OJEMDA

1 INDICATIONS AND USAGE OJEMDA is indicated for the treatment of patients 6 months of age and older with relapsed or refractory pediatric low-grade glioma (LGG) harboring a BRAF fusion or rearrangement, or BRAF V600 mutation. This indication is approved under accelerated approval based on response rate and duration of response [see Clinical Studies (14) ]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s). OJEMDA is a kinase inhibitor indicated for the treatment of patients 6 months of age and older with relapsed or refractory pediatric low-grade glioma (LGG) harboring a BRAF fusion or rearrangement, or BRAF V600 mutation. ( 1 ) This indication is approved under accelerated approval based on response rate and duration of response [see Clinical Studies (14) ]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).

2 DOSAGE AND ADMINISTRATION Confirm the presence of BRAF fusion or rearrangement, or BRAF V600 mutation prior to initiation of treatment with OJEMDA. ( 2.1 ) Recommended dosage of OJEMDA is based on body surface area ( see Tables 1 and 2 ). ( 2.3 ) Administer OJEMDA orally, once weekly, with or without food. ( 2.3 , 2.4 ). Tablets : Swallow tablets whole with water. Do not chew, cut, or crush. ( 2.4 ) For Oral Suspension : See full prescribing information for preparation and administration instructions. ( 2.4 ) 2.1 Patient Selection Select patients for treatment with OJEMDA based on the presence of BRAF fusion or rearrangement, or BRAF V600 mutation in tumor specimens [see Clinical Studies (14) ]. Information on FDA-approved tests for the detection of BRAF fusions, BRAF rearrangements, and BRAF V600 mutations is available at http://www.fda.gov/companiondiagnostics . 2.2 Recommended Testing Before Initiating OJEMDA Before initiating OJEMDA, evaluate liver function tests, including ALT, AST and bilirubin [see Warnings and Precautions (5.3) ]. 2.3 Recommended Dosage The recommended dosage of OJEMDA based on body surface area (BSA) is 380 mg/m 2 orally once weekly (the maximum recommended dosage is 600 mg orally once weekly) with or without food [see Administration (2.4) and Clinical Pharmacology (12.3) ] until disease progression or intolerable toxicity. OJEMDA may be administered as an immediate release tablet (see Table 1 ) or as an oral suspension (see Table 2 ). A recommended dosage for patients with BSA less than 0.3 m 2 has not been established. Table 1 Recommended OJEMDA Tablets Dosage Based on Body Surface Area Body Surface Area (m 2 ) Recommended Dosage 0.30-0.89 Administer OJEMDA oral suspension once weekly (see Table 2 ) 0.90-1.12 400 mg once weekly 1.13-1.39 500 mg once weekly ≥ 1.40 600 mg once weekly Table 2 Recommended Dosage for OJEMDA for Oral Suspension Based on Body Surface Area Body Surface Area (m 2 ) Dose Volume (mL) OJEMDA for oral suspension has a concentration of 25 mg/mL. Each bottle of OJEMDA for oral suspension delivers 300 mg/12 mL. Dosage 0.30-0.35 5 125 mg once weekly 0.36-0.42 6 150 mg once weekly 0.43-0.48 7 175 mg once weekly 0.49-0.54 8 200 mg once weekly 0.55-0.63 9 225 mg once weekly 0.64-0.77 11 275 mg once weekly 0.78-0.83 12 300 mg once weekly 0.84-0.89 14 350 mg once weekly 0.90-1.05 15 375 mg once weekly 1.06-1.25 18 450 mg once weekly 1.26-1.39 21 525 mg once weekly ≥1.40 24 600 mg once weekly Continue once weekly dosing until disease progression or intolerable toxicity. 2.4 Administration Take OJEMDA at a regularly scheduled time once weekly. OJEMDA may be taken with or without food [see Clinical Pharmacology (12.3) ]. If a dose is missed by: 3 days or less, take the missed dose as soon as possible, and take the next dose on its regularly scheduled day. more than 3 days, skip the missed dose and take the next dose on its regularly scheduled day. If vomiting occurs immediately after taking a dose, repeat that dose. OJEMDA tablets Swallow tablets whole with water. Do not chew, cut, or crush. OJEMDA for oral suspension Prior to first time use of OJEMDA for oral suspension, ensure that caregivers (and if appropriate, patients) read and understand the "Instructions for Use" before