4.1. Therapeutic indications

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) who are ineligible for cisplatin‑containing chemotherapy.

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.

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).

4.2. Posology and method of administration

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

When given in combination with pembrolizumab for the neoadjuvant and adjuvant treatment of MIBC, the recommended dose of enfortumab vedotin is 1.25 mg/kg (up to a maximum of 125 mg for patients ≥100 kg) administered as an intravenous infusion over 30 minutes. Enfortumab vedotin is administered as neoadjuvant treatment on Days 1 and 8 of each 3-week (21‑day) cycle for 3 cycles or until disease progression that precludes radical cystectomy (RC) or unacceptable toxicity, followed by adjuvant treatment on Days 1 and 8 of each 3‑week (21-day) cycle for 6 cycles or until disease recurrence or unacceptable toxicity.

When given in combination with pembrolizumab for the treatment of unresectable or metastatic urothelial cancer, the recommended dose of enfortumab vedotin is 1.25 mg/kg (up to a maximum of 125 mg for patients ≥100 kg) administered as an intravenous infusion over 30 minutes on Days 1 and 8 of every 3-week (21-day) cycle until disease progression or unacceptable toxicity. The recommended dose of pembrolizumab is either 200 mg every 3 weeks or 400 mg every 6 weeks administered as an intravenous infusion over 30 minutes.

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.

As monotherapy for the treatment of locally advanced or metastatic urothelial cancer, the recommended dose of enfortumab vedotin is 1.25 mg/kg (up to a maximum of 125 mg for patients ≥100 kg) administered as an intravenous infusion over 30 minutes on Days 1, 8 and 15 of a 28-day cycle until disease progression or unacceptable toxicity.

Table 1. Recommended dose reductions of enfortumab vedotin for adverse reactions

Dose reduction schedule

Dose level

Starting dose

1.25 mg/kg up to 125 mg

First dose reduction

1.0 mg/kg up to 100 mg

Second dose reduction

0.75 mg/kg up to 75 mg

Third dose reduction

0.5 mg/kg up to 50 mg

Dose modifications

Table 2. Dose interruption, reduction and discontinuation of enfortumab vedotin

Adverse reaction

Severity*

Dose modification*

Skin reactions

Suspected Stevens‑Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN) or bullous lesions

Immediately withhold and refer to specialised care.

Confirmed SJS or TEN; Grade 4 or recurrent Grade 3

Permanently discontinue.

Grade 2 worsening

Grade 2 with fever

Grade 3

• Withhold until Grade ≤1.

• Referral to specialised care should be considered.

• Resume at the same dose level or consider dose reduction by one dose level (see Table 1).

Hyperglycaemia

Blood glucose

>13.9 mmol/L (>250 mg/dL)

• Withhold until elevated blood glucose has improved to ≤13.9 mmol/L (≤250 mg/dL).

• Resume treatment at the same dose level.

Pneumonitis/ interstitial lung disease (ILD)

Grade 2

• Withhold until Grade ≤1, then resume at the same dose or consider dose reduction by one dose level (see Table 1).

Grade ≥3

Permanently discontinue.

Peripheral neuropathy

Grade 2

• Withhold until Grade ≤1.

• For first occurrence, resume treatment at the same dose level.

• For a recurrence, withhold until Grade ≤1, then resume treatment reduced by one dose level (see Table 1).

Grade ≥3

Permanently discontinue.

*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.

4.3. Contraindications

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

4.4. Special warnings and precautions for use

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 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

Serious infections such as sepsis or pneumonia (including fatal outcomes) have been reported in patients treated with Padcev. Patients should be carefully monitored during treatment for the emergence of possible serious 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 1). 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.

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.

4.5. Interaction with other medicinal products and other forms of interaction

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 Cmax and AUC exposure to a minor extent, with no change in 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).

4.6. Fertility, pregnancy and lactation

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.

4.7. Effects on ability to drive and use machines

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

4.8. Undesirable effects

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.

