Serious Warnings and Precautions
IBRANCE (palbociclib) should be prescribed and managed by a qualified physician who is experienced in the use of anti-cancer agents.
The following is a significant adverse drug reaction identified in clinical trials conducted with IBRANCE:
Effects on ability to drive and use machines
No studies of the effects of IBRANCE (palbociclib) on the ability to drive or operate machinery have been conducted. However, since fatigue and dizziness have been reported with the use of IBRANCE, patients should exercise caution when driving or operating machinery while taking IBRANCE.
An increased incidence of palbociclib-related microglial cell tumors was observed in the central nervous system of male rats; there were no neoplastic findings in female rats or in mice. The No Observed Effect Level [NOEL] for palbociclib-related carcinogenicity effects in rats was approximately 2-4 times the human clinical exposure based on AUC. The relevance of the male rat neoplastic finding to humans is unknown (see TOXICOLOGY, Carcinogenicity).
Cardiac Electrophysiology
The effect of palbociclib in combination with letrozole on the QT interval corrected for heart rate (QTc) was evaluated using time-matched electrocardiograms (ECGs) evaluating the change from baseline in 77 patients with breast cancer from an ECG substudy of PALOMA-2. This study suggested that palbociclib at 125 mg once daily (Schedule 3/1), when added to letrozole, had no large effect on QTc (i.e., >20 msec) (see ACTION AND CLINICAL PHARMACOLOGY).
Neutropenia was the most frequently reported adverse reaction in patients treated with IBRANCE plus letrozole (80%) or IBRANCE plus fulvestrant (83%). Grade 3 decreased neutrophil counts were observed in approximately half of all patients, and Grade 4 decreased neutrophil counts were observed in 5% and 11% of patients treated with IBRANCE in combination with letrozole or fulvestrant, respectively [see ADVERSE REACTIONS].
The median time to first episode of any grade neutropenia was 15 days and the median duration of Grade ≥3 neutropenia was 7 days.
Febrile neutropenia has been reported in 1.8% of patients across the IBRANCE clinical trials. One patient treated with IBRANCE plus fulvestrant died due to neutropenic sepsis. Physicians should inform patients to promptly report any episodes of fever.
Monitor complete blood count prior to the start of IBRANCE therapy at the beginning of each cycle, as well as on Day 15 of the first 2 cycles, and as clinically indicated [see WARNINGS AND PRECAUTIONS, Monitoring and Laboratory Tests]. 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]. For patients who experience Grade 3 neutropenia, consider repeating complete blood count monitoring one week later.
Decreases in leukocytes and platelets were observed in patients treated with either IBRANCE plus letrozole or IBRANCE plus fulvestrant. Grade 3 leukopenia was reported in 24% of IBRANCE plus letrozole patients and in 30% of IBRANCE plus fulvestrant patients. Decreased hemoglobin and lymphocytes were also observed in IBRANCE plus letrozole-treated patients [see ADVERSE REACTIONS].
In clinical trials with IBRANCE, anemia and leukopenia were usually managed with temporary IBRANCE discontinuation and/or dose reduction. Monitor complete blood count prior to the start of IBRANCE therapy, at the beginning of each cycle, as well as on Day 15 of the first 2 cycles, and as clinically indicated [see WARNINGS AND PRECAUTIONS, Monitoring and Laboratory Tests and DOSAGE AND ADMINISTRATION].
IBRANCE may predispose patients to infections. Infections have been more frequently reported in patients treated with IBRANCE plus letrozole (60%) and in patients treated with IBRANCE plus fulvestrant (47%) than those treated in the respective comparator arms (42% and 31%, respectively). Grade ≥3 infections occurred in 6% of patients treated with IBRANCE plus letrozole and in 3% of patients treated with letrozole alone. Grade ≥3 infections occurred in 3% of patients treated with either IBRANCE plus fulvestrant or placebo plus fulvestrant. Monitor patients for signs and symptoms of infection and treat as medically appropriate (see WARNINGS AND PRECAUTIONS, Monitoring and Laboratory Tests). Physicians should be aware of the increased risk of infection with IBRANCE and should inform patients to promptly report any episodes of fever.
