Approved Drug Label (PDF)
5
Warnings and Precautions
5.2 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 FEMARA CO-PACK. 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
FEMARA CO-PACK 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 Hepatobiliary Toxicity
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 and MONALEESA-7), 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 111 days for the KISQALI plus aromatase inhibitor treatment arm.
The median time to resolution to Grade ? 2 was 22 days in the KISQALI plus
aromatase inhibitor treatment arm. In MONALEESA-2, 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 4 (1%) patients and all patients recovered after discontinuation of KISQALI.
Perform liver function
tests (LFTs) in all patients before initiating KISQALI
FEMARA CO-PACK. 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)].
5.5 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 and MONALEESA-7), who received KISQALI plus NSAI, 79% had neutropenia, 66% had Grade 3 or 4 decrease
in neutrophil count
(based on laboratory findings), and 2% had
febrile neutropenia. The median time
to Grade ? 2 neutropenia was 16 days. The median time to resolution of Grade ?
3 neutropenia to Grade < 3 was 15 days. Treatment discontnuation due to
neutropenia was required in 1% of patients.
![]()
Perform a complete
blood count (CBC)
in all patients before initiating KISQALI
FEMARA CO-PACK. 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 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 a strong CYP3A4 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:
CYP3A4 Inducers
Coadministration of a strong CYP3A4 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 a 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 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
Additions and revisions underlined:
. . .
Embryo-Fetal Toxicity
Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females to inform
their healthcare provider of a known or suspected pregnancy.
Advise females of reproductive potential to use effective contraception during KISQALI FEMARA
CO-PACK therapy and for at
least 3 weeks after the last dose. [see
Warnings and Precautions (5.6), Use in Specific Populations (8.1, 8.3)].
Lactation
Advise lactating women not to breastfeed during
treatment with KISQALI FEMARA CO-PACK
and for at least 3 weeks
after the last dose [see Use in Specific
Populations (8.2)].
. . .
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:
. . .
KISQALI FEMARA
CO-PACK 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 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.
. . .
Before taking KISQALI FEMARA CO-PACK, tell your healthcare provider about all 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)
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.
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)].
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
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
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.
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