Erdafitinib - Dosage, Indications, and Side Effects

Overview

Erdafitinib is a kinase inhibitor used in the treatment of locally advanced or metastatic urothelial carcinoma in adult patients. It was granted under accelerated approval by the United States Food and Drug Administration (USFDA) on April 12th, 2019, based on the tumor response rate. Continued approval may depend on the verification and description of clinical benefits in the confirmatory trials. The patients are selected for the treatment using an FDA-approved companion diagnostic device.

How Does Erdafitinib Work?

Erdafitinib belongs to a class of kinase inhibitors (a drug that inhibits kinase enzyme, which promotes cell growth) and works by blocking the abnormal proteins that signal the cancer cells to multiply, in turn preventing or slowing the spread of cancer cells. It targets the susceptible FGFR genetic alterations in patients with metastatic bladder cancer. The introduction of Erdafitinib serves as a new option in the treatment of such prevalent medical conditions.

What Are the Indications of Erdafitinib?

The indications of Erdafitinib include;

• Treatment in adult patients with locally advanced or metastatic urothelial carcinoma (mUC) that has susceptible FGFR2 or FGFR3 genetic alterations and the disease has progressed during or after at least one dose of platinum-containing chemotherapy, along with 12 months of neoadjuvant or adjuvant platinum chemotherapy.

What Is the Recommended Dosage of Erdafitinib?

• Patients with locally advanced or metastatic urothelial carcinoma are selected for treatment with Erdafitinib based on the presence of susceptible FGFR gene variations in tumor specimens, which is detected by an FDA-approved companion diagnostic test.

• Erdafitinib is available as 3 mg, 4 mg, and 5 mg tablets. It is recommended at an initial dose of 8 mg (two 4 mg tablets) to be taken orally once daily.

• A gradual increase in dose to 9 mg (3 mg tablets) to be taken once daily is done based on the tolerance achieved at 14 to 21 days, with serum phosphate levels (PO4) less than 5.5 mg/dL, with no ocular disorders or grade 2 or severe adverse reactions. Phosphate levels are monitored monthly for hyperphosphatemia.

What Are the Warnings and Precautions of Erdafitinib?

• Embryo-fetal Toxicity: According to animal studies, Erdafitinib may cause fetal harm when administered to pregnant women. Therefore, pregnant women are advised of the potential risk to the fetus. Female patients of reproductive potential are advised to use effective contraception during the treatment with Erdafitinb and up to one month after the last dose.

• Eye Disorders: Erdafitinib may cause ocular disorders, which include central serous retinopathy (CSR) or retinal pigment epithelial detachment (RPED), and can lead to visual field defects. It was reported in approximately 25 percent of patients treated with Erdafitinib with the first onset of 50 days. Symptoms of dry eyes were also reported in some patients during the treatment, and hence all patients must receive ocular demulcents as prophylaxis. Ophthalmological examinations, including assessment of visual acuity, fundoscopy, optical coherence tomography, and slit lamp examination, are performed during the first four months of treatment and periodically every three months or immediately if any visual abnormalities are noticed. Treatment with Erdafitinib must be stopped if CSR occurs and permanently discontinued if the condition is of grade IV severity or if it does not resolve within four weeks.

• Hyperphosphatemia: Treatment with Erdafitinib can cause an increase in the phosphate levels, with an onset of approximately 20 days after the initiation of treatment. The patient is hence frequently monitored for hyperphosphatemia, and doses may be modified when required.

What Are the Adverse Effects of Erdafitinib?

Some of the serious adverse effects which must be reported immediately include;

• Visual changes such as blurred vision, loss of vision, etc.

• Muscle cramps, numbness, and tingling sensation around the mouth.

• Peeling of the skin on the palms and soles, nail changes.

• Itchy, painful, dry, or cracked skin and rash.

• Swelling, pain, and redness.

Some of the common side effects include;

• Nausea and vomiting.

• Dry mouth, sores on lips, throat, and mouth.

• Change in taste perception.

• Decreased appetite.

• Fever.

• Diarrhea.

• Hair loss or thinning of hair.

• Fatigue.

• Constipation.

• Shortness of breath.

• Burning sensation during urination.

• Muscle and joint pain.

For Patients

What Is Bladder Cancer?

Bladder cancer is known as urothelial carcinoma or transitional cell carcinoma. It is a common type of bladder cancer and begins in the cells that line the inner aspect of the bladder. It is associated with symptoms such as frequent and painful urination, blood in the urine (hematuria), low-grade fever, tiredness, weight loss, and persistent back pain.

What Is Erdafitinib?

Erdafitinib is a prescription medicine used in the treatment of bladder cancer in adult patients in whom the condition cannot be removed by surgery; it has a certain type of abnormal gene (FGFR gene). It is also indicated in patients who have undergone at least one other chemotherapy medicine containing platinum, which was not successful.

How Should Erdafitinib Be Stored?

Erdafitinib must be stored at room temperature at around 20 to 25 degrees Celsius (68 to 77 degrees Fahrenheit), out of the reach of children.

How Should Erdafitinib Be Taken?

• Erdafitinib must be taken exactly as prescribed by the healthcare provider. It must be taken once a day, and tablets must be swallowed as a whole with or without food. It must not be crushed, dissolved, or chewed.

• If a dose is missed, it must be taken as soon as possible on the same day, and the next dose must be taken on the next day at the regularly scheduled time. If a dose is vomited, another dose must not be taken, but the regular dose must be taken the next day.

• The dose of Erdafitinib must not be modified, skipped, or stopped without consultation with a healthcare professional.

• The dose may be modified, temporarily, or permanently discontinued in the presence of certain side effects.

What Are the Important Instructions About Erdafitinib?

• The healthcare provider will test cancer for certain types of abnormal genes to ensure the treatment is effective for the patient.

• Females must not become pregnant during the period of treatment with Erdafitinib and hence must follow effective contraceptive methods during the treatment and for one month after the last dose. A pregnancy test may be advised before beginning therapy with Erdafitinib.

• Breastfeeding must not be done during the treatment with Erdafitinib and for one month after the last dose.

• Phosphate levels are periodically monitored during the treatment, and dose changes may be done if needed.

What Must the Patients Inform the Doctor Before Taking Erdafitinib?

• The doctor must be informed if the patient is suffering from vision defects or any eye problems.

• Female patients must inform if they are pregnant or planning to get pregnant if they are breastfeeding or planning to breastfeed, as Erdafitinib may harm the fetus.

• Patients must inform the doctor if they are taking any medications, over-the-counter drugs (OTC), vitamins, or herbal supplements, before beginning the treatment with Erdafitinib.

What Are the Side Effects of Erdafitinib?

Serious side effects include;

• Eye problems such as dry eyes, inflamed eyes, blurred vision, disorders of the retina,

• Increased levels of phosphate in the blood.

Other side effects include;

• Dry mouth.

• Decreased appetite.

• Nausea and vomiting.

• Stomach pain.

• Diarrhea.

• Swelling and redness of hands and feet.

• Low sodium levels.

• Changes in taste.

• Nails separated from the nailbed.

• Constipation.

• Hair loss.

• Anemia.

For Doctors

Description

Erdafitinib belongs to a class of tyrosine kinase inhibitors, fibroblast growth factor receptors used in the treatment of adult patients with locally advanced or metastatic urothelial carcinoma. It is supplied as 3 mg, 4 mg, and 5 mg tablets for oral administration. The tablet Erdafitinib is the active ingredient, along with magnesium stearate, mannitol, croscarmellose sodium, meglumine, and microcrystalline cellulose. Other ingredients include; glycerol monocaprylocaprate type I, polyvinyl alcohol, sodium lauryl sulfate, titanium dioxide, ferrosoferric oxide, etc.

Clinical Pharmacology

Mechanism of Action

Erdafitinib binds and acts by inhibiting the enzymatic activity of FGFR, resulting in the inhibition of FGFR-related phosphorylation, and signal transduction pathways which result in decreased cell variability in cell lines demonstrating FGFR gene alterations. Therefore, it prevents tumor cell proliferation, causing cell death in FGFR- overexpressing tumor cells.

Pharmacokinetics

After an oral administration of 8 mg Erdafitinib, a steady state was observed at a plasma concentration was 1399 ng/mL, the area under the curve (AUC) was 29,268 ng h/ml, and the minimum plasma concentration was 936 ng/mL. After repeated daily doses, Erdafitinib exposure demonstrated a maximum plasma concentration, and AUC increased proportionally (dose range of 0.5 to 12 mg). A steady state was achieved after two weeks following a single daily dose.

• Absorption: No significant differences were observed with respect to the pharmacokinetics of Erdafitinib following a high-fat meal of approximately 800 to 1000 calories. A peak plasma concentration was achieved in 2.5 hours (approximately two to six hours).

• Distribution: The protein binding capacity of Erdafitinib was 99.8 percent (primarily to alpha-1- acid glycoprotein), and the mean apparent volume of distribution in patients was around 29 L.

• Metabolism: Erdafitinib is mainly metabolized by the enzymes CYP2C9 AND CYP3A4, and the total clearance is 39 percent and 20 percent, respectively. No circulating metabolites were present; however major drug-related moiety of unchanged Erdafitinib was in plasma.

• Excretion: Erdafitinib has a total apparent clearance of 0.362 L/h, and the mean effective half-life was 59 hours in patients. After administration of a single dose of Erdafitinib, 69 percent was recovered in feces, and 19 percent of the dose was recovered in urine.

Pharmacodynamics

After administration of Erdafitinib, it was observed that it increased serum phosphate levels as a result of FGFR inhibition. In order to manage this, phosphate binders were utilized, and concomitant use of agents that alter the serum phosphate levels was also avoided. Based on the evaluation of QTc interval, a dose expansion study with Erdafitinib in 187 patients showed no significant effects.

Results of Clinical Studies

An open-label, multicenter, single-arm study was conducted to evaluate the safety and efficacy of Erdafitinib in patients with locally advanced or metastatic urothelial carcinoma. The testing population consisted of a cohort of 87 patients with a disease that had progressed on or after at least one prior chemotherapy, along with at least one genetic alteration. Tumor samples from 69 patients were tested based on an FDA-approved test. Patients received an initial dose of 8 mg Erdafitinib once a day, with a gradual increase to 9 mg once a day in patients whose serum phosphate levels were below 5.5 mg/dL, between 14 to 17 days, until disease progression or unacceptable toxicity. Three percent of patients had disease progression following prior platinum-based therapy, and partial response was noted in 29.9 percent of patients.

Non-Clinical Toxicology

Carcinogenicity studies and fertility studies in animals have not been performed with Erdafitinib. The drug was not mutagenic in bacterial reverse mutation assay (Ames test). In a three-month toxicity study, Erdafitinib demonstrated certain effects on the female reproductive organs in rats at exposure levels less than the maximum recommended human dose.

Drug Interactions:

Some of the drugs that interact with Erdafitinib include;

• Alpelisib.

• Atorvastatin.

• Butabarbital.

• Calcium acetate.

• Calcium carbonate.

• Carbamazepine.

• Cetirizine.

• Chloramphenicol.

• Clarithromycin.

• Cyclosporin.

• Dexamethasone.

• Digoxin.

• Erythromycin.

• Fluconazole.

• Ibuprofen.

• Itraconazole.

• Methotrexate.

• Omeprazole.

• Verapamil.

• Voriconazole, etc.

Use of Erdafitinib in Specific Populations

• Pregnancy: There is no data available on the use of Erdafitinib in pregnant females to determine the drug-associated risks; however, according to animal studies, Erdafitinib can cause fetal harm when administered to pregnant females. On oral administration of Erdafitinib to pregnant rats, during the organogenesis phase, malformations and embryo-fetal death were observed at doses less than human exposure of the maximum recommended dose based on the AUC. Therefore, pregnant women are advised of the potential risk to the fetus.

• Nursing Mothers: No data is available on the presence of Erdafitinib in human milk or the effects of Erdafitinib on the breastfed child or milk production. Due to the potential risk of serious adverse reactions to the breastfed child, lactating women are advised not to breastfeed during the treatment and for one month after the last dose of Erdafitinib.

• Infertility: According to animal studies, Erdafitinib can impair fertility in females of reproductive potential.

• Pediatric Use: The safety and effectiveness of Erdafitinib have not been established with respect to pediatric patients.

• Geriatric Use: According to clinical studies, out of the 416 patients (45 percent above 65 years and 12 percent above 75 years), no significant changes were observed in comparison to younger patients.

• CYP2C9 Genotype: Plasma concentrations of Erdafitinib were higher in patients with the CYP2C9 genotype, and patients suspected to have such genotypes are frequently monitored for increased risk of adverse reactions.