Usual Adult Dose for Primary Immunoglobulin A Nephropathy

Initial dose: 200 mg orally once a day for 14 days
Maintenance dose: Following initial dose, increase to 400 mg orally once a day, as tolerated

Comments:

• Consider dose titration when resuming treatment after interruption: Start with initial dose for 14 days, then increase to recommended maintenance dose.

Use: To reduce proteinuria in adults with primary immunoglobulin A nephropathy at risk of rapid disease progression (generally a urine protein-to-creatinine ratio of 1.5 g/g or greater); indication is based on accelerated approval, and continued approval may be contingent on confirmatory clinical trial.

Renal Dose Adjustments

• No specific adjustments recommended.
• Use caution in patients whose renal function may depend in part on the activity of the renin-angiotensin system (e.g., patients with renal artery stenosis, chronic kidney disease, severe congestive heart failure, or volume depletion).
• Consider withholding or discontinuing therapy if clinically significant decreases in renal function occur during treatment.

Liver Dose Adjustments

• Initial use should be avoided in patients with baseline aminotransferase elevations greater than 3 times the upper limit of normal or in patients with any liver impairment (Child-Pugh A, B, or C) due to the increased risk of hepatotoxicity and difficulty monitoring.
• In patients who develop aminotransferases elevations while on therapy, follow dose adjustments below.

Dose Adjustments

Patients Developing Aminotransferase Elevations:

• If ALT/AST greater than 3 times the upper limit of normal (3 x ULN) and less than or equal to 8 x ULN: Confirm with another aminotransferase test; if confirmed, interrupt treatment, and monitor aminotransferase and bilirubin levels at least weekly, and INR as needed, until patient asymptomatic and levels return to pretreatment baseline. If aminotransferase levels return to pretreatment values, resume the treatment as appropriate, initiating therapy with 200 mg once a day; aminotransferase and bilirubin levels should be checked within 3 days with close monitoring thereafter.
• If ALT/AST greater than 8 x ULN: Treatment should be stopped permanently if no other cause found.
• Do not resume therapy if ALT or AST elevations are greater than 3 x ULN and total bilirubin is greater than 2 x ULN or INR is greater than 1.5, or if ALT or AST are greater than 3 x ULN with symptoms of hepatotoxicity and/or eosinophilia, or if ALT or ALT greater than 5 x ULN for more than two weeks.
• Do not resume this drug in patients who have experienced clinical symptoms of hepatotoxicity (e.g., nausea, vomiting, right upper quadrant pain, fatigue, anorexia, jaundice, dark urine, fever, or itching) or in patients whose hepatic enzymes and bilirubin do not return to pretreatment values.

Coadministration with Strong CYP450 3A Inhibitors:

• Avoid concomitant use; if use cannot be avoided interrupt treatment with this drug.

Precautions

The US FDA requires a Risk Evaluation and Mitigation Strategy (REMS) for sparsetan. It includes elements to assure safe use and implementation system. For additional information: www.accessdata.fda.gov/scripts/cder/rems/index.cfm

US BOXED WARNING:

• EMBRYOFETAL TOXICITY: This drug is contraindicated in pregnant women because it may cause fetal harm based on animal data. Pregnancy testing is required prior to starting treatment, monthly during treatment, and for 1 month after discontinuation of treatment. Patients who can become pregnant should be instructed to use acceptable methods of contraception prior to starting treatment, during treatment, and for 1 month after discontinuation of treatment.
• HEPATOTOXICITY: Liver failure, hepatotoxicity, and increases in aminotransferases (ALT or AST) have been caused by some endothelin receptor antagonists. Elevations of aminotransferase 3 x ULN can occur with this drug, including in cases confirmed with rechallenge. Assess serum aminotransferase and bilirubin levels prior to initiation of treatment, monthly for the first 12 months, and then every 3 months during treatment. Interrupt treatment in patients with aminotransferase elevations greater than 3x ULN; monitor closely. This drug should generally be avoided in patients with elevated aminotransferases (greater than 3 x ULN) at baseline because monitoring for hepatotoxicity may be more difficult.

CONTRAINDICATIONS:

• Pregnancy
• Coadministration with angiotensin receptor blockers, endothelin receptor antagonists, or aliskiren

Safety and efficacy have not been established in patients younger than 18 years.

Consult WARNINGS section for additional precautions.

Dialysis

Data not available; unlikely to be effective as this drug is highly protein-bound

Other Comments

Administration advice:

• Drug should be taken orally once a day prior to morning or evening meal; maintain same dosing pattern with regard to meals.
• Missed doses should be taken at next regularly scheduled time; do not double or take extra doses.

Storage requirements:

• Store tablets in original container at 20C to 25C (68F to 77F); excursions from 15C to 30C (59F to 86F) are permitted.

General:

• Overdose: Decreased blood pressure may occur with overdose and standard supportive measures should be taken as required; dialysis likely ineffective as drug is highly protein-bound. There are no data available to guide protocol.

Monitoring:

• All patients and prescribers must comply with monitoring requirements as determined by the Filspari REMS restricted distribution program.
• Hepatic: Measure liver aminotransferase and bilirubin levels prior to initiation of treatment, then monthly for first 12 months, and every 3 months thereafter while on this drug.
• Renal: Monitor kidney function periodically, especially in patients at high risk of developing acute kidney injury.
• Metabolic: Monitor serum potassium periodically, especially in patients taking concomitant potassium-sparing medications or potassium-containing salts or supplements.
• Pregnancy: Initiate treatment in females of reproductive potential only after a negative pregnancy test; obtain monthly pregnancy tests during treatment and 1 month after stopping treatment.

Patient advice:

• Read the Patient Information and Instructions for Use.
• Do not take this drug if you are pregnant; pregnancy testing is required monthly while on this drug, and 1 month after treatment discontinuation.
• Report any symptoms of potential hepatotoxicity immediately to your medical provider.
• Do not take this drug if you are currently taking an angiotensin receptor blocker, an endothelin receptor antagonist, or aliskiren.