Enfortumab vedotin is an antibody-drug conjugate that targets Nectin-4, an adhesion protein located on the surface of cells. It is indicated as monotherapy for the treatment of locally advanced or metastatic urothelial cancer in patients who have previously received a PD-1 or PD-L1 inhibitor and platinum-containing chemotherapy, or in patients who are ineligible for cisplatin-containing chemotherapy and have previously received at least 1 prior line of therapy. It is also indicated for the treatment of locally advanced or metastatic urothelial cancer in combination with pembrolizumab. Closely monitor patients for skin reactions, as severe and fatal cases including Stevens-Johnson syndrome and toxic epidermal necrolysis have occurred, predominantly during the first cycle of treatment but occasionally as a delayed reaction. Avoid the use of enfortumab vedotin in patients with moderate and severe hepatic impairment.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Hazardous Drugs Classification
-NIOSH (Draft) 2020 List: Table 1
-Approved by FDA after NIOSH 2016 list published. The manufacturer recommends this drug be handled as a hazardous drug.
-Observe and exercise appropriate precautions for handling, preparation, administration, and disposal of hazardous drugs.
-Use double chemotherapy gloves and a protective gown. Prepare in a biological safety cabinet or compounding aseptic containment isolator with a closed system drug transfer device. Eye/face and respiratory protection may be needed during preparation and administration.
Emetic Risk
-Low
-Administer routine antiemetic prophylaxis prior to treatment.
Extravasation Risk
-Skin and soft tissue reactions secondary to extravasation including erythema, swelling, increased temperature, and pain have been reported; reactions worsened until 2 to 7 days after extravasation and resolved within 1 to 4 weeks of peak; secondary cellulitis, bullae, or exfoliation have also been reported; extravasation reactions may be delayed.
-Ensure adequate venous access prior to starting an infusion of enfortumab vedotin and monitor for possible extravasation during administration. If extravasation occurs, stop the infusion and monitor for adverse reactions.
Route-Specific Administration
Injectable Administration
-Administer as an intravenous (IV) infusion only. Do NOT administer as an IV push or bolus.
-Do not mix with, or administer as an infusion with, other IV products.
-Consider the use of artificial tears for prophylaxis of dry eyes.
Intravenous Administration
Reconstitution:
-20 mg vial: Add 2.3 mL of Sterile Water for Injection, resulting in a concentration of 10 mg/mL. Direct the stream of Sterile Water for Injection along the walls of the vial and not directly onto the lyophilized powder.
-30 mg vial: Add 3.3 mL of Sterile Water for Injection, resulting in a concentration of 10 mg/mL. Direct the stream of Sterile Water for Injection along the walls of the vial and not directly onto the lyophilized powder.
-Slowly swirl each vial until the contents are completely dissolved; do not shake the vial.
-Allow reconstituted vials to settle for at least 1 minute until bubbles are gone. Do not expose to direct sunlight.
-Storage after reconstitution: If not used immediately, reconstituted vials may be stored for up to 4 hours in refrigeration at 2 to 8 degrees Celsius (36 to 46 degrees Fahrenheit). Do not freeze. Discard unused vials with reconstituted solution beyond the recommended storage time.
Dilution:
-Dilute reconstituted enfortumab vedotin in an infusion bag containing 5% Dextrose Injection, 0.9% Sodium Chloride Injection, or Lactated Ringer's Injection.
-The final concentration should be 0.3 mg/mL to 4 mg/mL.
-Mix the diluted solution by gentle inversion; do not shake. Do not expose to direct sunlight.
-Discard any unused portion left in the single-dose vials.
-Storage after dilution: If the infusion is not administered immediately, the prepared infusion bag may be stored for up to 8 hours in refrigeration at 2 to 8 degrees Celsius (36 to 46 degrees Fahrenheit). Discard any unused portion left in the single-dose vials.
Administration:
-Infuse over 30 minutes through an IV line.
Hyperglycemia occurred in 17% (grade 3 or 4, 7%) of patients treated with enfortumab vedotin monotherapy in a pooled safety population; fatal hyperglycemia and diabetic ketoacidosis each occurred in 1 patient (0.1%). The incidence of severe (grade 3 or 4) hyperglycemia was consistently increased in patients with a higher body mass index and in patients with a higher baseline hemoglobin A1c. The median time to onset of hyperglycemia was 0.5 months. Five percent (5%) of patients required the initiation of insulin therapy, and of these, 66% had discontinued insulin by the time of their last evaluation. In 2 individual clinical trials, hyperglycemia occurred in 10% to 16% (grade 3 or 4, 9% or fewer) patients who received monotherapy with enfortumab vedotin; increased non-fasting glucose concentrations occurred in 27% to 36% (grade 3 or 4, 8% to 13%) of these patients. Blood glucose increases from baseline were more common in patients who received combination therapy with enfortumab vedotin plus pembrolizumab (66% to 74%; grade 3 or 4, 13% to 14%). Closely monitor blood glucose levels; an interruption of therapy is necessary for patients with blood glucose levels greater than 250 mg/dL.
Peripheral neuropathy occurred in 53% (grade 3 or 4, 5%) of patients treated with enfortumab vedotin monotherapy in a pooled safety population, many of whom had received prior treatment with platinum-based chemotherapy. Of these patients most (38%) experienced sensory neuropathy, followed by muscular weakness (8%) and motor neuropathy (7%); there were additionally reports of burning sensation, demyelinating polyneuropathy, dysesthesia, hypoesthesia, muscle weakness, neuralgia, neurotoxicity, paresthesias, peripheral motor/sensory/sensorimotor neuropathy, peroneal nerve palsy, gait disturbance, polyneuropathy, and sensory loss. Peripheral neuropathy occurred at a higher rate in patients who received enfortumab vedotin in combination with pembrolizumab (67%; grade 3 or 4, 7%). Peripheral neuropathy occurred in patients with or without a pre-existing history of peripheral neuropathy, with a median time to onset of grade 2 or higher neuropathy of 4.9 to 6 months. Monitor patients for symptoms of new or worsening peripheral neuropathy; an interruption of therapy, dose reduction, or discontinuation of therapy may be necessary. Of patients who experienced neuropathy, 87% to 89% had residual neuropathy at their last evaluation.
Ocular disorders occurred in 40% of patients treated with enfortumab vedotin monotherapy who received scheduled ophthalmologic exams in a pooled safety analysis; the majority of these events involved the cornea and included events associated with dry eye such as keratitis, keratopathy, blurred vision, increased lacrimation, conjunctivitis, limbal stem cell deficiency, and other events associated with dry eyes. Xerophthalmia occurred in 24% to 40% of patients who received enfortumab vedotin as monotherapy or in combination with pembrolizumab, and blurred vision in 6% to 10% of patients. The median time to onset of a symptomatic ocular disorder was 1.7 months. Monitor patients for ocular disorders, and consider artificial tears for prophylaxis of dry eyes. Consider an ophthalmologic evaluation if ocular symptoms occur or do not resolve; ophthalmic topical steroids may be indicated after an ophthalmic exam. An interruption of therapy or dose reduction may be necessary for symptomatic ocular disorders.
