Enfortumab – Uses, Dosage, Side Effects, Interaction

The clinical development of enfortumab vedotin was the result of a collaboration between Astellas Pharma and Seattle Genetics [rx] and it was first approved for use in the United States in December 2019 under the brand name PadcevTM.[rx] Enfortumab vedotin was later approved by the European Commission on April 13, 2022.[rx]

Mechanism of action

Enfortumab vedotin is an antibody-drug conjugate comprised of multiple components.[rx] It contains a fully human monoclonal antibody directed against Nectin-4, an extracellular adhesion protein that is highly expressed in urothelial cancers,1 attached to a chemotherapeutic microtubule-disrupting agent, monomethyl auristatin E (MMAE). These two components are joined via a protease-cleavable linker. Enfortumab vedotin binds to cells expressing Nectin-4 and the resulting enfortumab-Nectin-4 complex is internalized into the cell. Once inside the cell, MMAE is released from enfortumab vedotin via proteolytic cleavage and goes on to disrupt the microtubule network within the cell, arresting the cell cycle and ultimately inducing apoptosis.[rx]

Enfortumab vedotin is an anti-cancer agent that destroys tumor cells by inhibiting their ability to replicate.[rx] Patients with moderate to severe hepatic impairment should not use enfortumab vedotin – although it has not been studied in this population, other MMAE-containing antibody-drug conjugates have demonstrated increased rates of adverse effects in patients with moderate-severe hepatic impairment.[rx] Enfortumab vedotin may also cause significant hyperglycemia leading, in some cases, to diabetic ketoacidosis, and should not be administered to patients with a blood glucose level >250 mg/dl.[rx]

Indications

  • Enfortumab vedotin is indicated for the treatment of adult patients with locally advanced or metastatic urothelial cancer who have previously received a programmed death receptor-1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibitor, and platinum-containing chemotherapy in the neoadjuvant/adjuvant, locally advanced, or metastatic setting.[rx,rx]
  • Enfortumab vedotin is an antibody-drug conjugate comprised of a fully human monoclonal antibody and microtubule-disrupting chemotherapeutic agent used in the treatment of advanced or metastatic urothelial cancer.
  • For locally advanced or metastatic urothelial cancer (mUC) who have previously received a programmed death receptor-1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibitor, and platinum-containing chemotherapy in the neoadjuvant/adjuvant, locally advanced or metastatic setting
  • Locally Advanced Urothelial Cancer
  • Metastatic Urothelial Cancer

Use in Cancer

Enfortumab vedotin-ejfv is approved to treat adults with:

  • Urothelial cancer (a type of cancer in the bladder or urinary tract) that has spread or cannot be removed by surgery. It is used in:
    • Patients who have received platinum chemotherapy and immunotherapy.
    • Patients who have received at least one other type of treatment and cannot receive cisplatin.

Enfortumab vedotin-ejfv is also being studied in the treatment of other types of cancer.

Contraindications

  • diabetes
  • a painful condition that affects the nerves in the legs and arms called peripheral neuropathy
  • high blood sugar
  • pregnancy
  • a patient who is producing milk and breastfeeding

Dosage

Strengths: ejfv 20 mg; ejfv 30 mg

Urothelial Carcinoma

  • 1.25 mg/kg (up to a maximum of 125 mg for patients 100 kg or greater) IV over 30 minutes on Days 1, 8. and 15 of a 28-day cycle until disease progression or unacceptable toxicity

Dose Adjustments

RECOMMENDED DOSE REDUCTION SCHEDULE:

  • Starting dose: 1.25 mg/kg up to 125 mg
  • First dose reduction: 1 mg/kg up to 100 mg
  • Second dose reduction: 0.75 mg/kg up to 75 mg
  • Third dose reduction: 0.5 mg/kg up to 50 mg

DOSE MODIFICATIONS:
HYPERGLYCEMIA:

  • Blood glucose greater than 250 mg/dL: Withhold this drug until elevated blood glucose has improved to 250 mg/dL or less then resume therapy at the same dose level.

