2.1 Recommended Dosage

The recommended dosage of ROMVIMZA is 30 mg orally taken twice weekly, with a minimum of 72 hours between doses, as directed on the blister package [see Clinical Pharmacology (12.3)]. Instruct patients to follow the schedule on the blister package and to take ROMVIMZA on the same days each week.

• ROMVIMZA may be taken with or without food.
• Swallow ROMVIMZA capsules whole. Do not open, break, or chew the capsules.
• If a dose is missed by 48 hours or less, take the missed dose as soon as possible and take the next dose on its regularly scheduled day. If a dose is missed by more than 48 hours, skip the missed dose, and take the next dose on its regularly scheduled day.
• If vomiting occurs within 30 minutes of taking a dose, repeat that dose. Otherwise, take the next dose on its regularly scheduled day.

2.2 Dose Modifications for Adverse Reactions

The recommended dose reductions for adverse reactions are provided in Table 1.

Permanently discontinue ROMVIMZA in patients who are unable to tolerate 14 mg orally twice weekly.

The recommended dosage modifications for hepatotoxicity are summarized in Table 2.

2.3 Dosage Modification for P-glycoprotein (P-gp) Substrates

Avoid concomitant use of ROMVIMZA with P-gp substrates. If concomitant use of a P-gp substrate is unavoidable, administer ROMVIMZA at least 4 hours before taking the P-gp substrate unless otherwise recommended in the substrate Prescribing Information [see Drug Interactions (7.1)].

5.1 Hepatotoxicity

Cases of serious and fatal liver injury have occurred with the use of another kinase inhibitor that targets CSF1R [see Clinical Pharmacology (12.1)]. Serious and fatal liver injury have not been observed with ROMVIMZA.

Across clinical trials in 253 patients treated with ROMVIMZA, 2% had Grade 3 increased AST, and 1% had Grade 3 increased ALT. Dose interruptions occurred in 2% of patients and dose reductions occurred in 1% of patients due to AST/ALT increase. One patient discontinued therapy due to Grade 3 AST increased.

Avoid ROMVIMZA in patients with pre-existing increased serum transaminases; total bilirubin or direct bilirubin (>ULN); or active liver or biliary tract disease, including ALP. Monitor liver tests, including AST, ALT, total bilirubin, direct bilirubin, ALP and gamma-glutamyl transferase (GGT), prior to initiation of ROMVIMZA, twice a month for the first two months and once every 3 months for the first year of therapy and as clinically indicated thereafter. Withhold and reduce the dose, or permanently discontinue ROMVIMZA based on the severity of the hepatotoxicity [see Dosage and Administration (2.2)].

5.2 Embryo-Fetal Toxicity

Based on data from animal studies and its mechanism of action, ROMVIMZA can cause fetal harm when administered to pregnant women. In female rats administered vimseltinib, fetal structural abnormalities occurred at exposures that were at least 3 times the recommended dose based on area under the curve (AUC). Advise pregnant women on the potential risk to the fetus.

Advise females of reproductive potential and males with female partners of reproductive potential to use effective contraception during treatment with ROMVIMZA and for 1 month after the last dose [see Use in Specific Populations (8.1, 8.3)].

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

ROMVIMZA 20 mg capsule contains FD&C Yellow No. 5 (tartrazine) which may cause allergic reactions (including bronchial asthma) in certain susceptible patients. Although the overall incidence of FD&C Yellow No. 5 (tartrazine) sensitivity in the general population is low, it is frequently seen in patients who also have aspirin sensitivity.

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

5.4 Increased Creatinine without Affecting Renal Function

In MOTION, serum creatinine increased (mean increase of 19 μmol/L) and reached a maximum mean increase by 10.4 weeks compared to baseline. These increases in serum creatinine may not be associated with changes in renal function. Increases in creatinine reversed upon ROMVIMZA discontinuation. The increases in serum creatinine may be due to inhibition of renal tubular secretion transporters [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)]. During ROMVIMZA treatment, use alternative measures that are not based on serum creatinine to assess renal function.

6.1 Clinical Trials Experience

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 pooled safety population described in the Warnings and Precautions reflects exposure to ROMVIMZA in 83 patients with TGCT enrolled in the double-blind portion and in 35 patients with TGCT in the open-label portion who crossed over to ROMVIMZA in MOTION, and in 135 patients with TGCT or solid tumors in other clinical trials.

