OJEMDA Tablet / Oral suspension Ref.[109717] Active ingredients: Tovorafenib

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 occurred in 15% of patients 18 years of age or younger, 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 [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 non-hormonal contraception during treatment with OJEMDA and for 28 days after the last dose, since OJEMDA can render some hormonal contraceptives ineffective [see Drug Interaction (7.2)]. 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 [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.

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)]

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 60 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 creatinine 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):

^a Includes terms erythema multiforme, eczema, rash erythematous, rash macular, rash follicular, rash pruritic, rash maculopapular, rash, rash popular, rash pustular, skin exfoliation, drug eruption, dermatitis, dermatitis bullous.
^b Includes terms lip edema, periorbital edema, edema peripheral, localized edema, face edema, vulval edema.
^c 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.
^d Includes terms retching, hematemesis.
^e Includes terms colitis, enterocolitis.
^f Includes terms mouth ulceration, mucosal inflammation, aphthous ulcer, cheilitis.
^g 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.
^* Includes one Grade 5 event.

Other clinically important adverse reactions observed in less than 20% of patients treated with OJEMDA were reductions in growth velocity [see Warnings and Precautions (5.4)] and photosensitivity [see Warnings and Precautions (5.2)].

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):

¹ Severity as defined by National Cancer Institute CTCAE v5.0
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 creatinine phosphokinase was a clinically important laboratory abnormality that worsened from baseline in patients treated with OJEMDA.

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:

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:

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.

Risk Summary

There are no data on the presence of tovorafenib or its metabolites in human milk, their effects on the breastfed child, or on milk production. Due to the potential for serious adverse reactions in breastfed children from OJEMDA, advise lactating women not to breastfeed during treatment with OJEMDA and for 2 weeks following the last dose.

OJEMDA can cause fetal harm when administered to pregnant women [see Use in Specific Populations (8.1)].

Pregnancy Testing

Verify pregnancy status in females of reproductive potential prior to initiating OJEMDA [see Use in Specific Populations (8.1)].

Contraception

Females

Advise females of reproductive potential to use effective non-hormonal contraception during treatment with OJEMDA and for 28 days after the last dose. OJEMDA can render hormonal contraceptives ineffective [see Drug Interactions (7.2)].

Males

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.

Infertility

Based on findings in animals, OJEMDA may impact fertility in males and females of reproductive potential. The effects on male fertility were reversible. The effects on female fertility were not reversible [see Nonclinical Toxicology (13.1)].

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 [see Clinical Studies (14)].

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 [see Adverse Reactions (6.1)]. 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 Zscores for height compared to age and sex-matched normative data. 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 [see Warnings and Precautions (5.4)].

No dose adjustment is recommended for patients with mild-to-moderate renal impairment (eGFR ≥30 mL/min/1.73 m² calculated by Schwartz equation or MDRD equation). OJEMDA has not been studied in patients with severe renal impairment (eGFR <30 mL/min/1.73 m²) [see Clinical Pharmacology (12.3)].

No dose adjustment is recommended for patients with mild (bilirubin ≤ upper limit of normal (ULN) and alanine aminotransferase (AST) > ULN or bilirubin > 1x to 1.5x ULN and any AST) hepatic impairment. OJEMDA has not been studied in patients with moderate (bilirubin > 1.5x to 3x ULN and any AST) to severe (bilirubin > 3x ULN and any AST) hepatic impairment [see Clinical Pharmacology (12.3)].