2.1 Important Administration Instructions

• LUPKYNIS capsules must be swallowed whole and must not be opened, crushed, or divided.
• LUPKYNIS should be taken on an empty stomach consistently as close to a 12-hour schedule as possible, and with a minimum of 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 [see Drug Interactions( 7.1)] .

2.2 Prior to Initiating LUPKYNIS Therapy

Establish an accurate baseline estimated glomerular filtration rate (eGFR). Use of LUPKYNIS is not recommended in patients with a baseline eGFR ≤45 mL/min/1.73 m 2 unless the benefit exceeds the risk; these patients may be at increased risk for acute and/or chronic nephrotoxicity [see Warnings and Precautions( 5.3)] .

Check blood pressure (BP) at baseline. Do not initiate LUPKYNIS in patients with BP >165/105 mmHg or with hypertensive emergency [see Warnings and Precautions( 5.4)] .

2.3 Dosage Recommendations

The recommended starting dose of LUPKYNIS is 23.7 mg twice a day.

Use LUPKYNIS in combination with mycophenolate mofetil (MMF) and corticosteroids [see Clinical Studies( 14)] .

Safety and efficacy of LUPKYNIS have not been established in combination with cyclophosphamide. Use of LUPKYNIS is not recommended in this situation.

• Assess eGFR every two weeks for the first month, every four weeks through the first year and quarterly thereafter.

Dosage of LUPKYNIS is based on the patient’s eGFR. Modify LUPKYNIS dosage based on eGFR [see Warnings and Precautions( 5.3)] :

• If eGFR <60 mL/min/1.73 m 2 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 2 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 [see Warnings and Precautions( 5.4)] . For patients with BP >165/105 mmHg or with hypertensive emergency, discontinue LUPKYNIS and initiate antihypertensive therapy.

If the patient does not experience therapeutic benefit by 24 weeks, consider discontinuation of LUPKYNIS.

2.4 Dosage Recommendations in Patients with Renal and Hepatic Impairment

Use of LUPKYNIS is not recommended in patients with a baseline eGFR ≤45 mL/min/1.73 m 2 unless the benefit exceeds the risk; LUPKYNIS has not been studied in patients with a baseline eGFR ≤45 mL/min/1.73 m 2. If used in patients with severe renal impairment at baseline, the recommended starting dose is 15.8 mg twice a day [see Use in Specific Populations( 8.6) and Clinical Pharmacology( 12.3)] .

In patients with mild and moderate hepatic impairment (Child-Pugh A and Child-Pugh B), the recommended dose is 15.8 mg twice daily. LUPKYNIS is not recommended to be used in patients with severe hepatic impairment (Child-Pugh C) [see Use in Specific Populations( 8.7) and Clinical Pharmacology( 12.3)] .

2.5 Dosage Adjustments due to Drug Interactions

When co-administering LUPKYNIS with moderate CYP3A4 inhibitors (e.g., verapamil, fluconazole, diltiazem), reduce LUPKYNIS daily dosage to 15.8 mg in the morning and 7.9 mg in the evening. No dose adjustment of LUPKYNIS is recommended when LUPKYNIS is co-administered with mild CYP3A4 inhibitors [see Drug Interactions( 7.1) and Clinical Pharmacology( 12.3)] .

5.1 Lymphoma and Other Malignancies

Immunosuppressants, including LUPKYNIS, increase the risk of developing lymphomas and other malignancies, particularly of the skin. The risk appears to be related to the intensity and duration of immunosuppression rather than to the use of any specific agent. Examine patients for skin changes and advise to avoid or limit sun exposure and to avoid artificial UV light (tanning beds, sun lamps) by wearing protective clothing and using a broad spectrum sunscreen with a high protection factor (SPF 30 or higher).

5.2 Serious Infections

Immunosuppressants, including LUPKYNIS, increase the risk of developing bacterial, viral, fungal, and protozoal infections, including opportunistic infections. These infections may lead to serious, including fatal, outcomes. Viral infections reported include cytomegalovirus and herpes zoster infections.

Monitor for the development of infection. Consider the benefits and risks for the individual patient; use the lowest effective dose needed to maintain response.

5.3 Nephrotoxicity

LUPKYNIS, like other calcineurin-inhibitors, can cause acute and/or chronic nephrotoxicity. Nephrotoxicity was reported in clinical trials [see Adverse Reactions( 6.1)] . Monitor eGFR regularly during treatment, and consider dose reduction or discontinuation in patients with decreases in eGFR from baseline [see Dosage and Administration( 2.3)] ; persistent decrease of eGFR should be evaluated for chronic calcineurin-inhibitor nephrotoxicity.

