Leaflet VORANIGO 40mg film-coated tablets

Voranigo 10 mg film-coated tablets

Voranigo 40 mg film-coated tablets

Voranigo 10 mg film-coated tablets

Each film-coated tablet contains 10 mg of vorasidenib (as hemicitric acid, hemihydrate).

Each film-coated tablet contains lactose monohydrate, equivalent to 0.60 mg lactose (see section 4.4).

Voranigo 40 mg film-coated tablets

Each film-coated tablet contains 40 mg of vorasidenib (as hemicitric acid, hemihydrate).

Each film-coated tablet contains lactose monohydrate, equivalent to 2.39 mg lactose (see section 4.4).

For the full list of excipients, see section 6.1.

Film-coated tablet

Voranigo 10 mg film-coated tablets

White to off-white, round tablets with a 6 mm diameter, imprinted with ‘10’ on one side.

Voranigo 40 mg film-coated tablets

White to off-white, oblong tablets with a length of 14.8 mm and width of 6.3 mm, imprinted with ‘40’on one side.

Voranigo as monotherapy is indicated for the treatment of predominantly non-enhancing Grade 2astrocytoma or oligodendroglioma with an IDH1 R132 or IDH2 R172 mutation in adult andadolescent patients aged 12 years and older and weighing at least 40 kg who only had surgicalintervention and are not in immediate need of radiotherapy or chemotherapy (see section 5.1).

Treatment should be initiated and supervised by a physician experienced in the use of anti-cancermedicinal products.

Before taking Voranigo, patients must have confirmation of an isocitrate dehydrogenase-1 (IDH1)

R132 or isocitrate dehydrogenase-2 (IDH2) R172 mutation using an appropriate diagnostic test. Thepresence of an IDH1 R132 or IDH2 R172 mutation should be asessed by a CE-marked in vitrodiagnostic (IVD) with the corresponding intended purpose. If the CE-marked IVD is not available,

IDH1 R132 or IDH2 R172 mutation should be assessed by an alternative validated test.

The recommended dose of Voranigo in adults and adolescents 12 years of age and older is 40 mg oncedaily for patients weighing at least 40 kg. No dose recommendation can be made in patients weighingless than 40 kg because of the lack of clinical data in this population.

Treatment should be continued as long as clinical benefit is observed or until treatment is no longertolerated by the patient.

Missed or delayed doses

If a dose is missed or not taken at the usual time, it should be taken as soon as possible within 6 hoursafter the missed dose. The next dose should be taken at the regularly scheduled time.

If a dose is missed by more than 6 hours, it should be skipped and the next dose should be taken at theregularly scheduled time.

If a dose is vomited, replacement tablets should not be taken. The tablets should be taken as usual thefollowing day.

Precautions to be taken prior to administration and monitoring

Complete blood counts and blood chemistries, including liver enzymes, should be assessed prior tostarting treatment, every 2 weeks during the first 2 months and then once monthly for the first 2 yearsof treatment, and as clinically indicated thereafter. Certain patients may require more frequent andongoing monitoring (see section 4.4).

Dose modifications for adverse reactions

Dose interruption or dose reduction may be required based on individual safety and tolerability. Therecommended dose reduction levels are provided in Table 1.

Table 1: Recommended dose reduction levels

Dose level Dose and schedule Number and strength of tablets

Starting dose 40 mg once daily One 40 mg tablet/once daily

First dose reduction 20 mg once daily Two 10 mg tablets/once daily

Second dose reduction 10 mg once daily One 10 mg tablet/once daily

The recommended Voranigo dose modifications and management for adverse reactions are providedin Table 2.

Table 2: Recommended Voranigo dose modifications and management for adverse reactions

Adverse reaction Severitya Management and dose modifications

Hepatotoxicity Grade 1 Continue Voranigo at current dose.(Elevation of ALT or ALT or AST increase >ULN to Monitor liver enzymes weekly until

AST) 3 x ULN without concurrent total recovery to <Grade 1.(see section 4.4) bilirubin >2 x ULN

Grade 2 First occurrence: Withhold Voranigo and

ALT or AST >3 to 5 x ULN monitor liver enzymes twice per week untilwithout concurrent total bilirubin recovery to ≤Grade 1 or baseline.>2 x ULN * Recovery in ≤28 days, resume

Voranigo at the same dose.

