DRUG INTERACTIONS-(Details)

1. Renin-Angiotensin System (RAS) Inhibitors and ERAs -                                      Do not coadminister FILSPARI with ARBs, ERAs, or aliskiren.

Combined use of these agents is associated with increased risks of hypotension, syncope, hyperkalemia, and changes in renal function (including acute renal failure).

2.. Strong and Moderate CYP3A Inhibitors-                                                                   Avoid concomitant use of FILSPARI with strong CYP3A inhibitors. If a strong CYP3A inhibitor cannot be avoided, interrupt treatment with FILSPARI. When resuming treatment with FILSPARI, consider dose titration.

Monitor blood pressure, serum potassium, edema, and kidney function regularly when used concomitantly with moderate CYP3A inhibitors.

 No FILSPARI dose adjustment is needed. Sparsentan is a CYP3A substrate. Concomitant use with a strong CYP3A inhibitor increases sparsentan Cmax and AUC , which may increase the risk of FILSPARI adverse reactions.

3.Strong CYP3A- Avoid concomitant use with a strong CYP3A inducer. Sparsentan is a CYP3A substrate. Concomitant use with a strong CYP3A inducer decreases sparsentan Cmax and AUC, which may reduce FILSPARI efficacy.

4. Antacids and Acid Reducing Agents-                                                                   Administer FILSPARI 2 hours before or after administration of antacids. Avoid concomitant use of acid reducing agents (histamine H2 receptor antagonist and PPI proton pump inhibitor) with FILSPARI. Sparsentan exhibits pH-dependent solubility. Antacids or acid reducing agents may decrease sparsentan exposure which may reduce FILSPARI efficacy.

5. Non-Steroidal Anti-Inflammatory Agents (NSAIDs), Including Selective Cyclooxygenase-2 (COX-2) Inhibitors-                                                                     Monitor for signs of worsening renal function with concomitant use with NSAIDs (including selective COX-2 inhibitors). In patients with volume depletion (including those on diuretic therapy) or with impaired kidney function, concomitant use of NSAIDs (including selective COX-2 inhibitors) with drugs that antagonize the angiotensin II receptor may result in deterioration of kidney function, including possible kidney failure . These effects are usually reversible.

6. CYP2B6, 2C9, and 2C19 Substrates-                                                                Monitor for efficacy of the concurrently administered CYP2B6, 2C9, and 2C19 substrates and consider dosage adjustment in accordance with the Prescribing Information. Sparsentan is an inducer of CYP2B6, 2C9, and 2C19. Sparsentan decreases exposure of these substrates., which may reduce efficacy related to these substrates.

7. P-gp and BCRP Substrates-                                                                                 Avoid concomitant use of sensitive substrates of P-gp and BCRP with FILSPARI. Sparsentan is an inhibitor of P-gp and BCRP. Sparsentan may increase exposure of these transporter substrates [see Clinical Pharmacology (12.3)], which may increase the risk of adverse reactions related to these substrates.

8. Agents Increasing Serum Potassium-                                                                 Monitor serum potassium frequently in patients treated with FILSPARI and other agents that increase serum potassium. Concomitant use of FILSPARI with potassium-sparing diuretics, potassium supplements, potassium-containing salt substitutes, or other drugs that raise serum potassium levels may result in hyperkalemia.

BRIEF SUMMARY-

SPARSENTAM-(Feb 2023)

Indcn- To  reduce proteinuria in adults with primary  immunoglbulin A ephropathy  at rapid disease progression       

Dosage-  Tablets: 200 mg and 400 mg .Initiate treatment with  200 mg orally once daily. After 1 days, increase to the recommended dose of 400 mg once daily, as tolerated

 ADR- Most common adverse reactions (=5%) are peripheral edema, hypotension (including orthostatic hypotension), dizziness, hyperkalemia, and anemia

CI- • Pregnancy

Hepatotoxicity 

WARNINGS- Hepatotoxicity,Embryo-Fetal Toxicity,Hypotension

Pat inform-                                                                                                         Hepatotoxicity -  Advise patients with symptoms suggesting hepatotoxicity (nausea, vomiting, right upper quadrant pain, fatigue, anorexia, jaundice, dark urine, fever, or itching) to immediately stop taking the medicine and seek medical attention

Embryo-Fetal Toxicity-  Educate and counsel patients who can become pregnant about the need to use reliable methods of contraception prior to treatment with the drug and, during treatment and for one month after treatment discontinuation.

