WARNING: INCREASED RISK OF DEATH, MYOCARDIAL INFARCTION, STROKE, VENOUS THROMBOEMBOLISM, and THROMBOSIS OF VASCULAR ACCESS VAFSEO increases the risk of thrombotic vascular events, including major adverse cardiovascular events (MACE) [see Warnings and Precautions ( 5.1 )] . Targeting a hemoglobin level greater than 11 g/dL is expected to further increase the risk of death and arterial and venous thrombotic events, as occurs with erythropoietin stimulating agents (ESAs), which also increase erythropoietin levels [see Warnings and Precautions ( 5.1 )] . No trial has identified a hemoglobin target level, dose of VAFSEO, or dosing strategy that does not increase these risks [see Dosage and Administration ( 2.4 )] . Use the lowest dose of VAFSEO sufficient to reduce the need for red blood cell transfusions [ see Dosage and Administration ( 2.4 )] . WARNING: INCREASED RISK OF DEATH, MYOCARDIAL INFARCTION, STROKE, VENOUS THROMBOEMBOLISM, and THROMBOSIS OF VASCULAR ACCESS. See full prescribing information for complete boxed warning. VAFSEO increases the risk of thrombotic vascular events, including major adverse cardiovascular events (MACE). ( 5.1 ) Targeting a hemoglobin level greater than 11 g/dL is expected to further increase the risk of death and arterial and venous thrombotic events, as occurs with erythropoietin stimulating agents (ESAs), which also increase erythropoietin levels. ( 5.1 ) No trial has identified a hemoglobin target level, dose of VAFSEO, or dosing strategy that does not increase these risks. ( 2.4 ) Use the lowest dose of VAFSEO sufficient to reduce the need for red blood cell transfusions. ( 2.4 )
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warnings and cautions
5 WARNINGS AND PRECAUTIONS Hepatotoxicity: Has been reported in patients taking VAFSEO. Measure ALT, AST and bilirubin prior to the initiation of VAFSEO, monthly after initiation for the first 6 months, then as clinically indicated. Discontinue VAFSEO if ALT or AST is persistently elevated or accompanied by elevated bilirubin. ( 5.2 ) Hypertension: Worsening hypertension, including hypertensive crisis may occur. Monitor blood pressure. Adjust anti-hypertensive therapy as needed. ( 5.3 ) Seizures: Seizures have occurred in patients with CKD taking VAFSEO. Monitor for new-onset seizures, premonitory symptoms, or change in seizure frequency. ( 5.4 ) Gastrointestinal Erosion: Gastric or esophageal erosions and gastrointestinal bleeding have been reported. ( 5.5 ) Malignancy: May have unfavorable effects on cancer growth. Not recommended if active malignancy. ( 5.7 ) 5.1 Increased Risk of Death, Myocardial Infarction (MI), Stroke, Venous Thromboembolism, and Thrombosis of Vascular Access VAFSEO increases the risk of arterial and venous thrombotic events, that may be fatal, including myocardial infarction, stroke, venous thromboembolism and vascular access thrombosis [see Boxed Warning , Adverse Reactions ( 6.1 )] . Patients with cardiovascular or cerebrovascular disease are at increased risk of these events. Avoid use in patients with a history of myocardial infarction, cerebrovascular event, or acute coronary syndrome within the 3 months prior to starting VAFSEO. A rate of hemoglobin rise of greater than 1 g/dL over 2 weeks may contribute to these risks. Targeting a hemoglobin level of greater than 11 g/dL is expected to further increase the risk of death and arterial and venous thrombotic events, as occurs with ESAs, which also increase erythropoietin levels. No trial has identified a hemoglobin target level, dose of VAFSEO, or dosing strategy that does not increase these risks. Use the lowest dose of VAFSEO sufficient to reduce the need for red blood cell transfusions. Adherence to dosing and hemoglobin monitoring recommendations is important to avoid excessive erythropoiesis [see Dosage and Administration ( 2.4 )] . Advise patients to seek immediate medical attention if they develop signs or symptoms of myocardial infarction, stroke, venous thromboembolism, or thrombosis of vascular access. Evaluate and manage promptly if these occur. 