DRUG INTERACTIONS- summary

 Concomitant use of strong inhibitors of CYP3A4 with PADCEV may increase the exposure to monomethyl auristatin E (MMAE). 

 DRUG INTERACTIONS

1. Effects of Other Drugs on PADCEV Strong CYP3A4 Inhibitors                           Concomitant use with a strong CYP3A4 inhibitor may increase free MMAE exposure ,which may increase the incidence or severity of PADCEV toxicities.

Closely monitor patients for signs of toxicity when PADCEV is given concomitantly with strong CYP3A4 inhibitors. 

• Peripheral neuropathy:                                                                                             Monitor patients for new or worsening peripheral neuropathy and consider dose interruption, dose reduction or discontinuation of the drug

 ADVERSE REACTIONS

 The most common adverse reactions (=20%) included fatigue, peripheral neuropathy, decreased appetite, rash, alopecia, nausea, dysgeusia, diarrhea, dry eye, pruritus and dry skin. 

• Peripheral neuropathy:                                                                                             Monitor patients for new or worsening peripheral neuropathy and consider dose interruption, dose reduction or discontinuation of PADCEV. 

• Ocular disorders:                                                                                                       Ocular disorders, including vision changes, may occur. Monitor patients for signs or symptoms of ocular disorders. Consider prophylactic artificial tears for dry eyes and treatment with ophthalmic topical steroids after an ophthalmic exam. Consider dose interruption or dose reduction of PADCEV when symptomatic ocular disorders occur. 

• Skin reactions:                                                                                                                If severe, withhold PADCEV until improvement or resolution. 

• Infusion Site Extravasation:                                                                                 Ensure adequate venous access prior to administration. Monitor the infusion site during PADCEV administration and stop the infusion immediately for suspected extravasation. 

• Embryo-fetal toxicity:                                                                                            PADCEV can cause fetal harm. Advise of the potential risk to a fetus and to use effective contraception. 

 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Patient Information).

Hyperglycemia

Inform patients about the risk of hyperglycemia and how to recognize associated symptoms

Peripheral Neuropathy

Inform patients to report to their healthcare provider any numbness and tingling of the hands or feet or muscle weakness 

Ocular disorders:

Advise patients to contact their healthcare provider if they experience any visual changes  

In order to prevent or treat dry eyes, advise patients to use artificial tear substitutes.

Skin Reactions

Inform patients that rashes and severe skin reactions have occurred after administration of PADCEV. Advise patients to contact their healthcare provider for signs and symptoms of progressive or intolerable skin reactions 

Infusion Site Extravasation

Inform patients that infusion site reactions have occurred after administration of PADCEV. These reactions generally occurred immediately after administration but, in some instances, had a delayed onset (e.g., 24 hours).

Instruct patients to contact their healthcare provider immediately if they experience an infusion site reaction 

Embryo-Fetal Toxicity

Advise pregnant women and females of reproductive potential of the potential risk to the fetus.

Advise females to inform their healthcare providers of a known or suspected pregnancy 

Females and Males of Reproductive Potential

Advise female patients of reproductive potential to use effective contraception during treatment with PADCEV and for 2 months after the last dose.

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 

Lactation

Advise women not to breastfeed during treatment with PADCEV and for 3 weeks after the last dose 

Infertility

Advise males of reproductive potential that PADCEV may impair fertility 

Manufactured and Marketed by:                                                                                  Astellas Pharma US, Inc. Northbrook, Illinois 60062

19 Distributed and Marketed by: Seattle Genetics, Inc. Bothell, WA 98021 1-855-4SEAGEN U.S. License 2124 PADCEVTM is a trademark jointly owned by Agensys, Inc. and Seattle Genetics, Inc. ©2019 Agensys, Inc. and Seattle Genetics, Inc

 CLINICAL PHARMACOLOGY

1. Mechanism of Action                                                                                            Enfortumab vedotin-ejfv is an ADC. The antibody is a human IgG1 directed against Nectin-4, an adhesion protein located on the surface of cells.

2. Pharmacodynamics                                                                                                     In an exposure-response analysis, higher enfortumab vedotin exposure was associated with higher incidence of some adverse reactions (e.g., Grade =2 peripheral neuropathy, Grade =3 hyperglycemia) and a lower exposure was associated with lower efficacy.

Cardiac Electrophysiology                                                                                             At the recommended dose, PADCEV had no large QTc prolongation (>20 msec).

3. Pharmacokinetics                                                                                                  Population pharmacokinetic analysis included data from 369 patients based on three Phase 1 studies and one Phase 2 study.

Enfortumab vedotin-ejfv pharmacokinetics were characterized after single and multiple doses in patients with locally advanced or metastatic urothelial carcinoma and other solid tumors.

Peak ADC concentrations were observed near the end of intravenous infusion while peak MMAE concentrations were observed approximately 2 days after enfortumab vedotin-ejfv dosing.

