KISQALI (ribociclib) has a consistent and generally manageable safety profile1–14
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.2,3
KISQALI is not recommended to be used in combination with tamoxifen2,3
Safety in MONALEESA-7 study
In MONALEESA-7, the majority of adverse events in pre- and perimenopausal HR+/HER2– aBC patients were generally manageable with dose modifications; few treatment discontinuations occurred due to adverse events.1,4,7,15
Subgroup analysis of all-causality adverse events in patients receiving NSAI
|KISQALI + NSAI + LHRH AGONIST
|PLACEBO + NSAI + LHRH AGONIST
|Dose reductions due to AEs, %||33||4|
|Discontinuations due to AEs, %||7||3|
|Any grade AEs observed in ≥20% of patients in the KISQALI arm, %||Neutropenia, 78.2; Arthralgia, 33.5; Hot flushes, 31.1; Nausea, 31.5; Leukopenia, 30.2; Fatigue, 23.4; Headache, 23.4; Alopecia, 20.6||
Neutropenia, 7.7; Arthralgia, 28.8; Hot flushes, 30.4; Nausea, 20.2; Leukopenia, 4.9; Fatigue, 25.1; Headache, 23.9; Alopecia, 13.4
|Most common grade 3 or 4 AEs (≥5%) in the KISQALI arm, %||
Neutropenia, 64.9; Leukopenia, 15.7*
|Neutropenia, 3.6; Leukopenia, 1.2|
Adapted from Bardia A, et al. 2018.7
MONALEESA-7: N=672, double-blind, placebo-controlled, 1:1 randomisation, phase III trial in pre- and perimenopausal women with HR+/HER2− aBC. As 1L in advanced disease and in patients who received 1 or fewer lines of chemotherapy for aBC. KISQALI 600 mg or placebo orally once daily (3 weeks on/1 week off) + NSAI (letrozole 2.5 mg or anastrozole 1 mg) or tamoxifen 20 mg orally once daily continuously + LHRH agonist (goserelin 3.6 mg subcutaneously on day 1 of every cycle).1–3 The primary endpoint was investigator-assessed progression-free survival. The key secondary endpoint was overall survival, defined as the time from randomisation to death from any cause. The other secondary endpoints included: proportion of patients who achieved an objective response, clinical benefit, time to response, duration of response, time to definitive deterioration of ECOG performance status from baseline, time to 10% deterioration of EORTC QLQ-C30 and safety.1,4
*In the MONALEESA-7 full safety set, grade 3/4 increased ALT was reported in 5% of patients.4
Few premenopausal HR+/HER2− aBC patients discontinued treatment because of adverse events in MONALEESA-74
The most common reasons for discontinuation of any component of study treatment owing to adverse events suspected to be related to study treatment in all patients in the Kisqali arm (which included NSAI or tamoxifen combination + LHRH agonist) is shown in the table.4
KISQALI is not recommended for use with tamoxifen.2,3
|KISQALI + ET + LHRH AGONIST
|PLACEBO + ET + LHRH AGONIST
|Alanine aminotransferase increased, % (n)||2.1 (7)||0.0 (0)|
|Aspartate aminotransferase increased, % (n)||1.2 (4)||0.3 (1)|
|Drug-induced liver injury, % (n)||0.9 (3)||0.3 (1)|
|Prolonged QTcF, % (n)||0.3 (1)||0.6 (2)|
Adapted from Tripathy D, et al. 2018.4
KISQALI + letrozole was generally well tolerated, with neutropenia and leukopenia the most common grade 3/4 AEs.*8
|KISQALI + letrozole
|PLACEBO + letrozole
|Dose reductions due to AEs, % (n)||54.5 (182)||4.2 (14)|
|Discontinuations due to AEs, % (n)||8.1 (27)||2.4 (8)|
|Any grade AEs observed in ≥20% of patients in the KISQALI arm, %||Neutropenia, 76.9; Nausea, 53.3; Fatigue, 41.3; Diarrhoea, 38.3; Alopecia, 34.4; Vomiting, 33.5; Arthralgia, 33.2; Leukopenia, 32.9; Constipation, 27.8; Headache, 26.9; Hot flushes, 24.6; Back pain, 24.3; Cough, 23.1; Rash, 22.2; Anaemia, 21.3; Decreased appetite, 20.7; Abnormal LFTs, 20.1||
Neutropenia, 5.8; Nausea, 30.6; Fatigue, 32.4; Diarrhoea, 24.5; Alopecia, 16.1; Vomiting, 16.7; Arthralgia, 32.7; Leukopenia, 4.5; Constipation, 21.5; Headache, 20.9; Hot flushes, 25.5; Back pain, 20.3; Cough, 21.2; Rash, 8.8; Anaemia, 5.8; Decreased appetite, 15.8; Abnormal LFTs, 6.4
|Most common grade 3 or 4 AEs (≥5%) in the KISQALI arm, %||Neutropenia, 62.0; Leukopenia, 21.3; Abnormal LFTs, 10.2||Neutropenia, 1.2; Leukopenia, 0.9; Abnormal LFTs, 2.4|
