Tovorafenib (Monograph)

Brand name: Ojemda
Drug class: Antineoplastic Agents

Medically reviewed by Drugs.com on Nov 10, 2024. Written by ASHP.

[Web]

Introduction

Antineoplastic agent; a Type II rapidly accelerated fibrosarcoma (RAF) kinase inhibitor.

Uses for Tovorafenib

Low-Grade Glioma

Treatment of relapsed or refractory pediatric low-grade glioma harboring a b-Raf serine-threonine kinase ( BRAF) fusion or rearrangement, or BRAF V600 mutation, in pediatric patients ≥6 months of age. Designated an orphan drug by FDA for treatment of malignant glioma. This indication is approved under accelerated approval based on response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).

Tovorafenib Dosage and Administration

General

Pretreatment Screening

Confirm the presence of BRAF fusion or rearrangement, or BRAF V600 mutation prior to initiation of treatment with tovorafenib. An FDA-approved test to detect BRAF fusion or rearrangement or BRAF V600 mutation in relapsed or refractory pediatric low-grade glioma patients is not currently available.
Evaluate liver function tests (e.g., ALT, AST, bilirubin).
Verify pregnancy status in females of reproductive potential.

Patient Monitoring

Monitor liver function tests, including ALT, AST, and bilirubin, 1 month after therapy initiation, every 3 months thereafter, and as clinically indicated during treatment.
Monitor for signs and symptoms of hemorrhage during treatment with tovorafenib and evaluate as clinically necessary.
Routinely monitor growth in pediatric patients during treatment.
Monitor for new or worsening skin reactions (e.g., rash, bumps or tiny papules, acne, peeling, redness, irritation, or blisters), including photosensitivity during treatment.

Other General Considerations

Advise patients to use precautionary measures against ultraviolet exposure (e.g., sunscreen, sunglasses, and/or protective clothing) during treatment with tovorafenib because of increased photosensitivity.

Administration

Oral Administration

Administer orally once weekly as immediate-release tablets or oral suspension with or without food.

If a dose is missed by ≤3 days, take the missed dose and resume dosing on the next regularly scheduled day. If a dose is missed by >3 days, skip the missed dose and resume regular dosing schedule.

If a dose is vomited immediately after administration, repeat the dose.

Oral Suspension

Reconstitute powder for oral suspension prior to use. Reconstitute each bottle with 14 mL of room temperature water to yield a final concentration of 25 mg/mL. If product foams after reconstitution, the deliverable volume is reduced.

Doses >300 mg: reconstitute 2 bottles and split dose as evenly as possible between the bottles (e.g., 6 mL and 7 mL for a 325 mg dose).

Administer immediately after reconstitution using supplied oral dosing syringe or via feeding tube (minimum 12-French). Discard solution after 15 minutes if not used.

Tablets

Swallow tablets whole with water. Do not chew, cut, or crush.

Dosage

Pediatric Patients

Low-Grade Glioma

Oral

Patients ≥6 months of age with BRAFfusion or rearrangement or BRAF V600 mutation and BSA ≥0.3 m²: 380 mg/m² once weekly (maximum 600 mg once weekly) until disease progression or intolerable toxicity occurs. Dosage not established for BSA <0.3 m². See Table 1 and Table 2 below for dosage recommendations based on BSA for the tablets or oral suspension.

Table 1. Recommended Tovorafenib Tablet Dosage Based on BSA1
BSA	Recommended Dosage
0.3—0.89 m²	Administer oral suspension (see Table 2)
0.9—1.12 m²	400 mg once weekly
1.13—1.39 m²	500 mg once weekly
≥1.4 m²	600 mg once weekly

The concentration of tovorafenib oral suspension is 25 mg/mL. Each bottle of suspension delivers 300 mg/12 mL.

