Active ingredients: Atovaquone, Proguanil (Proguanil hydrochloride)
Malarone 250 mg / 100 mg - Film-coated tablets
Indications Why is Malarone used? What is it for?
Malarone belongs to a group of medicines called antimalarials. It contains two active ingredients, atovaquone and proguanil hydrochloride.
What is Malarone for
Malarone is used in two cases:
- for the prevention of malaria
- for the treatment of malaria
See section 3, How to take Malarone.
Malaria is spread through the bite of an infected mosquito that transmits the malaria parasite (Plasmodium falciparum) into the bloodstream.
Malarone prevents malaria by killing this parasite. Malarone kills these parasites even in people already infected with malaria.
Protect yourself from the infection of 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, 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 doctor immediately if you have symptoms such as high fever, headache, chills and tiredness upon returning home.
Contraindications When Malarone should not be used
Do not take Malarone:
- if you are allergic to atovaquone, proguanil hydrochloride or any of the other ingredients of this medicine (listed in section 6)
- for the prevention of malaria, if you have severe kidney disease.
Tell your doctor if either case applies to you.
Precautions for use What you need to know before taking Malarone
Talk to your doctor or pharmacist before taking Malarone if:
- you have severe kidney disease
- your baby is being treated for Malaria and weighs less than 11 kg. There is another tablet strength to treat children who weigh less than 11 kg (see section 3).
Tell your doctor or pharmacist if any of the cases apply to you.
Interactions Which drugs or foods can modify the effect of Malarone
Other medicines and Malarone
Tell your doctor or pharmacist if you are taking, have recently taken, or might take any other medicines, even those obtained without a prescription.
Some medicines can affect the way Malarone works, or Malarone 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 you are taking any of these medicines. Your doctor may decide that Malarone is not suitable for you, or that you need to undergo further tests while taking Malarone.
Remember to tell your doctor if you start taking other medicines at the same time as Malarone
Malarone with food and drink
Take Malarone with food or a milk-based drink, if possible. This way your body will absorb more Malarone and the treatment will be more effective.
Warnings It is important to know that:
Pregnancy and breastfeeding
If you are pregnant, do not take Malarone unless your doctor recommends it.
Ask your doctor or pharmacist for advice before taking Malarone.
Do not breast-feed while taking Malarone as the components of Malarone can pass into breast milk and harm the baby.
Driving and using machines
If you feel dizzy, don't drive vehicles
Malarone 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: Posology
Always take this medicine exactly as your doctor or pharmacist has told you. If in doubt, consult your doctor or pharmacist.
Take Malarone with food or a milk-based drink, if possible.
It is best to take Malarone at the same time each day.
If you vomit
For the prevention of malaria:
- if you vomit within 1 hour of taking Malarone, take another dose immediately
- it is important to fully follow the cure with Malarone. If you need to take additional tablets due to vomiting, you may need another prescription.
- if you have been vomiting, it is especially important that you use additional means of protection, such as repellents and mosquito nets. Due to the small amount absorbed, Malarone may not be fully effective.
For the treatment of malaria:
- if you vomit and have diarrhea, please tell your doctor, you will need to have regular blood tests. Malarone will not be fully effective due to the reduced amount absorbed. The tests will check if the malaria parasite has been cleared from your blood.
To prevent malaria
The recommended dose in adults is 1 tablet once a day, taken as follows.
Not recommended for the prevention of malaria in children, or adults weighing less than 40 kg. Malarone Children tablets are recommended for the prevention of malaria in adults or children weighing less than 40 kg.
To prevent malaria in adults:
- start taking Malarone 1 or 2 days before you leave for a malarial area
- continue to take Malarone every day throughout your stay
- continue to take Malarone for another 7 days after returning to a malaria-free area.
For the treatment of malaria
The recommended dose in adults is 4 tablets once a day for 3 days.
For children, the dose depends on body weight:
- 11-20 kg - 1 tablet once a day for 3 days
- 21-30 kg - 2 tablets once a day for 3 days
- 31-40 kg - 3 tablets once a day for 3 days
- over 40 kg - see dosage for adults.
Not recommended for the treatment of malaria in children weighing less than 11 kg.
For children weighing less than 11 kg, talk to your doctor. A different formulation of Malarone tablets may be available in your country.
Overdose What to do if you have taken too much Malarone
If you take more Malarone than you should
Ask your doctor or pharmacist for advice. If possible, show him the pack of Malarone.
If you forget to take Malarone
It is very important to fully follow the cure with Malarone.
If you forget to take 1 dose, don't worry. Take 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 taking Malarone without advice
Continue to take Malarone for 7 days after returning to a malaria-free area. Follow the entire treatment with Malarone for maximum protection. Stopping her earlier exposes her to the risk of contracting malaria, as it takes 7 days to be sure that any parasites present in her 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
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 you get any of these symptoms. Stop taking Malarone 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 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 contains
The active ingredients are: 250 mg of atovaquone and 100 mg of proguanil hydrochloride in each tablet.
