Enfortumab Vedotin - Urothelial Cancer

Overview:

Individuals with bladder cancer and urinary tract (ureter, renal pelvis, or urethra) cancer that has spread or cannot be surgically removed can be treated with the prescription drug Enfortumab vedotin. The drug may be used if the patients have received platinum-containing chemotherapy and immunotherapy or have undergone one or more prior therapies and are ineligible to receive chemotherapy that involves the drug Cisplatin.

In such cases, an antibody-drug combination called Enfortumab vedotin is used to treat individuals with progressive, treatment-resistant urothelial malignancies. Monomethyl auristatin E (MMAE), a microtubule-disrupting chemotherapeutic drug and a completely human monoclonal antibody directed against Nectin-4, are connected by a protease-cleavable link. It is comparable to Brentuximab vedotin, another MMAE-conjugated antibody that targets CD-30 rather than Nectin-4.

Enfortumab vedotin was clinically developed as a consequence of a partnership between Astellas Pharma, a Japanese multinational pharmaceutical company, and Seattle Genetics, now known as Seagen, an American biotechnology company. It received its first approval to be used in the United States in December 2019 under the brand name PadcevTM. Later, in April 2022, the European Commission gave its approval to Enfortumab vedotin. The second targeted medication to be authorized for the treatment of advanced bladder cancer in 2019 was Enfortumab vedotin. Erdafitinib received fast approval from the FDA (United States Food and Drug Administration) earlier.

How Does Enfortumab Vedotin Work?

An antibody-drug combination called Enfortumab vedotin has several parts. Monomethyl auristatin E (MMAE), a chemotherapeutic microtubule-disrupting drug, is linked to a completely human monoclonal antibody directed against Nectin-4, an extracellular adhesion protein that is significantly expressed in urothelial malignancies. A linker that can be broken down by proteases connects these two parts. Nectin-4-expressing cells bind to Enfortumab vedotin, and the resulting Enfortumab-Nectin-4 complex is internalized by the cell. Once inside the cell, MMAE is liberated from Enfortumab vedotin through proteolytic cleavage, which disrupts the microtubule network, stops the cell cycle, and eventually triggers apoptosis.

Enfortumab vedotin, the active ingredient in Padcev, is made up of an antibody which is a type of protein and another molecule known as MMAE (monomethyl auristatin E). Before entering cancer cells, the antibody first binds to a protein on its surface. Once the active ingredient is inside the cells, MMAE disturbs the internal skeleton of the cells, leading to cell death and assisting in preventing cancer from worsening or spreading.

Indications for Usage:

Enfortumab vedotin is indicated to be used in adults patients with locally advanced or metastatic urothelial carcinoma who have previously had chemotherapy that contains a platinum-containing chemotherapy regimen and a PD-1 or PD-L1 inhibitor in the neoadjuvant or adjuvant, locally advanced, or metastatic setting or are ineligible for chemotherapy that contains Cisplatin and has already received one or more previous lines of treatment.

Dosage of Enfortumab Vedotin:

The prescribed dose of Enfortumab vedotin is such that on days first, eighth, and fifteenth of a 28-day cycle, an intravenous infusion should be given for 30 minutes at a dose of 1.25 mg/kg (milligram/kilogram) of the drug up to a limit of 125 mg for patients under or of 100 kilograms until disease progression or intolerable toxicity occurs.

What Are the Contraindications of the Drug?

There are no contraindications for this drug.

Warnings and Precautions:

1. Skin Reactions

   Patients receiving Enfortumab vedotin experienced severe cutaneous adverse effects, including fatal occurrences of Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN). The first phase of treatment was when Stevens-Johnson syndrome and toxic epidermal necrolysis predominantly occurred; however, they could happen later too. Out of the 680 patients receiving the drug treatment in clinical trials, 55 percent experienced skin responses; 33 percent of patients felt pruritus, and 23 percent of patients had a maculopapular rash, 13 percent of the patients experienced grade 3 to 4 skin responses, including maculopapular rash, erythematous rash, symmetrical drug-related intertriginous and flexural exanthema (SDRIFE), drug eruption, bullous dermatitis, exfoliative dermatitis, and palmar-plantar erythrodysesthesia. The median period for the emergence of serious cutaneous responses in clinical studies was six months. Patients who had a skin reaction that caused a dose interruption and then continued Enfortumab vedotin suffered recurrent serious skin reactions in 24 percent of cases when resuming at the same dose and in 16 percent of cases when starting at a lower dose. Throughout treatment, a watchful eye should be kept on the patients for any skin responses. If clinically necessary, take into account topical corticosteroids and antihistamines. Enfortumab vedotin should be withheld, and refer patients who appear to have Stevens-Johnson syndrome, toxic epidermal necrolysis, or severe skin reactions for expert care. Patients with proven Stevens-Johnson syndrome or toxic epidermal necrolysis, as well as grade 4 or repeated grade 3 skin reactions, should permanently stop taking Enfortumab vedotin.

