Version May 2024
Because of the risks of hepatotoxicity and birth defects, sparsentan is available only through a restricted program called the Filspari REMS. Under the REMS, prescribers, patients, and pharmacies must enroll in the program.
Some endothelin receptor antagonists have caused elevations of aminotransferases, hepatotoxicity, and liver failure. In clinical studies, elevations in aminotransferases (ALT or AST) of at least 3 × the ULN have been observed in up to 2.5% of sparsentan-treated patients, including cases confirmed with rechallenge. Measure transaminases and bilirubin before initiating treatment and monthly for the first 12 months, and then every 3 months during treatment. Interrupt treatment and closely monitor patients who develop aminotransferase elevations more than 3 × ULN. Sparsentan should generally be avoided in patients with elevated aminotransferases (>3 × ULN) at baseline because monitoring for hepatotoxicity may be more difficult and these patients may be at increased risk for serious hepatotoxicity.
Sparsentan can cause major birth defects if used by pregnant patients based on animal data. Therefore, pregnancy testing is required before the initiation of treatment, during treatment, and 1 month after discontinuation of treatment with sparsentan. Patients who can become pregnant must use effective contraception before the initiation of treatment, during treatment, and for 1 month after discontinuation of treatment with sparsentan.
IgA nephropathy, primary, nonvariant:
Note: May consider as an alternative nonimmunosuppressive therapy in patients at high risk of chronic kidney disease progression (eg, urine protein-to-creatinine ratio of ≥1.5 g/g) despite receiving optimized therapy (eg, maximally tolerated angiotensin converting enzyme [ACE] inhibitors or angiotensin receptor blockers [ARBs]) for at least 3 to 6 months (Ref). Safety: Prior to initiating therapy, discontinue renin-angiotensin-aldosterone system inhibitors (eg, ACE inhibitors and ARBs), endothelin receptor antagonists, and aliskiren. Consider adjusting or eliminating other medications that may decrease blood pressure in patients at risk for hypotension.
Oral: 200 mg once daily for 14 days, then increase to target dose of 400 mg once daily if tolerated.
Interruption of therapy: Consider restarting at 200 mg once daily after a treatment interruption. After 14 days, increase to target dose of 400 mg once daily if tolerated.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Kidney impairment prior to treatment initiation:
eGFR ≥30 mL/minute/1.73 m2: No dosage adjustments provided in the manufacturer’s labeling; however, need for dosage adjustment unlikely as no clinically significant differences in pharmacokinetics were observed in this population.
eGFR <30 mL/minute/1.73 m2: No dosage adjustments provided in the manufacturer’s labeling (has not been studied).
Acute kidney injury during treatment: Consider withholding or discontinuing in patients who develop a significant decrease in kidney function.
Hepatic impairment prior to treatment: Avoid use in patients with any hepatic impairment (Child-Pugh class A to C) due to the potential risk of serious liver injury.
Aminotransferase elevations during treatment:
ALT or AST >3 times and ≤8 times the ULN:
Confirm elevation with a repeat measure. If confirmed, interrupt treatment and monitor aminotransferase levels and bilirubin at least weekly (INR periodically as needed) until levels return to pretreatment values and patient is asymptomatic. Then may consider reinitiating therapy at 200 mg once daily with close monitoring, with reassessment of hepatic enzyme levels and bilirubin within 3 days.
Do not resume treatment if patient has experienced clinical symptoms of hepatotoxicity or the following occurs with no other identifiable cause:
ALT or AST > 3 times ULN and total bilirubin >2 times ULN or INR >1.5.
ALT or AST >3 times ULN with symptoms of fatigue, nausea, vomiting, right upper quadrant pain/tenderness, fever, rash, and/or eosinophilia (>5% eosinophils).
ALT or AST >5 times ULN for more than 2 weeks.
ALT or AST >8 times the ULN: Permanently discontinue treatment if no other cause for elevation identified.
Fluid retention: Determine underlying cause and evaluate potential need to initiate or modify diuretic treatments prior to reducing the dose of sparsentan.
Hyperkalemia: Reducing sparsentan dose or discontinuing sparsentan therapy may be required.
Hypotension (despite elimination or reduction of other antihypertensives): Consider reducing sparsentan dose or interrupting sparsentan therapy. Can consider reinitiating once BP is stabilized.
