Atovaquone/Proguanil Hydrochloride 250 mg/100 mg film-coated tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each Atovaquone/Proguanil Hydrochloride film-coated tablet contains 250 mg atovaquone and 100 mg proguanil hydrochloride.

Excipient with known effect:
Each film-coated tablet also contains 4.0183.82 mg of lactose monohydrate.

3. PHARMACEUTICAL FORM

Film-coated tablet (tablet)

Atovaquone/Proguanil Hydrochloride 250 mg/100 mg film-coated tablets are bBuff coloured, round, biconvex, film-coated tablets debossed with ‘A-P’ over ‘2’ on one side and ‘M’ on the other side.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Atovaquone/Proguanil Hydrochloride is 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. It is indicated for:

Prophylaxis of Plasmodium falciparum malaria.

Treatment of acute, uncomplicated Plasmodium falciparum malaria.

Because Atovaquone/Proguanil Hydrochloride is effective against drug sensitive and drug resistant P. falciparum it is especially recommended for prophylaxis and treatment of P. falciparum malaria where the pathogen may be resistant to other antimalarials.

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

4.2 Posology and method of administration

Prophylaxis:

In residents (semi-immune subjects) of endemic areas, the safety and effectiveness of Aatovaquone/Pproguanil Hydrochloride has been established in studies of up to 12 weeks.

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

Dosage in Adults
One Atovaquone/Proguanil Hydrochloride film-coated tablet daily

Treatment

Adults

Four Atovaquone/Proguanil Hydrochloride film-coated tablets as a single dose for three consecutive days.

Children

	Dosage/day
Body weight range (kg)	No. of tablets
11-20	One Atovaquone/Proguanil Hydrochloride film-coated tablet daily for three consecutive days
21-30	Two Atovaquone/Proguanil Hydrochloride film-coated tablets as a single dose for three consecutive days
31-40	Three Atovaquone/Proguanil Hydrochloride film-coated tablets as a single dose for three consecutive days
>40	Dose as for adults

4.4 Special warnings and precautions for use

The safety and effectiveness of Atovaquone/Proguanil Hydrochloride tablets for prophylaxis of malaria in patients who weigh less than 40 kg, or in the treatment of malaria in paediatric patients who weigh less than 11 kg has not been established.

This medicinal product contains Llactose monohydrate. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

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 which may lead to an increase in the risk of haemorrhage. The mechanism of this potential drug interaction has not been established. Caution is advised when initiating or withdrawing malaria prophylaxis or treatment with atovaquone/proguanil in patients on continuous treatment with oral anticoagulants. The dose of the oral anticoagulant may need to be adjusted during atovaquone/proguanil treatment or after its withdrawal, based on INR results.

4.6 Fertility, pregnancy and lactation

Fertility
No data are available regarding the effects of the combination on fertility, but in animal studies the individual components atovaquone and proguanil have shown no effects on fertility (see section 5.3).

4.8       Undesirable effects

There are limited long-term safety data in children. In particular, the long-term effects of Aatovaquone/Pproguanil Hydrochloride on growth, puberty and general development have not been studied.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antiprotozoals, antimalarials, biguanides
ATC code: P01B B51

5.2 Pharmacokinetic properties

Biotransformation

During administration of atovaquone-proguanil film-coated tablets at recommended doses proguanil metabolism status appears to have no implications for treatment or prophylaxis of malaria.

5.3 Preclinical safety data

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 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.

6.5 Nature and contents of container

Pack sizes: 12, 24, 30, 36, 48 tablets or 12 x 1, 24 x 1, 30 x 1, 36 x 1, 48 x 1 tablets in perforated unit dose blisters.

6.6 Special precautions for disposal and other handling

No special requirements.

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 31st May 2013
Date of latest renewal: 8th August 2017

10. DATE OF REVISION OF THE TEXT

September July 20167

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each Atovaquone/Proguanil Hydrochloride film-coated tablet contains 250 mg atovaquone and 100 mg proguanil hydrochloride.

Excipients with known effect:
Each film-coated tablet also contains 4.018 mg of lactose monohydrate.

For the full list of excipients, see section 6.1.

