Vimseltinib (Monograph)

Brand name: Romvimza
Drug class: Antineoplastic Agents

Introduction

Antineoplastic agent; kinase inhibitor that inhibits colony-stimulating factor 1 receptor (CSF-1R).

Uses for Vimseltinib

Tenosynovial Giant Cell Tumor

Treatment of adult patients with symptomatic tenosynovial giant cell tumor (TGCT) for which surgical resection will potentially cause worsening functional limitation or severe morbidity.

The mainstay of treatment for TGCT is surgery; however, surgery can cause significant joint damage, functional limitation, and morbidity. Treatment options for patients who cannot undergo surgery are limited.

Pexidartinib is another kinase inhibitor that is FDA-approved for treatment of TGCT; both pexidartinib and vimseltinib produced similar objective response rates in clinical trials.

Vimseltinib Dosage and Administration

General

Pretreatment Screening

Obtain liver function tests (i.e., AST, ALT, total bilirubin, direct bilirubin, alkaline phosphatase [ALP], and gamma-glutamyl transferase [GGT]) prior to initiation of therapy. Do not initiate in patients with preexisting elevations in AST, ALT, ALP, active liver or biliary tract disease, or total or direct bilirubin >ULN.
Verify pregnancy status in females of reproductive potential.

Patient Monitoring

Monitor liver function tests twice a month for the first 2 months of therapy and then once every 3 months through the first year of therapy; monitor as clinically indicated thereafter.

Administration

Administer orally twice weekly with or without food.

Administer doses at least 72 hours apart on the same days each week; follow dosing schedule provided by manufacturer on blister package.

Swallow capsules whole; do not open, break, or chew the capsules.

If a dose is missed by ≤48 hours, take dose as soon as possible; administer next dose at regularly scheduled time. If a dose is missed by >48 hours, skip the dose and take next dose at regularly scheduled time.

If vomiting occurs within 30 minutes of taking a dose, repeat dose. If more than 30 minutes have passed, take next dose at regularly scheduled time.

Dosage

Dosage of vimseltinib dihydrate is expressed in terms of vimseltinib.

Adults

Tenosynovial Giant Cell Tumor

Oral

30 mg orally twice weekly.

Continue therapy until disease progression or unacceptable toxicity occurs.

Dosage Modification for Hepatotoxicity

If hepatotoxicity occurs during therapy, temporary interruption of therapy, dosage reduction, and/or permanent discontinuance of the drug may be necessary.

If dosage reduction is required, reduce dosage according to Table 1. For recommended dosage modifications for hepatotoxicity, see Table 2. Permanently discontinue vimseltinib in patients who are unable to tolerate a dosage of 14 mg orally twice weekly.

Table 1: Recommended Dose Reductions for Vimseltinib Toxicity1
Dose Reduction	Twice Weekly Dose
First	20 mg
Second	14 mg

Table 2: Recommended Dosage Modifications for Hepatotoxicity1
Severity of Hepatotoxicity	Dosage Modification
ALT and/or AST >3–5 times the ULN and total bilirubin increases up to 2 times the ULN OR total bilirubin increases up to 2 times the ULN	Withhold therapy and monitor liver function tests until AST and ALT return to baseline or ≤3 times the ULN and bilirubin returns to baseline. Resume at next lower dose level (see Table 1) if high-risk drug-induced liver injury that can result in acute liver failure (Hy’s law) has been ruled out; permanently discontinue drug if adverse reaction does not resolve within 4 weeks
ALT and/or AST >3–5 times the ULN and total bilirubin increases >2 times the ULN or the international normalized ratio (INR) is >1.5 and ALP is <2 times the ULN OR total bilirubin >2 times the ULN	Withhold therapy and monitor liver function tests until AST and ALT return to baseline or ≤3 times the ULN and the bilirubin returns to baseline. Resume at next lower dose level (see Table 1) if Hy’s law has been ruled out; permanently discontinue vimseltinib if adverse reaction does not resolve within 4 weeks
AST and/or ALT increases to >5–8 times the ULN, and total bilirubin is ≤ULN and without clinical symptoms	Withhold therapy and monitor liver function tests until AST and ALT return to ≤3 times the ULN or to baseline; permanently discontinue vimseltinib if adverse reaction does not resolve within 4 weeks
AST and/or ALT increases >5-8 times the ULN and total bilirubin increases to >ULN, or the INR >1.5, or ALP >2 times the ULN	Permanently discontinue
AST and/or ALT increases >8 times the ULN	Permanently discontinue

Dosage Modification for Concomitant Use of P-glycoprotein Substrates

Avoid concomitant use with P-glycoprotein (P-gp) substrates. If concomitant use is unavoidable, administer vimseltinib at least 4 hours before taking the P-gp substrate unless otherwise recommended in the prescribing information for the substrate drug.

