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

HOS-097713 · has-adverse-reaction-information · PDF-Seite 10

Summary of the safety profile Studies in EGFR mutation-positive NSCLC patients The safety of TAGRISSO as a monotherapy is based on pooled data from 1956 patients with EGFR mutation-positive non-small cell lung cancer. These patients received TAGRISSO at a dose of 80 mg daily in five randomised Phase 3 studies (ADAURA, adjuvant; FLAURA, and FLAURA2 (monotherapy arm) first line; LAURA (post platinum‑based chemoradiation therapy) and AURA3, second line only), two Phase 2 single-arm studies (AURAex and AURA2, second line or later) and one Phase 1 study (AURA1, first-line or later) (see section 5.1). Most adverse reactions were Grade 1 or 2 in severity. The most commonly reported adverse drug reactions (ADRs) were diarrhoea (46%), rash (45%), paronychia (33%), dry skin (31%), and stomatitis (23%). Grade 3 and Grade 4 adverse reactions across the studies were 11% and 0.2%, respectively. In patients treated with TAGRISSO 80 mg once daily, dose reductions due to adverse reactions occurred in 3.4% of the patients. Discontinuation due to adverse reactions was 5.5%. The safety of TAGRISSO given in combination with pemetrexed and platinum-based chemotherapy is based on data in 276 patients with EGFR mutation-positive NSCLC and was consistent with TAGRISSO monotherapy and known safety profiles of pemetrexed and platinum-based chemotherapy. The most commonly reported ADRs when TAGRISSO was given in combination with pemetrexed and platinum-based chemotherapy were rash (49%), diarrhoea (43%), decreased appetite (31%), stomatitis (31%), paronychia (27%) and dry skin (24%). When TAGRISSO is administered as combination therapy, refer to the Summary of Product Characteristics for the respective combination therapy components prior to initiation of treatment. Patients with a medical history of ILD, drug-induced ILD, radiation pneumonitis that required steroid treatment, or any evidence of clinically active ILD were excluded from clinical studies. Patients with clinically important abnormalities in rhythm and conduction as measured by resting electrocardiogram (ECG) (e.g. QTc interval greater than 470 msec) were excluded from these studies. Patients were evaluated for LVEF at screening and every 12 weeks thereafter. Tabulated list of adverse reactions Adverse reactions have been assigned to the frequency categories in Table 2 where possible based on the incidence of comparable adverse event reports in a pooled dataset from the 1956 EGFR mutation-positive NSCLC patients wh

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HOS-097709 · has-contraindication-information · PDF-Seite 5

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. St. John’s Wort should not be used together with TAGRISSO (see section 4.5).

HOS-097708 · has-indication-information · PDF-Seite 2

TAGRISSO as monotherapy is indicated for: • the adjuvant treatment after complete tumour resection in adult patients with stage IB-IIIA non- small cell lung cancer (NSCLC) whose tumours have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations (see section 5.1). • the treatment of adult patients with locally advanced, unresectable NSCLC whose tumours have EGFR exon 19 deletions or exon 21 (L858R) substitution mutations and whose disease has not progressed during or following platinum-based chemoradiation therapy. 2 • the first-line treatment of adult patients with locally advanced or metastatic NSCLC with activating EGFR mutations. • the treatment of adult patients with locally advanced or metastatic EGFR T790M mutation- positive NSCLC. TAGRISSO is indicated in combination with: • pemetrexed and platinum-based chemotherapy for the first-line treatment of adult patients with advanced NSCLC whose tumours have EGFR exon 19 deletions or exon 21 (L858R) substitution mutations.

