Padcev

Enfortumab vedotin.

One vial of powder for concentrate for solution for infusion contains 20 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 the microtubule-disrupting agent monomethyl auristatin E (MMAE) via a protease-cleavable maleimidocaproyl valine-citrulline linker.
Excipients/Inactive Ingredients: Histidine, Histidine hydrochloride monohydrate, Trehalose dihydrate, Polysorbate 20.

Pharmacotherapeutic group: Antineoplastic agents, other antineoplastic agents, monoclonal antibodies. ATC code: L01FX13.
Pharmacology: Pharmacodynamics: Mechanism of action: Enfortumab vedotin is an antibody drug conjugate (ADC) targeting Nectin-4, an adhesion protein located on the surface of the urothelial cancer cells. It is comprised of a fully human IgG1-kappa antibody conjugated to the microtubule-disrupting agent MMAE via a protease-cleavable maleimidocaproyl valine-citrulline linker. Nonclinical data suggest that the anticancer activity of enfortumab vedotin is due to the binding of the ADC to Nectin-4-expressing cells, followed by internalisation of the ADC-Nectin-4 complex, and the release of MMAE via proteolytic cleavage. Release of MMAE disrupts the microtubule network within the cell, subsequently inducing cell cycle arrest and apoptotic cell death. MMAE released from enfortumab vedotin targeted cells can diffuse into nearby Nectin-4 low-expressing cells resulting in cytotoxic cell death.
Cardiac electrophysiology: At the recommended dose of 1.25 mg/kg, enfortumab vedotin did not prolong the mean QTc interval to any clinically relevant extent based on ECG data from a study in patients with advanced urothelial cancer.
Clinical efficacy and safety: Metastatic urothelial cancer: EV-301: The efficacy of PADCEV was evaluated in study EV-301, an open-label, randomised, phase 3, multicentre study that enrolled 608 patients with locally advanced or metastatic urothelial cancer who have previously received a platinum-containing chemotherapy and a programmed death receptor 1 (PD-1) or programmed death ligand 1 (PD-L1) inhibitor. The primary endpoint of the study was Overall Survival (OS) and secondary endpoints included Progression Free Survival (PFS) and Objective Response Rate (ORR) [PFS and ORR were evaluated by investigator assessment using RECIST v1.1]. Patients were randomised 1:1 to receive either enfortumab vedotin 1.25 mg/kg on Days 1, 8 and 15 of a 28-day cycle, or one of the following chemotherapies as decided by the investigator: docetaxel 75 mg/m² (38%), paclitaxel 175 mg/m² (36%) or vinflunine 320 mg/m² (25%) on Day 1 of a 21-day cycle.
Patients were excluded from the study if they had active CNS metastases, ongoing sensory or motor neuropathy ≥ Grade 2, known history of human immunodeficiency virus (HIV) infection (HIV 1 or 2), active Hepatitis B or C, or uncontrolled diabetes defined as HbA1c ≥8% or HbA1c ≥7% with associated diabetes symptoms.
The median age was 68 years (range: 30 to 88 years), 77% were male, and most patients were White (52%) or Asian (33%). All patients had a baseline Eastern Cooperative Oncology Group performance status of 0 (40%) or 1 (60%). Ninety-five percent (95%) of patients had metastatic disease and 5% had locally advanced disease. Eighty percent of patients had visceral metastases including 31% with liver metastases. Seventy-six percent of patients had urothelial carcinoma/transitional cell carcinoma (TCC) histology, 14% had urothelial carcinoma mixed and approximately 10% had other histologic variants. A total of 76 (13%) patients had received ≥3 lines of prior systemic therapy. Fifty-two percent (314) of patients had received prior PD-1 inhibitor, 47% (284) had received prior PD-L1 inhibitor, and an additional 1% (9) patients had received both PD-1 and PD-L1 inhibitors. Only 18% (111) of patients had a response to prior therapy with a PD-1 or PD-L1 inhibitor. Sixty-three percent (383) of patients had received prior cisplatin-based regimens, 26% (159) had received prior carboplatin-based regimens, and an additional 11% (65) had received both cisplatin- and carboplatin-based regimens.
Table 1 summarizes the efficacy results for the EV-301 study, after a median follow-up time of 11.1 months (95% CI: 10.6 to 11.6). (See Table 1 and figure.)