Refer to adult dosing.
Acute kidney injury (AKI) has been reported with sparsentan. In one clinical study, AKI was defined by decreases in serum creatinine between outpatient visits and rarely led to sparsentan discontinuation (Ref). Increases in serum creatinine secondary to angiotensin II receptor blockers usually stabilize within 20% to 30% from baseline and are expected; additional increases may indicate renal artery stenosis or volume depletion (Ref).
Mechanism: Related to pharmacologic action; angiotensin II receptor blockade inhibits efferent arteriolar vasoconstriction, lowering glomerular filtration pressure which can lead to a modest reduction in glomerular filtration rate (GFR) (Ref).
Onset: Intermediate; initial reduction in GFR generally occurs within 4 weeks of initiation and then stabilizes.
Risk factors:
• Volume depletion
• Severe congestive heart failure
• Concurrent diuretic, renin-angiotensin system inhibitor, and/or nonsteroidal anti-inflammatory use (Ref)
• Hypotension (Ref)
• Chronic kidney disease
• Patients with low renal blood flow (eg, renal artery stenosis) whose GFR is dependent on efferent arteriolar vasoconstriction by angiotensin II (Ref)
Increased serum alanine aminotransferase (ALT) and increased serum aspartate aminotransferase (AST) have been reported with sparsentan. Increased ALT and AST were ≥3 times the ULN, asymptomatic, and reversible. Although some endothelin receptor antagonists have caused hepatotoxicity and liver failure, there were no reports with sparsentan in clinical trials.
Risk factors:
• Elevated transaminases (>3 times the ULN) at baseline
Hyperkalemia has been reported with sparsentan. Most reported cases of hyperkalemia were mild to moderate and did not require therapy discontinuation (Ref).
Mechanism: Related to pharmacologic action; angiotensin II receptor blockade prevents angiotensin II from binding to the adrenal receptor and interferes with generation of angiotensin II within the adrenal cortex, decreasing aldosterone release and impairing kidney potassium excretion (Ref).
Onset: Generally occurs within 1 week of angiotensin receptor blocker initiation (Ref).
Risk factors:
• Advanced kidney disease
• Baseline elevated potassium (≥5 mmol/L) (Ref)
• Older patients (Ref)
• Diabetes (Ref)
• Concurrent use of medications known to decrease renin and aldosterone (eg, direct renin inhibitors, nonsteroidal anti-inflammatory drugs, cyclosporine, tacrolimus, beta-blockers, sulfamethoxazole/trimethoprim, azole antifungals) (Ref)
• Concomitant use of potassium supplements, potassium-sparing diuretics, and/or potassium-containing salt substitutes
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Adverse reactions reported in adults.
>10%:
Cardiovascular: Hypotension (14%; including orthostatic hypotension), peripheral edema (14%)
Endocrine & metabolic: Hyperkalemia (13%) (table 1)
|
Drug (Sparsentan) |
Comparator (Irbesartan) |
Number of Patients (Sparsentan) |
Number of Patients (Irbesartan) |
|---|---|---|---|
|
13% |
10% |
202 |
202 |
Nervous system: Dizziness (13%)
1% to 10%:
Hematologic & oncologic: Anemia (5%)
Hepatic: Increased serum transaminases (3%; including increased serum alanine aminotransferase and increased serum aspartate aminotransferase >3 × ULN) (table 2)
|
Drug (Sparsentan) |
Comparator (Irbesartan) |
Number of Patients (Sparsentan) |
Number of Patients (Irbesartan) |
Comments |
|---|---|---|---|---|
|
3% |
2% |
202 |
202 |
Including increased serum alanine aminotransferase and increased serum aspartate aminotransferase >3 × ULN |
Renal: Acute kidney injury (4%) (table 3)
|
Drug (Sparsentan) |
Comparator (Irbesartan) |
Number of Patients (Sparsentan) |
Number of Patients (Irbesartan) |
|---|---|---|---|
|
4% |
1% |
202 |
202 |
Pregnancy; coadministration with angiotensin receptor blockers, endothelin receptor antagonists, or aliskiren.
Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, Oral:
Filspari: 200 mg, 400 mg
No
Tablets (Filspari Oral)
200 mg (per each): $427.28
400 mg (per each): $427.28
Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.
