Kisqali

1 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 



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 This medicinal product is subject to additional monitoring. This will allow quick identification of 

new safety information. Healthcare professionals are asked to report any suspected adverse reactions. 

See section 4.8 for how to report adverse reactions. 

 

 

1. NAME OF THE MEDICINAL PRODUCT 
 

Kisqali 200 mg film-coated tablets 

 

 

2. 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 section 6.1. 

 

 

3. 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. 

 

 

4. CLINICAL PARTICULARS 
 

4.1 Therapeutic indications 
 

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. 

 

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 aromatase inhibitor or with 500 mg 

fulvestrant. 

 

  



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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. 

 

Dose modifications 

Management of severe or intolerable adverse events (AEs) 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 AEs. 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. 

 



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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. 

 



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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. 

* 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. 

 



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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* 
 

Other toxicities Grade 1 or 2** Grade 3** Grade 4** 

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, QT interval prolongation and ILD/pneumonitis. 

** 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. 

 

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 (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. 

 



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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 

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 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 tablet should be ingested if it is 

broken, cracked or otherwise not intact. 

 

4.3 Contraindications 
 

Hypersensitivity to the active substance or to peanut, soya or any of the excipients listed in section 6.1. 

 

4.4 Special warnings and precautions for use 
 

Critical visceral disease 

 

The efficacy and safety of ribociclib have not been studied in patients with critical visceral disease. 

 

Neutropenia 

 

Based on the severity of the neutropenia, treatment with Kisqali may have to be interrupted, reduced 

or discontinued as described in Table 2 (see sections 4.2 and 4.8). 

 

Hepatobiliary toxicity 

 

Liver function tests should be performed before initiating treatment with Kisqali. After initiating 

treatment, liver function should be monitored (see sections 4.2 and 4.8). 

 

Based on the severity of the transaminase elevations, treatment with Kisqali may have to be 

interrupted, reduced or discontinued as described in Table 3 (see sections 4.2 and 4.8). 

Recommendations for patients who have elevated AST/ALT grade ≥ 3 at baseline have not been 

established. 

 

QT interval prolongation 

 

In study E2301 (MONALEESA-7), a QTcF interval increase >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 non-steroidal aromatase inhibitor (NSAI). Kisqali is not recommended to be used in 

combination with tamoxifen (see sections 4.8 and 5.1). 

 

ECG should be assessed before initiating treatment. Treatment with Kisqali should be initiated only in 

patients with QTcF values less than 450 msec. ECG should be repeated at approximately day 14 of the 

first cycle and at the beginning of the second cycle, then as clinically indicated (see sections 4.2 and 

4.8). 

 

  



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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. 

 

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. 
 

The use of Kisqali with medicinal products known to prolong QTc interval and/or strong CYP3A4 

inhibitors should be avoided as this may lead to clinically meaningful prolongation of the QTcF 

interval (see sections 4.2, 4.5 and 5.1). If treatment with a strong CYP3A4 inhibitor cannot be avoided, 

the dose should be reduced to 400 mg once daily (see sections 4.2 and 4.5). 

 

Based on the observed QT prolongation during treatment, treatment with Kisqali may have to be 

interrupted, reduced or discontinued as described in Table 4 (see sections 4.2, 4.8 and 5.2). 

 

Severe cutaneous reactions 

 

Toxic epidermal necrolysis (TEN) has been reported with Kisqali treatment. If signs and symptoms 

suggestive of severe cutaneous reactions (e.g. progressive widespread skin rash often with blisters or 

mucosal lesions) appear, Kisqali should be discontinued immediately. 

 

Interstitial lung disease/pneumonitis 

 

ILD/pneumonitis has been reported with CDK4/6 inhibitors including Kisqali. In the 3 phase III 

clinical studies (MONALEESA-2 [A2301], MONALEESA-7 [E2301-NSAI] and MONALEESA-3 

[F2301]), ILD (any grade 0.3%, including 0.1% grade 3) was reported in the Kisqali-treated group, 

with no cases in the placebo-treated group. Pneumonitis was reported in both the Kisqali- and the 

placebo-treated groups (any grade 0.4%, with no grade 3 or 4 in either treatment group). 

 

Based on the severity of the ILD/pneumonitis, which may be fatal, Kisqali may require dose 

interruption, reduction or discontinuation as described in Table 5 (see section 4.2). 

 

Patients should be monitored for pulmonary symptoms indicative of ILD/pneumonitis which may 

include hypoxia, cough and dyspnoea and dose modifications should be managed in accordance with 

Table 5 (see section 4.2) 

 

CYP3A4 substrates 

 

Ribociclib is a strong CYP3A4 inhibitor at the 600 mg dose and a moderate CYP3A4 inhibitor at the 

400 mg dose. Thus, ribociclib may interact with medicinal products which are metabolised via 

CYP3A4, which may lead to increased serum concentrations of CYP3A4 substrates (see section 4.5). 

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. 

 

Women of childbearing potential 

 

Women of childbearing potential should be advised to use an effective method of contraception while 

taking Kisqali and for at least 21 days after the last dose (see section 4.6). 

 



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Soya lecithin 

 

Kisqali contains soya lecithin. Patients who are hypersensitive to peanut or soya should not take 

Kisqali (see section 4.3). 

 

4.5 Interaction with other medicinal products and other forms of interaction 
 

Substances that may increase ribociclib plasma concentrations 

 

Ribociclib is primarily metabolised by CYP3A4. Therefore, medicinal products that can influence 

CYP3A4 enzyme activity may alter the pharmacokinetics of ribociclib. Co-administration of the 

strong CYP3A4 inhibitor ritonavir (100 mg twice daily for 14 days) with a single 400 mg dose of 

ribociclib increased ribociclib exposure (AUCinf) and the peak concentration (Cmax) in healthy subjects 

3.2 and 1.7-fold, respectively, relative to a single 400 mg ribociclib dose given alone. Cmax and AUClast 

for LEQ803 (a prominent metabolite of ribociclib accounting for less than 10% of parent exposure) 

decreased by 96% and 98%, respectively. 

 

The concomitant use of strong CYP3A4 inhibitors including, but not limited to, the following must be 

avoided: clarithromycin, indinavir, itraconazole, ketoconazole, lopinavir, ritonavir, nefazodone, 

nelfinavir, posaconazole, saquinavir, telaprevir, telithromycin, verapamil and voriconazole (see 

section 4.4). Alternative concomitant medicinal products with less potential to inhibit CYP3A4 should 

be considered and patients should be monitored for ribociclib-related AEs (see sections 4.2, 4.4 and 

5.2). 

 

If co-administration of Kisqali with a strong CYP3A4 inhibitor cannot be avoided, the dose of Kisqali 

should be reduced as described in section 4.2. However, there are no clinical data with these dose 

adjustments. Due to inter-patient variability, the recommended dose adjustments may not be optimal 

in all patients, therefore close monitoring for ribociclib-related AEs is recommended. In the event of 

ribociclib-related toxicity, the dose should be modified or treatment should be interrupted until toxicity 

is resolved (see sections 4.2 and 5.2). If the strong CYP3A4 inhibitor is discontinued, and after at least 

5 half-lives of the CYP3A4 inhibitor (refer to the SmPC of the CYP3A4 inhibitor in question), Kisqali 

should be resumed at the same dose used prior to the initiation of the strong CYP3A4 inhibitor. 

 

Physiologically-based pharmacokinetic simulations suggested that at a 600 mg dose of ribociclib, a 

moderate CYP3A4 inhibitor (erythromycin) may increase ribociclib steady-state Cmax and AUC 

1.2-fold and 1.3-fold, respectively. For patients who had their ribociclib dose reduced to 400 mg once 

daily, the increase of the steady-state Cmax and AUC was estimated to be 1.4- and 2.1-fold, 

respectively. The effect at the 200 mg once-daily dose was predicted to be a 1.7- and 2.8-fold increase, 

respectively. No dose adjustments of ribociclib are required at initiation of treatment with mild or 

moderate CYP3A4 inhibitors. However, monitoring of ribociclib-related AEs is recommended. 

 

Patients should be instructed to avoid grapefruit or grapefruit juice. These are known to inhibit 

cytochrome CYP3A4 enzymes and may increase the exposure to ribociclib. 

 

Substances that may decrease ribociclib plasma concentrations 

 

Co-administration of the strong CYP3A4 inducer rifampicin (600 mg daily for 14 days) with a single 

600 mg dose of ribociclib decreased the ribociclib AUCinf and Cmax by 89% and 81%, respectively, 

relative to a single 600 mg ribociclib dose given alone in healthy subjects. LEQ803 Cmax increased 

1.7-fold and AUCinf decreased by 27%, respectively. The concomitant use of strong CYP3A4 inducers 

may therefore lead to decreased exposure and consequently a risk for lack of efficacy. The 

concomitant use of strong CYP3A4 inducers should be avoided, including, but not limited to, 

phenytoin, rifampicin, carbamazepine and St John’s Wort (Hypericum perforatum). An alternative 

concomitant medicinal product with no or minimal potential to induce CYP3A4 should be considered. 

 

  



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The effect of a moderate CYP3A4 inducer on ribociclib exposure has not been studied. 

Physiologically-based pharmacokinetic simulations suggested that a moderate CYP3A4 inducer 

(efavirenz) may decrease steady-state ribociclib Cmax and AUC by 51% and 70%, respectively. The 

concomitant use of moderate CYP3A4 inducers may therefore lead to decreased exposure and 

consequently a risk for impaired efficacy, in particular in patients treated with ribociclib at 400 mg or 

200 mg once daily. 

 

Substances that may have plasma concentrations altered by Kisqali 

 

Ribociclib is a moderate to strong CYP3A4 inhibitor and may interact with medicinal substrates that 

are metabolised via CYP3A4, which can lead to increased serum concentrations of the concomitantly 

used medicinal product. 

 

Co-administration of midazolam (CYP3A4 substrate) with multiple doses of Kisqali (400 mg) 

increased the midazolam exposure by 280% (3.80-fold) in healthy subjects, compared with 

administration of midazolam alone. Simulations using physiologically-based pharmacokinetic models 

suggested that Kisqali given at the clinically relevant dose of 600 mg is expected to increase the 

midazolam AUC by 5.2-fold. Therefore, in general, when ribociclib is co-administered with other 

medicinal products, the SmPC of the other medicinal product must be consulted for the 

recommendations regarding co-administration with CYP3A4 inhibitors. Caution is recommended in 

case of concomitant use with sensitive CYP3A4 substrates with a narrow therapeutic index (see 

section 4.4). The dose of a sensitive CYP3A4 substrate with a narrow therapeutic index, including but 

not limited to alfentanil, ciclosporin, everolimus, fentanyl, sirolimus and tacrolimus, may need to be 

reduced as ribociclib can increase their exposure. 

 

Concomitant administration of ribociclib at the 600 mg dose with the following CYP3A4 substrates 

should be avoided: alfuzosin, amiodarone, cisapride, pimozide, quinidine, ergotamine, 

dihydroergotamine, quetiapine, lovastatin, simvastatin, sildenafil, midazolam, triazolam. 

 

Co-administration of caffeine (CYP1A2 substrate) with multiple doses of Kisqali (400 mg) increased 

the caffeine exposure by 20% (1.20-fold) in healthy subjects, compared with administration of 

caffeine alone. At the clinically relevant dose of 600 mg, simulations using PBPK models predicted 

only weak inhibitory effects of ribociclib on CYP1A2 substrates (<2-fold increase in AUC). 

 

Substances that are substrates of transporters 

 

In vitro evaluations indicated that ribociclib has a potential to inhibit the activities of drug transporters 

P-gp, BCRP, OATP1B1/1B3, OCT1, OCT2, MATE1 and BSEP. Caution and monitoring for toxicity 

are advised during concomitant treatment with sensitive substrates of these transporters which exhibit 

a narrow therapeutic index, including but not limited to digoxin, pitavastatin, pravastatin, rosuvastatin 

and metformin. 

