Erdafitinib

Caution is advised when administering erdafitinib with medicinal products known to prolong the QT interval or medicinal products with a potential to induce torsades de pointes, such as class IA (e.g., quinidine, disopyramide) or class III (e.g., amiodarone, sotalol, ibutilide) antiarrhythmic medicinal products, macrolide antibiotics, SSRIs (e.g., citalopram, escitalopram), methadone, moxifloxacin, and antipsychotics (e.g., haloperidol and thioridazine).

Co-administration with a moderate CYP2C9 or strong CYP3A4 inhibitor increased erdafitinib exposure and may lead to increased drug-related toxicity. Erdafitinib mean ratios (90% CI) for C_max and AUC_∞ were 121% (99.9, 147) and 148% (120, 182), respectively, when co-administered with fluconazole, a moderate CYP2C9 and CYP3A4 inhibitor, relative to erdafitinib alone. C_max of erdafitinib was 105% (90% CI: 86.7, 127) and AUC_∞ was 134% (90% CI: 109, 164) when co-administered with itraconazole, a strong CYP3A4 inhibitor and P-gp inhibitor, relative to erdafitinib alone. Consider alternative agents with no or minimal enzyme inhibition potential. If erdafitinib is co-administered with a moderate CYP2C9 or strong CYP3A4 inhibitor (such as itraconazole, ketoconazole, posaconazole, voriconazole, fluconazole, miconazole, ceritinib, clarithromycin, telithromycin, elvitegravir, ritonavir, paritaprevir, saquinavir, nefazodone, nelfinavir, tipranavir, lopinavir, amiodarone, piperine), reduce the erdafitinib dose to the next lower dose based on tolerability. If the moderate CYP2C9 or strong CYP3A4 inhibitor is discontinued, the erdafitinib dose may be adjusted as tolerated.

Grapefruit or Seville oranges should be avoided while taking erdafitinib due to strong CYP3A4 inhibition.

Mean ratios of C_max and AUC_∞ for midazolam (a sensitive CYP3A4 substrate) were 86.3% (90% CI: 73.5, 101) and 82.1% (90% CI: 70.8, 95.2), respectively, when co-administered with erdafitinib relative to midazolam alone. Erdafitinib does not have a clinically meaningful effect on midazolam PK. However, it cannot be excluded that CYP3A4 induction after administration of erdafitinib alone or concomitant administration of other CYP3A4 inducers together with erdafitinib may reduce the efficacy of hormonal contraceptives.

Patients using hormonal contraceptives should be advised to use an alternative contraceptive not affected by enzyme inducers (e.g., non-hormonal intrauterine device) or an additional nonhormonal contraception (e.g., condom) during treatment with and until 1 month after the last dose of erdafitinib.

Erdafitinib is an inhibitor of P-gp. Concomitant administration of erdafitinib with P-gp substrates may increase their systemic exposure. Oral narrow therapeutic index P gp substrates (such as colchicine, digoxin, dabigatran, and apixaban) should be taken at least 6 hours before or after erdafitinib to minimise the potential for interactions.

Co-administration with carbamazepine, a strong CYP3A4 and weak CYP2C9 inducer leads to decreased erdafitinib exposure. Mean ratios of C_max and AUC_∞ for erdafitinib was 65.4% (90% CI: 60.8, 70.5) and 37.7% (90% CI: 35.4, 40.2), respectively, when co-administered with carbamazepine relative to erdafitinib alone. Avoid co-administration of erdafitinib with strong CYP3A4 inducers (such as apalutamide, enzalutamide, lumacaftor, ivosidenib, mitotane, rifapentine, rifampicin, carbamazepine, phenytoin, and St. John’s wort). If erdafitinib is co-administered with a moderate CYP3A4 inducer (such as dabrafenib, bosentan, cenobamate, elagolix, efavirenz, etravirine, lorlatinib, mitapivat, modafinil, pexidartinib, phenobarbital, primidone, repotrectinib, rifabutin, sotorasib, telotristat ethyl), the dose should be cautiously increased by 1 to 2 mg and adjusted gradually every two to three weeks based on clinical monitoring for adverse reactions, not to exceed 9 mg. If the moderate CYP3A4 inducer is discontinued, the erdafitinib dose may be adjusted as tolerated.

There are no data on the use of erdafitinib in patients with severe renal impairment. Alternative treatment should be considered in patients with severe renal impairment.

Limited data are available on the use of erdafitinib in patients with severe hepatic impairment. Alternative treatment should be considered in patients with severe hepatic impairment.

In patients receiving erdafitinib, medicinal products that can alter serum phosphate levels should be avoided until assessment of serum phosphate level between 14 and 21 days after initiating treatment due to potential impact on up-titration decision.