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Paediatric population: The European Medicines Agency has waived the obligation to submit the results of studies with enfortumab vedotin in all subsets of the paediatric population in urothelial cancer (see Dosage & Administration for information on paediatric use).
Pharmacokinetics: Distribution: The mean estimate of steady-state volume of distribution of ADC was 12.8 L following 1.25 mg/kg of enfortumab vedotin. In vitro, the binding of MMAE to human plasma proteins ranged from 68% to 82%. MMAE is not likely to displace or to be displaced by highly protein-bound medicinal products. In vitro studies indicate that MMAE is a substrate of P-glycoprotein.
Biotransformation: A small fraction of MMAE released from enfortumab vedotin is metabolised. In vitro data indicate that the metabolism of MMAE occurs primarily via oxidation by CYP3A4.
Elimination: The mean clearance of ADC and unconjugated MMAE in patients was 0.11 L/h and 2.11 L/h, respectively. ADC elimination exhibited a multi-exponential decline with a half-life of 3.6 days. Elimination of MMAE appeared to be limited by its rate of release from enfortumab vedotin. MMAE elimination exhibited a multi-exponential decline with a half-life of 2.6 days.
Excretion: The excretion of MMAE occurs mainly in faeces with a smaller proportion in urine. After a single dose of another ADC that contained MMAE, approximately 24% of the total MMAE administered was recovered in faeces and urine as unchanged MMAE over a 1-week period. The majority of recovered MMAE was excreted in faeces (72%). A similar excretion profile is expected for MMAE after enfortumab vedotin administration.
Special populations: Elderly: Population pharmacokinetic analysis indicates that age [range: 24 to 90 years; 60% (450/748) >65 years, 19% (143/748) >75 years] does not have a clinically meaningful effect on the pharmacokinetics of enfortumab vedotin.
Race and gender: Based on population pharmacokinetic analysis, race [69% (519/748) White, 21% (158/748) Asian, 1% (10/748) Black and 8% (61/748) others or unknown] and gender [73% (544/748) male] do not have a clinically meaningful effect on the pharmacokinetics of enfortumab vedotin.
Renal impairment: The pharmacokinetics of ADC and unconjugated MMAE were evaluated after the administration of 1.25 mg/kg of enfortumab vedotin to patients with mild (CrCL >60-90 mL/min; n=272), moderate (CrCL 30-60 mL/min; n=315) and severe (CrCL 15-<30 mL/min; n=25) renal impairment. No significant differences in AUC exposure of ADC or unconjugated MMAE were observed in patients with mild, moderate or severe renal impairment compared to patients with normal renal function. Enfortumab vedotin has not been evaluated in patients with end stage renal disease (CrCL <15 mL/min).
Hepatic impairment: Based on population pharmacokinetics analysis using data from clinical studies in patients with metastatic UC, there was no significant differences in ADC exposure and a 37% increase in unconjugated MMAE AUC were observed in patients with mild hepatic impairment (total bilirubin of 1 to 1.5 × ULN and AST any, or total bilirubin ≤ ULN and AST > ULN, n=65) compared to patients with normal hepatic function. Enfortumab vedotin has only been studied in a limited number of patients with moderate hepatic impairment (n=3) and has not been evaluated in patients with severe hepatic impairment. The effect of moderate or severe hepatic impairment (total bilirubin >1.5 × ULN and AST any) or liver transplantation on the pharmacokinetics of ADC or unconjugated MMAE is unknown.
Physiologically-based pharmacokinetic modeling predictions: Concomitant use of enfortumab vedotin with ketoconazole (a combined P-gp and strong CYP3A inhibitor) is predicted to increase unconjugated MMAE C_max and AUC exposure to a minor extent, with no change in ADC exposure.
Concomitant use of enfortumab vedotin with rifampin (a combined P-gp and strong CYP3A inducer) is predicted to decrease unconjugated MMAE C_max and AUC exposure with moderate effect, with no change in ADC exposure. The full impact of rifampin on the C_max of MMAE may be underestimated in the PBPK model.
Concomitant use of enfortumab vedotin is predicted not to affect exposure to midazolam (a sensitive CYP3A substrate). In vitro studies using human liver microsomes indicate that MMAE inhibits CYP3A4/5 but not other CYP450 isoforms. MMAE did not induce major CYP450 enzymes in human hepatocytes.
In vitro studies: In vitro studies indicate that MMAE is a substrate and not an inhibitor of the efflux transporter P-glycoprotein (P-gp). In vitro studies determined that MMAE was not a substrate of breast cancer resistance protein (BCRP), multidrug resistance-associated protein 2 (MRP2), organic anion transporting polypeptide 1B1 or 1B3 (OATP1B1 or OATP1B3), organic cation transporter 2 (OCT2), or organic anion transporter 1 or 3 (OAT1 or OAT3). MMAE was not an inhibitor of the bile salt export pump (BSEP), P-gp, BCRP, MRP2, OCT1, OCT2, OAT1, OAT3, OATP1B1, or OATP1B3 at clinically relevant concentrations.
Toxicology: Preclinical safety data: Genotoxicity studies showed that MMAE had no discernible genotoxic potential in a reverse mutation test in bacteria (Ames test) or in a L5178Y TK+/- mouse lymphoma mutation assay. MMAE did induce chromosomal aberrations in the micronucleus test in rats which is consistent with the pharmacological action of microtubule-disrupting agents.
Skin lesions were noted in repeat dose studies in rats (4- and 13-weeks) and in monkeys (4-weeks). The skin changes were fully reversible by the end of a 6-week recovery period.
Hyperglycaemia reported in the clinical studies was absent in both the rat and monkey toxicity studies and there were no histopathological findings in the pancreas of either species.
Foetal toxicity (reduced litter size or complete litter loss) was observed and decrease in the litter size was reflected in an increase in early resorptions. Mean foetal body weight in the surviving foetuses at the 2 mg/kg dose level were reduced compared with control.
Enfortumab vedotin associated foetal skeletal variations were considered developmental delays. A dose of 2 mg/kg (approximately similar to the exposure at the recommended human dose) resulted in maternal toxicity, embryo-foetal lethality and structural malformations that included gastroschisis, malrotated hindlimb, absent forepaw, malpositioned internal organs and fused cervical arch. Additionally, skeletal anomalies (asymmetric, fused, incompletely ossified, and misshapen sternebrae, misshapen cervical arch, and unilateral ossification of the thoracic centra) and decreased foetal weight were observed.
Testicular toxicity observed, only in rats, was partially reversed by the end of a 24-week recovery period.