 

Drug-food interactions 

 

Kisqali can be administered with or without food (see sections 4.2 and 5.2). 

 

Medicinal products that elevate gastric pH 

 

Ribociclib exhibits high solubility at or below pH 4.5 and in bio-relevant media (at pH 5.0 and 6.5). 

Co-administration of ribociclib with medicinal products that elevate the gastric pH was not evaluated 

in a clinical study; however, altered ribociclib absorption was not observed in population 

pharmacokinetic and non–compartmental pharmacokinetic analyses. 

 

  



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Drug-drug interaction between ribociclib and letrozole 

 

Data from a clinical study in patients with breast cancer and population pharmacokinetic analysis 

indicated no drug interaction between ribociclib and letrozole following co-administration of these 

medicinal products. 

 

Drug-drug interaction between ribociclib and anastrozole 

 

Data from a clinical study in patients with breast cancer indicated no clinically relevant drug 

interaction between ribociclib and anastrozole following co-administration of these medicinal 

products. 

 

Drug-drug interaction between ribociclib and fulvestrant 

 

Data from a clinical study in patients with breast cancer indicated no clinically relevant effects of 

fulvestrant on ribociclib exposure following co-administration of these medicinal products. 

 

Drug-drug interaction between ribociclib and tamoxifen 

 

Data from a clinical study in patients with breast cancer indicated that tamoxifen exposure was 

increased approximately 2-fold following co-administration of ribociclib and tamoxifen. 

 

Drug-drug interactions between ribociclib and oral contraceptives 

 

Drug-drug interaction studies between ribociclib and oral contraceptives have not been conducted (see 

section 4.6). 

 

Anticipated interactions 

 

Anti-arrhythmic medicinal products and other medicinal products that may prolong the QT interval 

Co-administration of Kisqali with medicinal products with a known potential to prolong the QT 

interval such as anti-arrhythmic medicinal products (including, but not limited to, amiodarone, 

disopyramide, procainamide, quinidine and sotalol), and other medicinal products that are known to 

prolong the QT interval (including, but not limited to, chloroquine, halofantrine, clarithromycin, 

ciprofloxacin, levofloxacin, azithromycin, haloperidol, methadone, moxifloxacin, bepridil, pimozide 

and intravenous ondansetron) should be avoided (see section 4.4). Kisqali is also not recommended to 

be used in combination with tamoxifen (see sections 4.1, 4.4 and 5.1). 

 

4.6 Fertility, pregnancy and lactation 
 

Women of childbearing potential/Contraception 

 

Pregnancy status should be verified prior to starting treatment with Kisqali. 

 

Women of childbearing potential who are receiving Kisqali should use effective contraception (e.g. 

double-barrier contraception) during therapy and for at least 21 days after stopping treatment with 

Kisqali. 

 

Pregnancy 

 

There are no adequate and well-controlled studies in pregnant women. Based on findings in animals, 

ribociclib can cause foetal harm when administered to a pregnant woman (see section 5.3). Kisqali is 

not recommended during pregnancy and in women of childbearing potential not using contraception. 

 

  



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Breast-feeding 

 

It is not known if ribociclib is present in human milk. There are no data on the effects of ribociclib on 

the breast-fed infant or the effects of ribociclib on milk production. Ribociclib and its metabolites 

readily passed into the milk of lactating rats. Patients receiving Kisqali should not breast-feed for at 

least 21 days after the last dose. 

 

Fertility 

 

There are no clinical data available regarding effects of ribociclib on fertility. Based on animal studies, 

ribociclib may impair fertility in males of reproductive potential (see section 5.3). 

 

4.7 Effects on ability to drive and use machines 
 

Kisqali may have minor influence on the ability to drive and use machines. Patients should be advised 

to be cautious when driving or using machines in case they experience fatigue, dizziness or vertigo 

during treatment with Kisqali (see section 4.8). 

 

4.8 Undesirable effects 
 

Summary of the safety profile 

 

The most common ADRs and the most common grade 3/4 ADRs (reported at a frequency ≥20% and 

≥2%, respectively) in the pooled dataset for which the frequency for Kisqali plus any combination 

exceeds the frequency for placebo plus any combination were infections, neutropenia, leukopenia, 

headache, cough, nausea, fatigue, diarrhoea, vomiting, constipation, alopecia and rash, and infections, 

neutropenia, leukopenia, anaemia, abnormal liver function tests, lymphopenia, hypophosphataemia 

and vomiting respectively. 

 

Dose reduction due to adverse events, regardless of causality, occurred in 37.3% of patients receiving 

Kisqali in the phase III clinical studies regardless of the combination and permanent discontinuation 

was reported in 7.0% of patients receiving Kisqali and any combination in the phase III clinical 

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 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) in HR-positive, HER2-negative advanced or metastatic breast cancer. 

Additional ADRs were identified post-marketing. 

 

The median duration of exposure to Kisqali treatment across the pooled phase III studies dataset was 

21.7 months, with 61.7% patients exposed ≥12 months. 

 

Adverse drug reactions from the phase III clinical studies (Table 7) are listed by MedDRA system 

organ class. Within each system organ class, the adverse drug reactions are ranked by frequency, with 

the most frequent reactions first. Within each frequency grouping, adverse drug reactions are 

presented in order of decreasing seriousness. In addition, the corresponding frequency category for 

each adverse drug 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). 

 



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Table 7 Adverse drug reactions observed in the three phase III clinical studies and during 

post-marketing experience 
 

Adverse drug 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 

Gastrointestinal disorders 

Nausea, diarrhoea, vomiting, constipation, stomatitis, abdominal pain2, 

dyspepsia 
Very common 

Dysgeusia Common 

Hepatobiliary disorders 

Hepatotoxicity3 Common 

Skin and subcutaneous tissue disorders 

Alopecia, rash4, pruritus Very common 

Erythema, dry skin, vitiligo Common 

Toxic epidermal necrolysis (TEN)* Not known 

Musculoskeletal and connective tissue disorders 

Back pain Very common 

General disorders and administration site conditions 

Fatigue, peripheral oedema, asthenia, pyrexia Very common 

Dry mouth, oropharyngeal pain 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: 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. 

* Adverse reactions reported during post-marketing experience. These are derived from 

spontaneous reports for which it is not always possible to reliably establish frequency or a causal 

relationship to exposure to the medicinal product. 

 

Description of selected adverse drug reactions 

 

Neutropenia 

Neutropenia was the most frequently reported adverse drug reaction (73.7%) and a grade 3 or 4 

decrease in neutrophil counts (based on laboratory findings) was reported in 58.6% of patients 

receiving Kisqali plus any combination in the phase III studies. 



14 

 

Among the patients who had grade 2, 3 or 4 neutropenia, the median time to onset was 16 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 1.4% 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 (23.2% versus 16.5%, respectively), with more grade 3/4 adverse events reported in the patients 

treated with Kisqali plus any combination (11.4% versus 5.4%, respectively). Increases in 

transaminases were observed. Grade 3 or 4 increases in ALT (9.7% versus 1.5%) and AST (6.7% 

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 10.4% of 

Kisqali plus any combination treated patients, primarily due to ALT increased (6.9%) and/or AST 

increased (6.1%). Discontinuation of treatment with Kisqali plus any combination due to abnormal 

liver function tests or hepatotoxicity occurred in 2.3% and 0.4% of patients respectively (see 

sections 4.2 and 4.4). 

 

In the phase III clinical studies, 83.2% (89/107) 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 85 days for the Kisqali plus any combination arms. The median time to 

resolution (to normalisation or grade ≤2) was 22 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 8.4% of patients in the Kisqali plus aromatase inhibitor or fulvestrant 

arms and 3.2% 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 

14 patients (1.3%) had >500 msec post-baseline QTcF value, and 59 patients (5.6%) 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 2.3% of Kisqali plus aromatase inhibitor or fulvestrant 

treated patients due to electrocardiogram QT prolonged and syncope. 

 

  



15 

The analysis of ECG data showed 52 patients (4.9%) and 11 patients (1.4%) 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 sections 4.2, 4.4 

and 5.2). 

 

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 

listed in Appendix V. 

 

4.9 Overdose 
 

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. 

 

 

5. PHARMACOLOGICAL PROPERTIES 
 

5.1 Pharmacodynamic properties 
 

Pharmacotherapeutic group: Antineoplastic agents, protein kinase inhibitors, ATC code: L01XE42 

 

Mechanism of action 

 

Ribociclib is a selective inhibitor of cyclin-dependent kinase (CDK) 4 and 6, resulting in 50% 

inhibition (IC50) values of 0.01 (4.3 ng/ml) and 0.039 μM (16.9 ng/ml) in biochemical assays, 

respectively. These kinases are activated upon binding to D-cyclins and play a crucial role in 

signalling pathways which lead to cell cycle progression and cellular proliferation. The cyclin 

D-CDK4/6 complex regulates cell cycle progression through phosphorylation of the retinoblastoma 

protein (pRb). 

 

In vitro, ribociclib decreased pRb phosphorylation, leading to arrest in the G1 phase of the cell cycle, 

and reduced cell proliferation in breast cancer cell lines. In vivo, treatment with single-agent ribociclib 

led to tumour regressions which correlated with inhibition of pRb phosphorylation. 

 

In vivo studies using patient-derived oestrogen receptor-positive breast cancer xenograft model 

combinations of ribociclib and antioestrogens (i.e. letrozole) resulted in superior tumour growth 

inhibition with sustained tumour regression and delayed tumour regrowth after stopping dosing 

compared to each substance alone. Additionally, in vivo antitumour activity of ribociclib in 

combination with fulvestrant was assessed in immune-deficient mice bearing the ZR751 ER+ human 

breast cancer xenografts and the combination with fulvestrant resulted in complete tumour growth 

inhibition. 

 

When tested in a panel of breast cancer cell lines with known ER status, ribociclib demonstrated to be 

more efficacious in ER+ breast cancer cell lines than in the ER- ones. In the preclinical models tested 

so far, intact pRb was required for ribociclib activity. 

 

  

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


16 

Cardiac electrophysiology 

Serial, triplicate ECGs were collected following a single dose and at steady state to evaluate the effect 

of ribociclib on the QTc interval in patients with advanced cancer. A 

pharmacokinetic-pharmacodynamic analysis included a total of 997 patients treated with ribociclib at 

doses ranging from 50 to 1200 mg. The analysis suggested that ribociclib causes 

concentration-dependent increases in the QTc interval. The estimated QTcF mean change from 

baseline for 600 mg Kisqali in combination with NSAI or fulvestrant was 22.0 msec (90% CI: 20.56, 

23.44) and 23.7 msec (90% CI: 22.31, 25.08), respectively at the geometric mean Cmax at steady-state 

compared to 34.7 msec (90% CI: 31.64, 37.78) in combination with tamoxifen (see section 4.4). 

 

Clinical efficacy and safety 

 

Study CLEE011A2301 (MONALEESA-2) 

Kisqali was evaluated in a randomised, double-blind, placebo-controlled, multicentre phase III clinical 

study in the treatment of postmenopausal women with hormone receptor-positive, HER2-negative, 

advanced breast cancer who received no prior therapy for advanced disease in combination with 

letrozole versus letrozole alone. 

 

A total of 668 patients were randomised in a 1:1 ratio to receive either Kisqali 600 mg and letrozole 

(n=334) or placebo and letrozole (n=334), stratified according to the presence of liver and/or lung 

metastases (Yes [n=292 (44%)]) versus No [n=376 (56%)]). Demographics and baseline disease 

characteristics were balanced and comparable between study arms. Kisqali was given orally at a dose 

of 600 mg daily for 21 consecutive days followed by 7 days off treatment in combination with 

letrozole 2.5 mg once daily for 28 days. Patients were not allowed to cross over from placebo to 

Kisqali during the study or after progression of disease. 