Table 2. Recommended Dosage for Tovorafenib Oral Suspension Based on BSA1
BSA	Dose Volume	Dosage
0.3—0.35 m²	5 mL	125 mg once weekly
0.36—0.42 m²	6 mL	150 mg once weekly
0.43—0.48 m²	7 mL	175 mg once weekly
0.49—0.54 m²	8 mL	200 mg once weekly
0.55—0.63 m²	9 mL	225 mg once weekly
0.64—0.77 m²	11 mL	275 mg once weekly
0.78—0.83 m²	12 mL	300 mg once weekly
0.84—0.89 m²	14 mL	350 mg once weekly
0.9—1.05 m²	15 mL	375 mg once weekly
1.06—1.25 m²	18 mL	450 mg once weekly
1.26—1.39 m²	21 mL	525 mg once weekly
≥1.4 m²	24 mL	600 mg once weekly

Dosage Modification for Toxicity

Dosage may be reduced or temporarily interrupted if adverse effects occur. Recommended dosage reductions for adverse reactions when using the tablets or oral suspension are provided in Table 3 or Table 4, respectively.

Table 3. Tovorafenib Tablet Dose Reductions for Adverse Reactions1
BSA	First Dosage Reduction	Second Dosage Reduction
0.3—1.12 m²	Administer oral suspension once weekly (see Table 4)	Administer oral suspension once weekly (see Table 4)
1.13—1.39 m²	400 mg once weekly	Administer oral suspension once weekly (see Table 4)
≥1.4 m²	500 mg once weekly	400 mg once weekly

Table 4. Tovorafenib Suspension for Dose Reductions for Adverse Reactions1
BSA	First Dosage Reduction	Second Dosage Reduction
0.3—0.35 m²	100 mg once weekly	75 mg once weekly
0.36—0.42 m²	125 mg once weekly	100 mg once weekly
0.43—0.48 m²	150 mg once weekly	125 mg once weekly
0.49—0.54 m²	175 mg once weekly	150 mg once weekly
0.55—0.63 m²	200 mg once weekly	150 mg once weekly
0.64—0.77 m²	225 mg once weekly	200 mg once weekly
0.78—0.83 m²	250 mg once weekly	200 mg once weekly
0.84—0.89 m²	300 mg once weekly	250 mg once weekly
0.9—1.05 m²	325 mg once weekly	275 mg once weekly
1.06—1.25 m²	375 mg once weekly	325 mg once weekly
1.26—1.39 m²	450 mg once weekly	375 mg once weekly
≥1.4 m²	500 mg once weekly	400 mg once weekly

Recommended dosage modifications for adverse reactions are listed in Table 5.

National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0.

Table 5. Dosage Modifications for Adverse Reactions1
Adverse Drug Reaction (ADR)	Dosage Modification Based on ADR Severity
Hemorrhage	Intolerable Grade 2 or any Grade 3 hemorrhage: Temporarily withhold tovorafenib; if hemorrhage improves to Grade 0—1, resume at lower dosage. If hemorrhage is not improved, consider permanent discontinuation First occurrence of any Grade 4 hemorrhage: Temporarily withhold tovorafenib; if hemorrhage improves to Grade 0—1, resume at lower dosage; alternatively, may permanently discontinue tovorafenib Recurrent Grade 4 hemorrhage: Permanently discontinue tovorafenib
Skin toxicity (including photosensitivity)	Intolerable Grade 2 or Grade 3—4 skin toxicity: Temporarily withhold tovorafenib; if skin toxicity improves to Grade 0—1, resume at lower dosage. If skin toxicity is not improved, consider permanent discontinuation
Hepatotoxicity	Grade 3 AST, ALT, or bilirubin: Temporarily withhold tovorafenib; if improvement to Grade ≤2 or baseline within 8 days, resume therapy at the same dose. If abnormality does not resolve within 8 days, resume at the next lower dosage First occurrence of Grade 4 hepatotoxicity: Temporarily withhold tovorafenib and if hepatotoxicity improves to Grade 0—1, resume at lower dosage; alternatively, may permanently discontinue Recurrent Grade 4 hepatotoxicity: Permanently discontinue tovorafenib
Other	Intolerable Grade 2 or any Grade 3: Temporarily withhold tovorafenib; if improvement to Grade 0—1, resume at lower dosage, if not improved, consider permanent discontinuation First occurrence of Grade 4: Temporarily withhold tovorafenib; if improvement to Grade 0—1, resume at lower dosage; alternatively, may consider permanent discontinuation Recurrent Grade 4: Permanently discontinue tovorafenib

Special Populations

Hepatic Impairment

Mild (bilirubin ≤ULN and AST >ULN, or bilirubin >1—1.5 times the ULN with any AST) hepatic impairment: No dosage adjustment necessary.

