Ibrance · 4.6 Fertility, pregnancy and lactation · 2

HOS-097237 · has-adverse-reaction-information · PDF-Seite 9

Summary of the safety profile The overall safety profile of IBRANCE is based on pooled data from 872 patients who received palbociclib in combination with endocrine therapy (N=527 in combination with letrozole and N=345 in combination with fulvestrant) in randomised clinical studies in HR-positive, HER2-negative advanced or metastatic breast cancer. The most common (≥ 20%) adverse reactions of any grade reported in patients receiving palbociclib in randomised clinical studies were neutropenia, infections, leukopenia, fatigue, nausea, stomatitis, anaemia, diarrhoea, alopecia and thrombocytopenia. The most common (≥ 2%) Grade ≥ 3 adverse 9 reactions of palbociclib were neutropenia, leukopenia, infections, anaemia, aspartate aminotransferase (AST) increased, fatigue, and alanine aminotransferase (ALT) increased. Dose reductions or dose modifications due to any adverse reaction occurred in 38.4% of patients receiving IBRANCE in randomised clinical studies regardless of the combination. Permanent discontinuation due to an adverse reaction occurred in 5.2% of patients receiving IBRANCE in randomised clinical studies regardless of the combination. Tabulated list of adverse reactions Table 4 reports the adverse reactions from the pooled dataset of 3 randomised studies. The median duration of palbociclib treatment across the pooled dataset at the time of the final overall survival (OS) analysis was 14.8 months. Table 5 reports the laboratory abnormalities observed in pooled datasets from 3 randomised studies. The adverse reactions are listed by system organ class and frequency category. Frequency categories are defined as: very common (≥ 1/10), common (≥ 1/100 to < 1/10), and uncommon (≥ 1/1,000 to < 1/100). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. Table 4. Adverse reactions based on pooled dataset from 3 randomised studies (N=872) and during post-marketing experience System organ class All Grades Grade 3 Grade 4 Frequency n (%) n (%) n (%) Preferred terma (PT) Infections and infestations Very common Infectionsb 516 (59.2) 49 (5.6) 8 (0.9) Blood and lymphatic system disorders Very common Neutropeniac

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HOS-097243 · has-adverse-reaction-information · PDF-Seite 33

Summary of the safety profile The overall safety profile of IBRANCE is based on pooled data from 872 patients who received palbociclib in combination with endocrine therapy (N=527 in combination with letrozole and N=345 in combination with fulvestrant) in randomised clinical studies in HR-positive, HER2-negative advanced or metastatic breast cancer. The most common (≥ 20%) adverse reactions of any grade reported in patients receiving palbociclib in randomised clinical studies were neutropenia, infections, leukopenia, fatigue, nausea, stomatitis, anaemia, diarrhoea, alopecia and thrombocytopenia. The most common (≥ 2%) Grade ≥ 3 adverse reactions of palbociclib were neutropenia, leukopenia, infections, anaemia, aspartate aminotransferase (AST) increased, fatigue, and alanine aminotransferase (ALT) increased. Dose reductions or dose modifications due to any adverse reaction occurred in 38.4% of patients receiving IBRANCE in randomised clinical studies regardless of the combination. Permanent discontinuation due to an adverse reaction occurred in 5.2% of patients receiving IBRANCE in randomised clinical studies regardless of the combination. Tabulated list of adverse reactions Table 4 reports the adverse reactions from the pooled dataset of 3 randomised studies. The median duration of palbociclib treatment across the pooled dataset at the time of the final OS analysis was 14.8 months. Table 5 reports the laboratory abnormalities observed in pooled datasets from 3 randomised studies. The adverse reactions are listed by system organ class and frequency category. Frequency categories are defined as: very common (≥ 1/10), common (≥ 1/100 to < 1/10), and uncommon (≥ 1/1,000 to < 1/100). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. Table 4. Adverse reactions based on pooled dataset from 3 randomised studies (N=872) and during post-marketing experience System Organ Class All Grades Grade 3 Grade 4 Frequency n (%) n (%) n (%) Preferred terma (PT) Infections and infestations 33 Table 4. Adverse reactions based on pooled dataset from 3 randomised studies (N=872) and during post-marketing experience System Organ Class All Grades Grade 3 Gra

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HOS-097233 · has-contraindication-information · PDF-Seite 5

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Use of preparations containing St. John’s Wort (see section 4.5).

