Padcev 20 mg powder for concentrate for solution for infusion

Muscle invasive bladder cancer (MIBC)

Padcev, in combination with pembrolizumab, as neoadjuvant treatment and then continued after radical cystectomy as adjuvant treatment, is indicated for the treatment of adult patients with resectable muscle invasive bladder cancer (MIBC).

Unresectable or metastatic urothelial cancer

Padcev, in combination with pembrolizumab, is indicated for the first-line treatment of adult patients with unresectable or metastatic urothelial cancer who are eligible for platinum‑containing chemotherapy.

Locally advanced or metastatic urothelial cancer

Padcev as monotherapy is indicated for the treatment of adult patients with locally advanced or metastatic urothelial cancer who have previously received a platinum-containing chemotherapy and a programmed death receptor-1 or programmed death-ligand 1 inhibitor (see section 5.1).

Treatment with Padcev should be initiated and supervised by a physician experienced in the use of anti-cancer therapies. Ensure good venous access prior to starting treatment (see section 4.4).

Posology

Table 1. Recommended dose for enfortumab vedotin in combination with pembrolizumab*

*Patients should be administered pembrolizumab after enfortumab vedotin when given on the same day. Refer to the pembrolizumab SmPC for additional dosing information of pembrolizumab.

Table 2. Recommended dose for enfortumab vedotin as monotherapy

Table 3. Recommended dose reductions of enfortumab vedotin for adverse reactions

Dose modifications

Table 4. Dose interruption, reduction and discontinuation of enfortumab vedotin

*Toxicity was graded per National Cancer Institute Common Terminology Criteria for Adverse Events Version 5.0 (NCI-CTCAE v5.0) where Grade 1 is mild, Grade 2 is moderate, Grade 3 is severe and Grade 4 is life‑threatening.

Special populations

Elderly

No dose adjustment is necessary in patients ≥65 years of age (see section 5.2).

Renal impairment

No dose adjustment is necessary in patients with mild [creatinine clearance (CrCL) >60 – 90 mL/min], moderate (CrCL 30–60 mL/min) or severe (CrCL 15‑<30 mL/min) renal impairment. Enfortumab vedotin has not been evaluated in patients with end stage renal disease (CrCL <15 mL/min) (see section 5.2).

Hepatic impairment

No dose adjustment is necessary in patients with mild hepatic impairment [total bilirubin of 1 to 1.5 × upper limit of normal (ULN) and AST any, or total bilirubin ≤ULN and AST >ULN]. Enfortumab vedotin has only been evaluated in a limited number of patients with moderate and severe hepatic impairment. Hepatic impairment is expected to increase the systemic exposure to MMAE (the cytotoxic drug); therefore, patients should be closely monitored for potential adverse events. Due to the sparsity of the data in patients with moderate and severe hepatic impairment, no specific dose recommendation can be given (see section 5.2).

Paediatric population

There is no relevant use of enfortumab vedotin in the paediatric population for the indication of locally advanced or metastatic urothelial cancer and MIBC.

Method of administration

Padcev is for intravenous use. The recommended dose must be administered by intravenous infusion over 30 minutes. Enfortumab vedotin must not be administered as an intravenous push or bolus injection.

For instructions on reconstitution and dilution of the medicinal product before administration, see section 6.6.

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

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.

Skin reactions

Skin reactions are associated with enfortumab vedotin as a result of enfortumab vedotin binding to Nectin-4 expressed in the skin. Fever or flu-like symptoms may be the first sign of a severe skin reaction, and patients should be observed, if this occurs.

Mild to moderate skin reactions, predominantly rash maculo-papular, have been reported with enfortumab vedotin. The incidence of skin reactions occurred at a higher rate when enfortumab vedotin was given in combination with pembrolizumab compared to enfortumab vedotin as monotherapy (see section 4.8). Severe cutaneous adverse reactions, including SJS and TEN, with fatal outcome have also occurred in patients treated with enfortumab vedotin, predominantly during the first cycle of treatment.

Patients should be monitored starting with the first cycle and throughout treatment for skin reactions. Appropriate treatment such as topical corticosteroids and antihistamines can be considered for mild to moderate skin reactions. For suspected SJS or TEN, or in case of bullous lesions onset, withhold treatment immediately and refer to specialised care; histologic confirmation, including consideration of multiple biopsies, is critical to early recognition, as diagnosis and intervention can improve prognosis. Permanently discontinue Padcev for confirmed SJS or TEN, Grade 4 or recurrent Grade 3 skin reactions. For Grade 2 worsening, Grade 2 with fever or Grade 3 skin reactions, treatment should be withheld until Grade ≤1 and referral for specialised care should be considered. Treatment should be resumed at the same dose level or consider dose reduction by one dose level (see section 4.2).

Pneumonitis/ILD

Severe, life-threatening or fatal pneumonitis/ILD have occurred in patients treated with enfortumab vedotin. The incidence of pneumonitis/ILD, including severe events occurred at a higher rate when enfortumab vedotin was given in combination with pembrolizumab compared to enfortumab vedotin as monotherapy (see section 4.8).

Monitor patients for signs and symptoms indicative of pneumonitis/ILD such as hypoxia, cough, dyspnoea or interstitial infiltrates on radiologic exams. Corticosteroids should be administered for Grade ≥2 events (e.g., initial dose of 1-2 mg/kg/day prednisone or equivalent followed by a taper).

Withhold Padcev for Grade 2 pneumonitis/ILD and consider dose reduction. Permanently discontinue Padcev for Grade ≥3 pneumonitis/ILD (see section 4.2).

Hyperglycaemia

Hyperglycaemia and diabetic ketoacidosis (DKA), including fatal events, occurred in patients with and without pre-existing diabetes mellitus, treated with enfortumab vedotin (see section 4.8). Hyperglycaemia occurred more frequently in patients with pre-existing hyperglycaemia or a high body mass index (≥30 kg/m²). Patients with baseline haemoglobin A1C (HbA1c) ≥8% were excluded from clinical studies. Blood glucose levels should be monitored prior to dosing and periodically throughout the course of treatment as clinically indicated in patients with or at risk for diabetes mellitus or hyperglycaemia. If blood glucose is elevated >13.9 mmol/L (>250 mg/dL), Padcev should be withheld until blood glucose is ≤13.9 mmol/L (≤250 mg/dL) and treat as appropriate (see section 4.2).

Serious infections and opportunistic infections

Serious infections such as sepsis or pneumonia (including fatal outcomes) and opportunistic infections such as fungal infections have been reported in patients treated with Padcev. Patients should be carefully monitored during treatment for the emergence of possible serious and opportunistic infections.

Peripheral neuropathy

Peripheral neuropathy, predominantly peripheral sensory neuropathy, has occurred with enfortumab vedotin, including Grade ≥3 reactions (see section 4.8). Patients with preexisting peripheral neuropathy Grade ≥2 were excluded from clinical studies. Patients should be monitored for symptoms of new or worsening peripheral neuropathy as these patients may require a delay, dose reduction or discontinuation of enfortumab vedotin (see Table 3). Padcev should be permanently discontinued for Grade ≥3 peripheral neuropathy (see section 4.2).

