Sparsentan (Monograph)

Drug class: Endothelin receptor antagonists

Medically reviewed by Drugs.com on Mar 10, 2024. Written by ASHP.

Warning

Risk Evaluation and Mitigation Strategy (REMS):

FDA approved a REMS for sparsentan to ensure that the benefits outweigh the risks. The REMS may apply to one or more preparations of sparsentan and consists of the following: medication guide, elements to assure safe use, and implementation system. See https://www.accessdata.fda.gov/scripts/cder/rems/.

Warning

Elevations of aminotransferases, hepatotoxicity, and liver failure reported with some endothelin receptor antagonists (ERAs).
Measure transaminases and bilirubin before treatment initiation, monthly for the first 12 months of treatment, and every 3 months thereafter.
Interrupt treatment and closely monitor patients who develop aminotransferase elevations >3 times ULN.

Can cause major birth defects if used during pregnancy, based on animal data.
Pregnancy testing required before treatment initiation, during treatment, and 1 month after treatment discontinuation.
Females of reproductive potential must use effective contraception prior to treatment initiation, during treatment, and for 1 month after treatment discontinuation.

Introduction

Endothelin type A receptor (ET_AR) and angiotensin II receptor (AT₁R) antagonist.

Uses for Sparsentan

Primary Immunoglobulin A Nephropathy

Reduction of proteinuria in adults with primary immunoglobulin A nephropathy (IgAN) at risk of rapid disease progression, generally a urine protein-to-creatinine ratio (UPCR) ≥1.5 g/g (designated an orphan drug by FDA for this use).

Approved under accelerated approval based on reduction of proteinuria; continued FDA approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory clinical trial. Not established whether sparsentan slows kidney function decline in patients with IgAN.

Treatment of IgAN includes supportive care, lifestyle modifications (exercise, weight control, smoking cessation, dietary sodium restriction), interventions to reduce cardiovascular risk, and BP management; pharmacotherapy may include ACE inhibitors, angiotensin receptor blockers (ARBs), and/or immunosuppressive therapy. Specific place in therapy for sparsentan not yet established.

Sparsentan Dosage and Administration

General

Pretreatment Screening

Measure liver function tests (AST, ALT, and total bilirubin) prior to treatment. Do not initiate in patients with elevated aminotransferases (>3 times ULN).
Verify pregnancy status in females of reproductive potential prior to initiating sparsentan; do not initiate unless a negative pregnancy test is confirmed.

Patient Monitoring

Monitor liver function tests (AST, ALT, and total bilirubin) monthly for the first 12 months of sparsentan therapy, and every 3 months thereafter.
In patients of reproductive potential, perform pregnancy testing monthly during sparsentan therapy and 1 month after discontinuing the drug.
Monitor for signs and symptoms of fluid retention and edema, hyperkalemia, acute kidney injury, and hypotension. Monitor serum potassium and kidney function periodically during therapy.

REMS

Due to risks of hepatotoxicity and birth defects, sparsentan is only available through a restricted distribution program called the Filspari Risk Evaluation and Mitigation Strategy (REMS) program. Prescribers, patients, and pharmacies must enroll in the program and agree to comply with its requirements prior to prescribing, receiving, or dispensing sparsentan. For additional information about the REMS program, consult the Filspari REMS website [Web].
Prescribers and pharmacies must be certified with the REMS program before prescribing or dispensing sparsentan.
Patients must enroll in the REMS program prior to initiating treatment and comply with required monitoring, including regular liver function monitoring and pregnancy testing (in females of reproductive potential).

Other General Considerations

Prior to initiation of sparsentan, discontinue use of renin-angiotensin-aldosterone system inhibitors, endothelin receptor antagonists (ERAs), and aliskiren.

Administration

Oral Administration

Administer orally.

Available as oral tablets containing sparsentan 200 mg or 400 mg.

Administer tablets whole with water once daily prior to the same meal (morning or evening) each day.

If missed dose, skip the missed dose and take the next dose at the regularly scheduled time.

