PADCEV 30mg powder for concentrate infusion solution medication leaflet

Padcev 20 mg powder for concentrate for solution for infusion

Padcev 30 mg powder for concentrate for solution for infusion

Padcev 20 mg powder for concentrate for solution for infusion

One vial of powder for concentrate for solution for infusion contains 20 mg enfortumab vedotin.

Padcev 30 mg powder for concentrate for solution for infusion

One vial of powder for concentrate for solution for infusion contains 30 mg enfortumab vedotin.

After reconstitution, each mL of solution contains 10 mg of enfortumab vedotin.

Enfortumab vedotin is comprised of a fully human IgG1 kappa antibody, conjugated to themicrotubule-disrupting agent monomethyl auristatin E (MMAE) via a protease-cleavablemaleimidocaproyl valine-citrulline linker.

For the full list of excipients, see section 6.1.

Powder for concentrate for solution for infusion.

White to off-white lyophilized powder.

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

Padcev as monotherapy is indicated for the treatment of adult patients with locally advanced ormetastatic urothelial cancer who have previously received a platinum-containing chemotherapy and aprogrammed 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 ofanti-cancer therapies. Ensure good venous access prior to starting treatment (see section 4.4).

As monotherapy, the recommended dose of enfortumab vedotin is 1.25 mg/kg (up to a maximum of125 mg for patients ≥100 kg) administered as an intravenous infusion over 30 minutes on Days 1, 8and 15 of a 28-day cycle until disease progression or unacceptable toxicity.

When given in combination with pembrolizumab, the recommended dose of enfortumab vedotin is1.25 mg/kg (up to a maximum of 125 mg for patients ≥100 kg) administered as an intravenousinfusion over 30 minutes on Days 1 and 8 of every 3-week (21-day) cycle until disease progression orunacceptable toxicity. The recommended dose of pembrolizumab is either 200 mg every 3 weeks or400 mg every 6 weeks administered as an intravenous infusion over 30 minutes. Patients should beadministered pembrolizumab after enfortumab vedotin when given on the same day. Refer to thepembrolizumab SmPC for additional dosing information of pembrolizumab.

Table 1. Recommended dose reductions of enfortumab vedotin foradverse reactions

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

Table 2. Dose interruption, reduction and discontinuation of enfortumab vedotin inpatients with locally advanced or metastatic urothelial cancer

Adverse reaction Severity* Dose modification*

Suspected Stevens-Johnsonsyndrome (SJS) or toxic

Immediately withhold and refer toepidermal necrolysis (TEN)specialised care.

orbullous lesions

Confirmed SJS or TEN;

Permanently discontinue.

Skin reactions Grade 4 or recurrent Grade 3

* Withhold until Grade ≤1.

* Referral to specialised care

Grade 2 worseningshould be considered.

Grade 2 with fever

* Resume at the same dose level or

Grade 3consider dose reduction by onedose level (see Table 1).

* Withhold until elevated bloodglucose has improved to

Blood glucose

Hyperglycaemia ≤13.9 mmol/L (≤250 mg/dL).>13.9 mmol/L (>250 mg/dL)

* Resume treatment at the samedose level.

* Withhold until Grade ≤1, then

Pneumonitis/ resume at the same dose or

Grade 2interstitial lung consider dose reduction by onedisease (ILD) dose level (see Table 1).

Grade ≥3 Permanently discontinue.

* Withhold until Grade ≤1.

* For first occurrence, resumetreatment at the same dose level.

Peripheral Grade 2 * For a recurrence, withhold untilneuropathy Grade ≤1, then resume treatmentreduced 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 issevere and Grade 4 is life-threatening.

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

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. Enfortumabvedotin has not been evaluated in patients with end stage renal disease (CrCL <15 mL/min) (seesection 5.2).

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]. Enfortumabvedotin has only been evaluated in a limited number of patients with moderate and severe hepaticimpairment. Hepatic impairment is expected to increase the systemic exposure to MMAE (thecytotoxic drug); therefore, patients should be closely monitored for potential adverse events. Due tothe sparsity of the data in patients with moderate and severe hepatic impairment, no specific doserecommendation can be given (see section 5.2).

There is no relevant use of enfortumab vedotin in the paediatric population for the indication of locallyadvanced or metastatic urothelial cancer.

Padcev is for intravenous use. The recommended dose must be administered by intravenous infusionover 30 minutes. Enfortumab vedotin must not be administered as an intravenous push or bolusinjection.