Severe, life-threatening, or fatal interstitial lung disease (ILD)/pneumonitis can occur in patients treated with IBRANCE when taken in combination with endocrine therapy.
Across clinical trials (PALOMA-1, PALOMA-2, PALOMA-3, n=872), 1.4% of IBRANCE-treated patients had ILD/pneumonitis of any grade, 0.1% had Grade 3 and no Grade 4 or fatal cases were reported. Additional cases of ILD/pneumonitis have been observed in the post-marketing setting (see ADVERSE REACTIONS, Postmarketing Experience), with fatalities reported.
Patients should be monitored 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 ILD/pneumonitis, interrupt IBRANCE immediately and evaluate the patient. IBRANCE should be permanently discontinued in patients diagnosed with severe drug-related ILD/pneumonitis (see DOSAGE AND ADMINSTRATION).
CYP3A inhibitors: Concomitant use of IBRANCE and CYP3A inhibitors (e.g. clarithromycin, itraconazole, ritonavir, ketoconazole, grapefruit or grapefruit juice) may increase exposure to palbociclib. In patients receiving IBRANCE, coadministration of a strong CYP3A inhibitor should be avoided (see DRUG INTERACTIONS).
CYP3A substrates: Concomitant use of IBRANCE and a CYP3A substrate may increase exposure to the CYP3A substrate. Caution is warranted when IBRANCE is co-administered with CYP3A substrates of narrow therapeutic index, such as alfentanil, cyclosporine, dihydroergotamine, or ergotamine (see DRUG INTERACTIONS).
CYP3A inducers: Concomitant use of IBRANCE and CYP3A inducers (e.g. strong inducers such as rifampin, carbamazepine, phenytoin, St John’s Wort, and moderate inducers such as nafcillin, bosentan, modafinil) may decrease palbociclib plasma concentration. In patients receiving IBRANCE, coadministration of strong CYP3A inducers should be avoided (see DRUG INTERACTIONS).
No clinical data have been obtained on fertility in humans. There were no effects on estrous cycle or mating and fertility in female rats in nonclinical studies. [see Special Populations]. Based on nonclinical safety findings in male reproductive tissues, male fertility may be impaired by treatment with IBRANCE [see PART II TOXICOLOGY, Reproductive and Developmental Toxicity]. Men should consider sperm preservation prior to beginning therapy with IBRANCE. Because of the potential for genotoxicity, male patients with female partners of childbearing potential should use adequate contraceptive methods during therapy and for at least 97 days after completing therapy.
Special Populations:
Pregnant Women: There are no adequate and well-controlled studies using IBRANCE in pregnant women.
IBRANCE may cause fetal harm when administered to a pregnant woman. In animal studies, palbociclib was shown to be fetotoxic in pregnant rats and rabbits [see PART II TOXICOLOGY].
IBRANCE should not be used during pregnancy. If IBRANCE is used in women of childbearing potential, advise the patient to avoid becoming pregnant with the use of adequate contraceptive methods during therapy and for at least 21 days after completing therapy. If the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.
Nursing Women: It is not known whether palbociclib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from IBRANCE, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the patient.
Pediatrics (< 18 years of age): Based on the limited data submitted and reviewed by Health Canada, the safety and efficacy of IBRANCE in pediatric patients have not been established; Therefore, Health Canada has not authorized an indication for pediatric use.
In a Phase 1 pediatric study the safety was evaluated in 34 patients (≥4 years and ≤21 years of age) including 30 pediatric patients (≥4 years and ˂ 18 years of age) with progressive or refractory brain tumors (except low grade gliomas) with intact Rb protein. The maximum tolerated dose was determined to be 75 mg/m2 administered orally once daily for 21 days of a 28-day cycle. Similar to the side effect profile in adults, the most common adverse events were related to myelosuppression with decrease in white blood cells, neutrophils, lymphocytes, and platelets being the most common. The overall safety profile was consistent with that reported from palbociclib use in adults and the diseases under study.
