What is mechanism of action?

mechanism of action is Organic Anion Transporting Polypeptide 1B1 Inhibitors [MoA], Organic Anion Transporting Polypeptide 1B3 Inhibitors [MoA], P-Glycoprotein Inhibitors [MoA] or Calcineurin Inhibitors [MoA]

Lupkynis

(Voclosporin)

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Lupkynis Prescribing Information

Increased risk for developing malignancies and serious infections with LUPKYNIS or other immunosuppressants that may lead to hospitalization or death

[see

5 WARNINGS AND PRECAUTIONS

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.
Hypersensitivity Reactions: Discontinue LUPKYNIS; treat and monitor until signs and symptoms resolve.
Immunizations: Avoid live vaccines.
Pure Red Cell Aplasia: Consider discontinuation.

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]

. Monitor eGFR regularly during treatment, and consider dose reduction or discontinuation in patients with decreases in eGFR from baseline

[see Dosage and Administration]

; 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]

. Some antihypertensive drugs can increase the risk for hyperkalemia

[see Warnings and Precautions(

5.6

)]

. Certain calcium-channel blocking agents (verapamil and diltiazem) may increase voclosporin blood concentrations and require dosage reduction of LUPKYNIS

[see Dosage and Administration and Drug Interactions]

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]

5.5 Neurotoxicity

LUPKYNIS, like other calcineurin-inhibitors, may cause a spectrum of neurotoxicities

[see Adverse Reactions]

. 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]

. 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]

. 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 Hypersensitivity Reactions

Postmarketing cases of hypersensitivity reactions, including anaphylaxis and angioedema, have been reported with LUPKYNIS. If signs or symptoms of a hypersensitivity reaction occur, discontinue LUPKYNIS; treat and monitor until signs and symptoms resolve

[see

Contraindications]

5.9 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.

5.10 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.

(

5.1 Lymphoma and Other Malignancies

5.2 Serious 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.

)].

LUPKYNIS is indicated in combination with a background immunosuppressive therapy regimen

[see

14 CLINICAL STUDIES

The safety and efficacy of LUPKYNIS were investigated in Study 1 (NCT03021499), a 52-week, randomized, double-blind, placebo-controlled trial in patients with a diagnosis of systemic lupus erythematosus and with International Society of Nephrology / Renal Pathology Society (ISN/RPS) biopsy-proven active Class III or IV LN (alone or in combination with Class V LN) or Class V LN. Patients with Class III or IV LN (alone or in combination with Class V LN) were required to have a urine protein to creatinine (UPCR) ratio of ≥1.5 mg/mg; patients with Class V LN were required to have a UPCR of ≥2 mg/mg.

A total of 357 patients with LN were randomized in a 1:1 ratio to receive either LUPKYNIS 23.7 mg twice daily or placebo.

Patients in both arms received background treatment with MMF and corticosteroids as follows:

Oral MMF at a target dose of 2 g/day (1 g twice a day). (Patients not already receiving MMF were started on MMF 500 mg twice a day with escalation to MMF 1 g twice a day after the first week.) Dose increases up to 3 g/day were allowed.
Intravenous (IV) methylprednisolone on Day 1 and Day 2 at a dose of 500 mg/day (body weight ≥45 kg) or 250 mg/day (body weight <45 kg) followed by a reducing taper of oral corticosteroids [oral prednisone 25 mg/day (body weight ≥45 kg) or 20 mg/day (body weight <45 kg); tapered to achieve a target dose of 2.5 mg/day by Week 16].

Throughout the study, patients were prohibited from using immunosuppressants (other than MMF and hydroxychloroquine/chloroquine) and from changing/commencing angiotensin II receptor blockers (ARBs) or angiotensin converting enzyme (ACE) inhibitors.

Patients with baseline eGFR ≤45 mL/min/1.73 m²were not enrolled in this study.

Dosage was adjusted based on eGFR and BP in a pre-defined dosage adjustment protocol. Dosage adjustments should follow the dosage recommendations

[see Dosage and Administration]

The median age of patients was 31 years (range 18 to 72). The proportion of women was 88%. Approximately 36.1% were White, 9.5% were Black, 30.5% were Asian, 1.1% were American Indian or Alaska Native, and 22.7% were multiple race or other. Approximately 32.5% were Hispanic or Latino.

The mean (SD) daily dose of voclosporin was 41.3 (±9.7) mg/day. The mean (SD) daily dose of MMF was 1.9 (±0.4) g/day; 9% received >2 but ≤3 g/day of MMF. The mean (SD) daily dose of IV methylprednisolone (on Day 1 was 495 (±90) mg/day and Day 2 was 487 (±55) mg/day). The mean (SD) starting oral corticosteroid dose (Day 3) was 22.8 (±4.8) mg/day; approximately 81% received ≤2.5 mg/day of oral corticosteroids at Week 16.

The distribution by kidney biopsy class was Class III or IV (60.8%), Class III or IV in combination with Class V (24.9%), and Class V (14.3%). Mean (SD) eGFR on entry was 91 (±30) mL/min/1.73 m². Mean (SD) UPCR on entry was 4.0 (±2.5) mg/mg.

The primary efficacy endpoint was the proportion of patients achieving complete renal response at Week 52. Complete renal response was defined as follows (both must be met):

UPCR of ≤0.5 mg/mg, and
eGFR ≥60 mL/min/1.73 m²or no confirmed decrease from baseline in eGFR of >20% or no treatment- or disease-related eGFR-associated event (defined as blood creatinine increased, creatinine renal clearance decreased, glomerular filtration rate decreased, serum creatinine increased, renal impairment, renal failure, or renal failure acute) at time of assessment.