Ocular disorders

Ocular disorders, predominantly dry eye, have occurred in patients treated with enfortumab vedotin (see section 4.8). Patients should be monitored for ocular disorders. Consider artificial tears for prophylaxis of dry eye and referral for ophthalmologic evaluation if ocular symptoms do not resolve or worsen.

Infusion site extravasation

Skin and soft tissue injury following enfortumab vedotin administration has been observed when extravasation occurred (see section 4.8). Ensure good venous access prior to starting Padcev and monitor for possible infusion site extravasation during administration. If extravasation occurs, stop the infusion and monitor for adverse reactions.

Embryo-foetal toxicity and contraception

Pregnant women should be informed of the potential risk to a foetus (see sections 4.6 and 5.3). Females of reproductive potential should be advised to have a pregnancy test within 7 days prior to starting treatment with enfortumab vedotin, to use effective contraception during treatment and for at least 6 months after stopping treatment. Men being treated with enfortumab vedotin are advised not to father a child during treatment and for at least 4 months following the last dose of Padcev.

Excipient information

This medicinal product contains 0.40 mg and 0.60 mg of polysorbate 20 in each 20 mg and 30 mg dose, respectively. Polysorbates may cause allergic reactions.

Patient information pack

The prescriber must discuss the risks of Padcev therapy, including combination therapy with pembrolizumab, with the patient. The patient should be provided with the patient information leaflet and patient card with each prescription.

Formal drug-drug interaction studies with enfortumab vedotin have not been conducted. Concomitant administration of enfortumab vedotin and CYP3A4 (substrates) metabolised medicinal products, has no clinically relevant risk of inducing pharmacokinetic interactions (see section 5.2).

Effects of other medicinal products on enfortumab vedotin

CYP3A4 inhibitors, substrates or inducers

Based on physiologically-based pharmacokinetic (PBPK) modelling, concomitant use of enfortumab vedotin with ketoconazole (a combined P-gp and strong CYP3A inhibitor) is predicted to increase unconjugated MMAE C_max and AUC exposure to a minor extent, with no change in antibody drug conjugate (ADC) exposure. Caution is advised in case of concomitant treatment with CYP3A4 inhibitors. Patients receiving concomitant strong CYP3A4 inhibitors (e.g., boceprevir, clarithromycin, cobicistat, indinavir, itraconazole, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, voriconazole) should be monitored more closely for signs of toxicities.

Unconjugated MMAE is not predicted to alter the AUC of concomitant medicines that are CYP3A4 substrates (e.g. midazolam).

Strong CYP3A4 inducers (e.g. rifampicin, carbamazepine, phenobarbital, phenytoin, St. John's wort [Hypericum perforatum]) may decrease the exposure of unconjugated MMAE with moderate effect (see section 5.2).

Women of childbearing potential/Contraception in males and females

Pregnancy testing is recommended for females of reproductive potential within 7 days prior to initiating treatment. Females of reproductive potential should be advised to use effective contraception during treatment and for at least 6 months after stopping treatment. Men being treated with enfortumab vedotin are advised not to father a child during treatment and for at least 4 months following the last dose of Padcev.

Pregnancy

Padcev can cause foetal harm when administered to pregnant women based upon findings from animal studies. Embryo‑foetal development studies in female rats have shown that intravenous administration of enfortumab vedotin resulted in reduced numbers of viable foetuses, reduced litter size, and increased early resorptions (see section 5.3). Padcev is not recommended during pregnancy and in women of childbearing potential not using effective contraception.

Breast-feeding

It is unknown whether enfortumab vedotin is excreted in human milk. A risk to breast-fed children cannot be excluded. Breastfeeding should be discontinued during Padcev treatment and for at least 6 months after the last dose.

Fertility

In rats, repeat dose administration of enfortumab vedotin, resulted in testicular toxicity and may alter male fertility. MMAE has been shown to have aneugenic properties (see section 5.3). Therefore, men being treated with this medicinal product are advised to have sperm samples frozen and stored before treatment. There are no data on the effect of Padcev on human fertility.

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

Summary of the safety profile

Enfortumab vedotin in combination with pembrolizumab

When enfortumab vedotin is administered in combination with pembrolizumab, refer to the SmPC for pembrolizumab prior to initiation of treatment.

The safety of enfortumab vedotin was evaluated in combination with pembrolizumab in 1 134 patients who received at least one dose of enfortumab vedotin 1.25 mg/kg in combination with pembrolizumab in one phase 2 study (EV-103) and three phase 3 studies (EV-302, EV-303 and EV-304) (see Table 5). Patients were exposed to the combination of enfortumab vedotin and pembrolizumab for a median duration of 9.2 months (range: 0.03 to 45.9 months). The median duration of exposure to enfortumab vedotin alone was 6.9 months (range: 0.03 to 45.9 months).

The most common adverse reactions with enfortumab vedotin in combination with pembrolizumab were pruritus (44.2%), diarrhoea (37.1%), alopecia (35.4%), fatigue (35%), peripheral sensory neuropathy (34%), decreased appetite (31.5%), anaemia (29.1%), weight decreased (29.1%), nausea (28.5%), rash maculo-papular (27.7%), dysgeusia (25.1%), aspartate aminotransferase increased (20.2%), alanine aminotransferase increased (20%), dry skin (16%), hyperglycaemia (15.5%), rash (14%), vomiting (13.2%), hypothyroidism (12.1%), neutropenia (12%) and dry eye (11.6%).

The most common serious adverse reactions (≥2%) were sepsis (3%), diarrhoea (2.6%), pneumonia (2.6%) and pneumonitis (2.2%). Thirty-eight percent of patients permanently discontinued enfortumab vedotin for adverse reactions; the most common adverse reaction (≥2%) leading to discontinuation was peripheral sensory neuropathy (9.1%).

Adverse reactions leading to dose interruption of enfortumab vedotin occurred in 59% of patients. The most common adverse reactions (≥2%) leading to dose interruption were peripheral sensory neuropathy (9.3%), rash maculo-papular (5.3%), diarrhoea (4.7%), neutropenia (3.7%), alanine aminotransferase increased (3.4%), hyperglycaemia (3%), fatigue (2.7%), pneumonitis (2.1%) and pruritus (2.1%).

Adverse reactions leading to dose reduction of enfortumab vedotin occurred in 31% of patients. The most common adverse reactions (≥2%) leading to dose reduction were peripheral sensory neuropathy (6%), rash maculo-papular (4.7%) and fatigue (2.1%).

Enfortumab vedotin as monotherapy

The safety of enfortumab vedotin was evaluated as monotherapy in 793 patients who received at least one dose of enfortumab vedotin 1.25 mg/kg in two phase 1 studies (EV-101 and EV‑102), three phase 2 studies (EV-103, EV-201 and EV-203) and one phase 3 study (EV‑301) (see Table 5). Patients were exposed to enfortumab vedotin for a median duration of 4.7 months (range: 0.3 to 55.7 months).