The safety of ROMVIMZA was evaluated in 83 adult patients with TGCT in MOTION [see Clinical Studies (14)]. MOTION excluded patients with bilirubin, AST, or ALT >ULN. All patients received ROMVIMZA twice weekly until disease progression or unacceptable toxicity. Among these patients, 82% were exposed for 6 months or longer and 30% were exposed for greater than one year.

Serious adverse reactions occurred in 2.4% of patients who received ROMVIMZA. Serious adverse reactions in ≥1% included subcutaneous abscess (1.2%) and cellulitis (1.2%).

Permanent discontinuation due to an adverse reaction occurred in 4.8% of patients who received ROMVIMZA. Adverse reactions leading to permanent discontinuation in one patient each included periorbital edema, neuropathy, rash, and hypertension.

Dose reductions due to an adverse reaction or laboratory abnormality occurred in 39% of patients who received ROMVIMZA. Adverse reactions leading to dose reductions in ≥2% of patients receiving ROMVIMZA were rash, periorbital edema, peripheral edema, fatigue, pruritus, face edema, increased CPK, neuropathy, and hypertension.

Dose interruptions due to an adverse reaction or laboratory abnormality occurred in 40% of patients who received ROMVIMZA. Adverse reactions leading to interruptions in ≥2% of patients included rash, fatigue, peripheral edema, increased CPK, periorbital edema, face edema, pruritus, neuropathy, and hypertension.

The most common (≥20%) adverse reactions, including laboratory abnormalities that occurred in patients receiving ROMVIMZA were increased AST, periorbital edema, fatigue, rash, increased cholesterol, peripheral edema, face edema, decreased neutrophils, decreased leukocytes, pruritus, and increased ALT. Table 3 and Table 4 summarize the adverse reactions and laboratory abnormalities in MOTION during the randomized phase through Week 25.

Other clinically significant adverse reactions occurring in <10% of patients treated with ROMVIMZA include blurred vision (6%).

Additional clinically significant laboratory abnormality: Increased Creatine Phosphokinase (CPK)

7.1 Effects of ROMVIMZA on Other Drugs

Table 5 describes drug interactions where concomitant use with ROMVIMZA affects another drug.

8.1 Pregnancy

8.2 Lactation

8.3 Females and Males of Reproductive Potential

ROMVIMZA can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)].

8.4 Pediatric Use

The safety and effectiveness of ROMVIMZA in pediatric patients have not been established.

8.5 Geriatric Use

Clinical studies of ROMVIMZA did not include a sufficient number of patients aged 65 years and older to determine whether they respond differently from younger patients.

8.6 Hepatic Impairment

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

12.1 Mechanism of Action

Vimseltinib is a kinase inhibitor that inhibits colony-stimulating factor 1 receptor (CSF1R). In vitro, vimseltinib inhibited CSF1R autophosphorylation, signaling induced by CSF1 ligand binding, and proliferation of cells expressing CSF1R.

12.2 Pharmacodynamics

12.3 Pharmacokinetics

Vimseltinib pharmacokinetic parameters were determined following a single oral dose of 30 mg or at steady state following multiple doses of 30 mg twice weekly and are provided as mean (CV%) unless otherwise specified.

Vimseltinib peak plasma concentration (Cmax) is 283 ng/mL (36%) or 747 ng/mL (39%) after a single dose or at steady state, respectively, and area under the time concentration curve (AUC0-inf) is 46,900 ng•h/mL (45%) after a single dose and AUC0-24hr is 13,400 ng•h/mL (45%) at steady state.

Vimseltinib pharmacokinetics are dose-proportional.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

In a 6-month transgenic mouse carcinogenicity study at doses up to 12.5 mg/kg/day, vimseltinib was negative for carcinogenic findings.

Vimseltinib was not mutagenic in the bacterial reverse mutation assay (Ames). In an in vitro micronucleus assay, vimseltinib increased micronuclei after a 24 -hour incubation in the absence of metabolic activation. In vivo, vimseltinib administered to rats at doses up to 200 mg/kg/day did not increase bone marrow micronucleated polychromatic erythrocytes, nor did vimseltinib increase liver DNA strand breaks.

