4.1. Therapeutic indications

Early breast cancer

Kisqali in combination with an aromatase inhibitor is indicated for the adjuvant treatment of patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative early breast cancer at high risk of recurrence (see section 5.1 for selection criteria).

In pre- or perimenopausal women, or in men, the aromatase inhibitor should be combined with a luteinising hormone-releasing hormone (LHRH) agonist.

Advanced or metastatic breast cancer

Kisqali is indicated for the treatment of women with HR-positive, 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 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.

HR-positive, HER2-negative testing

Patient selection for treatment with Kisqali based on the tumour expression of HR and HER2 should be assessed by a CE-marked in vitro diagnostic (IVD) medical device with the corresponding intended purpose. If the CE-marked IVD is not available, an alternative validated test should be used.

Posology

Early breast cancer

The recommended dose is 400 mg (two 200 mg film-coated tablets) of ribociclib once daily for 21 consecutive days followed by 7 days off treatment, resulting in a complete cycle of 28 days. In patients with early breast cancer, Kisqali should be taken until completion of 3 years of treatment or until disease recurrence or unacceptable toxicity occur.

When Kisqali is used in combination with an aromatase inhibitor (AI), the AI should be taken orally once daily continuously throughout the 28-day cycle. Please refer to the Summary of Product Characteristics (SmPC) of the AI for additional details.

In pre- or perimenopausal women, or in men, the aromatase inhibitor should be combined with a LHRH agonist.

Advanced or metastatic breast cancer

The recommended dose is 600 mg (three 200 mg film-coated tablets) of ribociclib once daily for 21 consecutive days followed by 7 days off treatment, resulting in a complete cycle of 28 days. In patients with advanced or metastatic breast cancer, the treatment should be continued as long as the patient is deriving clinical benefit from therapy or until unacceptable toxicity occurs.

When Kisqali is used in combination with an AI, the AI should be taken orally once daily continuously throughout the 28-day cycle. Please refer to the Summary of Product Characteristics (SmPC) of the AI for additional details.

When Kisqali is used in combination with fulvestrant, fulvestrant is administered intramuscularly on days 1, 15 and 29, and once monthly thereafter. Please refer to the SmPC of fulvestrant for additional details.

Treatment of pre- and perimenopausal women with the approved Kisqali combinations should also include an LHRH agonist in accordance with local clinical practice.

Dose modifications

Management of severe or intolerable adverse reactions (ARs) may require temporary dose interruption, reduction or discontinuation of Kisqali. If dose reduction is required, the recommended dose reduction guidelines are listed in Table 1.

Table 1 Recommended dose modification guidelines

Kisqali

Dose

Number of 200 mg tablets

Early breast cancer

Starting dose

400 mg/day

2

Dose reduction

200 mg*/day

1

Advanced or metastatic breast cancer

Starting dose

600 mg/day

3

First dose reduction

400 mg/day

2

Second dose reduction

200 mg*/day

1

* If further dose reduction below 200 mg/day is required, the treatment should be permanently discontinued.

Tables 2, 3, 4, 5 and 6 summarise recommendations for dose interruption, reduction or discontinuation of Kisqali in the management of specific ARs. The clinical judgement of the treating physician should guide the management plan of each patient based on individual benefit/risk assessment (see section 4.4).

Complete blood counts (CBC) should be performed before initiating treatment with Kisqali. After initiating treatment CBC should be monitored every 2 weeks for the first 2 cycles, at the beginning of each of the subsequent 4 cycles, then as clinically indicated.

Table 2 Dose modification and management – Neutropenia

Grade 1 or 2*

(ANC 1 000/mm3 - ≤LLN)

Grade 3*

(ANC 500 - <1 000/mm3)

Grade 3* febrile neutropenia**

Grade 4*

(ANC <500/mm3)

Neutropenia

No dose adjustment is required

Dose interruption until recovery to grade ≤2.

Resume Kisqali at the same dose level.

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

Dose interruption until recovery to grade ≤2. Resume Kisqali and reduce by 1 dose level

Dose interruption until recovery to grade ≤2.

Resume Kisqali and reduce by 1 dose level.

