Generic Name: Atovaquone
Class: Antiprotozoals, Miscellaneous
VA Class: AM900
Chemical Name: trans2-[4-(4-Chlorophenyl)cyclohexyl]-3-hydroxy-1,4-naphthalenedione
Molecular Formula: C22H19ClO3
CAS Number: 95233-18-4

Introduction

Antiprotozoal; hydroxynaphthoquinone derivative.1 7 8 10 15 17 .

Uses for Mepron

Pneumocystis jiroveci (Pneumocystis carinii) Pneumonia

Alternative for treatment or prevention of Pneumocystis jiroveci (formerly Pneumocystis carinii) pneumonia (PCP) in adults, adolescents, or children who do not tolerate co-trimoxazole.1 19 20 22 24 25 29 33 34 38 40 54 55 Designated an orphan drug by FDA for treatment or prevention of PCP pneumonia.22

Co-trimoxazole is initial drug of choice for treatment of PCP in most adults, adolescents, and children, including HIV-infected patients.29 34 40 54 55 Atovaquone is one of several alternatives for adults, adolescents, and children with mild to moderately severe PCP when co-trimoxazole cannot be used.29 34 40 54 55

Slideshow: It’s Buggin’ Me! How to Safely Use an Insect Repellent

One of several alternatives that can be used for prevention of initial episodes of PCP (primary prophylaxis) in adults, adolescents, and children at increased risk, including HIV-infected individuals, when co-trimoxazole (the drug of choice) cannot be used.25 29 40

One of several alternatives that can be used for long-term suppressive or chronic maintenance therapy (secondary prophylaxis) of PCP in adults, adolescents, and children when co-trimoxazole (the drug of choice) cannot be used.25 40 54 55

Toxoplasmosis

Alternative for treatment or prevention of toxoplasmosis caused by Toxoplasma gondii.25 29 42 43 54 Designated an orphan drug by FDA for treatment or prevention of toxoplasmosis.22

Sulfadiazine used in conjunction with pyrimethamine and leucovorin is the regimen of choice for treatment of toxoplasmosis in adults, adolescents, or children, including HIV-infected individuals.29 54 55 Atovaquone used in conjunction with pyrimethamine and leucovorin, atovaquone used in conjunction with sulfadiazine, or atovaquone monotherapy are alternative regimens for treatment of toxoplasmosis, including encephalitis and retinochoroiditis, in HIV-infected adults or adolescents when the regimen of choice cannot be used;29 54 not studied for treatment of toxoplasmosis in children.55

Atovaquone used with or without pyrimethamine and leucovorin is an alternative for prevention of T. gondii encephalitis (primary prophylaxis) in HIV-infected adults and adolescents when the regimen of choice (co-trimoxazole) cannot be use.25 29 54 Atovaquone monotherapy has been suggested as an alternative for primary prophylaxis in children,25 but the drug has not been studied for prevention of toxoplasmosis in children.55

Atovaquone used with or without pyrimethamine and leucovorin is an alternative for long-term suppressive or chronic maintenance therapy (secondary prophylaxis) to prevent relapse of toxoplasmosis in HIV-infected adults and adolescents who have completed treatment for the disease and cannot receive the regimen of choice for prophylaxis (sulfadiazine used in conjunction with pyrimethamine and leucovorin).25 54 Not studied for prevention of recurrence of toxoplasmosis in children.55

Babesiosis

Treatment of babesiosis caused by Babesia microti.29 40 56 57

Regimens of choice for babesiosis are atovaquone in conjunction with azithromycin or clindamycin in conjunction with quinine;29 40 56 57 the clindamycin and quinine regimen may be preferred for severe babesiosis.56 Also consider exchange transfusions in severely ill patients with high levels of parasitemia (>10%), significant hemolysis, or compromised renal, hepatic, or pulmonary function.29 40 56

Mepron Dosage and Administration

Administration

Administer orally.1 3 4 5 6 7 9 15 19

Must be taken with food to optimize GI absorption.1 24 Alternative therapy should be used in patients who have difficulty taking the drug with food.1

Shake multiple-dose bottle containing oral suspension gently before removing a dose.1

If single-dose foil pouch containing oral suspension is used, open pouch containing oral suspension by removing perforated tab and then ingest entire contents by mouth; the dose can be discharged into a dosing spoon or cup or directly into the mouth.1

