Atovaquone / Proguanil Hydrochloride

Brands of Atovaquone / Proguanil Hydrochloride in Kenya

Malanil®, GlaxoSmithKline Pharmaceutical Kenya Limited

MODE OF ACTION

This combination, 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 bc1 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.

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 more than 40 kg.
  • Treatment of acute, uncomplicated Plasmodium falciparum malaria in adults and in children weighing 11 kg or more.

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 drugs should be taken into consideration. Official guidelines will normally include World Health Organisation (WHO)and public health authorities’ guidelines.

DOSAGE AND ADMINISTRATION

Prophylaxis:

Prophylaxis should:

  • commence 24 to 48 hours prior to entering a malaria-endemic area ,
  • continue during the period of the stay,
  • continue for 7 days after leaving the area.

In residents (semi-immune subjects) of endemic areas, the safety and effectiveness of Atovaquone/Proguanil Hydrochloride 250 mg/100 mg film-coated tablets 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 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 <21 kg bodyweight. One tablet daily for three consecutive days.

≥ 21 to <31 kg bodyweight. Two tablets as a single dose for three consecutive days.

≥ 31 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 .

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 .

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 P. falciparum malaria should be recommended whenever possible .

CONTRAINDICATIONS

Atovaquone and proguanil hydrochloride is contraindicated in individuals with known hypersensitivity reactions (e.g., anaphylaxis, erythema multiforme or Stevens-Johnson syndrome, angioedema, vasculitis) to atovaquone or proguanil hydrochloride or any component of the formulation.

Atovaquone and proguanil hydrochloride is contraindicated for prophylaxis of P. falciparum malaria in patients with severe renal impairment (creatinine clearance < 30 mL/min) because of pancytopenia in patients with severe renal impairment treated with proguanil

DRUG INTERACTIONS

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 .

Concomitant treatment with metoclopramide has been associated with a significant decrease (about 50 %) in plasma concentrations of atovaquone . 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 .

Proguanil may potentiate the effect of warfarin and other coumarin based anticoagulants which may lead to an increase in 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.

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

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.

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

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 .

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.

ADVERSE EFFECTS

Blood and Lymphatic System Disorders

Neutropenia and anemia. Pancytopenia in patients with severe renal impairment treated with proguanil .

Immune System Disorders

Allergic reactions including anaphylaxis, angioedema, urticaria, and vasculitis.

Nervous System Disorders

Seizures and psychotic events (such as hallucinations); however, a causal relationship has not been established.

Gastrointestinal Disorders

Stomatitis.

Hepatobiliary Disorders

Elevated liver laboratory tests, hepatitis, cholestasis; hepatic failure requiring transplant has been reported.

Skin and Subcutaneous Tissue Disorders

Photosensitivity, rash, erythema multiforme, and Stevens-Johnson syndrome.

Reporting of suspected adverse reactions:

The PPB Department of Pharmacovigilance was set up with a vision to develop, implement and continuously upgrade an appropriate system for detecting, reporting, and monitoring adverse drug reactions (ADRs) and other relevant problems with medicines in Kenya. The department strives to ensure the safety and efficacy of pharmaceutical products in Kenya.
Reporting suspected adverse reactions after authorization of the medicinal product are important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals/ Patients are encouraged to report any suspected adverse reactions via Pharmacovigilance Yellow Form, pv@pharmacyboardkenya.org or clicking below button:


Atovaquone / Proguanil Hydrochloride in Kenya
Atovaquone / Proguanil Hydrochloride in Kenya
Atovaquone / Proguanil Hydrochloride in Kenya
Atovaquone / Proguanil Hydrochloride in Kenya
Atovaquone / Proguanil Hydrochloride in Kenya

Clinical | Pharmacokinetic data


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