Drug Safety-related Labeling Changes (SrLC)

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Drug Safety-related Labeling Changes (SrLC) Database

ANDA	Abbreviated New Drug Application
BLA	Biologics License Application
CDER	Center for Drug Evaluation and Research
MG	Medication Guide
NDA	New Drug Application
PCI	Patient Counseling Information
PI	Patient Information
PLR	Physician Labeling Rule
PLLR	Pregnancy and Lactation Labeling Rule
Italics	For the most part, italics indicate an FDA comment such as: Additions and/or revisions underlined These italics usually appear at the beginning of the section. In some cases, italics may be an inherent part of the label, and will most often appear in the body of the section.
Underlines	Any text that is underlined indicates text that has been added or revised. There are exceptions where underlining occurs in a section subtitle or heading. This is the case when there is just one word underlined in the body of the text.

Sections

BW	Box Warning
WP	Warnings and Precautions all in one section (PLR-format) Warnings as one section (pre-PLR format) Precautions as one section (pre-PLR format)
AR	Adverse Reactions (in pre-PLR format, this may be a subheading under precautions).
DI	Drug Interactions (in pre-PLR format, this may be a subheading under precautions).
USP	Use in Specific Populations (Inclusive on one or more of the following: Pregnancy; Lactation (PLLR- format); Nursing Mothers (pre-PLLR format); Females and Males of Reproductive Potential (PLLR format only); Pediatric Use, Geriatric Use, Renal Impairment, Hepatic Impairment, Sex, Race (these last six may be a subheading of precautions if label in pre-PLLR format.
PCI/PI/MG	Patient Counseling Information (PLR format only) - summarizes the information that a health care provider should convey to a patient (or caregiver when applicable) when a counseling discussion is taking place (e.g., a physician prescribing a drug during an office visit, a nurse providing discharge instructions at a hospital, or a pharmacist conveying information at a pharmacy). Patient Information - FDA approved patient labeling. Medication Guide - paper handouts that come with many prescription medicines. The guides address issues that are specific to particular drugs and drug classes, and they contain FDA-approved information that can help patients avoid serious adverse events.

Only NDAs and CDER regulated BLAs are included in this database. ANDAs are not included.

Applications that remain active, even if the product has been discontinued, undergo safety-related labeling changes.

IBRANCE (NDA-207103)

(PALBOCICLIB)

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

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09/06/2023 (SUPPL-18)

Approved Drug Label (PDF)

6 Adverse Reactions

6.2 Postmarketing Experience

Additions and/or revisions underlined:

…

Skin and Subcutaneous Tissue Disorders: Palmar-plantar erythrodysesthesia syndrome (PPES)

09/09/2019 (SUPPL-12)

Approved Drug Label (PDF)

5 Warnings and Precautions

Interstitial Lung Disease (ILD)/Pneumonitis

Newly added section:

Severe, life-threatening, or fatal interstitial lung disease (ILD) and/or pneumonitis can occur in patients treated with cyclin-dependent kinase 4/6 (CDK4/6) inhibitors, including IBRANCE when taken in combination with endocrine therapy.

Across clinical trials (PALOMA-1, PALOMA-2, PALOMA-3), 1.0% of IBRANCE-treated patients had ILD/pneumonitis of any grade, 0.1% had Grade 3 or 4 and no fatal cases were reported. 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 (e.g. hypoxia, cough, dyspnea). In patients who have new or worsening respiratory symptoms and are suspected to have developed pneumonitis, interrupt IBRANCE immediately and evaluate the patient. Permanently discontinue IBRANCE in patients with severe ILD or pneumonitis.

6 Adverse Reactions

Additions and/or revisions underlined:

The following clinically significant adverse reactions are described elsewhere in the labeling:

· Neutropenia

· 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.

04/04/2019 (SUPPL-8)

Approved Drug Label (PDF)

6 Adverse Reactions

6.2 Postmarketing Experience

(additions underlined)

…

Male patients with HR-positive, HER2-negative advanced or metastatic breast cancer

Based on limited data from postmarketing reports and electronic health records, the safety profile for men treated with IBRANCE is consistent with the safety profile in women treated with IBRANCE.

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

PATIENT COUNSELING INFORMATION

(additions underlined)

Dosing and Administration

…

Pre/perimenopausal women treated with IBRANCE should also be treated with LHRH agonists

Pregnancy, Lactation, and Infertility

…

Infertility: Inform males of reproductive potential that IBRANCE may cause infertility and to consider sperm preservation before taking IBRANCE

02/19/2019 (SUPPL-10)

Approved Drug Label (PDF)

6 Adverse Reactions

6.2 Postmarketing Experience

(Newly added subsection)

The following adverse reactions have been identified during post-approval use of IBRANCE. Because these reactions 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)/non-infectious pneumonitis.

