Adstiladrin · 4.3 Contraindications · 1

HOS-288667 · has-adverse-reaction-information · PDF-Seite 6

Summary of safety profile The most frequently reported adverse reactions were lower urinary tract signs and symptoms related to the intravesical instillation procedure, instillation site discharge (33.1 %), bladder spasm (19.7 %), micturition urgency (18.5 %), haematuria (16.6 %), dysuria (15.9 %), urinary tract infection (14.6 %), lower urinary tract pain (10.8 %), and pollakiuria (9.6 %). In addition, other adverse reactions such as fatigue (23.6 %), pyrexia (15.9 %), chills (15.3 %), headache (15.3 %), and diarrhoea (10.8 %) were also commonly reported. The most common severe adverse reactions (NCI CTCAE Grade ≥3) were micturition urgency (1.3 %), syncope (0.6 %), hypertension (0.6 %), bladder spasm (0.6 %), and urinary incontinence (0.6 %). The most common serious adverse reaction was syncope (0.6 %). The frequency of treatment discontinuation due to adverse reactions was 1.3 %. The most common adverse reactions leading to treatment discontinuation were instillation site discharge (0.6 %) and bladder spasm (0.6 %). The frequency of dose interruption due to adverse reactions was 34.4 %. The most common adverse reactions leading to dose interruption were instillation site discharge (24.2 %), micturition urgency (8.3 %), bladder spasm (8.3 %), and urinary incontinence (2.5 %). Tabulated list of adverse reactions In the pivotal, single-arm study CS-003, 157 patients were exposed to ADSTILADRIN. Table 1 lists the adverse reactions identified in patients with BCG-unresponsive NMIBC. Unless otherwise stated, the frequencies of adverse reactions are based on all-cause adverse event frequencies identified in 157 patients exposed to nadofaragene firadenovec during a median treatment duration of 3.4 months in clinical study CS-003. The adverse reaction frequencies in clinical study CS-003 are based on all- cause adverse event frequencies, where a proportion of the events for an adverse reaction may have other causes than the drug, such as the disease, the instillation procedure, other medication or unrelated causes. Adverse reactions are ranked according to the MedDRA system organ class and frequency grouping. Frequencies are 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) and not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in the order of decreasing serio

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HOS-288663 · has-contraindication-information · PDF-Seite 4

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

HOS-288662 · has-indication-information · PDF-Seite 2

ADSTILADRIN is indicated as monotherapy for the treatment of adult patients with Bacillus Calmette-Guérin (BCG)-unresponsive non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) with or without papillary tumours.

HOS-288665 · has-interaction-information · PDF-Seite 5

No interaction studies have been performed.

HOS-288666 · has-pregnancy-information · PDF-Seite 5

Women of childbearing potential / contraception in males and females Pregnancy status in women of childbearing potential should be verified prior to initiating ADSTILADRIN. Women of childbearing potential should use an effective (double) contraception method during treatment, and for 6 months following the last dose. Male patients with female partners of childbearing potential should use a barrier protection contraception method during treatment, and for 3 months following the last dose. Pregnancy There are no or limited amount of data from the use of nadofaragene firadenovec in pregnant women. Animal studies are insufficient with respect to reproductive toxicity (see section 5.3). ADSTILADRIN should not be used during pregnancy and in women of childbearing potential not using contraception unless the clinical condition of the woman requires treatment with nadofaragene firadenovec. 5 Breast-feeding It is unknown whether nadofaragene firadenovec is excreted in human milk. A risk to the suckling child cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from ADSTILADRIN therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman. Fertility No clinical data are available on the possible effects of nadofaragene firadenovec on fertility, and nonclinical studies have not been conducted (see section 5.3).

HOS-288664 · has-warning-information · PDF-Seite 4

Traceability In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded. Risk of muscle invasive and metastatic bladder cancer with delayed cystectomy Delaying cystectomy in patients with BCG-unresponsive CIS with or without papillary tumours could lead to development of muscle invasive or metastatic bladder cancer. Of the 107 patients with CIS treated with ADSTILADRIN in Study CS-003, 7.5% (n = 8) progressed to muscle invasive (pT2 or greater) and/or lymph node metastatic (pN+) bladder cancer. Four patients had progression during treatment at time of first recurrence with a median time from first dose to progression of 686 days (range: 76-1178). The remaining four patients were upstaged at the time of cystectomy with a median time from persistence or recurrence of CIS to cystectomy of 235 days (range: 64-335). If patients with CIS who are eligible for cystectomy do not have a complete response to treatment after 3 months or if CIS recurs, cystectomy should be considered. The risk of developing muscle-invasive or metastatic bladder cancer increases the longer cystectomy is delayed in the presence of persisting CIS. Urinary tract infection Urinary tract infection should be excluded before each bladder instillation (bladder mucous membrane inflammation may increase the risk of haematological dissemination of ADSTILADRIN). If a urinary tract infection is diagnosed during therapy, the therapy should be interrupted until the patient is asymptomatic and treatment with antibiotics is completed. Immunocompromised, immune-deficient and pregnant healthcare professionals Healthcare professionals who are immunocompromised, immune-deficient, or pregnant should not prepare, administer, or come in contact with ADSTILADRIN due to the theoretical risk of adenoviral infection (see section 6.6). Immunocompromised patients Immunocompromised patients, including those receiving immunosuppressant therapy, should not come into contact with ADSTILADRIN due to the theoretical risk of adenoviral infection Vector shedding Patients should be instructed to add two cups of virucidal agent (e.g. household bleach such as 5 % sodium hypochlorite) to the toilet bowl prior to voiding and wait 15 minutes before flushing the toilet. This should be done for the first 2 days after each treatment. Patients should be instructed to wash their hands after toilet use.

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