The excipients are:
tablet core: poloxamer 188, microcrystalline cellulose, hydroxypropyl cellulose, povidone K30, sodium carboxymethyl starch (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 without taking Malarone if you are allergic to any of these components.
Description of what Malarone looks like and contents of the pack
Malarone tablets are round, pink film coated, engraved with "GX CM3" on one side. 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 250 MG + 100 MG TABLETS COATED WITH FILM
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each Malarone tablet contains 250 mg of atovaquone and 100 mg of proguanil hydrochloride.
For the full list of excipients see section 6.1
03.0 PHARMACEUTICAL FORM
Film-coated tablets.
Round, biconvex, pink colored tablets, debossed with "GX CM3" on one side.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
Malarone is a "fixed dose combination of atovaquone and proguanil hydrochloride, with blood schizonticidal activity and with activity against liver schizonts of Plasmodium falciparum. It is indicated for:
Prophylaxis of malaria from Plasmodium falciparum.
Acute-phase treatment of uncomplicated malaria Plasmodium falciparum.
Since Malarone is effective against the P. falciparum both drug-sensitive and drug-resistant, it is particularly recommended for the prophylaxis and treatment of malaria P. falciparum where this pathogen may be resistant to other antimalarial drugs.
Official guidelines and local information on the prevalence of antimalarial drug resistance should be considered. Official guidelines will generally include those of 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 with food or a milk-based drink (to ensure maximum absorption) at the same time each day.
If patients are unable to tolerate food, Malarone 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.
Dosage
Prophylaxis
Prophylaxis must:
• start 24 or 48 hours before coming into contact with the malaria endemic area,
• 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 have been demonstrated in studies of up to 12 weeks.
In non-immune subjects, the mean duration of exposure in clinical trials was 27 days.
Dosage in adults
One Malarone tablet once a day.
Malarone tablets are not recommended for malaria prophylaxis in people with a body weight of less than 40 kg.
Treatment
Dosage in adults
Four Malarone tablets in a single administration for three consecutive days.
Dosage in children
Dosage in the elderly
A pharmacokinetic study indicates that no dosage adjustment is required in the elderly (see section 5.2).
Dosage in patients with impaired liver function
A pharmacokinetic study 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 dose adjustments can be anticipated (see section 5.2).
Dosage in patients with impaired renal function
Pharmacokinetic studies indicate that no dosage adjustment is required in patients with mild to moderate renal impairment. In patients with severe renal impairment (creatinine clearance P. falciparum in the acute phase (see sections 4.4 and 5.2). P. falciparum in patients with severe renal impairment see section 4.3.
04.3 Contraindications
Hypersensitivity to the active substances or to any of the excipients.
Malarone 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 for prophylaxis or treatment of malaria vomit within one "hour of administration, they should take a second dose. In case of diarrhea, normal administration should be continued. The 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 through compliance with 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 patients who flare up after Malarone treatment or in the event of failure of chemoprophylaxis after Malarone treatment, 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 (atovaquone 250 mg / proguanil hydrochloride 100 mg tablets) have not been established in the prophylaxis of malaria in patients weighing less than 40 kg, or in the treatment of malaria in pediatric patients weighing less than 11kg.
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.
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 45 mg / kg / day in children (n = 9) with acute lymphoblastic leukemia for PCP prophylaxis has been shown to increase 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
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 shown in pregnant rabbits during a teratogenic 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 fetus.
The proguanil component of Malarone works by inhibiting the parasite's dihydrofolate reductase. There are no clinical data suggesting that folate supplementation decreases drug efficacy. For women of childbearing age who are taking folate supplements to prevent neural tube defects in unborn babies, these supplements should be continued while taking Malarone.
Feeding time
Atovaquone milk concentrations in a rat study were 30% of the concomitant maternal plasma atovaquone concentrations. It is not known whether atovaquone is excreted in human breast milk.
Proguanil is excreted in human breast milk in modest quantities.
Malarone 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, operate machinery or perform any activities that may put themselves or others at risk.
04.8 Undesirable effects
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,
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.
1 Frequency derived from the Summary of Product Characteristics of the atovaquone.Patients participating in clinical trials with atovaquone received higher doses and often already experienced complications of advanced human immune deficiency disease (HIV). These events may have been observed at low frequency or not detected in clinical trials with atovaquone. proguanile.
2 Observed in post-marketing spontaneous reports, the frequency of which is therefore unknown
3 Observed with proguanil
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, atovaquone and proguanil hydrochloride, interfere with two different pathways involved in the biosynthesis of pyrimidines, which are necessary for the replication of nucleic acids.
