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warnings and cautions
5 WARNINGS AND PRECAUTIONS Hematological Changes: DUVYZAT can cause dose-related thrombocytopenia and other signs of myelosuppression, including anemia and neutropenia. Monitor platelets; dosage adjustment or discontinuation may be needed. ( 2.3 , 5.1 ) Increased Triglycerides: An increase in triglycerides can occur; dosage modification may be needed. Discontinuation may be needed. ( 2.3 , 5.2 ) Gastrointestinal Disturbances: Adjust dosage if moderate or severe diarrhea occurs. Antiemetics or antidiarrheal medications may be considered during treatment with DUVYZAT. Discontinue DUVYZAT if the symptoms persist. ( 2.3 , 5.3 ) QTc Prolongation: Avoid use of DUVYZAT in patients who are at an increased risk for ventricular arrhythmias. ( 2.1 , 5.4 , 7.2 ) 5.1 Hematological Changes DUVYZAT can cause dose-related thrombocytopenia and other signs of myelosuppression, including decreased hemoglobin and neutropenia. In Study 1 [see Clinical Studies (14) ] , thrombocytopenia occurred in 33% of patients treated with DUVYZAT compared to no patients on placebo. The maximum decrease in platelets occurred within the first 2 months of therapy and remained low throughout the course of therapy. In a few patients, thrombocytopenia was associated with bleeding events including epistaxis, hematoma or contusions. Low platelet counts resulted in DUVYZAT dose reduction in 28% of patients. Patients with baseline platelet counts below the lower limit of normal were excluded from the study. Decreased hemoglobin and decreased neutrophils were also observed in patients treated with DUVYZAT compared to placebo. Monitor blood counts every 2 weeks for the first 2 months of treatment, at month 3, and then every 3 months thereafter. Modify the dosage of DUVYZAT for confirmed thrombocytopenia [see Dosage and Administration (2.3) ] . Treatment should be permanently discontinued if the abnormalities worsen despite dose modification. If a patient develops signs or symptoms of thrombocytopenia, obtain a platelet count as soon as possible, and hold dosing until platelet count is confirmed. 5.2 Increased Triglycerides DUVYZAT can cause elevations in triglycerides. In Study 1 [see Clinical Studies (14) ] , hypertriglyceridemia occurred in 23% of patients treated with DUVYZAT (one of whom had familial hypertriglyceridemia) compared to 7% of patients on placebo. High triglycerides (i.e., levels greater than 300 mg/dL) resulted in discontinuation and led to dosage modification in 2% and 8%, respectively, of patients treated with DUVYZAT. Monitor triglycerides at 1 month, 3 months, 6 months, and then every 6 months thereafter. Modify the dosage if fasting triglycerides are verified > 300 mg/dL [see Dosage and Administration (2.3) ] . Treatment with DUVYZAT should be discontinued if triglycerides remain elevated despite adequate dietary intervention and dosage adjustment. 5.3 Gastrointestinal Disturbances Gastrointestinal disturbances, including diarrhea, nausea/vomiting, and abdominal pain were common adverse reactions in DUVYZAT clinical trials in DMD. In Study 1, diarrhea was reported in 37% of patients treated with DUVYZAT (with 1 severe case reported) compared to 20% of patients on placebo. Diarrhea usually occurred within the first few weeks of initiation of treatment with DUVYZAT. Vomiting and nausea, sometimes severe and usually occurring within the first 2 months of treatment, occurred in 32% of patients treated with DUVYZAT compared to 18% of patients on placebo. Abdominal pain occurred in 34% of patients treated with DUVYZAT compared to 25% of patients on placebo. One case of abdominal pain was serious. Antiemetics or antidiarrheal medications may be considered during treatment with DUVYZAT. Fluid and electrolytes should be replaced as needed to prevent dehydration [see Warnings and Precautions (5.4) ] . Modify the dosage of DUVYZAT in patients with moderate or severe diarrhea, and treatment should be discontinued if significant symptoms persist [see Dosage and Administration (2.3) ] . 5.4 QTc Prolongation DUVYZAT can cause prolongation of QTc interval [see Clinical Pharmacology (12.2) ] . Avoid use of DUVYZAT in patients who are at an increased risk for ventricular arrhythmias (including torsades de pointes), such as those with congenital long QT syndrome, coronary artery disease, electrolyte disturbance [see Warnings and Precautions (5.3) ] , concomitant use of other medicinal products known to cause QT prolongation [see Drug Interactions (7.2) ] . Obtain ECGs prior to initiating treatment with DUVYZAT in patients with underlying cardiac disease or in patients who are taking concomitant medications that cause QT prolongation [see Dosage and Administration (2.1) ] .
6 ADVERSE REACTIONS The following clinically significant adverse reactions are described below and elsewhere in the labeling: Hematological Changes [see Warnings and Precautions (5.1) ] Increased Triglycerides [see Warnings and Precautions (5.2) ] Gastrointestinal Disturbances [see Warnings and Precautions (5.3) ] QTc Prolongation [see Warnings and Precautions (5.4) ] Most common adverse reactions (≥10% in DUVYZAT-treated patients) are diarrhea, abdominal pain, thrombocytopenia, nausea/vomiting, hypertriglyceridemia, and pyrexia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact ITF Therapeutics, LLC. at 1-833-582-4312 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. In controlled and uncontrolled trials in patients with confirmed DMD, 222 male patients aged 6 years and older were treated with DUVYZAT, including 210 patients treated for ≥ 6 months, 187 patients for ≥ 12 months, and 105 patients for ≥ 24 months. The safety profile of DUVYZAT is based on a double-blind, placebo-controlled, 18-month study in a total of 179 ambulant DMD patients aged 6 years or older on concomitant steroid treatment (Study 1) [see Clinical Studies (14) ] . The dosage in Study 1 was weight-based [see Dosage and Administration (2.2) ] . Patients were excluded from the study if they had the following abnormalities at the screening visit: platelet, white blood cell, or hemoglobin counts less than the lower limit of normal, triglycerides > 300 mg/dL (3.42 mmol/L) in fasting condition, or had a baseline-corrected QT interval, Fridericia’s correction (QTcF) of > 450 msec (mean of 3 consecutive readings 5 minutes apart) or a history of additional risk factors for torsades de pointes (e.g., heart failure, hypokalemia, or family history of long QT syndrome). Overall, 2% of the patients discontinued the study because of adverse reactions. Adverse reactions reported in >5% of DUVYZAT-treated patients at a frequency at least 5% greater than that of the placebo group are presented in Table 3 below. Table 3. Adverse Reactions Reported in >5% of DUVYZAT-Treated Patients and at Least 5% Greater than Placebo in Study 1 Adverse Reaction DUVYZAT N=118 % Placebo N=61 % Diarrhea 37 20 Abdominal pain 34 25 Thrombocytopenia Thrombocytopenia includes platelet count decreased and thrombocytopenia 33 0 Nausea/Vomiting 32 18 Hypertriglyceridemia 23 7 Pyrexia 13 8 Myalgia 9 3 Rash 9 2 Arthralgia 8 2 Fatigue 8 0 Constipation 7 2 Decreased appetite 7 0 Less Common Adverse Reactions in Study 1 Adverse reactions of hypothyroidism and/or thyroid stimulating hormone (TSH) increased occurred in 5% of patients treated with DUVYZAT compared to 2% of patients who received placebo.