Oral: Swallow tablets whole with water prior to morning or evening meal. Maintain the same dosing pattern in relationship to meals.
An FDA-approved patient medication guide, which is available with the product information and at https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/216403s000lbl.pdf#page=22, must be dispensed with this medication.
IgA nephropathy, primary, nonvariant (alternative agent): To reduce proteinuria in adults with primary IgA nephropathy (IgAN) at high risk of chronic kidney disease progression, generally a urine protein-to-creatinine ratio ≥1.5 g/g. Note: Approved under accelerated approval based upon reduction in proteinuria. It has not been established whether sparsentan slows kidney function decline in patients with IgAN.
Substrate of BCRP/ABCG2, CYP3A4 (major), P-glycoprotein/ABCB1 (minor); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential; Induces CYP2B6 (weak)
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Alfuzosin: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Aliskiren: Sparsentan may enhance the adverse/toxic effect of Aliskiren. Risk X: Avoid combination
Amifostine: Blood Pressure Lowering Agents may enhance the hypotensive effect of Amifostine. Management: When used at chemotherapy doses, hold blood pressure lowering medications for 24 hours before amifostine administration. If blood pressure lowering therapy cannot be held, do not administer amifostine. Use caution with radiotherapy doses of amifostine. Risk D: Consider therapy modification
Amisulpride (Oral): May enhance the hypotensive effect of Hypotension-Associated Agents. Risk C: Monitor therapy
Angiotensin II: Receptor Blockers may diminish the therapeutic effect of Angiotensin II. Risk C: Monitor therapy
Angiotensin II Receptor Blockers: Sparsentan may enhance the adverse/toxic effect of Angiotensin II Receptor Blockers. Risk X: Avoid combination
Angiotensin-Converting Enzyme Inhibitors: Sparsentan may enhance the adverse/toxic effect of Angiotensin-Converting Enzyme Inhibitors. Risk X: Avoid combination
Antacids: May decrease the serum concentration of Sparsentan. Management: Administer sparsentan 2 hours before or 2 hours after antacids. Risk D: Consider therapy modification
Antipsychotic Agents (Second Generation [Atypical]): Blood Pressure Lowering Agents may enhance the hypotensive effect of Antipsychotic Agents (Second Generation [Atypical]). Risk C: Monitor therapy
Arginine: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Barbiturates: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
BCRP/ABCG2 Substrates (Clinically Relevant with Inhibitors): Sparsentan may increase the serum concentration of BCRP/ABCG2 Substrates (Clinically Relevant with Inhibitors). Risk X: Avoid combination
Benperidol: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Berotralstat: Sparsentan may increase the serum concentration of Berotralstat. Berotralstat may increase the serum concentration of Sparsentan. Risk X: Avoid combination
Blood Pressure Lowering Agents: May enhance the hypotensive effect of Hypotension-Associated Agents. Risk C: Monitor therapy
Brimonidine (Topical): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Bromperidol: May diminish the hypotensive effect of Blood Pressure Lowering Agents. Blood Pressure Lowering Agents may enhance the hypotensive effect of Bromperidol. Risk X: Avoid combination
BuPROPion: CYP2B6 Inducers (Weak) may decrease the serum concentration of BuPROPion. Risk C: Monitor therapy
Clofazimine: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk C: Monitor therapy
CycloSPORINE (Systemic): Sparsentan may increase the serum concentration of CycloSPORINE (Systemic). CycloSPORINE (Systemic) may increase the serum concentration of Sparsentan. Risk X: Avoid combination
CYP2C9 Substrates (Narrow Therapeutic Index/Sensitive with Inducers): Sparsentan may decrease the serum concentration of CYP2C9 Substrates (Narrow Therapeutic Index/Sensitive with Inducers). Risk C: Monitor therapy
CYP3A4 Inducers (Moderate): May decrease the serum concentration of Sparsentan. Risk C: Monitor therapy
CYP3A4 Inducers (Strong): May decrease the serum concentration of Sparsentan. Risk X: Avoid combination
CYP3A4 Inhibitors (Moderate): May increase the serum concentration of Sparsentan. Risk C: Monitor therapy
CYP3A4 Inhibitors (Strong): May increase the serum concentration of Sparsentan. Risk X: Avoid combination