PERIPHERAL NEUROPATHY:

  • Grade 2: Withhold until Grade 1 or less, then resume therapy at the same dose level (if first occurrence); for a recurrence, withhold until Grade 1 or less then, resume therapy reduced by one dose level.
  • Grade 3 or greater: Permanently discontinue this drug.

SKIN REACTIONS:

  • Grade 3 (severe): Withhold this drug until Grade 1 or less, then resume therapy at the same dose level or consider dose reduction by one dose level.
  • Grade 4 or recurrent Grade 3: Permanently discontinue this drug.

OTHER NONHEMATOLOGIC TOXICITY:

  • Grade 3: Withhold this drug until Grade 1 or less, then resume therapy at the same dose level or consider dose reduction by one dose level.
  • Grade 4: Permanently discontinue this drug.

HEMATOLOGIC TOXICITY:

  • Grade 3 or 3 thrombocytopenia: Withhold this drug until Grade 1 or less, then resume therapy at the same dose level or consider dose reduction by one dose level.
  • Grade 4 thrombocytopenia: Withhold until Grade 1 or less, then reduce dose by one dose level or discontinue therapy.

Administration advice:

  • After reconstitution, immediately administer the infusion IV over 30 minutes.
  • If the infusion is not administered immediately, the prepared infusion bag should not be stored longer than 8 hours at 2C to 8C (36 F to 46 F). NOTE: Do not freeze.
  • Do not administer this drug as an IV push or bolus.
  • Do not mix this drug with, or administer it as an infusion with, other medicinal products.

Side Effects

The Most Common

  • diarrhea
  • vomiting
  • nausea
  • loss of appetite
  • weight loss
  • taste changes
  • hair loss
  • dry skin
  • shortness of breath
  • trouble breathing
  • cough
  • pale skin
  • skin redness, swelling, fever, or pain at the injection site
  • blurred vision, loss of vision, eye pain or redness, or other visual changes
  • numbness, burning or tingling in hands or feet
  • muscle weakness
  • extreme tiredness or lack of energy

More common

  • Blurred vision
  • burning, dry, or itching eyes
  • burning, numbness, tingling, or painful sensations
  • discharge, excessive tearing
  • dry eyes
  • dry mouth
  • eye redness, irritation, or pain
  • flushed, dry skin
  • fruit-like breath odor
  • increased hunger
  • increased thirst
  • increased urination
  • lack or loss of strength
  • nausea
  • rash with flat lesions or small raised lesions on the skin
  • redness, pain, swelling of the eye, eyelid, or inner lining of the eyelid
  • stomach pain
  • sweating
  • trouble breathing
  • unexplained weight loss
  • unsteadiness or awkwardness
  • unusual tiredness or weakness
  • vomiting
  • weakness in the arms, hands, legs, or feet

Rare

  • Chest pain
  • chills
  • cough
  • fever
  • a general feeling of discomfort or illness
  • thickening of bronchial secretions
  • Blistering, peeling, or loosening of the skin
  • diarrhea
  • itching
  • joint or muscle pain
  • red irritated eyes
  • red skin lesions, often with a purple center
  • redness, tenderness, itching, burning, or peeling of the skin
  • sore throat
  • sores, ulcers, or white spots in the mouth or on the lips
  • Change in taste
  • cracks in the skin
  • decreased appetite
  • dry skin
  • hair loss or thinning of the hair
  • loss of heat from the body
  • loss of taste
  • nausea
  • painful blisters on the trunk of the body
  • red, swollen skin redness, swelling, or pain of the skin
  • scaling of the skin on the hands and feet
  • skin blisters
  • tingling of the hands and feet
  • ulceration of the skin
  • vomiting
  • Pain, redness, or swelling at the injection site

Drug Interactions

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Pregnancy and Lactation

US FDA pregnancy category Not Assigned

Pregnancy

This drug can harm a developing fetus. Adequate methods of contraception should be encouraged. Verify negative pregnancy status in females of reproductive potential prior to initiating therapy. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential harm to the fetus. Advise females of reproductive potential to use effective contraception during therapy and for 2 months after. Advise male patients with female partners of reproductive potential to use effective contraception during therapy and for 4 months after. This drug may impair male fertility.

Lactation

Use should be avoided. Excreted into human milk: Unknown Excreted into animal milk. Because of the potential for serious adverse reactions in a breastfed child, advise lactating women not to breastfeed during therapy and for at least 3 weeks after.

How should this medicine be used?

Enfortumab vedotin-ejfv injection comes as a powder to be mixed with liquid and injected intravenously (into a vein) over 30 minutes by a doctor or nurse in a hospital or medical facility. It is usually injected on days 1, 8, and 15 of a 28-day cycle for as long as your doctor recommends that you receive treatment.

Your doctor may delay or stop your treatment with enfortumab vedotin-ejfv injection, or treat you with additional medications, depending on your response to the medication and any side effects that you experience. Talk to your doctor about how you are feeling during your treatment. Ask your pharmacist or doctor for a copy of the manufacturer’s information for the patient.

What special precautions should I follow?

Before receiving enfortumab vedotin-ejfv injection,

  • tell your doctor and pharmacist if you are allergic to enfortumab vedotin-ejfv injection, any other medications, or any of the ingredients in enfortumab vedotin-ejfv injection. Ask your pharmacist for a list of the ingredients.
  • tell your doctor and pharmacist what other prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking or plan to take. Be sure to mention any of the following: clarithromycin (Biaxin); idelalisib (Zydelig); indinavir (Crixivan); ketoconazole (Nizoral); nefazodone; nelfinavir (Viracept); ritonavir (Norvir, in Kaletra); or saquinavir (Invirase); and rifampin (Rimactane). Many other medications may also interact with enfortumab vedotin-ejfv, so be sure to tell your doctor about all the medications you are taking, even those that do not appear on this list. Your doctor may need to change the doses of your medications or monitor you carefully for side effects.
  • tell your doctor if you have or have ever had peripheral neuropathy (a type of nerve damage that causes tingling, numbness, and pain in the hands and feet), diabetes or high blood sugar, lung problems, or liver disease.
  • tell your doctor if you are pregnant, plan to become pregnant, or if you plan to father a child. You or your partner should not become pregnant while you are receiving enfortumab vedotin-ejfv injection. Your doctor may perform a pregnancy test to be sure that you are not pregnant before you receive enfortumab vedotin-ejfv injection. If you are female, you should use birth control during your treatment and for 2 months after your final dose. If you are male, you and your female partner should use birth control during your treatment and for 4 months after your final dose. Talk to your doctor about birth control methods that will work for you. If you or your partner become pregnant while receiving enfortumab vedotin-ejfv injection, call your doctor. Enfortumab vedotin-ejfv injection may harm the fetus.
  • tell your doctor if you are breastfeeding. You should not breastfeed while you are receiving enfortumab vedotin-ejfv injection and for at least 3 weeks after your final dose.
  • you should know that this medication may decrease fertility in men. Talk to your doctor about the risks of receiving enfortumab vedotin-ejfv injection.
  • you should know that you may experience hyperglycemia (increases in your blood sugar) while you are receiving this medication, even if you do not already have diabetes. Tell your doctor immediately if you have any of the following symptoms while you are receiving enfortumab vedotin-ejfv injection: extreme thirst, frequent urination, extreme hunger, blurred vision, or weakness. It is very important to call your doctor as soon as you have any of these symptoms because high blood sugar that is not treated can cause a serious condition called ketoacidosis. Ketoacidosis may become life-threatening if it is not treated at an early stage. Symptoms of ketoacidosis include dry mouth, nausea and vomiting, shortness of breath, breath that smells fruity, and decreased consciousness.
  • you should know that this medication may cause dry eyes and other eye problems, which may be serious. Your doctor may tell you to use artificial tears or lubricant eye drops during your treatment with enfortumab vedotin-ejfv.

References