Regulatory Affairs
KISQALI® (ribociclib) 200 mg Film-coated tablets
National Succinct Statement (NSS)
Version 3.2
Effective date: 22-Jan-2024
Safety Label Change
(SLC) Tracking number: 2023-PSB/GLC-1396-s
Document status: Final
Property of Novartis
Confidential
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis
KISQALI®
Important note: Before prescribing, consult full prescribing information. US: https://www.fda.gov/
Disclaimer: This link will contain the most updated product information approved by the reference country.
Presentation: Film-coated tablets containing 200 mg of ribociclib.
Indications:
Early Breast Cancer
KISQALI is indicated in combination with an aromatase inhibitor for the adjuvant treatment of adults with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative stage II and III early breast cancer at high risk of recurrence.
Advanced or Metastatic Breast Cancer
KISQALI is indicated for the treatment of adults with HR-positive, HER2-negative advanced or metastatic breast cancer in combination with:
• an aromatase inhibitor as initial endocrine-based therapy; or
• fulvestrant as initial endocrine-based therapy or following disease progression on endocrine therapy.
Dosage and administration:
Recommended Dosage
Important Administration Instructions
KISQALI can be taken with or without food [see Clinical Pharmacology (12.3)].
Pre/perimenopausal women, or men, treated with the combination KISQALI plus an aromatase inhibitor or fulvestrant, should be treated with a luteinizing hormone-releasing hormone (LHRH) agonist according to current clinical practice standards.
Patients should take their dose of KISQALI at approximately the same time each day, preferably in the morning.
If the patient vomits after taking the dose, or misses a dose, no additional dose should be taken that day. The next prescribed dose should be taken at the usual time. KISQALI tablets should be swallowed whole (tablets should not be chewed, crushed or split prior to swallowing). No tablet should be ingested if it is broken, cracked, or otherwise not intact.
Early Breast Cancer
The recommended dosage of KISQALI is 400 mg (two 200 mg film-coated tablets) taken orally, once daily for 21 consecutive days followed by 7 days off in 28-day treatment cycles. KISQALI should be given in combination with an aromatase inhibitor. Refer to the Full Prescribing Information for the recommended dosage of the aromatase inhibitor.
In patients with early breast cancer, treatment with KISQALI should continue for 3 years or until disease recurrence or unacceptable toxicity occurs.
Advanced or Metastatic Breast Cancer
The recommended dosage of KISQALI is 600 mg (three 200 mg film-coated tablets) taken orally, once daily for 21 consecutive days followed by 7 days off in 28-day treatment cycles. KISQALI should be given in combination with endocrine therapy (fulvestrant or an aromatase inhibitor). Refer to the Full Prescribing Information for the recommended dose of endocrine therapy.
Dose Modifications
Dose Modifications for Adverse Reactions
The recommended dose modifications for adverse reactions are listed in Table 1.
Table 1: Recommended Dose Modification for Adverse Reactions
|
Level |
KISQALI |
|
|
|
Dose |
Number of tablets |
|
Early breast cancer |
|
|
|
Starting dose |
400 mg/day |
two 200 mg tablets |
|
Dose reduction |
200 mg/day* |
one 200 mg tablet |
|
Advanced or metastatic breast cancer |
||
|
Starting dose |
600 mg/day |
three 200 mg tablets |
|
First dose reduction |
400 mg/day |
two 200 mg tablets |
|
Second dose reduction |
200 mg/day* |
one 200 mg tablet |
|
*If dose reduction below 200 mg/day is required, discontinue KISQALI. |
||
Tables 2, 3, 4, 5, 6, and 7 summarize recommendations for dose interruption, reduction, or discontinuation of KISQALI in the management of specific adverse reactions. Dose modification of KISQALI is recommended based on individual patient safety and tolerability.
