VORASIDENIB: 264 Adverse Event Reports & Safety Profile

VORANIGO tablets contain vorasidenib, an isocitrate dehydrogenase-1 (IDH1) and isocitrate dehydrogenase-2 (IDH2) inhibitor. Vorasidenib is present as the hemicitric acid hemihydrate co-crystal. The chemical name of the co-crystal is 6-(6-chloropyridin-2-yl)- N 2 , N 4 -bis[(2 R )-1,1,1-trifluoropropan-2-yl]-1,3,5-triazine-2,4-diamine, 2-hydroxypropane-1,2,3-tricarboxylic acid, hydrate (2:1:1). It has the following chemical structure: The molecular formula is C 14 H 13 ClF 6 N 6

• ½ C 6 H 8 O 7• ½ H 2 O and the molecular weight is 519.8 g/mol. Vorasidenib hemicitric acid hemihydrate is a white to off-white solid practically insoluble in aqueous solutions between pH 1.2 to 6.8. VORANIGO is available as a 10 mg and 40 mg strength film-coated tablet for oral administration. The strengths reflect the amount of active ingredient vorasidenib in each tablet. 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.

Chemical

Structure

AND USAGE VORANIGO is indicated for the treatment of adult and pediatric patients 12 years and older with Grade 2 astrocytoma or oligodendroglioma with a susceptible isocitrate dehydrogenase-1 (IDH1) or isocitrate dehydrogenase-2 (IDH2) mutation, as detected by an FDA-approved test, following surgery including biopsy, sub-total resection, or gross total resection [see Dosage and Administration (2.1) , Clinical Pharmacology (12.1) and Clinical Studies (14) ] . VORANIGO is an isocitrate dehydrogenase-1 (IDH1) and isocitrate dehydrogenase-2 (IDH2) inhibitor indicated for the treatment of adult and pediatric patients 12 years and older with Grade 2 astrocytoma or oligodendroglioma with a susceptible IDH1 or IDH2 mutation, as detected by an FDA-approved test, following surgery including biopsy, sub-total resection, or gross total resection. ( 1 )

AND ADMINISTRATION Recommended dosage in adults: ( 2.3 ) 40 mg orally once daily Recommended dosage in pediatric patients 12 years of age and older based on body weight: ( 2.3 ) ≥40 kg : 40 mg orally once daily <40 kg : 20 mg orally once daily Take with or without food. ( 2.3 )

2.1 Recommended Evaluation Before Initiating VORANIGO Before initiating VORANIGO, evaluate blood chemistry and liver laboratory tests <span class="opacity-50 text-xs">[see Warnings and Precautions (5.1) and Adverse Reactions (6.1) ]</span>.

2.2 Patient Selection Select patients with Grade 2 astrocytoma or oligodendroglioma for treatment with VORANIGO based on the presence of IDH1 or IDH2 mutations in tumor specimens <span class="opacity-50 text-xs">[see Clinical Studies (14) ]</span> . Information on FDA-approved tests for detection of IDH1 or IDH2 mutations in Grade 2 astrocytoma or oligodendroglioma for selecting patients for treatment with VORANIGO is available at: https://www.fda.gov/CompanionDiagnostics.

2.3 Recommended Dosage and Administration Recommended Dosage 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.

Administration

Swallow VORANIGO tablets whole with water with or without food [see Clinical Pharmacology (12.3) ] . Do not split, crush or chew tablets.

Missed Dose

Take VORANIGO tablets at about the same time each day. If a dose is missed, take the missed dose as soon as possible within 6 hours. If a dose is missed by more than 6 hours, skip the missed dose and take the next dose at the scheduled time. Vomiting If vomiting occurs after taking a dose, do not take a replacement dose, and take the next dose at the scheduled time on the following day.

2.4 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 Dosage Reduction Recommended Dose and Schedule Adult patients and Pediatric patients 12 years and older weighing at least 40 kg First 20 mg once daily Second 10 mg once daily Pediatric patients 12 years and older weighing less than 40 kg First 10 mg once daily Permanently discontinue VORANIGO in patients unable to tolerate 10 mg once daily. 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 Adverse Reaction Severity Adverse reactions graded by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0. Management and Dosage Modifications Abbreviations: ALT = Alanine aminotransferase; AST = Aspartate aminotransferase; ULN = Upper limit of normal Hepatotoxicity (Elevation of ALT or AST) [see Warnings and Precautions (5.1) ]

Grade

1 ALT or AST increase >ULN to 3 × ULN without concurrent total bilirubin >2 × ULN Continue VORANIGO at current dose. Monitor liver laboratory tests weekly until recovery to <Grade 1.

Grade

2 ALT or AST >3 to 5 × ULN without concurrent total bilirubin >2 × ULN First Occurrence: Withhold VORANIGO 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 until recovery to ≤Grade 1 or baseline, and resume VORANIGO at reduced dose [see Table 1 ] .

Grade

3 ALT or AST >5 to 20 × ULN without concurrent total bilirubin >2 × ULN First Occurrence: Withhold VORANIGO 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.

