1.SmPC
 

NAME OF THE MEDICINAL PRODUCT. Kisqali 200 mg film-coated tablets. QUALITATIVE AND QUANTITATIVE COMPOSITION. Each film-coated tablet contains ribociclib succinate, equivalent to 200 mg ribociclib.Excipients with known effect. Each film-coated tablet contains 0.344 mg soya lecithin.For the full list of excipients, see full leaflet.PHARMACEUTICAL FORM. Film-coated tablet.Light greyish violet, unscored, round, curved with bevelled edges (approximate diameter: 11.1 mm), debossed with “RIC” on one side and “NVR” on the other side. THERAPEUTIC INDICATIONS. Early breast cancer. Kisqali in combination with an aromatase inhibitor is indicated for the adjuvant treatment of patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative early breast cancer at high risk of recurrence (see full leaflet for selection criteria). In pre- or perimenopausal women, or in men, the aromatase inhibitor should be combined with a luteinising hormone-releasing hormone (LHRH) agonist. Advanced or metastatic breast cancer. Kisqali is indicated for the treatment of women with HR-positive, HER2-negative locally advanced or metastatic breast cancer in combination with an aromatase inhibitor or fulvestrant as initial endocrine-based therapy, or in women who have received prior endocrine therapy. In pre- or perimenopausal women, the endocrine therapy should be combined with a LHRH agonist. POSOLOGY AND METHOD OF ADMINISTRATION.Treatment with Kisqali should be initiated by a physician experienced in the use of anticancer therapies. HR-positive, HER2-negative testing. Patient selection for treatment with Kisqali based on the tumour expression of HR and HER2 should be assessed by a CE-marked in vitro diagnostic (IVD) medical device with the corresponding intended purpose. If the CE-marked IVD is not available, an alternative validated test should be used. Posology. Early breast cancer. The recommended dose is 400 mg (two 200 mg film- coated tablets) of ribociclib once daily for 21 consecutive days followed by 7 days off treatment, resulting in a complete cycle of 28 days. In patients with early breast cancer, Kisqali should be taken until completion of 3 years of treatment or until disease recurrence or unacceptable toxicity occur. When Kisqali is used in combination with an aromatase inhibitor (AI), the AI should be taken orally once daily continuously throughout the 28-day cycle. Please refer to the Summary of Product Characteristics (SmPC) of the AI for additional details.In pre- or perimenopausal women, or in men, the aromatase inhibitor should be combined with a LHRH agonist.Advanced or metastatic breast cancer. The recommended dose is 600 mg (three 200 mg film-coated tablets) of ribociclib once daily for 21 consecutive days followed by 7 days off treatment, resulting in a complete cycle of 28 days. In patients with advanced or metastatic breast cancer, the treatment should be continued as long as the patient is deriving clinical benefit from therapy or until unacceptable toxicity occurs. When Kisqali is used in combination with an AI, the AI should be taken orally once daily continuously throughout the 28-day cycle. Please refer to the Summary of Product Characteristics (SmPC) of the AI for additional details. When Kisqali is used in combination with fulvestrant, fulvestrant is administered intramuscularly on days 1, 15 and 29, and once monthly thereafter. Please refer to the SmPC of fulvestrant for additional details. Treatment of pre- and perimenopausal women with the approved Kisqali combinations should also include an LHRH agonist in accordance with local clinical practice. Dose modifications. Management of severe or intolerable adverse reactions (ARs) may require temporary dose interruption, reduction or discontinuation of Kisqali. If dose reduction is required, the recommended dose reduction guidelines are listed in Table 1.

Table 1 Recommended dose modification guidelines.

Tables 2, 3, 4,5 and 6 summarise recommendations for dose interruption, reduction or discontinuation of Kisqali in the management of specific ARs. The clinical judgement of the treating physician should guide the management plan of each patient based on individual benefit/risk assessment (see full leaflet).Complete blood counts (CBC) should be performed before initiating treatment with Kisqali.

After initiating treatment CBC should be monitored every 2 weeks for the first 2 cycles, at the beginning of each of the subsequent 4 cycles, then as clinically indicated.
 

Table 2       Dose modification and management – Neutropenia

Liver function tests (LFTs) should be performed before initiating treatment with Kisqali. After initiating treatment LFTs should be performed every 2 weeks for the first 2 cycles, at the beginning of each of the subsequent 4 cycles, then as clinically indicated. If grade ≥2 abnormalities are noted, more frequent monitoring is recommended.
 

Table 3       Dose modification and management – Hepatobiliary toxicity

ECG should be assessed before initiating treatment with Kisqali in all patients.

Treatment with Kisqali should be initiated only in patients with QTcF values less than 450 msec. After initiating treatment, ECG should be repeated at approximately day 14 of the first cycle, then as clinically indicated. In case of QTcF prolongation during treatment, more frequent ECG monitoring is recommended in patients with early breast cancer and advanced or metastatic breast cancer.
 

