Active ingredients: Atovaquone, Proguanil (Proguanil hydrochloride)
Malarone Children 62.5 mg / 25 mg - Film-coated tablets
Why is Malarone Bambini used? What is it for?
Malarone Children belongs to a group of medicines called antimalarials. It contains two active ingredients, atovaquone and proguanil hydrochloride.
What Malarone Children is used for
Malarone Children is used in two cases:
- for the prevention of malaria (for children weighing between 11 kg and 40 kg)
- for the treatment of malaria (for children weighing in the range 5 kg -
See section 3, How to take Malarone Children.
Although this medicine is usually used in children and adolescents, it can also be prescribed for adults weighing less than 40 kg. 8.
Malaria is spread through the bite of an infected mosquito that transmits the malaria parasite (Plasmodium falciparum) into the bloodstream. Malarone Kids prevents malaria by killing this parasite. Malarone Children kills these parasites even in people already infected with malaria.
Protect your baby from getting malaria.
People of any age can contract malaria. It is a serious disease, but it can be prevented.
It is very important that, in addition to taking Malarone Bambini, you take precautions to avoid being bitten by mosquitoes.
- Use insect repellent on exposed skin areas.
- Use light-colored clothing that covers most of the body, especially after sunset as this is the period of greatest mosquito activity.
- Sleeping in a room protected by mosquito nets or sleeping under a mosquito net impregnated with insecticide.
- Close doors and windows at sunset if they are not fitted with mosquito nets.
- Use an insecticide (platelets, sprays, plug appliances) to clear the room of insects or prevent mosquitoes from entering it.
If you need more information, ask your doctor or pharmacist.
Despite these necessary precautions, it is still possible to get malaria. Some types of malarial infections cause symptoms after a long period of time, so the disease can manifest itself after many days, weeks or even months after returning from abroad.
See your child immediately if you have symptoms such as high fever, headache, chills and tiredness upon returning home.
Contraindications When Malarone Children should not be used
Do not take Malarone Children:
- if your child is allergic to "atovaquone, proguanil hydrochloride or any of the other ingredients of this medicine (listed in section 6)
- for the prevention of malaria, if your child has severe kidney disease.
Tell your doctor if either case involves your baby.
Precautions for use What you need to know before you take Malarone Children
Talk to your doctor or pharmacist before taking Malarone Children if:
- you / your child have severe kidney disease
- your child is being treated for Malaria and weighs less than 5 kg or is taking Malarone Children to prevent Malaria and weighs less than 11 kg
Tell your doctor or pharmacist if any of the cases apply to you.
Interactions Which drugs or foods can modify the effect of Malarone Children
Other medicines and Malarone Children
Tell your doctor or pharmacist if your child is taking, has recently taken, or might take any other medicines, even those obtained without a prescription.
Some medicines can affect the way Malarone Children work, or Malarone Children itself can increase 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
- efavirenz or some strong protease inhibitors used to treat HIV
- warfarin and other medicines that block blood clotting
- etoposide used for the treatment of cancer
Tell your doctor if your child is taking any of these medicines. Your doctor may decide that Malarone Kids is not suitable for you, or that you need to undergo further tests while taking Malarone Kids.
Remember to tell your doctor if your child starts taking other medicines at the same time as Malarone Kids.
Malarone Children with food and drink
Take Malarone Children with food or a milk-based drink, if possible. This way your body / your baby's body will absorb more Malarone Babies and the treatment will be more effective.
Warnings It is important to know that:
Pregnancy and breastfeeding
If you or the child are pregnant, do not take Malarone Children unless your doctor recommends it.
Ask your doctor or pharmacist for advice before taking Malarone Children.
Do not breast-feed while taking Malarone Infant as the components of Malarone Infant can pass into breast milk and harm the baby.
Driving and using machines
If you feel dizzy, don't drive vehicles
Malarone Children causes dizziness in some people. If this happens to you, do not drive vehicles, do not use machines, do not take part in activities that may put you or others at risk.