Adapted from Hortobagyi GN, et al. 2018.8
In the MONALEESA-2 protocol-specified final analysis of overall survival, no new safety signals were observed at a median follow-up of 6.6 years.13
MONALEESA-2: N=668, double-blind, placebo-controlled, 1:1 randomisation, multicentre, phase III trial in postmenopausal women with HR+/HER2− aBC. As 1L in advanced disease and no prior endocrine therapy for aBC. KISQALI 600 mg or placebo orally once daily (3 weeks on/1 week off) + AI (letrozole 2.5 mg continuous).8,9 The primary endpoint was locally assessed progression-free survival and the key secondary endpoint was overall survival. Other secondary endpoints included the overall response rate (complete or partial response), the clinical benefit rate (overall response plus stable disease lasting 24 weeks or more), safety, and quality-of-life assessments.9
*Results from a second interim analysis at a median duration of follow-up of 26.4 months.8
The most frequent AEs in postmenopausal HR+/HER2− aBC patients in MONALEESA-3 were neutropenia, nausea and fatigue*10
|KISQALI + FULVESTRANT
|PLACEBO + FULVESTRANT
|Dose reductions due to AEs, % (n)||33.1 (160)||3.3 (8)|
|Discontinuations due to AEs, % (n)||8.5 (41)||4.1 (10)|
|Any grade AEs observed in ≥20% of patients in the KISQALI arm, %||Neutropenia, 69.6; Nausea, 45.3; Fatigue, 31.5; Diarrhoea, 29.0; Leukopenia, 28.4; Vomiting, 26.7; Constipation, 24.8; Arthralgia, 24.0; Cough, 21.7; Headache, 21.5||
Neutropenia, 2.1; Nausea, 28.2; Fatigue, 33.2; Diarrhoea, 20.3; Leukopenia, 1.7; Vomiting, 12.9; Constipation, 11.6; Arthralgia, 26.6; Cough, 15.4; Headache, 20.3
|Most common grade 3 or 4 AEs (≥5%) in the KISQALI arm, %||Neutropenia, 53.4; Leukopenia, 14.1||Neutropenia, 0; Leukopenia, 0|
Adapted from Slamon DJ, et al. 2018.10
In a MONALEESA-3 exploratory analysis, there were no new safety signals detected at a median follow-up of ~4.5 years in HR+/HER2− postmenopausal women with aBC treated with KISQALI + fulvestrant.11
MONALEESA-3: N=726, double-blind, placebo-controlled, 2:1 randomisation, phase III trial. As 1L and 2L in advanced disease plus those with early relapse in postmenopausal women with HR+/HER2− aBC. KISQALI 600 mg or placebo orally once daily (3 weeks on/1 week off) + 500 mg fulvestrant (administered intramuscularly on Day 1 of each 28-day cycle, with an additional dose on Day 15 of cycle 1).10,11 The primary endpoint was locally assessed progression-free survival. Secondary endpoints included overall survival (OS), overall response rate (ORR), clinical benefit rate, and safety and tolerability.9 Analyses were performed in the following subgroups:10,12
- Patients receiving 1L therapy
- Patients receiving 2L therapy plus those with early relapse (within 12 months after completion of adjuvant or neoadjuvant endocrine therapy)
* Results from first interim analysis. Median time from random assignment to data cutoff was 20.4 months.10
The MONALEESA safety findings were supported by evidence from the CompLEEment-1 study – the largest phase IIIb CDK4/6 inhibitor trial in aBC to date†5,6
The CompLEEMent-1 study patient population included 1.2% male participants.5 KISQALI is not licensed for use in men.2,3
|KISQALI + LETROZOLE ± LHRH agonist
|Dose reductions due to AEs, %||AEs leading to dose adjustment/interruption 2,434 (75.0)|
Discontinuations due to treatment-related AEs, %
|AEs of special interest leading to dose reduction, %||Neutropenia, 18.4; ALT Increase, 1.5, AST increase, 0.9, QTcF prolongation, 0.6|
|Most common AEs observed in ≥20% of patients, %||
Neutropenia, 61.1; Nausea, 35.9; Fatigue, 23.4
|Grade 3 or 4 haematologic abnormalities and biochemical abnormalities (>5.0%), %||Decreased neutrophils, 54.8; Decreased leukocytes, 25.9; Decreased lymphocytes, 12.6; Increased ALT, 9.1; Increased AST, 6.7|
Adapted from De Laurentiis M, et al. 2020.5
