BALVERSA 3mg tablets medication leaflet

Balversa 3 mg film-coated tablets

Balversa 4 mg film-coated tablets

Balversa 5 mg film-coated tablets

Balversa 3 mg film-coated tablets

Each film-coated tablet contains 3 mg of erdafitinib.

Balversa 4 mg film-coated tablets

Each film-coated tablet contains 4 mg of erdafitinib.

Balversa 5 mg film-coated tablets

Each film-coated tablet contains 5 mg of erdafitinib.

For the full list of excipients, see section 6.1.

Film-coated tablet (tablet).

3 mg tablets

Yellow, round biconvex shaped film-coated tablet, 7.6 mm in diameter, debossed with “3” on oneside; and “EF” on the other side.

4 mg tablets

Orange, round biconvex shaped film-coated tablet, 8.1 mm in diameter, debossed with “4” on oneside; and “EF” on the other side.

5 mg tablets

Brown, round biconvex shaped film-coated tablet, 8.6 mm in diameter, debossed with “5” on one side;and “EF” on the other side.

Balversa as monotherapy is indicated for the treatment of adult patients with unresectable or metastaticurothelial carcinoma (UC), harbouring susceptible FGFR3 genetic alterations who have previouslyreceived at least one line of therapy containing a PD-1 or PD-L1 inhibitor in the unresectable ormetastatic treatment setting (see section 5.1).

Treatment with Balversa should be initiated and supervised by a physician experienced in the use ofanticancer therapies.

Before taking Balversa, the physician must have confirmation of (a) susceptible FGFR3 genealteration(s) (see section 5.1) assessed by a CE-marked in vitro diagnostic (IVD) medical device withthe corresponding intended purpose. If a CE-marked IVD is not available, an alternative validated testshould be used.

The recommended starting dose of Balversa is 8 mg orally once daily.

This dose should be maintained and serum phosphate level should be assessed between 14 and 21 daysafter initiating treatment. Up-titrate the dose to 9 mg once daily if the serum phosphate level is<9.0 mg/dL (<2.91 mmol/L), and there is no drug-related toxicity. If the phosphate level is 9.0 mg/dLor higher follow the relevant dose modifications in Table 2. After day 21 the serum phosphate levelshould not be used to guide up-titration decision.

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.

If a dose of Balversa is missed, it can be taken as soon as possible. The regular daily dose schedule for

Balversa should be resumed the next day. Extra tablets should not be taken to make up for the misseddose.

Dose reduction and management of adverse reactions

For recommended dose reduction schedule, see Tables 1 to 5.

Table 1: Balversa dose reduction schedule1st dose 2nd dose 3rd dose 4th dose 5th dose

Dose reduction reduction reduction reduction reduction9 mg 8 mg 6 mg 5 mg 4 mg Stop(e.g., three (e.g., two (two 3 mg (one 5 mg (one 4 mg3 mg tablets) 4 mg tablets) tablets) tablet) tablet)8 mg 6 mg 5 mg 4 mg Stop(e.g., two 4 mg (two 3 mg (one 5 mg (one 4 mgtablets) tablets) tablet) tablet)

Hyperphosphataemia management

Hyperphosphataemia is an expected, transient pharmacodynamic effect of FGFR inhibitors (seesections 4.4, pct. 4.8 and 5.1). Phosphate concentrations should be assessed prior to the first dose and thenmonitored monthly. For elevated phosphate concentrations in patients treated with Balversa dosemodification guidelines in Table 2 should be followed. For persistently elevated phosphateconcentrations, adding a non-calcium containing phosphate binder (e.g., sevelamer carbonate) shouldbe considered as needed (see Table 2).

Table 2: Recommended dose modifications based on serum phosphate concentrations withthe use of Balversa after up-titration

Serum phosphate Balversa managementconcentration

For phosphate concentrations ≥5.5 mg/dL (1.75 mmol/L), restrict phosphate intake to 600-800 mg/day.<6.99 mg/dL Continue Balversa at current dose.(<2.24 mmol/L)7.00-8.99 mg/dL Continue Balversa treatment.(2.25-2.90 mmol/L)

Start phosphate binder with food until phosphate level is<7.00 mg/dL.

A dose reduction should be implemented for a sustained serumphosphate level of ≥7.00 mg/dL for a period of 2 months or in thepresence of additional adverse events or additional electrolytedisturbances linked to prolonged hyperphosphataemia.

9.00-10.00 mg/dL Withhold Balversa treatment until serum phosphate level returns to(2.91-3.20 mmol/L) <7.00 mg/dL (weekly testing recommended).

Start phosphate binder with food until serum phosphate levelreturns to <7.00 mg/dL.

Re-start treatment at the same dose level (see Table 1).

A dose reduction should be implemented for sustained serumphosphate level of ≥9.00 mg/dL for a period of 1 month or in thepresence of additional adverse events or additional electrolytedisturbances linked to prolonged hyperphosphataemia.

>10.00 mg/dL Withhold Balversa treatment until serum phosphate level returns to(>3.20 mmol/L) <7.00 mg/dL (weekly testing recommended).

Re-start treatment at the first reduced dose level (see Table 1).

If serum phosphate level of ≥10.00 mg/dL is sustained for>2 weeks, Balversa should be discontinued permanently.

Medical management of symptoms as clinically appropriate (seesection 4.4).

Significant alteration from Balversa should be discontinued permanently.baseline renal function or

Grade 3 hypocalcaemia due Medical management as clinically appropriate.to hyperphosphataemia.

Eye disorder management

Treatment with Balversa should be discontinued or modified based on erdafitinib-related toxicity asdescribed in Table 3.