2. Peripheral Neuropathy

   52 percent of the 680 patients who received the drug in clinical trials developed peripheral neuropathy, including 39 percent who had sensory neuropathy, 7 percent who had muscle weakness, and 6 percent who had motor neuropathy; 4 percent had grade 3 to 4 responses. Patients receiving Enfortumab vedotin experienced peripheral neuropathy, irrespective of whether they already had it. It took four months on average for grade 2 peripheral neuropathy to start. Five percent of people with neuropathy stopped their medications. When peripheral neuropathy manifests, patients should be closely watched for any new or worsening symptoms, and the dose of the drug should be interrupted or reduced. Individuals who experience greater than grade 3 peripheral neuropathy, cease the administration of the drug permanently.

3. Hyperglycemia

   Patients receiving Enfortumab vedotin developed diabetic ketoacidosis, hyperglycemia, and some fatal episodes with or without diabetes mellitus history. In clinical studies, 7 percent of the 680 patients receiving Enfortumab vedotin experienced grade 3 to 4 hyperglycemia, making up about 14 percent of the patients who acquired hyperglycemia. Patients with greater body mass indexes and patients with elevated baseline A1Cs experienced a rise in the incidence of grade 3 to 4 hyperglycemia over time. For the treatment of hyperglycemia, 5 percent of patients required the start of insulin therapy. The median amount of time before hyperglycemia appeared was six months. Six percent of the patient population had their drug treatment stopped due to hyperglycemia. Patients with diabetes mellitus or those who are at risk for it should have their blood sugar levels closely monitored. Withhold Enfortumab vedotin if blood sugar is raised more than 250 mg/dL.

4. Ocular Disorders

   In clinical studies with planned ophthalmologic exams, patients receiving Enfortumab vedotin treatment with ocular problems were reported in 40 percent of cases. Most of these incidents affected the cornea and were related to dry eye, including keratitis, impaired vision, elevated lacrimation, conjunctivitis, limbal stem cell insufficiency, and keratopathy. During therapy with Enfortumab vedotin, dry eye symptoms appeared in 34 percent of patients and impaired vision in 13 percent of patients. It took an average of one and a half months for symptoms of eye disease to appear. Keep an eye out for eye problems with patients. Consider using artificial tears to prevent dry eyes and get an eye exam if any ocular symptoms arise or do not go away. After an eye exam, if therapy with topical ophthalmic steroids is recommended, do so. For symptomatic ocular illnesses, pausing the Enfortumab vedotin dose or dose-decrease may be an option.

5. Pneumonitis

   Pneumonitis that was severe, deadly, or life-threatening occurred in some individuals receiving Enfortumab vedotin. In clinical studies, 3.1 percent of the 680 patients who received the drug treatment suffered pneumonitis of any grade, and 0.7 percent had grade 3 to 4 pneumonitis. The median time to onset of pneumonitis in clinical trials was around three months. Watch for signs and symptoms of pneumonitis in patients, such as dyspnea, coughing, hypoxia, and interstitial infiltrates, on radiological tests. By doing the necessary investigations, determine and rule out infectious, neoplastic, and other reasons for these signs and symptoms. Withhold Enfortumab vedotin in patients who experience recurring or persistent grade 2 pneumonitis, and think about lowering the dose. In all patients with pneumonitis of grade 3 or 4, Enfortumab vedotin should be permanently discontinued.