Dose, Method and Time of Administration How to use Malarone Children: Posology
Always take this medicine exactly as your doctor or pharmacist has told you. If in doubt, consult your doctor or pharmacist.
Take Malarone Children with food or a milk-based drink, if possible. The tablets should be swallowed whole. However, for children who find it difficult to swallow them, they can be crushed just before they are taken and mixed with food or a milk-based drink.
It is best to take Malarone Kids at the same time each day.
If your baby vomits
For the prevention of malaria:
- if your child vomits within 1 hour of taking Malarone Children, give him another dose immediately
- it is important to follow the complete cycle with Malarone Kids. If your child has to take additional tablets due to vomiting, he or she may need another prescription.
- if your baby has been vomiting, it is especially important to use additional means of protection, such as repellents and mosquito nets. Due to the small amount absorbed, Malarone Children may not be fully effective.
For the treatment of malaria:
- if your child vomits and has diarrhea, please tell your doctor. Your baby will need to have regular blood tests. Malarone Children may not be fully effective due to the small amount absorbed. The tests will check if the malaria parasite has been cleared from your blood.
To prevent malaria
The recommended dose to prevent malaria depends on the weight of your child.
11-20 kg - 1 tablet once a day
21-30 kg - 2 tablets once daily (as a single dose)
31-40 kg - 3 tablets once daily (as a single dose)
To prevent malaria in adults:
- start taking Malarone Children 1 or 2 days before traveling to a malarial area
- continue to take Malarone Children every day throughout your stay
- continue to take Malarone Children for another 7 days after returning to a malaria-free area.
For maximum protection, your child must undergo the treatment in full.
For the treatment of malaria
The recommended dose for the treatment of malaria depends on the weight of your child.
5-8 kg - 2 tablets once a day for 3 days
9-10 kg - 3 tablets once a day for 3 days
Overdose What to do if you have taken too much Malarone Children
If your child takes more Malarone Children than they should
Ask your doctor or pharmacist for advice. If possible, show him the pack of Malarone Kids.
If you forget to take Malarone Children
It is very important that your child fully follows the treatment with Malarone Kids. If you forget to give your baby 1 dose, don't worry. Give him the next dose as soon as you remember. Then continue the treatment as before.
Do not take an additional dose to make up for a forgotten dose. Take the next dose at the usual time.
Do not stop treatment with Malarone Children without your doctor's advice
Continue to take Malarone Children for 7 days after returning to a malaria-free area.
Follow the entire treatment with Malarone for maximum protection. Stopping it earlier exposes your baby to the risk of contracting malaria, as it takes 7 days to be sure that any parasites present in the blood following an infected mosquito bite have been killed.
If you have any further questions on the use of this medicine, ask your doctor or pharmacist.
Side Effects What are the side effects of Malarone Children
Like all medicines, this medicine can cause side effects, although not everybody gets them.
Look out for the following serious reactions. These have occurred in a small number of people, but their exact frequency is unknown.
Severe allergic reactions - symptoms include:
- rash and itching
- sudden wheezing, tightness of the chest or throat or difficulty in breathing
- swelling of the eyelids, face, lips, tongue or other parts of the body
Contact a doctor immediately if your baby has any of these symptoms. Stop giving Malarone Kids immediately.
Severe skin reactions
- rash, which may have blisters and appear as small targets (dark central spots, surrounded by a lighter colored area with a dark ring around the edge) (erythema multiforme)
- severe widespread rash with blisters and peeling of the skin, particularly occurring around the mouth, nose, eyes and genitals (Stevens-Johnson syndrome)
If you notice any of these effects contact a doctor urgently.
Many of the other reported side effects were mild and of short duration:
Very common side effects
These can occur in more than 1 in every 10 people:
- headache
- feeling sick and being sick (nausea and vomiting)
- stomach ache
- diarrhea.
Common side effects
These can occur in up to 1 in every 10 people:
- dizziness
- sleep disturbances (insomnia)
- strange dreams
- depression
- loss of appetite
- fever
- rash which may be itchy
- cough.