* 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 38°C and above for more than one hour and/or concurrent infection)

ANC = absolute neutrophil count; LLN = lower limit of normal

Liver function tests (LFTs) should be performed before initiating treatment with Kisqali. After initiating treatment LFTs should be performed every 2 weeks for the first 2 cycles, at the beginning of each of the subsequent 4 cycles, then as clinically indicated. If grade ≥2 abnormalities are noted, more frequent monitoring is recommended.

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 in all patients.

Treatment with Kisqali should be initiated only in patients with QTcF values less than 450 msec. After initiating treatment, ECG should be repeated at approximately day 14 of the first cycle, then as clinically indicated.

In case of QTcF prolongation during treatment, more frequent ECG monitoring is recommended in patients with early breast cancer and advanced or metastatic breast cancer.

Table 4 Dose modification and management – QT prolongation

QTcF* prolongation

Early breast cancer

Advanced or metastatic breast cancer

>480 msec and ≤500 msec

Dose interruption of Kisqali until QTcF resolves to <481 msec.

Resume at the same dose level.

Reduce to the next lower dose level.

If QTcF ≥481 msec recurs, interrupt Kisqali treatment until QTcF resolves to <481 msec, then resume at next lower dose level.

>500 msec

Dose interruption of Kisqali until QTcF resolves to <481 msec, then resume at next lower dose level.

If QTcF >500 msec recurs, discontinue Kisqali.

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

Note: If further dose reductions are required at the 200 mg dose, Kisqali should be discontinued.

*QTcF = QT interval corrected by Fridericia's formula.

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 AI, 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 (see section 4.5).

In patients taking 600 mg ribociclib daily and in whom initiation of co-administration of a strong CYP3A4 inhibitor cannot be avoided, the dose should be reduced to 400 mg.

In patients taking 400 mg ribociclib daily and in whom initiation of co-administration of a strong CYP3A4 inhibitor cannot be avoided, the dose should be further reduced to 200 mg.

In patients who have had their dose reduced to 200 mg ribociclib daily and in whom initiation of co-administration of a strong CYP3A4 inhibitor cannot be avoided, Kisqali treatment should be interrupted.

Due to inter-patient variability, the recommended dose adjustments may not be optimal in all patients, therefore close monitoring of signs of toxicity is recommended. If the strong inhibitor is discontinued, the Kisqali dose should be changed to the dose used prior to the initiation of the strong CYP3A4 inhibitor after at least 5 half-lives of the strong CYP3A4 inhibitor (see sections 4.4, 4.5 and 5.2).

Special populations

Renal impairment

No dose adjustment is necessary in patients with mild or moderate renal impairment. A starting dose of 200 mg is recommended in patients with severe renal impairment. Kisqali has not been studied in breast cancer patients with severe renal impairment (see sections 4.4, 5.1 and 5.2).

Hepatic impairment

No dose adjustment is necessary in patients with early breast cancer with hepatic impairment (see section 5.2). In patients with advanced or metastatic breast cancer, 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. Currently available data on Kisqali in combination with topotecan and temozolomide (TOTEM) in paediatric patients are described in sections 5.1 and 5.2, but no recommendation on a posology can be made.

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 (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. 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

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 co-administration of Kisqali with a strong CYP3A4 inhibitor cannot be avoided, the Kisqali dose should be changed as described in section 4.2.

Based on the findings from study E2301 (MONALEESA-7), Kisqali is not recommended for use in combination with tamoxifen (see sections 4.8 and 5.1).

Early breast cancer

In study O12301C (NATALEE), a QTcF interval increase >60 msec from baseline was observed in 19 (0.8%) patients receiving Kisqali plus AI.

ECG should be assessed before initiating treatment. Treatment with Kisqali should be initiated only in patients with QTcF values less than 450 msec. ECG should be repeated at approximately day 14 of the first cycle, then as clinically indicated (see sections 4.2 and 4.8).

In patients with early breast cancer, appropriate monitoring of serum electrolytes (including potassium, calcium, phosphorus and magnesium) should be performed before initiating treatment, at the beginning of the first 6 cycles and then as clinically indicated. Any abnormality should be corrected before initiating treatment with Kisqali and during treatment with Kisqali.