preparing, measuring, and administering OJEMDA. Preparation and Administration Reconstitute the powder in each supplied bottle with exactly 14 mL of room temperature water to form the OJEMDA for oral suspension. After reconstitution each mL contains 25 mg of tovorafenib. Product foaming after reconstitution reduces the deliverable volume. Each bottle delivers 300 mg of tovorafenib in 12 mL. For doses greater than 300 mg, reconstitute two bottles to achieve the dose. Split the dose as equally as possible between the two bottles (e.g., 6 mL and 7 mL for a 325 mg dose). Prepare the first bottle and administer dose prior to preparing the second bottle. Administer OJEMDA for oral suspension using the supplied oral dosing syringe or feeding tube (minimum 12 French) immediately after preparation. If the OJEMDA for oral suspension is not administered within 15 minutes after preparation, instruct the patient to discard it. 2.5 Dosage Modifications for Adverse Reactions The recommended dosage reductions for adverse reactions for OJEMDA tablets are provided in Table 3 and OJEMDA for oral suspension in Table 4. Table 3 OJEMDA Tablets: Recommended Dosage Reductions for Adverse Reactions BSA (m 2 ) First Dosage Reduction Second Dosage Reduction 0.30-1.12 Administer the oral suspension once weekly (see Table 4 ) 1.13-1.39 400 mg once weekly Administer OJEMDA oral suspension once weekly (see Table 4 ) ≥1.40 500 mg once weekly 400 mg once weekly Table 4 OJEMDA for Oral Suspension: Recommended Dosage Reductions for Adverse Reactions BSA (m 2 ) First Dosage Reduction Second Dosage Reduction Volume (mL) Dose (mg) Volume (mL) Dose (mg) 0.30-0.35 4 100 mg once weekly 3 75 mg once weekly 0.36-0.42 5 125 mg once weekly 4 100 mg once weekly 0.43-0.48 6 150 mg once weekly 5 125 mg once weekly 0.49-0.54 7 175 mg once weekly 6 150 mg once weekly 0.55-0.63 8 200 mg once weekly 6 150 mg once weekly 0.64-0.77 9 225 mg once weekly 8 200 mg once weekly 0.78-0.83 10 250 mg once weekly 8 200 mg once weekly 0.84-0.89 12 300 mg once weekly 10 250 mg once weekly 0.90-1.05 13 325 mg once weekly 11 275 mg once weekly 1.06-1.25 15 375 mg once weekly 13 325 mg once weekly 1.26-1.39 18 450 mg once weekly 15 375 mg once weekly ≥1.40 20 500 mg once weekly 16 400 mg once weekly The recommended dosage modifications of OJEMDA for adverse reactions are in Table 5. Table 5 Recommended Dosage Modifications for Adverse Reactions Severity of ADR National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0. Dosage Modification See Table 3 and Table 4 for recommended dosage reductions. Hemorrhage [see Warnings and Precautions (5.1) ] Intolerable Grade 2 Any Grade 3 Withhold OJEMDA. If improved to Grade 0-1, resume at lower dosage. If not improved, consider permanent discontinuation of OJEMDA. First occurrence of any Grade 4 Withhold OJEMDA. If improved to Grade 0-1, resume at lower dosage. OR Permanently discontinue OJEMDA. Recurrent Grade 4 Permanently discontinue OJEMDA. Skin Toxicity including Photosensitivity [see Warnings and Precautions (5.2) ] Intolerable Grade 2 Grade 3 or 4 Withhold OJEMDA. If improved to Grade 0-1, resume at lower dosage. If not improved, consider permanent discontinuation of OJEMDA. Hepatotoxicity [see Warnings and Precautions (5.3) ] Grade 3 AST or ALT Grade 3 bilirubin Withhold OJEMDA. If improved to Grade ≤ 2 or baseline, resume as follows: If laboratory abnormality resolves within 8 days, resume OJEMDA at the same dose. If laboratory abnormality does not resolve within 8 days, resume OJEMDA at lower dosage. First occurrence of any Grade 4 Withhold OJEMDA. If improved to Grade 0-1, resume at lower dosage. OR Permanently discontinue OJEMDA Recurrent Grade 4 Permanently discontinue OJEMDA. Other Adverse Reactions [see Adverse Reactions (6.1) ] Intolerable Grade 2 Any Grade 3 Withhold OJEMDA. If improved to Grade 0-1, resume at lower dosage. If not improved, consider permanent discontinuation of OJEMDA. First occurrence of any Grade 4 Withhold OJEMDA. If improved to Grade 0-1, resume at lower dosage. OR Permanently discontinue OJEMDA. Recurrent Grade 4 Permanently discontinue OJEMDA.