4.1 Therapeutic indications

Atovaquone/Proguanil Hydrochloride is 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. It is indicated for:

Prophylaxis of Plasmodium falciparum malaria in adults and in children weighing at least 40 kg.

Treatment of acute, uncomplicated Plasmodium falciparum malaria in adults and in children weighing 11 kg or more.

4.2 Posology and method of administration

Dosage in Adults and children weighing at least 40 kg
One Atovaquone/Proguanil Hydrochloride film-coated tablet daily

Atovaquone/Proguanil Hydrochloride is not recommended for malaria prophylaxis in persons under 40 kg bodyweight. Other pharmaceutical strengths may be more appropriate for malaria prophylaxis in persons weighing under 40 kg

Treatment

Dosage in Adults

Four Atovaquone/Proguanil Hydrochloride film-coated tablets as a single dose for three consecutive days.

Dosage in Children weighing 11 kg or more

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 for treatment of acute P. falciparum malaria should be recommended whenever possible (See Sections 4.4 and 5.2). For prophylaxis of P. falciparum malaria in patients with several renal impairments see Section 4.3.

4.5 Interaction with other medicinal products and other forms of interaction

Concomitant administration of rifampicin or rifabutin is not recommended as it is known to reduce plasma concentrations of atovaquone levels by approximately 50% and 34%, respectively (see section 4.4). 

Concomitant treatment with metoclopramide has been associated with a significant decrease (about 50 %) in plasma concentrations of atovaquone (See Section 4.4).  Another antiemetic treatment should be given.

When given with efavirenz or boosted protease-inhibitors, atovaquone concentrations have been observed to decrease as much as 75%. This combination should be avoided whenever possible (see section 4.4)

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.

Proguanil may potentiate the anticoagulant effect of warfarin and other coumarin based anticoagulants which may lead to an increase in the risk of haemorrhage. The mechanism of this potential drug interaction has not been established. Caution is advised when initiating or withdrawing malaria prophylaxis or treatment with atovaquone/proguanil in patients on continuous treatment with oral anticoagulants. The dose of the oral anticoagulant may need to be adjusted during atovaquone/proguanil treatment or after its withdrawal, based on INR results.

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

The co-administration of atovaquone at doses of 45 mg/kg/day in children (n=9) with acute lymphoblastic leukaemia for prophylaxis of PCP was found to increase the plasma concentrations (AUC) of etoposide and its metabolite etoposide catechol by a median of 8.6% (P=0.055) and 28.4% (P=0.031) (respectively compared to the co-administration of etoposide and sulfamethoxazole-trimethoprim). Caution should be advised in patients receiving concomitant therapy with etoposide (see section 4.4).

Paediatric only
Although some children have received concomitant atovaquone-proguanil and metoclopramide in clinical trials without any evidence of decreased protection against malaria, the possibility of a clinically significant drug interaction cannot be ruled out.

Proguanil is primarily metabolised by CYP2C19. However, potential pharmacokinetic interactions with other substrates, inhibitors (e.g. moclobemide, fluvoxamine) or inducers (e.g. artemisinin, carbamazepine) of CYP2C19 are unknown (see section 5.2).

4.6  Fertility, Ppregnancy 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 (in rat and rabbit) showed no evidence for teratogenicity of the combination (see section 5.3). Due to the lack of teratogenicity in animals, malformations in humans are not expected.
The individual components have shown no malformative or foetotoxic effects in humans. Nevertheless, information is insufficient to exclude any risk.

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 Atovaquon/Proguanil Hydrochloride in pregnancy should only be considered if the expected benefit to the mother outweighs any potential risk to the foetus.

4.8 Undesirable effects

In clinical trials of atovaquone/proguanil for in the treatment of malaria, the most commonly reported adverse reactions were abdominal pain, headache, anorexia, nausea, vomiting, diarrhoea and coughing.

In clinical trials of atovaquone/proguanil for prophylaxis of malaria, the most commonly reported adverse reactions were headache, abdominal pain and diarrhoea.

