Alecensa · 4.8 Undesirable effects · 1

HOS-097791 · has-adverse-reaction-information · PDF-Seite 8

Summary of the safety profile The data described below reflect exposure to Alecensa in 533 patients with resected or advanced ALK-positive NSCLC. These patients received Alecensa at the recommended dose of 600 mg twice daily in pivotal clinical trials for adjuvant treatment of resected NSCLC (BO40336, ALINA) or for treatment of advanced NSCLC (BO28984, ALEX; NP28761; NP28673). See section 5.1 for further information on clinical trial participants. In BO40336 (ALINA; N = 128), the median duration of exposure to Alecensa was 23.9 months. In BO28984 (ALEX; N = 152) the median duration of exposure to Alecensa was 28.1 months. In the 8 phase II clinical trials (NP28761, NP28673; N = 253), the median duration of exposure to Alecensa was 11.2 months. The most common adverse drug reactions (ADRs) (≥ 20 %) were constipation, myalgia, oedema, increased bilirubin, increased AST, anaemia, rash and increased ALT. Tabulated list of adverse drug reactions Table 3 lists the ADRs occurring in patients who received Alecensa across clinical trials (BO40336, BO28984, NP28761, NP28673). The ADRs listed in Table 3 are presented by system organ class and frequency categories, defined using the following convention: 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). Within each system organ class, undesirable effects are presented in order of decreasing frequency and severity. Within the same frequency and severity grouping, undesirable effects are presented in order of decreasing seriousness. Table 3 ADRs reported in Alecensa clinical trials (BO40336, BO28984, NP28761, NP28673; N = 533) System organ class Alecensa ADRs (MedDRA) N = 533 Frequency category Frequency category (all grades) (grades 3-4) Blood and lymphatic system disorders Anaemia1) Very common Common 2) Haemolytic anaemia Common -* Nervous system disorders Dysgeusia3) Common Uncommon Eye disorders Vision disorders4) Common

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HOS-097787 · has-contraindication-information · PDF-Seite 5

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

HOS-097786 · has-indication-information · PDF-Seite 2

Adjuvant treatment of resected non-small cell lung cancer (NSCLC) Alecensa as monotherapy is indicated as adjuvant treatment following complete tumour resection for adult patients with ALK-positive NSCLC at high risk of recurrence (see section 5.1 for selection criteria). Treatment of advanced NSCLC Alecensa as monotherapy is indicated for the first-line treatment of adult patients with ALK-positive advanced NSCLC. Alecensa as monotherapy is indicated for the treatment of adult patients with ALK-positive advanced NSCLC previously treated with crizotinib.

HOS-097789 · has-interaction-information · PDF-Seite 6

Effects of other medicinal products on alectinib Based on in vitro data, CYP3A4 is the primary enzyme mediating the metabolism of both alectinib and its major active metabolite M4, and CYP3A contributes to 40 %  50 % of total hepatic metabolism. M4 has shown similar in vitro potency and activity against ALK. CYP3A inducers Co-administration of multiple oral doses of 600 mg rifampicin once daily, a strong CYP3A inducer, with a single oral dose of 600 mg alectinib reduced alectinib Cmax, and AUCinf by 51 % and 73 % respectively and increased M4 Cmax and AUCinf 2.20 and 1.79-fold respectively. The effect on the 6 combined exposure of alectinib and M4 was minor, reducing Cmax and AUCinf by 4 % and 18 %, respectively. Based on the effects on the combined exposure of alectinib and M4, no dose adjustments are required when Alecensa is co-administered with CYP3A inducers. Appropriate monitoring is recommended for patients taking concomitant strong CYP3A inducers (including, but not limited to, carbamazepine, phenobarbital, phenytoin, rifabutin, rifampicin and St. John’s Wort (Hypericum perforatum)). CYP3A inhibitors Co-administration of multiple oral doses of 400 mg posaconazole twice daily, a strong CYP3A inhibitor, with a single oral dose of 300 mg alectinib increased alectinib exposure Cmax and AUCinf by 1.18 and 1.75-fold respectively, and reduced M4 Cmax and AUCinf by 71 % and 25 % respectively. The effect on the combined exposure of alectinib and M4 was minor, reducing Cmax by 7 % and increasing AUCinf 1.36-fold. Based on the effects on the combined exposure of alectinib and M4, no dose adjustments are required when Alecensa is co-administered with CYP3A inhibitors. Appropriate monitoring is recommended for patients taking concomitant strong CYP3A inhibitors (including, but not limited to, ritonavir, saquinavir, telithromycin, ketoconazole, itraconazole, voriconazole, posaconazole nefazodone, grapefruit or Seville oranges). Medicinal products that increase gastric pH Multiple doses of esomeprazole, a proton pump inhibitor, 40 mg once daily, demonstrated no clinically relevant effect on the combined exposure of alectinib and M4. Therefore, no dose adjustments are required when Alecensa is co-administered with proton pump inhibitors or other medicinal products which raise gastric pH (e.g. H2 receptor antagonists or antacids). Effect of transporters on alectinib disposition M4 is a substrate of P-glycopr