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

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

In order to improve the traceability of biological medicinal products, the name and the batch numberof the administered product should be clearly recorded.

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 skinreaction, and patients should be observed, if this occurs.

Mild to moderate skin reactions, predominantly rash maculo-papular, have been reported withenfortumab vedotin. The incidence of skin reactions occurred at a higher rate when enfortumabvedotin was given in combination with pembrolizumab compared to enfortumab vedotin asmonotherapy (see section 4.8). Severe cutaneous adverse reactions, including SJS and TEN, with fataloutcome have also occurred in patients treated with enfortumab vedotin, predominantly during the firstcycle 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 tomoderate skin reactions. For suspected SJS or TEN, or in case of bullous lesions onset, withholdtreatment immediately and refer to specialised care; histologic confirmation, including considerationof multiple biopsies, is critical to early recognition, as diagnosis and intervention can improveprognosis. Permanently discontinue Padcev for confirmed SJS or TEN, Grade 4 or recurrent Grade 3skin reactions. For Grade 2 worsening, Grade 2 with fever or Grade 3 skin reactions, treatment shouldbe withheld until Grade ≤1 and referral for specialised care should be considered. Treatment should beresumed 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 enfortumabvedotin. The incidence of pneumonitis/ILD, including severe events occurred at a higher rate whenenfortumab vedotin was given in combination with pembrolizumab compared to enfortumab vedotinas 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 and diabetic ketoacidosis (DKA), including fatal events, occurred in patients with andwithout 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 bodymass 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 oftreatment as clinically indicated in patients with or at risk for diabetes mellitus or hyperglycaemia. Ifblood glucose is elevated >13.9 mmol/L (>250 mg/dL), Padcev should be withheld until blood glucoseis ≤13.9 mmol/L (≤250 mg/dL) and treat as appropriate (see section 4.2).

Serious infections such as sepsis (including fatal outcomes) have been reported in patients treated with

Padcev. Patients should be carefully monitored during treatment for the emergence of possible seriousinfections.

Peripheral neuropathy, predominantly peripheral sensory neuropathy, has occurred with enfortumabvedotin, including Grade ≥3 reactions (see section 4.8). Patients with preexisting peripheralneuropathy Grade ≥2 were excluded from clinical studies. Patients should be monitored for symptomsof new or worsening peripheral neuropathy as these patients may require a delay, dose reduction ordiscontinuation 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 forprophylaxis of dry eye and referral for ophthalmologic evaluation if ocular symptoms do not resolve orworsen.

Skin and soft tissue injury following enfortumab vedotin administration has been observed whenextravasation occurred (see section 4.8). Ensure good venous access prior to starting Padcev andmonitor for possible infusion site extravasation during administration. If extravasation occurs, stop theinfusion 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 tostarting treatment with enfortumab vedotin, to use effective contraception during treatment and for atleast 6 months after stopping treatment. Men being treated with enfortumab vedotin are advised not tofather 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 withpembrolizumab, with the patient. The patient should be provided with the patient information leafletand patient card with each prescription.

Formal drug-drug interaction studies with enfortumab vedotin have not been conducted. Concomitantadministration of enfortumab vedotin and CYP3A4 (substrates) metabolised medicinal products, hasno 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) modeling, concomitant use of enfortumabvedotin with ketoconazole (a combined P-gp and strong CYP3A inhibitor) is predicted to increaseunconjugated 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 receivingconcomitant 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 CYP3A4substrates (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).

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

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

It is unknown whether enfortumab vedotin is excreted in human milk. A risk to breast-fed childrencannot be excluded. Breastfeeding should be discontinued during Padcev treatment and for at least 6months after the last dose.

In rats, repeat dose administration of enfortumab vedotin, resulted in testicular toxicity and may altermale fertility. MMAE has been shown to have aneugenic properties (see section 5.3). Therefore, menbeing treated with this medicinal product are advised to have sperm samples frozen and stored beforetreatment. 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.

Enfortumab vedotin as monotherapy

The safety of enfortumab vedotin was evaluated as monotherapy in 793 patients who received at leastone dose of enfortumab vedotin 1.25 mg/kg in two phase 1 studies (EV-101 and EV-102), three phase2 studies (EV-103, EV-201 and EV-203) and one phase 3 study (EV-301) (see Table 3). Patients wereexposed 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%), decreasedappetite (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%), rashmaculo-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%) andrash (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 sensoryneuropathy (4.8%). Adverse reactions leading to dose interruption occurred in 62% of patients; themost common adverse reactions (≥2%) leading to dose interruption were peripheral sensoryneuropathy (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 mostcommon 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%).

