Vizimpro · 4.4 Special warnings and precautions for use · 1

HOS-098719 · has-adverse-reaction-information · PDF-Seite 7

Summary of safety profile The median duration of treatment with Vizimpro across the pooled data set was 66.7 weeks. The most common (> 20%) adverse reactions in patients receiving dacomitinib were diarrhoea (88.6%), rash (79.2%), stomatitis (71.8%), nail disorder (65.5%), dry skin (33.3%), decreased appetite (31.8%), conjunctivitis (24.7%), weight decreased (24.3%), alopecia (23.1%), pruritus (22.4%), transaminases increased (22.0%), and nausea (20.4%). Serious adverse reactions were reported in 6.7% of patients treated with dacomitinib. The most frequently (≥ 1%) reported serious adverse reactions in patients receiving dacomitinib were diarrhoea (2.0%), interstitial lung disease (1.2%), rash (1.2%), and decreased appetite (1.2%). Adverse reactions leading to dose reductions were reported in 52.2% of patients treated with dacomitinib. The most frequently reported (> 5%) reasons for dose reductions due to any adverse reactions in patients receiving dacomitinib were rash (32.2%), nail disorder (16.5%), and diarrhoea (7.5%). 7 Adverse reactions leading to permanent discontinuation were reported in 6.7% of patients treated with dacomitinib. The most common (> 0.5%) reasons for permanent discontinuations associated with adverse reactions in patients receiving dacomitinib were: rash (2.4%), interstitial lung disease (2.0%), and diarrhoea (0.8%). Tabulated list of adverse reactions Table 3 presents adverse reactions for Vizimpro. Adverse reactions are listed according to system organ class (SOC). Within each SOC, the adverse reactions are ranked by frequency, with the most frequent reactions first, using the following convention: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1000 to < 1/100); rare (≥ 1/10000 to < 1/1000). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. Table 3. Adverse reactions reported in dacomitinib clinical studies (N=255) System organ class Very common Common Metabolism and nutrition disorders Decreased appetite Dehydration Hypokalaemiaa Nervous system disorders Dysgeusia Eye disorders Conjunctivitisb Keratitis Respiratory, thoracic and mediastinal

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HOS-098715 · has-contraindication-information · PDF-Seite 4

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 4

HOS-098714 · has-indication-information · PDF-Seite 2

Vizimpro, as monotherapy, is indicated for the first-line treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR)-activating mutations. 2

HOS-098717 · has-interaction-information · PDF-Seite 6

Co-administration of dacomitinib with agents that increase gastric pH The aqueous solubility of dacomitinib is pH dependent, with low (acidic) pH resulting in higher solubility. Data from a study in 24 healthy subjects indicated that co-administration of a single 45 mg dacomitinib dose with the PPI rabeprazole 40 mg once daily for 7 days decreased dacomitinib Cmax, AUC0-96h (area under the concentration-time curve from time 0 to 96 hours), and AUCinf (AUC from time 0 to infinity) (n=14) by approximately 51%, 39%, and 29%, respectively, when compared to a single 45 mg dose of dacomitinib administered alone. PPIs should be avoided while receiving treatment with dacomitinib (see section 4.4). Based on data from observations in 8 patients from Study A7471001, there was no apparent effect of local antacid administration on Cmax and AUCinf of dacomitinib. Based on pooled data in patients, there was no apparent effect of histamine-2 (H2) receptor antagonists on steady-state trough concentration of dacomitinib (geometric mean ratio of 86% (90% CI: 73; 101). Local antacids and H2 receptor antagonists may be used if needed. Dacomitinib should be administered 2 hours before or at least 10 hours after taking H2 receptor antagonists. Co-administration of dacomitinib and CYP2D6 substrates Co-administration of single 45 mg oral dose of dacomitinib increased the mean exposure (AUClast and Cmax) of dextromethorphan, a probe CYP2D6 substrate, 855% and 874%, respectively, compared with administration of dextromethorphan alone. These results suggest that dacomitinib may increase exposure of other medicinal products (or decrease exposure to active metabolites) primarily metabolised by CYP2D6. Concomitant use of medicinal products predominantly metabolised by CYP2D6 should be avoided (see section 4.4). If concomitant use of such medicinal products is considered necessary, they should follow their respective labels for dose recommendation regarding co-administration with strong CYP2D6 inhibitors. Effect of dacomitinib on drug transporters Based on in vitro data, dacomitinib may have the potential to inhibit the activity of P-glycoprotein (P-gp) (in the gastrointestinal [GI] tract), Breast Cancer Resistance Protein (BCRP) (systemically and GI tract), and organic cation transporter (OCT)1 at clinically relevant concentrations (see section 5.2). 6

