Ojemda
(tovorafenib)Dosage & Administration
By using PrescriberAI, you agree to the AI Terms of Use.
Ojemda Prescribing Information
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).
Patient Selection
Confirm the presence of BRAF fusion or rearrangement, or BRAF V600 mutation prior to initiation of treatment with OJEMDA [see Warnings and Precautions (5.6), Clinical Studies (14)].
An FDA approved test for the detection of BRAF fusion or rearrangement, or BRAF V600 mutation in relapsed or refractory pediatric LGG is not currently available.
Recommended Testing Before Initiating OJEMDA
Before initiating OJEMDA, evaluate liver function tests, including ALT, AST and bilirubin [see Warnings and Precautions (5.3)].
Recommended Dosage
The recommended dosage of OJEMDA based on body surface area (BSA) is 380 mg/m2 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 m2 has not been established.
| Body Surface Area (m2) | 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 |
| Body Surface Area (m2) | Dose Volume (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.
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).
- 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.
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.
| BSA (m2) | 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 |
| BSA (m2) | 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.
| Severity of ADR * | Dosage Modification † |
|---|---|
| |
| Hemorrhage [see Warnings and Precautions (5.1)] | |
| Withhold OJEMDA.
|
| Withhold OJEMDA.
|
| Permanently discontinue OJEMDA. |
| Skin Toxicity including Photosensitivity [see Warnings and Precautions (5.2)] | |
| Withhold OJEMDA.
|
| Hepatotoxicity [see Warnings and Precautions (5.3)] | |
| Withhold OJEMDA. If improved to Grade ≤ 2 or baseline, resume as follows:
|
| Withhold OJEMDA.
|
| Permanently discontinue OJEMDA. |
| Other Adverse Reactions [see Adverse Reactions (6.1)] | |
| Withhold OJEMDA.
|
| Withhold OJEMDA.
|
| Permanently discontinue OJEMDA. |
Tablets:
- 100 mg: orange, film-coated, oval tablets debossed with "100" on one side and "D101" on the opposite side. Each tablet contains 100 mg of tovorafenib.
For Oral Suspension:
- 25 mg/mL: white to off white powder. After reconstitution, each mL of strawberry flavored tovorafenib suspension contains 25 mg of tovorafenib. Each bottle delivers 300 mg of tovorafenib in 12 mL.
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.
Lactation
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.
Females and Males of Reproductive Potential
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 nonhormonal 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)].
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 [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)]. Cmax 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 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)].
Hepatic Impairment
No dose adjustment is recommended for patients with mild (bilirubin ≤ upper limit of normal (ULN) and aspartate aminotransferase (AST) > ULN or bilirubin > 1× to 1.5× ULN and any AST) hepatic impairment. OJEMDA has not been studied in patients with moderate (bilirubin > 1.5× to 3× ULN and any AST) to severe (bilirubin > 3× ULN and any AST) hepatic impairment [see Clinical Pharmacology (12.3)].
Renal Impairment
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)].
None.
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)].
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)].
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)].
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)].
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 nonhormonal contraception during treatment with OJEMDA and for 2 weeks after the last dose [see Use in Specific Populations (8.1, 8.3)].
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.