Drug Interaction Report

GENERALLY AVOID: Coadministration with potent CYP450 3A4 inducers may significantly decrease the plasma concentrations and therapeutic effects of ribociclib, which is a substrate of the isoenzyme. In healthy study subjects, administration of a single 600 mg dose of ribociclib with multiple 600 mg daily doses of rifampin, a potent CYP450 3A4 inducer, resulted in an 81% and 89% decrease in ribociclib peak plasma concentration (Cmax) and systemic exposure (AUC), respectively, compared to ribociclib administered alone. In addition, administration of efavirenz, a moderate CYP450 3A4 inducer, is predicted to decrease ribociclib Cmax and AUC by 37% and 60%, respectively. In addition, when two or more medications with similar adverse effect profiles are given concurrently, the likelihood of experiencing these adverse reactions may be increased. For example, coadministration with other agents that can prolong the QT interval (e.g., apalutamide, encorafenib, enzalutamide) may result in additive effects and an increased risk of ventricular arrhythmias like torsade de pointes.

MANAGEMENT: Concomitant use of ribociclib with potent CYP450 3A4 inducers should generally be avoided. Alternative agents with no or minimal CYP450 3A4 induction potential are recommended whenever possible. If coadministration is necessary, dosage adjustments as well as clinical and laboratory monitoring should be considered whenever a potent CYP450 3A4 inducer is added to or withdrawn from therapy. Patients should be monitored for therapeutic failure. If the CYP450 3A4 inducer also carries a risk of prolonging the QT interval, then obtaining more frequent electrocardiograms (ECGs) to monitor the QT interval may be advisable. Patients should be counseled to seek immediate medical attention if they experience symptoms that could indicate the occurrence of torsade de pointes such as dizziness, lightheadedness, syncope, palpitations, irregular heartbeat, and/or shortness of breath.

GENERALLY AVOID: Coadministration with St. John's wort may alter the pharmacokinetics of antineoplastic agents that are substrates of the CYP450 3A4 isoenzyme (e.g., abiraterone, bexarotene, bortezomib, busulfan, cyclophosphamide, dasatinib, docetaxel, doxorubicin, etoposide, exemestane, ifosfamide, imatinib, irinotecan, letrozole, paclitaxel, sorafenib, sunitinib, tamoxifen, temsirolimus, teniposide, thiotepa, toremifene, tretinoin, vandetanib, vinca alkaloids). The mechanism is induction of CYP450 3A4 metabolism by constituents of St. John's wort, which is expected to reduce the systemic levels and pharmacologic effects of many of these agents. In contrast, some agents such as cyclophosphamide and ifosfamide are prodrugs that are converted to active metabolites by CYP450 3A4, thus pharmacologic effects may be enhanced by St. John's wort. However, clinical data are currently limited.

MANAGEMENT: Until more information is available, the use of St. John's wort should probably be avoided before and during the entire course of chemotherapy. It is not known how much time should elapse between the discontinuation of St. John's wort and initiation of chemotherapy. Patients should be advised to consult with their caregivers before using any herbal or alternative medicines.

MONITOR: Coadministration with ribociclib may increase the plasma concentrations and pharmacologic effects of drugs that are substrates of CYP450 3A4. The proposed mechanism is decreased clearance due to ribociclib-mediated inhibition of CYP450 3A4 metabolism. In healthy study subjects, administration of midazolam, a sensitive CYP450 3A4 substrate, with multiple 400 mg daily doses of ribociclib increased the midazolam peak plasma concentration (Cmax) and systemic exposure (AUC) by 2.1-fold and 3.8-fold, respectively, compared to midazolam administered alone. When given at a clinically relevant dose of 600 mg daily, ribociclib is predicted to increase midazolam Cmax and AUC by 2.4-fold and 5.2-fold, respectively.

MANAGEMENT: Caution is advised when ribociclib is used concomitantly with drugs that undergo metabolism by CYP450 3A4, particularly those with a narrow therapeutic range. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever ribociclib is added to or withdrawn from therapy.

GENERALLY AVOID: An isolated case report suggests that foods containing large amounts of tyramine may precipitate a hypertensive crisis in patients treated with St. John's wort. The mechanism of interaction is unknown, as St. John's wort is not thought to possess monoamine oxidase (MAO) inhibiting activity at concentrations achieved in vivo. The case patient was a 41-year-old man who had been taking St. John's wort for seven days prior to presentation at the emergency room with confusion and disorientation. The patient recalled last eating aged cheese and having a glass of red wine approximately 10 hours prior to admission. No other cause of delirium or hypertension could be identified. In addition, alcohol may potentiate some of the pharmacologic effects of St. John's wort. Use in combination may result in additive central nervous system depression and/or impairment of judgment, thinking, and psychomotor skills.

MANAGEMENT: Until further information is available, patients treated with St. John's wort should consider avoiding consumption of protein foods in which aging or breakdown of protein is used to increase flavor. These foods include cheese (particularly strong, aged or processed cheeses), sour cream, wine (particularly red wine), champagne, beer, pickled herring, anchovies, caviar, shrimp paste, liver (particularly chicken liver), dry sausage, figs, raisins, bananas, avocados, chocolate, soy sauce, bean curd, yogurt, papaya products, meat tenderizers, fava beans, protein extracts, and dietary supplements. Caffeine may also precipitate hypertensive crisis so its intake should be minimized as well. Patients should also be advised to avoid or limit consumption of alcohol.

GENERALLY AVOID: Pomegranates and grapefruit may increase the systemic exposure to ribociclib. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in these fruits. Increased exposure to ribociclib may increase the risk of adverse effects such as infections, neutropenia, leukopenia, anemia, thrombocytopenia, anorexia, nausea, vomiting, diarrhea, stomatitis, alopecia, fatigue, headache, and abnormal liver function may be increased.

MANAGEMENT: Patients receiving ribociclib should avoid consumption of pomegranates or pomegranate juice and grapefruit or grapefruit juice during treatment.