In a fertility and early embryonic development study, male rats were administered 1, 2.5, or 5 mg/kg/day of vimseltinib starting 10 weeks before cohabitation, during cohabitation with untreated females, and at least 2 weeks post-cohabitation. Lower epididymal and testes weights were observed at 5 mg/kg/day (approximately 12 times the exposure at the recommended dose based on AUC). There were no treatment-related effects on mating, fertility, or sperm parameters at any dose tested. Female rats were administered 2.5, 5, or 10 mg/kg/day of vimseltinib 2 weeks prior to cohabitation with untreated males and during cohabitation until gestational day 7. Although there were no treatment-related effects on mating or estrous cycles, vimseltinib administered daily resulted in post-implantation loss at 10 mg/kg/day in female rats (approximately 20 times the exposure at the recommended dose based on AUC).

In a 26-week repeat-dose general toxicology study, recovery male rats that were administered 2.5 or 5 mg/kg/day had moderate to marked reductions in sperm and marked testicular atrophy (1 of 5 and 2 of 5 animals, respectively) corresponding to approximately 6 and 12 times the exposure at the recommended dose based on AUC, respectively. In a 39-week repeat-dose general toxicology study, minimal to moderate epididymal mineralization occurred in male dogs administered ≥4 mg/kg/day corresponding to exposures lower than the exposure at the recommended dose based on AUC.

13.2 Animal Toxicology and/or Pharmacology

In a 26-week repeat-dose general toxicology study in rats, chronic progressive nephropathy occurred at vimseltinib doses of ≥2.5 mg/kg/day (approximately 6 times the exposure at the recommended dose based on AUC). Degeneration of blood vessels (perivascular inflammation and necrosis of arteries and arteriole walls) occurred in multiple tissues at 5 mg/kg/day (approximately 12 times the exposure at the recommended dose based on AUC).

In a 39-week repeat-dose general toxicology study in dogs, skin depigmentation in the head and legs occurred at vimseltinib doses of ≥4 mg/kg/day corresponding to exposures lower than the exposure at the recommended dose based on AUC.

Hepatotoxicity

Advise patients there may be a potential risk of hepatotoxicity and that they will need to undergo laboratory tests to monitor liver function and to immediately report any signs or symptoms of severe liver injury to their healthcare provider [see Warnings and Precautions (5.1)].

Embryo-Fetal Toxicity

• Advise pregnant women and females of reproductive potential of the potential risk to the fetus. Advise females of reproductive potential to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions (5.2), Use in Specific Populations (8.1, 8.3)].
• Advise females of reproductive potential to avoid pregnancy and to use effective contraception during treatment with ROMVIMZA and for 1 month after the last dose [see Warnings and Precautions (5.2), Use in Specific Populations (8.1, 8.3)].
• Advise males with female partners of reproductive potential to use effective contraception during treatment and for 1 month after the last dose of ROMVIMZA [see Warnings and Precautions (5.2) and Use in Specific Populations (8.3)].

Lactation

Advise females not to breastfeed during treatment with ROMVIMZA and for 1 month after the final dose [see Use in Specific Populations (8.2)].

Infertility

Advise patients that ROMVIMZA may impair fertility [see Use in Specific Populations (8.3), Nonclinical Toxicology (13.1)].

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

Advise patients that ROMVIMZA 20 mg contains FD&C Yellow No. 5 (tartrazine), which may cause allergic-type reactions (including bronchial asthma) in certain susceptible persons or in patients who also have aspirin hypersensitivity [see Warnings and Precautions (5.3)]. Advise patients ROMVIMZA 14 mg and ROMVIMZA 20 mg contains FD&C Yellow No. 6 (Sunset Yellow FCF) which may cause allergic-type reactions [see Warnings and Precautions (5.3)].

Administration

• Instruct patients that doses should be taken twice weekly at least 72 hours apart [see Dosage and Administration (2.1)].
• Instruct patients to swallow capsules whole (do not open, break, or chew) [see Dosage and Administration (2.1)].

Drug Interactions

Advise patients to inform their healthcare providers of all concomitant products, including over-the-counter products and supplements [see Dosage and Administration (2.3), Drug Interactions (7.1)].

Manufactured for and marketed by:

Deciphera Pharmaceuticals, LLC

200 Smith Street, Waltham, MA 02451