Dosage

Pediatric Patients

Pneumocystis jiroveci (Pneumocystis carinii) Pneumonia
Treatment of Mild to Moderate Infections
Oral

Infants 1–3 months of age: 30 mg/kg once daily for 21 days.29

Infants and children 4–24 months of age: 45 mg/kg once daily for 21 days.29

Children >24 months of age: 30 mg/kg once daily for 21 days.29

CDC, NIH, and IDSA recommend that children receive 15–20 mg/kg (up to 750 mg) twice daily for 21 days, although infants 3–24 months of age may require 45 mg/kg daily.55

Adolescents 13–16 years of age: 750 mg twice daily for 21 days.1 19 23 29 54

Prevention (Primary Prophylaxis)
Oral

Infants 1–3 months of age: 30 mg/kg once daily.25 29 40

Infants and children 4–24 months of age: 45 mg/kg once daily.25 29 40

Children >24 months of age: 30 mg/kg once daily.25 29 40

Adolescents 13–16 years of age: 1.5 g once daily.1 25 29 54

Primary prophylaxis against PCP should be initiated at 4–6 weeks of age in children born to HIV-infected mothers; discontinue prophylaxis in those subsequently found not to be infected with HIV, but continue prophylaxis for the first year of life in those whose HIV status remains unknown.25 40

In HIV-infected children 1–5 years of age, primary prophylaxis should be initiated if CD4+ T-cell counts are <500mm3 or CD4+ percentage is <15%.25 In HIV-infected children 6–12 years of age, primary prophylaxis should be initiated if CD4+ T-cell counts are <200/mm3 or CD4+ percentage is <15%.25

The safety of discontinuing primary PCP prophylaxis in HIV-infected children receiving potent antiretroviral therapy has not been extensively studied.25 40 Based on experience discontinuing primary PCP prophylaxis in adults and adolescents who have adequate CD4+ T-cell count, AAP states that discontinuing such prophylaxis also should be considered for children who have adequate CD4+ T-cell counts.40

Criteria for initiating or discontinuing primary PCP prophylaxis in HIV-infected adolescents is the same as that recommended for adults.25 54 (See Adult Dosage under Dosage and Administration.)

Prevention of Recurrence (Secondary Prophylaxis)
Oral

Infants 1–3 months of age: 30 mg/kg once daily.25 29

Infants and children 4–24 months of age: 45 mg/kg once daily.25 29

Children >24 months of age: 30 mg/kg once daily.25 29

Adolescents 13–16 years of age: 1.5 g once daily.1 25 29 54

The safety of discontinuing secondary prophylaxis against PCP in HIV-infected children receiving potent antiretroviral therapy has not been extensively studied.25 40 55 Children who have a history of PCP should receive life-long suppressive therapy to prevent recurrence.25 40 55

Criteria for initiating or discontinuing secondary PCP prophylaxis in adolescents are the same as those recommended for adults.54 (See Adult Dosage under Dosage and Administration.)

Toxoplasmosis
Treatment
Oral

Adolescents: 1.5 g twice daily.54

Alternatively, 1.5 g twice daily used in conjunction with oral pyrimethamine (200 mg once, then 50 mg once daily in those weighing <60 kg or 75 mg once daily in those weighing ≥60 kg) and oral leucovorin (at least 10–20 mg once daily).54

Alternatively, 1.5 g twice daily used in conjunction with oral sulfadiazine (1–1.5 g every 6 hours).54

Prevention (Primary Prophylaxis)
Oral

Infants 1–3 months of age: 30 mg/kg once daily.25

Infants and children 4–24 months of age: 45 mg/kg once daily.25

Children >24 months of age: 30 mg/kg once daily.25

Adolescents: 1.5 g once daily.25 Alternatively, 1.5 g once daily in conjunction with oral pyrimethamine (25 mg once daily) and oral leucovorin (10 mg once daily).25

Primary prophylaxis against T. gondii encephalitis should be initiated in all HIV-infected infants and children with severe immunosuppression who are seropositive for Toxoplasma IgG antibody.25 40

Criteria for initiating or discontinuing primary prophylaxis against T. gondii in adolescents are the same as those recommended for adults.54 (See Adult Dosage under Dosage and Administration.)