===============================================================

U.S.  APPROVED DRUGS DURING 2023                                        

Serial No 7

Name-        FILPARI

Acive  Ingredient -  Sparsentan

 Pharmacological clssificiation-        To  reduce proteinuria in adults with primary                                                                   immunoglbulin A nephropathy at rapid                                                                          disease progression                                                                                                                                                                                           Date of Approval-         2/17/2023                                              

HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to us                               FILSPARI™ safely and effectively.                                                                                See full prescribing information for FILSPARI™. FILSPARI™ (sparsentan) tablets, for oral use

Initial U.S. Approval: 2023

WARNING: HEPATOTOXICITY and EMBRYO-FETAL TOXICITY

See full prescribing information for complete boxed warning.

• FILSPARI is only available through a restricted distribution program called the FILSPARI Risk Evaluation and Mitigation Strategies (REMS) because of these risks

 • Some endothelin receptor antagonists have caused elevations of aminotransferases, hepatotoxicity, and liver failure

 • Measure liver aminotransferases and total bilirubin prior to initiation of treatment and ALT and AST monthly for 12 months, then every 3 months during treatmen

 • Interrupt treatment and closely monitor patients developing aminotransferase elevations more than 3x Upper Limit of Normal (ULN)

 • Based onanimal data, FILSPARI can cause major birth defects if used during pregnancy

 • Pregnancy testing is required before, during, and after treatment

. • Patients who can become pregnant must use effective contraception prior to initiation of treatment, during treatment, and for one month after

INDICATIONS AND USAGE-

 FILSPARI is an endothelin and angiotensin II receptor antagonist indicated to reduce 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

 This indication is approved under accelerated approval based on reduction of proteinuria. It has not been established whether FILSPARI slows kidney function decline in patients with IgAN. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory clinical trial.

ADVERSE REACTIONS

 Most common adverse reactions (=5%) are peripheral edema, hypotension (including orthostatic hypotension), dizziness, hyperkalemia, and anemia

CONTRAINDICATIONS-

 • Pregnancy

 • Do not coadminister FILSPARI with angiotensin receptor blockers, endothelin receptor antagonists, or aliskiren 

 WARNINGS AND PRECAUTIONS

 • Hepatotoxicity 

• Embryo-Fetal Toxicity

 • Hypotension

 • Acute Kidney Injury

 • Hyperkalemia 

 • Fluid Retention

DOSAGE AND ADMINISTRATION -

 • Prior to initiating treatment with FILSPARI, discontinue use of renin-angiotensin-aldosterone system (RAAS) inhibitors, endothelin receptor antagonists (ERAs) or aliskiren

 • Initiate treatment with FILSPARI at 200 mg orally once daily. After 14 days, increase to the recommended dose of 400 mg once daily, as tolerated. When resuming treatment with FILSPARI after an interruption, consider titration of FILSPARI, starting at 200 mg once daily. After 14 days, increase to the recommended dose of 400 mg once daily

 • Instruct patients to swallow tablets whole with water prior to the morning or evening meal 

 DOSAGE FORMS AND STRENGTHS-

 Tablets: 200 mg and 400 mg

PATIENT COUNSELING INFORMATION

Advise patients to read the FDA-approved patient labeling (Medication Guide).

Restricted access Advise the patient that FILSPARI is only available through a restricted access program called the FILSPARI REMS.

As a component of the FILSPARI REMS, prescribers must review the contents of the FILSPARI Medication Guide with the patient before initiating FILSPARI.

Instruct patients that the risks associated with FILSPARI include:

Hepatotoxicity -                                                                                                                 Advise patients with symptoms suggesting hepatotoxicity (nausea, vomiting, right upper quadrant pain, fatigue, anorexia, jaundice, dark urine, fever, or itching) to immediately stop taking FILSPARI and seek medical attention 

Embryo-Fetal Toxicity-                                                                                                    Educate and counsel patients who can become pregnant about the need to use reliable methods of contraception prior to treatment with FILSPARI, during treatment and for one month after treatment discontinuation.

Patients who can become pregnant must have pregnancy tests prior to treatment with FILSPARI, monthly during treatment, and one month after treatment discontinuation.

