Sprycel · 4.5 Interaction with other medicinal products and other forms of interaction · 1

HOS-094480 · has-adverse-reaction-information · PDF-Seite 49

Summary of the safety profile The data described below reflect the exposure to SPRYCEL as single-agent therapy at all doses tested in clinical studies (N=2,900), including 324 adult patients with newly diagnosed chronic phase CML, 2,388 adult patients with imatinib-resistant or -intolerant chronic or advanced phase CML or Ph+ ALL, and 188 paediatric patients. In the 2,712 adult patients with either chronic phase CML, advanced phase CML or Ph+ ALL, the median duration of therapy was 19.2 months (range 0 to 93.2 months). In a randomized trial in patients with newly diagnosed chronic phase CML, the median duration of therapy was approximately 60 months. The median duration of therapy in 1,618 adult patients with chronic phase CML was 29 months (range 0 to 92.9 months). The median duration of therapy in 1,094 adult patients with advanced phase CML or Ph+ ALL was 6.2 months (range 0 to 93.2 months). Among 188 patients in paediatric studies, the median duration of therapy was 26.3 months (range 0 to 99.6 months). In the subset of 130 chronic phase CML SPRYCEL-treated paediatric patients, the median duration of therapy was 42.3 months (range 0.1 to 99.6 months). The majority of SPRYCEL-treated patients experienced adverse reactions at some time. In the overall population of 2,712 SPRYCEL-treated adult subjects, 520 (19%) experienced adverse reactions leading to treatment discontinuation. The overall safety profile of SPRYCEL in the paediatric Ph+ CML-CP population was similar to that of the adult population, regardless of formulation. Of the 130 SPRYCEL-treated paediatric subjects with CML-CP, 2 (1.5%) experienced adverse reactions leading to treatment discontinuation. Tabulated list of adverse reactions The following adverse reactions, excluding laboratory abnormalities, were reported in patients treated with SPRYCEL used as single-agent therapy in clinical studies and post-marketing experience (Table 5). These reactions are presented by system organ class and by frequency. Frequencies are defined as: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); not known (cannot be estimated from available post-marketing data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. Table 5: Tabulated summary of adverse reactions Infections and infestations Very common infection (including bacterial, viral, fungal, non-specified) Common

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HOS-094474 · has-adverse-reaction-information · PDF-Seite 13

Summary of the safety profile The data described below reflect the exposure to SPRYCEL as single-agent therapy at all doses tested in clinical studies (N=2,900), including 324 adult patients with newly diagnosed chronic phase CML, 2,388 adult patients with imatinib-resistant or -intolerant chronic or advanced phase CML or Ph+ ALL, and 188 paediatric patients. In the 2,712 adult patients with either chronic phase CML, advanced phase CML or Ph+ ALL, the median duration of therapy was 19.2 months (range 0 to 93.2 months). In a randomized trial in patients with newly diagnosed chronic phase CML, the median duration of therapy was approximately 60 months. The median duration of therapy in 1,618 adult patients with chronic phase CML was 29 months (range 0 to 92.9 months). The median duration of therapy in 1,094 adult patients with advanced phase CML or Ph+ ALL was 6.2 months (range 0 to 93.2 months). Among 188 patients in paediatric studies, the median duration of therapy was 26.3 months (range 0 to 99.6 months). In the subset of 130 chronic phase CML SPRYCEL-treated paediatric patients, the median duration of therapy was 42.3 months (range 0.1 to 99.6 months). The majority of SPRYCEL-treated patients experienced adverse reactions at some time. In the overall population of 2,712 SPRYCEL-treated adult subjects, 520 (19%) experienced adverse reactions leading to treatment discontinuation. The overall safety profile of SPRYCEL in the paediatric Ph+ CML-CP population was similar to that of the adult population, regardless of formulation. Of the 130 SPRYCEL-treated paediatric subjects with CML-CP, 2 (1.5%) experienced adverse reactions leading to treatment discontinuation. Tabulated list of adverse reactions The following adverse reactions, excluding laboratory abnormalities, were reported in patients treated with SPRYCEL used as single-agent therapy in clinical studies and post-marketing experience (Table 5). These reactions are presented by system organ class and by frequency. Frequencies are defined as: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); not known (cannot be estimated from available post-marketing data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. Table 5: Tabulated summary of adverse reactions Infections and infestations Very common infection (including bacterial, viral, fungal, non-specified) Common

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HOS-094470 · has-contraindication-information · PDF-Seite 8

