This material is provided by Roche Products Ltd as a licence requirement for this medicine and forms part of the Risk Management Plan.
- 1. Name of the medicinal product
- 2. Qualitative and quantitative composition
- 3. Pharmaceutical form
- 4. Clinical particulars
- 4.1 Therapeutic indications
- 4.2 Posology and method of administration
- 4.3 Contraindications
- 4.4 Special warnings and precautions for use
- 4.5 Interaction with other medicinal products and other forms of interaction
- 4.6 Fertility, pregnancy and lactation
- 4.7 Effects on ability to drive and use machines
- 4.8 Undesirable effects
- 4.9 Overdose
- 5. Pharmacological properties
- 5.1 Pharmacodynamic properties
- 5.2 Pharmacokinetic properties
- 5.3 Preclinical safety data
- 6. Pharmaceutical particulars
- 6.1 List of excipients
- 6.2 Incompatibilities
- 6.3 Shelf life
- 6.4 Special precautions for storage
- 6.5 Nature and contents of container
- 6.6 Special precautions for disposal and other handling
- 7. Marketing authorisation holder
- 8. Marketing authorisation number(s)
- 9. Date of first authorisation/renewal of the authorisation
- 10. Date of revision of the text
ChemoprophylaxisFor malaria prophylaxis the stated dose of Lariam should be given once weekly, always on the same day. In order to ensure, before arrival in endemic area, that Lariam administration is well tolerated, it is recommended to start chemoprophylaxis with Lariam 10 days before departure (i.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 Lariam is 12 months.The following dosage schedule is given as a guide:
|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|
Curative treatmentThe recommended total therapeutic dose of Lariam for non-immune patients is 20 25 mg/kg. A lower total dose of 15 mg/kg may suffice for partially immune individuals.The recommended total therapeutic dosages of Lariam tablets relative to body weight and immune status are presented in the following table:
|Non-immune patients||Partially immune patients|
|< 20 kg *||¼ tablet / 2.5 3 kg 1 tablet / 10 12 kg||¼ tablet / 4 kg 1 tablet / 16 kg|
|20 30 kg||2 3 tablets||1¼ 2 tablets|
|> 30 45 kg||3 4 tablets||2 3 tablets|
|> 45 60 kg||4 5 tablets||3 4 tablets|
|> 60 kg **||6 tablets||4 6 tablets|
ElderlyNo specific adaptation of the usual adult dosage is required for elderly patients.
Neuropsychiatric Adverse Reactions
|Mefloquine may induce psychiatric symptoms such as anxiety disorders, paranoia, depression, hallucinations and psychosis. Psychiatric symptoms such as 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:Hypersensitivity reactions ranging from mild cutaneous events to anaphylaxis may occur (see section 4.8).
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.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.
Seizure disorders: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).
Neuropathy: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).
Eye disorders: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.
Impaired liver function: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.
Renal impairment:Due to limited data, mefloquine should be administered with caution in patients with renal impairment.
Pneumonitis: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.
Blood and lymphatic system disorders:Cases of agranulocytosis and aplastic anaemia have been reported during mefloquine therapy (see section 4.8).
Inhibitors and Inducers of CYP3A4: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).
Interaction with vaccines: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).
Long term use: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.
Galactose intolerance:Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Geographical drug resistance: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.
Hypoglycaemia: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.
Halofantrine: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.
Other drugs that prolong the QTc interval: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.
Anticonvulsants and drugs lowering the epileptogenic threshold: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).
Other Interactions/ Inhibitors and Inducers of CYP3A4: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).
Substrates and inhibitors of P-glycoprotein:It has been shown in vitro that mefloquine is a substrate and an inhibitor of P-glycoprotein. Therefore, drug-drug interactions could also occur with drugs that are substrates, or are known to modify the expression of this transporter. The clinical relevance of these interactions is not known to date.
Interaction with vaccines: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.
PregnancyMefloquine 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:- 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 Lariam is not considered as an indication for pregnancy termination. For use of mefloquine during pregnancy, current national and international guidelines should be consulted.
Breast-feedingMefloquine 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.
a) Summary of safety profileAt 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) Tabulated list of adverse reactionsIn 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.|
|Blood and Lymphatic System Disorders c)|
|Not known||Agranulocytosis, aplastic anaemia, leukopenia, leukocytosis, thrombocytopenia|
|Immune system disorders c)|
|Not known||Hypersensitivity from mild cutaneous events to anaphylaxis|
|Metabolism and nutrition disorders|
|Not known||Decreased appetite|
|Psychiatric disorders a),b, c)|
|Very common||Abnormal dreams, insomnia|
|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), b , c)|
|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)|
|Not known||Cataract, retinal disorders and optic neuropathy which may occur with latency during or after treatment, vision blurred|
|Ear and labyrinth disorders|
|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|
|Not known||Cardiovascular disorders (hypotension, hypertension, flushing)|
|Respiratory, thoracic and mediastinal disorders c)|
|Not known||Pneumonia, pneumonitis of possible allergic etiology, dyspnoea|
|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|
|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|
c) Description of selected adverse reactionsOf 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 reactionsIf 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/nightmaresAbnormal dreams are a very common adverse reaction 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 of suspected adverse reactionsReporting 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.
Symptoms and signsIn cases of overdosage with mefloquine, the symptoms mentioned under section 4.8 may be more pronounced.
TreatmentPatients should be managed by symptomatic and supportive care following mefloquine overdose. There are no specific antidotes. The use of oral activated charcoal to limit mefloquine absorption may be considered within one hour of ingestion of an overdose. 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 disorders. Elimination of mefloquine and its metabolites is limited by haemodialysis.
Table 3 Estimates of adverse events and minimum and maximum efficacy for malaria prophylaxis
|Subjects who received|
|Number of subjects who received study drug||493||483|
|Subjects with 60-day efficacy data available, no.||486||477|
|Subjects who developed circumsporozoite antibodies, no.||5||5|
|Subjects with confirmed malaria, no.||0||0|
|Minimum efficacy, % (95% CI)a||100 (48-100)||100 (48-100)|
|Maximum efficacy, % (95% CI)b||100 (99-100)||100 (99-100)|
|Occurrence of any adverse event||149||204|
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