In order to be considered a responder, the patient must not have received more than 10 mg prednisone for ≥3 consecutive days or for ≥7 days in total during Weeks 44 through 52. Patients who received rescue medication or withdrew from the study were considered non-responders.

A higher proportion of patients in the LUPKYNIS arm than the placebo arm achieved complete renal response at Week 52 (Table 4).

Table 4: Complete Renal Response at Week 52 (Study 1)
	LUPKYNIS (N=179)	Placebo (N=178)	Odds Ratio
CI = Confidence interval; eGFR = Estimated glomerular filtration rate; UPCR = Urine protein to creatinine ratio. a. In order to be considered a responder, the patient must not have received more than 10 mg prednisone for ≥3 consecutive days or for ≥7 days in total during Weeks 44 through 52. Patients who received rescue medication or withdrew from the study were considered non-responders. b.Treatment- or disease-related eGFR-associated event is defined as blood creatinine increased, creatinine renal clearance decreased, glomerular filtration rate decreased, serum creatinine increased, renal impairment, renal failure, or renal failure acute.
Primary Endpoint
Complete Renal Response at Week 52 [n (%)]^a	73 (40.8)	40 (22.5)	2.7 (95% CI: 1.6, 4.3); p<0.001
Components of Primary Endpoint
UPCR ≤0.5 mg/mg [n (%)]	81 (45.3)	41 (23.0)	3.1 (95% CI: 1.9, 5.0)
eGFR ≥60 mL/min/1.73 m²or no confirmed decrease from baseline in eGFR of >20% or no treatment- or disease-related eGFR-associated adverse event^bat time of assessment [n (%)]	147 (82.1)	135 (75.8)	1.5 (95% CI: 0.8, 2.5)

A higher proportion of patients in the LUPKYNIS arm than the placebo arm achieved complete renal response at Week 24 (32.4% vs. 19.7%; odds ratio: 2.2; 95% CI: 1.3, 3.7). Time to UPCR of ≤0.5 mg/mg was shorter in the LUPKYNIS arm than the placebo arm (median time of 169 days vs. 372 days; hazard ratio: 2.0; 95% CI: 1.5, 2.7).

A 2-year extension study (NCT03597464) followed Study 1. After reconsenting, patients remained on blinded randomized treatment. From the LUPKYNIS arm, 116 patients (64.8%) and from the placebo arm, 100 patients (56.2%) agreed to continue treatment for up to a further 2 years. Over 52% of the 357 patients completed the study (LUPKYNIS 56.4%, placebo 47.8%); 51.4% of LUPKYNIS patients and 41.0% of placebo patients were still on study treatment at the end of study.

Among the 179 LUPKYNIS patients and 178 placebo patients who entered Study 1, 36 (20.1%) LUPKYNIS patients and 21 (11.8%) placebo patients were observed to achieve sustained complete renal response, where achieving sustained complete renal response is defined as achieving renal response at Month 12 and maintaining the renal response at each subsequent study visit through Month 36 (the end of the extension study). Thirty-nine (21.8%) LUPKYNIS subjects and 41 (23.0%) placebo subjects had missing data either at the end of the first year or by the end of the 2 year extension and therefore have an unknown status for sustained complete renal response.

(

14 CLINICAL STUDIES

A total of 357 patients with LN were randomized in a 1:1 ratio to receive either LUPKYNIS 23.7 mg twice daily or placebo.

Patients in both arms received background treatment with MMF and corticosteroids as follows:

Oral MMF at a target dose of 2 g/day (1 g twice a day). (Patients not already receiving MMF were started on MMF 500 mg twice a day with escalation to MMF 1 g twice a day after the first week.) Dose increases up to 3 g/day were allowed.
Intravenous (IV) methylprednisolone on Day 1 and Day 2 at a dose of 500 mg/day (body weight ≥45 kg) or 250 mg/day (body weight <45 kg) followed by a reducing taper of oral corticosteroids [oral prednisone 25 mg/day (body weight ≥45 kg) or 20 mg/day (body weight <45 kg); tapered to achieve a target dose of 2.5 mg/day by Week 16].

Patients with baseline eGFR ≤45 mL/min/1.73 m²were not enrolled in this study.

Dosage was adjusted based on eGFR and BP in a pre-defined dosage adjustment protocol. Dosage adjustments should follow the dosage recommendations

[see Dosage and Administration]

The primary efficacy endpoint was the proportion of patients achieving complete renal response at Week 52. Complete renal response was defined as follows (both must be met):

UPCR of ≤0.5 mg/mg, and
eGFR ≥60 mL/min/1.73 m²or no confirmed decrease from baseline in eGFR of >20% or no treatment- or disease-related eGFR-associated event (defined as blood creatinine increased, creatinine renal clearance decreased, glomerular filtration rate decreased, serum creatinine increased, renal impairment, renal failure, or renal failure acute) at time of assessment.

A higher proportion of patients in the LUPKYNIS arm than the placebo arm achieved complete renal response at Week 52 (Table 4).

Table 4: Complete Renal Response at Week 52 (Study 1)
	LUPKYNIS (N=179)	Placebo (N=178)	Odds Ratio
CI = Confidence interval; eGFR = Estimated glomerular filtration rate; UPCR = Urine protein to creatinine ratio. a. In order to be considered a responder, the patient must not have received more than 10 mg prednisone for ≥3 consecutive days or for ≥7 days in total during Weeks 44 through 52. Patients who received rescue medication or withdrew from the study were considered non-responders. b.Treatment- or disease-related eGFR-associated event is defined as blood creatinine increased, creatinine renal clearance decreased, glomerular filtration rate decreased, serum creatinine increased, renal impairment, renal failure, or renal failure acute.
Primary Endpoint
Complete Renal Response at Week 52 [n (%)]^a	73 (40.8)	40 (22.5)	2.7 (95% CI: 1.6, 4.3); p<0.001
Components of Primary Endpoint
UPCR ≤0.5 mg/mg [n (%)]	81 (45.3)	41 (23.0)	3.1 (95% CI: 1.9, 5.0)
eGFR ≥60 mL/min/1.73 m²or no confirmed decrease from baseline in eGFR of >20% or no treatment- or disease-related eGFR-associated adverse event^bat time of assessment [n (%)]	147 (82.1)	135 (75.8)	1.5 (95% CI: 0.8, 2.5)

)]

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.