Geriatrics (≥ 65 years of age): Population pharmacokinetic analysis was performed on data from 183 patients with cancer in an age range from 22 to 89 years. There was no clinically important difference in palbociclib exposure in patients ≥65 years of age compared with patients <65 years of age. In IBRANCE plus letrozole-treated patients, anemia was reported more frequently in patients ≥65 years of age than in those <65 years of age, whereas similar incidences were reported in both age groups in patients treated with IBRANCE plus fulvestrant.
Hepatic Impairment: The pharmacokinetics of palbociclib has been studied in subjects with hepatic impairment. No dose adjustment is required for patients with mild or moderate hepatic impairment (Child-Pugh classes A and B). The recommended dose of IBRANCE for patients with severe hepatic impairment (Child-Pugh class C) is 75 mg once daily on Schedule 3/1 [see DOSAGE AND ADMINISTRATION and ACTION AND CLINICAL PHARMACOLOGY, Pharmacokinetics]. There are no efficacy and safety data available for IBRANCE in breast cancer patients with hepatic impairment. Monitor patients for signs of toxicity.
Renal Impairment: The pharmacokinetics of palbociclib has been studied in subjects with renal impairment. No dose adjustments are required for patients with mild, moderate, or severe renal impairment. The pharmacokinetics of palbociclib have not been studied in patients requiring hemodialysis [see DOSAGE AND ADMINISTRATION and ACTION AND CLINICAL PHARMACOLOGY, Pharmacokinetics]. There are no efficacy and safety data available for IBRANCE in breast cancer patients with renal impairment.
Patients treated with IBRANCE should be monitored for signs and symptoms of myelosuppression and infection. Dose modification may be required [see DOSAGE AND ADMINISTRATION].
Monitor complete blood count prior to starting IBRANCE therapy and at the beginning of each cycle, as well as on Day 15 of the first two cycles, and as clinically indicated.
For patients who experience Grade 3 neutropenia, consider repeating complete blood count monitoring one week later. For patients who develop Grade 3 or 4 neutropenia, refer to the dose modification tables [see DOSAGE AND ADMINISTRATION].
)Serious Warnings and Precautions
IBRANCE (palbociclib) should be prescribed and managed by a qualified physician who is experienced in the use of anti-cancer agents.
The following is a significant adverse drug reaction identified in clinical trials conducted with IBRANCE:
Effects on ability to drive and use machines
No studies of the effects of IBRANCE (palbociclib) on the ability to drive or operate machinery have been conducted. However, since fatigue and dizziness have been reported with the use of IBRANCE, patients should exercise caution when driving or operating machinery while taking IBRANCE.
An increased incidence of palbociclib-related microglial cell tumors was observed in the central nervous system of male rats; there were no neoplastic findings in female rats or in mice. The No Observed Effect Level [NOEL] for palbociclib-related carcinogenicity effects in rats was approximately 2-4 times the human clinical exposure based on AUC. The relevance of the male rat neoplastic finding to humans is unknown (see TOXICOLOGY, Carcinogenicity).
Cardiac Electrophysiology
The effect of palbociclib in combination with letrozole on the QT interval corrected for heart rate (QTc) was evaluated using time-matched electrocardiograms (ECGs) evaluating the change from baseline in 77 patients with breast cancer from an ECG substudy of PALOMA-2. This study suggested that palbociclib at 125 mg once daily (Schedule 3/1), when added to letrozole, had no large effect on QTc (i.e., >20 msec) (see ACTION AND CLINICAL PHARMACOLOGY).
Neutropenia was the most frequently reported adverse reaction in patients treated with IBRANCE plus letrozole (80%) or IBRANCE plus fulvestrant (83%). Grade 3 decreased neutrophil counts were observed in approximately half of all patients, and Grade 4 decreased neutrophil counts were observed in 5% and 11% of patients treated with IBRANCE in combination with letrozole or fulvestrant, respectively [see ADVERSE REACTIONS].
The median time to first episode of any grade neutropenia was 15 days and the median duration of Grade ≥3 neutropenia was 7 days.