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

HOS-094476 · has-contraindication-information · PDF-Seite 43

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

HOS-094469 · has-indication-information · PDF-Seite 3

SPRYCEL is indicated for the treatment of adult patients with: ▪ newly diagnosed Philadelphia chromosome positive (Ph+) chronic myelogenous leukaemia (CML) in the chronic phase. ▪ chronic, accelerated or blast phase CML with resistance or intolerance to prior therapy including imatinib. ▪ Ph+ acute lymphoblastic leukaemia (ALL) and lymphoid blast CML with resistance or intolerance to prior therapy. SPRYCEL is indicated for the treatment of paediatric patients with: ▪ newly diagnosed Ph+ CML in chronic phase (Ph+ CML-CP) or Ph+ CML-CP resistant or intolerant to prior therapy including imatinib. ▪ newly diagnosed Ph+ ALL in combination with chemotherapy.

HOS-094475 · has-indication-information · PDF-Seite 39

SPRYCEL is indicated for the treatment of paediatric patients with: ▪ newly diagnosed Philadelphia chromosome-positive chronic myelogenous leukaemia in chronic phase (Ph+ CML-CP) or Ph+ CML-CP resistant or intolerant to prior therapy including imatinib. ▪ newly diagnosed Ph+ acute lymphoblastic leukaemia (ALL) in combination with chemotherapy.

HOS-094472 · has-interaction-information · PDF-Seite 11

Active substances that may increase dasatinib plasma concentrations In vitro studies indicate that dasatinib is a CYP3A4 substrate. Concomitant use of dasatinib and medicinal products or substances which potently inhibit CYP3A4 (e.g. ketoconazole, itraconazole, erythromycin, clarithromycin, ritonavir, telithromycin, grapefruit juice) may increase exposure to dasatinib. Therefore, in patients receiving dasatinib, systemic administration of a potent CYP3A4 inhibitor is not recommended (see section 4.2). At clinically relevant concentrations, binding of dasatinib to plasma proteins is approximately 96% on the basis of in vitro experiments. No studies have been performed to evaluate dasatinib interaction with other protein-bound medicinal products. The potential for displacement and its clinical relevance are unknown. Active substances that may decrease dasatinib plasma concentrations When dasatinib was administered following 8 daily evening administrations of 600 mg rifampicin, a potent CYP3A4 inducer, the AUC of dasatinib was decreased by 82%. Other medicinal products that induce CYP3A4 activity (e.g. dexamethasone, phenytoin, carbamazepine, phenobarbital or herbal preparations containing Hypericum perforatum, also known as St. John´s Wort) may also increase metabolism and decrease dasatinib plasma concentrations. Therefore, concomitant use of potent CYP3A4 inducers with dasatinib is not recommended. In patients in whom rifampicin or other CYP3A4 inducers are indicated, alternative medicinal products with less enzyme induction potential should be used. Concomitant use of dexamethasone, a weak CYP3A4 inducer, with dasatinib is allowed; dasatinib AUC is predicted to decrease approximately 25% with concomitant use of dexamethasone, which is not likely to be clinically meaningful. Histamine-2 antagonists and proton pump inhibitors Long-term suppression of gastric acid secretion by H2 antagonists or proton pump inhibitors (e.g. famotidine and omeprazole) is likely to reduce dasatinib exposure. In a single-dose study in healthy subjects, the administration of famotidine 10 hours prior to a single dose of SPRYCEL reduced dasatinib exposure by 61%. In a study of 14 healthy subjects, administration of a single 100-mg dose 11 of SPRYCEL 22 hours following a 4-day, 40-mg omeprazole dose at steady state reduced the AUC of dasatinib by 43% and the Cmax of dasatinib by 42%. The use of antacids should be considered in

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HOS-094478 · has-interaction-information · PDF-Seite 47