Table 2: Dose Modification and Management for Interstitial Lung Disease/Pneumonitis
|
|
Grade 1 (asymptomatic) |
Grade 2 (symptomatic) |
Grade 3 (severe symptomatic) or 4 (life- threatening) |
|
ILD/Pneumonitis [see Warnings and Precautions (5.1)] |
No dose interruption or adjustment is required. Initiate appropriate medical therapy and monitor as clinically indicated. |
Dose interruption until recovery to Grade ≤ 1 then consider resuming KISQALI at the next lower dose level*. If Grade 2 recurs, discontinue KISQALI. |
Discontinue KISQALI. |
|
Abbreviation: ILD, interstitial lung disease. Grading according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. *An individualized benefit-risk assessment should be performed when considering resuming KISQALI. |
|||
Table 3: Dose Modification and Management for Cutaneous Adverse Reactions, Including SCARs
Cutaneous adverse reactions, including SCARs[see Warnings and Precautions (5.2)] |
Grade 1(< 10% body surface area (BSA) with active skin toxicity, no signs of systemic involvement) |
Grade 2(10%-30% BSA with active skin toxicity, no signs of systemic involvement) |
Grade 3(severe rash not responsive to medical management; > 30% BSA with active skin toxicity, signs of systemic involvement present; SJS*) |
Grade 4(any % BSA associated with extensive superinfection, with IV antibiotics indicated; life threatening consequences; TEN**) |
|
No dose adjustment is required.
Initiate appropriate medical therapy and monitor as clinically indicated. |
Interrupt KISQALI until the etiology of the reaction has been determined. If the etiology is a SCAR, permanently discontinue KISQALI. If the etiology is not a SCAR, interrupt dose until recovery to Grade ≤ 1, then resume KISQALI at same dose level. If the cutaneous adverse reaction still recurs at Grade 3, resume KISQALI at the next lower dose level. |
Permanently discontinue KISQALI. |
||
|
Abbreviations: BSA, body surface area; SCARs, severe cutaneous adverse reactions; SJS, Stevens-Johnson syndrome; TEN, toxic epidermal necrolysis. |
||||
|
**TEN (Grade 4) is defined as skin sloughing covering ≥ 30% BSA with associated symptoms (e.g., erythema, purpura, epidermal detachment, and mucous membrane detachment). |
||||
Table 4: Dose Modification and Management for QT Prolongation
|
QTcF* prolongation |
Early breast cancer |
Advanced or metastatic breast cancer |
|
> 480 ms and ≤ 500 ms |
Interrupt KISQALI treatment and wait until QTcF resolves to < 480 ms |
|
|
Resume at the same dose |
Reduce to the next lower dose level |
|
|
If QTcF > 480 ms recurs, interrupt KISQALI treatment and wait until QTcF resolves to < 480 ms, then resume at next lower dose level. |
||
|
> 500 ms |
Interrupt KISQALI treatment and wait until QTcF resolves to < 480 ms, then resume at next lower dose level. If QTcF > 500 ms recurs, discontinue KISQALI. |
|
|
Permanently discontinue KISQALI if QTcF interval prolongation is either > 500 ms or > 60 ms change from baseline AND associated with any of the following: Torsades de Pointes, polymorphic ventricular tachycardia, syncope, or signs/symptoms of serious arrhythmia. |
||
|
Note: If dose reduction below 200 mg/day is required, discontinue KISQALI. Electrocardiograms (ECGs) should be assessed prior to initiation of treatment in all patients. Repeat ECGs at approximately Day 14 of the first cycle, and as clinically indicated.In case of QTcF prolongation at any given time during treatment, monitor ECG more frequently, and as clinically indicated |
||
Table 5: Dose Modification and Management for 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 [see Warnings and Precautions (5.5)] |
No dose adjustment is required. |
Baseline* at < 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 until recovery to ≤ baseline* grade, then resume at next lower dose level. If Grade 3 recurs, discontinue KISQALI. |
Discontinue KISQALI. |
|
|
Baseline* at Grade 2: No dose interruption. |
|||
|
Combined elevations in AST and/or ALT WITH total bilirubin increase, in the absence of cholestasis [see Warnings and Precautions (5.5)] |
If patients develop ALT and/or AST > 3 x ULN along with total bilirubin > 2 x ULN irrespective of baseline grade, discontinue KISQALI. |
|||
|
Perform Liver Function Tests (LFTs) before initiating treatment with KISQALI.
