Safety
Warnings and Precautions
Warnings and precautions for OJEMDA1
Information on the safety population in FIREFLY-1
The safety population described in warnings and precautions reflects exposure to OJEMDA taken orally once weekly at a dosage based on body surface area in 140 patients with R/R pLGG or advanced solid tumors harboring a RAF alteration and a flat dosage of 600 mg in 32 adult patients with advanced solid tumors until disease progression or intolerable toxicity.
Hemorrhage
- Hemorrhage, including major hemorrhage defined as symptomatic bleeding in a critical area or organ, can occur with OJEMDA. In the pooled safety population, hemorrhagic events occurred in 37% of patients, including epistaxis in 26% and intratumoral hemorrhage in 9%
- Serious bleeding events 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
- 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
Skin toxicity including photosensitivity
- OJEMDA can cause rash, including maculopapular rash and photosensitivity. In the pooled safety population, rash occurred in 67% of patients treated with OJEMDA, including grade 3 rash in 12% of patients
- 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
- Photosensitivity
- -In the pooled safety population, 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
Hepatotoxicity
- OJEMDA can cause hepatotoxicity
- In the pooled safety population, increased ALT occurred in 42% (4% grade 3) and increased AST occurred in 74% (2% grade 3)
- 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)
- 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 starting OJEMDA, 1 month post-initiation, then every 3 months after
- Withhold and resume at the same or reduced dose upon improvement, or permanently discontinue OJEMDA based on the severity
Effect on growth
- OJEMDA can cause reductions in growth velocity
- In FIREFLY-1, TEAEs on growth occurred in 15% of patients ≤18 years of age, including grade 3 events in 5% of patients
- OJEMDA was permanently discontinued for reduction in growth velocity in 2% of patients (n=2)
- Growth velocity recovered after interruption of treatment with OJEMDA
- Routinely monitor patient growth during treatment with OJEMDA
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
- 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
- Advise male patients with female partners of reproductive potential to use effective nonhormonal contraception during treatment with OJEMDA and for 2 weeks after the last dose
NF1 associated tumors
- Based on nonclinical data in NF1 models without BRAF alterations, OJEMDA may promote tumor growth in patients with NF1 tumors
- Confirm evidence of a BRAF alteration prior to initiation of treatment with OJEMDA
Common Adverse Reactions
OJEMDA was generally well tolerated in FIREFLY‑12
The majority of adverse reactions were grade 1 or 21
- The safety of OJEMDA was evaluated in 137 patients with R/R pLGG harboring a BRAF alteration
- 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%)
- 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
Adverse reactions occurring in ≥20% of pediatric patients1
OJEMDA (N=137)
All grades
Grade 3 or 4
| Skin and subcutaneous tissue disorders |
|---|
Rash 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 26% 0% |
| Infections and infestations |
Viral infection 55% 7% |
Upper respiratory tract infection 31% 1.5% |
Paronychia 26% 1.5% |
| Gastrointestinal disorders |
Vomiting 50% 4% |
Constipation 33% 0% |
Nausea 33% 0% |
Abdominal pain 28% 0% |
Diarrhea 22% 1.5% |
Stomatitis 20% 0% |
| Nervous system disorders |
Headache 45% 1% |
| Vascular disorders |
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 and photosensitivity.1
Information on effect on growth with OJEMDA1
- Among 19 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
Events NOT observed as of data cutoff
Uveitis, retinal detachment, or retinal vascular occlusion were not observed3
No drug-related adverse reactions associated with impaired cardiac function were observed2
No patients experienced life-threatening skin reactions, and no keratoacanthomas developed2
Lab Abnormalities
Laboratory assessments and additional events in FIREFLY-1
Select laboratory abnormalities (≥20%) that worsened from baseline in patients who received OJEMDA in FIREFLY‑11
OJEMDA*
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% |
*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.
Increased creatine phosphokinase was a clinically important laboratory abnormality that worsened from baseline in patients treated with OJEMDA1.
In the clinical trial, most laboratory abnormalities had no clinical manifestations and did not require clinical intervention2
To learn more about AEs and management guidelines
Download the Dosing and AE Management Guide
Discontinuation Rates
Low treatment discontinuation rate due to adverse reactions in FIREFLY‑11
7%
Discontinuation rate
(n=9/137)
Adverse reactions that resulted in permanent discontinuation in more than 1 patient were:
- Tumor hemorrhage
- Reduction in growth velocity
76% of patients received a full dosage of OJEMDA without the need for a dosage reduction1
24%
Dosage
reduction
(n=33/137)
Adverse reactions which required dosage reduction in ≥2% of patients included:
- Rash
- Fatigue
57%
Dosage
interruption
(n=78/137)
Adverse reactions which required dosage interruption in ≥5% of patients included:
- Rash
- Pyrexia
- Vomiting
- Hemorrhage
The median duration of dosage interruption was 2 weeks2
AEs=adverse events; ALT=alanine aminotransferase; AST=aspartate aminotransferase; BRAF=v-Raf murine sarcoma viral oncogene homolog B1; CNS=central nervous system; LDH=lactate dehydrogenase; NF1=neurofibromatosis type 1; pLGG=pediatric low-grade glioma; RAF=rapidly accelerted fibrosarcoma; R/R=relapsed/refractory; TEAE=treatment-emergent adverse event.
See OJEMDA’s once-weekly dosing schedule
Learn more about dosing
References
- 1. OJEMDA™ [Package Insert]. Brisbane, CA: Day One Biopharmaceuticals, Inc.; 2024.
- 2. Kilburn LB, Khuong-Quang DA, Hansford JR, et al. The type II RAF inhibitor tovorafenib in relapsed/refractory pediatric low-grade glioma: the phase 2 FIREFLY-1 trial. Nat Med. Published online November 17, 2023. doi:10.1038/s41591-023-02668-y
- 3. Data on file. Clinical report. Day One Biopharmaceuticals, Inc.; August 29, 2023.