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).

Advanced or metastatic breast cancer

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).

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, then as clinically indicated (see sections 4.2 and 4.8).

In patients with advanced or metastatic breast cancer, appropriate monitoring of serum electrolytes (including potassium, calcium, phosphorus and magnesium) should be performed before initiating treatment, at the beginning of the first 6 cycles and then as clinically indicated. Any abnormality should be corrected before initiating treatment with Kisqali and during treatment with Kisqali.

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

Interstitial lung disease (ILD)/pneumonitis has been reported with Kisqali. 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).

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).

Blood creatinine increase

Ribociclib may cause blood creatinine increase as an inhibitor of the renal transporters organic cation transporter 2 (OCT2) and multidrug and toxin extrusion protein 1 (MATE1), which are involved in the active secretion of creatinine from the proximal tubules (see section 4.5). In case of blood creatinine increase while on treatment, it is recommended that further assessment of the renal function be performed to exclude renal impairment.

CYP3A4 substrates

Ribociclib is a strong CYP3A4 inhibitor at the 600 mg dose and a moderate CYP3A4 inhibitor at the 400 mg dose. 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.

Renal impairment

The recommended starting dose of 200 mg for patients with severe renal impairment is estimated to result in approximately 45% lower exposure compared with the standard starting dose of 600 mg in advanced or metastatic breast cancer patients with normal renal function. The efficacy at this starting dose has not been studied. Caution should be used in patients with severe renal impairment with close monitoring for signs of toxicity (see sections 4.2 and 5.2).

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).

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. Physiologically-based pharmacokinetic (PBPK) simulations with co-administered ritonavir (100 mg twice daily) estimated that the steady-state Cmax and AUC0-24h of ribociclib (400 mg once daily) increased by 1.5- and 1.8-fold, 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 ARs (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 changed 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 ARs 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.

PBPK simulations suggested that at a 600 mg dose of ribociclib, a moderate CYP3A4 inhibitor (erythromycin) may increase ribociclib steady-state Cmax and AUC 1.1- and 1.1-fold, respectively. PBPK simulations suggested that a moderate CYP3A4 inhibitor may increase Cmax and AUC of ribociclib 400 mg steady state by 1.1- and 1.2-fold, respectively. The effect at the 200 mg once-daily dose was predicted to be a 1.3- and 1.5-fold increase in steady-state Cmax and AUC, respectively. No dose adjustments of ribociclib are required at initiation of treatment with mild or moderate CYP3A4 inhibitors. However, monitoring of ribociclib-related ARs 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.

The effect of a moderate CYP3A4 inducer on ribociclib exposure has not been studied. PBPK simulations suggested that a moderate CYP3A4 inducer (efavirenz) may decrease steady-state ribociclib Cmax and AUC by 55% and 74%, respectively, at a ribociclib dose of 400 mg, and by 52% and 71%, respectively, at a ribociclib dose of 600 mg. 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. PBPK simulations suggested that Kisqali given at the 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 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.

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.

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

Early breast cancer

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

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

Dose reduction due to adverse events, regardless of causality, occurred in 22.8% of patients receiving Kisqali plus AI in the phase III clinical study. Permanent discontinuation was reported in 19.7% of patients receiving Kisqali plus AI in the phase III clinical study.

Advanced or metastatic breast cancer

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

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

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

Tabulated list of adverse reactions

Early breast cancer

The overall safety evaluation of Kisqali is based on the dataset from 2 525 patients who received Kisqali in combination with AI and who were included in the randomised, open-label phase III clinical study NATALEE.

The median duration of exposure to ribociclib across the study was 32.0 months, with 69.4% patients exposed for >24 months, and 42.8% patients completing the 36-month ribociclib regimen.

Advanced or metastatic breast cancer

The overall safety evaluation of Kisqali is based on the pooled dataset from 1 065 patients who received Kisqali in combination with endocrine therapy (N=582 in combination with an aromatase inhibitor and N=483 in combination with fulvestrant) and who were included in the randomised, double-blind, placebo-controlled phase III clinical studies MONALEESA-2, MONALEESA-7 NSAI subgroup and MONALEESA-3.

