Veraxanib 50 mg film-coated tablets

Veraxanib 50 mg film-coated tablets

Each film-coated tablet contains 50 mg of veraxanib (as veraxanib hydrochloride).

Excipient(s) with known effect: Each tablet contains 45 mg of lactose monohydrate and 0.15 mg of sunset yellow (E110).

For the full list of excipients, see section 6.1.

Film-coated tablet.

Orange, round, biconvex film-coated tablets approximately 9 mm in diameter, debossed with "VX50" on one face.

Veraxanib is indicated as monotherapy for the treatment of adult patients with locally advanced or metastatic fibroblast growth factor receptor 2 (FGFR2)-altered solid tumours that have progressed following at least one prior line of systemic therapy and for which there are no satisfactory alternative treatment options.

A companion diagnostic device is required to confirm tumour FGFR2 alteration status prior to initiating treatment with Veraxanib (see section 4.4).

The recommended dose of Veraxanib is 50 mg taken orally once daily, with or without food.

Treatment should be continued until disease progression or unacceptable toxicity.

Missed doses: If a dose is missed, it should be taken as soon as the patient remembers unless it is within 12 hours of the next scheduled dose. In that case, the missed dose should be skipped and the next dose taken at the usual scheduled time. Patients should not take two doses on the same day to make up for a missed dose.

Dose modifications: Dose reductions to 25 mg once daily may be required due to adverse reactions (see section 4.8). Veraxanib should be permanently discontinued in patients who cannot tolerate 25 mg once daily.

Hepatic impairment: No dose adjustment is required in patients with mild or moderate hepatic impairment. Veraxanib has not been studied in patients with severe hepatic impairment and is not recommended in this population.

Renal impairment: No dose adjustment is required in patients with mild to moderate renal impairment. Limited data are available in severe renal impairment; use with caution.

Paediatric population: The safety and efficacy of Veraxanib in children and adolescents below 18 years of age have not been established. No data are available.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Concomitant use of strong CYP3A4 inducers (see section 4.5).

FGFR2 alteration testing
Patients must have FGFR2 alterations confirmed by a validated companion diagnostic test before initiating treatment with Veraxanib (see section 4.1).

Hyperphosphataemia
Hyperphosphataemia is a class effect of FGFR inhibitors and was observed in the majority of patients in clinical trials. Serum phosphate levels should be monitored before starting treatment, monthly for the first 3 months, and periodically thereafter. Hyperphosphataemia should be managed with dietary phosphate restriction, phosphate binders, and, if required, dose modification or interruption (see section 4.2).

Ocular toxicity
Retinal pigment epithelial detachment (RPED) and central serous retinopathy have been observed with Veraxanib. Patients should undergo baseline ophthalmological examination before initiating treatment. Any new or worsening visual symptoms, including blurred vision, should prompt urgent ophthalmological re-evaluation. Dose modification or discontinuation may be required depending on severity.

Hepatic toxicity
Elevations in hepatic enzymes (ALT, AST) have been reported. Liver function tests should be performed before starting treatment and monitored every 4 weeks for the first 3 months, then periodically thereafter.

Effect of other medicinal products on Veraxanib
Veraxanib is primarily metabolised by CYP3A4. Concomitant use of strong CYP3A4 inducers (e.g. rifampicin, phenytoin, carbamazepine, St. John's Wort [Hypericum perforatum]) is contraindicated as they significantly decrease veraxanib exposure (see section 4.3). Caution is advised with moderate CYP3A4 inducers; close monitoring for reduced efficacy is recommended.

Concomitant use of strong CYP3A4 inhibitors (e.g. ketoconazole, itraconazole, clarithromycin) may increase veraxanib exposure. Use with caution and consider dose reduction if toxicity occurs.

Effect of Veraxanib on other medicinal products
In vitro data suggest veraxanib is a weak inhibitor of CYP2D6. Caution should be exercised when co-administering medicinal products that are CYP2D6 substrates with a narrow therapeutic index (e.g. certain antidepressants, antipsychotics).

Veraxanib may reduce the efficacy of oral hormonal contraceptives. Non-hormonal or additional contraceptive measures should be used concurrently and for at least one month after stopping Veraxanib (see section 4.6).

Pregnancy
There are no adequate data on the use of Veraxanib in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). Veraxanib is not recommended during pregnancy unless the clinical condition requires treatment with Veraxanib. If used during pregnancy, or if the patient becomes pregnant while receiving Veraxanib, the patient should be apprised of the potential hazard to the foetus.

Women of childbearing potential / Contraception
Women of childbearing potential must use effective non-hormonal contraception during treatment and for at least one month after stopping Veraxanib (see section 4.5).

Male patients with female partners of childbearing potential should use effective contraception during treatment and for at least one month after stopping Veraxanib.

Breast-feeding
It is unknown whether veraxanib is excreted in human milk. A risk to the suckling child cannot be excluded. Breast-feeding should be discontinued during treatment with Veraxanib and for one month following the final dose.

Fertility
Based on animal studies, Veraxanib may impair male fertility (see section 5.3). No data on the effect of Veraxanib on female human fertility are available.

Veraxanib has minor influence on the ability to drive and use machines. Fatigue and visual disturbances have been reported (see section 4.8). Patients experiencing these symptoms should be advised not to drive or operate machinery until symptoms resolve.

Summary of the safety profile
The most common adverse reactions (≥10%) were: hyperphosphataemia, fatigue, diarrhoea, nausea, decreased appetite, stomatitis, palmar-plantar erythrodysaesthesia syndrome, alopecia, and dry skin.

Tabulated list of adverse reactions
Adverse reactions reported in clinical trials with Veraxanib are listed below by system organ class and frequency. Frequencies are defined as: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100).

Metabolism and nutrition disorders: Very common: hyperphosphataemia, decreased appetite. Common: hyponatraemia.
General disorders: Very common: fatigue. Common: peripheral oedema, weight decreased.
Gastrointestinal disorders: Very common: diarrhoea, nausea, stomatitis. Common: vomiting, constipation, abdominal pain, dysgeusia.
Skin and subcutaneous tissue disorders: Very common: palmar-plantar erythrodysaesthesia syndrome, alopecia, dry skin. Common: nail disorder.
Investigations: Common: increased ALT, increased AST, increased blood creatinine, increased blood alkaline phosphatase.
Eye disorders: Common: retinal pigment epithelial detachment, blurred vision, central serous retinopathy.

Description of selected adverse reactions
Hyperphosphataemia: Hyperphosphataemia was observed in approximately 85% of patients and was generally manageable with dietary restriction and phosphate binders. Dose reduction was required in 12% of patients.

There is no known antidote to Veraxanib. In the event of overdose, general supportive measures should be taken. Veraxanib is not dialysable.

Pharmacotherapeutic group: Antineoplastic agents, protein kinase inhibitors, ATC code: L01EN05.

Mechanism of action
Veraxanib is a selective, potent, reversible inhibitor of fibroblast growth factor receptor 2 (FGFR2) kinase. It inhibits FGFR2 autophosphorylation and downstream signalling through the MAPK and PI3K/AKT pathways in tumour cells harbouring FGFR2 gene fusions or activating mutations, leading to inhibition of cell proliferation and induction of apoptosis.

Clinical efficacy
Efficacy was established in study VRXB-101, an open-label, single-arm trial in 112 patients with advanced FGFR2-altered solid tumours who had received at least one prior line of systemic therapy. The primary endpoint was overall response rate (ORR) by independent radiological review.

The ORR was 38% (95% CI: 29–47%), with a median duration of response of 9.3 months (95% CI: 7.2–12.1 months). Median progression-free survival was 7.1 months (95% CI: 5.8–8.6 months). Median overall survival was not yet reached at the time of analysis.

Absorption
Veraxanib is absorbed following oral administration with a median time to maximum plasma concentration (Tmax) of 2–4 hours. The absolute oral bioavailability is approximately 71%. Administration with a high-fat meal did not alter overall exposure (AUC) but delayed Tmax by approximately 1 hour; no food restriction is required (see section 4.2). Steady-state is reached within 7 days of once-daily dosing.

Distribution
The apparent volume of distribution at steady state is approximately 185 L. Plasma protein binding is approximately 97%, primarily to albumin.

Metabolism
Veraxanib is metabolised primarily by CYP3A4 to an active M1 metabolite, which accounts for approximately 15% of total exposure. In vitro, veraxanib is a weak inhibitor of CYP2D6 (Ki 18 µM).

Elimination
The mean elimination half-life is approximately 24 hours at steady state. The apparent oral clearance is approximately 7 L/h. Excretion is primarily faecal (72%) with renal excretion accounting for approximately 21% of the dose.

Veraxanib was not genotoxic in a standard battery of in vitro and in vivo tests.

In repeat-dose toxicity studies up to 26 weeks in rats and dogs, the main findings were hyperphosphataemia, weight loss, and hepatocellular changes at exposures consistent with human therapeutic exposure. No carcinogenicity studies have been conducted with Veraxanib.

Reproductive and developmental toxicity studies in rats showed embryofoetal lethality and skeletal malformations at doses causing maternal toxicity. Effects on male fertility (reduced spermatogenesis) were observed at exposures approximately 2-fold above the human AUC at the recommended dose.

Veraxanib was phototoxic in an in vitro phototoxicity assay. The clinical relevance is unknown.

Tablet core: microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, magnesium stearate.

Film coat: polyvinyl alcohol, titanium dioxide, macrogol 3350, talc, sunset yellow aluminium lake (E110).

Not applicable.

36 months.

Store below 25°C. Store in the original container to protect from moisture. Keep out of the reach of children.

High-density polyethylene (HDPE) bottle with child-resistant polypropylene closure and desiccant.

Pack sizes: 30 film-coated tablets and 90 film-coated tablets.

No special requirements for disposal.

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

Veracore Therapeutics GmbH
Musterstraße 14
10115 Berlin
Germany

EU/1/23/1842/001 (30 film-coated tablets)
EU/1/23/1842/002 (90 film-coated tablets)

Date of first authorisation: 15 March 2023

08 April 2024