Skin reactions occurred in 58% (grade 3 or 4, 14%) of patients in a pooled safety population treated with enfortumab vedotin monotherapy in clinical trials, with 23% experiencing a maculopapular rash and 34% with pruritus. The incidence of skin reactions was higher in patients who received enfortumab vedotin in combination with pembrolizumab (70%; grade 3 or 4, 17%), with the most common reactions including maculopapular rash, macular rash and papular rash. Serious (grade 3 or 4) skin reactions included bullous rash, exfoliative dermatitis, erythematous rash, maculopapular rash, palmar-plantar erythrodysesthesia (hand and foot syndrome), pemphigoid, symmetrical drug-related intertriginous and flexural exanthema (SDRIFE); the median time to onset to serious skin reactions was 0.6 to 1.7 months. In individual clinical trials, rash occurred in 52% to 66% (grade 3 or 4, 13% to 17%) of patients treated with enfortumab vedotin monotherapy and in 68% to 71% (grade 3 or 4, 15% to 21%) of patients who received enfortumab vedotin in combination with pembrolizumab. Additional dermatologic adverse reactions associated with enfortumab vedotin when used as monotherapy or in combination with pembrolizumab include xerosis (17% to 26%; grade 3 or 4, 1% or less) and pruritus (26% to 41%; grade 3 or 4, 1.1% to 3.3%). Epidermal necrosis, Stevens-Johnson syndrome, and toxic epidermal necrolysis have been reported in postmarketing experience with enfortumab vedotin; these reactions primarily occurred during the first cycle of treatment but may also occur later. Closely monitor patients for skin reactions and consider appropriate treatment (e.g., topical corticosteroids and antihistamines) as clinically indicated; an interruption of therapy, dose reduction, or discontinuation of therapy may be necessary depending on the severity.
Urinary tract infection (UTI) occurred in 17% to 30% of patients with locally advanced or metastatic urothelial cancer treated with enfortumab vedotin as monotherapy or in combination with pembrolizumab (grade 3 or 4, 5% to 12%); herpes zoster occurred in 3% of patients who received enfortumab vedotin monotherapy in 1 trial. Serious cases of urosepsis (5%), cellulitis (5%), pneumonia (2.3% to 5%), and sepsis (3% to 5%), and were also reported with enfortumab vedotin therapy. Twenty-two percent (22%) or fewer patients treated with enfortumab vedotin experienced a fever (grade 3 or 4, 2% or less); neutropenic fever occurred in 4% of patients in 1 clinical trial.
An injection site reaction/extravasation has been reported in patients treated with enfortumab vedotin. Skin and soft tissue reactions secondary to extravasation occurred in 1% of patients who received monotherapy with enfortumab vedotin in a pooled safety analysis (grade 3 or 4, 0.3%); reactions may be delayed. In these patients, erythema, swelling, increased temperature, and pain worsened until 2 to 7 days after extravasation and resolved within 1 to 4 weeks of peak. Two patients (0.3%) developed extravasation reactions with secondary cellulitis, bullae, or exfoliation. Ensure adequate venous access prior to starting an infusion of enfortumab vedotin and monitor for possible extravasation during administration. If extravasation occurs, stop the infusion and monitor for adverse reactions.
Fatigue including asthenia was reported in 48% to 60% (grade 3 or 4, 6% to 11%) of patients with locally advanced or metastatic urothelial cancer who received enfortumab vedotin as monotherapy or in combination with pembrolizumab in clinical trials.
Nausea (26% to 45%; grade 3 or 4, 0.8% to 3%) and vomiting (12% to 19.8%; grade 3 or 4, 2% or less) were reported in patients treated with enfortumab vedotin as monotherapy or in combination with pembrolizumab in clinical trials. Increased lipase levels occurred in 13% to 18% of patients who received enfortumab vedotin monotherapy (grade 3 or 4, 9% to 11%) and in 59% (grade 3 or 4, 32%) of patients who received combination therapy with pembrolizumab.
Dysgeusia was reported in 21% to 42% of patients with locally advanced or metastatic urothelial cancer treated with enfortumab vedotin as monotherapy or in combination with pembrolizumab.
Anorexia/decreased appetite was reported in 33% to 52% (grade 3 or 4, 0.8% to 6%) and weight loss in 16% to 48% (grade 3 or 4, 0.3% to 5%) of patients with locally advanced or metastatic urothelial cancer who received enfortumab vedotin as monotherapy or in combination with pembrolizumab.
Diarrhea was reported in 35% to 45% (grade 3 or 4, 4% to 8%) of patients treated with enfortumab vedotin as monotherapy or in combination with pembrolizumab in clinical trials. Constipation (26% to 28%; grade 3 or 4, 1% or less) and abdominal pain (20% or less; grade 3 or 4, 1% or less) were also reported patients who received enfortumab vedotin.
Alopecia was reported in 35% to 53% of patients treated with enfortumab vedotin as monotherapy or in combination with pembrolizumab in clinical trials (grade 3 or 4, 0.5% or less).
Lymphopenia, anemia, and neutropenia have been reported in patients who received enfortumab vedotin in clinical trials. Decreases from baseline in lymphocytes (32% to 43%; grade 3 or 4, 10% to 15%) and hemoglobin (28% to 34%; grade 3 or 4, 4% to 10%) occurred less frequently with monotherapy compared to decreases in lymphocytes (58% to 64%; grade 3 or 4, 15% to 17%) and hemoglobin (53% to 69%; grade 3 or 4, 7% to 15%) with combination therapy with pembrolizumab; severe anemia occurred in 2.5% of patients who received enfortumab vedotin with pembrolizumab in 1 clinical trial. Decreased neutrophils occurred in 14% to 32% of patients who received enfortumab vedotin as monotherapy or in combination with pembrolizumab (grade 3 or 4, 5% to 12%).
Hypercalcemia, hyperkalemia, hypokalemia, hyponatremia, hypophosphatemia have been reported in patients with locally advanced or metastatic urothelial cancer who received enfortumab vedotin monotherapy, including decreases from baseline in phosphate (25% to 39%; grade 3 or 4, 7% to 10%), potassium (16% to 19%; grade 3 or 4, 1% to 2%), and sodium (grade 3 or 4, 7% to 8%); an increase from baseline in potassium was reported in 8% of patients who received monotherapy with enfortumab vedotin in 1 study (grade 3 or 4, 6%). Electrolyte abnormalities were more common in patients with advanced urothelial cancer treated with enfortumab vedotin in combination with pembrolizumab including decreases from baseline in sodium (46% to 60%; grade 3 or 4, 13% to 19%), phosphate (44% to 51%; grade 3 or 4, 9% to 15%), and potassium (26% to 35%; grade 3 or 4, 5% to 8%), and increases in potassium (24% to 27%; grade 3 or 4, 1% to 1.7%) and calcium (21% to 27%; grade 3 or 4, 1% to 4.2%).
