enfortumab vedotin

General

High Alert Medication: This medication bears a heightened risk of causing significant patient harm when it is used in error.

Pronunciation:
en-fort-ue-mab ve-doe-tin

Trade Name(s)

Padcev

Ther. Class.

antineoplastics

Pharm. Class.

drug-antibody conjugates

Indications

Locally advanced or metastatic urothelial cancer in patients who are not eligible for cisplatin-containing chemotherapy (in combination with pembrolizumab).
Locally advanced or metastatic urothelial cancer in patients who have previously received a programmed death receptor-1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibitor and a platinum-containing chemotherapy.
Locally advanced or metastatic urothelial cancer in patients who are not eligible for cisplatin-containing chemotherapy and have previously received ≥1 line of therapy.

Action

Acts as an antibody-drug conjugate (ADC) composed of a humanized IgG1 monoclonal antibody directed against Nectin-4 (an adhesion protein located on cell surface), a cleavable linker, and monomethyl auristatin E (MMAE) (an agent that disrupts microtubles and subsequently causes apoptosis).

Therapeutic Effect(s):

Reduced progression of locally advanced or metastatic urothelial cancer.

Pharmacokinetics

Absorption: IV administration results in complete bioavailability.

Distribution: Minimally distributed to extravascular tissues.

Metabolism and Excretion: Monoclonal antibody component is degraded into smaller peptides via catabolism. MMAE is primarily metabolized in the liver via the CYP3A4 isoenzyme. 17% of MMAE excreted in feces, and 6% excreted in urine, primarily as unchanged drug.

Half-life: ADC: 3.4 days; MMAE: 2.4 days.

TIME/ACTION PROFILE (plasma concentrations)

ROUTE	ONSET	PEAK	DURATION
IV	unknown	ADC: end of infusion; MMAE: 2 days	unknown

Contraindication/Precautions

Contraindicated in:

Moderate or severe hepatic impairment;
OB: Pregnancy;
Lactation: Lactation.

Use Cautiously in:

Patients with or at risk for diabetes mellitus (↑ risk of hyperglycemia);
Rep: Women of reproductive potential and men with female partners of reproductive potential;
Pedi: Safety and effectiveness not established in children.

Adverse Reactions/Side Effects

Derm: alopecia, dry skin, palmar-plantar erythrodysesthesia, pruritus, rash, cellulitis, STEVENS-JOHNSON SYNDROME (SJS), TOXIC EPIDERMAL NECROLYSIS (TEN)

EENT: blurred vision, dry eye, keratitis

Endo: HYPERGLYCEMIA, DIABETIC KETOACIDOSIS, hyperuricemia

F and E: hypokalemia, hypophosphatemia, hyponatremia

GI: diarrhea, ↑ lipase, nausea, vomiting

GU: ↑ serum creatinine, acute kidney injury, ↓ fertility (males), urinary tract infection

Hemat: anemia, leukopenia, lymphocytopenia, neutropenia

Local: extravasation

Metabolic: ↓ appetite

Neuro: dysgeusia, peripheral neuropathy

Resp: PNEUMONITIS/INTERSTITIAL LUNG DISEASE, dyspnea

Misc: fatigue, herpes zoster infection

* CAPITALS indicate life-threatening.
Underline indicate most frequent.

Interactions

Drug-Drug

Strong CYP3A4 inhibitors, including ketoconazole, may ↑ levels and risk of toxicity of MMAE; monitor closely.

Route/Dosage

IV (Adults ≥100 kg): 125 mg on Days 1, 8, and 15 of a 28-day cycle; continue until disease progression or unacceptable toxicity.

IV (Adults <100 kg): 1.25 mg/kg on Days 1, 8, and 15 of a 28-day cycle; continue until disease progression or unacceptable toxicity.

Availability

Lyophilized powder for injection: 20 mg/vial, 30 mg/vial

Assessment

Monitor for symptoms of new or worsening peripheral neuropathy (burning, numbness, tingling in hands or feet; muscle weakness) during therapy. If Grade 2 neuropathy occurs, hold medication until Grade ≤1, then resume therapy at same dose (if first occurrence). For a recurrence, withhold until Grade ≤1 then, resume therapy reduced by one dose level. If Grade 3 neuropathy occurs, permanently discontinue enfortumab vedotin.
Monitor for signs and symptoms of skin reactions (maculopapular rash, pruritus) during therapy. Consider topical corticosteroids and antihistamines as clinically indicated. For persistent or recurrent Grade 2 skin reactions: consider holding dose until Grade ≤1; then resume treatment at the same dose level or dose reduce by one dose level. If Grade 3 skin reactions occur: hold dose until Grade ≤1; then resume treatment at same dose level or dose reduce by one dose level. If SJS or TEN are suspected: immediately hold dose; consult a specialist to confirm diagnosis. If not SJS/TEN, see Grade 2–4 skin reactions. If confirmed SJS or TEN and Grade 4 or recurrent Grade 3 skin reactions occur: permanently discontinue enfortumab vedotin.
Monitor patients for ocular disorders. Consider artificial tears for prophylaxis of dry eyes and ophthalmologic evaluation if ocular symptoms occur or do not resolve. May use ophthalmic topical steroids, if indicated after an ophthalmic exam. Consider interrupting therapy or reducing dose for symptomatic ocular disorders.
Monitor for extravasation during therapy. Delayed reaction symptoms (erythema, swelling, increased temperature, pain) may occur. If extravasation occurs, stop infusion and monitor for adverse reactions.

Lab Test Considerations:

Verify negative pregnancy test before starting therapy.

Monitor blood glucose closely in patients with or at risk for hyperglycemia or diabetes mellitus. If blood glucose >250 mg/dL, hold medication until blood glucose <250 mg/dL, then resume therapy at same dose.
May cause ↓ hemoglobin, lymphocytes, neutrophils and leukocytes.

Implementation

IV Administration

High Alert: Fatalities have occurred with chemotherapeutic agents. Before administering, clarify all ambiguous orders; double-check single, daily, and course-of-therapy dose limits; have second practitioner independently double-check original order, calculations, and infusion pump settings.
Dose Reduction Schedule: 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.
Solution should be prepared in a biologic cabinet. Wear gloves, gown, and mask while handling medication. If powder or solution comes in contact with skin or mucosa, wash thoroughly with soap and water. Discard equipment in specially designated containers.
Intermittent Infusion: Reconstitution: Reconstitute 20 mg vial with 2.3 mL and 30 mg vial with 3.3 mL of sterile water for injection. Direct stream to walls of vial, not to powder. Swirl vial to dissolve contents. Allow vial to settle for at least 1 min until bubbles are gone. Do not shake or expose to direct sunlight. Solution is clear to slightly opalescent, colorless to light yellow; do not administer solutions that are cloudy, discolored, or contain particulate matter. Dilution: 0.9% NaCl or LR. Concentration: 0.3–4 mg/mL.Mix diluted solution by gently inverting; do not shake or expose to direct sunlight. Solution is stable for up to 8 hr if refrigerated; do not freeze.
Rate: Infuse over 30 min; do not give IV push.
Y-Site Incompatibility: Do not mix or administer as an infusion with other medications.

Patient/Family Teaching

Explain purpose of medication to patient.
Advise patient to notify health care professional if signs and symptoms of hyperglycemia (frequent urination, increased thirst, blurred vision, confusion, drowsiness, loss of appetite, fruity breath smell, nausea, vomiting, stomach pain), difficulty controlling blood sugar, peripheral neuropathy, ocular disorders (visual changes), skin reactions, or infusion site reactions occur.
Discuss with patient the possibility of hair loss. Explore methods of coping.
Instruct patient to notify health care professional of all Rx or OTC medications, vitamins, or herbal products being taken and consult health care professional before taking any new medications.
Rep: May cause fetal harm. Advise females of reproductive potential to use effective contraception during and for 2 mo after last dose and males with female partners of reproductive potential to use effective contraception for 4 mo after last dose. Advise patient to avoid breastfeeding during and for at least 3 wk after last dose. Advise patient to notify health care professional immediately if pregnancy is suspected. May reversibly impair female fertility and may impair male fertility.

Evaluation/Desired Outcomes