Ibrance: Package Insert and Label Information

IBRANCE- palbociclib capsule
U.S. Pharmaceuticals

1 INDICATIONS AND USAGE

IBRANCE is indicated for the treatment of HR-positive, HER2-negative advanced or metastatic breast cancer in combination with:

  • letrozole as initial endocrine based therapy in postmenopausal women, or
  • fulvestrant in women with disease progression following endocrine therapy.

The indication in combination with letrozole is approved under accelerated approval based on progression-free survival (PFS) [see Clinical Studies (14)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

2 DOSAGE AND ADMINISTRATION

2.1 Recommended Dose and Schedule

The recommended dose of IBRANCE is a 125 mg capsule taken orally once daily for 21 consecutive days followed by 7 days off treatment to comprise a complete cycle of 28 days. IBRANCE should be taken with food [see Clinical Pharmacology (12.3)].

When coadministered with palbociclib, the recommended dose of letrozole is 2.5 mg taken once daily continuously throughout the 28-day cycle. Please refer to the full prescribing information of letrozole.

When coadministered with palbociclib, the recommended dose of fulvestrant is 500 mg administered on Days 1, 15, 29, and once monthly thereafter. Please refer to the full prescribing information of fulvestrant.

Patients should be encouraged to take their dose of IBRANCE at approximately the same time each day.

If the patient vomits or misses a dose, an additional dose should not be taken. The next prescribed dose should be taken at the usual time. IBRANCE capsules should be swallowed whole (do not chew, crush or open them prior to swallowing). Capsules should not be ingested if they are broken, cracked, or otherwise not intact.

Pre/perimenopausal women treated with the combination IBRANCE plus fulvestrant therapy should be treated with luteinizing hormone-releasing hormone (LHRH) agonists according to current clinical practice standards.

2.2 Dose Modification

The recommended dose modifications for adverse reactions are listed in Tables 1, 2 and 3.

Table 1. Recommended Dose Modification for Adverse Reactions
Dose Level Dose
*
If further dose reduction below 75 mg/day is required, discontinue.
Recommended starting dose 125 mg/day
First dose reduction 100 mg/day
Second dose reduction 75 mg/day *
Table 2. Dose Modification and Management – Hematologic Toxicities *
Grading according to CTCAE 4.0.
CTCAE=Common Terminology Criteria for Adverse Events; LLN=lower limit of normal.
*
Table applies to all hematologic adverse reactions except lymphopenia (unless associated with clinical events, e.g., opportunistic infections).
Absolute neutrophil count (ANC): Grade 1: ANC < LLN — 1500/mm3 ; Grade 2: ANC 1000 — <1500/mm3 ; Grade 3: ANC 500 — <1000/mm3 ; Grade 4: ANC <500/mm3
Monitor complete blood counts prior to the start of IBRANCE therapy and at the beginning of each cycle, as well as on Day 14 of the first 2 cycles, and as clinically indicated.
CTCAE Grade Dose Modifications
Grade 1 or 2 No dose adjustment is required.
Grade 3 Day 1 of cycle:Withhold IBRANCE, repeat complete blood count monitoring within 1 week. When recovered to Grade ≤2, start the next cycle at the same dose.Day 14 of first 2 cycles:Continue IBRANCE at current dose to complete cycle. Repeat complete blood count on Day 21.Consider dose reduction in cases of prolonged (>1 week) recovery from Grade 3 neutropenia or recurrent Grade 3 neutropenia in subsequent cycles.
Grade 3 neutropenia with fever ≥38.5 °C and/or infection Withhold IBRANCE until recovery to Grade ≤2.Resume at the next lower dose.
Grade 4 Withhold IBRANCE until recovery to Grade ≤2.Resume at the next lower dose.
Table 3. Dose Modification and Management – Non-Hematologic Toxicities
CTCAE Grade Dose Modifications
Grading according to CTCAE 4.0.CTCAE=Common Terminology Criteria for Adverse Events.
Grade 1 or 2 No dose adjustment is required.
Grade ≥3 non-hematologic toxicity (if persisting despite optimal medical treatment) Withhold until symptoms resolve to:
  • Grade ≤1;
  • Grade ≤2 (if not considered a safety risk for the patient)
Resume at the next lower dose.