The median duration of exposure to study treatment across the pooled phase III studies dataset was 19.2 months, with 61.7% patients exposed ≥12 months.

ADRs from the phase III clinical studies and post‑marketing experience (Table 7) in patients with early breast cancer and advanced or metastatic breast cancer are listed by MedDRA system organ class. Within each system organ class, the adverse reactions are ranked by frequency, with the most frequent reactions first. Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. In addition, the corresponding frequency category for each adverse reaction is based on the following convention (CIOMS III): very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1 000 to <1/100); rare (≥1/10 000 to <1/1 000); very rare (<1/10 000); and not known (cannot be estimated from the available data).

Table 7 Adverse drug reactions reported in the phase III clinical studies and during post‑marketing experience

Frequency

Patients with early breast cancer with starting dose 400 mg ribociclib

Patients with advanced or metastatic breast cancer with starting dose 600 mg ribociclib

Infections and infestations

Very common

Infections1

Infections1

Blood and lymphatic system disorders

Very common

Neutropenia, leukopenia

Neutropenia, leukopenia, anaemia, lymphopenia

Common

Anaemia, thrombocytopenia, lymphopenia

Thrombocytopenia, febrile neutropenia

Uncommon

Febrile neutropenia

-

Metabolism and nutrition disorders

Very common

-

Appetite decreased

Common

Hypocalcaemia, hypokalaemia, appetite decreased

Hypocalcaemia, hypokalaemia, hypophosphataemia

Nervous system disorders

Very common

Headache

Headache, dizziness

Common

Dizziness

Vertigo

Eye disorders

Common

-

Lacrimation increased, dry eye

Cardiac disorders

Common

-

Syncope

Respiratory, thoracic and mediastinal disorders

Very common

Cough

Dyspnoea, cough

Common

Dyspnoea, interstitial lung disease (ILD) / pneumonitis

Interstitial lung disease (ILD) / pneumonitis

Gastrointestinal disorders

Very common

Nausea, diarrhoea, constipation, abdominal pain2

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

Common

Vomiting, stomatitis3

Dysgeusia

Hepatobiliary disorders

Common

Hepatotoxicity4

Hepatotoxicity4

Skin and subcutaneous tissue disorders

Very common

Alopecia

Alopecia, rash5, pruritus

Common

Rash5, pruritus

Dry skin, erythema, vitiligo

Rare

-

Erythema multiforme

Not known

-

Toxic epidermal necrolysis (TEN)

Musculoskeletal and connective tissue disorders

Very common

-

Back pain

General disorders and administration site conditions

Very common

Fatigue, asthenia, pyrexia

Fatigue, peripheral oedema, pyrexia, asthenia

Common

Peripheral oedema, oropharyngeal pain

Oropharyngeal pain, dry mouth

Investigations

Very common

Abnormal liver function tests6

Abnormal liver function tests6

Common

Blood creatinine increased, electrocardiogram QT prolonged

Blood creatinine increased, electrocardiogram QT prolonged

1 Infections: urinary tract infections, respiratory tract infections, gastroenteritis (only in patients with advanced or metastatic breast cancer), sepsis (<1% only in patients with advanced or metastatic breast cancer).

2 Abdominal pain: abdominal pain, abdominal pain upper.

3 Stomatitis for early breast cancer includes: stomatitis, mucositis.

4 Hepatotoxicity: hepatic cytolysis, hepatocellular injury (only in patients with advanced or metastatic breast cancer), drug-induced liver injury (<1% in patients with early breast cancer and in patients with advanced or metastatic breast cancer), hepatotoxicity, hepatic failure (only in patients with advanced or metastatic breast cancer), autoimmune hepatitis.

5 Rash: rash, rash maculopapular, rash pruritic.

6 Abnormal liver function tests: ALT increased, AST increased, blood bilirubin increased.

Description of selected adverse reactions

Neutropenia

In the phase III study in patients with early breast cancer, neutropenia was the most frequently reported adverse reaction (62.5%) and a grade 3 or 4 decrease in neutrophil counts (based on laboratory findings) was reported in 45.1% of patients receiving Kisqali plus aromatase inhibitor (AI).

