therapy.
There is evidence that the use of halofantrine during mefloquine chemoprophylaxis or treatment of malaria, or within 15 weeks after the last dose of mefloquine, causes a significant lengthening of the QTc interval (see sections 4.3 and 4.4). Clinically significant QTc prolongation has not been found with mefloquine alone.
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.
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 (see section 4.4).
Mefloquine does not inhibit or induce the cytochrome P450 enzyme system. It is therefore not expected that the metabolism of drugs given concomitantly with mefloquine is affected. However, inducers (rifampicin, carbamazepine, phenytoin, efavirenz) or inhibitors of the isoenzyme CYP3A4 may modify the pharmacokinetics/metabolism of mefloquine, leading to an increase or decrease in mefloquine plasma concentration. The clinical consequences of these effects are unknown and a close clinical surveillance is warranted (see section 4.4).
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 (see section 4.4).
No other drug interactions are known. Nevertheless, the effects of mefloquine on travellers receiving co-medication, particularly those on anticoagulants or antidiabetics, should be checked before departure.
Mefloquine was teratogenic in mice and rats and embryotoxic in rabbits; however, large clinical experience with Lariam 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:
In case of unplanned pregnancy, malaria chemoprophylaxis with Lariam 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 (see section 4.8).
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.
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.
Not known: Agranulocytosis, aplastic anaemia, leukopenia, leukocytosis, thrombocytopenia
Not known: Hypersensitivity from mild cutaneous events to anaphylaxis
Not known: Decreased appetite
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
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
Common: Visual impairment
Not known: Cataract, retinal disorders and optic neuropathy which may occur with latency during or after treatment, vision blurred
Common: Vertigo
Not known: Vestibular disorders including tinnitus, partial deafness (sometimes prolonged), hearing impaired, hyperacusis
Not known: AV block, tachycardia, palpitation, bradycardia, irregular heart rate, extrasystoles, other transient conduction disorder
Not known: Cardiovascular disorders (hypotension, hypertension, flushing)
Not known: Pneumonia, pneumonitis of possible allergic etiology, dyspnoea
Common: Nausea, diarrhoea, abdominal pain, vomiting
Not known: Pancreatitis, dyspepsia
Not known: Hepatic failure, hepatitis, jaundice, asymptomatic transient transaminase (ALT, AST, GGT) increased
Common: Pruritus
Not known: Stevens-Johnson syndrome, erythema multiforme, rash, erythema, urticaria, alopecia, hyperhidrosis
Not known: Muscular weakness, muscle spasms, myalgia, arthralgia
Not known: Oedema, chest pain, asthenia, malaise, fatigue, chills, pyrexia
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.
b See section 4.8.
c See section 4.4.
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.
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 (see section 4.4).
Studies in vitro and in vivo showed no haemolysis associated with G6PD deficiency.
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 (see boxed warning section 4.4).
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
Not applicable.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.
