Consumer medicine information

Lariam

Mefloquine

BRAND INFORMATION

Brand name

Lariam

Active ingredient

Mefloquine

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Lariam.

SUMMARY CMI

Lariam®

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

1. Why am I using Lariam®?

Lariam® contains the active ingredient mefloquine. Lariam® is used to is used to prevent and treat malaria.

For more information, see Section 1. Why am I using Lariam®? in the full CMI.

2. What should I know before I use Lariam®?

Do not use if you have ever had an allergic reaction to mefloquine or any of the ingredients listed at the end of the CMI.

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before I use Lariam®? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with Lariam® and affect how it works.

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I use Lariam®?

  • Your doctor will tell you how many Lariam® tablets to take and how often to take them.
  • For treatment of malaria, the first dose of Lariam® is 3 tablets. This is followed by a second dose of 2 tablets, 6 - 8 hours later. The total dose of Lariam® is usually 5 tablets.
  • For prevention of malaria, the dose is 1 tablet of Lariam® once weekly, always on the same day. The first tablet should be taken one week before you arrive in the malarial area. Subsequently, take 1 tablet for each week that you remain in the malarial area and 1 tablet per week for two weeks after you have left the malarial area.

More instructions can be found in Section 4. How do I use Lariam®? in the full CMI.

5. What should I know while using Lariam®?

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are using Lariam®.
  • Tell your doctor if you feel Lariam® is not helping your condition or if for any reason you have not taken Lariam® exactly as prescribed.
  • Tell your doctor immediately if you become pregnant while taking Lariam®.
Things you should not do
  • Do not stop using this medicine suddenly or change the dose without consulting your doctor.
  • Do not use Lariam® to treat other complaints unless instructed by your doctor or share Lariam® with anyone else.
Driving or using machines
  • Lariam® may cause dizziness, drowsiness or loss of balance in some people. These effects may occur for some time after stopping Lariam® treatment.
  • Make sure you know how you react to Lariam® before doing anything that could be dangerous.
Drinking alcohol
  • Alcohol can worsen the dizziness, drowsiness or loss of balance caused by Lariam®.
Looking after your medicine
  • Keep your tablets in the blister pack until it is time to take them.
  • Keep Lariam® in a cool dry place where the temperature stays below 30°C and out of reach of children.

For more information, see Section 5. What should I know while using Lariam®? in the full CMI.

6. Are there any side effects?

The side effects of Lariam® can be similar to symptoms of Malaria and last months after you stop taking Lariam®. Lariam® can in rare cases cause serious side effects including mood related disorders or mental problems.

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.



FULL CMI

Lariam®

Active ingredient(s): mefloquine


Consumer Medicine Information (CMI)

This leaflet provides important information about using Lariam®. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using Lariam®.

Where to find information in this leaflet:

1. Why am I using Lariam®?
2. What should I know before I use Lariam®?
3. What if I am taking other medicines?
4. How do I use Lariam®?
5. What should I know while using Lariam®?
6. Are there any side effects?
7. Product details

1. Why am I using Lariam®?

Lariam® contains the active ingredient mefloquine.
Lariam® belongs to a group of medicines called quinolones (pronounced kwin-o-lones).

Lariam® is used to prevent and treat malaria.

Lariam® works by killing the parasites that may cause or have caused malaria.

2. What should I know before I use Lariam®?

Warnings

Do not use Lariam® if:

  • you are allergic to mefloquine, or related compounds quinine, quinidine or any of the ingredients listed at the end of this leaflet.
    Some of the symptoms of an allergic reaction may include:
    - shortness of breath
    - wheezing or difficult breathing
    - swelling of the face, lips, tongue or other parts of the body
    - rash, itching or hives on the skin
  • you have kidney disease
  • you have severe liver disease
  • the package is torn or shows signs of tampering or if the expiry date (EXP) printed on the pack has passed

Do not use Lariam® as a preventive medicine if:

  • you have depression or have a history of psychiatric disorders, such as depression or anxiety.
  • you have a history of seizures (epilepsy or convulsions).

Mental Problems

Some people who take Lariam® may have sudden serious mental problems. Symptoms of serious mental problems may include:

  • severe anxiety
  • hallucinations
  • depression
  • feeling restless
  • unusual behaviour
  • feeling confused

Check with your doctor if you:

  • have any other medical conditions, especially the following:
    - psychiatric disorders particularly mood disturbances (e.g., anxiety, depression)
    - heart conditions such as irregular heartbeat
    - epilepsy (fits or seizures) or convulsions
    - liver problems
    - malaria
  • have recently had a vaccination
  • are planning to travel to areas where Lariam® may not be an effective treatment (i.e., areas where there is an increased risk of drug resistance such as South-East Asia)
  • contact your doctor or travel health clinic before travelling for current advice on treatment and precautionary measures
  • take any medicines for any other condition

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

Check with your doctor if you are pregnant or intend to become pregnant.

If there is a need to take Lariam® during your pregnancy, your doctor will discuss with you the risks and benefits of using it.

Talk to your doctor if you are breastfeeding or intend to breastfeed.

Lariam® passes into breast milk and may affect your baby. Therefore, your doctor will discuss the risks and benefits of taking Lariam® if you are breastfeeding.

Precautions against malaria

The best protection against malaria is to avoid mosquito bites. The mosquito that causes malaria mainly bites between dusk and dawn. Therefore, the following precautionary measures are recommended:

  • during this period, wear light-coloured clothing that covers as much of your skin as possible.
  • apply mosquito repellent to your uncovered skin and to your clothes.
  • when sleeping in rooms that are not protected against mosquitoes, use an effective mosquito net well-tucked under the mattress.
  • additional protection is provided by smoke spirals, insect sprays and candles.

Symptoms of malaria

The symptoms of malaria may often be mild. However, malaria should be suspected if, after one week in a malarial area, you suffer unexplained fever with or without other symptoms such as headache, aching limbs, weakness, shaking, chills, and sometimes diarrhoea, vomiting and cough. These symptoms can easily be confused with influenza.

If these symptoms are due to the most dangerous form of malaria caused by the falciparum parasite, and they are not treated in time, severe organ damage, loss of consciousness and death can occur within a short period. The less dangerous forms of malaria, which are not life-threatening, can break out months or even years after the end of a stay in a malarial area.

Diagnosis and treatment of malaria

Early diagnosis is critical for successful treatment. Anyone suspected of having malaria should seek medical attention promptly and request that a blood sample be taken and examined microscopically for malaria parasites.

Most tourists and business travellers will normally be able to receive medical attention. However, if this is not readily available, anti-malarial drug treatment can be self-administered ('stand-by treatment').

Consult your doctor about the need to carry 'stand-by treatment' on your trip. Medical advice should still be sought after self-administered drug treatment.

There are many different types of medicines used for the treatment and prevention of malaria. Your doctor may have prescribed Lariam® for another purpose. Ask your doctor if you have any questions about why Lariam® has been prescribed for you.

Lariam® is not addictive.

3. What if I am taking other medicines?

Tell your doctor or pharmacist if you are taking any other medicines, including any medicines, vitamins or supplements that you buy without a prescription from your pharmacy, supermarket or health food shop.

Some medicines must not be taken with Lariam® or after Lariam® has been taken. It may cause serious heart problems.

Tell your doctor if you are taking or have taken recently:

  • halofantrine, a medicine used to treat malaria which is available overseas in some countries.
  • quinine, a medicine used to treat cramps or malaria.
  • quinidine, a medicine used to treat a heart problem called atrial fibrillation.
  • ketoconazole, an antifungal medicine used to treat infections.

Some medicines may interfere with Lariam® and affect how it works

These include:

  • chloroquine, a medicine used to treat or prevent malaria.
  • rifampicin, a medicine used to treat infections.
  • medicines used to treat fits, seizures or convulsions (epilepsy) such as valproic acid, carbamazepine, phenobarbital and phenytoin.
  • medicines used to treat or prevent irregular heartbeat.
  • medicines used to treat high blood pressure, including groups of medicines called beta-blockers and calcium channel blockers.
  • medicines used to lower blood sugar (treat diabetes).
  • medicines used to prevent blood clots.
  • some medicines used to treat depression and other mental disorders, including a group called tricyclic antidepressants.
  • some antihistamines and medicines used to prevent or relieve the symptoms of allergy, including promethazine and trimeprazine.
  • a group of medicines known as phenothiazines, used to treat mental problems, including prochlorperazine, chlorpromazine, trifluoperazine and fluphenazine.
  • typhoid vaccines. You should not be vaccinated against typhoid with a ‘live’ vaccine while taking Lariam®. Live typhoid vaccinations should be completed at least three days before the first dose of Lariam®. Ask your doctor or pharmacist if you are not sure if your vaccine is ‘live’.

These medicines may be affected by Lariam®,or may affect how well it works. You may need to take different amounts of your medicine, or you may need to take different medicines. Your doctor will advise you.

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect Lariam®.

4. How do I use Lariam®?

How much to take / use

  • Take Lariam® exactly as your doctor has prescribed.
  • Your doctor will tell you how many Lariam® tablets to take and how often to take them.
  • Follow the instructions provided and use Lariam® until your doctor tells you to stop.

For treatment of Malaria

  • The first dose of Lariam® is 3 tablets. This is followed by a second dose of 2 tablets, 6 - 8 hours later.
  • The total dose of Lariam® is usually 5 tablets.

For prevention of Malaria

  • The dose is 1 tablet of Lariam® once weekly, always on the same day. Take the first tablet one week before you arrive in the malarial area.
  • Take 1 tablet each week that you are in a malarial area.
  • Continue to take 1 tablet per week for two weeks after you have left the malarial area.

When to take / use Lariam®

It does not matter if you take Lariam® before or after food.

How to take Lariam®

Swallow tablets whole with a full glass of water.

If you forget to use Lariam® for treatment of Malaria

Lariam® should be used regularly at the same time each day. If you forget to take the second dose of Lariam® for the treatment of malaria, take it as soon as you remember and contact your doctor.

If it is almost time for your next dose, skip the dose you missed and take your next dose when you are meant to.

Do not take a double dose to make up for the dose you missed.

If you forget to use Lariam® for prevention of Malaria

Lariam® should be used regularly at the same time each week. If you forget to take a dose, take it as soon as you remember and then go back to taking it as you would normally once a week.

If you think you may have trouble remembering your dose, ask your pharmacist for some hints.

If you use too much Lariam®

If you think that you have used too much Lariam®, you may need urgent medical attention.

You should immediately:

  • phone the Poisons Information Centre
    (by calling 13 11 26), or
  • contact your doctor, or
  • go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

5. What should I know while using Lariam®?

Things you should do

Call your doctor straight away if you:

  • become pregnant while taking Lariam®.
  • Women of child-bearing potential should use effective contraception while taking Lariam® and for at least three months after taking the last dose.
  • Tell your doctor if, for any reason, you have not taken your medicine exactly as prescribed. Otherwise, your doctor may think that it was not effective and change your treatment unnecessarily.
  • If you are taking Lariam® for the treatment of malaria, tell your doctor if you feel it is not helping your condition.
  • Be sure to keep all of your appointments with your doctor so that your progress can be checked.

Remind any doctor, dentist or pharmacist you visit that you are using Lariam®.

Things you should not do

  • Do not stop taking Lariam® or change the dose without first checking with your doctor.
  • Do not let yourself run out of Lariam® over the weekend or on holidays.
  • Do not give Lariam® to anyone else even if they have the same condition as you.
  • Do not use Lariam® to treat other complaints unless your doctor says to.
  • Do not take any other medicines whether they require a prescription or not without first telling your doctor or consulting a pharmacist.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how Lariam® affects you.

Lariam® may cause dizziness, drowsiness or loss of balance in some people. These effects may occur for some time after stopping Lariam® treatment. Do not drive if you experience these side effects.

Drinking alcohol

Tell your doctor if you drink alcohol.

Alcohol may worsen the dizziness, drowsiness or loss of balance caused by Lariam®.

Looking after your medicine

Keep your tablets in the blister pack until it is time to take them. If you take the tablets out of the blister pack they will not keep well.

Keep Lariam® in a cool dry place where the temperature stays below 30°C.

Follow the instructions in the carton on how to take care of your medicine properly.

Store it in a cool dry place away from moisture, heat or sunlight; for example, do not store it:

  • in the bathroom or near a sink, or
  • in the car or on window sills.

Keep it where young children cannot reach it.

Getting rid of any unwanted medicine

If you no longer need to use this medicine or it is out of date, take it to any pharmacy for safe disposal.

Do not use this medicine after the expiry date.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

When Lariam® is used for treatment of malaria, side effects may occur more often than when it is used for prevention of malaria.

If you are taking Lariam® for the treatment of malaria, you may not be able to distinguish between the symptoms of malaria and the side effects of Lariam®.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Less serious side effects

Less serious side effectsWhat to do
  • dizziness, vertigo (a sense of spinning) or loss of balance; these may occur after Lariam® has been stopped
  • aching muscles, cramps, muscle tenderness or weakness, not caused by exercise
  • headache
  • fever, sweating or chills
  • nausea (feeling sick) or vomiting
  • diarrhoea, pain in the stomach
  • fatigue, tiredness or drowsiness
  • loss of appetite
  • tinnitus (buzzing, hissing, whistling, ringing or other persistent noise in the ears)
  • hair loss
  • itching
Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effectsWhat to do
  • insomnia (inability to sleep) or abnormal or strange dreams; these may occur after Lariam® has been stopped
  • change in mood, for example, excitement, depression, restlessness, confusion, agitation, aggression, feeling anxious or nervous, irrational ideas, hallucinations, suicidal thoughts or panic attacks, strange or disturbing thoughts or moods; these may also occur after Lariam® has been stopped
  • seizure (fit) or convulsion
  • irregular or racing heartbeat, chest pain
  • loss of consciousness
  • shaking or tremors
  • difficulty breathing, shortness of breath, chest tightness, coughing or wheezing
  • sudden tiredness, dizziness or sudden shortness of breath
  • tingling or numbness in the hands or feet
  • severe skin rash, blisters or bleeding in the lips, eyes, mouth, nose or genitals
  • yellowing of the skin or the eyes
  • problems with your eyes such as blurred vision or eye pain
Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

This medicine is only available with a doctor's prescription.

What Lariam® contains

Active ingredient
(main ingredient)
Mefloquine
Each Lariam® tablet contains 250 mg mefloquine as mefloquine hydrochloride.
Other ingredients
(inactive ingredients)
  • microcrystalline cellulose
  • lactose monohydrate
  • maize starch
  • crospovidone
  • ammonium calcium alginate
  • purified talc
  • magnesium stearate
  • poloxamer
Potential allergensLariam® does not contain sucrose, tartrazine or any other azo dyes.

Do not take this medicine if you are allergic to any of these ingredients.

What Lariam® looks like

Lariam® is available as pack of 8 tablets (250 mg).

The tablets are white, round, and marked with 'LA', 'RI', 'AM' and 'CP' on one side. They are cross-scored so that they can be easily broken into halves or into quarters. (Aust R 43321)

Who distributes Lariam®

Pharmaco (Australia) Ltd
Level 13, 465 Victoria Avenue
Chatswood NSW 2067
Australia
Phone: 1800 201 564

This leaflet was prepared in November 2022.

Published by MIMS February 2023

BRAND INFORMATION

Brand name

Lariam

Active ingredient

Mefloquine

Schedule

S4

 

1 Name of Medicine

Mefloquine hydrochloride.

2 Qualitative and Quantitative Composition

Lariam tablets contain 250 mg mefloquine in the form of mefloquine hydrochloride (274.09 mg). Lariam (mefloquine) is an antimalarial belonging to the quinoline methanol group of medicines and is structurally related to quinine.

Excipients with known effect.

Lactose monohydrate.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Tablets.
Lariam tablets are cylindrical biplanar, white to off-white, cross-scored with break bars on both faces and marked with "LA", "RI", "AM" and "CP" in each quadrant of one face.

4 Clinical Particulars

4.1 Therapeutic Indications

Malaria treatment.

Lariam is indicated for the treatment of acute attacks of malaria due to P. falciparum infection resistant to conventional antimalarial drugs.
Following therapy of mixed P. falciparum and P. vivax malaria with Lariam, relapse chemoprophylaxis with an 8-aminoquinoline derivative (e.g. primaquine) should be considered in order to eliminate hepatic forms of P. vivax.

Malaria chemoprophylaxis.

For travellers to countries with documented chloroquine and antifolate combination ([sulfadoxine/ pyrimethamine]/ [dapsone/ pyrimethamine]) resistant P. falciparum malaria, who are considered to be at high risk for malaria in view of their residence or travel (of up to 3 months duration) through rural areas (between the dusk to dawn period).
For travellers hypersensitive to sulphonamides and sulphones, who are considered to be at high risk for malaria in view of their residence or travel (of up to 3 months duration) through rural areas, (between the dusk to dawn period) in countries with high level chloroquine resistant P. falciparum malaria.

4.2 Dose and Method of Administration

Malaria treatment.

Adults and children of more than 45 kg bodyweight.

The recommended total dosage of Lariam, 1250 mg according to bodyweight, should be administered as follows:
A loading dose of 3 tablets (750 mg), followed 6 to 8 hours later by 2 tablets (500 mg).
For partially immune patients (i.e. for inhabitants of malaria endemic areas), a full standard dosage of Lariam should also be used.
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 has been administered without clinical cure, alternative treatments should be given. Similarly, if previous chemoprophylaxis with Lariam has failed, Lariam should not be used for curative treatment and physicians should carefully evaluate which antimalarial to use for therapy. See Section 4.4 Special Warnings and Precautions for Use; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions regarding the use of halofantrine.
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.
Artemisinin combination therapy (ACT) is recommended as the standard of care for treatment of P. falciparum malaria, regardless of region of acquisition. Mefloquine is a recommended partner molecule for inclusion in ACT. As parasite sensitivity can vary geographically and over time, it is recommended that treatment be guided by national and international guidelines.

Malaria chemoprophylaxis.

Chemoprophylaxis of malaria with Lariam should be initiated 1 week before arrival in a malarious area.
The following dosage schedule is given as a guide. (See Table 1.)
Lariam can be used for up to 3 months in the chemoprophylaxis of malaria.
The tablets should be swallowed whole with plenty of liquid.

4.3 Contraindications

Lariam is contraindicated in patients with known hypersensitivity to mefloquine or related compounds (e.g. quinine and quinidine) or any of the excipients in Lariam.
The use of Lariam is presently contraindicated in patients with renal insufficiency or severe impairment of liver function as no experience has been gained in such patients.
Patients with a past history of active depression, a recent history of depression, generalised anxiety disorder, psychosis or schizophrenia or other major psychiatric disorders or convulsions should not be prescribed Lariam prophylactically.

4.4 Special Warnings and Precautions for Use

Circumstances where special attention is required.

Due to the risk of a potentially fatal prolongation of the QTc interval, halofantrine must not be given during Lariam therapy for chemoprophylaxis or treatment of malaria or within 15 weeks after the last dose of Lariam (see Section 5.2 Pharmacokinetic Properties, Excretion; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Due to increased plasma concentrations and elimination half-life of mefloquine following coadministration with ketoconazole, the risk of QTc prolongation may also be expected if ketoconazole is taken during Lariam therapy for chemoprophylaxis or treatment of malaria, or within 15 weeks after the last dose of Lariam (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Concomitant administration of Lariam and quinine or quinidine may produce electrocardiographic abnormalities (see Section 4.4 Special Warnings and Precautions for Use, Cardiac effects; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Concomitant administration of Lariam and quinine or chloroquine may increase the risk of convulsions (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
In patients with epilepsy, Lariam, especially when used in high doses may increase the risk of convulsions. Therefore in such patients Lariam should be used only for curative treatment and only if there are compelling medical reasons (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Hypersensitivity reactions.

Hypersensitivity reactions ranging from mild cutaneous events to anaphylaxis cannot be predicted.

Cardiac effects.

As mefloquine is related structurally to quinine, its use in patients with cardiac disease should be avoided as data on the cardiac effects of mefloquine are at present inadequate to establish safety.
Although no cardiovascular action of Lariam, a myocardial suppressant, has been observed during clinical trials, parenteral studies in animals show that it possesses 20% of the antifibrillatory action of quinidine and produces 50% of the increase in the PR interval reported with quinine. The effect of Lariam on the compromised cardiovascular system has not been evaluated. However transitory and clinically silent ECG alterations have been reported during the use of Lariam. Alterations included sinus bradycardia, sinus arrhythmia, first degree AV block, prolongation of the QTc interval and abnormal T waves (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions; Section 4.8 Adverse Effects (Undesirable Effects)). The benefits of Lariam therapy should be weighed against the possibility of adverse effects in patients with cardiac disease.

Ocular effects.

Eye disorders, including but not limited to optic neuropathy and retinal disorders, have been reported during treatment with mefloquine. Any patient presenting with a visual disorder should be referred to the treating physician, as certain conditions may require stopping treatment with Lariam.

Neuropsychiatric effects.

Lariam may cause psychiatric symptoms in a number of patients, ranging from anxiety, paranoia, and depression to hallucinations and psychotic behaviour. On occasions, these symptoms have been reported to continue long after Lariam has been stopped. Lariam should not be prescribed in patients with a history of psychiatric symptoms (see Section 4.3 Contraindications) and should be used with caution in patients with a previous history of depression.
In chemoprophylaxis the safety profile of mefloquine is characterised by a predominance of neuropsychiatric adverse reactions. During prophylactic use, if signs of unexplained acute anxiety, depression, restlessness or confusion are noticed, these may be considered prodromal to a more serious event. In these cases, the drug must be discontinued. Because of the long half-life of mefloquine, adverse reactions to Lariam may occur or persist after discontinuation of the drug. In a small number of patients it has been reported that some neuropsychiatric events (including depression, dizziness or vertigo and loss of balance) may continue for months or longer after discontinuation of the drug. Therapy should be initiated one week before travel commences (see Section 4.2 Dose and Method of Administration), as acute psychiatric effects are more likely to manifest at the start of treatment.

Blood and lymphatic system disorders.

Cases of agranulocytosis and aplastic anaemia have been reported during Lariam therapy.

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 multidrug resistance in South East Asia. Cross resistance between Lariam and halofantrine and cross resistance between Lariam and quinine have been observed. For current advice on geographical resistance patterns competent national expert centres should be consulted.
The basic mode of action of mefloquine has not been elucidated.

Use in hepatic impairment.

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 (see Section 4.3 Contraindications).

Use in the elderly.

No data available.

Paediatric use.

Data are inadequate to establish the safety of Lariam in children below the age of 14 years.

Effects on laboratory tests.

See Section 4.5 Interactions with Other Medicines and Other Forms of Interactions, Effects on laboratory tests.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Medicine interactions with Lariam have not been explored in detail.

Beta blockers, quinine, quinidine or chloroquine.

Concomitant administration of Lariam and quinine, quinidine or medicines producing β-adrenergic blockade may produce electrocardiographic abnormalities or cardiac arrest.
Although no cardiovascular action of Lariam, a myocardial suppressant, has been observed during clinical trials, parenteral studies in animals show that it possesses 20% of the antifibrillatory action of quinidine and produces 50% of the increase in the PR interval reported with quinine. The effect of Lariam on the compromised cardiovascular system has not been evaluated. However transitory and clinically silent ECG alterations have been reported during the use of Lariam. Alterations included sinus bradycardia, sinus arrhythmia, first degree AV block, prolongation of the QTc interval and abnormal T waves. The benefits of Lariam therapy should be weighed against the possibility of adverse effects in patients with cardiac disease.
Theoretically, coadministration of other medicines known to prolong cardiac conduction (e.g. antiarrhythmic 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.
Concurrent administration of Lariam and the same related compounds (i.e. quinine, quinidine or chloroquine) could also increase the risk of convulsions.

Halofantrine.

There is evidence that the use of halofantrine during Lariam therapy for chemoprophylaxis or treatment of malaria or within 15 weeks of the last dose of Lariam causes a significant lengthening of the QTc interval (see Section 4.4 Special Warnings and Precautions for Use).

Ketoconazole.

Due to increased plasma concentrations and elimination half-life of Lariam following coadministration with ketoconazole, the risk of QTc prolongation may also be expected if ketoconazole is taken during Lariam therapy for chemoprophylaxis or treatment of malaria, or within 15 weeks after the last dose of Lariam.

Anticonvulsants.

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 anticonvulsant medication may be necessary in some cases.

Vaccines.

When Lariam is taken at the same time or shortly before oral live typhoid vaccines, attenuation of the immunisation induced by such vaccines cannot be excluded. Vaccinations with attenuated live bacteria should be completed at least three days before the first dose of Lariam, keeping in mind that Lariam chemoprophylaxis should be started one week before arrival in a malarious area.

Effects on laboratory tests.

The most frequently observed laboratory alterations which could be possibly attributable to drug administration were decreased haematocrit, transient elevation of transaminases, leukopenia and thrombocytopenia. These alterations were observed in patients with acute malaria who received treatment doses of the drug and were attributed to the disease itself.
During prophylactic administration of Lariam to indigenous populations in malaria endemic areas, the following occasional alterations in laboratory values were observed: transient elevation of transaminases, leukocytosis or thrombocytopenia.

Other potential interactions.

Mefloquine does not inhibit the cytochrome P450 isoenzymes CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6 or 3A4/5 at prophylactic concentrations. Mefloquine does not induce CYP3A4. Although no information is available with regard to induction of other cytochrome P450 enzymes, mefloquine is not expected to alter the metabolism of concomitantly administered medicines.
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, Lariam 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.
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.
No other medicine interactions are known. Since interactions with oral anti-diabetics and oral anticoagulants have not been tested, the relevant parameters should be checked when Lariam is taken for malaria chemoprophylaxis.
Periodic evaluation of hepatic function should be performed during prolonged chemoprophylaxis.

Inhibitors of CYP3A4.

One pharmacokinetic study in healthy volunteers showed that the coadministration 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.

Mefloquine is an inhibitor of P-glycoprotein (P-gp) in vitro. Therefore, interactions could potentially also occur with medicines that are substrates of this transporter. The clinical relevance of these interactions is not known to date. In a clinical interaction study in healthy volunteers, ritonavir, caused less than 7% changes with high precision (90% CIs: x 12% to 11%) in overall plasma exposure (AUC0, 168 h) and peak concentration (Cmax) of mefloquine, its two enantiomers, and carboxylic acid metabolite, and in the metabolite/mefloquine and enantiomeric AUC ratios. Mefloquine significantly decreased steady-state ritonavir plasma AUC0, 12 h by 31%, Cmax by 36% and predose levels by 43%, and did not affect ritonavir binding to plasma proteins.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Epididymal lesions were evident in rats treated with 20 mg/kg/day (5 times the prophylactic dose on a mg/m2 basis), while a lower number of viable spermatozoa and a lower fertility index were seen in male rats treated with 50 mg/kg/day (13 times the prophylactic dose).
Adverse effects on fertility were also evident in female rats treated with these doses. No adverse effects were observed in either male or female rats at 5 mg/kg/day, approximately equivalent to the prophylactic dose on a mg/m2 basis.
Administration of 250 mg/week of mefloquine (base) in adult males for 22 weeks failed to reveal any deleterious effects on human spermatozoa.
(Category B3)
The use of Lariam in the treatment of malaria is accepted because the small risk to the foetus is outweighed by the benefits to the mother and foetus.
Chemoprophylaxis in high risk situations is also justified.
Women of childbearing potential who are travelling to malaria endemic areas in which multidrug resistant P. falciparum is found should use an effective contraceptive throughout the therapy and for at least 3 months after taking the last dose of Lariam.
Mefloquine crosses the placenta and is detectable in the foetal circulation.
Administered at 3 to 12 times the therapeutic dose in humans, Lariam 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 chemoprophylaxis 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. For use of Lariam during pregnancy, current national and international guidelines should be consulted.
Mefloquine is excreted into breast milk in small amounts, the activity of which is unknown. Circumstantial evidence suggests that adverse effects do not occur in breastfed infants whose mothers are taking Lariam. For use of Lariam in nursing mothers, current national and international guidelines should be consulted.

4.7 Effects on Ability to Drive and Use Machines

Persons 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 medicine.

4.8 Adverse Effects (Undesirable Effects)

At the doses given for acute malaria, adverse reactions to Lariam may not be distinguishable from symptoms of the disease itself.
Among subjects who received Lariam for treatment, the most frequently observed adverse experiences included: dizziness, myalgia, nausea, fever, headache, vomiting, chills, diarrhoea, skin rash, abdominal pain, fatigue, loss of appetite and tinnitus. Those side effects occurring less frequently included bradycardia, hair loss, emotional problems, pruritus, asthenia, transient emotional disturbances and telogen effluvium (loss of resting hair). Seizures have also been reported.
The rate of adverse events associated with Lariam is published to be similar to that with other antimalarial prophylactic medications. In chemoprophylaxis the safety profile of Lariam adverse events is characterised by a predominance of neuropsychiatric adverse reactions (see Section 4.4 Special Warnings and Precautions for Use).

Clinical trials.

A systematic review published in 2009 identified a double blind, randomized study including 976 patients (483 patients on Lariam, 493 patients on atovaquone/proguanil), where treatment related neuropsychiatric adverse events occurred in 139/483 (28.8%) patients receiving Lariam compared to 69/493 (14%) patients receiving atovaquone-proguanil (see Tables 2 and 3). No drug attributable serious adverse events occurred in either group.

Post-marketing.

In Table 3, an overview of adverse reactions is presented, based on postmarketing data.
Adverse reactions are listed according to MedDRA system organ class and frequency category. Frequency categories are defined using the following convention: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), not known (cannot be estimated from available data).
Due to the long half-life of Lariam, adverse reactions to Lariam may occur or persist up to several weeks after the last dose. 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 medicine. There have been rare reports of suicidal ideations. No relationship to drug administration has been established.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration 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 at www.tga.gov.au/reporting-problems.

4.9 Overdose

Symptoms.

In cases of overdosage with Lariam, the symptoms mentioned under Section 4.8 Adverse Effects (Undesirable Effects) 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 disturbances.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

The effectiveness in the treatment of malaria is due essentially to destruction of the asexual intraerythrocytic forms of the human malarial parasites: Plasmodium falciparum, P. vivax, P. malariae and P. ovale. However data concerning the treatment of P. malariae and P. ovale were limited.
It is also effective against P. falciparum infections resistant to other antimalarials such as chloroquine and other 4-amino-quinoline derivatives, proguanil, pyrimethamine and pyrimethamine-sulfonamide combinations.
Laboratory animal studies have shown that resistance to mefloquine can be readily induced in the malarial parasite and that this resistance is stable during passage through the insect vector. Mefloquine resistance has also been seen in a few clinical isolates from patients receiving mefloquine.
Resistance of P. falciparum to mefloquine has been reported, mainly in parts of South East Asia. Cross resistance between mefloquine and halofantrine and cross resistance between mefloquine and quinine have been observed.
The basic mode of action of mefloquine has not been elucidated. However a number of studies of its actions in biochemical systems have been made.
Like quinine, mefloquine is able to form complexes with haemin. The ability to coordinate with haemin seems to correlate with the antimalarial activity of the compound. But, unlike chloroquine, quinacrine and quinine, mefloquine does not intercalate with DNA. Thus interaction with DNA does not seem to be involved in the antimalarial action of mefloquine.
Mefloquine does not exert antifolic activity and its antimalarial action is not antagonised by p-aminobenzoic acid.

Clinical trials.

In a randomised, double blind study, nonimmune travellers received malaria chemoprophylaxis with Lariam (483 subjects) and atovaquone-proguanil (493 subjects) who visited a malaria endemic area. Efficacy of chemoprophylaxis was evaluated as a secondary endpoint. The average duration of travel was ~2.5 weeks, and 79% of subjects travelled to Africa. 1013 subjects were initially randomised to receive Lariam (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 Lariam and atovaquone-proguanil was 100%). Overall, there were no cases of confirmed malaria in this study (maximum efficacy for both Lariam and atovaquone-proguanil was 100%). Results indicated that Lariam and atovaquone-proguanil are similarly effective for malaria chemoprophylaxis in nonimmune travellers (see Table 4).

5.2 Pharmacokinetic Properties

Absorption.

The absolute oral bioavailability of mefloquine has not been determined since an intravenous formulation is not available. The bioavailability of the tablet formulation compared with an oral solution was over 85%. The presence of food significantly enhances the rate and extent of absorption, leading to about a 40% increase in bioavailability. In patients, the absorption half life of mefloquine was 5 to 6 hours with plasma concentrations peaking 12 to 23 hours (mean about 16.6 hours). Maximum blood concentrations appear to be 2 to 3 times higher in Asian compared with non-Asian volunteers. Reasons for this ethnic difference are unclear. Also, plasma Cmax were higher in patients with acute uncomplicated P. falciparum malaria.
In healthy volunteers a dose of 250 mg once weekly produces maximum steady state plasma concentrations of 1000 to 2000 microgram/L, which are reached after 7 to 10 weeks.

Distribution.

In healthy adults, the apparent volume of distribution is approximately 20 L/kg, indicating extensive tissue distribution. Mefloquine may accumulate in parasitised erythrocytes. Experiments conducted in vitro with human blood using concentrations between 50 and 1000 mg/mL showed a relatively constant erythrocyte-to-plasma concentration ratio of about 2 to 1. The equilibrium reached in less than 30 minutes was found to be reversible. Mefloquine is approximately 98.2% protein bound.
Mefloquine crosses the placenta. Excretion into breast milk appears to be minimal (see Section 4.6 Fertility, Pregnancy and Lactation, Use in lactation).

Metabolism.

Mefloquine is extensively metabolised in the liver by the cytochrome P450 system. In vitro and in vivo studies strongly suggested that CYP3A4 is the major isoform involved. Two metabolites of mefloquine have been identified in humans. The main metabolite 2,8-bis-trifluoromethyl-4-quinoline carboxylic acid, is inactive in P. falciparum.
In a study in healthy volunteers, the carboxylic acid metabolite appeared in plasma 2 to 4 hours after a single oral dose. Maximum plasma concentrations of the metabolite, which were about 50% higher than those of mefloquine, were reached after 2 weeks. Thereafter, plasma levels of the main metabolite and mefloquine declined at a similar rate. The area under the plasma concentration time curve (AUC) of the main metabolite was 3 to 5 times larger than that of the parent drug.
In addition to the acid, other known metabolite is a mefloquine derivative with a hydroxy group in the piperidine moiety.

Excretion.

The average half-life of mefloquine in Caucasians is 21 days. Clinical studies carried out to date have shown that only a minute proportion of the active ingredient is excreted unchanged in the urine. Animal studies suggest that mefloquine is primarily excreted via the bile and faeces as unchanged drug and metabolites.

Pharmacokinetics in special populations.

Renal impairment.

As only a small proportion of mefloquine is eliminated renally, no pharmacokinetic studies have been performed in patients with renal insufficiency. Mefloquine and its main metabolite are not appreciably removed by haemodialysis. No special chemoprophylactic dosage adjustments are indicated for dialysis patients to achieve concentrations in plasma similar to those in healthy subjects.

Hepatic impairment.

Mefloquine is extensively metabolised in the liver by the CYP P450 system with CYP3A4 likely to be the major isoform. There have been no formal clinical studies in patients with hepatic impairment, so that the magnitude of effect of hepatic impairment on mefloquine pharmacokinetics is not known. However, it is considered likely that patients with impaired liver function will be exposed to higher plasma mefloquine levels due to reduced clearance and will be at higher risk of adverse effects (see Section 4.3 Contraindications).

5.3 Preclinical Safety Data

Genotoxicity.

The genotoxic potential of mefloquine was assessed in bacterial, yeast and mammalian mutagenicity tests, in a host mediated assay in mice and a mouse micronucleus assay at appropriate concentrations or doses. In vitro tests were performed with and without metabolic activation. All assays returned negative results for mefloquine.

Carcinogenicity.

The carcinogenic potential of mefloquine was investigated in 2 year feeding studies in mice and rats at doses up to 30 mg/kg/day, equivalent to 4 and 8 times the prophylactic dose on a mg/m2 basis. There were no treatment related increases in tumour incidence in either species.

6 Pharmaceutical Particulars

6.1 List of Excipients

Lariam tablets also contain the following excipients: poloxamer, microcrystalline cellulose, lactose monohydrate, maize starch, crospovidone, ammonium calcium alginate, purified talc and magnesium stearate.
See Section 2 Qualitative and Quantitative Composition.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 30°C. Store in original container. Protect from moisture.

6.5 Nature and Contents of Container

Packs of 8 tablets (cross-scored) each containing 250 mg mefloquine.

6.6 Special Precautions for Disposal

The release of medicines into the environment should be minimised. Medicines should not be disposed of via wastewater and disposal through household waste should be avoided. Unused or expired medicine should be returned to a pharmacy for disposal.

6.7 Physicochemical Properties

Chemical name: dl-erythro-alpha-2-piperidyl-2,8-bis(trifluoromethyl)-4-quinoline methanol. MW: 414.78.
Mefloquine is an odourless, bitter tasting, white crystalline powder. It is soluble in methanol and ethanol but practically insoluble in water. A 1% aqueous suspension has a pH of 5.6.

Chemical structure.


CAS number.

51773-92-3.

7 Medicine Schedule (Poisons Standard)

Schedule 4 - Prescription Only Medicine.

Summary Table of Changes