Moderate (bilirubin >1.5—3 times the ULN with any AST) to severe (bilirubin >3 times the ULN with any AST) hepatic impairment: Not studied.

Renal Impairment

Mild to moderate renal impairment (eGFR ≥30 mL/minute per 1.73 m² based on Schwartz equation or Modification of Diet in Renal Disease [MDRD] equation): no dosage adjustment necessary.

Severe renal impairment (eGFR <30 mL/minute per 1.73 m²): Not studied.

Geriatric Patients

Manufacturer makes no specific dosage recommendations in geriatric patients.

Cautions for Tovorafenib

Contraindications

None.

Warnings/Precautions

Hemorrhage

Hemorrhage, including major hemorrhage (e.g., symptomatic bleeding in a critical area or organ), reported.

Advise patients and caregivers of the risk of hemorrhage. Monitor patients for signs and symptoms of hemorrhage and evaluate as clinically necessary. Withhold and resume tovorafenib at a reduced dose after improvement of symptoms, or permanently discontinue based on reaction severity.

Skin Toxicity Including Photosensitivity

Rash, including maculopapular rash and photosensitivity, reported.

Monitor patients for new or worsening skin reactions and consider dermatologic consultation and initiation of supportive care as clinically necessary. Withhold, dose reduce, or permanently discontinue tovorafenib based on adverse reaction severity.

Advise patients to use precautionary measures against ultraviolet exposure (e.g., sunscreen, sunglasses, and/or protective clothing) during treatment with tovorafenib. Withhold, dose reduce, or permanently discontinue tovorafenib based on severity.

Hepatotoxicity

Hepatotoxicity reported. Median time to increased transaminases of 14 days.

Evaluate liver function tests (e.g., ALT, AST, bilirubin) prior to initiation, 1 month after initiation, and then every 3 months thereafter and as clinically indicated. Withhold tovorafenib and resume at the same or reduced dose upon improvement, or permanently discontinue depending on severity.

Growth Effects

Reductions in growth velocity reported; recovery in growth occurs with treatment interruption. Routinely monitor growth during treatment.

Fetal/Neonatal Morbidity and Mortality

Based on animal data and its mechanism of action, may cause fetal harm when administered during pregnancy.

Verify pregnancy status in females of reproductive potential before treatment initiation. Advise pregnant women and females of reproductive potential of the potential fetal risk.

Advise females of reproductive potential to use effective non-hormonal contraception while receiving tovorafenib and for 28 days following the final dose, as some hormonal contraceptives may not be effective during treatment.

Advise male patients with female partners of reproductive potential to use effective nonhormonal contraception while receiving tovorafenib and for 2 weeks following the final dose.

Neurofibromatosis Type 1 Associated Tumors

Nonclinical data in neurofibromatosis type 1 (NF1) models without BRAF alterations indicate that tovorafenib may promote tumor growth in NF1 tumors. Confirm evidence of a BRAF alteration prior to initiation.

Specific Populations

Pregnancy

No data available in pregnancy. May cause fetal harm based on animal data and mechanism of action.

Lactation

No data available on presence of tovorafenib or its metabolites in human milk. Due to the potential for serious adverse reactions in the breast-fed child, advise lactating women not to breast-feed while receiving therapy and for 2 weeks following the final dose.

Females and Males of Reproductive Potential

May cause fetal harm. Verify pregnancy status in females of reproductive potential prior to initiation.