4 CONTRAINDICATIONS None . None. ( 4 )

5 WARNINGS AND PRECAUTIONS Hemorrhage: Major hemorrhagic events can occur during treatment with OJEMDA. Withhold, resume at reduced dose, or permanently discontinue based on severity. ( 5.1 ) Skin Toxicity Including Photosensitivity : Advise patients to monitor for new or worsening skin reactions. Advise patients to limit direct ultraviolet exposure and use precautionary measures such as sunscreen, sunglasses and/or protective clothing during treatment with OJEMDA. Withhold, reduce the dose or permanently discontinue based on severity. ( 5.2 ) Hepatotoxicity: OJEMDA can cause hepatotoxicity. Monitor liver function tests prior to administration and during treatment. Withhold, reduce the dose or permanently discontinue based on severity. ( 5.3 ) Effect on Growth : Reductions in growth velocity have been reported. Routinely monitor growth in pediatric patients. ( 5.4 ) Embryo-Fetal Toxicity : Can cause fetal harm. Advise of the potential risk to a fetus and to use effective nonhormonal contraception. ( 5.5 , 8.1 , 8.3 ) NF1 Associated Tumors : Increased tumor growth may occur with OJEMDA. (5.6, 13.2) 5.1 Hemorrhage Hemorrhage, including major hemorrhage defined as symptomatic bleeding in a critical area or organ, can occur with OJEMDA. In the pooled safety population [see Adverse Reactions (6.1) ], hemorrhagic events occurred in 37% of patients, including epistaxis in 26% and intratumoral hemorrhage in 9%. Serious events of bleeding occurred in 5% of patients including Grade 5 tumor hemorrhage in 1 patient (0.6%). OJEMDA was permanently discontinued for hemorrhage in 2% of patients. Advise patients and caregivers of the risk of hemorrhage during treatment with OJEMDA. Monitor for signs and symptoms of hemorrhage and evaluate as clinically indicated . Withhold and resume at reduced dose upon improvement, or permanently discontinue based on severity [see Dosage and Administration (2.5) ]. 5.2 Skin Toxicity Including Photosensitivity OJEMDA can cause rash, including maculopapular rash and photosensitivity. In the pooled safety population [see Adverse Reactions (6.1) ], rash occurred in 67% of patients treated with OJEMDA, including Grade 3 rash in 12%. Rash resulted in dose interruption in 15% of patients and dose reduction in 7% of patients. OJEMDA was permanently discontinued due to rash in 1% of patients (n=2). In the pooled safety population, dermatitis acneiform occurred in 26% of patients treated with OJEMDA, including Grade 3 dermatitis acneiform in 0.6% of patients (n=1). Dose reduction was required in 2% of patients (n=3) due to dermatitis acneiform. Monitor for new or worsening skin reactions. Consider dermatologic consultation and initiate supportive care as clinically indicated. Withhold, reduce the dose, or permanently discontinue OJEMDA based on severity of adverse reaction [see Dosage and Administration (2.5) ]. Photosensitivity In the pooled safety population [see Adverse Reactions (6.1) ], photosensitivity occurred in 12% of patients treated with OJEMDA, including Grade 3 events in 0.6% of patients (n=1). Advise patients to use precautionary measures against ultraviolet exposure such as use of sunscreen, sunglasses, and/or protective clothing during treatment with OJEMDA. Withhold, reduce the dose, or permanently discontinue OJEMDA based on severity of adverse reaction [see Dosage and Administration (2.5) ]. 5.3 Hepatotoxicity OJEMDA can cause hepatotoxicity. In the pooled safety population [see Adverse Reactions (6.1) ] , increased alanine aminotransferase (ALT) occurred in 42% and increased aspartate aminotransferase (AST) occurred in 74%, including Grade 3 ALT in 4% and increased AST in 2% of patients treated with OJEMDA. The median time to onset of increased ALT or AST was 14 days (range: 3 to 280 days). Increased ALT or AST leading to dose interruption occurred in 5% of patients and dose reductions were required in 1.2% of patients. Increased bilirubin occurred in 23% of patients, including Grade 3 increased bilirubin in 0.6% of patients (n=1) treated with OJEMDA. Hyperbilirubinemia leading to dose discontinuation occurred in a single adult patient with an advanced non-CNS solid tumor. Monitor liver function tests, including ALT, AST and bilirubin, before initiation of OJEMDA, one month after initiation and then every three months thereafter and as clinically indicated. Withhold and resume at the same or reduced dose upon improvement, or permanently discontinue OJEMDA based on the severity [see Dosage and Administration (2.5) ]. 