MALARONE TABLETS FOR ADULTS

dizziness

sleeping problems (insomnia)

vivid dreams

loss of appetite

fever

rash which may be itchy

mouth ulcers

cough

weakness

visual difficulties.

Common side effects, which may show up in your blood tests are:

low levels of sodium in the blood (hyponatraemia).

Uncommon side effects

depression

anxiety

abnormal beating of the heart (palpitation).

Uncommon side effects that may show up in your blood tests:

an increase in amylase (an enzyme produced in the pancreas).

Other side effects

Other side effects have occurred in a small number of people but their exact frequency is unknown.

inflammation of the liver (hepatitis)

blockage of the bile ducts (cholestatis)

increase in heart rate (tachycardia)

inflammation of the blood vessels (vasculitis) which may be visible as red or purple raised spots on the

skin but can affect other parts of the body

fits (seizures)

seeing or hearing things that are not there (hallucinations)

severe mental health problem in which the person loses contact with reality and is unable to think and

judge clearly

peeling skin

increased sensitivity of the skin to sunlight

swelling and redness of the mouth.

Other side effects that may show up in your blood tests:

a decrease in all types of blood cells (pancytopenia)

reduced numbers of red blood cells (anaemia) which can cause tiredness, headaches and shortness of

breath

reduced numbers of white blood cells (neutropenia) which may make you more likely to catch

infections

an increase in liver enzymes.

If any of the side effects get worse or when you suffer from a side effect that has not been mentioned in

the leaflet, you should consult the physician.

5. How to store the medicine?

Avoid poisoning! This medicine and any other medicine should be kept in a closed place out of the

sight and reach of children and/or infants in order to avoid poisoning. Do not induce vomiting without

an explicit instruction from the physician.

Do not use the medicine after the expiry date (exp. date) appearing on the package. The expiry date

refers to the last day of that month.

Store below 30°C.

6. Additional information

In addition to the active ingredients the medicine also contains –

Low substituted hydroxypropyl cellulose, microcrystalline cellulose, povidone K30, sodium starch

glycollate (type A), magnesium stearate, poloxamer 188, hypromellose, titanium dioxide, macrogol 400,

red iron oxide (E172), polyethylene glycol 8000.

What does the medicine look like and what is the content of the package -

Malarone Tablets for Adults are pink, film-coated, round biconvex tablets marked with “GX CM3” on

one side. Blister pack containing 12, 24 tablets.

Malarone Paediatric Tablets are pink, film-coated, round biconvex tablets marked with “GX CG7” on

one side. Blister pack containing 12, 24 tablets.

Not all pack sizes may be marketed.

License Holder: GlaxoSmithKline (Israel) Ltd., 25 Basel St., Petach Tikva.

Manufacturer: Glaxo Wellcome S.A., Burgos, Spain.

This leaflet was checked and approved by the Ministry of Health in: March 2014.

Registration number of the medicine in the National Drug Registry of the Ministry of Health:

Malarone Tablets For Adults: 128-46-30733

Malarone Paediatric Tablets: 128-45-30732

Patient leaflet in accordance with the Pharmacists’ Regulations (Preparations) – 1986

The medicine is dispensed according to a physician’s prescription only

Malarone™ Tablets For Adults

250 mg/100 mg Film coated tablets

Malarone™ Paediatric Tablets

62.5 mg/25 mg Film coated tablets

The active ingredients and their quantity:

Malarone Tablets For Adults

Each tablet contains 250 mg atovaquone and 100 mg proguanil hydrochloride

Malarone Paediatric Tablets

Each tablet contains 62.5 mg atovaquone and 25 mg proguanil hydrochloride

List of the additional ingredients detailed in section 6.

Read the entire leaflet carefully before using the medicine. This leaflet contains concise information

about the medicine. If you have any other questions, refer to the physician or the pharmacist.

This medicine has been prescribed for you. Do not pass it on to others. It may harm them even if it seems

to you that their medical condition is similar.

1. What is the medicine intended for?

Prevention of Malaria

Malarone is indicated for the prophylaxis of Plasmodium falciparum malaria, including in areas where

chloroquine resistance has been reported.

Treatment of Malaria

Malarone is indicated for the treatment of acute, uncomplicated P. falciparum malaria. Malarone has been

shown to be effective in regions where the drugs chloroquine, halofantrine, mefloquine and amodiaquine

may have unacceptable treatment failure rates, presumably due to drug resistance.

Malarone Paediatric Tablets is recommended for paediatric patients who weigh over 11 kg.

Malaria is spread by the bite of an infected mosquito, which passes the malaria parasite (Plasmodium

falciparum) into the bloodstream. Malarone prevents malaria by killing this parasite. For people who are

already infected with malaria, Malarone also kills these parasites.

