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Atovaquone: Drug information

Atovaquone: Drug information
(For additional information see "Atovaquone: Patient drug information" and see "Atovaquone: Pediatric drug information")

For abbreviations, symbols, and age group definitions used in Lexicomp (show table)
Brand Names: US
  • Mepron
Brand Names: Canada
  • GLN-Atovaquone;
  • Mepron
Pharmacologic Category
  • Antiprotozoal
Dosing: Adult
Babesiosis

Babesiosis (off-label use): Oral: 750 mg twice daily in combination with azithromycin for 7 to 10 days; a longer duration of ≥6 weeks, including 2 weeks after resolution of parasitemia, may be necessary for patients at high risk of relapse (eg, highly immunocompromised patients) (IDSA [Krause 2021]; Krause 2000; Krause 2008; Sanchez 2016).

Pneumocystis jirovecii pneumonia

Pneumocystis jirovecii pneumonia:

Prophylaxis, HIV-uninfected (alternative agent): Oral: 1.5 g once daily.

Prophylaxis (primary and secondary), patients with HIV: Oral: 1.5 g once daily (as monotherapy or with pyrimethamine and leucovorin). Continue prophylaxis following initiation of antiretroviral therapy (ART) until CD4 count >200 cells/mm3 for >3 months; some experts discontinue prophylaxis in patients with a CD4 count between 100 to 200 cells/mm3 who are receiving ART and have had an undetectable viral load for ≥3 to 6 months (HHS [OI adult 2020]).

Treatment, mild to moderate disease (alternative agent): Oral: 750 mg twice daily for 21 days.

Toxoplasma gondii encephalitis in patients with HIV

Toxoplasma gondii encephalitis in patients with HIV (off-label use; alternative agent): Oral:

Primary prophylaxis: 1.5 g once daily (either as monotherapy or with pyrimethamine plus leucovorin); primary prophylaxis is indicated for Toxoplasma IgG-positive patients with CD4 count <100 cells/mm3. Continue primary prophylaxis following initiation of ART until CD4 count >200 cells/mm3 for >3 months; some experts discontinue primary prophylaxis in patients with a CD4 count between 100 to 200 cells/mm3 who are receiving ART and have had an undetectable viral load for ≥3 to 6 months (HHS [OI adult 2020]).

Treatment: 1.5 g twice daily (either with pyrimethamine plus leucovorin, or with sulfadiazine, or as monotherapy) for at least 6 weeks (longer if extensive disease or incomplete response) (HHS [OI adult 2020]).

Secondary prophylaxis (chronic maintenance): 750 mg to 1.5 g twice daily (either with pyrimethamine plus leucovorin, or with sulfadiazine, or as monotherapy); may discontinue when asymptomatic and CD4 count >200 cells/mm3 for >6 months in response to antiretrovirals (HHS [OI adult 2020]).

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Kidney Impairment: Adult

The renal dosing recommendations are based upon the best available evidence and clinical expertise. Senior Editorial Team: Bruce Mueller, PharmD, FCCP, FASN, FNKF; Jason A. Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC; Michael Heung, MD, MS.

Altered kidney function: No dosage adjustment necessary for any degree of kidney dysfunction (<1% excreted in the urine) (expert opinion).

Hemodialysis, intermittent (thrice weekly): Unlikely to be dialyzed (highly protein bound): No supplemental dose or dosage adjustment necessary (expert opinion).

Peritoneal dialysis: Unlikely to be dialyzed (highly protein bound): No dosage adjustment necessary (expert opinion).

CRRT: No dosage adjustment necessary (expert opinion).

PIRRT (eg, sustained, low-efficiency diafiltration): No dosage adjustment necessary (expert opinion).

Dosing: Hepatic Impairment: Adult

There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied). Atovaquone undergoes enterohepatic cycling and primarily hepatic excretion. Use caution in patients with severe impairment; monitor closely.