The most common adverse reactions with enfortumab vedotin were alopecia (47.7%), decreased appetite (47.2%), fatigue (46.8%), diarrhoea (39.1%), peripheral sensory neuropathy (38.5%), nausea (37.8%), pruritus (33.4%), dysgeusia (30.4%), anaemia (29.1%), weight decreased (25.2%), rash maculo-papular (23.6%), dry skin (21.8%), vomiting (18.7%), aspartate aminotransferase increased (17%), hyperglycaemia (14.9%), dry eye (12.7%), alanine aminotransferase increased (12.7%) and rash (11.6%).

The most common serious adverse reactions (≥2%) were diarrhoea (2.1%) and hyperglycaemia (2.1%). Twenty-one percent of patients permanently discontinued enfortumab vedotin for adverse reactions; the most common adverse reaction (≥2%) leading to dose discontinuation was peripheral sensory neuropathy (4.8%). Adverse reactions leading to dose interruption occurred in 62% of patients; the most common adverse reactions (≥2%) leading to dose interruption were peripheral sensory neuropathy (14.8%), fatigue (7.4%), rash maculo-papular (4%), aspartate aminotransferase increased (3.4%), alanine aminotransferase increased (3.2%), anaemia (3.2%), hyperglycaemia (3.2%), neutrophil count decreased (3%), diarrhoea (2.8%), rash (2.4%) and peripheral motor neuropathy (2.1%). Thirty-eight percent of patients required a dose reduction due to an adverse reaction; the most common adverse reactions (≥2%) leading to a dose reduction were peripheral sensory neuropathy (10.3%), fatigue (5.3%), rash maculo-papular (4.2%) and decreased appetite (2.1%).

Tabulated summary of adverse reactions

Adverse reactions observed during clinical studies of enfortumab vedotin as monotherapy or in combination with pembrolizumab, or reported from post-marketing use of enfortumab vedotin are listed in this section 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); not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 5. Adverse reactions in patients treated with enfortumab vedotin

¹Based on global post-marketing experience.

²Includes: acute respiratory distress syndrome, autoimmune lung disease, immune-mediated lung disease, interstitial lung disease, lung opacity, organising pneumonia, pneumonitis, pulmonary fibrosis, pulmonary toxicity, pulmonary sarcoidosis and sarcoidosis.

Description of selected adverse reactions

Immunogenicity

A total of 159 patients were tested for immunogenicity against enfortumab vedotin following enfortumab vedotin in combination with pembrolizumab for the treatment of MIBC; 3 patients were confirmed to be positive at baseline for anti-drug antibody (ADA), and in patients that were negative at baseline (n=156), a total of 2 (1.3%) were positive post baseline.

A total of 490 patients were tested for immunogenicity against enfortumab vedotin following enfortumab vedotin in combination with pembrolizumab for the treatment of unresectable or metastatic urothelial cancer; 24 patients were confirmed to be positive at baseline for ADA, and in patients that were negative at baseline (n=466), a total of 14 (3%) were positive post baseline.

A total of 697 patients were tested for immunogenicity to enfortumab vedotin 1.25 mg/kg as monotherapy; 16 patients were confirmed to be positive at baseline for ADA, and in patients that were negative at baseline (n=681), a total of 24 (3.5%) were positive post baseline.

The incidence of treatment-emergent anti-enfortumab vedotin antibody formation was consistent when assessed following enfortumab vedotin administration as monotherapy and in combination with pembrolizumab.

Due to the limited number of patients with antibodies against Padcev, no conclusions can be drawn concerning a potential effect of immunogenicity on efficacy, safety or pharmacokinetics.

Skin reactions

In clinical studies of enfortumab vedotin in combination with pembrolizumab, skin reactions occurred in 67% (763) of the 1 134 patients and a majority of these skin reactions included rash maculo-papular, rash and rash macular. Severe (Grade 3 or 4) skin reactions occurred in 15% (175) of patients (Grade 3: 14%, Grade 4: 1%). A fatal event of toxic epidermal necrolysis occurred in one patient. The median time to onset of severe skin reactions was 1.1 months (range: 0.1 to 24.0 months). Of the patients who experienced skin reactions and had data regarding resolution (n=761), 81% had complete resolution, 13% had partial improvement and 6% had no improvement at the time of their last evaluation. Of the 19% of patients with residual skin reactions at last evaluation, 30% had Grade ≥2 events.

In clinical studies of enfortumab vedotin as monotherapy, skin reactions occurred in 57% (452) of the 793 patients treated with enfortumab vedotin 1.25 mg/kg. Severe (Grade 3 or 4) skin reactions occurred in 14% (108) of patients and a majority of these reactions included rash maculo-papular, stomatitis, rash erythematous, rash or drug eruption. The median time to onset of severe skin reactions was 0.7 months (range: 0.1 to 8.2 months). Serious skin reactions occurred in 4.3% (34) of patients. Of the patients who experienced skin reactions and had data regarding resolution (n=366), 61% had complete resolution, 24% had partial improvement, and 15% had no improvement at the time of their last evaluation. Of the 39% of patients with residual skin reactions at last evaluation, 38% had Grade ≥2 events.

Pneumonitis/ILD

In clinical studies of enfortumab vedotin in combination with pembrolizumab, pneumonitis/ILD occurred in 8.8% (100) of the 1 134 patients. Severe (Grade 3 or 4) pneumonitis/ILD occurred in 30 patients (Grade 3: 2.0%, Grade 4: 0.6%). Pneumonitis/ILD led to discontinuation of enfortumab vedotin in 1.9% of patients. Three patients experienced a fatal event of pneumonitis/ILD. The median time to onset of any grade pneumonitis/ILD was 3.8 months (range: 0.3 to 26.2 months).

In clinical studies of enfortumab vedotin as monotherapy, pneumonitis/ILD occurred in 3.3% (26) of the 793 patients treated with enfortumab vedotin 1.25 mg/kg. Less than 1% of patients experienced severe (Grade 3 or 4) pneumonitis/ILD (Grade 3: 0.5%, Grade 4: 0.3%). Pneumonitis/ILD led to discontinuation of enfortumab vedotin in 0.5% of patients. There were no deaths from pneumonitis/ILD. The median time to onset of any grade pneumonitis/ILD was 2.7 months (range: 0.6 to 6.0 months) and the median duration for pneumonitis/ILD was 1.6 months (range: 0.1 to 43.0 months). Of the 26 patients who experienced pneumonitis/ILD, 8 (30.8%) had resolution of symptoms.