The mechanism of action of the atovaquone against the P. falciparum is expressed through the inhibition of the transport of mitochondrial electrons at the level of the cytochrome bc1 complex and the fall of the potential of the mitochondrial membrane. A mechanism of action of proguanil through its cycloguanil metabolite is the inhibition of dihydrofolate reductase, which interrupts the synthesis of deoxithymidylate. Proguanil also has an antimalarial activity independent of its metabolization into cycloguanil, and proguanil, but not cycloguanil, is able to enhance the ability of atovaquone to break down the potential of the mitochondrial membrane in malaria parasites. This latter mechanism may explain the 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).
Atovaquone does not show cross-resistance to other antimalarial drugs in current use. Among more than 30 isolates of P. falciparum resistance was discovered in vitro to chloroquine (41% of isolates), quinine (32% of isolates), mefloquine (29% of isolates) and halofantrine (48% of isolates) but not to atovaquone (0% of isolates).
The antimalarial activity of proguanil is exerted through the primary metabolite cycloguanil (IC50 in vitro against various strains of P. falciparum equal to 4-20 ng / mL; in vitro at concentrations of 600-3000 ng / mL there is some activity of proguanil and another metabolite, 4-chlorophenylbiguanide).
In the studies in vitro on the P. falciparum, the combination of atovaquone and proguanil has been shown to be synergistic. This increased efficacy has also been demonstrated in clinical trials in both immune and non-immune patients.
05.2 Pharmacokinetic properties
There are no pharmacokinetic interactions between atovaquone and proguanil at recommended doses.
In clinical studies, trough levels of atovaquone, proguanil and cycloguanil in children are generally within the range of actual values observed in adults after dose adjustment based on body weight.
Absorption
Atovaquone is a highly lipophilic compound with low water solubility. In HIV-infected patients, the absolute bioavailability of a single 750 mg dose of atovaquone tablets administered with food is 23% with an inter-subject variability of approximately 45%.
Dietary fats taken with 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 the fasted state. Patients are recommended to take Malarone 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 in vitro the other drugs with a high protein binding value: this indicates that no significant drug interactions are foreseeable following the "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 is approximately 20 to 42 L / kg.
In human plasma the binding of atovaquone and proguanil was not mutually influenced.
Metabolism
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 2-3 days in adults and 1-2 days in children.
The elimination half-life of proguanil and cycloguanil is approximately 12-15 hours in both adults and children.
The oral clearance of atovaquone and proguanil increases with weight gain and is approximately 70% higher in a subject weighing 80 kg than in a subject weighing 40 kg. The mean oral clearance in children and adults weighing including between 10 and 80 kg it varies 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 mean rate or extent of absorption of atovaquone or proguanil between elderly and young patients. Systemic availability of cycloguanil is higher in elderly patients than in young patients (AUC is increased by 140% and Cmax increased by "80%), but there is no clinically significant change in the elimination half-life (see section 4.2).
Pharmacokinetics in patients with impaired renal function
In patients with mild to moderate renal impairment, clearance after oral administration 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 patients with severe renal impairment.
In patients with severe renal impairment, the elimination half-life for proguanil (t1 / 2 39 hours) and cycloguanil (t1 / 2 37 hours) is prolonged resulting in potential drug accumulation with repeated dosing (see sections 4.2 and 4.4). .
Pharmacokinetics in patients with impaired hepatic function
In patients with mild to moderate hepatic impairment, there is no clinically significant change in atovaquone exposure when compared to healthy patients.
In 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 the Cmax and AUC of cycloguanil.
There are no data available in 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 atovaquone-proguanil hydrochloride combination were entirely traceable to proguanil and were observed at dosages that did not provide any significant exposure margin compared to the expected clinical exposure. 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
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 postnatal development, but studies on the individual components of Malarone have not shown 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.
Mutagenicity
A wide range of mutagenicity tests have shown that atovaquone and proguanil do not individually exhibit mutagenic activity.
Mutagenicity tests have not been conducted with atovaquone in combination with proguanil.
Cycloguanil, the active metabolite of proguanil, also produced a negative Ames test, but was positive in the mouse lymphoma test and the mouse micronucleus test.
These positive effects with cycloguanil (a dihydrofolate antagonist) were significantly reduced or completely abolished with folic acid supplementation.
Carcinogenicity
In mice, oncogenesis studies of atovaquone alone showed an increased incidence of hepatocellular adenomas and carcinomas. No similar findings were found in rats and mutagenicity tests were negative. These results appear to be due to the intrinsic sensitivity of the mice to atovaquone and are considered of no relevance in the clinical setting.
Oncogenicity 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-substitution hydroxypropylcellulose
Povidone K 30
Sodium carboxymethyl starch (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
07.0 MARKETING AUTHORIZATION HOLDER
GlaxoSmithKline S.p.A., Via A. Fleming, 2 - Verona
08.0 MARKETING AUTHORIZATION NUMBER
AIC n. 033299013 / M - 12 tablets
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
08/07/1997 - 02/03/2012
10.0 DATE OF REVISION OF THE TEXT
November 14, 2012