 

Patients enrolled in this study had a median age of 62 years (range 23 to 91). 44.2% patients were 

older than 65 years, including 69 patients older than 75 years. The patients included were Caucasian 

(82.2%), Asian (7.6%), and Black (2.5%). All patients had an ECOG performance status of 0 or 1. In 

the Kisqali arm 43.7% of patients had received chemotherapy in the neoadjuvant or adjuvant setting 

and 52.4% had received antihormonal therapy in the neoadjuvant or adjuvant setting prior to study 

entry. 34.1% of patients were de novo. 20.7% of patients had bone-only disease and 59.0% of patients 

had visceral disease. Patients with prior (neo)adjuvant therapy with anastrozole or letrozole must have 

completed this therapy at least 12 months before study randomisation. 

 

The primary endpoint for the study was met at the planned interim analysis conducted after observing 

80% of targeted progression-free survival (PFS) events using Response Evaluation Criteria in Solid 

Tumours (RECIST v1.1), based on the investigator assessment in the full population (all randomised 

patients), and confirmed by a blinded independent central radiological assessment. 

 

The efficacy results demonstrated a statistically significant improvement in PFS in patients receiving 

Kisqali plus letrozole compared to patients receiving placebo plus letrozole in the full analysis set 

(hazard ratio of 0.556, 95% CI: 0.429, 0.720, one sided stratified log-rank test p-value 0.00000329) 

with clinically meaningful treatment effect. 

 

The global health status/QoL data showed no relevant difference between the Kisqali plus letrozole 

arm and the placebo plus letrozole arm. 

 

A more mature update of efficacy data (02 January 2017 cut-off) is provided in Tables 8 and 9. 

 

Median PFS was 25.3 months (95% CI: 23.0, 30.3) for ribociclib plus letrozole treated patients and 

16.0 months (95% CI: 13.4, 18.2) for patients receiving placebo plus letrozole. 54.7% of patients 

receiving ribociclib plus letrozole were estimated to be progression-free at 24 months compared with 

35.9% in the placebo plus letrozole arm. 

 

  



17 

There was no statistically significant difference in overall survival (OS) between the Kisqali plus 

letrozole arm and the placebo plus letrozole arm (HR 0.746 [95% CI: 0.517, 1.078]). OS data remain 

immature. 

 

Table 8 MONALEESA-2 - Efficacy results (PFS) based on investigator radiological 

assessment (02 January 2017 cut-off) 
 

 Updated analysis (02 January 2017 cut-off) 

 Kisqali plus letrozole 

N=334 

Placebo plus letrozole 

N=334 

Progression-free survival 

Median PFS [months] (95% CI) 25.3 (23.0-30.3) 16.0 (13.4-18.2) 

Hazard ratio (95% CI) 0.568 (0.457-0.704)  

p-valuea 9.63×10-8 

CI=confidence interval; N=number of patients; 
ap-value is obtained from the one-sided stratified log-rank test. 

 

Figure 1 MONALEESA-2 - Kaplan-Meier plot of PFS based on investigator 

assessment02 January 2017 cut-off) 
 

 
 

 

 

 

A series of pre-specified subgroup PFS analyses was performed based on prognostic factors and 

baseline characteristics to investigate the internal consistency of treatment effect. A reduction in the 

risk of disease progression or death in favour of the Kisqali plus letrozole arm was observed in all 

individual patient subgroups of age, race, prior adjuvant or neoadjuvant chemotherapy or hormonal 

therapies, liver and/or lung involvement and bone-only metastatic disease. This was evident for 

patients with liver and/or lung metastases (HR of 0.561 [95% CI: 0.424, 0.743], median 

progression-free survival [mPFS] 24.8 months for Kisqali plus letrozole versus 13.4 months for 

letrozole alone), or without liver and/or lung metastases (HR of 0.597 [95% CI: 0.426, 0.837], mPFS 

27.6 months versus 18.2 months). 

 

  

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34

0

20

40

60

80

100

Censoring times 

Ribociclib (N=334) 

Placebo (N=334) 

No of events-   Ribociclib: 140, Placebo: 205 

Hazard Ratio = 0.568; 95% CI [0.457, 0.704] 

Kaplan-Meier median - Ribociclib: 25.3 months; Placebo: 16.0 months 

Log rank p-value = 9.63*10^(-8)  

                     Number of patients still at risk 

Time             0              2               4              6              8             10            12             14            16            18            20            22             24            26             28            30            32            34 

Ribociclib   334         294            277          257          240          227          207           196          188          176          164          132            97            46             17            11              1              0 

Placebo       334         279            265          239          219          196          179           156          138          124          110           93             63            34             10             7               2              0 

Time (Months) 

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18 

Updated results for overall response and clinical benefit rates are displayed in Table 9. 

 

Table 9 MONALEESA-2 - Efficacy results (ORR, CBR) based on investigator assessment 

(02 January 2017 cut-off) 

 

Analysis Kisqali + letrozole 

(%, 95% CI) 

Placebo + letrozole 

(%, 95% CI) 

p-valuec 

Full analysis set N=334 N=334  

Overall response ratea 42.5 (37.2, 47.8) 28.7 (23.9, 33.6) 9.18 × 10-5  

Clinical benefit rateb 79.9 (75.6, 84.2) 73.1 (68.3, 77.8) 0.018 

Patients with 

measurable disease 

n=257 n=245  

Overall response ratea 54.5 (48.4, 60.6) 38.8 (32.7, 44.9) 2.54 × 10-4 

Clinical benefit rateb 80.2 (75.3, 85.0) 71.8 (66.2, 77.5) 0.018 
a ORR: Overall response rate = proportion of patients with complete response + partial response 
b CBR: Clinical benefit rate = proportion of patients with complete response + partial response (+ 

stable disease or non-complete response/Non-progressive disease ≥24 weeks) 
c p-values are obtained from one-sided Cochran-Mantel-Haenszel chi-square test 

 

Study CLEE011E2301 (MONALEESA-7) 

Kisqali was evaluated in a randomised, double-blind, placebo-controlled, multicentre phase III clinical 

study in the treatment of pre- and perimenopausal women with hormone receptor-positive, 

HER2-negative advanced breast cancer in combination with a NSAI or tamoxifen plus goserelin 

versus placebo in combination with a NSAI or tamoxifen plus goserelin. Patients in MONALEESA-7 

had not received prior endocrine treatment in the advanced breast cancer setting. 

 

A total of 672 patients were randomised in a 1:1 ratio to receive either Kisqali 600 mg plus 

NSAI/tamoxifen plus goserelin (n=335) or placebo plus NSAI/tamoxifen plus goserelin (n=337), 

stratified according to: the presence of liver and/or lung metastases (Yes [n=344 (51.2%)] versus No 

[n=328 (48.8%)]), prior chemotherapy for advanced disease (Yes [n=120 (17.9%)] versus No [n=552 

(82.1%)]), and endocrine combination partner (NSAI and goserelin [n=493 (73.4%)] versus tamoxifen 

and goserelin [n=179 (26.6%)]). Demographics and baseline disease characteristics were balanced and 

comparable between study arms. Kisqali was given orally at a dose of 600 mg daily for 21 consecutive 

days followed by 7 days off treatment in combination with NSAI (letrozole 2.5 mg or anastrozole 

1 mg) or tamoxifen (20 mg) orally once daily for 28 days, and goserelin (3.6 mg) subcutaneously 

every 28 days, until disease progression or unacceptable toxicity. Patients were not allowed to cross 

over from placebo to Kisqali during the study or after disease progression. Switching the endocrine 

combination partners was also not permitted. 

 

Patients enrolled in this study had a median age of 44 years (range 25 to 58) and 27.7% of patients 

were younger than 40 years old. The majority of patients included were Caucasian (57.7%), Asian 

(29.5%) or Black (2.8%) and nearly all patients (99.0%) had a baseline ECOG performance status of 0 

or 1. Prior to study entry, of these 672 patients, 14% of patients had received prior chemotherapy for 

metastatic disease, 32.6% of patients had received chemotherapy in the adjuvant and 18.0% in the 

neoadjuvant setting; 39.6% had received endocrine therapy in the adjuvant setting and 0.7% in the 

neoadjuvant setting. In study E2301 40.2% of patients had de novo metastatic disease, 23.7% had 

bone-only disease, and 56.7% had visceral disease. 

 

The study met the primary endpoint at the primary analysis conducted after 318 progression-free 

survival (PFS) events based on the investigator assessment using RECIST v1.1 criteria in the full 

analysis set (all randomised patients). The primary efficacy results were supported by PFS results 

based on blinded independent central radiological assessment. The median follow-up time at the time 

of primary PFS analysis was 19.2 months. 

 

  



19 

In the overall study population, the efficacy results demonstrated a statistically significant 

improvement in PFS in patients receiving Kisqali plus NSAI/tamoxifen plus goserelin compared to 

patients receiving placebo plus NSAI/tamoxifen plus goserelin (hazard ratio of 0.553, 95% CI: 0.441, 

0.694, one-sided stratified log-rank test p-value 9.83x10-8) with clinically meaningful treatment effect. 

Median PFS was 23.8 months (95% CI: 19.2, NE) for Kisqali plus NSAI/tamoxifen plus goserelin 

treated patients and 13.0 months (95% CI: 11.0, 16.4) for patients receiving placebo plus 

NSAI/tamoxifen plus goserelin. 

 

Distribution of PFS is summarised in the Kaplan-Meier curve for PFS in Figure 2. 

 

Figure 2 MONALEESA-7 - Kaplan-Meier plot of PFS in overall population based on 

investigator assessment 

 

        
 

The results for PFS based on the blinded independent central radiological assessment of a randomly 

selected subset of approximately 40% of randomised patients were supportive of the primary efficacy 

results based on the investigator’s assessment (hazard ratio of 0.427; 95% CI: 0.288, 0.633). 

 

At the time of the primary PFS analysis overall survival data were not mature with 89 (13%) of deaths 

(HR 0. 916 [95% CI: 0.601, 1.396]). 

 

Overall response rate (ORR) per investigator assessment based on RECIST v1.1 was higher in the 

Kisqali arm (40.9%; 95% CI: 35.6, 46.2) compared to the placebo arm (29.7%; 95% CI: 24.8, 34.6, 

p=0.00098). The observed clinical benefit rate (CBR) was higher in Kisqali arm (79.1%; 95% CI: 

74.8:83.5) compared to placebo arm (69.7%; 95% CI: 64.8:74.6, p=0.002). 

 

In the pre-specified subgroup analysis of 495 patients who had received Kisqali or placebo in 

combination with NSAI plus goserelin, the median PFS was 27.5 months (95% CI: 19.1, NE) in the 

Kisqali plus NSAI subgroup and 13.8 months (95% CI: 12.6, 17.4) in the placebo plus NSAI subgroup 

[HR: 0.569; 95% CI: 0.436, 0.743]. Efficacy results are summarised in Table 10 and the Kaplan-Meier 

curves for PFS are provided in Figure 3. 

 

Time (Months) 

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Censoring times 

Ribociclib (N=335) 

Placebo (N=337) 

No of events 

Ribociclib: 131, Placebo: 187 

Hazard Ratio = 0.553 

95% CI [0.441, 0.694] 

Kaplan-Meier median  

Ribociclib: 23.8 months 

Placebo: 13.0 months 

Log rank p-value = 9.83*10^(-8)   

Number of patients still at risk 
Time (months) 

Ribociclib 

Placebo 



20 

Table 10 MONALEESA-7 - Efficacy results (PFS) in patients who received NSAI 

 

 Kisqali plus NSAI 

plus goserelin 

N=248 

Placebo plus NSAI 

plus goserelin 

N=247 

Progression free survivala 

Median PFS [months] (95% CI) 27.5 (19.1, NE) 13.8 (12.6 – 17.4) 

Hazard ratio (95% CI) 0.569 (0.436, 0.743) 

CI=confidence interval; N=number of patients; NE = Not estimable. 
a – PFS based on investigator radiological assessment 

 

Figure 3 MONALEESA-7 – Kaplan-Meier plot of PFS based on investigator assessment in 

patients who received NSAI 

 

      
 

Efficacy results for overall response rate (ORR) and clinical benefit rate (CBR) per investigator 

assessment based on RECIST v1.1 are provided in Table 11. 

