Drug Safety-related Labeling Changes (SrLC)

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KISQALI (NDA-209092)

(RIBOCICLIB SUCCINATE)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

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09/17/2024 (SUPPL-18)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Interstitial Lung Disease/Pneumonitis

Additions and revisions underlined:

Severe, life-threatening, or fatal interstitial lung disease (ILD) and/or pneumonitis can occur in patients treated with KISQALI and other CDK 4/6 inhibitors.

In patients with early breast cancer (NATALEE) who received 400 mg KISQALI plus a non-steroidal aromatase inhibitor

(NSAI), 1.5% of patients had ILD/pneumonitis (Grade 1-2).

In patients with advanced or metastatic breast cancer (MONALEESA-2, MONALEESA-3, MONALEESA-7), 1.6% of patients had ILD/pneumonitis (any Grade, 0.4% had Grade 3-4, and 0.1% had a fatal outcome). Additional cases of ILD/pneumonitis have occurred in the postmarketing setting, some resulting in death [see Adverse Reactions (6.2)].

Monitor patients for pulmonary symptoms indicative of ILD/pneumonitis which may include hypoxia, cough, and dyspnea. In patients who have new or worsening respiratory symptoms suspected to be due to ILD or pneumonitis, interrupt KISQALI immediately and evaluate the patient. Permanently discontinue KISQALI in patients with severe ILD/pneumonitis or any recurrent symptomatic ILD/pneumonitis. [see Dosage and Administration (2.2)].

5.3 QT Interval Prolongation

Additions and revisions underlined:

KISQALI has been shown to prolong the QT interval in a concentration-dependent manner [see Clinical Pharmacology (12.2)].

Avoid KISQALI in patients who are at significant risk of developing Torsades de Pointes (TdP), including those with:

• congenital long QT syndrome;

• uncontrolled or significant cardiac disease, recent myocardial infarction, heart failure, unstable angina, bradyarrhythmias, uncontrolled hypertension, high degree atrioventricular block, severe aortic stenosis, or uncontrolled hypothyroidism;

• electrolyte abnormalities;

• taking drugs known to prolong QT interval and/or strong CYP3A inhibitors as this may lead to prolongation of the QTcF interval.

Based on the observed QT prolongation during treatment, KISQALI may require dose interruption, reduction or discontinuation as described in Table 4 [see Dosage and Administration (2.2), Drug Interactions (7.4)].

In patients with early breast cancer (NATALEE) who received 400 mg KISQALI plus NSAI, 8 out of 2494 patients (0.3%) had > 500 ms post-baseline QTcF interval value and 50 out of 2494 patients (2%) had > 60 ms QTcF increase from baseline. QTcF prolongation was reversible with dose interruption. The majority of QTcF prolongation occurred within the first four weeks of KISQALI. There were no reported cases of Torsades de Pointes.

In patients with advanced or metastatic breast cancer (MONALEESA-2, MONALEESA-3, and MONALEESA-7) who received 600 mg KISQALI plus NSAI or fulvestrant, 15 out of 1054 patients (1.4%) had a > 500 ms post-baseline QTcF value and 61 out of 1054 patients (6%) had a > 60 ms QTcF increase from baseline. QTcF prolongation was reversible with dose interruption. The majority of QTcF prolongation occurred within the first four weeks of KISQALI. There were no reported cases of Torsades de Pointes.

In MONALEESA-2, in the KISQALI plus letrozole treatment arm, there was one (0.3%) sudden death in a patient with Grade 3 hypokalemia and Grade 2 QT prolongation. No cases of sudden death were reported in MONALEESA-7 or MONALEESA-3 [see Adverse Reactions (6)].

Perform ECG in all patients prior to starting KISQALI. Initiate treatment with KISQALI only in patients with QTcF values less than 450 ms. Repeat ECG at approximately Day 14 of the first cycle, and as clinically indicated.

Monitor serum electrolytes (including potassium, calcium, phosphorous and magnesium) prior to the initiation of KISQALI at the beginning of the first 6 cycles, and as clinically indicated. Correct any abnormality before starting KISQALI [see Dosage and Administration (2.2)].

