Atovaquone/Proguanil Hydrochloride 250mg/100mg Film-Coated Tablets
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Atovaquone/Proguanil Hydrochloride 250 mg/100 mg film-coated tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each Atovaquone/Proguanil Hydrochloride 250 mg/100 mg film-coated tablet contains 250 mg atovaquone and 100 mg proguanil hydrochloride.
For a full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Film-coated tablet.
Pinkish brown to brown coloured, circular, biconvex beveled edge film-coated tablets with’404’ debossed on one side and ‘G’ debossed on the other side.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
It is indicated for:
• Prophylaxis of Plasmodium falciparum malaria in adults and in children weighing more than 40 kg.
• Treatment of acute, uncomplicated Plasmodium falciparum malaria in adults and in children weighing 11 kg or more. .
Atovaquone/Proguanil Hydrochloride 250 mg/100 mg film-coated tablets are especially recommended for prophylaxis and treatment of Plasmodium falciparum malaria where the pathogen may be resistant to other antimalarials.
Official guidelines and local information on the prevalence of resistance to antimalarial drugs should be taken into consideration. Official guidelines will normally include World Health Organisation (WHO)and public health authorities' guidelines.
4.2 Posology and method of administration Method of administration
The daily dose should be taken with food or a milky drink (to ensure maximum absorption of atovaquone) at the same time each day.
The tablets should preferably not be crushed.
If patients are unable to tolerate food, Atovaquone/Proguanil Hydrochloride 250 mg/100 mg film-coated 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.
Posology
Prophylaxis:
Prophylaxis should:
• commence 24 hours prior to entering a malaria-endemic area or on the day of arrival,
• continue during the period of the stay,
• continue for 7 days after leaving the area.
Dosage in adults and adolescents more than 40 kg bodyweight:
One Atovaquone/Proguanil Hydrochloride 250 mg/100 mg film-coated tablet daily.
Atovaquone/Proguanil Hydrochloride 250 mg/100 mg film-coated tablets are not recommended for malaria prophylaxis in persons under 40 kg bodyweight.
Treatment:
Dosage in adults
Four Atovaquone/Proguanil Hydrochloride 250 mg/100 mg film-coated tablets as a single dose for three consecutive days.
Dosage in Children weighing 11 kg or more
>11 to <20 kg bodyweight. One tablet daily for three consecutive days.
>20 to <30 kg bodyweight. Two tablets as a single dose for three consecutive days. >30 to <40 kg bodyweight. Three tablets as a single does for three consecutive days. >40 kg bodyweight. Dose as for adults.
Dosage in the elderly
A pharmacokinetic study indicates that no dosage adjustments are needed in the elderly (See Section 5.2).
Dosage in hepatic impairment
A pharmacokinetic study 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
Pharmacokinetic studies indicate that no dosage adjustments are needed in patients with mild to moderate renal impairment. In patients with severe renal impairment (creatine clearance <30 mL/min) alternatives to Atovaquone/Proguanil Hydrochloride 250 mg/100 mg film-coated tablets for treatment of acute Plasmodium falciparum malaria should be recommended whenever possible (See Sections 4.4 and 5.2). For prophylaxis of Plasmodium falciparum malaria in patients with several renal impairments see Section 4.3
4.3
Contraindications
Hypersensitivity to the active substances or to any of the excipients.
Atovaquone/Proguanil Hydrochloride 250 mg/100 mg film-coated tablets is contraindicated for prophylaxis of Plasmodium falciparum malaria in patients with severe renal impairment (creatine clearance <30 mL/min)
4.4 Special warnings and precautions for use
Atovaquone/Proguanil Hydrochloride 250 mg/100 mg film-coated tablets (atovaquone 250 mg/proguanil hydrochloride 100 mg tablets) are not appropriate for prophylaxis of malaria in patients who weigh less than 40kg.