 

Table 11 MONALEESA-7 - Efficacy results (ORR, CBR) based on investigator assessment in 

patients who received NSAI 

 

Analysis Kisqali plus NSAI plus 

goserelin 

(%, 95% CI) 

Placebo plus NSAI plus 

goserelin 

(%, 95% CI) 

Full analysis set N=248 N=247 

Overall response rate (ORR)a  39.1 (33.0, 45.2) 29.1 (23.5, 34.8) 

Clinical benefit rate (CBR)b 80.2 (75.3, 85.2) 67.2 (61.4, 73.1) 

Patients with measurable 

disease 

n=192 n=199 

Overall response ratea 50.5 (43.4, 57.6) 36.2 (29.5, 42.9) 

Clinical benefit rateb 81.8 (76.3, 87.2) 63.8 (57.1, 70.5) 
aORR: proportion of patients with complete response + partial response 
bCBR: proportion of patients with complete response + partial response + (stable disease or 

non-complete response/Non-progressive disease ≥24 weeks) 

 

  

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Time (Months) 

Censoring times 

Ribociclib (N=248) 

Placebo (N=247) 

No of events 

Ribociclib: 92, Placebo: 132 

Hazard Ratio = 0.569 

95% CI [0.436, 0.743] 

Kaplan-Meier median  

Ribociclib: 27.5 months 

Placebo: 13.8 months 

Number of patients still at risk 

Time (months) 

Ribociclib 

Placebo 



21 

Results in the Kisqali plus NSAI subgroup were consistent across subgroups of age, race, prior 

adjuvant/ neoadjuvant chemotherapy or hormonal therapies, liver and/or lung involvement and 

bone-only metastatic disease. 

 

A more mature update of overall survival data (30 November 2018 cut-off) is provided in Table 12 

and Figures 4 and 5. 

 

In the second OS analysis the study met its key secondary endpoint demonstrating a statistically 

significant improvement in OS. 

 

Table 12 MONALEESA-7 – Efficacy results (OS) 
 

 Updated analysis (30 November 2018 cut-off) 

Overall survival, overall 

study population 

Ribociclib 600 mg 

N=335 

Placebo 

N=337 

Number of events – n [%] 83 (24.8) 109 (32.3) 

Median OS [months] (95% CI) NE (NE, NE) 40.9 (37.8, NE) 

Hazard ratio (95% CI) 0.712 (0.535, 0.948) 

p-valuea 0.00973 

Overall survival, NSAI 

subgroup 

Ribociclib 600 mg 

n=248 

Placebo 

n=247 

Number of events – n [%] 61 (24.6) 80 (32.4) 

Median OS [months] (95% CI) NE (NE, NE) 40.7 (37.4, NE) 

Hazard ratio (95% CI) 0.699 (0.501, 0.976) 

CI=confidence interval, NE=not estimable, N=number of patients; 
ap-value is obtained from the one-sided log-rank test stratified by lung and/or liver metastases, prior 

chemotherapy for advanced disease, and endocrine partner per IRT (interactive response 

technology). 

 

Figure 4 MONALEESA-7: Kaplan Meier plot of final OS analysis (30-Nov-2018 cut-off) 

 

 
Log-rank test and Cox model are stratified by lung and/or liver metastasis, prior chemotherapy for advanced 

disease, and endocrine combination partner per IRT 

 

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Censoring Times 

Ribociclib (N=335) 

Placebo (N=337) 

No of events 

Ribociclib: 83, Placebo: 109 

 

Hazard Ratio = 0.712 

95% CI [0.535, 0.948] 

Kaplan-Meier median  

Ribociclib: NE 

Placebo: 40.9 months 

Log-rank p-value = 0.00973 

Time (Months) 
Number of patients still at risk 

Time (months) 

Ribociclib 

Placebo 



22 

Figure 5 MONALEESA-7: Kaplan Meier plot of final OS analysis in patients who received 

NSAI (30-Nov-18 cut-off) 

 

 
Hazard ratio is based on unstratified Cox model. 

 

Additionally, the probability of progression on next-line therapy or death (PFS2) in patients who 

received prior ribociclib in the study was lower compared to patients in the placebo arm with an HR of 

0.692 (95% CI: 0.548, 0.875) in the overall study population. The median PFS2 was 32.3 months 

(95% CI: 27.6, 38.3) in the placebo arm and was not reached (95% CI: 39.4, NE) for the ribociclib 

arm. Similar results were observed for the NSAI subgroup, with an HR of 0.660 (95% CI: 0.503, 

0.868) and a median PFS2 of 32.3 months (95% CI: 26.9, 38.3) in the placebo arm versus not reached 

(95% CI: 39.4, NE) in the ribociclib arm. 

 

Study CLEE011F2301 (MONALEESA-3) 

Kisqali was evaluated in a 2:1 randomised double-blind, placebo-controlled, multicentre phase III 

clinical study in 726 postmenopausal women with hormone receptor-positive, HER2-negative 

advanced breast cancer who had received no or only one line of prior endocrine treatment, in 

combination with fulvestrant versus fulvestrant alone. 

 

Patients enrolled in this study had a median age of 63 years (range 31 to 89). 46.7% of patients were of 

age 65 years and older, including 13.8% patients of age 75 years and older. The patients included were 

Caucasian (85.3%), Asian (8.7%) or Black (0.7%) and nearly all patients (99.7%) had an ECOG 

performance status of 0 or 1. First and second line patients were enrolled in this study (of whom 

19.1% had de novo metastatic disease). Prior to study entry 42.7% of patients had received 

chemotherapy in the adjuvant and 13.1% in the neoadjuvant setting, while 58.5% had received 

endocrine therapy in the adjuvant and 1.4% in the neoadjuvant setting and 21% had received prior 

endocrine therapy in the advanced breast cancer setting. In study F2301 21.2% had bone-only disease 

and 60.5% had visceral disease. 

 

Primary analysis 

The study met the primary endpoint at the primary analysis conducted after 361 progression-free 

survival (PFS) events based on the investigator assessment and using RECIST v1.1 criteria in the full 

analysis set (all randomised patients, 03 November 2017 cut-off). The median follow-up time at the 

time of primary PFS analysis was 20.4 months. 

 

  

E
v

en
t-

fr
ee

 p
ro

b
ab

il
it

y
 (

%
) 

 

Censoring Times 

Ribociclib (N=248) 

Placebo (N=247) 

No of events 

Ribociclib: 61, Placebo: 80 

 

Hazard Ratio = 0.699 

95% CI [0.501, 0.976] 

Kaplan-Meier median  

Ribociclib: NE 

Placebo: 40.7 months 

Time (Months) 
Number of patients still at risk 

Time (months) 

Ribociclib 

Placebo 



23 

The primary efficacy results demonstrated a statistically significant improvement in PFS in patients 

receiving Kisqali plus fulvestrant compared to patients receiving placebo plus fulvestrant in the full 

analysis set (hazard ratio of 0.593, 95% CI: 0.480, 0.732, one-sided stratified log-rank test p-value 

4.1x10-7), with an estimated 41% reduction in relative risk of progression or death in favour of the 

Kisqali plus fulvestrant arm. 

 

The primary efficacy results were supported by a random central audit of 40% imaging subset by a 

blinded independent central radiological assessment (hazard ratio of 0.492; 95% CI: 0.345, 0.703). 

 

A descriptive update of PFS was performed at the time of the second OS interim analysis, and the 

updated PFS results on the overall population and the subgroups based on prior endocrine therapy are 

summarised in Table 13 and the Kaplan-Meier curve is provided in Figure 6. 

 

Table 13 MONALEESA-3 (F2301) - Updated PFS results based on investigator assessment 

(03-Jun-2019 cut-off) 

 

 Kisqali plus fulvestrant 

N=484 

Placebo plus fulvestrant 

N=242 

Progression free survival overall study population 

Number of events- n [%] 283 (58.5) 193 (79.8) 

Median PFS [months] (95% CI) 20.6 (18.6, 24.0) 12.8 (10.9, 16.3) 

Hazard ratio (95% CI) 0.587 (0.488, 0.705) 

First-line setting subgroupa Kisqali plus fulvestrant 

n=237 

Placebo plus fulvestrant 

n=128 

Number of events- n [%] 112 (47.3) 95 (74.2) 
Median PFS [months] (95% CI) 33.6 (27.1, 41.3) 19.2 (14.9, 23.6) 
Hazard ratio (95% CI) 0.546 (0.415, 0.718) 

Second-line setting or early 

relapse subgroupb 

Kisqali plus fulvestrant 

n=237 

Placebo plus fulvestrant 

n=109 

Number of events- n [%] 167 (70.5) 95 (87.2) 

Median PFS [months] (95% CI) 14.6 (12.5, 18.6) 9.1 (5.8, 11.0) 

Hazard ratio (95% CI) 0.571 (0.443, 0.737) 

CI=confidence interval 
a patients with de novo advanced breast cancer with no prior endocrine therapy, and patients who 
relapsed after 12 months of (neo)adjuvant endocrine therapy completion. 
b patients whose disease relapsed during adjuvant therapy or within 12 months of (neo)adjuvant 
endocrine therapy completion, and patients who had progression after one line of endocrine therapy 

for advanced disease. 

 

  



24 

Figure 6 MONALEESA-3 (F2301) – Kaplan-Meier plot of PFS based on investigator 

assessment (FAS) (03-Jun-2019 cut-off) 

 
 

 

 

 

 

 

 

 

 

 

 

 

 

 
 

 

 

Efficacy results for overall response rate (ORR) and clinical benefit rate (CBR) per investigator 

assessment based on RECIST v1.1 are provided in Table 14. 

 

Table 14 MONALEESA-3 - Efficacy results (ORR, CBR) based on investigator assessment (03-

Nov-2017 cut-off) 

 

Analysis Kisqali plus fulvestrant 

(%, 95% CI) 

Placebo plus fulvestrant 

(%, 95% CI) 

Full analysis set N=484 N=242 

Overall response rate (ORR)a  32.4 (28.3, 36.6) 21.5 (16.3, 26.7) 

Clinical benefit rate (CBR)b 70.2 (66.2, 74.3) 62.8 (56.7, 68.9) 

Patients with measurable disease n=379 n=181 

Overall response ratea 40.9 (35.9, 45.8) 28.7 (22.1, 35.3) 

Clinical benefit rateb 69.4 (64.8, 74.0). 59.7 (52.5, 66.8) 
aORR: proportion of patients with complete response + partial response 
bCBR: proportion of patients with complete response + partial response + (stable disease or 

non-complete response/Non-progressive disease ≥24 weeks) 

 

Hazard ratios based on pre-specified subgroup analysis of the patients treated with Kisqali plus 

fulvestrant showed consistent benefit across different subgroups including age, prior treatment (early 

or advanced), prior adjuvant/neoadjuvant chemotherapy or hormonal therapies, liver and/or lung 

involvement and bone-only metastatic disease. 

 

OS Analysis 

In the second OS analysis the study met its secondary endpoint, demonstrating a statistically 

significant improvement in OS. 

 

The results from this final OS analysis on the overall study population and the subgroups analysis are 

provided in Table 15 and Figure 7. 

