司帕生坦(Sparsentan)详细说明书

Sparsentan is a dual-receptor antagonist developed by TravereTherapeutics. It works by simultaneously blocking endothelin type A (ETA) and angiotensin type II1 (AT1) receptors. The drug received accelerated approval from the FDA to reduce proteinuria in patients with IgA nephropathy in February 2023, and was upgraded to full approval in May 2024, becoming the first targeted therapy drug approved to delay the deterioration of renal function in adult patients with primary IgA nephropathy.

1. Indications

IgA nephropathy

Sparsentan is suitable for slowing down the decline in renal function in adults with primary immunoglobulin A nephropathy (IgAN) who are at risk of disease progression.

2. Usage and dosage

1. Recommended dose

The initial dose of sparsentan treatment is 200 mg orally once a day. If well tolerated, it can be increased to the recommended dose of 400 mg once a day after 14 days; when treatment is resumed after interruption, it needs to be re-titrated from 200 mg once a day, and increased again to 400 mg once a day after 14 days.

2. Dosage management

Swallow the entire tablet of Sparsentan with water before breakfast or dinner. If a dose is missed, take the next dose at the regularly scheduled time. Do not take double or extra doses.

Due to limited space, please refer to the original instructions of the drug for details. Please follow the guidance of your doctor for specific medication.

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3. Dose adjustment

Dose adjustment for elevated transaminases

(1) ALT or AST>3 times the upper limit of normal (ULN), and total bilirubin>2 times ULN or INR>1.5.

(2) ALT or AST>3 times ULN, accompanied by symptoms such as fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%).

(3) ALT or AST>5 times ULN for more than two weeks.

(4) If treatment needs to be restarted, FILSPARI should be started at 200 mg once daily, and liver enzyme levels and bilirubin values ​​should be re-evaluated within 3 days. Such patients need to be closely monitored.

(5) ALT or AST> 8 times ULN, if no other reasons are found, please permanently stop sparsentan treatment.

(6) Do not resume treatment in patients who have clinical symptoms of hepatotoxicity or whose liver enzyme levels and bilirubin have not returned to pre-treatment levels.

IV. Dosage forms and specifications

The 200mg tablets are film-coated, modified oval, white to off-white, with "105" embossed on one side and "105" on the other side, 30 tablets in a bottle, with child safety cap.

The 400 mg tablets are film-coated, modified oval, white to off-white, embossed with "021" on one side and "021" on the other side, 30 tablets per bottle, with child safety cap.

5. Contraindications

1. Sparsentan is contraindicated in pregnant patients.

2. Do not combine sparsentan with ARB, ERA or aliskiren.

VI. Adverse reactions

Adverse reactions (≥5%)

The most common adverse reactions of sparsentan are hyperkalemia, hypotension (including orthostatic hypotension), peripheral edema, dizziness, anemia and acute kidney injury.

Due to limited space, please refer to the original instructions of the drug for details. Please follow the guidance of your doctor for specific medication.

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7. Precautions

1. Embryo-fetal toxicity

Sparsentan can cause harm to the fetus when taken by pregnant women and is contraindicated during pregnancy. Inform potentially pregnant patients of the potential risk to the fetus. Perform a pregnancy test before starting treatment with sparsentan, monthly during treatment, and one month after stopping treatment. Advise patients who may become pregnant to use effective contraception before initiating treatment, during treatment, and for one month after stopping treatment with sparsentan.

2. Hypotension

Hypotension has been observed in patients receiving ARBs and endothelin receptor antagonists. Patients treated with sparsentan had a higher incidence of hypotension-related adverse events compared with irbesartan, some of which were serious and included dizziness. In patients at risk for hypotension, consider discontinuing or adjusting other antihypertensive medications and maintaining appropriate volume status. If hypotension occurs despite elimination or reduction of other antihypertensive agents, consider a dose reduction or interruption of the dose of spaxentan. Transient hypotensive reactions are not a contraindication to further administration of sparsentan, which can be administered once blood pressure has stabilized.

3. Acute kidney injury

Monitor kidney function regularly. Drugs that inhibit the renin-angiotensin system (RAS) can cause kidney damage. Patients whose renal function may depend in part on RAS activity (e.g., patients with renal artery stenosis, chronic kidney disease, severe congestive heart failure, or volume depletion) may be particularly at risk for acute kidney injury while using spaxentan. Consider discontinuing or discontinuing treatment in patients who experience a clinically significant decrease in renal function while taking sparsentan.

4. Hyperkalemia

Regularly monitor serum potassium and treat appropriately. Patients with end-stage renal disease, who are concurrently taking potassium-increasing medications (e.g., potassium supplements, potassium-sparing diuretics), or who use potassium-containing salt substitutes are at increased risk for developing hyperkalemia. A dose reduction or discontinuation of sparsentan may be necessary.

5. Fluid retention

Endothelin receptor antagonists may cause fluid retention, and this has been observed in clinical studies of sparsentan. Sparsentan has not been evaluated in patients with heart failure. If clinically significant fluid retention occurs, the patient should be evaluated to determine the cause and the need to initiate or change the dose of diuretic therapy, and then consider adjusting the dose of sparsentan.

8. Medication for Special Populations

1. Pregnancy

Sparsentan has a clear risk of fetal toxicity. Animal reproduction studies have shown that when administered to pregnant rats at 10 times the maximum recommended human dose (MRHD), it can cause teratogenic effects such as craniofacial malformations, skeletal abnormalities, embryonic death and fetal development retardation. Existing clinical data are not sufficient to assess the specific risks of drug use during human pregnancy. Therefore, pregnant women are strictly prohibited from using this drug, and patients of childbearing age need to be fully informed of its potential teratogenic hazards.

2. Lactation period

There are no data on the presence of sparsentan in breast milk, its effects on breastfed infants, or its effects on milk production. Because breastfed infants may experience adverse reactions such as hypotension, patients are advised not to breastfeed during treatment with sparsentan.

3. People with reproductive potential

Sparsentan is contraindicated in pregnant women. Animal reproduction studies have confirmed that it can cause fetal birth defects or death. Patients of childbearing age must confirm that they are not pregnant before treatment, every month during treatment and 1 month after stopping the drug. If menstruation is delayed or pregnancy is suspected, the risk must be tested immediately and the risk assessed. At the same time, high-efficiency contraceptive measures must be continued from before treatment to 1 month after stopping the drug.

4. Pediatric patients

The safety and effectiveness of sparsentan in pediatric patients have not been determined.

5. Elderly patients

Among the total number of subjects in the PROTECT study of sparsentan, 15 (7.4%) were aged 65 and above. No overall differences in safety or efficacy were observed between these subjects and younger subjects.

6. Hepatic Impairment

Avoid using sparsentan in patients with any hepatic impairment (Child-Pugh A-C) due to the potential risk of severe liver injury.

9. Drug interactions

1. Renin-angiotensin system inhibitors and endothelin receptor antagonists

Do not combine Spartansen with angiotensin II receptor blockers (ARBs), endothelin receptor antagonists (ERAs) or aliskiren. Use of these drugs together may increase the risk of hypotension, syncope, hyperkalemia, and changes in renal function (including acute renal failure).

2. Strong and moderate CYP3A inhibitors

Avoid coadministration of spartamex with strong CYP3A inhibitors. If use of a strong CYP3A inhibitor cannot be avoided, treatment with spartansan should be interrupted. Dosage titration needs to be considered when reinitiating treatment with spartamex. Blood pressure, serum potassium, edema, and renal function should be monitored regularly when spartamex is used concomitantly with a moderate CYP3A inhibitor. No dose adjustment of Spartansen is required at this time. Spartamin is a CYP3A substrate. When combined with strong CYP3A inhibitors, the peak plasma concentration (Cmax) and area under the drug-time curve (AUC) of Spartansan will increase, which may increase the risk of adverse reactions of Spartansan.

3. Strong CYP3A inducers

Avoid the simultaneous use of Spartamex and strong CYP3A inducers. Spartamin is a CYP3A substrate. When combined with strong CYP3A inducers, the peak plasma concentration (Cmax) and area under the drug-time curve (AUC) of Spartansen will be reduced, which may reduce the efficacy of Spartansen.

4. Antacids and acid-suppressing agents

Spartamex should be taken 2 hours before or 2 hours after taking antacids. Avoid concurrent use of spartamex with acid-suppressing agents (histamine H2 receptor antagonists and proton pump inhibitors). The solubility of Spartamin is pH dependent. Antacids or acid-suppressants may decrease the exposure of spartansen and may reduce the efficacy of spartansen.

5. Non-steroidal anti-inflammatory drugs

When spartansan is used concomitantly with non-steroidal anti-inflammatory drugs (including selective cyclooxygenase-2 inhibitors), patients should be monitored for signs of worsening renal function. In patients who are volume-depleted (including those on diuretic therapy) or with compromised renal function, the concomitant use of NSAIDs, including selective cyclooxygenase-2 inhibitors, with drugs that antagonize angiotensin II receptors may result in worsening of renal function, including possible renal failure. These effects are usually reversible.

6. CYP2B6, 2C9 and 2C19 substrates

When Spartansan is used in combination with CYP2B6, 2C9 and 2C19 substrates, the efficacy of these substrates should be monitored and their dosage should be considered based on the prescribing information. Spartansan is an inducer of CYP2B6, 2C9 and 2C19. Spartansen decreases the exposure of these substrates, which may reduce the efficacy of these substrates.

7. Substrates for P-glycoprotein and breast cancer resistance protein

Avoid using Spartansin simultaneously with sensitive substrates for P-glycoprotein and breast cancer resistance protein. Spartansan is an inhibitor of P-glycoprotein and breast cancer resistance protein. Spartansen may increase the exposure of these transporter substrates, which may increase the risk of adverse reactions associated with these substrates.

8. Drugs that increase serum potassium

Serum potassium should be monitored frequently in patients receiving spartamex and other drugs that increase serum potassium. Concomitant use of spartamex with potassium-sparing diuretics, potassium supplements, potassium-containing salt substitutes, or other drugs that increase serum potassium levels may result in hyperkalemia.

10. Treatment of drug overdose

There is no experience in overdose of spasentan. Sparsentan has been administered at doses up to 1600 mg/day in healthy volunteers or up to 400 mg/day in patients with IgAN. Overdose of sparsentan may cause a drop in blood pressure. In case of overdose, standard supportive measures should be instituted as needed. Dialysis is unlikely to be effective because sparsentan is highly protein-bound.

11. Validity period

24 months.

12. Storage Conditions

Sparsentan is stored at 20°C to 25°C (68°F to 77°F), with an allowed excursion to 15°C to 30°C (59°F to 86°F). Store spasentan in its original container.

13. Pharmacokinetics

1. Absorption

After a single oral administration of 400 mg of spasentan, the median (shortest to maximum) time to reach peak plasma concentration is approximately 3 hours (2 to 8 hours).

2. Distribution

At the approved recommended dose, the apparent volume of distribution at steady state is 61.4L. Sparsentan is >99% bound to human plasma proteins.

3. Elimination

The clearance of spasentan is time-dependent, which may be related to the drug inducing its own metabolism over time. The apparent clearance (CL/F) of Leprodan was 3.88 L/h after the initial 400 mg dose and then increased to 5.11 L/h at steady state. The half-life of sparsentan at steady state is estimated to be 9.6 hours.

4. Metabolism

Cytochrome P4503A is the main isoenzyme responsible for the metabolism of spartan.

5. Excretion

After a single dose of 400 mg of radiolabeled spasentan in healthy subjects, approximately 80% of the dose was recovered in the feces (9% unchanged) and 2% was recovered in the urine (the amount was negligible). 82% of the dosed radioactivity was recovered within the 10-day collection period.