Muscle invasive bladder cancer

The safety of enfortumab vedotin was evaluated in combination with pembrolizumab in 167 patients who received at least one dose of enfortumab vedotin 1.25 mg/kg in combination with pembrolizumab in a phase 3 study (EV-303) (see Table 3). Patients were exposed to the combination of enfortumab vedotin and pembrolizumab for a median duration of 6.3 months (range: 0.03 to 19.7 months). The median duration of exposure to enfortumab vedotin alone was 5.5 months (range: 0.03 to 14.1 months).

Adverse reactions occurring in patients with MIBC receiving enfortumab vedotin in combination with pembrolizumab were generally similar to those occurring in patients with unresectable or metastatic urothelial cancer receiving enfortumab vedotin in combination with pembrolizumab.

The most common adverse reactions with enfortumab vedotin in combination with pembrolizumab were pruritus (47.3%), alopecia (34.7%), diarrhoea (34.1%), fatigue (32.3%), anaemia (30.5%), decreased appetite (28.1%), dysgeusia (28.1%), nausea (25.7%), rash (25.1%), aspartate aminotransferase increased (24%), weight decreased (19.8%), alanine aminotransferase increased (19.2%), rash maculo-papular (16.2%), dry skin (15%), hypothyroidism (14.4%), peripheral sensory neuropathy (13.8%), hyperglycaemia (12.6%) and neuropathy peripheral (10.2%).

The most common serious adverse reaction (≥2%) was diarrhoea (2.4%). Forty-one percent of patients permanently discontinued enfortumab vedotin for adverse reactions; the most common adverse reaction (≥2%) leading to discontinuation was peripheral sensory neuropathy (2.4%).

Adverse reactions leading to dose interruption of enfortumab vedotin occurred in 44% of patients. The most common adverse reactions (≥2%) leading to dose interruption were diarrhoea (4.2%), rash (4.2%), neutropenia (3.6%), fatigue (3%), hyperglycaemia (3%) and pruritus (2.4%).

Adverse reactions leading to dose reduction of enfortumab vedotin occurred in 17% of patients. The most common adverse reactions (≥2%) leading to dose reduction were rash (2.4%) and weight decreased (2.4%).

Unresectable or metastatic urothelial cancer

The safety of enfortumab vedotin was evaluated in combination with pembrolizumab in 564 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 one phase 3 study (EV-302) (see Table 3). Patients were exposed to enfortumab vedotin in combination with pembrolizumab for a median duration of 9.4 months (range: 0.3 to 34.4 months).

The most common adverse reactions with enfortumab vedotin in combination with pembrolizumab were peripheral sensory neuropathy (53.4%), pruritus (41.1%), fatigue (40.4%), diarrhoea (39.2%), alopecia (38.5%), rash maculo-papular (36%), weight decreased (36%), decreased appetite (33.9%), nausea (28.4%), anaemia (25.7%), dysgeusia (24.3%), dry skin (18.1%), alanine aminotransferase increased (16.8%), hyperglycaemia (16.7%), aspartate aminotransferase increased (15.4%), dry eye (14.4%), vomiting (13.3%), rash macular (11.3%), hypothyroidism (10.5%) and neutropenia (10.1%).

The most common serious adverse reactions (≥2%) were diarrhoea (3%) and pneumonitis (2.3%). Thirty-six percent of patients permanently discontinued enfortumab vedotin for adverse reactions; the most common adverse reactions (≥2%) leading to discontinuation were peripheral sensory neuropathy (12.2%) and rash maculo-papular (2%).

Adverse reactions leading to dose interruption of enfortumab vedotin occurred in 72% of patients. The most common adverse reactions (≥2%) leading to dose interruption were peripheral sensory neuropathy (17%), rash maculo-papular (6.9%), diarrhoea (4.8%), fatigue (3.7%), pneumonitis (3.7%), hyperglycaemia (3.4%), neutropenia (3.2%), alanine aminotransferase increased (3%), pruritus (2.3%) and anaemia (2%).