Refer to the full prescribing information for coadministered endocrine therapy dose adjustment guidelines in the event of toxicity and other relevant safety information or contraindications.

Dose Modifications for Use With Strong CYP3A Inhibitors

Avoid concomitant use of strong CYP3A inhibitors and consider an alternative concomitant medication with no or minimal CYP3A inhibition. If patients must be coadministered a strong CYP3A inhibitor, reduce the IBRANCE dose to 75 mg once daily. If the strong inhibitor is discontinued, increase the IBRANCE dose (after 3 to 5 half-lives of the inhibitor) to the dose used prior to the initiation of the strong CYP3A inhibitor [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)].

3 DOSAGE FORMS AND STRENGTHS

125 mg capsules: opaque hard gelatin capsules, size 0, with caramel cap and body, printed with white ink “Pfizer” on the cap, “PBC 125” on the body.

100 mg capsules: opaque hard gelatin capsules, size 1, with caramel cap and light orange body, printed with white ink “Pfizer” on the cap, “PBC 100” on the body.

75 mg capsules: opaque hard gelatin capsules, size 2, with light orange cap and body, printed with white ink “Pfizer” on the cap, “PBC 75” on the body.

4 CONTRAINDICATIONS

None.

5 WARNINGS AND PRECAUTIONS

5.1 Neutropenia

Neutropenia was the most frequently reported adverse reaction in both Study 1 (75%) and Study 2 (83%). A Grade ≥3 decrease in neutrophil counts was reported in 62% of patients receiving IBRANCE plus letrozole in Study 1 and 66% of patients receiving IBRANCE plus fulvestrant in Study 2. In Study 1 and 2, the median time to first episode of any grade neutropenia was 15 days and the median duration of Grade ≥3 neutropenia was 7 days [see Adverse Reactions (6.1)].

Monitor complete blood counts prior to starting IBRANCE therapy and at the beginning of each cycle, as well as on Day 14 of the first 2 cycles, and as clinically indicated. Dose interruption, dose reduction or delay in starting treatment cycles is recommended for patients who develop Grade 3 or 4 neutropenia [see Dosage and Administration (2.2)].

Febrile neutropenia has been reported in about 1% of patients exposed to IBRANCE. One death due to neutropenic sepsis was observed in Study 2. Physicians should inform patients to promptly report any episodes of fever [see Patient Counseling Information (17)].

5.2 Pulmonary Embolism

Pulmonary embolism has been reported at a higher rate in patients treated with IBRANCE plus letrozole in Study 1 (5%) and in patients treated with IBRANCE plus fulvestrant in Study 2 (1%) compared with no cases in patients treated either with letrozole alone or fulvestrant plus placebo. Monitor patients for signs and symptoms of pulmonary embolism and treat as medically appropriate.

5.3 Embryo-Fetal Toxicity

Based on findings from animal studies and its mechanism of action, IBRANCE can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of palbociclib to pregnant rats and rabbits during organogenesis resulted in embryo-fetal toxicity at maternal exposures that were ≥4 times the human clinical exposure based on area under the curve (AUC). Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with IBRANCE and for at least 3 weeks after the last dose [see Use in Specific Populations (8.1 and 8.3) and Clinical Pharmacology (12.1)].

6 ADVERSE REACTIONS

The following topics are described below and elsewhere in the labeling:

6.1 Clinical Studies Experience

Because clinical trials are conducted under varying conditions, the adverse reaction rates observed cannot be directly compared to rates in other trials and may not reflect the rates observed in clinical practice.

Study 1: IBRANCE plus Letrozole

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

The safety of IBRANCE (125 mg/day) plus letrozole (2.5 mg/day) versus letrozole alone was evaluated in Study 1. The data described below reflect exposure to IBRANCE in 83 out of 160 patients with ER-positive, HER2-negative advanced breast cancer who received at least 1 dose of treatment in Study 1. The median duration of treatment for IBRANCE was 13.8 months while the median duration of treatment for letrozole on the letrozole-alone arm was 7.6 months.

Dose reductions due to an adverse reaction of any grade occurred in 36% of patients receiving IBRANCE plus letrozole. No dose reduction was allowed for letrozole in Study 1.

