Source: European Medicines Agency (EU) Revision Year: 2024 Publisher: Astellas Pharma Europe B.V., Sylviusweg 62, 2333 BE Leiden, The Netherlands
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 number of 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 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).
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 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 trials. 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).
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 trials. 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, 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.
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.
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 12 months after stopping treatment. Men being treated with enfortumab vedotin are advised not to father a child during treatment and for up to 9 months following the last dose of Padcev.
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).
Based on physiologically-based pharmacokinetic (PBPK) modeling, 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).
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 12 months after stopping treatment. Men being treated with enfortumab vedotin are advised not to father a child during treatment and for up to 9 months following the last dose of Padcev.
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.
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.
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.
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 adose reduction were peripheral sensory neuropathy (10.3%), fatigue (5.3%), rash maculo-papular (4.2%) and decreased appetite (2.1%).
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 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%).
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:
| Monotherapy | In combination with pembrolizumab | |
|---|---|---|
| Blood and lymphatic system disorders | ||
| Very common | Anaemia | Anaemia |
| Not known1 | Neutropenia, febrile neutropenia, neutrophil count decreased | Neutropenia, febrile neutropenia, neutrophil count decreased |
| Endocrine disorders | ||
| Very common | Hypothyroidism | |
| Metabolism and nutrition disorders | ||
| Very common | Hyperglycaemia, decreased appetite | Hyperglycaemia, decreased appetite |
| Nervous system disorders | ||
| Very common | Peripheral sensory neuropathy, dysgeusia | Peripheral sensory neuropathy, dysgeusia |
| 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 |
| 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 |
| Eye disorders | ||
| Very common | Dry eye | Dry eye |
| Respiratory, thoracic, and mediastinal disorders | ||
| Very common | Pneumonitis/ILD2 | |
| Common | Pneumonitis/ILD2 | |
| Gastrointestinal disorders | ||
| Very common | Diarrhoea, vomiting, nausea | Diarrhoea, vomiting, nausea |
| Skin and subcutaneous tissue disorders | ||
| Very common | Alopecia, pruritus, rash, rash maculo-papular, dry skin | Alopecia, pruritus, rash maculo-papular, dry skin, rash macular |
| 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 |
| 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 |
| Not known1 | Toxic epidermal necrolysis, Stevens-Johnson syndrome, epidermal necrosis, symmetrical drug-related intertriginous and flexural exanthaema | Toxic epidermal necrolysis, Stevens-Johnson syndrome, epidermal necrosis, symmetrical drug-related intertriginous and flexural exanthaema |
| Musculoskeletal and connective tissue disorders | ||
| Common | Myositis | |
| General disorders and administration site conditions | ||
| Very common | Fatigue | Fatigue |
| Common | Infusion site extravasation | Infusion site extravasation |
| Investigations | ||
| Very common | Alanine aminotransferase increased, aspartate aminotransferase increased, weight decreased | Alanine aminotransferase increased, aspartate aminotransferase increased, weight decreased |
| Common | Lipase increased | |
1 Based on global post-marketing experience.
2 Includes: 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.
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.
A total of 490 patients were tested for immunogenicity against enfortumab vedotin following enfortumab vedotin in combination with pembrolizumab; 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. 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.
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.
In clinical studies of enfortumab vedotin in combination with pembrolizumab, 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, 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.
In clinical studies of enfortumab vedotin in combination with pembrolizumab, 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, 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). 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.
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 5months (range: 0.1 to 20.2). 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.
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).
Enfortumab vedotin in combination with pembrolizumab 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 suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
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