Version October 2024
Dosage guidance:
Dosage form information: Tovorafenib is available as oral suspension and tablets; BSA-band dosing is product specific due to product strengths.
Glioma, low grade, relapsed or refractory (with BRAF fusion or rearrangement or BRAF V600 mutation): Note: Confirm the presence of BRAF fusion or rearrangement, or BRAF V600 mutation prior to treatment initiation. Treatment should be continued until disease progression or intolerable toxicity.
Infants ≥6 months, Children, and Adolescents with BSA ≥0.3 m2:
BSA-directed dosing: Oral: 380 mg/m2/dose once weekly; maximum dose: 600 mg/dose.
Fixed dosing (BSA-banded dosing):
Oral suspension:
0.3 to <0.36 m2: Oral: 125 mg once weekly.
0.36 to <0.43 m2: Oral: 150 mg once weekly.
0.43 to <0.49 m2: Oral: 175 mg once weekly.
0.49 to <0.55 m2: Oral: 200 mg once weekly.
0.55 to <0.64 m2: Oral: 225 mg once weekly.
0.64 to <0.78 m2: Oral: 275 mg once weekly.
0.78 to <0.84 m2: Oral: 300 mg once weekly.
0.84 to <0.9 m2: Oral: 350 mg once weekly.
0.9 to <1.06 m2: Oral: 375 mg once weekly.
1.06 to <1.26 m2: Oral: 450 mg once weekly.
1.26 to <1.4 m2: Oral: 525 mg once weekly.
≥1.4 m2: Oral: 600 mg once weekly.
Oral tablet:
0.9 to <1.13 m2: Oral: 400 mg once weekly.
1.13 to <1.4 m2: Oral: 500 mg once weekly.
≥1.4 m2: Oral: 600 mg once weekly.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Dosing adjustment for toxicity:
Dose reduction levels: Note: Dosage adjustments are dosage form specific (oral suspension or tablets).
Infants ≥6 months, Children, and Adolescents: Oral:
|
BSA |
First dose reduction |
Second dose reduction |
|---|---|---|
|
0.3 to <0.36 m2 |
100 mg once weekly |
75 mg once weekly |
|
0.36 to <0.43 m2 |
125 mg once weekly |
100 mg once weekly |
|
0.43 to <0.49 m2 |
150 mg once weekly |
125 mg once weekly |
|
0.49 to <0.55 m2 |
175 mg once weekly |
150 mg once weekly |
|
0.55 to <0.64 m2 |
200 mg once weekly |
150 mg once weekly |
|
0.64 to <0.78 m2 |
225 mg once weekly |
200 mg once weekly |
|
0.78 to <0.84 m2 |
250 mg once weekly |
200 mg once weekly |
|
0.84 to <0.9 m2 |
300 mg once weekly |
250 mg once weekly |
|
0.9 to <1.06 m2 |
325 mg once weekly |
275 mg once weekly |
|
1.06 to <1.26 m2 |
375 mg once weekly |
325 mg once weekly |
|
1.26 to <1.4 m2 |
450 mg once weekly |
375 mg once weekly |
|
≥1.4 m2 |
500 mg once weekly |
400 mg once weekly |
|
BSA |
First dose reduction |
Second dose reduction |
|---|---|---|
|
a Refer to "Tovorafenib Oral Suspension Dosage Level Reductions" table. | ||
|
0.3 to <1.13 m2 |
Use oral suspensiona | |
|
1.13 to <1.4 m2 |
400 mg once weekly |
Use oral suspension to adjust dosea |
|
≥1.4 m2 |
500 mg once weekly |
400 mg once weekly |
Dosage adjustments:
|
Adverse reaction |
Description/severity |
Tovorafenib dosage modification |
|---|---|---|
|
Hemorrhage |
Intolerable grade 2 or any grade 3 hemorrhage |
Interrupt tovorafenib. If hemorrhage improves to a grade 0 or 1, then resume at a lower dosage. If no improvement, consider permanently discontinuing tovorafenib. |
|
Grade 4 hemorrhage, first occurrence |
Interrupt tovorafenib. If hemorrhage improves to grade 0 or 1, then resume at lower dosage. Alternatively, permanently discontinue tovorafenib. | |
|
Grade 4 hemorrhage, recurrent |
Permanently discontinue tovorafenib. | |
|
Skin toxicity (including photosensitivity) |
Intolerable grade 2, or any grade 3 or 4 |
Interrupt tovorafenib. If improves to a grade 0 or 1, then resume at lower dosage. If no improvement, consider permanently discontinuing tovorafenib. |
|
Other |
Intolerable grade 2 adverse reaction or any grade 3 adverse reaction |
Interrupt tovorafenib. If improves to a grade 0 or 1, then resume at lower dosage. If no improvement, consider permanently discontinuing tovorafenib. |
|
Grade 4 adverse reaction, first occurrence |
Interrupt tovorafenib. If improves to grade 0 or 1, then resume at lower dosage. Alternatively, permanently discontinue tovorafenib. | |
|
Grade 4 adverse reaction, recurrent |
Permanently discontinue tovorafenib. |
Altered kidney function:
Infants ≥6 months, Children, and Adolescents: Note: The manufacturer recommends calculating eGFR using the Schwartz or MDRD equation for dose adjustment purposes.
eGFR ≥30 mL/minute/1.73 m2: Oral: No dosage adjustment necessary.
eGFR <30 mL/minute/1.73 m2: Oral: There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).
