MALARONE PAEDIATRIC Film-coated tablet Ref.[51433] Active ingredients: Atovaquone Proguanil Proguanil and Atovaquone

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’.

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).

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.

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.

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).

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.

Not applicable.