Serious cases of acute kidney injury (renal failure) occurred in 2.2% to 7% of patients with locally advanced or metastatic urothelial cancer treated with enfortumab vedotin as monotherapy or in combination with pembrolizumab, including fatalities. An increase in creatinine was reported in 18% to 23% of patients receiving monotherapy with enfortumab vedotin (grade 3 or 4, 2% to 3%) and grade 3 or 4 increases in urate in 7% to 9% of patients treated with enfortumab vedotin monotherapy. Increases in creatinine were more frequent in patients with advanced urothelial cancer treated with enfortumab vedotin in combination with pembrolizumab (69% to 71%; grade 3 or 4, 3% to 3.3%); serious cases of urinary retention were also reported in 2.5% of patients who received combination therapy.
Antibody formation has been reported in patients treated with enfortumab vedotin in clinical trials. Anti-drug antibody (ADA) positivity occurred in 3.6% of patients who received enfortumab vedotin monotherapy at a dose of 1.25 mg/kg at one or more post-baseline time points (n = 617); the incidence was similar (3%) in patients treated with enfortumab vedotin in combination with pembrolizumab (n = 466). Due to the limited number of patients with ADA against enfortumab vedotin, no conclusions can be drawn concerning a potential effect of immunogenicity on efficacy, safety, or pharmacokinetics.
Pneumonitis/interstitial lung disease (ILD) occurred in 3% (grade 3 or 4, 0.8%) of patients treated with enfortumab vedotin monotherapy in clinical trials; the incidence was higher when enfortumab vedotin was given in combination with pembrolizumab (10%; grade 3 or 4, 4%). The median time to onset of any grade pneumonitis/ILD was 2.9 to 4 months. Monitor patients for signs and symptoms of pneumonitis including hypoxia, cough, dyspnea, or interstitial infiltrates on radiologic exams; evaluate and exclude other potential causes including infection and neoplasm. An interruption of therapy and possible dose reduction is necessary for patients who develop grade 2 pneumonitis; permanently discontinue therapy for patients with grade 3 or 4 pneumonitis. In individual clinical trials, the incidence of pneumonitis ranged from 2% to 4% in patients receiving enfortumab vedotin monotherapy and was 9% in patients who received combination therapy with pembrolizumab.
Musculoskeletal pain occurred in 25% (grade 3 or 4, 2%) of patients with locally advanced or metastatic urothelial cancer treated with enfortumab vedotin monotherapy in a randomized clinical trial. Arthralgia (23%; grade 3 or 4, 1.7%), myasthenia gravis (2.5%), and myositis (0.5% to 3.3%) were reported in patients treated with enfortumab vedotin in combination with pembrolizumab.
Hemorrhage/bleeding occurred in 17% (grade 3 or 4, 3%) of patients with locally advanced or metastatic urothelial cancer treated with enfortumab vedotin monotherapy in a randomized clinical trial. Serious cases of hematuria occurred in 3.3% of patients who received enfortumab vedotin in combination with pembrolizumab in 1 clinical trial.
Elevated hepatic enzymes including increased AST (12%) and increased ALT (9% to 10%) were reported in patients with locally advanced or metastatic urothelial cancer treated with enfortumab vedotin monotherapy in clinical trials; the incidence of increased AST (73% to 75%; grade 3 or 4, 5% to 9%) and ALT (59% to 60%; grade 3 or 4, 5% to 7%) was higher in patients who received treatment with enfortumab vedotin in combination with pembrolizumab.
Dizziness was reported in 23% of patients treated with enfortumab vedotin in combination with pembrolizumab in 3 cohorts of an open-label clinical trial.
Mild (grade 1 or 2) peripheral edema was reported in 26% of patient treated with enfortumab vedotin in combination with pembrolizumab in an open-label, multicohort trial.
Hypothyroidism occurred in 10% to 11% of patients with locally advanced or metastatic urothelial cancer treated with enfortumab vedotin in combination with pembrolizumab clinical trials.
Hypoalbuminemia has been reported in patients with advanced urothelial cancer treated with enfortumab vedotin in combination with pembrolizumab. A decrease from baseline in albumin concentrations occurred in 39% to 59% of patients who received combination therapy in an open-label, multicohort clinical trial (grade 3 or 4, 2% to 4.2%).
Use enfortumab vedotin with caution in patients with obesity, pre-existing hyperglycemia, or diabetes mellitus (including type 1 diabetes mellitus), or in patients at risk for these conditions; closely monitor blood glucose levels in these patients. An interruption of therapy is necessary for patients with blood glucose levels greater than 250 mg/dL. Hyperglycemia and diabetic ketoacidosis, including fatal events, has occurred in patients both with and without pre-existing diabetes who were treated with enfortumab vedotin; patients with a baseline hemoglobin A1c of 8% or higher were excluded from clinical trials. The incidence of severe hyperglycemia was consistently increased in patients with higher body mass index and in patients with higher baseline hemoglobin A1C.
Use enfortumab vedotin with caution in patients with pre-existing peripheral neuropathy. Monitor patients for symptoms of new or worsening peripheral neuropathy; an interruption of therapy, dose reduction, or discontinuation of therapy may be necessary. Peripheral neuropathy was reported in approximately half of the patients treated with enfortumab vedotin in clinical trials, including both patients with or without pre-existing peripheral neuropathy; sensory neuropathy was most common (75% of cases), with the remainder of cases consisting of muscular weakness or motor neuropathy.
Use enfortumab vedotin with caution in patients with a history of ocular disease. Monitor patients for ocular disorders, and consider artificial tears for prophylaxis of dry eyes. Ocular disorders, the majority of which involved the cornea, were reported in slightly less than half of the patients treated with enfortumab vedotin in clinical trials, including visual impairment, keratitis, keratopathy, blurred vision, limbal stem cell deficiency, increased lacrimation, and other events associated with dry eyes. Consider an ophthalmologic evaluation if ocular symptoms occur or do not resolve; ophthalmic topical steroids may be indicated after an ophthalmic exam. An interruption of therapy or dose reduction may be necessary for symptomatic ocular disorders.
Enfortumab vedotin can cause a serious rash which may be fatal, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN); these reactions primarily occurred during the first cycle of treatment, but may occur later. Dermatologic reactions occurred in approximately half of the patients treated with enfortumab vedotin monotherapy, and in 70% of patients who received enfortumab vedotin in combination with pembrolizumab in clinical trials. Closely monitor patients for skin reactions and consider appropriate treatment (e.g., topical corticosteroids and antihistamines) as clinically indicated. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for grade 2 or higher dermatologic reactions. For suspected SJS or TEN, immediately interrupt therapy and consult a specialist to confirm the diagnosis; permanently discontinue enfortumab vedotin for confirmed SJS or TEN, grade 4 skin reactions, or recurrent grade 3 skin reactions.
