Atovaquone

(BAN, USAN, rINN)
Atovaquone Chemical formula
Synonyms: Atovacuona; Atovakon; Atovakvon; Atovakvoni; Atovaquonum; BW-A566C; BW-566C; BW-566C80; 566C; 566C80. 2-[trans-4(4-Chlorophenyl)cyclohexyl]-3-hydroxy-1,4-naphthoquinone.
Cyrillic synonym: Атовахон.

💊 Chemical information

Chemical formula: C22H19O3Cl = 366.8.
CAS — 95233-18-4.
ATC — P01AX06.

Pharmacopoeias.

In US.

USP 31

(Atovaquone). A yellow powder. Insoluble in water; slightly soluble in alcohol, in butanediol, in ethyl acetate, in glycerol, in octanol, and in macrogol 200; sparingly soluble in acetone, in di-nbutyl adipate, in dimethyl sulfoxide, and in macrogol 400; soluble in chloroform; freely soluble in N-methyl-2-pyrrolidone and in tetrahydrofuran; very slightly soluble in 0.1N sodium hydroxide. Store in airtight containers. Protect from light.

💊 Adverse Effects and Precautions

Adverse reactions to atovaquone include skin rashes, headache, fever, insomnia, and gastrointestinal effects such as nausea, diarrhoea, and vomiting. Raised liver enzyme values, hyponatraemia, and haematological disturbances such as anaemia and neutropenia may occur occasionally. Atovaquone should be avoided in patients with gastrointestinal disorders that may limit absorption of the drug.

Effects on the skin.

Stevens-Johnson syndrome has been reported1 in a patient taking atovaquone with proguanil.
1. Emberger M, et al. Stevens-Johnson syndrome associated with Malarone antimalarial prophylaxis. Abstract: Clin Infect Dis 2003; 37: 158. Full version: http://www.journals.uchicago.edu/ doi/pdf/10.1086/375073 (accessed 17/07/08)

💊 Interactions

Use of atovaquone with either metoclopramide, tetracycline, or rifampicin (and possibly also rifabutin) may result in decreases in plasma-atovaquone concentrations. Other drugs which have produced small reductions in plasma-atovaquone concentrations include aciclovir, antidiarrhoeals, benzodiazepines, cephalosporins, laxatives, opioids, and paracetamol. Atovaquone is reported to decrease the metabolism of zidovudine resulting in moderate increases in zidovudine plasma concentrations. A decrease in trough concentrations of indinavir, and in the area under the indinavir time-concentration curve has been reported when atovaquone was also given. Small decreases in the plasma concentrations of co-trimoxazole have been noted in patients taking atovaquone. There is a theoretical possibility that atovaquone could displace other highly protein-bound drugs from plasma-protein binding sites.

💊 Pharmacokinetics

Atovaquone is poorly absorbed from the gastrointestinal tract after oral doses; bioavailability is especially poor in patients with AIDS. Bioavailability from commercial oral liquid formulations is better than from tablets and can be further improved if taken with food, particularly meals with a high fat content. Atovaquone is more than 99% bound to plasma proteins and has a long plasma half-life of 2 to 3 days, thought to be due to enterohepatic recycling. It is excreted almost exclusively in faeces as unchanged drug.
1. Hughes WT, 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
2. Rolan PE, et al. Examination of some factors responsible for a food-induced increase in absorption of atovaquone. Br J Clin Pharmacol 1994; 37: 13–20
3. Dixon R, et al. Single-dose and steady-state pharmacokinetics of a novel microfluidized suspension of atovaquone in human immunodeficiency virus-seropositive patients. Antimicrob Agents Chemother 1996; 40: 556–60
4. Hussein Z, et al. Population pharmacokinetics of atovaquone in patients with acute malaria caused by Plasmodium falciparum. Clin Pharmacol Ther 1997; 61: 518–30
5. Rolan PE, et al. Disposition of atovaquone in humans. Antimicrob Agents Chemother 1997; 41: 1319–21.

