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warnings and cautions
5 WARNINGS AND PRECAUTIONS Hepatotoxicity: Elevated AST and ALT can occur. Evaluate liver tests prior to initiation of treatment and during treatment. ( 2.2 , 5.1 ) Embryo-fetal toxicity: Can cause fetal harm. Advise patients of reproductive potential of the potential risk to a fetus and to use effective contraception. ( 5.2 , 8.1 , 8.3 ) Allergic Reactions to FD&C Yellow No. 5 (tartrazine) and No. 6 (Sunset Yellow FCF): 14 mg capsule contains FD&C Yellow No. 6 (Sunset Yellow FCF); 20 mg capsule contains FD&C Yellow No.5 (tartrazine) and No. 6 (Sunset Yellow FCF) as color additives, which may cause allergic reactions (including bronchial asthma) in certain susceptible patients. ( 5.3 ) Increased serum creatinine without affecting renal function: Increases in serum creatinine can occur. Use alternative measures that are not based on serum creatinine to assess renal function. ( 5.4 ) 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 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Hepatotoxicity [see Warnings and Precautions ( 5.1 )] Most common adverse reactions (incidence ≥20%), including laboratory abnormalities are increased AST, periorbital edema, fatigue, rash, increased cholesterol, peripheral edema, face edema, decreased neutrophils, decreased leukocytes, pruritus, and increased ALT. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Deciphera Pharmaceuticals, LLC at 1-888-724-3274 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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. 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 Adverse Reaction* ROMVIMZA N=83 Placebo N=39 All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) *The severity of adverse reactions was assessed using CTCAE v5.0. 1 Includes multiple related terms Eye disorders Periorbital edema 1 60 3.6 21 0 Lacrimation increased 12 0 0 0 Dry eye 1 10 0 0 0 General disorders and administration site conditions Fatigue 1 59 1.2 38 2.6 Peripheral edema 1 33 1.2 8 0 Face edema 31 1.2 8 0 Skin and subcutaneous tissue disorders Rash 1 47 3.6 5 0 Pruritus 29 2.4 8 0 Vascular disorders Hypertension 17 4.8 10 2.6 Nervous system disorders Neuropathy 1 12 1.2 2.6 0 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 Laboratory Abnormality a ROMVIMZA N=83 Placebo N=39 b All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) 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. Chemistry AST increased 92 0 11 0 Cholesterol increased 43 0 16 0 ALT increased 24 0 16 0 Creatinine increased 17 0 2.6 0 ALP increased 14 0 8 0 Magnesium increased 13 1.2 2.6 0 Calcium decreased 13 0 2.6 0 Hematology Neutrophils decreased 31 1.2 2.6 0 Leukocytes decreased 29 0 8 0 Additional clinically significant laboratory abnormality: Increased Creatine Phosphokinase (CPK)