Atovaquone interactions

Drug/Food interactions Administering atovaquone with food enhances its absorption by approximately 2-fold. 

Atovaquone (Mepron) [Antiprotozoal] Uses Rx prevention PCP Action 4- nucleic acid ATP synth Dose Rx 750 mg PO bid for 21 d Prevention 1500 mg PO once/d (w/ meals) Caution [C, ] Disp Susp SE FevCT, HA, anxiety, insomnia, rash, N/V Interactions X Effects W/ metoclopramide, rifabutin, rifampin, tetracycline EMS None OD Sxs unknown but may cause a rash symptomatic and supportive... 

Preparation of microfluidized particles of atovaquone 600 mL of a mixture consisting of 2.5% w/v atovaquone in 0.25% w/v aqueous Celacol M2500 and passed through fluidizer such as model 120B Microfluidizer connected to a 90-psi pneumatic supply and adjusted to produce a fluid pressure of 15,000 psi. Recirculate continuously through the interaction chamber for at least 45 minutes (65 to 77 passes) to achieve particle size less than 3 microns. 

Other compounds producing some inhibition of ZDV conjugation were oxazepam, salicylic acid, and acetylsalicyclic acid. More recently, Trapnell et al. examined the inhibition of ZDV at a more relevant concentration of 20 pM in bovine serum albumin (BSA)-activated microsomes by atovaquone, methadone, fluconazole, and valproic acid at therapeutically relevant concentrations (127). Both fluconazole and valproic acid inhibited ZDV glucuronidation by more than 50% at therapeutic concentrations. Clinical interaction studies have been conducted with methadone, fluconazole, naproxen, probenecid, rifampicin, and valproic acid (see Table 10). 

Trapnell CB, Klecker RW, Jamis-Dow C, et al. Glucuronidation of 3 -azido-3 -deoxythymidine (ZDV) by human liver microsomes relevance to clinical pharmacokinetic interactions with atovaquone, fluconazole, methadone, and valproic acid. Antimicrob Agents Chemother 1998 42(7) 1592-1596. 

FIGURE 5. (A) Interaction of atovaquone with the Fe-S center (on left) in the cytochrome bc complex via H-bonding with the coordinated His (Plate VIII). (B) The active center of a class 2 dihydroorotate dehydrogenase (PDB ID 1UUM) with a hound inhibitor atovaquone (top baU-and-stick stmcture), orotic acid (green) and riboflavin 5 -(dihydrogen phosphate) (FMN, pink) (Plate IX)... 

Clinically important, potentially hazardous interactions with amiodarone, amprenavir, anisindione, antacids, anticoagulants, aprepitant, atazanavir, atovaquone, beclomethasone, buprenorphine, corticosteroids, cortisone, cyclosporine, cyproterone, dabigatran, dapsone, darunavir, delavirdine, dexamethasone, dicumarol, digoxin, eszopiclone, flunisolide, fosamprenavir, gadoxetate, gestrinone, halothane, imatinib, isoniazid, itraconazole, ketoconazole, lapatinib, lorcainide, methylprednisolone, midazolam, nelfinavir, nifedipine, oral contraceptives, phenylbutazone, prednisone, protease inhibitors, pyrazinamide, ramelteon, ritonavir, saquinavir, solifenacin, sunitinib, tacrolimus, telithromycin, temsirolimus, tipranavir, tolvaptan, trabectedin, triamcinolone, triazolam, voriconazole, warfarin, zaleplon... 

This study shows there is no important pharmacokinetic interaction between atovaquone and co-trimoxazole. No dosage adjustments of either drug would be required on eoncurrent use. 

Falloon J, Sargent S, Piscitelli SC, Bechtel C, LaFon SW, Sadler B, Walker RE, Kovacs JA, Polls MA, Davey RT, Lan HC, Masur H. Atovaquone suspension in HIV-infected volunteers pharmacokinetics, pharmacodynamics, and TMP-SMX interaction study. Pharmaco erepy (1999) 19, 1050-6. 

Established interactions of clinical importance. Atovaquone suspension used for the treatment or prevention of Pneumocystis pneumonia must be taken with food, since this is likely to increase the likelihood of successful treatment and survival. Alternatively, an enteral nutritional supplement with a high-fat content appears to be suitable. In the US, the manufacturer says that, for patients who have difficulty taking atovaquone suspension with food, parenteral therapy for Pneumocystis pneumonia should be considered. ... 

There appears to be no clinically relevant pharmacokinetic interaction between atovaquone and proguanil. 

Atovaquone did not affeet the pharmaeokinetics of proguanil in a comparative study of 4 patients taking proguanil 200 mg twice daily for 3 days and 12 patients taking proguanil 200 mg twice daily with atovaquone 500 mg twice daily for 3 days. A similar lack of interaction was seen in 18 healthy subjects given proguanil 400 mg daily with atovaquone 1 g daily for 3 days. ... 

A pharmacokinetic interaction is not established, and is anyway of little elinieal relevanee, sinee the efficacy of the combination product for malaria prophylaxis up to 12 weeks is established. The enhaneed aetivity of the eombination may, in part, be due to proguanil lowering the effeetive eoneentration at whieh atovaquone collapses the mitoehondrial potential in malaria parasites. ... 

Gillotin C, Mamet JP, Veronese L. Lack of pharmacokinetic interaction between atovaquone and proguanil. EurJ Clin Pharmacol (1999) 55, 311-15. 

Information is limited but these pharmaeokinetie interactions appear to be established. Their clinical importance is unknown, but it seems highly likely that the efficacy of atovaquone will be reduced in the presence of rifampicin. The combination should therefore be avoided. 

Sadler BM, Caldwell P, Scott JD, Rogers M, Blum MR. Drug interaction between rifempin and atovaquone (Mepron ) in HIV+ asymptomatic volunteers. Intersci C[Pg.214]

The manufacturers suggest that parasitaemia should be closely monitored in patients taking atovaquone/proguanil tablets with tetracycline. In the UK, they also say that tetracycline should be given with caution to patients taking atovaquone suspension for Pneumocystis pneumonia, until the interaction has been further studied, whereas the US manufacturers of atovaquone suspension do not mention tetracycline. ... 

In 12 healthy subjects, atovaquone (1 g, given both twelve hours before and with a single 600-mg dose of phen i oin) did not affect the pharmacokinetics of phen i oin. It was concluded that a clinically important pharmacokinetic interaction is uniikeiy. ... 

A study in 9 children with acute lymphoblastic leukaemia or non-Hodg-kin s lymphoma found that the AUC of etoposide and its metabolite etoposide catechol were slightly increased, by 8.6% and 28.4%, respectively, following atovaquone 45 mg/kg daily, when compared with co-trimoxa-zole 150/750 mg/m daily. The mechanism by which this occurs is unclear, but atovaquone may affect the metabolism of etoposide by the cytochrome P450 isoenzyme CYP3A4 or its transport by P-glycoprotein. The authors considered that an interaction with co-trimoxazole was unlikely, so used it as a control, however, ideally this requires confirma-... 

The manufacturer of atovaquone notes that it decreased the AUC of didanosine by 24% in a multiple dose interaction study. There was no change in the pharmacokinetics of atovaquone. ... 

Preliminary results from a study in healthy subjects suggest that the concurrent use of atovaquone 750 mg twice daily and indinavir 800 mg three times daily results in a minor 5% decrease in the AUC of indinavir, and a 13% increase in the AUC of atovaquone. The UK manufacturer of atovaquone notes that concurrent use decreased the minimum level and AUC of indinavir by 23% and 9%, respectively. They recommend that caution should be exercised on concurrent use because of the potential risk of failure of indinavir treatment. However, note that the effect was small and that indinavir is often used with other antiretrovirals, which might modify the interaction by affecting indinavir levels. 

The manufacturer of ritonavir predicts that it will decrease the plasma levels of atovaquone, - by inducing atovaquone glucuronidation. They say that the clinical significance of this prediction is unknown, but that an increase in the atovaquone dose might be needed. Careful monitoring of serum levels and/or therapeutic effects is recommended when atovaquone is given with ritonavir as a pharmacokinetic enhancer or as an antiretroviral. This predicted interaction would therefore apply to lopinavir/ritonavir and any other boosted protease inhibitors. However, there does not appear to be any actual data to prove that the interaction occurs or is clinically relevant. 

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