Interactions : אינטראקציות

4.5   Interaction with other medicinal products and other forms of interaction

Substances that may increase ribociclib plasma concentrations
Ribociclib is primarily metabolised by CYP3A4. Therefore, medicinal products that can influence CYP3A4 enzyme activity may alter the pharmacokinetics of ribociclib. Co-administration of the strong CYP3A4 inhibitor ritonavir (100 mg twice daily for 14 days) with a single 400 mg dose of ribociclib increased ribociclib exposure (AUCinf) and the peak concentration (Cmax) in healthy subjects 3.2 and 1.7-fold, respectively, relative to a single 400 mg ribociclib dose given alone. Cmax and AUClast for LEQ803 (a prominent metabolite of ribociclib accounting for less than 10% of parent exposure) decreased by 96% and 98%, respectively. Physiologically-based pharmacokinetic (PBPK) simulation estimated that co-administration of ritonavir (100 mg twice daily) with multiple daily doses of ribociclib may increase ribociclib steady-state Cmax and AUC0-24h by 1.5- and 1.8-fold, respectively.

The concomitant use of strong CYP3A4 inhibitors including, but not limited to, the following must be avoided: clarithromycin, indinavir, itraconazole, ketoconazole, lopinavir, ritonavir, nefazodone, nelfinavir, posaconazole, saquinavir, telaprevir, telithromycin, verapamil and voriconazole (see section 4.4). Alternative concomitant medicinal products with less potential to inhibit CYP3A4 should be considered and patients should be monitored for ribociclib-related ARs (see sections 4.2, 4.4 and 5.2).

If co-administration of Kisqali with a strong CYP3A4 inhibitor cannot be avoided, the dose of Kisqali should be reduced as described in section 4.2. However, there are no clinical data with these dose adjustments. Due to inter-patient variability, the recommended dose adjustments may not be optimal in all patients, therefore close monitoring for ribociclib-related ARs is recommended. In the event of ribociclib-related toxicity, the dose should be modified or treatment should be interrupted until toxicity is resolved (see sections 4.2 and 5.2). If the strong CYP3A4 inhibitor is discontinued, and after at least 5 half-lives of the CYP3A4 inhibitor (refer to the Prescribing information of the CYP3A4 inhibitor in 
KIS API JUL24 V9                                                            EU SmPC JUN 24 8
question), Kisqali should be resumed at the same dose used prior to the initiation of the strong CYP3A4 inhibitor.

Physiologically-based pharmacokinetic simulations suggested that for a 600 mg dose of ribociclib, a moderate CYP3A4 inhibitor (erythromycin) may increase ribociclib steady-state Cmax and AUC 1.1-fold and 1.1-fold, respectively. For patients who had their ribociclib dose reduced to 400 mg once daily, the increase of the steady-state Cmax and AUC was estimated to be 1.1- and 1.2-fold, respectively. The effect at the 200 mg once-daily dose was predicted to be a 1.3- and 1.5-fold increase, respectively. No dose adjustments of ribociclib are required at initiation of treatment with mild or moderate CYP3A4 inhibitors. However, monitoring of ribociclib-related ARs is recommended.

Patients should be instructed to avoid grapefruit or grapefruit juice. These are known to inhibit cytochrome CYP3A4 enzymes and may increase the exposure to ribociclib.

Substances that may decrease ribociclib plasma concentrations

Co-administration of the strong CYP3A4 inducer rifampicin (600 mg daily for 14 days) with a single 600 mg dose of ribociclib decreased the ribociclib AUCinf and Cmax by 89% and 81%, respectively, relative to a single 600 mg ribociclib dose given alone in healthy subjects. LEQ803 Cmax increased 1.7-fold and AUCinf decreased by 27%, respectively. The concomitant use of strong CYP3A4 inducers may therefore lead to decreased exposure and consequently a risk for lack of efficacy. The concomitant use of strong CYP3A4 inducers should be avoided, including, but not limited to, phenytoin, rifampicin, carbamazepine and St John’s Wort (Hypericum perforatum). An alternative concomitant medicinal product with no or minimal potential to induce CYP3A4 should be considered.

The effect of a moderate CYP3A4 inducer on ribociclib exposure has not been studied.
Physiologically-based pharmacokinetic simulations suggested that a moderate CYP3A4 inducer (efavirenz) may decrease steady-state ribociclib Cmax and AUC by 51% and 70%, respectively. The concomitant use of moderate CYP3A4 inducers may therefore lead to decreased exposure and consequently a risk for impaired efficacy, in particular in patients treated with ribociclib at 400 mg or 200 mg once daily.

