Zykadia · 4.3 Contraindications · 1

HOS-097131 · has-adverse-reaction-information · PDF-Seite 10

Summary of the safety profile Adverse drug reactions (ADRs) described below reflect exposure to ceritinib 750 mg once daily fasted in 925 patients with ALK-positive advanced NSCLC across a pool of seven clinical studies including two randomised, active-controlled, phase 3 studies (studies A2301 and A2303). The median duration of exposure to ceritinib 750 mg fasted was 44.9 weeks (range: 0.1 to 200.1 weeks). ADRs with an incidence of ≥10% in patients treated with ceritinib 750 mg fasted were diarrhoea, nausea, vomiting, fatigue, liver laboratory test abnormalities, abdominal pain, decreased appetite, weight decreased, constipation, blood creatinine increased, rash, anaemia and oesophageal disorder. Grade 3-4 ADRs with an incidence of ≥5% in patients treated with ceritinib 750 mg fasted were liver laboratory test abnormalities, fatigue, vomiting, hyperglycaemia, nausea and diarrhoea. 10 In the dose optimisation study A2112 (ASCEND-8) in both previously treated and untreated patients with ALK-positive advanced NSCLC, the overall safety profile of ceritinib at the recommended dose of 450 mg with food (N=108) was consistent with ceritinib 750 mg fasted (N=110), except for a reduction in gastrointestinal adverse drug reactions, while achieving comparable steady-state exposure (see section 5.1 and subsection ‘Gastrointestinal adverse reactions’ below). Tabulated list of ADRs Table 2 shows the frequency category of ADRs reported for ceritinib in patients treated at a dose of 750 mg fasted (N=925) in seven clinical studies. The frequency of selected gastrointestinal ADRs (diarrhoea, nausea and vomiting) are based on patients treated with a dose of 450 mg once-daily with food (N=108). ADRs are listed according to MedDRA system organ class. Within each system organ class, the ADRs are ranked by frequency, with the most frequent reactions first. In addition, the corresponding frequency category using the following convention (CIOMS III) is also provided for each ADR: 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); very rare (<1/10,000); and not known (cannot be estimated from the available data). Within each frequency grouping, ADRs are presented in the order of decreasing seriousness. Table 2 ADRs in patients treated with ceritinib System organ class Ceritinib Frequency category

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HOS-097137 · has-adverse-reaction-information · PDF-Seite 36

Summary of the safety profile Adverse drug reactions (ADRs) described below reflect exposure to ceritinib 750 mg once daily fasted in 925 patients with ALK-positive advanced NSCLC across a pool of seven clinical studies including two randomised, active-controlled, phase 3 studies (studies A2301 and A2303). The median duration of exposure to ceritinib 750 mg fasted was 44.9 weeks (range: 0.1 to 200.1 weeks). ADRs with an incidence of ≥10% in patients treated with ceritinib 750 mg fasted were diarrhoea, nausea, vomiting, fatigue, liver laboratory test abnormalities, abdominal pain, decreased appetite, weight decreased, constipation, blood creatinine increased, rash, anaemia and oesophageal disorder. Grade 3-4 ADRs with an incidence of ≥5% in patients treated with ceritinib 750 mg fasted were liver laboratory test abnormalities, fatigue, vomiting, hyperglycaemia, nausea and diarrhoea. 36 In the dose optimisation study A2112 (ASCEND-8) in both previously treated and untreated patients with ALK-positive advanced NSCLC, the overall safety profile of ceritinib at the recommended dose of 450 mg with food (N=108) was consistent with ceritinib 750 mg fasted (N=110), except for a reduction in gastrointestinal adverse drug reactions, while achieving comparable steady-state exposure (see section 5.1 and subsection ‘Gastrointestinal adverse reactions’ below). Tabulated list of ADRs Table 2 shows the frequency category of ADRs reported for ceritinib in patients treated at a dose of 750 mg fasted (N=925) in seven clinical studies. The frequency of selected gastrointestinal ADRs (diarrhoea, nausea and vomiting) are based on patients treated with a dose of 450 mg once-daily with food (N=108). ADRs are listed according to MedDRA system organ class. Within each system organ class, the ADRs are ranked by frequency, with the most frequent reactions first. In addition, the corresponding frequency category using the following convention (CIOMS III) is also provided for each ADR: 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); very rare (<1/10,000); and not known (cannot be estimated from the available data). Within each frequency grouping, ADRs are presented in the order of decreasing seriousness. Table 2 ADRs in patients treated with ceritinib System organ class Ceritinib Frequency category