Persons taking Atovaquone/Proguanil Hydrochloride 250 mg/100 mg film-coated tablets for prophylaxis or treatment of malaria should take a repeat dose if they vomit within 1 hour of dosing. In the event of diarrhoea, normal dosing should be continued. Absorption of atovaquone may be reduced in patients with diarrhoea or vomiting, but in patients who did not withdraw, diarrhoea or vomiting was not associated with reduced efficacy in clinical trials of Atovaquone/Proguanil Hydrochloride 250 mg/100 mg film-coated tablets for malaria prophylaxis. However, as with other antimalarial agents, all subjects including those with diarrhoea or vomiting should be advised to continue to comply with personal protection measures (repellants, impregnated bednets).
In patients with acute malaria who present with diarrhoea or vomiting, alternative therapy should be considered. If Atovaquone/Proguanil Hydrochloride 250 mg/100 mg film-coated tablets are used to treat malaria in these patients, parasitaemia should be closely monitored.
Atovaquone/Proguanil Hydrochloride 250 mg/100 mg film-coated tablets have 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 Atovaquonc/Proguanil Hydrochloride 250 mg/100 mg film-coated tablets. If patients experience an allergic reaction (see section 4.8) Atovaquone/Proguanil Hydrochloride 250 mg/100 mg film-coated tablets should be discontinued promptly and appropriate treatment initiated.
Parasite relapse occurred commonly when Plasmodium vivax malaria was treated with Atovaquone/Proguanil Hydrochloride 250 mg/100 mg film-coated tablets alone. Travellers with intense exposure to Plasmodium vivax or Plasmodium 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 Plasmodium falciparum after treatment with Atovaquone/Proguanil Hydrochloride 250 mg/100 mg film-coated tablets. or failure of a good adhesion to chemoprophylaxis with Atovaquone/Proguanil Hydrochloride 250 mg/100 mg film-coated tablets. patients should be treated with a different blood schizonticide.
Parasitaemia should be closely monitored in patients receiving concurrent metoclopramide or tetracycline (see section 4.5).
The concomitant administration of Atovaquone/Proguanil Hydrochloride 250 mg/100 mg film-coated tablets and rifampicin or rifabutin is not recommended (see section 4.5).
In patients with severe renal impairment (creatinine clearance <30 mL/min) alternatives to Atovaquone/Proguanil Hydrochloride 250 mg/100 mg film-coated tablets for treatment of acute Plasmodium falciparum malaria should be recommended whenever possible (see sections 4.2, 4.3 and 5.2)
4.5 Interaction with other medicinal products and other forms of interaction
Proguanil may potentiate the anticoagulant effect of warfarin and other coumarin based anticoagulants. 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 coumarin based anticoagulants.
Concomitant treatment with metoclopramide and tetracycline has been associated with significant decreases in plasma concentrations of atovaquone (see section 4.4).
Concomitant administration of rifampicin or rifabutin is known to reduce atovaquone levels by approximately 50% and 34%. respectively. (see section 4.4).
Concomitant administration of atovaquone and indinavir results in a decrease in the Cmin of indinavir (23% decrease; 90% CI 8-35%). Caution should be exercised when prescribing atovaquone with indinavir due to the decrease in the trough levels of indinavir.
4.6 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 Atovaquone/Proguanil Hydrochloride 250 mg/100 mg film-coated tablets in pregnancy should only be considered if the expected benefit to the mother outweighs any potential risk to the foetus.
The proguanil component of Atovaquone/Proguanil Hydrochloride 250 mg/100 mg film-coated tablets acts by inhibiting parasitic dihydrofolate reductase. There are no clinical data indicating that folate supplementation diminishes drug efficacy. For pregnant women or women who have the intention to get pregnant receiving folate supplements to prevent neural tube birth defects, such supplements should be continued while taking Atovaquone/Proguanil Hydrochloride 250 mg/100 mg film-coated tablets.
Lactation
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.
Atovaquone/Proguanil Hydrochloride 250 mg/100 mg film-coated tablets should not be taken by breast-feeding women.