Enfortumab vedotin in combination with pembrolizumab

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

The safety of enfortumab vedotin was evaluated in combination with pembrolizumab in 564 patientswho received at least one dose of enfortumab vedotin 1.25 mg/kg in combination with pembrolizumabin one phase 2 study (EV-103) and one phase 3 study (EV-302) (see Table 3). Patients were exposed toenfortumab 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 pembrolizumabwere 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 aminotransferaseincreased (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; themost 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. Themost common adverse reactions (≥2%) leading to dose interruption were peripheral sensoryneuropathy (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. Themost 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%).

Adverse reactions observed during clinical studies of enfortumab vedotin as monotherapy or incombination with pembrolizumab, or reported from post-marketing use of enfortumab vedotin arelisted 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 frequencygrouping, adverse reactions are presented in order of decreasing seriousness.

Table 3. Adverse reactions in patients treated with enfortumab vedotin

Monotherapy In combination with pembrolizumab

Common Sepsis Sepsis

Very common Anaemia Anaemia

Neutropenia, febrile neutropenia, Neutropenia, febrile neutropenia,

Not known1 neutrophil count decreased neutrophil count decreased

Very common Hypothyroidism

Very common Hyperglycaemia, decreased appetite Hyperglycaemia, decreased appetite

Not known1 Diabetic ketoacidosis Diabetic ketoacidosis

Peripheral sensory neuropathy, Peripheral sensory neuropathy,

Very commondysgeusia dysgeusia

Neuropathy peripheral, peripheral Peripheral motor neuropathy,motor neuropathy, peripheral peripheral sensorimotor neuropathy,

Common sensorimotor neuropathy, paraesthesia, hypoaesthesia, gaitparaesthesia, hypoaesthesia, gait disturbance, muscular weaknessdisturbance, muscular weakness

Demyelinating polyneuropathy, Neurotoxicity, dysaesthesia,polyneuropathy, neurotoxicity, motor myasthenia gravis, neuralgia, peronealdysfunction, dysaesthesia, muscle nerve palsy, skin burning sensation

Uncommonatrophy, neuralgia, peroneal nervepalsy, sensory loss, skin burningsensation, burning sensation

Very common Dry eye Dry eye

Respiratory, thoracic, and mediastinal disorders

Very common Pneumonitis/ILD2

Common Pneumonitis/ILD2

Very common Diarrhoea, vomiting, nausea Diarrhoea, vomiting, nausea

Monotherapy In combination with pembrolizumab

Alopecia, pruritus, rash, rash Alopecia, pruritus, rash

Very commonmaculo-papular, dry skin maculo-papular, dry skin, rash macular

Drug eruption, skin exfoliation, Rash, skin exfoliation, conjunctivitis,conjunctivitis, dermatitis bullous, dermatitis bullous, blister, stomatitis,blister, stomatitis, palmar-plantar palmar-plantar erythrodysesthesia

Common erythrodysesthesia syndrome, eczema, syndrome, eczema, erythaema, rasherythaema, rash erythaematous, rash erythaematous, rash papular, rashmacular, rash papular, rash pruritic, pruritic, rash vesicular, erythaemarash vesicular multiforme, dermatitis

Dermatitis exfoliative generalised, Drug eruption, dermatitis exfoliativeerythaema multiforme, exfoliative generalised, exfoliative rash,rash, pemphigoid, rash pemphigoid, dermatitis contact,

Uncommon maculovesicular, dermatitis, dermatitis intertrigo, skin irritation, stasisallergic, dermatitis contact, intertrigo, dermatitisskin irritation, stasis dermatitis, bloodblister

Toxic epidermal necrolysis, skin Toxic epidermal necrolysis, skinhyperpigmentation, skin discoloration, hyperpigmentation, skin discoloration,pigmentation disorder, pigmentation disorder,

Not known1

Stevens-Johnson syndrome, epidermal Stevens-Johnson syndrome, epidermalnecrosis, symmetrical drug-related necrosis, symmetrical drug-relatedintertriginous and flexural exanthaema intertriginous and flexural exanthaema

Common Myositis

Very common Fatigue Fatigue

Common Infusion site extravasation Infusion site extravasation

Alanine aminotransferase increased, Alanine aminotransferase increased,

Very common aspartate aminotransferase increased, aspartate aminotransferase increased,weight decreased weight decreased

Common Lipase increased

Common Infusion related reaction Infusion related reaction1Based 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, pulmonarytoxicity and sarcoidosis.

