WARNING: HEPATOTOXICITY and EMBRYO-FETAL TOXICITY Because of the risk of hepatotoxicity, FILSPARI is available only through a restricted program called the FILSPARI REMS. Under the FILSPARI REMS, prescribers, patients, and pharmacies must enroll in the program [see Warnings and Precautions ( 5.1 , 5.2 )] . Hepatotoxicity Some Endothelin Receptor Antagonists (ERAs) have caused elevations of aminotransferases, hepatotoxicity, and liver failure. In clinical studies, elevations in aminotransferases (ALT or AST) of at least 3-times the Upper Limit of Normal (ULN) have been observed in up to 3.5% of FILSPARI-treated patients, including cases confirmed with rechallenge. Measure transaminases and bilirubin before initiating treatment and then every 3 months during treatment. Interrupt treatment and closely monitor patients who develop aminotransferase elevations more than 3-times ULN [see Dosage and Administration ( 2.2 , 2.6 ), Warnings and Precautions ( 5.1 )] . FILSPARI should generally be avoided in patients with elevated aminotransferases (>3-times ULN) at baseline because monitoring for hepatotoxicity may be more difficult and these patients may be at increased risk for serious hepatotoxicity [see Dosage and Administration ( 2.2 , 2.6 ), Warnings and Precautions ( 5.1 )] . Embryo-Fetal Toxicity FILSPARI is contraindicated for use during pregnancy because it may cause fetal harm if used by pregnant patients. Therefore, in patients who can become pregnant, exclude pregnancy prior to initiation of FILSPARI. Advise use of effective contraception before the initiation of treatment, during treatment, and for two weeks after discontinuation of treatment with FILSPARI. When pregnancy is detected, discontinue FILSPARI as soon as possible [see Dosage and Administration ( 2.3 ), Contraindications ( 4 ), Warnings and Precautions ( 5.3 ), Use in Specific Populations ( 8.1 , 8.3 )]. WARNING: HEPATOTOXICITY and EMBRYO-FETAL TOXICITY See full prescribing information for complete boxed warning. • FILSPARI is only available through a restricted distribution program called the FILSPARI Risk Evaluation and Mitigation Strategies (REMS) because of the risk of hepatotoxicity ( 5.2 ): • Some endothelin receptor antagonists have caused elevations of aminotransferases, hepatotoxicity, and liver failure ( 5.1 ). • Measure liver aminotransferases and total bilirubin prior to initiation of treatment and ALT and AST every 3 months during treatment ( 2.2 , 2.6 , 5.1 ). • Interrupt treatment and closely monitor patients developing aminotransferase elevations more than 3-times Upper Limit of Normal (ULN) ( 2.2 , 2.6 ). • Based on animal data, FILSPARI may cause fetal harm if used during pregnancy and is contraindicated in pregnancy ( 4 , 5.3 , 8.1 ). • For patients who can become pregnant, exclude pregnancy prior to the initiation of treatment with FILSPARI ( 2.3 , 5.3 , 8.3 ). • Use effective contraception prior to initiation of treatment, during treatment, and for two weeks after stopping FILSPARI ( 4 , 5.3 , 8.1 , 8.3 ). • When pregnancy is detected, discontinue FILSPARI as soon as possible ( 5.3 ).