5.2 Hepatotoxicity VAFSEO may cause hepatotoxicity. In clinical trials, hepatocellular injury attributed to VAFSEO was reported in less than 1% of patients, including one case of severe hepatocellular injury with jaundice. All events were asymptomatic and resolved after discontinuation of VAFSEO. The time to onset was generally within the first 3 months of treatment. Elevated serum ALT, AST, and bilirubin were seen in 1.8%, 1.8% and 0.3% of CKD patients treated with VAFSEO, respectively. Measure ALT, AST and bilirubin prior to the initiation of VAFSEO and monthly after initiation for the first 6 months and then monitor as clinically indicated [see Dosage and Administration ( 2.1 )] . Discontinue VAFSEO if there is persistent ALT or AST greater than 3 times ULN or if ALT or AST elevations greater than 3 times upper limit of normal (ULN) are accompanied by a bilirubin increase greater than 2 times ULN. VAFSEO is not recommended in patients with cirrhosis or active, acute liver disease. 5.3 Hypertension VAFSEO is contraindicated in patients with uncontrolled hypertension. In the INNO 2 VATE-1 and INNO 2 VATE-2 clinical trials, worsening of hypertension was reported in 14% (9.4 per 100 person-years [PY]) of patients receiving VAFSEO and 17% (11.8 per 100 PY) of patients receiving darbepoetin alfa. Serious worsening of hypertension was reported in 2.7% (1.7 per 100 PY) of patients receiving VAFSEO and 3% (1.8 per 100 PY) of patients receiving darbepoetin alfa. Cases of hypertensive crisis including hypertensive encephalopathy and seizures have also been reported in patients receiving VAFSEO. Periodically monitor blood pressure and adjust or initiate anti-hypertensive therapy as needed. 5.4 Seizures Seizures have occurred in patients treated with VAFSEO. In the INNO 2 VATE-1 and INNO 2 VATE-2 clinical trials, seizures occurred in 1.6% (1.0 per 100 PY) of patients who received VAFSEO and 1.6% (1.0 per 100 PY) of patients who received darbepoetin alfa. Following initiation of VAFSEO, monitor patients closely for premonitory neurologic symptoms. Advise patients to contact their healthcare practitioner for new-onset seizures, premonitory symptoms, or change in seizure frequency. 5.5 Gastrointestinal Erosion In the INNO 2 VATE-1 and INNO 2 VATE-2 clinical trials, gastric or esophageal erosions occurred in 6.4% (4.0 per 100 PY) of patients receiving VAFSEO and 5.3% (3.3 per 100 PY) of darbepoetin alfa-treated patients. Serious gastrointestinal erosions, including gastrointestinal bleeding and the need for red blood cell transfusions were reported in 3.4% (2.1 per 100 PY) and 3.3% (2.0 per 100 PY) of those receiving VAFSEO and darbepoetin alfa, respectively. Consider this risk particularly in patients at increased risk for gastrointestinal erosions, such as those with a history of gastrointestinal erosion, peptic ulcer disease, use of concomitant medications that increase the risk of gastrointestinal erosion, and current tobacco smokers and alcohol drinkers. Advise patients of the symptoms and signs of gastric and esophageal erosions and of gastrointestinal bleeding and to seek prompt medical care if these occur. 5.6 Serious Adverse Reactions in Patients with Anemia Due to Chronic Kidney Disease and Not on Dialysis The safety of VAFSEO has not been established for the treatment of anemia due to CKD in adults not on dialysis and its use is not recommended in this setting [see Indications and Usage ( 1 )] . In large clinical trials in adults with anemia of CKD who were not on dialysis (PRO 2 TECT-1 and PRO 2 TECT-2), an increased risk of mortality, stroke, myocardial infarction, serious acute kidney injury, serious hepatic injury, and serious gastrointestinal erosions was observed in patients treated with VAFSEO compared to darbepoetin alfa. 5.7 Malignancy Because increased hypoxia inducible factor (HIF)-1 levels may be associated with unfavorable effects on cancer growth, VAFSEO has not been studied and is not recommended in patients with active malignancies. In the INNO 2 VATE-1 and INNO 2 VATE-2 clinical trials, malignancies were observed in 2.2% (1.3 per 100 PY) of patients treated with VAFSEO and 3.0% (1.8 per 100 PY) of patients treated with darbepoetin alfa. No evidence of increased carcinogenicity was observed in animal studies [see Nonclinical Toxicology ( 13.1 )] .
6 ADVERSE REACTIONS The following clinically significant adverse reactions are discussed elsewhere in the labeling: Increased risk of death, myocardial infarction, stroke, venous thromboembolism, and thrombosis of vascular access [see Boxed Warning and Warnings and Precautions (5.1) ] Hepatotoxicity [see Warnings and Precautions ( 5.2 )] Hypertension [see Warnings and Precautions ( 5.3 )] Seizures [see Warnings and Precautions ( 5.4 )] Gastrointestinal erosion [see Warnings and Precautions ( 5.5 )] Serious adverse reactions in patients with anemia due to chronic kidney disease and not on dialysis [see Warnings and Precautions ( 5.6 )] The most common adverse reactions (occurring at ≥ 10%) were hypertension and diarrhea. ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Akebia Therapeutics, Inc. at 1-844-445-3799 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 safety of VAFSEO was evaluated in adults with dialysis-dependent chronic kidney disease (DD-CKD) with anemia in the INNO 2 VATE-1 and INNO 2 VATE-2 trials [see Clinical Studies ( 14.1 )] . Both trials randomized patients to VAFSEO or darbepoetin alfa. Results in this section are based on the pooled VAFSEO treatment arms and pooled darbepoetin alfa arms from these trials. There were 1947 patients treated with VAFSEO and 1955 patients treated with darbepoetin alfa. In the pooled VAFSEO treatment arm, 71% of the participants were treated continuously for at least 6 months of VAFSEO and 44% of participants received VAFSEO for at least 1 year. VAFSEO was non-inferior to darbepoetin alfa on the time to first occurrence of major adverse cardiovascular events (MACE) in adults with anemia due to CKD who were on dialysis [see Clinical Studies ( 14.1 )] . Permanent treatment discontinuation due to an adverse reaction was reported in 4.9% of patients treated with VAFSEO and 1.1% of patients treated with darbepoetin alfa. Gastrointestinal symptoms (nausea, vomiting and diarrhea) resulted in permanent treatment discontinuation in 1.8% of patients treated with VAFSEO. The most common adverse reactions (>10% of VAFSEO-treated patients) were hypertension and diarrhea. Table 1 lists the adverse reactions that occurred in at least 5% or greater of patients with DD-CKD treated with VAFSEO. Table 1 Adverse Reactions (≥5%) in Patients with DD-CKD During INNO 2 VATE-1 and INNO 2 VATE-2 * Grouped Terms Hypertension includes hypertensive crisis, pre-eclampsia and hypertensive encephalopathy. Headache includes occipital neuralgia. Fatigue includes asthenia, lethargy and malaise. Vomiting includes hematemesis. Gastrointestinal erosion includes duodenal ulcers and perforation, gastrointestinal ulcers and perforation, esophageal ulcers and perforation, and unspecified site or hematemesis, gastrointestinal hemorrhage, helicobacter duodenitis and gastritis, melaena, and gastric hemorrhage. Dizziness includes labyrinthitis, vertigo, vestibular neuronitis and presyncope. Dyspnea includes orthopnea and respiratory distress. Adverse Reactions VAFSEO N=1947 (%) Darbepoetin Alfa N=1955 (%) Hypertension * 14 17 Diarrhea 13 10 Headache * 9 8 Nausea 8 8 Fatigue * 8 5 Abdominal pain 7 7 Vomiting * 7 7 Gastrointestinal erosion * 6 5 Dizziness * 6 5 Dyspnea * 6 7 Arteriovenous fistula thrombosis 6 5 Dialysis related complication 5 7 Adjudicated fatal and non-fatal thrombotic vascular events were observed in 9.0 per 100 PY of patients in the pooled VAFSEO arm and in 8.7 per 100 PY of patients in the pooled darbepoetin alfa (see Table 2) . Table 2 Adjudicated Thrombotic Vascular Events in Patients with DD-CKD (Fatal and Non-fatal Events) * PY = Person Years * These data are not an adequate basis for comparison of rates between the study drug and active control. ** Based on time to first event analysis. Event VAFSEO (N = 1947) Darbepoetin Alfa (N = 1955) Rate per 100 PY ** Rate per 100 PY ** Vascular access thrombosis 4.8 3.9 Myocardial infarction 2.9 2.8 Stroke 1.1 1.4 Deep vein thrombosis 0.5 0.6 Pulmonary embolism 0.2 0.3 Arterial thrombosis 0.2 0.1