Protect yourself from catching malaria.

People of any age can get malaria. It is a serious disease, but is preventable.

As well as taking Malarone, it is very important that you also take steps to avoid being bitten by

mosquitoes.

Use insect repellent on exposed areas of the skin

Wear light coloured clothing that covers most of the body, especially after sunset as this is the time

when mosquitoes are most active

Sleep in a screened room or under a mosquito net impregnated with insecticide

Close windows and doors at sunset, if they are not screened

Consider using an insecticide (mats, spray, plug-ins) to clear a room of insects or to deter mosquitoes

from entering the room.

If you need further advice, talk to your physician or pharmacist.

It is still possible to get malaria after taking the necessary precautions. Some types of malaria

infection take a long time to cause symptoms, so the illness may not start until several days, weeks or

even months after returning from abroad.

See a physician immediately if you get symptoms such as high temperature, headache, shivering and

tiredness after returning home.

Therapeutic group

Malarone belongs to a group of medicines called antimalarials. It contains two active ingredients:

atovaquone and proguanil hydrochloride.

2. Before using the medicine

Do not use the medicine:

if you are sensitive (allergic) to atovaquone, proguanil hydrochloride or to any of the additional

ingredients contained in the medicine, as listed in section 6.

for preventing malaria, if you have severe kidney disease.

Tell your physician if either of these apply to you.

Special warnings regarding the use of the medicine

Before the treatment with Malarone, tell the physician if you have a severe renal impairment, or severe

or persistent diarrhea or vomiting.

If you are taking or have recently taken other medicines including non-prescription medicines and

food supplements, tell the physician or the pharmacist. Some medicines can affect the way Malarone

works, or Malarone itself can strengthen or weaken the effectiveness of other medicines taken at the

same time. These include:

metoclopramide, used to treat nausea and vomiting

the antibiotics, tetracycline, rifampicin and rifabutin

warfarin and other medicines that stop blood clotting

indinavir, highly active protease-inhibitor used to treat HIV.

Tell your physician if you are taking any of these. Your physician may decide that Malarone isn’t suitable

for you, or that you need extra check ups while you’re taking it.

Remember to tell your physician if you start taking any other medicines while you’re taking Malarone.

Using the medicine and food

Take Malarone with food or a milky drink, where possible. This will increase the amount of Malarone

your body can absorb, and make your treatment more effective.

Pregnancy and breast-feeding

If you are pregnant or breast-feeding, do not take Malarone unless your physician recommends it.

Ask your physician or pharmacist for advice before taking Malarone.

Driving and using machines

If you feel dizzy, do not drive.

Malarone makes some people feel dizzy. If this happens to you, do not drive, use machines or take part

in activities where you may put yourself or others at risk.

If you are sick (vomit)

For preventing malaria:

if you are sick (vomit) within 1 hour of taking your Malarone tablet, take another dose straight

away

it is important to take the full course of Malarone. If you have to take extra tablets due to sickness,

you may need another prescription.

if you have been vomiting, it is especially important to use extra protection, such as repellents and

bednets. Malarone may not be as effective, as the amount absorbed will be reduced.

For treating malaria:

if you have vomiting and diarrhoea tell your physician, you will need regular blood tests. Malarone will

not be as effective, as the amount absorbed will be reduced. The tests will check whether the malaria

parasite is being cleared from your blood.

3. How should you use the medicine?

Always use according to the physician’s instructions.

You should check with the physician or the pharmacist if you are unsure.

The dosage and treatment will be determined only by the physician. The usual dosage is:

To prevent malaria

Adults

The usual dose for adults is 1 Malarone tablet for adults (adult strength = 250 mg atovaquone/100 mg

proguanil hydrochloride) once a day.

Children

For children the dose depends on their body weight:

Weight

(kg)

Atovaquone/

Proguanil HCl

Total Daily Dose

Dosage Regimen

11-20

62.5 mg/25 mg

1 Malarone Paediatric Tablet daily

21-30

125 mg/50 mg

2 Malarone Paediatric Tablets as a single daily dose

31-40

187.5 mg/75 mg

3 Malarone Paediatric Tablets as a single daily dose

>40

250 mg/100 mg

1 Malarone Tablet For Adults as a single daily dose

To prevent malaria:

start taking Malarone 1 to 2 days before travelling to an area which has malaria

continue taking it every day during your stay

continue taking it for another 7 days after your return to a malaria-free area.

To treat malaria

Adults

The usual dose for adults is 4 tablets (adult strength; total daily dose 1 g atovaquone/400 mg proguanil

hydrochloride) once a day for 3 days.