A total of 697 patients were tested for immunogenicity to enfortumab vedotin 1.25 mg/kg asmonotherapy; 16 patients were confirmed to be positive at baseline for anti-drug antibody (ADA), andin patients that were negative at baseline (N=681), a total of 24 (3.5%) were positive post baseline.

A total of 490 patients were tested for immunogenicity against enfortumab vedotin followingenfortumab vedotin in combination with pembrolizumab; 24 patients were confirmed to be positive atbaseline for ADA, and in patients that were negative at baseline (N=466), a total of 14 (3%) werepositive post baseline. The incidence of treatment-emergent anti-enfortumab vedotin antibodyformation was consistent when assessed following enfortumab vedotin administration as monotherapyand in combination with pembrolizumab.

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

In clinical studies of enfortumab vedotin as monotherapy, skin reactions occurred in 57% (452) of the793 patients treated with enfortumab vedotin 1.25 mg/kg. Severe (Grade 3 or 4) skin reactionsoccurred 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 reactionswas 0.7 months (range: 0.1 to 8.2 months). Serious skin reactions occurred in 4.3% (34) of patients. Ofthe patients who experienced skin reactions and had data regarding resolution (N=366), 61% hadcomplete resolution, 24% had partial improvement, and 15% had no improvement at the time of theirlast evaluation. Of the 39% of patients with residual skin reactions at last evaluation, 38% had Grade≥2 events.

In clinical studies of enfortumab vedotin in combination with pembrolizumab, skin reactions occurredin 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 regardingresolution (N=391), 59% had complete resolution, 30% had partial improvement, and 10% had noimprovement at the time of their last evaluation. Of the 41% of patients with residual skin reactions atlast evaluation, 27% had Grade ≥2 events.

Pneumonitis/ILD

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

In clinical studies of enfortumab vedotin in combination with pembrolizumab, pneumonitis/ILDoccurred in 58 (10.3%) of the 564 patients. Severe (Grade 3 or 4) pneumonitis/ILD occurred in 20patients (Grade 3: 3.0%, Grade 4: 0.5%). Pneumonitis/ILD led to discontinuation of enfortumabvedotin in 2.1% of patients. Two patients experienced a fatal event of pneumonitis/ILD. The mediantime 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, 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 ofhyperglycaemia and diabetic ketoacidosis. The incidence of Grade 3-4 hyperglycaemia increasedconsistently 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). Of thepatients who experienced hyperglycaemia and had data regarding resolution (N=106), 66% hadcomplete resolution, 19% had partial improvement, and 15% had no improvement at the time of theirlast evaluation. Of the 34% of patients with residual hyperglycaemia at last evaluation, 64% had

Grade ≥2 events.

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 patientsexperienced severe (Grade 3 or 4) peripheral neuropathy including sensory and motor events. Themedian time to onset of Grade ≥2 peripheral neuropathy was 5 months (range: 0.1 to 20.2). Of thepatients who experienced neuropathy and had data regarding resolution (N=340), 14% had completeresolution, 46% had partial improvement, and 41% had no improvement at the time of their lastevaluation. Of the 86% of patients with residual neuropathy at last evaluation, 51% had Grade ≥2events.

Ocular disorders

In clinical studies of enfortumab vedotin as monotherapy, 30% of patients experienced dry eye duringtreatment with enfortumab vedotin 1.25 mg/kg. Treatment was interrupted in 1.5% of patients and0.1% of patients permanently discontinued treatment due to dry eye. Severe (Grade 3) dry eye onlyoccurred in 3 patients (0.4%). The median time to onset of dry eye was 1.7 months (range: 0 to30.6 months).

