Lariam 250 mg Tablets

Each tablet contains 250 mg mefloquine (as 274.09 mg mefloquine hydrochloride).

Each tablet contains 50.61 mg of lactose monohydrate.

For a full list of excipients, see section 6.1.

Tablets.

White to off-white cylindrical biplanar tablets, cross-scored and imprinted Roche on one face.

The tablet can be divided into equal halves to facilitate dosing.

Therapy and prophylaxis of malaria.

Therapy: Lariam is especially indicated for therapy of P. falciparum malaria in which the pathogen has become resistant to other antimalarial agents.

Following treatment of P. vivax malaria with Lariam, relapse prophylaxis with an 8-amino-quinoline derivative, for example primaquine, should be considered in order to eliminate parasites in the hepatic phase.

Prophylaxis: Malaria prophylaxis with Lariam is particularly recommended for travellers to malarious areas in which multiple resistant P. falciparum strains occur.

Curative treatment

The recommended total therapeutic dose of mefloquine 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:*

* Splitting the total curative dosage into 2 – 3 doses (e.g. 3 + 1, 3 + 2 or 3 + 2 + 1 tablets) taken 6 - 8 hours apart may reduce the occurrence or severity of adverse events.

** Experience with Lariam in infants less than 3 months old or weighing less than 5kg is limited.

*** There is no specific experience with total dosages of more than 6 tablets in very heavy patients.

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 Lariam does not lead to improvement within 48 - 72 hours, alternative treatments should be considered. When breakthrough malaria occurs during Lariam prophylaxis, physicians should carefully eva luate which antimalarial to use for therapy.

Lariam 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 (see Section 4.5).

In areas with multi-resistant malaria, initial treatment with artemisinin or a derivative, if available, followed by Lariam is also an option.

Malaria prophylaxis

Prophylaxis of malaria with Lariam should be initiated at least one week and up to 2 - 3 weeks before arrival in a malarious area. The stated dose to be given once weekly, always on the same day for a minimum of six weeks. Further doses at weekly intervals during, and for four weeks after visiting the malarious area. The following dosage schedule is given as a guide:

The maximum recommended duration of administration of Lariam is 12 months.

The tablets should be swallowed whole preferably after a meal with plenty of liquid.

Elderly

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

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.

Patients with a history of psychiatric disturbances (including depression) or convulsions should not be prescribed Lariam prophylactically, as it may precipitate these conditions (see sections 4.4, 4.5 and 4.8).

Lariam should not be administered to patients with a known hypersensitivity to mefloquine or related compounds, e.g. quinine.

Because of the danger of a potentially fatal prolongation of the QTc interval, halofantrine must not be given simultaneously with or subsequent to Lariam. No data are available where Lariam was given after halofantrine.

Women of childbearing potential travelling to malarious areas in which multiple resistant P. falciparum is found and who are receiving Lariam for the treatment and prophylaxis of malaria should take reliable contraceptive precautions for the entire duration of therapy and for three months after the last dose of Lariam (see section 4.6).

Lariam can cause neuropsychiatric disturbances. If psychiatric disturbances occur during prophylactic use, Lariam should be discontinued and an alternative prophylactic agent should be recommended (see section 4.3). Disturbances have ranged from confusion and anxiety to severe neuropsychiatric effects (including hallucinations, psychotic or paranoid reactions, depression), and symptoms may persist up to several weeks after discontinuation of the drug (see section 4.8).

Rare cases of suicidal ideation and suicide have been reported though no relationship to drug administration has been confirmed. Patients with a history of psychiatric disturbances should not be prescribed Lariam prophylactically (see section 4.3).

Experience with Lariam in infants less than 3 months old or weighing less than 5kg is limited.

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 Lariam in patients with impaired renal function.

In patients with epilepsy, mefloquine may increase the risk of convulsions. Therefore in such cases, Lariam should be used only for curative treatment and only if compelling reasons exist (see sections 4.3 and 4.5).

Lariam 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. Caution is particularly recommended in patients at risk of QT prolongation, including those with organic heart disease (myocardial infarction, congestive heart failure), electrolyte disturbances (e.g. hypokalaemia, hypocalcaemia) and liver disease.

The risk of electrocardiographic abnormalities and convulsions is increased with concomitant administration of other related compounds, such as quinine, quinidine and chloroquine (see section 4.5).

Due to the risk of a potentially fatal prolongation of the QTc interval, halofantrine must not be given during Lariam therapy for prophylaxis or treatment of malaria, or within 15 weeks after the last dose of Lariam. 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 Lariam therapy for prophylaxis or treatment of malaria, or within 15 weeks after the last dose of Lariam (see section 4.5).