* Recovery in >28 days, resume

Voranigo at reduced dose (see

Table 1).

Recurrence: Withhold Voranigo andmonitor liver enzymes twice per week untilrecovery to ≤Grade 1 or baseline, andresume Voranigo at reduced dose (see

Table 1).

Grade 3 First occurrence: Withhold Voranigo and

ALT or AST >5 to 20 x ULN monitor liver enzymes twice per week untilwithout concurrent total bilirubin recovery to ≤Grade 1 or baseline.>2 x ULN * Recovery in ≤28 days, resume

Voranigo at reduced dose (see

Table 1).

* If not recovered in ≤28 days,permanently discontinue Voranigo.

Recurrence: Permanently discontinue

Voranigo and monitor liver enzymes twiceper week until recovery to ≤Grade 1 orbaseline.

Grade 2 or 3 Permanently discontinue Voranigo and

Any ALT or AST >3 to 20 x ULN monitor liver enzymes twice per week untilwith concurrent total bilirubin recovery to ≤Grade 1 or baseline.>2 x ULN in absence of clearalternative explanation.b

Grade 4 Permanently discontinue Voranigo and

Any ALT or AST >20 x ULN monitor liver enzymes twice per week untilrecovery to ≤Grade 1 or baseline.

Other adverse Grade 3 First occurrence: Withhold Voranigo untilreactions recovery to ≤Grade 1 or baseline.

* Resume Voranigo at reduced dose(see Table 1).

Recurrence: Permanently discontinue

Voranigo.

Grade 4 Permanently discontinue Voranigo.

Abbreviations: ALT = Alanine aminotransferase; AST = Aspartate aminotransferase; ULN = Upper limitof normala Adverse reactions graded by the National Cancer Institute Common Terminology Criteria for Adverse

Events (NCI-CTCAE) version 5.0.b If an alternative aetiology is identified, consider resuming Voranigo at reduced dose (see Table 1)following resolution to Grade 1 or baseline.

No dose adjustment is recommended for patients ≥ 65 years of age (see section 5.2).

No starting dose adjustment is recommended for patients with renal impairment (estimated glomerularfiltration rate [eGFR] > 40 mL/min/1.73 m2). The pharmacokinetics of vorasidenib and metabolite

AGI-69460 have not been studied in patients with eGFR ≤ 40 mL/min/1.73 m2 or renal impairmentrequiring dialysis. Vorasidenib should not be used in patients with eGFR ≤ 40 mL/min/1.73 m2 or whorequire dialysis (see sections 4.4 and 5.2).

No starting dose adjustment is recommended for patients with mild or moderate (Child-Pugh class Aor B) hepatic impairment. The pharmacokinetics of vorasidenib and AGI-69460 have not been studiedin patients with severe hepatic impairment (Child-Pugh class C). Vorasidenib should be used withcaution in patients with severe hepatic impairment and this patient population should be closelymonitored. (see sections 4.4 and 5.2).

No clinical data are available in children aged 12 years to < 18 years (see section 5.1).

Voranigo is for oral use.

The tablets should be taken once daily at about the same time each day. Patients should not eat food atleast 2 hours before and 1 hour after taking Voranigo (see section 5.2). The tablets are to be swallowedwhole with a glass of water and should not be split, crushed or chewed as no data are available toconfirm similar bioavailability of the drug product when tablet manipulations are applied.

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

Drug-induced hepatotoxicity, including serious cases of hepatic failure, hepatic necrosis and hepatitisacute have been reported in patients treated with vorasidenib in the pivotal clinical study or in post-marketing experience (see section 4.8).

