Balversa is indicated for the treatment of adult patients with locally advanced or metastatic urothelial carcinoma (mUC), that has:

·      susceptible FGFR3 or FGFR2 genetic alterations, and

·      progressed during or following at least one line of prior platinum-containing chemotherapy, including within 12 months of neoadjuvant or adjuvant platinum-containing chemotherapy.

Balversa is for adult use only.

The recommended starting dose of Balversa is 8 mg (two 4 mg tablets) orally once daily, with a dose increase to 9 mg (three 3 mg tablets) once daily based on serum phosphate (PO4) levels and tolerability at 14 to 21 days.

Method of administration

Before taking BALVERSA, patients must have confirmation of certain FGFR gene alterations as confirmed by a validated test.

Swallow tablets whole with or without food. If vomiting occurs any time after taking Balversa, the next dose should be taken the next day. Treatment should continue until disease progression or unacceptable toxicity occurs.

Missed dose

If a dose of Balversa is missed, it can be taken as soon as possible on the same day. Resume the regular daily dose schedule for Balversa the next day. Extra tablets should not be taken to make up for the missed dose.

Dose Increase based on Serum Phosphate Levels

Assess serum phosphate levels 14 to 21 days after initiating treatment. Increase the dose of BALVERSA to 9 mg once daily if serum phosphate level is < 5.5 mg/dL and there are no ocular disorders or Grade 2 or greater adverse reactions. Monitor phosphate levels monthly for hyperphosphatemia.

The recommended dose modifications for adverse reactions are listed in the table below:

The following table summarizes recommendations for dose interruption, reduction, or discontinuation of Balversa in the management of specific adverse reactions.

^a           Dose adjustment graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAEv4.03).

Ocular Disorders

Balversa can cause ocular disorders, including central serous retinopathy/retinal pigment epithelial detachment (CSR/RPED) resulting in visual field defect.

CSR/RPED was reported in 25% of patients treated with Balversa, with a median time to first onset of 50 days. Grade 3 CSR/RPED, involving central field of vision, was reported in 3% of patients. CSR/RPED resolved in 13% of patients and was ongoing in 13% of patients at the study cutoff. CSR/RPED led to dose interruptions and reductions in 9% and 14% of patients, respectively and 3% of patients discontinued Balversa.

Dry eye symptoms occurred in 28% of patients during treatment with Balversa and were Grade 3 in 6% of patients. All patients should receive dry eye prophylaxis with ocular demulcents as needed.

Perform monthly ophthalmological examinations during the first 4 months of treatment and every 3 months afterwards, and urgently at any time for visual symptoms.

Ophthalmological examination should include assessment of visual acuity, slit lamp examination, fundoscopy, and optical coherence tomography.

Withhold Balversa when CSR occurs and permanently discontinue if it does not resolve within 4 weeks or if Grade 4 in severity. For ocular adverse reactions, follow the dose modification guidelines [see Posology and method of administration (4.2)].

Hyperphosphatemia and Soft Tissue Mineralization

Balversa can cause hyperphosphatemia leading to soft tissue mineralization, cutaneous calcinosis, non- uremic calciphylaxis and vascular calcification. Increases in phosphate levels are a pharmacodynamic effect of Balversa [see Pharmacodynamics (5.1)].

Hyperphosphatemia was reported as adverse reaction in 76% of patients treated with Balversa. The median onset time for any grade event of hyperphosphatemia was 20 days (range: 8 –116) after initiating Balversa. Thirty-two percent of patients received phosphate binders during treatment with Balversa.

Cutaneous calcinosis, non-uremic calciphylaxis and vascular calcification have been observed in 0.3% of patients treated with Balversa.

Monitor for hyperphosphatemia throughout treatment. In all patients, restrict phosphate intake to 600- 800 mg daily. If serum phosphate is above 7.0 mg/dL, consider adding an oral phosphate binder until serum phosphate level returns to <5.5 mg/dL. Withhold, dose reduce, or permanently discontinue Balversa based on duration and severity of hyperphosphatemia [see Posology and method of administration (4.2)]

Embryo-Fetal Toxicity

Based on the mechanism of action and findings in animal reproduction studies, BALVERSA can cause fetal harm when administered to a pregnant woman. In an embryo-fetal toxicity study, oral administration of erdafitinib to pregnant rats during the period of organogenesis caused malformations and embryo-fetal death at maternal exposures that were less than the human exposures at the maximum human recommended dose based on area under the curve (AUC). Advise pregnant women of the potential risk to the fetus. Advise female patients of reproductive potential to use effective contraception during treatment with BALVERSA and for one month after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with BALVERSA and for one month after the last dose [see mechanism of action (5.1) and fertility, pregnancy and lactation (4.6)]

Drug Interaction Studies

Clinical Studies and Model-Based Approaches

Moderate CYP2C9 Inhibitors:

Erdafitinib mean ratios (90% CI) for Cmax and AUCinf 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.