Dosing: Pediatric

(For additional information see "Atovaquone: Pediatric drug information")

Pneumocystis jirovecii pneumonia, HIV-exposed/-infected

Pneumocystis jirovecii pneumonia (PCP), HIV-exposed/-infected (HHS [adult OI 2017, pediatric OI 2016]): Limited data available in ages <13 years:

Prophylaxis; primary or secondary:

Infants and Children: Oral:

1 to 3 months: 30 mg/kg/day once daily

4 to 24 months: 45 mg/kg/day once daily

>24 months: 30 mg/kg/day once daily; maximum daily dose: 1,500 mg/day

Adolescents: Oral: 1,500 mg once daily

Treatment; mild to moderate infection: Treatment duration: 21 days

Infants and Children: Oral:

1 to 3 months: 30 to 40 mg/kg/day divided once or twice daily

4 to 24 months: 45 mg/kg/day divided once or twice daily

>24 months: 30 to 40 mg/kg/day divided once or twice daily; maximum daily dose: 1,500 mg/day

Adolescent: Oral: 750 mg twice daily

Toxoplasmosis; encephalitis, HIV-exposed/-infected

Toxoplasmosis (toxoplasma gondii); encephalitis, HIV-exposed/-infected (HHS [adult OI 2017, pediatric OI 2016]): Limited data available:

Primary prophylaxis:

Infants and Children: Oral:

1 to 3 months: 30 mg/kg/day once daily

4 to 24 months: 45 mg/kg/day once daily; with or without pyrimethamine/leucovorin

>24 months: 30 mg/kg/day once daily; maximum daily dose: 1,500 mg/day

Adolescents: Oral: 1,500 mg once daily; with or without pyrimethamine/leucovorin

Treatment (encephalitis): Adolescents: Oral: 1,500 mg twice daily for at least 6 weeks (longer if extensive disease or incomplete response); use in combination with pyrimethamine/leucovorin or sulfadiazine is preferred

Secondary prophylaxis/chronic maintenance therapy (suppressive):

Infants and Children: Oral:

1 to 3 months: 30 mg/kg/day once daily with leucovorin

4 to 24 months: 45 mg/kg/day once daily; with or without pyrimethamine/leucovorin

>24 months: 30 mg/kg/day once daily; maximum daily dose: 1,500 mg/day; with leucovorin

Adolescents: Oral: 750 to 1,500 mg twice daily; use in combination with pyrimethamine/leucovorin or sulfadiazine is preferred

Babesiosis

Babesiosis: Limited data available (IDSA [Wormser 2006]):

Infants and Children: Oral: 40 mg/kg/day divided twice daily; maximum daily dose: 1,500 mg/day with azithromycin for 7 to 10 days

Adolescents: Oral: 750 mg twice daily for 7 to 10 days with azithromycin

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Kidney Impairment: Pediatric

Adolescents ≥13 years: There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied). However, atovaquone is not appreciably renally excreted.

Dosing: Hepatic Impairment: Pediatric

Adolescents ≥13 years: There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied). Atovaquone undergoes enterohepatic cycling and primarily hepatic excretion. Use caution in patients with severe impairment; monitor closely.

Dosing: Older Adult

Refer to adult dosing.

Dosage Forms: US

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Suspension, Oral:

Mepron: 750 mg/5 mL (5 mL, 210 mL) [contains benzyl alcohol; citrus flavor]

Generic: 750 mg/5 mL (5 mL, 10 mL, 210 mL)

Generic Equivalent Available: US

Yes

Dosage Forms: Canada

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Suspension, Oral:

Mepron: 750 mg/5 mL (210 mL) [contains benzyl alcohol, saccharin sodium]

Generic: 750 mg/5 mL (210 mL)

Administration: Adult

Oral: Must administer with food. Shake suspension gently before use. Once opened, a foil pouch can be emptied on a dosing spoon, in a cup, or directly into the mouth.

Administration: Pediatric

Oral: Must administer with food or a high-fat meal. Shake suspension gently before use. Once opened, a foil pouch can be emptied on a dosing spoon, in a cup, or directly into the mouth.