Permanent discontinuation associated with an adverse reaction occurred in 7 of 83 (8%) patients receiving IBRANCE plus letrozole and in 2 of 77 (3%) patients receiving letrozole alone. Adverse reactions leading to discontinuation for those patients receiving IBRANCE plus letrozole included neutropenia (6%), asthenia (1%), and fatigue (1%).

The most common adverse reactions (≥10%) of any grade reported in patients in the IBRANCE plus letrozole arm were neutropenia, leukopenia, fatigue, anemia, upper respiratory infection, nausea, stomatitis, alopecia, diarrhea, thrombocytopenia, decreased appetite, vomiting, asthenia, peripheral neuropathy, and epistaxis.

The most frequently reported serious adverse reactions in patients receiving IBRANCE plus letrozole were pulmonary embolism (3 of 83; 4%) and diarrhea (2 of 83; 2%).

An increased incidence of infections was observed in the IBRANCE plus letrozole arm (55%) compared to the letrozole alone arm (34%). Febrile neutropenia has been reported in the IBRANCE clinical program, although no cases were observed in Study 1. Grade ≥3 neutropenia was managed by dose reductions and/or dose delay or temporary discontinuation consistent with a permanent discontinuation rate of 6% due to neutropenia [see Dosage and Administration (2.2)].

Adverse reactions (≥10%) reported in patients who received IBRANCE plus letrozole or letrozole alone in Study 1 are listed in Table 4.

Table 4. Adverse Reactions* (≥10%) in Study 1
Adverse Reaction IBRANCE plus Letrozole(N=83) Letrozole Alone(N=77)
All Grades% Grade 3% Grade 4% All Grades% Grade 3% Grade 4%
Grading according to CTCAE 3.0.
CTCAE=Common Terminology Criteria for Adverse Events; N=number of patients; N/A=not applicable; URI=Upper respiratory infection.
*
URI includes: influenza, influenza like illness, laryngitis, nasopharyngitis, pharyngitis, rhinitis, sinusitis, upper respiratory tract infection.
Peripheral neuropathy includes: neuropathy peripheral, peripheral sensory neuropathy.
Stomatitis includes: aphthous stomatitis, cheilitis, glossitis, glossodynia, mouth ulceration, mucosal inflammation, oral pain, oral discomfort, oropharyngeal pain, stomatitis.
§
Grade 1 events – 21%; Grade 2 events – 1%.
Grade 1 events – 3%.
Infections and infestations
URI * 31 1 0 18 0 0
Blood and lymphatic system disorders
Neutropenia 75 48 6 5 1 0
Leukopenia 43 19 0 3 0 0
Anemia 35 5 1 7 1 0
Thrombocytopenia 17 2 0 1 0 0
Metabolism and nutrition disorders
Decreased appetite 16 1 0 7 0 0
Nervous system disorders
Peripheral neuropathy 13 0 0 5 0 0
Respiratory, thoracic and mediastinal disorders
Epistaxis 11 0 0 1 0 0
Gastrointestinal disorders
Stomatitis 25 0 0 7 1 0
Nausea 25 2 0 13 1 0
Diarrhea 21 4 0 10 0 0
Vomiting 15 0 0 4 1 0
Skin and subcutaneous tissue disorders
Alopecia 22§ N/A N/A 3 N/A N/A
General disorders and administration site conditions
Fatigue 41 2 2 23 1 0
Asthenia 13 2 0 4 0 0
Table 5. Laboratory Abnormalities in Study 1
Laboratory Abnormality IBRANCE plus Letrozole(N=83) Letrozole Alone(N=77)
All Grades% Grade 3% Grade 4% All Grades% Grade 3% Grade 4%
N=number of patients; WBC=white blood cells
WBC decreased 95 44 0 26 0 0
Neutrophils decreased 94 57 5 17 3 0
Lymphocytes decreased 81 17 1 35 3 0
Hemoglobin decreased 83 5 1 40 3 0
Platelets decreased 61 3 0 16 3 0

Study 2: IBRANCE plus Fulvestrant

Patients with HR-positive, HER2-negative advanced or metastatic breast cancer who have had disease progression on or after prior adjuvant or metastatic endocrine therapy

The safety of IBRANCE (125 mg/day) plus fulvestrant (500 mg) versus placebo plus fulvestrant was evaluated in Study 2. 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 treatment in Study 2.

