Dosage & Administration
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Padcev Prescribing Information
- • PADCEV can cause severe and fatal cutaneous adverse reactions including Stevens-Johnson syndrome (SJS) and Toxic Epidermal Necrolysis (TEN), which occurred predominantly during the first cycle of treatment, but may occur later.
- • Closely monitor patients for skin reactions.
- • Immediately withhold PADCEV and consider referral for specialized care for suspected SJS or TEN or severe skin reactions.
- • Permanently discontinue PADCEV in patients with confirmed SJS or TEN; or Grade 4 or recurrent Grade 3 skin reactions [see Dosage and Administration , Warnings and Precautions and Adverse Reactions ].
PADCEV®, in combination with pembrolizumab, is indicated for the treatment of adult patients with locally advanced or metastatic urothelial cancer (mUC).
PADCEV, as a single agent, is indicated for the treatment of adult patients with locally advanced or mUC who:
- •
- have previously received a programmed death receptor-1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibitor and platinum-containing chemotherapy, or
- •
- are ineligible for cisplatin-containing chemotherapy and have previously received one or more prior lines of therapy.
Recommended Dosage
When given in combination with pembrolizumab, the recommended dose of PADCEV 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 a 21-day cycle until disease progression or unacceptable toxicity. Refer to the pembrolizumab Prescribing Information for the recommended dosing information of pembrolizumab.
The recommended dose of PADCEV as a single agent 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.
Dose Modifications
| Adverse Reaction | Severity * | Dose Modification * |
|---|---|---|
| ||
Skin Reactions [see Boxed Warning, Warnings and Precautions ] | For persistent or recurrent Grade 2 skin reactions | Consider withholding until Grade ≤1, then resume treatment at the same dose level or dose reduce by one dose level. |
Grade 3 skin reactions | Withhold until Grade ≤1, then resume treatment at the same dose level or dose reduce by one dose level. | |
Suspected SJS or TEN | Immediately withhold, consult a specialist to confirm the diagnosis. If not SJS/TEN, see Grade 2-4 skin reactions. | |
Confirmed SJS or TEN; Grade 4 or recurrent Grade 3 skin reactions | Permanently discontinue. | |
Hyperglycemia [see Warnings and Precautions ] | Blood glucose >250 mg/dL | Withhold until elevated blood glucose has improved to ≤250 mg/dL, then resume treatment at the same dose level. |
Pneumonitis/Interstitial Lung Disease (ILD) [see Warnings and Precautions ] | Grade 2 | Withhold until Grade ≤1, then resume treatment at the same dose level or consider dose reduction by one dose level. |
Grade ≥3 | Permanently discontinue. | |
Peripheral Neuropathy [see Warnings and Precautions ] | Grade 2 | Withhold until Grade ≤1, then resume treatment at the same dose level (if first occurrence). For a recurrence, withhold until Grade ≤1, then resume treatment reduced by one dose level. |
Grade ≥3 | Permanently discontinue. | |
Other nonhematologic toxicity [see Adverse Reactions ] | Grade 3 | Withhold until Grade ≤1, then resume treatment at the same dose level or consider dose reduction by one dose level. |
Grade 4 | Permanently discontinue. | |
Hematologic toxicity [see Adverse Reactions ] | Grade 3, or Grade 2 thrombocytopenia | Withhold until Grade ≤1, then resume treatment at the same dose level or consider dose reduction by one dose level. |
Grade 4 | Withhold until Grade ≤1, then reduce dose by one dose level or discontinue treatment. | |
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 |
Instructions for Preparation and Administration
- •
- Administer PADCEV as an intravenous infusion only.
- •
- PADCEV is a hazardous drug. Follow applicable special handling and disposal procedures.1
Prior to administration, the PADCEV vial is reconstituted with Sterile Water for Injection (SWFI). The reconstituted solution is subsequently diluted in an intravenous infusion bag containing either 5% Dextrose Injection, USP, 0.9% Sodium Chloride Injection, USP, or Lactated Ringer’s Injection, USP.
Reconstitution in Single-dose Vial
- 1.
- Follow procedures for proper handling and disposal of anticancer drugs.
- 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 SWFI along the walls of the vial and not directly onto the lyophilized powder:
- a.
- 20 mg vial: Add 2.3 mL of SWFI, resulting in 10 mg/mL PADCEV.
- b.
- 30 mg vial: Add 3.3 mL of SWFI, resulting in 10 mg/mL PADCEV.
- 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.
- Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. The reconstituted solution should be clear to slightly opalescent, colorless to light yellow and free of visible particles. Discard any vial with visible particles or discoloration.
- 7.
- Based upon the calculated dose amount, the reconstituted solution from the vial(s) should be added to the infusion bag immediately. This product does not contain a preservative. If not used immediately, reconstituted vials may be stored for up to 24 hours in refrigeration at 2°C to 8°C (36°F to 46°F). DO NOT FREEZE. Discard unused vials with reconstituted solution beyond the recommended storage time.
Dilution in Infusion Bag
- 1.