Grade

2 or 3 Any ALT or AST >3 to 20 × ULN with concurrent total bilirubin >2 × ULN 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 Any ALT or AST >20 × ULN Permanently discontinue VORANIGO.

Other Adverse

Reactions [see Adverse Reactions (6.1) ]

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.

None. None. ( 4 )

REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Hepatotoxicity [see Warnings and Precautions (5.1) ] The most common (≥15%) adverse reactions include fatigue, headache, COVID-19, musculoskeletal pain, diarrhea, nausea, and seizure.

Grade

3 or 4 (≥2%) laboratory abnormalities were ALT increased, AST increased, GGT increased, and neutrophils decreased. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Servier Pharmaceuticals at 1-800-807-6124 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adverse reactions described in the WARNINGS AND PRECAUTIONS reflect exposure to VORANIGO 40 mg orally once daily until disease progression or unacceptable toxicity in the 244 patients with astrocytoma or oligodendroglioma with susceptible IDH1 or IDH2 mutation in trials AG881-C-002 (NCT02481154, n=11), AG120-881-001 (NCT03343197, n=14) and INDIGO (NCT04164901, n=167 randomized patients and n=52 crossover patients). Among the 244 patients who received VORANIGO, 78% were exposed for 6 months or longer and 44% were exposed for greater than one year. In this pooled safety population, the most common (≥15%) adverse reactions were fatigue (33%), headache (28%), COVID-19 (28%), musculoskeletal pain (24%), diarrhea (21%), nausea (20%), and seizure (16%). In this pooled safety population, the most common (≥2%)

Grade

3 or 4 laboratory abnormalities were increased ALT (9%), increased AST (4.8%), increased GGT (2.2%), and decreased neutrophils (2.2%).

Indigo

The safety of VORANIGO was evaluated in 330 patients with Grade 2 astrocytoma or oligodendroglioma with an IDH1 or IDH2 mutation who received at least one dose of either VORANIGO 40 mg daily (N=167) or placebo (N=163) in the INDIGO trial [see Clinical Studies (14) ] . Patients received VORANIGO 40 mg orally once daily or placebo orally once daily until disease progression or unacceptable toxicity. Among the 167 patients who were randomized and received VORANIGO, the median duration of exposure to VORANIGO was 12.7 months (range: 1 to 30 months) with 153 patients (92%) exposed to VORANIGO for at least 6 months and 89 (53%) exposed for at least 1 year. The demographics of patients randomized to VORANIGO were: median age 41 years (range: 21 to 71 years); 60% male, 74% White, 20% race not reported, 3% Asian, and 1.2% Black or African American; and 5% were Hispanic or Latino. Serious adverse reactions occurred in 7% of patients who received VORANIGO. The most common serious adverse reactions occurring in ≥2% of patients who received VORANIGO includes seizure (3%). Permanent discontinuation of VORANIGO due to an adverse reaction occurred in 3.6% of patients. Adverse reactions which resulted in permanent discontinuation of VORANIGO in ≥2% of patients included ALT increased (3%). Dosage interruptions of VORANIGO due to an adverse reaction occurred in 30% of patients. Adverse reactions which required dose interruption in ≥5% of patients included ALT increased (14%), COVID-19 (9%), and AST increased (6%). Dose reductions of VORANIGO due to an adverse reaction occurred in 11% of patients. Adverse reactions which required dose reduction in ≥5% of patients included ALT increased (8%). The most common (≥15%) adverse reactions were fatigue (37%), COVID-19 (33%), musculoskeletal pain (26%), diarrhea (25%), and seizure (16%).

Grade

3 or 4 (≥2%) laboratory abnormalities were ALT increased (10%), AST increased (4.8%), GGT increased (3%) and neutrophil decreased (2.4%). Adverse reactions and select laboratory abnormalities reported in the INDIGO trial are shown in Tables 3 and 4.

Table

3: Adverse Reactions (≥5%) in Patients with Grade 2 IDH1/2 Mutant Glioma Who Received VORANIGO Compared with Placebo in the INDIGO Trial VORANIGO 40 mg daily (n=167) Placebo (n=163)

Adverse Reaction

Adverse reactions are based on NCI CTCAE v5.0.

All

Grades (%)

Grades

3 or 4 (%)

All

Grades (%)

Grades

3 or 4 (%)

General Disorders Fatigue

Grouped term includes asthenia. 37 0.6 36

1.2 Infections and Infestations COVID-19 33 0 29 0 Nervous System Disorders Seizure Grouped term includes partial seizures, generalized tonic-clonic seizure, epilepsy, clonic convulsion, and simple partial seizures. 16 4.2 15

3.7 Musculoskeletal and Connective Tissue Disorders Musculoskeletal pain Grouped term includes arthralgia, back pain, non-cardiac chest pain, pain in extremity, myalgia, neck pain, musculoskeletal chest pain, arthritis, and musculoskeletal stiffness. 26 0 25

1.8 Gastrointestinal Disorders Diarrhea Grouped term includes feces soft and frequent bowel movements. 25 0.6 17

0.6 Constipation 13 0 12 0 Abdominal pain Grouped term includes abdominal pain upper, abdominal discomfort, abdominal pain lower, abdominal tenderness, and epigastric discomfort. 13 0 12 0 Decreased appetite 9 0 3.7 0 Table 4: Select Laboratory Abnormalities (≥5%)