 

  

No. of events 

Ribociclib+Fulvestrant: 283, Placebo+Fulvestyrant: 193 

 

Hazard Ratio = 0.587 

95% CI [0.488, 0.705] 

 

Kaplan-Meier median 

Ribociclib+Fluvestrant: 20.6 Months 

Placebo+Fulvestrant: 12.8 Months 

Censoring Times 

Ribociclib+Fulvestrant (N = 484) 

Placebo+Fulvestrant (N = 242) 

10
0 

8
0 

6
0 

4
0 

2
0 

0 

0 2 4 6 8 1
0 

1
2 

1
4 

1
6 

1
8 

2
0 

2
2 

2
4 

2
6 

2
8 

3
0 

3
2 

3
4 

3
6 

3
8 

4
0 

4
2 

4
4 

4
6 

Placeb
o 

Ribocicl
ib 

48
4 

40
3 

36
4 

34
6 

32
3 

30
5 

28
2 

25
8 

23
9 

22
5 

20
5 

19
8 

18
1 

17
4 

15
9 

15
6 

14
9 

12
7 

9
2 

6
5 

2
9 

1
1 

4 0 
24
2 

19
5 

16
8 

15
6 

14
4 

13
4 

11
6 

10
6 

9
8 

8
8 

8
2 

6
8 

6
2 

5
9 

5
1 

4
7 

4
5 

4
1 

2
1 

1
3 

6 2 1 0 

Time (months) 

E
v
e

n
t-

fr
e

e
 p

ro
b

a
b

il
it

y
 (

%
) 



25 

Table 15 MONALEESA-3 (F2301) efficacy results (OS) (03-Jun-19 cut-off) 

 

 
Kisqali plus fulvestrant 

 

Placebo plus fulvestrant 

 

Overall study population N=484 N=242 

Number of events - n [%] 167 (34.5) 108 (44.6) 

Median OS [months] (95% 

CI) NE, (NE, NE) 40 (37, NE) 

HR (95% CI)a 0.724 (0.568, 0.924) 

p valueb 0.00455 

First line setting subgroup n=237 n=128 

Number of events - n [%] 63 (26.6) 47 (36.7) 

HR (95% CI)c 0.700 (0.479, 1.021) 

Second-line setting or early 

relapse subgroup 
n=237 n=109 

Number of events - n [%] 102 (43.0)  60 (55.0) 

HR (95% CI)c 0.730 (0.530, 1.004) 

NE = Not estimable 
a Hazard ratio is obtained from the Cox PH model stratified by lung and/or liver metastasis, previous 

endocrine therapy. 
b One-sided P-value is obtained from log-rank test stratified by lung and/or liver metastasis, 

previous endocrine therapy per IRT. P-value is one-sided and is compared against a threshold of 

0.01129 as determined by the Lan-DeMets (O’Brien-Fleming) alpha-spending function for an 

overall significance level of 0.025. 
c Hazard ratio is obtained from the unstratified Cox PH model. 

 

Figure 7 MONALEESA-3 (F2301) Kaplan-Meier plot of OS (full analysis set [FAS]) (03-Jun-

2019 cut-off) 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Log-rank test and Cox model are stratified by lung and/or liver metastasis, prior chemotherapy for 

advanced disease, and endocrine combination partner per IRT 

 

Time to progression on next-line therapy or death (PFS2) in patients in the Kisqali arm was longer 

compared to patients in the placebo arm (HR: 0.670 [95% CI: 0.542, 0.830]) in the overall study 

population. The median PFS2 was 39.8 months (95% CI: 32.5, NE) for the Kisqali arm and 

29.4 months (95% CI: 24.1, 33.1) in the placebo arm. 

No. of events 

Ribociclib+Fulvestrant: 167, Placebo+Fulvestyrant: 108 

 

Hazard Ratio = 0.724 

95% CI [0.568, 0.924] 

 

Kaplan-Meier median 

Ribociclib+Fluvestrant: NE 

Placebo+Fulvestrant: 40.0 Months 

 

Log-rant p-value = 0.00455 

Censoring Times 

Ribociclib+Fulvestrant (N = 484) 

Placebo+Fulvestrant (N = 242) 

24
2 

23
3 

22
7 

22
3 

21
8 

21
3 

20
7 

19
9 

19
4 

18
7 

18
4 

17
4 

16
9 

15
9 

15
5 

14
7 

14
1 

13
4 

10
7 

6
4 

3
7 

1
4 

3 0 0 

10
0 

8
0 

6
0 

4
0 

2
0 

0 

0 2 4 6 8 1
0 

1
2 

1
4 

1
6 

1
8 

2
0 

2
2 

2
4 

2
6 

2
8 

3
0 

3
2 

3
4 

3
6 

3
8 

4
0 

4
2 

4
4 

4
6 

4
8 

48
4 

47
0 

45
4 

44
4 

43
6 

42
8 

41
4 

40
2 

39
7 

38
9 

37
4 

36
5 

34
8 

33
4 

32
6 

30
9 

30
0 

28
7 

23
7 

15
9 

9
2 

4
1 

1
4 

2 0 

Time (months) 

E
v
e

n
t-

fr
e

e
 p

ro
b

a
b

il
it

y
 (

%
) 

Placeb
o 

Ribocicl
ib 



26 

 

Elderly patients 
Of all patients who received Kisqali in studies MONALEESA-2 and MONALEESA-3, representative 

proportions of patients were ≥65 years and ≥75 years of age (see section 5.1). No overall differences in 

safety or effectiveness of Kisqali were observed between these patients and younger patients (see 

section 4.2). 

 

Paediatric population 

 

The European Medicines Agency has waived the obligation to submit the results of studies with 

Kisqali in all subsets of the paediatric population in breast cancer (see section 4.2 for information on 

paediatric use). 

 

5.2 Pharmacokinetic properties 
 

The pharmacokinetics of ribociclib were investigated in patients with advanced cancer following oral 

daily doses of 50 mg to 1200 mg. Healthy subjects received single oral doses ranging from 400 mg to 

600 mg or repeated daily doses (8 days) at 400 mg. 

 

Absorption 

 

The absolute bioavailability of ribociclib is not known. 
 

The time to reach Cmax (Tmax) following ribociclib oral administration was between 1 and 4 hours. 

Ribociclib exhibited slightly over-proportional increases in exposure (Cmax and AUC) across the dose 

range tested (50 to 1200 mg). Following repeated once-daily dosing, steady state was generally 

achieved after 8 days and ribociclib accumulated with a geometric mean accumulation ratio of 2.51 

(range: 0.97 to 6.40). 

 

Food effect 

Compared to the fasted state, oral administration of a single 600 mg dose of ribociclib film-coated 

tablets with a high-fat, high-calorie meal had no effect on the rate and extent of absorption of 

ribociclib. 

 

Distribution 

 

Binding of ribociclib to human plasma proteins in vitro was approximately 70% and was independent 

of concentration (10 to 10000 ng/ml). Ribociclib was equally distributed between red blood cells and 

plasma with a mean in vivo blood-to-plasma ratio of 1.04. The apparent volume of distribution at 

steady state (Vss/F) was 1090 L based on population pharmacokinetic analysis. 

 

Biotransformation 

 

In vitro and in vivo studies indicated ribociclib is eliminated primarily via hepatic metabolism mainly 

via CYP3A4 in humans. Following oral administration of a single 600 mg dose of [14C] ribociclib to 

humans, the primary metabolic pathways for ribociclib involved oxidation (dealkylation, C and/or 

N-oxygenation, oxidation (-2H)) and combinations thereof. Phase II conjugates of ribociclib phase I 

metabolites involved N-acetylation, sulfation, cysteine conjugation, glycosylation and glucuronidation. 

Ribociclib was the major circulating drug-derived entity in plasma. The major circulating metabolites 

included metabolite M13 (CCI284, N-hydroxylation), M4 (LEQ803, N-demethylation), and M1 

(secondary glucuronide). Clinical activity (pharmacological and safety) of ribociclib was due primarily 

to parent drug, with negligible contribution from circulating metabolites. 

 

  



27 

Ribociclib was extensively metabolised, with unchanged drug accounting for 17.3% and 12.1% of the 

dose in faeces and urine, respectively. Metabolite LEQ803 was a significant metabolite in excreta and 

represented approximately 13.9% and 3.74% of the administered dose in faeces and urine, 

respectively. Numerous other metabolites were detected in both faeces and urine in minor amounts 

(≤2.78% of the administered dose). 

 

Elimination 

 

The geometric mean plasma effective half-life (based on accumulation ratio) was 32.0 hours (63% 

CV) and the geometric mean apparent oral clearance (CL/F) was 25.5 l/hr (66% CV) at steady state at 

600 mg in patients with advanced cancer. The geometric mean apparent plasma terminal half-life (T1/2) 

of ribociclib ranged from 29.7 to 54.7 hours and the geometric mean CL/F of ribociclib ranged from 

39.9 to 77.5 l/hr at 600 mg across studies in healthy subjects. 

 

Ribociclib and its metabolites are eliminated mainly via faeces, with a small contribution of the renal 

route. In 6 healthy male subjects, following a single oral dose of [14C] ribociclib, 91.7% of the total 

administered radioactive dose was recovered within 22 days; faeces was the major route of excretion 

(69.1%), with 22.6% of the dose recovered in urine. 

 

Linearity/non-linearity 

 

Ribociclib exhibited slightly over-proportional increases in exposure (Cmax and AUC) across the dose 

range of 50 mg to 1200 mg following both single dose and repeated doses. This analysis is limited by 

the small sample sizes for most of the dose cohorts with a majority of the data coming from the 

600 mg dose cohort. 

 

Special populations 

 

Renal impairment 

Based on a population pharmacokinetic analysis that included 77 patients with normal renal function 

(eGFR ≥90 ml/min/1.73 m2), 76 patients with mild renal impairment (eGFR 60 to 

<90 ml/min/1.73 m2) and 35 patients with moderate renal impairment (eGFR 30 to 

<60 ml/min/1.73 m2), mild and moderate renal impairment had no effect on the exposure of ribociclib 

(see section 4.2). The pharmacokinetics of ribociclib in breast cancer patients with severe renal 

impairment have not been studied. 
 

The effect of renal impairment on the pharmacokinetics of ribociclib was also assessed in a renal 

impairment study that included 7 healthy subjects with normal renal function (absolute GFR [aGFR] 

≥90 ml/min), 7 non-cancer subjects with severe renal impairment (aGFR 15 to <30 ml/min) and 3 non-

cancer subjects with end-stage renal disease (ESRD) (aGFR <15 ml/min) at a single ribociclib dose of 

400 mg. In non-cancer subjects with severe renal impairment AUCinf increased 1.96-fold, and Cmax 

increased 1.51-fold compared to healthy subjects with normal renal function (see section 4.2). Data in 

subjects with ESRD are limited (n=3) but indicate a similar or somewhat larger increase in ribociclib 

exposure compared to subjects with severe renal impairment. 

 

Hepatic impairment 

Based on a pharmacokinetic study in non-cancer subjects with hepatic impairment, mild hepatic 

impairment had no effect on the exposure of ribociclib (see section 4.2). The mean exposure for 

ribociclib was increased less than 2-fold in patients with moderate (geometric mean ratio [GMR]: 1.44 

for Cmax; 1.28 for AUCinf) and severe (GMR: 1.32 for Cmax; 1.29 for AUCinf) hepatic impairment (see 

section 4.2). 

 

Based on a population pharmacokinetic analysis that included 160 breast cancer patients with normal 

hepatic function and 47 patients with mild hepatic impairment, mild hepatic impairment had no effect 

on the exposure of ribociclib, further supporting the findings from the dedicated hepatic impairment 

study. Ribociclib has not been studied in breast cancer patients with moderate or severe hepatic 

impairment. 



28 

 

Effect of age, weight, gender and race 

Population pharmacokinetic analysis showed that there are no clinically relevant effects of age, body 

weight or gender on the systemic exposure of ribociclib that would require a dose adjustment. Data on 

differences in pharmacokinetics due to race are too limited to draw conclusions. 
 

