ROMVIMZA Capsule Ref.[115532] Active ingredients: Vimseltinib

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.

The following clinically significant adverse reactions are described elsewhere in the labeling:

• Hepatotoxicity [see Warnings and Precautions (5.1)]

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.

Table 3. Adverse Reactions Occurring in ≥10% of Patients Receiving ROMVIMZA with a Difference Between Arms of >5% Compared to Placebo Through Week 25 in MOTION:

^* The severity of adverse reactions was assessed using CTCAE v5.0.
¹ Includes multiple related terms

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

Table 4. Laboratory Abnormalities Worsening from Baseline in ≥10% of Patients Receiving ROMVIMZA with a Difference Between Arms of >5% Compared to Placebo Through Week 25 in MOTION:

AST – aspartate aminotransferase, ALT – alanine aminotransferase, ALP – alkaline phosphatase
^a The severity of adverse reactions was assessed using CTCAE v5.0.
^b The denominator used to calculate the rate was 83 for ROMVIMZA and 38 for placebo based on the number of patients with a baseline value and at least one post-treatment value.

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

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

Table 5. Effect of ROMVIMZA on Other Drugs:

Risk Summary

Based on data from animal studies and its mechanism of action, ROMVIMZA can cause fetal harm when administered to a pregnant woman. There are no available data on vimseltinib use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In female rats administered vimseltinib during the period of organogenesis, fetal structural abnormalities occurred at exposures that were at least 3 times the recommended dose based on AUC (see Data). Advise pregnant women of the potential risk to a fetus.

The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. 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 a rat embryo-fetal development study, pregnant female rats were dosed once daily during the period of organogenesis (gestational days 6 to 17) at doses of 2.5, 5, or 15 mg/kg/day. Structural abnormalities (skeletal variations) occurred at ≥2.5 mg/kg/day (approximately 3 times the exposure at the recommended dose based on AUC). Additional structural abnormalities (cardiac malformations) were observed at the highest dose of 15 mg/kg/day (approximately 23 times the exposure at the recommended dose based on AUC).

Risk Summary

There are no data on the presence of vimseltinib or its metabolites in either human or animal milk or its effects on a breastfed child or on milk production. Because of the potential for serious adverse reactions in the breastfed child, advise women not to breastfeed during treatment with ROMVIMZA and for 1 month after the last dose.

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

Pregnancy Testing

Verify pregnancy status in females of reproductive potential prior to the initiation of ROMVIMZA [see Use in Specific Populations (8.1)].

Contraception

Females

Advise females of reproductive potential to use effective contraception during treatment with ROMVIMZA and for 1 month after the last dose [see Warnings and Precautions (5.2), Nonclinical Toxicology (13.1)].

Males

Advise males that are partnered with females of reproductive potential to use effective contraception during treatment with ROMVIMZA and for 1 month after the last dose [see Warnings and Precautions (5.2), Nonclinical Toxicology (13.1)].

Infertility

Females and Males

Based on findings from animal studies, ROMVIMZA may impair fertility [see Nonclinical Toxicology (13.1)].

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

Animal Toxicity Data

In a 26-week repeat-dose toxicology study, rats administered vimseltinib at ≥2.5 mg/kg/day had physeal thickening and decay of the incisors and molars. Bone and tooth toxicities occurred at exposures at least 8 times the recommended dose based on AUC.

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.

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)].