Dosage

Adults

Immunoglobulin A Nephropathy (IgAN)

Oral

Initial: 200 mg once daily for 14 days. After 14 days, may increase to 400 mg once daily, as tolerated.

When resuming sparsentan after interruption, consider dosage titration, starting at 200 mg once daily; after 14 days, increase to 400 mg once daily.

Dosage Modification for Toxicity

If elevations in AST or ALT occur in patients receiving sparsentan, adjust monitoring and treatment (see Table 1). Do not resume sparsentan in patients who have experienced clinical symptoms of hepatotoxicity or in patients whose hepatic enzymes and bilirubin levels have not returned to baseline levels.

Table 1. Recommended Dosage Adjustment and Monitoring for Sparsentan in Patients with Transaminase Elevations1
AST/ALT Levels	Treatment and Monitoring Recommendations
>3 times and ≤8 times ULN	Confirm AST/ALT elevations with repeat measurement. Once elevations are confirmed, temporarily interrupt treatment and monitor AST/ALT and bilirubin levels at least weekly, and INR levels as needed, until levels return to baseline and patient is asymptomatic. Do not resume sparsentan therapy if any of the following occurs without another identified cause: AST or ALT >3 times ULN and total bilrubin >2 times ULN or INR >1.5 AST or ALT >3 times ULN with concomitant fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash or eosinophilia (>5% eosinophils) AST or ALT >5 times ULN for >2 weeks If re-initiating sparsentan, initiate at a dosage of 200 mg once daily, and reassess AST/ALT and bilirubin levels within 3 days. Monitor patients closely. The dosage may be increased to 400 mg once daily after 14 days, as tolerated.
>8 times ULN	Discontinue sparsentan therapy permanently if no other cause identified.

Special Populations

Hepatic Impairment

Avoid use with any degree of hepatic impairment (Child-Pugh class A, B, or C); potential for serious liver injury.

Renal Impairment

No specific dosage recommendations.

Geriatric Patients

No specific dosage recommendations.

Cautions for Sparsentan

Contraindications

Pregnancy.
Concomitant use with angiotensin receptor blockers (ARBs), endothelin receptor antagonists (ERAs), or aliskiren.

Warnings/Precautions

Warnings

Hepatotoxicity

Hepatotoxicity reported (see Boxed Warning).

Monitor AST, ALT and total bilirubin prior to initiation of sparsentan, monthly during the first year of treatment, and every 3 months thereafter.

Advise patients to immediately discontinue sparsentan and seek medical attention if symptoms of hepatotoxicity occur (e.g., nausea, vomiting, right upper quadrant pain, fatigue, anorexia, jaundice, dark urine, fever, itching). If AST or ALT elevations occur any time during treatment, temporarily interrupt sparsentan therapy and monitor as recommended.

Only consider re-initiation of sparsentan after hepatic enzymes and bilirubin have returned to baseline levels and only in patients who have not experienced clinical symptoms of hepatotoxicity.

If AST or ALT >3 times ULN prior to therapy initiation, do not initiate sparsentan therapy.

Only available through a REMS program because of risk of hepatotoxicity. For further information, consult the website ([Web]) or call 833-513-1325.

Fetal/Neonatal Morbidity and Mortality

Can cause fetal harm based on animal findings (see Boxed Warning). Contraindicated in pregnant individuals.

Obtain pregnancy test prior to sparsentan initiation, monthly during treatment, and 1 month after discontinuing sparsentan. Advise females of reproductive potential to use effective contraception prior to sparsentan initiation, during treatment, and for 1 month after discontinuation of sparsentan. Apprise patients of potential hazard to fetus if sparsentan used in pregnancy.

Only available through a REMS program because of the risk of embryo-fetal toxicity. For further information, consult the website ([Web]) or call 833-513-1325.

Other Warnings and Precautions

Hypotension

Hypotension reported.

Consider elimination or adjustment of other antihypertensive drugs and maintaining appropriate volume status in patients at risk for hypotension.