CompLEEment-1: N=3246, Phase IIIb, open-label study in men* and women (any menopausal status) with HR+/HER2- aBC. In 1L setting for advanced disease. 1 line of prior CT therapy permitted for aBC. Patients received KISQALI 600 mg once daily (3 weeks on/1 week off) + letrozole 2.5 mg once daily. Men* and premenopausal women received concomitant goserelin (3.6 mg subcutaneous implant every 28 days). Primary endpoints were safety and tolerability.5,6 Secondary endpoints included time to progression, ORR, CBR and patient reported outcomes.16
*KISQALI is not licensed for use in men.2,3
†Mean duration of follow-up was 25.4 months.
Hypersensitivity to the active substance or to peanut, soya or any of the excipients listed in section 6.1 of the Summary of Product Characteristics.2,3
Special warnings and precautions
Critical visceral disease
The efficacy and safety of ribociclib have not been studied in patients with critical visceral disease.2,3
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 of the Summary of Product Characteristics).2,3
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 of the Summary of Product Characteristics).
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 of the Summary of Product Characteristics). Recommendations for patients who have elevated AST/ALT grade ≥ 3 at baseline have not been established.2,3
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 of the Summary of Product Characteristics).2,3
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 of the Summary of Product Characteristics).2,3
Appropriate monitoring of serum electrolytes (including potassium, calcium, phosphorus and magnesium) should be performed before initiating treatment, at the beginning of the first 6 cycles and then as clinically indicated. Any abnormality should be corrected before initiating treatment with KISQALI and during treatment with KISQALI.2,3
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:2,3
- 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 of the Summary of Product Characteristics). 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 of the Summary of Product Characteristics).2,3
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 of the Summary of Product Characteristics).2,3
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.2,3
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 of the Summary of Product Characteristics).2,3
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 of the Summary of Product Characteristics).2,3
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 of the Summary of Product Characteristics). 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.2,3
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 of the Summary of Product Characteristics). 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.2,3
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 in 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 of the Summary of Product Characteristics).2,3
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 of the Summary of Product Characteristics).2,3
KISQALI contains soya lecithin. Patients who are hypersensitive to peanut or soya should not take KISQALI (see section 4.3 of the Summary of Product Characteristics).2,3
Substances that may increase KISQALI plasma concentrations2,3
KISQALI is primarily metabolised by CYP3A4. Therefore, medicinal products that can influence CYP3A4 enzyme activity may alter the pharmacokinetics of KISQALI. Co-administration of the strong CYP3A4 inhibitor ritonavir (100 mg twice daily for 14 days) with a single 400 mg dose of KISQALI increased KISQALI exposure (AUCinf) and the peak concentration (Cmax) in healthy subjects 3.2 and 1.7-fold, respectively, relative to a single 400 mg KISQALI dose given alone. Cmax and AUClast for LEQ803 (a prominent metabolite of KISQALI 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. Alternative concomitant medicinal products with less potential to inhibit CYP3A4 should be considered and patients should be monitored for KISQALI-related ARs.