HOS-097239 · has-contraindication-information · PDF-Seite 29

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Use of preparations containing St. John’s Wort (see section 4.5).

HOS-097238 · has-indication-information · PDF-Seite 26

IBRANCE is indicated for the treatment of hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative locally advanced or metastatic breast cancer: - in combination with an aromatase inhibitor; - in combination with fulvestrant in women who have received prior endocrine therapy (see section 5.1). In pre- or perimenopausal women, the endocrine therapy should be combined with a luteinizing hormone-releasing hormone (LHRH) agonist.

HOS-097232 · has-indication-information · PDF-Seite 3

IBRANCE is indicated for the treatment of hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative locally advanced or metastatic breast cancer: - in combination with an aromatase inhibitor; - in combination with fulvestrant in women who have received prior endocrine therapy (see section 5.1). In pre- or perimenopausal women, the endocrine therapy should be combined with a luteinizing hormone-releasing hormone (LHRH) agonist.

HOS-097241 · has-interaction-information · PDF-Seite 30

30 Palbociclib is primarily metabolised by CYP3A and sulphotransferase (SULT) enzyme SULT2A1. In vivo, palbociclib is a weak, time-dependent inhibitor of CYP3A. Effects of other medicinal products on the pharmacokinetics of palbociclib Effect of CYP3A inhibitors Coadministration of multiple 200 mg doses of itraconazole with a single 125 mg palbociclib dose increased palbociclib total exposure (AUCinf) and the peak concentration (Cmax) by approximately 87% and 34%, respectively, relative to a single 125 mg palbociclib dose given alone. The concomitant use of strong CYP3A inhibitors including, but not limited to: clarithromycin, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, posaconazole, saquinavir, telaprevir, telithromycin, voriconazole, and grapefruit or grapefruit juice, should be avoided (see sections 4.2 and 4.4). No dose adjustments are needed for mild and moderate CYP3A inhibitors. Effect of CYP3A inducers Coadministration of multiple 600 mg doses of rifampin with a single 125 mg palbociclib dose decreased palbociclib AUCinf and Cmax by 85% and 70%, respectively, relative to a single 125 mg palbociclib dose given alone. The concomitant use of strong CYP3A inducers including, but not limited to: carbamazepine, enzalutamide, phenytoin, rifampin, and St. John’s Wort should be avoided (see sections 4.3 and 4.4). Coadministration of multiple 400 mg daily doses of modafinil, a moderate CYP3A inducer, with a single 125 mg IBRANCE dose decreased palbociclib AUCinf and Cmax by 32% and 11%, respectively, relative to a single 125 mg IBRANCE dose given alone. No dose adjustments are required for moderate CYP3A inducers (see section 4.4). Effect of acid reducing agents Coadministration of multiple doses of the PPI rabeprazole with a single 125 mg IBRANCE tablet under fasted conditions had no effect on the rate and extent of absorption of palbociclib when compared to a single 125 mg IBRANCE tablet administered alone. Given the reduced effect on gastric pH of H2-receptor antagonists and local antacids compared to PPIs, no clinically relevant effect of H2-receptor antagonists or local antacids on palbociclib exposure is expected. Effects of palbociclib on the pharmacokinetics of other medicinal products Palbociclib is a weak, time-dependent inhibitor of CYP3A following daily 125 mg dosing at steady state. Coadministration of multiple doses of palbociclib with midazolam increased the midazolam AUCinf and Cmax values

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HOS-097235 · has-interaction-information · PDF-Seite 7