Table 4       Dose modification and management – QT prolongation

Table 5       Dose modification and management – ILD/pneumonitis

Table 6       Dose modification and management – Other toxicities*

Refer to the SmPC for the co-administered AI, fulvestrant or LHRH agonist for dose modification guidelines and other relevant safety information in the event of toxicity. Dose modification for use of Kisqali with strong CYP3A4 inhibitors. Concomitant use of strong CYP3A4 inhibitors should be avoided and an alternative concomitant medicinal product with less potential to inhibit CYP3A4 inhibition should be considered. If patients must be given a strong CYP3A4 inhibitor concomitantly with ribociclib, the Kisqali dose should be reduced (see full leaflet). In patients taking 600 mg ribociclib daily and in whom initiation of co-administration of a strong CYP3A4 inhibitor cannot be avoided, the dose should be reduced to 400 mg. In patients taking 400 mg ribociclib daily and in whom initiation of co-administration of a strong CYP3A4 inhibitor cannot be avoided, the dose should be further reduced to 200 mg. In patients who have had their dose reduced to 200 mg ribociclib daily and in whom initiation of co-administration of a strong CYP3A4 inhibitor cannot be avoided, Kisqali treatment should be interrupted. Due to inter-patient variability, the recommended dose adjustments may not be optimal in all patients, therefore close monitoring of signs of toxicity is recommended. If the strong inhibitor is discontinued, the Kisqali dose should be changed to the dose used prior to the initiation of the strong CYP3A4 inhibitor after at least 5 half-lives of the strong CYP3A4 inhibitor (see full leaflet). Special populations. Renal impairment. No dose adjustment is necessary in patients with mild or moderate renal impairment. A starting dose of 200 mg is recommended in patients with severe renal impairment. Kisqali has not been studied in breast cancer patients with severe renal impairment (see full leaflet). Hepatic impairment. No dose adjustment is necessary in patients with early breast cancer with hepatic impairment (see full leaflet). In patients with advanced or metastatic breast cancer, no dose adjustment is necessary in patients with mild hepatic impairment (Child-Pugh class A); patients with moderate (Child-Pugh class B) and severe hepatic impairment (Child-Pugh class C) can have increased (less than 2-fold) exposure to ribociclib and the starting dose of 400 mg Kisqali once daily is recommended (see full leaflet). Paediatric population. The safety and efficacy of Kisqali in children and adolescents aged below 18 years have not been established. No data are available.Elderly. No dose adjustment is required in patients over 65 years of age (see full leaflet). Method of administration. Kisqali should be taken orally once daily with or without food (see full leaflet). Patients should be encouraged to take their dose at approximately the same time each day, preferably in the morning. If the patient vomits after taking the dose or misses a dose, an additional dose should not be taken that day. The next prescribed dose should be taken at the usual time. The tablets should be swallowed whole and should not be chewed, crushed or split prior to swallowing. No tablet should be ingested if it is broken, cracked or otherwise not intact. CONTRA-INDICATIONS. Hypersensitivity to the active substance or to peanut, soya or any of the excipients listed in the full leaflet.UNDESIRABLE EFFECTS. Summary of the safety profile. Early breast cancer. The overall safety evaluation of Kisqali is based on the dataset from 2 525 patients who received Kisqali in combination with AI and who were included in the randomised, open-label phase III clinical study NATALEE. The median duration of exposure to ribociclib across the study was 33.0 months, with 69.4% patients exposed for >24 months, and 42.8% patients completing the 36-month ribociclib regimen. Advanced or metastatic breast cancer. The overall safety evaluation of Kisqali is based on the pooled dataset from 1 065 patients who received Kisqali in combination with endocrine therapy (N=582 in combination with an aromatase inhibitor and N=483 in combination with fulvestrant) and who were included in the randomised, double-blind, placebo-controlled phase III clinical studies MONALEESA-2, MONALEESA-7 NSAI subgroup and MONALEESA-3. The median duration of exposure to study treatment across the pooled phase III studies dataset was 19.2 months, with 61.7% patients exposed ≥12 months. ADRs from the phase III clinical studies (Table 7) in patients with early breast cancer and advanced or metastatic breast cancer are listed by MedDRA system organ class. Within each system organ class, the adverse reactions are ranked by frequency, with the most frequent reactions first. Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. In addition, the corresponding frequency category for each adverse reaction is based on the following convention (CIOMS III): very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1 000 to <1/100); rare (≥1/10 000 to <1/1 000); very rare (<1/10 000); and not known (cannot be estimated from the available data).