LUPKYNIS is contraindicated in:

Patients concomitantly using strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin) because these medications can significantly increase exposure to LUPKYNIS which may increase the risk of acute and/or chronic nephrotoxicity

[see

5 WARNINGS AND PRECAUTIONS

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.
Hypersensitivity Reactions: Discontinue LUPKYNIS; treat and monitor until signs and symptoms resolve.
Immunizations: Avoid live vaccines.
Pure Red Cell Aplasia: Consider discontinuation.

5.1 Lymphoma and Other Malignancies

5.2 Serious 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]

. Monitor eGFR regularly during treatment, and consider dose reduction or discontinuation in patients with decreases in eGFR from baseline

[see Dosage and Administration]

; persistent decrease of eGFR should be evaluated for chronic calcineurin-inhibitor nephrotoxicity.

5.4 Hypertension

Hypertension is a common adverse reaction of LUPKYNIS therapy and may require antihypertensive therapy

[see Adverse Reactions]

. Some antihypertensive drugs can increase the risk for hyperkalemia

[see Warnings and Precautions(

5.6

)]

. Certain calcium-channel blocking agents (verapamil and diltiazem) may increase voclosporin blood concentrations and require dosage reduction of LUPKYNIS

[see Dosage and Administration and Drug Interactions]

[see Dosage and Administration]

5.5 Neurotoxicity

LUPKYNIS, like other calcineurin-inhibitors, may cause a spectrum of neurotoxicities

[see Adverse Reactions]

5.6 Hyperkalemia

Hyperkalemia, which may be serious and require treatment, has been reported with calcineurin inhibitors including LUPKYNIS

[see Adverse Reactions]

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]

. The use of LUPKYNIS in combination with other drugs that are known to prolong QTc may result in clinically significant QT prolongation.

5.8 Hypersensitivity Reactions

[see

Contraindications]

5.9 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.

5.10 Pure Red Cell Aplasia

(

5.3 Nephrotoxicity

LUPKYNIS, like other calcineurin-inhibitors, can cause acute and/or chronic nephrotoxicity. Nephrotoxicity was reported in clinical trials

[see Adverse Reactions]

. Monitor eGFR regularly during treatment, and consider dose reduction or discontinuation in patients with decreases in eGFR from baseline

[see Dosage and Administration]

; persistent decrease of eGFR should be evaluated for chronic calcineurin-inhibitor nephrotoxicity.

7 DRUG INTERACTIONS

Moderate CYP3A4 inhibitors: Reduce LUPKYNIS daily dosage to 15.8 mg in the morning and 7.9 mg in the evening.
Strong and moderate CYP3A4 inducers: Avoid co-administration.
Certain P-gp substrates: Reduce dosage of certain P-gp substrates with a narrow therapeutic window when co-administered with LUPKYNIS.

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]

, 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]

. Reduce LUPKYNIS dosage when co-administered with moderate CYP3A4 inhibitors (e.g., verapamil, fluconazole, diltiazem)

[see Dosage and Administration(

2.5

]

. 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]

, 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]

, 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_maxand AUC of the active metabolite simvastatin acid (an OATP1B1 substrate) by 3.1-fold and 1.8-fold, respectively

[see Clinical Pharmacology]

. 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.

(

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]

, 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]

. Reduce LUPKYNIS dosage when co-administered with moderate CYP3A4 inhibitors (e.g., verapamil, fluconazole, diltiazem)

[see Dosage and Administration(

2.5

]

. 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]

, which may decrease the efficacy of LUPKYNIS. Avoid co-administration of LUPKYNIS with strong or moderate CYP3A4 inducers.

), and

12 CLINICAL PHARMACOLOGY

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.

Absorption

The median T_maxof voclosporin is 1.5 hours (1 to 4 hours) when administered on an empty stomach.

Effect of Food

Co-administration of voclosporin with food decreased both the rate and extent of absorption: with either low- or high-fat meals, C_maxand AUC of voclosporin were reduced by 29% to 53% and 15% to 25%, respectively.

Distribution

The apparent volume of distribution (V_ss/F) of voclosporin is 2,154 L.

Protein binding of voclosporin is 97%. Voclosporin partitions extensively into red blood cells and distribution between whole blood and plasma is concentration- and temperature-dependent.

Elimination

The mean apparent clearance at steady-state (CL_ss/F) of voclosporin is 63.6 L/h, and mean terminal half-life (t_1/2) is approximately 30 hours (24.9 to 36.5 hours).

Metabolism

Voclosporin is predominantly metabolized by CYP3A4. Voclosporin is the major circulating component and the pharmacologic activity is mainly attributed to the parent molecule. A major metabolite in human whole blood represented 16.7% of total exposure and is about 8-fold less potent than the parent molecule.

Excretion

Following single oral administration of radiolabeled voclosporin 70 mg, 92.7% of the radioactivity was recovered in feces (including 5% as unchanged voclosporin), and 2.1% was recovered in urine (including 0.25% as unchanged voclosporin).