Monitor LFTs every 2 weeks for the first 2 cycles, at the beginning of each subsequent 4 cycles, and as clinically indicated.
If Grade ≥ 2 abnormalities are noted, monitor more frequently, and as clinically indicated.
|
||||
|
Abbreviations: AST, aspartate aminotransferase; ALT, alanine aminotransferase; ULN, upper limit of normal.
*Baseline = prior to treatment initiation. Grading according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.
|
||||
Table 6: Dose Modification and Management for 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 [see Warnings and Precautions (5.6)] |
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, then resume KISQALI at the next lower dose level. |
Dose interruption until recovery of neutropenia to Grade ≤ 2. Resume KISQALI at the next lower dose level. |
Dose interruption until recovery to Grade ≤ 2. Resume KISQALI at the next lower dose level. |
|
Perform complete blood counts (CBCs) before initiating treatment with KISQALI.
Monitor CBC every 2 weeks for the first 2 cycles, at the beginning of each subsequent 4 cycles, and as clinically indicated.
|
||||
|
Abbreviations: ANC, absolute neutrophil count; LLN, lower limit of normal.
*Grade 3 neutropenia with single episode of fever > 38.3°C (or) 38°C or above for more than one hour and/or concurrent infection.
Grading according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.
|
||||
Table 7: Dose Modification and Management for 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 same dose level. If Grade 3 recurs, resume KISQALI at the next lower dose level. |
Discontinue KISQALI |
|
|
*Excluding interstitial lung disease (ILD)/pneumonitis, cutaneous adverse reactions, including severe cutaneous adverse reactions (SCARs), QT interval prolongation, hepatobiliary toxicity, and neutropenia. Grading according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. |
|||
Refer to the Full Prescribing Information for the coadministered aromatase inhibitor or fulvestrant for dose modification guidelines in the event of toxicity and other relevant safety information.
Dose Modification for Use with Strong CYP3A Inhibitors
Avoid concomitant use of KISQALI with strong CYP3A inhibitors and consider an alternative concomitant medication with less potential for CYP3A inhibition [see Drug Interactions (7.1)].
If a strong CYP3A inhibitor must be coadministered, reduce the KISQALI dose as shown in Table 8.
Table 8: Dose Modification for Use with Strong CYP3A Inhibitors
|
Indication |
Co-administration with Strong CYP3A Inhibitors |
|
Early breast cancer |
Reduce the KISQALI dose to 200 mg once daily. |
|
Advanced or metastatic breast cancer |
Reduce the KISQALI dose to 400 mg once daily. |
If the strong inhibitor is discontinued, change the KISQALI dose (after at least 5 half-lives of the strong CYP3A inhibitor) to the dose used prior to the initiation of the strong CYP3A inhibitor [see Drug Interactions (7.1), Clinical Pharmacology (12.3)].
Dose Modification for Hepatic Impairment
The recommended dose modifications for patients with hepatic impairment are shown in Table 9 [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)].
Table 9: Dose Modification for Hepatic Impairment
|
Indication |
Mild hepatic impairment (Child-Pugh class A) |
Moderate and severe hepatic impairment (Child-Pugh class B or C) |
|
Early breast cancer |
No dose adjustment is necessary |
No dose adjustment is necessary |
|
Advanced or metastatic breast cancer |
No dose adjustment is necessary |
KISQALI 400 mg once daily |
Review the Full Prescribing Information for the co-administered aromatase inhibitor or fulvestrant for dose modifications related to hepatic impairment.
Dose Modification for Severe Renal Impairment
The recommended starting dose is 200 mg KISQALI once daily for patients with severe renal impairment [see Use in Specific Populations (8.7), Clinical Pharmacology (12.3)]..
Contraindications: ♦Hypersensitivity to ribociclib or to any excipient.
