Special Warning : אזהרת שימוש

5       WARNINGS AND PRECAUTIONS

5.1     Neutropenia

Neutropenia was the most frequently reported adverse reaction in PALOMA-2 with an incidence of 80% and 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 PALOMA-2 and 66% of patients receiving IBRANCE plus fulvestrant in PALOMA-3. In PALOMA-2 and PALOMA-3, 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 PALOMA-2 and PALOMA-3. One death due to neutropenic sepsis was observed in PALOMA-3. Physicians should inform patients to promptly report any episodes of fever [see Patient Counseling Information (17)].

5.2     Interstitial Lung Disease (ILD)/Pneumonitis

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 postmarketing setting, with fatalities reported [see Adverse Reactions (6.2)].

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 [see Dosage and Administration (2.2)].

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)].

5.4      Lactose

This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption should not take this medicine.

5.5      Sodium

This medicinal product contains less than 1 mmol (23 mg) sodium per capsule, that is to say essentially ‘sodium-free’.

5.6      Driving and using machines

Fatigue is a very common side effect. Patients should take special care when driving or using machines.
5.7 Venous thromboembolism

Venous thromboembolic events were reported in patients treated with IBRANCE (see section ADVERSE REACTIONS). Patients should be monitored for signs and symptoms of deep vein thrombosis and pulmonary embolism, and treated as medically appropriate.


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.

PALOMA-2: 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 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 PALOMA-2. 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 PALOMA-2.

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 PALOMA-2 are listed in Table 4.



                                 Table 4. Adverse Reactions (≥10%) in PALOMA-2
IBRANCE plus Letrozole                     Placebo plus Letrozole
(N=444)                                     (N=222)
Adverse Reaction                       All Grades Grade 3     Grade 4           All Grades Grade 3        Grade 4 %         %          %                   %            %            %
Infections and infestations
Infectionsa                               60b             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
Stomatitisc                               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                                  33d          N/A            N/A            16e            N/A          N/A f
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 Grading according to CTCAE 4.0.
CTCAE=Common Terminology Criteria for Adverse Events; N=number of patients; N/A=not applicable; a
Infections includes all reported preferred terms (PTs) that are part of the System Organ Class Infections and infestations.
b
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.
c
Stomatitis includes: aphthous stomatitis, cheilitis, glossitis, glossodynia, mouth ulceration, mucosal inflammation, oral pain, oral discomfort, oropharyngeal pain, and stomatitis.
d
Grade 1 events – 30%; Grade 2 events – 3%.
e
Grade 1 events – 15%; Grade 2 events – 1%.
f
Rash includes the following PTs: rash, rash maculo-papular, rash pruritic, rash erythematous, rash papular, dermatitis, dermatitis acneiform, and toxic skin eruption.

Additional adverse reactions occurring at an overall incidence of <10.0% of patients receiving IBRANCE plus letrozole in PALOMA-2 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 PALOMA-2
IBRANCE plus Letrozole         Placebo plus Letrozole
(N=444)                         (N=222)
Laboratory Abnormality         All   Grade     Grade 4      All      Grade 3 Grade 4 Grades     3        %         Grades      %          %
%       %                    %
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                      52       3         0         34          1          0 aminotransferase increased
Alanine aminotransferase    43            2           <1    30        0         0 increased
N=number of patients; WBC=white blood cells.

PALOMA-3: 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 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 PALOMA-3. 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 PALOMA-3.

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 PALOMA-3 are listed in Table 6.



                              Table 6. Adverse Reactions (≥10%) in PALOMA-3
IBRANCE plus Fulvestrant                   Placebo plus Fulvestrant
(N=345)                                     (N=172)
Adverse Reaction
All Grades Grade 3     Grade 4            All Grades Grade 3        Grade 4 %        %            %                   %           %           %
Infections and infestations
Infectionsa                     47b            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 Stomatitisc                     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                      18d            N/A            N/A            6e           N/A           N/A f
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 Grading according to CTCAE 4.0.
CTCAE=Common Terminology Criteria for Adverse Events; N=number of patients; N/A=not applicable.
a
Infections includes all reported preferred terms (PTs) that are part of the System Organ Class Infections and infestations.
b
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.
c
Stomatitis includes: aphthous stomatitis, cheilitis, glossitis, glossodynia, mouth ulceration, mucosal inflammation, oral pain, oropharyngeal discomfort, oropharyngeal pain, stomatitis.
d
Grade 1 events – 17%; Grade 2 events – 1%.
e
Grade 1 events – 6%.
f
Rash includes: rash, rash maculo-papular, rash pruritic, rash erythematous, rash papular, dermatitis, dermatitis acneiform, toxic skin eruption.

Additional adverse reactions occurring at an overall incidence of <10.0% of patients receiving IBRANCE plus fulvestrant in PALOMA-3 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 PALOMA-3
IBRANCE plus Fulvestrant          Placebo plus Fulvestrant
(N=345)                           (N=172)
Laboratory Abnormality
All Grades  Grade 3   Grade 4   All Grades    Grade 3     Grade 4
%         %          %          %           %           %
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
43            4           0      48           4           0 increased
Alanine aminotransferase
36            2           0      34           0           0 increased
N=number of patients; WBC=white blood cells.

6.2     Postmarketing Experience

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 Skin and Subcutaneous Tissue Disorders: Palmar-plantar erythrodysesthesia syndrome (PPES) Vascular disorders: Venous thromboembolism - Venous thromboembolism includes the following PTs: pulmonary embolism, embolism, deep vein thrombosis, peripheral embolism, thrombosis.

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.

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product.
Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form https://sideeffects.health.gov.il.

Effects on Driving