Roche Products Limited

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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.

Patients with a history ofLariam should not be prescribed for prophylaxis in persons with active depression or with a history of major psychiatric disorders or convulsions. psychiatric disturbances (including depression) or convulsions should not be prescribed Lariam prophylactically, as it may precipitate these conditions (see sections 4.4 Special warnings anl precautions for use and section 4.5 Interaction with other medicinal products and other forms of interaction).

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.

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).

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 Interaction with other Medicinal Products and other Forms of Interaction).

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 Contraindications and section 4.5 Interaction with other medicinal products and other forms of interaction).

Neuropsychiatric Adverse Reactions:

 In chemoprophylaxis the safety profile of mefloquine is characterised by a predominance of neuropsychiatric adverse reactions. If psychiatric disturbancesacute 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 Contraindications).

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.

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

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).

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.

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 Pregnancy and lactation).

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.

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 bbeta‑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 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 and potential risk of adverse reactions. Therefore, mefloquine should be used with caution when administered concomitantly with CYP3A4 inbitors., respectively.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.

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.

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.

5.            PHARMACOLOGICAL PROPERTIES

5.1.        Pharmacodynamic properties

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. 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. 

In a randomized, double-blind study, non-immune travelers who visited a malaria-endemic areareceived malaria prophylaxis with received either mefloquine (483 subjects) andor atovaquoine-proguanil (493 subjects). who visited a malaria-endemic area. 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 traveled to Africa. 1013 subjects were initially randomized to receive mefloquine (n=505) or atovaquone-proguanil (n=508).  Thirty-seven subjects withdrew due to a variety of reasons.  Of the 976 subjects who received ≥1 dose of study drug, 966 (99%) completed the trial and 963 completed the 60-day follow-up period and had efficacy information recorded. Although 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%). Overall, there were no cases of confirmed malaria in this study (maximum 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.

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4.6.      Pregnancy and lactation

There is too little clinical experience in humans to assess any possible damaging effects of Lariam during pregnancy.  However, mefloquine is teratogenic when administered to rats and mice in early gestation.  Therefore, Lariam should be used in pregnancy only if there are compelling medical reasons.  In the absence of clinical experience, prophylactic use during pregnancy should be avoided as a matter of principle.

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.

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4.4.      Special warnings and precautions for 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).

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 after mefloquine during Lariam therapy for prophylaxis or treatment of malaria, or within 15 weeks of 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.

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.

4.7.      Effects on ability to drive and use machines

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 the last dosediscontinuation 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.

Common adverse reactions

Nausea, vomiting, dizziness or vertigo, loss of balance, headache, somnolence, sleep disorders (insomnia, abnormal dreams), loose stools or diarrhoea and abdominal pain.

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: Less frequently reported are lLeucopenia or leucocystosis and thrombocytopenia.

Immune System Disorders: There have been rare reports of anaphylaxis in patients taking Lariam.

Metabolism and Nutrition Disorders:  A less frequently reported event is aAnorexia.

Psychiatric Disorders: Most frequently reported are sSleep disorders (insomnia, abnormal dreams).  Less frequently reported are, 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: Most frequently reported are dDizziness, loss of balance, headache and somnolence. Less frequently reported are, syncope, convulsions, memory impairment, sensory and motor neuropathies (including paraesthesia, tremor and ataxia). Isolated cases of encephalopathy have been reported.

Eye Disorders: Less frequently reported are vVisual disturbances.

Ear and Labyrinth Disorders: Most frequently reported is vVertigo,. Less frequently reported are vestibular disorders including tinnitus and hearing impairment.

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

Vascular Disorders: Less frequently reported are cCirculatory disturbances (hypotension, hypertension, flushing).

Respiratory, Thoracic and Mediastinal Disorders: Less frequently reported is dDyspnoea. Very rare cases of pneumonitis of possible allergic etiology have been reported.

Gastrointestinal Disorders: Most frequently reported are nNausea, vomiting, diarrhoea and abdominal pain,. Less frequently reported is dyspepsia.

Hepatobiliary disorders: Less frequently reported is tTransient elevation of transaminases.

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

Musculoskeletal and Connective Tissue Disorders: Less frequently reported are mMuscle weakness, muscle cramps, myalgia, arthralgia.

General Disorders and Administration Site Disorders: Less frequently reported are oedema, chest pain, asthenia, malaise, fatigue, chills, pyrexia.

5.2.      Pharmacokinetic properties

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.

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4.8       Undesirable effects

Uncommon adverse reactions

Respiratory system: Dyspnoea.   Very rare cases of pneumonitis of possible allergic aetiology have been reported.

General symptoms:  Asthenia, malaise, fatigue, fever, sweating, chills, loss of appetite, and dyspepsia and dyspnoea.

4.9       Overdose

Treatment

Countermeasures:  Induce vomiting or perform gastric lavage as appropriate. 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.

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4.2              Posology and method of administration

Malaria prophylaxis

For malaria prophylaxis the stated dose of Lariam should be given once weekly, always on the same day.   TreatmentProphylaxis of malaria with Lariam 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 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.