Specific Populations

There were no clinically significant differences in the pharmacokinetics of voclosporin based on age (18 to 66 years), sex, race (Caucasian, Black, Asian, other), or body weight (37 to 133 kg).

Patients with Renal Impairment

Voclosporin C_maxand AUC were similar in volunteers with mild (CL_Cr60 to 89 mL/min as estimated by Cockcroft-Gault) and moderate (CL_Cr30 to 59 mL/min) renal impairment compared to volunteers with normal renal function (CL_Cr≥90 mL/min). The C_maxand AUC increased 1.5- and 1.7-fold, respectively, in volunteers with severe renal impairment (CL_Cr<30 mL/min). The effect of end-stage renal disease (ESRD) with or without hemodialysis on the pharmacokinetics of voclosporin is unknown.

Patients with Hepatic Impairment

Voclosporin C_maxand AUC increased approximately 1.5- to 2.0-fold in volunteers with mild hepatic impairment (Child-Pugh A) or moderate hepatic impairment (Child-Pugh B). The effect of severe hepatic impairment (Child-Pugh C) on the pharmacokinetics of voclosporin is unknown.

Drug Interaction Studies

Effect of Other Drugs on LUPKYNIS

The effect of co‑administered drugs on the exposure of voclosporin is shown in Table 2.

Table 2: Change in Pharmacokinetics of Voclosporin in the Presence of Co-administered Drugs
Co-administered Drug	Regimen of Co-administered Drug	Ratio (90% CI)¹
Notes: CI = Confidence interval; CYP = Cytochrome P450; P-gp = P-glycoprotein; QD = once daily; TID = every 8 hours. ¹Ratios for C_maxand AUC compare co-administration of the medication with voclosporin vs. administration of voclosporin alone.
Co-administered Drug	Regimen of Co-administered Drug	C_max	AUC
Ketoconazole (strong CYP3A4 inhibitor)	400 mg QD for 9 days	6.45 (5.02, 8.29)	18.55 (15.89, 21.65)
Verapamil (moderate CYP3A4 and strong P-gp inhibitor)	80 mg TID for 10 days	2.08 (1.89, 2.28)	2.71 (2.56, 2.87)
Rifampin (strong CYP3A4 inducer)	600 mg QD for 10 days	0.32 (0.28, 0.37)	0.13 (0.11, 0.15)

Moderate CYP3A inhibitors:
Co-administration of multiple doses of fluconazole or diltiazem is predicted to increase voclosporin C_maxand AUC_0-12approximately 2- and 3-fold, respectively.
Weak CYP3A inhibitors:
Co-administration of multiple doses of fluvoxamine and cimetidine is predicted to have minimal effects on voclosporin C_maxand AUC_0-12.
Moderate CYP3A inducers:
Co-administration of multiple doses of efavirenz is predicted to decrease voclosporin C_maxand AUC_0-12by 61% and 70%, respectively.

In vitro, voclosporin is not a substrate for breast cancer resistance protein (BCRP) or organic anion transporting polypeptides OATP1B1 and OATP1B3.

Effect of LUPKYNIS on other Drugs

Voclosporin was studied on a background therapy that included MMF. Voclosporin 23.7 mg twice a day in patients with SLE (with or without LN) had no effect on mycophenolic acid (MPA) exposure. Also, clinical studies indicate that voclosporin is a weak inhibitor of P-gp and has no clinically relevant effects on the pharmacokinetics of the sensitive CYP3A4 substrate midazolam. However, voclosporin increased the systemic exposure of OATP1B1 substrated simvastatin and simvastatin acid. Summary of the results from clinical studies which evaluated the effect of voclosporin on other drugs is provided in Table 3.

Table 3: Change in Pharmacokinetics of Co-administered Drugs in the Presence of Voclosporin
Co-administered Drug	Multiple Dose Regimen of Voclosporin	Ratio (90% CI)¹
Notes: BID = twice daily; CI = Confidence interval; CYP = Cytochrome P450; MMF = mycophenolate mofetil; P-gp = P-glycoprotein. ¹Ratios for C_maxand AUC compare co-administration of the medication with voclosporin vs administration of the medication alone. ²Observed effect of voclosporin on MPA. ³Co-administration of voclosporin with simvastatin increased the C_maxof parent drug simvastatin by 1.6-fold but did not change AUC of simvastatin
Co-administered Drug	Multiple Dose Regimen of Voclosporin	C_max	AUC
MMF²(immunosuppressant)	23.7 mg BID	0.94 (0.77, 1.16)	1.09 (0.94, 1.26)
Digoxin (P-gp substrate)	0.4 mg/kg BID	1.51 (1.40, 1.63)	1.25 (1.19, 1.31)
Midazolam (sensitive CYP3A4 substrate)	0.4 mg/kg BID	0.89 (0.80, 0.99)	1.02 (0.93, 1.12)
Simvastatin acid (OATP1B1 substrate)³	23.7 mg BID	3.10 (2.58, 3.73)	1.84 (1.53, 2.20)

Based on in vitro studies, voclosporin does not inhibit BCRP, CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, or induce CYP1A2, 2B6, 3A4. Voclosporin is an inhibitor of OATP1B1 and OATP1B3.

(

12.3 Pharmacokinetics

Absorption

The median T_maxof voclosporin is 1.5 hours (1 to 4 hours) when administered on an empty stomach.

Effect of Food

Distribution

The apparent volume of distribution (V_ss/F) of voclosporin is 2,154 L.

Protein binding of voclosporin is 97%. Voclosporin partitions extensively into red blood cells and distribution between whole blood and plasma is concentration- and temperature-dependent.

