ANKTIVA Concentrate for intravesical suspension Ref.[116339] Active ingredients: Nogapendekin alfa

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.

For intravesical use only. ANKTIVA should NOT be administered by subcutaneous or intravenous or intramuscular use.

Severe systemic BCG-infections/reactions

The possibility of severe systemic BCG-infections with the necessity of anti-tuberculosis therapy should be considered before initiating the BCG-therapy. See Summary of product Characteristics for the specific BCG being used.

Risk of progression to muscle invasive and metastatic bladder cancer with delayed cystectomy

Delaying cystectomy in patients with BCG-unresponsive NMIBC with CIS, with or without papillary tumours, treated with ANKTIVA therapy in combination with BCG could lead to development of muscle invasive or metastatic bladder cancer.

Of the 100 evaluable patients with BCG-unresponsive CIS treated with ANKTIVA in combination with BCG in QUILT-3.032, 10% (n=10; 95% CI 4.9-17.6%), progressed to muscle-invasive (T2 or greater) bladder cancer, including 2 cases occuring during the treatment period. Among these 10 patients, 3 achieved a complete response (CR) before progression (treatment period 16.1-108.0 weeks), while 7 had not reached CR (treatment period 5.3-24.1 weeks). Four out of these 7 subjects without CR received a second induction (re-induction). Four patients had progression determined at the time of cystectomy. The median time between determination of persistent or recurrent CIS and progression to muscle-invasive disease was 224 days (range: 0-854). Among all study participants in QUILT-3.032 with up to 63.5 months of follow up, 5% of participants developed metastatic disease by 24 months (none at 12 months). Progression to muscle invasive or metastatic disease occurred in five of seventy (5/70) patients who were not re-inducted, and in five of thirty (5/30) patients that received a second induction course (re-induction).

In patients who received re-induction (n=30, 30%) the CR rate was 50% (95% CI: 31.3, 68.7) and the duration of complete response (DoR) was 12.0 months (95% CI: 3.9, 21.5). In the subgroup of patients who did not need re-induction (n=70), the CR rate was 80% (95% CI: 68.7, 88.6) and the DoR was 28.7 months (95% CI: 20.7, not reached).

If patients with CIS that are medically eligible for cystectomy have not achieved a CR (absence of disease or low-grade Ta) to treatment after an induction course of ANKTIVA in combination with BCG at the 12-weeks assessment, cystectomy should be reconsidered as an alternative to re-induction (see section 4.2.). The risk of developing muscle-invasive or metastatic bladder cancer increases the longer cystectomy is delayed in the presence of persisting CIS.

Excipients

This medicinal product contains potassium, less than 1 mmol (39 mg) per dose, i.e. essentially 'potassium-free'.

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially 'sodium-free'.

No interaction studies have been performed.

Women of childbearing potential / contraception

Women of childbearing potential have to use effective contraception during treatment and for 1 week after the last dose.

Pregnancy

There are no data on the use of treatment in pregnant women. Animal reproduction studies have not been conducted with ANKTIVA; however, in murine models of pregnancy, IL-15 pathway increases uterine natural killer cells, whereby producing interferon-gamma (IFN-γ). This disrupts maternal tolerance to the foetus and results in an increase in embryofoetal loss (see section 5.3). These results indicate a potential risk. Treatment is not recommended during pregnancy and in women of childbearing potential not using effective contraception.

Breast-feeding

No effects on the breastfed newborn/infant are anticipated since the systemic exposure (see section 5.2) of the breast-feeding woman to nogapendekin alfa inbakicept (ANKTIVA) following intravesical administration is negligible (below the limit of quantitation). There are no data on the presence of nogapendekin alfa inbakicept (ANKTIVA) in human milk, or the effects on the breastfed child, or on milk production. Treatment can be used during breast-feeding.

Fertility

There are no clinical data on the effects of treatment on fertility. No effects on fertility are expected since systemic exposure to nogapendekin alfa inbakicept following intravesical administration is below the limit of quantitation.

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

Summary of the safety profile

The most common adverse drug reactions from QUILT-3.032 were: dysuria (35%), haematuria (35%), pollakiuria (32%), urinary tract infection (24%), micturition urgency (22%), fatigue (20%), chills (13%), musculoskeletal pain (11%), and pyrexia (10%). Adverse drug reaction frequencies presented may not be fully attributable to the drug alone but may contain contributions from the underlying disease or from other drugs used in a combination.

More than one patient experienced the following grade >3 adverse reactions: urinary tract infection (4 patients, 2%), bacteraemia (2 patients, 1%), sepsis (2 patients, 1%), haematuria (5 patients, 3%), musculoskeletal pain (2 patients, 1%), and myalgia (2 patients, 1%).

More than one patient experienced the following serious adverse reactions: urinary tract infection (3 patients, 2%), bacteraemia (2 patients, 1%), haematuria (5 patients, 3%).

Tabulated list of adverse reactions

Table 1 lists adverse reactions in a clinical study (n=180) where ANKTIVA in combination with BCG was administered to subjects (aged 46 to 93 years).

Adverse reaction frequency was determined according to the following criteria: 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). Adverse drug reactions are listed by MedDRA System Organ Class (SOC) and by frequency.

Table 1. Adverse reactions with ANKTIVA in combination with BCG:

^a includes bacteriuria, asymptomatic bacteriuria and bacterial test positive
^b includes anaemia and anaemia macrocytic
^c includes abdominal pain, abdominal pain lower and suprapubic pain
^d includes musculoskeletal pain, back pain, flank pain and pain in extremity
^e includes myalgia and pain
^f includes haematuria, cystitis haemorrhagic and blood urine present
^g includes urinary tract pain and urinary tract discomfort
^h includes bladder pain, bladder discomfort and bladder irritation
ⁱ includes leukocyturia and white blood cells in urine
^j includes penile pain, penile burning sensation, vulvovaginal burning sensation

Immune-related adverse events

Given the immune-activating mechanism of nogapendekin alfa inabakicept, immune-related toxicities cannot be excluded, although systemic exposure following intravesical administration is below the limit of quantitation.

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.

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.