Dapoxetine: May enhance the orthostatic hypotensive effect of Angiotensin II Receptor Blockers. Risk C: Monitor therapy
Diazoxide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Drospirenone-Containing Products: May enhance the hyperkalemic effect of Angiotensin II Receptor Blockers. Risk C: Monitor therapy
DULoxetine: Blood Pressure Lowering Agents may enhance the hypotensive effect of DULoxetine. Risk C: Monitor therapy
Endothelin Receptor Antagonists: Sparsentan may enhance the adverse/toxic effect of Endothelin Receptor Antagonists. Risk X: Avoid combination
Eplerenone: May enhance the hyperkalemic effect of Angiotensin II Receptor Blockers. Risk C: Monitor therapy
Fexinidazole: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination
Finerenone: Angiotensin II Receptor Blockers may enhance the hyperkalemic effect of Finerenone. Risk C: Monitor therapy
Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination
Heparin: May enhance the hyperkalemic effect of Angiotensin II Receptor Blockers. Risk C: Monitor therapy
Heparins (Low Molecular Weight): May enhance the hyperkalemic effect of Angiotensin II Receptor Blockers. Risk C: Monitor therapy
Herbal Products with Blood Pressure Lowering Effects: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Histamine H2 Receptor Antagonists: May decrease the serum concentration of Sparsentan. Risk X: Avoid combination
Hypotension-Associated Agents: Blood Pressure Lowering Agents may enhance the hypotensive effect of Hypotension-Associated Agents. Risk C: Monitor therapy
Inhibitors of the Proton Pump (PPIs and PCABs): May decrease the serum concentration of Sparsentan. Risk X: Avoid combination
Lefamulin: Sparsentan may increase the serum concentration of Lefamulin. Lefamulin may increase the serum concentration of Sparsentan. Specifically, the use of oral lefamulin may increase sparsentan concentrations. Risk X: Avoid combination
Levodopa-Foslevodopa: Blood Pressure Lowering Agents may enhance the hypotensive effect of Levodopa-Foslevodopa. Risk C: Monitor therapy
Lithium: Angiotensin II Receptor Blockers may increase the serum concentration of Lithium. Management: Initiate lithium at lower doses in patients receiving an angiotensin II receptor blocker (ARB). Consider lithium dose reductions in patients stable on lithium therapy who are initiating an ARB. Monitor lithium concentrations closely when combined. Risk D: Consider therapy modification
Loop Diuretics: May enhance the hypotensive effect of Angiotensin II Receptor Blockers. Loop Diuretics may enhance the nephrotoxic effect of Angiotensin II Receptor Blockers. Risk C: Monitor therapy
Lormetazepam: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Molsidomine: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Naftopidil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Nicergoline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Nicorandil: May enhance the hyperkalemic effect of Angiotensin II Receptor Blockers. Risk C: Monitor therapy
Nicorandil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Nitroprusside: Blood Pressure Lowering Agents may enhance the hypotensive effect of Nitroprusside. Risk C: Monitor therapy
Nonsteroidal Anti-Inflammatory Agents: Angiotensin II Receptor Blockers may enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents. Specifically, the combination may result in a significant decrease in renal function. Nonsteroidal Anti-Inflammatory Agents may diminish the therapeutic effect of Angiotensin II Receptor Blockers. The combination of these two agents may also significantly decrease glomerular filtration and renal function. Risk C: Monitor therapy
Nonsteroidal Anti-Inflammatory Agents (Topical): May diminish the therapeutic effect of Angiotensin II Receptor Blockers. Risk C: Monitor therapy
Obinutuzumab: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Management: Consider temporarily withholding blood pressure lowering medications beginning 12 hours prior to obinutuzumab infusion and continuing until 1 hour after the end of the infusion. Risk D: Consider therapy modification
Pentoxifylline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
P-glycoprotein/ABCB1 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors): Sparsentan may increase the serum concentration of P-glycoprotein/ABCB1 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk X: Avoid combination
Pholcodine: Blood Pressure Lowering Agents may enhance the hypotensive effect of Pholcodine. Risk C: Monitor therapy