Patients should be instructed to immediately contact their physician if they suspect they may be pregnant.

Patients should seek additional contraceptive advice from a gynecologist or similar expert as needed.

Educate and counsel patients who can become pregnant on the use of emergency contraception in the event of unprotected sex or contraceptive failure

 Advise patients to contact their gynecologist or healthcare provider if they want to change the form of birth control which is used to ensure that another acceptable form of birth control is selected.

Advise the patient that FILSPARI is available only from certified pharmacies that are enrolled in the FILSPARI REMS. Patients must sign the FILSPARI REMS

Patient Enrollment Form to confirm that they understand the risks of FILSPARI. Lactation Advise patients not to breastfeed during treatment with FILSPARI.

Drug Interactions-                                                                                                     Advise patients to inform their healthcare provider of all concomitant medications, including prescription medications, over-the-counter drugs, vitamins/supplements, herbal products, and grapefruit .

Other Risks Associated with FILSPARI Inform patients of other risks associated with FILSPARI, including                                                                                                            • Hypotension: Advise patients to remain hydrated..

• Hyperkalemia: Advise patients not to use potassium supplements or salt substitutes that contain potassium without consulting their healthcare provider.

Dosing Advise patients to take the full daily dose with water prior to the morning or evening meal. Maintain the same dosing pattern in relationship to meals.

If a dose is missed, take the next dose at the regularly scheduled time. Do not take double or extra doses.

Distributed by Travere Therapeutics, Inc., San Diego, CA 92130 FILSPARI is a registered trademark of Travere Therapeutics, Inc.

CLINICAL PHARMACOLOGY

1. Mechanism of Action

Sparsentan is a single molecule with antagonism of the endothelin type A receptor (ETAR) and the angiotensin II type 1 receptor (AT1R). Sparsentan has high affinity for both the ETAR (Ki= 12.8 nM) and the AT1R (Ki=0.36 nM), and greater than 500-fold selectivity for these receptors over the endothelin type B and angiotensin II subtype 2 receptors.

Endothelin-1 and angiotensin II are thought to contribute to the pathogenesis of IgAN via the ETAR and AT1R, respectively.

2. Pharmacodynamics Dose-response information is not available. At the recommended dose regimen, no statistically significant exposure-response (E-R) relationship was identified between sparsentan exposure and the percentage reduction from baseline in UPCR at Week 36 over the observed sparsentan exposure range.

Cardiac Electrophysiology In a randomized, positive-, and placebo-controlled study in healthy subjects, sparsentan caused QTcF prolongation with maximal mean effect of 8.8 msec (90% CI: 5.9, 11.8) at 800 mg and 8.1 msec (90% CI: 5.2, 11.0) at 1600 mg.

At the recommended dose, no clinically relevant QTc prolongation (i.e., >20 msec) is expected.

3. Pharmacokinetics The pharmacokinetics of sparsentan are presented as geometric mean (% coefficient of variation) unless otherwise specified.

The Cmax and AUC of sparsentan increase less than proportionally following administration of single doses of 200 mg to 1600 mg. Sparsentan showed time-dependent pharmacokinetics which may be related to the drug inducing its own metabolism over time.

Steady-state plasma levels are reached within 7 days with no accumulation of exposure at the approved recommended dosage.

4. Absorption- Following a single oral dose of 400 mg sparsentan, the median (minimum to maximum) time to peak plasma concentration is approximately 3 hours (2 to 8 hours).

Effect of Food Sparsentan AUC and Cmax increased by 22% and 108%, respectively, following administration of a single oral 800 mg dose with a high fat, high calorie meal (1000 kcal, 50% fat)

No clinically significant differences in sparsentan pharmacokinetics were observed following administration of a single 200 mg dose with a high fat, high calorie meal.

Distribution The apparent volume of distribution at steady state is 61.4 L at the approved recommended dosage. Sparsentan is >99% bound to human plasma proteins.

Elimination The clearance of sparsentan is time-dependent which may be related to the drug inducing its own metabolism over time. The apparent clearance (CL/F) of sparsentan is 3.88 L/h following the initial 400 mg dose then increases to 5.11 L/h at steady state.

The half-life of sparsentan is estimated to be 9.6 hours at steady state.

Metabolism Cytochrome P450 3A is the major isozyme responsible for the metabolism of sparsentan.

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

Specific Populations No clinically significant differences in the pharmacokinetics of sparsentan were observed based on age (18 – 73 years), sex, race, mild to moderate renal impairment (eGFR 30 to 89 mL/min/1.73 m2), or mild to moderate hepatic impairment (Child-Pugh class A or B).

Patients with severe hepatic impairment (Child-Pugh class C) and eGFR <30 mL/min/1.73 m2 have not been studied.

Drug Interaction Studies- Clinical Studies and Model-Informed Approaches Effect of Other Drugs on Sparsentan Strong CYP3A inhibitors: Concomitant use with itraconazole (strong CYP3A inhibitor) increased sparsentan Cmax by 25% and AUC by 174%.

Moderate CYP3A inhibitors: Concomitant use with cyclosporine (moderate CYP3A inhibitor) increased sparsentan Cmax by 41% and AUC by 70%.

Strong CYP3A inducers: Coadministration of rifampin (strong CYP3A inducer) is predicted to decrease sparsentan Cmax by 23% and AUC0-inf by 47% at steady state.

Effect of Sparsentan on Other Drugs- No clinically significant differences in the pharmacokinetics of midazolam (sensitive CYP3A4 substrate) or pitavastatin (OATP1B1, OATP1B3, P-gp, and BCRP substrate) were observed when co-administered with sparsentan.

CYP2B6 substrates: Concomitant use with sparsentan decreased the exposure of bupropion (CYP2B6 substrate) Cmax by 32% and AUC by 33%.

In Vitro Studies CYP Enzymes: Sparsentan is a substrate of CYP3A. Sparsentan is both an inhibitor and inducer of CYP3A and an inducer of CYP2B6, CYP2C9, and CYP2C19.

Transporters: Sparsentan is a substrate of P-gp and BCRP but is not a substrate of OATP1B1 or OATP1B3. Sparsentan is an inhibitor of P-gp, BCRP, OATP1B3, and OAT3 but does not inhibit MRP, OATP1B1, NTCP, OCT2, OAT1, MATE1, or MATE2K at relevant concentrations.

USE IN SPECIFIC POPULATIONS

1. Pregnancy Risk Summary

Based on data from animal reproductive toxicity studies, FILSPARI can cause fetal harm, including birth defects and fetal death, when administered to a pregnant patient and is contraindicated during pregnancy.

Available data from reports of pregnancy in clinical trials with FILSPARI are insufficient to identify a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes.

In animal reproduction studies, oral administration of sparsentan to pregnant rats throughout organogenesis at 10-times the maximum recommended human dose (MRHD) in mg/day caused teratogenic effects in rats, including craniofacial malformations, skeletal abnormalities, increased embryo-fetal lethality, and reduced fetal weights 

. Advise pregnant patients of the potential risk to the fetus.

The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15- 20%, respectively.

2 Lactation-.human milk, the effects on the breastfed infant, or the effect on milk production. Because of the potential for adverse reactions, such as hypotension in breastfed infants, advise patients not to breastfeed during treatment with FILSPARI.

3. Females and Males of Reproductive Potential Based on data from animal reproductive toxicity studies, FILSPARI can cause fetal harm, including birth defects and fetal death, when administered to a pregnant patient and is contraindicated during pregnancy .

Pregnancy Testing- Verify that patients who can become pregnant are not pregnant prior to initiating FILSPARI, monthly during treatment, and one month after discontinuation of treatment.

The patient should contact their physician immediately for pregnancy testing if onset of menses is delayed or pregnancy is suspected.

If the pregnancy test is positive, the physician and patient must discuss the risks to their pregnancy and the fetus.

Contraception- Patients who can become pregnant who are using FILSPARI must use an effective method of contraception prior to initiation of treatment, during treatment, and for one month after discontinuation of treatment with FILSPARI to prevent pregnancy..

4. Pediatric Use The safety and efficacy of FILSPARI in pediatric patients have not been established. 

5. Geriatric Use Of the total number of subjects in the PROTECT study of FILSPARI, 15 (7.4%) were 65 and older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects.

6. Hepatic Impairment Avoid use of FILSPARI in patients with any hepatic impairment (Child-Pugh class A-C) because of the potential risk of serious liver inju

OVERDOSE-.

In the event of an overdose, standard supportive measures should be taken, as required. Dialysis is unlikely to be effective because sparsentan is highly protein-bound.