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warnings and cautions
5 WARNINGS AND PRECAUTIONS • Hypotension ( 5.4 ) • Acute Kidney Injury ( 5.5 ) • Hyperkalemia ( 5.6 ) • Fluid Retention ( 5.7 ) 5.1 Hepatotoxicity Elevations in ALT or AST of at least 3-fold ULN have been observed in up to 3.5% of FILSPARI-treated patients, including cases confirmed with rechallenge [see Adverse Reactions ( 6.1 )] . While no concurrent elevations in bilirubin greater than 2-times ULN or cases of liver failure were observed in FILSPARI-treated patients in clinical trials, some endothelin receptor antagonists have caused elevations of aminotransferases, hepatotoxicity, and liver failure. To reduce the risk of potential serious hepatotoxicity, measure serum aminotransferase levels and total bilirubin prior to initiation of treatment and then every 3 months during treatment [see Dosage and Administration ( 2.2 )] . Advise patients with symptoms suggesting hepatotoxicity (nausea, vomiting, right upper quadrant pain, fatigue, anorexia, jaundice, dark urine, fever, or itching) to immediately stop treatment with FILSPARI and seek medical attention. If aminotransferase levels are abnormal at any time during treatment, interrupt FILSPARI and monitor as recommended [see Dosage and Administration ( 2.6 )] . Consider re-initiation of FILSPARI only when hepatic enzyme levels and bilirubin return to pretreatment values and only in patients who have not experienced clinical symptoms of hepatotoxicity [see Dosage and Administration ( 2.2 , 2.6 )] . Avoid initiation of FILSPARI in patients with elevated aminotransferases (greater than 3-times ULN) because monitoring hepatotoxicity in these patients may be more difficult and these patients may be at increased risk for serious hepatotoxicity [see Dosage and Administration ( 2.2 , 2.6 ), and Warnings and Precautions ( 5.2 )]. 5.2 FILSPARI REMS For all patients, FILSPARI is available only through a restricted program under a REMS called the FILSPARI REMS because of the risk of hepatotoxicity [see Warnings and Precautions ( 5.1 )]. Important requirements of the FILSPARI REMS include the following: • Prescribers must be certified with the FILSPARI REMS by enrolling and completing training. • All patients must enroll in the FILSPARI REMS prior to initiating treatment and comply with monitoring requirements [see Dosage and Administration ( 2.2 , 2.6 ), Warnings and Precautions ( 5.1 )]. • Pharmacies that dispense FILSPARI must be certified with the FILSPARI REMS and must dispense only to patients who are authorized to receive FILSPARI. Further information is available at www.filsparirems.com or 1-833-513-1325. 5.3 Embryo-Fetal Toxicity Based on data from animal reproduction studies, FILSPARI may cause fetal harm when administered to a pregnant patient and is contraindicated for use during pregnancy. The available human data for endothelin receptor antagonists do not establish the presence or absence of fetal harm related to the use of FILSPARI. Counsel patients who can become pregnant of the potential risk to a fetus. Exclude pregnancy before initiating treatment with FILSPARI. Advise patients who can become pregnant to use effective contraception prior to initiation of treatment, during treatment, and for two weeks after discontinuation of treatment with FILSPARI. Advise pre-pubertal females and/or their guardian(s) of the fetal risk and the need to use effective contraception once they reach reproductive potential. When pregnancy is detected, discontinue FILSPARI as soon as possible [see Dosage and Administration ( 2.3 ), Contraindications ( 4 ), Use in Specific Populations ( 8.1 , 8.3 )] . 5.4 Hypotension Hypotension has been observed in patients treated with ARBs and endothelin receptor antagonists (ERAs) and was observed in clinical studies with FILSPARI. In clinical trials, there was a greater incidence of hypotension-associated adverse events, some serious, including dizziness, in patients treated with FILSPARI compared to irbesartan [see Adverse Reactions ( 6.1 )]. In patients at risk for hypotension, consider eliminating or adjusting other antihypertensive medications and maintaining appropriate volume status. If hypotension develops, despite elimination or reduction of other antihypertensive medications, consider a dose reduction or dose interruption of FILSPARI. A transient hypotensive response is not a contraindication to further dosing of FILSPARI, which can be given once blood pressure has stabilized. 5.5 Acute Kidney Injury Monitor kidney function periodically. Drugs that inhibit the renin-angiotensin system can cause acute kidney injury. Patients whose kidney function may depend in part on the activity of the renin-angiotensin system (e.g., patients with renal artery stenosis, chronic kidney disease, severe congestive heart failure, or volume depletion) may be at particular risk of developing acute kidney injury on FILSPARI. Consider withholding or discontinuing therapy in patients who develop a clinically significant decrease in kidney function while on FILSPARI. 5.6 Hyperkalemia Monitor serum potassium periodically and treat appropriately. Patients with advanced kidney disease or taking concomitant potassium-increasing drugs (e.g., potassium supplements, potassium-sparing diuretics) or using potassium-containing salt substitutes are at increased risk for developing hyperkalemia. Dosage reduction or discontinuation of FILSPARI may be required [see Dosage and Administration ( 2.4 ), Adverse Reactions ( 6.1 )] . 5.7 Fluid Retention Fluid retention may occur with endothelin receptor antagonists and has been observed in clinical studies with FILSPARI [see Adverse Reactions ( 6.1 )] . FILSPARI has not been evaluated in patients with heart failure. If clinically significant fluid retention develops, evaluate the patient to determine the cause and the potential need to initiate or modify the dose of diuretic treatment, then consider modifying the dose of FILSPARI.
