VORANIGO is indicated for the treatment of adult and paediatric patients 12 years and older with Grade 2 astrocytoma or oligodendroglioma with a susceptible isocitrate dehydrogenase-1 (IDH1) or isocitrate dehydrogenase-2 (IDH2) mutation following surgery including biopsy, sub-total resection, or gross total resection.

Before initiating VORANIGO, evaluate blood chemistry and liver laboratory tests (see sections 4.4 and 4.8).
Select patients with Grade 2 astrocytoma or oligodendroglioma for treatment with VORANIGO based on the presence of IDH1 or IDH2 mutations in tumour specimens. Before taking Voranigo, patients must have confirmation of an isocitrate dehydrogenase-1 (IDH1) or isocitrate dehydrogenase-2 (IDH2) mutation using an appropriate diagnostic test. Posology Adult Patients The recommended dosage of VORANIGO in adult patients is 40 mg orally once daily until disease progression or unacceptable toxicity. Pediatric Patients 12 Years and Older The recommended dosage of VORANIGO in pediatric patients 12 years and older is based on body weight:
• Patients weighing ≥ 40 kg: 40 mg orally once daily
• Patients weighing < 40 kg: 20 mg orally once daily Continue treatment with VORANIGO until disease progression or unacceptable toxicity.
Dosage Modifications, Management and Monitoring for Adverse Reactions The recommended VORANIGO dosage reductions for adverse reactions are provided in Table 1.

Table 1: Recommended VORANIGO Dosage Reductions for Adverse Reactions

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

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

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 (NCICTCAE) version 5.0.

Special populations

Geriatric use

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

Renal impairment

No dosage adjustment is recommended for patients with creatinine clearance (CLcr) >40 mL/min. The pharmacokinetics and safety of vorasidenib in patients with CLcr ≤40 mL/min or renal impairment requiring dialysis have not been studied (see section 5.2). For patients with CLcr ≤40 mL/min or who require dialysis, monitor for increased adverse reactions and modify the dosage for adverse reactions as recommended (see sections 4.2 and 5.2).

Hepatic impairment

No dosage adjustment is recommended for patients with mild or moderate (Child-Pugh Class A or B) hepatic impairment (see section 5.2). The pharmacokinetics and safety of vorasidenib in patients with severe hepatic impairment (Child-Pugh Class C) have not been studied. For patients with severe hepatic impairment, monitor for increased adverse reactions and modify the dosage for adverse reactions as recommended (see sections 4.2 and 5.2).5

Paediatric use

The safety and efficacy of VORANIGO have not been established in paediatric patients younger than 12 years of age.

Method of administration

VORANIGO is for oral use.

Patients should be advised to swallow tablets whole with a glass of water, with or without food, and to not split, crush or chew VORANIGO tablets.

If a patient misses a dose by less than 6 hours, instruct patients to take the missed dose right away. If a patient misses a dose by 6 or more hours, instruct patients to skip the dose for that day. Advise patients to take the next dose at the usual time.

If a patient vomits a dose, instruct patients not to take another dose. Advise patients to take the next dose at the usual time.