Children

For children the dose depends on their body weight:

Weight

(kg)

Atovaquone/

Proguanil HCl

Total Daily Dose

Dosage Regimen

11-20

250 mg/100 mg

1 Malarone Tablet For Adults daily for 3 consecutive days

21-30

500 mg/200 mg

2 Malarone Tablet For Adults as a single daily dose for 3 consecutive

days

31-40

750 mg/300 mg

3 Malarone Tablet For Adults as a single daily dose for 3 consecutive

days

>40

1 g/400 mg

4 Malarone Tablet For Adults as a single daily dose for 3 consecutive

days

Malarone tablets are not recommended for treating malaria in children who weigh less than 11 kg.

It is best to take Malarone at the same time each day.

Do not exceed the recommended dose

The tablets should be swallowed whole. However, for children who find them difficult to swallow, they

may be crushed just before being taken and mixed with food or a milky drink.

If you accidently have taken a higher dosage you should contact a physician or pharmacist for advice.

If possible show them the Malarone pack.

If you have taken an overdose or if a child has accidentally swallowed the medicine, refer immediately to

a physician or to a hospital emergency room and bring the package of the medicine with you.

If you forgot to take the medicine

It is very important that you take the full course of Malarone.

If you forgot to take this medicine at the scheduled time take a dose as soon as you remember, however

do not take a double dose. Take the next dose at the usual time and consult the physician. Then persist

with the treatment as recommended by the physician.

Don’t stop Malarone without advice

Keep taking Malarone for 7 days after you return to a malaria-free area. Take the full course of Malarone

for maximum protection. Stopping early puts you at risk of getting malaria, as it takes 7 days to ensure that

any parasites that may be in your blood following a bite from an infected mosquito are killed.

Do not take medicines in the dark! Check the label and the dose each time you take a medicine. Wear

glasses if you need them.

If you have any other questions regarding the use of the medicine, consult the physician or the

pharmacist.

4. Side effects

As with any medicine, use of Malarone may cause side effects in some of the users. Do not be alarmed

by reading the list of side effects. You may not experience any of them.

Look out for the following severe reactions. They have occurred in a small number of people, but their

exact frequency is unknown.

Severe allergic reactions - signs include:

rash and itching

sudden wheezing, tightness of the chest or throat, or difficulty breathing

swollen eyelids, face, lips, tongue or other part of the body.

Contact a physician immediately if you get any of these symptoms. Stop taking Malarone.

Severe skin reactions

skin rash, which may blister and looks like small targets (central dark spots, surrounded by paler area

with a dark ring around the edge) (erythema multiforme)

severe widespread rash with blisters and peeling skin, particularly occurring around the mouth, nose,

eyes and genitals (Stevens-Johnson syndrome)

If you notice any of these symptoms contact a physician urgently.

Additional side effects

Common side effects

headache

nausea and vomiting (feeling sick and being sick)

stomach pain

diarrhoea

Mal PT v3 21773

NAME OF THE MEDICINAL PRODUCT

Malarone tablets for adults

Malarone paediatric tablets

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each Malarone tablet for adults contains 250 mg atovaquone and 100 mg proguanil hydrochloride.

Each Malarone

paediatric tablets contains 62.5 mg atovaquone and 25 mg proguanil hydrochloride.

For the full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

Film coated tablet.

Malarone

paediatric tablets – Round biconvex, pink tablets engraved ‘GX CG7’ on one side.

Malarone tablets for adults – Round, biconvex, pink tablets engraved ‘GX CM3’ on one side.

4.

CLINICAL PARTICULARS

4.1

Therapeutic indications

Prevention of Malaria

Malarone is indicated for the prophylaxis of

Plasmodium falciparum

malaria, including in areas where

chloroquine resistance has been reported.

Treatment of Malaria

Malarone is indicated for the treatment of acute, uncomplicated

P. falciparum

malaria. Malarone has

been shown to be effective in regions where the drugs chloroquine, halofantrine, mefloquine, and

amodiaquine may have unacceptable failure rates, presumably due to drug resistance.

4.2

Posology and method of administration

The daily dose should be taken at the same time each day with food or a milky drink. In the event of

vomiting within 1 hour after dosing, a repeat dose should be taken.

Malarone Paediatric Tablets:

Malarone may be crushed and mixed with condensed milk just prior to administration to patients who

may have difficulty swallowing tablets.

Malarone Tablets for adults:

There is no data regarding crush/divide/chew

Prevention of Malaria

Start prophylactic treatment with Malarone 1 or 2 days before entering a malaria-endemic area and

continue daily during the stay and for 7 days after return.

Adults:

tablet

Malarone

Tablets

Adults

(250 mg

atovaquone/100 mg

proguanil

hydrochloride) per day.