Among the patients with early breast cancer who had grade 2, 3 or 4 neutropenia, the median time to onset was 0.6 months, for those patients who had an event. The median time to resolution of grade ≥3 (to normalisation or grade <3) was 0.3 months in the Kisqali plus AI arm following treatment interruption and/or reduction and/or discontinuation. Febrile neutropenia was reported in 0.3% of patients exposed to Kisqali plus AI. Treatment discontinuation due to neutropenia was low (1.1%) in patients receiving Kisqali plus AI (see sections 4.2 and 4.4).

In the phase III studies in patients with advanced or metastatic breast cancer neutropenia was the most frequently reported adverse reaction (75.4%) and a grade 3 or 4 decrease in neutrophil counts (based on laboratory findings) was reported in 62.0% of patients receiving Kisqali plus any combination.

Among the patients with advanced or metastatic breast cancer who had grade 2, 3 or 4 neutropenia, the median time to onset was 17 days, for those patients who had an event. The median time to resolution of grade ≥3 (to normalisation or grade <3) was 12 days in the Kisqali plus any combination arms following treatment interruption and/or reduction and/or discontinuation. Febrile neutropenia was reported in about 1.7% of patients exposed to Kisqali in the phase III studies. Treatment discontinuation due to neutropenia was low (0.8%) (see sections 4.2 and 4.4).

All patients should be instructed to report any fever promptly.

Hepatobiliary toxicity

In the phase III clinical studies in patients with early breast cancer and advanced or metastatic breast cancer, increases in transaminases were observed.

In the phase III study in patients with early breast cancer, hepatobiliary toxicity events occurred in a higher proportion of patients in the Kisqali plus AI arm versus the AI alone arm (26.4% versus 11.2%, respectively), with more grade 3/4 adverse events reported in patients treated with Kisqali plus AI (8.6% versus 1.7%, respectively). Concurrent elevations of 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 levels, occurred in 8 patients treated with Kisqali plus AI (in 6 patients ALT or AST levels recovered to normal within 65 to 303 days after discontinuation of Kisqali).

Dose interruptions due to hepatobiliary toxicity events were reported in 12.4% of patients with early breast cancer treated with Kisqali plus AI, primarily due to ALT increased (10.1%) and/or AST increased (6.8%). Dose adjustment due to hepatobiliary toxicity events was reported in 2.6% of patients treated with Kisqali plus AI, primarily due to ALT increased (1.9%) and/or AST increased (0.6%). Discontinuation of treatment with Kisqali due to abnormal liver function tests or hepatotoxicity occurred in 8.9% and 0.1% of patients, respectively (see sections 4.2 and 4.4).

In the phase III clinical study in patients with early breast cancer, 80.9% (165/204) 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 2.8 months for the Kisqali plus AI arm. The median time to resolution (to normalisation or grade ≤2) was 0.7 months in the Kisqali plus AI arm.

In the phase III clinical studies in patients with advanced or metastatic breast cancer, hepatobiliary toxicity events occurred in a higher proportion of patients in the Kisqali plus any combination arms compared with the placebo plus any combination arms (27.3% versus 19.6%, respectively), with more grade 3/4 adverse events reported in the patients treated with Kisqali plus any combination (13.2% versus 6.1%, respectively). Grade 3 or 4 increases in ALT (11.2% versus 1.7%) and AST (7.8% versus 2.1%) were reported in the Kisqali and placebo arms, respectively. Concurrent elevations in ALT or AST greater than three times the upper limit of normal and total bilirubin greater than two times the upper limit of normal, with normal alkaline phosphatase, in the absence of cholestasis occurred in 6 patients (4 patients in Study A2301 [MONALEESA-2], whose levels recovered to normal within 154 days and 2 patients in Study F2301 [MONALEESA-3], whose levels recovered to normal in 121 and 532 days, respectively, after discontinuation of Kisqali). There were no such cases reported in Study E2301 (MONALEESA-7).

Dose interruptions and/or adjustments due to hepatobiliary toxicity events were reported in 12.3% of Kisqali plus any combination treated patients with advanced or metastatic breast cancer, primarily due to ALT increased (7.9%) and/or AST increased (7.3%). Discontinuation of treatment with Kisqali plus any combination due to abnormal liver function tests or hepatotoxicity occurred in 2.4% and 0.3% of patients respectively (see sections 4.2 and 4.4).