6. Toxicity to the Fetus or Embryo

   According to its method of action and its results in animals, Enfortumab vedotin can harm an unborn child if it is given to a pregnant woman. Enfortumab vedotin administration to pregnant rats during the organogenesis phase resulted in maternal toxicity, structural malformations, embryo-fetal lethality, and skeletal anomalies at maternal exposures that were roughly comparable to the clinical exposures at the advised human dose of 1.25 mg/kg. Inform patients of any potential fetal risk. Inform female patients who are capable of becoming pregnant to use reliable contraception for the duration of their Enfortumab vedotin treatment, and for two months following the final dosage. Male patients should be advised of the usage of reliable contraception while using Enfortumab vedotin, and for four months following the final dosage if they have female partners who are able to become pregnant.

7. Extravasation at the Infusion Site

   After the administration of Enfortumab vedotin, extravasation-related skin, and soft tissue responses have been noted. 1.6 percent of the 680 patients had soft tissue and skin reactions, with 0.3 percent having grade 3 to 4 reactions. Reactions could be slow. Pain, erythema, edema, and elevated body temperature all get worse until two to seven days following extravasation, and then go away within one to four weeks of the peak symptoms. Extravasation responses with subsequent cellulitis, exfoliation, or bullae occurred in two patients. Before beginning Enfortumab vedotin, make sure one has sufficient venous access and keep an eye out for any extravasation that might occur. Stop the infusion if extravasation occurs, and keep an eye out for any negative effects.

Adverse Reactions to Enfortumab Vedotin:

The following serious adverse reactions are described as well:

• Body rash.

• Variations in kidney and liver function tests.

• A rise in blood sugar (glucose) levels.

• Fatigue.

• Muscle weakness or numbness in hands, feet, or other body parts.

• Reduced red blood cell, platelet, and white blood cell numbers.

• Hair fall.

• A decline in appetite.

• Vomiting.

• Reduced levels of albumin, sodium, and phosphate in the blood.

• Tingling.

• Alteration in taste.

• Elevated blood uric acid levels.

• A rise in lipase (a blood test done to check the pancreas).

• Loss of weight.

• Dry skin.

The healthcare practitioner may lower the dose, or temporarily or permanently discontinue the drug treatment if the patient experiences specific side effects. Males who have Enfortumab vedotin may experience issues with their fertility, which could impact their ability to have children. If you have questions concerning fertility, consult your doctor.

For Patients:

What Is Urothelial Cancer?

When the cells that form the urinary bladder begin to proliferate out of control, bladder cancer develops. A tumor can emerge when additional cancer cells grow, and over time, that tumor may spread to other areas of the body. The most typical type of bladder cancer is urothelial carcinoma. Urothelial carcinoma is virtually always the type of bladder cancer that patients have. Urothelial cells, which line the ureter, bladder, urethra, renal pelvis, and several other organs, are where cancer develops first. Transitional cells are another name for urothelial cells. These cells can stretch and alter their shape without disintegrating. Urothelial cancer is also known as cancer of transitional cells. The renal pelvis, which is the portion of the kidney that links to the ureter and the urethra, is all lined by urothelial cells. The entire urinary tract needs to be investigated for tumors because bladder cancer patients occasionally have them in these sites as well.

What Causes Urothelial Cancer?

The specific cause of the majority of bladder malignancies is unknown. However, researchers have identified several risk factors, and are beginning to comprehend how they lead to cancerous bladder cells. Regular bladder cells can become cancerous if specific DNA (deoxyribonucleic acid) alterations cause them to proliferate abnormally. Our genes, which regulate how our cells work, are made up of DNA, a material found in our cells. Our parents are the origin of our DNA, so we typically resemble them, but DNA has an effect on more than just our looks. Some genes regulate the growth, division, and death of cells. Oncogenes are genes that aid in cell growth, division, and survival. Tumor suppressor genes are those that normally assist in regulating cell division, correcting DNA errors, or causing cells to die at the appropriate moment. DNA alterations or gene mutations that activate oncogenes or silence tumor suppressor genes that can result in cancer. For a cell to develop into cancer, several distinct gene alterations are often required.

The majority of bladder cancer-related gene alterations are acquired rather than inherited before birth. A few of these acquired gene alterations are the result of radiation or chemical exposure that causes cancer. For instance, the chemicals in cigarette smoke. The bladder may be exposed to other substances in the same way. Gene alterations, however, may occasionally merely pose arbitrary cellular occurrences with no external cause. Not everyone experiences the same gene alterations that cause bladder cancer. Some bladder tumors are thought to be influenced by acquired alterations in specific genes.