Cmax = maximum concentration, AUC0-28d = area under the concentration-time curve from time zero to 28 days, Ctrough,0-28d = pre-dose concentration on day 28

Distribution

The estimated mean steady-state volume of distribution of ADC was 11 liters following administration of enfortumab vedotin-ejfv. Plasma protein binding of MMAE ranged from 68% to 82%, in vitro.

Elimination

ADC and MMAE exhibited multi-exponential declines with an elimination half-life of 3.4 days and 2.4 days, respectively. The mean clearance (CL) of enfortumab vedotin-ejfv and free MMAE in patients was 0.10 L/h and 2.7 L/h, respectively, in patients.

Elimination of MMAE appeared to be limited by its rate of release from enfortumab vedotin-ejfv.

Metabolism

Enfortumab vedotin-ejfv catabolism has not been studied in humans; however, it is expected to undergo catabolism to small peptides, amino acids, unconjugated MMAE, and unconjugated MMAE-related catabolites. 

Enfortumab vedotin-ejfv releases MMAE via proteolytic cleavage, and MMAE is primarily metabolized by CYP3A4 in vitro.

Excretion

The excretion of enfortumab vedotin-ejfv is not fully characterized. Following a single-dose of another ADC that contains MMAE, 17% of the total MMAE administered was recovered in feces and 6% in urine over a 1- week period, primarily as unchanged drug.

A similar excretion profile of MMAE is expected after enfortumab vedotin-ejfv administration.

Specific Populations

Based on population pharmacokinetic analysis, no clinically significant differences in the pharmacokinetics of enfortumab vedotin-ejfv were observed based on age (24 to 87 years), sex, or race/ethnicity (Caucasian, Asian, Black, or others).

Hepatic Impairment

Based on population pharmacokinetics analysis, there was a 48% AUC increase in unconjugated MMAE exposure observed in patients with mild hepatic impairment (bilirubin of 1 to 1.5 × ULN and AST ULN, n=31) compared to normal hepatic function. 

The effect of moderate or severe hepatic impairment (AST or ALT >2.5 x ULN or total bilirubin >1.5 x ULN) or liver transplantation on the pharmacokinetics of ADC or unconjugated MMAE is unknown.

Renal Impairment

The pharmacokinetics of enfortumab vedotin-ejfv and MMAE were evaluated after the administration of 1.25 mg/kg of enfortumab vedotin-ejfv to patients with mild (creatinine clearance; CrCL >60–90 mL/min; n=135), moderate (CrCL 30–60 mL/min; n=147) and severe (CrCL <30 mL/min; n=8) renal impairment.

No significant differences in exposure (AUC) of ADC and MMAE were observed in patients with mild, moderate or severe renal impairment compared to patients with normal renal function.

The effect of end stage renal disease with or without dialysis on the pharmacokinetics of ADC or unconjugated MMAE is unknown.

Drug Interaction Studies

Clinical Studies No clinical studies evaluating the drug-drug interaction potential of enfortumab vedotin-ejfv have been conducted.

Strong CYP3A4 Inhibitors:                                                                                           Another ADC that contains MMAE co-administered with ketoconazole (a strong CYP3A4 inhibitor) increased MMAE Cmax by 25% and AUC by 34%, with no change in ADC exposure.

The concomitant use of strong inhibitors of CYP3A4 with PADCEV would likely result in similar effects on free MMAE and ADC.

Strong CYP3A4 Inducers:                                                                                      Another ADC that contains MMAE co-administered with rifampin (a strong CYP3A4 inducer) decreased MMAE Cmax by 44% and AUC by 46%, with no change in ADC exposure.

The concomitant use of strong inducers of CYP3A4 with PADCEV would likely result in similar effects on free MMAE and ADC. 

 USE IN SPECIFIC POPULATIONS

1. Pregnancy Risk Summary                                                                                   Based on the mechanism of action and findings in animals, PADCEV can cause fetal harm when administered to a pregnant woman 

There are no available human data on PADCEV use in pregnant women to inform a drug-associated risk.

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.

2. 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 at least 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 

Contraception Females                                                                                           PADCEV can cause fetal harm when administered to a pregnant woman  

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 Males Based on findings from animal studies, PADCEV may impair male fertility

4. Pediatric Use                                                                                                            Safety and effectiveness of PADCEV in pediatric patients have not been established.

5. Geriatric Use                                                                                                                 Of the 310 patients treated with PADCEV in clinical studies, 187 (60%) were 65 years or older and 80 (26%) were 75 years or older. No overall differences in safety or effectiveness were observed between these patients and younger patients 

6. Hepatic Impairment                                                                                                 Avoid the use of PADCEV in patients with moderate or severe hepatic impairment. PADCEV has not been studied in patients with moderate or severe hepatic impairment 

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.

No adjustment in the starting dose is required when administering PADCEV to patients with mild hepatic impairment.

7. Renal Impairment                                                                                                       No dose adjustment is required in patients with mild (CrCL >60-90 mL/min), moderate (CrCL 30-60 mL/min) or severe (CrCL <30 mL/min) renal impairment