Paediatric Patients: The dosage for prevention of malaria in paediatric patients is based upon body

weight (Table 1).

Table 1. Dosage for Prevention of Malaria in Paediatric Patients

Weight

(kg)

Atovaquone/

Proguanil HCl

Total Daily Dose

Dosage Regimen

11-20

62.5 mg/25 mg

1 Malarone Paediatric Tablet daily

21-30

125 mg/50 mg

2 Malarone Paediatric Tablets as a single daily dose

31-40

187.5 mg/75 mg

3 Malarone Paediatric Tablets as a single daily dose

>40

250 mg/100 mg

1 Malarone Tablets For Adults as a single daily dose

Treatment of Acute Malaria

Adults:

Four

Malarone

Tablets

Adults

(total

daily

dose

atovaquone/400 mg

proguanil

hydrochloride) as a single daily dose for 3 consecutive days.

Paediatric Patients: The dosage for treatment of acute malaria in paediatric patients is based upon body

weight (Table 2).

Table 2. Dosage for Treatment of Acute Malaria in Paediatric Patients

Weight

(kg)

Atovaquone/

Proguanil HCl

Total Daily Dose

Dosage Regimen

125 mg/50 mg

2 Malarone Paediatric Talets for 3 consecutive days.

9-10

187.5 mg/75 mg

3 Malarone Paediatric Tablets daily for 3 consecutive days.

11-20

250 mg/100 mg

1 Malarone Tablet For Adults daily for 3 consecutive days

21-30

500 mg/200 mg

2 Malarone

Tablets For Adults

a single daily dose for

3 consecutive days

31-40

750 mg/300 mg

3 Malarone

Tablets For Adults

a single daily dose for

3 consecutive days

>40

1 g/400 mg

4 Malarone

Tablets For Adults

a single daily dose for

3 consecutive days

Renal Impairment

Do not use Malarone for malaria prophylaxis in patients with severe renal impairment (creatinine

clearance <30 mL/min)

[see Contraindications (4.2)]

. Use with caution for the treatment of malaria in

patients with severe renal impairment, only if the benefits of the 3-day treatment regimen outweigh the

potential risks associated with increased drug exposure. No dosage adjustments are needed in patients

with mild (creatinine clearance 50 to 80 mL/min) or moderate (creatinine clearance 30 to 50 mL/min)

renal impairment.

[See Clinical Pharmacology (12.3).]

Hepatic Impairment

No dosage adjustments are needed in patients with mild or moderate hepatic impairment. No trials have

been conducted in patients with severe hepatic impairment.

Paediatric Use

Prophylaxis of Malaria: Safety and effectiveness for the treatment and prophylaxis of malaria have not

been established in paediatric patients who weigh less than 11 kg.

Geriatric Use

Clinical trials of Malarone did not include sufficient numbers of subjects aged 65 years and older to

determine whether they respond differently from younger subjects. In general, dose selection for an

elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac

function, the higher systemic exposure to cycloguanil, and the greater frequency of concomitant disease

or other drug therapy.

4.3

Contraindications

Hypersensitivity to the active substances or to any of the excipients listed in section 6.1.

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

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, subjects with diarrhoea or vomiting should be advised to continue with

malaria prevention measures by complying 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 and the patient’s clinical

condition should be closely monitored.

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.

Occasionally, severe allergic reactions (including anaphylaxis) have been reported in patients taking

Malarone. If patients experience an allergic reaction (see section 4.8) Malarone should be discontinued

promptly and appropriate treatment initiated.

Malarone has been shown to have no efficacy against hypnozoites of Plasmodium vivax as parasite

relapse occurred commonly when

P. vivax

malaria was treated with Malarone alone. Travellers with

intense exposure to

P. vivax

P. ovale

, and those who develop malaria caused by either of these

parasites, will require additional treatment with a drug that is active against hypnozoites.

In the event of recrudescent infections due to

P. falciparum

after treatment with Malarone, or failure of

chemoprophylaxis with Malarone, patients should be treated with a different blood schizonticide as such

events can reflect a resistance of the parasite.

Parasitaemia should be closely monitored in patients receiving concurrent tetracycline (see section 4.5).

The concomitant administration of Malarone and efavirenz or boosted protease-inhibitors should be

avoided whenever possible (see section 4.5).

The concomitant administration of Malarone and rifampicin or rifabutin is not recommended (see

section 4.5).

Concurrent use of metoclopramide is not recommended. Another antiemetic treatment should be given

(see section 4.5).

Caution is advised when initiating or withdrawing malaria prophylaxis or treatment with Malarone in

patients on continuous treatment with warfarin and other coumarin based anticoagulants (see section

4.5).

Atovaquone can increase the levels of etoposide and its metabolite (see section 4.5).