Special Populations

Hepatic Impairment

No dosage adjustment recommended in patients with mild (bilirubin ≤ULN and AST >ULN or bilirubin >1 to 1.5x ULN and any AST) hepatic impairment.

Not studied in moderate (bilirubin >1.5 to 3x ULN and any AST) or severe (bilirubin >3x ULN and any AST) hepatic impairment.

Renal Impairment

No clinically significant differences in pharmacokinetics observed in mild to moderate renal impairment (eGFR ≥30 mL/min).

No specific dosage recommendations for severe renal impairment (eGFR <30 mL/min).

Geriatric Patients

No specific dosage recommendations.

Cautions for Vimseltinib

Contraindications

None.

Warnings/Precautions

Hepatotoxicity

Serious and fatal hepatotoxicity reported with another tyrosine kinase inhibitor that targets CSF1R.

Avoid use in patients with preexisting elevated AST or ALT concentrations; total bilirubin or direct bilirubin >ULN; or active liver or biliary tract disease, including increased ALP.

Monitor liver tests, including AST, ALT, total bilirubin, direct bilirubin, ALP, and GGT prior to initiation of therapy, twice a month for the first 2 months, and then once every 3 months for the first year of therapy; thereafter, monitor as clinically indicated.

Temporary interruption of therapy, dosage reduction, or permanent discontinuance of the drug may be necessary.

Fetal/Neonatal Morbidity and Mortality

Based on animal data, may cause fetal harm.

Human data do not establish the presence or absence of major birth defects or miscarriage.

Verify pregnancy status in females of reproductive potential prior to initiation of therapy.

Allergic Reactions to FD&C Yellow No. 5 (Tartrazine) and No. 6 (Sunset Yellow FCF)

20 mg capsules contain FD&C Yellow No. 5 (tartrazine), which may cause allergic reactions (including bronchial asthma) in certain susceptible patients.

14 mg and 20 mg capsules contain FD&C Yellow No. 6 (Sunset Yellow FCF), which may cause allergic reactions.

Increased Creatinine without Affecting Renal Function

Increases in serum creatinine observed do not affect renal function.

Use alternative measures that are not based on serum creatinine to assess renal function.

May increase serum creatinine by inhibiting renal transporters, OCT 2 and MATE1.

Specific Populations

Pregnancy

No data on use during pregnancy to evaluate for drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes.

Lactation

Not known whether distributed into human milk.

Effects on breast-fed infants or on milk production also unknown.

Advise patients not to breast-feed while receiving the drug and for at least 1 month after last dose.

Females and Males of Reproductive Potential

Verify pregnancy status in females of reproductive potential prior to the initiation of vimseltinib.

Advise females of reproductive potential to use effective contraception during treatment with vimseltinib and for 1 month after the final dose.

Advise male patients with female partners of reproductive potential to use effective contraception during treatment with vimseltinib and for 1 month after the final dose.

Effect on human fertility is unknown.

Pediatric Use

Safety and efficacy not established.

Geriatric Use

Insufficient numbers of older adults in clinical studies to determine if patients ≥65 years of age respond differently than younger patients.

Hepatic Impairment

Not studied in moderate to severe (total bilirubin >1.5 times the ULN with any AST) hepatic impairment.

Renal Impairment

No clinically significant differences in pharmacokinetics in patients with mild to moderate renal impairment (eGFR ≥30 mL/min).

Not studied in patients with severe renal impairment (eGFR <30 mL/min).

May increase serum creatinine concentrations by decreasing renal tubular secretion of creatinine, but may not affect renal function; use alternative method that does not depend on serum creatinine to assess renal function.

Common Adverse Effects

Most common adverse effects (≥20%): Increased AST concentrations, increased ALT concentrations, periorbital edema, fatigue, rash, increased cholesterol, peripheral edema, facial edema, decreased neutrophils, decreased leukocytes, pruritus.

Drug Interactions

Not a substrate of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A4.

Does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A4.

Does not induce CYP1A2, CYP2B5, or CYP3A4.

Inhibits P-gp, breast cancer resistance protein (BCRP), bile salt exchange pump (BSEP), organic anion transporter protein (OATP) 1B1, OATP1B3, organic cationic transporter (OCT) 2, multidrug and toxin extrusion protein (MATE) 1, and MATE2-K.