Strong CYP3A4 Inhibitors:

Erdafitinib mean ratios (90% CI) for Cmax and AUCinf were 105% (86.7, 127) and 134% (109, 164), respectively, when co-administered with itraconazole (a strong CYP3A4 inhibitor and P-gp inhibitor) relative to Erdafitinib alone.

Strong CYP3A4/2C9 Inducers:

Simulations suggested that rifampicin (a strong CYP3A4/2C9 inducer) may significantly decrease Erdafitinib Cmax and AUC.

In vitro Studies:

CYP Substrates:

Erdafitinib is a time dependent inhibitor and inducer of CYP3A4. The effect of erdafitinib on a sensitive CYP3A4 substrate is unknown. Erdafitinib is not an inhibitor of other major CYP isozymes at clinically relevant concentrations.

Transporters:

Erdafitinib is a substrate and inhibitor of P-gp. P-gp inhibitors are not expected to affect erdafitinib exposure to a clinically relevant extent. Erdafitinib is an inhibitor of OCT2.

Erdafitinib does not inhibit BCRP, OATP1B, OATP1B3, OAT1, OAT3, OCT1, MATE-1, or MATE-2K at clinically relevant concentrations.

Acid-Lowering Agents:

Erdafitinib has adequate solubility across the pH range of 1 to 7.4. Acid-lowering agents (e.g., antacids, H2-antagonists, proton pump inhibitors) are not expected to affect the bioavailability of erdafitinib.

Interactions can be summarized as follows: Effect of other drugs on Balversa

Effect of Balversa on other drugs

Pregnancy

There are no available data on Balversa use in pregnant women to inform a drug-associated risk. Based on the mechanism of action and findings in animal reproduction studies, Balversa can cause fetal harm when administered to a pregnant woman [see Pharmacological Properties (5)].

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. Lactation

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 Balversa and for one month following the last dose.

Females and Males of Reproductive Potential

Pregnancy Testing

Pregnancy testing is recommended for females of reproductive potential prior to initiating treatment with Balversa.

Contraception

Females

Balversa can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment with Balversa and for one month after the last dose.

Males

Advise male patients with female partners of reproductive potential to use effective contraception during treatment with Balversa and for one month after the last dose.

Infertility

Females

Based on findings from animal studies, Balversa may impair fertility in females of reproductive potential [see preclinical safety (5.3)].

Eye disorders such as central serous retinopathy or keratitis have been noted with FGFR inhibitors and with TRADENAME 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 profile

The most common adverse reactions (ARs) ≥15% were hyperphosphatemia, stomatitis, diarrhea, dry mouth, decreased appetite, dry skin, alopecia, palmar-plantar erythrodysesthesia syndrome, dry eye, onycholysis, paronychia,nail dystrophy and weight decreased. The most common G3 ARs >1% were stomatitis, hyponatremia,  nail dystrophy, palmar- plantar erythrodysesthesia syndrome, paronychia, nail disorder, keratitis, onycholysis, acute kidney injury and hyperphosphatemia. Adverse reactions leading to dose reduction occurred in patients, including for eye disorders. Patients experienced ARs leading to treatment discontinuation, including for eye disorders.

Below table presents ARs reported in ≥1% of patients treated with Balversa at 8 mg once daily in study BLC2001

Tabulated list of adverse reactions

The frequency categories of adverse reactions is defined as follows: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1000 to <1/100); rare (≥1/10000 to <1/1000); very rare (<1/10000); not known (cannot be estimated from the available data). Following this definition, the adverse reaction categories reported in patients treated with Balversa in study BLC2001(N=99) were either very common (≥1/10) or common (≥1/100 to <1/10).

Adverse events were coded using MedDRA version 20.0. In MedDRA version 20.0, the preferred terms of "Paronychia" and "Conjunctivitis" are coded to the system organ class of "Infections and infestations." In this analysis, they have been coded to the system organ classes of "Skin and subcutaneous tissue disorders" and "Eye disorders", respectively.

ⁱ Mod 2.5/ Section 5 (Clinical Overview, Update to the CCDS Regarding the Addition of Dysgeusia, Onychomadesis, Calciphylaxis and Cutaneous calcification as an Adverse Drug Reaction (ADR), EDMS-RIM-762621.

ii Mod 2.5/ Section 5 (Clinical Overview, Update to the CCDS Regarding the Addition of Dysgeusia, Onychomadesis,

Calciphylaxis and Cutaneous calcification as an Adverse Drug Reaction (ADR), EDMS-RIM-762621.