Febrile neutropenia has been reported in 1.8% of patients across the IBRANCE clinical trials. One patient treated with IBRANCE plus fulvestrant died due to neutropenic sepsis. Physicians should inform patients to promptly report any episodes of fever.
Monitor complete blood count prior to the start of IBRANCE therapy at the beginning of each cycle, as well as on Day 15 of the first 2 cycles, and as clinically indicated [see WARNINGS AND PRECAUTIONS, Monitoring and Laboratory Tests]. 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]. For patients who experience Grade 3 neutropenia, consider repeating complete blood count monitoring one week later.
Decreases in leukocytes and platelets were observed in patients treated with either IBRANCE plus letrozole or IBRANCE plus fulvestrant. Grade 3 leukopenia was reported in 24% of IBRANCE plus letrozole patients and in 30% of IBRANCE plus fulvestrant patients. Decreased hemoglobin and lymphocytes were also observed in IBRANCE plus letrozole-treated patients [see ADVERSE REACTIONS].
In clinical trials with IBRANCE, anemia and leukopenia were usually managed with temporary IBRANCE discontinuation and/or dose reduction. Monitor complete blood count prior to the start of IBRANCE therapy, at the beginning of each cycle, as well as on Day 15 of the first 2 cycles, and as clinically indicated [see WARNINGS AND PRECAUTIONS, Monitoring and Laboratory Tests and DOSAGE AND ADMINISTRATION].
IBRANCE may predispose patients to infections. Infections have been more frequently reported in patients treated with IBRANCE plus letrozole (60%) and in patients treated with IBRANCE plus fulvestrant (47%) than those treated in the respective comparator arms (42% and 31%, respectively). Grade ≥3 infections occurred in 6% of patients treated with IBRANCE plus letrozole and in 3% of patients treated with letrozole alone. Grade ≥3 infections occurred in 3% of patients treated with either IBRANCE plus fulvestrant or placebo plus fulvestrant. Monitor patients for signs and symptoms of infection and treat as medically appropriate (see WARNINGS AND PRECAUTIONS, Monitoring and Laboratory Tests). Physicians should be aware of the increased risk of infection with IBRANCE and should inform patients to promptly report any episodes of fever.
Severe, life-threatening, or fatal interstitial lung disease (ILD)/pneumonitis can occur in patients treated with IBRANCE when taken in combination with endocrine therapy.
Across clinical trials (PALOMA-1, PALOMA-2, PALOMA-3, n=872), 1.4% of IBRANCE-treated patients had ILD/pneumonitis of any grade, 0.1% had Grade 3 and no Grade 4 or fatal cases were reported. Additional cases of ILD/pneumonitis have been observed in the post-marketing setting (see ADVERSE REACTIONS, Postmarketing Experience), with fatalities reported.
Patients should be monitored 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 ILD/pneumonitis, interrupt IBRANCE immediately and evaluate the patient. IBRANCE should be permanently discontinued in patients diagnosed with severe drug-related ILD/pneumonitis (see DOSAGE AND ADMINSTRATION).
CYP3A inhibitors: Concomitant use of IBRANCE and CYP3A inhibitors (e.g. clarithromycin, itraconazole, ritonavir, ketoconazole, grapefruit or grapefruit juice) may increase exposure to palbociclib. In patients receiving IBRANCE, coadministration of a strong CYP3A inhibitor should be avoided (see DRUG INTERACTIONS).
CYP3A substrates: Concomitant use of IBRANCE and a CYP3A substrate may increase exposure to the CYP3A substrate. Caution is warranted when IBRANCE is co-administered with CYP3A substrates of narrow therapeutic index, such as alfentanil, cyclosporine, dihydroergotamine, or ergotamine (see DRUG INTERACTIONS).
CYP3A inducers: Concomitant use of IBRANCE and CYP3A inducers (e.g. strong inducers such as rifampin, carbamazepine, phenytoin, St John’s Wort, and moderate inducers such as nafcillin, bosentan, modafinil) may decrease palbociclib plasma concentration. In patients receiving IBRANCE, coadministration of strong CYP3A inducers should be avoided (see DRUG INTERACTIONS).