Hyperglycaemia

In clinical studies of enfortumab vedotin as monotherapy, hyperglycaemia (blood glucose >13.9 mmol/L) occurred in 17% (133) of the 793 patients treated with enfortumab vedotin 1.25 mg/kg. Serious events of hyperglycaemia occurred in 2.5% of patients, 7% of patients developed severe (Grade 3 or 4) hyperglycaemia and 0.3% of patients experienced fatal events, one event each of hyperglycaemia and diabetic ketoacidosis. The incidence of Grade 3-4 hyperglycaemia increased consistently in patients with higher body mass index and in patients with higher baseline haemoglobin A1C (HbA1c). The median time to onset of hyperglycaemia was 0.5 months (range: 0 to 20.3 months).

Of the patients who experienced hyperglycaemia and had data regarding resolution (n=106), 66% had complete resolution, 19% had partial improvement and 15% had no improvement at the time of their last evaluation. Of the 34% of patients with residual hyperglycaemia at last evaluation, 64% had Grade ≥2 events.

Peripheral neuropathy

In clinical studies of enfortumab vedotin as monotherapy, peripheral neuropathy occurred in 53% (422) of the 793 patients treated with enfortumab vedotin 1.25 mg/kg. Five percent of patients experienced severe (Grade 3 or 4) peripheral neuropathy including sensory and motor events. The median time to onset of Grade ≥2 peripheral neuropathy was 5 months (range: 0.1 to 20.2 months).

Of the patients who experienced neuropathy and had data regarding resolution (n=340), 14% had complete resolution, 46% had partial improvement and 41% had no improvement at the time of their last evaluation. Of the 86% of patients with residual neuropathy at last evaluation, 51% had Grade ≥2 events.

Ocular disorders

In clinical studies of enfortumab vedotin as monotherapy, 30% of patients experienced dry eye during treatment with enfortumab vedotin 1.25 mg/kg. Treatment was interrupted in 1.5% of patients and 0.1% of patients permanently discontinued treatment due to dry eye. Severe (Grade 3) dry eye only occurred in 3 patients (0.4%). The median time to onset of dry eye was 1.7 months (range: 0 to 30.6 months).

Special populations

Elderly

Enfortumab vedotin in combination with pembrolizumab has been studied in 359 patients <65 years and 775 patients ≥65 years.

Generally, adverse event frequencies were higher in patients ≥65 years of age compared to <65 years of age, particularly for serious adverse events (61.3% and 47.9%, respectively) and Grade ≥3 events (79.2% and 68.2%, respectively), similar to observations with the chemotherapy comparator.

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 Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

There is no known antidote for overdosage with enfortumab vedotin. In case of overdosage, the patient should be closely monitored for adverse reactions, and supportive treatment should be administered as appropriate taking into consideration the half-life of 3.6 days (ADC) and 2.6 days (MMAE).

Pharmacotherapeutic group: Antineoplastic agents, other antineoplastic agents, monoclonal antibodies, ATC code: L01FX13.

Mechanism of action

Enfortumab vedotin is an ADC targeting Nectin-4, an adhesion protein located on the surface of the urothelial cancer cells. It is comprised of a fully human IgG1-kappa antibody conjugated to the microtubule-disrupting agent MMAE via a protease‑cleavable maleimidocaproyl valine-citrulline linker. Nonclinical data suggest that the anticancer activity of enfortumab vedotin is due to the binding of the ADC to Nectin‑4‑expressing cells, followed by internalisation of the ADC-Nectin-4 complex, and the release of MMAE via proteolytic cleavage. Release of MMAE disrupts the microtubule network within the cell, subsequently inducing cell cycle arrest, apoptosis and immunogenic cell death. MMAE released from enfortumab vedotin targeted cells can diffuse into nearby Nectin-4 low‑expressing cells resulting in cytotoxic cell death. Combination of enfortumab vedotin with programmed death receptor-1 (PD-1) inhibitors results in enhanced anti-tumour activity, consistent with the complementary mechanisms of MMAE induced cell cytotoxicity and induction of immunogenic cell death, plus the up-regulation of immune function by PD-1 inhibition.

Cardiac electrophysiology

At the recommended dose of 1.25 mg/kg, enfortumab vedotin did not prolong the mean QTc interval to any clinically relevant extent based on ECG data from a study in patients with advanced urothelial cancer.

Clinical efficacy and safety

Enfortumab vedotin in combination with pembrolizumab

Neoadjuvant and adjuvant treatment of cisplatin-eligible patients with muscle invasive bladder cancer (MIBC)

EV-304 (KEYNOTE-B15)

The efficacy of Padcev in combination with pembrolizumab as neoadjuvant treatment and then continued after radical cystectomy (RC) as adjuvant treatment was evaluated in study EV-304 (KEYNOTE-B15), an open‑label, randomised, phase 3, multicentre study that enrolled patients who received neoadjuvant and adjuvant enfortumab vedotin and pembrolizumab versus neoadjuvant gemcitabine and cisplatin. Key eligibility criteria were previously untreated cT2-T4aN0M0 or cT1-T4aN1M0 MIBC in patients who were eligible for cisplatin-based chemotherapy and were eligible for RC and pelvic lymph node dissection (PLND), regardless of programmed death ligand-1 (PD-L1) status. Patients with active autoimmune disease that required systemic therapy within 2 years of treatment or a medical condition that required immunosuppression were ineligible.

Patients were randomised 1:1 to one of the following treatment arms:

• Enfortumab vedotin in combination with pembrolizumab (n=405): Neoadjuvant enfortumab vedotin 1.25 mg/kg as an intravenous infusion over 30 minutes on Days 1 and 8 and neoadjuvant pembrolizumab 200 mg over 30 minutes on Day 1 of each 3‑week (21-day) cycle for 4 cycles. Following RC and PLND, adjuvant enfortumab vedotin 1.25 mg/kg over 30 minutes on Days 1 and 8 of each 3-week (21-day) cycle for 5 cycles and adjuvant pembrolizumab 200 mg over 30 minutes on Day 1 of each 3‑week (21-day) cycle for 13 cycles.

• Gemcitabine and cisplatin (n=403): Neoadjuvant gemcitabine 1000 mg/m² on Days 1 and 8 and cisplatin 70 mg/m² on Day 1 of each 3-week (21-day) cycle for 4 cycles. Following RC and PLND, followed by observation.

Treatment continued until completion of the treatment, disease progression that precluded RC and PLND, not undergoing or refusal of RC and PLND, disease recurrence in the adjuvant phase or unacceptable toxicity. Assessment of tumour status was performed at baseline, within 5 weeks prior to RC and PLND and at 6 weeks post-surgery. Following RC and PLND, assessment of tumour status was performed every 12 weeks up to 2 years, and every 24 weeks thereafter. Randomisation was stratified by tumor stage (T2N0 versus T3/T4aN0 versus T1-T4aN1), PD-L1 combined positive score (CPS ≥10 versus CPS <10) and geographic region (United States versus European Union versus Rest of World).

The median age was 66 years (range: 35 to 85 years); 81% were male; and 80% White. Patients had a baseline Eastern Cooperative Oncology Group (ECOG) performance status of 0 (78%) or 1 (22%). Fifty-seven percent were CPS ≥10 and 43% CPS <10. Nineteen percent were T2N0, 73% T3/T4aN0 and 8% T1-T4aN1. Ninety percent of patients had urothelial carcinoma histology; 5% had urothelial carcinoma with squamous differentiation, 3% had urothelial carcinoma with glandular differentiation and 3% had urothelial carcinoma with other variant histology.

In the overall population, 351 (87%) patients in the enfortumab vedotin in combination with pembrolizumab arm and 361 (90%) patients in the gemcitabine and cisplatin arm underwent RC and PLND.

The trial was not designed to isolate the effect of Padcev in combination with intravenous pembrolizumab in each phase (neoadjuvant or adjuvant) of treatment.

The primary efficacy outcome measure was event-free survival (EFS) as assessed by blinded independent central review (BICR). Secondary efficacy outcome measures were overall survival (OS) and pathological complete response (pCR) rate as assessed by blinded independent pathology review (BIPR).

The study showed statistically significant improvements in EFS, OS and pCR in patients treated with neoadjuvant and adjuvant enfortumab vedotin in combination with pembrolizumab compared with neoadjuvant gemcitabine and cisplatin. Efficacy results were consistent across all prespecified patient subgroups. The median follow-up time for this study was 30.8 months (range: 0.5 to 53.6 months).

A total of 95 patients aged ≥ 75 years were enrolled in EV-304 (48 in the enfortumab vedotin in combination with pembrolizumab arm and 47 in the gemcitabine and cisplatin-based chemotherapy arm). Data about efficacy of enfortumab vedotin in combination with pembrolizumab are limited in this patient population. Data from these patients are too limited to draw any conclusion on efficacy in this population.

Table 6, Figures 1 and 2 summarise the efficacy results for EV-304.

Table 6. Efficacy results in EV-304

NR = Not reached.

a. EFS is defined as time from randomisation to any of the following events: Radiographic disease progression precluding a curative intent surgery as assessed by BICR prior to RC + PLND; Failure to undergo surgery for participants with residual muscle invasive disease and any radiographic disease present; Gross residual disease left behind at time of surgery (surgeon unable to complete curative intent surgery due to unresectable tumor or newly discovered metastatic disease); Local or distant recurrence post-RC + PLND as assessed by CT or MRI by BICR and/or biopsy – if biopsy is not feasible due to participant safety, CT/MRI alone will be sufficient; Death from any cause.

b. Based on Kaplan-Meier estimates.

c. Based on stratified Cox regression model with Efron's method of tie handling with treatment as a covariate.

d. Based on stratified log-rank test.

e. Based on stratified Miettinen and Nurminen method.

Figure 1. Kaplan Meier plot of event-free survival, EV-304

Figure 2. Kaplan Meier plot of overall survival, EV-304

Neoadjuvant and adjuvant treatment of cisplatin-ineligible patients with muscle invasive bladder cancer (MIBC)

EV-303 (KEYNOTE-905)

The efficacy of Padcev in combination with pembrolizumab as neoadjuvant treatment and then continued after RC as adjuvant treatment was evaluated in study EV-303 (KEYNOTE‑905), an open‑label, randomised, phase 3, multicentre study that enrolled patients who received neoadjuvant and adjuvant enfortumab vedotin and pembrolizumab versus RC and PLND. Key eligibility criteria were previously untreated cT2‑T4aN0M0 or cT1-T4aN1M0 MIBC in patients who were ineligible for or declined cisplatin-based chemotherapy and were eligible for RC and PLND, regardless of PD‑L1 status. Patients with active autoimmune disease that required systemic therapy within 2 years of treatment or a medical condition that required immunosuppression were ineligible.

Patients were randomised 1:1:1 to receive neoadjuvant and adjuvant enfortumab vedotin in combination with pembrolizumab, neoadjuvant and adjuvant pembrolizumab monotherapy or RC and PLND alone. The hypothesis testing was updated to prioritize the comparison of the enfortumab vedotin in combination with pembrolizumab arm versus the RC and PLND alone arm for EFS; therefore, randomisation to the pembrolizumab monotherapy arm was stopped early. The evaluation of efficacy was based on the comparison between the following treatment arms:

• Enfortumab vedotin in combination with pembrolizumab (n=170): Neoadjuvant enfortumab vedotin 1.25 mg/kg as an intravenous infusion over 30 minutes on Days 1 and 8 and neoadjuvant pembrolizumab 200 mg over 30 minutes on Day 1 of each 3‑week (21-day) cycle for 3 cycles. Following RC and PLND, adjuvant enfortumab vedotin 1.25 mg/kg over 30 minutes on Days 1 and 8 of each 3-week (21-day) cycle for 6 cycles and adjuvant pembrolizumab 200 mg over 30 minutes on Day 1 of each 3‑week (21-day) cycle for 14 cycles.

• RC and PLND alone (n=174).

Treatment continued until completion of the treatment, disease progression that precluded RC and PLND, not undergoing or refusal of RC and PLND, disease recurrence in the adjuvant phase or unacceptable toxicity. Assessment of tumour status was performed at baseline, within 5 weeks prior to RC and PLND and at 6 weeks post-surgery. Following RC and PLND, assessment of tumour status was performed every 12 weeks up to 2 years, and every 24 weeks thereafter. Randomisation was stratified by tumor stage (T2N0 versus T3/T4aN0 versus T1‑T4aN1), cisplatin-eligibility (cisplatin‑ineligible versus cisplatin-eligible but declined) and geographic region (United States versus European Union versus Rest of World).

The median age was 73 years (range: 46 to 87 years); 78% were male; and 78% White. Patients had a baseline ECOG performance status of 0-1 (86%) or 2 (14%). Forty-seven percent were CPS ≥10 and 52% CPS <10. Eighteen percent were T2N0, 77% T3/T4aN0 and 5% T1-T4aN1. Forty-one percent of patients had baseline creatinine clearance of ≥60 mL/min, 59% had <60 mL/min but ≥30 mL/min and 0.3% had <30 mL/min, respectively. Ninety-one percent of patients had urothelial carcinoma histology; 4% had urothelial carcinoma with squamous differentiation, 3% had urothelial carcinoma with glandular differentiation and 2% had urothelial carcinoma with other variant histology.

In the overall population, 149 (88%) patients in the enfortumab vedotin in combination with pembrolizumab arm and 156 (90%) patients in the RC and PLND alone arm underwent RC and PLND.

Of the patients treated with enfortumab vedotin in combination with pembrolizumab, 100 patients initiated adjuvant treatment and 43 patients completed all planned cycles.

The primary efficacy outcome measure was EFS as assessed by BICR. Secondary efficacy outcome measures were OS and pCR rate as assessed by blinded independent pathology review (BIPR).

The study showed statistically significant improvements in EFS, OS, and pCR in patients treated with neoadjuvant and adjuvant enfortumab vedotin in combination with pembrolizumab compared with RC and PLND alone. The median follow-up time for this study was 18.5 months (range: 0.6 to 53.7 months).

