Atovaquone/ Proguanil

These indications are based on manufacturer information for both originator and generic products. For product specific registered indications, please refer to product specific manufacturer information

Registered South African indications:

• Prophylaxis of drug sensitive and drug resistant Plasmodium falciparum malaria

Contraindications

• Hypersensitivity to the active ingredient or of the excipients in this combination product
• Severe renal impairment
• Breasfeeding

Cautions

• Pregnancy
• Vomiting
• Diarrhoea
• Treatment of complicated malaria
• Plasmodium vivax and ovale 
• Recent treatment with atovaquone/ proguanil
• Paediatric patients weighing < 11kg
• Ability to drive or operate machinery

Forms avail. in SA and covered in this monograph: tab

Infections caused by: Plasmodium falciparum (prophylaxis)

Specific doses based on individual indications

Please note that the dosages below should be used in combination with regional guidelines, taking into account local antibiotic sensitivities

Malaria prophylaxis

Atovaquone/ Proguanil hydrochloride
250/100 (mg)

• < 40kg: Not established for use
• > 40kg: Oral (tab): 1 tab, dly

Prophylaxis to be started 1-2 days prior to entry into malaria-endemic area and should continue during the stay and for 7 days after leaving the area

To be taken with food or milk at the same time each day

In the event of vomiting within 1 hour of dosing a repeat dose should be taken

Malaria treatment

Atovaquone/ Proguanil hydrochloride
250/100 (mg)

• < 40kg: Not established for use
• > 40kg: Oral (tab): 4 tabs as a single dose for 3 consecutive days

Paed. forms avail. in SA and covered in this monograph: tab

Infections caused by: Plasmodium falciparum (prophylaxis)

Specific doses based on individual indications

Please note that the dosages below should be used in combination with regional guidelines, taking into account local antibiotic sensitivities

Malaria prophylaxis

Atovaquone/ Proguanil hydrochloride
62.5/25 (mg)

• < 11kg: Not established for use
• 11-20kg: Oral (tab): 1 tab, dly
• 21-30kg: Oral (tab): 2 tab, dly
• 31-40kg: Oral (tab): 3 tab, dly
• > 40kg: See adult dosing 

Prophylaxis to be started 1-2 days prior to entry into malaria-endemic area and should continue during the stay and for 7 days after leaving the area

To be taken with food or milk at the same time each day

In the event of vomiting within 1 hour of dosing a repeat dose should be taken

Malaria treatment

Atovaquone/ Proguanil hydrochloride
250/100 (mg)

• < 11kg: Not established for use
• > 11-< 21kg: Oral (tab): 1 tab, dly for 3 consecutive days
• > 21-< 31kg: Oral (tab): 2 tabs as a single dose, dly for 3 consecutive days
• > 31-< 40kg: Oral (tab): 3 tabs as a single dose, dly for 3 consecutive days
• > 40kg: See adult dosing

Pregnancy

• Caution
• 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. The use of atovaquone and proguanil hydrochloride in pregnancy should only be considered if the expected benefit to the mother outweighs any potential risk to the foetus
• Proguanil acts by inhibiting parasitic dihydrofolate reductase. There are no clinical data indicating that folate supplementation diminishes drug efficacy. For women of childbearing age receiving folate supplements to prevent neural tube birth defects, such supplements should be continued while taking atovaquone and proguanil hydrochloride

Breastfeeding

• Contraindicated
• Atovaquone and proguanil hydrochloride should not be taken by breastfeeding women
• Proguanil is excreted in human milk in small quantities
• 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
• The potential for serious adverse effects in a nursing infant, such as gastrointestinal symptoms, rash, fever, headache, hepatic toxicity, and carcinogenicity, suggests that nursing mothers (even HIV-negative) should not breastfeed if they are taking this drug

Fertility

• None or insufficient data regarding male and female fertility

Renal Impairment

• Mild to moderate: No dose adjustment recommended
• Severe: Contraindicated

Hepatic Impairment

• No dose adjustment recommended

Elderly

• No dose adjustment recommended

Porphyria Information

• Probably not porphyrinogenic (PNP)

Drugs in Sport

• Permitted - No warnings

Central Nervous System Disorders

• Headache
• Insomnia
• Dizziness
• Seizures
• Abnormal dreams
• Depression
• Anxiety
• Hallucinations
• Panic attack
• Crying
• Nightmares
• Psychotic disorder

Cardiovascular Disorders

• Palpitations
• Tachycardia

Respiratory Disorders

• Cough

Gastrointestinal disorders

• Nausea and vomiting
• Diarrhoea
• Abdominal pain
• Stomatitis
• Gastric intolerance
• Oral ulceration

Hepatobiliary Disorders

• Increased hepatic enzymes
• Hepatitis
• Cholestasis

Endocrine and Metabolic Disorders

• Hyponatraemia
• Anorexia
• Increased amylase levels

Skin and Subcutaneous Tissue Disorders

• Pruritus
• Rash
• Hair loss
• Urticaria
• Stevens-Johnson syndrome
• Erythema multiforme
• Blister
• Skin exfoliation
• Photosensitivity reactions

Immune, Blood and Lymphatic System Disorders

• Allergic reactions
• Angioedema
• Anaphylaxis
• Vasculitis
• Anaemia
• Neutropenia
• Pancytopenia
• Fever

• Tetracyclines
• Efavirenz
• Protease inhibitor
• Rifampicin
• Rifabutin
• Metoclopramide
• Warfarin
• Etoposide
• CYP2C19 substrates
• Moclobemide
• Fluvoxamine
• CYP2C19 inhibitors
• CYP2C19 inducers
• Artemisinin
• Carbamazepine
• Indinavir

None routine. Specific cases may require

• Hepatic function
• Renal function

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 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.

Spectrum of activity: Plasmodium falciparum 

COMBINATION PREPARATIONS

Atovaquone/ Proguanil

Tablet 62.5mg/ 25mg

• Malani paediatric (Litha Pharma) originator

Tablet 250mg/ 100mg

• Malagen (Mylan)
• Malanil (Litha Pharma) originator
• Malateq (Forrester Pharma)
• Mozitec (Glenmark)
• Numal (Cipla)