Adverse reactions leading to dose reduction of enfortumab vedotin occurred in 42.4% of patients. The most common adverse reactions (≥2%) leading to dose reduction were peripheral sensory neuropathy (9.9%), rash maculo-papular (6.4%), fatigue (3.2%), diarrhoea (2.3%) and neutropenia (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 3). 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 3. Adverse reactions in patients treated with enfortumab vedotin

Frequency

Monotherapy

In combination with pembrolizumab for the treatment of unresectable or metastatic urothelial cancer

In combination with pembrolizumab for the treatment of MIBC

Infections and infestations

Common

Sepsis, pneumonia

Sepsis, pneumonia

Blood and lymphatic system disorders

Very common

Anaemia

Anaemia

Anaemia

Common

Thrombocytopenia

Thrombocytopenia

Neutropenia, febrile neutropenia, thrombocytopenia

Not known1

Neutropenia, febrile neutropenia, neutrophil count decreased

Neutropenia, febrile neutropenia, neutrophil count decreased

Endocrine disorders

Very common

Hypothyroidism

Hypothyroidism

Metabolism and nutrition disorders

Very common

Hyperglycaemia, decreased appetite

Hyperglycaemia, decreased appetite

Hyperglycaemia, decreased appetite

Not known1

Diabetic ketoacidosis

Diabetic ketoacidosis

Nervous system disorders

Very common

Peripheral sensory neuropathy, dysgeusia

Peripheral sensory neuropathy, dysgeusia

Peripheral sensory neuropathy, dysgeusia, neuropathy peripheral

Common

Neuropathy peripheral, peripheral motor neuropathy, peripheral sensorimotor neuropathy, paraesthesia, hypoaesthesia, gait disturbance, muscular weakness

Peripheral motor neuropathy, peripheral sensorimotor neuropathy, paraesthesia, hypoaesthesia, gait disturbance, muscular weakness

Peripheral motor neuropathy, paraesthesia, hypoaesthesia, muscular weakness, polyneuropathy, neurotoxicity

Uncommon

Demyelinating polyneuropathy, polyneuropathy, neurotoxicity, motor dysfunction, dysaesthesia, muscle atrophy, neuralgia, peroneal nerve palsy, sensory loss, skin burning sensation, burning sensation

Neurotoxicity, dysaesthesia, myasthenia gravis, neuralgia, peroneal nerve palsy, skin burning sensation

Peripheral sensorimotor neuropathy, gait disturbance, myasthenia gravis, peroneal nerve palsy, skin burning sensation

Eye disorders

Very common

Dry eye

Dry eye

Common

Dry eye

Respiratory, thoracic, and mediastinal disorders

Very common

Pneumonitis/ILD2

Common

Pneumonitis/ILD2

Pneumonitis/ILD2

Gastrointestinal disorders

Very common

Diarrhoea, vomiting, nausea

Diarrhoea, vomiting, nausea

Diarrhoea, nausea

Common

Vomiting

Skin and subcutaneous tissue disorders

Very common

Alopecia, pruritus, rash, rash maculo‑papular, dry skin

Alopecia, pruritus, rash maculo‑papular, dry skin, rash macular

Alopecia, pruritus, rash, rash maculo‑papular, dry skin

Common

Drug eruption, skin exfoliation, conjunctivitis, dermatitis bullous, blister, stomatitis, palmar-plantar erythrodysesthesia syndrome, eczema, erythaema, rash erythaematous, rash macular, rash papular, rash pruritic, rash vesicular

Rash, skin exfoliation, conjunctivitis, dermatitis bullous, blister, stomatitis, palmar-plantar erythrodysesthesia syndrome, eczema, erythaema, rash erythaematous, rash papular, rash pruritic, rash vesicular, erythaema multiforme, dermatitis

Skin exfoliation, conjunctivitis, blister, stomatitis, palmar-plantar erythrodysesthesia syndrome, eczema, erythaema, rash papular, rash pruritic, dermatitis exfoliative generalised, exfoliative rash, dermatitis, toxic epidermal necrolysis, skin hyperpigmentation, skin discoloration

Uncommon

Dermatitis exfoliative generalised, erythaema multiforme, exfoliative rash, pemphigoid, rash maculovesicular, dermatitis, dermatitis allergic, dermatitis contact, intertrigo, skin irritation, stasis dermatitis, blood blister

Drug eruption, dermatitis exfoliative generalised, exfoliative rash, pemphigoid, dermatitis contact, intertrigo, skin irritation, stasis dermatitis

Drug eruption, dermatitis bullous, rash vesicular, pemphigoid, symmetrical drug‑related intertriginous and flexural exanthaema