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 Pharmacology: Pharmacodynamics under Actions).

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 Precautions).
Posology: 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. (See Table 2.)

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Dose modifications: See Table 3.

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Special populations: Elderly: No dose adjustment is necessary in patients ≥65 years of age (see Pharmacology: Pharmacokinetics under Actions).
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 Pharmacology: Pharmacokinetics under Actions).
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 hepatic impairment and has not been evaluated in patients with severe hepatic impairment (see Pharmacology: Pharmacokinetics under Actions).
Paediatric population: There is no relevant use of enfortumab vedotin in the paediatric population for the indication of locally advanced or metastatic urothelial cancer.
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 Special precautions for disposal and other handling under Cautions for Usage.

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).

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

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 maculo-papular rash, have been reported (see Adverse Reactions). 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. In clinical trials, the median time to onset of severe skin reactions was 0.6 months (range: 0.1 to 6.4).
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 severe 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 Dosage & Administration).
Pneumonitis/ILD: Severe, life-threatening or fatal pneumonitis/ILD have occurred in patients treated with enfortumab vedotin (see Adverse Reactions). 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 Dosage & Administration).
Hyperglycaemia: Hyperglycaemia and diabetic ketoacidosis (DKA), including fatal events, occurred in patients with and without pre-existing diabetes mellitus, treated with enfortumab vedotin (see Adverse Reactions). 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 Dosage & Administration).
Peripheral neuropathy: Peripheral neuropathy, predominantly peripheral sensory neuropathy, has occurred with enfortumab vedotin, including Grade ≥3 reactions (see Adverse Reactions). Patients with pre-existing 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 2). PADCEV should be permanently discontinued for Grade ≥3 peripheral neuropathy (see Dosage & Administration).
Ocular disorders: Ocular disorders, predominantly dry eye, have occurred in patients treated with enfortumab vedotin (see Adverse Reactions). 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 Adverse Reactions). 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 Use in Pregnancy & Lactation and Pharmacology: Toxicology: Preclinical safety data under Actions). 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.
Effects on ability to drive and use machines: PADCEV has no or negligible influence on the ability to drive and use machines.

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 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.
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 Pharmacology: Toxicology: Preclinical safety data under Actions). 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. Breast-feeding 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 Pharmacology: Toxicology: Preclinical safety data under Actions). 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.

Summary of the safety profile: The most common adverse reactions with enfortumab vedotin were alopecia (48.8%), fatigue (46.8%), decreased appetite (44.9%), peripheral sensory neuropathy (38.7%), diarrhoea (37.6%), nausea (36%), pruritus (33.4%), dysgeusia (29.9%), anaemia (26.5%), weight decreased (23.4%), rash maculo-papular (22.9%), dry skin (21.6%), vomiting (18.4%), aspartate aminotransferase increased (15.3%), hyperglycaemia (13.1%), dry eye (12.8%), alanine aminotransferase increased (12.1%) and rash (10.4%).
The most common serious adverse reactions were diarrhoea (2%) and hyperglycaemia (2%). Nine 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%). Adverse reactions leading to dose interruption occurred in 44% of patients; the most common adverse reactions (≥2%) leading to dose interruption were peripheral sensory neuropathy (15%), fatigue (7%), rash maculo-papular (4%), aspartate aminotransferase increased (4%), alanine aminotransferase increased (4%), anaemia (3%), diarrhoea (3%) and hyperglycaemia (3%). Thirty 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%), fatigue (5%), rash maculo-papular (4%) and decreased appetite (2%).
Tabulated summary of adverse reactions: The safety of enfortumab vedotin as monotherapy has been evaluated in 680 patients with locally advanced or metastatic urothelial cancer receiving 1.25 mg/kg on Days 1, 8 and 15 of a 28-day cycle in clinical studies (see Table 4). Patients were exposed to enfortumab vedotin for a median duration of 4.7 months (range: 0.3 to 34.8 months).
Adverse reactions observed during clinical studies are listed as follows 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. (See Table 4.)

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Description of selected adverse reactions: Immunogenicity: A total of 590 patients were tested for immunogenicity to enfortumab vedotin 1.25 mg/kg; 15 patients were confirmed to be positive at baseline for anti-drug antibody (ADA), and in patients that were negative at baseline (N=575), a total of 16 (2.8%) were positive postbaseline (13 transiently and 3 persistently). 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, skin reactions occurred in 55% (375) of the 680 patients treated with enfortumab vedotin 1.25 mg/kg. Severe (Grade 3 or 4) skin reactions occurred in 13% (85) of patients and a majority of these reactions included maculo-papular rash, rash erythematous, rash or drug eruption. The median time to onset of severe skin reactions was 0.62 months (range: 0.1 to 6.4 months). Serious skin reactions occurred in 3.8% (26) of patients.
In the EV-201 (N=214) clinical study, of the patients who experienced skin reactions, 75% had complete resolution and 14% had partial improvement (see Precautions).
Pneumonitis/ILD: In clinical studies, pneumonitis occurred in 15 (2.2%) and ILD occurred in 2 (0.3%) of the 680 patients treated with enfortumab vedotin 1.25 mg/kg. Less than 1% of patients experienced severe (Grade 3-4) pneumonitis or ILD. Pneumonitis or ILD led to discontinuation of enfortumab vedotin in 0.1% and 0.3% of patients, respectively. There were no deaths from ILD or pneumonitis. The median time to onset of any grade pneumonitis or ILD was 3.6 months (range: 0.8 to 6.0 months) and the median duration was 1.4 months (range: 0.2 to 27.5 months). Of the 17 patients who experienced pneumonitis or ILD, 6 (35.3%) had resolution of symptoms.
Hyperglycaemia: In clinical studies, hyperglycaemia (blood glucose >13.9 mmol/L) occurred in 14% (98) of the 680 patients treated with enfortumab vedotin 1.25 mg/kg. Serious events of hyperglycaemia occurred in 2.2% of patients, 7% of patients developed severe (Grade 3-4) 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 hyperglycemia was 0.6 months (range: 0.1 to 20.3).
In the EV-201 (N=214) clinical study, at the time of their last evaluation, 61% of patients had complete resolution, and 19% of patients had partial improvement (see Precautions).
Peripheral neuropathy: In clinical studies, peripheral neuropathy occurred in 52% (352) of the 680 patients treated with enfortumab vedotin 1.25 mg/kg. Four percent of patients experienced severe (Grade 3-4) peripheral neuropathy including sensory and motor events. The median time to onset of Grade ≥2 was 4.6 months (range: 0.1 to 15.8).
In the EV-201 (N=214) clinical study, at the time of their last evaluation, 19% of patients had complete resolution, and 39% of patients had partial improvement (see Precautions).
Ocular disorders: In clinical studies, 30% of patients experienced dry eye during treatment with enfortumab vedotin 1.25 mg/kg. Treatment was interrupted in 1.3% 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 19.1 months) (see Precautions).
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.

