Drug Interactions between Provera and tovorafenib

GENERALLY AVOID: Coadministration with tovorafenib may decrease the plasma concentration and efficacy of contraceptive hormones. The proposed mechanism is increased clearance due to tovorafenib-mediated induction of CYP450 3A4, the isoenzyme partially responsible for the metabolic clearance of sex hormones and other steroids. According to the manufacturer, tovorafenib is predicted to decrease the peak plasma concentration and systemic exposure of sensitive 3A4 substrate midazolam by at least 20%. However, data from formal clinical drug interaction studies are not available. In addition, tovorafenib may cause fetal harm when administered to a pregnant woman.

MANAGEMENT: The manufacturer recommends that concomitant use of tovorafenib with hormonal contraceptives should generally be avoided. However, if use is considered clinically necessary, women using hormonal contraceptives should be advised of the risk of breakthrough bleeding and unintended pregnancy during coadministration with tovorafenib. Alternative or additional methods of non-hormonal birth control should be used during and for at least 28 days after tovorafenib has been ceased. In addition, male patients with female partners of reproductive potential should use effective non-hormonal contraception during treatment with tovorafenib and for at least 2 weeks after stopping tovorafenib. No precautions or recommendations are available for women using hormone-releasing intrauterine systems, but a significant interaction with these systems is thought to be unlikely due to their local action. Input from a gynecologist or similar expert on adequate contraception, including emergency contraception, should be sought as needed.