Balversa · 4.3 Contraindications · 1

HOS-100449 · has-adverse-reaction-information · PDF-Seite 11

Summary of the safety profile The most common adverse reactions were hyperphosphataemia (78.5%), diarrhoea (55.5%), stomatitis (52.8%), dry mouth (39.9%), decreased appetite (31.7%), anaemia (28.2%), dry skin (28.0%), central serous retinopathy (28.0%), constipation (27.3%), dysgeusia (26.3%), palmar-plantar erythrodysaesthesia syndrome (PPES) (25.5%), alopecia (23.2%), asthenia (23.0%), alanine aminotransferase increased (21.7%), onycholysis (21.7%), fatigue (20.3%), nausea (18.6%), weight decreased (18.4%), aspartate aminotransferase increased (18.0%), dry eye (16.7%), nail discolouration (15.9%), vomiting (13.8%), blood creatinine increased (13.8%), hyponatraemia (13.4%), paronychia (12.5%), nail dystrophy (11.9%), onychomadesis (11.5%), epistaxis (10.6%), nail disorder (10.2%) and abdominal pain (10.0%). Most common Grade 3 or higher ADRs were stomatitis (10.6%), hyponatraemia (8.8%), palmar-plantar erythrodysaesthesia syndrome (7.9%), onycholysis (4.8%), diarrhoea (4.0%), hyperphosphataemia (2.9%), decreased appetite (2.5%), and nail dystrophy (2.5%). Grade 3 or 4 related TEAEs (47.6% vs 43.5%) and related serious adverse events (14.6% vs 10.5%) were reported more frequently for patients 65 years and older versus patients <65 years. Adverse reactions leading to dose reduction occurred in 59.7% of patients. Stomatitis (15.4%), palmar-plantar erythrodysaesthesia syndrome (9.6%), onycholysis (7.3%) and hyperphosphataemia (5.2%) were the most common adverse events leading to dose reduction. Adverse reactions leading to treatment discontinuation occurred in 19.4% of patients. Detachment of retinal pigment epithelium (1.7%) and stomatitis (1.5%) were the most common adverse events leading to treatment discontinuations. Tabulated list of adverse reactions The safety profile is based on pooled data from 479 locally advanced unresectable or metastatic urothelial carcinoma patients who were treated with Balversa in clinical studies. Patients were treated with Balversa at 8/9 mg starting dose orally once daily. Median duration of treatment was 4.8 months (range 0.1 to 43.4 months). Adverse reactions observed during clinical studies are listed below in Table 6 by frequency category. Frequency categories are defined as follows: 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 frequency grouping, undesirable effects are presented in order of decreasing serious

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HOS-100445 · has-contraindication-information · PDF-Seite 6

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

HOS-100444 · has-indication-information · PDF-Seite 2

Balversa as monotherapy is indicated for the treatment of adult patients with unresectable or metastatic urothelial carcinoma (UC), harbouring susceptible FGFR3 genetic alterations who have previously received at least one line of therapy containing a PD-1 or PD-L1 inhibitor in the unresectable or metastatic treatment setting (see section 5.1).

HOS-100447 · has-interaction-information · PDF-Seite 9

Effect of other medicinal products on Balversa Moderate CYP2C9 or strong CYP3A4 inhibitors Co-administration with a moderate CYP2C9 or strong CYP3A4 inhibitor increased erdafitinib exposure and may lead to increased drug-related toxicity. Erdafitinib mean ratios (90% CI) for Cmax and AUC∞ were 121% (99.9, 147) and 148% (120, 182), respectively, when co-administered with fluconazole, a moderate CYP2C9 and CYP3A4 inhibitor, relative to erdafitinib alone. Cmax of erdafitinib was 105% (90% CI: 86.7, 127) and AUC∞ was 134% (90% CI: 109, 164) when co- administered with itraconazole, a strong CYP3A4 inhibitor and P-gp inhibitor, relative to erdafitinib alone. Consider alternative agents with no or minimal enzyme inhibition potential. If Balversa is co-administered with a moderate CYP2C9 or strong CYP3A4 inhibitor (such as itraconazole, ketoconazole, posaconazole, voriconazole, fluconazole, miconazole, ceritinib, clarithromycin, telithromycin, elvitegravir, ritonavir, paritaprevir, saquinavir, nefazodone, nelfinavir, tipranavir, lopinavir, amiodarone, piperine), reduce the Balversa dose to the next lower dose based on tolerability (see section 4.2). If the moderate CYP2C9 or strong CYP3A4 inhibitor is discontinued, the Balversa dose may be adjusted as tolerated (see section 4.4). Grapefruit or Seville oranges should be avoided while taking Balversa due to strong CYP3A4 inhibition (see section 4.2). Strong or moderate CYP3A4 inducers Co-administration with carbamazepine, a strong CYP3A4 and weak CYP2C9 inducer leads to decreased erdafitinib exposure. Mean ratios of Cmax and AUC∞ for erdafitinib was 65.4% (90% CI: 60.8, 70.5) and 37.7% (90% CI: 35.4, 40.2), respectively, when co-administered with carbamazepine relative to erdafitinib alone. Avoid co-administration of Balversa with strong CYP3A4 inducers (such as apalutamide, enzalutamide, lumacaftor, ivosidenib, mitotane, rifapentine, rifampicin, carbamazepine, phenytoin, and St. John’s wort). If Balversa is co-administered with a moderate CYP3A4 inducer (such as dabrafenib, bosentan, cenobamate, elagolix, efavirenz, etravirine, lorlatinib, mitapivat, modafinil, pexidartinib, phenobarbital, primidone, repotrectinib, rifabutin, sotorasib, telotristat ethyl), the dose should be cautiously increased by 1 to 2 mg and adjusted gradually every two to three weeks based on clinical monitoring for adverse reactions, not to exceed 9 mg. If the moderate CYP3A4 inducer is discontinued, the Balversa dose may be adjusted as to

