Drug Safety-related Labeling Changes (SrLC)

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KISQALI FEMARA CO-PACK (COPACKAGED) (NDA-209935)

(LETROZOLE; RIBOCICLIB SUCCINATE)

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

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10/03/2022 (SUPPL-21)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Interstitial Lung Disease/Pneumonitis

Additions and/or revisions underlined:

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-7), 1.2% of KISQALI-treated patients had ILD/pneumonitis of any grade and 0.3% had Grade 3 or 4. 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), Drug Interactions (7.4)].

In MONALEESA-2 and MONALEESA-7, in patients with advanced or metastatic breast cancer who received the combination of KISQALI plus an aromatase inhibitor, 67 out of 574 patients (1%) had > 500 ms post-baseline QTcF value, and 2829 out of 574 patients (5%) had a > 60 ms increase from baseline in QTcF intervals.In MONALEESA-2 and MONALEESA-7, in patients with advanced or metastatic breast cancer who received the combination of KISQALI plus an aromatase inhibitor, 7 out of 574 patients (1%) had > 500 ms post-baseline QTcF value, and 29 out of 574 patients (5%) had a > 60 ms increase from baseline in QTcF intervals.

…

5.4 Hepatobiliary Toxicity

Additions and/or revisions underlined:

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

Among the patients who had Grade greater than or equal 3 ALT/AST elevation, the median time-to-onset was 111 days for the KISQALI plus aromatase inhibitor treatment group. The median time to resolution to Grade less than or equal to 2 was 22 days in the KISQALI plus aromatase inhibitor treatment group.

…

5.5 Neutropenia

Additions and/or revisions underlined:

In MONALEESA-2 and MONALEESA-7, neutropenia was the most frequently reported adverse reaction (79%) and a Grade 3/4 decrease in neutrophil count (based on laboratory findings) was reported in 66% of patients receiving KISQALI plus an aromatase inhibitor. 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 3 (to normalization or Grade < 3) was 15 days in the KISQALI plus aromatase inhibitor treatment group. Febrile neutropenia was reported in 2% of patients receiving KISQALI plus an aromatase inhibitor. 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 plus letrozole in MONALEESA-2, 150 patients (45%) were greater than or equal to 65 years of age and 35 patients (11%) were greater than to equal to 75 years of age. No overall differences in safety or effectiveness of KISQALI plus letrozole were observed between these patients and younger patients. Of 248 patients who received KISQALI in MONALEESA-7, no patients were greater than to equal to 65 years of age.

09/15/2021 (SUPPL-13)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.2 Severe Cutaneous Adverse Reactions

(Section title revised)

(Additions and/or revisions underlined)

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.

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, 14 out of 1054 patients (1%) had a > 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 [see Adverse Reactions (6)].

5.4 Increased QT Prolongation With Concomitant Use of Tamoxifen

(Newly added section)

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 (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)].

5.6 Neutropenia

(Additions and/or revisions underlined)

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 > or equal to 2 neutropenia was 16 days. The median time to resolution of Grade ? 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%.

Perform complete blood count (CBC) before initiating therapy with 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

6.1 Clinical Trial Experience

(Newly added information)

MONALEESA-3: KISQALI in Combination with Fulvestrant

Postmenopausal Patients with HR-positive, HER2-negative Advanced or Metastatic Breast Cancer for Initial Endocrine-Based Therapy or After Disease Progression on Endocrine Therapy

The safety data reported below are based on MONALEESA-3, a clinical study of 724 postmenopausal women receiving KISQALI plus fulvestrant or placebo plus fulvestrant. The median duration of exposure to KISQALI plus fulvestrant was

15.8 months with 58% of patients exposed for ? 12 months.

Dose reductions due to ARs occurred in 32% of patients receiving KISQALI plus fulvestrant and in 3% of patients receiving placebo plus fulvestrant. Among patients receiving KISQALI plus fulvestrant, 8% were reported to have permanently discontinued both KISQALI and fulvestrant and 9% were reported to have discontinued KISQALI alone due to ARs.

Among patients receiving placebo plus fulvestrant, 4% were reported to have permanently discontinued both and 2% were

reported to have discontinued placebo alone due to ARs. Adverse reactions leading to treatment discontinuation of KISQALI in patients receiving KISQALI plus fulvestrant (as compared to the placebo arm) were ALT increased (5% vs. 0%), AST increased (3% vs. 0.6%), and vomiting (1% vs. 0%).

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.

The most common ARs (reported at a frequency ? 20% on the KISQALI arm and ? 2% higher than placebo) were neutropenia, infections, leukopenia, cough, nausea, diarrhea, vomiting, constipation, pruritus, and rash. The most common Grade 3/4 ARs (reported at a frequency ? 5%) were neutropenia, leukopenia, infections, and abnormal liver function tests. See Table 12.

Adverse reactions and laboratory abnormalities occurring in patients in MONALEESA-3 are listed in Table 12 and Table 13, respectively.

