Drug Interactions between bortezomib and mitotane

ADJUST DOSING INTERVAL: Fat-rich food enhances the absorption of mitotane. One study evaluated blood levels of mitotane (o,p'-DDD) after subjects ingested a single dose of 2 g administered using various delivery vehicles (e.g., tablets, granules, milk, chocolate or oil emulsion). Mitotane plasma levels were significantly higher for milk, chocolate, and oil emulsion when compared to those who received tablets or granules alone. In the same study, mitotane levels were evaluated in subjects following long-term treatment (total dose of 200 g over 30 to 60 days) in tablet, oil emulsion, or milk formulations. Significantly higher mean plasma levels were recorded in subjects who received mitotane as an oil emulsion or mixed in milk, when compared to tablets alone. Additionally, the recovery of o,p'-DDD from the feces was about 5 times higher in subjects who received tablets alone, suggesting absorption was reduced when compared to subjects who received mitotane mixed with a fat-rich vehicle (e.g., oil emulsion or milk).

GENERALLY AVOID: Concomitant use of mitotane with central nervous system (CNS) depressants, including alcohol, may potentiate adverse effects such as somnolence and sedation.

MANAGEMENT: According to product labeling, mitotane tablets should be taken during meals containing fat-rich food (e.g., milk, chocolate, or oil) and with a full glass of water. Patients should be advised to avoid or limit consumption of alcohol and to avoid activities requiring mental alertness such as driving or operating hazardous machinery until they know how the medication affects them.

GENERALLY AVOID: Data from in vitro and animal (mice) studies suggest that green tea may antagonize the cytotoxic effects of bortezomib. Polyphenols in green tea such as (-)-epigallocatechin gallate (EGCG) have been shown to block the proteasome inhibitory action of bortezomib in multiple myeloma and glioblastoma cancer cell lines. The mechanism appears to involve a direct chemical reaction between the boronic acid moiety of bortezomib and the 1,2-benzenediol groups present in certain polyphenols leading to inactivation of bortezomib. However, one group of investigators reported that no antagonism of bortezomib was observed in preclinical in vivo experiments where EGCG plasma concentrations are commensurate with dietary or supplemental intake.

MANAGEMENT: Until more data are available, it may be advisable to avoid or limit consumption of green tea and green tea products during treatment with bortezomib. The interaction has not been demonstrated for other, non-boronic acid proteasome inhibitors.