- Withdraw the calculated dose amount of reconstituted solution from the vial(s) and transfer into an infusion bag.
- 2.
- Dilute PADCEV with either 5% Dextrose Injection, 0.9% Sodium Chloride Injection, or Lactated Ringer's Injection. The infusion bag size should allow enough diluent to achieve a final concentration of 0.3 mg/mL to 4 mg/mL PADCEV.
- 3.
- Mix diluted solution by gentle inversion. DO NOT SHAKE THE BAG. Do not expose to direct sunlight.
- 4.
- Visually inspect the infusion bag for any particulate matter or discoloration prior to use. The reconstituted solution should be clear to slightly opalescent, colorless to light yellow and free of visible particles. DO NOT USE the infusion bag if particulate matter or discoloration is observed.
- 5.
- Discard any unused portion left in the single-dose vials.
Administration
- 1.
- Immediately administer the infusion over 30 minutes through an intravenous line.
- 2.
- If the infusion is not administered immediately, the prepared infusion bag should not be stored longer than 8 hours at 2°C to 8°C (36°F to 46°F). DO NOT FREEZE.
DO NOT administer PADCEV as an intravenous push or bolus.
DO NOT mix PADCEV with, or administer as an infusion with, other medicinal products.
For Injection: 20 mg and 30 mg of enfortumab vedotin-ejfv as a white to off-white lyophilized powder in a single-dose vial for reconstitution.
Pregnancy
Risk Summary
Based on the mechanism of action and findings in animals, PADCEV can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology ]. There are no available human data on PADCEV use in pregnant women to inform a drug-associated risk. In an animal reproduction study, administration of enfortumab vedotin-ejfv to pregnant rats during organogenesis caused maternal toxicity, embryo-fetal lethality, structural malformations and skeletal anomalies at maternal exposures similar to the exposures at the recommended human dose of 1.25 mg/kg (see Data). Advise patients of the potential risk to the fetus.
The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%-4% and 15%-20%, respectively.
Data
Animal Data
In a rat pilot embryo-fetal development study, administration of enfortumab vedotin-ejfv on gestation day 6 and 13 during the period of organogenesis resulted in a complete litter loss in all pregnant rats at the maternally toxic dose of 5 mg/kg (approximately 3 times the exposure at the recommended human dose). A dose of 2 mg/kg (similar to the exposure at the recommended human dose) resulted in maternal toxicity, embryo-fetal 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 fetal weight were observed.
Lactation
Risk Summary
There are no data on the presence of enfortumab vedotin-ejfv in human milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in a breastfed child, advise lactating women not to breastfeed during treatment with PADCEV and for 3 weeks after the last dose.
Females and Males of Reproductive Potential
Pregnancy Testing
Verify pregnancy status in females of reproductive potential prior to initiating PADCEV treatment [see Use in Specific Populations ].
Contraception
Females
PADCEV can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations ]. Advise females of reproductive potential to use effective contraception during treatment with PADCEV and for 2 months after the last dose.
Males
Advise male patients with female partners of reproductive potential to use effective contraception during treatment with PADCEV and for 4 months after the last dose.
Infertility
Females
Based on findings in animal studies with MMAE-containing antibody-drug conjugates (ADCs), PADCEV may impair female fertility. The effect on fertility is reversible [see Nonclinical Toxicology ].
Males
Based on findings from animal studies, PADCEV may impair male fertility [see Nonclinical Toxicology ].
Pediatric Use
Safety and effectiveness of PADCEV in pediatric patients have not been established.
Geriatric Use
Of the 564 patients treated with PADCEV in combination with pembrolizumab, 44% (n=247) were 65-74 years and 26% (n=144) were 75 years or older. Of the 720 patients treated with PADCEV as a single agent in clinical trials, 39% (n=282) were 65-74 years and 24% (n=170) were 75 years or older. No overall differences in effectiveness were observed between patients 65 years of age or older and younger patients.
Patients 75 years of age or older treated with PADCEV in combination with pembrolizumab experienced a higher incidence of fatal adverse reactions than younger patients. The incidence of fatal adverse reactions was 4% in patients younger than 75 and 7% in patients 75 years or older.
Patients 75 years of age or older treated with PADCEV as a single agent experienced a higher incidence of fatal adverse reactions than younger patients. The incidence of fatal adverse reactions was 6% in patients younger than 75 years, and 11% in patients 75 years or older.
No significant difference was observed in the pharmacokinetics of PADCEV between patients 65 years and older and younger patients [see Clinical Pharmacology ].
Hepatic Impairment
Avoid the use of PADCEV in patients with moderate or severe hepatic impairment (total bilirubin >1.5 x ULN and any AST). PADCEV has only been studied in a limited number of patients with moderate or severe hepatic impairment [see Clinical Pharmacology ( 12.3)]. In another ADC that contains MMAE, the frequency of ≥ Grade 3 adverse reactions and deaths was greater in patients with moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic impairment compared to patients with normal hepatic function.
None.