Table 7       Adverse drug reactions reported in the phase III clinical studies and during post‑marketing experience

Description of selected adverse reactions. Neutropenia. In the phase III study in patients with early breast cancer, neutropenia was the most frequently reported adverse reaction (62.5%) and a grade 3 or 4 decrease in neutrophil counts (based on laboratory findings) was reported in 45.1% of patients receiving Kisqali plus aromatase inhibitor (AI). Among the patients with early breast cancer who had grade 2, 3 or 4 neutropenia, the median time to onset was 0.6 months, for those patients who had an event. The median time to resolution of grade ≥3 (to normalisation or grade <3) was 0.3 months in the Kisqali plus AI arm following treatment interruption and/or reduction and/or discontinuation. Febrile neutropenia was reported in 0.3% of patients exposed to Kisqali plus AI. Treatment discontinuation due to neutropenia was low (1.1%) in patients receiving Kisqali plus AI (see full leaflet). In the phase III studies in patients with advanced or metastatic breast cancer neutropenia was the most frequently reported adverse reaction (75.4%) and a grade 3 or 4 decrease in neutrophil counts (based on laboratory findings) was reported in 62.0% of patients receiving Kisqali plus any combination. Among the patients with advanced or metastatic breast cancer who had grade 2, 3 or 4 neutropenia, the median time to onset was 17 days, for those patients who had an event. The median time to resolution of grade ≥3 (to normalisation or grade <3) was 12 days in the Kisqali plus any combination arms following treatment interruption and/or reduction and/or discontinuation. Febrile neutropenia was reported in about 1.7% of patients exposed to Kisqali in the phase III studies. Treatment discontinuation due to neutropenia was low (0.8%) (see full leaflet). All patients should be instructed to report any fever promptly. Hepatobiliary toxicity. In the phase III clinical studies in patients with early breast cancer and advanced or metastatic breast cancer, increases in transaminases were observed. In the phase III study in patients with early breast cancer, hepatobiliary toxicity events occurred in a higher proportion of patients in the Kisqali plus AI arm versus the AI alone arm (26.4% versus 11.2%, respectively), with more grade 3/4 adverse events reported in patients treated with Kisqali plus AI (8.6% versus 1.7%, respectively). Concurrent elevations of ALT or AST greater than three times the upper limit of normal and total bilirubin greater than two times the upper limit of normal, with normal alkaline phosphatase levels, occurred in 8 patients treated with Kisqali plus AI (in 6 patients ALT or AST levels recovered to normal within 65 to 303 days after discontinuation of Kisqali). Dose interruptions due to hepatobiliary toxicity events were reported in 12.4% of patients with early breast cancer treated with Kisqali plus AI, primarily due to ALT increased (10.1%) and/or AST increased (6.8%). Dose adjustment due to hepatobiliary toxicity events was reported in 2.6% of patients treated with Kisqali plus AI, primarily due to ALT increased (1.9%) and/or AST increased (0.6%). Discontinuation of treatment with Kisqali due to abnormal liver function tests or hepatotoxicity occurred in 8.9% and 0.1% of patients, respectively (see full leaflet). In the phase III clinical study in patients with early breast cancer, 80.9% (165/204) of grade 3 or 4 ALT or AST elevation events occurred within the first 6 months of treatment. Among the patients who had grade 3 or 4 ALT/AST elevation, the median time to onset was 2.8 months for the Kisqali plus AI arm. The median time to resolution (to normalisation or grade ≤2) was 0.7 months in the Kisqali plus AI arm. In the phase III clinical studies in patients with advanced or metastatic breast cancer, hepatobiliary toxicity events occurred in a higher proportion of patients in the Kisqali plus any combination arms compared with the placebo plus any combination arms (27.3% versus 19.6%, respectively), with more grade 3/4 adverse events reported in the patients treated with Kisqali plus any combination (13.2% versus 6.1%, respectively). Grade 3 or 4 increases in ALT (11.2% versus 1.7%) and AST (7.8% versus 2.1%) were reported in the Kisqali and placebo arms, respectively. Concurrent elevations in ALT or AST greater than three times the upper limit of normal and total bilirubin greater than two times the upper limit of normal, with normal alkaline phosphatase, in the absence of cholestasis occurred in 6 patients (4 patients in Study A2301 [MONALEESA-2], whose levels recovered to normal within 154 days and 2 patients in Study F2301 [MONALEESA-3], whose levels recovered to normal in 121 and 532 days, respectively, after discontinuation of Kisqali). There were no such cases reported in Study E2301 (MONALEESA-7). Dose interruptions and/or adjustments due to hepatobiliary toxicity events were reported in 12.3% of Kisqali plus any combination treated patients with advanced or metastatic breast cancer, primarily due to ALT increased (7.9%) and/or AST increased (7.3%). Discontinuation of treatment with Kisqali plus any combination due to