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HOS-097790 · has-pregnancy-information · PDF-Seite 8

Women of childbearing potential Women of childbearing potential must be advised to avoid pregnancy while on Alecensa (see section 4.4). Contraception in female patients Female patients of childbearing potential receiving Alecensa must use highly effective contraceptive methods during treatment and for at least 5 weeks following the last dose of Alecensa (see sections 4.4 and 4.5). Contraception in male patients Male patients with female partners of childbearing potential must use highly effective contraceptive methods during treatment and for at least 3 months following the last dose of Alecensa (see section 4.4). Pregnancy There are no or limited amount of data from the use of alectinib in pregnant women. Based on its mechanism of action, alectinib may cause foetal harm when administered to a pregnant woman. Studies in animals have shown reproductive toxicity (see section 5.3). Female patients who become pregnant while taking Alecensa or during the 5 weeks following the last dose of Alecensa must contact their doctor and should be advised of the potential harm to the foetus. Male patients with female partners who become pregnant while the male patient is taking Alecensa, or during the 3 months following the last dose of Alecensa, must contact their doctor, and their female partner should seek medical advice due to the potential harm to the foetus based on its aneugenic potential (see section 5.3). Breast-feeding It is unknown whether alectinib and/or its metabolites are excreted in human milk. A risk to the newborn/infant cannot be excluded. Mothers should be advised against breast-feeding while receiving Alecensa. Fertility No fertility studies in animals have been performed to evaluate the effect of alectinib. No adverse effects on male and female reproductive organs were observed in general toxicology studies (see section 5.3).

HOS-097788 · has-warning-information · PDF-Seite 5

Interstitial lung disease (ILD)/pneumonitis Cases of ILD/pneumonitis have been reported in clinical trials with Alecensa (see section 4.8). Patients should be monitored for pulmonary symptoms indicative of pneumonitis. Alecensa should be immediately interrupted in patients diagnosed with ILD/pneumonitis and should be permanently discontinued if no other potential causes of ILD/pneumonitis have been identified (see section 4.2). Hepatotoxicity Elevations in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) greater than 5 times the upper limit of normal (ULN) as well as bilirubin elevations of more than 3 times the ULN occurred in patients in pivotal clinical trials with Alecensa (see section 4.8). The majority of these events occurred during the first 3 months of treatment. In the pivotal Alecensa clinical trials it was reported that three patients with Grade 3-4 AST/ALT elevations had drug induced liver injury. Concurrent elevations in ALT or AST greater than or equal 3 times the ULN and total bilirubin greater than or equal 2 times the ULN, with normal alkaline phosphatase, occurred in one patient treated in Alecensa clinical trials. Liver function, including ALT, AST, and total bilirubin should be monitored at baseline and then every 2 weeks during the first 3 months of treatment. Thereafter, monitoring should be performed periodically, since events may occur later than 3 months, with more frequent testing in patients who develop aminotransferase and bilirubin elevations. Based on the severity of the adverse drug reaction, Alecensa should be withheld and resumed at a reduced dose, or permanently discontinued as described in Table 2 (see section 4.2). Severe myalgia and creatine phosphokinase (CPK) elevation Myalgia or musculoskeletal pain was reported in patients in pivotal trials with Alecensa, including Grade 3 events (see section 4.8). Elevations of CPK occurred in pivotal trials with Alecensa, including Grade 3 events (see section 4.8). Median time to Grade ≥ 3 CPK elevation was 15 days across clinical trials (BO40336, BO28984, NP28761, NP28673). Patients should be advised to report any unexplained muscle pain, tenderness, or weakness. CPK levels should be assessed every two weeks for the first month of treatment and as clinically indicated in patients reporting symptoms. Based on the severity of the CPK elevation, Alecensa should be withheld, then resumed or dose reduced (see section 4.2).

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