(a TOE va kwone & pro GWA nil)
Malaria prevention: Prophylaxis of Plasmodium falciparum malaria, including areas where chloroquine resistance has been reported
Malaria treatment: Treatment of acute, uncomplicated P. falciparum malaria
Hypersensitivity to atovaquone, proguanil, or any component of the formulation; prophylactic use in severe renal impairment (CrCl <30 mL/minute)
Prevention of malaria: Oral: Atovaquone/proguanil 250 mg/100 mg once daily; start 1-2 days prior to entering a malaria-endemic area, continue throughout the stay and for 7 days after returning.
Treatment of acute malaria: Oral: Atovaquone/proguanil 1000 mg/400 mg as a single dose, once daily for 3 consecutive days
Refer to adult dosing.
Prevention of malaria: Oral: Start 1-2 days prior to entering a malaria-endemic area, continue throughout the stay and for 7 days after returning. Take as a single dose, once daily.
5-8 kg (off-label dosing): Atovaquone/proguanil 31.25 mg/12.5 mg (Boggild, 2007)
9-10 kg (off-label dosing): Atovaquone/proguanil 46.8 mg/18.75 mg (Boggild, 2007)
11-20 kg: Atovaquone/proguanil 62.5 mg/25 mg
21-30 kg: Atovaquone/proguanil 125 mg/50 mg
31-40 kg: Atovaquone/proguanil 187.5 mg/75 mg
>40 kg: Atovaquone/proguanil 250 mg/100 mg
Treatment of acute malaria: Oral: Take as a single dose, once daily for 3 consecutive days.
5-8 kg: Atovaquone/proguanil 125 mg/50 mg
9-10 kg: Atovaquone/proguanil 187.5 mg/75 mg
11-20 kg: Atovaquone/proguanil 250 mg/100 mg
21-30 kg: Atovaquone/proguanil 500 mg/200 mg
31-40 kg: Atovaquone/proguanil 750 mg/300 mg
>40 kg: Atovaquone/proguanil 1000 mg/400 mg
CrCl ≥30 mL/minute: No dosage adjustment necessary.
CrCl <30 mL/minute:
Prophylaxis: Use is contraindicated.
Treatment: No dosage adjustment necessary; however, use with extreme caution and only if the benefits outweigh the risks.
Mild-to-moderate impairment: No dosage adjustment necessary.
Severe impairment; No dosage adjustment provided in manufacturer 's labeling (has not been studied).
Administer with food or milk-based drink at the same time each day. If vomiting occurs within 1 hour of administration, repeat the dose. For patients who have difficulty swallowing tablets, tablets may be crushed and mixed with condensed milk just prior to administration.
Must be taken with food or milk-based drink.
Store at 25 ‚ °C (77 ‚ °F); excursions permitted to 15 ‚ °C to 30 ‚ °C (59 ‚ °F to 86 ‚ °F).
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, oral: Atovaquone 250 mg and proguanil hydrochloride 100 mg
Malarone ‚ ®: Atovaquone 250 mg and proguanil hydrochloride 100 mg
Tablet, oral [pediatric]:
Malarone ‚ ®: Atovaquone 62.5 mg and proguanil hydrochloride 25 mg
Antihepaciviral Combination Products: May decrease the serum concentration of Proguanil. Monitor therapy
Antipsychotic Agents (Phenothiazines): Antimalarial Agents may increase the serum concentration of Antipsychotic Agents (Phenothiazines). Monitor therapy
Artemether: May enhance the adverse/toxic effect of Antimalarial Agents. Management: Artemether/Lumefantrine (combination product) should not be used with other antimalarials unless there is no other treatment option. Avoid combination
Dapsone (Systemic): Antimalarial Agents may enhance the adverse/toxic effect of Dapsone (Systemic). Specifically, concomitant use of antimalarial agents with dapsone may increase the risk of hemolytic reactions. Dapsone (Systemic) may enhance the adverse/toxic effect of Antimalarial Agents. Specifically, concomitant use of dapsone with antimalarial agents may increase the risk for hemolytic reactions. Management: Closely monitor patients for signs/symptoms of hemolytic reactions with concomitant use of dapsone and antimalarial agents, particularly in patients deficient in glucose-6-phosphate dehydrogenase (G6PD), methemoglobin reductase, or with hemoglobin M. Consider therapy modification