Elimination

The mean apparent clearance at steady-state (CL_ss/F) of voclosporin is 63.6 L/h, and mean terminal half-life (t_1/2) is approximately 30 hours (24.9 to 36.5 hours).

Metabolism

Excretion

Specific Populations

There were no clinically significant differences in the pharmacokinetics of voclosporin based on age (18 to 66 years), sex, race (Caucasian, Black, Asian, other), or body weight (37 to 133 kg).

Patients with Renal Impairment

Patients with Hepatic Impairment

Drug Interaction Studies

Effect of Other Drugs on LUPKYNIS

The effect of co‑administered drugs on the exposure of voclosporin is shown in Table 2.

Table 2: Change in Pharmacokinetics of Voclosporin in the Presence of Co-administered Drugs
Co-administered Drug	Regimen of Co-administered Drug	Ratio (90% CI)¹
Notes: CI = Confidence interval; CYP = Cytochrome P450; P-gp = P-glycoprotein; QD = once daily; TID = every 8 hours. ¹Ratios for C_maxand AUC compare co-administration of the medication with voclosporin vs. administration of voclosporin alone.
Co-administered Drug	Regimen of Co-administered Drug	C_max	AUC
Ketoconazole (strong CYP3A4 inhibitor)	400 mg QD for 9 days	6.45 (5.02, 8.29)	18.55 (15.89, 21.65)
Verapamil (moderate CYP3A4 and strong P-gp inhibitor)	80 mg TID for 10 days	2.08 (1.89, 2.28)	2.71 (2.56, 2.87)
Rifampin (strong CYP3A4 inducer)	600 mg QD for 10 days	0.32 (0.28, 0.37)	0.13 (0.11, 0.15)

Moderate CYP3A inhibitors:
Co-administration of multiple doses of fluconazole or diltiazem is predicted to increase voclosporin C_maxand AUC_0-12approximately 2- and 3-fold, respectively.
Weak CYP3A inhibitors:
Co-administration of multiple doses of fluvoxamine and cimetidine is predicted to have minimal effects on voclosporin C_maxand AUC_0-12.
Moderate CYP3A inducers:
Co-administration of multiple doses of efavirenz is predicted to decrease voclosporin C_maxand AUC_0-12by 61% and 70%, respectively.

In vitro, voclosporin is not a substrate for breast cancer resistance protein (BCRP) or organic anion transporting polypeptides OATP1B1 and OATP1B3.

Effect of LUPKYNIS on other Drugs

Table 3: Change in Pharmacokinetics of Co-administered Drugs in the Presence of Voclosporin
Co-administered Drug	Multiple Dose Regimen of Voclosporin	Ratio (90% CI)¹
Notes: BID = twice daily; CI = Confidence interval; CYP = Cytochrome P450; MMF = mycophenolate mofetil; P-gp = P-glycoprotein. ¹Ratios for C_maxand AUC compare co-administration of the medication with voclosporin vs administration of the medication alone. ²Observed effect of voclosporin on MPA. ³Co-administration of voclosporin with simvastatin increased the C_maxof parent drug simvastatin by 1.6-fold but did not change AUC of simvastatin
Co-administered Drug	Multiple Dose Regimen of Voclosporin	C_max	AUC
MMF²(immunosuppressant)	23.7 mg BID	0.94 (0.77, 1.16)	1.09 (0.94, 1.26)
Digoxin (P-gp substrate)	0.4 mg/kg BID	1.51 (1.40, 1.63)	1.25 (1.19, 1.31)
Midazolam (sensitive CYP3A4 substrate)	0.4 mg/kg BID	0.89 (0.80, 0.99)	1.02 (0.93, 1.12)
Simvastatin acid (OATP1B1 substrate)³	23.7 mg BID	3.10 (2.58, 3.73)	1.84 (1.53, 2.20)

Based on in vitro studies, voclosporin does not inhibit BCRP, CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, or induce CYP1A2, 2B6, 3A4. Voclosporin is an inhibitor of OATP1B1 and OATP1B3.

)]

Patients with a history of serious or severe hypersensitivity reaction, including anaphylaxis, to LUPKYNIS or any of its excipients
[see
5 WARNINGS AND PRECAUTIONS
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.
Hypersensitivity Reactions: Discontinue LUPKYNIS; treat and monitor until signs and symptoms resolve.
Immunizations: Avoid live vaccines.
Pure Red Cell Aplasia: Consider discontinuation.
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]
. Monitor eGFR regularly during treatment, and consider dose reduction or discontinuation in patients with decreases in eGFR from baseline
[see Dosage and Administration]
; 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]
. Some antihypertensive drugs can increase the risk for hyperkalemia
[see Warnings and Precautions(
5.6
)]
. Certain calcium-channel blocking agents (verapamil and diltiazem) may increase voclosporin blood concentrations and require dosage reduction of LUPKYNIS
[see Dosage and Administration and Drug Interactions]
.
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]
.
5.5 Neurotoxicity
LUPKYNIS, like other calcineurin-inhibitors, may cause a spectrum of neurotoxicities
[see Adverse Reactions]
. 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]
. 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]
. 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 Hypersensitivity Reactions
Postmarketing cases of hypersensitivity reactions, including anaphylaxis and angioedema, have been reported with LUPKYNIS. If signs or symptoms of a hypersensitivity reaction occur, discontinue LUPKYNIS; treat and monitor until signs and symptoms resolve
[see
Contraindications]
.
5.9 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.
5.10 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.
(
5.8 Hypersensitivity Reactions
Postmarketing cases of hypersensitivity reactions, including anaphylaxis and angioedema, have been reported with LUPKYNIS. If signs or symptoms of a hypersensitivity reaction occur, discontinue LUPKYNIS; treat and monitor until signs and symptoms resolve
[see
Contraindications]
.
)]
.