Infants ≥6 months, Children, and Adolescents: Oral:
Baseline hepatic impairment:
Mild impairment (bilirubin ≤ ULN and AST > ULN or bilirubin >1 to 1.5 times ULN with any AST): No dosage adjustment necessary.
Moderate (bilirubin >1.5 to 3 times ULN and any AST) to severe (bilirubin >3 times ULN and any AST) impairment: There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).
Hepatotoxicity during treatment:
Grade 3 AST, ALT, or bilirubin: Withhold tovorafenib.
Recovery to baseline or grade ≤2:
If within 8 days, resume at same dose.
If abnormality does not resolve within 8 days, resume at the next lower dose based on dosage reduction level tables.
Grade 4, first occurrence: Withhold tovorafenib; if improved to grade 0 or 1, resume at next lower dose based on dosage reduction level tables. Alternatively, permanently discontinue tovorafenib.
Grade 4, recurrent: Permanently discontinue tovorafenib.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Adverse reactions reported in children, adolescents, and young adults.
>10%:
Cardiovascular: Edema (26%)
Dermatologic: Acneiform eruption (31%), hair discoloration (76%), paronychia (26%), pruritus (26%), skin photosensitivity (<20%), skin rash (77%), xeroderma (36%)
Endocrine & metabolic: Decreased serum albumin (24%), decreased serum phosphate (87%), decreased serum potassium (51%), decreased serum sodium (20%)
Gastrointestinal: Abdominal pain (28%), constipation (33%), diarrhea (including colitis: 22%; grades 3/4: 2%), nausea (33%), stomatitis (20%), vomiting (50%; grades 3/4: 4%)
Hematologic & oncologic: Decreased hemoglobin (90%; grades 3/4: 15%), hemorrhage (42%; grades 3/4: 5%), leukopenia (31%; grades 3/4: 2%), lymphocytopenia (50%; grades 3/4: 2%), lymphocytosis (23%)
Hepatic: Increased serum alanine aminotransferase (50%), increased serum aspartate aminotransferase (83%), increased serum bilirubin (22%)
Infection: Viral infection (55%)
Nervous system: Fatigue (55%), headache (45%)
Neuromuscular & skeletal: Increased creatine phosphokinase in blood specimen (83%), linear skeletal growth rate below expectation (15%)
Respiratory: Upper respiratory tract infection (31%)
Miscellaneous: Fever (39%)
1% to 10%:
Infection: Sepsis (4%)
Respiratory: Pneumonia (4%)
Frequency not defined: Hematologic & oncologic: Tumor hemorrhage
There are no contraindications listed in the manufacturer's labeling.
Concerns related to adverse effects:
• Dermatologic toxicity: Tovorafenib may cause rash, including maculopapular rash and photosensitivity. Rash has occurred in approximately two-thirds of tovorafenib-treated patients; grade 3 rash has been reported. Rash has resulted in dose interruption, dose reduction, and in rare cases, permanent discontinuation. Dermatitis acneiform occurred in over one-fourth of tovorafenib-treated patients, including grade 3 dermatitis acneiform (rare). Dose reduction due to dermatitis acneiform occurred in a small percentage of patients.
• Hemorrhage: Hemorrhage, including major hemorrhage (defined as symptomatic bleeding in a critical area or organ) may occur with tovorafenib. Hemorrhagic events (including epistaxis and intratumoral hemorrhage) occurred in over one-third of patients. Serious bleeding events occurred in a small percentage of patients, including one fatal case of tumor hemorrhage. Tovorafenib was permanently discontinued for hemorrhage in a small number of patients. Advise patients and caregivers of the risk of hemorrhage during treatment with tovorafenib.
• Hepatotoxicity: Tovorafenib may cause hepatotoxicity. ALT elevation occurred in almost half of patients and AST elevations occurred in nearly three-fourths of patients; grade 3 ALT and/or AST elevations occurred in a small percentage of tovorafenib-treated patients. The median time to onset of ALT or AST elevations was 14 days (range: 3 to 280 days). ALT or AST elevations leading to dose interruption or dose reductions have occurred. Bilirubin elevations occurred in nearly one-fourth of patients, including rare grade 3 events. Hyperbilirubinemia leading to tovorafenib discontinuation occurred in one adult patient with an advanced non-CNS solid tumor.