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 sections 4.2,

4.3 and 5.2).

Malarone Tablets for adults

The safety and effectiveness of Malarone tablets for adults (atovaquone 250mg/proguanil hydrochloride

100mg tablets) has not been established for prophylaxis of malaria in patients who weigh less than 40kg,

or in the treatment of malaria in paediatric patients who weigh less than 11kg.

Malarone Paediatric Tablets

safety and effectiveness of Malarone paediatric tablets for the prophylaxis of malaria in children

who weigh less than 11 kg and the treatment of malaria in children who weigh less than 5 kg have not

been established.

Malarone paediatric tablets are not indicated for the treatment of acute uncomplicated

P. falciparum

malaria in individuals weighing 11-40 kg. Malarone tablets for adults (atovaquone 250mg/proguanil

hydrochloride 100mg tablets) should be used in these individuals (see section 4.2).

4.5

Interaction with other medicinal products and other forms of interaction

Concomitant administration of rifampicin or rifabutin is not recommended as it is known to reduce

plasma concentrations of atovaquone levels by approximately 50% and 34%, respectively (see section

4.4).

Concomitant treatment with metoclopramide has been associated with a significant decrease (about 50

%) in plasma concentrations of atovaquone (see section 4.4). Another antiemetic treatment should be

given.

Although some children have received concomitant Malarone and metoclopramide in clinical trials

without any evidence of decreased protection against malaria, the possibility of a clinically significant

drug interaction cannot be ruled out.

When given with efavirenz or boosted protease-inhibitors, atovaquone concentrations have been

observed to decrease as much as 75%. This combination should be avoided whenever possible (see

section 4.4)

Proguanil may potentiate the anticoagulant effect of warfarin and other coumarin based anticoagulants

which may lead to an increase in the risk of haemorrhage. The mechanism of this potential drug

interaction has not been established. Caution is advised when initiating or withdrawing malaria

prophylaxis or treatment with atovaquone-proguanil in patients on continuous treatment with oral

anticoagulants. The dose of the oral anticoagulant may need to be adjusted during Malarone treatment

or after its withdrawal, based on INR results.

Concomitant treatment with tetracycline has been associated with decreases in plasma concentrations of

atovaquone.

co-administration

atovaquone

doses

45mg/kg/day

children

(n=9)

with

acute

lymphoblastic leukaemia for prophylaxis of PCP was found to increase the plasma concentrations

(AUC) of etoposide and its metabolite etoposide catechol by a median of 8.6% (P=0.055) and 28.4%

(P=0.031)

(respectively

compared

co-administration

etoposide

sulfamethoxazole-

trimethoprim). Caution should be advised in patients receiving concomitant therapy with etoposide (see

section 4.4).

Proguanil is primarily metabolised by CYP2C19. However, potential pharmacokinetic interactions with

other

substrates,

inhibitors

(e.g.

moclobemide,

fluvoxamine)

inducers

(e.g.

artemisinin,

carbamazepine) of CYP2C19 are unknown (see section 5.2).

4.6

Fertility, pregnancy and lactation

Pregnancy

The safety of atovaquone and proguanil hydrochloride

when administered concurrently for use in human

pregnancy has not been established and the potential risk is unknown.

Animal studies showed no evidence for teratogenicity of the combination. The individual components

have shown no effects on parturition or pre- and post-natal development. Maternal toxicity was seen in

pregnant rabbits during a teratogenicity study (see section 5.3).

The use of Malarone in pregnancy should only be considered if the expected benefit to the mother

outweighs any potential risk to the foetus.

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

should be continued while taking Malarone.

Breast-feeding

The atovaquone concentrations in milk, in a rat study, were 30% of the concurrent atovaquone

concentrations in maternal plasma. It is not known whether atovaquone is excreted in human milk.

Proguanil is excreted in human milk in small quantities.

Malarone should not be taken by breast-feeding women.

4.7

Effects on ability to drive and use machines

Dizziness has been reported. Patients should be warned that if affected they should not drive, operate

machinery or take part in activities where this may put themselves or others at risk.

4.8

Undesirable effects

Malarone Paediatric Tablets

In clinical trials of Malarone paediatric tablets for prophylaxis of malaria, 357 children or adolescents

11 to

40 kg body weight received Malarone paediatric tablets. Most of these were residents of endemic

areas and took Malarone paediatric tablets for about 12 weeks. The rest were travelling to endemic

areas, and most took Malarone paediatric tablets for 2-4 weeks.

Open label clinical studies investigating the treatment of children weighing between ≥5 kg and <11 kg

have indicated that the safety profile is similar to that in children weighing between 11 kg and 40 kg,

and adults.

