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Sparsentan

FDA Drug Information • Also known as: Filspari

Brand Names
Filspari
Dosage Form
POWDER
Product Type
BULK INGREDIENT

⚠ Boxed Warning (Black Box)

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 ).

    • Description

    11 DESCRIPTION FILSPARI (sparsentan) is an endothelin and angiotensin II receptor antagonist. The chemical name of sparsentan is 2-[4-[(2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl]-2-(ethoxymethyl)phenyl]-N-(4,5-dimethyl-1,2-oxazol-3-yl)benzenesulfonamide. Sparsentan is a white to off-white powder, which is practically insoluble in water. Sparsentan has pH-dependent solubility, with intrinsic solubility of 1.48 and 0.055 mg/mL under pH 1.2 and 6.8, respectively. Sparsentan has a molecular weight of 592.76 g/mol, a molecular formula of C 32 H 40 N 4 O 5 S, and the following structure: FILSPARI is available as film-coated 200 mg and 400 mg strength immediate release tablets for oral administration. The inactive ingredients in FILSPARI are colloidal silicon dioxide, lactose anhydrous, magnesium stearate, silicified microcrystalline cellulose, and sodium starch glycolate. Film-coating is composed of macrogol/polyethylene glycol, polyvinyl alcohol-partially hydrolyzed, talc, and titanium dioxide. Sparsentan Structure

    What Is Sparsentan Used For?

    1 INDICATIONS AND USAGE FILSPARI is indicated to slow kidney function decline in adults with primary immunoglobulin A nephropathy (IgAN) who are at risk for disease progression. FILSPARI is an endothelin and angiotensin II receptor antagonist indicated to slow kidney function decline in adults with primary immunoglobulin A nephropathy (IgAN) who are at risk for disease progression ( 1 , 12.1 ).

    Dosage and Administration

    2 DOSAGE AND ADMINISTRATION

  • Prior to initiating treatment with FILSPARI, discontinue use of renin- angiotensin-aldosterone system (RAAS) inhibitors and endothelin receptor antagonists (ERAs) ( 2.1 , 4 , 7.1 ).
  • Initiate treatment with FILSPARI at 200 mg orally once daily. After 14 days, increase to 400 mg once daily, as tolerated. When resuming FILSPARI after an interruption, consider re-titration ( 2.4 ).
  • Instruct patients to swallow tablets whole with water prior to the morning or evening meal ( 2.5 ). 2.1 General Considerations Prior to initiating treatment with FILSPARI, discontinue use of renin-angiotensin-aldosterone system (RAAS) inhibitors and endothelin receptor antagonists (ERAs) [see Contraindications ( 4 ), Drug Interactions ( 7.1 )] . 2.2 Monitoring Initiate treatment with FILSPARI only after measuring aminotransferase levels and total bilirubin. Avoid initiation in patients with elevated aminotransferases greater than 3 times ULN. Continue required monitoring every 3 months during treatment with FILSPARI [see Dosage and Administration ( 2.6 ), Warnings and Precautions ( 5.1 )]. 2.3 Pregnancy Testing Exclude pregnancy before initiating treatment with FILSPARI [see Warnings and Precautions ( 5.3 ), Use in Specific Populations ( 8.1 , 8.3 )]. 2.4 Recommended Dosage Initiate treatment with FILSPARI at 200 mg orally once daily. After 14 days, increase to the recommended dose of 400 mg once daily, as tolerated. When resuming treatment with FILSPARI after an interruption, consider titration of FILSPARI, starting at 200 mg once daily. After 14 days, increase to the recommended dose of 400 mg once daily [see Drug Interactions ( 7.2 )] . 2.5 Administration
  • Instruct patient to swallow tablets whole with water prior to the morning or evening meal.
  • Maintain the same dosing pattern in relationship to meals.
  • If a dose is missed, take the next dose at the regularly scheduled time. Do not take double or extra doses. 2.6 Dosage Adjustment for Aminotransferase Elevations If aminotransferase levels increase, adjust monitoring and treatment plan according to Table 1 . Do not resume treatment in patients who have experienced clinical symptoms of hepatotoxicity or in patients whose hepatic enzyme levels and bilirubin have not returned to pretreatment levels. Table 1: Dosage Adjustment and Monitoring in Patients Developing Aminotransferase Elevations Greater Than 3 Times ULN ALT = alanine aminotransferase; AST = aspartate aminotransferase; INR = international normalized ratio; ULN = upper limit of normal. ALT/AST levels Treatment and monitoring recommendations Greater than 3 times and less than or equal to 8 times ULN Confirm elevation with a repeat measure. If confirmed, interrupt treatment, and monitor aminotransferase levels and bilirubin at least weekly, and INR as needed, until the levels return to pretreatment values and the patient is asymptomatic. Do not resume treatment if any of the following occurs without other cause found:
  • ALT or...

