Posology : מינונים

4.2    Posology and method of administration

Treatment with Kisqali should be initiated by a physician experienced in the use of anticancer therapies.

Posology

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. The treatment should be continued as long as the patient is deriving clinical benefit from therapy or until unacceptable toxicity occurs.

Kisqali should be used together with 2.5 mg letrozole or another non-steroidal aromatase inhibitor or with 500 mg fulvestrant.

When Kisqali is used in combination with a non-steroidal aromatase inhibitor, the non steroidal aromatase inhibitor should be taken orally once daily continuously throughout the 28-day cycle. Please refer to the Prescribing information of the non-steroidal aromatase inhibitor for additional details.
1
KIS SPI 03JUL24 V9                                                          EU SmPC JUN 24 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 Prescribing information 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.

Kisqali can be taken with or without food (see section 4.5). 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.

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

Kisqali
Dose                              Number of 200 mg tablets
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. The clinical judgement of the treating physician should guide the management plan of each patient based on individual benefit/risk assessment (see section 4.4).

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.



KIS API JUL24 V9                                                          EU SmPC JUN 24 2
Table 2      Dose modification and management – Neutropenia

Grade 1 or 2*             Grade 3*             Grade 3* febrile Grade 4* (ANC                      (ANC                 neutropenia**     (ANC <500/mm3) 1000/mm3 - ≤LLN)          500 - <1000/mm )   3

Neutropenia      No dose adjustment is     Dose interruption Dose interruption Dose interruption required                  until recovery to    until recovery to until recovery to grade ≤2.            grade ≤2. Resume grade ≤2.
Resume Kisqali at Kisqali and          Resume Kisqali the same dose        reduce by 1 dose  and reduce by level.               level.            1 dose level.
If toxicity recurs at grade 3: dose interruption until recovery to grade ≤2, then resume Kisqali and reduce by
1 dose level.
* Grading according to CTCAE Version 4.03 (CTCAE = Common Terminology Criteria for Adverse Events)
** Grade 3 neutropenia with a single fever >38.3°C (or above 38°C 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.



KIS API JUL24 V9                                                           EU SmPC JUN 24 3
Table 3      Dose modification and management – Hepatobiliary toxicity 
Grade 1*       Grade 2*                  Grade 3*                  Grade 4* (> ULN –       (>3 to 5 x ULN)           (>5 to 20 x ULN)          (>20 x ULN) 3 x ULN)
AST and/or          No dose         Baseline grade <2:        Dose interruption of  Discontinue ALT elevations      adjustment      Dose interruption until Kisqali until recovery Kisqali.
from                is required.    recovery to ≤ baseline    to ≤ baseline grade, baseline**,                         grade, then resume        then resume at next without                             Kisqali at same dose      lower dose level.
increase in total                   level. If grade 2 recurs, If grade 3 recurs, bilirubin above                     resume Kisqali at next discontinue Kisqali.
2 x ULN                             lower dose level.
Baseline grade = 2:
No dose interruption.
Combined            If patients develop ALT and/or AST >3 x ULN along with total bilirubin >2 x elevations in       ULN irrespective of baseline grade, discontinue Kisqali.
AST and/or
ALT together with total bilirubin increase, in the absence of cholestasis
* Grading according to CTCAE Version 4.03 (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. After initiating treatment, ECG should be repeated at approximately day 14 of the first cycle and at the beginning of the second cycle, then as clinically indicated. In case of QTcF prolongation during treatment, more frequent ECG monitoring is recommended.

Table 4      Dose modification and management – QT prolongation

ECGs with               1.    The dose should be interrupted.
QTcF >480 msec          2.    If QTcF prolongation resolves to <481 msec, resume treatment at the next lower dose level.
3.    If QTcF ≥481 msec recurs, interrupt dose until QTcF resolves to <481 msec and then resume Kisqali at the next lower dose level.
ECGs with               If QTcF is greater than 500 msec, interrupt Kisqali until QTcF is <481 msec QTcF >500 msec          then resume Kisqali at next lower dose level.

If QTcF interval prolongation to greater than 500 msec or greater than 60 msec change from baseline occurs in combination with torsade de pointes or polymorphic ventricular tachycardia or signs/symptoms of serious arrhythmia, permanently discontinue Kisqali.



KIS API JUL24 V9                                                          EU SmPC JUN 24 4
Table 5      Dose modification and management – ILD/pneumonitis

Grade 1*                Grade 2*                Grade 3 or 4*
(asymptomatic)          (symptomatic)           (severe)
ILD/pneumonitis             No dose adjustment is   Dose interruption until Discontinue Kisqali required. Initiate      recovery to grade ≤1,
appropriate medical     then resume Kisqali at therapy and monitor as the next lower dose clinically indicated.   level**.
*Grading according to CTCAE Version 4.03 (CTCAE = Common Terminology Criteria for Adverse Events)
**An individualised benefit-risk assessment should be performed when considering resuming Kisqali ILD = interstitial lung disease


Table 6      Dose modification and management – Other toxicities*
Other toxicities           Grade 1 or 2**           Grade 3**                Grade 4** No dose adjustment is    Dose interruption until Discontinue Kisqali.
required. Initiate       recovery to grade ≤1,
appropriate medical      then resume Kisqali at therapy and monitor as   the same dose level.
clinically indicated.    If grade 3 recurs,
resume Kisqali at the next lower dose level.
* Excluding neutropenia, hepatotoxicity, QT interval prolongation and ILD/pneumonitis.
** Grading according to CTCAE Version 4.03 (CTCAE = Common Terminology Criteria for Adverse Events)

Refer to the Prescribing information for the co-administered non-steroidal aromatase inhibitor, 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 to 400 mg once daily (see section 4.5).

In patients who have had their dose reduced to 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 sections 4.4, 4.5 and 5.2).

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 
KIS API JUL24 V9                                                           EU SmPC JUN 24 5
breast cancer patients with severe renal impairment (see sections 4.4, 5.1 and 5.2).
Caution should be used in patients with severe renal impairment, ESRD (End Stage Renal Disease) or on dialysis treatment with close monitoring for signs of toxicity as there is no experience with Kisqali in this patient population.

Hepatic impairment
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 section 5.2).

Paediatric population
Kisqali is not indicated for use in children and adolescents.

Elderly
No dose adjustment is required in patients over 65 years of age (see section 5.2).
Method of administration

Kisqali should be taken orally once daily with or without food. The tablets should be swallowed whole and should not be chewed, crushed or split prior to swallowing (No information about crushing/ splitting/ chewing is available). No tablet should be ingested if it is broken, cracked or otherwise not intact.