Table 3: Guideline for management of eye disorders with use of Balversa

Severity grading Balversa dose management

Grade 1 Refer for an ophthalmologic examination (OE). If an OE cannot be

Asymptomatic or mild performed within 7 days, withhold Balversa until an OE can besymptoms; clinical or performed.diagnostic observations If no evidence of eye toxicity on OE, continue Balversa at same doseonly, or abnormal level.

Amsler grid test. If diagnosis from OE is keratitis or retinal abnormality (e.g., CSRa),withhold Balversa until resolution. If reversible in 4 weeks on OE,resume at next lower dose.

Upon restarting Balversa, monitor for recurrence every 1-2 weeks for amonth and as clinically appropriate thereafter. Consider dose re-escalation if no recurrence.

Grade 2 Immediately withhold Balversa and refer for an OE.

Moderate; limiting age If there is no evidence of eye toxicity, resume erdafitinib therapy at theappropriate instrumental next lower dose level upon resolution.activities of daily living If resolved (complete resolution or stabilisation and asymptomatic)(ADL). within 4 weeks on OE, resume Balversa at the next lower dose level.

Upon restarting Balversa, monitor for recurrence every 1 to 2 weeks fora month and as clinically appropriate thereafter.

Grade 3 Immediately withhold Balversa and refer for an OE.

Severe or medically If resolved (complete resolution or stabilisation and asymptomatic)significant but not within 4 weeks, then Balversa may be resumed at 2 dose levels lower.immediate Upon restarting Balversa, monitor for recurrence every 1 to 2 weeks forsight-threatening; a month and as clinically appropriate thereafter.limiting self-care ADL. Consider permanent discontinuation of Balversa for recurrence.

Grade 4 Permanently discontinue Balversa.

Sight-threatening Monitor until complete resolution or stabilisation.consequences; blindness(20/200 or worse).a CSR-central serous retinopathy, see section 4.4

Nail, skin, and mucosal changes

Nail, skin, and mucosal changes have been observed with Balversa. Treatment with Balversa shouldbe discontinued or modified based on erdafitinib-related toxicity as described in Table 4.

Table 4: Recommended dose modifications for nail, skin and mucosal adverse reactionswith use of Balversa

Severity of adverse reaction Balversa

Nail disorder Balversa dose management

Grade 1 Continue Balversa at current dose.

Grade 2 Withhold Balversa with reassessment in 1-2 weeks.

If first occurrence and it resolves to ≤Grade 1 or baseline within2 weeks, restart at same dose.

If recurrent event or takes >2 weeks to resolve to ≤Grade 1 orbaseline, then restart at next lower dose.

Grade 3 Withhold Balversa, with reassessment in 1-2 weeks.

When resolves to ≤Grade 1 or baseline, restart at next lower dose.

Grade 4 Discontinue Balversa.

Dry skin and skin toxicity

Grade 1 Continue Balversa at current dose.

Grade 2 Continue Balversa at current dose.

Grade 3 Withhold Balversa (for up to 28 days), with weekly reassessmentsof clinical condition.

When resolves to ≤Grade 1 or baseline, restart at next lower dose.

Grade 4 Discontinue Balversa.

Oral mucositis

Grade 1 Continue Balversa at current dose.

Grade 2 Withhold Balversa if the subject has other concomitant erdafitinibrelated Grade 2 adverse reactions.

Withhold Balversa if the subject was already on symptommanagement for more than a week.

If Balversa is withheld, reassess in 1-2 weeks.

If this is the first occurrence of toxicity and resolves to ≤Grade 1 orbaseline within 2 weeks, restart at same dose.

If recurrent event or takes >2 weeks to resolve to ≤Grade 1 orbaseline, then restart at next lower dose.

Grade 3 Withhold Balversa, with reassessments of clinical condition in1-2 weeks.

When resolves to ≤Grade 1 or baseline, restart at next lower dose.

Grade 4 Discontinue Balversa.

Dry mouth

Grade 1 Continue Balversa at current dose.

Grade 2 Continue Balversa at current dose.

Grade 3 Withhold Balversa (for up to 28 days), with weekly reassessmentsof clinical condition.

When resolved to ≤Grade 1 or baseline, restart at next lower dose.

Table 5: Recommended dose modifications for other adverse reactions with use of Balversa

Other adverse reactionsa

Grade 3 Withhold Balversa until toxicity resolves to Grade 1 or baseline, thenmay resume Balversa at the next lower dose.

Grade 4 Permanently discontinue.a Dose adjustment graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI

CTCAEv5.0).

Based on population pharmacokinetic (PK) analyses, no dose adjustment is required for patients withmild or moderate renal impairment (see section 5.2). There are no data on the use of Balversa inpatients with severe renal impairment. Alternative treatment should be considered in patients withsevere renal impairment (see section 5.2).

No dose adjustment is required for patients with mild or moderate hepatic impairment (seesection 5.2). Limited data are available on the use of Balversa in patients with severe hepaticimpairment. Alternative treatment should be considered in patients with severe hepatic impairment(see section 5.2).

No specific dose adjustments are considered necessary for elderly patients (see section 5.2).

Limited data are available in patients older than 85 years old.

There is no relevant use of erdafitinib in the paediatric population for the treatment of urothelialcarcinoma.

Balversa is for oral use. The tablets should be swallowed whole with or without food at about the sametime each day.

Grapefruit or Seville oranges should be avoided while taking Balversa due to strong CYP3A4inhibition (see section 4.5).

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

Ocular disorders

Prior to initiating Balversa, a baseline ophthalmological exam including an Amsler grid test,fundoscopy, visual acuity and, if available, an optical coherence tomography (OCT) should beperformed.

Balversa can cause ocular disorders, including central serous retinopathy (CSR) (a grouped termincluding retinal pigment epithelial detachment (RPED)) resulting in visual field defect (seesections 4.7 and 4.8). The overall incidence of central serous retinopathy was higher in patients≥65 years of age (33.3%) compared with patients <65 years of age (28.8%). Events of RPED werereported more frequently in patients ≥65 years of age (6.3%) compared with patients <65 years of age(2.1%). Close clinical monitoring is recommended in patients aged 65 years and older as well as withpatients that have clinically significant medical eye disorders, such as retinal disorders, including butnot limited to, central serous retinopathy, macular/retinal degeneration, diabetic retinopathy, andprevious retinal detachment (see section 4.8).

Dry eye symptoms occurred in 16.7% of patients during treatment with Balversa and were Grade 3 or4 in 0.3% of patients (see section 4.8). All patients should receive dry eye prophylaxis or treatmentwith ocular demulcents (for example artificial tear substitutes, hydrating or lubricating eye gels orointment) at least every 2 hours during waking hours. Severe treatment-related dry eye should beevaluated by an ophthalmologist.

Perform monthly ophthalmological examinations including an Amsler grid test during the first4 months of treatment and every 3 months afterwards, and urgently at any time for visual symptoms(see section 4.2). If any abnormality is observed, follow the management guidelines in Table 3.

Ophthalmological examination should include assessment of visual acuity, slit lamp examination,fundoscopy, and optical coherence tomography. Close monitoring including clinical ophthalmologicalexaminations should be performed in patients who have restarted Balversa after an ocular adverseevent.

When CSR occurs Balversa should be withheld and permanently discontinued if it does not resolvewithin 4 weeks or if Grade 4 in severity. For ocular adverse reactions, follow the dose modificationguidelines (see section 4.2, Eye disorder management).

Hyperphosphataemia

Balversa can cause hyperphosphataemia. Prolonged hyperphosphataemia can lead to soft tissuemineralisation, cutaneous calcinosis, non-uraemic calciphylaxis, hypocalcaemia, anaemia, secondaryhyperparathyroidism, muscle cramps, seizure activity, QT interval prolongation and arrhythmias.

Hyperphosphataemia was reported early during Balversa treatment, with most events occurring withinthe first 3-4 months and Grade 3 events occurring within the first month.

Monitor for hyperphosphataemia throughout treatment. Dietary phosphate intake (600-800 mg daily)should be restricted and concomitant use of agents that may increase serum phosphate levels should beavoided for serum phosphate levels ≥5.5 mg/dL (see section 4.2). Supplementation with vitamin D inpatients receiving erdafitinib is not recommended due to potential contribution to increased serumphosphate and calcium levels.

If serum phosphate is above 7.0 mg/dL, consider adding an oral phosphate binder until serumphosphate level returns to <7.0 mg/dL. Consider withholding, reducing the dose, or permanentlydiscontinuing Balversa based on duration and severity of hyperphosphataemia, according to Table 2(see section 4.2).

Caution is advised when administering Balversa with medicinal products known to prolong the QTinterval 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 medicinalproducts, macrolide antibiotics, SSRIs (e.g., citalopram, escitalopram), methadone, moxifloxacin, andantipsychotics (e.g., haloperidol and thioridazine).

Hypophosphataemia

Hypophosphataemia can occur during treatment with Balversa. Serum phosphate level should bemonitored during erdafitinib treatment and erdafitinib treatment breaks. If the serum phosphate levelfalls below normal, phosphate-lowering therapy and dietary phosphate restrictions (if applicable)should be discontinued. Severe hypophosphataemia may present with confusion, seizures, focalneurologic findings, heart failure, respiratory failure, muscle weakness, rhabdomyolysis, andhaemolytic anaemia. For dose modifications see section 4.2. Hypophosphataemia reactions were

Grade 3-4 in 1.0% of patients.

Nail disorders

Nail disorders including onycholysis, nail discolouration and paronychia can occur very commonlywith Balversa treatment (see section 4.8).

Patients should be monitored for signs and symptoms of nail toxicities. Patients should be advised onpreventative treatment such as good hygiene practices, over-the-counter nail strengthener as neededand monitor for signs of infection. Treatment with Balversa should be discontinued or modified basedon erdafitinib-related toxicity as described in Table 4.

Skin disorders including dry skin, palmar-plantar erythrodysaesthesia (PPES) syndrome, alopecia andpruritus can occur very commonly with Balversa treatment (see section 4.8). Patients should bemonitored and provided supportive care such as avoiding unnecessary exposure to sunlight andexcessive use of soap and bathing. Patients should use moisturisers regularly and avoid perfumedproducts. Treatment with Balversa should be discontinued or modified based on erdafitinib-relatedtoxicity as described in Table 4.

Photosensitivity reactions

Care should be taken with sun exposure by wearing protective clothing and/or sunscreen due to thepotential risk of phototoxicity reactions associated with Balversa treatment.

Mucosal disorders

Stomatitis and dry mouth can occur very commonly with Balversa treatment (see section 4.8). Patientsshould be counselled to seek medical attention should symptoms worsen. Patients should be monitoredand provided supportive care as such as good oral hygiene, baking soda mouthwashes 3 or 4 times perday as needed and avoidance of spicy and/or acidic foods. Treatment with Balversa should bediscontinued or modified based on erdafitinib-related toxicity as described in Table 4.

Creatinine elevations, hyponatraemia, transaminase elevations, and anaemia have been reported inpatients receiving Balversa (see section 4.8). Complete blood counts and serum chemistries should beperformed regularly during treatment with Balversa to monitor for these changes.