The following clinically significant adverse reactions are described elsewhere in the labeling:

Lymphoma and Other Malignancies
[see
5 WARNINGS AND PRECAUTIONS
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.
Hypersensitivity Reactions: Discontinue LUPKYNIS; treat and monitor until signs and symptoms resolve.
Immunizations: Avoid live vaccines.
Pure Red Cell Aplasia: Consider discontinuation.
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]
. Monitor eGFR regularly during treatment, and consider dose reduction or discontinuation in patients with decreases in eGFR from baseline
[see Dosage and Administration]
; 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]
. Some antihypertensive drugs can increase the risk for hyperkalemia
[see Warnings and Precautions(
5.6
)]
. Certain calcium-channel blocking agents (verapamil and diltiazem) may increase voclosporin blood concentrations and require dosage reduction of LUPKYNIS
[see Dosage and Administration and Drug Interactions]
.
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]
.
5.5 Neurotoxicity
LUPKYNIS, like other calcineurin-inhibitors, may cause a spectrum of neurotoxicities
[see Adverse Reactions]
. 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]
. 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]
. 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 Hypersensitivity Reactions
Postmarketing cases of hypersensitivity reactions, including anaphylaxis and angioedema, have been reported with LUPKYNIS. If signs or symptoms of a hypersensitivity reaction occur, discontinue LUPKYNIS; treat and monitor until signs and symptoms resolve
[see
Contraindications]
.
5.9 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.
5.10 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.
(
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).
)]
Serious Infections
[see
5 WARNINGS AND PRECAUTIONS
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.
Hypersensitivity Reactions: Discontinue LUPKYNIS; treat and monitor until signs and symptoms resolve.
Immunizations: Avoid live vaccines.
Pure Red Cell Aplasia: Consider discontinuation.
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]
. Monitor eGFR regularly during treatment, and consider dose reduction or discontinuation in patients with decreases in eGFR from baseline
[see Dosage and Administration]
; 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]
. Some antihypertensive drugs can increase the risk for hyperkalemia
[see Warnings and Precautions(
5.6
)]
. Certain calcium-channel blocking agents (verapamil and diltiazem) may increase voclosporin blood concentrations and require dosage reduction of LUPKYNIS
[see Dosage and Administration and Drug Interactions]
.
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]
.
5.5 Neurotoxicity
LUPKYNIS, like other calcineurin-inhibitors, may cause a spectrum of neurotoxicities
[see Adverse Reactions]
. 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]
. 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]
. 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 Hypersensitivity Reactions
Postmarketing cases of hypersensitivity reactions, including anaphylaxis and angioedema, have been reported with LUPKYNIS. If signs or symptoms of a hypersensitivity reaction occur, discontinue LUPKYNIS; treat and monitor until signs and symptoms resolve
[see
Contraindications]
.
5.9 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.
5.10 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.
(
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.
)]
Nephrotoxicity due to LUPKYNIS and Drug Interactions
[see
5 WARNINGS AND PRECAUTIONS
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.
Hypersensitivity Reactions: Discontinue LUPKYNIS; treat and monitor until signs and symptoms resolve.
Immunizations: Avoid live vaccines.
Pure Red Cell Aplasia: Consider discontinuation.
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]
. Monitor eGFR regularly during treatment, and consider dose reduction or discontinuation in patients with decreases in eGFR from baseline
[see Dosage and Administration]
; 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]
. Some antihypertensive drugs can increase the risk for hyperkalemia
[see Warnings and Precautions(
5.6
)]
. Certain calcium-channel blocking agents (verapamil and diltiazem) may increase voclosporin blood concentrations and require dosage reduction of LUPKYNIS
[see Dosage and Administration and Drug Interactions]
.
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]
.
5.5 Neurotoxicity
LUPKYNIS, like other calcineurin-inhibitors, may cause a spectrum of neurotoxicities
[see Adverse Reactions]
. 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]
. 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]
. 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 Hypersensitivity Reactions
Postmarketing cases of hypersensitivity reactions, including anaphylaxis and angioedema, have been reported with LUPKYNIS. If signs or symptoms of a hypersensitivity reaction occur, discontinue LUPKYNIS; treat and monitor until signs and symptoms resolve
[see
Contraindications]
.
5.9 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.
5.10 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.
(
5.3 Nephrotoxicity
LUPKYNIS, like other calcineurin-inhibitors, can cause acute and/or chronic nephrotoxicity. Nephrotoxicity was reported in clinical trials
[see Adverse Reactions]
. Monitor eGFR regularly during treatment, and consider dose reduction or discontinuation in patients with decreases in eGFR from baseline
[see Dosage and Administration]
; 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.
)]
Hypertension
[see
5 WARNINGS AND PRECAUTIONS
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.
Hypersensitivity Reactions: Discontinue LUPKYNIS; treat and monitor until signs and symptoms resolve.
Immunizations: Avoid live vaccines.
Pure Red Cell Aplasia: Consider discontinuation.
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]
. Monitor eGFR regularly during treatment, and consider dose reduction or discontinuation in patients with decreases in eGFR from baseline
[see Dosage and Administration]
; 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]
. Some antihypertensive drugs can increase the risk for hyperkalemia
[see Warnings and Precautions(
5.6
)]
. Certain calcium-channel blocking agents (verapamil and diltiazem) may increase voclosporin blood concentrations and require dosage reduction of LUPKYNIS
[see Dosage and Administration and Drug Interactions]
.
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]
.
5.5 Neurotoxicity
LUPKYNIS, like other calcineurin-inhibitors, may cause a spectrum of neurotoxicities
[see Adverse Reactions]
. 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]
. 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]
. 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 Hypersensitivity Reactions
Postmarketing cases of hypersensitivity reactions, including anaphylaxis and angioedema, have been reported with LUPKYNIS. If signs or symptoms of a hypersensitivity reaction occur, discontinue LUPKYNIS; treat and monitor until signs and symptoms resolve
[see
Contraindications]
.
5.9 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.
5.10 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.
(
5.4 Hypertension
Hypertension is a common adverse reaction of LUPKYNIS therapy and may require antihypertensive therapy
[see Adverse Reactions]
. Some antihypertensive drugs can increase the risk for hyperkalemia
[see Warnings and Precautions(
5.6
)]
. Certain calcium-channel blocking agents (verapamil and diltiazem) may increase voclosporin blood concentrations and require dosage reduction of LUPKYNIS
[see Dosage and Administration and Drug Interactions]
.
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]
.
)]
Neurotoxicity
[see
5 WARNINGS AND PRECAUTIONS
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.
Hypersensitivity Reactions: Discontinue LUPKYNIS; treat and monitor until signs and symptoms resolve.
Immunizations: Avoid live vaccines.
Pure Red Cell Aplasia: Consider discontinuation.
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]
. Monitor eGFR regularly during treatment, and consider dose reduction or discontinuation in patients with decreases in eGFR from baseline
[see Dosage and Administration]
; 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]
. Some antihypertensive drugs can increase the risk for hyperkalemia
[see Warnings and Precautions(
5.6
)]
. Certain calcium-channel blocking agents (verapamil and diltiazem) may increase voclosporin blood concentrations and require dosage reduction of LUPKYNIS
[see Dosage and Administration and Drug Interactions]
.
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]
.
5.5 Neurotoxicity
LUPKYNIS, like other calcineurin-inhibitors, may cause a spectrum of neurotoxicities
[see Adverse Reactions]
. 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]
. 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]
. 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 Hypersensitivity Reactions
Postmarketing cases of hypersensitivity reactions, including anaphylaxis and angioedema, have been reported with LUPKYNIS. If signs or symptoms of a hypersensitivity reaction occur, discontinue LUPKYNIS; treat and monitor until signs and symptoms resolve
[see
Contraindications]
.
5.9 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.
5.10 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.
(
5.5 Neurotoxicity
LUPKYNIS, like other calcineurin-inhibitors, may cause a spectrum of neurotoxicities
[see Adverse Reactions]
. 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.
)]
Hyperkalemia
[see
5 WARNINGS AND PRECAUTIONS
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.
Hypersensitivity Reactions: Discontinue LUPKYNIS; treat and monitor until signs and symptoms resolve.
Immunizations: Avoid live vaccines.
Pure Red Cell Aplasia: Consider discontinuation.
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]
. Monitor eGFR regularly during treatment, and consider dose reduction or discontinuation in patients with decreases in eGFR from baseline
[see Dosage and Administration]
; 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]
. Some antihypertensive drugs can increase the risk for hyperkalemia
[see Warnings and Precautions(
5.6
)]
. Certain calcium-channel blocking agents (verapamil and diltiazem) may increase voclosporin blood concentrations and require dosage reduction of LUPKYNIS
[see Dosage and Administration and Drug Interactions]
.
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]
.
5.5 Neurotoxicity
LUPKYNIS, like other calcineurin-inhibitors, may cause a spectrum of neurotoxicities
[see Adverse Reactions]
. 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]
. 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]
. 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 Hypersensitivity Reactions
Postmarketing cases of hypersensitivity reactions, including anaphylaxis and angioedema, have been reported with LUPKYNIS. If signs or symptoms of a hypersensitivity reaction occur, discontinue LUPKYNIS; treat and monitor until signs and symptoms resolve
[see
Contraindications]
.
5.9 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.
5.10 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.
(
5.6 Hyperkalemia
Hyperkalemia, which may be serious and require treatment, has been reported with calcineurin inhibitors including LUPKYNIS
[see Adverse Reactions]
. 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.
)]
QTc Prolongation
[see
5 WARNINGS AND PRECAUTIONS
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.
Hypersensitivity Reactions: Discontinue LUPKYNIS; treat and monitor until signs and symptoms resolve.
Immunizations: Avoid live vaccines.
Pure Red Cell Aplasia: Consider discontinuation.
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]
. Monitor eGFR regularly during treatment, and consider dose reduction or discontinuation in patients with decreases in eGFR from baseline
[see Dosage and Administration]
; 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]
. Some antihypertensive drugs can increase the risk for hyperkalemia
[see Warnings and Precautions(
5.6
)]
. Certain calcium-channel blocking agents (verapamil and diltiazem) may increase voclosporin blood concentrations and require dosage reduction of LUPKYNIS
[see Dosage and Administration and Drug Interactions]
.
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]
.
5.5 Neurotoxicity
LUPKYNIS, like other calcineurin-inhibitors, may cause a spectrum of neurotoxicities
[see Adverse Reactions]
. 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]
. 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]
. 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 Hypersensitivity Reactions
Postmarketing cases of hypersensitivity reactions, including anaphylaxis and angioedema, have been reported with LUPKYNIS. If signs or symptoms of a hypersensitivity reaction occur, discontinue LUPKYNIS; treat and monitor until signs and symptoms resolve
[see
Contraindications]
.
5.9 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.
5.10 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.
(
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]
. 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.
)]
Hypersensitivity Reactions
[see
5 WARNINGS AND PRECAUTIONS
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.
Hypersensitivity Reactions: Discontinue LUPKYNIS; treat and monitor until signs and symptoms resolve.
Immunizations: Avoid live vaccines.
Pure Red Cell Aplasia: Consider discontinuation.
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]
. Monitor eGFR regularly during treatment, and consider dose reduction or discontinuation in patients with decreases in eGFR from baseline
[see Dosage and Administration]
; 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]
. Some antihypertensive drugs can increase the risk for hyperkalemia
[see Warnings and Precautions(
5.6
)]
. Certain calcium-channel blocking agents (verapamil and diltiazem) may increase voclosporin blood concentrations and require dosage reduction of LUPKYNIS
[see Dosage and Administration and Drug Interactions]
.
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]
.
5.5 Neurotoxicity
LUPKYNIS, like other calcineurin-inhibitors, may cause a spectrum of neurotoxicities
[see Adverse Reactions]
. 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]
. 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]
. 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 Hypersensitivity Reactions
Postmarketing cases of hypersensitivity reactions, including anaphylaxis and angioedema, have been reported with LUPKYNIS. If signs or symptoms of a hypersensitivity reaction occur, discontinue LUPKYNIS; treat and monitor until signs and symptoms resolve
[see
Contraindications]
.
5.9 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.
5.10 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.
(
5.8 Hypersensitivity Reactions
Postmarketing cases of hypersensitivity reactions, including anaphylaxis and angioedema, have been reported with LUPKYNIS. If signs or symptoms of a hypersensitivity reaction occur, discontinue LUPKYNIS; treat and monitor until signs and symptoms resolve
[see
Contraindications]
.
)]
Immunizations
[see
5 WARNINGS AND PRECAUTIONS
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.
Hypersensitivity Reactions: Discontinue LUPKYNIS; treat and monitor until signs and symptoms resolve.
Immunizations: Avoid live vaccines.
Pure Red Cell Aplasia: Consider discontinuation.
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]
. Monitor eGFR regularly during treatment, and consider dose reduction or discontinuation in patients with decreases in eGFR from baseline
[see Dosage and Administration]
; 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]
. Some antihypertensive drugs can increase the risk for hyperkalemia
[see Warnings and Precautions(
5.6
)]
. Certain calcium-channel blocking agents (verapamil and diltiazem) may increase voclosporin blood concentrations and require dosage reduction of LUPKYNIS
[see Dosage and Administration and Drug Interactions]
.
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]
.
5.5 Neurotoxicity
LUPKYNIS, like other calcineurin-inhibitors, may cause a spectrum of neurotoxicities
[see Adverse Reactions]
. 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]
. 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]
. 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 Hypersensitivity Reactions
Postmarketing cases of hypersensitivity reactions, including anaphylaxis and angioedema, have been reported with LUPKYNIS. If signs or symptoms of a hypersensitivity reaction occur, discontinue LUPKYNIS; treat and monitor until signs and symptoms resolve
[see
Contraindications]
.
5.9 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.
5.10 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.
(
5.9 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.
)
]
Pure Red Cell Aplasia
[see
5 WARNINGS AND PRECAUTIONS
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.
Hypersensitivity Reactions: Discontinue LUPKYNIS; treat and monitor until signs and symptoms resolve.
Immunizations: Avoid live vaccines.
Pure Red Cell Aplasia: Consider discontinuation.
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]
. Monitor eGFR regularly during treatment, and consider dose reduction or discontinuation in patients with decreases in eGFR from baseline
[see Dosage and Administration]
; 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]
. Some antihypertensive drugs can increase the risk for hyperkalemia
[see Warnings and Precautions(
5.6
)]
. Certain calcium-channel blocking agents (verapamil and diltiazem) may increase voclosporin blood concentrations and require dosage reduction of LUPKYNIS
[see Dosage and Administration and Drug Interactions]
.
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]
.
5.5 Neurotoxicity
LUPKYNIS, like other calcineurin-inhibitors, may cause a spectrum of neurotoxicities
[see Adverse Reactions]
. 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]
. 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]
. 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 Hypersensitivity Reactions
Postmarketing cases of hypersensitivity reactions, including anaphylaxis and angioedema, have been reported with LUPKYNIS. If signs or symptoms of a hypersensitivity reaction occur, discontinue LUPKYNIS; treat and monitor until signs and symptoms resolve
[see
Contraindications]
.
5.9 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.
5.10 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.
(
5.10 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.
)]

