Ibrance: Package Insert and Label Information

IBRANCE- palbociclib capsule
Pfizer Laboratories Div Pfizer Inc

1 INDICATIONS AND USAGE

IBRANCE is indicated for the treatment of adult patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer in combination with:

an aromatase inhibitor as initial endocrine-based therapy; or
fulvestrant in patients with disease progression following endocrine therapy.

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)].

Administer the recommended dose of an aromatase inhibitor when given with IBRANCE. Please refer to the Full Prescribing Information for the aromatase inhibitor being used.

When given with IBRANCE, 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 an aromatase inhibitor or fulvestrant therapy should also be treated with luteinizing hormone-releasing hormone (LHRH) agonists according to current clinical practice standards.

For men treated with combination IBRANCE plus aromatase inhibitor therapy, consider treatment with an LHRH agonist 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 15 of the first 2 cycles, and as clinically indicated.For patients who experience a maximum of Grade 1 or 2 neutropenia in the first 6 cycles, monitor complete blood counts for subsequent cycles every 3 months, prior to the beginning of a cycle 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 15 of first 2 cycles:If Grade 3 on Day 15, continue IBRANCE at current dose to complete cycle and repeat complete blood count on Day 22.If Grade 4 on Day 22, see Grade 4 dose modification guidelines below.Consider dose reduction in cases of prolonged (>1 week) recovery from Grade 3 neutropenia or recurrent Grade 3 neutropenia on Day 1 of subsequent cycles.

Grade 3 neutropenia with fever ≥38.5 ºC and/or infection

At any time:Withhold IBRANCE until recovery to Grade ≤2.Resume at the next lower dose.

Grade 4

At any time: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.

Permanently discontinue IBRANCE in patients with severe interstitial lung disease (ILD)/pneumonitis.

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)].

Dose Modifications for Hepatic Impairment

No dose adjustment is required for 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 [see Use in Specific Populations (8.6) 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 Study 1 (PALOMA-2) with an incidence of 80% and Study 2 (PALOMA-3) with an incidence of 83%. A Grade ≥3 decrease in neutrophil counts was reported in 66% 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 15 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 1.8% of patients exposed to IBRANCE across Studies 1 and 2. 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 Interstitial Lung Disease (ILD)/Pneumonitis

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 clinically significant adverse reactions are described elsewhere in the labeling:

Neutropenia [see Warnings and Precautions (5.1)]
ILD/Pneumonitis [see Warnings and Precautions (5.2)]

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 estrogen receptor (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 placebo plus letrozole was evaluated in Study 1 (PALOMA-2). The data described below reflect exposure to IBRANCE in 444 out of 666 patients with ER-positive, HER2-negative advanced breast cancer who received at least 1 dose of IBRANCE plus letrozole in Study 1. The median duration of treatment for IBRANCE plus letrozole was 19.8 months while the median duration of treatment for placebo plus letrozole arm was 13.8 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 43 of 444 (9.7%) patients receiving IBRANCE plus letrozole and in 13 of 222 (5.9%) patients receiving placebo plus letrozole. Adverse reactions leading to permanent discontinuation for patients receiving IBRANCE plus letrozole included neutropenia (1.1%) and alanine aminotransferase increase (0.7%).

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 ≥3 adverse reactions (≥5%) in patients receiving IBRANCE plus letrozole by descending frequency were neutropenia, leukopenia, infections, and anemia.

Adverse reactions (≥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 (≥10%) in Study 1
IBRANCE plus Letrozole (N=444) Placebo plus Letrozole (N=222)
Adverse Reaction 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;
*
Infections includes all reported preferred terms (PTs) that are part of the System Organ Class Infections and infestations.
Most common infections (≥1%) include: nasopharyngitis, upper respiratory tract infection, urinary tract infection, oral herpes, sinusitis, rhinitis, bronchitis, influenza, pneumonia, gastroenteritis, conjunctivitis, herpes zoster, pharyngitis, cellulitis, cystitis, lower respiratory tract infection, tooth infection, gingivitis, skin infection, gastroenteritis viral, respiratory tract infection, respiratory tract infection viral, and folliculitis.
Stomatitis includes: aphthous stomatitis, cheilitis, glossitis, glossodynia, mouth ulceration, mucosal inflammation, oral pain, oral discomfort, oropharyngeal pain, and stomatitis.
§
Grade 1 events – 30%; Grade 2 events – 3%.
Grade 1 events – 15%; Grade 2 events – 1%.
#
Rash includes the following PTs: rash, rash maculo-papular, rash pruritic, rash erythematous, rash papular, dermatitis, dermatitis acneiform, and toxic skin eruption.

Infections and infestations

Infections *

60

6

1

42

3

0

Blood and lymphatic system disorders

Neutropenia

80

56

10

6

1

1

Leukopenia

39

24

1

2

0

0

Anemia

24

5

<1

9

2

0

Thrombocytopenia

16

1

<1

1

0

0

Metabolism and nutrition disorders

Decreased appetite

15

1

0

9

0

0

Nervous system disorders

Dysgeusia

10

0

0

5

0

0

Gastrointestinal disorders

Stomatitis

30

1

0

14

0

0

Nausea

35

<1

0

26

2

0

Diarrhea

26

1

0

19

1

0

Vomiting

16

1

0

17

1

0

Skin and subcutaneous tissue disorders

Alopecia

33§

N/A

N/A

16

N/A

N/A

Rash #

18

1

0

12

1

0

Dry skin

12

0

0

6

0

0

General disorders and administration site conditions

Fatigue

37

2

0

28

1

0

Asthenia

17

2

0

12

0

0

Pyrexia

12

0

0

9

0

0

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%).

Table 5. Laboratory Abnormalities in Study 1
IBRANCE plus Letrozole (N=444) Placebo plus Letrozole (N=222)
Laboratory Abnormality All Grades % Grade 3 % Grade 4 % All Grades % Grade 3 % Grade 4 %
N=number of patients; WBC=white blood cells.

WBC decreased

97

35

1

25

1

0

Neutrophils decreased

95

56

12

20

1

1

Anemia

78

6

0

42

2

0

Platelets decreased

63

1

1

14

0

0

Aspartate aminotransferase increased

52

3

0

34

1

0

Alanine aminotransferase increased

43

2

<1

30

0

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 (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.

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 by descending frequency were neutropenia, leukopenia, infections, fatigue, nausea, anemia, stomatitis, diarrhea, thrombocytopenia, vomiting, alopecia, rash, decreased appetite, and pyrexia.

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

Adverse reactions (≥10%) reported in patients who received IBRANCE plus fulvestrant or placebo plus fulvestrant in Study 2 are listed in Table 6.

Table 6. Adverse Reactions (≥10%) 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.
*
Infections includes all reported preferred terms (PTs) that are part of the System Organ Class Infections and infestations.
Most common infections (≥1%) include: nasopharyngitis, upper respiratory infection, urinary tract infection, bronchitis, rhinitis, influenza, conjunctivitis, sinusitis, pneumonia, cystitis, oral herpes, respiratory tract infection, gastroenteritis, tooth infection, pharyngitis, eye infection, herpes simplex, and paronychia.
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

Neutropenia

83

55

11

4

1

0

Leukopenia

53

30

1

5

1

1

Anemia

30

4

0

13

2

0

Thrombocytopenia

23

2

1

0

0

0

Metabolism and nutrition disorders

Decreased appetite

16

1

0

8

1

0

Gastrointestinal disorders

Nausea

34

0

0

28

1

0

Stomatitis

28

1

0

13

0

0

Diarrhea

24

0

0

19

1

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

General disorders and administration site conditions

Fatigue

41

2

0

29

1

0

Pyrexia

13

<1

0

5

0

0

Additional adverse reactions occurring at an overall incidence of <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%).

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

Aspartate aminotransferase increased

43

4

0

48

4

0

Alanine aminotransferase increased

36

2

0

34

0

0

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