6 ADVERSE REACTIONS Clinically significant adverse reactions that appear in other sections of the label include: • Hepatotoxicity [see Warnings and Precautions ( 5.1 )] • Embryo-Fetal Toxicity [see Warnings and Precautions ( 5.3 )] • Hypotension [see Warnings and Precautions ( 5.4 )] • Acute Kidney Injury [see Warnings and Precautions ( 5.5 )] • Hyperkalemia [see Warnings and Precautions ( 5.6 )] • Fluid Retention [see Warnings and Precautions ( 5.7 )] Most common adverse reactions in patients with IgAN (≥5%) are hyperkalemia, hypotension (including orthostatic hypotension), peripheral edema, dizziness, anemia, and acute kidney injury ( 6.1 ). Most common adverse reactions in patients with FSGS (≥5%) are peripheral edema, hypotension (including orthostatic hypotension), hyperkalemia, dizziness, and anemia ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Travere Therapeutics at 1-877-659-5518 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. IgAN The safety of FILSPARI was evaluated in PROTECT ( NCT03762850 ), a randomized, double-blind, active-controlled clinical study in adults with IgAN. The data below reflect FILSPARI exposure in 202 patients with a median duration of 110 weeks. The most common adverse reactions are presented in Table 3 . Table 3: Adverse Reactions Reported in 2% or More of Subjects with IgAN Treated with FILSPARI (PROTECT) 1 Includes related terms. 2 Elevations in ALT or AST greater than 3-fold ULN. FILSPARI (N = 202) n (%) Irbesartan (N = 202) n (%) Hyperkalemia 1 34 (17) 27 (13) Hypotension (including orthostatic hypotension) 33 (16) 13 (6) Peripheral edema 1 33 (16) 29 (14) Dizziness 1 32 (16) 14 (7) Anemia 16 (8) 9 (4) Acute kidney injury 12 (6) 5 (2) Transaminase elevations 2 7 (3.5) 8 (4.0) FSGS The safety of FILSPARI was evaluated in DUPLEX ( NCT03493685 ), a randomized, double-blind, active-controlled clinical study in adult and pediatric patients with FSGS [see Clinical Trials ( 14.2 )] . The data below reflects FILSPARI exposure in adult (n=168) and pediatric patients 9 years and older (n=16) with FSGS who received FILSPARI at the recommended dosing regimens for a median duration of 108 weeks The most common adverse reactions reported in adult and pediatric patients 9 years of age and older are presented in Table 4 . Table 4: Adverse Reactions Reported in 2% or More of Subjects with FSGS Treated with FILSPARI (Overall DUPLEX Population) 1 Includes related terms. 2 Elevations in ALT or AST greater than 3-fold ULN. FILSPARI (N=184) n (%) Irbesartan (N = 187) n (%) Peripheral edema 1 42 (23) 45 (24) Hypotension (including orthostatic hypotension) 38 (21) 25 (13) Hyperkalemia 1 37 (20) 21 (11) Dizziness 1 25 (14) 21 (11) Anemia 24 (13) 10 (5) Acute kidney injury 8 (4) 13 (7) Transaminase elevations 2 7 (4) 5 (3) Laboratory Tests The incidence of a hemoglobin decrease >2 g/dL compared to baseline and below the lower limit of normal was greater for the FILSPARI arm compared to the irbesartan arm (19% vs 13% in PROTECT; 45% vs 18% in DUPLEX). This decrease is thought to be in part due to hemodilution. There were no treatment discontinuations due to anemia or hemoglobin decrease in the PROTECT or DUPLEX clinical studies.