Use: Labeled Indications

Pneumocystis jirovecii pneumonia (PCP), prophylaxis: Prevention of PCP in adults and adolescents 13 years and older who are intolerant to trimethoprim-sulfamethoxazole (TMP-SMZ)

Pneumocystis jirovecii pneumonia (PCP), treatment: Acute oral treatment of mild to moderate PCP in adults and adolescents 13 years and older who are intolerant to TMP-SMZ

Use: Off-Label: Adult

Babesiosis; Toxoplasma gondii encephalitis (prophylaxis/treatment/chronic maintenance) in patients with HIV

Adverse Reactions

The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Frequency not always defined. Adverse reaction statistics have been compiled from studies including patients with advanced HIV disease. Consequently, it is difficult to distinguish reactions attributed to atovaquone from those caused by the underlying disease or a combination thereof.

>10%:

Central nervous system: Headache (16% to 31%), insomnia (10% to 19%), depression, pain

Dermatologic: Skin rash (22% to 46%), pruritus (5% to ≥10%), diaphoresis

Gastrointestinal: Diarrhea (19% to 42%), nausea (21% to 32%), vomiting (14% to 22%), abdominal pain (4% to 21%)

Infection: Infection (18% to 22%)

Neuromuscular & skeletal: Weakness (8% to 31%), myalgia

Respiratory: Cough (14% to 25%), rhinitis (5% to 24%), dyspnea (15% to 21%), sinusitis (7% to ≥10%), flu-like symptoms

Miscellaneous: Fever (14% to 40%)

1% to 10%:

Cardiovascular: Hypotension (≤1%)

Central nervous system: Dizziness (3% to 8%), anxiety (≤7%)

Endocrine & metabolic: Hyponatremia (7% to 10%), hyperglycemia (≤9%), increased amylase (7% to 8%), hypoglycemia (≤1%)

Gastrointestinal: Oral candidiasis (5% to 10%), anorexia (≤7%), dyspepsia (≤5%), constipation (≤3%), dysgeusia (≤3%)

Hematologic & oncologic: Anemia (4% to 6%), neutropenia (3% to 5%)

Hepatic: Increased liver enzymes (4% to 8%)

Renal: Increased blood urea nitrogen (≤1%), increased serum creatinine (≤1%)

Respiratory: Bronchospasm (2% to 4%)

<1%, postmarketing, and/or case reports: Acute renal failure, angioedema, constriction of the pharynx, corneal disease (vortex keratopathy), desquamation, erythema multiforme, hepatic failure (rare), hepatitis (rare), hypersensitivity reaction, methemoglobinemia, pancreatitis, Stevens-Johnson syndrome, thrombocytopenia, urticaria

Contraindications

Hypersensitivity to atovaquone or any component of the formulation

Warnings/Precautions

Concerns related to adverse effects:

• Diarrhea/vomiting: Absorption 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 antiprotozoal.

• Hypersensitivity: Hypersensitivity reactions (eg, angioedema, bronchospasm, throat tightness, urticaria) have occurred.

Disease-related concerns:

• Gastrointestinal disorders: Consider parenteral therapy with alternative agents in patients who have difficulty taking atovaquone with food. Gastrointestinal disorders may limit absorption of oral medications; may not achieve adequate plasma levels.

• Hepatic impairment: Use with caution in patients with severe hepatic impairment; monitor closely; rare cases of cholestatic hepatitis, elevated liver function tests, and fatal liver failure have been reported.

Pneumocystis jirovecii pneumonia (PCP): Appropriate use: When used for treatment, has only been indicated in mild to moderate PCP; not studied for use in severe PCP; atovaquone has less adverse effects than trimethoprim-sulfamethoxazole (TMP-SMZ) (the treatment of choice for mild to moderate PCP), although atovaquone is less effective than TMP-SMZ (HHS [OI adult 2020]).

Special populations:

• Older adult: Use with caution in elderly patients.

Dosage form specific issues:

• Benzyl alcohol and derivatives: Some dosage forms may contain benzyl alcohol; large amounts of benzyl alcohol (≥99 mg/kg/day) have been associated with a potentially fatal toxicity (“gasping syndrome”) in neonates; the “gasping syndrome” consists of metabolic acidosis, respiratory distress, gasping respirations, CNS dysfunction (including convulsions, intracranial hemorrhage), hypotension and cardiovascular collapse (AAP ["Inactive" 1997]; CDC 1982); some data suggests that benzoate displaces bilirubin from protein binding sites (Ahlfors 2001); avoid or use dosage forms containing benzyl alcohol with caution in neonates. See manufacturer’s labeling.