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HOS-097127 · has-contraindication-information · PDF-Seite 5

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

HOS-097133 · has-contraindication-information · PDF-Seite 31

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

HOS-097126 · has-indication-information · PDF-Seite 2

Zykadia as monotherapy is indicated for the first-line treatment of adult patients with anaplastic lymphoma kinase (ALK)-positive advanced non-small cell lung cancer (NSCLC). Zykadia as monotherapy is indicated for the treatment of adult patients with anaplastic lymphoma kinase (ALK)-positive advanced non-small cell lung cancer (NSCLC) previously treated with crizotinib.

HOS-097132 · has-indication-information · PDF-Seite 28

Zykadia as monotherapy is indicated for the first-line treatment of adult patients with anaplastic lymphoma kinase (ALK)-positive advanced non-small cell lung cancer (NSCLC). Zykadia as monotherapy is indicated for the treatment of adult patients with anaplastic lymphoma kinase (ALK)-positive advanced non-small cell lung cancer (NSCLC) previously treated with crizotinib.

HOS-097135 · has-interaction-information · PDF-Seite 33

Agents that may increase ceritinib plasma concentrations Strong CYP3A inhibitors In healthy subjects, co-administration of a single 450 mg fasted ceritinib dose with ketoconazole (200 mg twice daily for 14 days), a strong CYP3A/P-gp inhibitor, resulted in 2.9-fold and 1.2-fold increase in ceritinib AUCinf and Cmax, respectively, compared to when ceritinib was given alone. The steady-state AUC of ceritinib at reduced doses after co-administration with ketoconazole 200 mg twice daily for 14 days was predicted by simulations to be similar to the steady-state AUC of ceritinib alone. Concomitant use of strong CYP3A inhibitors should be avoided during treatment with ceritinib. If it is not possible to avoid concomitant use with strong CYP3A inhibitors (including, but not limited to, ritonavir, saquinavir, telithromycin, ketoconazole, itraconazole, voriconazole, posaconazole and nefazodone), the dose of ceritinib should be reduced by approximately one third, rounded to the 33 nearest multiple of the 150 mg dose strength. After discontinuation of a strong CYP3A inhibitor, ceritinib should be resumed at the dose that was taken prior to initiating the strong CYP3A inhibitor. P-gp inhibitors Based on in vitro data, ceritinib is a substrate of the efflux transporter P-glycoprotein (P-gp). If ceritinib is administered with medicinal products that inhibit P-gp, an increase in ceritinib concentration is likely. Caution should be exercised with concomitant use of P-gp inhibitors and ADRs carefully monitored. Agents that may decrease ceritinib plasma concentrations Strong CYP3A and P-gp inducers In healthy subjects, co-administration of a single 750 mg fasted ceritinib dose with rifampicin (600 mg daily for 14 days), a strong CYP3A/P-gp inducer, resulted in 70% and 44% decreases in ceritinib AUCinf and Cmax, respectively, compared to when ceritinib was given alone. Co-administration of ceritinib with strong CYP3A/P-gp inducers decreases ceritinib plasma concentrations. Concomitant use of strong CYP3A inducers should be avoided; this includes, but is not limited to, carbamazepine, phenobarbital, phenytoin, rifabutin, rifampicin and St. John’s Wort (Hypericum perforatum). Caution should be exercised with concomitant use of P-gp inducers. Agents that affect gastric pH Ceritinib demonstrates pH-dependent solubility and becomes poorly soluble as pH increases in vitro. Acid reducing agents (e.g., proton pump inhibitors, H

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HOS-097129 · has-interaction-information · PDF-Seite 7