Prevention of Recurrence (Secondary Prophylaxis)
Oral

Adolescents: 750 mg every 6–12 hours.25 54 Alternatively, 750 mg every 6–12 hours in conjunction with oral pyrimethamine (25 mg once daily) and oral leucovorin (10 mg once daily).25 54

Initiate long-term suppressive therapy or chronic maintenance therapy (secondary prophylaxis) in all patients who have completed initial treatment of toxoplasmosis encephalitis (TE).25 54

Secondary prophylaxis against toxoplasmosis generally is continued for life.25 54 The safety of discontinuing secondary toxoplasmosis prophylaxis in HIV-infected infants and children receiving potent antiretroviral therapy has not been extensively studied.25

Criteria for initiating or discontinuing secondary toxoplasmosis prophylaxis in adolescents are the same as those recommended for adults.54 (See Adult Dosage under Dosage and Administration.)

Babesiosis
Oral

20 mg/kg (up to 750 mg) twice daily for 7–10 days recommended by IDSA and others;29 56 used in conjunction with oral azithromycin (10 mg/kg [up to 500 mg] once on day 1, then 5 mg/kg [up to 250 mg] once daily for total of 7–10 days).56

Adults

Pneumocystis jiroveci (Pneumocystis carinii) Pneumonia
Treatment
Oral

750 mg twice daily for 21 days.1 19 23 29 54

Prevention (Primary Prophylaxis)
Oral

1.5 g once daily.1 25 29

Initiate primary prophylaxis against PCP in HIV-infected patients with CD4+ T-cell counts <200/mm3 or a history of oropharyngeal candidiasis.25 Also consider primary prophylaxis if CD4+ T-cell percentage is <14% or there is a history of an AIDS-defining illness.25

Primary prophylaxis can be discontinued in adults and adolescents responding to potent antiretroviral therapy who have a sustained (≥3 months) increase in CD4+ T-cell counts from <200/mm3 to >200/mm3.25

Reinitiate primary prophylaxis if CD4+ T-cell count decreases to <200/mm3.25

Prevention of Recurrence (Secondary Prophylaxis)
Oral

1.5 g once daily.1 25 29 54

Initiate long-term suppressive therapy or chronic maintenance therapy (secondary prophylaxis) to prevent recurrence in those with a history of PCP.25 54

Discontinuance of secondary prophylaxis is recommended in those who have a sustained (≥3 months) increase in CD4+ T-cell counts to >200/mm325 54 since such prophylaxis appears to add little benefit in terms of disease prevention and discontinuance reduces the medication burden, the potential for toxicity, drug interactions, selection of drug-resistant pathogens, and cost.25

Reinitiate secondary prophylaxis if CD4+ T-cell count decreases to <200/mm3 or if PCP recurs at a CD4+ T-cell count >200/mm3.25 54 It probably is prudent to continue secondary prophylaxis for life in those who had PCP episodes when they had CD4+ T-cell counts >200/mm3.25

Toxoplasmosis
Treatment
Oral

1.5 g twice daily.54 Alternatively, 1.5 g twice daily used in conjunction with oral pyrimethamine (200 mg once, then 50 mg once daily in those weighing <60 kg or 75 mg once daily in those weighing ≥60 kg) and oral leucovorin (at least 10–20 mg once daily).54

Alternatively, 1.5 g twice daily used in conjunction with oral sulfadiazine (1–1.5 g every 6 hours).54

Prevention (Primary Prophylaxis)
Oral

1.5 g once daily with or without pyrimethamine (25 mg once daily) and oral leucovorin (10 mg once daily).25

Discontinuance of primary toxoplasmosis prophylaxis is recommended in HIV-infected adults and adolescents who have a sustained (3 months or longer) increase in CD4+ T-cell counts to >200/ mm3 because such prophylaxis appears to add little benefit in terms of disease prevention for toxoplasmosis, and discontinuance reduces the medication burden, the potential for toxicity, drug interactions, selection of drug-resistant pathogens, and cost.25

Reinitiate primary prophylaxis if the CD4+ T-cell count decreases to <100–200/mm3.25

Prevention of Recurrence (Secondary Prophylaxis)
Oral

750 mg every 6–12 hours.25 54 Alternatively, 750 mg every 6–12 hours in conjunction with oral pyrimethamine (25 mg once daily) and oral leucovorin (10 mg once daily).25 54

Initiate long-term suppressive therapy or chronic maintenance therapy (secondary prophylaxis) in all patients who have completed initial treatment of toxoplasmosis encephalitis (TE).25 54

Consideration can be given to discontinuing secondary prophylaxis in adults or adolescents who successfully completed initial treatment for TE, are asymptomatic with respect to TE, and have a sustained (≥6 months) increase in CD4+ T-cell counts to >200/mm3.25 54

Reinitiate secondary prophylaxis if CD4+ T-cell count decreases to <200/mm3.25 54

Babesiosis
Oral

750 mg twice daily for 7–10 days recommended by IDSA and others;29 56 used in conjunction with oral azithromycin (0.5–1 g on day 1, then 250 mg once daily for total of 7–10 days; 0.6–1 g daily in immunocompromised patients).56

Prescribing Limits

Pediatric Patients

Babesiosis
Oral

Maximum 750 mg twice daily.29 56

Special Populations

No special population dosage recommendation at this time.1

Cautions for Mepron

Contraindications

  • Hypersensitivity to atovaquone or any ingredient in the formulation.1

Warnings/Precautions

Warnings

Precautions Related to Pneumocystis jiroveci (Pneumocystis carinii) Pneumonia

Clinical experience with atovaquone for treatment of P. jiroveci pneumonia (PCP) has been limited to patients with mild to moderate infections.1 Treatment of more severe episodes and efficacy in patients who are failing therapy with co-trimoxazole have not been systematically studied.1

Not effective therapy for concurrent pulmonary conditions such as bacterial, viral, or fungal pneumonia or mycobacterial diseases.1 Clinical deterioration during atovaquone therapy could represent secondary infection with a nonsusceptible pathogen and/or progression of PCP.1 Evaluate all patients with acute PCP for other possible causes of pulmonary disease and treat with additional agents as appropriate.1

General Precautions

Administration Precautions

Must be administered with food to enhance GI absorption of the drug and provide adequate plasma concentrations.1 Plasma atovaquone concentrations correlate with treatment response and survival.1

Consider alternative therapy in patients unable to take the drug with food.1

Use with caution in patients with GI disorders that may impair absorption (e.g., chronic diarrhea, malabsorption syndrome).1

Specific Populations

Pregnancy

Category C.1

Lactation

Distributed into milk in rats; not known whether distributed into human milk.1 Caution advised.1

Pediatric Use

Safety and efficacy not established in children.1

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine if they respond differently than younger adults; clinical experience has not identified differences.1

Select dosage with caution because of possible age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.1

Hepatic Impairment

Use caution and close monitoring in patients with severe hepatic impairment.1

Common Adverse Effects

Rash, diarrhea, nausea, headache, vomiting, fever, asthenia.1

Interactions for Mepron

Protein-bound Drugs

Highly bound to plasma proteins; use with caution in patients receiving highly protein-bound drugs with narrow therapeutic indices since competition for binding sites may occur.1

Specific Drugs

Drug

Interaction

Comments

Antimycobacterials, rifamycins

Rifampin: Decreased atovaquone concentrations and half-life; increased rifampin concentrations1

Rifabutin: Specific studies not available but pharmacokinetic interactions similar to those reported with rifampin may occur1

Rifampin: Concomitant use not recommended1

Co-trimoxazole

Slightly decreased concentrations of trimethoprim and sulfamethoxazole; no change in atovaquone concentrations1

Effect not expected to be clinically important1

Metoclopramide

Decreased bioavailability of atovaquone reported with the fixed combination of atovaquone and proguanil hydrochloride (Malarone)58

Use concomitantly only if other antiemetics not available58

Phenytoin

No effect on protein binding of either drug1

Tetracycline

Decreased atovaquone concentrations reported with the fixed combination of atovaquone and proguanil hydrochloride (Malarone)58

Zidovudine

Increased zidovudine AUC; no change in atovaquone pharmacokinetics1

Effect not expected to be clinically important1

Mepron Pharmacokinetics

Absorption

Bioavailability

Absorption highly dependent on formulation and diet. 1 Bioavailability of suspension formulation is about twice that of previously available tablet formulation.1

Food

Food, especially that high in fat, increases absorption by twofold to threefold.1 25 Should be taken with food to ensure adequate plasma concentrations.1

Special Populations

Absorption may be limited in patients with GI disorders.1

Distribution

Plasma Protein Binding

Extensively bound to plasma proteins (99.9%).1

Distributed into milk in rats in concentrations approximately 30% of concurrent plasma concentrations.1 Not known whether distributed into human milk.1

Elimination

Metabolism

Minimally metabolized; no metabolite identified. 1

Elimination Route

Enterohepatic recirculation and eventual elimination in feces; greater than 94% of a dose is excreted unchanged in feces over 21 days.1 Minimal excretion in urine (<0.6%).1

Half-life

67–78 hours.1

Special Populations

Hepatic impairment: Studies using the fixed combination of atovaquone and proguanil hydrochloride (Malarone) indicate no marked differences in the rate or extent of systemic exposure to atovaquone in patients with mild to moderate hepatic impairment, but elimination half-life of atovaquone is prolonged in those with moderate hepatic impairment.58

Renal impairment: Studies using the fixed combination of atovaquone and proguanil hydrochloride (Malarone) indicate clearance of atovaquone in patients with mild to moderate renal impairment is similar to that in those with normal renal function,58 but plasma concentrations and AUC of atovaquone are decreased in those with severe renal impairment (Clcr <30 mL/minute).58

Stability

Storage

Oral

Suspension

15°–25°C. Do not freeze.1

Actions and Spectrum

  • Synthetic hydroxynaphthoquinone-derivative antiprotozoal agent.1 7 8 10 15 17

  • Selectively inhibits mitochondrial electron transport with consequent inhibition of de novo pyrimidine synthesis.3 5 7 8 10 11 12 13 15 17 19 24

  • Active in vitro and/or in vivo against a variety of protozoa,3 5 11 12 14 15 16 17 including Pneumocystis jiroveci (formerly Pneumocystis carinii),3 5 7 12 15 16 17 Plasmodium spp.,14 15 41 and Toxoplasma gondii.11 15

Advice to Patients

  • Importance of taking atovaquone concomitantly with food.1

  • Advise patients using the multiple-dose bottle containing the oral suspension to shake it gently before removing a dose.1 Advise those using the single-dose foil pouch containing the oral suspension to ingest entire contents by mouth by discharging the dose into a dosing spoon or cup or directly into the mouth.1

  • Importance of completing full course of therapy, even if feeling better after a few days.1

  • Importance of recognizing pulmonary manifestations of possibly concurrent bacterial, viral, fungal, or mycobacterial infections associated with HIV infection and/or progression of the underlying PCP and contacting a clinician if pulmonary symptomatology develops or worsens during atovaquone therapy.1 20

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs.1

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Atovaquone

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Suspension

750 mg/5 mL

Mepron (with benzyl alcohol)

GlaxoSmithKline

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 02/2014. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Mepron 750MG/5ML Suspension (GLAXO SMITH KLINE): 210/$1,124.69 or 630/$3,277.90

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions February 1, 2008. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

1. GlaxoSmithKline. Mepron (atovaquone) suspension prescribing information. Research Triangle Park, NC; 2006 Nov.

2. Nightingale SL. From the Food and Drug Administration. JAMA. 1992; 267:339. [PubMed 1727943]

3. Falloon J, Kovacs J, Hughes W et al. A preliminary evaluation of 566C80 for the treatment of pneumocystis pneumonia in patients with the acquired immunodeficiency syndrome. New Engl J Med. 1991; 325:1534-8. [IDIS 289180] [PubMed 1944437]

4. Hughes WT. A new drug (566C80) for the treatment of pneumocystis carinii pneumonia. Ann Intern Med. 1992; 116:953-4. [IDIS 296797] [PubMed 1580456]

5. Hughes WT, Kennedy W, Shenep JL et al. Safety and pharmacokinetics of 566C80, a hydroxynaphthoquinone with anti-pneumocystis carinii activity: a phase I study in human immunodeficiency virus (HIV)-infected men. J Infect Dis. 1991; 163:843-8. [IDIS 279851] [PubMed 2010637]

6. Anon. FDA authorizes wider use of new oral medication for AIDS. Oncology. 1991; 5:59.

7. Dohn MN, Frame PT, Baughman RP et al. Open-label efficacy and safety trial of 42 days of 566C80 for Pneumocystis carinii pneumonia in AIDS patients. J Protozool. 1991; 38:220-1S.

8. Hudson AT, Randall AW, Fry M et al. Novel anti-malarial hydroxynaphthoquinones with potent broad spectrum anti-protozoal activity. Parasitology. 1985; 90:45-55. [PubMed 3920634]

9. Wong RJ. Highlights of the Seventh International Conference on AIDS. Clin Pharm. 1991; 10:809-22. [IDIS 286982] [PubMed 1686580]

10. Gutteridge WE. Antimalarial drugs currently in development. J R Soc Med. 1989; 17:63-6.

11. Araujo FG, Huskinson J, Remington JS. Remarkable in vitro and in vivo activities of the hydroxynaphthoquinone 566C80 against tachyzoites and tissue cysts of Toxoplasma gondii. Antimicrob Agents Chemother. 1991; 35: 293-9.

12. Hughes WT, Gray VL, Gutteridge WE et al. Efficacy of a hydroxynaphthoquinone, 566C80, in experimental Pneumocystis carinii pneumonitis. Antimicrob Agents Chemother. 1990; 34:225-8. [PubMed 2327770]

13. Hammond DJ, Burchell JR, Pudney M. Inhibition of pyrimidine biosynthesis de novo in Plasmodium falciparum by 2-(4-t-butylcyclohexyl)-3-hydroxy-1, 4-naphthoquinone in vitro. Mol Biochem Parasitol. 1985; 14:97-109. [PubMed 3885032]

14. Davies CS, Pudney M, Matthews PJ et al. The causal prophylactic activity of the novel hydroxynaphthoquinone 566C80 against Plasmodium berghei infections in rats. Acta Leiden. 1989; 58:115-28. [PubMed 2489391]

15. Burroughs Wellcome, Research Triangle Park, NC: Personal communication.

16. Sattler FR, Feinberg J. New developments in the treatment of Pneumocystis carinii pneumonia. Chest. 1992; 101:451-7. [IDIS 291546] [PubMed 1531191]

17. Gutteridge WE. 566C80, an antimalarial hydroxynaphthoquinone with broad spectrum: experimental activity against opportunistic parasitic infections of AIDS patients. J Protozool. 1991; 38:141-3S.

18. Fry M, Pudney M. Site of action of the antimalarial hydroxynaphthoquinone, 2-[trans-4-(4′-chlorophenyl) cyclohexyl]-3-hydroxy-1,4-naphthoquinone (566C80). Biochem Pharmacol. 1992; 43:1545-53. [PubMed 1314606]

19. Anon. Atovaquone for Pneumocystis carinii pneumonia. Med Lett Drugs Ther. 1993; 35:28-9. [PubMed 8450807]

20. Burroughs Wellcome. Formulary information: new Mepron atovaquone 250 mg tablets. Research Triangle Park, NC; 1992 Nov.

21. Murray JF, Felton CP, Garay SM et al. Pulmonary complications of the acquired immunodeficiency syndrome. Report of a National Heart, Lung, and Blood Institute Workshop. N Engl J Med. 1984; 310:1682-8. [PubMed 6328301]

22. Food and Drug Adminstration. Orphan designations pursuant to Section 526 of the Federal Food and Cosmetic Act as amended by the Orphan Drug Act (P.L. 97-414), to March 31, 1993. Rockville, MD; 1993 Apr.

23. Anon. New oral agent for PCP is effective, well tolerated. Oncology. 1992; 6:88. [PubMed 1449979]

24. Hughes W, Leoung G, Kramer F et al. Comparison of atovaquone (566C80) with trimethoprim-sulfamethoxazole to treat Pneumocystis carinii pneumonia in patients with AIDS. N Engl J Med. 1993; 328:1521-7. [IDIS 314638] [PubMed 8479489]

25. US Public Health Service (USPHS) and Infectious Diseases Society of America (IDSA) Prevention of Opportunistic Infections Working Group. 2001 USPHS/IDSA guidelines for the prevention of opportunistic infections in persons with human immunodeficiency virus. From the US Department of Health and Human Services HIV/AIDS Information Services (AIDSinfo) website ().

26. Dohn MN, Weinberg WG, Torres RA et al. Oral atovaquone compared with intravenous pentamidine for Pneumocystis carinii pneumonia in patients with AIDS. Ann Intern Med. 1994; 121:174-80. [IDIS 332897] [PubMed 7880228]

27. Kovacs JA and the NIAID-Clinical Center Intramural AIDS Program. Efficacy of atovaquone in treatment of toxoplasmosis in patients with AIDS. Lancet. 1992; 340:637-8. [IDIS 374759] [PubMed 1355212]

28. Hughes W, Leoung G, Kramer F et al. Comparison of 566C80 & trimethoprim-sulfamethoxazole (TMP-SMZ) for the treatment of P. carinii pneumonitis (PCP). Int Conf AIDS 1992. Abstract No. WeB 1019.