💊 Uses and Administration

Atovaquone is a hydroxynaphthoquinone antiprotozoal that is also active against the fungus Pneumocystis jirovecii. It is used in the treatment and prophylaxis of pneumocystis pneumonia in patients unable to tolerate co-trimoxazole, and with proguanil in the treatment and prophylaxis of malaria. In the treatment of mild to moderate pneumocystis pneumonia, atovaquone is given orally in a dose of 750 mg with food twice daily as a suspension, for 21 days. For prophylaxis 1500 mg of the suspension is given once daily with food. Prophylaxis of falciparum malaria should start 1 to 2 days before travel to the malarious area, continue daily throughout exposure, and for 7 days after leaving the area. The following doses may be given once daily:
adults and children over 40 kg: atovaquone 250 mg with proguanil hydrochloride 100 mg
children 11 to 20 kg: one-quarter the adult dose
children 21 to 30 kg: one-half the adult dose
children 31 to 40 kg: three-quarters the adult dose
In the treatment of uncomplicated falciparum malaria, the following doses are given as a single daily dose for 3 days:
adults and children over 40 kg: atovaquone 1000 mg with proguanil hydrochloride 400 mg
children 5 to 8 kg: one-eighth the adult dose
children 9 to 10 kg: three-sixteenths the adult dose
children 11 to 20 kg: one-quarter the adult dose
children 21 to 30 kg: one-half the adult dose
children 31 to 40 kg: three-quarters the adult dose
Atovaquone with proguanil is one of the antimalarial drugs recommended by some experts to be carried as a standby for the emergency treatment of malaria. The dose recommended for self-treatment is the same as that for treatment of uncomplicated falciparum malaria.
1. Haile LG, Flaherty JF. Atovaquone: a review. Ann Pharmacother 1993; 27: 1488–94
2. Artymowicz RJ, James VE. Atovaquone: a new antipneumocystis agent. Clin Pharm 1993; 12: 563–70
3. Spencer CM, Goa KL. Atovaquone: a review of its pharmacological properties and therapeutic efficacy in opportunistic infections. Drugs 1995; 50: 176–96
4. Baggish AL, Hill DR. Antiparasitic agent atovaquone. Antimicrob Agents Chemother 2002; 46: 1163–73
5. McKeage K, Scott LJ. Atovaquone/proguanil: a review of its use for the prophylaxis of Plasmodium falciparum malaria. Drugs 2003; 63: 597–623
6. Marra F, et al. Atovaquone-proguanil for prophylaxis and treatment of malaria. Ann Pharmacother 2003; 37: 1266–75.

Babesiosis.

In a prospective, randomised study1 involving 58 patients with babesiosis, atovaquone with azithromycin was found to be as effective as, and associated with fewer adverse effects than, standard therapy with quinine and clindamycin. Atovaquone 750 mg twice daily with azithromycin 600 mg once daily, or 500 to 1000 mg on day 1 followed by 250 mg once daily thereafter, both orally for 7 to 10 days, has been recommended by some experts2,3 in the USA for the treatment of Babesia microti infections. Children may be given atovaquone 20 mg/kg twice daily with azithromycin 12 mg/kg once daily, or 10 mg/kg on day 1 followed by 5 mg/kg once daily thereafter, both by mouth for 7 to 10 days.
1. Krause PJ, et al. Atovaquone and azithromycin for the treatment of babesiosis. N Engl J Med 2000; 343: 1454–8
2. Wormser GP, 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: 1089–1134. Also available at: http://www.journals.uchicago.edu/ doi/pdf/10.1086/375073 (accessed 17/07/08
3. Abramowicz M, ed. Drugs for parasitic infections. 1st ed. New Rochelle NY: The Medical Letter, 2007.

Malaria.

Atovaquone with proguanil (Malarone) is used in the treatment and prophylaxis of uncomplicated malaria caused by Plasmodium falciparum. Atovaquone, a blood schizontocide, is associated with an unacceptably high rate of recrudescence when used alone1,2 for treatment but is more successful in malaria when used with proguanil,2,3 including that produced by multidrug-resistant strains.4Use of the combination to treat P. ovale and P. malariae malarias has also been studied.5 Atovaquone with proguanil followed by primaquine may also be effective for the treatment of P. vivax malaria.6 Atovaquone with proguanil has also been found to be useful for prophylaxis of falciparum malaria in both children7 and adults8in endemic areas. It may also be used for prophylaxis in nonimmune travellers9,10 and appears to be well tolerated.10,11
1. Chiodini PL, et al. Evaluation of atovaquone in the treatment of patients with uncomplicated Plasmodium falciparum malaria. J Antimicrob Chemother 1995; 36; 1073–5
2. Looareesuwan S, 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
3. Radloff PD, et al. Atovaquone and proguanil for Plasmodium falciparum malaria. Lancet 1996; 347: 1511–14
4. Sabchareon A, et al. Efficacy and pharmacokinetics of atovaquone and proguanil in children with multidrug-resistant Plasmodium falciparum malaria. Trans R Soc Trop Med Hyg 1998; 92: 201–6
5. Radloff PD, et al. Atovaquone plus proguanil is an effective treatment for Plasmodium ovale and P. malariae malaria. Trans R Soc Trop Med Hyg 1996; 90: 682
6. Looareesuwan S, et al. Atovaquone and proguanil hydrochloride followed by primaquine for treatment of plasmodium vivax malaria in Thailand. Trans R Soc Trop Med Hyg 1999; 93: 637–40
7. Lell B, et al. Randomised placebo-controlled study of atovaquone plus proguanil for malaria prophylaxis in children. Lancet 1998; 351: 709–13
8. Shanks GD, et al. Efficacy and safety of atovaquone/proguanil as suppressive prophylaxis for Plasmodium falciparum malaria. Clin Infect Dis 1998; 27: 494–9
9. Overbosch D, et al. Atovaquone-proguanil versus mefloquine for malaria prophylaxis in nonimmune travelers: results from a randomized, double-blind study. Clin Infect Dis 2001; 33: 1015–21
10. Nakato H, et al. A systematic review and meta-analysis of the effectiveness and safety of atovaquone proguanil (Malarone) for chemoprophylaxis against malaria. J Antimicrob Chemother 2007; 60: 929–36
11. Høgh B, et al. Atovaquone-proguanil versus chloroquine-proguanil for malaria prophylaxis in non-immune travellers: a randomised, double-blind study. Lancet 2000; 356: 1888–94.

Microsporidiosis.

There is no established effective treatment for microsporidiosis. Beneficial responses were reported with atovaquone in a preliminary study.1
1. Anwar-Bruni DM, et al. Atovaquone is effective treatment for the symptoms of gastrointestinal microsporidiosis in HIV-1-infected patients. AIDS 1996; 10: 619–23.

Pneumocystis pneumonia.

Atovaquone is one alternative to co-trimoxazole for the treatment of pneumocystis pneumonia. In open studies, a clinical response to atovaquone was reported in 78% of patients with mild to moderate disease and in 56% of patients with severe disease who were intolerant of, or who failed to respond to, both co-trimoxazole and pentamidine.1Comparative studies have shown atovaquone to be less effective than co-trimoxazole2 and probably less effective than pentamidine,3,4 but to produce fewer treatment-limiting adverse effects than either. Atovaquone is also an alternative to co-trimoxazole for both primary or secondary prophylaxis, and was as effective as dapsone5or inhaled pentamidine6 in studies in patients intolerant of cotrimoxazole.
1. White A, et al. Clinical experience with atovaquone on a treatment investigational new drug protocol for Pneumocystis carinii pneumonia. J Acquir Immune Defic Syndr Hum Retrovirol 1995; 9: 280–5
2. Hughes W, 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
3. Dohn MN, et al. Oral atovaquone compared with intravenous pentamidine for Pneumocystis carinii pneumonia in patients with AIDS. Ann Intern Med 1994; 121: 174–80
4. Lederman MM, van der Horst C. Atovaquone for Pneumocystis carinii pneumonia. Ann Intern Med 1995; 122: 314
5. El-Sadr WM, 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
6. Chan C, et al. Atovaquone suspension compared with aerosolized pentamidine for prevention of Pneumocystis carinii pneumonia in human immunodeficiency virus-infected subjects intolerant of trimethoprim or sulfonamides. J Infect Dis 1999; 180: 369–76.

Toxoplasmosis.

Atovaquone, either alone or with pyrimethamine or sulfadiazine, has produced encouraging results for treatment1-3 or long-term suppression2-4 of toxoplasmosis in patients with AIDS.
1. Kovacs JA, et al. Efficacy of atovaquone in treatment of toxoplasmosis in patients with AIDS. Lancet 1992; 340: 637–8
2. Torres RA, et al. Atovaquone for salvage treatment and suppression of toxoplasmic encephalitis in patients with AIDS. Clin Infect Dis 1997; 24: 422–9
3. Chirgwin K, et al. Randomized phase II trial of atovaquone with pyrimethamine or sulfadiazine for treatment of toxoplasmic encephalitis in patients with acquired immunodeficiency syndrome: ACTG 237/ANRS 039 Study. Clin Infect Dis 2002; 34: 1243–50
4. Katlama C, et al. Atovaquone as long-term suppressive therapy for toxoplasmic encephalitis in patients with AIDS and multiple drug intolerance. AIDS 1996; 10: 1107–12.

💊 Preparations

USP 31: Atovaquone Oral Suspension.

Proprietary Preparations

Austral.: Wellvone; Austria: Wellvone; Belg.: Wellvone; Canad.: Mepron; Fr.: Wellvone; Ger.: Wellvone; Gr.: Wellvone; Ital.: Wellvone; Neth.: Wellvone; Port.: Wellvone; S.Afr.: Wellvone; Spain: Wellvone; Swed.: Wellvone; Switz.: Wellvone; UK: Wellvone; USA: Mepron. Multi-ingredient: Austral.: Malarone; Austria: Malarone; Promal; Belg.: Malarone; Canad.: Malarone; Cz.: Malarone; Denm.: Malarone; Fr.: Malarone; Ger.: Malarone; Gr.: Malarone; Hong Kong: Malarone; Hung.: Malarone; Irl.: Malarone; Israel: Malarone; Ital.: Malarone; Malaysia: Malarone; Neth.: Malarone; Norw.: Malarone; NZ: Malarone; Pol.: Malarone; S.Afr.: Malanil; Singapore: Malarone; Spain: Malarone; Swed.: Malarone; Switz.: Malarone; UK: Malarone; USA: Malarone.
Published October 15, 2018.