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warnings and cautions
5 WARNINGS AND PRECAUTIONS Acute Hemolysis: Avoid abrupt interruption or abrupt discontinuation of PYRUKYND to minimize the risk of acute hemolysis. A gradual reduction in dosing rather than abrupt cessation is recommended when possible. ( 5.1 ) Hepatocellular Injury in Another Condition: Obtain liver tests prior to the initiation of PYRUKYND and monthly thereafter for the first 6 months and as clinically indicated. Interrupt PYRUKYND if clinically significant increases in liver tests are observed or alanine aminotransferase is >5 times the upper limit of normal (ULN). Discontinue PYRUKYND if hepatic injury due to PYRUKYND is suspected. ( 5.2 ) 5.1 Acute Hemolysis with Abrupt Treatment Interruption Acute hemolysis with subsequent anemia has been observed following abrupt interruption or discontinuation of PYRUKYND in a dose-ranging study. Avoid abruptly discontinuing PYRUKYND. Gradually taper the dose of PYRUKYND to discontinue treatment if possible [see Dosage and Administration ( 2.3 , 2.6 )] . When discontinuing treatment, monitor patients for signs of acute hemolysis and anemia including jaundice, scleral icterus, dark urine, dizziness, confusion, fatigue, or shortness of breath . 5.2 Hepatocellular Injury in Another Condition In patients with another condition treated with mitapivat at a higher dose than that recommended for patients with PK deficiency, liver injury has been observed. These events were characterized by a time to onset within the first 6 months of treatment with peak elevations of alanine aminotransferase of >5×ULN with or without jaundice. All patients discontinued treatment with PYRUKYND, and these events improved upon treatment discontinuation. Obtain liver tests prior to the initiation of PYRUKYND and monthly thereafter for the first 6 months and as clinically indicated. Interrupt PYRUKYND if clinically significant increases in liver tests are observed or alanine aminotransferase is >5 times the upper limit of normal (ULN). Discontinue PYRUKYND if hepatic injury due to PYRUKYND is suspected.
6 ADVERSE REACTIONS The following clinically significant adverse reaction is described elsewhere in labeling: Acute Hemolysis with Abrupt Treatment Discontinuation [see Warn ings and Preca utions (5.1) ]. Hepatocellular Injury in Another Condition [see Warnings and Precautions (5.2) ] . The most common adverse reactions including laboratory abnormalities (≥ 10%) in patients with PK deficiency were estrone decreased (males), increased urate, back pain, estradiol decreased (males), and arthralgia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Agios Pharmaceuticals at 1-833-228-8474 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trial 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. A total of 155 patients received PYRUKYND, 79% of whom were exposed for longer than 24 weeks. PYRUKYND was administered up to 50 mg orally twice daily in 67 patients with PK deficiency in the ACTIVATE trial (N=40) and the ACTIVATE-T trial (N=27) [see Clinical Studies (14) ] . ACTIVATE Trial In the ACTIVATE trial patients with PK deficiency who were not regularly transfused received PYRUKYND in incremental doses up to 50 mg twice daily (N=40) or placebo (N=39). Serious adverse reactions occurred in 10% of patients receiving PYRUKYND in the ACTIVATE Trial, including atrial fibrillation, gastroenteritis, rib fracture, and musculoskeletal pain, which each occurred in 1 patient. In the ACTIVATE trial, the most common adverse reactions including laboratory abnormalities (≥10%) in patients with PK deficiency were estrone decreased (males), increased urate, back pain, estradiol decreased (males), and arthralgia. Table 3 summarizes the adverse reactions in the ACTIVATE trial. Table 3: Adverse Reactions (≥ 5%) in Patients Receiving PYRUKYND in ACTIVATE PYRUKYND (N=40) Placebo (N=39) Adverse Reaction All Grades (%) Grade ≥3 (%) All Grades (%) Grade ≥3 (%) Back pain a 15% 0 8% 0 Arthralgia b 10% 0 5% 0 Hypertriglyceridemia c 8% 5% 3% 0 Gastroenteritis 8% 3% 0 0 Hot flush d 8% 0 0 0 Oropharyngeal pain 8% 0 5% 0 Hypertension 5% 5% 0 0 Arrhythmia e 5% 0 0 0 Breast discomfort 5% 0 0 0 Constipation 5% 0 0 0 Dry mouth f 5% 0 0 0 Paresthesia 5% 0 0 0 Grades: Per the CTCAE definition. Grouped Term Definitions a Includes back pain, sciatica, and flank pain. b Includes arthralgia and joint swelling. c Includes hypertriglyceridemia and blood triglycerides increased. d Includes hot flush and flushing. e Includes arrhythmia, tachycardia, heart rate increased and atrial fibrillation. f Includes dry mouth and dry lip. Laboratory abnormalities of PYRUKYND included increased urate (15%). Variations in Reproductive Hormones In ACTIVATE, increases in serum testosterone and decreases in serum estrone and estradiol were observed in men receiving PYRUKYND (Table 4). These changes in hormones persisted throughout the study period. In patients who discontinued PYRUKYND and had follow-up hormone measurements, the hormone changes returned close to the baseline levels 28 days after discontinuing PYRUKYND. In female patients, sex hormone analysis was limited due to physiologic variations in hormones during the menstrual cycle and the use of hormonal contraceptives. Table 4: Laboratory Abnormalities in Reproductive Hormones in Men Receiving PYRUKYND ACTIVATE Parameter PYRUKYND (16 males) n (%) Placebo (15 males)n (%) Reproductive hormone analyses a Estrone decreased (males) Estradiol decreased (males) Blood testosterone increased (males) 9 (56.3) 2 (12.5) 1 (6.3) 0 1 (6.7) 1 (6.7) a Decreases in estrone and estradiol to below the lower limit of the reference range and increases in testosterone to above the upper limit of the reference range where baseline was within normal limits. ACTIVATE-T Trial The adverse reactions reported in the population of patients who were regularly transfused (ACTIVATE-T) were consistent with that seen in ACTIVATE.