There are limited long term safety data in children. In particular, the long-term effects of Malarone on

growth, puberty and general development have not been studied.

Malarone Tablets for Adults

In clinical trials of Malarone in the treatment of malaria the most commonly reported adverse reactions

were abdominal pain, headache, anorexia, nausea, vomiting, diarrhoea and coughing. In clinical trials

of Malarone for prophylaxis of malaria, the most commonly reported adverse reactions were headache,

abdominal pain and diarrhoea.

Malarone Tablets for Adults and Malarone Paediatric Tablets

The following table provides a summary of adverse reactions that have been reported to have a suspected

(at least possible) causal relationship to treatment with atovaquone-proguanil in clinical trials and

spontaneous post-marketing reports. The following convention is used for the classification of

frequency: 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); not known (cannot be estimated from the available data).

There are limited long term safety data in children. In particular, the long-term effects of Malarone on

growth, puberty and general development have not been studied.

System Organ

Class

Very

Common

Common

Uncommon

Rare

Not known

2

Blood and

lymphatic

disorders

Anaemia

Neutropenia

Pancytopenia

Immune

system

disorders

Allergic

reactions

Angioedema

Anaphylaxis

(see section 4.4)

Vasculitis

Metabolism

and nutrition

disorders

Hyponatraemia

Anorexia

Elevated

amylase

levels

Psychiatric

disorders

Abnormal

dreams

Depression

Anxiety

Hallucinations

Panic attack

Crying

Nightmares

Psychotic

disorder

Nervous

system

disorders

Headache

Insomnia

Dizziness

Seizure

Cardiac

disorders

Palpitations

Tachycardia

Gastrointestina

l disorders

Nausea

Vomiting

Diarrhoea

Abdomina

l pain

Stomatitis

Gastric

intolerance

Oral ulceration

Hepatobiliary

disorders

Elevated liver

enzymes

Hepatitis

Cholestasis

Skin and

subcutaneous

tissue

disorders

Pruritus

Rash

Hair loss

Urticaria

Stevens-Johnson

Syndrome

Erythema

multiforme

Blister

Skin exfoliation

Photosensitivity

reactions

General

disorders and

administration

site conditions

Fever

Respiratory,

thoracic and

mediastinal

disorders

Cough

Frequency taken from atovaquone label. Patients participating in clinical trials with atovaquone have

received higher doses and have often had complications of advance Human Immunodeficiency Virus

(HIV) disease. These events may have been seen at a lower frequency or not at all in clinical trials with

atovaquone-proguanil.

Observed from post-marketing spontaneous reports and the frequency is therefore unknown

Observed with proguanil.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows

continued monitoring of the benefit/risk balance of the medicinal product.

Any suspected adverse events should be reported to the Ministry of Health according to the National

Regulation by using an online form https://sideeffects.health.gov.il/

Additionally, you should also report to GSK Israel (il.safety@gsk.com).

4.9

Overdose

There is insufficient experience to predict the consequences or suggest specific management of

Malarone overdose. However, in the reported cases of atovaquone overdose, the observed effects were

consistent with known undesirable effects of the drug. If overdose occurs, the patient should be

monitored and standard supportive treatment applied.

5.

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties

Pharmacotherapeutic group: Antimalarials, ATC Code: P01B B51

Mode of Action

The constituents of Malarone, atovaquone and proguanil hydrochloride, interfere with two different

pathways involved 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 bc

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

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.

Microbiology

Atovaquone has potent activity against

Plasmodium

in vitro

against

P. falciparum

0.23-1.43

ng/mL).

Atovaquone is not cross-resistant with any other antimalarial drugs in current use. Among more than

P. falciparum

isolates,

in vitro

resistance was detected against chloroquine (41% of isolates), quinine

(32% of isolates), mefloquine (29% of isolates), and halofantrine (48% of isolates) but not atovaquone

(0% of isolates).

The antimalarial activity of proguanil is exerted via the primary metabolite cycloguanil (

in vitro

against various

P. falciparum

strains of 4-20 ng/mL; some activity of proguanil and another metabolite,

4-chlorophenylbiguanide, is seen

in vitro

at 600-3000

ng/mL).

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 in both immune and non-

immune patients.

Clinical Efficacy- Malarone paediatric tablets

Prophylaxis

The efficacy in non-immune paediatric travellers has not been directly established, but may be assumed

through extrapolation by the results on safety and efficacy in studies of up to 12 weeks in paediatric

residents (semi-immune) of endemic areas, and from results of safety and efficacy in both semi-immune

and non-immune adults.