Not known1

Toxic epidermal necrolysis, skin hyperpigmentation, skin discoloration, pigmentation disorder, Stevens‑Johnson syndrome, epidermal necrosis, symmetrical drug‑related intertriginous and flexural exanthaema

Toxic epidermal necrolysis, skin hyperpigmentation, skin discoloration, pigmentation disorder, Stevens‑Johnson syndrome, epidermal necrosis, symmetrical drug‑related intertriginous and flexural exanthaema

Musculoskeletal and connective tissue disorders

Common

Myositis

Uncommon

Myositis

General disorders and administration site conditions

Very common

Fatigue

Fatigue

Fatigue

Common

Infusion site extravasation

Infusion site extravasation

Uncommon

Infusion site extravasation

Investigations

Very common

Alanine aminotransferase increased, aspartate aminotransferase increased, weight decreased

Alanine aminotransferase increased, aspartate aminotransferase increased, weight decreased

Alanine aminotransferase increased, aspartate aminotransferase increased, weight decreased

Common

Lipase increased

Lipase increased

Injury, poisoning and procedural complications

Common

Infusion related reaction

Infusion related reaction

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 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 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 anti-drug antibody (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 for the treatment of MIBC, skin reactions occurred in 61% (102) of the 167 patients and a majority of these skin reactions included rash and rash maculo-papular. Severe (Grade 3 or 4) skin reactions occurred in 10% (17) of patients (Grade 3: 9%, Grade 4: 1%). A fatal event of toxic epidermal necrolysis occurred in one patient. The median time to onset of severe skin reactions was 0.6 months (range: 0.2 to 8.8 months). Of the patients who experienced skin reactions and had data regarding resolution (n=102), 83% had complete resolution, 6% had partial improvement and 11% had no improvement at the time of their last evaluation. Of the 17% of patients with residual skin reactions at last evaluation, 29% had Grade ≥2 events.

In clinical studies of enfortumab vedotin in combination with pembrolizumab for the treatment of unresectable or metastatic urothelial cancer, skin reactions occurred in 70% (392) of the 564 patients and a majority of these skin reactions included rash maculo-papular, rash macular and rash papular. Severe (Grade 3 or 4) skin reactions occurred in 17% (97) of patients (Grade 3: 16%, Grade 4: 1%). The median time to onset of severe skin reactions was 1.7 months (range: 0.1 to 17.2 months). Of the patients who experienced skin reactions and had data regarding resolution (n=391), 59% had complete resolution, 30% had partial improvement, and 10% had no improvement at the time of their last evaluation. Of the 41% of patients with residual skin reactions at last evaluation, 27% 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 for the treatment of MIBC, pneumonitis/ILD occurred in 7 (4.2%) of the 167 patients. All events were Grade 1-2. Pneumonitis/ILD led to discontinuation of enfortumab vedotin in 0.6% of patients. The median time to onset of any grade pneumonitis/ILD was 2.5 months (range: 1.9 to 9.7 months).

In clinical studies of enfortumab vedotin in combination with pembrolizumab for the treatment of unresectable or metastatic urothelial cancer, pneumonitis/ILD occurred in 58 (10.3%) of the 564 patients. Severe (Grade 3 or 4) pneumonitis/ILD occurred in 20 patients (Grade 3: 3.0%, Grade 4: 0.5%). Pneumonitis/ILD led to discontinuation of enfortumab vedotin in 2.1% of patients. Two patients experienced a fatal event of pneumonitis/ILD. The median time to onset of any grade pneumonitis/ILD was 4 months (range: 0.3 to 26.2 months).

In clinical studies of enfortumab vedotin as monotherapy, pneumonitis/ILD occurred in 26 (3.3%) 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 for the treatment of MIBC has been studied in 29 patients <65 years and 138 patients ≥65 years. Generally, adverse event frequencies were consistent in patients ≥65 years of age and <65 years of age.

Enfortumab vedotin in combination with pembrolizumab for the treatment of unresectable or metastatic urothelial cancer has been studied in 173 patients <65 years and 391 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 (56.3% and 35.3%, respectively) and Grade ≥3 events (80.3% and 64.2%, 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.

4.9. Overdose

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).