In the phase III clinical studies in patients with advanced or metastatic breast cancer, 70.9% (90/127) 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 92 days for the Kisqali plus any combination arms. The median time to resolution (to normalisation or grade ≤2) was 21 days in the Kisqali plus any combination arms.

QT prolongation

In the phase III study in patients with early breast cancer, 5.3% of patients in the Kisqali plus AI arm and 1.4% of patients in the AI alone arm reported events of QT interval prolongation. In the Kisqali plus AI arm QT interval prolongation events were presented primarily by ECG QT prolonged (4.3%) which was the only confirmed adverse reaction with Kisqali. Dose interruptions due to ECG QT prolonged and syncope were reported in 1.1% of patients treated with Kisqali. Dose adjustments due to ECG QT prolonged were reported in 0.1% of patients treated with Kisqali.

A central analysis of ECG data showed 10 patients (0.4%) and 4 patients (0.2%) with at least one post-baseline QTcF interval >480 msec for the Kisqali plus AI arm and the AI alone arm, respectively. Among the patients who had QTcF interval prolongation of >480 msec in the Kisqali plus AI arm, the median time to onset was 15 days and these changes were reversible with dose interruption and/or dose adjustment. QTcF interval >60 msec change from baseline was observed in 19 patients (0.8%) in the Kisqali plus AI arm and post-baseline QTcF interval >500 msec was observed in 3 patients (0.1%) in the Kisqali plus AI arm.

In study E2301 (MONALEESA-7) in patients with advanced or metastatic breast cancer, the observed mean QTcF increase from baseline was approximately 10 msec higher in the tamoxifen plus placebo subgroup compared with the NSAI plus placebo subgroup, suggesting that tamoxifen alone had a QTcF prolongation effect which can contribute to the QTcF values observed in the Kisqali plus tamoxifen group. In the placebo arm, a QTcF interval increase of >60 msec from baseline occurred in 6/90 (6.7%) patients receiving tamoxifen and in no patients receiving a NSAI (see section 5.2). A QTcF interval increase of >60 msec from baseline was observed in 14/87 (16.1%) patients receiving Kisqali plus tamoxifen and in 18/245 (7.3%) patients receiving Kisqali plus a NSAI. Kisqali is not recommended to be used in combination with tamoxifen (see section 5.1).

In the phase III clinical studies 9.3% of patients with advanced or metastatic breast cancer in the Kisqali plus aromatase inhibitor or fulvestrant arms and 3.5% in the placebo plus aromatase inhibitor or fulvestrant arms had at least one event of QT interval prolongation (including ECG QT prolonged and syncope). Review of ECG data showed 15 patients (1.4%) had >500 msec post-baseline QTcF value, and 61 patients (5.8%) had a >60 msec increase from baseline in QTcF intervals. There were no reported cases of torsade de pointes. Dose interruptions/adjustments were reported in 2.9% of Kisqali plus aromatase inhibitor or fulvestrant treated patients due to electrocardiogram QT prolonged and syncope.

The analysis of ECG data showed 55 patients (5.2%) and 12 patients (1.5%) with at least one >480 msec post-baseline QTcF for the Kisqali plus 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).

Patients with renal impairment

In the phase III clinical study in patients with early breast cancer, 983 patients with mild renal impairment and 71 patients with moderate renal impairment were treated with ribociclib. No patient with severe renal impairment was enrolled (see section 5.1).

In the three pivotal studies, 341 patients with advanced or metastatic breast cancer with mild renal impairment and 97 patients with moderate renal impairment were treated with ribociclib. No patient with severe renal impairment was enrolled (see section 5.1). There was a correlation between the degree of renal impairment at baseline and blood creatinine values during the treatment. Slightly increased rates of QT prolongation and thrombocytopenia were observed in patients with mild or moderate renal impairment. For monitoring and dose adjustment recommendations for these toxicities see sections 4.2. and 4.4.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

There is only limited experience with reported cases of overdose 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 overdose as necessary.