Dose reductions due to an adverse reaction of any grade occurred in 36% of patients receiving IBRANCE plus fulvestrant. No dose reduction was allowed for fulvestrant in Study 2.

Permanent discontinuation associated with an adverse reaction occurred in 19 of 345 (6%) patients receiving IBRANCE plus fulvestrant, and in 6 of 172 (3%) patients receiving placebo plus fulvestrant. Adverse reactions leading to discontinuation for those patients receiving IBRANCE plus fulvestrant included fatigue (0.6%), infections (0.6%), and thrombocytopenia (0.6%).

The most common adverse reactions (≥10%) of any grade reported in patients in the IBRANCE plus fulvestrant arm were neutropenia, leukopenia, infections, fatigue, nausea, anemia, stomatitis, headache, diarrhea, thrombocytopenia, constipation, vomiting, alopecia, rash, decreased appetite, and pyrexia.

The most frequently reported serious adverse reactions in patients receiving IBRANCE plus fulvestrant were infections (3%), pyrexia (1%), neutropenia (1%), and pulmonary embolism (1%).

Adverse reactions reported in patients who received IBRANCE plus fulvestrant or placebo plus fulvestrant in Study 2 are listed in Table 6.

Table 6. Adverse Reactions in Study 2
Adverse Reaction IBRANCE plus Fulvestrant(N=345) Placebo plus Fulvestrant(N=172)
All Grades% Grade 3% Grade 4% All Grades% Grade 3% Grade 4%
Grading according to CTCAE 4.0.
CTCAE=Common Terminology Criteria for Adverse Events; N=number of patients; N/A=not applicable.
*
Most common infections (>1%) include: nasopharyngitis, upper respiratory infection, urinary tract infection, influenza, bronchitis, rhinitis, conjunctivitis, pneumonia, sinusitis, cystitis, oral herpes, respiratory tract infection.
Stomatitis includes: aphthous stomatitis, cheilitis, glossitis, glossodynia, mouth ulceration, mucosal inflammation, oral pain, oropharyngeal discomfort, oropharyngeal pain, stomatitis.
Grade 1 events – 17%; Grade 2 events – 1%.
§
Grade 1 events – 6%.
Rash includes: rash, rash maculo-papular, rash pruritic, rash erythematous, rash papular, dermatitis, dermatitis acneiform, toxic skin eruption.
Infections and infestations
Infections * 47 3 1 31 3 0
Blood and lymphatic system disorders
Febrile neutropenia 1 1 0 1 0 1
Neutropenia 83 55 11 4 1 0
Leukopenia 53 30 1 5 1 1
Anemia 30 3 0 13 2 0
Thrombocytopenia 23 2 1 0 0 0
Eye disorders
Vision blurred 6 0 0 2 0 0
Lacrimation increased 6 0 0 1 0 0
Dry eye 4 0 0 2 0 0
Metabolism and nutrition disorders
Decreased appetite 16 1 0 8 1 0
Nervous system disorders
Headache 26 1 0 20 0 0
Dysgeusia 7 0 0 3 0 0
Respiratory, thoracic and mediastinal disorders
Epistaxis 7 0 0 2 0 0
Gastrointestinal disorders
Nausea 34 0 0 28 1 0
Stomatitis 28 1 0 13 0 0
Diarrhea 24 0 0 19 1 0
Constipation 20 0 0 16 0 0
Vomiting 19 1 0 15 1 0
Skin and subcutaneous tissue disorders
Alopecia 18 N/A N/A 6§ N/A N/A
Rash 17 1 0 6 0 0
Dry skin 6 0 0 1 0 0
General disorders and administration site conditions
Fatigue 41 2 0 29 1 0
Asthenia 8 0 0 5 1 0
Pyrexia 13 <1 0 5 0 0
Table 7. Laboratory Abnormalities in Study 2
Laboratory Abnormality IBRANCE plus Fulvestrant(N=345) Placebo plus Fulvestrant(N=172)
All Grades% Grade 3% Grade 4% All Grades% Grade 3% Grade 4%
N=number of patients; WBC=white blood cells.
WBC decreased 99 45 1 26 0 1
Neutrophils decreased 96 56 11 14 0 1
Anemia 78 3 0 40 2 0
Platelets decreased 62 2 1 10 0 0
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