That

Worsened from Baseline in Patients with Grade 2 IDH1/2 Mutant Glioma Who Received VORANIGO in the INDIGO Trial VORANIGO 40 mg daily N=167 Placebo N=163 Parameter All Grades Based on NCI CTCAE v5.0. (% The denominator used to calculate percentages is N, the number of subjects in the Safety Analysis Set within each treatment group. )

Grades

3 or 4 (% )

All

Grades (% )

Grades

3 or 4 (% ) Abbreviations: AST = Aspartate Aminotransferase; ALT = Alanine Aminotransferase; GGT = Gamma-Glutamyl Transferase; ALP = Alkaline Phosphatase Chemistry Increased ALT 59 10 25 0 Increased AST 46 4.8 20 0 Increased Creatinine 11 0.6 7 0 Decreased Calcium 10 0 7 0 Increased Glucose Includes adverse reaction term hyperglycemia. 10 0 4.3 0 Increased GGT 38 3 10

1.8 Decreased Phosphate Includes adverse reaction terms hypophosphatemia and blood phosphorus decreased. 8 0.6 4.9 0 Increased Potassium 23 0.6 20 0 Increased ALP 10 1.2 7

0.6 Hematology Increased Hemoglobin 13 0 3.1 0 Decreased Lymphocytes 11 1.8 8

0.6 Decreased Leukocytes 13 0.6 12

0.6 Decreased Neutrophils 14 2.4 12

1.8 Decreased Platelets 12 0 4.3 0

AND PRECAUTIONS Hepatotoxicity : Monitor liver function tests every 2 weeks during the first 2 months of treatment, then monthly for the first 2 years of treatment, and as clinically indicated. Withhold, reduce the dose or discontinue VORANIGO based on severity. ( 2.3 , 5.1 ) Embryo-Fetal Toxicity : VORANIGO can cause fetal harm. Advise patients of the potential risk to a fetus and to use effective nonhormonal contraception. ( 5.2 , 8.1 , 8.3 )

5.1 Hepatotoxicity VORANIGO can cause hepatic transaminase elevations, which can lead to hepatic failure, hepatic necrosis, and autoimmune hepatitis. In the pooled safety population <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span> , 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. Reduce the dose, withhold, or permanently discontinue VORANIGO based on severity [see Dosage and Administration (2.3) and Adverse Reactions (6.1) ].

5.2 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 <span class="opacity-50 text-xs">[see Drug Interactions (7.2) ]</span> . 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 <span class="opacity-50 text-xs">[see Use in Specific Populations (8.1 , 8.3) ]</span> .

INTERACTIONS CYP1A2 Inhibitors : Avoid concomitant use of strong and moderate CYP1A2 inhibitors. ( 7.1 ) CYP1A2 Inducers : Avoid concomitant use of moderate CYP1A2 inducers and smoking tobacco. ( 7.1 ) Certain CYP3A Substrates : Avoid concomitant use with CYP3A substrates, where a minimal concentration change can reduce efficacy. ( 7.2 )

Hormonal

Contraception : If concomitant use cannot be avoided, use with nonhormonal contraception methods. ( 7.2 )

7.1 Effect of Other Drugs on VORANIGO Table 5: Effect of Other Drugs on VORANIGO Strong and Moderate CYP1A2 Inhibitors Clinical Impact Concomitant use of VORANIGO with a strong or moderate CYP1A2 inhibitor may increase vorasidenib plasma concentrations <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span> , which may increase the risk of adverse reactions. Prevention or Management Avoid concomitant use of VORANIGO with strong and moderate CYP1A2 inhibitors. If concomitant use of moderate CYP1A2 inhibitors cannot be avoided, monitor for increased adverse reactions and modify the dosage for adverse reactions as recommended <span class="opacity-50 text-xs">[see Dosage and Administration (2.4) ]</span> . Moderate CYP1A2 Inducers Clinical Impact Concomitant use of VORANIGO with moderate CYP1A2 inducers and smoking tobacco may decrease vorasidenib plasma concentrations <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span> , which may reduce the anti-tumor activity of VORANIGO. Prevention or Management Avoid concomitant use of VORANIGO with moderate CYP1A2 inducers and smoking tobacco.

7.2 Effect of VORANIGO on Other Drugs Table 6: Effect of VORANIGO on Other Drugs Certain CYP3A Substrates Clinical Impact Concomitant use of VORANIGO with CYP3A substrates may decrease plasma concentrations of CYP3A substrates. Prevention or Management Avoid concomitant use of VORANIGO with CYP3A substrates, where a minimal concentration change may lead to reduced therapeutic effect.

Hormonal Contraception Clinical Impact

Concomitant use of VORANIGO may decrease the concentrations of hormonal contraceptives, which may lead to contraception failure and/or an increase in breakthrough bleeding. Prevention or Management If concomitant use cannot be avoided, use with nonhormonal contraception methods.