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HOS-100448 · has-pregnancy-information · PDF-Seite 10

Women of childbearing potential/Contraception in males and females Based on the mechanism of action and findings in animal reproduction studies, erdafitinib can cause foetal harm when administered to pregnant women. Female patients of child-bearing potential should be advised to use highly effective contraception prior to and during treatment, and for 1 month after the last dose of Balversa. Male patients should be advised to use effective contraception (e.g., condom) and not donate or store semen during treatment with and for 1 month after the last dose of Balversa. Concomitant administration of Balversa may reduce the efficacy of hormonal contraceptives. Patients using hormonal contraceptives should be advised to use an alternative contraceptive not affected by enzyme inducers (e.g., non-hormonal intrauterine device) or an additional nonhormonal contraception (e.g., condom) during treatment with and for 1 month after the last dose of Balversa (see section 4.5). Pregnancy testing Pregnancy testing with a highly sensitive assay is recommended for females of reproductive potential prior to initiating Balversa. Pregnancy There are no data from the use of erdafitinib in pregnant women. Animal studies have shown reproductive toxicity (see section 5.3). Based on the mechanism of action of erdafitinib and the findings in animal reproduction studies, Balversa should not be used during pregnancy unless the clinical condition of the women requires treatment with erdafitinib. If Balversa is used during pregnancy, or if the patient becomes pregnant while taking Balversa, advise the patient of the potential hazard to the foetus and counsel the patient about her clinical and therapeutic options. Patients should be advised to contact their healthcare professional if they become pregnant or pregnancy is suspected while being treated with Balversa and up to 1 month afterwards. Breast-feeding There are no data on the presence of erdafitinib in human milk, or the effects of erdafitinib on the breast-fed infant, or on milk production. A risk to the suckling child cannot be excluded. Breast-feeding should be discontinued during treatment and for 1 month following the last dose of Balversa. 10 Fertility There are no human data on the impact of erdafitinib on fertility. Dedicated animal fertility studies have not been conducted with erdafitinib (see section 5.3). Based on preliminary fertility assessment in general anim

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HOS-100446 · has-warning-information · PDF-Seite 6

Ocular disorders Prior to initiating Balversa, a baseline ophthalmological exam including an Amsler grid test, fundoscopy, visual acuity and, if available, an optical coherence tomography (OCT) should be performed. Balversa can cause ocular disorders, including central serous retinopathy (CSR) (a grouped term including retinal pigment epithelial detachment (RPED)) resulting in visual field defect (see 6 sections 4.7 and 4.8). The overall incidence of central serous retinopathy was higher in patients ≥65 years of age (33.3%) compared with patients <65 years of age (28.8%). Events of RPED were reported more frequently in patients ≥65 years of age (6.3%) compared with patients <65 years of age (2.1%). Close clinical monitoring is recommended in patients aged 65 years and older as well as with patients that have clinically significant medical eye disorders, such as retinal disorders, including but not limited to, central serous retinopathy, macular/retinal degeneration, diabetic retinopathy, and previous retinal detachment (see section 4.8). Dry eye symptoms occurred in 16.7% of patients during treatment with Balversa and were Grade 3 or 4 in 0.3% of patients (see section 4.8). All patients should receive dry eye prophylaxis or treatment with ocular demulcents (for example artificial tear substitutes, hydrating or lubricating eye gels or ointment) at least every 2 hours during waking hours. Severe treatment-related dry eye should be evaluated by an ophthalmologist. Perform monthly ophthalmological examinations including an Amsler grid test during the first 4 months of treatment and every 3 months afterwards, and urgently at any time for visual symptoms (see section 4.2). If any abnormality is observed, follow the management guidelines in Table 3. Ophthalmological examination should include assessment of visual acuity, slit lamp examination, fundoscopy, and optical coherence tomography. Close monitoring including clinical ophthalmological examinations should be performed in patients who have restarted Balversa after an ocular adverse event. When CSR occurs Balversa should be withheld and permanently discontinued if it does not resolve within 4 weeks or if Grade 4 in severity. For ocular adverse reactions, follow the dose modification guidelines (see section 4.2, Eye disorder management). Hyperphosphataemia Balversa can cause hyperphosphataemia. Prolonged hyperphosphataemia can lead to soft tissue m

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