Patients should not disregard the possibility that re-infection or recrudescence may occur after effective antimalarial therapy.

As with many medications, potential hypersensitivity reactions ranging from mild cutaneous adverse events to anaphylaxis cannot be predicted.

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Concomitant administration of Lariam and other related compounds (e.g. quinine, quinidine and chloroquine) may produce electrocardiographic abnormalities and increase the risk of convulsions. There is evidence that the use of halofantrine during Lariam therapy for prophylaxis or treatment of malaria, or within 15 weeks after the last dose of Lariam, causes a significant lengthening of the QTc interval (see section 4.4). Clinically significant QTc prolongation has not been found with mefloquine alone.

This appears to be the only clinically relevant interaction of this kind with Lariam, although theoretically co-administration of other drugs known to alter cardiac conduction (e.g. anti-arrhythmic or β-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 taking an anticonvulsant (e.g. valproic acid, carbamazepine, phenobarbital or phenytoin), the concomitant use of Lariam may reduce seizure control by lowering the plasma levels of the anticonvulsant. Dosage adjustments of anti-seizure medication may be necessary in some cases (see sections 4.3 and 4.4).

When Lariam 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 Lariam.

Other Potential Interactions

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, inhibitors or inducers of the isoenzyme CYP3A4 may modify the pharmacokinetics/metabolism of mefloquine, leading to an increase or decrease in mefloquine plasma concentrations, respectively.

Inhibitors of CYP3A4

One pharmacokinetic study in healthy volunteers showed that the co-administration of ketoconazole, a strong inhibitor of CYP3A4, increased the plasma concentrations and elimination half-life of mefloquine.

Inducers of CYP3A4

The long-term use of rifampicin, a potent inducer of CYP3A4, reduced the plasma concentrations and elimination half-life of mefloquine.

Substrates and inhibitors of P-glycoprotein

It has been shown in vitro that mefloquine is a substrate and an inhibitor of P-glycoprotein. Although the clinical relevance of this is not known to date, there is a theoretical risk that drug-drug interactions could occur with drugs that are substrates, or are known to modify the expression of this transporter.

No other drug interactions are known. Nevertheless, the effects of Lariam on travellers receiving comedication, particularly those on anticoagulants or antidiabetics, should be checked before departure.

Administered at 5-20 times the therapeutic dose in man, mefloquine was teratogenic in mice and rats and embryotoxic in rabbits; however, clinical experience with Lariam has not revealed an embryotoxic or teratogenic effect. Nevertheless, Lariam should be used during the first trimester only if the expected benefit justifies the potential risk to the foetus. Women of childbearing potential should be advised to practice contraception during malaria prophylaxis with Lariam and for up to 3 months thereafter. However, in the case of unplanned pregnancy, malaria chemoprophylaxis with Lariam is not considered an indication for pregnancy termination.

As mefloquine is secreted into the breast milk, nursing mothers should not breast-feed while taking Lariam.

Patients experiencing dizziness and loss of balance or other disorders of the central or peripheral nervous system should be cautious with regard to driving, piloting aircraft, operating machines, deep-sea diving, or other activities requiring alertness and fine motor coordination.

In a small number of patients it has been reported that dizziness or vertigo and loss of balance may continue for months after discontinuation of the drug (see section 4.8).

At the doses given for acute malaria, adverse reactions to Lariam may not be distinguishable from symptoms of the disease itself. The profile of mefloquine adverse events is predominantly characterised by neuro-psychological adverse events.

Because of the long half-life of mefloquine, adverse reactions to Lariam may occur or persist up to several weeks after discontinuation of the drug. In a small number of patients, it has been reported that dizziness or vertigo and loss of balance may continue for months after discontinuation of the drug.

Patients should be advised to obtain medical advice before the next weekly dose of Lariam, if any concerning or neuropsychiatric symptoms develop. Discontinuation of Lariam should be considered, particularly if neuropsychiatric reactions occur. The need for alternative antimalarial therapy or prophylaxis can then be eva luated.

The following adverse events have been reported, although their absolute frequencies are not known (cannot be estimated from the available data):

Blood and Lymphatic System Disorders: Leucopenia or leucocystosis and thrombocytopenia.

Immune system disorders: There have been rare reports of anaphylaxis in patients taking Lariam.

Metabolism and Nutrition Disorders: Anorexia.

Psychiatric Disorders: Sleep disorders (insomnia, abnormal dreams), agitation, restlessness, anxiety, depression, mood swings, panic attacks, confusional state, hallucinations, aggression, psychotic or paranoid reactions.

