Padcev · 4.3 Contraindications · 1

HOS-099609 · has-adverse-reaction-information · PDF-Seite 10

Summary of the safety profile Enfortumab vedotin in combination with pembrolizumab When enfortumab vedotin is administered in combination with pembrolizumab, refer to the SmPC for pembrolizumab prior to initiation of treatment. The safety of enfortumab vedotin was evaluated in combination with pembrolizumab in 1 134 patients who received at least one dose of enfortumab vedotin 1.25 mg/kg in combination with pembrolizumab in one phase 2 study (EV-103) and three phase 3 studies (EV-302, EV-303 and EV-304) (see Table 5). Patients were exposed to the combination of enfortumab vedotin and pembrolizumab for a median duration of 9.2 months (range: 0.03 to 45.9 months). The median duration of exposure to enfortumab vedotin alone was 6.9 months (range: 0.03 to 45.9 months). The most common adverse reactions with enfortumab vedotin in combination with pembrolizumab were pruritus (44.2%), diarrhoea (37.1%), alopecia (35.4%), fatigue (35%), peripheral sensory neuropathy (34%), decreased appetite (31.5%), anaemia (29.1%), weight decreased (29.1%), nausea (28.5%), rash maculo-papular (27.7%), dysgeusia (25.1%), aspartate aminotransferase increased (20.2%), alanine aminotransferase increased (20%), dry skin (16%), hyperglycaemia (15.5%), rash (14%), vomiting (13.2%), hypothyroidism (12.1%), neutropenia (12%) and dry eye (11.6%). The most common serious adverse reactions (≥2%) were sepsis (3%), diarrhoea (2.6%), pneumonia (2.6%) and pneumonitis (2.2%). Thirty-eight percent of patients permanently discontinued enfortumab vedotin for adverse reactions; the most common adverse reaction (≥2%) leading to discontinuation was peripheral sensory neuropathy (9.1%). Adverse reactions leading to dose interruption of enfortumab vedotin occurred in 59% of patients. The most common adverse reactions (≥2%) leading to dose interruption were peripheral sensory neuropathy (9.3%), rash maculo-papular (5.3%), diarrhoea (4.7%), neutropenia (3.7%), alanine aminotransferase increased (3.4%), hyperglycaemia (3%), fatigue (2.7%), pneumonitis (2.1%) and pruritus (2.1%). Adverse reactions leading to dose reduction of enfortumab vedotin occurred in 31% of patients. The most common adverse reactions (≥2%) leading to dose reduction were peripheral sensory neuropathy (6%), rash maculo-papular (4.7%) and fatigue (2.1%). 10 Enfortumab vedotin as monotherapy The safety of enfortumab vedotin was evaluated as monotherapy in 793 patients who rec

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HOS-099605 · has-contraindication-information · PDF-Seite 6

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

HOS-099604 · has-indication-information · PDF-Seite 2

Muscle invasive bladder cancer (MIBC) Padcev, in combination with pembrolizumab, as neoadjuvant treatment and then continued after radical cystectomy as adjuvant treatment, is indicated for the treatment of adult patients with resectable muscle invasive bladder cancer (MIBC). Unresectable or metastatic urothelial cancer Padcev, in combination with pembrolizumab, is indicated for the first-line treatment of adult patients with unresectable or metastatic urothelial cancer who are eligible for platinum-containing chemotherapy. 2 Locally advanced or metastatic urothelial cancer Padcev as monotherapy is indicated for the treatment of adult patients with locally advanced or metastatic urothelial cancer who have previously received a platinum-containing chemotherapy and a programmed death receptor-1 or programmed death-ligand 1 inhibitor (see section 5.1).

HOS-099607 · has-interaction-information · PDF-Seite 9

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) 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 antibody drug conjugate (ADC) exposure. Caution is advised in case of concomitant treatment with CYP3A4 inhibitors. Patients receiving concomitant strong CYP3A4 inhibitors (e.g., boceprevir, clarithromycin, cobicistat, indinavir, itraconazole, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, voriconazole) should be monitored more closely for signs of toxicities. Unconjugated MMAE is not predicted to alter the AUC of concomitant medicines that are CYP3A4 substrates (e.g. midazolam). Strong CYP3A4 inducers (e.g. rifampicin, carbamazepine, phenobarbital, phenytoin, St. John's wort [Hypericum perforatum]) may decrease the exposure of unconjugated MMAE with moderate effect (see section 5.2).

HOS-099608 · has-pregnancy-information · PDF-Seite 9

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. 9 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.

HOS-099606 · has-warning-information · PDF-Seite 6

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. 6 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 predni

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