abnormal liver function tests or hepatotoxicity occurred in 2.4% and 0.3% of patients respectively (see full leaflet). In the phase III clinical studies in patients with advanced or metastatic breast cancer, 70.9% (90/127) of grade 3 or 4 ALT or AST elevation events occurred within the first 6 months of treatment. Among the patients who had grade 3 or 4 ALT/AST elevation, the median time to onset was 92 days for the Kisqali plus any combination arms. The median time to resolution (to normalisation or grade ≤2) was 21 days in the Kisqali plus any combination arms. QT prolongation. In the phase III study in patients with early breast cancer, 5.3% of patients in the Kisqali plus AI arm and 1.4% of patients in the AI alone arm reported events of QT interval prolongation. In the Kisqali plus AI arm QT interval prolongation events were presented primarily by ECG QT prolonged (4.3%) which was the only confirmed adverse reaction with Kisqali. Dose interruptions due to ECG QT prolonged and syncope were reported in 1.1% of patients treated with Kisqali. Dose adjustments due to ECG QT prolonged were reported in 0.1% of patients treated with Kisqali. A central analysis of ECG data showed 10 patients (0.4%) and 4 patients (0.2%) with at least one post-baseline QTcF interval >480 msec for the Kisqali plus AI arm and the AI alone arm, respectively. Among the patients who had QTcF interval prolongation of >480 msec in the Kisqali plus AI arm, the median time to onset was 15 days and these changes were reversible with dose interruption and/or dose adjustment. QTcF interval >60 msec change from baseline was observed in 19 patients (0.8%) in the Kisqali plus AI arm and post-baseline QTcF interval >500 msec was observed in 3 patients (0.1%) in the Kisqali plus AI arm. In study E2301 (MONALEESA-7) in patients with advanced or metastatic breast cancer, the observed mean QTcF increase from baseline was approximately 10 msec higher in the tamoxifen plus placebo subgroup compared with the NSAI plus placebo subgroup, suggesting that tamoxifen alone had a QTcF prolongation effect which can contribute to the QTcF values observed in the Kisqali plus tamoxifen group. In the placebo arm, a QTcF interval increase of >60 msec from baseline occurred in 6/90 (6.7%) patients receiving tamoxifen and in no patients receiving a NSAI (see full leaflet). A QTcF interval increase of >60 msec from baseline was observed in 14/87 (16.1%) patients receiving Kisqali plus tamoxifen and in 18/245 (7.3%) patients receiving Kisqali plus a NSAI. Kisqali is not recommended to be used in combination with tamoxifen (see full leaflet). In the phase III clinical studies 9.3% of patients with advanced or metastatic breast cancer in the Kisqali plus aromatase inhibitor or fulvestrant arms and 3.5% in the placebo plus aromatase inhibitor or fulvestrant arms had at least one event of QT interval prolongation (including ECG QT prolonged and syncope). Review of ECG data showed 15 patients (1.4%) had >500 msec post-baseline QTcF value, and 61 patients (5.8%) had a >60 msec increase from baseline in QTcF intervals. There were no reported cases of torsade de pointes. Dose interruptions/adjustments were reported in 2.9% of Kisqali plus aromatase inhibitor or fulvestrant treated patients due to electrocardiogram QT prolonged and syncope. The analysis of ECG data showed 55 patients (5.2%) and 12 patients (1.5%) with at least one >480 msec post-baseline QTcF for the Kisqali plus aromatase inhibitor or fulvestrant arms and the placebo plus aromatase inhibitor or fulvestrant arms, respectively. Amongst the patients who had QTcF prolongation >480 msec, the median time to onset was 15 days regardless of the combination and these changes were reversible with dose interruption and/or dose reduction (see full leaflet). Patients with renal impairment. In the phase III clinical study in patients with early breast cancer, 983 patients with mild renal impairment and 71 patients with moderate renal impairment were treated with ribociclib. No patient with severe renal impairment was enrolled (see full leaflet). In the three pivotal studies, 341 patients with mild renal impairment and 97 patients with moderate renal impairment were treated with ribociclib. No patient with severe renal impairment was enrolled. There was a correlation between the degree of renal impairment at baseline and blood creatinine values during the treatment. Slightly increased rates of QT prolongation and thrombocytopenia were observed in patients with mild or moderate renal impairment. For monitoring and dose adjustment recommendations for these toxicities see full leaflet. Reporting of suspected adverse reactions. Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product.
Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system. MARKETING AUTHORISATION HOLDER. Novartis Europharm Limited, Vista Building, Elm Park, Merrion Road, Dublin 4, Ireland. MARKETING AUTHORISATION NUMBER(S). EU/1/17/1221/001-012. MODE OF DELIVERY. Medicinal product subject to medical prescription. DATE OF REVISION OF THE TEXT. 24 April 2025. Detailed information on this medicinal product is available on the website of the European Medicines Agency https://www.ema.europa.eu.