Phosphodiesterase 5 Inhibitors: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Polyethylene Glycol-Electrolyte Solution: Angiotensin II Receptor Blockers may enhance the nephrotoxic effect of Polyethylene Glycol-Electrolyte Solution. Risk C: Monitor therapy
Potassium Salts: May enhance the hyperkalemic effect of Angiotensin II Receptor Blockers. Risk C: Monitor therapy
Potassium-Sparing Diuretics: Angiotensin II Receptor Blockers may enhance the hyperkalemic effect of Potassium-Sparing Diuretics. Risk C: Monitor therapy
Prostacyclin Analogues: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Quinagolide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Ranolazine: May enhance the adverse/toxic effect of Angiotensin II Receptor Blockers. Risk C: Monitor therapy
Silodosin: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Sodium Phosphates: Angiotensin II Receptor Blockers may enhance the nephrotoxic effect of Sodium Phosphates. Specifically, the risk of acute phosphate nephropathy may be enhanced. Risk C: Monitor therapy
Tolvaptan: May enhance the hyperkalemic effect of Angiotensin II Receptor Blockers. Risk C: Monitor therapy
Trimethoprim: May enhance the hyperkalemic effect of Angiotensin II Receptor Blockers. Risk C: Monitor therapy
Evaluate pregnancy status prior to use; verify the patient is not pregnant prior to treatment initiation in patients who could become pregnant. A negative pregnancy test is required prior to treatment initiation, monthly during treatment, and 1 month after the last dose of sparsentan in patients who could become pregnant. Additional pregnancy testing is also recommended if menses is delayed or whenever pregnancy is suspected.
Patients who could become pregnant should use effective contraception during therapy and for 1 month after the last sparsentan dose. Options for effective birth control include one of the following (also refer to prescribing information):
Option 1: Copper IUD, levonorgestrel IUD, tubal sterilization, or progesterone implant.
Option 2: Oral estrogen/progestin contraceptive, transdermal estrogen/progesterone patch, vaginal ring, or progesterone injection, and use of a male condom, diaphragm with spermicide or cervical cap with spermicide.
Option 3: Diaphragm with spermicide or cervical cap with spermicide and use of a male condom.
Option 4: Partner’s vasectomy and use of a male condom, diaphragm with spermicide, cervical cap with spermicide, oral estrogen/progestin contraceptive, transdermal estrogen/progesterone patch, vaginal ring, or progesterone injection.
Based on the mechanism of action and data from animal reproduction studies, in utero exposure to sparsentan may cause fetal harm. Use is contraindicated in patients who are pregnant.
It is not known if sparsentan is present in breast milk.
Due to the potential for serious adverse reactions in the breastfed infant (including hypotension), breastfeeding is not recommended by the manufacturer.
Periodically monitor BP, serum creatinine, serum potassium, signs and symptoms of fluid retention or hepatotoxicity (eg, nausea, vomiting, right upper quadrant pain/tenderness, fatigue, anorexia, jaundice, dark urine, fever, itching).
ALT, AST, and bilirubin: Prior to treatment initiation (do not initiate treatment in patients with ALT or AST >3 times the ULN), monthly for the first 12 months after initiation or restarting after treatment interruption for aminotransferase elevations, and every 3 months thereafter.
Pregnancy testing (in patients who can become pregnant): A negative pregnancy test is required prior to treatment initiation, monthly during treatment, and 1 month after the last dose of sparsentan. Additional pregnancy testing is also recommended if menses is delayed or whenever pregnancy is suspected.
Sparsentan is an endothelin type A receptor (ETAR) and angiotensin II type 1 receptor (AT1R) antagonist. Endothelin-1 and angiotensin II are thought to contribute to the pathogenesis of immunoglobulin A nephropathy (IgAN) via these receptors, and sparsentan has a high affinity for them, with a greater than 500-fold selectivity over the endothelin type B and angiotensin II subtype 2 receptors.
Distribution: Vdss: 61.4 L.
Protein binding: >99%.
Metabolism: Cytochrome P450 3A.
Half-life elimination: 9.6 hours.
Time to peak: ~3 hours (range: 2 to 8 hours).
Excretion: Feces: ~80% (9% as unchanged drug); Urine: 2%.
Clearance (steady state): 5.11 L/hour.
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