Ensure adequate venous access prior to starting an infusion of enfortumab vedotin and monitor for possible extravasation during administration. If extravasation occurs, stop the infusion and monitor for adverse reactions. In a pooled safety analysis, skin and soft tissue reactions secondary to extravasation were observed including erythema, swelling, increased temperature, and pain which worsened until 2 to 7 days after extravasation and resolved within 1 to 4 weeks of peak; secondary cellulitis, bullae, or exfoliation have also been reported. Extravasation reactions may be delayed.
Avoid the use of enfortumab vedotin in patients with moderate or severe hepatic disease (total bilirubin greater than 1.5 times the upper limit of normal [ULN] and any AST). Enfortumab vedotin has only been studied in few patients with moderate hepatic impairment, and has not been evaluated in patients with severe hepatic impairment. Another antibody-drug conjugate that also contains monomethyl auristatin E (MMAE) had an increased frequency of grade 3 or higher adverse reactions and deaths in patients with moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic impairment compared to patients with normal hepatic function.
Severe, life-threatening, or fatal pneumonitis/interstitial lung disease (ILD) has occurred in patients treated with enfortumab vedotin. Monitor patients for signs and symptoms of pneumonitis including hypoxia, cough, dyspnea, or interstitial infiltrates on radiologic exams; evaluate and exclude other potential causes including infection and neoplasm. An interruption of therapy and possible dose reduction is necessary for patients who develop grade 2 pneumonitis; permanently discontinue therapy for patients with grade 3 or 4 pneumonitis.
Monitor geriatric patients for an increased incidence of adverse reactions. While there were no overall differences in safety or efficacy between younger (n = 420) and older (n = 144) patients, those 75 years of age or older experienced a higher incidence of fatal adverse reactions compared to younger patients when treated with enfortumab vedotin monotherapy (11% vs. 6%) as well as in combination with pembrolizumab (7% vs. 4%).
Pregnancy should be avoided by females of reproductive potential during enfortumab vedotin treatment and for 2 months after the last dose. Although there are no adequately controlled studies in pregnant animals or humans, enfortumab vedotin can cause fetal harm or death when administered during pregnancy based on its mechanism of action and animal studies. Women who are pregnant or who become pregnant while receiving regorafenib should be apprised of the potential hazard to the fetus. In animal reproduction studies, administration of enfortumab vedotin to pregnant rats during the period of organogenesis caused maternal toxicity, embryo-fetal lethality, structural malformations (i.e., gastroschisis, malrotated hindlimb, absent forepaw, malpositioned internal organs, and fused cervical arch), and skeletal anomalies (i.e., asymmetric, fused, incompletely ossified, and misshapen sternebrae, misshapen cervical arch, and unilateral ossification of the thoracic centra) at maternal exposures approximately similar to the clinical exposures at the recommended human dose of 1.25 mg/kg. Administration to rats during 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).
Counsel patients about the reproductive risk and contraception requirements during enfortumab vedotin treatment. Enfortumab vedotin can be teratogenic if taken by the mother during pregnancy. Females of reproductive potential should avoid pregnancy and use effective contraception during and for 2 months after treatment with enfortumab vedotin. Due to the risk of male-mediated teratogenicity, males with female partners of reproductive potential should use effective contraception during and for 4 months after treatment with enfortumab vedotin. Females of reproductive potential should undergo pregnancy testing prior to initiation of enfortumab vedotin. Women who become pregnant while receiving enfortumab vedotin should be apprised of the potential hazard to the fetus. Although there are no data regarding the effect of enfortumab vedotin on human fertility, male infertility has been observed in animal studies.
Due to the potential for serious adverse reactions in nursing infants from enfortumab vedotin, advise women to discontinue breast-feeding during treatment and for 3 weeks after the final dose. It is not known whether enfortumab vedotin is present in human milk, although many drugs are excreted in human milk.
For the treatment of urothelial carcinoma:
-for the treatment of locally advanced or metastatic urothelial carcinoma in patients who have previously received a PD-1 or PD-L1 inhibitor and a platinum-containing chemotherapy, as monotherapy:
Intravenous dosage:
Adults: 1.25 mg/kg (maximum, 125 mg) IV on days 1, 8, and 15, every 28 days until disease progression or unacceptable toxicity. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Treatment with enfortumab vedotin resulted in a confirmed objective response rate of 44% (complete response, 12%) for a median duration of 7.6 months in patients with locally advanced or metastatic urothelial cancer who received prior treatment with a PD-1 or PD-L1 inhibitor and platinum-based chemotherapy in Cohort 1 of a multicenter, noncomparative trial (EV-201). At a prespecified interim analysis of a randomized, open-label, phase 3 trial (EV-301), treatment with enfortumab vedotin significantly improved the median overall survival, median progression-free survival (5.6 months vs. 3.7 months), and the overall response rate (40.6% vs. 17.9%) compared with chemotherapy in patients with locally advanced or metastatic urothelial cancer who had previously received platinum-based chemotherapy and a PD-1 or PD-L1 inhibitor; a complete response occurred in 4.9% versus 2.7% of patients, respectively.
-for the treatment of locally advanced or metastatic urothelial cancer in patients who are ineligible for cisplatin-containing chemotherapy and have previously received one or more prior lines of therapy, as monotherapy:
Intravenous dosage:
Adults: 1.25 mg/kg (maximum, 125 mg) IV on days 1, 8, and 15, every 28 days until disease progression or unacceptable toxicity. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Treatment with enfortumab vedotin resulted in a confirmed objective response rate of 51% (complete response, 22%) for a median duration of 13.8 months in patients with locally advanced or metastatic urothelial cancer who received prior treatment with a PD-1 or PD-L1 inhibitor, were ineligible for cisplatin, and did not receive platinum in the locally advanced or metastatic setting in Cohort 2 of a multicenter, noncomparative trial (EV-201).
-for the treatment of locally advanced or metastatic urothelial cancer, in combination with pembrolizumab:
Intravenous dosage:
Adults: 1.25 mg/kg (maximum, 125 mg) IV on days 1 and 8, in combination with pembrolizumab (200 mg IV repeated every 3 weeks OR 400 mg IV repeated every 6 weeks until disease progression or up to 24 months in patients without disease progression), every 21 days until disease progression or unacceptable toxicity. Administer pembrolizumab after completion of enfortumab vedotin when given on the same day. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. In a multicenter, randomized, open-label clinical trial (KEYNOTE-A39), treatment with pembrolizumab plus enfortumab vedotin significantly improved overall survival (31.5 months vs. 16.1 months), progression-free survival (12.5 months vs. 6.3 months), and objective response rate (68% vs. 44%; complete response [CR], 29% vs. 12%) compared with platinum-based chemotherapy in patients with locally advanced or metastatic urothelial cancer with no prior systemic treatment for advanced disease. In an open-label, multicohort trial (KEYNOTE-869), treatment with pembrolizumab plus enfortumab vedotin resulted in a confirmed overall response rate of 68% (CR, 12%) in 3 cohorts of patients with previously untreated locally advanced or metastatic urothelial cancer who were ineligible for cisplatin-containing chemotherapy; the median duration of response was 22.1 months in 2 cohorts and was not reached in the third.