Agents that may increase ceritinib plasma concentrations Strong CYP3A inhibitors In healthy subjects, co-administration of a single 450 mg fasted ceritinib dose with ketoconazole (200 mg twice daily for 14 days), a strong CYP3A/P-gp inhibitor, resulted in 2.9-fold and 1.2-fold increase in ceritinib AUCinf and Cmax, respectively, compared to when ceritinib was given alone. The steady-state AUC of ceritinib at reduced doses after co-administration with ketoconazole 200 mg twice daily for 14 days was predicted by simulations to be similar to the steady-state AUC of ceritinib alone. Concomitant use of strong CYP3A inhibitors should be avoided during treatment with ceritinib. If it is not possible to avoid concomitant use with strong CYP3A inhibitors (including, but not limited to, ritonavir, saquinavir, telithromycin, ketoconazole, itraconazole, voriconazole, posaconazole and 7 nefazodone), the dose of ceritinib should be reduced by approximately one third, rounded to the nearest multiple of the 150 mg dose strength. After discontinuation of a strong CYP3A inhibitor, ceritinib should be resumed at the dose that was taken prior to initiating the strong CYP3A inhibitor. P-gp inhibitors Based on in vitro data, ceritinib is a substrate of the efflux transporter P-glycoprotein (P-gp). If ceritinib is administered with medicinal products that inhibit P-gp, an increase in ceritinib concentration is likely. Caution should be exercised with concomitant use of P-gp inhibitors and ADRs carefully monitored. Agents that may decrease ceritinib plasma concentrations Strong CYP3A and P-gp inducers In healthy subjects, co-administration of a single 750 mg fasted ceritinib dose with rifampicin (600 mg daily for 14 days), a strong CYP3A/P-gp inducer, resulted in 70% and 44% decreases in ceritinib AUCinf and Cmax, respectively, compared to when ceritinib was given alone. Co-administration of ceritinib with strong CYP3A/P-gp inducers decreases ceritinib plasma concentrations. Concomitant use of strong CYP3A inducers should be avoided; this includes, but is not limited to, carbamazepine, phenobarbital, phenytoin, rifabutin, rifampicin and St. John’s Wort (Hypericum perforatum). Caution should be exercised with concomitant use of P-gp inducers. Agents that affect gastric pH Ceritinib demonstrates pH-dependent solubility and becomes poorly soluble as pH increases in vitro. Acid reducing agents (e.g., proton pump inhibitors, H

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HOS-097136 · has-pregnancy-information · PDF-Seite 36

Women of childbearing potential/Contraception Women of childbearing potential should be advised to use a highly effective method of contraception while taking ceritinib and for up to 3 months after discontinuing treatment (see section 4.5). Pregnancy There are no or limited amount of data from the use of ceritinib in pregnant women. Animal studies are insufficient with respect to reproductive toxicity (see section 5.3). Ceritinib should not be used during pregnancy unless the clinical condition of the woman requires treatment with ceritinib. Breast-feeding It is unknown whether ceritinib/metabolites are excreted in human milk. A risk to the newborn/infant cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from ceritinib therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman (see section 5.3). Fertility The potential for ceritinib to cause infertility in male and female patients is unknown (see section 5.3).

HOS-097130 · has-pregnancy-information · PDF-Seite 10

Women of childbearing potential/Contraception Women of childbearing potential should be advised to use a highly effective method of contraception while taking ceritinib and for up to 3 months after discontinuing treatment (see section 4.5). Pregnancy There are no or limited amount of data from the use of ceritinib in pregnant women. Animal studies are insufficient with respect to reproductive toxicity (see section 5.3). Ceritinib should not be used during pregnancy unless the clinical condition of the woman requires treatment with ceritinib. Breast-feeding It is unknown whether ceritinib/metabolites are excreted in human milk. A risk to the newborn/infant cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from ceritinib therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman (see section 5.3). Fertility The potential for ceritinib to cause infertility in male and female patients is unknown (see section 5.3).