Hepatotoxicity
VORANIGO can cause hepatic transaminase elevations, which can lead to hepatic failure, hepatic necrosis, and autoimmune hepatitis.
In the pooled safety population (see section 4.8), 58% of patients treated with VORANIGO experienced increased ALT and 44% of patients experienced increased AST. Grade 3 or 4 increased ALT or AST occurred in 9% and 4.8% of patients respectively. Among these patients, 4.1% (10/244) had concurrent Grade 3 to 4 ALT or AST elevations. A total of 34% of patients treated with VORANIGO had increased gamma-glutamyl transferase (GGT), of these 2.2% were Grade 3 or 4. Bilirubin increases occurred in 4.8% of patients treated with VORANIGO, with 0.4% Grade 3 or 4. Nine percent of patients treated with VORANIGO had increased alkaline phosphatase, with 0.9% Grade 3 or 4.
Two patients met the laboratory criteria for Hy’s Law and had concurrent elevations in ALT or AST >3 times the upper limit of normal and total bilirubin >2 times the upper limit of normal; these events were associated with cases of autoimmune hepatitis and hepatic failure. The median time to first onset of increased ALT or AST was 57 days (range: 1 to 1049).
Permanent discontinuation of VORANIGO was required for 2.9% of patients with ALT elevations, 1.6% of AST elevations, and 0.4% of GGT elevations. Dosage reductions of VORANIGO were required for 7% of patients with ALT elevations, 1.2% of AST elevations, and 0.4% of GGT elevations. Dosage interruptions were required in 14% of patients with ALT elevations, 6% of AST elevations, and 1.6% of GGT elevations.
Monitor liver laboratory tests (AST, ALT, GGT, total bilirubin and alkaline phosphatase) prior to the start of VORANIGO, every 2 weeks during the first 2 months of treatment, then monthly for the first 2 years of treatment, and as clinically indicated, with more frequent testing in patients who develop transaminase elevations.
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Reduce the dose, withhold, or permanently discontinue VORANIGO based on severity (see sections 4.2 and 4.8).
Embryo-Fetal Toxicity
Based on findings from animal studies, VORANIGO can cause fetal harm when administered to a pregnant woman. In animal embryo-fetal development studies, oral administration of vorasidenib to pregnant rats during the period of organogenesis caused embryo-fetal toxicities at doses ≥45 times the human exposure based on the area under the concentration-time curve (AUC) at the highest recommended dose. Oral administration of vorasidenib to pregnant rabbits during the period of organogenesis resulted in embryo-fetal toxicity at doses ≥8 times the human exposure based on the AUC at the highest recommended dose.
Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective nonhormonal contraception during treatment with VORANIGO and for 3 months after the last dose, since VORANIGO can render some hormonal contraceptives ineffective (see section 4.5). Advise male patients with female partners of reproductive potential to use effective contraception during treatment with VORANIGO and for 3 months after the last dose (see section 4.6).

Table 3: Effect of Other Drugs on VORANIGO

Table 4: Effect of VORANIGO on Other Drugs

Contraception in males and females
Pregnancy testing is recommended in women of childbearing potential prior to starting treatment with VORANIGO (see section 4.4).
Women of childbearing potential and males with female partners of childbearing potential should use effective contraception during treatment with VORANIGO 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-fetal development toxicity (see section 5.3). VORANIGO can cause fetal harm when administered to pregnant women. VORANIGO is not recommended 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 fetus.
Lactation
It is unknown whether vorasidenib and its metabolites are excreted in human milk. Breast-feeding should be discontinued during treatment with VORANIGO 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 (see section 5.3). The clinical relevance of these effects is unknown. Patients who are planning to conceive a child should be advised to seek reproductive counseling before starting treatment.

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

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 diarrhea (24.6%).
The most common grade 3 or 4 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%).
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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
Adverse reactions reported in patients treated with vorasidenib in the INDIGO trial (Study AG881-C-004) are listed below in Table 1 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 1: Adverse Drug Reactions Reported in Patients Treated with Vorasidenib in the INDIGO Trial (Study AG881-C-004) (N=167)

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

b Grouped term includes hypophosphatemia 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 diarrhea, feces soft and frequent bowel movements.

e Grouped term includes fatigue and asthenia

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).

To report any side effect(s):

•                    Saudi Arabia:

- National Pharmacovigilance Center (NPC)

- SFDA call Center 19999

- E-mail: npc.drug@sfda.gov.sa

- Website: https://ade.sfda.gov.sa

•                    Other GCC states:

- Please contact the relevant competent authority.

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.