Substances that may have plasma concentrations altered by Kisqali

Ribociclib is a moderate to strong CYP3A4 inhibitor and may interact with medicinal substrates that are metabolised via CYP3A4, which can lead to increased serum concentrations of the concomitantly used medicinal product.

Co-administration of midazolam (CYP3A4 substrate) with multiple doses of Kisqali (400 mg) increased the midazolam exposure by 280% (3.80-fold) in healthy subjects, compared with administration of midazolam alone. Simulations using physiologically-based pharmacokinetic models suggested that Kisqali given at the clinically relevant dose of 600 mg is expected to increase the midazolam AUC by 5.2-fold. Therefore, in general, when ribociclib is co-administered with other medicinal products, the Prescribing Information of the other medicinal product must be consulted for the recommendations regarding co-administration with CYP3A4 inhibitors. Caution is recommended in case of concomitant use with sensitive CYP3A4 substrates with a narrow therapeutic index (see section 4.4). The dose of a sensitive CYP3A4 substrate with a narrow therapeutic index, including but not limited to alfentanil, ciclosporin, everolimus, fentanyl, sirolimus and tacrolimus, may need to be reduced as ribociclib can increase their exposure.

Concomitant administration of ribociclib at the 600 mg dose with the following CYP3A4 substrates should be avoided: alfuzosin, amiodarone, cisapride, pimozide, quinidine, ergotamine, dihydroergotamine, quetiapine, lovastatin, simvastatin, sildenafil, midazolam, triazolam.

Co-administration of caffeine (CYP1A2 substrate) with multiple doses of Kisqali (400 mg) increased the caffeine exposure by 20% (1.20-fold) in healthy subjects, compared with administration of 
KIS API JUL24 V9                                                            EU SmPC JUN 24 9
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).

Substances that are substrates of transporters

In vitro evaluations indicated that ribociclib has a potential to inhibit the activities of drug transporters P-gp, BCRP, OATP1B1/1B3, OCT1, OCT2, MATE1 and BSEP. Caution and monitoring for toxicity are advised during concomitant treatment with sensitive substrates of these transporters which exhibit a narrow therapeutic index, including but not limited to digoxin, pitavastatin, pravastatin, rosuvastatin and metformin.

Drug-food interactions

Kisqali can be administered with or without food (see sections 4.2 and 5.2).
Medicinal products that elevate gastric pH

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 study; however, altered ribociclib absorption was not observed in population pharmacokinetic and non–compartmental pharmacokinetic analyses.

Drug-drug interaction between ribociclib and letrozole

Data from a clinical study in patients with breast cancer and population pharmacokinetic analysis indicated no drug interaction between ribociclib and letrozole following co-administration of these medicinal products.

Drug-drug interaction between ribociclib and anastrozole

Data from a clinical study in patients with breast cancer indicated no clinically relevant drug interaction between ribociclib and anastrozole following co-administration of these medicinal products.

Drug-drug interaction between ribociclib and fulvestrant

Data from a clinical study in patients with breast cancer indicated no clinically relevant effects of fulvestrant on ribociclib exposure following co-administration of these medicinal products.

Drug-drug interaction between ribociclib and tamoxifen

Data from a clinical study in patients with breast cancer indicated that tamoxifen exposure was increased approximately 2-fold following co-administration of ribociclib and tamoxifen.

Drug-drug interactions between ribociclib and oral contraceptives

Drug-drug interaction studies between ribociclib and oral contraceptives have not been conducted (see section 4.6).

Anticipated interactions

Anti-arrhythmic medicinal products and other medicinal products that may prolong the QT interval Co-administration of Kisqali with medicinal products with a known potential to prolong the QT interval such as anti-arrhythmic medicinal products (including, but not limited to, amiodarone, disopyramide, procainamide, quinidine and sotalol), and other medicinal products that are known to prolong the QT interval (including, but not limited to, chloroquine, halofantrine, clarithromycin, 
KIS API JUL24 V9                                                              EU SmPC JUN 24 10
ciprofloxacin, levofloxacin, azithromycin, haloperidol, methadone, moxifloxacin, bepridil, pimozide and intravenous ondansetron) should be avoided (see section 4.4). Kisqali is also not recommended to be used in combination with tamoxifen (see sections 4.1, 4.4 and 5.1).