HOS-097128 · has-warning-information · PDF-Seite 5

Hepatotoxicity Cases of hepatotoxicity occurred in 1.1% of patients receiving ceritinib in clinical studies. Increases to grade 3 or 4 ALT elevations were observed in 25% of patients. The majority of cases were manageable with dose interruption and/or dose reduction. Few events required discontinuation of treatment. Patients should be monitored with liver laboratory tests (including ALT, AST and total bilirubin) prior to the start of treatment, every 2 weeks during the first three months of treatment and monthly 5 thereafter. In patients who develop transaminase elevations, more frequent monitoring of liver transaminases and total bilirubin should be carried out as clinically indicated (see sections 4.2 and 4.8). Particular caution should be exercised when treating patients with severe hepatic impairment, and the dose should be adjusted (see section 4.2). Limited experience in these patients showed a worsening of the underlying condition (hepatic encephalopathy) in 2 out of 10 patients exposed to 750 mg single doses of ceritinib under fasted conditions (see sections 4.2, 4.8 and 5.2). Other factors apart from study treatment could have impacted on observed events of hepatic encephalopathy, however, the relation between study treatment and events cannot be fully ruled out. No dose adjustment is necessary in patients with mild or moderate hepatic impairment (see section 4.2). Interstitial lung disease/Pneumonitis Severe, life-threatening or fatal ILD/pneumonitis have been observed in patients treated with ceritinib in clinical studies. Most of these severe/life-threatening cases improved or resolved with interruption of treatment. Patients should be monitored for pulmonary symptoms indicative of ILD/pneumonitis. Other potential causes of ILD/pneumonitis should be excluded, and ceritinib should be permanently discontinued in patients diagnosed with any grade treatment-related ILD/pneumonitis (see sections 4.2 and 4.8). QT interval prolongation QTc prolongation has been observed in clinical studies in patients treated with ceritinib (see sections 4.8 and 5.2), which may lead to an increased risk for ventricular tachyarrhythmias (e.g. torsade de pointes) or sudden death. Use of ceritinib in patients with congenital long QT syndrome should be avoided. The benefits and potential risks of ceritinib should be considered before beginning therapy in patients who have pre-existing bradycardia (heart rate les

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HOS-097134 · has-warning-information · PDF-Seite 31

Hepatotoxicity Cases of hepatotoxicity occurred in 1.1% of patients receiving ceritinib in clinical studies. Increases to grade 3 or 4 ALT elevations were observed in 25% of patients. The majority of cases were manageable with dose interruption and/or dose reduction. Few events required discontinuation of treatment. Patients should be monitored with liver laboratory tests (including ALT, AST and total bilirubin) prior to the start of treatment, every 2 weeks during the first three months of treatment and monthly thereafter. In patients who develop transaminase elevations, more frequent monitoring of liver 31 transaminases and total bilirubin should be carried out as clinically indicated (see sections 4.2 and 4.8). Particular caution should be exercised when treating patients with severe hepatic impairment, and the dose should be adjusted (see section 4.2). Limited experience in these patients showed a worsening of the underlying condition (hepatic encephalopathy) in 2 out of 10 patients exposed to 750 mg single doses of ceritinib under fasted conditions (see sections 4.2, 4.8 and 5.2). Other factors apart from study treatment could have impacted on observed events of hepatic encephalopathy, however, the relation between study treatment and events cannot be fully ruled out. No dose adjustment is necessary in patients with mild or moderate hepatic impairment (see section 4.2). Interstitial lung disease/Pneumonitis Severe, life-threatening or fatal ILD/pneumonitis have been observed in patients treated with ceritinib in clinical studies. Most of these severe/life-threatening cases improved or resolved with interruption of treatment. Patients should be monitored for pulmonary symptoms indicative of ILD/pneumonitis. Other potential causes of ILD/pneumonitis should be excluded, and ceritinib should be permanently discontinued in patients diagnosed with any grade treatment-related ILD/pneumonitis (see sections 4.2 and 4.8). QT interval prolongation QTc prolongation has been observed in clinical studies in patients treated with ceritinib (see sections 4.8 and 5.2), which may lead to an increased risk for ventricular tachyarrhythmias (e.g. torsade de pointes) or sudden death. Use of ceritinib in patients with congenital long QT syndrome should be avoided. The benefits and potential risks of ceritinib should be considered before beginning therapy in patients who have pre-existing bradycardia (heart rate le

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