Kisqali

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. 4 Table 1 Recommended dose modification guidelines Kisqali Dose Number of 200 mg tablets Early breast cancer Starting dose 400 mg/day 2 Dose reduction 200 mg*/day 1 Advanced or metastatic breast cancer Starting dose 600 mg/day 3 First dose reduction 400 mg/day 2 Second dose reduction 200 mg*/day 1 * If further dose reduction below 200 mg/day is required, the treatment should be permanently discontinued.

Tables 2, 3, 4, 5 and 6 summarise recommendations for dose interruption, reduction or discontinuation of Kisqali in the management of specific ARs. 4). 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 Grade 1 or 2* (ANC 1 000/mm3 - ≤LLN) Grade 3* (ANC 500 - <1 000/mm3) Grade 3* febrile neutropenia** Grade 4* (ANC <500/mm3) Neutropenia No dose adjustment is required Dose interruption until recovery to grade ≤2.

Resume Kisqali at the same dose level. If toxicity recurs at grade 3: dose interruption until recovery to grade ≤2, then resume Kisqali and reduce by 1 dose level. Dose interruption until recovery to grade ≤2. Resume Kisqali and reduce by 1 dose level Dose interruption until recovery to grade ≤2.

Resume Kisqali and reduce by 1 dose level. 3°C (or 38°C and above for more than one hour and/or concurrent infection) ANC = absolute neutrophil count; LLN = lower limit of normal 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.

5 Table 3 Dose modification and management – Hepatobiliary toxicity Grade 1* (> ULN – 3 x ULN) Grade 2* (>3 to 5 x ULN) Grade 3* (>5 to 20 x ULN) Grade 4* (>20 x ULN) AST and/or ALT elevations from baseline**, without increase in total bilirubin above 2 x ULN No dose adjustment is required.

Baseline grade <2:

Dose interruption until recovery to ≤ baseline grade, then resume Kisqali at same dose level. If grade 2 recurs, resume Kisqali at next lower dose level. Dose interruption of Kisqali until recovery to ≤ baseline grade, then resume at next lower dose level.

If grade 3 recurs, discontinue Kisqali. Discontinue Kisqali.

Baseline grade = 2:

No dose interruption. Combined elevations in AST and/or ALT together with total bilirubin increase, in the absence of cholestasis If patients develop ALT and/or AST >3 x ULN along with total bilirubin >2 x ULN irrespective of baseline grade, discontinue Kisqali.

03 (CTCAE = Common Terminology Criteria for Adverse Events) ** Baseline = prior to treatment initiation ULN = upper limit of normal 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 […]

Summary of the safety profile Early breast cancer The most common adverse drug reactions (ADRs) (reported at a frequency ≥20%) in the dataset for which the frequency for Kisqali plus aromatase inhibitor (AI) exceeds the frequency for AI alone were neutropenia, infections, nausea, headache, fatigue, leukopenia and abnormal liver function tests.

The most common grade 3/4 ADRs (reported at a frequency of ≥2%) in the dataset for which the frequency for Kisqali plus AI exceeds the frequency for AI alone were neutropenia, abnormal liver function tests and leukopenia. 8% of patients receiving Kisqali plus AI in the phase III clinical study.

7% of patients receiving Kisqali plus AI in the phase III clinical study. Advanced or metastatic breast cancer The most common adverse drug reactions (ADRs) (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 ADRs (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.

5% of patients receiving Kisqali in the phase III clinical studies regardless of the combination. 7% of patients receiving Kisqali and any combination in the phase III clinical studies. 14 Tabulated list of adverse reactions 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.

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.

7% patients exposed ≥12 months. ADRs from the phase III clinical studies and post-marketing experience (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).