5.4 Increased QT Prolongation with Concomitant Use of Tamoxifen

Additions and revisions underlined:

Avoid use of tamoxifen with KISQALI. In MONALEESA-7, the observed mean QTcF increase from baseline was > 10 ms higher in the tamoxifen plus placebo subgroup compared with the non-steroidal aromatase inhibitors (NSAIs) plus placebo subgroup. In the placebo arm, an increase of > 60 ms from baseline occurred in 6/90 (7%) of patients receiving tamoxifen, and in no patients receiving an NSAI. An increase of > 60 ms from baseline in the QTcF interval was observed in 14/87 (16%) of patients in the KISQALI and tamoxifen combination and in 18/245 (7%) of patients receiving KISQALI plus an NSAI [see Clinical Pharmacology (12.2)].

5.5 Hepatotoxicity

Additions and revisions underlined:

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 [see Dosage and Administration (2.2)].

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) [see Dosage and Administration (2.2)].

5.6 Neutropenia

Additions and revisions underlined:

KISQALI causes concentration-dependent neutropenia.

In patients with early breast cancer (NATALEE) who received KISQALI plus NSAI, 94%, including 45% of Grade 3 or 4, had a decrease in neutrophil counts (based on laboratory findings), 63% had an adverse reaction of neutropenia, and 0.3% had febrile neutropenia. The median time to Grade ? 2 neutropenia was 18 days. The median time to resolution of Grade ? 3 neutropenia to Grade < 3 was 10 days. Treatment discontinuation due to neutropenia was required in 1.1% of patients.

In patients with advanced or metastatic breast cancer (MONALEESA-2, MONALEESA-7, and MONALEESA-3) who received KISQALI plus NSAI or fulvestrant, 75% had neutropenia, 62% had Grade 3 or 4 decrease in neutrophil count (based on laboratory findings), and 1.7% had febrile neutropenia. The median time to Grade ? 2 neutropenia was 17 days. The median time to resolution of Grade ? 3 neutropenia to Grade < 3 was 12 days. Treatment discontinuation due to neutropenia was required in 1% of patients.

Perform a complete blood count (CBC) in all patients before initiating KISQALI. Monitor CBC every 2 weeks for the first 2 cycles, at the beginning of each subsequent 4 cycles, and as clinically indicated.

Based on the severity of the neutropenia, KISQALI may require dose interruption, reduction, or discontinuation as described in Table 6 [see Dosage and Administration (2.2)].

6 Adverse Reactions

Additions and revisions underlined:

The following adverse reactions are discussed in greater detail in other sections of the labeling:

• Interstitial Lung Disease/Pneumonitis [see Warnings and Precautions (5.1)]

• Severe Cutaneous Adverse Reactions [see Warnings and Precautions (5.2)]

• QT Interval Prolongation [see Warnings and Precautions (5.3, 5.4)]

• Hepatotoxicity [see Warnings and Precautions (5.5)]

• Neutropenia [see Warnings and Precautions (5.6)]

6.1 Clinical Trials Experience

Extensive changes; please refer to label

7 Drug Interactions

7.1 Drugs That May Increase Ribociclib Plasma Concentrations

Additions and revisions underlined:

CYP3A4 Inhibitors

Coadministration of strong CYP3A inhibitors increases ribociclib exposure [see Clinical Pharmacology (12.3)]. Increased ribociclib concentrations may increase the incidence and severity of adverse reactions, including QTcF prolongation [see Warnings and Precautions (5.3)]. Avoid concomitant use of strong CYP3A inhibitors with KISQALI and consider alternative concomitant medications with less potential for CYP3A inhibition.

In patients with early breast cancer, if coadministration of KISQALI with a strong CYP3A inhibitor cannot be avoided, reduce the dose of KISQALI to 200 mg once daily. In patients with advanced or metastatic breast cancer, if coadministration of KISQALI with a strong CYP3A inhibitor cannot be avoided, reduce the dose of KISQALI to 400 mg once daily [see Dosage and Administration (2.2)].

7.2 Drugs That May Decrease Ribociclib Plasma Concentrations

Additions and revisions underlined:

CYP3A Inducers

Coadministration of strong CYP3A inducers decreases the plasma exposure of ribociclib [see Clinical Pharmacology (12.3)]. Avoid concomitant use of strong CYP3A inducers and consider an alternate concomitant medication with no or minimal potential to induce CYP3A.