Data in the paediatric population are available from two trials that primarily evaluated the safety of

Malarone paediatric tablets in (non-immune) travellers to endemic areas. In these trials, a total of 93

travellers weighing <40 kg were given Malarone and 93 received another prophylactic antimalarial

regimen (81 chloroquine/proguanil and 12 mefloquine). The majority of travellers went to Africa and

the mean duration of stay was between 2-3 weeks. There were no cases of malaria recorded in any

subjects who took part in these studies.

Treatment

An open-label, randomised, parallel-group trial was undertaken in Gabon in 200 children weighing

≥5 kg and <11 kg with confirmed, uncomplicated

P. falciparum

malaria. Treatment was with Malarone

paediatric tablets or amodiaquine suspension. In the intent-to-treat population, the 28-day cure rate was

87% in the Malarone group (87/100 subjects). In the per-protocol population, the 28-day cure rate was

95% in the Malarone group (87/92 subjects). The parasitological cure rates for the Malarone group were

88% and 95% for the ITT and PP populations, respectively.

5.2

Pharmacokinetic properties

There are no pharmacokinetic interactions between atovaquone and proguanil at the recommended dose.

In clinical trials, where children have received Malarone dosed by bodyweight, trough levels of

atovaquone, proguanil and cycloguanil in children are generally within the range observed in adults.

In prophylaxis

clinical trials

where children have received Malarone dosed by bodyweight, trough levels

of atovaquone, proguanil and cycloguanil in children are generally within the range observed in adults

(see following table).

Trough Plasma Concentrations [Mean

SD, (range)] of Atovaquone, Proguanil and Cycloguanil during

Prophylaxis with Malarone in Children* and Adults

Atovaquone:Proguanil

HCl Daily Dose

62.5 mg:25 mg

125 mg:50 mg

187.5 mg:75 mg

250mg:100 mg

[Weight Category]

[11-20 kg]

[21-30 kg]

[31-40 kg]

Adult ( >40 kg)

Atovaquone (

g/mL)

No. Subjects

2.2 + 1.1

(0.2-5.8)

n=87

3.2 + 1.8

(0.2-10.9)

n=88

4.1 + 1.8

(0.7-8.8)

n=76

2.1 + 1.2

(0.1-5.7)

n=100

Proguanil (ng/mL)

No. Subjects

12.3 + 14.4

(<5.0-14.3)

n=72

18.8 + 11.2

(<5.0-87.0)

n=83

26.8 + 17.1

(5.1-55.9)

n=75

26.8 + 14.0

(5.2-73.2)

n=95

Cycloguanil (ng/mL)

No. Subjects

7.7 + 7.2

(<5.0-43.5)

n=58

8.1 + 6.3

(<5.0-44.1)

n=69

8.7 + 7.3

(6.4-17.0)

n=66

10.9 + 5.6

(5.0-37.8)

n=95

* Pooled data from two studies

Absorption

Atovaquone is a highly lipophilic compound with low aqueous solubility. In HIV-infected patients, the

absolute bioavailability of a 750 mg single dose of atovaquone tablets taken with food is 23% with an

inter-subject variability of about 45%.

Dietary fat taken with atovaquone increases the rate and extent of absorption, increasing AUC 2-3 times

and C

5 times over fasting. Patients are recommended to take Malarone tablets with food or a milky

drink

(see section 4.2).

Proguanil hydrochloride is rapidly and extensively absorbed regardless of food intake.

Distribution

Apparent volume of distribution of atovaquone and proguanil is a function of bodyweight.

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 8.8 L/kg.

Proguanil is 75% protein bound. Following oral administration, the volume of distribution of proguanil

in adults and children ranged from 20 to 42 L/kg.

In human plasma the binding of atovaquone and proguanil was unaffected by the presence of the other.

Biotransformation

There is no evidence that atovaquone is metabolised and there is negligible excretion of atovaquone in

urine with the parent drug being predominantly (

90%) eliminated unchanged in faeces.

Proguanil hydrochloride is partially metabolised, primarily by the polymorphic cytochrome P450

isoenzyme 2C19, with less than 40% being excreted unchanged in the urine. Its metabolites, cycloguanil

and 4

-

chlorophenylbiguanide, are also excreted in the urine.

During administration of Malarone at recommended doses proguanil metabolism status appears to have

no implications for treatment or prophylaxis of malaria.

Elimination

The elimination half life of atovaquone is about 2-3 days in adults and 1-2 days in children.

The elimination half lives of proguanil and cycloguanil are about 12-15 hours in both adults and

children.

Malarone Paediatric Tablets

Oral clearance for atovaquone and proguanil increases with increased body weight and is about 70%

higher in a 40 kg subject relative to a 20 kg subject. The mean oral clearance in paediatric and adult

patients weighing 5 to 40 kg ranged from 0.5 to 6.3 L/h for atovaquone and from 8.7 to 64 L/h for

proguanil.