Enfortumab vedotin in combination with pembrolizumab has been studied in 173 patients <65 yearsand 391 patients ≥65 years. Generally, adverse event frequencies were higher in patients ≥65 years ofage 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 thechemotherapy comparator.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

There is no known antidote for overdosage with enfortumab vedotin. In case of overdosage, the patientshould be closely monitored for adverse reactions, and supportive treatment should be administered asappropriate 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

Enfortumab vedotin is an antibody drug conjugate (ADC) targeting Nectin-4, an adhesion proteinlocated on the surface of the urothelial cancer cells. It is comprised of a fully human IgG1-kappaantibody conjugated to the microtubule-disrupting agent MMAE via a protease-cleavablemaleimidocaproyl valine-citrulline linker. Nonclinical data suggest that the anticancer activity ofenfortumab vedotin is due to the binding of the ADC to Nectin-4-expressing cells, followed byinternalisation 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 cyclearrest, apoptosis, and immunogenic cell death. MMAE released from enfortumab vedotin targeted cellscan diffuse into nearby Nectin-4 low-expressing cells resulting in cytotoxic cell death. Combination ofenfortumab vedotin with PD-1 inhibitors results in enhanced anti-tumour activity, consistent with thecomplementary mechanisms of MMAE induced cell cytotoxicity and induction of immunogenic celldeath, plus the up-regulation of immune function by PD-1 inhibition.

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

Enfortumab vedotin in combination with pembrolizumab

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 patientswith unresectable or metastatic urothelial cancer who had not received prior systemic therapy forlocally advanced or metastatic disease. Patients that received neoadjuvant chemotherapy or patientsthat received adjuvant chemotherapy following cystectomy were included in the study if recurrencewas >12 months from completion of therapy. Patients were considered cisplatin-ineligible if they hadat least one of the following criteria: glomerular filtration rate (GFR) between 30-59 mL/min, Eastern

Cooperative Oncology Group (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 withpembrolizumab (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 over30 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 gemcitabine1000 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 themaximum 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 toreceive maintenance immunotherapy (e.g., avelumab). Randomisation was stratified by cisplatineligibility (eligible versus ineligible), PD-L1 expression (CPS≥10 versus CPS<10), and presence ofliver metastases (present versus absent). PD-L1 expression was based on the PD-L1 IHC 22C3pharmDx kit.

Patients were excluded from the study if they had active CNS metastases, ongoing sensory or motorneuropathy Grade ≥2, uncontrolled diabetes defined as haemoglobin A1C (HbA1c) ≥8% or

HbA1c ≥7% with associated diabetes symptoms, autoimmune disease or a medical condition thatrequired immunosuppression, pneumonitis or other forms of interstitial lung disease.

The median age was 69 years (range: 22 to 91); 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-sevenpercent of patients had a documented baseline HbA1c of <5.7%. At baseline, 95% of patients hadmetastatic urothelial cancer and 5% of patients had unresectable urothelial cancer. Seventy-twopercent of patients had visceral metastasis at baseline including 22% with liver metastases. Eighty-fivepercent of patients had urothelial carcinoma (UC) histology, 6% had UC mixed squamousdifferentiation and 2% had UC mixed other histologic variants. Forty-six percent of patients werecisplatin-ineligible and 54% were cisplatin-eligible at time of randomisation. Of the 877 patients testedwho had tissue evaluable for PD-L1 expression, 58% of patients had tumours that expressed PD-L1with a CPS ≥10 and 42% had tumours that expressed PD-L1 with a CPS <10. The median follow-uptime was 17.3 months (range: 0.3 to 37.2).

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 measuresincluded 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 randomisedto enfortumab vedotin in combination with pembrolizumab as compared to gemcitabine and platinum-based chemotherapy.

Table 4, Figures 1 and 2 summarise the efficacy results for EV-302.

Table 4. Efficacy Results in EV-302

Padcev + Gemcitabinepembrolizumab +platinum

Endpoint n=442 n=444

Overall Survival

Number (%) of patients with events 133 (30.1) 226 (50.9)

Median in months (95% CI)a 31.5 (25.4, -) 16.1 (13.9, 18.3)

Hazard ratiob (95% CI) 0.468 (0.376, 0.582)2-sided p-valuec <0.00001

Progression Free Survivald

Number (%) of patients with events 223 (50.5) 307 (69.1)

Median in months (95% CI)a 12.5 (10.4, 16.6) 6.3 (6.2, 6.5)

Hazard ratiob (95% CI) 0.450 (0.377, 0.538)2-sided p-valuec <0.00001

Objective Response Rate (CR + PR)d,f

Confirmed ORR (%) (95% CI)e 67.7 (63.1, 72.1) 44.4 (39.7, 49.2)2-sided p-valueg <0.00001

Duration of Responsed,f

Median in months (95% CI)a NR (20.2, -) 7.0 (6.2, 10.2)

NR = 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 incombination with pembrolizumab arm.

c. Based on stratified log-rank test.