Therapeutic Drug Monitoring:
Dosage Adjustments for Treatment-Related Toxicities: Interrupt enfortumab vedotin therapy per specific instructions below. Restart enfortumab vedotin as appropriate at the following reduced doses:
-Starting dose: 1.25 mg/kg (maximum, 125 mg)
-First dose reduction: 1 mg/kg (maximum, 100 mg)
-Second dose reduction: 0.75 mg/kg (maximum, 75 mg)
-Third dose reduction: 0.5 mg/kg (maximum, 50 mg)
Dermatologic Reactions
-Suspected Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN): Immediately interrupt enfortumab vedotin therapy and consult a specialist to confirm the diagnosis. If SJS or TEN is confirmed, permanently discontinue enfortumab vedotin; if not SJS or TEN, see management of other Grade 2 to 4 skin reactions.
-Persistent or recurrent grade 2 skin reactions: Consider an interruption of therapy. When the dermatologic reaction improves to grade 1 or less, resume treatment at the same dose or reduce the dose by 1 dose level.
-Grade 3 (severe) dermatologic reactions: Hold enfortumab vedotin therapy. When the dermatologic reaction improves to grade 1 or less, for the first occurrence treatment may be resumed at the same dose or consideration could be given to reducing the dose by one dose level; do not reduce the dose below 0.5 mg/kg (maximum, 50 mg). For a recurrence of grade 3 dermatologic reactions, permanently discontinue enfortumab vedotin.
-Grade 4 dermatologic reactions: Permanently discontinue enfortumab vedotin.
Hematologic Toxicities
-Grade 3, or Grade 2 thrombocytopenia: Hold enfortumab vedotin therapy. When the hematologic toxicity improves to grade 1 or less, treatment may be resumed at the same dose or consideration could be given to reducing the dose by one dose level; do not reduce the dose below 0.5 mg/kg (maximum, 50 mg).
-Grade 4: Hold enfortumab vedotin therapy. When the reaction improves to grade 1 or less, treatment may be resumed at a dose that has been reduced by one dose level, or discontinue treatment.
Hyperglycemia
-Blood glucose greater than 250 mg/dL: Hold enfortumab vedotin therapy. When blood glucose improves to 250 mg/dL or less, resume treatment at the same dose.
Peripheral Neuropathy
-Grade 2: Hold enfortumab vedotin therapy. When peripheral neuropathy improves to grade 1 or less, for the first occurrence treatment may be resumed at the same dose. For a recurrence, treatment should be resumed at a dose that has been reduced by one dose level; do not resume therapy in patients with recurrent grade 2 peripheral neuropathy who are unable to tolerate a dose of 0.5 mg/kg (maximum, 50 mg).
-Grade 3 or 4: Permanently discontinue enfortumab vedotin.
Pneumonitis/Interstitial Lung Disease
-Grade 2: Hold enfortumab vedotin therapy. When pneumonitis recovers to grade 1 or less, resume treatment at the same dose level or consider reducing the dose by 1 dose level and resume therapy; do not resume therapy in patients with recurrent grade 2 pneumonitis who are unable to tolerate a dose of 0.5 mg/kg (maximum, 50 mg).
-Grade 3 or 4: Permanently discontinue enfortumab vedotin.
Other Nonhematologic Toxicity
-Grade 3: Hold enfortumab vedotin therapy. When the reaction improves to grade 1 or less, treatment may be resumed at the same dose or consideration could be given to reducing the dose by one dose level; do not reduce the dose below 0.5 mg/kg (maximum, 50 mg).
-Grade 4: Permanently discontinue enfortumab vedotin.
Maximum Dosage Limits:
-Adults
1.25 mg/kg (Max: 125 mg) IV
-Geriatric
1.25 mg/kg (Max: 125 mg) IV
-Adolescents
Safety and effectiveness have not been established.
-Children
Safety and effectiveness have not been established.
Patients with Hepatic Impairment Dosing
Baseline Hepatic Impairment
-Mild hepatic impairment (total bilirubin 1.5 times the upper limit of normal [ULN] or less and any AST; or total bilirubin within normal limits and AST greater than ULN): It appears that no dose adjustment is necessary.
-Moderate to severe hepatic impairment (total bilirubin greater than 1.5 times ULN and any AST): Avoid the use of enfortumab vedotin.
Patients with Renal Impairment Dosing
Baseline Renal Impairment
-Mild (CrCl 61 to 90 mL/min), moderate (CrCl 30 to 60 mL/min), or severe (CrCl less than 30 mL/min) renal impairment: It appears that no dose adjustment is necessary.
*non-FDA-approved indication
Amoxicillin; Clarithromycin; Omeprazole: (Moderate) Closely monitor for signs of enfortumab vedotin-related adverse reactions if concurrent use with clarithromycin is necessary. Concomitant use may increase unconjugated monomethyl auristatin E (MMAE) exposure, which may increase the incidence or severity of enfortumab-vedotin toxicities. MMAE, the microtubule-disrupting component of enfortumab vedotin, is a CYP3A4 and P-gp substrate; clarithromycin is a dual P-gp/strong CYP3A4 inhibitor. Based on physiologically-based pharmacokinetic (PBPK) modeling predictions, concomitant use of enfortumab vedotin with another dual P-gp/strong CYP3A4 inhibitor is predicted to increase the exposure of unconjugated MMAE by 38%.
Atazanavir; Cobicistat: (Moderate) Closely monitor for signs of enfortumab vedotin-related adverse reactions if concurrent use with cobicistat is necessary. Concomitant use may increase unconjugated monomethyl auristatin E (MMAE) exposure, which may increase the incidence or severity of enfortumab-vedotin toxicities. MMAE, the microtubule-disrupting component of enfortumab vedotin, is a CYP3A4 and P-gp substrate; cobicistat is a dual P-gp/strong CYP3A4 inhibitor. Based on physiologically-based pharmacokinetic (PBPK) modeling predictions, concomitant use of enfortumab vedotin with another dual P-gp/strong CYP3A4 inhibitor is predicted to increase the exposure of unconjugated MMAE by 38%.
Cholera Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the live cholera vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to cholera bacteria after receiving the vaccine.