Consider the risks and benefits of LUPKYNIS treatment in light of the patient’s treatment response and risk of worsening nephrotoxicity, including co-administration with drugs associated with nephrotoxicity. The risk for acute and/or chronic nephrotoxicity is increased when LUPKYNIS is concomitantly administered with drugs associated with nephrotoxicity.

5.4 Hypertension

Hypertension is a common adverse reaction of LUPKYNIS therapy and may require antihypertensive therapy [see Adverse Reactions( 6.1)] . Some antihypertensive drugs can increase the risk for hyperkalemia [see Warnings and Precautions( 5.7)] . Certain calcium-channel blocking agents (verapamil and diltiazem) may increase voclosporin blood concentrations and require dosage reduction of LUPKYNIS [see Dosage and Administration( 2.5) and Drug Interactions( 7.2)] .

Monitor blood pressure regularly during treatment and treat new-onset hypertension and exacerbations of pre-existing hypertension. If a patient experiences increases in blood pressure that cannot be managed with dose reduction of LUPKYNIS or other appropriate medical intervention, consider discontinuation of LUPKYNIS [see Dosage and Administration( 2.3)] .

5.5 Neurotoxicity

LUPKYNIS, like other calcineurin-inhibitors, may cause a spectrum of neurotoxicities [see Adverse Reactions( 6.1)] . The most severe neurotoxicities include posterior reversible encephalopathy syndrome (PRES), delirium, seizure, and coma; others include tremors, paresthesias, headache, mental status changes, and changes in motor and sensory functions. Monitor for neurologic symptoms and consider dosage reduction or discontinuation of LUPKYNIS if neurotoxicity occurs.

5.6 Hyperkalemia

Hyperkalemia, which may be serious and require treatment, has been reported with calcineurin-inhibitors including LUPKYNIS [see Adverse Reactions( 6.1)] . Concomitant use of agents associated with hyperkalemia (e.g., potassium-sparing diuretics, ACE inhibitors, angiotensin receptor blockers) may increase the risk for hyperkalemia. Monitor serum potassium levels periodically during treatment.

5.7 QTc Prolongation

LUPKYNIS prolongs the QTc interval in a dose-dependent manner after single dose administration at a dose higher than the recommended lupus nephritis therapeutic dose [see Clinical Pharmacology( 12.2)] . The use of LUPKYNIS in combination with other drugs that are known to prolong QTc may result in clinically significant QT prolongation.

Certain circumstances may increase the risk of the occurrence of torsade de pointes and/or sudden death in association with the use of drugs that prolong the QTc interval, including (1) bradycardia; (2) hypokalemia or hypomagnesemia; (3) concomitant use of other drugs that prolong the QTc interval; and (4) presence of congenital prolongation of the QT interval.

5.8 Immunizations

Avoid the use of live attenuated vaccines during treatment with LUPKYNIS (e.g., intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and TY21a typhoid vaccines).

Inactivated vaccines noted to be safe for administration may not be sufficiently immunogenic during treatment with LUPKYNIS.

5.9 Pure Red Cell Aplasia

Cases of pure red cell aplasia (PRCA) have been reported in patients treated with another calcineurin-inhibitor immunosuppressant. All of these patients reported risk factors for PRCA such as parvovirus B19 infection, underlying disease, or concomitant medications associated with PRCA. A mechanism for calcineurin-inhibitor-induced PRCA has not been elucidated. If PRCA is diagnosed, consider discontinuation of LUPKYNIS.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

A total of 355 patients with LN were treated with voclosporin in the Phase 2 and 3 clinical studies with 224 exposed for at least 48 weeks, and 92 exposed for 3 years.

Patients in Study 1 were randomized to LUPKYNIS 23.7 mg twice a day or placebo. A proportion of patients (n=216, 60%) in Study 1 continued in Study 1 extension, double-blinded continuation study, and these patients were observed for up to 2 additional years [see Clinical Studies( 14)] . Patients in Study 2 were randomized to LUPKYNIS 23.7 mg twice a day, voclosporin 39.5 mg twice a day, or placebo.

Patients received background treatment with MMF 2 g daily and an IV bolus of corticosteroids followed by a pre-specified oral corticosteroid taper dosing schedule; LUPKYNIS dosing was adjusted based on eGFR and BP.

A total of 267 patients received at least 1 dose of LUPKYNIS 23.7 mg twice a day with 184 exposed for at least 48 weeks. A total of 88 patients received at least 1 dose of voclosporin 39.5 mg twice a day with 40 exposed for 48 weeks.

Table 1 lists common adverse reactions occurring in at least 3% of patients receiving LUPKYNIS and at an incidence at least 2% greater than placebo in Studies 1 and 2.

Other adverse reactions reported in less than 3% of patients in the LUPKYNIS 23.7 mg group and at a 2% higher rate than in the placebo group through 48/52 weeks included gingivitis and hypertrichosis.

The overall profile of adverse events seen in Study 1 extension (representing 203 patient-years of additional exposure) were similar in both nature and severity to those seen in the first year of treatment (Study 1). The annual incidence of adverse reactions reduced each successive year in both treatment groups.

The integrated LN dataset is presented in the Specific Adverse Reactions section:

Placebo-controlled Studies: Studies 1 and 2 were integrated to represent safety through 48/52 weeks for placebo (n=266), LUPKYNIS 23.7 mg twice a day (n=267), and voclosporin 39.5 mg twice a day (n=88). Among patients from Study 1, 100 patients (56.2%) on placebo twice a day and 116 patients (64.8%) on LUPKYNIS 23.7 mg twice a day continued in a follow-on study period for up to 2 additional years (Study 1 extension), with safety assessments through a total of up to 3 years.

Exposure adjusted incidence rates were adjusted by study for all the adverse events reported in this section.

7.1 Effect of Other Drugs on LUPKYNIS

Strong and Moderate CYP3A4 Inhibitors

Voclosporin is a sensitive CYP3A4 substrate. Co-administration with strong or moderate CYP3A4 inhibitors increases voclosporin exposure [see Clinical Pharmacology( 12.3)] , which may increase the risk of LUPKYNIS adverse reactions. Co-administration of LUPKYNIS with strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin) is contraindicated [see Contraindications( 4)] . Reduce LUPKYNIS dosage when co-administered with moderate CYP3A4 inhibitors (e.g., verapamil, fluconazole, diltiazem) [see Dosage and Administration( 2.4)] . Avoid food or drink containing grapefruit when taking LUPKYNIS.

Strong and Moderate CYP3A4 Inducers

Voclosporin is a sensitive CYP3A4 substrate. Co-administration with strong or moderate CYP3A4 inducers decreases voclosporin exposure [see Clinical Pharmacology( 12.3)] , which may decrease the efficacy of LUPKYNIS. Avoid co-administration of LUPKYNIS with strong or moderate CYP3A4 inducers.

7.2 Effect of LUPKYNIS on Other Drugs

Certain P-gp Substrates

Voclosporin is a P-gp inhibitor. Co-administration of voclosporin increases exposure of P-gp substrates [see Clinical Pharmacology( 12.3)] , which may increase the risk of adverse reactions of these substrates. For certain P-gp substrates with a narrow therapeutic window, reduce the dosage of the substrate as recommended in its prescribing information, if needed.

OATP1B1 Substrates

Voclosporin is an inhibitor of OATP1B1 and OATP1B3 transporters. In one clinical study the concomitant administration of a single 40 mg dose of simvastatin with 23.7 mg BID voclosporin increased C max and AUC of the active metabolite simvastatin acid (an OATP1B1 substrate) by 3.1-fold and 1.8-fold, respectively [see Clinical Pharmacology( 12.3)] . Monitor for adverse reactions such as myopathy and rhabdomyolysis when OATP1B1/OATP1B3 substrates (e.g., simvastatin, atorvastatin, pravastatin, rosuvastatin, pitavastatin, fluvastatin) are used concomitantly with LUPKYNIS and reduce the dosage of these substrates as recommended in their prescribing information. For example, when taking LUPKYNIS with simvastatin, limit the simvastatin dosage to 20 mg daily, or 40 mg daily for patients who have previously tolerated simvastatin 80 mg daily for at least one year without evidence of muscle toxicity.

8.1 Pregnancy

8.2 Lactation

Risk Summary

The available human data from a clinical lactation study detected small amounts of voclosporin in human milk. Following a single dose to lactating subjects, a fully breastfed infant was estimated to receive a daily infant dose of 0.00675 mg/kg, and relative infant dose of 1.4% the maternal weight-adjusted dose. No change is expected for infant exposure at steady state with maternal twice daily dosing (see Data). Available data from the clinical study and published scientific literature are insufficient to determine the effects of LUPKYNIS on the breastfed infant or on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for LUPKYNIS and any potential adverse effects on the breastfed infant from LUPKYNIS or from the medical condition of the mother.

Data

Following a single 23.7 mg dose of voclosporin in healthy lactating subjects, an average of 0.00472 mg voclosporin was excreted in breast milk. Data showed that the voclosporin milk to maternal blood exposure ratio was in the range of 0.42 to 0.95. Based on the infant milk intake of 200 mL/kg/day, the highest estimated voclosporin dose ingested by fully breastfed infant was 1.4% of maternal weight-adjusted dose, which equals estimated daily infant dose of 0.00675 mg/kg/day. At steady state following maternal twice daily dosing regimen, the percent of voclosporin dose present in breast milk is expected to be similar to that following maternal single dose.