5.4 Effect on Growth OJEMDA can cause reductions in growth velocity. In FIREFLY-1 [see Adverse Reactions (6.1) ] , treatment-emergent adverse effects on growth were reported in 46% of 133 patients 18 years of age or younger; 35% were Grade 3 or higher. Reduction in growth velocity resulted in dose interruption in 5% of patients, dose reduction in 2.3% of patients, and permanent discontinuation in 3% of patients. The median change from baseline in height percentile was -14 (z-score change -0.6) for evaluable patients on study for 12 months (N=107) and -20 (z-score change -0.9) for evaluable patients on study for 18 months (N=95). Growth velocity improved after interruption of treatment with OJEMDA. Among 81 evaluable patients, the median annualized growth velocity ranged from 0.86 to 1.8 cm/year during the 2-year treatment period. Of those, 17 patients had height measurements recorded at least 90 days off-treatment and had a 4.2 cm/year median annualized growth velocity. Routinely monitor patient growth during treatment with OJEMDA [see Adverse Reactions (6) , Use in Specific Populations (8.4) ]. 5.5 Embryo-Fetal Toxicity Based on findings from animal studies and its mechanism of action, OJEMDA may cause fetal harm when administered to a pregnant woman. Tovorafenib was embryo lethal in rats at doses approximately 0.8-fold the human exposure at the recommended dose based on area under the curve (AUC). 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 OJEMDA and for 28 days after the last dose, since OJEMDA can render some hormonal contraceptives ineffective [see Drug Interactions (7.2) ] . Advise male patients with female partners of reproductive potential to use effective contraception during treatment with OJEMDA and for 2 weeks after the last dose [see Use in Specific Populations (8.1 , 8.3) ]. 5.6 NF1 Associated Tumors Based on nonclinical data in NF1 models without BRAF alterations, tovorafenib may promote tumor growth in patients with NF1 tumors [see Nonclinical Toxicology (13.2) ]. Confirm evidence of a BRAF alteration prior to initiation of treatment with OJEMDA .

7 DRUG INTERACTIONS Moderate and Strong CYP2C8 Inhibitors : Avoid coadministration with OJEMDA. ( 7.1 ). Moderate and Strong CYP2C8 Inducers : Avoid coadministration with OJEMDA. ( 7.1 ). Certain CYP3A Substrates : Avoid coadministration of OJEMDA with CYP3A substrates where minimal concentration changes can cause reduced efficacy. ( 7.2 ). Hormonal contraceptives : Avoid coadministration with OJEMDA. ( 7.2 ). 7.1 Effects of Other Drugs on OJEMDA Table 8 describes drug interactions where coadministration with another drug affects OJEMDA. Table 8 Coadministration with Other Drugs that Affect the Use of OJEMDA Strong or Moderate CYP2C8 Inhibitors Prevention or Management Avoid coadministration of OJEMDA with a strong or moderate CYP2C8 inhibitor. Mechanism and Clinical Effect(s) Tovorafenib is a CYP2C8 substrate. Strong or moderate CYP2C8 inhibitors are predicted to increase tovorafenib exposure based on a mechanistic understanding of its elimination [see Clinical Pharmacology (12.3) ], which may increase the risk of adverse reactions with OJEMDA. Strong or Moderate CYP2C8 Inducers Prevention or Management Avoid coadministration of OJEMDA with a strong or moderate CYP2C8 inducer. Mechanism and Clinical Effect(s) Tovorafenib is a CYP2C8 substrate. Strong or moderate CYP2C8 inducers are predicted to decrease tovorafenib exposure based on a mechanistic understanding of its elimination [see Clinical Pharmacology (12.3) ], which may reduce the effectiveness of OJEMDA. 7.2 Effects of OJEMDA on Other Drugs Table 9 describes drug interactions where coadministration with OJEMDA affects another drug. Table 9 Coadministration with OJEMDA that Affects the Use of Other Drugs CYP3A Substrates Prevention or Management Hormonal Contraceptives : Avoid coadministration of hormonal contraceptives with OJEMDA. If coadministration is unavoidable, use an additional effective nonhormonal contraceptive method during coadministration and for 28 days after discontinuation of OJEMDA. Other CYP3A Substrates: Avoid coadministration of OJEMDA with certain CYP3A substrates where minimal concentration changes may lead to serious therapeutic failures. If coadministration is unavoidable, monitor patients for loss of efficacy unless otherwise recommended in the Prescribing Information for CYP3A substrates. Mechanism and Clinical Effect(s) Tovorafenib is a CYP3A inducer. Tovorafenib is predicted to decrease exposure of certain CYP3A substrates where minimal concentration changes may lead to serious therapeutic failures [see Clinical Pharmacology (12.3) ], which may reduce the effectiveness of these substrates. Coadministration with hormonal contraceptives (CYP3A substrate) may decrease progestin-x and ethinyl estradiol exposure, which may lead to contraceptive failure and/or an increase in breakthrough bleeding [see Warnings and Precautions (5.5) , Use in Specific Populations (8.3) ].

