LUPKYNIS is a calcineurin-inhibitor immunosuppressant. The mechanism of voclosporin suppression of calcineurin has not been fully established. Activation of lymphocytes involves an increase in intracellular calcium concentrations that bind to the calcineurin regulatory site and activate calmodulin binding catalytic subunit and through dephosphorylation activates the transcription factor, Nuclear Factor of Activated T-Cell Cytoplasmic (NFATc). The immunosuppressant activity results in inhibition of lymphocyte proliferation, T-cell cytokine production, and expression of T-cell activation surface antigens. Studies in animal models also support a non-immunological role for calcineurin inhibition in kidney function to stabilize actin cytoskeleton and stress fibers in podocytes leading to increased podocyte integrity in glomeruli

• LUPKYNIS is a calcineurin-inhibitor immunosuppressant indicated in combination with a background immunosuppressive therapy regimen for the treatment of adult patients with active lupus nephritis (LN).
• Limitations of Use: Safety and efficacy of LUPKYNIS have not been established in combination with cyclophosphamide. Use of LUPKYNIS is not recommended in this situation.

Administration:

• LUPKYNIS must be swallowed whole on an empty stomach. 
• Administer consistently as close to a 12-hour schedule as possible, and with at least 8 hours between doses.
• If a dose is missed, instruct the patient to take it as soon as possible within 4 hours after missing the dose. Beyond the 4-hour time frame, instruct the patient to wait until the usual scheduled time to take the next regular dose. Instruct the patient not to double the next dose. 
• Instruct patients to avoid eating grapefruit or drinking grapefruit juice while taking LUPKYNIS.

Dosage Recommendations:

• Before initiating LUPKYNIS, establish an accurate baseline estimated glomerular filtration rate (eGFR) and check blood pressure (BP).
• Use of LUPKYNIS is not recommended in patients with a baseline eGFR ≤45 mL/min/1.73 m unless the benefit exceeds the risk; these patients may be at increased risk for acute and/or chronic nephrotoxicity. ( 2.2, 5.3) Do not initiate LUPKYNIS in patients with baseline BP >165/105 mmHg or with hypertensive emergency. ( 2.2, 5.4) Recommended starting dose: 23.7 mg orally, twice a day. 
• Use LUPKYNIS in combination with mycophenolate mofetil (MMF) and corticosteroids. ( 2.3) Modify the LUPKYNIS dose based on eGFR:
• Assess eGFR every two weeks for the first month, every four weeks through the first year, and quarterly thereafter. If eGFR <60 mL/min/1.73 m and reduced from baseline by >20% and <30%, reduce the dose by 7.9 mg twice a day. Re-assess eGFR within two weeks; if eGFR is still reduced from baseline by >20%, reduce the dose again by 7.9 mg twice a day. If eGFR <60 mL/min/1.73 m and reduced from baseline by ≥30%, discontinue LUPKYNIS. Re-assess eGFR within two weeks; consider re-initiating LUPKYNIS at a lower dose (7.9 mg twice a day) only if eGFR has returned to ≥80% of baseline. For patients that had a decrease in dose due to eGFR, consider increasing the dose by 7.9 mg twice a day for each eGFR measurement that is ≥80% of baseline; do not exceed the starting dose.
• Monitor blood pressure every two weeks for the first month after initiating LUPKYNIS, and as clinically indicated thereafter. For patients with BP >165/105 mmHg or with hypertensive emergency, discontinue LUPKYNIS and initiate antihypertensive therapy.
• If the patient has not experienced therapeutic benefit by 24 weeks, consider discontinuation of LUPKYNIS. 

Dosage Adjustments:

• Patients with severe renal impairment: the recommended dose is 15.8 mg twice daily.
• Patients with mild and moderate hepatic impairment: the recommended dose is 15.8 mg twice daily. 

The most commonly reported adverse reactions (≥3%) were: glomerular filtration rate decreased, hypertension, diarrhea, headache, anemia, cough, urinary tract infection, abdominal pain upper, dyspepsia, alopecia, renal impairment, abdominal pain, mouth ulceration, fatigue, tremor, acute kidney injury, and decreased appetite

Patients concomitantly using strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin).
Known serious or severe hypersensitivity reaction to LUPKYNIS or any of its excipients

• Nephrotoxicity (acute and/or chronic): May occur due to LUPKYNIS or concomitant nephrotoxic drugs.
• Monitor renal function; consider dosage reduction. 
• Hypertension: May require antihypertensive therapy; monitor relevant drug interactions. 
• Neurotoxicity: Including risk of posterior reversible encephalopathy syndrome (PRES); monitor for neurologic abnormalities; reduce dosage or discontinue LUPKYNIS. 
• Hyperkalemia: Risk may be increased with other agents associated with hyperkalemia; monitor serum potassium levels.
• QT Prolongation: Consider obtaining electrocardiograms and monitoring electrolytes in patients at high risk. 
• Immunizations: Avoid live vaccines. 
• Pure Red Cell Aplasia: Consider discontinuation.