Special populations:
• Pediatric: Tovorafenib may cause reductions in growth velocity. In the clinical trial, treatment-emergent adverse effects on growth (decrease in height Z-scores from baseline) occurred in 15% of patients ≤18 years of age, including grade 3 events in 5% of patients. Tovorafenib was permanently discontinued due to reduction in growth velocity in 2% of patients. Growth velocity recovered after stopping tovorafenib treatment.
Other warnings/precautions:
• Photosensitivity: Photosensitivity has occurred with tovorafenib, including cases of grade 3 events. Advise patients to use precautionary measures against ultraviolet exposure such as use of sunscreen, sunglasses, and/or protective clothing during tovorafenib treatment.
• Tumor growth potential/appropriate use: Confirm evidence of a BRAF alteration prior to initiation of treatment with tovorafenib. Based on nonclinical data in NF1 models without BRAF alterations, tovorafenib may promote tumor growth in patients with NF1 tumors.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Suspension Reconstituted, Oral:
Ojemda: 25 mg/mL (12 mL)
Tablet, Oral:
Ojemda: 100 mg
No
Suspension (reconstituted) (Ojemda Oral)
25 mg/mL (per mL): $847.90
Tablets (Ojemda Oral)
100 mg (per each): $2,034.96
Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.
Tovorafenib is available through specialty pharmacies. Access information from the manufacturer may be found at https://www.ojemda.com/get-resources/EveryDay-Support-From-Day-One-Overview.pdf.
Oral: Administer with or without food at a regularly scheduled time.
Oral suspension: Prior to administration, reconstitute each 300 mg bottle of tovorafenib with exactly 14 mL of room temperature water (do NOT use cold water) using the provided oral dosing syringe; see manufacturer's labeling for details. Ensure that no solids remain after reconstitution; allow bottle to sit for 60 seconds to allow foam to settle prior to drawing up dose. The reconstituted suspension is 25 mg/mL; no more than 12 mL should be used from each bottle. Doses >300 mg will require 2 bottles; split the dose as equally as possible between the two bottles (eg, for a 325 mg dose, administer 6 mL from the first bottle and 7 mL from the second). Dose must be administered within 15 minutes of preparation; if not administered within 15 minutes, suspension must be discarded. Discard oral dosing syringe after preparation and administration; do not re-use.
Oral administration: Measure and administer appropriate dose using the provided 20 mL oral dosing syringe.
Feeding tube administration (≥12 French): Flush feeding tube prior to administering dose according to feeding tube manufacturer's instructions. Measure and administer dose using a 20 mL ENFit syringe and an ENFit adaptor (not provided). Flush feeding tube after each dose.
Tablet: Swallow whole with water; do not chew, cut, or crush.
Missed dose:
If dose missed by ≤3 days: Administer the missed dose as soon as possible; administer the next dose on its regularly scheduled day.
If dose is missed by >3 days: Skip the missed dose; administer the next dose on its regularly scheduled day.
Vomit: If patient vomits immediately after taking dose, repeat dose.
This medication is not on the NIOSH (2016) list; however, it may meet the criteria for a hazardous drug. Tovorafenib may cause teratogenicity, reproductive toxicity, and has a structural and/or toxicity profiles similar to existing hazardous agents.
Use appropriate precautions for receiving, handling, storage, preparation, dispensing, transporting, administration, and disposal. Follow NIOSH and USP 800 recommendations and institution-specific policies/procedures for appropriate containment strategy (NIOSH 2016; USP-NF 2020).
Note: Facilities may perform risk assessment of some hazardous drugs to determine if appropriate for alternative handling and containment strategies (USP-NF 2020). Refer to institution-specific handling policies/procedures.
Tablets: Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F). Dispense in the original package. Tablets should not be removed from blisters until immediately before use.
Suspension: Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F). Do not use if safety seal under cap is broken or missing. Suspension must be used immediately after reconstitution. Discard the bottle (including any unused portion) and syringe after dosing.
Treatment of relapsed or refractory pediatric low-grade glioma harboring a BRAF fusion or rearrangement, or BRAF V600 mutation (FDA approved in ages ≥6 months).
Note: Indication received accelerated approval based on response rate and duration of response; continued approval may be contingent upon confirmatory trials.
Tovorafenib may be confused with dabrafenib, encorafenib, regorafenib, sorafenib, tepotinib, tivozanib, tucatinib, vemurafenib.
The Institute for Safe Medication Practices (ISMP) includes this medication among its list of drug classes (chemotherapeutic agent, parenteral and oral) which have a heightened risk of causing significant patient harm when used in error (High-Alert Medications in Acute Care, Community/Ambulatory Care, and Long-Term Care Settings).