02/06/2018 (SUPPL-7)

Approved Drug Label (PDF)

8 Use in Specific Populations

8.6 Hepatic Impairment

Additions and/or revisions underlined:

No dose adjustment is required in patients with mild or moderate hepatic impairment (Child-Pugh classes A and B). For patients with severe hepatic impairment (Child-Pugh class C), the recommended dose of IBRANCE is 75 mg once daily for 21 consecutive days followed by 7 days off treatment to comprise a complete cycle of 28 days. Based on a pharmacokinetic trial in subjects with varying degrees of hepatic function, the palbociclib unbound exposure (unbound AUCINF) decreased by 17% in subjects with mild hepatic impairment (Child-Pugh class A), and increased by 34% and 77% in subjects with moderate (Child-Pugh class B) and severe (Child-Pugh class C) hepatic impairment, respectively, relative to subjects with normal hepatic function. Peak palbociclib unbound exposure (unbound Cmax) increased by 7%, 38% and 72% for mild, moderate and severe hepatic impairment, respectively, relative to subjects with normal hepatic function.

Review the Full Prescribing Information for the aromatase inhibitor or fulvestrant for dose modifications related to hepatic impairment.

8.7 Renal Impairment

Additions and/or revisions underlined:

No dose adjustment is required in patients with mild, moderate, or severe renal impairment (CrCl greater than 15 mL/min). Based on a pharmacokinetic trial in subjects with varying degrees of renal function, the total palbociclib exposure (AUCINF) increased by 39%, 42%, and 31% with mild (60 mL/min less than or equal to CrCl less than 90 mL/min), moderate (30 mL/min less than or equal to CrCl less than 60 mL/min), and severe (CrCl less than 30 mL/min) renal impairment, respectively, relative to subjects with normal renal function. Peak palbociclib exposure (Cmax) increased by 17%, 12%, and 15% for mild, moderate, and severe renal impairment, respectively, relative to subjects with normal renal function. The pharmacokinetics of palbociclib have not been studied in patients requiring hemodialysis.

03/31/2017 (SUPPL-4)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Neutropenia

Additions and/or revisions underlined:

Neutropenia was the most frequently reported adverse reaction in Study 1 ( PALOMA-2) with an incidence of 80% and Study 2 (PALOMA-3) with an incidence of 83%. A Grade greater than or equal to 3 decrease in neutrophil counts was reported …

Monitor complete blood counts prior to starting IBRANCE therapy and at the beginning of each cycle, as well as on Day 15 of the first 2 cycles …

Febrile neutropenia has been reported in 1.8% of patients exposed to IBRANCE across Studies 1 and 2. One death due to neutropenic sepsis …

6 Adverse Reactions

6.1 Clinical Studies Experience

Additions and/or revisions underlined:

Study 1: IBRANCE plus Letrozole

Patients with estrogen receptor (ER)-positive, HER2-negative advanced or metastatic breast cancer for initial endocrine based therapy

… The most common adverse reactions (?10%) of any grade reported in patients in the IBRANCE plus letrozole arm by descending frequency were neutropenia, infections, leukopenia, fatigue, nausea, alopecia, stomatitis, diarrhea, anemia, rash, asthenia, thrombocytopenia, vomiting, decreased appetite, dry skin, pyrexia, and dysgeusia.

The most frequently reported Grade greater than3 adverse reactions (greater than or equal to 5%) in patients receiving IBRANCE plus letrozole by descending frequency were neutropenia, leukopenia, infections, and anemia.

Adverse reactions (greater than or equal to 10%) reported in patients who received IBRANCE plus letrozole or placebo plus letrozole in Study 1 are listed in Table 4.

Table 4. Adverse Reactions (greater than or equal to 10%) in Study 1

Additional adverse reactions occurring at an overall incidence of <10.0% of patients receiving IBRANCE plus letrozole in Study 1 included alanine aminotransferase increased (9.9%), aspartate aminotransferase increased (9.7%), epistaxis (9.2%), lacrimation increased (5.6%), dry eye (4.1%), vision blurred (3.6%), and febrile neutropenia (2.5%).