Dapsone (Topical): Antimalarial Agents may enhance the adverse/toxic effect of Dapsone (Topical). Specifically, the risk of hemolytic reactions may be increased. Management: Closely monitor for signs/symptoms of hemolytic reactions with concomitant use of topical dapsone and antimalarial agents. Patients with glucose-6-phosphate dehydrogenase deficiency may be at particularly high risk for adverse hematologic effects. Consider therapy modification
Efavirenz: May decrease the serum concentration of Atovaquone. Management: Consider alternatives to the use of atovaquone with efavirenz when possible. If this combination must be used, monitor for evidence of reduced atovaquone clinical effectiveness. Consider therapy modification
Etoposide: Atovaquone may increase the serum concentration of Etoposide. Management: Consider separating the administration of atovaquone and etoposide by at least 1 to 2 days. Monitor therapy
Etoposide Phosphate: Atovaquone may increase the serum concentration of Etoposide Phosphate. Management: Consider separating the administration of atovaquone and etoposide by at least 1 to 2 days. Monitor therapy
Indinavir: Atovaquone may decrease the serum concentration of Indinavir. Monitor therapy
Lumefantrine: Antimalarial Agents may enhance the adverse/toxic effect of Lumefantrine. Management: Artemether/Lumefantrine (combination product) should not be used with other antimalarials unless there is no other treatment option. Avoid combination
Metoclopramide: May decrease the serum concentration of Atovaquone. Management: Consider alternatives to metoclopramide when possible; atovaquone should only be used with metoclopramide if no other antiemetics are available. Consider therapy modification
Rifamycin Derivatives: May decrease the serum concentration of Atovaquone. Avoid combination
Ritonavir: May decrease the serum concentration of Atovaquone. Avoid combination
Tetracycline: May decrease the serum concentration of Atovaquone. Monitor therapy
Typhoid Vaccine: Proguanil may diminish the therapeutic effect of Typhoid Vaccine. This applies only to the oral (live) typhoid vaccine. Management: Vaccination with live attenuated typhoid vaccine (Ty21a) should be avoided in patients being treated with proguanil. When possible, proguanil should not be started within 10 days of the last vaccine dose. Consider therapy modification
Warfarin: Proguanil may enhance the anticoagulant effect of Warfarin. Monitor therapy
Liver and renal function; closely monitor response to treatment in patients with vomiting or diarrhea and in patients >100 kg (Durand, 2008)
The following adverse reactions were reported in patients being treated for malaria. When used for prophylaxis, reactions are similar to those seen with placebo.
>10%:
Gastrointestinal: Abdominal pain (17%), nausea (12%), vomiting (children: 10% to 13%; adults: 12%)
Hepatic: Increased serum ALT (27%; increased liver function test values typically normalized after ~ 4 weeks), increased serum AST (17%; increased liver function test values typically normalized after ~4 weeks)
1% to 10%:
Central nervous system: Headache (10%), dizziness (5%)
Dermatologic: Pruritus (children: 6%)
Gastrointestinal: Diarrhea (children: 6%; adults: 8%), anorexia (5%)
Neuromuscular & skeletal: Weakness (8%)
<1% (Limited to important or life-threatening): Anaphylaxis (rare), anemia (rare), angioedema, cholestasis, erythema multiforme (rare), hallucination, hepatic failure (case report), hepatitis (rare), neutropenia, pancytopenia (with severe renal impairment), psychotic reaction (rare), seizure (rare), skin photosensitivity, skin rash, Stevens-Johnson syndrome (rare), stomatitis, urticaria, vasculitis (rare)
In patients with moderate renal impairment (CrCl 30-50 mL/minute), mean oral clearance for proguanil was reduced by ~35% compared with patients with normal renal function CrCl >80 mL/minute). In patients with severe renal impairment (CrCl <30 mL/minute), atovaquone Cmax and AUC are reduced, but the elimination half-lives for proguanil and cycloguanil are prolonged, with corresponding increases in AUC, resulting in the potential of drug accumulation and toxicity with repeated dosing.
Atovaquone elimination half-life was increased in patients with moderate hepatic impairment. Proguanil AUC, Cmax, and elimination half-life were increased and cycloguanil (metabolite) AUC and Cmax were decreased and elimination half-life was increased in patients with mild hepatic impairment. Proguanil AUC and Cmax were increased in patients with moderate hepatic impairment. The pharmacokinetics of atovaquone, proguanil, and cycloguanil have not been studied in patients with severe hepatic impairment.
AUC was increased, Tmax was longer, and elimination half-life was longer in elderly subjects (~15 hours) compared to younger subjects (~8 hours).
Concerns related to adverse events:
- Hepatic effects: Increased transaminase levels and hepatitis have been reported with prophylactic use; single case report of hepatic failure requiring transplantation documented. Monitor closely and use caution in patients with existing hepatic impairment. Elevations in AST/ALT may persist for up to 4 weeks following treatment (Looareesuwan, 1999).
Disease-related concerns:
- Diarrhea/vomiting: Absorption of atovaquone may be decreased in patients who have diarrhea or vomiting; monitor closely and consider use of an antiemetic. If severe, consider use of an alternative antimalarial.
- Malaria: Appropriate use: Not indicated for cerebral malaria or other severe manifestations of complicated malaria. Delayed cases of P. falciparum malaria may occur after stopping prophylaxis; travelers returning from endemic areas who develop febrile illnesses should be evaluated for malaria. Recrudescent infections or infections following prophylaxis with this agent should be treated with alternative agent(s).
- Renal impairment: Use with caution in patients with preexisting renal disease. May use with caution for treatment of malaria in patients with severe renal impairment (CrCl <30 mL/minute) if benefit outweighs risk. Contraindicated for prophylactic use in severe renal impairment due to the risk of pancytopenia in patients with severe renal impairment treated with proguanil.
Special populations:
- Obesity: Treatment failures have been reported in patients >100 kg (case reports); follow-up monitoring is recommended (Durand, 2008).
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Adverse events were not observed with the combination of atovaquone/proguanil in animal reproduction studies. The pharmacokinetics of atovaquone and proguanil may be altered during pregnancy (Wilby 2011). Malaria infection in pregnant women may be more severe than in nonpregnant women. Because P. falciparum malaria can cause maternal death and fetal loss, pregnant women traveling to malaria-endemic areas must use personal protection against mosquito bites. Atovaquone/proguanil may be used as an alternative treatment of malaria in pregnant women; consult current CDC guidelines (CDC 2013).
Atovaquone: Selectively inhibits parasite mitochondrial electron transport.
Proguanil: The metabolite cycloguanil inhibits dihydrofolate reductase, disrupting deoxythymidylate synthesis. Together, atovaquone/cycloguanil affect the erythrocytic and exoerythrocytic stages of development.
Atovaquone: The rate and extent of absorption is increased when administered with dietary fat.
Proguanil: Extensive
Vd:
Atovaquone: Children and Adults: ~8.8 L/kg
Proguanil: Children >15 years and Adults and 31-110 kg: 1617-2502 L; Pediatric patients ≤15 years and 11-56 kg: 462-966 L; concentrated in erythrocytes
Proguanil: Hepatic to active metabolites, cycloguanil (via CYP2C19) and 4-chlorophenylbiguanide
Atovaquone: Feces (>94% as unchanged drug); urine (<0.6%)
Proguanil: Urine (40% to 60%)
Atovaquone: 2-3 days (adults), 1-2 days (children)
Proguanil: 12-21 hours
Atovaquone: >99%
Proguanil: 75%
- Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)
- Patient may experience headache, cough, nausea, vomiting, diarrhea, or abdominal pain. Have patient report immediately to prescriber signs of liver problems (dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or jaundice), fever, or signs of Stevens-Johnson syndrome/toxic epidermal necrolysis (red, swollen, blistered, or peeling skin [with or without fever]; red or irritated eyes; or sores in mouth, throat, nose, or eyes) (HCAHPS).
- Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.
Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.