Pharmacotherapeutic group: Antineoplastic agents; other antineoplastic agents
ATC code: L01XM04
Mechanism of action
Vorasidenib is a small molecule inhibitor that targets isocitrate dehydrogenase-1 and 2 (IDH1 and IDH2) enzymes. In vitro, vorasidenib inhibited the IDH1 wild type and mutant variants, including R132H and the IDH2 wild type and mutant variants. In cell-based and in vivo tumor models expressing IDH1 or IDH2 mutated proteins, vorasidenib decreased production of 2-hydroxyglutarate (2-HG) and partially restored cellular differentiation.
Pharmacodynamic effects
Exposure-Response Relationships
Vorasidenib decreases 2-HG tumor concentrations in patients with IDH1 or IDH2 mutated glioma. Relative to tumors from patients in the untreated group, the posterior median percentage reduction (95% credible interval) in tumor 2-HG was 64% (22%, 88%) to 93% (76%, 98%) in tumors from patients who received vorasidenib at exposures that were 0.3 to 0.8 times the exposure observed with the highest recommended dosage.
The exposure-response relationship and time course of pharmacodynamic response for the safety and effectiveness of vorasidenib have not been fully characterized.
Cardiac Electrophysiology
When the recommended dose of VORANIGO is administered 1 hour prior to a meal, a mean increase in the QTc interval >20 msec is unlikely. There is insufficient information to characterize the QTc effects of VORANIGO at higher vorasidenib concentrations, e.g., when administered with a meal or
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when co-administered with a moderate CYP1A2 inhibitor (see section 5.2).
Clinical efficacy and safety
The efficacy of VORANIGO was evaluated in the INDIGO trial (Study AG881-C-004), a randomized,
multicenter, double-blind, placebo-controlled study of 331 patients (NCT04164901). Eligible patients
were required to have IDH1- or IDH2-mutant Grade 2 astrocytoma or oligodendroglioma with prior
surgery including biopsy, sub-total resection, or gross total resection. Patients were required to have
measurable, non-enhancing disease; patients with centrally confirmed minimal, non-nodular,
non-measurable enhancement were eligible. Patients who received prior anti-cancer treatment,
including chemotherapy or radiation therapy were excluded. Patients were randomized to receive
either VORANIGO 40 mg orally once daily or placebo orally once daily until disease progression or
unacceptable toxicity. IDH1 or IDH2 mutation status was prospectively determined by the Life
Technologies Corporation Oncomine Dx Target Test.
Randomization was stratified by local 1p19q status (co-deleted or not co-deleted) and baseline tumor
size (diameter ≥2 cm or <2 cm). Patients who were randomized to placebo were allowed to cross
over to receive VORANIGO after documented radiographic disease progression. Tumor assessments
were performed every 12 weeks.
A total of 331 patients were randomized, 168 to the VORANIGO arm and 163 to the placebo arm.
The median age was 40 years (range: 16 to 71); 57% were male; 78% were White, 4% were Asian,
1% were Black or African American and 16% had race not reported; 78% were not Hispanic or Latino; 52% oligodendroglioma and 48% astrocytoma; 79% had one prior surgery and 21% had ≥2 prior surgeries. In the VORANIGO arm, 14% of patients had biopsy, 48% had sub-total resection and 51% had gross-total resection. The majority of IDH1 mutations consisted of R132H (87%). The other
alleles were reported as follows: R132C (5%), R132G (3%), R132L (1%), and R132S (1%). IDH2
mutations consisted of R172K (2%) and R172G (1%).
The major efficacy outcome was progression-free survival (PFS) as evaluated by a blinded
independent review committee (BIRC) per modified Response Assessment in Neuro-Oncology for
Low Grade Glioma (RANO-LGG) criteria.
Efficacy results are summarized in Table 6 and Figure 1.

Table 6: Efficacy Results for the INDIGO Trial (Study AG881-C-004)

a Stratified Cox proportional hazard model, stratified by 1p19q status and baseline tumor size.

b Based on one-sided stratified log-rank test compared to the pre-specified α of 0.000359 (one-sided).

Figure 1: Kaplan-Meier Curve for Progression-Free Survival per BIRC for the INDIGO Trial

The major efficacy analyses are supported by a prospectively defined key secondary outcome measure time to next intervention (defined as the time from randomization to the initiation of first subsequent anticancer therapy or death due to any cause). The median time to next intervention was not reached for patients in the VORANIGO arm and 17.8 months for patients in the placebo arm (HR=0.26; 95% CI: [0.15, 0.43], p <0.0001).

