PADCEV
Clinical safety rating
cautionComprehensive clinical and safety monograph for PADCEV (PADCEV).
Comprehensive clinical and safety monograph for PADCEV (PADCEV).
FDA-approved: Treatment of adult patients with locally advanced or metastatic urothelial carcinoma who have received a programmed death receptor-1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibitor and a platinum-containing chemotherapy.Off-label: None established.
Enfortumab vedotin is an antibody-drug conjugate (ADC) directed against Nectin-4, a cell adhesion molecule expressed on urothelial carcinoma cells. The antibody portion binds to Nectin-4, leading to internalization and release of the microtubule-disrupting agent monomethyl auristatin E (MMAE) via proteolytic cleavage. MMAE binds to tubulin and inhibits microtubule polymerization, inducing G2/M phase arrest and apoptosis.
| Metabolism | The small molecule MMAE is metabolized primarily by CYP3A4. Enfortumab, the antibody component, is catabolized to small peptides and amino acids. |
| Excretion | Primarily metabolized via catabolism into small peptides and amino acids; minimal renal excretion (<5% unchanged drug in urine). No biliary/fecal data available. |
| Half-life | Approximately 3.4 days (range 2.8-4.2 days) at steady state, supporting every-3-week dosing. Terminal half-life consistent with IgG1 clearance. |
| Protein binding | No specific protein binding data; as a monoclonal antibody, it is not highly bound to plasma proteins (expected <10%). |
| Volume of Distribution | Approximately 0.07 L/kg (7.0 L in 70 kg patient), indicating limited extravascular distribution and consistent with distribution into vascular and interstitial spaces. |
| Bioavailability | Administered intravenously only; bioavailability 100% by IV route. |
| Onset of Action | Clinical response observed within 6-8 weeks after first dose; maximum effect typically seen after 2-3 cycles. |
| Duration of Action | Duration of response varies, with median response duration approximately 5-7 months in trials. Continuous exposure maintained with every-3-week dosing. |
| Molecular Weight | Approximately 152,000 Da (enfortumab vedotin is a conjugate; antibody ~150,000 Da, MMAE ~718 Da) |
1.25 mg/kg (up to 125 mg) intravenously on days 1, 8, and 15 of a 28-day cycle
| Dosage form | INJECTABLE |
| Renal impairment | No dose adjustment recommended for mild to moderate renal impairment (eGFR ≥30 mL/min/1.73m2). Use not recommended in severe renal impairment (eGFR <30 mL/min/1.73m2) or ESRD. |
| Liver impairment | No formal studies; mild (Child-Pugh A) and moderate (Child-Pugh B) may use with caution; not recommended in severe (Child-Pugh C). |
| Pediatric use | Safety and effectiveness in pediatric patients have not been established. |
| Geriatric use | No specific dose adjustment recommended based on age alone; monitor closely for adverse effects due to potential comorbidities and polypharmacy. |
| 1st trimester | Based on its mechanism of action (Nectin-4-directed antibody-drug conjugate) and animal studies, there is potential for fetal harm. No adequate human data exist. Avoid use during first trimester unless benefit outweighs risk. |
| 2nd trimester | May cause fetal harm based on mechanism and animal data. Avoid use during second trimester unless benefit clearly outweighs risk. |
| 3rd trimester | May cause fetal harm, particularly due to the tubulin inhibitor payload (MMAE). Avoid use in third trimester. If used, monitor for neonatal toxicity. |
Clinical note
Comprehensive clinical and safety monograph for PADCEV (PADCEV).
| Placental transfer | Based on molecular weight and properties of the antibody-drug conjugate, there is potential for transfer across the placenta. Animal studies indicate embryo-fetal toxicity, consistent with placental transfer. |
| Breastfeeding | It is not known whether enfortumab vedotin or its metabolite MMAE is excreted in human milk. Because of the potential for serious adverse reactions in the breastfed infant, advise women not to breastfeed during treatment and for at least 3 weeks after the last dose. |
| Lactation Rating | L5 (Contraindicated) |
| Teratogenic Risk | PADCEV (enfortumab vedotin) is a pregnancy category D drug. Based on its mechanism of action (MMAE-mediated disruption of microtubules), there is a potential risk of fetal harm. Advise pregnant women of the potential risk to the fetus. First trimester: Highest risk of major congenital malformations. Second and third trimesters: Risk of fetal growth restriction and oligohydramnios due to MMAE's anti-mitotic effects. |
| Fetal Monitoring | Monitor pregnant women for fetal growth restriction and oligohydramnios via serial ultrasounds. Assess for signs of fetal distress. Monitor maternal liver function and peripheral neuropathy due to drug toxicity. Monitor for infusion-related reactions. |
| Fertility Effects | Based on animal studies, enfortumab vedotin may impair male and female fertility. MMAE is an anti-mitotic agent that may cause testicular toxicity and ovarian failure. Advise men and women of reproductive potential to use effective contraception during treatment and for at least 3 weeks (women) or 4 months (men) after the last dose. |
■ FDA Black Box Warning
WARNING: SERIOUS SKIN REACTIONS. PADCEV can cause severe, life-threatening or fatal cutaneous adverse reactions including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). Discontinue PADCEV immediately if signs or symptoms of SJS or TEN occur and permanently discontinue if confirmed.
| Serious Effects |
Hypersensitivity to enfortumab vedotin or any of its excipients
| Precautions | Cutaneous adverse reactions: Monitor for severe skin reactions; interrupt or discontinue as appropriate., Hyperglycemia: Monitor blood glucose levels, especially in patients with diabetes or risk factors; manage with antihyperglycemics., Ocular disorders: May cause keratitis, dry eye, or blurred vision; monitor and refer to ophthalmologist., Peripheral neuropathy: Monitor for new or worsening neuropathy; dose adjustment may be required., Pneumonitis or interstitial lung disease: Monitor for signs and symptoms; discontinue if confirmed. |
| Food/Dietary | No specific food interactions reported. However, patients should maintain adequate hydration. Avoid grapefruit and grapefruit juice if taking concurrent CYP3A4 substrates. |
| Clinical Pearls | PADCEV (enfortumab vedotin-ejfv) is a Nectin-4-directed antibody-drug conjugate used in locally advanced or metastatic urothelial carcinoma. Monitor for peripheral neuropathy, skin reactions, and hyperglycemia. Premedicate with antihistamines and antipyretics to reduce infusion reactions. Dose reductions may be needed for Grade 3 or higher adverse events. |
| Patient Advice | Report any new or worsening numbness, tingling, or pain in hands or feet immediately. · Monitor for signs of skin reactions such as rash, itching, or blisters, and avoid sun exposure. · Check blood glucose regularly if you have diabetes or are at risk for hyperglycemia. · Use effective contraception during treatment and for at least 2 weeks after the last dose. · Avoid live vaccines during treatment. |
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