Clarithromycin: (Moderate) Closely monitor for signs of enfortumab vedotin-related adverse reactions if concurrent use with clarithromycin is necessary. Concomitant use may increase unconjugated monomethyl auristatin E (MMAE) exposure, which may increase the incidence or severity of enfortumab-vedotin toxicities. MMAE, the microtubule-disrupting component of enfortumab vedotin, is a CYP3A4 and P-gp substrate; clarithromycin is a dual P-gp/strong CYP3A4 inhibitor. Based on physiologically-based pharmacokinetic (PBPK) modeling predictions, concomitant use of enfortumab vedotin with another dual P-gp/strong CYP3A4 inhibitor is predicted to increase the exposure of unconjugated MMAE by 38%.
Cobicistat: (Moderate) Closely monitor for signs of enfortumab vedotin-related adverse reactions if concurrent use with cobicistat is necessary. Concomitant use may increase unconjugated monomethyl auristatin E (MMAE) exposure, which may increase the incidence or severity of enfortumab-vedotin toxicities. MMAE, the microtubule-disrupting component of enfortumab vedotin, is a CYP3A4 and P-gp substrate; cobicistat is a dual P-gp/strong CYP3A4 inhibitor. Based on physiologically-based pharmacokinetic (PBPK) modeling predictions, concomitant use of enfortumab vedotin with another dual P-gp/strong CYP3A4 inhibitor is predicted to increase the exposure of unconjugated MMAE by 38%.
Darunavir; Cobicistat: (Moderate) Closely monitor for signs of enfortumab vedotin-related adverse reactions if concurrent use with cobicistat is necessary. Concomitant use may increase unconjugated monomethyl auristatin E (MMAE) exposure, which may increase the incidence or severity of enfortumab-vedotin toxicities. MMAE, the microtubule-disrupting component of enfortumab vedotin, is a CYP3A4 and P-gp substrate; cobicistat is a dual P-gp/strong CYP3A4 inhibitor. Based on physiologically-based pharmacokinetic (PBPK) modeling predictions, concomitant use of enfortumab vedotin with another dual P-gp/strong CYP3A4 inhibitor is predicted to increase the exposure of unconjugated MMAE by 38%.
Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Moderate) Closely monitor for signs of enfortumab vedotin-related adverse reactions if concurrent use with cobicistat is necessary. Concomitant use may increase unconjugated monomethyl auristatin E (MMAE) exposure, which may increase the incidence or severity of enfortumab-vedotin toxicities. MMAE, the microtubule-disrupting component of enfortumab vedotin, is a CYP3A4 and P-gp substrate; cobicistat is a dual P-gp/strong CYP3A4 inhibitor. Based on physiologically-based pharmacokinetic (PBPK) modeling predictions, concomitant use of enfortumab vedotin with another dual P-gp/strong CYP3A4 inhibitor is predicted to increase the exposure of unconjugated MMAE by 38%.
Dengue Tetravalent Vaccine, Live: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the dengue virus vaccine. When feasible, administer indicated vaccines at least 2 weeks prior to initiating immunosuppressant medications. If vaccine administration is necessary, consider revaccination following restoration of immune competence. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure after receiving the vaccine.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Moderate) Closely monitor for signs of enfortumab vedotin-related adverse reactions if concurrent use with cobicistat is necessary. Concomitant use may increase unconjugated monomethyl auristatin E (MMAE) exposure, which may increase the incidence or severity of enfortumab-vedotin toxicities. MMAE, the microtubule-disrupting component of enfortumab vedotin, is a CYP3A4 and P-gp substrate; cobicistat is a dual P-gp/strong CYP3A4 inhibitor. Based on physiologically-based pharmacokinetic (PBPK) modeling predictions, concomitant use of enfortumab vedotin with another dual P-gp/strong CYP3A4 inhibitor is predicted to increase the exposure of unconjugated MMAE by 38%.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Closely monitor for signs of enfortumab vedotin-related adverse reactions if concurrent use with cobicistat is necessary. Concomitant use may increase unconjugated monomethyl auristatin E (MMAE) exposure, which may increase the incidence or severity of enfortumab-vedotin toxicities. MMAE, the microtubule-disrupting component of enfortumab vedotin, is a CYP3A4 and P-gp substrate; cobicistat is a dual P-gp/strong CYP3A4 inhibitor. Based on physiologically-based pharmacokinetic (PBPK) modeling predictions, concomitant use of enfortumab vedotin with another dual P-gp/strong CYP3A4 inhibitor is predicted to increase the exposure of unconjugated MMAE by 38%.
Grapefruit juice: (Major) Advise patients to avoid grapefruit juice while taking enfortumab vedotin due to a likely increased risk of exposure to unconjugated monomethyl auristatin E (MMAE), which may increase the incidence or severity of enfortumab-vedotin toxicities. MMAE, the microtubule-disrupting component of enfortumab vedotin, is a CYP3A4 and P-gp substrate; grapefruit juice is a dual P-gp/strong CYP3A4 inhibitor.
Itraconazole: (Moderate) Closely monitor for signs of enfortumab vedotin-related adverse reactions if concurrent use with itraconazole is necessary. Concomitant use may increase unconjugated monomethyl auristatin E (MMAE) exposure, which may increase the incidence or severity of enfortumab-vedotin toxicities. MMAE, the microtubule-disrupting component of enfortumab vedotin, is a CYP3A4 and P-gp substrate; itraconazole is a dual P-gp/strong CYP3A4 inhibitor. Based on physiologically-based pharmacokinetic (PBPK) modeling predictions, concomitant use of enfortumab vedotin with another dual P-gp/strong CYP3A4 inhibitor is predicted to increase the exposure of unconjugated MMAE by 38%.
Ketoconazole: (Moderate) Closely monitor for signs of enfortumab vedotin-related adverse reactions if concurrent use with ketoconazole is necessary. Concomitant use may increase unconjugated monomethyl auristatin E (MMAE) exposure, which may increase the incidence or severity of enfortumab-vedotin toxicities. MMAE, the microtubule-disrupting component of enfortumab vedotin, is a CYP3A4 and P-gp substrate; ketoconazole is a dual P-gp/strong CYP3A4 inhibitor. Based on physiologically-based pharmacokinetic (PBPK) modeling predictions, concomitant use of enfortumab vedotin with another dual P-gp/strong CYP3A4 inhibitor is predicted to increase the exposure of unconjugated MMAE by 38%.
Lansoprazole; Amoxicillin; Clarithromycin: (Moderate) Closely monitor for signs of enfortumab vedotin-related adverse reactions if concurrent use with clarithromycin is necessary. Concomitant use may increase unconjugated monomethyl auristatin E (MMAE) exposure, which may increase the incidence or severity of enfortumab-vedotin toxicities. MMAE, the microtubule-disrupting component of enfortumab vedotin, is a CYP3A4 and P-gp substrate; clarithromycin is a dual P-gp/strong CYP3A4 inhibitor. Based on physiologically-based pharmacokinetic (PBPK) modeling predictions, concomitant use of enfortumab vedotin with another dual P-gp/strong CYP3A4 inhibitor is predicted to increase the exposure of unconjugated MMAE by 38%.