HOS-098718 · has-pregnancy-information · PDF-Seite 7

Woman of childbearing potential/Contraception Women of childbearing potential should be advised to avoid becoming pregnant while receiving Vizimpro. Women of childbearing potential who are receiving this medicinal product should use adequate contraceptive methods during therapy and for at least 17 days (5 half-lives) after completing therapy. Pregnancy There are no data on the use of dacomitinib in pregnant women. Studies in animals have shown limited effects on reproductive toxicity (lower maternal body weight gain and food consumption in rats and rabbits, and lower foetal body weight and higher incidence of unossified metatarsals in rats only) (see section 5.3). Based on its mechanism of action, dacomitinib may cause foetal harm when administered to a pregnant woman. Dacomitinib should not be used during pregnancy. Female patients taking dacomitinib during pregnancy or who become pregnant while taking dacomitinib should be apprised of the potential hazard to the foetus. Breast-feeding It is not known whether dacomitinib and its metabolites are excreted in human milk. Because many medicinal products are excreted in human milk, and because of the potential for serious adverse reactions in breast-fed infants from exposure to dacomitinib, mothers should be advised against breast-feeding while receiving this medicinal product. Fertility Fertility studies have not been performed with dacomitinib. Non-clinical safety studies showed reversible epithelial atrophy in the cervix and vagina of rats (see section 5.3).

HOS-098716 · has-warning-information · PDF-Seite 5

Assessment of EGFR mutation status When assessing the EGFR mutation status of a patient, it is important that a well-validated and robust methodology is chosen to avoid false negative or false positive determinations. Interstitial lung disease (ILD)/Pneumonitis ILD/pneumonitis, which could be fatal, has been reported in patients receiving Vizimpro (see section 4.8). Patients with a history of ILD have not been studied. Careful assessment of all patients with an acute onset or unexplained worsening of pulmonary symptoms (e.g., dyspnoea, cough, fever) should be performed to exclude ILD/pneumonitis. Treatment with dacomitinib should be withheld pending investigation of these symptoms. If ILD/pneumonitis is confirmed, dacomitinib should be permanently discontinued and appropriate treatment instituted as necessary (see section 4.2). Diarrhoea Diarrhoea, including severe diarrhoea, has been very commonly reported during treatment with Vizimpro (see section 4.8). Diarrhoea may result in dehydration with or without renal impairment, which could be fatal if not adequately treated. Proactive management of diarrhoea should start at the first sign of diarrhoea especially within the first 2 weeks of starting dacomitinib, including adequate hydration combined with anti-diarrhoeal medicinal products and continued until loose bowel movements cease for 12 hours. Anti-diarrhoeal medicinal products (e.g., loperamide) should be used and, if necessary, escalated to the highest recommended approved dose. Patients may require dosing interruption and/or dose reduction of therapy with dacomitinib. Patients should maintain adequate oral hydration and patients who become dehydrated may require administration of intravenous fluids and electrolytes (see section 4.2). Skin-related adverse reactions Rash, erythematous and exfoliative skin conditions have been reported in patients treated with Vizimpro (see section 4.8). For prevention of dry skin, initiate treatment with moisturizers, and upon development of rash, initiate treatment with topical antibiotics, emollients, and topical steroids. Start oral antibiotics and topical steroids in patients who develop exfoliative skin conditions. Consider adding broad spectrum oral or intravenous antibiotics if any of these conditions worsen to greater than or equal to Grade 2 severity. Rash, erythematous and exfoliative skin conditions may occur or worsen in areas exposed to the sun. Advise patients to use protective clothing and sunsc

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