Warnings and precautions:
♦Neutropenia was the most frequently reported ADR with Kisqali. Febrile neutropenia reported in 0.3% patients with eBC on Kisqali in phase III clinical study and in 1.7% patients with a/mBC on Kisqali in phase III clinical studies. Based on the severity, of neutropenia, Kisqali may require dose interruption, reduction, or discontinuation. A complete blood count should be performed before initiating therapy and should be monitored every 2 weeks for the first 2 cycles, at the beginning of each of the subsequent 4 cycles and then as clinically indicated. ♦Increases in ALT and AST have been reported, the majority of without concurrent elevations of bilirubin. Liver function tests should be performed before initiating therapy with Kisqali. LFTs should be monitored every 2 weeks for the first 2 cycles at the beginning of each of the subsequent 4 cycles and then as clinically indicated. Based on the severity of transaminase elevations, Kisqali may require dose interruption, reduction, or discontinuation. ♦QT interval prolongation has been reported with Kisqali. Kisqali should not be used in patients with a significant risk of QTc interval prolongation. The ECG should be assessed prior treatment. Treatment with Kisqali should be initiated only in patients with QTcF values <450 ms. ECG should be repeated at approximately Day 14 of the first cycle, and then as clinically indicated. Monitoring of serum electrolytes including potassium, calcium, phosphorous, and magnesium should be performed prior to treatment initiation, at the beginning of the first 6 cycles and then as clinically indicated. Abnormalities should be corrected before the start of Kisqali therapy. Based on observed QT prolongation during treatment, Kisqali may require dose interruption, reduction, or discontinuation. Kisqali is not recommended in combination with tamoxifen.
♦Severe cutaneous reactions: Severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug-induced hypersensitivity syndrome (DiHS)/drug reaction with eosinophilia and systemic symptoms (DRESS) can occur in patients treated with KISQALI. If signs and symptoms suggestive of severe cutaneous reactions appear, Kisqali should be immediately and permanently discontinued.
♦Interstitial lung disease (ILD) / Pneumonitis: ILD/pneumonitis has been reported with CDK4/6 inhibitors including Kisqali. Patients should be monitored for pulmonary symptoms indicative of ILD/pneumonitis. Based on the severity, patients may require treatment interruption, dose reduction, or permanent discontinuation.
♦Hepatotoxicity In patients with early and advanced or metastatic breast cancer, drug-induced liver injury and increases in transaminases occurred with KISQALI.
In patients with early breast cancer (NATALEE) treated with KISQALI, drug-induced liver injury was reported in 9 patients (0.4%), of which 5 were Grade ≥ 3, and 8 had resolved as of the data cutoff. There were 8 (0.3%) clinically confirmed Hy’s Law cases (including 4 out of 9 drug-induced liver injury mentioned above), 6 of which had resolved within 303 days and 2 of which were improving, all after discontinuation of KISQALI. Grade 3 or 4 increases in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) occurred in 8% and 4.7% respectively; including Grade 4 increases in ALT (1.5%) and AST (0.8%).
In patients with advanced or metastatic breast cancer (MONALEESA-2, MONALEESA-7 and MONALEESA-3) treated with KISQALI Grade 3 or 4 increases in ALT and AST occurred in 11% and 8%, respectively. Among the patients who had Grade ≥ 3 ALT/AST elevation, the median time-to-onset was 92 days for the KISQALI plus aromatase inhibitor or fulvestrant treatment arms. The median time to resolution to Grade ≤ 2 was 21 days in the KISQALI plus aromatase inhibitor or fulvestrant treatment arms. In MONALEESA-2 and MONALEESA-3, concurrent elevations in ALT or AST greater than three times the ULN and total bilirubin greater than two times the ULN, with normal alkaline phosphatase, in the absence of cholestasis (Hy’s Law) occurred in 6 (1%) patients and all patients recovered after discontinuation of KISQALI.
Perform liver function tests (LFTs) in all patients before initiating KISQALI. Monitor LFTs every 2 weeks for first 2 cycles, at the beginning of each of the subsequent 4 cycles, and as clinically indicated.
Based on the severity of the transaminase elevations, KISQALI may require dose interruption, reduction, or discontinuation as described in Table 5 (Dose Modification and Management for Hepatobiliary Toxicity).