Table 7, Figures 3 and 4 summarise the efficacy results for EV-303.

Table 7. Efficacy results in EV-303

NR = Not reached.

a. EFS is defined as time from randomisation to any of the following events: Radiographic disease progression precluding a curative intent surgery as assessed by BICR prior to RC + PLND; Failure to undergo surgery for participants with residual muscle invasive disease and any radiographic disease present; Gross residual disease left behind at time of surgery (surgeon unable to complete curative intent surgery due to unresectable tumor or newly discovered metastatic disease); Local or distant recurrence post-RC + PLND as assessed by CT or MRI by BICR and/or biopsy – if biopsy is not feasible due to participant safety, CT/MRI alone will be sufficient; Death from any cause.

b. Based on Kaplan-Meier estimates.

c. Based on stratified Cox regression model with Efron's method of tie handling with treatment as a covariate.

d. Based on stratified log-rank test.

e. Based on stratified Miettinen and Nurminen method.

Figure 3. Kaplan Meier plot of event-free survival, EV-303

Figure 4. Kaplan Meier plot of overall survival, EV-303

Previously untreated locally advanced or metastatic urothelial cancer

EV-302 (KEYNOTE-A39)

The efficacy of Padcev in combination with pembrolizumab was evaluated in study EV-302 (KEYNOTE-A39), an open‑label, randomised, phase 3, multicentre study that enrolled 886 patients with unresectable or metastatic urothelial cancer who had not received prior systemic therapy for locally advanced or metastatic disease. Patients that received neoadjuvant chemotherapy or patients that received adjuvant chemotherapy following cystectomy were included in the study if recurrence was >12 months from completion of therapy. Patients were considered cisplatin-ineligible if they had at least one of the following criteria: glomerular filtration rate (GFR) between 30-59 mL/min, ECOG performance status ≥2, Grade ≥2 hearing loss or New York Heart Association (NYHA) Class III heart failure.

Patients were randomised 1:1 to receive either enfortumab vedotin in combination with pembrolizumab (arm A) or gemcitabine and platinum-based chemotherapy (cisplatin or carboplatin) (arm B). Patients in arm A received enfortumab vedotin 1.25 mg/kg as an intravenous infusion over 30 minutes on Days 1 and 8 of a 21-day cycle, followed by pembrolizumab 200 mg on Day 1 of a 21-day cycle approximately 30 minutes after enfortumab vedotin. Patients in arm B received gemcitabine 1000 mg/m² administered on Days 1 and 8 of a 21-day cycle with cisplatin 70 mg/m² or carboplatin (AUC = 4.5 or 5 mg/mL/min according to local guidelines) administered on Day 1 of a 21-day cycle. Treatment was continued until disease progression, unacceptable toxicity or completion of the maximum number of treatment cycles (chemotherapy, 6 cycles; pembrolizumab, 35 cycles; enfortumab vedotin, no set maximum).

Patients randomised to the gemcitabine and platinum-based chemotherapy arm were permitted to receive maintenance immunotherapy (e.g., avelumab). Randomisation was stratified by cisplatin eligibility (eligible versus ineligible), PD-L1 expression (CPS≥10 versus CPS<10) and presence of liver metastases (present versus absent). PD-L1 expression was based on the PD-L1 IHC 22C3 pharmDx kit.

Patients were excluded from the study if they had active CNS metastases, ongoing sensory or motor neuropathy Grade ≥2, uncontrolled diabetes defined as haemoglobin A1C (HbA1c) ≥8% or HbA1c ≥7% with associated diabetes symptoms, autoimmune disease or a medical condition that required immunosuppression, pneumonitis or other forms of interstitial lung disease.

The median age was 69 years (range: 22 to 91 years); 77% were male; and most were White (67%) or Asian (22%). Patients had a baseline ECOG performance status of 0 (49%), 1 (47%) or 2 (3%). Forty-seven percent of patients had a documented baseline HbA1c of <5.7%. At baseline, 95% of patients had metastatic urothelial cancer and 5% of patients had unresectable urothelial cancer. Seventy-two percent of patients had visceral metastasis at baseline including 22% with liver metastases. Eighty-five percent of patients had urothelial carcinoma (UC) histology, 6% had UC mixed squamous differentiation and 2% had UC mixed other histologic variants. Forty-six percent of patients were cisplatin-ineligible and 54% were cisplatin-eligible at time of randomisation. Of the 877 patients tested who had tissue evaluable for PD-L1 expression, 58% of patients had tumours that expressed PD-L1 with a CPS ≥10 and 42% had tumours that expressed PD-L1 with a CPS <10. The median follow-up time was 17.3 months (range: 0.3 to 37.2 months).

The primary efficacy outcome measures were Overall Survival (OS) and Progression Free Survival (PFS) as assessed by BICR according to RECIST v1.1. Secondary efficacy outcome measures included Objective Response Rate (ORR) as assessed by BICR according to RECIST v1.1.

The study showed statistically significant improvements in OS, PFS and ORR for patients randomised to enfortumab vedotin in combination with pembrolizumab as compared to gemcitabine and platinum-based chemotherapy.

Table 8, Figures 5 and 6 summarise the efficacy results for EV-302.

Table 8. Efficacy Results in EV-302

NR = Not reached.

a. Based on the complementary log-log transformation method (Collett, 1994).

b. Based on stratified Cox proportional hazards model. A hazard ratio <1 favors the enfortumab vedotin in combination with pembrolizumab arm.

c. Based on stratified log-rank test.

d. Evaluated by BICR using RECIST v1.1.

e. Based on the Clopper-Pearson method (Clopper 1934).

f. Includes only patients with measurable disease at baseline (n=437 for enfortumab vedotin in combination with pembrolizumab, n=441 for gemcitabine plus platinum). The duration of response was estimated for responders.

g. Based on Cochran-Mantel-Haenszel test stratified by PD-L1 expression, cisplatin eligibility and liver metastases.

Figure 5. Kaplan Meier plot of overall survival, EV-302

Figure 6. Kaplan Meier plot of progression-free survival, EV-302

Enfortumab vedotin as monotherapy

Previously treated locally advanced or metastatic urothelial cancer

EV-301

The efficacy of Padcev as monotherapy was evaluated in study EV-301, an open-label, randomised, phase 3, multicentre study that enrolled 608 patients with locally advanced or metastatic urothelial cancer who have previously received a platinum-containing chemotherapy and a programmed death receptor 1 (PD-1) or programmed death ligand 1 (PD‑L1) inhibitor. The primary endpoint of the study was Overall Survival (OS) and secondary endpoints included Progression Free Survival (PFS) and Objective Response Rate (ORR) [PFS and ORR were evaluated by investigator assessment using RECIST v1.1]. Patients were randomised 1:1 to receive either enfortumab vedotin 1.25 mg/kg on Days 1, 8 and 15 of a 28‑day cycle, or one of the following chemotherapies as decided by the investigator: docetaxel 75 mg/m² (38%), paclitaxel 175 mg/m² (36%) or vinflunine 320 mg/m² (25%) on Day 1 of a 21-day cycle.

