Drug Interactions between conjugated estrogens / medroxyprogesterone and pralsetinib

ADDITIONAL CONTRACEPTION RECOMMENDED: Coadministration with pralsetinib may render hormonal contraceptives ineffective. The mechanism for the potential interaction has not been established. In vitro studies indicate that pralsetinib, at clinically relevant concentrations, may be both an inhibitor and inducer of CYP450 3A4, the isoenzyme generally considered responsible for the metabolic clearance of sex hormones (e.g., estrogen, progesterone). Pralsetinib may therefore either decrease clearance via inhibition or increase clearance via induction of this isoenzyme, resulting in increased or decreased plasma concentrations of agents that are metabolized via CYP450 3A4. However, clinical data regarding the use of pralsetinib with hormonal contraceptives are not available. Pralsetinib may also cause fetal harm when administered to a pregnant woman.

MANAGEMENT: Until further data are available, females of reproductive potential should be advised to use effective non-hormonal contraception during treatment and for 2 weeks after the final dose of pralsetinib. In addition, male patients with female partners of reproductive potential should use effective contraception during treatment and for 1 week after the final dose of pralsetinib. Some authorities also recommend using a condom in combination with hormonal contraception if the hormonal method is clinically necessary. Input from a gynecologist or similar expert on adequate contraception, including emergency contraception, should be sought as needed. Intrauterine systems are unlikely to be significantly affected because of their local action.

MONITOR: Coadministration with pralsetinib may alter the plasma concentrations of drugs that are substrates of CYP450 2C8, 2C9, 3A4, and/or 3A5. In vitro studies indicate that pralsetinib is both an inhibitor as well as an inducer of CYP450 2C8, 2C9, 3A4, and 3A5. Therefore, pralsetinib may decrease clearance via inhibition or increase clearance via induction of these isoenzymes, resulting in increased or decreased plasma concentrations of agents that are metabolized by one or more of these isoenzymes. Clinical and pharmacokinetic data are currently lacking.

MANAGEMENT: Caution is advised if pralsetinib is used concomitantly with drugs that are substrates of CYP450 2C8, 2C9, 3A4, and/or 3A5, particularly sensitive substrates or those with a narrow therapeutic range. Some authorities recommend avoiding coadministration of pralsetinib with CYP450 2C8, 2C9, 3A4, and/or 3A5 substrates for which minimal concentration changes may lead to therapeutic failure or serious toxicities. If coadministration is required, dosage adjustments as well as clinical and laboratory monitoring may be appropriate whenever pralsetinib is added to or withdrawn from therapy. The prescribing information for concomitant medications should be consulted to assess the benefits versus risks of coadministration and for any dosage adjustments that may be required.