Liver enzymes (including ALT, AST and gamma-glutamyl transferase (GGT)) and total bilirubin mustbe monitored prior to starting treatment, every 2 weeks during the first 2 months of treatment and thenonce monthly for the first 2 years of treatment, and as clinically indicated thereafter. Consider weeklymonitoring for ALT or AST elevations ≤ 3 times the ULN. Withhold, reduce dose or permanentlydiscontinue treatment based on the severity of the liver enzyme abnormalities (see section 4.2).

Carcinogenicity risk

Animal findings may be suggestive of potential carcinogenic risk (notably in liver, see section 5.3).

Carcinogenicity studies have not been conducted yet and long-term clinical safety data are insufficient.

Therefore, a carcinogenicity risk in humans could not be excluded.

Vorasidenib could cause foetal harm when administered to a pregnant woman. Pregnancy testing isrecommended in women of childbearing potential prior to starting treatment. Women of childbearingpotential should use effective contraception during treatment and for at least 2 months after the lastdose. Women who are planning to conceive a child should be advised to seek reproductivecounselling.

Vorasidenib may decrease concentrations of hormonal contraceptives and, therefore, concomitant useof a barrier method of contraception is recommended during treatment and for at least 2 months afterthe last dose (see sections 4.5 and 4.6).

Male patients

Males with female partners of childbearing potential should use effective contraception duringtreatment and for at least 2 months after the last dose. Men should seek advice on cryo-preservation ofsperm prior to treatment (see section 4.6).

The safety and efficacy of vorasidenib have not been established in patients with severe hepaticimpairment (Child-Pugh class C). Vorasidenib should be used with caution in patients withpre-existing severe hepatic impairment (Child-Pugh class C) and this patient population should beclosely monitored (see sections 4.2 and 5.2).

The pharmacokinetics and safety of vorasidenib have not been studied in patients with renalimpairment (eGFR ≤ 40 mL/min/1.73 m2) or renal impairment requiring dialysis. Vorasidenib shouldnot be used in these patients (see sections 4.2 and 5.2).

Voranigo contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactasedeficiency or glucose-galactose malabsorption should not take this medicinal product.

This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially‘sodium-free’.

Based on in vitro experiments vorasidenib is a strong inducer by means of pregnane X receptor (PXR)activation and may affect the plasma exposure of co-administered medicines that are metabolised ortransported by enzymes or transporters whose expression is mediated by PXR.

Effect of other medicinal products on vorasidenib

Strong CYP1A2 inhibitors

Co-administration of vorasidenib with strong CYP1A2 inhibitors (fluvoxamine and ciprofloxacin)may increase vorasidenib plasma concentration. Concomitant use of strong CYP1A2 inhibitors shouldbe avoided and consider alternative therapies that are not strong inhibitors of CYP1A2 duringtreatment with vorasidenib.

In an in vivo drug-drug interaction study, co-administration of 20 mg vorasidenib with a strong

CYP1A2 inhibitor (500 mg ciprofloxacin twice daily for 14 days) increased vorasidenib maximumplasma concentration (Cmax) by 29% and area under the plasma time-concentration curve (AUC) by153%.

Moderate CYP1A2 inducers

Co-administration of vorasidenib with moderate CYP1A2 inducers (phenytoin and rifampicin) maydecrease vorasidenib plasma concentration. Consider alternative therapies that are not moderate

CYP1A2 inducers during treatment with vorasidenib.

Gastric acid reducing agents

No clinically significant differences in vorasidenib pharmacokinetics were observed followingco-administration of vorasidenib with the gastric acid reducing agent omeprazole.

Effect of vorasidenib on other medicinal products

Cytochrome P450 (CYP) substrates with narrow therapeutic index

Co-administration of vorasidenib with CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP3A4 substrateswith narrow therapeutic index (including, but not limited to, amitriptyline, alfentanil, carbamazepine,ciclosporin, dosulepin, everolimus, fentanyl, fosphenytoin, ifosfamide, imipramine, phenobarbital,phenytoin, pimozide, quinidine, sirolimus, tacrolimus, tamoxifen, trimipramine, valproic acid, andwarfarin) may decrease the plasma concentrations of these medicinal products. Concomitant use ofsubstrates of these enzymes with narrow therapeutic index should be avoided in patients takingvorasidenib.

