WARNING: HEPATOCELLULAR INJURY AQVESME can cause serious hepatocellular injury. Measure liver laboratory tests (ALT, AST, alkaline phosphatase, and total bilirubin with fractionation) at baseline and every 4 weeks for 24 weeks and then as clinically indicated. Avoid use of AQVESME in patients with cirrhosis. Discontinue AQVESME if hepatic injury is suspected [see Warnings and Precautions ( 5.1 )] . Because of the risk of hepatocellular injury, AQVESME is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the AQVESME REMS [see Warnings and Precautions ( 5.2 )] . WARNING: HEPATOCELLULAR INJURY See full prescribing information for complete boxed warning. AQVESME can cause serious hepatocellular injury. Measure liver laboratory tests (ALT, AST, alkaline phosphatase, and total bilirubin with fractionation) at baseline and every 4 weeks for 24 weeks and then as clinically indicated. Avoid use of AQVESME in patients with cirrhosis. Discontinue AQVESME if hepatocellular injury is suspected. ( 5.1 ) AQVESME is available only through a restricted program called the AQVESME REMS. ( 5.2 )
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warnings and cautions
5 WARNINGS AND PRECAUTIONS 5.1 Hepatocellular Injury AQVESME can cause hepatocellular injury. Avoid use of AQVESME in patients with cirrhosis. In patients with thalassemia treated with AQVESME, liver injury with and without jaundice has been observed within the first 6 months of exposure. Obtain liver tests (including ALT, AST, alkaline phosphatase, total bilirubin with fractionation) prior to the initiation of AQVESME, then every 4 weeks for the first 24 weeks, and as clinically indicated thereafter. Interrupt AQVESME if clinically significant increases in liver tests are observed or alanine aminotransferase is >5 times the upper limit of normal (ULN). Complete a comprehensive evaluation to rule out other causes of liver injury when drug-induced liver injury (DILI) is suspected. Discontinue AQVESME if hepatocellular injury due to AQVESME is suspected [see Dosage and Administration (2.3) ] . Symptoms and signs of early liver injury may mimic those of thalassemia. Advise patients to report new or worsening symptoms of loss of appetite, nausea, right upper quadrant abdominal pain, vomiting, scleral icterus, jaundice, or dark urine while on AQVESME treatment. During the double-blind period, 2 of 301 patients (0.66%) with thalassemia treated with AQVESME experienced adverse reactions suggestive of hepatocellular injury. Three additional patients experienced adverse reactions suggestive of hepatocellular injury during the open-label extension periods after switching from placebo to AQVESME. Of these 5 patients, two had serious liver injury and were hospitalized including 1 patient who developed jaundice (peak bilirubin 32 mg/dL). Another patient developed jaundice (peak bilirubin 4 mg/dL) without being hospitalized. These reactions 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 AQVESME, and these reactions improved upon treatment discontinuation. AQVESME is available only through a restricted program under a REMS [see Warnings and Precautions (5.2) ] . 5.2 AQVESME REMS AQVESME is available only through a restricted program under a REMS called the AQVESME REMS because of the risk of hepatocellular injury. Notable requirements of the AQVESME REMS include the following: Prescribers must be certified by enrolling in the REMS and completing training. Prescribers must counsel patients receiving AQVESME about the risk of hepatocellular injury. Prescribers must monitor liver tests (including ALT, AST, alkaline phosphatase, total bilirubin with fractionation, and other tests as clinically indicated) to determine if the patient is appropriate to receive AQVESME treatment. Patients must enroll in the REMS and comply with the monitoring requirements. Pharmacies must be certified by enrolling in the REMS and must only dispense to patients who are authorized to receive AQVESME. Further information is available at www.aqvesmerems.com or 1-800-625-9951.
