Myelosuppression: Neutropenia: Decreased neutrophil counts have been observed very commonly in clinical studies with IBRANCE. In patients receiving IBRANCE in combination with letrozole (PALOMA-1 and PALOMA-2), Grade 3 (ANC 500 <1000/mm3) and Grade 4 (ANC <500/mm3) decreased neutrophil counts were reported.
In PALOMA-1 and PALOMA-2 the median time to first episode of any grade neutropenia was 15 days (12-700 days) and 28 days (range 12-854) for Grade ≥3 neutropenia. The median duration of Grade ≥3 neutropenia was 33 days (range 1-534).
An increase in palbociclib exposure has been associated with more severe neutropenia; in Asian subjects, frequency of Grade ≥3 neutropenia is higher than in White subjects (see Pharmacology: Pharmacokinetics: Special Populations: Asian race under Actions). Febrile neutropenia has been reported in 1.6% of patients receiving palbociclib in combination with letrozole in PALOMA-2. Febrile neutropenia has not been reported in PALOMA-1. Febrile neutropenia has been reported in about 2% of patients exposed to IBRANCE across the overall clinical program (see Infections as follows).
Monitor complete blood count 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.
Dosing interruption, dose reduction or delay in starting treatment cycles is recommended for patients who develop Grade 3 or 4 neutropenia. Appropriate monitoring should be performed (see Table 3 under Dosage & Administration).
Anaemia: Anaemia has been observed very commonly in clinical studies with IBRANCE. In patients receiving IBRANCE in combination with letrozole (PALOMA-1 and PALOMA-2), Grade 3 and Grade 4 anaemia was observed. In PALOMA-1 and PALOMA-2 the median time to first episode of any grade anaemia was 29 days (range 1-777 days) and 195 days (range 14-760) for Grade ≥3 anaemia. The median duration of Grade ≥3 anaemia was 7 days (range 1-125). Across both studies, supportive treatment with red blood cell growth factors and transfusions was administered.
Thrombocytopenia: Thrombocytopenia has been observed very commonly in clinical studies with IBRANCE. In patients receiving IBRANCE in combination with letrozole (PALOMA-1 and PALOMA-2), Grade 3 and Grade 4 thrombocytopenia was observed. In PALOMA-1 and PALOMA-2 the median time to first episode of any grade thrombocytopenia was 27 days (range 2-875 days) and 256 days (range 21-652 days) for Grade ≥3 thrombocytopenia. The median duration of Grade ≥3 thrombocytopenia was 7 days (range 1-28 days).
Interstitial lung disease/pneumonitis: Severe, life-threatening, or fatal ILD and/or pneumonitis can occur in patients treated with cyclin-dependent kinase 4/6 (CDK 4/6) inhibitors, including IBRANCE when taken in combination with endocrine therapy. Across clinical trials, 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), 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 ILD/pneumonitis, interrupt IBRANCE immediately and evaluate the patient. Permanently discontinue IBRANCE in patients with severe ILD or pneumonitis (see Dosage & Administration).
Infections: Since IBRANCE has myelosuppressive properties, it may predispose to infections.
Infections have been reported at a higher rate in patients treated with IBRANCE in randomized clinical studies compared to patients treated in the respective comparator arm. Grades 3 and 4 infections occurred in 4.4% and 0.7%, respectively, in patients treated with IBRANCE in either combination compared to patients treated in the respective comparator arms (2.5% and 0%, respectively).
Monitor patients for signs and symptoms of infection and treat as medically appropriate (see Adverse Reactions).
Physicians should inform patients to promptly report any episodes of fever.
Pre/perimenopausal women: Ovarian ablation or suppression with an LHRH agonist is mandatory when pre/perimenopausal women are administered IBRANCE in combination with an aromatase inhibitor, due to the mechanism of action of aromatase inhibitors. Palbociclib in combination with fulvestrant in pre/perimenopausal women has only been studied in combination with an LHRH agonist.
Critical visceral disease: The efficacy and safety of palbociclib have not been studied in patients with critical visceral disease (see Pharmacology: Pharmacodynamics under Actions).
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 to use effective contraception during treatment with IBRANCE and for at least 3 weeks after the last dose.
Hepatic impairment: Administer IBRANCE with caution to patients with moderate or severe hepatic impairment, with close monitoring of signs of toxicity (see Dosage & Administration and Pharmacology: Pharmacokinetics under Actions).
Renal impairment: Administer IBRANCE with caution to patients with moderate or severe renal impairment, with close monitoring of signs of toxicity (see Dosage & Administration and Pharmacology: Pharmacokinetics under Actions).
Concomitant treatment with inhibitors or inducers of CYP3A4: Strong inhibitors of CYP3A4 may lead to increased toxicity (see Interactions). Concomitant use of strong CYP3A inhibitors during treatment with palbociclib should be avoided. Coadministration should only be considered after careful evaluation of the potential benefits and risks. If coadministration with a strong CYP3A inhibitor is unavoidable, reduce the IBRANCE dose to 75 mg once daily. When the strong inhibitor is discontinued, increase the IBRANCE dose (after 3-5 half-lives of the inhibitor) to the dose used prior to the initiation of the strong CYP3A inhibitor (see Interactions).
Coadministration of CYP3A inducers may lead to decreased palbociclib exposure and consequently a risk for lack of efficacy. Therefore, concomitant use of palbociclib with strong CYP3A4 inducers should be avoided. No dose adjustments are required for coadministration of palbociclib with moderate CYP3A inducers (see Interactions).
Women of child bearing potential or their partners: Women of childbearing potential or their male partners must use a highly effective method of contraception while taking IBRANCE (see Use in Pregnancy & Lactation).
Lactose: This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicine.
Effects on ability to drive and use machines: IBRANCE has minor influence on the ability to drive and use machines. However, patients experiencing fatigue while taking IBRANCE should exercise caution when driving or operating machinery.