FILSPARI (Sparsentan): Indications, Dose, MOA, Side effects

Brand Name: Filspari

Drug Name: Sparsentan

Drug Class: Dual endothelin and angiotensin II receptor blocker

FDA Approval: 17th Feb 2023 [Ref]

Primary Indications: Ig A Nephropathy

FILSPARI (Sparsentan) is a new kind of medicine that blocks both endothelin receptors and angiotensin receptors.

It has been approved by the FDA for the treatment of patients with IgA nephropathy, also called Berger’s disease.

It is only indicated in high-risk individuals who have a urine protein to creatinine ratio of 1.5 g/g or more.

The drug has been granted accelerated approval by the FDA for its anti-proteinuric effects but whether it slows the progression to ESRD or advanced kidney disease is not yet clear.

Important Safety Information for FILSPARI:

FILSPARI is associated with an increased risk of liver injury and birth defects. Strict monitoring is recommended.

Hepatotoxicity

• The drug has been associated with liver injury in about 2.5% of the study population.
• Monitoring at monthly intervals is recommended during the first 12 months and every 3 months thereafter.
• The treatment may be stopped or the dose reduced in patients whose LFTs start getting deranged.

Birth defects:

The drug is contraindicated in pregnant women and nursing mothers. A pregnancy test is recommended before initiating the treatment and at monthly intervals thereafter. In addition, women should be advised about effective contraception.

Filspari REMS program:

Filspari is only available to patients who have been enrolled in the REMS program. It is to be prescribed by physicians who have received training about Filspari and have been certified.

Pharmacies can only dispense the drug to enrolled patients.

FILSPARI (Sparsentan) Dosing Recommendations:

Before prescribing FILSPARI (Sparsentan), it is important to stop all drugs that act on the Renin-Angiotensin-Aldosterone Pathway and endothelin receptors. These include:

• RAAS inhibitors (ACE-I, ARBs, MRA),
• ERAs (endothelin receptor antagonists such as Bosentan and ambrisentan), and
• Renin-inhibitors like Aliskiren

In addition, monitor LFTs before prescribing the drug. If ALT at baseline is more than 3 times the ULN, do not prescribe FILSPARI (Sparsentan).

Once you start the patient on Sparsentan, check LFTs every 3 months. However, if the patient develops transaminitis during the treatment, withhold the treatment. Check LFTs every month for the first year on re-initiation of the treatment.

Also, perform pregnancy testing in females before the start of treatment and monthly thereafter.

Recommended Dose of FILSPARI (Sparsentan):

• The recommended starting dose is 200 mg orally once daily.
• If the drug is tolerated, the dose is then increased to 400 mg orally once daily after two weeks.
• If due to some reasons (or because of side effects or hepatotoxicity) the treatment is interrupted, restart the treatment at a low dose of 200 mg once daily and then increase the dose after 14 days.

How to take FILSPARI Tablets?

• Swallow the tablets whole with a glass of water before dinner or before breakfast. Do not chew or crush the tablets.
• If you are taking it before dinner, take it daily at the same time. Do not switch the morning dose to the evening and vice versa.
• In case, a dose is missed, do not take two doses to make up for the missed doses. Wait for the scheduled time of the next dose.

Dosage Adjustment and Monitoring Recommendations

• In case of hepatotoxicity, repeat the test to confirm it especially if the levels are 3 to 8 times the ULN.
• If on repeat testing, the liver enzymes are still deranged, stop the treatment and then monitor at weekly intervals until the LFTs come down to normal baseline values. Also, monitor INR if needed.
• If the ALT is more than 3 times the ULN, the INR is more than 1.5 and the total bilirubin is more than 2  times the ULN, do not restart the treatment.
• It is not recommended to restart the treatment in patients who have isolated raised ALT of more than 3 times the ULN but the patient has liver-related symptoms such as fatigue, nausea, vomiting, right upper abdominal pain, and eosinophilia exceeding 5%.
• In addition, those patients who have persistently elevated ALT of more than 5 times the ULN for more than 2 weeks, should avoid taking the drug.
• Treatment should be reinitiated at low doses of 200 mg per day. Check LFTs after 3 days and then frequently.

FILSPARI (Sparsentan) Contraindications:

• Avoid in pregnant patients and patients using angiotensin receptor blockers (ARBs), ERAs, or aliskiren.

Warning and Precautions:

• Hepatotoxicity:

Hepatotoxicity is one of the common side effects of Filspari. It has been observed in up to 2.5% of the study patients.

LFTs should be checked at monthly intervals for the first year of treatment and then every three months thereafter.

Patients should be asked to report symptoms of hepatotoxicity such as upper abdominal pain, nausea, and vomiting.

• FILSPARI REMS:

The drug is only available via the REMS program called FILSPARI REMS. In this program, the prescribers must be certified with the REMS program after they are trained. All patients must enroll in the program so that adverse events are monitored.

In addition, the drug must be dispensed only to authorized patients by pharmacies that are enrolled in the Filspari REMS program.

• Hypotension:

Hypotension is an expected side effect of the drug as it blocks the angiotensin receptors as well. It is recommended to reduce the dose of concomitant antihypertensive.

If despite reducing the dose of antihypertensive, hypotension persists, reduce the dose of Filspari. In rare cases, treatment may need to be withheld.

• Acute Kidney Injury

Renal functions should be monitored frequently as there is an increased risk of acute kidney injury.

Conditions that increase the risk of AKI include:

• Renal artery stenosis,
• Chronic kidney disease,
• Congestive heart failure, or
• Dehydrated patients.

The treatment may need to be discontinued in such cases or in mild cases, the dose may need to be reduced.

• Hyperkalemia

Like all ARBs and ACE-Inhibitors, there is an increased risk of hyperkalemia. Serum potassium should be periodically monitored.

The risk of hyperkalemia is especially increased if concomitant medications are given along with Sparsentan that cause hyperkalemia in patients with advanced kidney disease.

It is better to monitor and reduce the dose of Sparsentan in such cases.

• Fluid Retention

Fluid retention is one of the side effects of Sparsentan as it inhibits the endothelin receptors. There is an increased risk of fluid overload especially in patients with a compromised heart.

Patients may need to be given diuretics. If the patient is already on a diuretic, the dose may need to be increased if edema is noted.

Rarely, the dose of Sparsentan may be reduced if symptoms of heart failure develop.

FILSPARI (Sparsentan) Side Effects:

The side effects are summarized with their frequencies in the table below:

Note that the frequency categories are defined as follows:

• Common side effects: ≥1% and <10%.
• Uncommon side effects: ≥0.1% and <1%.
• Rare: <0.1%.

Safety of FILSPARI in Clinical Trials:

The safety of FILSPARI was evaluated in a randomized, double-blind, active-controlled clinical study called PROTECT (NCT03762850) [Ref]

The study involved 202 adults with IgAN who were exposed to FILSPARI for a median duration of 73 weeks (up to 110 weeks).

The following adverse reactions were reported in 2% or more of patients treated with FILSPARI:

• Edema
• Low blood pressure (including orthostatic hypotension)
• Blackouts
• High potassium
• Anemia
• Acute kidney injury
• Transaminase elevations

Effect of Sparsentan on eGFR and hemoglobin:

• Patients who begin FILSPARI therapy may experience a small initial decrease in their estimated glomerular filtration rate (eGFR), but this decrease stabilizes within four weeks of treatment.
• In addition, a drop in hemoglobin levels of more than 2 g/dL was observed in 11% of the patients in the Sparsentan group compared to 5% in the Irbesartan group.

FILSPARI (Sparsentan) Drug Interactions:

Use in Pregnancy and Lactation:

Use in pregnant and lactating women is contraindicated. A pregnancy test is recommended before treatment initiation, monthly during the treatment, and one month after treatment discontinuation.

Women should use effective forms of contraception to avoid getting pregnant while on treatment.

Use in Children:

• Use in children is not recommended because of limited data.

How to manage Filspari Overdose:

There is limited data on humans, however, up to a dose of 1600 mg has been used in healthy people.

Possible effects of Overdose:

• May cause hyperkalemia, hepatitis, and hypotension.

Standard Supportive Measures

• Manage the patients supportively, keep them hydrated, monitor electrolytes, and test for hepatotoxicity.
• Since Sparsentan is highly protein bound, it is not removed from the body by dialysis.

Mechanism of Action of Sparsentan:

Sparsentan is highly selective for endothelin type A receptor (ETAR) and angiotensin II type 1 receptor (AT1R) compared to endothelin type B and angiotensin II subtype 2 receptors.

It inhibits both the endothelin and angiotensin II receptors which are primarily involved in the pathogenesis of IgA nephropathy.

Effect on QTc prolongation: Mild QTc prolongation can occur (however, no clinically significant QTc prolongation has been observed when the drug is given at the recommended dose).

Pharmacokinetics:

Patient Counseling for FILSPARI:

• Advise patients to read the FDA prescribing information leaflet.
• FILSPARI is only available through a restricted access program known as FILSPARI REMS.
• Patients must be warned of the possible side effects such as hepatotoxic effects, fetal toxicity, and effects of the drug on electrolytes (hyperkalemia) and blood pressure (hypotension).
• Patients must inform their prescribers about all the drugs they are taking including OTC and herbal medicines.
• Breastfeeding is not recommended and pregnancy should be strictly avoided.
• The drug should be taken before the morning or evening meal with a glass of water. Overdosing should be avoided.