Nadofaragene firadenovec

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. Nadofaragene firadenovec 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.

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 nadofaragene firadenovec therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

Women of childbearing potential/contraception in males and females

Pregnancy status in women of childbearing potential should be verified prior to initiating nadofaragene firadenovec.

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.

Fertility

No clinical data are available on the possible effects of nadofaragene firadenovec on fertility, and nonclinical studies have not been conducted.

Nadofaragene firadenovec 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 nadofaragene firadenovec. The table below 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.

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.