Drug information of atovaquone/proguanil

atovaquone/proguanil

Drug group: Antimalarials

Atovaquone and proguanil is a combination medicine used to treat or prevent malaria, a disease caused by parasites. These medicines work by interfering with the growth of parasites in the red blood cells of the human body

Mechanism of effect

Atovaquone: Selective inhibitor of parasite mitochondrial electron transport

Proguanil: Primary effect through metabolite cycloguanil, a dihydrofolate reductase inhibitor in malaria parasite, which leads to disruption of deoxythymidylate synthesis

Pharmacokinetics

Bioavailability: Oral absorption of atovaquone is poor but increases to 23% with high-fat meal (AUC increased 2-3 times and Cmax 5 times over fasting); administer with food or milk; proguanil is extensively absorbed

Protein bound: Atovaquone, >99%; proguanil, 75%

Vd: Atovaquone, 8.8 L/kg

Proguanil is metabolized to cycloguanil (primarily by CYP2C19)

Half-life: Atovaquone, 2-3 days; proguanil, 12-21 hr

Clearance: Atovaquone, 1.32-6.61 L/hr; proguanil, 29.5-67.9 L/hr

Excretion: Atovaquone, feces as unchanged drug (94%); proguanil, urine (40-60%)

 

Drug indications

Malaria due to Plasmodium falciparum, prevention

Malaria (uncomplicated) due to P. falciparum, treatment

Dosage

ADULT

Prophylaxis

  • 250 mg/100 mg (1 tablet) PO daily, beginning 1-2 days before travel to malaria-endemic area and continued until 7 days after return

Treatment

  • 1 g/400 mg (4 tablets) PO daily for 3 days

PEDIATRIC

Prophylaxis

  • <11 kg: Safety and efficacy not established
  • 11-20 kg: 62.5 mg/25 mg (1 pediatric tablet) PO daily
  • 21-30 kg: 125 mg/50 mg (2 pediatric tablets) PO daily
  • 31-40 kg: 187.5 mg/75 mg (3 pediatric tablets) PO daily
  • >40 kg: 250 mg/100 mg (1 adult tablet) PO daily, beginning 1-2 days before travel to malaria-endemic area and continued until 7 days after return

Treatment

  • <5 kg: Safety and efficacy not established
  • 5-8 kg: 125 mg/50 mg (2 pediatric tablets) PO daily for 3 days
  • 9-10 kg: 187.5 mg/75 mg (3 pediatric tablets) PO daily for 3 days
  • 11-20 kg: 250 mg/100 mg (1 adult tablet) PO daily for 3 days
  • 21-30 kg: 500 mg/200 mg (2 adult tablets) PO daily for 3 days
  • 31-40 kg: 750 mg/300 mg (3 adult tablets) PO daily for 3 days
  • >40 kg: 1 g/400 mg (4 adult tablets) PO daily for 3 days

 

Drug contraindications

Hypersensitivity to this drug , Severe Renal Impairment

Hypersensitivity

Prophylaxis in severe renal impairment (CrCl <30 mL/min)

Side effects

Diarrhea , Headache , abdominal pain , Seizures , Angioedema , vertigo , fever , anorexia , itching , allergic reactions , Digestive complaints

Abdominal pain-Transaminase increases-Headache-Vomiting-Nausea-Asthenia-Diarrhea-Pruritus-Anorexia-Dizziness-Dyspepsia-Gastritis-Fever-Cough- Neutropenia, anemia , pancytopenia , Allergic reactions, angioedema, urticaria, and rare cases of anaphylaxis and vasculitis,Rare cases of seizures and psychotic events

Stomatitis,Elevated liver function tests (LFTs), rare cases of hepatitis, cholestasis,Photosensitivity, rash, and rare cases of erythema multiforme and Stevens-Johnson syndrome

asparaginase erwinia chrysanthemi-asparaginase escherichia coli-auranofin-aurothioglucose-black cohosh-calaspargase pegol-dicumarol-gold sodium thiomalate-

Alerts

Patients with severe malaria are not candidates for oral therapy; not evaluated in treatment of cerebral malaria or severe manifestations of malaria (eg, hyperparasitemia, pulmonary edema, renal failure)

Hepatitis and increased transaminase levels reported with prophylactic use; monitor closely; use caution with existing hepatic impairment

Absorption may be reduced in patients with diarrhea or vomiting; monitor closely, and consider antiemetic use; if severe, use alternative antimalarial

Monotherapy may result in parasite relapse of P vivax malaria

Prophylaxis should not be prematurely discontinued; delayed cases of P. falciparum malaria may occur

Treatment failure reported in patients >100 kg; monitoring and follow up recommended in this patient group

P falciparum malaria carries higher risk of death and serious complications in pregnant women; patient should discuss risks and benefits of travel, and if travel cannot be avoided, additional prophylaxis, including protective clothing, must be employed

CrCl <30 mL/min: Prophylactic use not recommended; only use for treatment if benefits of therapy greatly outweigh risks

Points of recommendation

Complete prophylaxis includes therapy, protective clothing, insect repellents, and bednets

Take at same time daily with food or milky drink

For children with difficulty swallowing, may be crushed and mixed with condensed milk just before administration

In event of vomiting within 1 hour of dose, repeat dose

In geriatric patients, cautious dose selection is necessary because of decreased hepatic/renal/cardiac function and increased systemic exposure to cycloguanil

Pregnancy level

C

 Falciparum malaria carries a higher risk of morbidity and mortality in pregnant women causing both maternal death and fetal loss. Pregnant women who must travel to malaria-endemic areas should be instructed to use personal protection against mosquito bites in addition to antimalarials.

Animal studies conducted with the combination product have failed to reveal evidence of teratogenicity at plasma concentrations equal to the estimated human exposure during treatment of malaria.

Breast feeding warning

Proguanil is excreted into milk in small quantities, but excretion of atovaquone is unknown; use with caution.

Related drugs

Atovaquone

Drug forms

Malarone

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