Active substances that may increase dasatinib plasma concentrations In vitro studies indicate that dasatinib is a CYP3A4 substrate. Concomitant use of dasatinib and medicinal products or substances which potently inhibit CYP3A4 (e.g. ketoconazole, itraconazole, erythromycin, clarithromycin, ritonavir, telithromycin, grapefruit juice) may increase exposure to dasatinib. Therefore, in patients receiving dasatinib, systemic administration of a potent CYP3A4 inhibitor is not recommended (see section 4.2). At clinically relevant concentrations, binding of dasatinib to plasma proteins is approximately 96% on the basis of in vitro experiments. No studies have been performed to evaluate dasatinib interaction with other protein-bound medicinal products. The potential for displacement and its clinical relevance are unknown. Active substances that may decrease dasatinib plasma concentrations When dasatinib was administered following 8 daily evening administrations of 600 mg rifampicin, a potent CYP3A4 inducer, the AUC of dasatinib was decreased by 82%. Other medicinal products that induce CYP3A4 activity (e.g. dexamethasone, phenytoin, carbamazepine, phenobarbital or herbal preparations containing Hypericum perforatum, also known as St. John´s Wort) may also increase metabolism and decrease dasatinib plasma concentrations. Therefore, concomitant use of potent CYP3A4 inducers with dasatinib is not recommended. In patients in whom rifampicin or other CYP3A4 inducers are indicated, alternative medicinal products with less enzyme induction potential should be used. Concomitant use of dexamethasone, a weak CYP3A4 inducer, with dasatinib is allowed; dasatinib AUC is predicted to decrease approximately 25% with concomitant use of dexamethasone, which is not likely to be clinically meaningful. Histamine-2 antagonists and proton pump inhibitors Long-term suppression of gastric acid secretion by H2 antagonists or proton pump inhibitors (e.g. famotidine and omeprazole) is likely to reduce dasatinib exposure. In a single-dose study in healthy subjects, the administration of famotidine 10 hours prior to a single dose of SPRYCEL reduced dasatinib exposure by 61%. In a study of 14 healthy subjects, administration of a single 100-mg dose of SPRYCEL 22 hours following a 4-day, 40-mg omeprazole dose at steady state reduced the AUC of dasatinib by 43% and the Cmax of dasatinib by 42%. The use of antacids should be considered in place of H2 antagonists or proton pump inhibitors in pa

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HOS-094473 · has-pregnancy-information · PDF-Seite 12

Women of childbearing potential/contraception in males and females Both sexually active men and women of childbearing potential should use effective methods of contraception during treatment. Pregnancy Based on human experience, dasatinib is suspected to cause congenital malformations including neural tube defects, and harmful pharmacological effects on the foetus when administered during pregnancy. Studies in animals have shown reproductive toxicity (see section 5.3). SPRYCEL should not be used during pregnancy unless the clinical condition of the woman requires treatment with dasatinib. If SPRYCEL is used during pregnancy, the patient must be informed of the potential risk to the foetus. Breast-feeding There is insufficient/limited information on the excretion of dasatinib in human or animal breast milk. Physico-chemical and available pharmacodynamic/toxicological data on dasatinib point to excretion in breast milk and a risk to the suckling child cannot be excluded. Breast-feeding should be stopped during treatment with SPRYCEL. Fertility In animal studies, the fertility of male and female rats was not affected by treatment with dasatinib (see section 5.3). Physicians and other healthcare providers should counsel male patients of appropriate age about possible effects of SPRYCEL on fertility, and this counseling may include consideration of semen deposition.

HOS-094479 · has-pregnancy-information · PDF-Seite 48

Women of childbearing potential/contraception in males and females Both sexually active men and women of childbearing potential should use effective methods of contraception during treatment. Pregnancy Based on human experience, dasatinib is suspected to cause congenital malformations including neural tube defects, and harmful pharmacological effects on the foetus when administered during pregnancy. Studies in animals have shown reproductive toxicity (see section 5.3). SPRYCEL should not be used during pregnancy unless the clinical condition of the woman requires treatment with dasatinib. If SPRYCEL is used during pregnancy, the patient must be informed of the potential risk to the foetus. Breast-feeding There is insufficient/limited information on the excretion of dasatinib in human or animal breast milk. Physico-chemical and available pharmacodynamic/toxicological data on dasatinib point to excretion in breast milk and a risk to the suckling child cannot be excluded. Breast-feeding should be stopped during treatment with SPRYCEL. Pregnant or breast-feeding women should avoid exposure to SPRYCEL powder for oral suspension. Fertility In animal studies, the fertility of male and female rats was not affected by treatment with dasatinib (see section 5.3). Physicians and other healthcare providers should counsel male patients of appropriate age about possible effects of SPRYCEL on fertility, and this counseling may include consideration of semen deposition.