In vitro interaction data 

 

Effect of ribociclib on cytochrome P450 enzymes 

In vitro, ribociclib is a reversible inhibitor of CYP1A2, CYP2E1 and CYP3A4/5 and a time-dependent 

inhibitor of CYP3A4/5, at clinically relevant concentrations. In vitro evaluations indicated that 

ribociclib has no potential to inhibit the activities of CYP2A6, CYP2B6, CYP2C8, CYP2C9, 

CYP2C19, and CYP2D6 at clinically relevant concentrations. Ribociclib has no potential for 

time-dependent inhibition of CYP1A2, CYP2C9, and CYP2D6. 

 
In vitro data indicate that ribociclib has no potential to induce UGT enzymes or the CYP enzymes 

CYP2C9, CYP2C19 and CYP3A4 via PXR. Therefore, Kisqali is unlikely to affect substrates of these 

enzymes. In vitro data are not sufficient to exclude a potential of ribociclib to induce CYP2B6 via 

CAR. 

 

Effect of transporters on ribociclib 

Ribociclib is a substrate for P-gp in vitro, but based on mass balance data inhibition of P-gp or BCRP 

is unlikely to affect ribociclib exposure at therapeutic doses. Ribociclib is not a substrate for hepatic 

uptake transporters OATP1B1, OATP1B3 or OCT-1 in vitro. 

 

Effect of ribociclib on transporters 

In vitro evaluations indicated that ribociclib has a potential to inhibit the activities of drug transporters 

P-gp, BCRP, OATP1B1/1B3, OCT1, OCT2, MATE1 and BSEP. Ribociclib did not inhibit OAT1, 

OAT3 or MRP2 at clinically relevant concentrations in vitro. 

 

5.3 Preclinical safety data 
 

Safety pharmacology 

 

In vivo cardiac safety studies in dogs demonstrated dose and concentration related QTc interval 

prolongation at an exposure that would be expected to be achieved in patients following the 

recommended dose of 600 mg. There is also potential to induce incidences of premature ventricular 

contractions (PVCs) at elevated exposures (approximately 5-fold the anticipated clinical Cmax). 

 

Repeated-dose toxicity 

 

Repeated-dose toxicity studies (treatment schedule of 3 weeks on/1 week off) of up to 27 weeks’ 

duration in rats and up to 39 weeks’ duration in dogs, revealed the hepatobiliary system (proliferative 

changes, cholestasis, sand-like gallbladder calculi, and inspissated bile) as the primary target organ of 

toxicity of ribociclib. Target organs associated with the pharmacological action of ribociclib in 

repeat-dose studies include bone marrow (hypocellularity), lymphoid system (lymphoid depletion), 

intestinal mucosa (atrophy), skin (atrophy), bone (decreased bone formation), kidney (concurrent 

degeneration and regeneration of tubular epithelial cells) and testes (atrophy). Besides the atrophic 

changes seen in the testes, which showed a trend towards reversibility, all other changes were fully 

reversible after a 4-week treatment-free period. Exposure to ribociclib in animals in the toxicity 

studies was generally less than or equal to that observed in patients receiving multiple doses of 

600 mg/day (based on AUC). 

 

  



29 

Reproductive toxicity/Fertility 

 

Ribociclib showed foetotoxicity and teratogenicity at doses which did not show maternal toxicity in 

the rats or rabbits. Following prenatal exposure, increased incidences of post-implantation loss and 

reduced foetal weights were observed in rats and ribociclib was teratogenic in rabbits at exposures 

lower than or 1.5 times the exposure in humans, respectively, at the highest recommended dose of 

600 mg/day based on AUC. 

 

In rats, reduced foetal weights accompanied by skeletal changes considered to be transitory and/or 

related to the lower foetal weights were noted. In rabbits, there were adverse effects on embryo-foetal 

development as evidenced by increased incidences of foetal abnormalities (malformations and 

external, visceral and skeletal variants) and foetal growth (lower foetal weights). These findings 

included reduced/small lung lobes and additional vessel on the aortic arch and diaphragmatic hernia, 

absent accessory lobe or (partly) fused lung lobes and reduced/small accessory lung lobe (30 and 

60 mg/kg), extra/rudimentary thirteenth ribs and misshapen hyoid bone and reduced number of 

phalanges in the pollex. There was no evidence of embryo-foetal mortality. 

 

In a fertility study in female rats, ribociclib did not affect reproductive function, fertility or early 

embryonic development at any dose up to 300 mg/kg/day (which is likely at an exposure lower than or 

equal to patients’ clinical exposure at the highest recommended dose of 600 mg/day based on AUC). 

 

Ribociclib has not been evaluated in male fertility studies. However, atrophic changes in testes were 

reported in rat and dog toxicity studies at exposures that were less than or equal to human exposure at 

the highest recommended daily dose of 600 mg/day based on AUC. These effects can be linked to a 

direct anti-proliferative effects on the testicular germ cells resulting in atrophy of the seminiferous 

tubules. 

 

Ribociclib and its metabolites passed readily into rat milk. The exposure to ribociclib was higher in 

milk than in plasma. 
 

Genotoxicity 

 

Genotoxicity studies in bacterial in vitro systems and in mammalian in vitro and in vivo systems with 

and without metabolic activation did not reveal any evidence for a genotoxic potential of ribociclib. 

 

 

6. PHARMACEUTICAL PARTICULARS 
 

6.1 List of excipients 
 

Tablet core 

 

Microcrystalline cellulose 

Crospovidone type A 

Low-substituted hydroxypropylcellulose 

Magnesium stearate 

Colloidal anhydrous silica 

 

Film coating 

 

Iron oxide black (E172) 

Iron oxide red (E172) 

Soya lecithin (E322) 

Polyvinyl alcohol (partially hydrolysed) 

Talc 

Titanium dioxide (E171) 

Xanthan gum 



30 

 

6.2 Incompatibilities 
 

Not applicable. 

 

6.3 Shelf life 
 

3 years. 

 

6.4 Special precautions for storage 
 

This medicinal product does not require any special storage conditions. 

 

6.5 Nature and contents of container 
 

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. 

 

6.6 Special precautions for disposal 
 

Any unused medicinal product or waste material should be disposed of in accordance with local 

requirements. 

 

 

7. MARKETING AUTHORISATION HOLDER 
 

Novartis Europharm Limited 

Vista Building 

Elm Park, Merrion Road 

Dublin 4 

Ireland 

 

 

8. MARKETING AUTHORISATION NUMBER(S) 
 

EU/1/17/1221/001-012 

 

 

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 

22 August 2017 

 

 

10. DATE OF REVISION OF THE TEXT 
 

 

Detailed information on this medicinal product is available on the website of the European Medicines 

Agency http://www.ema.europa.eu. 

 

  

http://www.ema.europa.eu/


31 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

ANNEX II 

 

A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE 

 

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 

 

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 

 

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 

 



32 

A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE 

 

Name and address of the manufacturer(s) responsible for batch release 

 

Novartis Pharma GmbH 

Roonstrasse 25 

90429 Nuremberg 

Germany 

 

 

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 

 

Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product 

Characteristics, section 4.2). 

 

 

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 

 

 Periodic safety update reports (PSURs) 
 

The requirements for submission of PSURs for this medicinal product are set out in the list of Union 

reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and any 

subsequent updates published on the European medicines web-portal. 

 

The marketing authorisation holder (MAH) shall submit the first PSUR for this product within 

6 months following authorisation. 

 

 

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 

 

 Risk management plan (RMP) 
 

The marketing authorisation holder (MAH) shall perform the required pharmacovigilance activities 

and interventions detailed in the agreed RMP presented in Module 1.8.2 of the marketing authorisation 

and any agreed subsequent updates of the RMP. 

 

An updated RMP should be submitted: 

 At the request of the European Medicines Agency; 

 Whenever the risk management system is modified, especially as the result of new information 
being received that may lead to a significant change to the benefit/risk profile or as the result of 

an important (pharmacovigilance or risk minimisation) milestone being reached. 

 

  



33 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

ANNEX III 

 

LABELLING AND PACKAGE LEAFLET 

  



34 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

A. LABELLING 
  



35 

 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

 

OUTER CARTON OF UNIT PACK 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Kisqali 200 mg film-coated tablets 

ribociclib 

 

 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 

Each film-coated tablet contains ribociclib succinate, equivalent to 200 mg ribociclib. 

 

 

3. LIST OF EXCIPIENTS 

 

Contains soya lecithin. See leaflet for further information. 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

Film-coated tablet 

 

21 film-coated tablets 

42 film-coated tablets 

63 film-coated tablets 

 

 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

 

Oral use 

Read the package leaflet before use. 

Enter weekdays starting with the 1st day of treatment. Mark off circle for every tablet you take. 

Take your dose once a day for 3 weeks followed by a 1-week break. 

No Kisqali this week. 

Day 

Week 
 

 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 

 

Keep out of the sight and reach of children. 

 

 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 

 

 

8. EXPIRY DATE 

 

EXP 

 



36 

 

9. SPECIAL STORAGE CONDITIONS 

 

 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 

APPROPRIATE 

 

 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 

Novartis Europharm Limited 

Vista Building 

Elm Park, Merrion Road 

Dublin 4 

Ireland 

 

 

12. MARKETING AUTHORISATION NUMBER(S) 

 

EU/1/17/1221/001 21 film-coated tablets (in PCTFE/PVC blisters) 

EU/1/17/1221/002 21 film-coated tablets (in PA/alu/PVC blisters) 

EU/1/17/1221/003 42 film-coated tablets (in PCTFE/PVC blisters) 

EU/1/17/1221/004 42 film-coated tablets (in PA/alu/PVC blisters) 

EU/1/17/1221/005 63 film-coated tablets (in PCTFE/PVC blisters) 

EU/1/17/1221/006 63 film-coated tablets (in PA/alu/PVC blisters) 

 

 

13. BATCH NUMBER 

 

Lot 

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

 

15. INSTRUCTIONS ON USE 

 

 

16. INFORMATION IN BRAILLE 

 

Kisqali 200 mg 

 

 

17. UNIQUE IDENTIFIER – 2D BARCODE 

 

2D barcode carrying the unique identifier included. 

 

 

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 

 

PC 

SN 
NN 

  



37 

 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

 

OUTER CARTON OF MULTIPACK (INCLUDING BLUE BOX) 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Kisqali 200 mg film-coated tablets 

ribociclib 

 

 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 

Each film-coated tablet contains ribociclib succinate, equivalent to 200 mg ribociclib. 

 

 

3. LIST OF EXCIPIENTS 

 

Contains soya lecithin. See leaflet for further information. 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

Film-coated tablet 

 

Multipack: 63 (3 packs of 21) film-coated tablets 

Multipack: 126 (3 packs of 42) film-coated tablets 

Multipack: 189 (3 packs of 63) film-coated tablets 
 

 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

 

Oral use 

Read the package leaflet before use. 

 

 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 

 

Keep out of the sight and reach of children. 

 

 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 

 

 

8. EXPIRY DATE 

 

EXP 

 

 

9. SPECIAL STORAGE CONDITIONS 

 

 



38 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 

APPROPRIATE 

 

 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 

Novartis Europharm Limited 

Vista Building 

Elm Park, Merrion Road 

Dublin 4 

Ireland 

 

 

12. MARKETING AUTHORISATION NUMBER(S) 

 

EU/1/17/1221/007 63 (3 x 21) film-coated tablets (in PCTFE/PVC blisters) 

EU/1/17/1221/008 63 (3 x 21) film-coated tablets (in PA/alu/PVC blisters) 

EU/1/17/1221/009 126 (3 x 42) film-coated tablets (in PCTFE/PVC blisters) 

EU/1/17/1221/010 126 (3 x 42) film-coated tablets (in PA/alu/PVC blisters) 

EU/1/17/1221/011 189 (3 x 63) film-coated tablets (in PCTFE/PVC blisters) 

EU/1/17/1221/012 189 (3 x 63) film-coated tablets (in PA/alu/PVC blisters) 

 

 

13. BATCH NUMBER 

 

Lot 

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

 

15. INSTRUCTIONS ON USE 

 

 

16. INFORMATION IN BRAILLE 

 

Kisqali 200 mg 

 

 

17. UNIQUE IDENTIFIER – 2D BARCODE 

 

2D barcode carrying the unique identifier included. 

