sparsentan

Sparsentan is a new drug approved by the FDA in February, 2023, to reduce protein excretion in urine (proteinuria) in adults with primary immunoglobulin A nephropathy (IgAN) who are at risk for disease progression. Currently, sparsentan is the only approved drug in a novel class of drugs known as dual endothelin angiotensin receptor antagonists (DEARAs), the first non-immunosuppressive therapy for reducing proteinuria in IgAN (also known as Berger disease).

Immunoglobulin A nephropathy is a progressive kidney disease caused by a buildup of immunoglobulin A (IgA) deposits that inflame and scar the kidney. IgA is an antibody produced by the body to fight infections. In IgAN, IgA deposits in kidney damage glomeruli, the tiny functioning kidney units with looping blood vessels that filter wastes, which results in leakage of blood and protein in the urine and progressive loss of kidney function.

Sparsentan helps reduce the leakage of protein in urine by blocking the activity of endothelin-1 and angiotensin-II. Endothelin-1 is a protein particle (peptide) secreted by endothelial cells that form the inner lining of blood vessels. Endothelin-1 makes blood vessels constrict, raising the blood pressure. Angiotensin II is a peptide hormone that increases blood pressure and induces water and sodium retention in the kidneys.

Endothelin-1 and angiotensin-II are believed to contribute to inflammation and disease progression in IgA nephropathy by stimulating endothelin 1A receptors (ETAR) and angiotensin II type 1 (AT1R) receptors respectively, in the kidneys and vascular smooth muscles. Sparsentan selectively blocks endothelin 1A receptors (ETAR) and angiotensin II type 1 (AT1R) receptors, preventing their stimulation and reducing inflammation and proteinuria.

Sparsentan was developed by merging the structural elements of irbesartan, an angiotensin II antagonist, and biphenylsulfonamide, an endothelin-1 antagonist. Sparsentan was initially developed to treat hypertension, however, it was shown to be effective in reducing proteinuria in IgA nephropathy and was granted accelerated approval by the FDA. It has not been established, however, if sparsentan also slows down decline of kidney function in IgAN patients.

• Do not use sparsentan in pregnant women. Advise nursing mothers to discontinue breastfeeding while on treatment with sparsentan.
• Do not use sparsentan concurrently with the following medications:
  • Renin-angiotensin-aldosterone system (RAAS) inhibitors
  • Angiotensin receptor blockers (ARBs)
  • Endothelin receptor antagonists (ERAs)
  • Aliskiren, an antihypertensive drug
• Sparsentan is toxic to the liver and causes elevation in serum transaminase levels. The risk of liver toxicity is higher in patients with elevated levels at baseline.
  • Evaluate the levels of ALT, AST and bilirubin before initiating treatment, and monitor every month for the first 12 months and once in 3 months thereafter.
  • Avoid initiating sparsentan in patients with already elevated levels.
  • Interrupt sparsentan in patients with signs of liver toxicity and withhold treatment until transaminase levels return to pretreatment levels. Do not resume treatment in patients with clinical symptoms of hepatotoxicity.
  • Advise patients to discontinue sparsentan and report immediately if they experience symptoms of hepatotoxicity.
• Sparsentan can cause fetal harm. Screen women for pregnancy before initiation of treatment and advise women of reproductive potential of the risk to the fetus and to use effective contraception before treatment initiation, during treatment and for 1 month after discontinuation.
• Sparsentan can lower blood pressure and the risk is higher if it is used concomitantly with other drugs that can reduce blood pressure such as ARBs and ERAs. Monitor patients at risk for hypotension, and consider adjusting or eliminating other antihypertensive drugs. If hypotension is not resolved, reduce sparsentan dose or interrupt treatment until blood pressure stabilizes.
• Sparsentan can cause acute kidney injury. Monitor kidney function periodically and consider interrupting or discontinuing treatment in patients who develop a clinically significant impairment in kidney function.
• Sparsentan can cause fluid retention. The safety of sparsentan use in heart failure has not been evaluated. If a patient develops signs of fluid retention, evaluate and determine the cause, initiate or modify diuretic dose, and if necessary, consider modifying sparsentan dose.
• Sparsentan may increase blood potassium levels (hyperkalemia). Patients with advanced kidney disease and those taking potassium containing or potassium increasing drugs are at a greater risk for hyperkalemia. Monitor potassium levels and adjust dosage or discontinue sparsentan, if required.
• Sparsentan is available only through a restricted program called the Filspari REMS because of the risks of liver toxicity and birth defects. Prescribers, patients, and pharmacies must enroll in the Risk Evaluation and Mitigation Strategies (REMS) program.

Common side effects of sparsentan include:

• Swelling of extremities (peripheral edema)
• Low blood pressure (hypotension)
• Drop in blood pressure when standing up from sitting or lying down (orthostatic hypotension)
• Dizziness
• High blood potassium (hyperkalemia)
• Anemia
• Acute kidney injury
• Elevation of liver enzymes (transaminases)

Call your doctor immediately if you experience any of the following symptoms or serious side effects while using this drug:

• Serious heart symptoms include fast or pounding heartbeats, fluttering in your chest, shortness of breath, and sudden dizziness;
• Severe headache, confusion, slurred speech, severe weakness, vomiting, loss of coordination, feeling unsteady;
• Severe nervous system reaction with very stiff muscles, high fever, sweating, confusion, fast or uneven heartbeats, tremors, and feeling like you might pass out; or
• Serious eye symptoms include blurred vision, tunnel vision, eye pain or swelling, or seeing halos around lights.

This is not a complete list of all side effects or adverse reactions that may occur from the use of this drug. Call your doctor for medical advice about serious side effects or adverse reactions. You may also report side effects or health problems to the FDA at 1-800-FDA-1088.

Tablet

• 200 mg
• 400 mg

Adult:

IgA Nephropathy

• Indicated to reduce proteinuria in adults with primary immunoglobulin A nephropathy (IgAN; also known as Berger disease) at risk of rapid disease progression, generally a urine protein-to-creatinine ratio (UPCR) 1.5 g/g or higher
• 200 mg orally every day initially; after 14 days, increase to recommended dose of 400 mg every day, as tolerated
• When resuming treatment after an interruption, consider starting at 200 mg/day, then after 14 days, increase to 400 mg/day

Dosage Modifications

ALT/AST above 3 times up to 8 times upper limit of normal (ULN)

• Confirm elevation with repeat measure
• If confirmed, interrupt treatment, and monitor ALT/AST levels and bilirubin at least weekly, and INR as needed, until 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/AST above 3 times ULN and total bilirubin above 2 times ULN or international normalized ratio (INR) above 1.5
  • ALT/AST above 3 times ULN, with symptoms of fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, and/or eosinophilia (over 5% eosinophils)
  • ALT/AST above 5 times ULN for longer than 2 weeks
• If treatment resumed, initiate at 200 mg every day, with reassessment of hepatic enzyme levels and bilirubin within 3 days; close monitoring required in these patients

ALT/AST above 8 times ULN

• Permanently discontinue if no other cause found

Coadministration of strong CYP3A4 inhibitors

• Avoid coadministration
• If use is unavoidable, interrupt sparsentan

Renal impairment

• Mild-to-moderate (eGFR 30-89 mL/min/1.73 m2): No clinically significant differences in pharmacokinetics observed
• Severe (eGFR below 30 mL/min/1.73 m2): Not studied

Hepatic impairment

• Mild, moderate, or severe (Child-Pugh A-C): Avoid use with any hepatic impairment because of risk of serious liver injury

Dosing Considerations

Before initiating

• Verify females of reproductive potential are not pregnant and are using effect contraception
• Measure ALT, AST, and bilirubin; avoid initiating if above 3 times ULN
• Discontinue use of renin-angiotensin-aldosterone system (RAAS) inhibitors, endothelin receptor antagonists (ERAs), and aliskiren

Monitoring

• Monitor ALT, AST, and bilirubin before initiating, monthly for first 12 months, and then every 3 months during treatment
• Verify females of reproductive potential are not pregnant monthly during treatment and 1 month after discontinuing drug

Pediatric:

Safety and efficacy not established

Overdose

There is no experience with sparsentan overdose. Sparsentan doses of up to 1600 mg/day in healthy volunteers and 400 mg/day in patients have been administered. Overdose of sparsentan may lower blood pressure. Overdose may be treated with supportive care.

Inform your doctor of all medications you are currently taking, who can advise you on any possible drug interactions. Never begin taking, suddenly discontinue, or change the dosage of any medication without your doctor’s recommendation.

• Severe interactions of sparsentan include:
  • aliskiren
  • ambrisentan
  • aprocitentan
  • azilsartan
  • bosentan
  • candesartan
  • eprosartan
  • irbesartan
  • losartan
  • macitentan
  • olmesartan
  • sacubitril/valsartan
  • telmisartan
  • valsartan
• Sparsentan has serious interactions with at least 50 different drugs.
• Sparsentan has moderate interactions with at least 154 different drugs.
• Sparsentan has no known mild interactions with other drugs.

The drug interactions listed above are not all of the possible interactions or adverse effects. For more information on drug interactions, visit the RxList Drug Interaction Checker.

It is important to always tell your doctor, pharmacist, or health care provider of all prescription and over-the-counter medications you use, as well as the dosage for each, and keep a list of the information. Check with your doctor or health care provider if you have any questions about the medication.

• Do not administer sparsentan to pregnant women. Animal studies show sparsentan can cause fetal harm including birth defects and loss of pregnancy.
• Women of pregnancy potential must use effective contraception before initiation of treatment with sparsentan, during treatment and for one month after discontinuation.
• There is no information on the presence of sparsentan in breastmilk, and its effects on milk production or the breastfed infant. Do not breastfeed while on treatment with sparsentan because of the potential for serious adverse reactions in the breastfed infant, including low blood pressure (hypotension).

• Take sparsentan exactly as prescribed.
• Sparsentan is available only through a restricted program called the FILSPARI REMS. You will be required to enroll in the FILSPARI REMS program prior to initiation of treatment and must comply with monitoring requirements.
• You will need periodic blood tests, follow up with your physician and do not miss your appointments.
• Discontinue sparsentan and report to your physician immediately if you develop symptoms of liver toxicity such as nausea, vomiting, right upper quadrant pain, fatigue, loss of appetite (anorexia), jaundice, dark urine, fever, or itching.
• Store sparsentan safely out of reach of children.
• In case of overdose, seek medical help or contact Poison Control.