Common side effects that may show up in blood tests are:
- low number of red blood cells (anemia) which can cause tiredness, headache and shortness of breath
- reduced number of white blood cells (neutropenia) which can make you more susceptible to infections
- low levels of sodium in the blood (hyponatremia)
- an increase in liver enzymes.
Uncommon side effects
These can occur in up to 1 in every 100 people:
- anxiety
- an unusual awareness of abnormal heartbeats (palpitations)
- swelling and redness of the mouth
- hair loss
Uncommon side effects that may show up in blood tests:
- an increase in amylase (an enzyme produced by the pancreas)
Rare side effects
These can occur in up to 1 in every 1,000 people:
- seeing or hearing things that are not there (hallucinations)
Other side effects
Other side effects have occurred in a small number of people but their exact frequency remains unknown.
- inflammation of the liver (hepatitis)
- obstruction of the bile ducts (cholestasis)
- increased heart rate (tachycardia)
- inflammation of blood vessels (vasculitis) which may appear as raised red or purple spots on the skin, but which can also affect other parts of the body
- convulsions
- panic attacks, crying
- nightmares
- formation of ulcers in the mouth
- vesicles
- skin exfoliation
- increased sensitivity of the skin to sunlight
- severe mental health problem in which the person loses touch with reality and is unable to think and judge clearly
Other side effects that may show up in blood tests:
- Decrease in all types of blood cells (pancytopenia)
Reporting of side effects
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the Italian Medicines Agency, website: https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse By reporting side effects you can help provide more information about the safety of this medicine
Expiry and Retention
Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date which is stated on the carton.
Malarone Bambini does not require any particular storage conditions.
Do not throw any medicines via wastewater or household waste. Ask your pharmacist how to dispose of medicines you no longer use. This will help protect the environment..0
Composition and pharmaceutical form
What Malarone Children contains
The active ingredients are: 62.5 mg of atovaquone and 25 mg of proguanil hydrochloride in each tablet.
The excipients are:
tablet core: poloxamer 188, microcrystalline cellulose, hydroxypropylcellulose, povidone K30, sodium starch glycolate (type A), magnesium stearate
tablet coating: hypromellose, titanium dioxide (E171), red iron oxide (E172), macrogol 400 and polyethylene glycol 8000 (see section 2).
Tell your doctor before giving Malarone Children to your child if they are allergic to any of these ingredients.
What Malarone Children looks like and contents of the pack
Malarone Kids tablets are round, pink film-coated tablets. They are packaged in blisters containing 12 tablets.
Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.
01.0 NAME OF THE MEDICINAL PRODUCT
MALARONE CHILDREN 62.5 MG / 25 MG TABLETS COATED WITH FILM
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet of Malarone Children contains 62.5 mg of atovaquone and 25 mg of proguanil hydrochloride.
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM
Pink, round, biconvex, film-coated tablets debossed with "GX CG7" on one side.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
Malarone Bambini is a "fixed-dose combination of atovaquone and proguanil hydrochloride, with blood schizonticide activity and also with activity against liver schizonts. Plasmodium falciparum. It is indicated for:
Prophylaxis of malaria from P. falciparum in subjects weighing 11-40 kg.
Treatment of acute malaria, not complicated by P. falciparum in children weighing ≥5 kg e
For the treatment of uncomplicated acute malaria P. falciparum in subjects weighing 11-40 kg, reference should be made to the Summary of Product Characteristics of MALARONE.
Malarone can be effective against the P. falciparum resistant to one or more of the other antimalarial agents. Consequently, Malarone may be particularly suitable for prophylaxis and in the treatment of infections from P. falciparum in those areas where this species is known to be resistant to one or more of the other antimalarial agents and also for the treatment of patients who have been infected with P. falciparum in the same areas.
Official guidelines and local information on the prevalence of antimalarial drug resistance should be considered. Official guidelines generally include those published by the World Health Organization and guidelines from health authorities.
04.2 Posology and method of administration
Method of administration
The daily dose should be taken in a single daily dose with food or a milk-based drink (to ensure maximum absorption) at the same time each day.