Advise females of reproductive potential to use effective non-hormonal contraception during tovorafenib therapy and for 28 days following the final dose, as some hormonal contraceptives may not be effective during treatment.

Advise male patients with female partners of reproductive potential to use effective nonhormonal contraception during tovorafenib therapy and for 2 weeks following the final dose.

May impact fertility.

Pediatric Use

Safety and efficacy established in pediatric patients aged ≥6 months. Safety and efficacy in patients aged <6 months not established. Exposure to tovorafenib in pediatric patients aged 11 months to 17 years similar to range observed in adults using the same dosage based on BSA.

Reductions from baseline in Z-scores compared to normal values for age and sex were observed in patients with low-grade glioma treated with tovorafenib for up to 24 months. No evidence of premature closure of epiphyseal growth plates or advancement of bone age in patients with reduced growth velocity. Following treatment interruption, recovery in growth and an increase in Z-scores was observed. Monitor growth routinely during treatment.

Geriatric Use

No pharmacokinetic differences based on age (1—94 years).

Hepatic Impairment

No pharmacokinetic differences in mild (bilirubin ≤ULN and AST >ULN or bilirubin >1—1.5 times ULN and any AST) hepatic impairment. Not studied in moderate (bilirubin >1.5—3 times ULN and any AST) to severe (bilirubin >3 times ULN and any AST) hepatic impairment.

Renal Impairment

No pharmacokinetic differences in mild to moderate renal impairment (eGFR ≥30 mL/min per 1.73 m² calculated by Schwartz equation or Modification of Diet in Renal Disease [MDRD] equation). Not studied in patients with severe renal impairment (eGFR <30 mL/min per 1.73 m²).

Common Adverse Effects

Adverse effects (≥30%): rash, hair color changes, fatigue, viral infection, vomiting, headache, hemorrhage, pyrexia, dry skin, constipation, nausea, dermatitis acneiform, upper respiratory tract infection.

Drug Interactions

In vitro, both an inhibitor and inducer of CYP3A, CYP2C8, CYP2C9, and CYP2C19. Inducer of CYP1A2 and CYP2B6, but does not inhibit CYP1A2, CYP2B6, or CYP2D6. Inhibits breast cancer resistance protein (BCRP), but is not a substrate of BCRP, P-glycoprotein (P-gp), organic anion transporter polypeptide (OATP) 1B1, or OATP1B3. Not evaluated if substrate of organic anion transporter (OAT)1, OAT3, multidrug and toxin extrusion (MATE)1, MATE2-K, or organic cation transporter (OCT)2.

Drugs Affecting Hepatic Microsomal Enzymes

Moderate and Strong CYP2C8 Inhibitors

Concomitant use of tovorafenib (a CYP2C8 substrate), with a moderate or strong CYP2C8 inhibitor is predicted to increase tovorafenib exposure, thereby increasing the risk of adverse effects from tovorafenib. Avoid concomitant use of tovorafenib and moderate or strong CYP2C8 inhibitors.

Moderate and Strong CYP2C8 Inducers

Concomitant use of tovorafenib (a CYP2C8 substrate), with a moderate or strong CYP2C8 inducer is predicted to decrease tovorafenib exposure, potentially reducing its efficacy. Avoid concomitant use of tovorafenib and moderate or strong CYP2C8 inducers.

Drugs Affected by Hepatic Microsomal Enzymes

Predicted to decrease the exposure of certain CYP3A substrates. Avoid concomitant use of tovorafenib with certain CYP3A substates where minimal concentration changes could result in loss of therapeutic efficacy. If concomitant use of tovorafenib with the CYP3A substrate cannot be avoided, monitor patients for loss of therapeutic efficacy unless otherwise indicated in the substrate prescribing information.