8.3 Females and Males of Reproductive Potential

LUPKYNIS may be used in combination with a background immunosuppressive therapy regimen that includes MMF. If LUPKYNIS is administered with MMF, the information for MMF regarding pregnancy testing, contraception, and infertility also applies to this combination regimen. Refer to MMF prescribing information for additional information.

8.4 Pediatric Use

The safety and efficacy of LUPKYNIS in pediatric patients has not been established.

8.5 Geriatric Use

Clinical studies of LUPKYNIS did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

8.6 Renal Impairment

Use of LUPKYNIS is not recommended in patients with a baseline eGFR ≤45 mL/min/1.73 m 2 unless the benefit exceeds the risk. If used in patients with severe renal impairment at baseline, LUPKYNIS should be used at a reduced dose [see Dosage and Administration( 2.4)] . No dosage adjustment is recommended in patients with mild or moderate renal impairment at baseline [see Clinical Pharmacology( 12.3)] . Monitor eGFR closely.

After initiating therapy, dosing adjustments should be made based on eGFR [see Dosage and Administration( 2.3)] .

8.7 Hepatic Impairment

In patients with mild and moderate hepatic impairment (Child-Pugh A and Child-Pugh B), reduce the LUPKYNIS dosage [see Dosage and Administration( 2.4)] . Avoid LUPKYNIS in patients with severe hepatic impairment (Child-Pugh C)  [see Clinical Pharmacology( 12.3)] .

12.1 Mechanism of Action

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.

12.2 Pharmacodynamics

Calcineurin inhibition

Concentration-dependent calcineurin inhibition, measured as the percent of maximum calcineurin inhibition, was observed after oral administration of voclosporin twice daily in healthy volunteers. There is little or no lag time between the time to maximum drug concentration and the time to maximum calcineurin inhibition. Voclosporin inhibits calcineurin in a dose-dependent manner up to a maximum dose of 1.0 mg/kg.

Cardiac Electrophysiology

In a randomized, placebo- and active-controlled (moxifloxacin 400 mg), single dose study with parallel study design, dose-dependent QT prolonging effect was detected with LUPKYNIS in the dose range of 0.5–4.5 mg/kg (up to 9-fold coverage of the therapeutic exposure). Dose-dependent QT prolongation effect was observed with a time to maximum QTc increase occurring at 4–6-hour postdose across different dose levels. The maximum mean placebo-adjusted changes of QTcF from baseline after LUPKYNIS 0.5 mg/kg, 1.5 mg/kg, 3.0 mg/kg, and 4.5 mg/kg dose were 6.4 msec, 17.5 msec, 25.7 msec, and 34.6 msec, respectively.

In a separate, randomized, placebo-controlled, crossover study in 31 healthy subjects, an absence of large mean increases (i.e., >20 msec) was observed following 7 days of treatment with LUPKYNIS at 0.3, 0.5 and 1.5 mg/kg twice daily (approximately 6-fold coverage of the therapeutic exposure).

The mechanism for the QT prolonging effect as observed in the single-dose and multiple-dose studies is unknown.

12.3 Pharmacokinetics

The whole blood voclosporin pharmacokinetics increase in a greater than dose-proportional manner over the therapeutic range. With a twice daily dosing regimen, voclosporin achieves steady-state after 6 days and the accumulation is approximately 2-fold.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

In a 2-year mouse carcinogenicity study, administration of voclosporin at oral doses of 3, 10, or 30 mg/kg/day resulted in an increased incidence of malignant lymphoma in high dose females (7.5 times the MRHD on an AUC basis) and a dose-responsive trend for increase in malignant lymphoma in males. Malignant lymphoma was considered drug related in mice. In a 2-year rat carcinogenicity study, oral administration of voclosporin at doses up to 1.25 mg/kg/day in males and 2.5 mg/kg/day in females (doses that result in approximately similar drug exposures in rats) resulted in no statistically significant increases of tumor incidences.

In a 39-week oral toxicology study with monkeys, malignant lymphomas occurred at a dose of 150 mg/kg/day (approximately 4- and 7-times MRHD based on AUC for male and female animals, respectively). [At this dose, monkeys experienced high levels of immunosuppression as indicated by maximum calcineurin inhibition levels (E max) of greater than 80%.]

Voclosporin was not mutagenic or clastogenic in a standard battery of genetic toxicity studies that included the in vitro bacterial reverse mutation assay, in vitro Chinese hamster ovary cell chromosomal aberration assay, and in vivo rat micronucleus assay.

Voclosporin had no effect on fertility at doses up to 25 mg/kg/day in male and female rats (16- and 9-times MRHD based on AUC, respectively).