Levoketoconazole: (Moderate) Closely monitor for signs of enfortumab vedotin-related adverse reactions if concurrent use with ketoconazole is necessary. Concomitant use may increase unconjugated monomethyl auristatin E (MMAE) exposure, which may increase the incidence or severity of enfortumab-vedotin toxicities. MMAE, the microtubule-disrupting component of enfortumab vedotin, is a CYP3A4 and P-gp substrate; ketoconazole is a dual P-gp/strong CYP3A4 inhibitor. Based on physiologically-based pharmacokinetic (PBPK) modeling predictions, concomitant use of enfortumab vedotin with another dual P-gp/strong CYP3A4 inhibitor is predicted to increase the exposure of unconjugated MMAE by 38%.
Lonafarnib: (Moderate) Closely monitor for signs of enfortumab vedotin-related adverse reactions if concurrent use with lonafarnib is necessary. Concomitant use may increase unconjugated monomethyl auristatin E (MMAE) exposure, which may increase the incidence or severity of enfortumab-vedotin toxicities. MMAE, the microtubule-disrupting component of enfortumab vedotin, is a CYP3A4 and P-gp substrate; lonafarnib is a dual P-gp/strong CYP3A4 inhibitor. Based on physiologically-based pharmacokinetic (PBPK) modeling predictions, concomitant use of enfortumab vedotin with another dual P-gp/strong CYP3A4 inhibitor is predicted to increase the exposure of unconjugated MMAE by 38%.
Lopinavir; Ritonavir: (Moderate) Closely monitor for signs of enfortumab vedotin-related adverse reactions if concurrent use with ritonavir is necessary. Concomitant use may increase unconjugated monomethyl auristatin E (MMAE) exposure, which may increase the incidence or severity of enfortumab-vedotin toxicities. MMAE, the microtubule-disrupting component of enfortumab vedotin, is a CYP3A4 and P-gp substrate; ritonavir is a dual P-gp/strong CYP3A4 inhibitor. Based on physiologically-based pharmacokinetic (PBPK) modeling predictions, concomitant use of enfortumab vedotin with another dual P-gp/strong CYP3A4 inhibitor is predicted to increase the exposure of unconjugated MMAE by 38%.
Mifepristone: (Moderate) Closely monitor for signs of enfortumab vedotin-related adverse reactions if concurrent use with mifepristone is necessary. Concomitant use may increase unconjugated monomethyl auristatin E (MMAE) exposure, which may increase the incidence or severity of enfortumab-vedotin toxicities. MMAE, the microtubule-disrupting component of enfortumab vedotin, is a CYP3A4 and P-gp substrate; mifepristone is a dual P-gp/strong CYP3A4 inhibitor. Based on physiologically-based pharmacokinetic (PBPK) modeling predictions, concomitant use of enfortumab vedotin with another dual P-gp/strong CYP3A4 inhibitor is predicted to increase the exposure of unconjugated MMAE by 38%. The clinical significance of this interaction with the short-term use of mifepristone for termination of pregnancy is unknown.
Nelfinavir: (Moderate) Closely monitor for signs of enfortumab vedotin-related adverse reactions if concurrent use with nelfinavir is necessary. Concomitant use may increase unconjugated monomethyl auristatin E (MMAE) exposure, which may increase the incidence or severity of enfortumab-vedotin toxicities. MMAE, the microtubule-disrupting component of enfortumab vedotin, is a CYP3A4 and P-gp substrate; nelfinavir is a dual P-gp/strong CYP3A4 inhibitor. Based on physiologically-based pharmacokinetic (PBPK) modeling predictions, concomitant use of enfortumab vedotin with another dual P-gp/strong CYP3A4 inhibitor is predicted to increase the exposure of unconjugated MMAE by 38%.
Nirmatrelvir; Ritonavir: (Moderate) Closely monitor for signs of enfortumab vedotin-related adverse reactions if concurrent use with ritonavir is necessary. Concomitant use may increase unconjugated monomethyl auristatin E (MMAE) exposure, which may increase the incidence or severity of enfortumab-vedotin toxicities. MMAE, the microtubule-disrupting component of enfortumab vedotin, is a CYP3A4 and P-gp substrate; ritonavir is a dual P-gp/strong CYP3A4 inhibitor. Based on physiologically-based pharmacokinetic (PBPK) modeling predictions, concomitant use of enfortumab vedotin with another dual P-gp/strong CYP3A4 inhibitor is predicted to increase the exposure of unconjugated MMAE by 38%.
Posaconazole: (Moderate) Closely monitor for signs of enfortumab vedotin-related adverse reactions if concurrent use with posaconazole is necessary. Concomitant use may increase unconjugated monomethyl auristatin E (MMAE) exposure, which may increase the incidence or severity of enfortumab-vedotin toxicities. MMAE, the microtubule-disrupting component of enfortumab vedotin, is a CYP3A4 and P-gp substrate; posaconazole is a dual P-gp/strong CYP3A4 inhibitor. Based on physiologically-based pharmacokinetic (PBPK) modeling predictions, concomitant use of enfortumab vedotin with another dual P-gp/strong CYP3A4 inhibitor is predicted to increase the exposure of unconjugated MMAE by 38%.
Ritonavir: (Moderate) Closely monitor for signs of enfortumab vedotin-related adverse reactions if concurrent use with ritonavir is necessary. Concomitant use may increase unconjugated monomethyl auristatin E (MMAE) exposure, which may increase the incidence or severity of enfortumab-vedotin toxicities. MMAE, the microtubule-disrupting component of enfortumab vedotin, is a CYP3A4 and P-gp substrate; ritonavir is a dual P-gp/strong CYP3A4 inhibitor. Based on physiologically-based pharmacokinetic (PBPK) modeling predictions, concomitant use of enfortumab vedotin with another dual P-gp/strong CYP3A4 inhibitor is predicted to increase the exposure of unconjugated MMAE by 38%.
Saquinavir: (Moderate) Closely monitor for signs of enfortumab vedotin-related adverse reactions if concurrent use with saquinavir is necessary. Concomitant use may increase unconjugated monomethyl auristatin E (MMAE) exposure, which may increase the incidence or severity of enfortumab-vedotin toxicities. MMAE, the microtubule-disrupting component of enfortumab vedotin, is a CYP3A4 and P-gp substrate; saquinavir is a dual P-gp/strong CYP3A4 inhibitor. Based on physiologically-based pharmacokinetic (PBPK) modeling predictions, concomitant use of enfortumab vedotin with another dual P-gp/strong CYP3A4 inhibitor is predicted to increase the exposure of unconjugated MMAE by 38%.