If patients are unable to take food, Malarone Children should be administered, but the systemic exposure of atovaquone will be reduced. If vomiting occurs within one hour of administration, a second dose should be taken.
Malarone Children should preferably be swallowed whole. If difficulties are encountered in administering to young children, the tablets can be crushed and mixed with food or a milk-based drink just prior to administration.
Dosage
Dosage for prophylaxis and treatment of acute malaria, not complicated by P. falciparum in children it is based on their body weight.
Prophylaxis
Dosage in subjects weighing 11-40 kg
Daily dosage
The safety and efficacy of Malarone Bambini in the prophylaxis of malaria in children weighing less than 11 kg have not been evaluated.
Prophylaxis must:
• start 24 or 48 hours before entering an "area where malaria is endemic,
• continue during the period of stay,
• continue for 7 days after leaving the area.
In residents in endemic areas (semi-immune subjects), the safety and efficacy of Malarone Children have been demonstrated in studies of up to 12 weeks duration (see section 5.1).
In non-immune subjects, the mean duration of exposure in clinical trials was 27 days.
Treatment
Dosage in subjects weighing 5-
Daily dosage
The safety and efficacy of Malarone Bambini for the treatment of malaria in children weighing less than 5 kg have not been evaluated.
For individuals weighing 11 kg or more, the first choice for the treatment of acute malaria, not complicated by P. falciparum is Malarone tablets (250/100 mg). Please see the Summary of Product Characteristics of Malarone tablets for the recommended dosage for this weight range. Malarone tablets have a dosage four times higher than that of Malarone Children.
Malarone Children can be used in cases where Malarone tablets are not available.
Dosage in patients with impaired liver function
There are no studies in children with impaired liver function. However, a pharmacokinetic study conducted in adults indicates that no dosage adjustment is required 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 adjustments are expected (see section 5.2).
Dosage in patients with impaired renal function
There are no studies in children with impaired kidney function. However, pharmacokinetic studies in adults indicate that no dosage adjustment is required in patients with mild to moderate renal impairment. Due to the lack of information on the appropriateness of dosage, Malarone is contraindicated in the prophylaxis of malaria in adults and children with severe renal insufficiency (creatinine clearance
04.3 Contraindications
Hypersensitivity to the active substances or to any of the excipients listed in section 6.1.
Malarone Children is contraindicated in the prophylaxis of malaria from P. falciparum in patients with severe renal impairment (creatinine clearance
04.4 Special warnings and appropriate precautions for use
If people taking Malarone Children for malaria prophylaxis or treatment vomit within one hour of administration, they should take a second dose. In case of diarrhea, normal administration should be continued. Absorption of atovaquone may be reduced. in patients with diarrhea or vomiting, but these conditions have not been associated with reduced efficacy in clinical trials of Malarone for malaria prophylaxis. However, as with other antimalarial agents, individuals with diarrhea or vomiting should be advised to continue with malaria prevention measures by respecting personal protective measures (insecticides, mosquito nets).
In patients with acute malaria who experience diarrhea 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 malaria with complications, including hyperparasitaemia, pulmonary edema, or renal failure.
Occasionally serious allergic reactions (including anaphylaxis) have been reported in patients taking Malarone. If patients experience an allergic reaction (see section 4.8) the intake of Malarone should be stopped immediately and appropriate treatment initiated.
Malarone has been shown to be ineffective against Plasmodium vivax hypnozoites as relapses commonly occur when malaria causes P. vivax she was treated with Malarone alone. Travelers who are intensely exposed to the P. vivax or al P. ovale and those who develop malaria caused by both parasites will require additional treatment with a drug that is active against hypnozoites.
In the case of infections caused by the P. falciparum who flare up after treatment with Malarone or in the event of failure of chemoprophylaxis after treatment with Malarone Children, patients should be treated with a different blood schizonticidal agent as these events may reflect parasite resistance.
Parasitaemia should be carefully monitored in patients receiving concomitant treatment with tetracycline (see section 4.5).