Padcev + Gemcitabinepembrolizumab +platinum

Endpoint n=442 n=444

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 combinationwith pembrolizumab, n=441 for gemcitabine plus platinum). The duration of response was estimated forresponders.

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

Figure 1. Kaplan Meier plot of overall survival, EV-302

Figure 2. 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 urothelialcancer who have previously received a platinum-containing chemotherapy and a programmed deathreceptor 1 (PD-1) or programmed death ligand 1 (PD-L1) inhibitor. The primary endpoint of the studywas 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 Days1, 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 a21-day cycle.

Patients were excluded from the study if they had active CNS metastases, ongoing sensory or motorneuropathy ≥ 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% withassociated 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-sixpercent of patients had urothelial carcinoma/transitional cell carcinoma (TCC) histology, 14% hadurothelial 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 hadreceived 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 toprior therapy with a PD-1 or PD-L1 inhibitor. Sixty-three percent (383) of patients had received priorcisplatin-based regimens, 26% (159) had received prior carboplatin-based regimens, and an additional11% (65) had received both cisplatin and carboplatin-based regimens.

Table 5 summarises the efficacy results for the EV-301 study, after a median follow-up time of 11.1months (95% CI: 10.6 to 11.6).

Table 5. Efficacy results in EV-301

Padcev Chemotherapy

Endpoint n=301 n=307

Overall Survival

Number (%) of patients with events 134 (44.5) 167 (54.4)

Median in months (95% CI) 12.9 (10.6, 15.2) 9.0 (8.1, 10.7)

Hazard ratio (95% CI) 0.702 (0.556, 0.886)1-sided p-value 0.00142*

Progression Free Survival†

Number (%) of patients with events 201 (66.8) 231 (75.2)

Median in months (95% CI) 5.6 (5.3, 5.8) 3.7 (3.5, 3.9)

Hazard ratio (95% CI) 0.615 (0.505, 0.748)1-sided p-value <0.00001‡

Objective Response Rate (CR + PR)†

ORR (%) (95% CI) 40.6 (35.0, 46.5) 17.9 (13.7, 22.8)1-sided p-value <0.001§

Complete response rate (%) 4.9 2.7

Partial response rate (%) 35.8 15.2

Duration of Response for responders

Median in months (95% CI) 7.4 (5.6, 9.5) 8.1 (5.7, 9.6)

*pre-determined efficacy boundary = 0.00679, 1-sided (adjusted by observed deaths of 301)†evaluated by investigator assessment using RECIST v1.1‡pre-determined efficacy boundary = 0.02189, 1-sided (adjusted by observed PFS1 events of 432)§pre-determined efficacy boundary = 0.025, 1-sided (adjusted by 100% information fraction)

Figure 3. Kaplan Meier plot of overall survival, EV-301

The European Medicines Agency has waived the obligation to submit the results of studies withenfortumab vedotin in all subsets of the paediatric population in urothelial cancer (see section 4.2 forinformation on paediatric use).

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

P-glycoprotein.

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

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 enfortumabvedotin. Unconjugated MMAE elimination exhibited a multi-exponential decline with a half-life of2.6 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 thetotal 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 vedotinadministration.

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 thepharmacokinetics of enfortumab vedotin.

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 nothave a clinically meaningful effect on the pharmacokinetics of enfortumab vedotin.

The pharmacokinetics of ADC and unconjugated MMAE were evaluated after the administration of1.25 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 AUCexposure of ADC or unconjugated MMAE were observed in patients with mild, moderate or severerenal impairment compared to patients with normal renal function. Enfortumab vedotin has not beenevaluated in patients with end stage renal disease (CrCL <15 mL/min).

Based on population pharmacokinetics analysis using data from clinical studies in patients withmetastatic UC, there was no significant differences in ADC exposure and a 37% and 16% increase inunconjugated MMAE average concentrations in patients with previously treated and previouslyuntreated 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) comparedto patients with normal hepatic function. Enfortumab vedotin has only been studied in a limitednumber of patients with moderate hepatic impairment (n=5) or severe hepatic impairment (n=1). Theeffect of moderate or severe hepatic impairment (total bilirubin >1.5 x ULN and AST any) or livertransplantation on the pharmacokinetics of ADC or unconjugated MMAE is unknown.