The following table provides a summary of adverse reactions that have been reported to have a suspected (at least possible) causal relationship to treatment with atovaquone/proguanil in clinical trials and spontaneous post-marketing reports. The following convention is used for the classification of frequency: very common ( 1/10); common ( 1/100 to <1/10); uncommon ( 1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); not known (cannot be estimated from the available data).

There are limited long-term safety data in children. In particular, the long-term effects of Atovaquone/Proguanil Hydrochloride on growth, puberty and general development have not been studied.

System Organ Class	Very Common	Common	Uncommon	Rare	Not known2
Blood and lymphatic system disorders		Anaemia Neutropenia1			Pancytopenia
Immune system disorders		Allergic reactions			Angioedema3, Anaphylaxis (see section 4.4) Vasculitis3
Metabolism and nutrition disorders		Hyponatraemia1 Anorexia	Elevated amylase levels1
Psychiatric disorders		Abnormal dreams Depression	Anxiety	Hallucinations	Panic attack Crying Hallucinations Nightmares Psychotic disorder
Nervous system disorders	Headache	Insomnia Dizziness			Seizure
Cardiac disorders			Palpitations		Tachycardia
Respiratory, thoracic and mediastinal disorders		Cough
Gastrointestinal disorders	Nausea1 Vomiting Diarrhoea Abdominal pain		Stomatitis		Gastric intolerance3 Oral ulceration3
Hepatobiliary disorders		Elevated liver enzymes1			Hepatitis Cholestasis3
Skin and subcutaneous tissue disorders		Pruritus Rash	Hair loss Urticaria		Stevens-Johnson Syndrome Erythema multiforme Blister Skin exfoliation Photosensitivity reactions
General disorders and administration site conditions		Fever

5.1  Pharmacodynamic properties

Pharmacotherapeutic group: Antiprotozoals, Aantimalarials, ATC code: P01B B51

Resistance
Atovaquone is not cross-resistant with any other antimalarial drugs in current use.In in-vitro studies with more than 30 P. falciparum isolates, resistance had been detected against chloroquine (41 % of isolates), quinine (32 % of isolates), mefloquine (29 % of isolates), and halofantrine (48 % of isolates) and not against atovaquone (0% of isolates).

The antimalarial activity of proguanil is exerted via the primary metabolite cycloguanil (in vitro IC50 against various P. falciparum strains of 4-20 ng/mL; some activity of proguanil and another metabolite, 4-chlorophenylbiguanide, is seen in vitro at 600-3000 ng/mL).

In in vitro studies of P. falciparum the combination of atovaquone and proguanil was shown to be synergistic. This enhanced efficacy was also demonstrated in clinical studies in both immune and non-immune patients.

However, regarding in vivo data, cases of failures to respond to atovaquone-proguanil associated with resistance of P. falciparum strains have been published. The mechanism of resistance has not been entirely elucidated. It may include involvement of point mutations in the target gene of atovaquone, P. falciparum mitochondrial cytochrome b gene.

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

Biotransformation 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 film-coated tablets at recommended doses proguanil metabolism status appears to have no implications for treatment or prophylaxis of malaria.

Section 6.5:

Pack sizes: 12, 24, 30, 36, 48 tablets or 12 x 1, 24 x 1, 30 x 1, 36 x 1, 48 x 1 tablets

Section 4.8:

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via:

Ireland
HPRA Pharmacovigilance, Section
Irish Medicines Board
Kevin O’Malley House
Earlsfort Centre
Earlsfort Terrace,
IRL - Dublin 2;
Tel: +353 1 6764971;
Fax: +353 1 67678366762517.
Website: www.imb.ie www.hpra.ie;
eE-mail: imbpharmacovigilance@imb.ie medsafety@hpra.ie.


Section 6.3:

PVC-Aluminium foil blister: 2 years.
OPA/Aluminium/PVC – Aluminium foil blister: 2 years.
PVC/PVdC – Aluminium foil blister: 3 years.

Section 6.5:
PVC-Aluminium foil blister
OPA/Aluminium/PVC – Aluminium foil blister
PVC/PVdC – Aluminium foil blister

Pack sizes: 12, 24 tablets or 12 x 1, 24 x 1 tablets

Not all pack sizes may be marketed

None provided