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 Pharmacology: Pharmacokinetics under Actions).
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 C_max 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 Pharmacology: Pharmacokinetics under Actions).

Special precautions for disposal and other handling: Instructions for preparation and administration: Reconstitution in single-dose vial: 1. Follow procedures for proper handling and disposal of anticancer medicinal products.
2. Use appropriate aseptic technique for reconstitution and preparation of dosing solutions.
3. Calculate the recommended dose based on the patient's weight to determine the number and strength (20 mg) of vials needed.
4. Reconstitute each vial as follows and, if possible, direct the stream of sterile water for injection along the walls of the vial and not directly onto the lyophilized powder: 20 mg vial: Add 2.3 mL of sterile water for injection, resulting in 10 mg/mL enfortumab vedotin.
5. Slowly swirl each vial until the contents are completely dissolved. Allow the reconstituted vial(s) to settle for at least 1 minute until the bubbles are gone. Do not shake the vial.
6. Visually inspect the solution for particulate matter and discolouration. The reconstituted solution should be clear to slightly opalescent, colourless to light yellow and free of visible particles. Discard any vial with visible particles or discolouration.
Dilution in infusion bag: 7. Withdraw the calculated dose amount of reconstituted solution from the vial(s) and transfer into an infusion bag.
8. Dilute enfortumab vedotin with dextrose 50 mg/mL (5%), sodium chloride 9 mg/mL (0.9%) or Lactated Ringer's solution for injection. The infusion bag size should allow enough solvent to achieve a final concentration of 0.3 mg/mL to 4 mg/mL enfortumab vedotin.
Diluted dosing solution of enfortumab vedotin is compatible with intravenous infusion bags composed of polyvinyl chloride (PVC), ethylvinyl acetate, polyolefin such as polypropylene (PP), or IV bottles comprised of polyethylene (PE), polyethylene terephthalate glycol-modified, and infusion sets composed of PVC with either plasticizer (bis(2-ethylhexyl) phthalate (DEHP) or tris(2-ethylhexyl) trimellitate (TOTM)), PE and with filter membranes (pore size: 0.2-1.2 μm) composed of polyethersulfone, polyvinylidene difluoride, or mixed cellulose esters.
9. Mix diluted solution by gentle inversion. Do not shake the bag.
10. Visually inspect the infusion bag for any particulate matter or discolouration prior to use. The reconstituted solution should be clear to slightly opalescent, colourless to light yellow and free of visible particles. Do not use the infusion bag if particulate matter or discolouration is observed.
11. Discard any unused portion left in the single-dose vials.
Administration: 12. Administer the infusion over 30 minutes through an intravenous line. Do not administer as an intravenous push or bolus.
No incompatibilities have been observed with closed system transfer device composed of acrylonitrile butadiene styrene (ABS), acrylic, activated charcoal, ethylene propylene diene monomer, methacrylate ABS, polycarbonate, polyisoprene, polyoxymethylene, PP, silicone, stainless steel, thermoplastic elastomer for reconstituted solution.
13. Do not co-administer other medicinal products through the same infusion line.
14. In-line filters or syringe filters (pore size: 0.2-1.2 μm, recommended materials: polyethersulfone, polyvinylidene difluoride, mixed cellulose esters) are recommended to be used during administration.
Disposal: Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
Incompatibilities: In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

Store unopened vials in a refrigerator (2°C to 8°C). Do not freeze.
Shelf life: Unopened vial: 3 years.
Reconstituted solution in the vial: From a microbiological point of view, after reconstitution, the solution from the vial(s) should be added to the infusion bag immediately. If not used immediately, storage times and conditions prior to use of the reconstituted vials are the responsibility of the user and would normally not be longer than 24 hours in refrigeration at 2°C to 8°C. Do not freeze.
Diluted dosing solution in the infusion bag: From a microbiological point of view, after dilution into the infusion bag, the diluted solution in the bag should be administered to the patient immediately. If not used immediately, storage times and conditions prior to use of the diluted dosing solution is the responsibility of the user and would normally not be longer than 16 hours in refrigeration at 2°C to 8°C including infusion time. Do not freeze.

Targeted Cancer Therapy

L01FX13 - enfortumab vedotin ; Belongs to the class of other monoclonal antibodies and antibody drug conjugates. Used in the treatment of cancer.

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