Metabolism/Transport Effects

None known.

Drug Interactions

Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.

Amodiaquine: May enhance the adverse/toxic effect of Atovaquone. Specifically, the risk for extrapyramidal side effects may be increased. Risk C: Monitor therapy

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. Risk D: 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. Risk C: 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. Risk C: Monitor therapy

Indinavir: Atovaquone may decrease the serum concentration of Indinavir. Risk C: Monitor therapy

Ketoconazole (Systemic): May increase the serum concentration of Atovaquone. Risk C: Monitor therapy

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. Risk D: Consider therapy modification

Nirmatrelvir and Ritonavir: May decrease the serum concentration of Atovaquone. Risk C: Monitor therapy

Rifabutin: Atovaquone may decrease the serum concentration of Rifabutin. Rifabutin may decrease the serum concentration of Atovaquone. Risk X: Avoid combination

RifAMPin: Atovaquone may increase the serum concentration of RifAMPin. RifAMPin may decrease the serum concentration of Atovaquone. Risk X: Avoid combination

Ritonavir: May decrease the serum concentration of Atovaquone. Risk C: Monitor therapy

Tetracycline (Systemic): May decrease the serum concentration of Atovaquone. Risk C: Monitor therapy

Food Interactions

Ingestion with a fatty meal increases absorption. Management: Administer with food, preferably high-fat meals (peanuts or ice cream).

Pregnancy Considerations

Information specific to the use of atovaquone in pregnancy is limited.

Diagnosis and treatment of Pneumocystis jirovecii pneumonia (PCP) in pregnant women is the same as in nonpregnant women. Atovaquone may be used as an alternative agent for PCP and Toxoplasma gondii infections when needed in pregnancy (HHS [OI adult 2020]).

Breastfeeding Considerations

It is not known if atovaquone is present in breast milk.

Females with HIV infection should completely avoid breastfeeding to decrease the potential transmission of HIV.

Dietary Considerations

Must be taken with food.

Monitoring Parameters

Hepatic function at baseline (monitor closely during treatment in patients with severe hepatic impairment), hypersensitivity reactions, CD4 count (for chronic maintenance treatment in toxoplasmosis), patient’s food tolerance/ability to take atovaquone, post-dose vomiting, diarrhea

Mechanism of Action

Inhibits electron transport in mitochondria resulting in the inhibition of key metabolic enzymes responsible for the synthesis of nucleic acids and ATP

Pharmacokinetics

Absorption: Enhanced ~2-fold with food

Distribution: Vdss: 0.6 ± 0.17 L/kg; CSF concentration is <1% of the plasma concentration

Protein binding: >99%

Metabolism: Unknown

Bioavailability: Suspension (administered with food): 47% ± 15%

Half-life elimination: Range: 67 ± 33.4 hours to 77.6 ± 23.1 hours

Excretion: Feces (>94% as unchanged drug); urine (<1%)

Pricing: US

Suspension (Atovaquone Oral)

750 mg/5 mL (per mL): $3.87 - $10.06

Suspension (Mepron Oral)

750 mg/5 mL (per mL): $7.96

Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.

Brand Names: International
  • Mepron (BB, BM, BS, BZ, GY, JM, PL, SR, TT);
  • Samtirel (JP);
  • Wellvone (AT, AU, BE, CH, DE, DK, ES, FR, GB, GR, IE, IT, LU, NL, PT, SE, SI, ZA)


For country code abbreviations (show table)
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  2. American Academy of Pediatrics (AAP). In: Kimberlin DW, Brady MT, Jackson MA, Long SA, eds. Red Book: 2015 Report of the Committee on Infectious Diseases. 30th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2015.
  3. Artymowicz RJ and James VE, “Atovaquone: A New Antipneumocystis Agent,” Clin Pharm, 1993, 12(8):563-70. [PubMed 8222520]
  4. Behbahani R, Moshfeghi M, and Baxter JD, “Therapeutic Approaches for AIDS-Related Toxoplasmosis,” Ann Pharmacother, 1995, 29(7-8):760-8. [PubMed 8520094]
  5. Centers for Disease Control (CDC). Neonatal deaths associated with use of benzyl alcohol—United States. MMWR Morb Mortal Wkly Rep. 1982;31(22):290-291. http://www.cdc.gov/mmwr/preview/mmwrhtml/00001109.htm [PubMed 6810084]
  6. El-Sadr WM, Murphy RL, Yurik TM, et al, “Atovaquone Compared With Dapsone for the Prevention of Pneumocystis carinii in Patients With HIV Infection Who Cannot Tolerate Trimethoprim, Sulfonamides, or Both,” N Engl J Med, 1998, 339(26):1889-95. [PubMed 9862944]
  7. Haile LG and Flaherty JF, “Atovaquone: A Review,” Ann Pharmacother, 1993, 27(12):1488-94. [PubMed 8305784]
  8. Hughes W, Dorenbaum A, Yogev R, et al, “Phase I Safety and Pharmacokinetics Study of Micronized Atovaquone Human Immunodeficiency Virus-Infected Infants and Children. Pediatric AIDS Clinical Trials Group,” Antimicrob Agents Chemother, 1998, 42(6):1315-8. [PubMed 9624466]
  9. 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(21):1521-7. [PubMed 8479489]
  10. "Inactive" ingredients in pharmaceutical products: update (subject review). American Academy of Pediatrics (AAP) Committee on Drugs. Pediatrics. 1997;99(2):268-278. [PubMed 9024461]
  11. 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(10):1107-12. [PubMed 8874627]
  12. Krause PJ, Auwaerter PG, Bannuru RR, et al. Clinical practice guidelines by the Infectious Diseases Society of America (IDSA): 2020 guideline on diagnosis and management of babesiosis. Clin Infect Dis. 2021;72(2):185-189. doi:10.1093/cid/ciab050 [PubMed 33501959]
  13. Krause PJ, Gewurz BE, Hill D, et al. Persistent and relapsing babesiosis in immunocompromised patients. Clin Infect Dis. 2008;46(3):370-376. doi:10.1086/525852 [PubMed 18181735]
  14. Krause PJ, Lepore T, Sikand VK, et al. Atovaquone and azithromycin for the treatment of babesiosis. N Engl J Med. 2000;343(20):1454-1458. doi:10.1056/NEJM200011163432004 [PubMed 11078770]
  15. Mepron (atovaquone) [prescribing information]. Research Triangle Park, NC: GlaxoSmithKline; October 2020.
  16. Pagano G, Kennedy W, Weller S, et al, “The Safety and Pharmacokinetics of Atovaquone in Immunocompromised Children,” Abstracts of the IX International Conference on AIDS in Affiliation With the IV STD World Congress: Berlin, 1993, June 6-11; Abs No PO-B10-1455.
  17. Sanchez E, Vannier E, Wormser GP, Hu LT. Diagnosis, treatment, and prevention of Lyme disease, human granulocytic anaplasmosis, and babesiosis: a review. JAMA. 2016;315(16):1767-1777. doi:10.1001/jama.2016.2884 [PubMed 27115378]
  18. Spencer CM and Goa KL, “Atovaquone. A Review of Its Pharmacological Properties and Therapeutic Efficacy in Opportunistic Infections,” Drugs, 1995, 50(1):176-96. [PubMed 7588086]
  19. US Department of Health and Human Services (HHS) Panel on Opportunistic Infections in Adults and Adolescents with HIV. Guidelines for the prevention and treatment of opportunistic infections in adults and adolescents with HIV: recommendations from the Centers for Disease Control and Prevention, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America. http://aidsinfo.nih.gov/contentfiles/lvguidelines/adult_oi.pdf. Accessed April 29, 2020.
  20. US Department of Health and Human Services (HHS) Panel on Opportunistic Infections in HIV-Exposed and HIV-Infected Children. Guidelines for the Prevention and Treatment of Opportunistic Infections in HIV-Exposed and HIV-Infected Children. Department of Health and Human Services. November 2013. http://aidsinfo.nih.gov/contentfiles/lvguidelines/oi_guidelines_pediatrics.pdf.
  21. 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(9):1089-134. [PubMed 17029130]
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