Palbociclib is primarily metabolised by CYP3A and sulphotransferase (SULT) enzyme SULT2A1. In vivo, palbociclib is a weak, time-dependent inhibitor of CYP3A. Effects of other medicinal products on the pharmacokinetics of palbociclib Effect of CYP3A inhibitors Coadministration of multiple 200 mg doses of itraconazole with a single 125 mg palbociclib dose increased palbociclib total exposure (AUCinf) and the peak concentration (Cmax) by approximately 87% and 34%, respectively, relative to a single 125 mg palbociclib dose given alone. The concomitant use of strong CYP3A inhibitors including, but not limited to: clarithromycin, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, posaconazole, saquinavir, telaprevir, telithromycin, voriconazole, and grapefruit or grapefruit juice, should be avoided (see sections 4.2 and 4.4). No dose adjustments are needed for mild and moderate CYP3A inhibitors. Effect of CYP3A inducers Coadministration of multiple 600 mg doses of rifampin with a single 125 mg palbociclib dose decreased palbociclib AUCinf and Cmax by 85% and 70%, respectively, relative to a single 125 mg palbociclib dose given alone. The concomitant use of strong CYP3A inducers including, but not limited to: carbamazepine, enzalutamide, phenytoin, rifampin, and St. John’s Wort should be avoided (see sections 4.3 and 4.4). Coadministration of multiple 400 mg daily doses of modafinil, a moderate CYP3A inducer, with a single 125 mg IBRANCE dose decreased palbociclib AUCinf and Cmax by 32% and 11%, respectively, relative to a single 125 mg IBRANCE dose given alone. No dose adjustments are required for moderate CYP3A inducers (see section 4.4). Effect of acid reducing agents Under fed conditions (intake of a moderate-fat meal), coadministration of multiple doses of the proton pump inhibitor (PPI) rabeprazole with a single dose of 125 mg IBRANCE decreased palbociclib Cmax 7 by 41%, but had limited impact on AUCinf (13% decrease) compared with a single dose of 125 mg IBRANCE administered alone. Under fasting conditions, the coadministration of multiple doses of the PPI rabeprazole with a single dose of 125 mg IBRANCE decreased palbociclib AUCinf and Cmax by 62% and 80%, respectively. Therefore, IBRANCE should be taken with food, preferably a meal (see sections 4.2 and 5.2). Given the reduced effect on gastric pH of H2-receptor antagonists and local antacids compared to PPI

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HOS-097236 · has-pregnancy-information · PDF-Seite 9

Women of childbearing potential/Contraception in males and females Females of childbearing potential who are receiving this medicinal product, or their male partners should use adequate contraceptive methods (e.g., double-barrier contraception) during therapy and for at least 3 weeks or 14 weeks after completing therapy for females and males, respectively (see section 4.5). Pregnancy There are no or limited amount of data from the use of palbociclib in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). IBRANCE is not recommended during pregnancy and in women of childbearing potential not using contraception. Breast-feeding No studies have been conducted in humans or animals to assess the effect of palbociclib on milk production, its presence in breast milk, or its effects on the breast-fed child. It is unknown whether palbociclib is excreted in human milk. Patients receiving palbociclib should not breast-feed. Fertility There were no effects on oestrous cycle (female rats) or mating and fertility in rats (male or female) in non-clinical reproductive studies. However, no clinical data have been obtained on fertility in humans. Based on male reproductive organ findings (seminiferous tubule degeneration in testis, epididymal hypospermia, lower sperm motility and density, and decreased prostate secretion) in nonclinical safety studies, male fertility may be compromised by treatment with palbociclib (see section 5.3). Thus, men may consider sperm preservation prior to beginning therapy with IBRANCE.