Specific Drugs

Drug

Interaction

Comments

Hormonal contraceptives (CYP3A substrate)

Possible decreased exposure to progestin and ethinyl estradiol, which can result in contraceptive failure and/or breakthrough bleeding

Avoid concomitant use

If concomitant use cannot be avoided, use additional non-hormonal method of contraception during treatment and for 28 days following the final dose

Midazolam (CYP3A substrate)

Predicted to decrease peak plasma concentrations and AUC by 20%

Monitor for loss of therapeutic efficacy unless otherwise indicated in the substrate prescribing information

Tovorafenib Pharmacokinetics

Absorption

Bioavailability

Following a single oral dose of tablets or suspension, peak plasma concentrations achieved after a median of 3 hours (range: 1.5—4 hours).

Steady state attained after 12 days.

Exhibits dose proportional increases at recommended doses with no clinically significant accumulation.

Food

Administration of tablets with a high-fat meal does not alter total exposure or peak plasma concentrations, but delays time to peak plasma concentration to 6.5 hours.

Special Populations

Pharmacokinetics not affected by age (1—94 years), sex, race (White, Black, Asian), mild hepatic impairment (bilirubin ≤ULN and AST >ULN or bilirubin >1—1.5 times ULN and any AST), and mild to moderate renal impairment (eGFR ≥30 mL/min per 1.73 m² calculated by Schwartz equation or Modification of Diet in Renal Disease [MDRD] equation).

Distribution

Extent

Not known if excreted into human milk.

Plasma Protein Binding

97.5%.

Elimination

Metabolism

Metabolized principally by aldehyde oxidase and CYP2C8 in vitro, and to a lesser extent by CYP3A, CYP2C9, and CYP2C19.

Elimination Route

Eliminated in feces (65% [8.6% as unchanged drug]) and urine (27% [0.2% as unchanged drug]).

Half-life

56 hours.

Stability

Storage

Oral

Oral suspension

Store at 20—25ºC; excursions permitted to 15—30ºC.

Tablets

Store at 20—25ºC; excursions permitted to 15—30ºC.

Actions

Type II RAF kinase inhibitor of mutant BRAF V600E, wild-type BRAF, and wild-type CRAF kinases.
Exhibits antitumor activity in cell cultures and xenograft tumor models harboring BRAFV600E and V600D mutations. Demonstrates antitumor activity in xenograft tumor models harboringBRAF fusion.

Advice to Patients

Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use).
Advise patients that tovorafenib can cause bleeding and to contact their healthcare provider for signs or symptoms of bleeding.
Advise patients that tovorafenib can cause skin toxicities and to contact their healthcare provider for worsening or intolerable rash.
Advise patients that tovorafenib can cause photosensitivity. Advise patients to limit direct ultraviolet exposure during treatment with tovorafenib. Recommend that patients use precautionary measures such as use of sunscreen, sunglasses, and/or protective clothing during treatment with tovorafenib.
Advise patients that tovorafenib can cause liver toxicity and to contact their healthcare provider for signs or symptoms of liver dysfunction. Advise patients that serial testing of serum liver tests (ALT, AST, bilirubin) is recommended during treatment with tovorafenib.
Advise patients and caregivers that treatment with tovorafenib may cause a reduction in growth velocity, and that growth will be monitored during treatment.
Prior to use of the oral suspension, ensure patients or caregivers receive training on proper dosing, preparation, and administration.
Advise patients not to take the tovorafenib tablets out of the blister pack until ready to use.
Advise patients to inform their clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.
Advise males and females of reproductive potential of the potential risk for impaired fertility with tovorafenib.
Advise females to inform their healthcare provider of a known or suspected pregnancy during treatment with tovorafenib, or if they plan to breastfeed. Inform patients of the potential fetal risk with tovorafenib use during pregnancy. Advise females of reproductive potential to use effective nonhormonal contraception during treatment and for 28 days after discontinuation of treatment with tovorafenib. Advise male patients with female partners of reproductive potential to use effective nonhormonal contraception during treatment with tovorafenib and for 2 weeks after the last dose. Breastfeeding should be avoided during treatment with tovorafenib and for 2 weeks after the last dose of tovorafenib.
Inform patients of other important precautionary information.

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care. For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at [Web].

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Tovorafenib is available only from a designated specialty pharmacy. Contact manufacturer for additional information.