There is no evidence that inherited genetic mutations are a substantial contributor to bladder cancer, and the disease does not frequently run in families. Some individuals appear to be born with a decreased capacity to detoxify or break down and eliminate specific classes of cancer-causing substances. These people are more susceptible to the cancer-causing effects of industrial toxins and tobacco smoke.

What Are the Signs and Symptoms Seen?

• Hematuria, or the presence of blood in urine, is the initial indicator of bladder cancer. If there is enough blood, the urine may turn pink, orange-pink, or dark red. Sometimes, when a urine test (urinalysis) is performed due to various symptoms or as part of a general medical examination, minute traces of blood are discovered despite the urine's normal color.

• More frequent urination than normal.

• Having pain or burning sensation while urinating.

• Having the urge to pee immediately even though the bladder is not full.

• Having a weak pee stream or having difficulty urinating.

• Wake up very frequently through the night to use the restroom.

• One sided or lower back discomfort.

• Appetite and weight loss.

• Being worn out or fragile.

• Inflammation in the feet.

• Bone pain.

A lot of symptoms among these are more likely to be brought on by other conditions than by bladder cancer, but it is still vital to get them evaluated. The practitioner will use one or more examinations or tests to determine whether someone has bladder cancer or something else if there is a reason to believe they might have the disease.

How Is Urothelial Cancer Diagnosed?

Cancer can be detected by conducting a complete medical history taking, and physical examination along with a urine laboratory test. Cystoscopy is also conducted, where a cystoscope is inserted to check for tissue proliferation. Transurethral resection of bladder tumor (TURBT) is the method performed to biopsy an abnormal area. Other imaging tests such as CT (computed tomography) scans and magnetic resonance imaging (MRI) scans are performed along with ultrasounds, X-rays, and bone scans.

What Is the Treatment for Urothelial Cancer?

The optimal solution frequently entails a combination of different types of treatments. Most bladder malignancies are treated with surgery, either by itself or in combination with other therapies. Bladder tumors that are in the early stages can frequently be eliminated. However, a significant concern for those with early-stage bladder cancer is the propensity for new tumors to develop over time in other bladder regions. One option to prevent this is to remove the entire bladder (a procedure known as a radical cystectomy), but this has serious side effects. Other therapies may be done to try to lower the risk of future malignancies if the whole bladder is not removed. Close follow-up is required to look for indications of new bladder malignancies and whether or not additional therapies are to be administered.

More About the Drug:

What Is the Dosage Form of the Drug and Its Strength?

Twenty milligrams and thirty milligrams of Enfortumab vedotin-ejfv are available for injection as a white to off-white lyophilized powder in a single-dose vial.

Dosage and Administration of the Drug:

1. What Is the Recommended Dosage?

   On days one, eight, and fifteen of a 28-day cycle, an intravenous infusion should be given for 30 minutes at a dose of 1.25 mg/kg of Enfortumab vedotin up to a maximum dose of 125 mg for patients under 100 kg until disease progression or intolerable toxicity occurs.

2. Directions for Administration and Preparation:

   Enfortumab vedotin is a dangerous medicine; it should only be administered intravenously. Observe any particular handling or disposal instructions that may apply. Sterile water for injection is used to rehydrate the Enfortumab vedotin vial before administration. An intravenous infusion package containing either 5 percent dextrose injection, USP, 0.9 percent sodium chloride injection, USP, or lactated Ringer's injection, USP, is used to subsequently dilute the reconstituted solution.

Reconstitution in a Vial for a Single Dose

1. Comply with the required handling and disposal procedures for anti-cancer medications.
2. When preparing and reconstituting dosage solutions, use the proper aseptic methods.
3. Determine the required quantity and vial strength (20 mg or 30 mg) using the suggested dose and the patient's weight.
4. Reconstitute each vial as follows, making sure to aim the SWFI stream at the walls of the vial rather than straight onto the lyophilized powder, if at all possible: A 20 mg vial should contain 2.3 mL of sterile water for injection (SWFI) to produce 10 mg/mL Enfortumab vedotin. 3.3 mL of sterile water for injection (SWFI) added to a 30 mg vial will produce 10 mg/mL Enfortumab vedotin.Swirl each vial slowly until the liquid inside has completely dissolved. The bubbles should disappear after letting the vial(s) sit for at least a minute. Avoid shaking the vial. Avoid direct sunlight exposure.
5. When the solution and container allow, parenteral medication preparations should be visually scrutinized for particle matter and discoloration before administration. The reconstituted solution needs to be; clear to just barely opalescent, colorless to light yellow, and particle-free. Any vial with noticeable flecks or discoloration should be discarded.
6. The reconstituted solution from the vial(s) should be introduced to the infusion bag right away based on the estimated dose amount. A preservative is not present in this product. Reconstituted vials can be kept in the refrigerator for up to 24 hours at 2 to 8 degrees Celsius or 36 to 46 degrees Fahrenheit, if not used right away. Avoid freezing.
7. After the suggested storage period, discard any unused vials containing the reconstituted solution.