HOS-097242 · has-pregnancy-information · PDF-Seite 32

Women of childbearing potential/Contraception in males and females Females of childbearing potential who are receiving this medicinal product, or their male partners should use adequate contraceptive methods (e.g., double-barrier contraception) during therapy and for at least 3 weeks or 14 weeks after completing therapy for females and males, respectively (see section 4.5). Pregnancy There are no or limited amount of data from the use of palbociclib in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). IBRANCE is not recommended during pregnancy and in women of childbearing potential not using contraception. Breast-feeding 32 No studies have been conducted in humans or animals to assess the effect of palbociclib on milk production, its presence in breast milk, or its effects on the breast-fed child. It is unknown whether palbociclib is excreted in human milk. Patients receiving palbociclib should not breast-feed. Fertility There were no effects on oestrous cycle (female rats) or mating and fertility in rats (male or female) in non-clinical reproductive studies. However, no clinical data have been obtained on fertility in humans. Based on male reproductive organ findings (seminiferous tubule degeneration in testis, epididymal hypospermia, lower sperm motility and density, and decreased prostate secretion) in non-clinical safety studies, male fertility may be compromised by treatment with palbociclib (see section 5.3). Thus, men may consider sperm preservation prior to beginning therapy with IBRANCE.

HOS-097240 · has-warning-information · PDF-Seite 29

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 section 5.1). Haematological disorders Dose 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 sections 4.2 and 4.8). Interstitial lung disease/pneumonitis Severe, life-threatening, or fatal ILD and/or pneumonitis can occur in patients treated with IBRANCE when taken in combination with endocrine therapy. Across clinical studies (PALOMA-1, PALOMA-2, PALOMA-3), 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, with fatalities reported (see section 4.8). Patients should be monitored for pulmonary symptoms indicative of ILD/pneumonitis (e.g. hypoxia, cough, dyspnoea). In patients who have new or worsening respiratory symptoms and are suspected to 29 have developed ILD/pneumonitis, IBRANCE should be immediately interrupted and the patient should be evaluated. IBRANCE should be permanently discontinued in patients with severe ILD or pneumonitis (see section 4.2). Infections Since IBRANCE has myelosuppressive properties, it may predispose patients to infections. Infections have been reported at a higher rate in patients treated with IBRANCE in randomised clinical studies compared to patients treated in the respective comparator arm. Grade 3 and Grade 4 infections occurred respectively in 5.6% and 0.9% of patients treated with IBRANCE in any combination (see section 4.8). Patients should be monitored for signs and symptoms of infection and treated as medically appropriate (see section 4.2). Physicians should inform patients to promptly report any episodes of fever. Venous thromboembolism Venous thromboembolic events were reported in patients treated with IBRANCE (see section 4.8). Patients should be m

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HOS-097234 · has-warning-information · PDF-Seite 5

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 section 5.1). Haematological disorders Dose 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 sections 4.2 and 4.8). 5 Interstitial lung disease/pneumonitis Severe, life-threatening, or fatal ILD and/or pneumonitis can occur in patients treated with IBRANCE when taken in combination with endocrine therapy. Across clinical studies (PALOMA-1, PALOMA-2, PALOMA-3), 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, with fatalities reported (see section 4.8). Patients should be monitored for pulmonary symptoms indicative of ILD/pneumonitis (e.g. hypoxia, cough, dyspnoea). In patients who have new or worsening respiratory symptoms and are suspected to have developed ILD/pneumonitis, IBRANCE should be immediately interrupted and the patient should be evaluated. IBRANCE should be permanently discontinued in patients with severe ILD or pneumonitis (see section 4.2). Infections Since IBRANCE has myelosuppressive properties, it may predispose patients to infections. Infections have been reported at a higher rate in patients treated with IBRANCE in randomised clinical studies compared to patients treated in the respective comparator arm. Grade 3 and Grade 4 infections occurred respectively in 5.6% and 0.9% of patients treated with IBRANCE in any combination (see section 4.8). Patients should be monitored for signs and symptoms of infection and treated as medically appropriate (see section 4.2). Physicians should inform patients to promptly report any episodes of fever. Venous thromboembolism Venous thromboembolic events were reported in patients treated with IBRANCE (see section 4.8). Patients should be m

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