    • Side Effects (Adverse Reactions)

    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 (≥5%) are hyperkalemia, hypotension (including orthostatic hypotension), peripheral edema, dizziness, anemia, and acute kidney injury ( 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. 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 2 . Table 2: Adverse Reactions Reported in 2% or More of Subjects Treated with FILSPARI 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) Laboratory Tests Initiation of FILSPARI may cause an initial small decrease in estimated glomerular filtration rate (eGFR) that occurs within the first 4 weeks of starting therapy and then stabilizes. 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 (19%) compared to the irbesartan arm (13%). 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 study.

    • Drug Interactions

    7 DRUG INTERACTIONS

  • Strong CYP3A inhibitors: Avoid concomitant use. Increased sparsentan exposure ( 2.7 , 7.2 , 12.3 ).
  • Moderate CYP3A inhibitors: Monitor adverse reactions. Increased sparsentan exposure ( 7.2 , 12.3 ).
  • Strong CYP3A inducers: Avoid concomitant use. Decreased sparsentan exposure ( 7.3 , 12.3 ).
  • Antacids: Avoid use within 2 hours before or after use of sparsentan. May decrease exposure to sparsentan ( 7.4 , 11 ).
  • Acid reducing agents: Avoid concomitant use. May decrease exposure to sparsentan ( 7.4 ).
  • Non-steroidal anti-inflammatory drugs (NSAIDs) including selective cyclooxygenase (COX-2) inhibitors: Monitor for signs of worsening renal function. Increased risk of kidney injury ( 7.5 ).
  • CYP2B6, 2C9, and 2C19 substrates: Monitor for substrate efficacy. Decreased exposure of these substrates ( 7.6 , 12.3 ).
  • Sensitive P-gp and BCRP substrates: Avoid concomitant use. Increased exposure to substrates ( 7.7 , 12.3 ).
  • Agents Increasing Serum Potassium: Increased risk of hyperkalemia, monitor serum potassium frequently ( 5.6 , 7.8 ). 7.1 Renin-Angiotensin System Inhibitors and ERAs Do not coadminister FILSPARI with ARBs, ERAs, or aliskiren [see Dosage and Administration ( 2.1 ), Contraindications ( 4 )] . Combined use of these agents is associated with increased risks of hypotension, syncope, hyperkalemia, and changes in renal function (including acute renal failure). 7.2 Strong and Moderate CYP3A Inhibitors Avoid concomitant use of FILSPARI with strong CYP3A inhibitors. If a strong CYP3A inhibitor cannot be avoided, interrupt treatment with FILSPARI. When resuming treatment with FILSPARI, consider dose titration [see Dosage and Administration ( 2.4 , 2.7 ), Clinical Pharmacology ( 12.3 )] . Monitor blood pressure, serum potassium, edema, and kidney function regularly when used concomitantly with moderate CYP3A inhibitors [see Warnings and Precautions ( 5.4 , 5.5 , 5.6 , 5.7 )] . No FILSPARI dose adjustment is needed. Sparsentan is a CYP3A substrate. Concomitant use with a strong CYP3A inhibitor increases sparsentan C max and AUC [see Clinical Pharmacology ( 12.3 )] , which may increase the risk of FILSPARI adverse reactions. 7.3 Strong CYP3A Inducers Avoid concomitant use with a strong CYP3A inducer. Sparsentan is a CYP3A substrate. Concomitant use with a strong CYP3A inducer decreases sparsentan C max and AUC [see Clinical Pharmacology ( 12.3 )] , which may reduce FILSPARI efficacy. 7.4 Antacids and Acid Reducing Agents Administer FILSPARI 2 hours before or after administration of antacids. Avoid concomitant use of acid reducing agents (histamine H2 receptor antagonist and PPI proton pump inhibitor) with FILSPARI. Sparsentan exhibits pH-dependent solubility [see Description ( 11 )] . Antacids or acid reducing agents may decrease sparsentan exposure which may reduce FILSPARI efficacy. 7.5 Non-Steroidal Anti-Inflammatory Agents (NSAIDs), Including Selective Cyclooxygenase-2 (COX-2) Inhibitors Monitor for signs of...

    • Contraindications

    4 CONTRAINDICATIONS Use of FILSPARI is contraindicated in patients who are pregnant [see Dosage and Administration ( 2.3 ), Warnings and Precautions ( 5.3 ), Use in Specific Populations ( 8.1 )] . Do not coadminister FILSPARI with ARBs, ERAs, or aliskiren [see Dosage and Administration ( 2.1 ), Drug Interactions ( 7.1 )].

  • Pregnancy ( 4 ).
  • Concomitant use with angiotensin receptor blockers (ARBs), ERAs, or aliskiren ( 4 ).

    • Pregnancy and Breastfeeding

    8.1 Pregnancy Risk Summary Based on data from animal reproductive toxicity studies, FILSPARI may cause fetal harm, including birth defects and fetal death, when administered to a pregnant patient and is contraindicated during pregnancy [see Contraindications ( 4 )] . Available data from reports of pregnancy in clinical trials with FILSPARI are insufficient to identify a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. Available data from postmarketing reports and published literature over decades of use with ERA in the same class as FILSPARI have not identified an increased risk of fetal harm; however, these data are limited. Methodological limitations of these postmarketing reports and published literature include lack of a control group; limited information regarding dose, duration, and timing of drug exposure; and missing data. These limitations preclude establishing a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal ERA use. In animal reproduction studies, oral administration of sparsentan to pregnant rats throughout organogenesis at 10-times the maximum recommended human dose (MRHD) in mg/day caused teratogenic effects in rats, including craniofacial malformations, skeletal abnormalities, increased embryo-fetal lethality, and reduced fetal weights (see Data) . Advise pregnant patients of the potential risk to the fetus. The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Data Animal Data In embryo-fetal development studies in pregnant rats and rabbits, teratogenicity and/or developmental toxicity were observed, which were attributed to the antagonism of endothelin type A...

    Overdosage

    10 OVERDOSAGE There is no experience with overdose with FILSPARI. Sparsentan has been given in doses up to 1600 mg/day in healthy volunteers, or up to 400 mg/day in IgAN patients. Overdose of FILSPARI may result in decreased blood pressure. In the event of an overdose, standard supportive measures should be taken, as required. Dialysis is unlikely to be effective because sparsentan is highly protein-bound.

    How Supplied

    16 HOW SUPPLIED/STORAGE AND HANDLING FILSPARI is supplied in bottles of 30 film-coated tablets.

  • 200 mg tablets are film-coated, modified oval, white to off-white, debossed with “105” on one side and plain on the other side, available in bottles of 30 tablets with child-resistant caps (NDC 68974-200-30).
  • 400 mg tablets are film-coated, modified oval, white to off-white, debossed with “021” on one side and plain on the other side, available in bottles of 30 tablets with child-resistant caps (NDC 68974-400-30). Storage Store at 20°C to 25°C (68°F to 77°F), excursions permitted to 15°C to 30°C (59°F to 86°F). Store FILSPARI in its original container.

    • About This Information

    This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.

    What are side effects?

    Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.

    What are drug interactions?

    Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.