No clinical data have been obtained on fertility in humans. There were no effects on estrous cycle or mating and fertility in female rats in nonclinical studies. [see Special Populations]. Based on nonclinical safety findings in male reproductive tissues, male fertility may be impaired by treatment with IBRANCE [see PART II TOXICOLOGY, Reproductive and Developmental Toxicity]. Men should consider sperm preservation prior to beginning therapy with IBRANCE. Because of the potential for genotoxicity, male patients with female partners of childbearing potential should use adequate contraceptive methods during therapy and for at least 97 days after completing therapy.
Special Populations:
Pregnant Women: There are no adequate and well-controlled studies using IBRANCE in pregnant women.
IBRANCE may cause fetal harm when administered to a pregnant woman. In animal studies, palbociclib was shown to be fetotoxic in pregnant rats and rabbits [see PART II TOXICOLOGY].
IBRANCE should not be used during pregnancy. If IBRANCE is used in women of childbearing potential, advise the patient to avoid becoming pregnant with the use of adequate contraceptive methods during therapy and for at least 21 days after completing therapy. If the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.
Nursing Women: It is not known whether palbociclib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from IBRANCE, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the patient.
Pediatrics (< 18 years of age): Based on the limited data submitted and reviewed by Health Canada, the safety and efficacy of IBRANCE in pediatric patients have not been established; Therefore, Health Canada has not authorized an indication for pediatric use.
In a Phase 1 pediatric study the safety was evaluated in 34 patients (≥4 years and ≤21 years of age) including 30 pediatric patients (≥4 years and ˂ 18 years of age) with progressive or refractory brain tumors (except low grade gliomas) with intact Rb protein. The maximum tolerated dose was determined to be 75 mg/m2 administered orally once daily for 21 days of a 28-day cycle. Similar to the side effect profile in adults, the most common adverse events were related to myelosuppression with decrease in white blood cells, neutrophils, lymphocytes, and platelets being the most common. The overall safety profile was consistent with that reported from palbociclib use in adults and the diseases under study.
Geriatrics (≥ 65 years of age): Population pharmacokinetic analysis was performed on data from 183 patients with cancer in an age range from 22 to 89 years. There was no clinically important difference in palbociclib exposure in patients ≥65 years of age compared with patients <65 years of age. In IBRANCE plus letrozole-treated patients, anemia was reported more frequently in patients ≥65 years of age than in those <65 years of age, whereas similar incidences were reported in both age groups in patients treated with IBRANCE plus fulvestrant.
Hepatic Impairment: The pharmacokinetics of palbociclib has been studied in subjects with hepatic impairment. No dose adjustment is required for patients with mild or moderate hepatic impairment (Child-Pugh classes A and B). The recommended dose of IBRANCE for patients with severe hepatic impairment (Child-Pugh class C) is 75 mg once daily on Schedule 3/1 [see DOSAGE AND ADMINISTRATION and ACTION AND CLINICAL PHARMACOLOGY, Pharmacokinetics]. There are no efficacy and safety data available for IBRANCE in breast cancer patients with hepatic impairment. Monitor patients for signs of toxicity.
Renal Impairment: The pharmacokinetics of palbociclib has been studied in subjects with renal impairment. No dose adjustments are required for patients with mild, moderate, or severe renal impairment. The pharmacokinetics of palbociclib have not been studied in patients requiring hemodialysis [see DOSAGE AND ADMINISTRATION and ACTION AND CLINICAL PHARMACOLOGY, Pharmacokinetics]. There are no efficacy and safety data available for IBRANCE in breast cancer patients with renal impairment.
Patients treated with IBRANCE should be monitored for signs and symptoms of myelosuppression and infection. Dose modification may be required [see DOSAGE AND ADMINISTRATION].
Monitor complete blood count prior to starting IBRANCE therapy and at the beginning of each cycle, as well as on Day 15 of the first two cycles, and as clinically indicated.
For patients who experience Grade 3 neutropenia, consider repeating complete blood count monitoring one week later. For patients who develop Grade 3 or 4 neutropenia, refer to the dose modification tables [see DOSAGE AND ADMINISTRATION].
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