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Ribociclib is primarily metabolized by CYP3A and is a time-dependent inhibitor of CYP3A in vivo. Therefore, medicinal products which can influence CYP3A enzyme activity may alter the pharmacokinetics of ribociclib.
Medicinal products that may increase ribociclib plasma concentrations: Co-administration of a strong CYP3A4 inhibitor (ritonavir) increased ribociclib exposure in healthy subjects by 3.21-fold. Concomitant use of strong CYP3A inhibitors, including but not limited to clarithromycin, indinavir, itraconazole, ketoconazole, lopinavir, ritonavir, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, verapamil, and voriconazole (see PRECAUTIONS), should be avoided. Alternative concomitant medications with a low potential to inhibit CYP3A should be considered and patients should be monitored for ADRs (see DOSAGE & ADMINISTRATION, PRECAUTIONS and PHARMACOLOGY under ACTIONS).
If co-administration of ribociclib with a strong CYP3A inhibitor cannot be avoided, the ribociclib dose should be reduced to 200 mg. However, there are no clinical data with this dose adjustment (see DOSAGE & ADMINISTRATION). If the strong inhibitor is discontinued, the ribociclib dose should be resumed (after at least 5 elimination half-lives of the CYP3A inhibitor) to the dose used prior to the initiation of the strong CYP3A inhibitor. Due to inter-patient variability, the recommended dose adjustments may not be optimal in all patients, therefore, close monitoring for ADRs is recommended. In the event of ribociclib-related toxicity, the dose should be modified (see DOSAGE & ADMINISTRATION), or treatment should be interrupted until toxicity has resolved (see DOSAGE & ADMINISTRATION and PHARMACOLOGY under ACTIONS).
Patients should be instructed to avoid grapefruits or grapefruit juice, all of which are known to inhibit cytochrome CYP3A enzymes and may increase the exposure to ribociclib.
Medicinal products that may decrease ribociclib plasma concentrations: Co-administration of a strong CYP3A4 inducer (rifampin) decreased the plasma exposure of ribociclib in healthy subjects by 89%. Avoid concomitant use of strong CYP3A inducers, including but not limited to phenytoin, rifampin, carbamazepine and St John's Wort (Hypericum perforatum). An alternate concomitant medication with no or minimal potential to induce CYP3A should be considered (see PRECAUTIONS and PHARMACOLOGY under ACTIONS).
Medicinal products that may have their plasma concentrations altered by ribociclib: Co-administration of midazolam (CYP3A4 substrate) with multiple doses of ribociclib (400 mg) increased the midazolam exposure by 280% (3.80-fold) in healthy subjects compared with administration of midazolam alone. Simulations using physiologically-based PK (PBPK) models suggested that ribociclib given at the clinically relevant dose of 600 mg is expected to increase the midazolam AUC by 5.2-fold. Therefore, caution is recommended when ribociclib is administered with CYP3A substrates with a narrow therapeutic index. The dose of a sensitive CYP3A substrate with a narrow therapeutic index, including but not limited to alfentanil, cyclosporine, dihydroergotamine, ergotamine, everolimus, fentanyl, pimozide, quinidine, sirolimus and tacrolimus, may need to be reduced as ribociclib has the potential to increase their exposure (see PHARMACOLOGY under ACTIONS).
Co-administration of caffeine (CYP1A2 substrate) with multiple doses of ribociclib (400 mg) increased caffeine exposure by 20% (1.20-fold) in healthy subjects, compared with administration of caffeine alone. At the clinically relevant dose of 600 mg, simulations using PBPK models predicted only weak inhibitory effects of ribociclib on CYP1A2 substrates (<2-fold increase in AUC) (see PHARMACOLOGY under ACTIONS).
Medicinal products that are substrates of transporters: In vitro evaluations indicated that ribociclib has a low potential to inhibit the activities of drug transporters P-gp, OAT1/3, OATP1B1/B3, MATE2K and OCT1 at clinically relevant concentrations. Ribociclib may inhibit BCRP, OCT2, MATE1, and human BSEP at clinically relevant concentrations (see PHARMACOLOGY under ACTIONS).
Drug-food interactions: Ribociclib can be administered with or without food (see DOSAGE & ADMINISTRATION).
Compared to the fasted state, oral administration of a single 600 mg dose of ribociclib film-coated tablets with a high-fat, high-calorie meal had no effect on the rate and extent of absorption of ribociclib (Cmax GMR: 1.00; 90% CI: 0.898, 1.11; AUCinf GMR: 1.06; 90% CI: 1.01, 1.12 (see PHARMACOLOGY under ACTIONS).
Gastric pH elevating medications: Ribociclib exhibits high solubility at or below pH 4.5 and in bio-relevant media (at pH 5.0 and 6.5). Co-administration of ribociclib with medicinal products that elevate the gastric pH was not evaluated in a clinical trial; however, altered ribociclib absorption was not observed in the population pharmacokinetic analysis nor in simulations using PBPK models (see PHARMACOLOGY under ACTIONS).
Anticipated interactions: Antiarrhythmic medicines and other medicinal products that may prolong the QT interval: Co-administration of ribociclib should be avoided with medicinal products with known potential to prolong the QT interval such as antiarrhythmic medicines. Concomitant use of anti-arrhythmic medicines (including but not limited to amiodarone, disopyramide, procainamide, quinidine, and sotalol), other medicinal products that are known to prolong the QT interval, including but not limited to chloroquine, halofantrine, clarithromycin, ciprofloxacin, levofloxacin, azithromycin, haloperidol, methadone, moxifloxacin, bepridil, pimozide and ondansetron (i.v), should be avoided. Ribociclib is not recommended for use in combination with tamoxifen (see PRECAUTIONS).