4.7 Effects on ability to drive and use machines
No studies on the effects on the ability to drive and use machines have been performed.
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
The following table provides a summary of adverse reactions reported with Atovaquone/Proguanil Hydrochloride 250 mg/100 mg film-coated tablets, atovaquone or 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); not known (cannot be estimated from the available data).
In clinical trials of atovaquone-proguanil for treatment of malaria, the most commonly reported adverse events, independent of attributability, were abdominal pain, headache, anorexia, nausea, vomiting, diarrhoea and coughing, and were generally reported in a similar proportion of patients receiving atovaquone-proguanil or a comparator antimalarial drug.
In clinical trials of atovaquone-proguanil for prophylaxis of malaria, the most commonly reported adverse events, independent of attributability, were headache, abdominal pain and diarrhoea, and were reported in a similar proportion of subjects receiving atovaquone-proguanil or placebo.
|
System Organ Class |
Very Common (>1/10) |
Common (i 1/100 to <1/10) |
Uncommon (* 1/1,000 to <1/100) |
Unknown (cannot be estimated from the available data) |
|
Blood and lymphatic disorders |
Anaemia1 Neutropenia |
Pancytopenia in patients with severe renal 4 impairment | ||
|
Immune system disorders |
Allergic reactions |
Angioedema3 3 Anaphylaxis Vasculitis4 | ||
|
Metabolism and nutrition disorders |
2 Hyponatraemia Anorexia1 |
Elevated amylase levels2 | ||
|
Psychiatric disorders |
Abnormal dreams1 Depression1 |
Anxiety1 |
3 Panic attack Crying3 Hallucinations3 3 Nightmares | |
|
Nervous system disorders |
Headache1 |
Insomnia1 Dizziness1 |
Seizure3 | |
|
Cardiac disorders |
3 Palpatations |
Tachycardia3 | ||
|
Gastrointestinal disorders |
2 Nausea Vomiting1 Diarrhoea1 |
Stomatitis1 |
Gastric intolerance4 Oral ulceration4 |
|
Abdominal pain1 | ||||
|
Hepatobiliary disorders |
Elevated liver enzymes2,5 |
• • 3 Hepatitis Cholestasis4 | ||
|
Skin and subcutaneous tissue disorders |
Rash1 |
Hair loss1 Urticaria1 |
Stevens-Johnson syndrome3 Erythema multiforme3 Blister3 3 Skin exfoliation | |
|
General disorders and administration site conditions |
Fever1 | |||
|
Respiratory, thoracic and mediastinal disorders |
Cough1 |
1. Frequency calculated from Atovaquone/Proguanil Hydrochloride 250 mg/100 mg film-coated tablets clinical trials.
2. 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. Therefore, the causal relationship between the adverse experiences and atovaquone is difficult to evaluate. These events may have been seen at a lower frequency or not at all in clinical trials with atovaquone-proguanil.
3. Observed from post-marketing spontaneous reports. The frequency is unknown
4. Observed with proguanil. The frequency is unknown.
5. Clinical trial data for atovaquone-proguanil indicated that abnormalities in liver function tests were reversible and not associated with untoward clinical events.
4.9 Overdose
No case of overdose has been reported. In cases of suspected overdosage symptomatic and supportive therapy should be given as appropriate.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: ANTIMALARIALS, Biguanides, Proguanil, combinations ATC Code: P01BB51
Atovaquone/Proguanil 250 mg/100 mg film-coated tablets are a fixed dose combination of atovaquone and proguanil hydrochloride which acts as a blood schizonticide and also has activity against hepatic schizonts of Plasmodium falciparum.