Dilution in the Infusion Bag

1. Remove the vial(s) containing the calculated dose quantity of the reconstituted solution and place it in an infusion bag.

2. Add 5 percent dextrose injection, 0.9 percent sodium chloride injection, or lactate Ringer's injection to Enfortumab vedotin to dilute it. A final concentration of between 0.3 mg/mL and 4 mg/mL Enfortumab vedotin should be possible with the infusion bag's size.

3. Gently invert the diluted solution. Avoid shaking the bag. Avoid exposure to sunlight.

4. Before using the infusion bag, visually check it for any debris or discoloration. The reconstituted solution needs to be; clear to just barely opalescent, colorless to light yellow, and particle-free. If there is visible debris or discoloration, do not use the infusion bag.

5. Throw away any remaining medication in the single-dose vials.

Administration

1. Start giving the 30-minute infusion right away via an intravenous line.

2. The prepped infusion bag should not be kept at 2°C to 8°C (36 °F to 46 °F) for more than 8 hours if the infusion is not given right away. Avoid freezing.

Enfortumab vedotin should not be injected as a push or bolus. Do not give Enfortumab vedotin as an infusion, or mix it with other medications.

Recommendation of Schedule for Dose Reduction:

1.25 mg/kg to 125 mg as the starting dose.

1.0 mg/kg to 100 mg during initial dosage reduction.

0.75 mg/kg to 75 mg during the second dose reduction.

0.5 mg/kg up to 50 mg during the third dose reduction.

For Medical Doctors:

Chemical Taxonomy:

Mechanism of Action:

An antibody-drug combination called Enfortumab vedotin has several parts. Monomethyl auristatin E (MMAE), a chemotherapeutic microtubule-disrupting drug, is linked to a completely human monoclonal antibody aimed against Nectin-4, an extracellular adhesion protein that is significantly expressed in urothelial malignancies. A linker that can be broken down by proteases connects these two parts. Nectin-4-expressing cells bind to Enfortumab vedotin, and the resulting Enfortumab-Nectin-4 complex is internalized by the cell. When monomethyl auristatin E (MMAE) is liberated from Enfortumab vedotin inside the cell, the cell's microtubule network is disrupted, the cell cycle is arrested, and eventually, apoptosis is brought on.

Pharmacodynamics

An anti-cancer drug called Enfortumab vedotin kills tumor cells by preventing them from replicating. Although Enfortumab vedotin has not been tested in this population, previous MMAE or monomethyl auristatin E-containing antibody-drug conjugates have shown elevated rates of side events in individuals with moderate-severe hepatic impairment. These patients should not use Enfortumab vedotin. Enfortumab vedotin should not be given to patients whose blood glucose levels are higher than 250 mg/dl since it has the potential to induce substantial hyperglycemia and, in some situations, diabetic ketoacidosis.

Pharmacokinetics

Seven hundred forty-eight patients' data from five studies were used from the population for pharmacokinetic analysis. After single and several doses, individuals with locally advanced or metastatic urothelial carcinoma and other solid tumors had their Enfortumab vedotin-ejfv pharmacokinetics assessed. Peak monomethyl auristatin E concentrations were seen about two days following the

Enfortumab vedotin-ejfv dosage, while peak antibody-drug conjugate (ADC) concentrations were seen at the end of intravenous infusion. Repeated dosing of Enfortumab vedotin-ejfv to patients resulted in minimal antibody-drug conjugate and monomethyl auristatin E (MMAE) accumulation. After one treatment cycle, steady-state levels of antibody-drug conjugate and monomethyl auristatin E were attained.

Distribution

After administering Enfortumab vedotin-ejfv, the estimated average steady-state volume of distribution of antibody-drug conjugate was 12.8 liters. In vitro, the plasma protein binding of monomethyl auristatin E ranged from 68 to 82 percent.

Elimination

With an elimination half-life of 3.6 and 2.6 days, respectively, antibody-drug conjugate and monomethyl auristatin E, showed multi-exponential reductions. Enfortumab vedotin-ejfv and unconjugated MMAE had respective mean clearances (CL) of 0.11 L/h and 2.11 L/h in patients. The pace at which MMAE was released from Enfortumab vedotin-ejfv looked to be a limiting factor in its elimination. Excretion kinetics have not been fully determined, but data from another MMAE-containing antibody-drug conjugate may be used to extrapolate them. Kinetic studies of this drug showed that over the course of a week, 17 percent of the total monomethyl auristatin E administered was recovered in feces, and 6 percent was recovered in urine, mostly as an unchanged drug.

Metabolism

Although the catabolism of Enfortumab vedotin-ejfv in people has not been investigated, it is predicted that it will break down into tiny peptides, unconjugated MMAE, amino acids, and unconjugated MMAE-related catabolites.

Toxicity

Enfortumab vedotin's toxicity data are not easily available. Patients who have taken too much medication are probably more prone to experience serious side effects such as severe nausea, vomiting, neuropathy, or dermatitis. Supportive and symptomatic measures are advised.

Immunogenicity

There is a chance of immunogenicity, as there is with all therapeutic proteins. A number of elements, such as the assay's technique, sample handling, the timing of sample collection, concurrent drugs, and underlying diseases, may have an impact on the recorded incidence of antibodies (including neutralizing antibodies) present in an assay. Due to these factors, it may be deceptive to compare the prevalence of antibodies in the studies detailed below, with the prevalence of antibodies in other trials or in Enfortumab vedotin-ejfv products. At one or more post-baseline time points after receiving Enfortumab vedotin, patients tested positive for an anti-therapeutic antibody (ATA) against Enfortumab vedotin-ejfv. Regarding the possible impact of immunogenicity on efficacy, safety, or pharmacokinetics, no inferences can be formed based on the number of patients who have ATA against Enfortumab vedotin-ejfv.

Nonclinical Toxicology- Mutagenesis, Carcinogenesis, and Fertility Impairment

Enfortumab vedotin-ejfv or the small molecule cytotoxic agent MMAE have not been the subject of any investigations on their ability to cause cancer. In the rat bone marrow micronucleus investigation, MMAE was genotoxic via an aneugenic mechanism. This result is in line with MMAE's pharmacological ability to break microtubules. There have not been any Enfortumab vedotin-ejfv or MMAE fertility studies. However, the results of research on the toxicity of repeated doses in rats suggest that Enfortumab vedotin-ejfv may reduce male fertility and reproductive function. Enfortumab vedotin-ejfv was administered repeatedly to rats in repeat-dose toxicology studies for up to 13 weeks. At an exposures rate comparable to those at the recommended dose in humans, the drug caused seminiferous tubule degeneration, spermatid or spermatocyte depletion in the testes, and cell debris, sperm granuloma, and hypospermia or abnormal spermatids in the epididymis. By the end of the healing time, findings in the testes and epididymis had not reversed.

Clinical Trial Results:

Because adverse reaction rates in clinical trials are determined under a variety of different circumstances, they cannot be directly compared to adverse reaction rates in clinical trials of other drugs and may not accurately represent rates seen in actual clinical practice. The pooled safety population included in the warning and precautions section includes 680 patients from studies who were exposed to the drug. 36 percent of the 680 patients receiving the drug were exposed for more than six months, while 9 percent were exposed for less than twelve months. Aspartate aminotransferase increase, glucose increase, creatinine increase, fatigue, peripheral neuropathy, decreased appetite, hemoglobin decrease, diarrhea, sodium decline, nausea, pruritus, phosphate decrease, dysgeusia, alanine aminotransferase increase, anemia, albumin decrease, neutrophils decrease, and rash were the most frequent adverse reactions present in this pooled population.

Patients who have locally advanced or metastatic urothelial cancer, who received at least one dose of Enfortumab vedotin and had previously received treatment with a PD-1 or PD-L1 inhibitor, as well as platinum-based chemotherapy, were included in the study to assess the safety of Enfortumab vedotin. Exposure to the drug was experienced for a median of 5 months. In 47 % of individuals receiving the drug, serious adverse events occurred. Urinary tract infection, acute renal injury, and pneumonia were the most frequent major adverse responses. Three percent of patients experienced fatal adverse events, including pelvic abscess, multiorgan failure, hepatic dysfunction, septic shock, hyperglycemia, and pneumonitis. Seventeen percent of patients experienced adverse responses that caused drug cessation; rash and peripheral neuropathy were the most typical of them. Sixty-one percent of patients experienced adverse reactions that required dose interruption; the most frequent of them were fatigue, rash, and peripheral neuropathy. Thirty-four percent of patients experienced adverse events that necessitated a dose reduction; the most frequent of such events were peripheral neuropathy, rash, decreased appetite, and fatigue.

Drug Interaction- Effect of Other Drugs on Enfortumab Vedotin

Concurrent use of powerful CYP3A4 inhibitors and dual P-gp may result in increased exposure to unconjugated MMAE, which may lead to an increase in the frequency or severity of Enfortumab vedotin toxicities. When Enfortumab vedotin is used concurrently with dual P-gp and potent CYP3A4 inhibitors, patients should be closely watched for symptoms of toxicity.

Usage of the Drug in a Specific Population:

1. Patients With Hepatic Impairment

   Patients with moderate to severe hepatic impairment should not use Enfortumab vedotin as they have not been tested for the drug; only a small group of patients with moderate hepatic impairment have been studied. In another MMAE-containing antibody-drug conjugate, patients with moderate or severe hepatic impairment experienced more grade 3 adverse events and fatalities than those with normal hepatic function. When administering Enfortumab vedotin to patients who have a mild hepatic impairment, there is no need to change the starting dose.

2. Patients With Renal Impairment

   Patients who have mild, moderate, or severe renal impairment do not need their doses to be adjusted.

3. Pregnant Patients

   When given to a pregnant woman, the drug has the potential to harm the fetus based on its mode of action and results seen in animals. There are no human studies on drug use in expectant mothers that may be used to determine a drug's potential risks. Enfortumab vedotin-ejfv was administered to pregnant rats during organogenesis in an animal reproduction study, and at maternal exposures roughly equivalent to those at the recommended human dose, it caused maternal toxicity, embryo-fetal lethality, structural malformations, and skeletal anomalies.

   Enfortumab vedotin-ejfv was administered to pregnant rats in a rat pilot study on embryo-fetal development on gestation days 6 and 13 during the phase of organogenesis. At the maternally lethal dose, all pregnant rats lost their whole litter. A dose about equivalent to the exposure at the authorized human level caused anatomical deformities such as gastroschisis, malrotated hindlimbs, nonexistent forepaws, misplaced internal organs, and fused cervical arches, as well as maternal toxicity and embryo-fetal death. In addition, there were fetal weight reductions and skeletal abnormalities such as asymmetric, fused, incompletely ossified, and malformed sternebrae, a deformed cervical arch, and unilateral ossification of the thoracic centra.

4. Lactating Patient

   There is no information on Enfortumab vedotin-ejfv's presence in human milk, its effects on breastfed infants, or its impact on milk production. Lactating mothers are advised not to breastfeed throughout the treatment with Enfortumab vedotin, and for at least three weeks after the final dosage due to the possibility of major adverse events in an infant who is nursed.

5. Sexually Active Females and Males

   Females:

   Testing for pregnancy:

   Before beginning the medication, check the pregnant status of females with reproductive potential.

   Contraception:

   When given to a pregnant woman, the drug can harm the fetus. Females with the ability to become pregnant should be advised to utilize effective contraception while receiving the drug and for two months following the final dosage.

   Males:

   Male patients should be advised to use reliable contraception while using the drug and for four months following the final dosage if they have female partners who are able to become pregnant. Observations from animal research suggest that the drug may reduce male fertility.

6. Geriatric Patients

   Out of the 680 patients who received the drug treatment in clinical trials were 75 years of age or older. Between these patients and the younger patients, there were no general changes in safety or effectiveness.

7. Pediatric Patients

   Enfortumab vedotin has not been proven to be safe or beneficial in pediatric patients.