1. Name Of The Medicinal Product
Lariam 250mg tablets
2. Qualitative And Quantitative Composition
Each tablet contains 250mg mefloquine (as 274.09mg mefloquine hydrochloride).
For excipients, see section 6.1.
3. Pharmaceutical Form
Tablet. White to off-white cylindrical biplanar tablets, cross scored and imprinted with Roche on one face.
4. Clinical Particulars
4.1 Therapeutic Indications
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).
4.2 Posology And Method Of Administration
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.*
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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.
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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.
4.3 Contraindications
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 section 4.4 Special warnings anl precautions for use and section 4.5 Interaction with other medicinal products and other forms of interaction).
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.
4.4 Special Warnings And Precautions For Use
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 Pregnancy and lactation).
If psychiatric disturbances occur during prophylactic use, Lariam should be discontinued and an alternative prophylactic agent should be recommended (see section 4.3 Contraindications).
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 section 4.3 Contraindications and section 4.5 Interaction with other medicinal products and other forms of interaction).
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 4.5 Interaction with other Medicinal Products and other Forms of Interaction).
Patients should not disregard the possibility that re-infection or recrudescence may occur after effective antimalarial therapy.
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
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 4.4 Special warnings and precautions for use). 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 β1-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 section 4.3 Contraindications and section 4.4 Special warnings and precautions for use).
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. 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
4.6 Pregnancy And Lactation
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.
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.
4.7 Effects On Ability To Drive And Use Machines
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).
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.
4.9 Overdose
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.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
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
5.2 Pharmacokinetic Properties
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.
5.3 Preclinical Safety Data
Mefloquine crosses the placenta and is teratogenic when administered to rats and mice in early gestation (see section 4.6 Pregnancy and lactation).
6. Pharmaceutical Particulars
6.1 List Of Excipients
Microcrystalline cellulose
lactose
crospovidone
maize starch
ammonium-calcium alginate
poloxamer (polyoxyethylene-polyoxypropylene copolymer)
talc
magnesium stearate
6.2 Incompatibilities
Not applicable.
6.3 Shelf Life
3 years.
6.4 Special Precautions For Storage
Store in the original package.
6.5 Nature And Contents Of Container
Aluminium foil packs containing 8 tablets.
6.6 Special Precautions For Disposal And Other Handling
Not applicable.
7. Marketing Authorisation Holder
Roche Products Limited
6 Falcon Way
Shire Park
Welwyn Garden City
AL7 1TW
United Kingdom
8. Marketing Authorisation Number(S)
PL 00031/0236
9. Date Of First Authorisation/Renewal Of The Authorisation
5 October 1989 / 1 February 2004
10. Date Of Revision Of The Text
27 August 2009
LEGAL STATUS
POM
Lariam is a registered trade mark
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