29. Anon. Drugs for parasitic infections. Med Lett Drugs Ther. Aug 2004. From the Medical Letter website ().

30. Pagano G, Kennedy W, Weller S et al. The safety and pharmacokinetics of atovaquone in immunocompromised children. In: Program and Abstracts of the IXth International Conference on AIDS. Berlin, Germany; 1993 June 6-11:378. Abstract No. PO-B10-1455.

31. Lee BL, Tauber MG, Sadler B et al. Atovaquone inhibits the glucuronidation and increases the serum concentrations of zidovudine (ZDV). Proceedings of ICAAC Orlando 1994. Abstract No. A46.

32. LaFon S, Masur H, Sattler F et al. The relationship of treatment-limiting adverse events (TLAE) to time on therapy and plasma drug concentrations in a randomized trial of trimethoprim/sulfamethoxazole (T/S) vs. atovaquone (ATQ) for the therapy of AIDS related Pneumocystis pneumonia (PCP). In: Program and Abstracts of the IXth International Conference on AIDS. Berlin, Germany; 1993 June 6-11:377. Abstract No. PO-B10-1454.

33. El-Sadr WM, Murphy RS, Yurik TM et al. Atovaquone compared with dapsone for the prevention of Pneumocystis carinii pneumonia in patients with HIV infection who cannot tolerate trimethoprim, sulfonamides, or both. N Engl J Med. 1998; 339:1889-95. [IDIS 418176] [PubMed 9862944]

34. Fishman JA. Treatment of infection due to Pneumocystis carinii. Antimicrob Agents Chemother. 1998; 42:1309-14. [IDIS 408066] [PubMed 9624465]

35. Weverling GJ, Mocroft A, Ledergerber B et al. Discontinuation of Pneumocystis carinii pneumonia prophylaxis after start of highly active antiretroviral therapy in HIV-1 infection: EuroSIDA study group. Lancet. 1999; 353:1293-8. [PubMed 10218526]

36. Schneider MME, Borleffs JCC, Stolk RP et al. Discontinuation of prophylaxis for Pneumocystis carinii pneumonia in HIV-1 infected patients treated with highly active antiretroviral therapy. Lancet. 1999;353:201-3.

37. Furrer H, Egger M, Opravil M et al. Discontinuation of primary prophylaxis against Pneumocystis carinii pneumonia in HIV-1 infected adults treated with combination antiretroviral therapy. N Engl J Med. 1999; 340:1301-6. [IDIS 425566] [PubMed 10219064]

38. Chan C, Montaner J, Lefebvre EA et al. Atovaquone suspension compared with aerosolized pentamidine for prevention of Pneumocystis carinii pneumonia in human immunodeficiency virus-infected subjects intolerant of trimethoprim or sulfomamides. J Infect Dis. 1999; 180:369-76. [IDIS 433825] [PubMed 10395851]

39. Katlama C, Mouthon B, Gourdon D et al. Atovaquone as long-term suppressive therapy for toxoplasmic encephalitis in patients with AIDS and multiple drug intolerance: atovaquone expanded access group. AIDS. 1996; 10:1107-12. [PubMed 8874627]

40. American Academy of Pediatrics. 2006 Red Book: Report of the Committee on Infectious Diseases. 27th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2006.

41. GlaxoWellcome. Malarone (atovaquone and proguanil hydrochloride) tablets and pediatric tablets prescribing information. Research Triangle Park, NC; 2000 Jul.

42. Pearson PA, Piracha AR, Sen HA et al. Atovaquone for the treatment of toxoplasma retinochoroiditis in immunocompetent patients. Ophthalmology. 1999; 106:148-53. [IDIS 428388] [PubMed 9917796]

43. Torres RA, Weinberg W, Stansell J et al. Atovaquone for salvage treatment and suppression of toxoplasmic encephalitis in patients with AIDS. Atovaquone/Toxoplasmic Encephalitis Study Group. Clin Infect Dis. 1997; 24:422-9. [IDIS 382956] [PubMed 9114194]

44. Looareesuwan S, Chulay JD, Canfield CJ et al. Malarone (atovaquone and proguanil hydrochloride): a review of its clinical development for treatment of malaria. Malarone Clinical Trials Study Group. Am J Trop Med Hyg. 1999; 60:533-41. [IDIS 428141] [PubMed 10348225]

45. Looareesuwan S, Viravan C, Webster HK et al. Clinical studies of atovaquone, alone or in combination with other antimalarial drugs, for treatment of acute uncomplicated malaria in Thailand. Am J Trop Med Hyg. 1996; 54:62-6. [IDIS 363233] [PubMed 8651372]

46. Dworkin MS, Hanson DL, Kaplan JE et al. Risk for preventable opportunistic infections in persons with AIDS after antiretroviral therapy increases CD4+ T lymphocyte counts above prophylaxis thresholds. J Infect Dis. 2000; 182:611-5. [PubMed 10915098]

47. Mussini C, Pezzotto P, Govoni A et al. Discontinuation of primary prophylaxis for Pneumocystis carinii pneumonia and toxoplasmic encephalitis in human immunodeficient virus type 1-infected patients: the changes in opportunistic prophylaxis study. J Infect Dis. 2000; 181:1635-42. [IDIS 447385] [PubMed 10823763]

48. Lopez Bernaldo de Quiros JC, Miro JM, Pena JM et al. A randomized trial of the discontinuation of primary and secondary prophylaxis against Pneumocystis carinii pneumonia after highly active antiretroviral therapy in patients with HIV infection: Grupo de Estudio del SIDA 04/98. N Engl J Med. 2001; 344:159-67. [IDIS 458267] [PubMed 11172138]

49. Furrer H, Opravil M, Rossi M et al. Discontinuation of primary prophylaxis in HIV-infected patients at high risk of Pneumocystis carinii pneumonia: prospective multicentre study. AIDS. 2001; 15:501-7. [PubMed 11242147]

50. Kirk O, Lundgren JD, Pedersen C et al. Can chemoprophylaxis against opportunistic infections be discontinued after an increase in CD4 cells induced by highly active antiretroviral therapy? AIDS. 1999; 13:1647-51.

51. Soriano V, Dona C, Rodriguez-Rosado R et al. Discontinuation of secondary prophylaxis for opportunistic infections in HIV-infected patients receiving highly active antiretroviral therapy. AIDS. 2000; 14:383-6. [PubMed 10770540]

52. Ledergerber B, Mocroft A, Reiss P et al. Discontinuation of secondary prophylaxis against Pneumocystis carinii pneumonia in patients with HIV infection who have a response to antiretroviral therapy. N Engl J Med. 2001; 344:168-74. [IDIS 458268] [PubMed 11188837]

53. Furrer H, Opravil M. Bernasconi E et al. Stopping primary prophylaxis in HIV-1-infected patients at high risk of toxoplasma encephalitis: Swiss HIV cohort study. Lancet. 2000; 355:2217-8. [IDIS 448523] [PubMed 10881897]

54. Centers for Disease Control and Prevention. Treating opportunistic infections among HIV-infected adults and adolescents: recommendations from CDC, the National Institutes of Health, and the HIV Medicine Association/Infectious Diseases Society of America. MMWR Recomm Rep. 2004; 53(RR-15):1-112.

55. Centers for Disease Control and Prevention. Treating opportunistic infections among HIV-exposed and infected children: recommendations from CDC, the National Institutes of Health, and the Infectious Diseases Society of America. MMWR Recomm Rep. 2004; 53(RR-14):1-92.

56. Wormser GP, Dattwyler RJ, Shapiro ED et al. The clinical assessment, treatment, and prevention of lyme disease, human granulocytic anaplasmosis, and babesiosis: clinical practice guidelines by the Infectious Diseases Society of America. Clin Infect Dis. 2006; 43:1089-134. [PubMed 17029130]

57. Krause PJ, Lepore T, Sikand VK et al. Atovaquone and azithromycin for the treatment of babesiosis. N Engl J Med. 2000; 343:1454-8. [IDIS 455399] [PubMed 11078770]

58. GlaxoSmithKline. Malarone (atovaquone and proguanil hydrochloride) tablets and pediatric tablets prescribing information. Research Triangle Park, NC. 2006 Nov.

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