4.1. Therapeutic indications

Malarone paediatric tablets contain a fixed dose combination of atovaquone and proguanil hydrochloride, which acts as a blood schizontocide and also has activity against hepatic schizonts of Plasmodium falciparum. They are indicated for:

Prophylaxis of P. falciparum malaria in individuals weighing 11-40 kg.

Treatment of acute, uncomplicated P. falciparum malaria in children weighing ≥5 kg and <11 kg.

For treatment of acute, uncomplicated P. falciparum malaria in individuals weighing 11-40 kg please refer to the Summary of Product Characteristics for Malarone tablets.

Malarone may be active against P. falciparum that are resistant to one or more other antimalarial agents. Therefore, Malarone may be particularly suitable for prophylaxis and treatment against P. falciparum infections in areas where this species is known to be commonly resistant to one or more other antimalarial agents and also for treatment of patients infected with P. falciparum malaria whilst in these areas.

Official guidelines and local information on the prevalence of resistance to antimalarial drugs should be taken into consideration. Official guidelines will normally include WHO and public health authorities' guidelines.

4.2. Posology and method of administration

Method of administration

The daily dose should be taken once daily with food or a milky drink (to ensure maximum absorption) at the same time each day.

If patients are unable to tolerate food Malarone paediatric tablets should be administered, but systemic exposure of atovaquone will be reduced. In the event of vomiting within 1-hour of dosing a repeat dose should be taken.

Malarone paediatric tablets should preferably be swallowed whole. If difficulties are encountered when dosing young children, the tablets may be crushed and mixed with food or a milky drink just prior to administration.

Posology

The dosage for the prophylaxis and treatment of acute, uncomplicated P. falciparum malaria in children is based on body weight.

Prophylaxis

Dosage in individuals weighing 11-40 kg

Dosage/day

Body Weight Range (kg)

Atovaquone (mg)

Proguanil (mg)

No of Tablets

11-20

62.5

25

One Malarone paediatric tablet

21-30

125

50

Two Malarone paediatric tablets

31-40

187.5

75

Three Malarone paediatric tablet

>40

250

100

Subjects of >40 kg should receive ONE Malarone 250/100 mg tablet daily

Refer to Malarone 250/100 mg Tablets SmPC

The safety and effectiveness of Malarone paediatric tablets for prophylaxis of malaria in children who weigh less than 11 kg has not been established.

Prophylaxis should

• commence 24 or 48 hours prior to entering a malaria-endemic area,

• continue during the period of the stay,

• continue for 7 days after leaving the area.

The safety and effectiveness of Malarone paediatric tablets have been established in studies of up to 12 weeks in residents (semi-immune) of endemic areas. (see section 5.1).

In non-immune subjects, the average duration of exposure in clinical studies was 27 days.

Treatment

Dosage in individuals weighing 5-<11 kg

Dosage/day

Body Weight Range (kg)

Atovaquone (mg)

Proguanil (mg)

Dosage Regimen

5-8

125

50

Two Malarone paediatric tablets daily for 3 consecutive days

9-10

187.5

75

Three Malarone paediatric tablets daily for 3 consecutive days.

≥11

Refer to Malarone 250/100 mg Tablets SmPC

The safety and effectiveness of Malarone paediatric tablets for the treatment of malaria in children who weigh less than 5 kg has not been established.

For individuals who weigh 11 kg or more, the first choice for the treatment of acute, uncomplicated P. falciparum malaria is Malarone tablets (250/100 mg). Please consult the Malarone tablets SmPC for the recommended dosage for this weight range. Malarone tablets are four-times the strength of Malarone paediatric tablets.

In circumstances when sufficient Malarone tablets are not available, then Malarone paediatric tablets may be used.

Dosage in Hepatic Impairment

There are no studies in children with hepatic impairment. However, a pharmacokinetic study in adults indicates that no dosage adjustments are needed in patients with mild to moderate hepatic impairment. Although no studies have been conducted in patients with severe hepatic impairment, no special precautions or dosage adjustment are anticipated (see section 5.2).

Dosage in Renal Impairment

There are no studies in children with renal impairment. However, pharmacokinetic studies in adults indicate that no dosage adjustments are needed in those with mild to moderate renal impairment. Due to the lack of information regarding appropriate dosing, Malarone is contraindicated for the prophylaxis of malaria in adults and children with severe renal impairment (creatinine clearance <30 mL/min; see sections 4.3 and 5.2).

4.3. Contraindications

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

Malarone paediatric tablets are 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 paediatric tablets for prophylaxis or treatment of malaria should take a repeat dose if they vomit within 1hour of dosing. In the event of diarrhoea, normal dosing should be continued. Absorption of atovaquone may be reduced in individuals 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 or 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 paediatric tablets, 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).

The 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 (atovaquone 250mg/proguanil hydrochloride 100mg tablets) should be used in these individuals (see section 4.2).

This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially 'sodium free'.

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 atovaquone-proguanil treatment or after its withdrawal, based on INR results.

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

The co-administration of atovaquone at doses of 45mg/kg/day in 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 to the co-administration of etoposide and 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) or 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 paediatric tablets in pregnancy should only be considered if the expected benefit to the mother outweighs any potential risk to the foetus.

Proguanil 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 paediatric tablets.

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 paediatric tablets 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

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.

In clinical trials of Malarone for 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.

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).

System Organ Class

Very Common

Common

Uncommon

Rare

Not known2

Blood and lymphatic disorders

Anaemia

Neutropenia 1

Pancytopenia

Immune system disorders

Allergic reactions

Angioedema3

Anaphylaxis (see section 4.4)

Vasculitis3

Metabolism and nutrition disorders

Hyponatraemia1

Anorexia

Elevated amylase levels1

Psychiatric disorders

Abnormal dreams

Depression

Anxiety

Hallucinations

Panic attack

Crying

Nightmares

Psychotic disorder

Nervous system disorders

Headache

Insomnia

Dizziness

Seizure

Cardiac disorders

Palpitations

Tachycardia

Gastrointestinal disorders

Nausea1

Vomiting

Diarrhoea

Abdominal pain

Stomatitis

Gastric intolerance3

Oral ulceration3

Hepatobiliary disorders

Elevated liver enzymes1

Hepatitis

Cholestasis3

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

1. 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.

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

3. 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. Healthcare professionals are asked to report any suspected adverse reactions via Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

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.