Substrate of CYP2C19 (minor), CYP2C8 (major), CYP2C9 (minor), CYP3A4 (minor); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the drug interactions program by clicking on the “Launch drug interactions program” link above.
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the drug interactions program
Aminolevulinic Acid (Systemic): Photosensitizing Agents may enhance the photosensitizing effect of Aminolevulinic Acid (Systemic). Risk X: Avoid combination
Aminolevulinic Acid (Topical): Photosensitizing Agents may enhance the photosensitizing effect of Aminolevulinic Acid (Topical). Risk C: Monitor therapy
CYP2C8 Inducers (Moderate): May decrease the serum concentration of Tovorafenib. Risk X: Avoid combination
CYP2C8 Inhibitors (Moderate): May increase the serum concentration of Tovorafenib. Risk X: Avoid combination
CYP2C8 Inhibitors (Strong): May increase the serum concentration of Tovorafenib. Risk X: Avoid combination
CYP3A4 Substrates (Narrow Therapeutic Index/Sensitive with Inducers): Tovorafenib may decrease the serum concentration of CYP3A4 Substrates (Narrow Therapeutic Index/Sensitive with Inducers). Management: Avoid concurrent use whenever possible; if the combination cannot be avoided, monitor closely for reduced effectiveness of the CYP3A4 substrate. Risk D: Consider therapy modification
Hormonal Contraceptives: Tovorafenib may decrease the serum concentration of Hormonal Contraceptives. Management: Avoid concurrent use when possible. If combined use is unavoidable, use of an additional nonhormonal method of contraception is recommended during combined use and for 28 days after stopping tovorafenib. Risk D: Consider therapy modification
Lumacaftor and Ivacaftor: May decrease the serum concentration of CYP2C8 Substrates (High Risk with Inhibitors or Inducers). Lumacaftor and Ivacaftor may increase the serum concentration of CYP2C8 Substrates (High Risk with Inhibitors or Inducers). Risk C: Monitor therapy
Methoxsalen (Systemic): Photosensitizing Agents may enhance the photosensitizing effect of Methoxsalen (Systemic). Risk C: Monitor therapy
Porfimer: Photosensitizing Agents may enhance the photosensitizing effect of Porfimer. Risk C: Monitor therapy
Verteporfin: Photosensitizing Agents may enhance the photosensitizing effect of Verteporfin. Risk C: Monitor therapy
Verify pregnancy status prior to use in patients who could become pregnant.
Patients who could become pregnant should use effective nonhormonal contraception during therapy and for 28 days after the last tovorafenib dose. Patients with partners who could become pregnant should also use effective nonhormonal contraception during therapy and for 2 weeks after the last dose of tovorafenib.
Hormonal contraceptive may be ineffective during tovorafenib treatment. Consult drug interactions database for more detailed information related to the use of tovorafenib and specific contraceptives.
Adverse effects to male fertility (reversible) and female fertility (nonreversible) were observed in animal toxicology studies; data are lacking on possible fertility effects in humans.
Based on the mechanism of action and data from animal reproduction studies, in utero exposure to tovorafenib may cause fetal harm. Early resorptions and total litter loss were observed when tovorafenib was administered orally to pregnant rats at doses equivalent to 0.8 times the recommended human exposure (based on AUC).
BRAF fusion or rearrangement, or BRAF V600 mutation status prior to treatment initiation. Pregnancy status prior to treatment initiation (in patients who could become pregnant). Liver function tests (including ALT, AST, and bilirubin) prior to treatment initiation, 1 month after initiation, and then every 3 months thereafter, and as clinically indicated. Growth (especially height) routinely during treatment. Monitor for new or worsening skin reactions (consider dermatologic consultation if clinically indicated) and signs/symptoms of bleeding.
Tovorafenib is a selective type II RAF kinase inhibitor that has CNS penetration (Ref). Tovorafenib inhibits mutant BRAF V600E, wild-type BRAF, and wild-type CRAF kinases. In animal models, tovorafenib exhibited antitumor activity in cells and tumor models harboring BRAF V600E and V600D mutations, as well as models harboring a BRAF fusion.
Note: There are no clinically significant pharmacokinetic differences based on age between the range of 1 to 94 years.
Distribution: Vd: 60 L/m2.
Protein binding: 97.5%; to human plasma proteins.
Metabolism: Primarily via aldehyde oxidase and CYP2C8 in vitro; also via CYP3A, CYP2C9, and CYP2C19 to a minor extent.
Half-life elimination: ~56 hours.
Time to peak: 3 hours; delayed to 6.5 hours in a fed state (high-fat meal [~859 calories; 54% fat]).
Excretion: Feces: 65% (8.6% unchanged drug); urine: 27% (<1% as unchanged drug).
Clearance: 0.7 L/hour/m2.
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