Vorasidenib maximum plasma concentration ( Cmax) and AUC increased approximately proportionally over the dose range of 10 to 200 mg (0.2 to 4 times the exposure of the highest approved recommended dosage) following once daily administration of single and multiple doses. At the highest approved recommended dosage, steady state mean (CV%) Cmax is 133 ng/mL (73%) and AUC is 1,988 h•ng/mL (95%). Steady state is achieved within 28 days of once daily dosing and the mean accumulation ratio of AUC is 4.4.
Absorption
The median (minimum, maximum) time to maximum plasma concentrations (tmax) at steady state is 2 hours (0.5 to 4 hours).
The mean absolute bioavailability of vorasidenib is 34%.
Food Effect
A high-fat and high-calorie (total 800-1,000 calories, of which 500-600 from fat) meal increased vorasidenib Cmax 3.1-fold and AUC 1.4-fold, compared to the fasting conditions.
A low-fat and low-calorie (total 400-500 calories, of which 100-125 from fat) meal increased vorasidenib Cmax 2.3-fold and AUC 1.4-fold, compared to the fasting conditions.
Distribution
The mean (CV%) volume of distribution at steady state of vorasidenib is 3,930 L (40%).
The protein binding is 97% in human plasma independent of vorasidenib concentrations in vitro.
The brain tumor-to-plasma concentration ratio is 1.6.
Elimination
The mean (CV%) steady state terminal half-life is 10 days (57%) and oral clearance is 14 L/h (56%).
Metabolism
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Vorasidenib is primarily metabolized by CYP1A2 with minor contributions from CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A. Non-CYP pathways may contribute up to 30% of its metabolism.
Excretion
Following a single oral radiolabeled dose of vorasidenib, 85% of the dose was recovered in feces (56% unchanged) and 4.5% was recovered in urine. Specific Populations No clinically significant effects on the pharmacokinetics of vorasidenib were observed based on age (16 to 75 years), sex, race (White, Black or African American, Asian, American Indian/Alaskan Native, Native Hawaiian or Other Pacific Islander), ethnicity (Hispanic and non-Hispanic), body weight (43.5 to 168 kg), mild or moderate hepatic impairment (Child-Pugh Class A or B) or CLcr >40 mL/min (as Cockcroft-Gault). The pharmacokinetics of vorasidenib has not been studied in patients with severe hepatic impairment (Child-Pugh Class C), in patients with CLcr ≤40 mL/min or in patients with renal impairment who require dialysis. Pediatric Patients The safety and effectiveness of VORANIGO have been established in pediatric patients aged 12 years and older for the treatment of Grade 2 IDH1- or IDH2-mutant astrocytoma or oligodendroglioma. Use of VORANIGO for this indication in this age group is supported by evidence from an adequate and well-controlled study of VORANIGO in adult and pediatric patients with additional population pharmacokinetic data demonstrating that age had no clinically meaningful effect on the pharmacokinetics of vorasidenib. In addition, the course of IDH1- or IDH2-mutant astrocytoma or oligodendroglioma is sufficiently similar between adults and pediatric patients to allow extrapolation of pharmacokinetic data in adults to pediatric patients (see sections 4.8 and 5.2). The exposure of vorasidenib in pediatric patients ≥12 years of age is predicted to be within range of that observed in adults at the approved recommended dosage. Elderly Population Of the 167 patients who were randomized and received VORANIGO 40 mg once daily in the INDIGO trial, 1.2% (2 patients) were 65 years or older. Clinical studies of VORANIGO did not include sufficient numbers of patients aged ≥65 to determine whether they respond differently from younger subjects. Drug Interaction Studies Clinical Studies and Model-Informed Approaches Effect of Other Drugs on Vorasidenib Strong and Moderate CYP1A2 Inhibitors: Concomitant use of ciprofloxacin (moderate CYP1A2 inhibitor) increased vorasidenib plasma Cmax 1.3-fold and AUC 2.5-fold. Concomitant use with fluvoxamine (strong CYP1A2 inhibitor) is predicted to increase vorasidenib Cmax and AUC by ≥5-fold. Moderate CYP1A2 Inducers: Concomitant use with phenytoin or rifampicin (moderate CYP1A2 inducers) is predicted to decrease vorasidenib steady-state Cmax by 30% and AUC by 40%. Gastric Acid Reducing Agents: No clinically significant difference in vorasidenib pharmacokinetics was observed following concomitant use with omeprazole (an acid-reducing agent). Effect of Vorasidenib on Other Drugs CYP3A Substrates: Concomitant use of multiple doses of vorasidenib with CYP3A substrates is predicted to decrease the concentrations of these substrates. UGT1A4 Substrate: No clinically significant difference in lamotrigine pharmacokinetics was observed following the administration of lamotrigine with multiple doses of vorasidenib. P-gp and BCRP Substrates: No clinically significant difference in the pharmacokinetics of digoxin (P-gp substrate) or rosuvastatin (BCRP substrate) is predicted when used concomitantly with vorasidenib. In vitro Studies
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Vorasidenib is an inducer of CYP2B6, CYP2C8, CYP2C9, CYP2C19 and CYP3A and UGT1A4. Vorasidenib is not a substrate of P-gp, BCRP, or OATP1B1 and OATP1B3. Vorasidenib is an inhibitor of BCRP. Vorasidenib does not inhibit P-gp and OATP1B1.

Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenicity studies have not been conducted with vorasidenib. Vorasidenib and its major circulating metabolite, AGI-69460, were not mutagenic in an in vitro bacterial reverse mutation (Ames) assay. Vorasidenib was not clastogenic in an in vitro human lymphocyte micronucleus assay, or an in vivo rat bone marrow micronucleus assay.
Fertility studies in animals have not been conducted with vorasidenib. In repeat-dose toxicity studies up to 13 weeks in duration with oral administration of vorasidenib in rats, adverse effects in female reproductive organs included atrophy, decreased/absent corpora lutea, increased atretic follicles, and interstitial cell vacuolation of the ovaries, atrophy, hypertrophy, and metaplasia of the uterus, hyperplasia of the cervix, atrophy, hyperplasia, and mucification of the vagina, and estrous cycle variations at doses ≥3 mg/kg/day (≥12 times the exposure based on AUC in humans at the highest recommended dose). Adverse effects in male reproductive organs in rats included tubular degeneration and atrophy of the testes, degeneration of seminiferous tubules, cellular debris in the epididymides, epithelial atrophy and inflammation in the prostate, and atrophy in the seminal vesicles at doses ≥3 mg/kg/day (≥12 times the exposure based on AUC in humans at the highest recommended dose). Findings in the male rats were not reversible. In the 4-week repeat-dose toxicity studies in monkeys, oral administration of vorasidenib led to adverse effects in male and female reproductive organs including fibrotic hypoplasia of the testes in males at doses ≥10 mg/kg/day (approximately 17 times the exposure based on AUC in humans at the highest recommended dose) and decreased uterine weights in females at doses ≥10 mg/kg/day (approximately 22 times the exposure based on AUC in humans at the highest recommended dose). Findings in male and female monkeys were reversible. Animal Toxicology and Pharmacology
In repeat-dose toxicity studies, oral administration of vorasidenib to rats for 28 days led to ototoxicity findings of reversible neutrophil infiltration of the epithelial lining of the middle ear and Eustachian tube at doses >3 mg/kg/day (>12-times the human exposure based on the AUC at the highest recommended dose). Additional findings in a 28-day ototoxicity study included edema in the tympanic cavity at doses >30 mg/kg/day. In addition, oral administration of vorasidenib to monkeys for 13 weeks resulted in dilated cardiomyopathy and secondary congestive heart failure at a dose of 20 mg/kg/day (105 times the human exposure based on the AUC at the highest recommended dose). Skeletal muscle was a target organ in the repeat dose toxicology studies in rats and monkeys at doses ≥13 times the AUC in patients at the highest recommended dose. Findings included decreased hind limb muscle tone, abnormal gait with limited hind limb usage, and low carriage, associated with small size and atrophy of the muscle in rats and necrosis and mononuclear/mixed cell infiltrates in the muscle in monkeys.

Each tablet core contains the following inactive ingredients: croscarmellose sodium, magnesium stearate, microcrystalline cellulose, silicified microcrystalline cellulose and sodium lauryl sulfate. The tablet coating includes hypromellose, lactose monohydrate, macrogol and titanium dioxide. Each tablet is printed with black ink that contains black iron oxide, hypromellose and propylene glycol.

Not applicable.

Do not store above 30°C.

- Each carton contains one 30-count bottle of 10 mg tablets with desiccant canister(s) and child-resistant cap. - Each carton contains one 30-count bottle of 40 mg tablets with desiccant canister(s) and child-resistant cap.

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