Does not inhibit organic anion transport (OAT)1 or OAT3.

Substrate of P-gp, but not of BCRP, BSEP, OATP1B1, OATP1B3, OAT1, OAT3, OCT2, MATE1, or MATE2-K.

Drugs Affecting or Affected by Transport Systems

P-gp substrates: Vimseltinib may increase systemic exposure of P-gp substrates. Avoid concomitant use. If concomitant use cannot be avoided, administer vimseltinib at least 4 hours prior to taking the P-gp substrate unless otherwise recommended in the prescribing information for the substrate drug.

P-gp inhibitors: No clinically significant differences in vimseltinib pharmacokinetics observed when used concomitantly with a P-gp inhibitor.

BCRP substrates: Concomitant use of vimseltinib with BCRP substrates may increase systemic exposure of the substrate drug. Avoid concomitant use of vimseltinib with BCRP substrates. If concomitant use cannot be avoided, refer to the prescribing information for the BCRP substrate for dose modifications.

OCT2 substrates: Concomitant use of vimseltinib with OCT2 substrates may increase systemic exposure of the substrate drug. Avoid concomitant use of vimseltinib with OCT2 substrates. If concomitant use cannot be avoided, refer to the prescribing information for the OCT2 substrate for dose modifications.

Specific Drugs

Drug

Interaction

Comments

Dabigatran

Concomitant use expected to increase systemic exposure and peak plasma concentrations of dabigatran by 2- to 3-fold

When dabigatran is administered 4 hours after vimseltinib, systemic exposure and peak plasma concentrations are predicted to increase up to 1.3-fold

Avoid concomitant use; If concomitant use cannot be avoided, administer vimseltinib at least 4 hours prior to taking dabigatran unless otherwise recommended in the prescribing information for dabigatran

Itraconazole

No clinically significant differences in vimseltinib pharmacokinetics observed when used concomitantly with itraconazole, a P-gp inhibitor

Rabeprazole

No clinically significant differences in vimseltinib pharmacokinetics observed when used concomitantly with rabeprazole

Vimseltinib Pharmacokinetics

Absorption

Plasma Concentrations

Pharmacokinetics are dose proportional.

Not affected by a high-fat diet or fasting state.

Distribution

Plasma Protein Binding

96.5% bound to human serum albumin.

Elimination

Metabolism

Principally undergoes oxidation, N-demethylation, and N-dealkylation with secondary biotransformation pathways including N-demethylation, dehydrogenation, and oxidation.

Elimination Route

Following oral administration of a single radiolabeled dose, approximately 43% of the radioactivity was recovered in feces (9.1% as unchanged drug) and 38% was recovered in urine (5.1% unchanged).

Half-life

Mean elimination half-life is approximately 6 days.

Special Populations

No clinically significant difference in pharmacokinetics based on race or sex.

Stability

Storage

Oral

Capsules

Store at room temperature (20–25°C; with excursions permitted to 15–30°C) in original blister packs until ready for use.

Advice to Patients

Advise patients to read the FDA approved patient labeling (Medication Guide).
Instruct patients to take doses twice weekly at least 72 hours apart and to also swallow capsules whole (do not open, break, or chew).
Advise patients of the risk of hepatotoxicity and that they will need to undergo monitoring for liver injury and to immediately report any signs or symptoms of severe liver injury to their healthcare provider.
Advise patients to inform their healthcare provider of a known or suspected pregnancy. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential, and male patients with female partners of reproductive potential, to use effective contraception during treatment with vimseltinib and for one month after the final dose.
Advise patients not to breast-feed during treatment with vimseltinib and for 1 month after the final dose.
Advise patients that vimseltinib 20 mg capsules contain FD&C Yellow No 5 (tartrazine), which can cause allergic-type reactions (including bronchial asthma) in susceptible patients.
Advise patients that vimseltinib 14 mg and 20 mg capsules contain FD&C Yellow No. 6 (Sunset Yellow FCF), which may cause allergic-type reactions.
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.
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.

Vimseltinib is only available through select specialty pharmacies. For more information, visit [Web].

Vimseltinib Dihydrate
Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Capsules	14 mg (of vimseltinib)	Romvimza	Deciphera Pharmaceuticals
		20 mg (of vimseltinib)	Romvimza	Deciphera Pharmaceuticals
		30 mg (of vimseltinib)	Romvimza	Deciphera Pharmaceuticals