♦Embryo-Fetal Toxicity Based on findings from animal studies and the mechanism of action, KISQALI can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of ribociclib to pregnant rats and rabbits during organogenesis caused embryo-fetal toxicities at maternal exposures that were 0.6 and 1.5 times the human clinical exposure, respectively, based on area under the curve (AUC). Advise pregnant women of the potential risk to a fetus. Advise women of reproductive potential to use effective contraception during therapy with KISQALI and for at least 3 weeks after the last dose
Pregnancy, lactation, females and males of reproductive potential:
Pregnancy: Kisqali may cause fetal harm when administered to a pregnant woman. Patient should be advised of the risk to a fetus if Kisqali is used during pregnancy or if patient becomes pregnant while taking Kisqali.
Lactation: A decision to discontinue either Kisqali or nursing should be made taking into account the importance of Kisqali to the mother. Do not breastfeed while taking Kisqali and for at least 21 days after the last dose of Kisqali.
Females and males of reproductive potential: ♦Pregnancy testing: For females of reproductive potential pregnancy status should be verified prior to initiating treatment with Kisqali. ♦Contraception: Sexually active females of reproductive potential should use effective contraception (methods that result in < 1 % pregnancy rates) when using Kisqali during treatment and for 21 days after discontinuation. ♦Infertility: Impairment of fertility in males of reproductive potential indicated in animal studies.
Adverse drug reactions:
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The data described in WARNINGS AND PRECAUTIONS reflect exposure to KISQALI plus non-steroidal aromatase inhibitor (NSAI) in 2526 patients with early breast cancer (NATALEE), of whom 51% completed 36 months of KISQALI treatment. The most common (≥ 20%) adverse reactions, including laboratory abnormalities, were lymphocytes decreased (97%), leukocytes decreased (95%), neutrophils decreased (94%), hemoglobin decreased (47%), alanine aminotransferase increased (45%), aspartate aminotransferase increased (44%), infections (37%), creatinine increased (33%), platelets decreased (28%), headache (23%), nausea (23%), and fatigue (22%).
In addition, the pooled safety population described in the WARNINGS AND PRECAUTIONS reflects exposure to KISQALI in 1065 patients with advanced or metastatic breast cancer (MONALEESA-2, MONALEESA-3, MONALEESA-7), of whom 76% were exposed for 6 months or longer, and 62% were exposed for greater than one year. The most common (≥ 20%) adverse reactions, including laboratory abnormalities, were leukocytes decreased (95%), neutrophils decreased (93%), hemoglobin decreased (68%), lymphocytes decreased (66%), aspartate aminotransferase increased (55%), gamma-glutamyl transferase increased (53%), alanine aminotransferase increased (52%), infections (47%), nausea (47%),
creatinine increased (42%), fatigue (35%), platelets decreased (34%), diarrhea (33%),
vomiting (29%), headache (27%), constipation (25%), alopecia (25%), cough (24%), rash
(24%), back pain (24%), and glucose serum decreased (20%).
Interactions: ♦Concomitant use of strong CYP3A inhibitors should be avoided. Alternative medications with less potential to inhibit CYP3A should be considered. Patients should be monitored for ADRs. eBC: If concomitant use of a strong CYP3A inhibitor cannot be avoided, patients should be monitored for adverse reactions and, if necessary, a reduction of Kisqali dose to 200 mg should be considered. a/mBC: If concomitant use of a strong CYP3A inhibitor cannot be avoided, the Kisqali dose should be reduced to 400 mg. Grapefruit or grapefruit juice should be avoided. ♦Concomitant use of strong CYP3A inducers should be avoided. Alternative medications with no or minimal potential to induce CYP3A should be considered. ♦Caution is advised when Kisqali is co-administered with CYP3A substrates with narrow therapeutic index; their dose may need to be reduced. ♦Co-administration of Kisqali with medications with known potential to prolong the QT interval should be avoided. Kisqali is not recommended for use in combination with tamoxifen.
Packs and prices: Country-specific.
Legal classification: Country-specific.
Leaflet revision date: September 2024.
NSS version number: 3.2
Leaflet presentation: R02