Sensitive substrates of CYP enzymes without narrow therapeutic index

Co-administration of vorasidenib with sensitive substrates of CYP2B6, CYP2C8, CYP2C9,

CYP2C19, or CYP3A4 without narrow therapeutic index (including, but not limited to, bupropion,buspirone, celecoxib, darunavir, ibrutinib, midazolam, repaglinide, saquinavir, tipranavir, andtriazolam) may decrease the plasma concentrations of these medicinal products. Consider alternativetherapies that are not sensitive substrates of these enzymes during treatment with vorasidenib.

Interactions with transporters

In vitro, vorasidenib is an inhibitor of breast cancer resistance protein (BCRP) (see section 5.2).

Caution should be exercised when administering vorasidenib with BCRP substrates (including, but notlimited to, rosuvastatin).

Vorasidenib may decrease concentrations of hormonal contraceptives and, therefore, concomitant useof a barrier method of contraception is recommended during treatment and for at least 2 months afterthe last dose (see sections 4.4 and 4.6).

Pregnancy testing is recommended in women of childbearing potential prior to starting treatment withvorasidenib (see section 4.4).

Women of childbearing potential and males with female partners of childbearing potential should useeffective contraception during treatment and for at least 2 months after the last dose. Since the effectof vorasidenib on the metabolism and efficacy of systemically acting hormonal contraceptives has notbeen investigated, barrier methods should be applied as a second form of contraception to avoidpregnancy (see sections 4.4 and 4.5).

There are no or limited amount of data from the use of vorasidenib in pregnant women. Studies inanimals have shown embryo-foetal development toxicity (see section 5.3).

Vorasidenib should not be used during pregnancy and in women of childbearing potential not usingcontraception. Women of childbearing potential or male patients with female partners of childbearingpotential should be advised on the potential risk to a foetus.

It is unknown whether vorasidenib and its metabolites are excreted in human milk. Breast-feedingshould be discontinued during treatment and for at least 2 months after the last dose.

There are no human data on the effect of vorasidenib on fertility. Findings on reproductive organswere observed during repeat-dose toxicity studies in female and male animals (see section 5.3). Theclinical relevance of these effects is unknown. Male and female patients who are planning to conceivea child should be advised to seek reproductive counselling, and men should seek advice oncryo-preservation of sperm prior to treatment (see section 4.4).

Vorasidenib has no or negligible influence on the ability to drive and use machines.

The most common adverse reactions, including laboratory abnormalities, were ALT increased(59.3%), AST increased (45.5%), GGT increased (37.7%), fatigue (36.5%) and diarrhoea (24.6%).

The most common grade ≥ 3 adverse reactions were ALT increased (9.6%), AST increased (4.2%) and

GGT increased (3.0%).

Serious adverse reactions of hepatic failure, autoimmune hepatitis and ALT increased each occurred in0.6% of patients who received Voranigo.

Permanent discontinuation of vorasidenib due to grade ≥ 3 ALT increased or autoimmune hepatitiswas reported in 3.0% and 0.6% of patients, respectively.

Dose interruptions due to an adverse reaction occurred in 18.6% of patients treated with vorasidenib.

The most common adverse reactions requiring dose interruption were ALT increased (14.4%) and

AST increased (6.0%).

Dose reductions of vorasidenib due to an adverse reaction occurred in 9.6% of patients. The mostcommon adverse reaction requiring dose reduction was ALT increased (7.8%).

The adverse reactions described in this section are derived from study data (INDIGO study [N=167])and post-marketing experience with Voranigo.

The adverse reactions reported in patients treated with vorasidenib are listed below in Table 3 by

MedDRA system organ class and by frequency.

Frequencies are defined as very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1 000to < 1/100), rare (≥ 1/10 000 to < 1/1 000), very rare (< 1/10 000), not known (cannot be estimatedfrom available data). Within each frequency grouping, adverse reactions are presented in order ofdecreasing seriousness.

