Drug Interaction Report

GENERALLY AVOID: Coadministration with inhibitors of CYP450 3A4 may increase exposure to the cytotoxic component of ado-trastuzumab emtansine known as DM1, which has been shown in vitro to be primarily metabolized by CYP450 3A4 and to a lesser extent by CYP450 3A5. No formal drug interaction studies have been conducted. Theoretically, the risk of toxicity may be increased.

MANAGEMENT: The use of ado-trastuzumab emtansine in combination with potent CYP450 3A4 inhibitors such as itraconazole, ketoconazole, posaconazole, voriconazole, conivaptan, nefazodone, cobicistat, delavirdine, protease inhibitors, and ketolide and certain macrolide antibiotics should generally be avoided. Some authorities recommend avoiding concomitant use of ado-trastuzumab emtansine during and for 2 weeks after treatment with itraconazole. Alternative agents with no or minimal CYP450 3A4 inhibitory potential are recommended whenever possible. If no alternatives exist, consider delaying initiation of ado-trastuzumab emtansine until therapy with the potent CYP450 3A4 inhibitor is complete and the drug has cleared from the circulation, or approximately 3 elimination half-lives. When concomitant administration is necessary, patients should be closely monitored for adverse reactions such as hepatic impairment, left ventricular dysfunction, peripheral neuropathy, and thrombocytopenia.

Grapefruit juice may delay the gastrointestinal absorption of clarithromycin but does not appear to affect the overall extent of absorption or inhibit the metabolism of clarithromycin. The mechanism of interaction is unknown but may be related to competition for intestinal CYP450 3A4 and/or absorptive sites. In an open-label, randomized, crossover study consisting of 12 healthy subjects, coadministration with grapefruit juice increased the time to reach peak plasma concentration (Tmax) of both clarithromycin and 14-hydroxyclarithromycin (the active metabolite) by 80% and 104%, respectively, compared to water. Other pharmacokinetic parameters were not significantly altered. This interaction is unlikely to be of clinical significance.