The following ARs were reported with the administration of BALVERSA in BLC2001 and other studies: Ocular Disorders

Balversa can cause ocular disorders, including central serous retinopathy/retinal pigment epithelial detachment (CSR/RPED) resulting in visual field defect.

CSR/RPED was reported in 25% of patients treated with Balversa, with a median time to first onset of 50 days. Grade 3 CSR/RPED, involving central field of vision, was reported in 3% of patients. CSR/RPED resolved in 13% of patients and was ongoing in 13% of patients at the study cutoff. CSR/RPED led to dose interruptions and reductions in 9% and 14% of patients, respectively and 3% of patients discontinued Balversa.

Dry eye symptoms occurred in 28% of patients during treatment with Balversa and were Grade 3 in 6% of patients. All patients should receive dry eye prophylaxis with ocular demulcents as needed.

Perform monthly ophthalmological examinations during the first 4 months of treatment and every 3 months afterwards, and urgently at any time for visual symptoms. Ophthalmological examination should include assessment of visual acuity, slit lamp examination, fundoscopy, and optical coherence tomography.

Withhold Balversa when CSR occurs and permanently discontinue if it does not resolve within 4 weeks or if Grade 4 in severity. For ocular adverse reactions, follow the dose modification guidelines [see Posology and method of administration (4.2) ].

Hyperphosphatemia

Increases in phosphate concentrations are an expected and transient laboratory abnormality. Hyperphosphatemia was reported as an adverse event in patients treated with Balversa. No event of hyperphosphatemia was reported as serious. The median onset time for any grade event of hyperphosphatemia was 20 days. Mean phosphate elevations peaked approximately 6 weeks after the start of Balversa and subsequently decreased to below 4.5 mg/dL by approximately month 5.

Electrolyte Abnormalities

In addition, the following electrolyte imbalances were reported;

calcium increased, phosphate decreased , sodium decreased, and magnesium decreased.

Elevated liver enzymes

An increase in alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase were reported.

Gastrointestinal disorders

Abdominal pain, nausea, constipation, and diarrhea were reported.

Others

Fatigue, dysgeusia, musculoskeletal pain, increased creatinine, decreased albumin, and decreased hemoglobin were reported.

Embryo-Fetal Toxicity

Based on the mechanism of action and findings in animal reproduction studies, Balversa can cause fetal harm when administered to a pregnant woman. In an embryo-fetal toxicity study, oral administration of erdafitinib to pregnant rats during the period of organogenesis caused malformations and embryo-fetal death at maternal exposures that were less than the human exposures at the maximum human recommended dose based on area under the curve (AUC). Advise pregnant women of the potential risk to the fetus. Advise female patients of reproductive potential to use effective contraception during treatment with Balversa and for one month after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with Balversa and for one month after the last dose [ Fertility, pregnancy and lactation (4.6) and Pharmacological Properties (5)].

To report any side effect(s):

Saudi Arabia:

Other GCC States:

In the event of an overdose, stop BALVERSA, undertake general supportive measures until clinical toxicity has diminished or resolved.

1.1 Pharmacotherapeutic group: ATC code: L01EN01 Mechanism of Action

Erdafitinib is a kinase inhibitor that binds to and inhibits enzymatic activity of FGFR1, FGFR2, FGFR3 and FGFR4 based on in vitro data. Erdafitinib also binds to RET, CSF1R, PDGFRA, PDGFRB, FLT4, KIT, and VEGFR2. Erdafitinib inhibited FGFR phosphorylation and signaling and 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.

Pharmacodynamic effects

Cardiac Electrophysiology

Based on 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.

Serum Phosphate

Erdafitinib increased serum phosphate level as a consequence of FGFR inhibition. Balversa 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 [see posology and method of administration (4.2)].

In Erdafitinib clinical trials, the use of drugs which can 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 exist. To manage phosphate elevation, phosphate binders were permitted. Avoid concomitant use with agents that can alter serum phosphate levels before the initial dose increase period based on serum phosphate levels.

Clinical efficacy and safety

Urothelial Carcinoma with Susceptible FGFR Genetic Alterations

Study BLC2001 (NCT02365597) was a multicenter, open-label, single-arm study to evaluate the efficacy and safety of Balversa in patients with locally advanced or metastatic urothelial carcinoma (mUC).

Fibroblast growth factor receptor (FGFR) mutation status for screening and enrollment of patients was determined by a clinical trial assay (CTA). The efficacy population consists of a cohort of eighty-seven patients who were enrolled in this study with disease that had progressed on or after at least one prior chemotherapy and that had at least 1 of the following genetic alterations: FGFR3 gene mutations (R248C, S249C, G370C, Y373C) or FGFR gene fusions (FGFR3-TACC3, FGFR3-BAIAP2L1, FGFR2-BICC1,

FGFR2-CASP7), as determined by the CTA performed at a central laboratory. Tumor samples from 69 patients were tested retrospectively by the QIAGEN therascreen® FGFR RGQ RT-PCR Kit, which is the FDA-approved test for selection of patients with mUC for BALVERSA.

Patients received a starting dose of BALVERSA at 8 mg once daily with a dose increase to 9 mg once daily in patients whose serum phosphate levels were below the target of 5.5 mg/dL between days 14 and 17; a dose increase occurred in 41% of patients.

Balversa was administered until disease progression or unacceptable toxicity. The major efficacy outcome measures were objective response rate (ORR) and duration of response (DoR), as determined by blinded independent review committee (BIRC) according to RECIST v1.1.

The median age was 67 years (range: 36 to 87 years), 79% were male, and 74% were Caucasian. Most patients (92%) had a baseline Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Sixty-six percent of patients had visceral metastases. Eighty-four (97%) patients received at least one of cisplatin or carboplatin previously. Fifty-six percent of patients only received prior cisplatin-based regimens, 29% received only prior carboplatin-based regimens, and 10% received both cisplatin and carboplatin-based regimens. Three (3%) patients had disease progression following prior platinum- containing neoadjuvant or adjuvant therapy only. Twenty-four percent of patients had been treated with prior anti PD-L1/PD-1 therapy. Overall response rate was 32.2%. Responders included patients who had previously not responded to anti PDL1/PD-1 therapy.

Following administration of 8 mg once daily, the mean (coefficient of variation [CV%]) erdafitinib 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.

Absorption

Median time to achieve peak plasma concentration (tmax) was 2.5 hours (range: 2 to 6 hours).

Effect of Food

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.

Distribution

The mean apparent volume of distribution of Erdafitinib was 29 L in patients.

Erdafitinib protein binding was 99.8% in patients, primarily to alpha-1-acid glycoprotein.

Elimination

The mean total apparent clearance (CL/F) of Erdafitinib was 0.362 L/h in patients. The mean effective half-life of Erdafitinib was 59 hours in patients.

Metabolism

Erdafitinib is primarily metabolized by CYP2C9 and CYP3A4. The contribution of

CYP2C9 and CYP3A4 in the total clearance of Erdafitinib is estimated to be 39% and 20% respectively. Unchanged Erdafitinib was the major drug-related moiety in plasma, there were no circulating metabolites.

Excretion

Following a single oral dose of radiolabeled Erdafitinib, approximately 69% of the dose was recovered in feces (19% as unchanged) and 19% in urine (13% as unchanged).

Specific Populations

No clinically meaningful trends in the pharmacokinetics of Erdafitinib were observed based on age (21-88 years), sex, race, body weight (36-132 kg), mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment, or mild to moderate renal impairment (eGFR 30 to 89 mL/min/1.73 m²) .Limited data are available in patients with severe (Child-Pugh C) hepatic impairment.

The pharmacokinetics of erdafitinib in patients with severe renal impairment and renal impairment requiring dialysis is unknown.

Renal Impairment

No dose adjustment is recommended for patients with mild to moderate renal impairment [estimated glomerular filtration rate (eGFR) 30 to 89 mL/min/1.73 m²]. No data are available in patients with severe renal impairment.

Hepatic Impairment

No dose adjustment is recommended for patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment. Limited data are available in patients with severe (Child-Pugh C) hepatic impairment.

CYP2C9 Poor Metabolizers

CYP2C9*3/*3 Genotype: 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.

Carcinogenesis

Carcinogenicity studies have not been conducted with Erdafitinib.

Mutagenesis

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.

Impairment of Fertility

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.

Tablet Core: Croscarmellose sodium, Magnesium stearate (from vegetable source), Mannitol, Meglumine, and Microcrystalline Cellulose.

Film Coating: (Opadry amb II): Glycerol monocaprylocaprate Type I, Polyvinyl alcoholpartially hydrolyzed, Sodium lauryl sulfate, Talc, Titanium dioxide, Iron oxide yellow,Iron oxide red (for the orange and brown tablets only), Ferrosoferric oxide/iron oxide black (for the brown tablets only).

Not applicable

Do not store above 30°C

For 3 mg tablets available in:

Bottle of 56-tablets with child resistant closure. Bottle of 84-tablets with child resistant closure.

For 4 mg tablets available in:

Bottle of 28-tablets with child resistant closure. Bottle of 56-tablets with child resistant closure.

For 5 mg tablets available in:

Bottle of 28-tablets with child resistant closure.

Balversa is available in a white 40 cc HDPE bottle with a child-resistant polypropylene closure and 2 x 1 g desiccant pouches.

Not all pack sizes may be marketed

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.