Mode of Action
The constituents of Atovaquone/Proguanil Hydrochloride 250 mg/100 mg film-coated tablets, atovaquone and proguanil hydrochloride, interfere with two different pathways involved in the biosynthesis of pyrimidines required for nucleic acid replication. The mechanism of action of atovaquone against P. falciparum is via inhibition of mitochondrial electron transport, at the level of the cytochrome bci complex, and collapse of mitochondrial membrane potential. One mechanism of action of proguanil, via its metabolite cycloguanil, is inhibition of dihydrofolate reductase, which disrupts deoxythymidylate synthesis. Proguanil also has antimalarial activity independent of its metabolism to cycloguanil, and proguanil, but not cycloguanil, is able to potentiate the ability of atovaquone to collapse mitochondrial membrane potential in malaria parasites. This latter mechanism may explain the synergy seen when atovaquone and proguanil are used in combination.
Resistance
Cases of failures to respond to atovaquone-proguanil associated with resistance of P. falciparum strains have been published in the literature. The mechanism of resistance may include involvement of point mutations in the target gene of atovaquone, P. falciparum mitochondrial cytochrome b gene. However, the mechanism of resistance has not been elucidated entirely.
The prevalence of resistance may vary geographically and with time. Information on resistance can be obtained from official guidelines such as public health authorities’ and WHO guidelines.
5.2 Pharmacokinetic properties
There are no pharmacokinetic interactions between atovaquone and proguanil at the recommended dose. In clinical trials, where children have received
Atovaquone/Proguanil Hydrochloride 250 mg/100 mg film-coated tablets dosed by bodyweight, trough levels of atovaquone, proguanil and cycloguanil in children are generally within the range observed in adults.
Atovaquone is highly protein bound (>99%) but does not displace other highly protein bound drugs in vitro, indicating significant drug interactions arising from displacement are unlikely
Absorption
Atovaquone is a highly lipophilic compound with low aqueous solubility. In HIV-infected patients, the absolute bioavailability of a 750 mg single dose of atovaquone tablets taken with food is 23% with an inter-subject variability of about 45%.
Dietary fat taken with atovaquone increases the rate and extent of absorption, increasing AUC 2-3 times and Cmax 5 times over fasting. Patients are recommended to take Atovaquone/Proguanil Hydrochloride 250 mg/100 mg film-coated tablets with food, preferably a fatty meal or a milky drink (see section 4.2).
Proguanil hydrochloride is rapidly and extensively absorbed regardless of food intake.
Distribution
Apparent volume of distribution of atovaquone and proguanil is a function of bodyweight.
Atovaquone is highly protein bound (>99%) but does not displace other highly protein bound drugs in vitro, indicating that significant drug interactions arising from displacement are unlikely.
Following oral administration, the volume of distribution of atovaquone in adults and children is approximately 8.8 L/kg.
Proguanil is 75% protein bound. Following oral administration, the volume of distribution of proguanil in adults and children ranged from 20 to 42 L/kg.
In human plasma the binding of atovaquone and proguanil was unaffected by the presence of the other.
Metabolism
There is no evidence that atovaquone is metabolised and there is negligible excretion of atovaquone in urine with the parent drug being predominantly (>90%) eliminated unchanged in faeces.
Proguanil hydrochloride is partially metabolised, primarily by the polymorphic cytochrome P450 isoenzyme 2C19, with less than 40% being excreted unchanged in the urine. Its metabolites, cycloguanil and 4-chlorophenylbiguanide, are also excreted in the urine.
During administration of Atovaquone/Proguanil Hydrochloride 250 mg/100 mg film-coated tablets at recommended doses proguanil metabolism status appears to have no implications for treatment or prophylaxis of malaria.
Elimination
The elimination half life of atovaquone is about 2-3 days in adults and 1-2 days in children.
The elimination half lives of proguanil and cycloguanil are about 12-15 hours in both adults and children.
Oral clearance for atovaquone and proguanil increases with increased bodyweight and is about 70% higher in an 80 kg subject relative to a 40 kg subject. The mean oral clearance in paediatric and adult patients weighing 10 to 80 kg ranged from 0.8 to 10.8 L/h for atovaquone and from 15 to 106 L/h for proguanil.