7.3 Effect of KISQALI on Other Drugs

Additions and revisions underlined:

CYP3A Substrates

Coadministration of sensitive CYP3A4 substrates with multiple doses of KISQALI increases the substrate exposure [see Clinical Pharmacology (12.3)]. For CYP3A substrates where minimal increases in the concentration may increase CYP3A substrate adverse reactions, monitor for increased adverse reactions of the CYP3A substrate during treatment with KISQALI. The dose of the sensitive CYP3A substrate may need to be reduced as KISQALI can increase its exposure.

7.4 Drugs That Prolong the QT Interval

Additions and revisions underlined:

Avoid coadministration of KISQALI with products with a known potential to prolong QT interval, such as antiarrhythmic drugs and other drugs that are known to prolong the QT interval. If concomitant use cannot be avoided, monitor ECG when initiating, during concomitant use, and as clinically indicated [see Warnings and Precautions (5.3), Clinical Pharmacology (12.2)].

8 Use in Specific Populations

8.5 Geriatric Use

Additions and revisions underlined:

Of the 2549 adults with early breast cancer who received KISQALI in NATALEE, 407 patients (16%) were ? 65 years of age and 123 patients (2.4%) were > 75 years of age. No overall differences in safety or effectiveness of KISQALI were observed between older and younger adults with early breast cancer.

Of 334 patients with advanced or metastatic breast cancer who received KISQALI in MONALEESA-2, 150 patients (45%) were ? 65 years of age and 35 patients (11%) were ? 75 years of age. Of 484 patients with advanced or metastatic breast cancer who received KISQALI in MONALEESA-3, 226 patients (47%) were ? 65 years of age and 65 patients (14%) were

? 75 years of age. Of 248 patients with advanced or metastatic breast cancer who received KISQALI in MONALEESA-7, no patients were ? 65 years of age. No overall differences in safety or effectiveness of KISQALI were observed between older and younger adults with advanced or metastatic breast cancer.

8.6 Hepatic Impairment

Additions and revisions underlined:

No dose adjustment is necessary in patients with breast cancer who have mild hepatic impairment (Child-Pugh class A) [see Clinical Pharmacology (12.3)]. A reduced starting dose of 400 mg is recommended in patients with advanced or metastatic breast cancer who have moderate (Child-Pugh class B) and severe hepatic impairment (Child-Pugh class C) [see Dosage and Administration (2.2)].

8.7 Renal Impairment

Additions and revisions underlined:

No dose adjustment is necessary in patients with breast cancer who have mild to moderate (30 mL/min to 89 mL/min/1.73 m2 ? estimated glomerular filtration rate (eGFR)) renal impairment. A reduced starting dose of 200 mg is recommended in patients with breast cancer who have severe renal impairment [see Dosage and Administration (2.2), Clinical Pharmacology (12.3)].

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

Newly added information:

Storage

• After dispensing, advise patients to store at room temperature at 20°C to 25°C (68°F to 77°F) for up to 2 months.

Patient Information

Additions and revisions underlined:

What is KISQALI?

KISQALI is a prescription medicine used to treat adults with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer:

• in combination with an aromatase inhibitor for stage II and III early breast cancer with a high risk of coming back.

• that has gotten worse or has spread to other parts of the body (advanced or metastatic breast cancer) in combination with:

  • an aromatase inhibitor as the first endocrine-based therapy, or

  • fulvestrant as the first endocrine-based therapy or following disease progression on endocrine therapy.

It is not known if KISQALI is safe and effective in children.

Before taking KISQALI, tell your healthcare provider about all of your medical conditions, including if you:

• have any heart problems, including heart failure, irregular heartbeats, and QT prolongation

• have ever had a heart attack

• have a slow heartbeat (bradycardia)

• have high blood pressure that is not controlled

• have decreased thyroid gland function (hypothyroidism)

• have problems with the amount of potassium, calcium, phosphorus, or magnesium in your blood

• have fever, chills, or any other signs or symptoms of infection

• have liver problems

• have kidney problems

• are pregnant, or plan to become pregnant. KISQALI can harm your unborn baby.

  • If you are able to become pregnant, your healthcare provider should do a pregnancy test before you start treatment with KISQALI.

Females who are able to become pregnant and who take KISQALI should use effective birth control during treatment and for at least 3 weeks after the last dose of KISQALI.

• about birth control methods that may be right for you during this time.

• If you become pregnant or think you are pregnant, tell your healthcare provider right away.