(Newly added Table 12 and 13: Adverse Reactions and Laboratory Abnormalities in MONALEESA-3)

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 ? 75 years of age. Of 484 patients who received KISQALI in MONALEESA-3, 226 patients (47%) were ? 65 years of age and 65 patients (14%) were ? 75 years of age. No overall differences in safety or effectiveness of KISQALI were observed between these patients and younger patients.

8.6 Hepatic Impairment

(Additions and/or revisions underlined)

No dose adjustment is necessary in patients with mild hepatic impairment (Child-Pugh class A). A reduced starting dose of 400 mg is recommended in patients with moderate (Child-Pugh class B) and severe hepatic impairment (Child-Pugh class

C) [see Dosage and Administration (2.2)]. Based on a pharmacokinetic trial in patients with hepatic impairment, mild

hepatic impairment had no effect on the exposure of ribociclib. The mean exposure for ribociclib was increased less than 2- fold in patients with moderate (geometric mean ratio [GMR]: 1.44 for Cmax; 1.28 for AUCinf ) and severe (GMR: 1.32 for Cmax ; 1.29 for AUCinf) hepatic impairment [see Clinical Pharmacology (12.3)].

07/06/2020 (SUPPL-8)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.2 Severe Cutaneous 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 severe cutaneous reactions during KISQALI treatment.

6 Adverse Reactions

(Additions underlined)

…

• Severe Cutaneous 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, , 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 Reactions

Inform patients of the signs and symptoms of severe cutaneous 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 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-6)

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. Refer to the Full Prescribing Information for KISQALI.

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

(Extensive changes; please refer to label)

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-7)

Approved Drug Label (PDF)

5 Warnings and Precautions

Interstitial Lung Disease/Pneumonitis

New 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 post-marketing 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. Refer to the Full Prescribing Information for KISQALI®.

6 Adverse Reactions

Newly added to bulleted line listing:

·       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%).

Postmarketing Experience

Newly added section:

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

02/13/2019 (SUPPL-2)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 QT Interval Prolongation

(Additions and/or revisions are 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. In MONALEESA-2 and MONALEESA-7, in patients with advanced or metastatic breast cancer who received the combination of KISQALI plus an aromatase inhibitor, 6 out of 574 patients (1%) had > 500 ms post-baseline QTcF value, and 28 out of 574 patients (5%) 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, 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.

Based on the observed QT prolongation during treatment, KISQALI may require dose interruption, reduction or discontinuation as described in Table 4. KISQALI is not indicated for concomitant use with tamoxifen. Refer to the Full Prescribing Information for KISQALI.

5.2 Hepatobiliary Toxicity

(Additions and/or revisions are underlined)

In MONALEESA-2 and MONALEESA-7, increases in transaminases were observed, with Grade 3 or 4 increases in ALT (9% versus 1%) and AST (6% versus 2%) reported in the KISQALI plus aromatase inhibitor 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 treatment group. The median time to resolution to Grade less than or equal to 2 was 23 days in the KISQALI plus aromatase inhibitor treatment group.

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 4 (1%) patients in MONALEESA-2 and all patients recovered after discontinuation of KISQALI. No cases occurred in MONALEESA-7.

5.3 Neutropenia

(Additions and/or revisions are underlined)

In MONALEESA-2 and MONALEESA-7, neutropenia was the most frequently reported adverse reaction (77%) and a Grade 3/4 decrease in neutrophil count (based on laboratory findings) was reported in 63% of patients receiving KISQALI plus an aromatase inhibitor. 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 15 days in the KISQALI plus aromatase inhibitor treatment group. Febrile neutropenia was reported in 2% of patients receiving KISQALI plus an aromatase inhibitor. Treatment discontinuation due to neutropenia was 0.7%.

6 Adverse Reactions

6.1 Clinical Trial Experience

(Extensive changes; please refer to labeling)

7 Drug Interactions

7.1 Drugs That May Increase Ribociclib Plasma Concentrations

(Additions and/or revisions are underlined)

CYP3A4 Inhibitors

Instruct patients to avoid grapefruit or grapefruit juice, which are known to inhibit cytochrome CYP3A enzymes and may increase the exposure to ribociclib.

8 Use in Specific Populations

8.7 Renal Impairment

(Additions and/or revisions are underlined)

Based on a population pharmacokinetic analysis, no dose adjustment of KISQALI 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 ribociclib 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 of KISQALI is recommended. KISQALI has not been studied in breast cancer patients with severe renal impairment.

No dosage adjustment of FEMARA is required for patients with renal impairment if creatinine clearance is greater than or equal to 10 mL/min.

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

17 PATIENT COUNSELING INFORMATION

(Additions and/or revisions are underlined)

Dosing

• Instruct patients to take the doses of KISQALI FEMARA CO-PACK at approximately the same time every day and to swallow tablets 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 FEMARA CO-PACK may be taken with or without food.

04/23/2018 (SUPPL-1)

Approved Drug Label (PDF)

4 Contraindications

(Additions and/or revisions are underlined)

Known hypersensitivity to the active substance (letrozole), or to any of the excipients of FEMARA. Refer to FEMARA Prescribing Information.