Patients were excluded from the study if they had active CNS metastases, ongoing sensory or motor neuropathy ≥Grade 2, known history of human immunodeficiency virus (HIV) infection (HIV 1 or 2), active Hepatitis B or C, or uncontrolled diabetes defined as HbA1c ≥8% or HbA1c ≥7% with associated diabetes symptoms.

The median age was 68 years (range: 30 to 88 years), 77% were male, and most patients were White (52%) or Asian (33%). All patients had a baseline ECOG performance status of 0 (40%) or 1 (60%). Ninety-five percent (95%) of patients had metastatic disease and 5% had locally advanced disease. Eighty percent of patients had visceral metastases including 31% with liver metastases. Seventy-six percent of patients had urothelial carcinoma/transitional cell carcinoma (TCC) histology, 14% had urothelial carcinoma mixed and approximately 10% had other histologic variants. A total of 76 (13%) patients had received ≥3 lines of prior systemic therapy. Fifty-two percent (314) of patients had received prior PD-1 inhibitor, 47% (284) had received prior PD-L1 inhibitor, and an additional 1% (9) patients had received both PD-1 and PD-L1 inhibitors. Only 18% (111) of patients had a response to prior therapy with a PD-1 or PD-L1 inhibitor. Sixty-three percent (383) of patients had received prior cisplatin-based regimens, 26% (159) had received prior carboplatin-based regimens, and an additional 11% (65) had received both cisplatin and carboplatin-based regimens.

Table 9 summarises the efficacy results for the EV-301 study, after a median follow‑up time of 11.1 months (95% CI: 10.6 to 11.6).

Table 9. Efficacy results in EV‑301

a. pre‑determined efficacy boundary = 0.00679, 1‑sided (adjusted by observed deaths of 301)

b. evaluated by investigator assessment using RECIST v1.1

c. pre‑determined efficacy boundary = 0.02189, 1‑sided (adjusted by observed PFS1 events of 432)

d. pre‑determined efficacy boundary = 0.025, 1‑sided (adjusted by 100% information fraction)

Figure 7. Kaplan Meier plot of overall survival, EV-301

Paediatric population

The Licensing Authority has waived the obligation to submit the results of studies with enfortumab vedotin in all subsets of the paediatric population in urothelial cancer (see section 4.2 for information on paediatric use).

Distribution

The mean estimate of steady-state volume of distribution of ADC was 12.8 L following 1.25 mg/kg of enfortumab vedotin. In vitro, the binding of unconjugated MMAE to human plasma proteins ranged from 68% to 82%. Unconjugated MMAE is not likely to displace or to be displaced by highly protein‑bound medicinal products. In vitro studies indicate that unconjugated MMAE is a substrate of P‑glycoprotein.

Biotransformation

A small fraction of unconjugated MMAE released from enfortumab vedotin is metabolised. In vitro data indicate that the metabolism of unconjugated MMAE occurs primarily via oxidation by CYP3A4.

Elimination

The mean clearance of ADC and unconjugated MMAE in patients was 0.11 L/h and 2.11 L/h, respectively. ADC elimination exhibited a multi-exponential decline with a half-life of 3.6 days.

Elimination of unconjugated MMAE appeared to be limited by its rate of release from enfortumab vedotin. Unconjugated MMAE elimination exhibited a multi-exponential decline with a half-life of 2.6 days.

Excretion

The excretion of unconjugated MMAE occurs mainly in faeces with a smaller proportion in urine. After a single dose of another ADC that contained unconjugated MMAE, approximately 24% of the total unconjugated MMAE administered was recovered in faeces and urine as unchanged unconjugated MMAE over a 1-week period. The majority of recovered unconjugated MMAE was excreted in faeces (72%). A similar excretion profile is expected for unconjugated MMAE after enfortumab vedotin administration.

Special populations

Elderly

Population pharmacokinetic analysis indicates that age [range: 24 to 90 years; 60% (450/748) >65 years, 19% (143/748) >75 years] does not have a clinically meaningful effect on the pharmacokinetics of enfortumab vedotin.

Race and gender

Based on population pharmacokinetic analysis, race [69% (519/748) White, 21% (158/748) Asian, 1% (10/748) Black and 8% (61/748) others or unknown] and gender [73% (544/748) male] do not have a clinically meaningful effect on the pharmacokinetics of enfortumab vedotin.

Renal impairment

The pharmacokinetics of ADC and unconjugated MMAE were evaluated after the administration of 1.25 mg/kg of enfortumab vedotin to patients with mild (CrCL >60‑90 mL/min), moderate (CrCL 30–60 mL/min) and severe (CrCL 15–<30 mL/min) renal impairment. No significant differences in AUC exposure of ADC or unconjugated MMAE were observed in patients with mild, moderate or severe renal impairment compared to patients with normal renal function. Enfortumab vedotin has not been evaluated in patients with end stage renal disease (CrCL <15 mL/min).

Hepatic impairment

Based on population pharmacokinetics analysis using data from clinical studies in patients with metastatic UC, there was no significant differences in ADC exposure and a 37% and 16% increase in unconjugated MMAE average concentrations in patients with previously treated and previously untreated locally advanced or metastatic urothelial cancer, respectively, with mild hepatic impairment (total bilirubin of 1 to 1.5 × ULN and AST any, or total bilirubin ≤ULN and AST >ULN) compared to patients with normal hepatic function. Enfortumab vedotin has only been studied in a limited number of patients with moderate hepatic impairment (n=5) or severe hepatic impairment (n=1). The effect of moderate or severe hepatic impairment (total bilirubin >1.5 × ULN and AST any) or liver transplantation on the pharmacokinetics of ADC or unconjugated MMAE is unknown.

Physiologically-based pharmacokinetic modelling predictions

Concomitant use of enfortumab vedotin with ketoconazole (a combined P-gp and strong CYP3A inhibitor) is predicted to increase unconjugated MMAE C_max and AUC exposure to a minor extent, with no change in ADC exposure.

Concomitant use of enfortumab vedotin with rifampin (a combined P-gp and strong CYP3A inducer) is predicted to decrease unconjugated MMAE C_max and AUC exposure with moderate effect, with no change in ADC exposure. The full impact of rifampin on the C_max of unconjugated MMAE may be underestimated in the PBPK model.

Concomitant use of enfortumab vedotin is predicted not to affect exposure to midazolam (a sensitive CYP3A substrate). In vitro studies using human liver microsomes indicate that unconjugated MMAE inhibits CYP3A4/5 but not other CYP450 isoforms. Unconjugated MMAE did not induce major CYP450 enzymes in human hepatocytes.