• are breastfeeding or plan to breastfeed. It is not known if KISQALI passes into your breast milk. Do not breastfeed during treatment with KISQALI and for at least 3 weeks after the last dose of KISQALI.

  Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. KISQALI and other medicines may affect each other causing side effects.

Know the medicines you take. Keep a list of them to show your healthcare provider or pharmacist when you get a new medicine.

How should I take KISQALI?

• Take KISQALI exactly as your healthcare provider tells you.

• Do not change your dose or stop taking KISQALI without talking to your healthcare provider.

• Swallow KISQALI tablets whole. Do not chew, crush, or split KISQALI tablets before swallowing them.

• Take KISQALI each day at about the same time, preferably in the morning.

• Take KISQALI with or without food.

• Do not take any KISQALI tablets that are broken, cracked, or that look damaged.

If you miss a dose of KISQALI or vomit after taking a dose of KISQALI, do not take another dose on that day. Take your next dose at your regular time.

What are the possible side effects of KISQALI? KISQALI may cause serious side effects, including:

• See "What is the most important information I should know about KISQALI?"

  The most common side effects of KISQALI in people with early breast cancer include:

  • decreased white blood cell counts                                   · decreased platelet counts

  • decreased red blood cell counts                                      · nausea

  • increased liver function tests                                           ·  headache

  • infections                                                                      ·  tiredness

  • increased kidney function test

    The most common side effects of KISQALI in people with advanced or metastatic breast cancer include:

  • decreased white blood cell           · nausea                                     · diarrhea                                       · cough counts                                         · increased kidney function test                      · vomiting                                     · rash

  • decreased red blood cell counts     · tiredness                                   · headache                                     · back pain

increased liver function tests

How should I store KISQALI?

• Store KISQALI at room temperature between 68°F to 77°F (20°C to 25°C) for up to 2 months.

• Store KISQALI in the original blister pack.

10/03/2022 (SUPPL-13)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Interstitial Lung Disease/Pneumonitis

Additions and/or revisions underlined:

…

Across clinical trials (MONALEESA-2, MONALEESA-3, MONALEESA-7), 1.6% of KISQALI-treated patients had ILD/pneumonitis of any grade, 0.4% had Grade 3 or 4, and 0.1% had a fatal outcome. Additional cases of ILD/pneumonitis have been observed in the postmarketing setting, with fatalities reported [see Adverse Reactions (6.2)].

5.3 QT Interval Prolongation

Additions and/or revisions underlined:

KISQALI has been shown to prolong the QT interval in a concentration-dependent manner [see Clinical Pharmacology (12.2)]. Based on the observed QT prolongation during treatment, KISQALI may require dose interruption, reduction or discontinuation as described in Table 4 [see Dosage and Administration (2.2) and Drug Interactions (7.4)].

Across MONALEESA-2, MONALEESA-7, and MONALEESA-3 in patients with advanced or metastatic breast cancer who received the combination of KISQALI plus an aromatase inhibitor or fulvestrant, 15 out of 1054 patients (1.4%) had a > 500 ms post-baseline QTcF value, and 61 out of 1054 patients (6%) had a > 60 ms increase from baseline in QTcF intervals.

…

5.5 Hepatobiliary Toxicity

Additions and/or revisions underlined:

In MONALEESA-2, MONALEESA-7 and MONALEESA-3, increases in transaminases were observed. Across all studies, Grade 3 or 4 increases in alanine aminotransferase (ALT) (11% vs. 2.1%) and aspartate aminotransferase (AST) (8% vs. 2%) were reported in the KISQALI and placebo arms, respectively.

Among the patients who had Grade greater than or equal to 3 ALT/AST elevation, the median time-to-onset was 92 days for the KISQALI plus aromatase inhibitor or fulvestrant treatment group. The median time to resolution to Grade less than or equal to 2 was 21 days in the KISQALI plus aromatase inhibitor or fulvestrant treatment group. 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 occurred in 6 (1%) patients and all patients recovered after discontinuation of KISQALI. No cases occurred in MONALEESA-7.