Study 2: IBRANCE plus Fulvestrant

The safety of IBRANCE (125 mg/day) plus fulvestrant (500 mg) versus placebo plus fulvestrant was evaluated in Study 2 (PALOMA-3). The data described below reflect exposure to IBRANCE in 345 out of 517 patients with HR-positive, HER2-negative advanced or metastatic breast cancer who received at least 1 dose of IBRANCE plus fulvestrant in Study 2. The median duration of treatment for IBRANCE plus fulvestrant was 10.8 months while the median duration of treatment for placebo plus fulvestrant

arm was 4.8 months.

… The most common adverse reactions (greater than or equal to 10%) of any grade reported in patients in the IBRANCE plus fulvestrant arm by descending frequency were neutropenia, leukopenia, infections …

The most frequently reported Grade greater than or equal to 3 adverse reactions (greater than or equal to 5%) in patients receiving IBRANCE plus fulvestrant in descending frequency were neutropenia and leukopenia.

Adverse reactions (greater than or equal to 10%) reported in patients who received IBRANCE …

Table 6. Adverse Reactions (greater than or equal to 10%) in Study 2

Additional adverse reactions occurring at an overall incidence of less than 10.0% of patients receiving IBRANCE plus fulvestrant in Study 2 included asthenia (7.5%), aspartate aminotransferase increased (7.5%), dysgeusia (6.7%), epistaxis (6.7%), lacrimation increased (6.4%), dry skin (6.1%), alanine aminotransferase increased (5.8%), vision blurred (5.8%), dry eye (3.8%), and febrile neutropenia (0.9%).

8 Use in Specific Populations

8.3 Females and Males of Reproductive Potential

Addition of the following:

Pregnancy Testing

Based on animal studies, IBRANCE can cause fetal harm when administered to a pregnant woman. Females of reproductive potential should have a pregnancy test prior to starting treatment with IBRANCE.

Contraception …

8.4 Pediatric Use

The safety and efficacy of IBRANCE in pediatric patients have not been studied.

Addition of the following:

Altered glucose metabolism (glycosuria, hyperglycemia, decreased insulin) associated with changes in the pancreas (islet cell vacuolation), eye (cataracts, lens degeneration), kidney (tubule vacuolation, chronic progressive nephropathy) and adipose tissue (atrophy) were identified in a 27 week repeat-dose toxicology study in rats that were immature at the beginning of the studies and were most prevalent in males at oral palbociclib doses ? 30 mg/kg/day (approximately 11 times the adult human exposure [AUC] at the recommended dose). Some of these findings (glycosuria/hyperglycemia, pancreatic islet cell vacuolation, and kidney tubule vacuolation) were present with lower incidence and severity in a 15 week repeat-dose toxicology study in immature rats. Altered glucose metabolism or associated changes in the pancreas, eye, kidney and adipose tissue were not identified in a 27-week repeat-dose toxicology study in rats that were mature at the beginning of the study and in dogs in repeat-dose toxicology studies up to 39 weeks duration.

Toxicities in teeth independent of altered glucose metabolism were observed in rats. Administration of

100 mg/kg palbociclib for 27 weeks (approximately 15 times the adult human exposure [AUC] at the recommended dose) resulted in abnormalities in growing incisor teeth (discolored, ameloblast degeneration/necrosis, mononuclear cell infiltrate). Other toxicities of potential concern to pediatric patients have not been evaluated in juvenile animals.

8.5 Geriatric Use

Of 444 patients who received IBRANCE in Study 1, 181 patients (41%) were ?65 years of age and

848 patients (11%) were greater than or equal to75 years of age. Of 347 patients who received IBRANCE in Study 2, 86 patients (25%) were greater than or equal to 65 years of age and 27 patients (8%) were greater than or equal to 75 years of age. No overall differences in safety or effectiveness …

8.6 Hepatic Impairment

Additions and/or revisions underlined:

The pharmacokinetics of palbociclib have not been studied in patients with severe renal impairment … Review the Full Prescribing Information for the aromatase inhibitor or fulvestrant for dose modifications related to hepatic impairment.

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

PATIENT INFORMATION

Additions and/or revisions underlined:

What is IBRANCE?

IBRANCE is a prescription medicine used to treat hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer that has spread to other parts of the body (metastatic) in combination with:

an aromatase inhibitor as the first hormonal based …
What are the possible side effects of IBRANCE?
IBRANCE may cause serious side effects. See “What is the most important information I should know about IBRANCE?”
Common side effects of IBRANCE when used with either letrozole or fulvestrant include:
abnormalities in liver blood tests