HOS-097711 · has-interaction-information · PDF-Seite 8

Pharmacokinetic interactions Strong CYP3A4 inducers can decrease the exposure of osimertinib. Osimertinib may increase the exposure of breast cancer resistant protein (BCRP) and P-glycoprotein (P-gp) substrates. Active substances that may increase osimertinib plasma concentrations In vitro studies have demonstrated that the Phase I metabolism of osimertinib is predominantly via CYP3A4 and CYP3A5. In a clinical pharmacokinetic study in patients, co-administration with 200 mg itraconazole twice daily (a strong CYP3A4 inhibitor) had no clinically significant effect on the exposure of osimertinib (area under the curve (AUC) increased by 24% and Cmax decreased by 20%). Therefore, CYP3A4 inhibitors are not likely to affect the exposure of osimertinib. Further catalysing enzymes have not been identified. Active substances that may decrease osimertinib plasma concentrations In a clinical pharmacokinetic study in patients, the steady-state AUC of osimertinib was reduced by 78% when co-administered with rifampicin (600 mg daily for 21 days). Similarly, the exposure to metabolite AZ5104 decreased by 82% for the AUC and 78% for Cmax. It is recommended that concomitant use of strong CYP3A inducers (e.g. Phenytoin, rifampicin and carbamazepine) with TAGRISSO should be avoided. Moderate CYP3A4 inducers (e.g. bosentan, efavirenz, etravirine, modafinil) may also decrease osimertinib exposure and should be used with caution or avoided when possible. There are no clinical data available to recommend a dose adjustment of TAGRISSO. Concomitant use of St. John’s Wort is contraindicated (see section 4.3). Effect of gastric acid reducing active substances on osimertinib In a clinical pharmacokinetic study, co-administration of omeprazole did not result in clinically relevant changes in osimertinib exposures. Gastric pH modifying agents can be concomitantly used with TAGRISSO without any restrictions. Active substances whose plasma concentrations may be altered by TAGRISSO Based on in vitro studies, osimertinib is a competitive inhibitor of BCRP transporters. 8 In a clinical PK study, co-administration of TAGRISSO with rosuvastatin (sensitive BCRP substrate) increased the AUC and Cmax of rosuvastatin by 35% and 72%, respectively. Patients taking concomitant medicinal products with disposition dependent upon BCRP and with narrow therapeutic index should be closely monitored for signs of changed tolerability of the conco

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HOS-097712 · has-pregnancy-information · PDF-Seite 9

Women of childbearing potential/Contraception in males and females Women of childbearing potential should be advised to avoid becoming pregnant while receiving TAGRISSO. Patients should be advised to use effective contraception for the following periods after completion of treatment with this medicinal product: at least 2 months for females and 4 months for males. A risk for decreased exposure of hormonal contraceptives cannot be excluded. Pregnancy There are no or limited amount of data from the use of osimertinib in pregnant women. Studies in animals have shown reproductive toxicity (embryo lethality, reduced foetal growth, and neonatal death, see section 5.3). Based on its mechanism of action and preclinical data, osimertinib may cause foetal harm when administered to a pregnant woman. TAGRISSO should not be used during pregnancy unless the clinical condition of the woman requires treatment with osimertinib. Breast-feeding It is unknown whether osimertinib/metabolites are excreted in human milk. There is insufficient information on the excretion of osimertinib/metabolites in animal milk. However, osimertinib and its metabolites were detected in the suckling pups and there was poor pup growth and a reduction in pup survival (see section 5.3). A risk to the suckling child cannot be excluded. Breast-feeding should be discontinued during treatment with TAGRISSO. Fertility There are no data on the effect of TAGRISSO on human fertility. Results from animal studies have shown that osimertinib has effects on male and female reproductive organs and could impair fertility (see section 5.3).

HOS-097710 · has-warning-information · PDF-Seite 5

Assessment of EGFR mutation status When considering the use of TAGRISSO as adjuvant treatment after complete tumour resection in patients with NSCLC, EGFR mutation positive status (exon 19 deletions [Ex19del] or exon 21 L858R substitution mutations [L858R]) indicates treatment eligibility. A validated test should be performed in a clinical laboratory using tumour tissue DNA from biopsy or surgical specimen. When considering the use of TAGRISSO in patients with locally advanced, unresectable NSCLC and whose disease has not progressed during or following platinum-based chemoradiation therapy, EGFR mutation positive status (exon 19 deletions or exon 21 [L858R] substitution mutations) indicates treatment eligibility. A validated test should be performed in a clinical laboratory using tumour tissue DNA from a biopsy specimen. 5 When considering the use of TAGRISSO as a treatment for locally advanced or metastatic NSCLC, it is important that the EGFR mutation positive status is determined. A validated test should be performed using either tumour DNA derived from a tissue sample or circulating tumour DNA (ctDNA) obtained from a plasma sample. Positive determination of EGFR mutation status (activating EGFR mutations for first-line treatment, exon 19 deletion or exon 21 (L858R) substitution mutations when TAGRISSO is given in combination with pemetrexed and platinum-based chemotherapy for first-line treatment, or T790M mutations following progression on or after EGFR TKI therapy) using either a tissue-based or plasma-based test, indicates eligibility for treatment with TAGRISSO. However, if a plasma-based ctDNA test is used and the result is negative, it is advisable to follow-up with a tissue test wherever possible due to the potential for false negative results using a plasma-based test. Only robust, reliable and sensitive tests with demonstrated utility for the determination of EGFR mutation status should be used. Interstitial Lung Disease (ILD) Severe, life-threatening or fatal ILD or ILD-like adverse reactions (e.g. pneumonitis) have been observed in patients treated with TAGRISSO in clinical studies, including TAGRISSO following definitive platinum-based chemoradiation therapy. Most cases improved or resolved with interruption of treatment. Patients with a past medical history of ILD, drug-induced ILD, radiation pneumonitis that required steroid treatment, or any evidence of clinically active ILD, w

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