HOS-094477 · has-warning-information · PDF-Seite 43

Clinically relevant interactions Dasatinib is a substrate and an inhibitor of cytochrome P450 (CYP) 3A4. Therefore, there is a potential for interaction with other concomitantly administered medicinal products that are metabolised primarily by or modulate the activity of CYP3A4 (see section 4.5). Concomitant use of dasatinib and medicinal products or substances that potently inhibit CYP3A4 (e.g. ketoconazole, itraconazole, erythromycin, clarithromycin, ritonavir, telithromycin, grapefruit juice) may increase exposure to dasatinib. Therefore, in patients receiving dasatinib, coadministration of a potent CYP3A4 inhibitor is not recommended (see section 4.5). Concomitant use of dasatinib and medicinal products that induce CYP3A4 (e.g. dexamethasone, phenytoin, carbamazepine, rifampicin, phenobarbital or herbal preparations containing Hypericum perforatum, also known as St. John's Wort) may substantially reduce exposure to dasatinib, potentially increasing the risk of therapeutic failure. Therefore, in patients receiving dasatinib, coadministration of alternative medicinal products with less potential for CYP3A4 induction should be selected (see section 4.5). Concomitant use of dasatinib and a CYP3A4 substrate may increase exposure to the CYP3A4 substrate. Therefore, caution is warranted when dasatinib is coadministered with CYP3A4 substrates of narrow therapeutic index, such as astemizole, terfenadine, cisapride, pimozide, quinidine, bepridil or ergot alkaloids (ergotamine, dihydroergotamine) (see section 4.5). The concomitant use of dasatinib and a histamine-2 (H2) antagonist (e.g. famotidine), proton pump inhibitor (e.g. omeprazole), or aluminium hydroxide/magnesium hydroxide may reduce the exposure to dasatinib. Thus, H2 antagonists and proton pump inhibitors are not recommended and aluminium hydroxide/magnesium hydroxide products should be administered up to 2 hours prior to, or 2 hours following the administration of dasatinib (see section 4.5). Special populations Based on the findings from a single-dose pharmacokinetic study, patients with mild, moderate or severe hepatic impairment may receive the recommended starting dose (see section 5.2). Due to the 43 limitations of this clinical study, caution is recommended when administering dasatinib to patients with hepatic impairment. Important adverse reactions Myelosuppression Treatment with dasatinib is associated with anaemia, neutropaenia and

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HOS-094471 · has-warning-information · PDF-Seite 8

Clinically relevant interactions Dasatinib is a substrate and an inhibitor of cytochrome P450 (CYP) 3A4. Therefore, there is a potential for interaction with other concomitantly administered medicinal products that are metabolised primarily by or modulate the activity of CYP3A4 (see section 4.5). Concomitant use of dasatinib and medicinal products or substances that potently inhibit CYP3A4 (e.g. ketoconazole, itraconazole, erythromycin, clarithromycin, ritonavir, telithromycin, grapefruit juice) may increase exposure to dasatinib. Therefore, in patients receiving dasatinib, coadministration of a potent CYP3A4 inhibitor is not recommended (see section 4.5). Concomitant use of dasatinib and medicinal products that induce CYP3A4 (e.g. dexamethasone, phenytoin, carbamazepine, rifampicin, phenobarbital or herbal preparations containing Hypericum perforatum, also known as St. John's Wort) may substantially reduce exposure to dasatinib, potentially increasing the risk of therapeutic failure. Therefore, in patients receiving dasatinib, coadministration of alternative medicinal products with less potential for CYP3A4 induction should be selected (see section 4.5). Concomitant use of dasatinib and a CYP3A4 substrate may increase exposure to the CYP3A4 substrate. Therefore, caution is warranted when dasatinib is coadministered with CYP3A4 substrates of narrow therapeutic index, such as astemizole, terfenadine, cisapride, pimozide, quinidine, bepridil or ergot alkaloids (ergotamine, dihydroergotamine) (see section 4.5). The concomitant use of dasatinib and a histamine-2 (H2) antagonist (e.g. famotidine), proton pump inhibitor (e.g. omeprazole), or aluminium hydroxide/magnesium hydroxide may reduce the exposure to dasatinib. Thus, H2 antagonists and proton pump inhibitors are not recommended and aluminium hydroxide/magnesium hydroxide products should be administered up to 2 hours prior to, or 2 hours following the administration of dasatinib (see section 4.5). Special populations Based on the findings from a single-dose pharmacokinetic study, patients with mild, moderate or severe hepatic impairment may receive the recommended starting dose (see section 5.2). Due to the limitations of this clinical study, caution is recommended when administering dasatinib to patients with hepatic impairment. Important adverse reactions Myelosuppression Treatment with dasatinib is associated with anaemia, neutropaenia and thrombocytopaenia. Their occurrence is earlier and more fr

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