There have been rare reports of suicidal ideation and suicide, but no relationship to drug administration has been established.

Nervous System Disorders: Dizziness, loss of balance, headache and somnolence, syncope, convulsions, memory impairment, sensory and motor neuropathies (including paraesthesia, tremor and ataxia). Isolated cases of encephalopathy have been reported.

Eye Disorders: Visual disturbances.

Ear and Labyrinth Disorders: Vertigo, vestibular disorders including tinnitus and hearing impairment.

Cardiac Disorders: Tachycardia, palpitation, bradycardia, irregular heart rate, extrasystoles, other transient cardiac conduction alterations. Isolated cases of AV-block have been reported.

Vascular Disorders: Circulatory disturbances (hypotension, hypertension, flushing).

Respiratory, Thoracic and Mediastinal Disorders: Dyspnoea. Very rare cases of pneumonitis of possible allergic etiology have been reported.

Gastrointestinal Disorders: Nausea, vomiting, diarrhoea and abdominal pain, dyspepsia.

Hepatobiliary disorders: Transient elevation of transaminases.

Skin and Subcutaneous Tissue Disorders: Rash, exanthema, erythema, urticaria, pruritus, alopecia, hyperhidrosis. Isolated cases of erythema multiforme and Stevens-Johnson syndrome have been reported.

Musculoskeletal and Connective Tissue Disorders: Muscle weakness, muscle cramps, myalgia, arthralgia.

General Disorders and Administration Site Disorders: Oedema, chest pain, asthenia, malaise, fatigue, chills, pyrexia.

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

Symptoms and signs

In cases of overdosage with Lariam, the symptoms mentioned under section 4.8 may be more pronounced.

Treatment

Patients should be managed by symptomatic and supportive care following Lariam overdose. There are no specific antidotes. 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.

Pharmacotherapeutic group: Methanolquinolines, ATC code: P01BC02

The effectiveness of Lariam in the therapy and prophylaxis of malaria is due essentially to destruction of the asexual forms of the malarial pathogens that affect humans (Plasmodium falciparum, P. vivax, P. malariae, P. ovale).

Lariam is also effective against malarial parasites resistant to other antimalarials such as chloroquine and other 4-aminoquinoline derivatives, proguanil, pyrimethamine and pyrimethamine-sulphonamide combinations. However, strains of P. falciparum resistant to mefloquine have been reported (e.g. in parts of Indochina). Cross-resistance between mefloquine and halofantrine has been observed.

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

Absorption: The maximum plasma concentration is reached within 6 to 24 hours after a single oral dose of Lariam. The level in micrograms per litre is roughly equivalent to the dose in milligrams (for example approximately 1000 micrograms/l after a single dose of 1000 mg). The presence of food significantly enhances the rate and extent of absorption.

At a dose of 250 mg once weekly, maximum steady state plasma concentrations of 1000-2000 micrograms/l are reached after 7-10 weeks. The RBC concentration is almost twice as high as the plasma level. Plasma protein binding is about 98%. Clinical experience suggests a minimal suppressive plasma concentration of mefloquine in the order of 600 micrograms/l.

Metabolism: Mefloquine is extensively metabolised in the liver by the cytochrome P450 system. In vitro and in vivo studies strongly suggest that CYP3A4 is the major isoform involved.

Elimination: The average half-life of mefloquine in Europeans is 21 days. There is evidence that mefloquine is excreted mainly in the bile and faeces. In volunteers, urinary excretion of unchanged mefloquine and its main metabolite accounted for about 9% and 4% of the dose, respectively.

Special clinical situations: The pharmacokinetics of mefloquine may be altered in acute malaria. Pharmacokinetic differences have been observed between various ethnic populations. In practice however, these are of minor importance compared with the host immune status and sensitivity of the parasite.

Mefloquine crosses the placenta. Excretion into breast milk appears to be minimal.

Mefloquine crosses the placenta and is teratogenic when administered to rats and mice in early gestation. (See section 4.6).

Poloxamer

Microcrystalline cellulose

Lactose monohydrate

Maize starch

Crospovidone

Ammonium calcium alginate

Talc

Magnesium stearate

Not applicable.

3 years.

Store in the original package to protect from moisture.

Aluminium foil packs containing 8 tablets.

No special requirements.

Roche Products Limited

6 Falcon Way

Shire Park,

Welwyn Garden City

AL7 1TW

United Kingdom

PA 50/73/1

November 2010

Further information is available from Roche Products (Ireland) Limited, 3004 Lake Drive, City West, Naas Road, Dublin 24, Ireland.