5.6 Neutropenia

Additions and/or revisions underlined:

In MONALEESA-2, MONALEESA-7, and MONALEESA-3, neutropenia was the most frequently reported adverse reaction (75%), and a Grade 3/4 decrease in neutrophil count (based on laboratory findings) was reported in 62% of patients receiving KISQALI plus an aromatase inhibitor or fulvestrant. Among the patients who had Grade 2, 3, or 4 neutropenia, the median time to Grade greater than or equal to 2 neutropenia was 17 days. The median time to resolution of Grade greater than or equal to 3 (to normalization or Grade < 3) was 12 days in the KISQALI plus aromatase inhibitor or fulvestrant treatment group. Febrile neutropenia was reported in 1.7% of patients receiving KISQALI plus an aromatase inhibitor or fulvestrant. Treatment discontinuation due to neutropenia was 1%.

6 Adverse Reactions

6.1 Clinical Trials Experience

Extensive additions and/or revisions – please refer to labeling

8 Use in Specific Populations

8.5 Geriatric Use

Additions and/or revisions underlined:

Of 334 patients who received KISQALI in MONALEESA-2, 150 patients (45%) were ? 65 years of age and 35 patients (11%) were greater than or equal to 75 years of age. Of 484 patients who received KISQALI in MONALEESA-3, 226 patients (47%) were greater than or equal 65 years of age and 65 patients (14%) were greater than or equal 75 years of age. Of 248 patients who received KISQALI in MONALEESA-7, no patients were greater than or equal 65 years of age. No overall differences in safety or effectiveness of KISQALI were observed between these patients and younger patients.

09/15/2021 (SUPPL-9)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.5 Hepatobiliary Toxicity

(Additions and/or revisions underlined)

In MONALEESA-2, MONALEESA-7 and MONALEESA-3, increases in transaminases were observed. Across all studies, Grade 3 or 4 increases in alanine aminotransferase (ALT) (10% vs. 2%) and aspartate aminotransferase (AST) (7% vs. 2%) were reported in the KISQALI and placebo arms, respectively.

Perform liver function tests (LFTs) before initiating therapy with KISQALI. Monitor LFTs every 2 weeks for first 2 cycles, at the beginning of each subsequent 4 cycles, and as clinically indicated [see Dosage and Administration (2.2)].

07/06/2020 (SUPPL-5)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.2 Severe Cutaneous Adverse Reactions

(New subsection added)

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 [see Adverse Reactions (6.2)].

If signs or symptoms of severe cutaneous reactions occur, interrupt KISQALI until the etiology of the reaction has been determined [see Dosage and Administration (2.2)]. Early consultation with a dermatologist is recommended to ensure greater diagnostic accuracy and appropriate management.

If SJS, TEN, or DiHS/DRESS is confirmed, permanently discontinue KISQALI. Do not reintroduce KISQALI in patients who have experienced SCARs or other life threatening cutaneous reactions during KISQALI treatment.

6 Adverse Reactions

(Additions underlined)

…

• Severe Cutaneous Adverse Reactions [see Warnings and Precautions (5.2)]

  …

  6.2       Postmarketing Experience

  (Additions underlined)

  …

  Skin and Subcutaneous Tissue Disorders: Stevens-Johnson Syndrome (SJS), Toxic epidermal necrolysis (TEN), Drug- induced hypersensitivity syndrome (DiHS)/Drug reaction with eosinophilia and systemic symptoms (DRESS)

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

(additions underlined)

…

Severe Cutaneous Adverse Reactions

Inform patients of the signs and symptoms of severe cutaneous adverse reactions (e.g., skin pain/burning, rapidly-spreading skin rash, and/or mucosal lesions accompanied by fever or flu-like symptoms). Advise patients to contact their healthcare provider immediately if they develop signs and symptoms of severe cutaneous adverse reactions [see Warnings and Precautions (5.2)].

PATIENT INFORMATION

(Additions underlined)

…

• Severe skin reactions. Tell your healthcare provider or get medical help right away if you get severe rash or rash that keeps getting worse, reddened skin, flu-like symptoms, skin pain/burning, blistering of the lips, eyes or mouth, blisters on the skin or skin peeling, with or without fever.

  …

01/21/2020 (SUPPL-3)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Interstitial Lung Disease/Pneumonitis

(Newly added subsection)

Severe, life-threatening, or fatal interstitial lung disease (ILD) and/or pneumonitis can occur in patients treated with KISQALI and other CDK4/6 inhibitors.

Across clinical trials (MONALEESA-2, MONALEESA-3, MONALEESA-7), 1.1% of KISQALI-treated patients had ILD/pneumonitis of any grade, 0.3% had Grade 3 or 4, and 0.1% had a fatal outcome. Additional cases of ILD/pneumonitis have been observed in the postmarketing setting, with fatalities reported.

Monitor patients for pulmonary symptoms indicative of ILD/pneumonitis which may include hypoxia, cough, and dyspnea. In patients who have new or worsening respiratory symptoms suspected to be due to ILD or pneumonitis, interrupt KISQALI immediately and evaluate the patient. Permanently discontinue KISQALI in patients with recurrent symptomatic or severe ILD/pneumonitis.

5.3 Increased QT Prolongation with Concomitant Use of Tamoxifen

(Additions and/or revisions underlined)

KISQALI is not indicated for concomitant use with tamoxifen. In MONALEESA-7, the observed mean QTcF increase from baseline was > 10 ms higher in the tamoxifen plus placebo subgroup compared with the non-steroidal aromatase inhibitors (NSAI) plus placebo subgroup. In the placebo arm, an increase of > 60 ms from baseline occurred in 6/90 (7%) of patients receiving tamoxifen, and in no patients receiving an NSAI. An increase of > 60 ms from baseline in the QTcF interval was observed in 14/87 (16%) of patients in the KISQALI and tamoxifen combination and in 18/245 (7%) of  patients receiving KISQALI plus an NSAI.

6 Adverse Reactions

(Additions and/or revisions underlined)

The following adverse reactions are discussed in greater detail in other sections of the labeling:

• ILD/Pneumonitis

• QT Interval Prolongation

• Hepatobiliary Toxicity

• Neutropenia

6.1 Clinical Trials Experience

(Additions and/or revisions underlined)

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.

MONALEESA-2: KISQALI in Combination with Letrozole

Adverse reactions and laboratory abnormalities occurring in patients in MONALEESA-2 are listed in Table 7 and Table 8, respectively.

Additional adverse reactions in MONALEESA-2 for patients receiving KISQALI plus letrozole included interstitial lung disease (0.3%), lung infiltration (0.3%), pneumonitis (0.3%), and pulmonary fibrosis (0.6%).

MONALEESA-7: KISQALI in Combination with an Aromatase Inhibitor

Pre/perimenopausal Patients with HR-positive, HER2-negative Advanced or Metastatic Breast Cancer for Initial Endocrine Based Therapy

MONALEESA-7 was conducted in 672 pre/perimenopausal patients with HR-positive, HER2-negative advanced or metastatic breast cancer receiving either KISQALI plus a non-steroidal aromatase inhibitor (NSAI) or tamoxifen plus goserelin or placebo plus NSAI or tamoxifen plus goserelin. The median duration of exposure on the KISQALI arm was 15.2 months with 66% of patients exposed for greater than or equal to 12 months. The safety data reported below are based on 495 pre/perimenopausal patients receiving KISQALI plus NSAI plus goserelin or placebo plus NSAI plus goserelin.

Dose reductions due to ARs occurred in 33% of patients receiving KISQALI plus NSAI plus goserelin, and in 4% of patients receiving placebo plus NSAI plus goserelin. Among patients receiving KISQALI plus NSAI, 3% were reported to have permanently discontinued both KISQALI and NSAI and 3% were reported to have permanently discontinued KISQALI alone due to ARs. Among patients receiving placebo plus NSAI, 2% were reported to have permanently discontinued both and 0.8% were reported to have permanently discontinued placebo alone due to ARs. Adverse reactions leading to treatment discontinuation on KISQALI in patients receiving KISQALI plus NSAI (as compared to the placebo arm) were ALT increased (2% vs. 0.8%), AST increased (2% vs. 0.8%), drug-induced liver injury (1% vs. 0.4%). One patient (0.4%) died while on treatment with KISQALI plus NSAI plus goserelin due to the underlying malignancy.

MONALEESA-3: KISQALI in Combination with Fulvestrant

On-treatment deaths, regardless of causality, were reported in seven patients (1.4%) due to the underlying malignancy and six patients (1.2%) due to other causes while on treatment with KISQALI plus fulvestrant. Causes of death included one pulmonary embolism, one acute respiratory distress syndrome, one cardiac failure, one pneumonia, one hemorrhagic shock, and one ventricular arrhythmia. Seven patients (2.9%) died due to the underlying malignancy and 1 patient (0.4%) died due to pulmonary embolism while on placebo plus fulvestrant.

Additional adverse reactions in MONALEESA-3 for patients receiving KISQALI plus fulvestrant included asthenia (14%), dyspepsia (10%), thrombocytopenia (9%) dry skin (8%), dysgeusia (7%), dry mouth (5%), vertigo (5%), dry eye (5%), lacrimation increased (4%), erythema (4%), hypocalcemia (4%), blood bilirubin increased (1%), syncope (1%), interstitial lung disease (0.4%), pneumonitis (0.4%), hypersensitivity pneumonitis (0.2%), and acute respiratory distress syndrome (0.2%).

6.2 Postmarketing Experience

(Newly added subsection)

The following adverse events have been reported during post-approval use of KISQALI. Because these events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Respiratory disorders: Interstitial lung disease (ILD)/pneumonitis.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

17 PATIENT COUNSELING INFORMATION

(Additions and/or revisions underlined)

Advise the patient to read the FDA-approved patient labeling (Patient Information).

Interstitial Lung Disease/Pneumonitis

Advise patients to immediately report new or worsening respiratory symptoms

09/09/2019 (SUPPL-4)

Approved Drug Label (PDF)

5 Warnings and Precautions

Interstitial Lung Disease/Pneumonitis

Newly added section:

Severe, life-threatening, or fatal interstitial lung disease (ILD) and/or pneumonitis can occur in patients treated with KISQALI and other CDK4/6 inhibitors.

Across clinical trials (MONALEESA-2, MONALEESA-3, MONALEESA-7), 1.1% of KISQALI-treated patients had ILD/pneumonitis of any grade, 0.3% had Grade 3 or 4, and 0.1% had a fatal outcome. Additional cases of ILD/pneumonitis have been observed in the postmarketing setting, with fatalities reported.

Monitor patients for pulmonary symptoms indicative of ILD/pneumonitis which may include hypoxia, cough, and dyspnea. In patients who have new or worsening respiratory symptoms suspected to be due to ILD or pneumonitis, interrupt KISQALI immediately and evaluate the patient. Permanently discontinue KISQALI in patients with recurrent symptomatic or severe ILD/pneumonitis.

6 Adverse Reactions

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·       ILD/Pneumonitis

Clinical Trial Experience

Additions and/or revisions underlined:

Additional adverse reactions in MONALEESA-2 for patients receiving KISQALI plus letrozole included interstitial lung disease (0.3%), lung infiltration (0.3%), pneumonitis (0.3%), and pulmonary fibrosis (0.6%).

One patient (0.4%) died while on treatment with KISQALI plus NSAI plus goserelin due to the underlying malignancy.

Additional adverse reactions in MONALEESA-7 for patients receiving KISQALI plus NSAI included asthenia (12%), thrombocytopenia (9%), dry skin (8%), oropharyngeal pain (7%), dyspepsia (5%), lacrimation increased (4%), dry eye (4%), vitiligo (3%), hypocalcemia, (2%), blood bilirubin increased (1%), syncope (0.4%), and pneumonitis (0.4%)

On-treatment deaths, regardless of causality, were reported in seven patients (1.4%) due to the underlying malignancy and six patients (1.2%) due to other causes while on treatment with KISQALI plus fulvestrant. Causes of death included one pulmonary embolism, one acute respiratory distress syndrome, one cardiac failure, one pneumonia, one hemorrhagic shock, and one ventricular arrhythmia. Seven patients (2.9%) died due to the underlying malignancy and 1 patient (0.4%) died due to pulmonary embolism while on placebo plus fulvestrant.

Postmarketing Experience

The following adverse events have been reported during post-approval use of KISQALI. Because these events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Respiratory disorders: Interstitial lung disease (ILD)/pneumonitis

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

Newly added information:

Interstitial Lung Disease/Pneumonitis

Advise patients to immediately report new or worsening respiratory symptoms

07/18/2018 (SUPPL-1)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 QT Interval Prolongation

(additions underlined)

KISQALI has been shown to prolong the QT interval in a concentration-dependent manner. Based on the observed QT prolongation during treatment, KISQALI may require dose interruption, reduction or discontinuation as described in Table 4.

Across MONALEESA-2, MONALEESA-7, and MONALEESA-3 in patients with advanced or metastatic breast cancer who received the combination of KISQALI plus an aromatase inhibitor or fulvestrant, 14 out of 1054 patients (1%) had

>500 ms post-baseline QTcF value, and 59 out of 1054 patients (6%) had a >60 ms increase from baseline in QTcF intervals.

These ECG changes were reversible with dose interruption and the majority occurred within the first four weeks of treatment. There were no reported cases of Torsades de Pointes.

In MONALEESA-2, on the KISQALI plus letrozole treatment arm, there was one (0.3%) sudden death in a patient with Grade 3 hypokalemia and Grade 2 QT prolongation. No cases of sudden death were reported in MONALEESA-7 or MONALEESA-3.

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5.2 Increased QT Prolongation with Concomitant Use of Tamoxifen

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KISQALI is not indicated for concomitant use with tamoxifen. In MONALEESA-7, the observed mean QTcF increase from baseline was >10 ms higher in the tamoxifen plus placebo subgroup compared with the NSAI plus placebo subgroup. In the placebo arm, an increase of >60 ms from baseline occurred in 6/90 (7%) of patients receiving tamoxifen, and in no patients receiving an NSAI. An increase of >60 ms from baseline in the QTcF interval was observed in 14/87 (16%) of patients in the KISQALI and tamoxifen combination and in 18/245 (7%) of patients receiving KISQALI plus an  NSAI.

5.3 Hepatobiliary Toxicity

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In MONALEESA-2, MONALEESA-7 and MONALEESA-3, increases in transaminases were observed. Across all studies, Grade 3 or 4 increases in ALT (10% versus 2%) and AST (7% versus 2%) were reported in the KISQALI and placebo arms, respectively.

Among the patients who had Grade greater than or equal to 3 ALT/AST elevation, the median time-to-onset was 85 days for the KISQALI plus aromatase inhibitor or fulvestrant treatment group. The median time to resolution to Grade less than or equal to 2 was 22 days in the KISQALI plus aromatase inhibitor or fulvestrant treatment group. 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 occurred in 6 (1%) patients and all patients recovered after discontinuation of KISQALI. No cases occurred in MONALEESA-7.

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5.4 Neutropenia

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In MONALEESA-2, MONALEESA-7 and MONALEESA-3, neutropenia was the most frequently reported adverse reaction (74%) and a Grade 3/4 decrease in neutrophil count (based on laboratory findings) was reported in 58% of patients receiving KISQALI plus an aromatase inhibitor or fulvestrant. Among the patients who had Grade 2, 3, or 4 neutropenia, the median time to Grade greater than or equal to 2 neutropenia was 16 days. The median time to resolution of Grade greater than or equal to 3 (to normalization or Grade <3) was 12 days in the KISQALI plus aromatase inhibitor or fulvestrant treatment group. Febrile neutropenia was reported in 1% of patients receiving KISQALI plus an aromatase inhibitor or fulvestrant. Treatment discontinuation due to neutropenia was 0.8%.

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6 Adverse Reactions

6.1 Clinical Trial Experience

(extensive additions, please refer to label)

8 Use in Specific Populations

8.5 Geriatric Use

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Of 334 patients who received KISQALI in MONALEESA-2, 150 patients (45%) were greater than or equal to 65 years of age and 35 patients (11%) were greater than or equal to 75 years of age. Of 484 patients who received KISQALI in MONALEESA-3, 226 patients (47%) were greater than or equal to 65 years of age and 65 patients (14%) were greater than or equal to 75 years of age. No overall differences in safety or effectiveness of KISQALI were observed between these patients and younger patients.

8.7 Renal Impairment

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Based on a population pharmacokinetic analysis, no dose adjustment is necessary in patients with mild (60 mL/min/1.73m2 less than or equal to estimated glomerular filtration rate (eGFR) < 90 mL/min/1.73m2) or moderate (30 mL/min/1.73m2 less than or equal to eGFR < 60 mL/min/1.73m2) renal impairment. Based on a renal impairment study in healthy subjects and non-cancer subjects with severe renal impairment (eGFR 15 to < 30 mL/min/1.73m2), a starting dose of 200 mg is recommended. KISQALI has not been studied in breast cancer patients with severe renal impairment.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

(additions underlined)

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Dosing

• Instruct patients to take the doses of KISQALI at approximately the same time every day and to swallow whole (do not chew, crush, or split them prior to swallowing).

• If patient vomits or misses a dose, advise the patient to take the next prescribed dose at the usual time.

• Advise the patient that KISQALI may be taken with or without food.