Table 3: Adverse drug reactions reported in patients treated with vorasidenib

System organ class Frequency Adverse reactions

Blood and lymphatic systemdisorders Very common Platelet count decreaseda

Metabolism and nutrition Common Hyperglycaemiadisorders Decreased appetite

Hypophosphataemia

Nervous system disorders Very common Dizziness

Respiratory, thoracic andmediastinal disorders Common Dyspnoea

Gastrointestinal disorders Very common Diarrhoea

Abdominal pain

Common Gastro-oesophageal reflux disease

Alanine aminotransferase increaseda

Very common Aspartate aminotransferase increaseda

Gamma-glutamyl transferase increaseda

Common Alkaline phosphatase increaseda

Hepatobiliary disorders Blood bilirubin increaseda

Hepatic failure

Uncommon Autoimmune hepatitis

Hepatic necrosis

Not known Drug-induced liver injury*

Hepatitis acute*

General disorders andadministration site conditions Very common Fatigue

*Identified during post-approval use.aLaboratory abnormality is defined as new or worsened by at least one grade from baseline, or baseline isunknown.

In the INDIGO study, of the 167 patients treated with vorasidenib, 18.6% experienced elevations in

ALT > 3 times the ULN and 8.4% experienced elevations in AST > 3 times the ULN. Among thesepatients, 1.2% had concurrent elevations in ALT or AST > 3 times the ULN and total bilirubin > 2 timesthe ULN. Liver enzyme and bilirubin increases were transient and improved or resolved with dosemodification or permanent discontinuation of treatment (see sections 4.2 and 4.4). The median time tofirst event onset for AST and ALT increased (any grade) was 85.0 days (range: 14 - 451 days) and 57.0days (range: 1 - 506 days). Each of the following adverse reactions, hepatic failure, hepatic necrosis andautoimmune hepatitis, was reported once with vorasidenib in the INDIGO study (see section 4.4).

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allowscontinued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals areasked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

In the event of overdose, toxicity is likely to manifest as exacerbation of the adverse reactionsassociated with vorasidenib (see section 4.8). Patients should be closely monitored and provided withappropriate supportive care (see sections 4.2 and 4.4). There is no specific antidote for vorasideniboverdose.

Pharmacotherapeutic group: Antineoplastic agents; other antineoplastic agents

ATC code: L01XM04

Vorasidenib is an inhibitor that targets the mutant IDH1 and IDH2 enzymes. In patients withastrocytoma or oligodendroglioma, IDH1 and IDH2 mutations lead to overproduction of theoncogenic metabolite 2-hydroxyglutarate (2-HG), resulting in impaired cellular differentiationcontributing to oncogenesis. Inhibition of the IDH1- and IDH2-mutated proteins by vorasidenibinhibits the abnormal production of 2-HG leading to differentiation of malignant cells and a reductionin their proliferation. Pre-clinical studies investigating the ability of vorasidenib to decrease tumoursize were not performed.

A therapeutic daily dose of vorasidenib was observed to decrease 2-HG tumour concentrations insubjects with IDH1 or IDH2 mutated glioma.

The efficacy and safety of vorasidenib were evaluated in the INDIGO trial, a phase 3, randomised(1:1), multicentre, double-blind, placebo-controlled study of 331 adults and adolescents ≥ 12 years oldweighing ≥ 40 kg. Eligible patients were required to have Grade 2 astrocytoma or oligodendrogliomaas defined by 2016 WHO criteria with an IDH1 R132 mutation or IDH2 R172 mutation, had surgeryincluding biopsy, sub-total resection, or gross-total resection as their only treatment and were not inimmediate need of chemotherapy or radiotherapy in the opinion of the investigator. Patients who had

MRI-evaluable, measurable, non-enhancing disease, as confirmed by the blinded independent reviewcommittee (BIRC) were enrolled. Patients with centrally-confirmed enhancing disease were permittedto enrol provided that the enhancement was minimal, non-nodular, non-measurable and had notchanged between the 2 most recent scans. The INDIGO trial excluded patients who received prioranti-cancer treatment, including chemotherapy or radiation therapy. IDH1 or IDH2 mutation statuswas prospectively determined using the Oncomine Dx Target Test.

Patients were randomised to receive either vorasidenib 40 mg orally once daily or matched placebountil radiographic disease progression or unacceptable toxicity. Randomisation was stratified by local1p19q status (co-deleted or not co-deleted) and baseline tumour size (diameter ≥ 2 cm or < 2 cm).

Patients who were randomised to placebo were allowed to cross over to receive vorasidenib afterdocumented radiographic disease progression provided that they were not in need of immediatechemotherapy or radiotherapy in the opinion of the investigator.

The primary efficacy outcome measure was radiographic progression-free survival (PFS) as evaluatedby a BIRC according to modified response assessment in neuro-oncology for low grade glioma(RANO-LGG) criteria (radiographic progression only).

Patient demographics and disease characteristics were balanced between the treatment arms. Amongthe 168 patients randomised to vorasidenib, the median age was 41 years (range: 21 to 71 years), with98.8% aged 18-64 years. A single paediatric patient aged 16 years was randomised to placebo, and nopatient under the age of 18 was randomised to vorasidenib. A majority of patients were male (60.1%),74.4% were White, 3.0% Asian, 1.2% Black, 1.2% other, 19.6% not reported and 53.6% had a

Karnofsky Performance Status (KPS) score of 100, 45.8% had a KPS score of 90-80, and 0.6% had a

KPS score of 70-60. Most patients had at least 1 prior surgery for glioma (75%) and 25% had ≥ 2 priorsurgeries. Across both arms, 95% of patients had an IDH1 R132 mutation and 5% had an IDH2 R172mutation.

Efficacy results for PFS are summarised in Table 4 and Figure 1.

Table 4: Efficacy results for the INDIGO trial (Study AG881-C-004)

Voranigo

Efficacy parameter 40 mg daily Placebo(n=168) (n=163)

Progression-free survival (PFS)

Number of events, n (%)

Progressive disease 47 (28.0) 88 (54.0)

Death 0 0

Median PFS, months (95% CI)a 27.7 (17.0, NE) 11.1 (11.0, 13.7)

Hazard ratio (95% CI)b 0.39 (0.27, 0.56)p-valuec 0.000000067

Abbreviations: CI = Confidence interval; NE = Not estimable

The full analysis set included all patients who had undergone randomisation.a The 95% confidence interval for the median was calculated using the Brookmeyer and Crowley method.b Estimated with Cox proportional hazard model adjusted by the following stratification factors: 1p19qstatus and baseline tumour size.c Estimated from one-sided stratified log-rank test. PFS was tested at a one-sided efficacy α-level of0.000359, based on an updated efficacy boundary corresponding to the 82% information fraction.

Figure 1: Kaplan-Meier curve for progression-free survival per BIRC review in INDIGO trial

An updated PFS by BIRC analysis, carried out at 96% (N = 158) of events, confirmed the benefit ofvorasidenib compared to placebo (hazard ratio: 0.35 [95% CI: 0.25, 0.49]). At 24 months, theprogression-free survival rate was 59% (95% CI: 48.4, 67.8) in the vorasidenib arm and 26%(95% CI: 17.9, 35.3) in the placebo arm. The median PFS was not estimable (95% CI: 22.1, NE) forthe vorasidenib arm and was 11.4 (95% CI: 11.1, 13.9) months for the placebo arm.

Adolescents from 12 to less than 18 years of age

Use of vorasidenib in patients aged 12 years to less than 18 years with IDH1 or IDH2 mutantastrocytoma or oligodendroglioma is supported by pharmacokinetic data demonstrating that age hadno clinically meaningful effect on the pharmacokinetics of vorasidenib (see section 5.2).

The pharmacokinetics of vorasidenib have been characterised in patients with low-grade glioma withan IDH1 or IDH2 mutation and in healthy subjects. The pharmacokinetic profile of vorasidenib issimilar between patients with low-grade glioma and healthy subjects.

After a single 40 mg oral dose, the median time to Cmax (Tmax) for vorasidenib was 2.0 hours, thegeometric mean Cmax was 75.4 ng/mL (CV%: 44), and the geometric mean AUC was 2,860 hr*ng/mL(CV%: 56). At steady-state, vorasidenib geometric mean Cmax was 133 ng/mL (CV%: 73) andgeometric mean AUC was 1,988 hr*ng/mL (CV%: 95). In most patients, a second plasmaconcentration peak occurred within 24 hours after drug administration but was lower than the observed

Cmax at 2 hours post-dose. Although absolute bioavailability has not been directly determined, theabsorption of vorasidenib is estimated to be moderate to high for the 40 mg film-coated tablets.

Accumulation ratios were approximately 3.8 for Cmax and 4.4 for AUC. Steady-state plasma levelswere reached after 2 to 3 weeks of once-daily dosing.

The mean Cmax and AUC of vorasidenib increased by 3.1-fold and 1.4-fold, respectively, whenvorasidenib was administered with a high-fat meal. Administration of vorasidenib with a low-fat mealresulted in increases in vorasidenib Cmax and AUC of 2.3- and 1.4-fold, respectively (see section 4.2).

Vorasidenib has a mean apparent volume of distribution of 3,930 L (CV%: 40). The vorasidenibvolume of distribution following a single 0.1 mg IV microdose is 1,110 L. The bound plasma proteinfraction for vorasidenib and AGI-69460 was 97% and 87%, respectively. Both vorasidenib and

AGI-69460 exhibit preferential binding to serum albumin over alpha-1 acid glycoprotein. Vorasidenibblood to plasma ratio is 0.87, AGI-69460 blood to plasma ratio is 1.38, and vorasidenib brain tumourto plasma concentration ratio is 1.6.

Vorasidenib is primarily metabolised by CYP1A2 with negligible to minor contributions from

CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4/5. Non-CYP pathways maycontribute up to 30% of vorasidenib liver metabolic clearance.

AGI-69460 is a downstream active metabolite of vorasidenib. After a single 40 mg vorasideniboral dose, the observed Tmax for metabolite AGI-69460 was 336 hours, the observed geometricmean Cmax was 3.32 ng/mL (CV%: 55.6), and the geometric mean AUC0-t was 1,172 hr*ng/mL(CV%: 61). At steady-state, geometric mean AGI-69460 Cmin,ss was 111 ng/mL (CV%: 58) andgeometric mean AUC0-4 at cycle 2 day 1 was 190 hr*ng/mL (CV%: 90).

In vitro, vorasidenib has a strong induction effect on sensitive CYP3A4 substrates and a moderateinduction effect on sensitive CYP2B6 and CYP2C19 substrates (see section 4.5).

In vitro data indicate that vorasidenib is an inhibitor of BCRP. Vorasidenib does not inhibit

P-glycoprotein (P-gp) and hepatic transporter organic anion transporting polypeptide (OATP)1B1. Invitro, AGI-69460 is an inhibitor of BCRP and OATP1B3.

Vorasidenib is not a substrate of P-gp, BCRP, or hepatic transporters OATP1B1 and OATP1B3.

Approximately 89% of the administered vorasidenib radioactive dose, using a powder-in-capsuleformulation with an absolute bioavailability of < 34%, was recovered over 44 days, with 85% infaeces and 4.5% in urine. Most of the administered radioactivity that was recovered in faeces wasunchanged vorasidenib (55%) while no unchanged vorasidenib was detected in urine.

The mean terminal half-life of vorasidenib is 238 hours (CV%: 57), the effective half-life is 63.2 hours(CV%: 75) and the mean apparent clearance is 14.0 L/h (CV%: 56).

Following administration of Voranigo, vorasidenib Cmax and AUC increases in a proportional mannerbetween 10 and 40 mg.

No clinically meaningful effects on the pharmacokinetics of vorasidenib were observed in olderpatients up to 75 years (see section 4.2).

Renal impairment (eGFR > 40 mL/min/1.73 m2) had no clinically significant effect on thepharmacokinetics of vorasidenib. The pharmacokinetics of vorasidenib in patients witheGFR ≤ 40 mL/min/1.73 m2 or renal impairment requiring dialysis are unknown.

Moderate hepatic impairment (Child-Pugh class B) had no clinically significant effects on vorasideniband AGI-69460 pharmacokinetics. There were no clinically relevant changes in total or free (unbound)vorasidenib concentrations (similar vorasidenib Cmax values and an increase of 26.0% in vorasidenib

AUC0-t were observed, while decreased AGI-69460 exposure was observed) in patients with moderatehepatic impairment following a single oral dose of 20 mg vorasidenib. The pharmacokinetics ofvorasidenib and AGI-69460 in patients with severe hepatic impairment (Child-Pugh class C) areunknown (see sections 4.2 and 4.4).

No clinically significant effects on the pharmacokinetics of vorasidenib were observed based on age(16 to 75 years), race, ethnicity and body weight (43.5 to 168 kg). Female patients were observed tohave a 1.6-fold higher vorasidenib exposure as compared to male patients.

Pharmacokinetic data demonstrated that age had no clinically meaningful effect on thepharmacokinetics of vorasidenib. The exposure of vorasidenib is expected to be similar betweenadults and adolescent patients aged 12 years and older.

The main target toxicities identified during repeat-dose toxicity studies concern liver, gastrointestinaltract, skin, kidney, skeletal muscle, reproductive organs and mammary gland.

Vorasidenib was not genotoxic in the in vitro bacterial reverse mutation (Ames) assay, in vitro humanlymphocyte micronucleus and in vivo rat bone marrow micronucleus assays. AGI-69460, its majorcirculating metabolite, was not genotoxic in the Ames assay, the in vitro human lymphocytemicronucleus assay, and the in vivo rat bone marrow micronucleus and Comet assays.

In the 13-week study in monkeys, Kupffer cell hyperplasia were observed at primary necropsy andworsened after recovery period at 8-fold the clinical exposure. In addition, findings from rat toxicitystudies suggested hormonal perturbation. Such findings may be suggestive of potential carcinogenicrisk. Carcinogenicity studies have not been conducted yet with vorasidenib.

Fertility studies in animals have not been conducted with vorasidenib. Effects on reproductive organswere noted during repeat-dose toxicity studies after administration of vorasidenib in rats. Adverseeffects in female reproductive organs included atrophy of the ovaries, uterus, cervix and vagina andoestrous cycle variations. In male rats, effects were noted on the epididymis (cellular debris), seminalvesicle/prostate (atrophy), and testis (weights, tubular degeneration). These findings were observed atthe lowest tested dose of 5 mg/kg/day in the 13-week rat study, resulting in an exposure level26-fold higher than the human exposure at 50 mg daily dose.

Vorasidenib caused embryo-foetal toxicity in pregnant rats and rabbits (higher incidence ofresorptions, delayed ossification, visceral malformations for kidney and testes in rats). These effectsoccurred at doses that were higher compared to patients receiving the therapeutic daily dose. Theexposure ratios at the NOAEL for embryo-foetal development in rats and rabbits were 8.0 to 28.5 and1.1 to 4.9, respectively, on gestation days 6 and 17 for rat and 6 and 19 for rabbit.

Microcrystalline cellulose (E460)

Croscarmellose sodium

Silicified microcrystalline cellulose (contains microcrystalline cellulose and silica colloidal anhydrous)

Magnesium stearate (E470b)

Sodium lauryl sulfate (E487)

Hypromellose

Titanium dioxide (E171)

Lactose monohydrate

Macrogol (E1521)

Black iron oxide (E172)

Propylene glycol (E1520)

Hypromellose (E464)

Not applicable.

36 months.

This medicinal product does not require any special storage conditions.

White HDPE bottle with a polypropylene (PP) child-resistant closure and polyethylene (PE) facedinduction heat seal liner including three silica gel desiccants in HDPE canisters. Pack-size of30 film-coated tablets.

Patients should be advised not to swallow the silica gel desiccant found in the tablet bottle.

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

Les Laboratoires Servier50, rue Carnot92284 Suresnes cedex

France

EU/1/25/1912/001

EU/1/25/1912/002

Date of first authorisation: 17 September 2025

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

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