 

 

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 

 

PC 

SN 

NN 

  



39 

 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

 

INTERMEDIATE CARTON OF MULTIPACK (WITHOUT BLUE BOX) 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Kisqali 200 mg film-coated tablets 

ribociclib 

 

 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 

Each film-coated tablet contains ribociclib succinate, equivalent to 200 mg ribociclib. 

 

 

3. LIST OF EXCIPIENTS 

 

Contains soya lecithin. See leaflet for further information. 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

Film-coated tablet 

 

21 film-coated tablets. Component of a multipack. Not to be sold separately. 

42 film-coated tablets. Component of a multipack. Not to be sold separately. 

63 film-coated tablets. Component of a multipack. Not to be sold separately. 
 

 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

 

Oral use 

Read the package leaflet before use. 

Enter weekdays starting with the 1st day of treatment. Mark off circle for every tablet you take. 

Take your dose once a day for 3 weeks followed by a 1-week break. 

No Kisqali this week. 

Day 

Week 
 

 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 

 

Keep out of the sight and reach of children. 

 

 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 

 

 

8. EXPIRY DATE 

 

EXP 

 



40 

 

9. SPECIAL STORAGE CONDITIONS 

 

 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 

APPROPRIATE 

 

 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 

Novartis Europharm Limited 

Vista Building 

Elm Park, Merrion Road 

Dublin 4 

Ireland 

 

 

12. MARKETING AUTHORISATION NUMBER(S) 

 

EU/1/17/1221/007 63 (3 x 21) film-coated tablets (in PCTFE/PVC blisters) 

EU/1/17/1221/008 63 (3 x 21) film-coated tablets (in PA/alu/PVC blisters) 

EU/1/17/1221/009 126 (3 x 42) film-coated tablets (in PCTFE/PVC blisters) 

EU/1/17/1221/010 126 (3 x 42) film-coated tablets (in PA/alu/PVC blisters) 

EU/1/17/1221/011 189 (3 x 63) film-coated tablets (in PCTFE/PVC blisters) 

EU/1/17/1221/012 189 (3 x 63) film-coated tablets (in PA/alu/PVC blisters) 

 

 

13. BATCH NUMBER 

 

Lot 

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

 

15. INSTRUCTIONS ON USE 

 

 

16. INFORMATION IN BRAILLE 

 

Kisqali 200 mg 

 

 

17. UNIQUE IDENTIFIER – 2D BARCODE 

 

 

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 

 

  



41 

 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 

 

BLISTERS 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Kisqali 200 mg film-coated tablets 

ribociclib 

 

 

2. NAME OF THE MARKETING AUTHORISATION HOLDER 

 

Novartis Europharm Limited 

 

 

3. EXPIRY DATE 

 

EXP 

 

 

4. BATCH NUMBER 

 

Lot 

 

 

5. OTHER 

 

Monday 

Tuesday 

Wednesday 

Thursday 

Friday 

Saturday 

Sunday 

  



42 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

B. PACKAGE LEAFLET 



43 

Package leaflet: Information for the patient 
 

Kisqali 200 mg film-coated tablets 

ribociclib 

 

 This medicine is subject to additional monitoring. This will allow quick identification of new 

safety information. You can help by reporting any side effects you may get. See the end of section 4 

for how to report side effects. 

 

Read all of this leaflet carefully before you start taking this medicine because it contains 

important information for you. 
- Keep this leaflet. You may need to read it again. 
- If you have any further questions, ask your doctor, pharmacist or nurse. 
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours. 

- If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible 
side effects not listed in this leaflet. See section 4. 

 

What is in this leaflet 

 

1. What Kisqali is and what it is used for 

2. What you need to know before you take Kisqali 

3. How to take Kisqali 

4. Possible side effects 

5. How to store Kisqali 

6. Contents of the pack and other information 

 

 

1. What Kisqali is and what it is used for 

 

What Kisqali is 
Kisqali contains the active substance ribociclib, which belongs to a group of medicines called 

cyclin-dependent kinase (CDK) inhibitors. 

 

What Kisqali is used for 
Kisqali is used in women with a type of breast cancer called hormone receptor-positive, human 

epidermal growth factor receptor 2-negative breast cancer that is locally advanced or has spread to 

other parts of the body (metastatic). It is used in combination with an aromatase inhibitor or 

fulvestrant, which are used as hormonal anticancer therapies. 

 

Women who have not reached menopause will also be treated with a medicine called a luteinising 

hormone releasing hormone (LHRH) agonist. 

 

How Kisqali works 
Kisqali works by blocking proteins called cyclin-dependent kinases 4 and 6, which are important for 

the growth and division of cells. Blocking these proteins can slow down the growth of cancer cells and 

delay the progression of your cancer. 

 

If you have any questions about how Kisqali works or why this medicine has been prescribed for you, 

ask your doctor, pharmacist or nurse. 

 

 

  



44 

2. What you need to know before you take Kisqali 
 

Follow all of your doctor’s instructions carefully. They may differ from the general information in this 

leaflet. 

 

Do not take Kisqali: 
- if you are allergic to ribociclib, peanut, soya or any of the other ingredients of this medicine 

(listed in section 6). 

If you think you may be allergic, ask your doctor for advice. 

 

Warnings and precautions 
Talk to your doctor, pharmacist or nurse before taking Kisqali. 

 

If any of the following apply to you before taking Kisqali, tell your doctor or pharmacist: 

 If you have a fever, sore throat or mouth ulcers due to infections (signs of a low level of white 
blood cells). 

 If you have any problems with your liver or have previously had any type of liver disease. 

 If you have or have had heart disorders or heart rhythm disorders, such as an irregular heartbeat, 
including a condition called prolonged QT syndrome (QT interval prolongation) or low levels of 

potassium, magnesium, calcium or phosphorus in your blood. 

 

If any of the following apply to you during your treatment with Kisqali, tell your doctor or 

pharmacist: 

 If you have a combination of any of the following symptoms: rash, red skin, blistering of the 
lips, eyes or mouth, skin peeling, high fever, flu-like symptoms and enlarged lymph nodes 

(signs of a severe skin reaction). 

In case of a severe skin reaction, your doctor will ask you to immediately stop treatment with 

Kisqali. 

 Trouble breathing, cough and shortness of breath (may be signs of lung or breathing problems). 
If necessary, your doctor may interrupt or reduce your dose of Kisqali or decide to stop 

treatment with Kisqali permanently. 

 

Monitoring during your treatment with Kisqali 
You will have regular blood tests before and during treatment with Kisqali to check your liver function 

and the amount of blood cells (white blood cells, red blood cells and platelets) and electrolytes (blood 

salts including potassium, calcium, magnesium and phosphate) in your body. Your heart activity will 

also be monitored before and during treatment with Kisqali with a test called an electrocardiogram 

(ECG). If necessary, your doctor may reduce your dose of Kisqali or temporarily stop it to allow your 

liver, blood cells, electrolyte levels or heart activity to recover. Your doctor may also decide to stop 

treatment with Kisqali permanently. 

 

Children and adolescents 
Kisqali is not to be used in children and adolescents under 18 years of age. 

 

Other medicines and Kisqali 
Before you take Kisqali, tell your doctor or pharmacist if you are taking, have recently taken or might 

take any other medicines, including medicines or supplements obtained without a prescription, 

because these may influence the effect of Kisqali. This includes in particular: 

 Tamoxifen, another medicine for the treatment of breast cancer. 

 Some medicines used to treat fungal infections, such as ketoconazole, itraconazole, 
voriconazole or posaconazole. 

 Some medicines used to treat HIV/AIDS such as ritonavir, saquinavir, indinavir, lopinavir, 
nelfinavir, telaprevir and efavirenz. 

 Some medicines used to treat seizures or fits (anti-epileptics) such as carbamazepine and 
phenytoin. 

  



45 

 St. John’s Wort (also known as Hypericum perforatum) - a herbal product used to treat 
depression and other conditions. 

 Some medicines used to treat heart rhythm problems or high blood pressure such as 
amiodarone, disopyramide, procainamide, quinidine, sotalol and verapamil. 

 Antimalarials such as chloroquine. 

 Antibiotics such as clarithromycin, telithromycin, moxifloxacin, rifampicin, ciprofloxacin, 
levofloxacin and azithromycin. 

 Some medicines used for sedation or anaesthesia such as midazolam. 

 Some medicines used as antipsychotics such as haloperidol. 

 Medicines used to treat angina such as bepridil. 

 Methadone, used to treat pain or addiction to opioids. 

 Medicines like intravenous ondansetron, used to prevent nausea and vomiting caused by 
chemotherapy (treatment with cancer medicines). 

 

Kisqali may increase or decrease your blood levels of some other medicines. This includes in 

particular: 

 Medicines used to treat symptoms of benign prostatic hyperplasia such as alfuzosin. 

 Tamoxifen, another medicine used for the treatment of breast cancer. 

 Antiarrhythmics such as amiodarone or quinidine. 

 Antipsychotics such as pimozide or quetiapine. 

 Medicines used to improve blood fat levels such as simvastatin or lovastatin, pitavastatin, 
pravastatin or rosuvastatin. 

 Medicines used to treat high blood sugar levels (e.g. diabetes) such as metformin. 

 Medicines used to treat cardiac disorders such as digoxin 

 Medicines used to treat pulmonary arterial hypertension and erectile dysfunction such as 
sildenafil. 

 Medicines used to treat low blood pressure or migraine such as ergotamine or 
dihydroergotamine. 

 Some medicines used to treat epileptic fits or which are used for sedation or anaesthesia such as 
midazolam. 

 Medicines used to treat sleep disorders such as triazolam. 

 Analgesics such as alfentanil and fentanyl. 

 Medicines used for the treatment of gastrointestinal disorders such as cisapride. 

 Medicines used to prevent the rejection of an organ transplant such as tacrolimus, sirolimus and 
ciclosporin (also used to treat inflammation in rheumatoid arthritis and psoriasis). 

 Everolimus, used for several types of cancer and tuberous sclerosis (also used to prevent the 
rejection of an organ transplant). 

 

Make sure you tell your doctor of all medicines and supplements, including herbal medicines, that you 

are taking before you start treatment with Kisqali and if you are prescribed a new medicine after you 

have started treatment with Kisqali. 

 

Ask your doctor or pharmacist if you are not sure if your medicine is one of the medicines listed 

above. 

 

Kisqali with food and drink 

You should not eat grapefruits or drink grapefruit juice during your treatment with Kisqali. It may 

change how Kisqali is processed in your body and may increase the amount of Kisqali in your 

bloodstream. 

 

  



46 

Pregnancy and breast-feeding 
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask 

your doctor for advice before taking this medicine. 

 

Your doctor will discuss with you the potential risks of taking Kisqali during pregnancy. 

 

Pregnancy and women of childbearing potential 

Kisqali should not be used during pregnancy since it may harm your unborn baby. If you are a woman 

of childbearing potential you should have a negative pregnancy test before starting treatment with 

Kisqali. You should use effective contraception (e.g. double-barrier contraception such as condom and 

diaphragm) while taking Kisqali and for at least 21 days after the last dose. Ask your doctor about 

options for effective contraception. 

 

Breast-feeding 

You should not breast-feed while taking Kisqali and for at least 21 days after the last dose. 

 
Driving and using machines 
Treatment with Kisqali may lead to tiredness, dizziness or spinning sensation. You should therefore be 

cautious when driving or using machines during your treatment with Kisqali. 

 

Kisqali contains soya lecithin 

If you are allergic to peanut or soya, do not use this medicine. 

 

 

3. How to take Kisqali 
 

Always take this medicine exactly as your doctor, pharmacist or nurse has told you. Your doctor, 

pharmacist or nurse will tell you exactly how many tablets to take and which days to take them on. 

Check with your doctor, pharmacist or nurse if you are not sure. Do not change the Kisqali dose or 

schedule without talking to your doctor. 

 

Do not exceed the recommended dose prescribed by your doctor. 

 

How much Kisqali to take 

 The recommended starting dose of Kisqali is 600 mg (3 tablets of 200 mg) once daily. Your 
doctor will tell you exactly how many tablets of Kisqali to take; in certain situations your doctor 

may instruct you to take a lower dose of Kisqali, e.g. 400 mg (2 tablets of 200 mg) once daily or 

200 mg (1 tablet of 200 mg) once daily. 

 A treatment cycle lasts 28 days. Take Kisqali once a day only on days 1 to 21 of a 28-day cycle. 
The outer carton of the Kisqali pack includes a “calendar tool” which allows you to track your 

daily Kisqali dose by marking off a circle for every tablet you take over the 28-day cycle. 

You should not take Kisqali on days 22 to 28 of the cycle. 

 

It is very important to follow your doctor’s instructions. If you get certain side effects your doctor may 

ask you to take a lower dose, interrupt your treatment with Kisqali, or stop it permanently. 

 

When to take Kisqali 
Take Kisqali once daily at the same time each day, preferably in the morning. This will help you to 

remember to take your medicine. 

 

How to take Kisqali 
Kisqali tablets should be swallowed whole (tablets should not be chewed, crushed or split before 

swallowing). Do not take a tablet that is broken, cracked or otherwise damaged. 

 

Kisqali with food and drink 

You should take Kisqali once daily every day at the same time, preferably in the morning. You may 

take it with or without food. 



47 

 

How long to take Kisqali 
Take Kisqali once a day on days 1 to 21 of a 28-day cycle. Continue Kisqali treatment for as long as 

your doctor tells you to. 

 

This is a long-term treatment, possibly lasting for months or years. Your doctor will regularly monitor 

your condition to check that the treatment is having the desired effect. 

 

If you take more Kisqali than you should 
If you take too many tablets, or if someone else takes your medicine, contact a doctor or hospital for 

advice immediately. Show the Kisqali packet. Medical treatment may be necessary. 

 

If you miss a dose of Kisqali 
If you vomit after taking the dose or forget a dose, skip the missed dose that day. Take the next dose at 

your usual time. 

 

Do not take a double dose to make up for a missed dose. Instead, wait until it is time for your next 

dose and then take your usual dose. 

 

If you stop taking Kisqali 
Stopping your treatment with Kisqali may cause your condition to get worse. Do not stop taking 

Kisqali unless your doctor tells you to. 

 

If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse. 

 

 

4. Possible side effects 
 

Like all medicines, this medicine can cause side effects, although not everybody gets them. 

 

Some side effects could be serious 

Tell your doctor immediately if you get any of the following symptoms during treatment with 

Kisqali: 

 Fever, chills, weakness and frequent infections with symptoms such as sore throat or mouth 
ulcers (signs of a low level of different types of blood cells). Very common (may affect more 

than 1 in 10 people). 

 Tiredness, itchy yellow skin or yellowing of the whites of your eyes, nausea or vomiting, loss of 
appetite, pain in the upper right side of the belly (abdomen), dark or brown urine, bleeding or 

bruising more easily than normal (these may be signs of a liver problem). Common (may affect 

up to 1 in 10 people). 

 Chest pain or discomfort, changes in heart beat (fast or slow), palpitations, lightheadedness, 
fainting, dizziness, lips turning blue colour, shortness of breath, swelling (oedema) of your 

lower limbs or skin (these may be signs of heart problems). Common (may affect up to 1 in 

10 people). 

 Serious infection with increased heart rate, shortness of breath or rapid breathing, fever and 
chills (these may be signs of sepsis which is an infection in the blood system which may be life 

threatening). Uncommon (may affect up to 1 in 100 people). 

 Severe skin reaction that might include a combination of any of the following symptoms: rash, 
red skin, blistering of the lips, eyes or mouth, skin peeling, high fever, flu-like symptoms, 

enlarged lymph nodes (toxic epidermal necrolysis [TEN]). Frequency not known (frequency 

cannot be estimated from the available data). 

Your doctor may ask you to take a lower dose, interrupt your treatment with Kisqali, or stop it 

permanently. 

 

  



48 

Other possible side effects 
Other side effects include the following listed below. If these side effects become severe, tell your 

doctor, pharmacist or nurse. 

 

Very common (may affect more than 1 in 10 people) 

 Tiredness, pale skin (potential sign of a low level of red blood cells, anaemia) 

 Sore throat, runny nose, fever (signs of a respiratory tract infection) 

 Painful and frequent urination (signs of a urinary tract infection) 

 Reduced appetite 

 Shortness of breath, difficulty breathing 

 Back pain 

 Nausea (feeling sick) 

 Diarrhoea 

 Vomiting 

 Constipation 

 Mouth sores with gum inflammation (stomatitis) 

 Abdominal (belly) pain 

 Upset stomach, indigestion, heartburn (dyspepsia) 

 Hair loss or hair thinning (alopecia) 

 Rash 

 Itching (pruritus) 

 Tiredness (fatigue) 

 Weakness (asthenia) 

 Fever (pyrexia) 

 Headache 

 Swollen hands, ankles or feet (peripheral oedema) 

 Dizziness or light headedness 

 Cough 
 

Common (may affect up to 1 in 10 people) 

 Abdominal pain, nausea, vomiting and diarrhoea (signs of gastroenteritis, which is an infection 
of the gastrointestinal tract) 

 Spontaneous bleeding or bruising (signs of a low level of blood platelets) 

 Watering eyes 

 Dry eyes 

 Reduced level of calcium in the blood, which may sometimes lead to cramps 

 Reduced level of phosphate in the blood 

 Strange taste in the mouth (dysgeusia) 

 Abnormal kidney blood test result (high level of creatinine in the blood) 

 Skin reddening (erythema) 

 Spinning sensation (vertigo) 

 Dry skin 

 Loss of skin colour in patches (vitiligo) 

 Dry mouth 

 Sore throat (oropharyngeal pain) 
 

Reporting of side effects 
If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side 

effects not listed in this leaflet. You can also report side effects directly via the national reporting 

system listed in Appendix V. By reporting side effects you can help provide more information on the 

safety of this medicine. 

 

 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


49 

5. How to store Kisqali 
 

Keep this medicine out of the sight and reach of children. 

 

Do not use this medicine after the expiry date which is stated on the carton and the blister. The expiry 

date refers to the last day of that month. 

 

This medicine does not require any special storage conditions. 

 

Do not take this medicine if you notice any damage to the packaging or if there are any signs of 

tampering. 

 

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 

throw away medicines you no longer use. These measures will help protect the environment. 

 

 

6. Contents of the pack and other information 
 

What Kisqali contains 
- The active substance is ribociclib. Each film-coated tablet contains ribociclib succinate 

equivalent to 200 mg ribociclib. 

- The other ingredients are: 

Tablet core: microcrystalline cellulose; crospovidone type A; low-substituted 

hydroxypropylcellulose; magnesium stearate; colloidal anhydrous silica. 
Coating material: iron oxide black (E172); iron oxide red (E172); soya lecithin (E322); 

polyvinyl alcohol (partially hydrolysed); talc; titanium dioxide (E171); xanthan gum. 

 

What Kisqali looks like and contents of the pack 
Kisqali is supplied as film-coated tablets in aluminum blisters. 

 

The film-coated tablets are light greyish violet in colour, unscored, round, debossed with “RIC” on 

one side and “NVR” on the other side. 

 

The following pack sizes are available: 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. 

Kisqali packs containing 63 tablets are intended for use by patients taking the full ribociclib daily dose 

of 600 mg (3 tablets once daily). 

Kisqali packs containing 42 tablets are intended for use by patients taking the reduced ribociclib daily 

dose of 400 mg (2 tablets once daily). 

Kisqali packs containing 21 tablets are intended for use by patients taking the lowest ribociclib daily 

dose of 200 mg (1 tablet once daily). 

 

Not all pack sizes may be marketed. 

 

Marketing Authorisation Holder 
Novartis Europharm Limited 

Vista Building 

Elm Park, Merrion Road 

Dublin 4 

Ireland 

 

Manufacturer 
Novartis Pharma GmbH 

Roonstrasse 25 

90429 Nuremberg 

Germany 



50 

 

For any information about this medicine, please contact the local representative of the Marketing 

Authorisation Holder: 

 

België/Belgique/Belgien 
Novartis Pharma N.V. 

Tél/Tel: +32 2 246 16 11 

 

Lietuva 

SIA Novartis Baltics Lietuvos filialas 

Tel: +370 5 269 16 50 

 

България 

Novartis Bulgaria EOOD 

Тел: +359 2 489 98 28 

 

Luxembourg/Luxemburg 

Novartis Pharma N.V. 

Tél/Tel: +32 2 246 16 11 

 

Česká republika 

Novartis s.r.o. 

Tel: +420 225 775 111 

 

Magyarország 

Novartis Hungária Kft. 

Tel.: +36 1 457 65 00 

Danmark 

Novartis Healthcare A/S 

Tlf: +45 39 16 84 00 

 

Malta 

Novartis Pharma Services Inc. 

Tel: +356 2122 2872 

Deutschland 

Novartis Pharma GmbH 

Tel: +49 911 273 0 

 

Nederland 

Novartis Pharma B.V. 

Tel: +31 88 04 52 555 

Eesti 

SIA Novartis Baltics Eesti filiaal 

Tel: +372 66 30 810 

 

Norge 

Novartis Norge AS 

Tlf: +47 23 05 20 00 

Ελλάδα 

Novartis (Hellas) A.E.B.E. 

Τηλ: +30 210 281 17 12 

 

Österreich 

Novartis Pharma GmbH 

Tel: +43 1 86 6570 

España 

Novartis Farmacéutica, S.A. 

Tel: +34 93 306 42 00 

 

Polska 

Novartis Poland Sp. z o.o. 

Tel.: +48 22 375 4888 

France 

Novartis Pharma S.A.S. 

Tél: +33 1 55 47 66 00 

 

Portugal 

Novartis Farma - Produtos Farmacêuticos, S.A. 

Tel: +351 21 000 8600 

Hrvatska 

Novartis Hrvatska d.o.o. 

Tel. +385 1 6274 220 

 

România 

Novartis Pharma Services Romania SRL 

Tel: +40 21 31299 01 

Ireland 

Novartis Ireland Limited 

Tel: +353 1 260 12 55 

 

Slovenija 

Novartis Pharma Services Inc. 

Tel: +386 1 300 75 50 

Ísland 

Vistor hf. 

Sími: +354 535 7000 

 

Slovenská republika 

Novartis Slovakia s.r.o. 

Tel: +421 2 5542 5439 

 

Italia 

Novartis Farma S.p.A. 

Tel: +39 02 96 54 1 

Suomi/Finland 

Novartis Finland Oy 

Puh/Tel: +358 (0)10 6133 200 

 



51 

Κύπρος 

Novartis Pharma Services Inc. 

Τηλ: +357 22 690 690 

 

Sverige 

Novartis Sverige AB 

Tel: +46 8 732 32 00 

 

Latvija 

SIA Novartis Baltics 

Tel: +371 67 887 070 

 

United Kingdom 

Novartis Pharmaceuticals UK Ltd. 

Tel: +44 1276 698370 

 

 

This leaflet was last revised in 
 

 

Other sources of information 
Detailed information on this medicine is available on the European Medicines Agency web site: 

http://www.ema.europa.eu 

 


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET