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Drug Interactions between busulfan and Noxafil

This report displays the potential drug interactions for the following 2 drugs:

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Interactions between your drugs

Moderate

busulfan posaconazole

Applies to: busulfan and Noxafil (posaconazole)

MONITOR: Itraconazole has been reported to inhibit the clearance of busulfan. The mechanism of interaction has not been established. Itraconazole is a potent inhibitor of the CYP450 3A4 isoenzyme and P-glycoprotein (P-gp) efflux transporter, although there is little evidence to suggest that busulfan is a substrate of either. In one study, mean busulfan clearance decreased by approximately 18% in bone marrow transplant patients who received itraconazole 6 mg/kg once daily compared to matched controls who did not receive itraconazole, resulting in 24% higher steady-state concentrations. The clinical significance of these changes is unknown. In contrast, patients who received fluconazole showed no difference in busulfan clearance relative to controls. Whether, or how, other azole antifungal agents may affect the clearance of busulfan is uncertain. In a study of 136 pediatric autologous bone marrow transplant patients who received high-dose busulfan as part of a conditioning regimen, concomitant ketoconazole therapy was identified as a risk factor for the development of hepatic veno-occlusive disease (HVOD). Since HVOD may be a concentration-dependent toxicity of busulfan, the study data would suggest a pharmacokinetic interaction with ketoconazole. No data are available for posaconazole or voriconazole, which are known inhibitors of CYP450 3A4 but not P-gp, although posaconazole is a substrate for P-gp.

MANAGEMENT: Patients prescribed busulfan with itraconazole or ketoconazole should be monitored for potentially increased myelotoxic, hepatotoxic, neurotoxic, and gastrointestinal toxic effects. Some experts also recommend the same precaution during coadministration with posaconazole or voriconazole, although clinical data are lacking.

References (3)
  1. Buggia I, Zecca M, Alessandrino EP, Locatelli F, Rosti G, Bosi A, Pession A, Rotoli B, Majolino I, Dallorso A, Regazzi MB (1996) "Itraconazole can increase systemic exposure to busulfan in patients given bone marrow transplantation." Anticancer Res, 16, p. 2083-8
  2. (2004) "Product Information. Busulfex (busulfan)." ESP Pharma Inc
  3. Glotzbecker B, Duncan C, Alyea E 3rd, Campbell B, Soiffer R (2012) "Important drug interactions in hematopoietic stem cell transplantation: what every physician should know." Biol Blood Marrow Transplant, 18, p. 989-1006

Drug and food interactions

Moderate

posaconazole food

Applies to: Noxafil (posaconazole)

ADJUST DOSING INTERVAL: Food significantly increases the absorption of posaconazole from the oral suspension but only modestly from the delayed-release tablet. Following single-dose administration, posaconazole mean peak plasma concentration (Cmax) and systemic exposure (AUC) are approximately 2.5 to 3 times higher when the oral suspension is given with a nonfat meal or a nutritional supplement (14 grams of fat) than when given under fasting conditions, and approximately 3.5 to 4 times higher when given during or 20 minutes after a high-fat meal (50 grams of fat) than under fasting conditions. Acidic beverages may also increase posaconazole absorption. In 12 healthy volunteers, administration of a single 400 mg dose of posaconazole suspension with 12 ounces of ginger ale increased posaconazole Cmax by 92% and AUC by 70% compared to administration after fasting. In contrast, the Cmax and AUC of posaconazole increased by just 16% and 51%, respectively, when posaconazole tablets were given as a single 300 mg dose to healthy volunteers after a high-fat meal relative to a fasted state.

GENERALLY AVOID Concomitant use of alcohol and posaconazole administered in the form of delayed-release oral suspension may lead to a faster release of posaconazole. An in vitro dissolution study determined a potential for alcohol-induced dose-dumping with the delayed-release oral suspension of posaconazole.

MONITOR: In 5 study subjects, posaconazole Cmax decreased by 27% to 53% and AUC decreased by 33% to 51% when the oral suspension was administered via a nasogastric tube as opposed to orally.

MANAGEMENT: Posaconazole tablets should be taken with food, whereas posaconazole oral suspension should be administered during or immediately (i.e., within 20 minutes) following a full meal to enhance bioavailability. Patients who cannot eat a full meal should take the suspension with a liquid nutritional supplement or an acidic carbonated beverage such as ginger ale. In patients who cannot eat a full meal or tolerate an oral nutritional supplement or an acidic carbonated beverage and who do not have the option of taking another formulation of posaconazole, alternative antifungal therapy should be considered; otherwise, monitor patients closely for breakthrough fungal infections. Patients receiving posaconazole via a nasogastric tube should also be closely monitored due to increased risk of treatment failure associated with lower plasma exposure. Administration of alcohol with posaconazole from the delayed-release oral suspension formulation is not recommended.

References (4)
  1. (2006) "Product Information. Noxafil (posaconazole)." Schering-Plough Corporation
  2. Sansone-Parsons A, Krishna G, Calzetta A, et al. (2006) "Effect of a nutritional supplement on posaconazole pharmacokinetics following oral administration to healthy volunteers." Antimicrob Agents Chemother, 50, p. 1881-3
  3. Krishna G, Moton A, Ma L, Malavade D, Medlock M, McLeod J (2008) "Effect of gastric pH, dosing regimen and prandial state, food and meal timing relative to dose, and gastro-intestinal motility on absorption and pharmacokinetics of the antifungal posaconazole." 18th European Congress of Clinical Microbiology and Infectious Diseases, April, p. 20
  4. Walravens J, Brouwers J, Spriet I, Tack J, Annaert P, Augustijns P (2011) "Effect of pH and Comedication on Gastrointestinal Absorption of Posaconazole: Monitoring of Intraluminal and Plasma Drug Concentrations." Clin Pharmacokinet, 50, p. 725-34

Therapeutic duplication warnings

No warnings were found for your selected drugs.

Therapeutic duplication warnings are only returned when drugs within the same group exceed the recommended therapeutic duplication maximum.

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Drug Interaction Classification

These classifications are only a guideline. The relevance of a particular drug interaction to a specific individual is difficult to determine. Always consult your healthcare provider before starting or stopping any medication.
Major Highly clinically significant. Avoid combinations; the risk of the interaction outweighs the benefit.
Moderate Moderately clinically significant. Usually avoid combinations; use it only under special circumstances.
Minor Minimally clinically significant. Minimize risk; assess risk and consider an alternative drug, take steps to circumvent the interaction risk and/or institute a monitoring plan.
Unknown No interaction information available.

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