There are no data from the use of erdafitinib in pregnant women. Animal studies have shown reproductive toxicity. Based on the mechanism of action of erdafitinib and the findings in animal reproduction studies, erdafitinib should not be used during pregnancy unless the clinical condition of the women requires treatment with erdafitinib.

If erdafitinib is used during pregnancy, or if the patient becomes pregnant while taking erdafitinib, advise the patient of the potential hazard to the foetus and counsel the patient about her clinical and therapeutic options. Patients should be advised to contact their healthcare professional if they become pregnant or pregnancy is suspected while being treated with erdafitinib and up to 1 month afterwards.

There are no data on the presence of erdafitinib in human milk, or the effects of erdafitinib on the breast-fed infant, or on milk production.

A risk to the suckling child cannot be excluded. Breast-feeding should be discontinued during treatment and for 1 month following the last dose of erdafitinib.

Women of childbearing potential/Contraception in males and females

Based on the mechanism of action and findings in animal reproduction studies, erdafitinib can cause foetal harm when administered to pregnant women. Female patients of child-bearing potential should be advised to use highly effective contraception prior to and during treatment, and for 1 month after the last dose of erdafitinib. Male patients should be advised to use effective contraception (e.g., condom) and not donate or store semen during treatment with and for 1 month after the last dose of erdafitinib.

Concomitant administration of erdafitinib may reduce the efficacy of hormonal contraceptives. Patients using hormonal contraceptives should be advised to use an alternative contraceptive not affected by enzyme inducers (e.g., non-hormonal intrauterine device) or an additional nonhormonal contraception (e.g., condom) during treatment with and for 1 month after the last dose of erdafitinib.

Pregnancy testing

Pregnancy testing with a highly sensitive assay is recommended for females of reproductive potential prior to initiating erdafitinib.

Fertility

There are no human data on the impact of erdafitinib on fertility. Dedicated animal fertility studies have not been conducted with erdafitinib. Based on preliminary fertility assessment in general animal studies and on the pharmacology of erdafitinib, impairment of male and female fertility cannot be excluded.

Erdafitinib has moderate influence on the ability to drive and use machines. Eye disorders such as central serous retinopathy or keratitis have been noted with FGFR inhibitors and with erdafitinib treatment. If patients experience treatment related symptoms affecting their vision, it is recommended that they do not drive or use machines until the effect subsides.

Summary of the safety profileSummary of the safety profile

The most common adverse reactions were hyperphosphataemia (78.5%), diarrhoea (55.5%), stomatitis (52.8%), dry mouth (39.9%), decreased appetite (31.7%) dry skin (28.0%), anaemia (28.2%), constipation (27.3%), dysgeusia (26.3%), palmar-plantar erythrodysaesthesia syndrome (PPES) (25.5%), alopecia (23.2%), alanine aminotransferase increased (21.7%), onycholysis (21.7%), nausea (18.6%), weight decreased (21.7%), aspartate aminotransferase increased (18%), dry eye (16.7%), nail discolouration (15.9%), vomiting (13.8%), blood creatinine increased (13.8%), hyponatraemia (13.4%), paronychia (12.5%), nail dystrophy (11.9%), onychomadesis (11.5%), epistaxis (10.6%) and nail disorder (10.2%).

Most common Grade 3 or higher ADRs were stomatitis (10.6%), hyponatraemia (8.8%), palmar-plantar erythrodysaesthesia syndrome (7.9%), onycholysis (4.8%), diarrhoea (4.0%), hyperphosphataemia (2.9%), decreased appetite (2.5%), and nail dystrophy (2.5%). Grade 3 or 4 related TEAEs (47.6% vs 43.5%) and related serious adverse events (14.6% vs 10.5%) were reported more frequently for patients 65 years and older versus patients <65 years.

Adverse reactions leading to dose reduction occurred in 59.7% of patients. Stomatitis (15.4%), palmar-plantar erythrodysaesthesia syndrome (9.6%), onycholysis (7.3%) and hyperphosphataemia (5.2%) were the most common adverse events leading to dose reduction.

Adverse reactions leading to treatment discontinuation occurred in 19.4% of patients. Detachment of retinal pigment epithelium (1.7%) and stomatitis (1.5%) were the most common adverse events leading to treatment discontinuations.

Tabulated list of adverse reactions

The safety profile is based on pooled data from 479 locally advanced unresectable or metastatic urothelial carcinoma patients who were treated with erdafitinib in clinical studies. Patients were treated with erdafitinib at 8/9 mg starting dose orally once daily. Median duration of treatment was 4.8 months (range 0.1 to 43.4 months).

