Source: European Medicines Agency (EU) Revision Year: 2020 Publisher: Novartis Europharm Limited, Vista Building, Elm Park, Merrion Road, Dublin 4, Ireland
Kisqali is indicated for the treatment of women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (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 luteinising hormone-releasing hormone (LHRH) agonist.
Treatment with Kisqali should be initiated by a physician experienced in the use of anticancer therapies.
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 aromatase inhibitor or with 500 mg fulvestrant.
When Kisqali is used in combination with an aromatase inhibitor, the aromatase inhibitor should be taken orally once daily continuously throughout the 28-day cycle. Please refer to the Summary of Product Characteristics (SmPC) of the aromatase inhibitor 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.
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.
Management of severe or intolerable adverse drug reactions (ADRs) 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 and 5 summarise recommendations for dose interruption, reduction or discontinuation of Kisqali in the management of specific ADRs. 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.
Table 2. Dose modification and management – Neutropenia:
| Grade 1 or 2* (ANC 1000/mm3 - ≤LLN) | Grade 3* (ANC 500 - <1000/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. |
* 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.
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. Baseline grade = 2: No dose interruption. | Dose interruption of Kisqali until recovery to ≤baseline grade, then resume at next lower dose level. If grade 3 recurs, discontinue Kisqali. | Discontinue Kisqali. |
| 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. | |||
* 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 QTcF >480 msec | 1. The dose should be interrupted. |
| 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 QTcF >500 msec | If QTcF is greater than 500 msec, interrupt Kisqali until QTcF is <481 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. |
Table 5. Dose modification and management – ILD/pneumonitis:
| Grade 1* (asymptomatic) | Grade 2* (symptomatic) | Grade 3 or 4* (severe) | |
|---|---|---|---|
| ILD/pneumonitis | No dose adjustment is required. Initiate appropriate medical therapy and monitor as clinically indicated. | Dose interruption until recovery to grade ≤1, then resume Kisqali at the next lower dose level**. | Discontinue Kisqali. |
* 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*
| Grade 1 or 2** | Grade 3** | Grade 4** | |
|---|---|---|---|
| Other toxicities | No dose adjustment is required. Initiate appropriate medical therapy and monitor as clinically indicated. | Dose interruption until recovery to grade ≤1, then resume Kisqali at the same dose level. If grade 3 recurs, resume Kisqali at the next lower dose level. | Discontinue Kisqali. |
* Excluding neutropenia, hepatotoxicity and QT interval prolongation.
** Grading according to CTCAE Version 4.03 (CTCAE = Common Terminology Criteria for Adverse Events).
Refer to the SmPC for the co-administered aromatase inhibitor, fulvestrant or LHRH agonist for dose modification guidelines and other relevant safety information in the event of toxicity.
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).
No dose adjustment is necessary in patients with mild or moderate renal impairment (see section 5.2). A starting dose of 400 mg is recommended in patients with severe renal impairment (see section 5.2). Caution should be used in patients with severe renal impairment with close monitoring for signs of toxicity.
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).
The safety and efficacy of Kisqali in children and adolescents aged below 18 years have not been established. No data are available.
No dose adjustment is required in patients over 65 years of age (see section 5.2).
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 tablet should be ingested if it is broken, cracked or otherwise not intact.
There is only limited experience with reported cases of overdosage with Kisqali. In the event of an overdose, symptoms such as nausea and vomiting may occur. In addition, haematological (e.g. neutropenia, thrombocytopenia) toxicity and possible QTc prolongation may occur. General supportive care should be initiated in all cases of overdosage as necessary.
Shelf life: 3 years.
This medicinal product does not require any special storage conditions.
PVC/PCTFE (polyvinylchloride/polychlorotrifluoroethylene) or PA/alu/PVC (polyamide/aluminium/polyvinylchloride) blisters containing 14 or 21 film-coated tablets.
Unit packs containing 21, 42 or 63 film-coated tablets and multipacks containing 63 (3 packs of 21), 126 (3 packs of 42) or 189 (3 packs of 63) film-coated tablets.
Not all pack sizes may be marketed.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
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