6 ADVERSE REACTIONS The following clinically significant adverse reaction is described elsewhere in labeling: Hepatocellular Injury [see Warnings and Precautions (5.1) ]. The most common adverse reactions were headache and insomnia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Agios Pharmaceuticals, Inc. at 1-833-228-8474 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. Alpha- and Beta-Thalassemia A total of 301 patients with thalassemia received AQVESME, administered at 100 mg orally twice daily, for up to 59.9 weeks in the ENERGIZE trial (N=129) and the ENERGIZE-T trial (N=172) [see Clinical Studies (14) ] . ENERGIZE Trial Patients with non-transfusion-dependent thalassemia received AQVESME (N=129) or placebo (N=63). The most common adverse reactions (≥5% and at least 5% higher in the AQVESME arm) in patients with non-transfusion-dependent thalassemia were headache and insomnia. ENERGIZE-T Trial Patients with transfusion-dependent thalassemia received AQVESME (N=172) or placebo (N=85). The most common adverse reactions (≥5% and at least 5% higher in the AQVESME arm) in patients with transfusion-dependent thalassemia were headache and insomnia. Serious adverse reactions occurred in 1.3% of patients with thalassemia treated with AQVESME, including supraventricular arrhythmia and supraventricular tachycardia. Permanent discontinuations of AQVESME due to an adverse reaction occurred in 1.3% of patients and included elevated hepatic transaminases and insomnia. Table 1 summarizes the adverse reactions in the ENERGIZE and the ENERGIZE-T trials, individually and combined. Table 1: Adverse Reactions a in Patients with Alpha- and Beta-Thalassemia Receiving AQVESME ENERGIZE (Non-transfusion-dependent) ENERGIZE-T (Transfusion-dependent) Total Adverse Reactions AQVESME (N=129) n (%) Placebo (N=63) n (%) AQVESME (N=172) n (%) Placebo (N=85) n (%) AQVESME (N=301) n (%) Placebo (N=148) n (%) Headache 29 (22.5) 6 (9.5) 46 (26.7) 10 (11.8) 75 (24.9) 16 (10.8) Insomnia b 35 (27.1) 5 (7.9) 38 (22.1) 8 (9.4) 73 (24.3) 13 (8.8) a Included adverse reactions that occurred in at least 5% of patients in the AQVESME arm and at least 5% higher than the placebo arm. b Term includes initial insomnia, middle insomnia, and terminal insomnia. Variations in Reproductive Hormones Increases in serum testosterone (T) concentrations and decreases in serum estradiol (E2) concentrations were observed in men receiving AQVESME (Table 2). These changes in hormones were maintained during treatment with AQVESME. In 3 male patients who discontinued AQVESME and in whom reproductive hormone data were available following discontinuation of AQVESME, the hormone changes were reversible. 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 2: Abnormalities in Reproductive Hormones in Men with Thalassemia Receiving AQVESME ENERGIZE (Non-transfusion-dependent) ENERGIZE-T (Transfusion-dependent) Parameter AQVESME (46 males) Placebo (25 males) AQVESME (64 males) Placebo (31 males) Reproductive hormone analyses Testosterone (T) Serum T concentration (mean) Baseline Change from baseline 613 ng/dL 228 ng/dL 505 ng/dL -2.8 ng/dL 625 ng/dL 108 ng/dL 666 ng/dL 66 ng/dL Serum T increased a Baseline Change from baseline 2.2% 18.6% 4.3% 0% 3.3% 13.5% 10% 6.9% Estradiol (E2) Serum E2 concentration (mean) Baseline Change from baseline 29.6 pg/mL -8.7 pg/mL 27.3 pg/mL 0 pg/mL 26.4 pg/mL -5.0 pg/mL 28.9 pg/mL 1.6 pg/mL Serum E2 decreased b Baseline Change from baseline 0% 2.5% 9.5% 0% 10.2% 8.5% 6.9% 3.6% a Percentage of subjects with serum T concentration above the upper limit of normal (greater than 1050 ng/dL) at baseline and percentage of subjects with serum T increases from baseline to above the upper limit of normal where baseline was within normal limits. b Percentage of subjects with serum E2 concentration below the lower limit of normal at baseline and percentage of subjects with serum E2 decreases from baseline to below the lower limit of normal where baseline was within normal limits. Note: Results from the ENERGIZE-T study do not include data from patients who received concomitant testosterone replacement therapies.