ADSTILADRIN Intravesical suspension Ref.[116667] Active ingredients: Nadofaragene firadenovec

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.

Urinary tract injury and contamination

Because of the intravesical route of administration, care should be taken not to traumatise the urinary tract or to introduce contaminants into the urinary system.

Contraceptive measures in males and females

Male patients with female partners of childbearing potential should use a barrier protection contraceptive method during treatment, and for 3 months following the last dose to avoid exposing sexual partners to virus (see section 4.6).

Women of childbearing potential should use an effective (double) contraceptive method during treatment, and for a period of 6 months following the last dose to avoid the theoretical risk of exposing foetal cells to virus (see section 4.6).

Blood, organ, tissue and cell donation

Patients treated with ADSTILADRIN should not donate blood, organs, tissues and cells for transplantation.

Anticholinergic pretreatment

Premedication with a single dose of an anticholinergic medicinal product before each instillation is recommended (unless contraindicated) to reduce potential bladder irritation and to prevent premature voiding of the bladder.

Excipient with known effect

ADSTILADRIN contains polysorbate 80, which can cause allergic reactions.

No interaction studies have been performed.

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.

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).

ADSTILADRIN has no or negligible influence on the ability to drive and use machines.

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 seriousness.

Table 1. Tabulated list of adverse reactions:

¹ Includes Abdominal pain, Abdominal pain upper, Abdominal pain lower, and Abdominal discomfort
² Includes Haematuria and Blood urine present
³ Includes Bladder pain, Urethral pain, Bladder discomfort, and Bladder irritation
⁴ Includes Urinary incontinence and Urge incontinence
⁵ Includes Fatigue and Asthenia

Description of selected adverse reactions

Syncope (0.6%) was reported as an adverse reaction with an onset of 4 days from treatment. A fall resulting from the loss of consciousness led to injuries requiring urgent medical care. The syncope resolved 3 days after the onset and did not recur with subsequent treatments.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

Do not use catheters coated or embedded with silver or antibiotics. In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.