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Hemorrhage [see Warnings and Precautions (5.1) ] Skin Toxicity Including Photosensitivity [see Warnings and Precautions (5.2) ] Hepatotoxicity [see Warnings and Precautions (5.3) ] Effect on Growth [see Warnings and Precautions (5.4) ] The most common adverse reactions (≥30%) were rash, hair color changes, fatigue, viral infection, vomiting, headache, hemorrhage, pyrexia, dry skin, constipation, nausea, dermatitis acneiform, and upper respiratory tract infection. ( 6.1 ) The most common Grade 3 or 4 laboratory abnormalities (≥2%) were decreased phosphate, decreased hemoglobin, increased creatine phosphokinase, increased alanine aminotransferase, decreased albumin, decreased lymphocytes, decreased leukocytes, increased aspartate aminotransferase, decreased potassium, and decreased sodium. To report SUSPECTED ADVERSE REACTIONS, contact Day One Biopharmaceuticals at toll-free phone # 1-877-204-2820 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. The safety population described in WARNINGS AND PRECAUTIONS reflects exposure to OJEMDA taken orally once weekly at a dose based on body surface area [see Clinical Studies (14) ] in 140 patients with relapsed or refractory pediatric LGG or advanced solid tumors harboring a RAF alteration and a flat dose of 600 mg in 32 adult patients with advanced solid tumors until disease progression or intolerable toxicity. Among 172 patients treated with OJEMDA, 86% were exposed for 6 months or longer and 49% were exposed for 1 year or longer. Pediatric Low-grade Glioma The safety of OJEMDA was evaluated in 137 patients with relapsed or refractory pediatric LGG harboring a BRAF alteration in FIREFLY-1 (Arms 1 and 2) [see Clinical Studies (14) ]. Patients received OJEMDA at a dose based on body surface area [see Dosage and Administration (2.3 ] orally once weekly until disease progression or intolerable toxicity. The median age of patients was 9 years (range 1 to 24 years); 53% male; 58% White, 7% Asian, 2% Black or African American, 6% other races, 25% race was not reported; 2.9% were Hispanic or Latino; and 90% Karnofsky/Lansky performance status of 80 to 100. Serious adverse reactions occurred in 45% of patients who received OJEMDA. Serious adverse reactions in >2% of patients included viral infection (9%), pneumonia (4%), and sepsis (4%). A fatal adverse reaction of tumor hemorrhage occurred in 1 patient (1%). Permanent discontinuation of OJEMDA due to an adverse reaction occurred in 7% of patients. Adverse reactions which resulted in permanent discontinuation of OJEMDA in more than one patient were tumor hemorrhage and reduction in growth velocity. Dosage interruptions of OJEMDA due to an adverse reaction occurred in 57% of patients. Adverse reactions which required dose interruption in ≥5% of patients included rash, pyrexia, vomiting, and hemorrhage. Dosage reductions of OJEMDA due to an adverse reaction occurred in 24% of patients. Adverse reactions which required dose reduction in ≥2% of patients included rash, and fatigue. The most common adverse reactions (≥30%) were rash, hair color changes, fatigue, viral infection, vomiting, headache, hemorrhage, pyrexia, dry skin, constipation, nausea, dermatitis acneiform, and upper respiratory tract infection. The most common Grade 3 or 4 laboratory abnormalities (≥2%) were decreased phosphate, decreased hemoglobin, increased creatine phosphokinase, increased alanine aminotransferase, decreased albumin, decreased lymphocytes, decreased leukocytes, increased aspartate transferase, decreased potassium, and decreased sodium. Table 6 and Table 7 present adverse reactions and laboratory abnormalities, respectively, identified in FIREFLY-1 (Arms 1 and 2). Table 6 Adverse Reactions (≥20%) in Patients with Pediatric LGG Who Received OJEMDA in FIREFLY-1 (Arms 1 and 2) Adverse Reaction OJEMDA (N=137) All Grades (%) Grade 3 or 4 (%) Skin and Subcutaneous Tissue Disorders Rash Includes terms erythema multiforme, eczema, rash erythematous, rash macular, rash follicular, rash pruritic, rash maculopapular, rash, rash papular, rash pustular, skin exfoliation, drug eruption, dermatitis, dermatitis bullous. 