Pharmacokinetics in the elderly
There is no clinically significant change in the average rate or extent of absorption of atovaquone or proguanil between elderly and young patients. Systemic availability of cycloguanil is higher in the elderly compared to the young patients (AUC is increased by 140% and Cmax is increased by 80%), but there is no clinically significant change in its elimination half life (see section 4.2).
Pharmacokinetics in renal impairment
In patients with mild to moderate renal impairment, oral clearance and/or AUC data for atovaquone, proguanil and cycloguanil are within the range of values observed in patients with normal renal function.
Atovaquone 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 lives for proguanil (t/2 39h) and cycloguanil (t/2 37 h) are prolonged, resulting in the potential for drug accumulation with repeated dosing (see sections 4.2 and 4.4).
Pharmacokinetics in hepatic impairment
In patients with mild to moderate hepatic impairment there is no clinically significant change in exposure to atovaquone when compared to healthy patients.
In patients with mild to moderate hepatic impairment there is an 85% increase in proguanil AUC with no change in elimination half life and there is a 6568% decrease in Cmax and AUC for cycloguanil.
No data are available in patients with severe hepatic impairment (see section 4.2).
5.3 Preclinical safety data
Repeat dose toxicity:
Findings in repeat dose toxicity studies with atovaquone-proguanil hydrochloride combination were entirely proguanil related and were observed at doses providing no significant margin of exposure in comparison with the expected clinical exposure. As proguanil has been used extensively and safely in the treatment and prophylaxis of malaria at doses similar to those used in the combination, these findings are considered of little relevance to the clinical situation.
Reproductive toxicity studies:
In rats and rabbits there was no evidence of teratogenicity for the combination. No data are available regarding the effects of the combination on fertility or pre- and post-natal development, but studies on the individual components of Atovaquone/Proguanil Hydrochloride 250 mg/100 mg film-coated tablets have shown no effects on these parameters. In a rabbit teratogenicity study using the combination, unexplained maternal toxicity was found at a systemic exposure similar to that observed in humans following clinical use.
Mutagenicity:
A wide range of mutagenicity tests have shown no evidence that atovaquone or proguanil have mutagenic activity as single agents.
Mutagenicity studies have not been performed with atovaquone in combination with proguanil.
Cycloguanil, the active metabolite of proguanil, was also negative in the Ames test, but was positive in the Mouse Lymphoma assay and the Mouse Micronucleus assay. These positive effects with cycloguanil (a dihydrofolate antagonist) were significantly reduced or abolished with folinic acid supplementation.
Carcinogencity:
Oncogenicity studies of atovaquone alone in mice showed an increased incidence of hepatocellular adenomas and carcinomas. No such findings were observed in rats and mutagenicity tests were negative. These findings appear to be due to the inherent susceptibility of mice to atovaquone and are considered of no relevance in the clinical situation.
Oncogenicity studies on proguanil alone showed no evidence of carcinogenicity in rats and mice.
Oncogenicity studies on proguanil in combination with atovaquone have not been performed.
6.1 List of excipients
Core
Poloxamer 188 Microcrystalline Cellulose Low-substituted Hydroxypropyl Cellulose Povidone K30
Sodium Starch Glycolate Type A
Silica colloidal anhydrous
Magnesium Stearate
Coating
Hypromellose
Titanium Dioxide E171
Iron Oxide Red E172
Macrogol 400
Macrogol 8000
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
36 months
6.4 Special precautions for storage
This medicinal product does not require any special storage conditions
6.5
Nature and contents of container
PVC/PVDC (clear) and hard tempered PVC/PVDC-Aluminium foil blisters containing 12 tablets
Pack size: 12, 24, 36, 60
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
7 MARKETING AUTHORISATION HOLDER
Glenmark Pharmaceuticals Europe Limited Laxmi House, 2B Draycott Avenue,
Kenton, Middlesex HA3 0BU,
United Kingdom
8 MARKETING AUTHORISATION NUMBER(S)
PL 25258/0064
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
25/11/2010
10 DATE OF REVISION OF THE TEXT
04/07/2014