Adverse reactions : תופעות לוואי

4.8    Undesirable effects
Summary of the safety profile

The most common adverse reactions (ARs) (reported at a frequency ≥20%) in the pooled dataset for which the frequency for Kisqali plus any combination exceeds the frequency for placebo plus any combination were neutropenia, infections, nausea, fatigue, diarrhoea, leukopenia, vomiting, headache, constipation, alopecia, cough, rash, back pain, anaemia and abnormal liver function tests.

The most common grade 3/4 ARs (reported at a frequency of >2%) in the pooled dataset for which the frequency for Kisqali plus any combination exceeds the frequency for placebo plus any combination were neutropenia, leukopenia, abnormal liver function tests, lymphopenia, infections, back pain, anaemia, fatigue, hypophosphataemia and vomiting.

Dose reduction due to adverse events, regardless of causality, occurred in 39.5% of patients receiving Kisqali in the phase III clinical studies regardless of the combination and permanent discontinuation was reported in 8.7% of patients receiving Kisqali and any combination in the phase III clinical 
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studies.

Tabulated list of adverse reactions

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 a non-steroidal 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) in HR-positive, HER2-negative advanced or metastatic breast cancer.
Additional ADRs were identified post-marketing.

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.

Adverse reactions from the phase III clinical studies (Table 7) 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 reactions reported in the three phase III clinical studies and during post-marketing experience
Adverse reaction                                                                  Frequency Infections and infestations
Infections1                                                                       Very common Blood and lymphatic system disorders
Neutropenia, leukopenia, anaemia, lymphopenia                                     Very common Thrombocytopenia, febrile neutropenia                                             Common Metabolism and nutrition disorders
Decreased appetite                                                                Very common Hypocalcaemia, hypokalaemia, hypophosphataemia                                    Common Nervous system disorders
Headache, dizziness                                                               Very common Vertigo                                                                           Common Eye disorders
Lacrimation increased, dry eye                                                    Common Cardiac disorders
Syncope                                                                           Common Respiratory, thoracic and mediastinal disorders
Dyspnoea, cough                                                                   Very common Interstitial lung disease (ILD)/pneumonitis                                       Common Gastrointestinal disorders
Nausea, diarrhoea, vomiting, constipation, abdominal pain2, stomatitis, Very common dyspepsia
Dysgeusia                                                                         Common Hepatobiliary disorders
Hepatotoxicity3                                                                   Common Skin and subcutaneous tissue disorders
Alopecia, rash4, pruritus                                                         Very common Dry skin, erythema, vitiligo                                                      Common Erythema multiforme                                                               Rare 
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Toxic epidermal necrolysis (TEN)                                                         Not known Musculoskeletal and connective tissue disorders
Back pain                                                                                Very common General disorders and administration site conditions
Fatigue, peripheral oedema, pyrexia, asthenia                                            Very common Oropharyngeal pain, dry mouth                                                            Common Investigations
Abnormal liver function tests5                                                           Very common Blood creatinine increased, electrocardiogram QT prolonged                               Common 1
Infections: urinary tract infections, respiratory tract infections, gastroenteritis, sepsis (<1%).
2
Abdominal pain: abdominal pain, abdominal pain upper.
3
Hepatotoxicity: hepatic cytolysis, hepatocellular injury, drug-induced liver injury (<1%), hepatotoxicity, hepatic failure, autoimmune hepatitis (single case).
4
Rash: rash, rash maculopapular, rash pruritic.
5
Abnormal liver function tests: ALT increased, AST increased, blood bilirubin increased.


Description of selected adverse reactions
Neutropenia
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 in the phase III studies.

Among the patients 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. Patients should be instructed to report any fever promptly.

Based on its severity, neutropenia was managed by laboratory monitoring, dose interruption and/or dose modification. Treatment discontinuation due to neutropenia was low (0.8%) (see sections 4.2 and 4.4).

Hepatobiliary toxicity
In the phase III clinical studies, 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). Increases in transaminases were observed. 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, 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 sections 4.2 and 4.4).

In the phase III clinical studies, 70.9% (90/127) of grade 3 or 4 ALT or AST elevation events occurred 

KIS API JUL24 V9                                                            EU SmPC JUN 24 13
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 study E2301 (MONALEESA-7), 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 section 5.2). 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 section 5.1).

In the phase III clinical studies 9.3% of patients 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 non-steroidal 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 non-steroidal aromatase inhibitor or fulvestrant arms and the placebo plus non-steroidal 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 sections 4.2, 4.4 and 5.2).

Patients with renal impairment
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 (see section 5.1). 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 sections 4.2. and 4.4.

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.
Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form https://sideeffects.health.gov.il/
And to Novartis using the following email address: Safetydesk.israel@novartis.com