Ojemda Drug Information

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 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). Patients received OJEMDA at a dose based on body surface area 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

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

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 skin discoloration, myalgia, photosensitivity reaction , 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.

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, 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, which may reduce the effectiveness of OJEMDA.

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, 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.

Pregnancy Risk Summary Based on findings from animal studies and its mechanism of action, 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.

Pediatric Use The safety and effectiveness of OJEMDA in pediatric patients 6 months of age and older with relapsed or refractory pediatric LGG harboring a BRAF fusion or rearrangement, or BRAF V600 mutation have been established based on data from a multicenter, open-label, single-arm clinical trial . The efficacy of OJEMDA was evaluated in 76 patients with relapsed or refractory pediatric LGG. The safety of OJEMDA was evaluated in 137 patients with relapsed or refractory pediatric LGG in FIREFLY-1 (Arms 1 and 2). Of these 137 patients, 2% (n=3) were 6 month to < 2 years of age, 67% (n=92) were 2 years to < 12 years of age, and 31% (n=42) were >12 years of age. C max and AUC in pediatric patients aged 11 months to 17 years were within the range of values observed in adults given the same dose per body surface area. The safety and effectiveness of OJEMDA in patients younger than 6 months of age have not been established.

Effect on Growth Patients with pediatric LGG treated with OJEMDA for up to 24 months showed reductions from baseline in Z-scores for height compared to age and sex-matched normative data. Among 35 patients who experienced reductions in growth velocity who had hand radiographs taken to assess bone age, there was no evidence of premature closure of the epiphyseal growth plates or advancement of bone age. Patients followed after interruption of treatment with OJEMDA showed recovery of growth and increase in Z-scores.

Monitor growth routinely during treatment.