77 12 Hair color changes 76 0 Dry skin 36 0 Dermatitis acneiform 31 1 Pruritus 26 1 General Disorders Fatigue 55 4 Pyrexia 39 4 Edema Includes terms lip edema, periorbital edema, edema peripheral, localized edema, face edema, vulval edema. 26 0 Infections and Infestations Viral infection Includes terms viral infection, rhinovirus infection, enterovirus infection, viral upper respiratory tract infection, enterocolitis viral, oral herpes, gastroenteritis viral, influenza, influenza like illness, respiratory syncytial virus infection, enterovirus infection, coronavirus infection, COVID-19, SARS-COV-2 test positive, herpes simplex, parainfluenza virus infection, adenoviral upper respiratory infection, viraemia, adenovirus infection, conjunctivitis viral, eye infection viral, metapneumovirus infection, parvovirus infection, respiratory syncytial virus bronchiolitis, respiratory tract infection viral, viral pharyngitis, viral rhinitis, viral tonsillitis. 55 7 Upper respiratory tract infection 31 1.5 Paronychia 26 1.5 Gastrointestinal Disorders Vomiting Includes terms retching, hematemesis. 50 4 Constipation 33 0 Nausea 33 0 Abdominal pain 28 0 Diarrhea Includes terms colitis, enterocolitis. 22 1.5 Stomatitis Includes terms mouth ulceration, mucosal inflammation, aphthous ulcer, cheilitis. 20 0 Nervous system disorders Headache 45 1 Vascular Disorders Hemorrhage Includes terms tumor hemorrhage, gastrointestinal hemorrhage, subdural hemorrhage, epistaxis, intracranial tumor hemorrhage, upper gastrointestinal hemorrhage, lower gastrointestinal hemorrhage, vaginal hemorrhage, gingival bleeding, post procedural hemorrhage, hemoptysis, anal hemorrhage. 42 5 Includes one Grade 5 event. Other clinically important adverse reactions observed in <20% of patients treated with OJEMDA were reductions in growth velocity [see Warnings and Precautions (5.4) ] skin discoloration, myalgia, photosensitivity reaction [see Warnings and Precautions (5.2) ] , and arthralgia. Table 7 Select Laboratory Abnormalities (≥20%) that Worsened from Baseline in Patients with Pediatric LGG Who Received OJEMDA in FIREFLY-1 (Arms 1 and 2) Laboratory Abnormality Severity as defined by National Cancer Institute CTCAE v5.0 OJEMDA The denominator for each laboratory parameter is based on the number of patients with a baseline and post-treatment laboratory value available which ranged from 67 to 137 patients. All Grades (%) Grade 3 or 4 (%) Hematology Decreased hemoglobin 90 15 Decreased lymphocytes 50 2 Decreased leukocytes 31 2 Increased lymphocytes 23 0 Chemistry Decreased phosphate 87 25 Increased AST 83 2 Increased creatine phosphokinase 83 11 Increased LDH 73 0 Decreased potassium 51 2 Increased ALT 50 5 Increased bilirubin 22 1 Decreased albumin 24 5 Decreased sodium 20 2 Increased creatine phosphokinase was a clinically important laboratory abnormality that worsened from baseline in patients treated with OJEMDA.

8.1 Pregnancy Risk Summary Based on findings from animal studies and its mechanism of action [see Clinical Pharmacology (12.1) ], OJEMDA can cause fetal harm when administered to a pregnant woman. There are no available data on the use of OJEMDA in pregnant women. Oral administration of tovorafenib to pregnant rats during the period of organogenesis resulted in embryo lethality at exposures 0.8 times the human exposure at the recommended dose based on AUC ( see Data ). Advise pregnant women of the potential risk to a fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data In an embryo-fetal development study, once daily oral administration of tovorafenib to pregnant rats during the period of organogenesis from gestation days 7 through 17 at doses of 37.5, 75, and 150 mg/kg resulted in early resorptions and total litter loss at all doses. The dose of 37.5 mg/kg/day is approximately 0.8-fold the human exposure at the recommended dose based on AUC.