If co-administration of Kisqali with a strong CYP3A4 inhibitor cannot be avoided, the dose of KISQALI should be reduced. 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 KISQALI-related ARs is recommended. In the event of KISQALI-related toxicity, the dose should be modified or treatment should be interrupted until toxicity is resolved. 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 KISQALI, a moderate CYP3A4 inhibitor (erythromycin) may increase KISQALI steady-state Cmax and AUC 1.2-fold and 1.3-fold, respectively. For patients who had their KISQALI 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 KISQALI are required at initiation of treatment with mild or moderate CYP3A4 inhibitors. However, monitoring of KISQALI-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 KISQALI.
Substances that may decrease KISQALI plasma concentrations2,3
Co-administration of the strong CYP3A4 inducer rifampicin (600 mg daily for 14 days) with a single 600 mg dose of KISQALI decreased the KISQALI AUCinf and Cmax by 89% and 81%, respectively, relative to a single 600 mg KISQALI 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 KISQALI exposure has not been studied. Physiologically-based pharmacokinetic simulations suggested that a moderate CYP3A4 inducer (efavirenz) may decrease steady-state KISQALI 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 KISQALI at 400 mg or 200 mg once daily.
Substances that may have plasma concentrations altered by KISQALI2,3
KISQALI 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 KISQALI 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. 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 KISQALI can increase their exposure.
Concomitant administration of KISQALI 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 KISQALI on CYP1A2 substrates (<2-fold increase in AUC).
Substances that are substrates of transporters2,3
In vitro evaluations indicated that KISQALI 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.
KISQALI can be administered with or without food.
Medicinal products that elevate gastric pH2,3
KISQALI exhibits high solubility at or below pH 4.5 and in bio-relevant media (at pH 5.0 and 6.5). Co-administration of KISQALI with medicinal products that elevate the gastric pH was not evaluated in a clinical study; however, altered KISQALI absorption was not observed in population pharmacokinetic and non–compartmental pharmacokinetic analyses.
Drug-drug interaction between KISQALI and letrozole2,3
Data from a clinical study in patients with breast cancer and population pharmacokinetic analysis indicated no drug interaction between KISQALI and letrozole following co-administration of these medicinal products.
Drug-drug interaction between KISQALI and anastrozole2,3
Data from a clinical study in patients with breast cancer indicated no clinically relevant drug interaction between KISQALI and anastrozole following co-administration of these medicinal products.
Drug-drug interaction between KISQALI and fulvestrant2,3
Data from a clinical study in patients with breast cancer indicated no clinically relevant effects of fulvestrant on KISQALI exposure following co-administration of these medicinal products.
Drug-drug interaction between KISQALI and tamoxifen2,3
Data from a clinical study in patients with breast cancer indicated that tamoxifen exposure was increased approximately 2-fold following co-administration of KISQALI and tamoxifen.
Drug-drug interactions between KISQALI and oral contraceptives2,3
Drug-drug interaction studies between KISQALI and oral contraceptives have not been conducted.
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. KISQALI is also not recommended to be used in combination with tamoxifen.
Women of childbearing potential/Contraception2,3
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.
There are no adequate and well-controlled studies in pregnant women. Based on findings in animals, KISQALI can cause foetal harm when administered to a pregnant woman. KISQALI is not recommended during pregnancy and in women of childbearing potential not using contraception.
It is not known if KISQALI is present in human milk. There are no data on the effects of KISQALI on the breast-fed infant or the effects of KISQALI on milk production. KISQALI 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.
There are no clinical data available regarding effects of KISQALI on fertility. Based on animal studies, KISQALI may impair fertility in males of reproductive potential.
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.2,3
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.2,3
Adverse reactions from the Phase III clinical studies (below) 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).2,3
For information on how to manage select adverse reactions, please refer to the Dosing & Monitoring page of the KISQALI Summary of Product Characteristics.2,3
Adverse reactions observed in the three phase III clinical studies and during post-marketing experience.2,3
|Infections and infestations|
|Blood and lymphatic system disorders|
|Neutropenia, leukopenia, anaemia, lymphopenia
Thrombocytopenia, febrile neutropenia
|Metabolism and nutrition disorders|
Hypocalcaemia, hypokalaemia, hypophosphataemia
|Nervous system disorders|
|Lacrimation increased, dry eye||Common|
|Respiratory, thoracic and mediastinal disorders|
Interstitial lung disease (ILD)/pneumonitis*
|Nausea, diarrhoea, vomiting, constipation, abdominal pain,2 stomatitis, dyspepsia
|Skin and subcutaneous tissue disorders|
|Alopecia, rash,4 pruritus
Dry skin, erythema, vitiligo
Toxic epidermal necrolysis (TEN)*
|Musculoskeletal and connective tissue disorders|
|Back pain||Very common|
|General disorders and administration site conditions|
|Fatigue, peripheral oedema, pyrexia, asthenia
Oropharyngeal pain, dry mouth
|Abnormal liver function tests5
Blood creatinine increased, electrocardiogram QT prolonged
|*Adverse reaction reported during post-marketing experience.
1Infections: urinary tract infections, respiratory tract infections, gastroenteritis, sepsis (<1%).
2Abdominal pain: abdominal pain, abdominal pain upper.
3Hepatotoxicity: hepatic cytolysis, hepatocellular injury, drug -induced liver injury (<1%), hepatotoxicity, hepatic failure, autoimmune hepatitis (single case).
4Rash: rash, rash maculopapular, rash pruritic.
5Abnormal liver function tests: ALT increased, AST increased, blood bilirubin increased.
1L, first line; 2L, second line; aBC, advanced breast cancer; AE, adverse event; AI, aromatase inhibitor; ALT, alanine aminotransferase; AST, aspartate aminotransferase; AUC, area under curve; AUCinf, area under curve from zero to infinity; CBR, clinical benefit rate; CDK4/6, cyclin-dependent kinase 4 and 6; Cmax, maximum concentration; CT, chemotherapy; CYP3A4, cytochrome P450 3A4; ECOG, Eastern Cooperative Oncology Group; EORTC QLQ-C30, European Organisation for Research and Treatment of Cancer Core 30 Quality of Life questionnaire; ET, endocrine therapy; GB, Great Britain; HR+/HER2–, hormone receptor-positive/human epidermal growth factor receptor 2-negative; LFT, liver function test; LHRH, luteinising hormone-releasing hormone; NI, Northern Ireland; NSAI, nonsteroidal aromatase inhibitor; ORR, overall response rate; QTcF, QT interval corrected for Fridericia’s formula.
- Im S-A, et al. N Engl J Med. 2019;381(4):307–316.
- KISQALI (ribociclib). Summary of Product Characteristics, Great Britain; September 2023.
- KISQALI (ribociclib). Summary of Product Characteristics, Northern Ireland; June 2023.
- Tripathy D, et al. Lancet Oncol. 2018;19(7):904–915.
- De Laurentiis M, et al. J Clin Oncol. 2020;38(15):1055–1055.
- De Laurentiis M, et al. J Clin Oncol. 2018;36(15):1056–1056.
- Bardia A, et al. Poster 330P. Presentation at European Society for Medical Oncology Congress, 19–23 October, 2018, Munich, Germany.
- Hortobagyi GN, et al. Ann Oncol. 2018;29(7):1541–1547.
- Hortobagyi GN, et al. N Engl J Med. 2016;375(18):1738–1748.
- Slamon DJ, et al. J Clin Oncol. 2018;36(24):2465–2472.
- Slamon DJ, et al. Presented at ASCO Annual Meeting, 4–8 June 2021.
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