Concomitant administration of Malarone and efavirenz or boosted protease inhibitors should be avoided whenever possible (see section 4.5).
Concomitant administration of Malarone and rifampicin or rifabutin is not recommended (see section 4.5).
Concomitant use of metoclopramide is not recommended. Other antiemetic treatment should be given (see section 4.5).
Caution is advised when initiating or discontinuing malaria prophylaxis or treatment with Malarone in patients on continuous treatment with warfarin or other coumarin-based anticoagulants (see section 4.5).
Atovaquone may increase the levels of etoposide and its metabolite (see section 4.5).
In patients with severe renal impairment (creatinine clearance P. falciparum in the acute phase (see sections 4.2, 4.3 and 5.2).
The efficacy and safety of Malarone Children have not been established for the prophylaxis of malaria in children who have a body weight of less than 11 kg and for the treatment of malaria in children who have a body weight of less than 5 kg.
Malarone Children is not indicated in the treatment of acute uncomplicated malaria P. falciparum in subjects with a body weight of 11-40 kg. Malarone tablets (atovaquone 250mg / proguanil hydrochloride 100mg tablets) should be used in these individuals (see section 4.2).
04.5 Interactions with other medicinal products and other forms of interaction
Concomitant administration of rifampicin or rifabutin is not recommended as they are known to reduce plasma concentrations of atovaquone levels by 50% and 34%, respectively (see section 4.4).
Concomitant treatment with metoclopramide was associated with a significant decrease (approximately 50%) in the plasma concentrations of atovaquone (see section 4.4). Another antiemetic treatment should be given.
Although some children received Malarone and metoclopramide concurrently, and although clinical studies did not show a decrease in protection against malaria, the possibility of a clinically significant drug interaction cannot be excluded.
Concentrations of atovaquone, when administered with efavirenz or boosted protease inhibitors, have been observed to decrease by up to 75%. This combination should be avoided whenever possible (see section 4.4).
Proguanil may potentiate the effect of warfarin and other coumarin anticoagulants, resulting in an increased risk of bleeding.
The mechanism of this potential drug interaction has not been established. Caution is advised when initiating or discontinuing malaria prophylaxis or treatment with atovaquone-proguanil in patients on continuous treatment with oral anticoagulants. It may be necessary to adjust the dose of the oral anticoagulant during treatment with Malarone or after its discontinuation, based on the results of the prothrombin time (INR = International Normalized Ratio).
Concomitant treatment with tetracycline has been associated with a reduction in plasma concentrations of atovaquone.
Co-administration of atovaquone at doses of 45mg / kg / day in children (n = 9) with acute lymphoblastic leukemia for PCP prophylaxis has been shown to increase the plasma concentrations (AUC) of etoposide and its metabolite catechol etoposide. a median of 8.6% (P = 0.055) and 28.4% (P = 0.031) (compared with the co-administration of etoposide and sulfamethoxazole-trimethoprim, respectively).
Caution should be exercised in patients receiving concomitant therapy with etoposide (See section 4.4).
Proguanil is mainly 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).
04.6 Pregnancy and lactation
Pregnancy
The safety of atovaquone and proguanil hydrochloride administered concurrently during human pregnancy has not been established and therefore the potential risk is unknown.
Studies in animals have shown no evidence of teratogenicity of the combination. The individual components showed no effect on parturition or pre- and postnatal development. Maternal toxicity was found in pregnant rabbits during a teratogenic study (see section 5.3).
The use of Malarone pregnant children should only be considered if the expected benefit to the mother outweighs any potential risk to the fetus.
Proguanil works by inhibiting the parasite's dihydrofolate reductase. There are no clinical data indicative that a "folate supplementation determines the decrease in the efficacy of the drug." For women of childbearing potential who are taking folate supplements to prevent neural tube defects in unborn babies, these supplements should be continued while taking Malarone Children.
Breastfeeding
In a study in rats, atovaquone concentrations in milk were 30% of the corresponding maternal plasma concentrations. It is not known whether atovaquone is excreted in human breast milk.
