Lariam 250mg tablets

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

For excipients, see section 6.1.

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

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.

For current advice on geographical resistance patterns and appropriate chemoprophylaxis, current guidelines or the Malaria Reference Laboratory should be consulted, details of which can be found in the British National Formulary (BNF).

Curative treatment

The recommended total therapeutic dose of mefloquine for non-immune patients is 20 – 25mg/kg. A lower total dose of 15mg/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.*

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 evaluate 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 Interaction with other medicinal products and other forms of interaction).

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

Malaria prophylaxis

For malaria prophylaxis the stated dose of Lariam should be given once weekly, always on the same day. Treatment should be initiated at least one week and up to 2-3 weeks before arrival in a malarious area and continued for 4 weeks after leaving (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.

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.

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

Lariam should not be prescribed for prophylaxis in persons with active depression or with a history of major psychiatric disorders or convulsions. (see sections 4.4 and 4.5).

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.

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.

Hypersensitivity:

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

Cardiac conduction abnormalities:

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.

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).

Seizure disorders:

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).

Neuropsychiatric Adverse Reactions:

In chemoprophylaxis the safety profile of mefloquine is characterised by a predominance of neuropsychiatric adverse reactions. If acute anxiety, depression, restlessness or confusion occur during prophylactic use, Lariam should be discontinued and an alternative prophylactic agent should be recommended (see section 4.3).

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.

Impaired renal function:

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.

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.

Blood and lymphatic system disorders:

Cases of agranulocytosis and aplastic anaemia have been reported during Lariam therapy (see section 4.8).

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 prophylaxis 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 quinine have been observed in some regions. For current advice on geographical resistance patterns competent national expert centres should be consulted.

Contraceptive measures:

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).

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

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

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 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 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 of the isoenzyme CYP3A4 may modify the pharmacokinetics/metabolism of mefloquine, leading to an increase in mefloquine plasma concentrations and potential risk of adverse reactions. Therefore, mefloquine should be used with caution when administered concomitantly with CYP3A4 inhibitors. Similarly, inducers of the isoenzyme CYP3A4 may modify the pharmacokinetics/metabolism of mefloquine, leading to a decrease in mefloquine plasma concentrations.

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. 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.

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

Lariam has been shown to be teratogenic in mice and rats and embryotoxic in rabbits. 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.

Lariam should not be used during pregnancy particularly in the first trimester unless the expected benefit justifies the potential risk to the foetus.

For use of mefloquine during pregnancy, current national and international guidelines should be consulted.

Women of childbearing potential should be advised to practice contraception during malaria prophylaxis with Lariam and for up to 3 months thereafter.

As mefloquine is secreted into the breast milk, nursing mothers should not breast-feed while taking Lariam. For use of melfloquine during pregnancy, current national and international guidelines should be consulted.

Mefloquine can cause dizziness or disturbed sense of balance. It is consequently recommended not to drive or carry out tasks demanding fine co-ordination and spatial discrimination during treatment with mefloquine. Patients should avoid such tasks for at least 3 weeks following therapeutic use, as dizziness, a disturbed sense of balance or neuropsychiatric reactions have been reported up to three weeks after the use of Lariam.

Prophylactic use

Caution should be exercised with regard to driving, piloting aircraft and operating machines, as dizziness, a disturbed sense of balance or neuropsychiatric reactions have been reported during and up to three weeks after use of Lariam.

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 Undesirable Effects).

At the doses given for acute malaria, adverse reactions to Lariam may not be distinguishable from symptoms of the disease itself. The overall incidence of adverse events reported during mefloquine prophylaxis is comparable to that reported for other chemoprophylactic regimens. However, the profile of mefloquine adverse events is predominantly characterised by neuropsychological adverse events.

Because of the long half-life of mefloquine, adverse reactions to Lariam may occur or persist for more than 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 evaluated.

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 (Undesirable effects) may be more pronounced.

Treatment

Patients should be managed by symptomatic and supportive care following Lariam 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.

Pharmaco-therapeutic group: Antiprotozoal agent, ATC code P01BC02

Lariam acts on and destroys the asexual intraerythocytic forms of the human malaria parasites: Plasmodium falciparum, P. vivax. P. malariae and P. ovale. It is effective in the treatment and prophylaxis of malaria.

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.

In a randomized, double-blind study, non-immune travellers who visited a malaria-endemic area received either mefloquine (483 subjects) or atovaquoine-proguanil (493 subjects). The primary endpoint was the overall frequency of adverse events, assessed 7 days after leaving the malaria endemic area. Efficacy of chemoprophylaxis was evaluated as a secondary end point. The average duration of travel was ~2.5 weeks, and 79% of subjects travelled to Africa. 10 subjects (5 in each study arm) were identified with circumsporozoite antibodies, none of them developed malaria (minimum efficacy for both mefloquine and atovaquone-proguanil was 100%). Results indicated that mefloquine and atovaquone-proguanil are similarly effective for malaria prophylaxis in non-immune travelers (see Table 3).

However, patients in the mefloquine group exhibited a predominance of neuropsychiatric adverse reactions compared to those treated with atovaquone-proguanil (see also sections 4.4 and 4.8).

Table 3 Estimates of adverse events and minimum and maximum efficacy for malaria prophylaxis

a Minimum efficacy = 100 x [1 – (no. of subjects with confirmed malaria/no. with circumsporozoite antibodies)]

b Maximum efficacy = 100 x [1 – (no. of subjects with confirmed malaria/no. with 60-day efficacy data)]

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 1000μg/l after a single dose of 1000mg). The presence of food significantly enhances the rate and extent of absorption.

At a dose of 250mg once weekly, maximum steady state plasma concentrations of 1000 – 2000μg/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 600μg/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 Pregnancy and lactation).

Microcrystalline cellulose

lactose

crospovidone

maize starch

ammonium-calcium alginate

poloxamer (polyoxyethylene-polyoxypropylene copolymer)

talc

magnesium stearate

Not applicable.

3 years.

Store in the original package.

Aluminium foil packs containing 8 tablets.

Not applicable.

Roche Products Limited

6 Falcon Way

Shire Park

Welwyn Garden City

AL7 1TW

United Kingdom

PL 00031/0236

5 October 1989 / 1 February 2004

29 November 2011

Lariam is a registered trade mark