Source: European Medicines Agency (EU) Revision Year: 2024 Publisher: Astellas Pharma Europe B.V., Sylviusweg 62, 2333 BE Leiden, The Netherlands
Padcev, in combination with pembrolizumab, is indicated for the first-line treatment of adult patients with unresectable or metastatic urothelial cancer who are eligible for platinum-containing chemotherapy.
Padcev as monotherapy is indicated for the treatment of adult patients with locally advanced or metastatic urothelial cancer who have previously received a platinum-containing chemotherapy and a programmed death receptor-1 or programmed death-ligand 1 inhibitor (see section 5.1).
Treatment with Padcev should be initiated and supervised by a physician experienced in the use of anti-cancer therapies. Ensure good venous access prior to starting treatment (see section 4.4).
As monotherapy, 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.
When given in combination with pembrolizumab, the recommended dose of enfortumab vedotin is 1.25 mg/kg (up to a maximum of 125 mg for patients ≥100 kg)administered as an intravenous infusion over 30 minutes on Days 1 and 8 of every 3-week (21-day) cycle until disease progression or unacceptable toxicity. The recommended dose of pembrolizumab is either 200 mg every 3 weeks or 400 mg every 6 weeks administered as an intravenous infusion over 30 minutes. Patients should be administered pembrolizumab after enfortumab vedotin when given on the same day. Refer to the pembrolizumab SmPC for additional dosing information of pembrolizumab.
Table 1. Recommended dose reductions of enfortumab vedotin for adverse 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 in patients with locally advanced or metastatic urothelial cancer:
| Adverse reaction | Severity* | Dose modification* |
|---|---|---|
| Skin reactions | Suspected Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN) or bullous lesions | Immediately withhold and refer to specialised care |
| Confirmed SJS or TEN; Grade 4 or recurrent Grade 3 | Permanently discontinue. | |
| Grade 2 worsening Grade 2 with fever Grade 3 | • Withhold until Grade ≤1 • Referral to specialised care should be considered • Resume at the same dose level or consider dose reduction by one dose level (see Table 1) | |
| Hyperglycaemia | Blood glucose >13.9 mmol/L (>250 mg/dL) | • Withhold until elevated blood glucose has improved to ≤13.9 mmol/L (≤250 mg/dL) • Resume treatment at the same dose level |
| Pneumonitis/ interstitial lung disease (ILD) | Grade 2 | • Withhold until Grade ≤1, then resume at the same dose or consider dose reduction by one dose level (see Table 1). |
| Grade ≥3 | Permanently discontinue. | |
| Peripheral neuropathy | Grade 2 | • Withhold until Grade ≤1 • For first occurrence, resume treatment at the same dose level • For a recurrence, withhold until Grade ≤1 then, resume treatment reduced by one dose level (see Table 1) |
| Grade ≥3 | Permanently discontinue. |
* Toxicity was graded per National Cancer Institute Common Terminology Criteria for Adverse Events Version 5.0 (NCI-CTCAE v5.0) where Grade 1 is mild, Grade 2 is moderate, Grade 3 is severe and Grade 4 is life-threatening.
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. Enfortumab vedotin has not been evaluated in patients with end stage renal disease (CrCL <15 mL/min) (see section 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]. Enfortumab vedotin has only been evaluated in a limited number of patients with moderate and severe hepatic impairment. Hepatic impairment is expected to increase the systemic exposure to MMAE (the cytotoxic drug); therefore, patients should be closely monitored for potential adverse events. Due to the sparsity of the data in patients with moderate and severe hepatic impairment, no specific dose recommendation can be given (see section 5.2).
There is no relevant use of enfortumab vedotin in the paediatric population for the indication of locally advanced or metastatic urothelial cancer.
Padcev is for intravenous use. The recommended dose must be administered by intravenous infusion over 30 minutes. Enfortumab vedotin must not be administered as an intravenous push or bolus injection.
For instructions on reconstitution and dilution of the medicinal product before administration, see section 6.6.
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).
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.
Unopened vials:
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 vial:
10 mL Type I glass vial with gray bromobutyl rubber stopper, 20 mm aluminum seal with a green ring and green cap. Each carton contains 1 vial.
Padcev 30 mg powder for concentrate for solution for infusion vial:
10 mL Type I glass vial with gray bromobutyl rubber stopper, 20 mm aluminum seal with a silver ring and yellow cap. Each carton contains 1 vial.
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 or 30 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:
a. 20 mg vial: Add 2.3 mL of sterile water for injection, resulting in 10 mg/mL enfortumab vedotin.
b. 30 mg vial: Add 3.3 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. Do not expose to direct sunlight.
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. Do not expose to direct sunlight.
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 (the 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.
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