Based on the mechanism of action and findings in animal reproduction studies, erdafitinib isembryotoxic and teratogenic (see section 5.3). Pregnant women should be advised of the potential riskto the foetus. Female patients of reproductive potential should be advised to use highly effectivecontraception prior to and during treatment, and for 1 month after the last dose (see section 4.6). Malepatients should be counselled to use effective contraception (e.g., condom) and not donate or storesemen during treatment with and for 1 month after the last dose of Balversa (see section 4.6).

Pregnancy testing with a highly sensitive assay is recommended for females of reproductive potentialprior to initiating Balversa.

Combination with strong or moderate CYP2C9 or CYP3A4 inhibitors

Concomitant use of Balversa with moderate CYP2C9 or strong CYP3A4 inhibitors requires doseadjustment (see section 4.5).

Combination with strong or moderate CYP3A4 inducers

Concomitant use of Balversa with strong CYP3A4 inducers is not recommended. Concomitant use of

Balversa with moderate CYP3A4 inducers requires dose adjustment (see section 4.5).

Combination with hormonal contraceptives

Concomitant administration of Balversa may reduce the efficacy of hormonal contraceptives. Patientsusing hormonal contraceptives should be advised to use an alternative contraceptive not affected byenzyme 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 Balversa (see sections 4.5and 4.6).

Each film-coated tablet contains less than 1 mmol sodium (23 mg), that is to say essentially‘sodium-free’.

Effect of other medicinal products on Balversa

Moderate CYP2C9 or strong CYP3A4 inhibitors

Co-administration with a moderate CYP2C9 or strong CYP3A4 inhibitor increased erdafitinibexposure and may lead to increased drug-related toxicity. Erdafitinib mean ratios (90% CI) for Cmaxand AUC∞ were 121% (99.9, 147) and 148% (120, 182), respectively, when co-administered withfluconazole, a moderate CYP2C9 and CYP3A4 inhibitor, relative to erdafitinib alone. Cmax oferdafitinib was 105% (90% CI: 86.7, 127) and AUC∞ was 134% (90% CI: 109, 164) whenco- administered with itraconazole, a strong CYP3A4 inhibitor and P-gp inhibitor, relative toerdafitinib alone. Consider alternative agents with no or minimal enzyme inhibition potential. If

Balversa is co-administered with a moderate CYP2C9 or strong CYP3A4 inhibitor (such asitraconazole, ketoconazole, posaconazole, voriconazole, fluconazole, miconazole, ceritinib,clarithromycin, telithromycin, elvitegravir, ritonavir, paritaprevir, saquinavir, nefazodone, nelfinavir,tipranavir, lopinavir, amiodarone, piperine), reduce the Balversa dose to the next lower dose based ontolerability (see section 4.2). If the moderate CYP2C9 or strong CYP3A4 inhibitor is discontinued, the

Balversa dose may be adjusted as tolerated (see section 4.4).

Grapefruit or Seville oranges should be avoided while taking Balversa due to strong CYP3A4inhibition (see section 4.2).

Strong or moderate CYP3A4 inducers

Co-administration with carbamazepine, a strong CYP3A4 and weak CYP2C9 inducer leads todecreased erdafitinib exposure. Mean ratios of Cmax 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 carbamazepinerelative to erdafitinib alone. Avoid co-administration of Balversa with strong CYP3A4 inducers (suchas apalutamide, enzalutamide, lumacaftor, ivosidenib, mitotane, rifapentine, rifampicin,carbamazepine, phenytoin, and St. John’s wort). If Balversa 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 everytwo to three weeks based on clinical monitoring for adverse reactions, not to exceed 9 mg. If themoderate CYP3A4 inducer is discontinued, the Balversa dose may be adjusted as tolerated (seesections 4.2 and 4.4).

Effect of Balversa on other medicinal products

Major CYP isoform substrates (including hormonal contraceptives)

Mean ratios of Cmax 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 erdafitinibrelative 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 Balversa alone orconcomitant administration of other CYP3A4 inducers together with Balversa may reduce the efficacyof hormonal contraceptives.

Patients using hormonal contraceptives should be advised to use an alternative contraceptive notaffected by enzyme inducers (e.g., non-hormonal intrauterine device) or an additional nonhormonalcontraception (e.g., condom) during treatment with and until 1 month after the last dose of Balversa(see section 4.4).

P-Glycoprotein (P-gp) substrates

Erdafitinib is an inhibitor of P-gp. Concomitant administration of Balversa with P-gp substrates mayincrease 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 tominimise the potential for interactions.

Organic cation transporter 2 (OCT2) substrates

Mean ratios of Cmax and AUC∞ for metformin (a sensitive OCT2 substrate) were 109% (90% CI: 90.3,131) and 114% (90% CI: 93.2, 139), respectively, when co-administered with erdafitinib relative tometformin alone. Erdafitinib does not have a clinically meaningful effect on metformin PK.

Medicinal products that can alter serum phosphate levels

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

Based on the mechanism of action and findings in animal reproduction studies, erdafitinib can causefoetal harm when administered to pregnant women. Female patients of child-bearing potential shouldbe advised to use highly effective contraception prior to and during treatment, and for 1 month afterthe last dose of Balversa. 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

Balversa.

Concomitant administration of Balversa may reduce the efficacy of hormonal contraceptives. Patientsusing hormonal contraceptives should be advised to use an alternative contraceptive not affected byenzyme 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 Balversa (see section 4.5).

Pregnancy testing with a highly sensitive assay is recommended for females of reproductive potentialprior to initiating Balversa.

There are no data from the use of erdafitinib in pregnant women. Animal studies have shownreproductive toxicity (see section 5.3). Based on the mechanism of action of erdafitinib and thefindings in animal reproduction studies, Balversa should not be used during pregnancy unless theclinical condition of the women requires treatment with erdafitinib.

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

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

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

There are no human data on the impact of erdafitinib on fertility. Dedicated animal fertility studieshave not been conducted with erdafitinib (see section 5.3). Based on preliminary fertility assessment ingeneral animal studies (see section 5.3) and on the pharmacology of erdafitinib, impairment of maleand female fertility cannot be excluded.

Balversa has moderate influence on the ability to drive and use machines. Eye disorders such ascentral serous retinopathy or keratitis have been noted with FGFR inhibitors and with Balversatreatment. If patients experience treatment related symptoms affecting their vision, it is recommendedthat they do not drive or use machines until the effect subsides (see section 4.4).

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%), central serous retinopathy(28.0%), anaemia (28.2%), constipation (27.3%), dysgeusia (26.3%), palmar-plantarerythrodysaesthesia syndrome (PPES) (25.5%), alopecia (23.2%), asthenia (23.0%), alanineaminotransferase increased (21.7%), onycholysis (21.7%), fatigue (20.3%), nausea (18.6%), weightdecreased (18.4%), aspartate aminotransferase increased (18.0%), 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%), nail disorder (10.2%)and abdominal pain (10.0%).

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 4related TEAEs (47.6% vs 43.5%) and related serious adverse events (14.6% vs 10.5%) were reportedmore 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 ofretinal pigment epithelium (1.7%) and stomatitis (1.5%) were the most common adverse eventsleading to treatment discontinuations.

The safety profile is based on pooled data from 479 locally advanced unresectable or metastaticurothelial carcinoma patients who were treated with Balversa in clinical studies. Patients were treatedwith Balversa 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 Table 6 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.

Table 6: Adverse reactions identified in clinical studies

System organ class Frequency Adverse reaction

Endocrine disorders common hyperparathyroidism

Metabolism and nutrition very common hyperphosphataemia, hyponatraemia,disorders decreased appetitecommon Hypercalcaemia, hypophosphataemia

Nervous system disorders very common dysgeusia

Eye disorders very common central serous retinopathya, dry eyecommon ulcerative keratitis, keratitis, conjunctivitis,xerophthalmia, cataract, blepharitis,lacrimation increased

Vascular disorders uncommon vascular calcification

Respiratory, thoracic and very common epistaxismediastinal disorders common nasal dryness

Gastrointestinal disorders very common diarrhoea, stomatitisb, dry mouth,constipation, nausea, vomiting, abdominalpaincommon dyspepsia

Skin and subcutaneous tissue very common paronychia, onycholysis, onychomadesis,disorders nail dystrophy, nail disorder, naildiscolouration, palmar-plantarerythrodysaesthesia syndrome, alopecia, dryskincommon onychalgia, onychoclasis, nail ridging, skinfissures, pruritus, skin exfoliation,xeroderma, hyperkeratosis, skin lesion,eczema, rashuncommon nail bed bleeding, nail discomfort, skinatrophy, palmar erythema, skin toxicity

Renal and urinary disorders common acute kidney injury, renal impairment, renalfailure

Hepatobiliary disorders common hepatic cytolysis, hepatic function abnormal,hyperbilirubinaemia

General disorders and very common asthenia, fatigueadministration site conditions uncommon mucosal dryness

Blood and lymphatic system very common anaemiadisorders

Investigations very common weight decreased, blood creatinine increased,alanine aminotransferase increased, aspartateaminotransferase increaseda 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, Serousretinopathy, Maculopathy, Choroidal effusion, vision blurred, visual impairment, visual acuity reduced.

b Stomatitis includes mouth ulceration.

Central serous retinopathy (CSR)

Adverse reactions of CSR were reported in 31.5% of patients with a median time to first onset, for anevent of any grade, of 51 days (see section 4.4). The most commonly reported events were visionblurred, chorioretinopathy, detachment of RPE, visual acuity reduced, visual impairment, retinaldetachment, retinopathy, and subretinal fluid. Grade 3 or 4 CSR was reported in 2.7% of patients. Themajority of central serous retinopathy events occurred within the first 90 days of treatment. At the timeof data cutoff, CSR had resolved for 43.0% of patients. In patients with CSR, 11.3% had doseinterruptions and 14.6% had dose reductions. There were 3.3% of patients who discontinued Balversadue 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%), andsubretinal fluid (0.2%).

Other eye disorders

Eye disorders (other than central serous retinopathy) were reported in 36.3% of patients. The mostcommonly reported events were dry eye (16.7%), conjunctivitis (9.8%) and lacrimation increased(9.2%). Of patients with events, pct. 4.8% had dose reductions and 6.7% had dose interruptions. Therewere 1.3% who discontinued erdafitinib due to eye disorders. The median time to first onset for eyedisorders was 53 days (see section 4.4).

Nail disorders

Nail disorders were reported in 62.6% of patients. The most commonly reported events includedonycholysis (21.7%), nail discolouration (15.9%), paronychia (12.5%), nail dystrophy (11.9%) andonychomadesis (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 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 anygrade skin disorder was 47 days.

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

Hyperphosphataemia and soft tissue mineralisation

Erdafitinib can cause hyperphosphataemia. Increases in phosphate concentrations are an expected andtransient pharmacodynamic effect (see section 5.1). Hyperphosphataemia was reported as an adverseevent in 78.5% of patients treated with Balversa. Hyperphosphataemia was reported early duringerdafitinib 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 ofhyperphosphataemia was 16 days. Vascular calcification has been observed in 0.2% of patients treatedwith Balversa (see section 4.2). Hypercalcaemia and hyperparathyroidism have been observed in 6.1%and 2.9%, respectively, in patients treated with Balversa (see Table 2 in section 4.2).

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), alanineaminotransferase 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 onset57 days; 44.1% (30/68) resolved), and hyponatraemia (13.4% (64 patients); median time to onset55 days; 51.6% (33/64) resolved).

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

There is no known specific antidote for Balversa overdose. In the event of an overdose, stop Balversa,undertake general supportive measures until clinical toxicity has diminished or resolved.

Pharmacotherapeutic group: antineoplastic agents, protein kinase inhibitors. ATC code: L01EN01

Erdafitinib is a pan-fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor.

Serum phosphate

Erdafitinib increases serum phosphate concentration, a secondary effect of FGFR inhibition (seesections 4.2 and 4.8).

The efficacy of Balversa was evaluated in BLC3001 Study Cohort 1, a Phase 3, randomised,open-label, multicentre study to evaluate the overall survival (OS) of erdafitinib versus chemotherapy(docetaxel or vinflunine) in patients with advanced (unresectable or metastatic) urothelial cancerharbouring selected FGFR alterations, who have progressed after 1 or 2 prior treatments, at least 1 ofwhich includes a programmed death receptor-1 (PD-1) or programmed death-ligand 1 (PD-L1)inhibitor (anti-PD-(L)1) used in the locally advanced unresectable or metastatic treatment setting.

Patients who received neoadjuvant or adjuvant chemotherapy or immunotherapy and showed diseaseprogression within 12 months of the last dose are considered to have received systemic therapy in themetastatic setting. Patients with uncontrolled cardiovascular disease within the preceding 3 months orwith grade 2 or higher (≥481 ms) QTc prolongation and impaired wound healing were excluded fromthe study, as well as patients with central serous retinopathy or retinal pigment epithelial detachmentof any grade.

Main efficacy data are based on 266 patients who received prior anti-PD-(L)1 treatment and wererandomised to erdafitinib (8 mg with individualised up-titration to 9 mg if the serum phosphate level is<9.0 mg/dL, and there was no drug-related toxicity) versus chemotherapy (docetaxel 75 mg/m2 onceevery 3 weeks or vinflunine 320 mg/m2 once every 3 weeks).

In the study, eligible patients were required to have at least 1 of the following FGFR fusions:

FGFR2-BICC1, FGFR2-CASP7, FGFR3-TACC3, FGFR3-BAIAP2L1; or 1 of the following FGFR3gene mutations: R248C, S249C, G370C, Y373C. Molecular eligibility was determined using central(74.6%) or local (25.4%) FGFR results. Tumour samples were tested for FGFR genetic alterationswith the Qiagen Therascreen FGFR RGQ RT-PCR Kit at the central laboratory. Local historical teston tumour or blood samples were based on local next generation sequencing (NGS) tests. Among thelimited number of patients enrolled by local tests who had tumour samples available for confirmationtesting, a 75.6% agreement was observed when tested using the central test.

In the study cohort, 99.2% of patients had FGFR genetic alterations (2 patients did not have FGFRalterations: 80.8% of patients had FGFR3 mutations, 16.5% of patients had FGFR3 fusions, and 1.9%of patients had both FGFR3 mutations and fusions). No patients were observed with FGFR2alterations in this study cohort. A tumour harbouring susceptible FGFR3 genetic alterations is atumour with at least 1 of the following FGFR fusions: FGFR3-TACC3, FGFR3-BAIAP2L1; or 1 ofthe following FGFR3 gene mutations: R248C, S249C, G370C, Y373C. All patients in the study cohortwith FGFR alterations had at least 1 FGFR3 alteration. FGFR3-S249C was the most prevalentalteration (46.6%) followed by FGFR3-Y373C (16.9%), and FGFR3-TACC3 fusion (9.8%).

The demographic characteristics were balanced across the erdafitinib and chemotherapy treatmentgroups. The median age at full-study screening was 67 years (range: 32 to 86 years). The majority ofpatients were 65 years or older: 19.9% 65 to 69 years; 19.9% 70 to 74 years; 21.1% 75 years or older.

The majority of patients were male (71.4%), white (54.1%), and from Europe (60.9%).

All patients had transitional cell carcinoma, with a small percentage (5.3%) of patients having minorcomponents (<50% overall) of variant histology. The primary tumour location was the upper tract for33.5% of patients and lower tract for 66.5%. Patients had baseline ECOG scores of 0 (42.9%), 1(47.7%), or 2 (9.4%).

All patients received at least 1 prior line of anti-cancer therapy and must have included an anti-

PD-(L)-1. The most frequently received anti-PD-(L)1 therapies, included pembrolizumab (35.3%),avelumab (22.2%) and atezolizumab (19.5%). Prior treatment with chemotherapy was not required,however, the majority of patients (89.1%) received at least one line of prior chemotherapy. Almost allpatients received platinum-based chemotherapy (89.7% in erdafitinib group, 85.4% in chemotherapygroup): most frequently cisplatin (55.9% in erdafitinib group, 45.4% in chemotherapy group) followedby carboplatin (27.2% in erdafitinib group, 31.5% in chemotherapy group).

The primary efficacy endpoint was Overall Survival. Assessment of radiographic response wasperformed by investigators according to RECIST (Response Evaluation Criteria in Solid Tumours

Version 1.1) until disease progression, intolerable toxicity, withdrawal of consent, or decision by theinvestigator to discontinue treatment, or the end of the study, whichever occurred first.

Progression-Free Survival (PFS), Objective Response Rate (ORR) and Duration of Response wereincluded as secondary efficacy endpoints.

Treatment with erdafitinib showed a statistically significant improvement in OS for patients treatedwith erdafitinib, with erdafitinib prolonging OS compared to treatment with chemotherapy (median

OS of 12.1 vs 7.8 months) (see Table 7).

Efficacy results are summarised in Table 7.

Table 7: Overview of Efficacy Results for Study BLC3001 Cohort 1

Erdafitinib Chemotherapy(N=136) (N=130)

Overall Survival (OS)

Number of events (%) 77 (56.6%) 78 (60.0%)

Median, months (95% CI) 12.06 (10.28, 16.36) 7.79 (6.54, 11.07)

HR (95% CI) 0.64 (0.44, 0.93)a

P-value 0.0050

Progression-free survival (PFS)

Number of events (%) 101 (74.3%) 90 (69.2%)

Median, months (95% CI) 5.55 (4.40, 5.65) 2.73 (1.81, 3.68)

HR (95% CI) 0.58 (0.41, 0.82)a

P-value 0.0002

Objective response rate (ORR),confirmed

ORR (CR + PR) 48 (35.3%) 11 (8.5%)

Duration of response (DoR),investigator assessed, confirmed

Median, months (95% CI) 5.55 (4.17, 8.31) 5.75 (4.86, 7.16)

All p-values reported are 2-sided.a Repeated confidence intervals are provided.

The Kaplan-Meier OS curve for the two treatment arms is presented in Figure 1.

Figure 1. Kaplan-Meier Plot of Overall Survival - Unstratified Analysis (BLC3001 Study

Cohort 1)

Log-rank p value 0.0050

Months since randomisation

Subjects at risk

Erdafitinib

Chemotherapy

Erdafitinib Chemotherapy

In the clinical study of Balversa, 60.9% of patients were 65 years and older (39.8% were 65-<75 yearsold and 21.1% of patients were 75 years and older). No overall difference in efficacy was observedbetween elderly and younger adult patients.

The European Medicines Agency has waived the obligation to submit the results of studies witherdafitinib in all subsets of the paediatric population in urothelial carcinoma (see section 4.2 forinformation on paediatric use).

Following single and repeat once daily dosing, erdafitinib exposure (maximum observed plasmaconcentration [Cmax] and area under the plasma concentration time curve [AUC]) increased in adose-proportional manner across the dose range of 0.5 to 12 mg. Steady state was achieved after2 weeks with once daily dosing and the mean accumulation ratio was 4-fold in patients with cancer.

Following administration of 8 mg once daily, the proposed starting dose, mean (coefficient ofvariation [CV%]) erdafitinib steady-state Cmax, AUCτ, and minimum observed plasma concentration(Cmin) were 1399 ng/mL (50.8%), 29268 ng.h/mL (59.9%), and 936 ng/mL (64.9%) in patients withcancer. Daily fluctuations in erdafitinib plasma concentrations were low, with a mean (CV%) peak-to-trough ratio of 1.47 (23%) at steady state upon daily dosing.

OS probability (%)

After single dose oral administration, median time to achieve peak plasma concentration (tmax) was2.5 hours (range: 2 to 6 hours) in healthy volunteers and oral absorption is near complete.

Administration of erdafitinib to healthy volunteers under fasting conditions and with a high-fat mealdid not result in clinically relevant changes in Cmax and AUC. The mean AUC∞ and Cmax decreased by6% and 14%, respectively, when erdafitinib is co-administered with a high-fat meal. Median time toreach tmax was delayed about 1.5 hours with food (see section 4.2).

The mean apparent volume of distribution of erdafitinib in patients with cancer was 0.411 L/kg.

Erdafitinib was 99.7% bound to human plasma proteins, preferentially to α1 acid glycoprotein.

Metabolism is the main route of elimination for erdafitinib. Erdafitinib is primarily metabolised inhuman by CYP2C9 and CYP3A4 to form the O demethylated major metabolite. 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 nocirculating metabolites.

Mean total apparent clearance (CL/F) of erdafitinib was 0.362 L/h in patients with cancer.

The mean effective half-life of erdafitinib in patients with cancer was 58.9 hours.

Up to 16 days following a single oral administration of radiolabelled [14C]-erdafitinib, 69% of the dosewas recovered in faeces (14-21% as unchanged erdafitinib) and 19% in urine (13% as unchangederdafitinib) in healthy volunteers.

No clinically meaningful differences in the pharmacokinetics of erdafitinib were observed based onage (21-92 years), sex, race (White, Hispanic or Asian), body weight (36-166 kg), mild or moderaterenal impairment and mild or moderate hepatic impairment.

Pharmacokinetics of erdafitinib has not been studied in paediatric patients.

No clinically meaningful differences in the pharmacokinetics of erdafitinib were observed betweensubjects with normal renal function (absolute GFR-MDRD [absolute glomerular filtration ratemodification of diet in renal disease] ≥90 mL/min), and subjects with mild (absolute GFR‑MDRD 60to 89 mL/min) and moderate renal impairment (absolute GFR‑MDRD 30 to 59 mL/min) based onpopulation PK analysis. No information is available for subjects with severe renal impairment(absolute GFR‑MDRD less than 30 mL/min) or renal impairment requiring dialysis due to scarcity of

PK data (n=7, 0.8%).

The pharmacokinetics of erdafitinib was examined in participants with preexisting mild n=8) ormoderate n=8) hepatic impairment (Child-Pugh Class A and B, respectively) and in healthy controlparticipants with normal hepatic function (n=8). The total AUC∞ were 82% and 61% in participantswith mild and moderate hepatic impairment compared with participants with normal hepatic function,respectively. The total Cmax were 83% and 74% in participants with mild and moderate hepaticimpairment compared with participants with normal hepatic function, respectively. The free AUC∞were 95% and 88% in participants with mild and moderate hepatic impairment compared withparticipants with normal hepatic function, respectively. The free Cmax were 96% and 105% inparticipants with mild and moderate hepatic impairment compared with participants with normalhepatic function, respectively. No clinically meaningful differences in the pharmacokinetics oferdafitinib were observed in subjects with mild (Child-Pugh A) or moderate (Child-Pugh B) hepaticimpairment and subjects with normal hepatic function. The pharmacokinetics of erdafitinib in subjectswith severe hepatic impairment is unknown due to limited data.

Effect of P-gp inhibitors on erdafitinib

Erdafitinib is a substrate for P-gp. P-gp inhibitors are not expected to affect the PK of erdafitinib in aclinically relevant manner.

Effect of acid lowering agents on erdafitinib

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

Effect of Sevelamer on erdafitinib

No clinically meaningful differences in the pharmacokinetics of erdafitinib were observed in patientstaking sevelamer.

The main toxicological findings following repeat-dose administration of erdafitinib in both rats anddogs were related to the pharmacological activity of erdafitinib as an irreversible inhibitor of FGFR,including increased inorganic phosphorus and calcium in plasma, ectopic mineralisation in variousorgans and tissues, lesions in bone/cartilage at erdafitinib exposures lower than the human exposure atthe recommended clinical dose. Corneal atrophy (thinning of the corneal epithelium) was seen in ratsand lacrimal gland atrophy, changes to haircoat and nails as well as dental changes after 3 months oftreatment was seen in rats and dogs. Disturbance of phosphate homeostasis was observed in rats anddogs at exposures less than the human exposures at all doses studied.

Soft tissue mineralisations (except for the aorta mineralisation in dogs) and chondroid dysplasia in ratsand dogs and mammary gland atrophy in rats were partially to fully recovered at the end of a 4-weekdrug-free recovery period.

Erdafitinib is an intrinsic human ether-à-go-go-related gene (hERG) blocker with a proarrhythmicliability which translated into a prolonged repolarisation (corrected QT interval) after intravenousdosing in the anaesthetised dog and guinea pig, and after oral dosing in the conscious dog. The noeffect level represents a safety margin of 2.4 relative to the clinical steady-state free maximum plasmaconcentration (Cmax, u) for a 9 mg once daily dose.

Long-term animal studies have not been conducted to evaluate the carcinogenic potential oferdafitinib. Erdafitinib was considered not genotoxic in the standard panel of good laboratory practice(GLP) genotoxicity assays.

Erdafitinib was teratogenic and embryotoxic in rats at exposures less than the human exposures. Foetaltoxicity was characterised by hand/foot defects and malformations of some major blood vessels, suchas the aorta (see sections 4.4 and 4.6).

Dedicated animal fertility studies have not been conducted with erdafitinib. However, in the 3-monthgeneral toxicity study, erdafitinib showed effects on female reproductive organs (necrosis of thecorpora lutea) in rats at an exposure approximating the AUC in patients at maximum recommendeddose of 9 mg, QD.

Balversa 3 mg film-coated tablets

Croscarmellose sodium

Magnesium stearate (E572)

Mannitol (E421)

Meglumine

Microcrystalline cellulose (E460)

Film-coating (Opadry amb II)

Glycerol monocaprylocaprate Type I

Polyvinyl alcohol-partially hydrolysed

Sodium lauryl sulfate

Talc

Titanium dioxide (E171)

Iron oxide yellow (E172)

Balversa 4 mg film-coated tablets

Croscarmellose sodium

Magnesium stearate (E572)

Mannitol (E421)

Meglumine

Microcrystalline cellulose (E460)

Film-coating (Opadry amb II)

Glycerol monocaprylocaprate Type I

Polyvinyl alcohol-partially hydrolysed

Sodium lauryl sulfate

Talc

Titanium dioxide (E171)

Iron oxide yellow (E172)

Iron oxide red (E172)

Balversa 5 mg film-coated tablets

Croscarmellose sodium

Magnesium stearate (E572)

Mannitol (E421)

Meglumine

Microcrystalline cellulose (E460)

Film-coating (Opadry amb II)

Glycerol monocaprylocaprate Type I

Polyvinyl alcohol-partially hydrolysed

Sodium lauryl sulfate

Talc

Titanium dioxide (E171)

Iron oxide yellow (E172)

Iron oxide red (E172)

Iron oxide black (E172)

Not applicable.

Bottles4 years

This medicinal product does not require any special storage conditions.

HDPE (high-density polyethylene) bottle with a child-resistant PP (polypropylene) closure andinduction seal liner. Each carton contains one bottle with 28, 56 or 84 film-coated tablets.

3 mg tablet:

- Each carton of 56 film-coated tablets contains one bottle of 56 tablets.

- Each carton of 84 film-coated tablets contains one bottle of 84 tablets.

4 mg tablet:

- Each carton of 28 film-coated tablets contains one bottle of 28 tablets.

- Each carton of 56 film-coated tablets contains one bottle of 56 tablets.

5 mg tablet:

- Each carton of 28 film-coated tablets contains one bottle of 28 tablets.

Not all pack sizes may be marketed.

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

Janssen-Cilag International NV

Turnhoutseweg 30

B-2340 Beerse

Belgium

EU/1/24/1841/003

EU/1/24/1841/004

EU/1/24/1841/008

EU/1/24/1841/009

EU/1/24/1841/011

Date of first authorisation: 22 August 2024

Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu.