N1-(3,5-Dimethoxyphenyl)-N2-(1-methylethyl)-N1-[3-(1-methyl-1H-pyrazol-4-yl)-6-quinoxalinyl]-1,2-ethanediamine

446.54

446.54

890E37NHMV

C103273

L - Antineoplastic and immunomodulating agents

77.3

3.2

1.2±0.1 g/cm3

354.4±31.5 °C

1.618

<1 mg/mL

|Danger|H302 (100%): Harmful if swallowed [Warning Acute toxicity, oral]|P201, P202, P260, P261, P264, P270, P272, P273, P280, P281, P301+P312, P302+P352, P305+P351+P338, P308+P313, P310, P314, P321, P330, P333+P313, P363, P405, and P501|Aggregated GHS information provided by 2 companies from 2 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

Based on the mechanism of action and findings in animal reproduction studies, erdafitinib can cause fetal harm when administered to a pregnant woman. There are no available data on erdafitinib use in pregnant women to inform a drug-associated risk. Oral administration of erdafitinib to pregnant rats during organogenesis caused malformations and embryo- fetal death at maternal exposures that were less than the human exposures at the maximum recommended human dose based on AUC. Advise pregnant women and females of reproductive potential of the potential risk to the fetus. There are no data on the presence of erdafitinib in human milk, or the effects of erdafitinib on the breastfed child, or on milk production. Because of the potential for serious adverse reactions from erdafitinib in a breastfed child, advise lactating women not to breastfeed during treatment with erdafitinib and for one month following the last dose. Pregnancy testing is recommended for females of reproductive potential prior to initiating treatment with erdafitinib. Erdafitinib can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment with erdafitinib and for one month after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with erdafitinib and for one month after the last dose. Based on findings from animal studies, erdafitinib may impair fertility in females of reproductive potential. Safety and effectiveness of erdafitinib in pediatric patients have not been established. No overall differences in safety or effectiveness were observed between these patients and younger patients in the use of erdafitinib. Erdafitinib plasma concentrations were predicted to be higher in patients with the CYP2C9*3/*3 genotype. Monitor for increased adverse reactions in patients who are known or suspected to have CYP2C9*3/*3 genotype. Carcinogenicity studies have not been conducted with erdafitinib. Erdafitinib was not mutagenic in a bacterial reverse mutation (Ames) assay and was not clastogenic in an in vitro micronucleus or an in vivo rat bone marrow micronucleus assay. Fertility studies in animals have not been conducted with erdafitinib. In the 3-month repeat-dose toxicity study, erdafitinib showed effects on female reproductive organs (necrosis of the ovarian corpora lutea) in rats at an exposure less than the human exposure (AUC) at maximum recommended human dose.

In the prelicensure clinical trials of erdafitinib in patients with urothelial carcinoma, liver test abnormalities were frequent although usually mild. Some degree of ALT elevation arose in up to 41% of erdafitinib treated patients, but were above 5 times the upper limit of normal (ULN) in only 1% to 2%. In these trials that enrolled approximately 400 patients, there were no reports of serious or clinically apparent liver injury, or liver related deaths.

The protein binding recorded for erdafitinib is approximately 99.8%, and it was determined to be primarily bound to alpha-1-acid glycoprotein.

Erdafitinib is a pan-fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor that is indicated for the treatment of adult patients with locally advanced or metastatic urothelial carcinoma that has: i) susceptible FGFR3 or FGFR2 genetic alterations and has, ii) progressed during or following at least one line of prior platinum-containing chemotherapy including within 12 months of neoadjuvant or adjuvant platinum-containing chemotherapy. The selection of patients for the treatment of locally advanced or metastatic urothelial carcinoma with erdafitinib should be based on the presence of susceptible FGFR genetic alterations in tumor specimens as detected by an FDA-approved companion diagnostic like the FDA approved therascreen FGFR RGQ RT-PCR Kit as developed by QIAGEN. This above indication is approved under accelerated approval by the US FDA based on tumor response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.|FDA Label|Treatment of urothelial carcinoma

Erdafitinib is an oral small molecule inhibitor of fibroblast growth factor receptors (FGFR) 1 to 4 that is used in the therapy of locally advanced, unresectable or metastatic urothelial carcinoma. Erdafitinib has been associated with a high rate of serum enzyme elevations during therapy, but has not been linked to cases of clinically apparent acute liver injury.

Antineoplastic Agents

Upon administration, it was observed that erdafitinib increased serum phosphate level as a consequence of FGFR inhibition. Erdafitinib should be increased to the maximum recommended dose to achieve target serum phosphate levels of 5.5– 7.0 mg/dL in early cycles with continuous daily dosing. Subsequently, in erfatinib clinical trials, the use of drugs which could increase serum phosphate levels, such as potassium phosphate supplements, vitamin D supplements, antacids, phosphate-containing enemas or laxatives, and medications known to have phosphate as an excipient were prohibited unless no alternatives existed. To manage phosphate elevation, phosphate binders were utilized. Additionally, the concomitant use of agents that can alter serum phosphate levels before the initial erfatinib dose increase period based on serum phosphate levels was also avoided. Furthermore, based on the evaluation of QTc interval in an open-label, dose escalation, and dose expansion study in 187 patients with cancer, erdafitinib had no large effect (i.e., > 20 ms) on the QTc interval.

Following administration of erdafitinib 8 mg once daily, the mean (coefficient of variation [CV%]) steady-state maximum observed plasma concentration (Cmax), area under the curve (AUCtau), and minimum observed plasma concentration (Cmin) were 1,399 ng/mL (51%), 29,268 ng·h/mL (60%), and 936 ng/mL (65%), respectively. Following single and repeat once daily dosing, erdafitinib exposure (maximum observed plasma concentration [Cmax] and area under the plasma concentration time curve [AUC]) increased proportionally across the dose range of 0.5 to 12 mg (0.06 to 1.3 times the maximum approved recommended dose). Steady state was achieved after 2 weeks with once daily dosing and the mean accumulation ratio was 4-fold. The median time to achieve peak plasma concentration (tmax) was 2.5 hours (range: 2 to 6 hours). And finally, no clinically meaningful differences with erdafitinib pharmacokinetics were observed following administration of a high-fat and high-calorie meal (800 calories to 1,000 calories with approximately 50% of total caloric content of the meal from fat) in healthy subjects.|After administering a single oral dose of radiolabeled erdafitinib, about 69% of the dose was recovered in feces (19% as unchanged) and 19% in urine (13% as unchanged).|The mean apparent volume of distribution determined for erdafitinib is about 26 to 29 L in patients.|The mean total apparent clearance (CL/F) documented for erdafitinib is about 0.362 L/h, while the oral clearance has been observed to be approximately 0.26 L/h.

It has been determined that erdafitinib is primarily metabolized by the cytochrome CYP2C9 and CYP3A4 isoenzymes. The contribution of CYP2C9 and CYP3A4 in the total clearance of erdafitinib is estimated to be 39% and 20% respectively. Unchanged erdafitinib was ultimately the predominant drug-related moiety found in the plasma - there were no circulating metabolites observed.

The mean effective half-life documented for erdafitinib is 59 hours, although it has also been observed between 50 to 60 hours.

Urothelial cancer is statistically the fourth most common kind of cancer in the world. In general, such urothelial cancers originate in the urothelium - or the transitional epithelium - a membrane that covers the renal pelvis to the ureter, the bladder, and the proximal two-thirds of the urethra. While 90 to 95% of urothelial cancers are bladder cancers and the other 5 to 10% are upper tract urothelial cancers, the bladder cancers can also be either superficial or invasive (either not having or having invaded the deeper layers of the bladder). Moreover, fibroblast growth factor receptor (FGFR) is a transmembrane protein that is expressed ubiquitously in normal tissues and is involved in various endogenous bio-physiological processes including the homeostasis of phosphate and vitamin D, cell proliferation, cell anti-apoptotic signaling, and cell migration in a variety of cell types. Concurrently, genetic mutations or changes like deregulation of FGFR pathways and FGFR aberrations such as gene amplification, point mutations, and chromosomal translocations have been implicated in the pathogenesis of urothelial cancer, including the possibility of such changes to all four FGFR genes (FGFR1, FGFR2, FGFR3, and FGFR4). Changes to the FGFR genes are consequently thought to promote cell proliferation, migration, angiogenesis, and anti-apoptosis in many cancers including urothelial cancer. Erdafitinib is subsequently an oral selective pan-FGFR kinase inhibitor that binds to and inhibits the enzymatic activity of expressed FGFR1, FGFR2, FGFR3, and FGFR4 based on in vitro data. In particular, erdafitinib demonstrates inhibition of FGFR phosphorylation and signaling as well as decreased cell viability in cell lines expressing FGFR genetic alterations, including point mutations, amplifications, and fusions. Erdafitinib demonstrated antitumor activity in FGFR-expressing cell lines and xenograft models derived from tumor types, including bladder cancer.

Balversa

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