4.1. Therapeutic indications

VORANIGO is indicated for the treatment of Grade 2 astrocytoma or oligodendroglioma with a susceptible isocitrate dehydrogenase-1 (IDH1) mutation or isocitrate dehydrogenase-2 (IDH2) mutation in adults and paediatric patients 12 years and older, who are not in need of immediate chemotherapy or radiotherapy following surgical intervention (see section 5.1).

4.2. Posology and method of administration

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

Select patients for the treatment of astrocytoma or oligodendroglioma with Voranigo based on the presence of IDH1 or IDH2 mutations in tumor specimens using an appropriate diagnostic test prior to initiation of treatment with vorasidenib.

Posology

The recommended dose of Voranigo in adults:

• 40 mg taken orally once daily

The recommended dose of Voranigo in adolescents 12 years of age and older:

• 40 mg taken orally once daily for patients weighing at least 40 kg

• 20 mg taken orally once daily for patients weighing less than 40 kg

Treatment should be continued as long as clinical benefit is observed or until treatment is no longer tolerated 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 hours after 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 the regularly scheduled time.

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

Precautions to be taken prior to administration and monitoring

Complete blood counts and blood chemistries, including liver enzymes, should be assessed prior to starting treatment, every 2 weeks during the first 2 months and then monthly for the first 2 years of treatment, and as clinically indicated thereafter. Certain patients may require more frequent and ongoing monitoring (see section 4.4). Manage any abnormalities promptly (see section 4.8).

Dosage modifications for adverse reactions

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

Table 1: Recommended dosage reduction levels

Dosage level

Dose and schedule

Number and strength of tablets

Adult patients and Paediatric patients 12 years and older weighing at least 40 kg

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

Paediatric patients 12 years and older weighing less than 40 kg

Starting dose

20 mg once daily

Two 10 mg tablets / once daily

First dose reduction

10 mg once daily

One 10 mg tablet / once daily

Permanently discontinue Voranigo in patients unable to tolerate 10 mg once daily.

The recommended Voranigo dosage modifications and management for adverse reactions are provided in Table 2.

Table 2: Recommended Voranigo Dosage Modifications and Management for Adverse Reactions

Adverse Reaction

Severitya

Management and Dosage Modifications

Hepatotoxicity (Elevation of ALT or AST)

(see section 4.4)

Grade 1

ALT or AST increase >ULN to 3 x ULN without concurrent total bilirubin >2 x ULN

Continue Voranigo at current dose. Monitor liver enzymes weekly until recovery to <Grade 1.

Grade 2

ALT or AST >3 to 5 x ULN without concurrent total bilirubin >2 x ULN

First Occurrence: Withhold Voranigo and monitor liver enzymes twice per week until recovery to ≤Grade 1 or baseline.

• 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 and monitor liver enzymes twice per week until recovery to ≤Grade 1 or baseline, and resume Voranigo at reduced dose (see Table 1).

Grade 3

ALT or AST >5 to 20 x ULN without concurrent total bilirubin >2 x ULN

First Occurrence: Withhold Voranigo and monitor liver enzymes twice per week until recovery to ≤Grade 1 or baseline.

• 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 twice per week until recovery to ≤Grade 1 or baseline.

Grade 2 or 3

Any ALT or AST >3 to 20 x ULN with concurrent total bilirubin >2 x ULN in absence of clear alternative explanation.b

Permanently discontinue Voranigo and monitor liver enzymes twice per week until recovery to ≤Grade 1 or baseline.

Grade 4

Any ALT or AST >20 x ULN

Permanently discontinue Voranigo and monitor liver enzymes twice per week until recovery to ≤Grade 1 or baseline.

Other Adverse Reactions

Grade 3

First Occurrence: Withhold Voranigo until 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 limit of normal

a 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.

Special populations

Elderly

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

Renal impairment

No starting dose adjustment is recommended for patients with renal impairment (estimated glomerular filtration rate [eGFR] > 40 mL/min/1.73 m2). The pharmacokinetics and safety of vorasidenib and metabolite AGI-69460 have not been studied in patients with eGFR ≤ 40 mL/min/1.73 m2 or renal impairment requiring dialysis. Vorasidenib should be used with caution in patients with eGFR ≤ 40 mL/min/1.73 m2 or who require dialysis (see sections 4.4 and 5.2).