LUPKYNIS (voclosporin) capsules, a calcineurin-inhibitor immunosuppressant, is available for administration as soft gelatin capsules containing 7.9 mg voclosporin per capsule. Inactive ingredients include alcohol, Vitamin E polyethylene glycol succinate (NF), polysorbate 40 (NF), medium-chain triglycerides (NF), gelatin, sorbitol, glycerin, iron oxide yellow, iron oxide red, titanium dioxide, and water.

Voclosporin (90 to 95%

trans

-isomer) is the active ingredient in LUPKYNIS. Chemically, voclosporin is named: Cyclo{{(6E)-(2S,3R,4R)-3-hydroxy-4-methyl-2-(methylamino)-6,8-nonadienoyl}-L-2-aminobutyryl-N-methyl-glycyl-N-methyl-L-leucyl-L-valyl-N-methyl-L-leucyl-L-alanyl-D-alanyl-N-methyl-L-leucyl-N-methyl-L-leucyl-N-methyl-L-valyl}. The chemical structure of voclosporin is:
Referenced Image

Voclosporin has an empirical formula of C
₆₃H
₁₁₁N
₁₁O
₁₂and a molecular weight of 1214.6 g/mole. It appears as white to off-white solid matter. At ambient temperature, voclosporin is freely soluble in acetone, acetonitrile, ethanol, and methanol, and practically insoluble in heptanes (USP). Voclosporin is practically insoluble (less than 0.1 g/L at 20ºC) in water and melts above 144ºC with decomposition.

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