Physiologically based pharmacokinetic modeling predictions

Concomitant use of enfortumab vedotin with ketoconazole (a combined P-gp and strong CYP3Ainhibitor) is predicted to increase unconjugated MMAE Cmax 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 Cmax and AUC exposure with moderate effect, with nochange in ADC exposure. The full impact of rifampin on the Cmax of unconjugated MMAE may beunderestimated 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 MMAEinhibits CYP3A4/5 but not other CYP450 isoforms. Unconjugated MMAE did not induce major

CYP450 enzymes in human hepatocytes.

In vitro studies indicate that unconjugated MMAE is a substrate and not an inhibitor of the effluxtransporter P-glycoprotein (P-gp). In vitro studies determined that unconjugated MMAE was not asubstrate of breast cancer resistance protein (BCRP), multidrug resistance-associated protein 2(MRP2), organic anion transporting polypeptide 1B1 or 1B3 (OATP1B1 or OATP1B3), organic cationtransporter 2 (OCT2), or organic anion transporter 1 or 3 (OAT1 or OAT3). Unconjugated MMAEwas 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 mutationtest in bacteria (Ames test) or in a L5178Y TK+/- mouse lymphoma mutation assay. MMAE didinduce chromosomal aberrations in the micronucleus test in rats which is consistent with thepharmacological 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 studiesand 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 sizewas reflected in an increase in early resorptions. Mean foetal body weight in the surviving foetuses atthe 2 mg/kg dose level were reduced compared with control.

Enfortumab vedotin associated foetal skeletal variations were considered developmental delays. Adose of 2 mg/kg (approximately similar to the exposure at the recommended human dose) resulted inmaternal 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 weightwere observed.

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

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

Histidine

Histidine hydrochloride monohydrate

Trehalose dihydrate

Polysorbate 20

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

Unopened vial4 years.

Reconstituted solution in the vial

From a microbiological point of view, after reconstitution, the solution from the vial(s) should beadded to the infusion bag immediately. If not used immediately, storage times and conditions prior touse of the reconstituted vials are the responsibility of the user and would normally not be longer than24 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 thebag should be administered to the patient immediately. If not used immediately, storage times andconditions prior to use of the diluted dosing solution is the responsibility of the user and wouldnormally not be longer than 16 hours in refrigeration at 2°C to 8°C including infusion time. Do notfreeze.

Store in a refrigerator (2ºC to 8ºC).

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 vial10 mL Type I glass vial with gray bromobutyl rubber stopper, 20 mm aluminum seal with a green ringand green cap. Each carton contains 1 vial.

Padcev 30 mg powder for concentrate for solution for infusion vial10 mL Type I glass vial with gray bromobutyl rubber stopper, 20 mm aluminum seal with a silver ringand yellow cap. Each carton contains 1 vial.

Instructions for preparation and administration

Reconstitution in single-dose vial1. 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 andstrength (20 mg or 30 mg) of vials needed.

4. Reconstitute each vial as follows and, if possible, direct the stream of sterile water for injectionalong 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 enfortumabvedotin.

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

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

6. Visually inspect the solution for particulate matter and discolouration. The reconstituted solutionshould 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 bag7. Withdraw the calculated dose amount of reconstituted solution from the vial(s) and transfer intoan 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 enoughsolvent 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 composedof polyvinyl chloride (PVC), ethylvinyl acetate, polyolefin such as polypropylene (PP), or IV bottlescomprised of polyethylene (PE), polyethylene terephthalate glycol-modified, and infusion setscomposed 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 ofpolyethersulfone, 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. Thereconstituted solution should be clear to slightly opalescent, colourless to light yellow and freeof visible particles. Do not use the infusion bag if particulate matter or discolouration isobserved.

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

Administration12. Administer the infusion over 30 minutes through an intravenous line. Do not administer as anintravenous push or bolus.

No incompatibilities have been observed with closed system transfer device composed of acrylonitrilebutadiene styrene (ABS), acrylic, activated charcoal, ethylene propylene diene monomer, methacrylate

ABS, polycarbonate, polyisoprene, polyoxymethylene, PP, silicone, stainless steel, thermoplasticelastomer 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 beused during administration.

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

Astellas Pharma Europe B.V.

Sylviusweg 622333 BE Leiden

The Netherlands

EU/1/21/1615/001

EU/1/21/1615/002

Date of first authorisation: 13 April 2022

Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu.