DRUG INTERACTIONS- (summary)

 • 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.

DRUG INTERACTIONS(details)

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, which may increase the risk of LUPKYNIS adverse reactions. Co-administration of LUPKYNIS with strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin) is contraindicated

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

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

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 ], 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 The effect of LUPKYNIS on OATP1B1 substrates (e.g., statins) has not been studied clinically.

However, voclosporin is an OATP1B1 inhibitor in vitro, and information suggests an increase in the concentration of these substrates is possible. Monitor for adverse reactions of OATP1B1 substrates when used concomitantly with LUPKYNIS.

BRIEF SUMMARY

VOCLOSPORIN- (Jan 2021)

Indn-  To treat lupus nephritis

Comp- Capsules: 7.9 mg . Administer consistently as close to a 12-hour schedule as possible, and with at least 8 hours between doses.

  If a dose is missed, instruct the patient to take it as soon as possible within 4 hours after missing the dose. Beyond the 4-hour time frame, instruct the patient to wait until the usual scheduled time to take the next regular dose. Instruct the patient not to double the next dose.

ADR- The most commonly reported adverse reactions (=3%) were: glomerular filtration rate decreased, hypertension, diarrhea, headache, anemia, cough, urinary tract infection, abdominal pain upper, dyspepsia, alopecia, renal impairment,

CI- Known serious or severe hypersensitivity reaction to LUPKYNIS or any of its excipients.

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.

Pat inform

 • Swallow capsules whole, and not to open, crush, or divide capsules.

 • Take  on an empty stomach consistently as close to a 12-hour schedule as possible, and with a minimum of 8 hours between doses.

• If a dose is missed, take it as soon as possible within 4 hours after missing the dose. Beyond the 4-hour time frame, wait until the usual scheduled time to take the next regular dose. Do not double the next dose.

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

U.S. FDA APPROVED DRUGS SURING 2021                                          

Serial No 3

Name of the Drug-    LUPKYNIS

Active Ingredient -     Voclosporin

Pharmacological Classification-   To treat lupus nephritis

Date of Approval-          1/22/2021

HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use                            LUPKYNISTM safely and effectively.                                                                                  See full prescribing information for LUPKYNIS. LUPKYNIS (voclosporin) capsules, for oral use

Initial U.S. Approval: 2021

WARNING: MALIGNANCIES AND SERIOUS INFECTIONS-

See full prescribing information for complete boxed warning. Increased risk for developing serious infections and malignancies with LUPKYNIS or other immunosuppressants that may lead to hospitalization or death.

INDICATIONS AND USAGE-

 LUPKYNIS is a calcineurin-inhibitor immunosuppressant indicated in combination with a background immunosuppressive therapy regimen for the treatment of adult patients with active lupus nephritis (LN).

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

DOSAGE AND ADMINISTRATION-

 Administration:                                                                                                                 •  LUPKYNIS must be swallowed whole on an empty stomach.

 • Administer consistently as close to a 12-hour schedule as possible, and with at least 8 hours between doses.

 • If a dose is missed, instruct the patient to take it as soon as possible within 4 hours after missing the dose. Beyond the 4-hour time frame, instruct the patient to wait until the usual scheduled time to take the next regular dose. Instruct the patient not to double the next dose.

 • Instruct patients to avoid eating grapefruit or drinking grapefruit juice while taking LUPKYNIS.

 Dosage Recommendations:                                                                                              • Before initiating LUPKYNIS, establish an accurate baseline estimated glomerular filtration rate (eGFR) and check blood pressure (BP). o Use of LUPKYNIS is not recommended in patients with a baseline eGFR =45 mL/min/1.73 m2 unless the benefit exceeds the risk; these patients may be at increased risk for acute and/or chronic nephrotoxicity. (2.2, 5.3) o Do not initiate LUPKYNIS in patients with baseline BP >165/105 mmHg or with hypertensive emergency.

 • Recommended starting dose: 23.7 mg orally, twice a day.

 • Use LUPKYNIS in combination with mycophenolate mofetil (MMF) and corticosteroids.

 • Modify the LUPKYNIS dose based on eGFR (2.3, 5.3):                                                  o Assess eGFR every two weeks for the first month, and every four weeks thereafter.     

o If eGFR <60 mL/min/1.73 m2 and reduced from baseline by >20% and <30%, reduce the dose by 7.9 mg twice a day. Reassess eGFR within two weeks; if eGFR is still reduced from baseline by >20%, reduce the dose again by 7.9 mg twice a day.               

o If eGFR <60 mL/min/1.73 m2 and reduced from baseline by =30%, discontinue LUPKYNIS. Re-assess eGFR within two weeks; consider re-initiating LUPKYNIS at a lower dose (7.9 mg twice a day) only if eGFR has returned to =80% of baseline.

o For patients that had a decrease in dose due to eGFR, consider increasing the dose by 7.9 mg twice a day for each eGFR measurement that is =80% of baseline; do not exceed the starting dose.

• Monitor blood pressure every two weeks for the first month after initiating LUPKYNIS, and as clinically indicated thereafter. For patients with BP >165/105 mmHg or with hypertensive emergency, discontinue LUPKYNIS and initiate antihypertensive therapy.

 • If the patient has not experienced therapeutic benefit by 24 weeks, consider discontinuation of LUPKYNIS. 

ADVERSE REACTIONS-

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

CONTRAINDICATIONS-

 • Patients concomitantly using strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin).

 • Known serious or severe hypersensitivity reaction to LUPKYNIS or any of its excipients.

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.

 • Immunizations: Avoid live vaccines.

 • Pure Red Cell Aplasia: Consider discontinuation. 

DOSAGE AND ADMINISTRATION-

 Administration:                                                                                                                 •  LUPKYNIS must be swallowed whole on an empty stomach.

 • Administer consistently as close to a 12-hour schedule as possible, and with at least 8 hours between doses.

 • If a dose is missed, instruct the patient to take it as soon as possible within 4 hours after missing the dose. Beyond the 4-hour time frame, instruct the patient to wait until the usual scheduled time to take the next regular dose. Instruct the patient not to double the next dose.

 • Instruct patients to avoid eating grapefruit or drinking grapefruit juice while taking LUPKYNIS.

 Dosage Recommendations:                                                                                              • Before initiating LUPKYNIS, establish an accurate baseline estimated glomerular filtration rate (eGFR) and check blood pressure (BP). o Use of LUPKYNIS is not recommended in patients with a baseline eGFR =45 mL/min/1.73 m2 unless the benefit exceeds the risk; these patients may be at increased risk for acute and/or chronic nephrotoxicity. (2.2, 5.3) o Do not initiate LUPKYNIS in patients with baseline BP >165/105 mmHg or with hypertensive emergency.

 • Recommended starting dose: 23.7 mg orally, twice a day.

 • Use LUPKYNIS in combination with mycophenolate mofetil (MMF) and corticosteroids.

 • Modify the LUPKYNIS dose based on eGFR (2.3, 5.3):                                                  o Assess eGFR every two weeks for the first month, and every four weeks thereafter.     

o If eGFR <60 mL/min/1.73 m2 and reduced from baseline by >20% and <30%, reduce the dose by 7.9 mg twice a day. Reassess eGFR within two weeks; if eGFR is still reduced from baseline by >20%, reduce the dose again by 7.9 mg twice a day.               

o If eGFR <60 mL/min/1.73 m2 and reduced from baseline by =30%, discontinue LUPKYNIS. Re-assess eGFR within two weeks; consider re-initiating LUPKYNIS at a lower dose (7.9 mg twice a day) only if eGFR has returned to =80% of baseline.

o For patients that had a decrease in dose due to eGFR, consider increasing the dose by 7.9 mg twice a day for each eGFR measurement that is =80% of baseline; do not exceed the starting dose.

• Monitor blood pressure every two weeks for the first month after initiating LUPKYNIS, and as clinically indicated thereafter. For patients with BP >165/105 mmHg or with hypertensive emergency, discontinue LUPKYNIS and initiate antihypertensive therapy.

 • If the patient has not experienced therapeutic benefit by 24 weeks, consider discontinuation of LUPKYNIS. 

Consider the risks and benefits of LUPKYNIS treatment beyond one year in light of the patient’s treatment response and risk of worsening nephrotoxicity.

 Dosage Adjustments:                                                                                                       • Patients with severe renal impairment: the recommended dose is 15.8 mg twice daily.

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

DOSAGE FORMS AND STRENGTHS-                                                                     Capsules: 7.9 mg 

17 PATIENT COUNSELING INFORMATION -                                                                   Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Administration Advise patients to:                                                                                      • Swallow LUPKYNIS capsules whole, and not to open, crush, or divide LUPKYNIS capsules.

 • Take LUPKYNIS on an empty stomach consistently as close to a 12-hour schedule as possible, and with a minimum of 8 hours between doses.

• If a dose is missed, take it as soon as possible within 4 hours after missing the dose. Beyond the 4-hour time frame, wait until the usual scheduled time to take the next regular dose. Do not double the next dose.

• Avoid eating grapefruit or drinking grapefruit juice while taking LUPKYNIS. Development of Lymphoma and Other Malignancies Inform patients that they are at an increased risk of developing lymphomas and other malignancies, particularly of the skin, due to immunosuppression.

Advise patients to limit exposure to sunlight and ultraviolet (UV) light by wearing protective clothing and use a sunscreen with a high protection factor 

Increased Risk of Infection Inform patients that they are at an increased risk of developing a variety of infections, including opportunistic infections, due to immunosuppression and to contact their physician if they develop any symptoms of infection such as fever, sweats or chills, cough or flu-like symptoms, muscle aches, or warm, red, painful areas on the skin [see Boxed Warning and Warnings and Precautions (5.2)].

Nephrotoxicity (Acute and/or Chronic) Inform patients that LUPKYNIS can have toxic effects on the kidney that should be monitored. Advise patients to attend all visits and complete all blood tests ordered by their medical team .

Hypertension Inform patients that LUPKYNIS can cause high blood pressure which may require treatment with antihypertensive therapy.

Advise patients to monitor their blood pressure [see Warnings and Precautions (5.4)].

Neurotoxicity Inform patients that they are at risk of developing adverse neurologic effects including seizure, altered mental status, and tremor.

Advise patients to contact their physician should they develop vision changes, delirium, or tremors [see Warnings and Precautions (5.5)].

Hyperkalemia Inform patients that LUPKYNIS can cause hyperkalemia. Monitoring of potassium levels may be necessary, especially with concomitant use of other drugs known to cause hyperkalemia.

Drug Interactions-                                                                                                             Advise patients to tell their healthcare provider when they start or stop taking any concomitant medications.

Strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin) are contraindicated with LUPKYNIS, and other CYP3A4 enzyme modulating drugs can alter LUPKYNIS exposure

Pregnancy-                                                                                                                         Inform female patients of the potential risk to a fetus and to avoid use of LUPKYNIS during pregnancy. When LUPKYNIS is administered in combination with MMF, refer patients to the MMF medication guide.

Advise females to inform their healthcare provider if they are pregnant or become pregnant 

Lactation-                                                                                                                         Advise women not to breastfeed during treatment with LUPKYNIS and for 7 days after the last dose of LUPKYNIS 

Immunizations-                                                                                                                        Inform patients that LUPKYNIS can interfere with the usual response to immunizations and that they should avoid live vaccines 

Manufactured for: Aurinia Pharmaceuticals Inc. #1203-4464 Markham Street Victoria, BC V8Z7X8 Canada Distributed by: Aurinia Pharma U.S., Inc. 77 Upper Rock Circle Suite 700 Rockville, MD 20850 USA Reference ID: 4735432

Medication Guide LUPKYNIS™ (loop kye’ nis) (voclosporin) capsules, for oral use Read this Medication Guide before you start taking LUPKYNIS and each time you get a refill. There may be new information. This information does not take the place of talking with your healthcare provider about your medical condition or your treatment. If you have any questions about LUPKYNIS, ask your healthcare provider or pharmacist. What is the most important information I should know about LUPKYNIS? LUPKYNIS can cause serious side effects, including: • Increased risk of cancer. People who take LUPKYNIS have an increased risk of getting certain kinds of cancer, including skin cancer and cancer of the lymph glands (lymphoma). • Increased risk of infection. LUPKYNIS is a medicine that affects your immune system. LUPKYNIS can lower the ability of your immune system to fight infections. Serious infections can happen in people receiving LUPKYNIS that can lead to hospitalizations and can cause death. