Consumer medicine information

Malarone Tablets (250/100) Malarone Junior Tablets (62.5/25)

Atovaquone; Proguanil hydrochloride

BRAND INFORMATION

Brand name

Malarone Tablets (250/100), Malarone Junior Tablets (62.5/25)

Active ingredient

Atovaquone; Proguanil hydrochloride

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Malarone Tablets (250/100) Malarone Junior Tablets (62.5/25).

SUMMARY CMI

MALARONE TABLETS & MALARONE JUNIOR TABLETS

Consumer Medicine Information (CMI) summary

The information for MALARONE in this document applies to both MALARONE TABLETS and MALARONE JUNIOR TABLETS unless explicitly referenced.

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 taking MALARONE?

MALARONE contains the active ingredients atovaquone and proguanil hydrochloride. MALARONE is used to prevent or treat a certain type of malaria known as plasmodium falciparum malaria.
For more information, see Section 1. Why am I taking MALARONE? in the full CMI.

2. What should I know before I take MALARONE?

Do not use if you have ever had an allergic reaction to MALARONE or any of the ingredients listed at the end of the CMI.
Talk to your doctor if you have any other medical conditions, if you have severe kidney disease, 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 take MALARONE? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with MALARONE 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 take MALARONE?

  • Prevention of malaria: adults and children over 40 kg take one MALARONE TABLETS once a day. Children 11 to 40 kg will depend on bodyweight. Take MALARONE 1 to 2 days before you visit a malaria area, whilst you are there and for 7 days afterwards.
  • Treatment of malaria: adults and children over 40 kg take four MALARONE TABLETS once a day. Children 11 to 40 kg will depend on bodyweight. Take MALARONE TABLETS for 3 consecutive days.
  • Take with food or a milky drink. The tablets can be crushed and mixed with milk immediately before serving for children.

More instructions can be found in Section 4. How do I take MALARONE? in the full CMI.

5. What should I know while taking MALARONE?

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are taking MALARONE.
  • Use of personal protection such as permethrin impregnated bed nets and topical insect repellants is strongly recommended when in malarial areas.
Things you should not do
  • Do not take MALARONE to treat malaria caused by other types of parasites.
Driving or using machines
  • Be careful before you drive, ride a bike or use any machines or tools until you know how MALARONE affects you.
Looking after your medicine
  • Store MALARONE below 30°C. Keep the tablets in the pack until it is time to take them.

For more information, see Section 5. What should I know while taking MALARONE? in the full CMI.

6. Are there any side effects?

Side effects which have been reported with the use of MALARONE include: diarrhoea, vomiting, feeling sick (nausea), abdominal pain, indigestion, mouth ulcers, rash, itching, hair loss, cough, vision or hearing disturbances, decreased appetite, headache, insomnia (difficulty sleeping), fatigue (feeling tired), yellow discolouration of skin or eyes (jaundice), inflammation of blood vessels, dizziness and fever.
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

MALARONE TABLETS & MALARONE JUNIOR TABLETS

Active ingredient(s): atovaquone and proguanil hydrochloride

Consumer Medicine Information (CMI)

The information for MALARONE in this document applies to both MALARONE TABLETS and MALARONE JUNIOR TABLETS unless explicitly referenced.

This leaflet provides important information about using MALARONE. 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 MALARONE.

Where to find information in this leaflet:

1. Why am I taking MALARONE?
2. What should I know before I take MALARONE?
3. What if I am taking other medicines?
4. How do I take MALARONE?
5. What should I know whilst taking MALARONE?
6. Are there any side effects?
7. Product details

1. Why am I taking MALARONE?

MALARONE contains the active ingredients atovaquone and proguanil hydrochloride. MALARONE belongs to a group of medicines called antimalarials.

MALARONE is used to prevent or treat the type of malaria known as Plasmodium falciparum malaria. Plasmodium falciparum belongs to one particular family of the malaria parasites. MALARONE works by killing this parasite.

Malaria in humans is caused by four species of Plasmodium parasites. Plasmodium falciparum is the most common species in tropical areas and is transmitted primarily during the rainy season.

Malaria is a debilitating infectious disease characterised by chills, shaking, and periodic bouts of intense fever. Malaria is transmitted from person to person by the bite of female mosquitos.

2. What should I know before I take MALARONE?

Warnings

Do not take MALARONE if:

  • you are allergic to either atovaquone or proguanil hydrochloride, or any of the ingredients listed at the end of this leaflet.
  • Always check the ingredients to make sure you can use this medicine.
  • you have severe kidney disease.

Check with your doctor if you:

  • have any other medical conditions.
  • take any medicines for any other condition.
  • currently have diarrhoea.
  • have any kidney problems.
  • have been treated for malaria caused by Plasmodium falciparum in the past and it has occurred again.
  • You are an adult who weighs less than 40kg.

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.

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

Use in children

  • MALARONE JUNIOR TABLETS should be used only in children weighing more than 11 kg.
  • MALARONE is not recommended for the treatment of malaria in children under the age of 3.

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 may interfere with MALARONE and affect how it works.

  • warfarin, a medicine used to thin the blood.
  • antibiotic medicines such as tetracycline, rifabutin and cephalosporin used to treat bacterial infections.
  • metoclopramide, a medicine used to treat nausea (feeling sick) and vomiting.
  • rifampicin, a medicine used to treat tuberculosis.
  • paracetamol and opiates, medicines used to treat pain.
  • benzodiazepines, used to treat depression, anxiety, insomnia.
  • aciclovir, an antiviral medicine.
  • indinavir and efavirenz, medicines used to treat HIV.

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

4. How do I take MALARONE?

PREVENTION OF MALARIA

How much to take

Adults and children over 40 kg:

  • Take one MALARONE TABLETS once a day.

Children 11 to 40 kg:

  • Depending on bodyweight, your child will take one, two or three MALARONE JUNIOR TABLETS once a day.

When to take

  • Begin taking this medicine 1 to 2 days before entering a place where you are at risk of getting malaria.
  • Continue to take MALARONE each day whilst you are there and then for 7 days after you have left.

TREATMENT OF MALARIA

How much to take

Adults and children over 40 kg:

  • Take four MALARONE TABLETS once a day.

Children 11 to 40 kg:

  • Depending on bodyweight, your child will take one, two or three MALARONE TABLETS once a day.

When to take

  • Take MALARONE TABLETS for 3 days in a row.

How to take MALARONE

  • Swallow the tablet whole with food or a milky drink.
  • For children who find the tablets difficult to swallow, they may be crushed and mixed with food or a milky drink right before being taken.
  • If you vomit within 1 hour of taking MALARONE take another dose as soon as you can.
  • In the event of diarrhoea, normal dosing should be continued.

If you forget to take MALARONE

MALARONE should be taken regularly at the same time each day.

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 take too much MALARONE

If you think that you or anyone else have taken too much MALARONE, 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 whilst taking MALARONE?

Things you should do

  • When in a known malarial area, use of personal protection such as permethrin impregnated bed nets and topical insect repellants is strongly recommended.

Call your doctor straight away if you:

  • feel the symptoms of your malaria have returned after taking MALARONE.

Remind any doctor, dentist or pharmacist you visit that you are taking MALARONE.

Things you should not do

  • Do not take MALARONE to prevent or treat malaria caused by other types of parasites.

Driving or using machines

Be careful before you drive, ride a bike or use any machines or tools until you know how MALARONE affects you.

Looking after your medicine

  • Store MALARONE below 30°C.

Follow the instructions on 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.

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
Gastrointestinal
  • diarrhoea
  • stomach pain
  • vomiting, feeling sick (nausea)
  • abdominal pain
  • indigestion
  • mouth ulcers
Skin and subcutaneous tissue disorders
  • rash, itching
  • hair loss
Respiratory, thoracic and mediastinal disorders
  • cough
Eye disorders
  • vision disturbances
Metabolism and nutritional disorders
  • decreased appetite
Nervous system disorders
  • headache
  • insomnia (difficulty sleeping)
  • fatigue (feeling tired)
  • vivid or strange dreams
  • dizziness
General disorders and administration site conditions
  • fever
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
Hepatobiliary disorders
  • yellowing of the skin or eyes (jaundice)
Skin and subcutaneous tissue disorders
  • inflammation of the blood vessels which may be visible on the skin as red or purple raised spots (vasculitis)
  • skin rash which may blister and look like small targets (central dark spot surrounded by a paler area with a dark ring around the edge) (erythema multiforme)
  • widespread rash with blisters and peeling skin, particularly occurring around the mouth, nose, eyes and genitals (Stevens-Johnson syndrome)
Psychiatric disorders
  • seeing or hearing things that aren't there (hallucinations)
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.

Sometimes MALARONE is associated with abnormal blood tests of liver function. If this does happen it is most likely a temporary change, as blood tests of liver function become normal after completing the treatment.

Other abnormal blood tests reported with MALARONE include:

  • a reduction in the number of red blood cells (anaemia), white blood cells (neutropenia), or platelets (cells necessary for blood clotting).
  • an increase in amylase, which is an enzyme produced by the pancreas.
  • low sodium (hyponatraemia).

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 MALARONE contains

Active ingredient
(main ingredient)		atovaquone
proguanil hydrochloride
Other ingredients
(inactive ingredients)		hyprolose
hypromellose
iron oxide red
macrogol 400
macrogol 8000
magnesium stearate
microcrystalline cellulose
poloxamer
povidone
sodium starch glycollate
titanium dioxide

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

What MALARONE looks like

MALARONE TABLETS are round, biconvex, pink film-coated tablets, branded "GX CM3" (AUST R 61100).

MALARONE TABLETS are available in packs of 12 or 24 tablets.

MALARONE JUNIOR TABLETS are round, biconvex, pink film-coated tablets, branded "GX CG7" (AUST R 92855).

MALARONE JUNIOR TABLETS are available in packs of 12, 24 or 60 tablets.

Not all pack sizes and presentations may be marketed in Australia.

Who distributes MALARONE

GlaxoSmithKline Australia Pty Ltd
Level 4, 436 Johnston Street,
Abbotsford, Victoria, 3067
Phone: 1800 033 109
www.gsk.com.au

This leaflet was prepared in January 2025.

Version 9.0

Trade marks are owned by or licensed to the GSK group of companies.

© 2025 GSK group of companies or its licensor.

Published by MIMS April 2025

BRAND INFORMATION

Brand name

Malarone Tablets (250/100), Malarone Junior Tablets (62.5/25)

Active ingredient

Atovaquone; Proguanil hydrochloride

Schedule

S4

 

1 Name of Medicine

Atovaquone and proguanil hydrochloride.

2 Qualitative and Quantitative Composition

Malarone Tablets (250/100) and Malarone Junior Tablets (62.5/25) are fixed combination products containing atovaquone and proguanil hydrochloride. Each Malarone Tablets (250/100) contains atovaquone 250 mg and proguanil hydrochloride 100 mg. Each Malarone Junior Tablets (62.5/25) contains atovaquone 62.5 mg and proguanil hydrochloride 25 mg.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Malarone Tablets (250/100).

Round, biconvex, pink film-coated tablets, branded "GX CM3". Each tablet contains the active ingredients atovaquone 250 mg and proguanil hydrochloride 100 mg.

Malarone Junior Tablets (62.5/25).

Round, biconvex, pink film-coated tablets, branded "GX CG7". Each tablet contains the active ingredients atovaquone 62.5 mg and proguanil hydrochloride 25 mg.

4 Clinical Particulars

4.1 Therapeutic Indications

Malarone is indicated for:
Prophylaxis of Plasmodium falciparum malaria in adults and children ≥ 11 kg.
Treatment of Plasmodium falciparum malaria in adults and children aged 3 years or older.

4.2 Dose and Method of Administration

The daily dose should be taken with food or a milky drink at the same time each day.
In the event of vomiting, within 1 hour of dosing, a repeat dose should be taken.
Malarone (250/100) or Malarone Junior tablets (62.5/25) should preferably be swallowed whole. If difficulties are encountered when dosing young children, the tablet(s) may be crushed and added to a small amount of milk, all of which should be consumed immediately.

Prophylaxis.

Prophylaxis should start 1 to 2 days before entering a malaria endemic area, and be continued daily until seven days after leaving the area.
If patients are unable to tolerate food, Malarone Tablets should be administered, but systemic exposure of atovaquone will be reduced.

Dosage in adults.

One Malarone Tablet (250/100) daily.

Dosage in children.

See Table 1.

Treatment.

Dosage in adults.

Four tablets as a single dose for three consecutive days.

Dosage in children.

See Table 2.

Dosage in the elderly (prophylaxis and treatment).

A pharmacokinetic study indicates that no dosage adjustments are needed in the elderly (see Section 5.2 Pharmacokinetic Properties).

Dosage in hepatic impairment (prophylaxis and treatment).

A pharmacokinetic study indicates that no dosage adjustments are needed in patients with mild to moderate hepatic impairment. No studies have been conducted in patients with severe hepatic impairment (see Section 5.2 Pharmacokinetic Properties).

Dosage in renal impairment (prophylaxis and treatment).

Pharmacokinetic studies indicate that no dosage adjustments are needed in patients with mild to moderate renal impairment. In patients with severe renal impairment (creatinine clearance < 30 mL/min) alternatives to Malarone should be recommended for the treatment of acute P. falciparum malaria whenever possible (see Section 4.4 Special Warnings and Precautions for Use; Section 5.2 Pharmacokinetic Properties). For prophylaxis of P. falciparum malaria in patients with severe renal impairment, see Section 4.3 Contraindications.

4.3 Contraindications

Malarone is contraindicated in individuals with known hypersensitivity to atovaquone or proguanil hydrochloride or to any component of the formulation.
Malarone is contraindicated for prophylaxis of P. falciparum malaria in patients with severe renal impairment (creatinine clearance < 30 mL/min).

4.4 Special Warnings and Precautions for Use

Malarone has not been evaluated for the treatment of cerebral malaria or other severe manifestations of complicated malaria including hyperparasitaemia, pulmonary oedema or renal failure.
Safety and efficacy of Malarone for the treatment and prophylaxis of malaria in paediatric patients who weigh less than 11 kg have not been established.
In the event of recrudescent infections due to P. falciparum or failure of chemoprophylaxis, patients should be treated with a different blood schizonticide.
Parasite relapse occurred commonly when P. vivax malaria was treated with Malarone alone. Travellers with intense exposure to P. vivax or P. ovale, and those who develop malaria caused by either of these parasites, will require additional treatment with a drug, such as primaquine, that is active against hypnozoites.
Persons taking Malarone for prophylaxis or treatment of malaria should take a repeat dose if they vomit within 1 hour of dosing. In the event of diarrhoea, normal dosing should be continued. Absorption of atovaquone may be reduced in patients with diarrhoea or vomiting, but diarrhoea or vomiting was not associated with reduced efficacy in clinical trials of Malarone for malaria prophylaxis. However, as with other antimalarial agents, patients with diarrhoea or vomiting should be advised to continue to comply with personal protection measures (repellants, bednets).
In patients with acute malaria who present with diarrhoea or vomiting, alternative therapy should be considered. If Malarone is used to treat malaria in these patients, parasitaemia should be closely monitored.
The coadministration of Malarone with other antimalarial drugs has not been evaluated.
Parasitaemia should be closely monitored in patients receiving concurrent metoclopramide or tetracycline (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
The concomitant administration of Malarone and rifampicin or rifabutin is not recommended (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Use in hepatic impairment.

Pharmacokinetic studies indicate that no dosage adjustments are needed in patients with mild to moderate hepatic impairment. Malarone has not been specifically studied in patients with severe hepatic impairment.

Use in renal impairment.

Pharmacokinetic studies indicate that no dosage adjustments are needed in patients with mild to moderate renal impairment. In patients with severe renal impairment (creatinine clearance < 30 mL/min) alternatives to Malarone for treatment of acute P. falciparum malaria should be recommended whenever possible (see Section 4.2 Dose and Method of Administration; Section 4.3 Contraindications; Section 5.2 Pharmacokinetic Properties).

Use in the elderly.

Pharmacokinetic studies indicate that no dosage adjustments are needed in the elderly.

Paediatric use.

Dosage recommendations in children are based on bodyweight (see Section 4.2 Dose and Method of Administration).

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Proguanil may potentiate the anticoagulant effect of warfarin and other coumarin based anticoagulants. The mechanism of this potential drug interaction has not been established. Caution is advised when initiating or withdrawing malaria prophylaxis or treatment with Malarone in patients on continuous treatment with coumarin based anticoagulants.
Concomitant treatment with tetracycline, metoclopramide, rifampicin and rifabutin have been associated with significant decreases in plasma concentration of atovaquone (see Section 4.4 Special Warnings and Precautions for Use). Concomitant administration of tetracycline and Malarone reduced the plasma concentrations of atovaquone but had no effect on the efficacy of Malarone in curing Plasmodium falciparum malaria.
Concomitant administration of atovaquone and indinavir results in a 23% decrease in the Cmin of indinavir in healthy individuals. Caution should be exercised when prescribing atovaquone with indinavir due to the decrease in trough levels of indinavir.
In clinical studies of atovaquone in the treatment of diseases other than malaria, small decreases in plasma concentrations were associated with concomitant use of paracetamol, benzodiazepines, aciclovir, opiates, cephalosporins, antidiarrhoeal agents and laxatives. The implications of these observations for use with Malarone are not known. In the same series of studies, the following medications were not associated with a change in steady-state plasma concentrations of atovaquone: fluconazole, clotrimazole, ketoconazole, antacids, systemic corticosteroids, nonsteroidal anti-inflammatory drugs, antiemetic drugs (excluding metoclopramide) and H2-antagonists.
There is no information available on whether interactions occur between atovaquone and terfenadine or cisapride.
Atovaquone is highly protein bound (> 99%) but does not displace other highly protein bound drugs in vitro, indicating significant drug interactions arising from drug displacement are unlikely.
Coadministration of efavirenz with Malarone may result in a decrease in exposure to atovaquone and proguanil. When given with efavirenz or boosted protease inhibitors, atovaquone concentrations have been observed to decrease as much as 75%. Since decreased concentrations of atovaquone and proguanil may result in a decrease of antimalarial efficacy, concomitant administration should be avoided whenever possible.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

There are no data on the effect of atovaquone on human fertility. Data from animal studies show that atovaquone does not affect reproductive potential or performance at oral doses of up to 1000 mg/kg (approximately 6.5 times human exposure at the maximum recommended clinical treatment dose, based on AUC). A study in rats showed no impairment of male or female fertility at oral proguanil doses up to 16 mg/kg/day (approximately 0.03 times human exposure at the recommended clinical treatment dose, based on AUC). However, there is some evidence from published animal studies that proguanil and/or its main metabolite, cycloguanil, may cause impairment of fertility/ early embryonic loss. No fertility studies have been performed in animals with atovaquone in combination with proguanil.
Findings in repeat dose studies with the atovaquone and proguanil hydrochloride combination were entirely proguanil related. As proguanil has been used extensively and safely in the treatment and prophylaxis of malaria at doses similar to those used in Malarone, these findings are considered of little relevance in the clinical situation.
(Category B2)
The safety of the drug combination in human pregnancy has not been established. There is no information on effects of atovaquone administration during human pregnancy. Foetal death and malformation have rarely been reported in association with the use of proguanil. The relationship of these events to proguanil is not certain, and the overall number of reported events is low, given that the drug has been used in pregnant women for many years. Foetal loss is a known complication of Plasmodium falciparum malaria in pregnancy.
The proguanil component of Malarone acts by inhibiting parasitic dihydrofolate reductase. There are no clinical data indicating that folate supplementation diminishes drug efficacy. For women of childbearing age receiving folate supplements to prevent neural tube birth defects, such supplements may be continued while taking Malarone.
Embryofoetal development studies in animals with the combination of atovaquone and proguanil did not indicate any teratogenic potential in rats at doses up to 50:20 mg/kg/day (approximately 5 times the human exposure to atovaquone and 0.3 times human exposure to proguanil, based on treatment AUCs), nor in rabbits at doses up to 100:40 mg/kg/day (approximately 1 times the human exposure to atovaquone and 0.5 times the exposure to proguanil, based on treatment AUCs). In rabbits given atovaquone alone at 1200 mg/kg/day (approximately 1.4 times the estimated human exposure during treatment of malaria), an increased incidence of resorptions and decreased length and weight of foetuses was noted. These effects were observed only in the presence of maternal toxicity.
In a peri-postnatal study in rats dosed with proguanil alone up to 16 mg/kg/day (0.03 times the human exposure, based on treatment AUC), no treatment related effects were seen in reproductive or other parameters in the F0, F1 and F2 generations.
However, as animal studies are not always predictive of human response, the use of atovaquone/ proguanil in pregnancy should only be considered if the expected benefit to the mother outweighs the risk to the foetus.
 It is not known whether atovaquone is excreted into human milk. In a rat study, the atovaquone concentrations in milk were 30% of the concurrent atovaquone concentrations in maternal plasma. Proguanil is excreted in human milk in small quantities. Breastfeeding is not recommended during treatment with Malarone.

4.7 Effects on Ability to Drive and Use Machines

There have been no studies to investigate the effect of atovaquone and proguanil hydrochloride on driving performance or the ability to operate machinery. Detrimental effect on such activities is not predicted from the pharmacology of the component drugs.

4.8 Adverse Effects (Undesirable Effects)

As Malarone contains atovaquone and proguanil hydrochloride, the type and severity of adverse reactions associated with each of the compounds may be expected. However, at the doses employed for both treatment and prophylaxis of malaria, adverse reactions are generally mild and of limited duration. There is no evidence of added toxicity following concurrent administration of the two compounds.

Prophylaxis.

Individuals > 40 kg.

The nature and frequency of adverse reactions reported in clinical trials of Malarone (atovaquone and proguanil hydrochloride) for the prophylaxis of malaria in individuals weighing > 40 kg were similar to those reported with placebo or the active comparator drug (mefloquine or chloroquine/ proguanil). However, patients receiving Malarone had fewer neuropsychiatric and gastrointestinal adverse reactions than patients receiving mefloquine and chloroquine/ proguanil respectively. Overall, Malarone has a better safety profile than mefloquine or chloroquine/ proguanil (see Tables 3 and 4).

Individuals 11-40 kg.

The incidence of adverse reactions reported in clinical trials using Malarone Junior Tablets (62.5/25) for the prophylaxis of malaria in individuals weighing 11-40 kg were similar to those reported with placebo (MALB3003 and MAL30015). In studies MAL30010 and MAL30012, the incidence of drug related adverse events was higher in the chloroquine/ proguanil group (15% vs 11% for Malarone) during active treatment. Due to the low number of patients in study MAL30010 (n = 12), no drug related adverse events were reported by the mefloquine recipients. Tables 5 and 6 list the common drug related adverse reactions reported during chemoprophylaxis by treatment group.

Treatment.

The nature and frequency of adverse experiences reported in controlled clinical trials of atovaquone and proguanil hydrochloride for the treatment of malaria were generally similar in patients treated with the combination or with a comparator antimalarial drug. This suggests that the adverse experiences are largely due to the disease rather than to study drugs (see Table 7).
A similar profile of clinical adverse events was reported in children with malaria treated with atovaquone and proguanil hydrochloride in phase III trials as occurred in the adult studies. Regardless of attributability, the following were also commonly reported (> 2%) in children: dehydration, tinnitus and anorexia.
Of the seven severe or treatment limiting adverse experiences reported in clinical trials with atovaquone and proguanil hydrochloride, three were considered to be treatment related; two were reports of nausea and/or vomiting and one report of an anaphylactic reaction. During clinical trials, two subjects receiving atovaquone monotherapy experienced psychiatric symptoms. One subject had a history of psychiatric illness and the other a history of drug and alcohol abuse. Two subjects receiving atovaquone/ proguanil hydrochloride had seizures; in one of these cases the patient successfully continued treatment. Both subjects had a prior history of seizures and the investigators did not consider the events attributable to the Malarone treatment.
Adverse events are listed below by system organ class and frequency. Frequencies are defined as: very common (≥ 1/10), common (≥ 1/100 and < 1/10), uncommon (≥ 1/1000 and < 1/100), rare (≥ 1/10,000 and < 1/1000) and very rare (< 1/10,000). Very common, common and uncommon events were determined from clinical trial data. Rare and very rare events were generally derived from spontaneous data. The frequency classification 'not known' has been applied to those events where a frequency could not be estimated from the available data.
A summary of adverse events identified during worldwide postapproval use of Malarone or its components, atovaquone and proguanil hydrochloride, is provided below.

Blood and lymphatic system disorders.

Common: anaemia1, neutropenia2. Not known: pancytopenia in patients with severe renal impairment4.

Immune system disorders.

Not known: angioedema4, anaphylaxis3, vasculitis.

Metabolism and nutritional disorders.

Common: anorexia1, hyponatraemia2. Uncommon: elevated amylase levels2 occurred in patients treated with atovaquone.

Psychiatric disorders.

Rare: hallucinations1.

Nervous system disorders.

Very common: headache1. Common: insomnia1, dizziness1.

Gastrointestinal disorders.

Very common: abdominal pain1, nausea2, vomiting1, diarrhoea1. Uncommon: stomatitis1. Not known: gastric intolerance4, oral ulceration4.

Hepatobiliary disorders.

Common: elevated liver enzyme levels2. Not known: hepatitis3, cholestasis.
Clinical trial data for Malarone indicated that abnormalities in liver function tests were reversible and not associated with untoward clinical events.

Skin and subcutaneous tissue disorders.

Common: rash1. Uncommon: hair loss1, urticaria1. Not known: Stevens-Johnson syndrome3, erythema multiforme3.

General disorders and administration site conditions.

Common: fever1.

Respiratory, thoracic and mediastinal disorders.

Common: cough1.
1 Frequency calculated from atovaquone/ proguanil clinical trials.
2 Frequency taken from atovaquone label. Patients participating in clinical trials with atovaquone have received higher doses and have often had complications of advanced human immunodeficiency virus (HIV) disease. Therefore, the causal relationship between the adverse experiences and atovaquone is difficult to evaluate. These events may have been seen at a lower frequency or not at all in clinical trials with atovaquone/ proguanil.
3 Observed from postmarketing spontaneous reports and the frequency is therefore not known.
4 Observed with proguanil and the frequency is therefore not known.

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

In cases of suspected overdose, symptomatic and supportive therapy should be given as appropriate.
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 constituents of Malarone, atovaquone and proguanil hydrochloride, interfere with two different pathways in the biosynthesis of pyrimidines, required for nucleic acid replication. The mechanism of action of atovaquone against P. falciparum is via inhibition of mitochondrial electron transport, at the level of the cytochrome bc1 complex, and collapse of mitochondrial membrane potential. One mechanism of action of proguanil, via its metabolite cycloguanil, is inhibition of dihydrofolate reductase, which disrupts deoxythymidylate synthesis. Proguanil also has antimalarial activity independent of its metabolism to cycloguanil, and proguanil, but not cycloguanil, is able to potentiate the ability of atovaquone to collapse mitochondrial membrane potential in malaria parasites. This latter mechanism may explain the synergy seen when atovaquone and proguanil are used in combination, as in Malarone.

Microbiology.

Atovaquone is active against Plasmodium spp. (in vitro IC50 against P. falciparum 0.23-1.43 nanogram/mL).
The antimalarial activity of proguanil is exerted via the primary metabolite cycloguanil (in vitro IC50 against various P. falciparum strains of 4-20 nanogram/mL). Some activity of proguanil and another metabolite, 4-chlorophenylbiguanide, is seen in vitro at 0.6-3.0 microgram/mL.
In in vitro studies of P. falciparum, the combination of atovaquone and proguanil was shown to be synergistic. This enhanced efficacy was also demonstrated in clinical studies.

Clinical trials.

The safety and effectiveness of Malarone Tablets (250/100) and Malarone Junior Tablets (62.5/25) have been established in studies of up to 12 weeks in adult and paediatric subjects.

Prophylaxis of malaria (individuals > 40 kg).

The safety and efficacy of Malarone Tablets (250/100) in the prophylaxis of P. falciparum malaria was demonstrated in five randomised, double blind clinical studies. Three placebo controlled parallel group studies were conducted in residents of malaria endemic areas (MALB2001, MALB3001 and MALB3003), and two active controlled studies were conducted in nonimmune travellers (MALB30010 and MALB30011).
There were 473 patients in placebo controlled studies, 232 of whom received one Malarone Tablet (250/100) daily for 10-12 weeks of chemoprophylaxis, and 241 received placebo. Prevention of parasitaemia was the primary endpoint in the studies. Malarone had an overall efficacy of 97% (range 95-100%) for prevention of P. falciparum parasitaemia and an adverse event profile similar to placebo.
MALB3003 included 204 children (weighing 11-40 kg) who received a lower dose of Malarone or placebo based on bodyweight (see Prophylaxis of malaria (individuals 11-40 kg)).
There were 1975 patients in active controlled studies, 993 of whom received one Malarone Tablet (250/100) daily at the recommended dose (see Section 4.2 Dose and Method of Administration), 471 received mefloquine weekly (1 to 3 weeks before until 4 weeks after travel) and 511 patients received chloroquine weekly (1 week before until 4 weeks after travel) plus daily proguanil (1-2 days before until 4 weeks after travel). Frequency of adverse events was the primary endpoint and development of confirmed falciparum malaria within 60 days after leaving the malaria endemic area was the secondary endpoint in the studies. No patients receiving Malarone or mefloquine contracted malaria (efficacy 100%), and 3 patients receiving chloroquine/ proguanil contracted malaria (efficacy at least 70%). Patients receiving Malarone experienced fewer neuropsychiatric and gastrointestinal adverse reactions than patients receiving mefloquine and chloroquine/ proguanil respectively.

Prophylaxis of malaria (individuals 11-40 kg).

The efficacy and safety of Malarone Junior Tablets (62.5/25) in the prophylaxis of P. falciparum malaria in patients weighing 11-40 kg was demonstrated in two randomised, placebo controlled, double blind studies of 12 week duration conducted in residents of malaria endemic areas. A total of 534 patients (11-40 kg) were enrolled in the studies, of which 264 received the recommended dose of Malarone Junior Tablets (62.5/25) based on bodyweight; 11-20 kg: 1 Junior tablet containing 62.5 mg atovaquone + 25 mg proguanil hydrochloride; 21-30 kg: 2 Junior tablets; 31-40 kg: 3 Junior tablets (MALB3003 and MAL30015).
In the combined data from the two studies (per protocol population), only one of 238 patients (0.4%) in the Malarone group developed P. falciparum parasitaemia during chemoprophylaxis over 12 weeks, compared with 50 of 245 (20.4%) patients in the placebo group. The protective efficacy of Malarone was calculated to be 97.9% in this population. The safety findings with regard to adverse events during chemosuppression showed no differences between Malarone and placebo.
The safety profile of Malarone was assessed in two active controlled studies in travellers to malaria endemic areas (studies MAL30010: mefloquine and MAL30012: chloroquine/ proguanil) (see Section 4.8 Adverse Effects (Undesirable Effects)). With respect to efficacy, in combined data from the two active controlled studies (n = 186; 93 in the Malarone group), there was no confirmed cases of P. falciparum during chemoprophylaxis or in follow-up to day 60.

Treatment of malaria.

Eight clinical studies (5 controlled and 3 uncontrolled) were conducted in 1115 patients of atovaquone and/or proguanil hydrochloride administered for the treatment of falciparum malaria. Studies in children were conducted at doses of atovaquone and proguanil hydrochloride based on bodyweight; 466 patients (adults and children) received concurrent atovaquone and proguanil hydrochloride at the recommended dose (see Section 4.2 Dose and Method of Administration).
The primary efficacy endpoint was the proportion of evaluable patients cured of acute malaria. Cure was defined by clearance of asexual parasitaemia within 7 days of initiation of treatment, without subsequent recrudescence during the 28 day follow-up period.
In the controlled clinical trials, the study population included only patients with uncomplicated falciparum malaria. The comparator was standard antimalarial therapy within the country in which the study was conducted. Treatment with a combination of atovaquone and proguanil hydrochloride was curative in 98% of evaluable patients (combined result). The concurrent administration of atovaquone and proguanil hydrochloride was more efficacious in three studies and of equivalent efficacy in two trials as the respective comparator antimalarial regimen (see Table 8).
In uncontrolled studies conducted in Thailand using the recommended dose of atovaquone and proguanil hydrochloride, the cure rate of malaria was 100% in adults (n = 24, P. falciparum) and 100% in children (n = 26, P. falciparum).

5.2 Pharmacokinetic Properties

There are no pharmacokinetic interactions between atovaquone and proguanil at the recommended dose. In clinical trials, trough levels of atovaquone, proguanil and cycloguanil in children (weighing 11-40 kg) are within the effective range observed in adults after adjusting for bodyweight.

Absorption.

Atovaquone is a highly lipophilic compound with low aqueous solubility and poor oral bioavailability that varies with dose and diet.
Although there are no atovaquone bioavailability data in healthy subjects, in HIV infected patients the absolute bioavailability of a 750 mg single dose of atovaquone tablets taken with food is 21% (90% CI: 17%-27%).
Dietary fat taken with atovaquone increases the rate and extent of absorption. When taken with a standard breakfast containing 23 g of fat, AUC was increased 2-3 times and Cmax 5 times compared with fasting. Patients are recommended to take Malarone tablets with food or a milky drink (see Section 4.2 Dose and Method of Administration).
Proguanil hydrochloride is rapidly and extensively absorbed regardless of food intake. Peak plasma concentrations occur between 2-4 hours after a single 200 mg dose. The absolute bioavailability is not known.
In a comparative bioavailability study in healthy adult volunteers, Malarone administered as a single dose was bioequivalent to separate tablets of atovaquone 250 mg and proguanil hydrochloride 100 mg given concomitantly. In healthy adult subjects treated for 3 days, the pharmacokinetics of atovaquone, and proguanil and its metabolite cycloguanil, were not modified when atovaquone and proguanil were given alone or in combination as Malarone.

Distribution.

Atovaquone is highly protein bound (> 99%) but does not displace other highly protein bound drugs in vitro, indicating significant drug interactions arising from displacement are unlikely.
Following oral administration, the volume of distribution of atovaquone in adults and children is approximately 7 to 8 L/kg.
Proguanil is 75% protein bound. Following oral administration, the volume of distribution of proguanil in adults is 25 L/kg. In children (weighing 11-40 kg), the volume of distribution is approximately 27 to 30 L/kg.
In human plasma, the protein binding of atovaquone or proguanil was unaffected by the presence of the other drug.

Metabolism.

There is no evidence that atovaquone is metabolised. Greater than 90% of atovaquone is eliminated unchanged in the faeces with negligible excretion in urine.
Proguanil hydrochloride is partially metabolised to cycloguanil and 4-chlorophenylbiguanide with less than 40% being excreted unchanged in urine. These metabolites are also excreted in the urine. Conversion of proguanil to cycloguanil is mediated in the liver by cytochrome P450 3A4 and 2C19. Conversion of proguanil to cycloguanil may be reduced in some individuals, due to genetic polymorphism of the metabolising enzyme. During administration with Malarone, at the recommended doses, proguanil metabolism status appears to have no implications for treatment or prophylaxis of malaria.

Excretion.

The elimination half-life of atovaquone is about 2-3 days in adults and 1-2 days in children.
Following oral administration, the clearance of atovaquone in adults and children (weighing 40 kg) is approximately 0.04 to 0.05 L/h/kg. In children (weighing 11-40 kg), the clearance is approximately 0.12 to 0.05 L/h/kg, respectively.
Following oral administration, the clearance of proguanil in adults is 1.3 L/h/kg. In children (11-40 kg bodyweight), after adjusting for differences in bodyweight, clearance is higher in an 11 kg child (0.12 L/h/kg) and decreases with increasing weight to 0.05 L/h/kg in a 40 kg child.
In both adults and children, the elimination half-life for proguanil or cycloguanil is about 12-15 hours.

Pharmacokinetics in the elderly.

There is no clinically significant change in the average rate or extent of absorption of atovaquone or proguanil between elderly and young patients. Systemic availability of cyloguanil is higher in the elderly compared with young patients, but there is no clinically significant change in its elimination half-life (see Section 4.2 Dose and Method of Administration).

Pharmacokinetics in renal impairment.

In patients with mild to moderate renal impairment, oral clearance and/or AUC data for atovaquone, proguanil and cycloguanil are within the range of values observed in patients with normal renal function. Atovaquone Cmax and AUC are reduced in patients with severe renal impairment. The elimination half-lives for proguanil and cycloguanil are prolonged in patients with severe renal impairment with corresponding increases in AUC, resulting in the potential of drug accumulation with repeated dosing (see Section 4.2 Dose and Method of Administration; Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use).

Pharmacokinetics in hepatic impairment.

In patients with mild to moderate hepatic impairment, there is no clinically significant change in exposure to atovaquone compared with healthy patients. In patients with mild to moderate hepatic impairment there is an increase in proguanil AUC with no change in its elimination half-life and there is a decrease in Cmax and AUC for cycloguanil. No data are available in patients with severe hepatic impairment (see Section 4.2 Dose and Method of Administration; Section 4.4 Special Warnings and Precautions for Use).

5.3 Preclinical Safety Data

Genotoxicity.

There was no evidence that either atovaquone or proguanil alone were mutagenic in bacterial and mammalian cell gene mutation assays in vitro, and in mouse bone marrow micronucleus assays for chromosome damage in vivo. Cycloguanil, an active metabolite of proguanil, was negative in a bacterial mutagenicity assay but positive in both a mammalian cell mutagenicity assay and a mouse micronucleus test. As the genotoxicity of cycloguanil is prevented or moderated by the coadministration of folinic acid, it appears to be related to the inhibition of mammalian dihydrofolate reductase, causing a reduction in the nucleotide pool and a consequent perturbation of DNA synthesis rather than a direct interaction with DNA. Neither proguanil nor cycloguanil is likely to present a genotoxic risk at clinical exposure levels. Mutagenicity studies have not been performed with atovaquone in combination with proguanil.

Carcinogenicity.

Oncogenicity studies of atovaquone alone in mice showed an increased incidence of hepatocellular adenomas and carcinomas at all dose levels tested, yielding exposures approximately 5 to 8 times the average steady-state plasma concentrations in humans during prophylaxis of malaria. The pattern of associated histological findings observed in the liver is consistent with a species specific, nongenotoxic, neoplastic response. Studies in rats at oral dose levels of up to 500 mg/kg/day were negative. Atovaquone is unlikely to present a carcinogenic risk to humans at therapeutic doses.
Oncogenicity studies on proguanil alone showed no evidence of carcinogenicity in rats and mice at doses resulting in exposures approximately equal to those obtained in humans during prophylaxis of malaria, but considerably below exposures obtained during treatment of malaria. Carcinogenicity studies have not been conducted with atovaquone in combination with proguanil.

6 Pharmaceutical Particulars

6.1 List of Excipients

The tablets also contain: hyprolose, magnesium stearate, microcrystalline cellulose, poloxamer, povidone and sodium starch glycollate.
The film coating on the tablets also contains: hypromellose, iron oxide red, macrogol 400, macrogol 8000 and titanium dioxide.

6.2 Incompatibilities

See Section 4.5 Interactions with Other Medicines and Other Forms of Interactions.

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 tablets below 30°C.

6.5 Nature and Contents of Container

Each tablet strength is provided in PVC aluminium foil blister packs or PVC-aluminium/paper child resistant foil blister packs* in the following pack sizes:

Malarone Tablets (250/100).

12 and 24 tablets.

Malarone Junior Tablets (62.5/25).

12, 24 and 60 tablets.
* Complies with European Standard EN 14375:2003 Child-resistant Non-reclosable Packaging for Pharmaceutical Products - Requirements And Testing.
Not all strengths and/or pack sizes may be distributed in Australia.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Chemical structure.

The chemical name of atovaquone is trans-2-[4-(4-chlorophenyl) cyclohexyl]-3-hydroxy-1,4-naphthoquinone. The molecular formula of atovaquone is C22H19ClO3 and it has a molecular weight of 366.84. Atovaquone is virtually insoluble in water (less than 2 x 10-4 mg/mL) and slightly soluble (1.7 mg/mL) in 0.1 M sodium hydroxide. The structural formula is shown below:
The chemical name of proguanil hydrochloride is 1-(4-chlorophenyl)-5-isopropyl-biguanide hydrochloride. The molecular formula of proguanil hydrochloride is C11H16ClN5.HCl and it has a molecular weight of 290.20. Proguanil hydrochloride is slightly soluble at 1 part in 110 parts of water and is sparingly soluble in alcohol (1 part in 40 parts of alcohol). The structural formula is shown below:

CAS number.

Atovaquone.

95233-18-4.

Proguanil hydrochloride.

637-32-1.

7 Medicine Schedule (Poisons Standard)

Schedule 4 - Prescription Only Medicine.

Summary Table of Changes