If hypotension occurs despite eliminating or reducing other antihypertensive drugs, consider sparsentan dosage reduction or interruption. Transient hypotension not a contraindication to continuation of sparsentan therapy; may resume sparsentan after stabilization of BP.

Acute Kidney Injury

Acute kidney injury can occur; potential increased risk in patients with renal function that depends in part on activity of the renin-angiotensin system (e.g., patients with renal artery stenosis, chronic kidney disease, severe congestive heart failure, or volume depletion).

Monitor kidney function periodically. Consider withholding or discontinuing sparsentan in patients who develop a clinically significant decrease in kidney function.

Hyperkalemia

Patients with advanced kidney disease or those taking concomitant potassium-increasing agents (e.g., potassium supplements, potassium-sparing diuretics, potassium-containing salt substitutes) at increased risk.

Monitor serum potassium periodically and treat appropriately. If hyperkalemia develops, consider dosage reduction or discontinuation of sparsentan.

Fluid Retention

Fluid retention reported. Sparsentan not studied in patients with heart failure.

If clinically significant fluid retention occurs, determine the underlying cause and the need to initiate or modify diuretic therapy, then consider modifying sparsentan dosage.

Specific Populations

Pregnancy

Can cause fetal harm based on animal data; contraindicated in pregnancy.

Perform pregnancy testing prior to sparsentan initiation, monthly during treatment, and 1 month after discontinuation of the drug. Apprise patients of potential hazard to fetus if sparsentan used during pregnancy.

Lactation

Not known if sparsentan present in human milk. Effects on breast-fed infant and milk production unknown.

Advise patients to avoid breast-feeding during therapy due to the potential for adverse reactions (e.g., hypotension) in the breast-fed infant.

Females and Males of Reproductive Potential

Contraindicated during pregnancy. Negative pregnancy test required prior to sparsentan initiation, monthly during treatment, and 1 month after discontinuing sparsentan. Advise females of reproductive potential to immediately inform their prescriber if menses onset delayed or pregnancy suspected. After a positive pregnancy test, discuss the risks of sparsentan use to the pregnancy and the fetus with the patient.

Females of reproductive potential must use an effective method of contraception prior to sparsentan initiation, during treatment, and for 1 month after discontinuing the drug.

Pediatric Use

Safety and efficacy not established.

Geriatric Use

No overall differences in sparsentan safety or efficacy observed between geriatric patients (≥65 years of age) and younger adults.

Hepatic Impairment

Do not use in patients with any degree of hepatic impairment (Child-Pugh class A, B, or C); potential risk of serious liver injury. No clinically significant differences in sparsentan pharmacokinetics observed in mild to moderate hepatic impairment (Child-Pugh class A or B); sparsentan pharmacokinetics not studied in severe hepatic impairment (Child-Pugh class C).

Renal Impairment

No clinically significant differences in sparsentan pharmacokinetics observed in mild to moderate renal impairment (eGFR 30—89 mL/minute per 1.73 m²); sparsentan pharmacokinetics not studied in severe renal impairment (eGFR <30 mL/minute per 1.73 m²).

Common Adverse Effects

The most common adverse effects (≥5%) are peripheral edema, hypotension (including orthostatic hypotension), dizziness, hyperkalemia, anemia.

Drug Interactions

Inhibits and induces CYP3A in vitro. Induces CYP2B6, CYP2C9, and CYP2C19.

Substrate of CYP3A, P-glycoprotein (P-gp), and breast cancer resistance protein (BCRP) in vitro; nota substrate of organic anion transporter polypeptide (OATP) 1B1 or 1B3.

Inhibits P-gp, BCRP, OATP1B3, and organic anion transporter (OAT) 3 at clinically relevant concentrations; does notinhibit multidrug resistance-associated proteins (MRP), OATP1B1, sodium/taurocholate cotransporting polypeptide (NTCP), organic cation transporter (OCT) 2, OAT1, multidrug and toxin extrusion (MATE) 1, or MATE2K.

Drugs Affecting Hepatic Microsomal Enzymes

Strong CYP3A inhibitors: Possible increased peak plasma concentrations and AUC of sparsentan, and increased incidence of adverse effects. Avoid concomitant use. If concomitant use cannot be avoided, interrupt sparsentan treatment. Upon resumption of sparsentan therapy, consider dosage titration.

Moderate CYP3A inhibitors: No sparsentan dosage adjustment necessary. Monitor BP, serum potassium, edema, and kidney function regularly.

Strong CYP3A inducers: Possible decreased peak plasma concentrations and AUC of sparsentan, resulting in a loss of therapeutic efficacy. Avoid concomitant use.

Drugs Metabolized by Hepatic Microsomal Enzymes

CYP2B6, CYP2C9, or CYP2C19 substrates: Possible decreased exposure and reduced efficacy of the substrate. Monitor for clinical efficacy of the substrate; consider dosage adjustment of the substrate if needed.

Drugs Affected by Transport Systems

Sensitive P-gp and BCRP substrates: Possible increased exposure of the substrate, and increased risk of adverse effects from the substrate. Avoid concomitant use.

Drugs that Increase Serum Potassium

Increased risk of hyperkalemia with concomitant use of sparsentan and agents that increase serum potassium (e.g., potassium-sparing diuretics, potassium supplements, potassium-containing salt substitutes).

Monitor serum potassium levels frequently if used concomitantly.

Specific Drugs

Drug	Interaction	Comments
Antacids	Solubility of sparsentan pH-dependent Concomitant use may reduce exposure and therapeutic efficacy of sparsentan	Administer sparsentan 2 hours before or after antacids
Aliskiren	Potential increased risk of hypotension, syncope, hyperkalemia, and changes in renal function (including acute renal failure)	Concomitant use contraindicated
Bupropion	Decreased peak plasma concentration and AUC of bupropion by 32 and 33%, respectively	Monitor for clinical efficacy of bupropion; consider bupropion dosage adjustment if needed
Cyclosporine	Increased peak plasma concentration and AUC of sparsentan by 41 and 70%, respectively	No dosage adjustment of sparsentan required; monitor BP, serum potassium, edema, and kidney function regularly
Endothelin receptor antagonists	Potential increased risk of hypotension, syncope, hyperkalemia, and changes in renal function (including acute renal failure)	Concomitant use contraindicated
Histamine 2 (H₂) receptor antagonists	Solubility of sparsentan pH-dependent Concomitant use may reduce exposure and therapeutic efficacy of sparsentan	Avoid concomitant use
Itraconazole	Increased peak plasma concentration and AUC of sparsentan by 25 and 174%, respectively	Avoid concomitant use. If concomitant use cannot be avoided, interrupt sparsentan treatment; upon resumption of sparsentan therapy, consider dosage titration of sparsentan
Midazolam	No clinically significant effects on midazolam pharmacokinetics
NSAIAs (including selective COX-2 inhibitors)	Concomitant use may worsen renal function, especially in volume-depleted patients or patients with renal impairment; effects typically reversible	Monitor for signs of worsening renal function
Pitavastatin	No clinically significant effects on pitavastatin pharmacokinetics
Proton pump inhibitors (PPIs)	Solubility of sparsentan pH-dependent Concomitant use may reduce exposure and therapeutic efficacy of sparsentan	Avoid concomitant use
Renin-angiotensin system inhibitors (e.g., angiotensin receptor blockers)	Potential increased risk of hypotension, syncope, hyperkalemia, and changes in renal function (including acute renal failure)	Concomitant use contraindicated
Rifampin	Predicted to decrease peak plasma concentration and AUC of sparsentan by 23 and 47%, respectively, at steady state	Avoid concomitant use

Sparsentan Pharmacokinetics

Absorption

Bioavailability

Peak plasma concentration and AUC increase less than proportionally after administration of single doses of sparsentan 200—1600 mg.

Time-dependent pharmacokinetics (possibly due to sparsentan inducing its own metabolism over time).

Peak plasma concentration achieved approximately 3 hours following oral administration.

Steady-state plasma levels achieved within 7 days; no exposure accumulation.

Food

Administration of sparsentan (single dose of 800 mg) with a high fat, high calorie meal (1000 kcal, 50% from fat) increased sparsentan AUC and peak plasma concentrations by 22 and 108%, respectively.

Administration of sparsentan (single dose of 200 mg) with a high fat, high calorie meal did not affect sparsentan pharmacokinetics to a clinically significant extent.

Special Populations

Pharmacokinetics not affected by age (18—73 years), sex, race, mild to moderate renal impairment (eGFR 30—89 mL/minute per 1.73 m²), or mild to moderate hepatic impairment (Child-Pugh class A or B).

Pharmacokinetics not studied in severe renal impairment (eGFR <30 mL/minute per 1.73 m²) or severe hepatic impairment (Child-Pugh class C).

Distribution

Extent

Not known if distributed into human milk.

Plasma Protein Binding

>99%.

Elimination

Metabolism

Metabolized principally by CYP3A.

Induces own metabolism; clearance time-dependent.

Elimination Route

Eliminated in feces (80% [9% as unchanged drug]) and urine (2% [negligible amount of unchanged drug]).

Half-life

9.6 hours.

Stability

Storage

Oral

Tablets

20—25ºC in original container (excursions permitted between 15—30ºC).

Actions

Antagonist of the endothelin type A receptor (ET_AR) and the angiotensin II type 1 receptor (AT₁R).
Endothelin-1 and angiotensin II thought to contribute to pathogenesis of immunoglobulin A nephropathy via these receptors.
Shows high affinity for both the ET_AR and the AT₁R receptors; shows >500-fold selectivity for these receptors over endothelin type B and angiotensin II subtype 2 receptors.

Advice to Patients

Advise patients to read the FDA-approved patient labeling (Medication Guide).
Inform patients that sparsentan is only available through a restricted access program called Filspari REMS, and that this program requires prescribers to review the contents of the Medication Guide with the patient before initiating sparsentan. Inform patients that sparsentan is available only from certified pharmacies enrolled in the Filspari REMS program. Inform patients that the Filspari REMS Patient Enrollment Form must be signed to confirm that they understand the risks of sparsentan.
Advise patients to take sparsentan with water daily prior to the morning or evening meal, and to maintain the same dosing pattern in relationship to meals. If a dose is missed, instruct patients to take the next dose at the regularly scheduled time; advise patients to not take double or extra doses.
Advise patients to immediately discontinue sparsentan and seek medical attention if symptoms of hepatotoxicity occur (e.g., nausea, vomiting, right upper quadrant pain, fatigue, anorexia, jaundice, dark urine, fever, itching).
Counsel females of reproductive potential to use reliable contraception prior to treatment with sparsentan, during treatment, and for 1 month following discontinuation of the drug. Counsel females of reproductive potential on the use of emergency contraception if unprotected sex or contraceptive failure occurs. Advise patients to contact their clinician or gynecologist if they want to change their form of birth control, in order to ensure that an acceptable form of contraception is selected. Advise patients to seek additional contraceptive advice from a gynecologist or similar expert as needed.
Advise patients of the potential hazard to the fetus if sparsentan is used during pregnancy. Inform females of reproductive potential that a negative pregnancy test is required prior to treatment with sparsentan, monthly during treatment, and 1 month following discontinuation of the drug. Instruct patients to immediately contact their clinician if they suspect they may be pregnant.
Inform patients of the risk of hypotension while taking sparsentan. Advise patients to maintain adequate hydration during sparsentan treatment.
Inform patients of the risk of hyperkalemia while taking sparsentan. Advise patients to avoid using potassium supplements or salt substitutes that contain potassium without prior consultation with their clinician.
Advise patients to inform their clinician of existing or contemplated concomitant therapy (including prescription and OTC drugs and dietary or herbal supplements) and grapefruit, as well as any concomitant illnesses.
Advise women to inform their clinician if they plan to breast-feed. Advise patients to avoid breast-feeding during treatment with sparsentan.
Inform patients of other important precautionary information.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Distribution of sparsentan is restricted. (See REMS under Dosage and Administration)