Proguanil is excreted in human breast milk in small quantities.
Malarone Children should not be taken by women who are breastfeeding.
04.7 Effects on ability to drive and use machines
Dizziness has been reported. Patients should be advised that if they experience dizziness they should not drive vehicles, operate machinery or perform activities that may put themselves or others at risk.
04.8 Undesirable effects
In clinical trials conducted with Malarone Children for malaria prophylaxis, 357 children or adolescents weighing between 11 and 40 kg were treated with Malarone Children. Most of these subjects were resident in endemic areas and took Malarone Babies for approximately 12 weeks. The remainder were travelers to endemic areas, and mostly took Malarone Babies for 2-4 weeks.
Open-label clinical studies relating to the treatment of children with a body weight between 5 and 11 kg have shown that the safety profile is similar to that observed in children with a body weight between 11 and 40 kg and in adults.
There are limited long-term safety data in children. In particular, the long-term effects of Malarone on growth, puberty and development in general have not been studied.
In clinical trials of Malarone for the treatment of malaria, the most commonly reported adverse reactions were abdominal pain, headache, anorexia, nausea, vomiting, diarrhea and cough.
In clinical trials of Malarone for malaria prophylaxis, the most commonly reported adverse reactions were headache, abdominal pain and diarrhea.
The following table provides a summary of adverse reactions that have been reported to have a suspected (or at least possible) causal relationship with treatment with atovaquone proguanil in clinical trials and post-marketing spontaneous reports. The following convention is used for frequency classification: very common (≥1 / 10); common (≥1 / 100,
1 Frequency derived from the Summary of Product Characteristics of atovaquone. Patients participating in clinical trials with atovaquone received higher doses and were often already experiencing complications of advanced human immune deficiency disease (HIV). These events may have been observed with low frequency or may not have been detected in clinical studies with atovaquone-proguanil.
2 Observed in post-marketing spontaneous reports, the frequency of which is therefore unknown
3 Observed with proguanil
Reporting of suspected adverse reactions
The reporting of suspected adverse reactions that occur after the authorization of the medicinal product is important, as it allows continuous monitoring of the benefit / risk ratio of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Italian Medicines Agency. , website: https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse
By reporting side effects you can help provide more information on the safety of this medicine.
04.9 Overdose
There is insufficient experience to predict the consequences or suggest specific management in the event of an overdose of Malarone. However, in the reported cases of atovaquone overdose, the observed effects were consistent with the known undesirable effects of the drug. If overdose occurs, the patient should be monitored and standard supportive treatment given.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: antimalarials. ATC code: P01BB51.
Mechanism of action
The constituents of Malarone Bambini, atovaquone and proguanil hydrochloride, interfere with two different pathways involved in the biosynthesis of pyrimidines, necessary for the replication of nucleic acids. The mechanism of action of the atovaquone against the P. falciparum it is expressed through the inhibition of the transport of mitochondrial electrons at the level of the cytochrome bc1 complex and the reduction of the mitochondrial membrane potential. One mechanism of action of proguanil through its cycloguanyl metabolite is the inhibition of dihydrofolate reductase, which disrupts the synthesis of deoxithimidylate. Proguanil also has antimalarial activity independent of its metabolization into cycloguanil. Proguanil, but not cycloguanil, is able to enhance the ability of atovaquone to break down the mitochondrial membrane potential in malaria parasites. This latter mechanism could explain the antimalarial synergy observed when atovaquone and proguanil are used in combination.
Microbiology
The atovaquone exerts a powerful activity against Plasmodium spp(IC50 in vitro against the P. falciparum equal to 0.23-1.43 ng / mL).
Cross-resistance between atovaquone and other antimalarial agents belonging to different drug classes was not detected among more than 30 isolates of P. falciparum who have shown resistance in vitro chloroquine (41% of isolates), quinine (32% of isolates), mefloquine (29% of isolates) and halofantrine (48% of isolates).
The IC50 of the primary metabolite of proguanyl-cycloguanil against various strains of P. falciparum was found to be 4-20 ng / mL. Some activity of proguanil and another metabolite, 4-chlorophenylbiguanide, has been observed in vitro at doses between 600-3000 ng / mL.
The combination of atovaquone and proguanil has been shown to be synergistic against P. falciparum in vitro. The combination was found to be more effective in both immune and non-immune patients than the single active substances in clinical trials of malaria treatment.
Clinical efficacy
Prophylaxis
The efficacy of the product in non-immune pediatric travelers has not been directly established, although it can be extrapolated from the safety and efficacy results obtained from 12-week studies in the pediatric (semi-immune) population of endemic areas, and from safety and efficacy results for both semi-immune and non-immune adults.
Data in the pediatric population are available from two studies that predominantly assessed the safety of Malarone Infant tablets in (non-immune) travelers to endemic areas. In these studies, a total of 93 bodyweight travelers
Treatment
An "open label" parallel group randomized clinical trial was conducted in Gabon in 200 children with a body weight> 5 kg and P. falciparum. The treatment was carried out with Malarone Bambini or with amodiaquine suspension. In the intent-to-treat population, the treatment response rate at day 28 was 87% in the Malarone group (87/100 subjects). In the per-protocol population, the treatment response rate at day 28 it was 95% in the Malarone group (87/92 subjects). Response rates to parasitological treatment in the Malarone group were 88% for the intent-to-treat population and 95% for the per-protocol population.
05.2 Pharmacokinetic properties
There are no pharmacokinetic interactions between atovaquone and proguanil at recommended doses.
In clinical prophylaxis studies, where children received doses of Malarone based on body weight, trough levels of atovaquone, proguanil and cycloguanil in children are generally within the range of actual values observed in adults (see table below).
Trough plasma concentrations [Mean ± SD, (range)] of atovaquone, proguanil and cycloguanil during Malarone prophylaxis in children * and adults
* overall data derived from the two studies
Absorption
Atovaquone is a highly lipophilic compound with low water solubility.
Although there are no data on the bioavailability of atovaquone in healthy subjects, the absolute bioavailability of a single 750 mg dose of atovaquone tablets administered with food is 21% (90% CI, 17- 27%).
Dietary fats taken at the same time as atovaquone increase the rate and degree of absorption, increasing AUC by 2-3 times and Cmax by 5 times compared to the values observed in fasting. Patients are recommended to take Malarone Children tablets with food or milk-based drinks (see section 4.2).
Proguanil hydrochloride is rapidly and extensively absorbed, regardless of food intake.
Distribution
The apparent volume of distribution of atovaquone and proguanil is a function of body weight.
Atovaquone is highly protein bound (> 99%), but does not displace other high protein binding drugs in vitro, indicating that no significant drug interactions are to be expected following "displacement".
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 (> 5 kg) ranges from approximately 20 to 79 L / kg.
In human plasma the binding of atovaquone and proguanil was not mutually influenced.
Biotransformation
There is no evidence that atovaquone is metabolised and there is negligible excretion of atovaquone in the urine, being predominantly eliminated (> 90%) unchanged in the faeces.
Proguanil hydrochloride is partially metabolised primarily by the 2C19 isoenzyme of polymorphic cytochrome P450 with less than 40% excreted unchanged in the urine. Its metabolites cycloguanyl and 4-chlorophenylbiguanide are also excreted in the urine.
During administration of Malarone at recommended doses, the metabolic status of proguanil does not appear to have implications for the treatment or prophylaxis of malaria.
Elimination
The elimination half-life of atovaquone is approximately 1-2 days in the child.
The elimination half-life of proguanil and cycloguanil in children is approximately 12-15 hours.
Oral clearance of atovaquone and proguanil increases with weight gain and is approximately 70% higher in a 40 kg subject than in a 20 kg subject.
The mean oral clearance in patients weighing 5 to 40 kg ranges from 0.5 to 6.3 L / h for atovaquone and 8.7 to 64 L / h for proguanil.
Pharmacokinetics in renal insufficiency
There are no studies in children with impaired kidney function.
In adult patients with mild to moderate renal impairment, oral clearance and / or AUC data for atovaquone, proguanil and cycloguanil fall within the range of values observed in patients with normal renal function.
Atovaquone Cmax and AUC are reduced by 64% and 54%, respectively, in adult patients with severe renal impairment (creatinine clearance 2).
In adult patients with severe renal insufficiency, the elimination half-life for proguanil (t½ 39 hours) and the elimination half-life for cycloguanil (t½ 37 hours) are prolonged; there is a potential risk of drug accumulation upon repeated administration (see sections 4.2 and 4.4).
Pharmacokinetics in hepatic insufficiency
There are no studies in children with impaired liver function.
In adult patients with mild to moderate hepatic impairment, there is no clinically significant change in atovaquone exposure compared to healthy subjects.
In adult patients with mild to moderate hepatic impairment there is an 85% increase in the AUC of proguanil, with no change in the elimination half-life, and there is a 65-68% decrease in Cmax and AUC of proguanil. cycloguanil.
No data are available in adult patients with severe hepatic impairment (see section 4.2).
05.3 Preclinical safety data
Repeated dose toxicity:
Observations in repeat dose toxicity studies with the combination atovaquone / proguanil hydrochloride were found to be fully traceable to proguanil and were observed at dosages that did not provide any significant exposure margin compared to the expected clinical exposure. However, as proguanil has been used extensively and safely in the treatment and prophylaxis of malaria at similar dosages to those used in the combination, these observations are considered of little relevance in clinical practice.
Reproductive toxicity studies:
There was no evidence of combination-related teratogenicity in rats and rabbits. No data are available regarding the effects of the combination on fertility or pre- and postnatal development, but studies on the individual components of Malarone Children are not available. showed no effect on these parameters. In a rabbit teratogenic study using the combination, unexplained maternal toxicity was found at systemic exposure similar to that observed in humans in clinical use.
Mutagenesis:
A wide range of mutagenicity tests have shown that there is no evidence of the mutagenic activity of atovaquone or proguanil, taken individually.
Mutagenicity studies have not been conducted with atovaquone in combination with proguanil.
Cycloguanil, the active metabolite of proguanil, produced a negative Ames test, but was positive in the mouse lymphoma test and the mouse micronucleus test.
Positive test results with cycloguanyl (a dihydrofolate antagonist) were significantly reduced or completely abolished with folic acid supplementation.
Carcinogenesis:
In mice, oncogenesis studies of atovaquone alone showed an increased incidence of hepatocellular adenomas and carcinomas. In rats no similar findings were found and mutagenicity tests were negative. These results appear to be determined by the intrinsic sensitivity of the mice to atovaquone and are considered of no relevance in the clinical setting.
Oncogenesis studies on proguanil alone did not demonstrate evidence of carcinogenicity in rats and mice.
Oncogenesis studies on proguanil in combination with atovaquone have not been undertaken.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Nucleus
Poloxamer 188; microcrystalline cellulose; low-substituted hydroxypropylcellulose; povidone K 30; sodium starch glycolate (Type A); magnesium stearate.
Coating
Hypromellose; titanium dioxide E171; red iron oxide E172; macrogol 400; polyethylene glycol 8000.
06.2 Incompatibility
Not relevant.
06.3 Period of validity
5 years.
06.4 Special precautions for storage
This medicinal product does not require any special storage conditions.
06.5 Nature of the immediate packaging and contents of the package
PVC / aluminum blister containing 12 tablets.
06.6 Instructions for use and handling
No special instructions.
Unused medicine and wastes derived from this medicine must be disposed of in accordance with local regulations.
07.0 MARKETING AUTHORIZATION HOLDER
GlaxoSmithKline S.p.A. - Via A. Fleming, 2 - Verona
08.0 MARKETING AUTHORIZATION NUMBER
12 tablets - AIC: 033299037
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
17 September 2007 - 18 September 2012
10.0 DATE OF REVISION OF THE TEXT
December 2013