In vitro studies

In vitro studies indicate that unconjugated MMAE is a substrate and not an inhibitor of the efflux transporter P-glycoprotein (P-gp). In vitro studies determined that unconjugated MMAE was not a substrate of breast cancer resistance protein (BCRP), multidrug resistance‑associated protein 2 (MRP2), organic anion transporting polypeptide 1B1 or 1B3 (OATP1B1 or OATP1B3), organic cation transporter 2 (OCT2), or organic anion transporter 1 or 3 (OAT1 or OAT3). Unconjugated MMAE was not an inhibitor of the bile salt export pump (BSEP), P-gp, BCRP, MRP2, OCT1, OCT2, OAT1, OAT3, OATP1B1 or OATP1B3 at clinically relevant concentrations.

Genotoxicity studies showed that MMAE had no discernible genotoxic potential in a reverse mutation test in bacteria (Ames test) or in a L5178Y TK+/- mouse lymphoma mutation assay. MMAE did induce chromosomal aberrations in the micronucleus test in rats which is consistent with the pharmacological action of microtubule-disrupting agents.

Skin lesions were noted in repeat dose studies in rats (4- and 13-weeks) and in monkeys (4‑weeks). The skin changes were fully reversible by the end of a 6-week recovery period.

Hyperglycaemia reported in the clinical studies was absent in both the rat and monkey toxicity studies and there were no histopathological findings in the pancreas of either species.

Foetal toxicity (reduced litter size or complete litter loss) was observed and decrease in the litter size was reflected in an increase in early resorptions. Mean foetal body weight in the surviving foetuses at the 2 mg/kg dose level were reduced compared with control.

Enfortumab vedotin associated foetal skeletal variations were considered developmental delays. A dose of 2 mg/kg (approximately similar to the exposure at the recommended human dose) resulted in maternal toxicity, embryo-foetal lethality and structural malformations that included gastroschisis, malrotated hindlimb, absent forepaw, malpositioned internal organs and fused cervical arch. Additionally, skeletal anomalies (asymmetric, fused, incompletely ossified, and misshapen sternebrae, misshapen cervical arch, and unilateral ossification of the thoracic centra) and decreased foetal weight were observed.

Testicular toxicity observed, only in rats, was partially reversed by the end of a 24-week recovery period.

No dedicated preclinical safety studies were conducted with enfortumab vedotin in combination with pembrolizumab.

Histidine

Histidine hydrochloride monohydrate

Trehalose dihydrate

Polysorbate 20 (E 432)

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

Unopened vial

4 years.

Reconstituted solution in the vial

From a microbiological point of view, after reconstitution, the solution from the vial(s) should be added to the infusion bag immediately. If not used immediately, storage times and conditions prior to use of the reconstituted vials are the responsibility of the user and would normally not be longer than 24 hours in refrigeration at 2°C to 8°C. Do not freeze.

Diluted dosing solution in the infusion bag

From a microbiological point of view, after dilution into the infusion bag, the diluted solution in the bag should be administered to the patient immediately. If not used immediately, storage times and conditions prior to use of the diluted dosing solution is the responsibility of the user and would normally not be longer than 16 hours in refrigeration at 2°C to 8°C including infusion time. Do not freeze.

Unopened vials

Store in a refrigerator (2°C to 8°C).

Do not freeze.

For storage conditions after reconstitution and dilution of the medicinal product, see section 6.3.

Padcev 20 mg powder for concentrate for solution for infusion vial

10 mL Type I glass vial with grey bromobutyl rubber stopper, 20 mm aluminium seal with a green ring and green cap. Each carton contains 1 vial.

Padcev 30 mg powder for concentrate for solution for infusion vial

10 mL Type I glass vial with grey bromobutyl rubber stopper, 20 mm aluminium seal with a silver ring and yellow cap. Each carton contains 1 vial.

Instructions for preparation and administration

Reconstitution in single-dose vial

1. Follow procedures for proper handling and disposal of anticancer medicinal products.

2. Use appropriate aseptic technique for reconstitution and preparation of dosing solutions.

3. Calculate the recommended dose based on the patient's weight to determine the number and strength (20 mg or 30 mg) of vials needed.

4. Reconstitute each vial as follows and, if possible, direct the stream of sterile water for injection along the walls of the vial and not directly onto the lyophilized powder:

a. 20 mg vial: Add 2.3 mL of sterile water for injection, resulting in 10 mg/mL enfortumab vedotin.

b. 30 mg vial: Add 3.3 mL of sterile water for injection, resulting in 10 mg/mL enfortumab vedotin.

5. Slowly swirl each vial until the contents are completely dissolved. Allow the reconstituted vial(s) to settle for at least 1 minute until the bubbles are gone. Do not shake the vial. Do not expose to direct sunlight.

6. Visually inspect the solution for particulate matter and discolouration. The reconstituted solution should be clear to slightly opalescent, colourless to light yellow and free of visible particles. Discard any vial with visible particles or discolouration.

Dilution in infusion bag

7. Withdraw the calculated dose amount of reconstituted solution from the vial(s) and transfer into an infusion bag.

8. Dilute enfortumab vedotin with either dextrose 50 mg/mL (5%), sodium chloride 9 mg/mL (0.9%) or Lactated Ringer's solution for injection. The infusion bag size should allow enough solvent to achieve a final concentration of 0.3 mg/mL to 4 mg/mL enfortumab vedotin.

Diluted dosing solution of enfortumab vedotin is compatible with intravenous infusion bags composed of polyvinyl chloride (PVC), ethylvinyl acetate, polyolefin such as polypropylene (PP), or IV bottles comprised of polyethylene (PE), polyethylene terephthalate glycol-modified, and infusion sets composed of PVC with either plasticizer (bis(2-ethylhexyl) phthalate (DEHP) or tris(2-ethylhexyl) trimellitate (TOTM)), PE and with filter membranes (pore size: 0.2-1.2 μm) composed of polyethersulfone, polyvinylidene difluoride, or mixed cellulose esters.

9. Mix diluted solution by gentle inversion. Do not shake the bag. Do not expose to direct sunlight.

10. Visually inspect the infusion bag for any particulate matter or discolouration prior to use. The reconstituted solution should be clear to slightly opalescent, colourless to light yellow and free of visible particles. Do not use the infusion bag if particulate matter or discolouration is observed.

11. Discard any unused portion left in the single-dose vials.

Administration

12. Administer the infusion over 30 minutes through an intravenous line. Do not administer as an intravenous push or bolus.

No incompatibilities have been observed with closed system transfer device composed of acrylonitrile butadiene styrene (ABS), acrylic, activated charcoal, ethylene propylene diene monomer, methacrylate ABS, polycarbonate, polyisoprene, polyoxymethylene, PP, silicone, stainless steel, thermoplastic elastomer for reconstituted solution.

13. Do not co-administer other medicinal products through the same infusion line.

14. In-line filters or syringe filters (the pore size: 0.2-1.2 μm, recommended materials: polyethersulfone, polyvinylidene difluoride, mixed cellulose esters) are recommended to be used during administration.

Disposal

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.