Adverse reactions observed during clinical studies are listed below in the table below by frequency category. Frequency categories are defined as follows: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1 000 to <1/100); rare (≥1/10 000 to <1/1 000); very rare (<1/10 000).

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Adverse reactions identified in clinical studies:

^a Central serous retinopathy includes Retinal detachment, Vitreous detachment, Retinal oedema, Retinopathy, Chorioretinopathy, Detachment of retinal pigment epithelium, Detachment of macular retinal pigment epithelium, Macular detachment, Serous retinal detachment, Subretinal fluid, Retinal thickening, Chorioretinitis, Serous retinopathy, Maculopathy, Choroidal effusion, vision blurred, visual impairment, visual acuity reduced.
^b Stomatitis includes mouth ulceration.

Description of selected adverse reactions

Central serous retinopathy (CSR)

Adverse reactions of CSR were reported in 31.5% of patients with a median time to first onset, for an event of any grade, of 51 days. The most commonly reported events were vision blurred, chorioretinopathy, detachment of RPE, visual acuity reduced, visual impairment, retinal detachment, retinopathy, and subretinal fluid. Grade 3 or 4 CSR was reported in 2.7% of patients. The majority of central serous retinopathy events occurred within the first 90 days of treatment. At the time of data cutoff, CSR had resolved for 43.0% of patients. In patients with CSR, 11.3% had dose interruptions and 14.6% had dose reductions. There were 3.3% of patients who discontinued erdafitinib due to: detachment of RPE (1.7%), chorioretinopathy ( 0.6%), visual acuity reduced (0.6%), maculopathy (0.4%), vision blurred (0.2%), visual impairment (0.2%), retinal detachment (0.2%), and subretinal fluid (0.2%).

Other eye disorders

Eye disorders (other than central serous retinopathy) were reported in 36.3% of patients. The most commonly reported events were dry eye (16.7%), conjunctivitis (9.8%) and lacrimation increased (9.2%). Of patients with events, 4.8% had dose reductions and 6.7% had dose interruptions. There were 1.3% who discontinued erdafitinib due to eye disorders. The median time to first onset for eye disorders was 53 days.

Nail disorders

Nail disorders were reported in 62.6% of patients. The most commonly reported events included onycholysis (21.7%), nail discolouration (15.9%), paronychia (12.5%), nail dystrophy (11.9%) and onychomadesis (11.5%). The incidence of nail disorders increased after the first month of exposure. The median time to onset for any grade nail disorder was 63 days.

Skin disorders

Skin disorders were reported in 54.5% of patients. The most commonly reported events were dry skin (28%), and palmar-plantar erythrodysaesthesia syndrome (25.5%). The median time to onset for any grade skin disorder was 47 days.

Gastrointestinal disorders

Gastrointestinal disorders were reported in 83.9% of patients. The most commonly reported events were diarrhoea (55.5%), stomatitis (52.8%), and dry mouth (39.9%). The median time to onset for any grade gastrointestinal disorder was 15 days.

Hyperphosphataemia and soft tissue mineralisation

Erdafitinib can cause hyperphosphataemia. Increases in phosphate concentrations are an expected and transient pharmacodynamic effect. Hyperphosphataemia was reported as an adverse event in 78.5% of patients treated with erdafitinib. Hyperphosphataemia was reported early during erdafitinib treatment, with Grade 1-2 events generally occurring within the first 3 or 4 months and Grade 3 events occurring within the first month. The median onset time for any grade event of hyperphosphataemia was 16 days. Vascular calcification has been observed in 0.2% of patients treated with erdafitinib. Hypercalcaemia and hyperparathyroidism have been observed in 6.1% and 2.9%, respectively, in patients treated with erdafitinib.

Hypophosphataemia

Erdafitinib can cause hypophosphataemia. Hypophosphataemia occurred in 5.6% of patients. Hypophosphataemia reactions were Grade 3-4 in 1.0% of patients. The median time to onset for Grade 3 was 140 days. None of the events were serious, led to discontinuation or to dose reduction. Dose interruption occurred in 0.2% of patients.

Abnormal laboratory findings

Abnormal laboratory findings (other than hyperphosphataemia, which is described separately), occurred in 53.4% of patients. The most commonly reported laboratory abnormalities were anaemia (28.2% (135 patients); median time to onset 44 days, 38.5% (52/135) resolved), alanine aminotransferase increased (21.7% (104 patients); median time to onset 41 days; 75% (78/104) resolved)), aspartate aminotransferase increased (18% (86 patients); median time to onset 37 days; 73.3% (63/86) resolved)), blood creatinine increased (14.2% (68 patients); median time to onset 57 days; 44.1% (30/68) resolved), and hyponatraemia (13.4% (64 patients); median time to onset 55 days; 51.6% (33/64) resolved).