Malarone Tablets for Adults

Oral clearance for atovaquone and proguanil increases with increased bodyweight and is about 70%

higher in an 80 kg subject relative to a 40 kg subject. The mean oral clearance in paediatric and adult

patients weighing 10 to 80 kg ranged from 0.8 to 10.8 L/h for atovaquone and from 15 to 106 L/h for

proguanil.

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 cycloguanil is higher in the

elderly compared to the young patients (AUC is increased by 140% and C

is increased by 80%), but

there is no clinically significant change in its elimination half life (see section 4.2).

Pharmacokinetics in renal impairment

There are no studies in children with renal impairment.

In adult 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 C

and AUC are reduced by 64% and 54%, respectively, in adult patients with severe

renal impairment (<30 mL/min/1.73 m

In adult patients with severe renal impairment, the elimination half lives for proguanil (t

h) and

cycloguanil (t

37 h) are prolonged, resulting in the potential for drug accumulation with repeated dosing

(see sections 4.2 and 4.4).

Pharmacokinetics in hepatic impairment

There are no studies in children with hepatic impairment.

In adult patients with mild to moderate hepatic impairment there is no clinically significant change in

exposure to atovaquone when compared to healthy patients.

In adult patients with mild to moderate hepatic impairment there is an 85% increase in proguanil AUC

with no change in elimination half life and there is a 65-68% decrease in C

and AUC for cycloguanil.

No data are available in adult patients with severe hepatic impairment (see section 4.2).

5.3

Preclinical safety data

Repeat dose toxicity:

Findings in repeat dose toxicity studies with atovaquone-proguanil hydrochloride combination were

entirely proguanil related and were observed at doses providing no significant margin of exposure in

comparison with the expected clinical exposure. As proguanil has been used extensively and safely in

the treatment and prophylaxis of malaria at doses similar to those used in the combination, these findings

are considered of little relevance to the clinical situation.

Reproductive toxicity studies:

In rats and rabbits there was no evidence of teratogenicity for the combination. No data are available

regarding the effects of the combination on fertility or pre- and post-natal development, but studies on

the individual components of Malarone have shown no effects on these parameters. In a rabbit

teratogenicity study using the combination, unexplained maternal toxicity was found at a systemic

exposure similar to that observed in humans following clinical use

.

Mutagenicity:

A wide range of mutagenicity tests have shown no evidence that atovaquone or proguanil have

mutagenic activity as single agents.

Mutagenicity studies have not been performed with atovaquone in combination with proguanil.

Cycloguanil, the active metabolite of proguanil, was also negative in the Ames test, but was positive in

the Mouse Lymphoma assay and the Mouse Micronucleus assay. These positive effects with

cycloguanil (a dihydrofolate antagonist) were significantly reduced or abolished with folinic acid

supplementation.

Carcinogencity:

Oncogenicity studies of atovaquone alone in mice showed an increased incidence of hepatocellular

adenomas and carcinomas. No such findings were observed in rats and mutagenicity tests were negative.

These findings appear to be due to the inherent susceptibility of mice to atovaquone and are considered

of no relevance in the clinical situation.

Oncogenicity studies on proguanil alone showed no evidence of carcinogenicity in rats and mice.

Oncogenicity studies on proguanil in combination with atovaquone have not been performed.

6.

PHARMACEUTICAL PARTICULARS

6.1

List of excipients

Core

Low-substituted Hydroxypropyl Cellulose

Microcrystalline Cellulose

Povidone K30

Sodium Starch Glycollate (Type A)

Magnesium Stearate

Poloxamer

Coating

Pink colour concentrate OY-SR-24972 (Hypromellose, Titanium Dioxide E171, Macrogol 400, Iron

Oxide)

Macrogol 400

Polyethylene Glycol 8000

6.2

Incompatibilities

Not applicable.

6.3

Shelf life

The expiry date of the product is indicated on the packaging materials.

6.4

Special precautions for storage

Store below 30

6.5

Nature and contents of container

PVC-aluminium/paper child-resistant foil blister pack/s containing either 12 or 24 tablets.

Not all pack size shall be marketed

6.6

Special precautions for disposal

No special requirements.

Any unused medicinal product or waste material should be disposed of in accordance with local

requirements.

7.

LICENSE HOLDER AND IMPORTER

GlaxoSmithKline (Israel) Ltd., 25 Basel St., Petach Tikva.

8.

LICENSE NUMBER

Malarone Tablets For Adults : 128-46-30733

Malarone Paediatric Tablets: 128-45-30732

9.

MANUFACTURER

Glaxo Wellcome S.A., Burgos, Spain.

Revised in: 09/2020

Mal DR v5