Hepatic impairment

No starting dose adjustment is recommended for patients with mild or moderate (Child-Pugh class A or B) hepatic impairment. The pharmacokinetics and safety of vorasidenib and AGI-69460 have not been studied in patients with severe hepatic impairment (Child-Pugh class C). Vorasidenib should not be used in patients with pre-existing severe hepatic impairment (see sections 4.4 and 5.2).

Paediatric population

The safety and efficacy of Voranigo in children under 12 years of age have not been established. No data are available (see section 5.1).

Method of administration

Voranigo is for oral use.

The tablets should be taken once daily at about the same time each day. Patients should not eat food at least 2 hours before and 1 hour after taking Voranigo (see section 5.2). The tablets are to be swallowed whole with a glass of water and should not be split, crushed or chewed.

4.3. Contraindications

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

4.4. Special warnings and precautions for use

Hepatotoxicity

Elevations in liver enzymes, including alanine aminotransferase (ALT) and aspartate aminotransferase (AST) > 3 times the upper limit of normal (ULN), with elevation in total bilirubin > 2 times the ULN have been reported in patients treated with vorasidenib (see section 4.8). Hepatic failure and hepatic necrosis were observed in one patient treated with vorasidenib and autoimmune hepatitis was observed in one patient treated with vorasidenib.

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

Women of childbearing potential / Contraception

Vorasidenib could cause foetal harm when administered to a pregnant woman. Pregnancy testing is recommended in women of childbearing potential prior to starting treatment. Women of childbearing potential should use effective contraception during treatment and for at least 3 months after the last dose. Women who are planning to conceive a child should be advised to seek reproductive counselling.

Vorasidenib may decrease concentrations of hormonal contraceptives and, therefore, concomitant use of a barrier method of contraception is recommended during treatment and for at least 3 months after the last dose (see sections 4.5 and 4.6).

Male patients

Males with female partners of childbearing potential should use effective contraception during treatment and for at least 3 months after the last dose.

Hepatic impairment

Vorasidenib should not be used in patients with pre-existing severe hepatic impairment (Child-Pugh class C) (see sections 4.2 and 5.2).

Renal impairment

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

Lactose

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

Sodium

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

Paediatric population

Adolescents from 12 to less than 18 years of age

Only limited data are available on the safety and effectiveness of Voranigo in adolescent patients aged 12 years to less than 18 years for IDH1 or IDH2 mutant astrocytoma or oligodendroglioma. Use of Voranigo in this age group is supported by evidence from the INDIGO study (see section 5.1). At the recommended doses, exposure of vorasidenib is expected to be similar between adults and adolescent patients aged 12 years and older. The course of IDH1 or IDH2 mutant astrocytoma or oligodendroglioma is sufficiently similar in adults and adolescent patients to allow extrapolation of data in adults to adolescent patients.

Children under 12 years of age

The safety and effectiveness of Voranigo has not been established in the paediatric population under 12 years of age with predominantly non-enhancing astrocytoma or oligodendroglioma who have an IDH1 or IDH2 mutation. Use in children less than 12 years of age is not recommended.

4.5. Interaction with other medicinal products and other forms of interaction

Effect of other medicinal products on vorasidenib

Strong or Moderate CYP1A2 inhibitors

Co-administration of vorasidenib with strong or moderate CYP1A2 inhibitors (fluvoxamine and ciprofloxacin) may increase vorasidenib plasma concentrations. Concomitant use of strong or moderate CYP1A2 inhibitors should be avoided and consider alternative therapies that are not strong or moderate inhibitors of CYP1A2 during treatment with vorasidenib.

Moderate CYP1A2 inducers

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

Concomitant use of vorasidenib with smoking tobacco may decrease vorasidenib plasma concentrations which may reduce the anti-tumor activity of vorasidenib. Consider advising that smoking tobacco should be avoided during treatment with vorasidenib.

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 substrates with 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, and warfarin) may decrease the plasma concentrations of these medicinal products. Concomitant use of substrates of these enzymes with narrow therapeutic index should be avoided in patients taking vorasidenib.

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, and triazolam) may decrease the plasma concentrations of these medicinal products. Consider alternative therapies 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 not limited to, rosuvastatin).

Hormonal contraceptives

Vorasidenib may decrease concentrations of hormonal contraceptives and, therefore, concomitant use of a barrier method of contraception is recommended during treatment and for at least 3 months after the last dose (see sections 4.4 and 4.6).

4.6. Fertility, pregnancy and lactation

Women of childbearing potential / Contraception

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

Women of childbearing potential and males with female partners of childbearing potential should use effective contraception during treatment and for at least 3 months after the last dose. Since the effect of vorasidenib on the metabolism and efficacy of systemically acting hormonal contraceptives has not been investigated, barrier methods should be applied as a second form of contraception to avoid pregnancy (see sections 4.4 and 4.5).

Pregnancy

There is a limited amount of data from the use of vorasidenib in pregnant women. Studies in animals have shown embryo-foetal development toxicity (see section 5.3). Voranigo can cause fetal harm when administered to pregnant women.

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

Breast-feeding

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

Fertility

There are no human data on the effect of vorasidenib on fertility. No fertility studies in animals have been conducted to evaluate the effect of vorasidenib. Findings on reproductive organs were observed during repeat-dose toxicity studies in female and male animals (see section 5.3). The clinical relevance of these effects is unknown. Male and female patients who are planning to conceive a child should be advised to seek reproductive counselling, prior to treatment (see section 4.4).

4.7. Effects on ability to drive and use machines

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

4.8. Undesirable effects

Summary of safety profile

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 (4.8%) and GGT increased (3.0%).

Serious adverse reactions were reported in 1 of 167 patients (0.6% ) who received Voranigo. The most common serious adverse reaction was ALT increased (0.6%).

Permanent discontinuation of Voranigo due to an adverse reaction was reported in 5 of 167 patients (3.0%). The most common grade 3 or 4 adverse reactions leading to permanent discontinuation was ALT increased (3.0%).

Dose interruptions due to an adverse reaction occurred in 32 of 167 patients (19.2%) treated with Voranigo. The most common adverse reactions requiring dose interruption were ALT increased (14.4%) and AST increased (6.0%).

Dose reductions of Voranigo due to an adverse reaction occurred in 16 of 167 patients (9.6%). The most common adverse reaction requiring dose reduction was ALT increased (7.8%).

Tabulated list of adverse reactions

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

The adverse reactions reported in patients treated with vorasidenib in the INDIGO trial (Study AG881-C- 004) 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 (≥ 1/1 000 to < 1/100), rare (≥ 1/10 000 to < 1/1 000), very rare (< 1/10 000), not known (cannot be estimated from available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

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

System organ class

Frequency

Adverse reactions

Blood and lymphatic system disorders

Very common

Platelet count decreaseda

Metabolism and nutrition disorders

Common

Hyperglycaemia

Decreased appetite

Hypophosphataemiab

Gastrointestinal disorders

Very common

Abdominal painc

Diarrhoead

Hepatobiliary disorders

Very common

Alanine aminotransferase increaseda

Aspartate aminotransferase increaseda

Gamma-glutamyl transferase increaseda

Common

Alkaline phosphatase increaseda

Not known

Blood bilirubin increased*

Drug-induced liver injury*

Autoimmune hepatitis*

Hepatic necrosis*

Hepatitis acute*

General disorders

Very common

Fatiguee

a Laboratory abnormality is defined as new or worsened by at least one grade from baseline, or baseline is unknown.

b Grouped term includes hypophosphataemia and blood phosphorus decreased.

c Grouped term includes abdominal pain, abdominal pain upper, abdominal discomfort, abdominal pain lower, epigastric discomfort, and abdominal tenderness.

d Grouped term includes diarrhoea, feces soft and frequent bowel movements.

e Grouped term includes fatigue and asthenia.

*Identified during post-approval use.

Description of selected adverse reactions

Hepatobiliary disorders

In the INDIGO clinical trial (Study AG881-C-004), 18.6% (31/167) of patients treated with Voranigo experienced ALT elevations >3 times the ULN and 8.4% (14/167) experienced AST elevations >3 times the ULN. In INDIGO, 1.2% of patients (2/167) had concurrent ALT or AST elevations >3 times the ULN and total bilirubin >2 times the ULN. Liver enzyme and bilirubin increases were transient and improved or resolved with dose modification or permanent discontinuation of treatment (see sections 4.2 and 4.4).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme website at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

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