SARS-CoV-2 (COVID-19) vaccines: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) Adenovirus Vector Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) mRNA Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) Recombinant Spike Protein Nanoparticle Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
Tucatinib: (Moderate) Closely monitor for signs of enfortumab vedotin-related adverse reactions if concurrent use with tucatinib is necessary. Concomitant use may increase unconjugated monomethyl auristatin E (MMAE) exposure, which may increase the incidence or severity of enfortumab-vedotin toxicities. MMAE, the microtubule-disrupting component of enfortumab vedotin, is a CYP3A4 and P-gp substrate; tucatinib is a dual P-gp/strong CYP3A4 inhibitor. Based on physiologically-based pharmacokinetic (PBPK) modeling predictions, concomitant use of enfortumab vedotin with another dual P-gp/strong CYP3A4 inhibitor is predicted to increase the exposure of unconjugated MMAE by 38%.
Vonoprazan; Amoxicillin; Clarithromycin: (Moderate) Closely monitor for signs of enfortumab vedotin-related adverse reactions if concurrent use with clarithromycin is necessary. Concomitant use may increase unconjugated monomethyl auristatin E (MMAE) exposure, which may increase the incidence or severity of enfortumab-vedotin toxicities. MMAE, the microtubule-disrupting component of enfortumab vedotin, is a CYP3A4 and P-gp substrate; clarithromycin is a dual P-gp/strong CYP3A4 inhibitor. Based on physiologically-based pharmacokinetic (PBPK) modeling predictions, concomitant use of enfortumab vedotin with another dual P-gp/strong CYP3A4 inhibitor is predicted to increase the exposure of unconjugated MMAE by 38%.
Enfortumab vedotin is a Nectin-4-directed antibody-drug conjugate (ADC) consisting of 3 components including the fully human IgG1 kappa antibody anti-Nectin-4 (ACS-22C3); the small molecule microtubule disrupting agent monomethyl auristatin E (MMAE); and a protease-cleavable maleimidocaproyl valine-citrulline linker that attaches MMAE to ACS-22C3 (SGD-1006). Conjugation takes place on cysteine residues that comprise the interchain disulfide bonds of the antibody to yield a drug-to-antibody ratio of approximately 3.8 to 1. Nectin-4 is an adhesion protein located on the surface of cells. Nonclinical data suggest that the anticancer activity of enfortumab vedotin is due to the binding of the ADC to Nectin-4-expressing cells, followed by the internalization of the ADC-Nectin-4 complex and the release of MMAE via proteolytic cleavage. MMAE binds to tubulin and disrupts the microtubule network within the cell, inducing cell cycle arrest and apoptotic death of the cells. Combination therapy with a PD-1 blocking antibody results in upregulation of immune function and increased antitumor activity in syngeneic mouse tumor models expressing Nectin-4.
Enfortumab vedotin is administered intravenously. In vitro, plasma protein binding of unconjugated monomethyl auristatin E (MMAE) ranged from 68% to 82%. The estimated mean steady-state volume of distribution of the antibody-drug conjugate (ADC) was 12.8 liters. Both the ADC and MMAE exhibit multi-exponential declines with an elimination half-life of 3.6 days and 2.6 days, respectively. The mean clearance of enfortumab vedotin was 0.11 liters/hour, and the mean clearance of unconjugated MMAE was 2.11 liters/hour. Steady-state concentrations of the ADC were reached after 1 treatment cycle for the ADC as a single agent and in combination with pembrolizumab. The excretion of enfortumab vedotin is not fully characterized; elimination of unconjugated MMAE appears to be limited by its rate of release from enfortumab vedotin. Following a single dose of another ADC containing unconjugated MMAE, 17% of the total unconjugated MMAE administered was recovered in feces and 6% in urine over a 1-week period, primarily as unchanged drug. A similar excretion profile of unconjugated MMAE is expected after enfortumab vedotin administration.
Affected cytochrome P450 isoenzymes and drug transporters: CYP3A4, P-glycoprotein (P-gp)
The catabolism of enfortumab vedotin has not been studied in humans, but it is expected to undergo catabolism to small peptides, amino acids, unconjugated MMAE, and unconjugated MMAE-related catabolites. Enfortumab vedotin releases MMAE via proteolytic cleavage. Unconjugated MMAE is primarily metabolized by CYP3A4 in vitro, but is also a substrate of P-gp. Clinical trials evaluating the drug-drug interaction potential of enfortumab vedotin have not been conducted. However, in physiologically based pharmacokinetic (PBPK) modeling predictions, concomitant use with dual P-gp and strong CYP3A4 inhibitors is predicted to increase the Cmax and AUC of unconjugated MMAE by 15% and 38%, respectively. Concomitant use with dual P-gp and strong CYP3A4 inducers is predicted to decrease the Cmax and AUC of unconjugated MMAE by 28% and 53%, respectively. Enfortumab vedotin is not predicted to affect exposure to sensitive CYP3A substrates.
-Route-Specific Pharmacokinetics
Intravenous Route
The mean Cmax of ADC after the first treatment cycle was 28 mcg/mL (+/- 6.1 mcg/mL); the mean Cmax of unconjugated MMAE was 5.5 ng/mL (+/- 3 ng/mL). Peak ADC concentrations were observed near the end of the IV infusion, while peak unconjugated MMAE concentrations were observed approximately 2 days after enfortumab vedotin dosing. The mean AUC of ADC after the first cycle of treatment was 110 mcg x day/mL (+/- 26 mcg x day/mL); the mean AUC of unconjugated MMAE was 85 ng x day/mL (+/- 50 ng x day/mL). The mean pre-dose (trough) concentration of ADC on day 28 after the first cycle of treatment was 0.31 mcg/mL (+/- 0.18 mcg/mL); the mean pre-dose concentration of unconjugated MMAE on day 28 was 0.81 ng/mL (+/- 0.88 ng/mL), respectively. Minimal accumulation of the ADC and unconjugated MMAE was observed following repeat administration. The exposure-response relationship for efficacy has not been fully characterized.
-Special Populations
Hepatic Impairment
Mild hepatic impairment (total bilirubin 1 to 1.5 times the upper limit of normal [ULN] and any AST; OR total bilirubin less than or equal to ULN and AST greater than UNL) does not have a clinically significant effect on the pharmacokinetics of enfortumab vedotin or unconjugated MMAE. The effect of moderate or severe hepatic impairment (total bilirubin greater than 1.5 times ULN and any AST) on the pharmacokinetics of enfortumab vedotin or unconjugated MMAE is unknown.
Renal Impairment
Renal impairment does not have a clinically significant effect on the pharmacokinetics of enfortumab vedotin or unconjugated MMAE. The effect of end-stage renal disease (ESRD) with or without dialysis on the pharmacokinetics of enfortumab vedotin or unconjugated MMAE is unknown.
Geriatric
Age (24 to 90 years) does not have a clinically significant effect on the pharmacokinetics of enfortumab vedotin or unconjugated MMAE.
Gender Differences
Gender does not have a clinically significant effect on the pharmacokinetics of enfortumab vedotin or unconjugated MMAE.
Ethnic Differences
Race/ethnicity (Caucasian, Asian, or Black) does not have a clinically significant effect on the pharmacokinetics of enfortumab vedotin or unconjugated MMAE.