15 Table 7 Adverse drug reactions reported in the phase III clinical studies and during post‑marketing experience Frequency Patients with early breast cancer with starting dose 400 mg ribociclib Patients with advanced or metastatic breast cancer with starting dose 600 mg ribociclib Infections and infestations Very common Infections1 Infections1 Blood and lymphatic system disorders Very common Neutropenia, leukopenia Neutropenia, leukopenia, anaemia, lymphopenia Common Anaemia, thrombocytopenia, lymphopenia Thrombocytopenia, febrile neutropenia Uncommon Febrile neutropenia - Metabolism and nutrition disorders Very common - Appetite decreased Common Hypocalcaemia, hypokalaemia, appetite decreased Hypocalcaemia, hypokalaemia, hypophosphataemia Nervous system disorders Very common Headache Headache, dizziness Common Dizziness Vertigo Eye disorders Common - Lacrimation increased, dry eye Cardiac disorders Common - Syncope Respiratory, thoracic and mediastinal disorders Very common Cough Dyspnoea, cough Common Dyspnoea, interstitial lung disease (ILD) / pneumonitis Interstitial lung disease (ILD) / pneumonitis Gastrointestinal disorders Very common Nausea, diarrhoea, constipation, abdominal pain2 Nausea, diarrhoea, vomiting, constipation, abdominal pain2, stomatitis, dyspepsia Common Vomiting, stomatitis3 Dysgeusia Hepatobiliary disorders Common Hepatotoxicity4 Hepatotoxicity4 Skin and subcutaneous tissue disorders Very common Alopecia Alopecia, rash5, pruritus Common Rash5, pruritus Dry skin, erythema, vitiligo Rare - Erythema multiforme Not known - Toxic epidermal necrolysis (TEN) Musculoskeletal and connective tissue disorders Very common - Back pain General disorders and administration site conditions Very common Fatigue, asthenia, pyrexia Fatigue, peripheral oedema, pyrexia, asthenia Common Peripheral oedema, oropharyngeal pain Oropharyngeal pain, dry mouth 16 Investigations Very common Abnormal liver function tests6 Abnormal liver function tests6 Common Blood creatinine increased, electrocardiogram QT prolonged Blood creatinine increased, electrocardiogram QT prolonged 1 Infections: urinary tract infections, respiratory tract infections, gastroenteritis (only in patients with advanced or metastatic breast cancer), sepsis (<1% only in patients with […]

Critical visceral disease The efficacy and safety of ribociclib have not been studied in patients with critical visceral disease. 8). Hepatobiliary toxicity Liver function tests should be performed before initiating treatment with Kisqali.

8). 8). Recommendations for patients who have elevated AST/ALT grade ≥ 3 at baseline have not been established. 8 QT interval prolongation The use of Kisqali should be avoided in patients who already have or who are at significant risk of developing QTc prolongation.

This includes patients: • with long QT syndrome; • with uncontrolled or significant cardiac disease, including recent myocardial infarction, congestive heart failure, unstable angina and bradyarrhythmias; • with electrolyte abnormalities.

1). 2. 1). 8%) patients receiving Kisqali plus AI. ECG should be assessed before initiating treatment. Treatment with Kisqali should be initiated only in patients with QTcF values less than 450 msec. 8). In patients with early breast cancer, appropriate monitoring of serum electrolytes (including potassium, calcium, phosphorus and magnesium) should be performed before initiating treatment, at the beginning of the first 6 cycles and then as clinically indicated.

Any abnormality should be corrected before initiating treatment with Kisqali and during treatment with Kisqali. 2). 3%) patients receiving Kisqali plus a non-steroidal aromatase inhibitor (NSAI). ECG should be assessed before initiating treatment.

Treatment with Kisqali should be initiated only in patients with QTcF values less than 450 msec. 8). In patients with advanced or metastatic breast cancer, appropriate monitoring of serum electrolytes (including potassium, calcium, phosphorus and magnesium) should be performed before initiating treatment, at the beginning of the first 6 cycles and then as clinically indicated.

Any abnormality should be corrected before initiating treatment with Kisqali and during treatment with Kisqali. 2). Severe cutaneous reactions Toxic epidermal necrolysis (TEN) has been reported with Kisqali treatment. g. progressive widespread skin rash often with blisters or mucosal lesions) appear, Kisqali should be discontinued immediately.

9 Interstitial lung disease/pneumonitis Interstitial lung disease (ILD)/pneumonitis has been reported with Kisqali. 2). 2). 5). In case of blood creatinine increase while on treatment, it is recommended that further assessment of the renal function be performed to exclude renal impairment.

CYP3A4 substrates Ribociclib is a strong CYP3A4 inhibitor at the 600 mg dose and a moderate CYP3A4 inhibitor at the 400 mg dose. 5). Caution is recommended in case of concomitant use with sensitive CYP3A4 substrates with a narrow therapeutic index and the SmPC of the other product should be consulted for the recommendations regarding co-administration with CYP3A4 inhibitors.

Renal impairment The recommended starting dose of 200 mg for patients with severe renal impairment is estimated to result in approximately 45% lower exposure compared with the standard starting dose of 600 mg in advanced or metastatic breast cancer patients with normal renal function.

The efficacy at this starting dose has not been […]

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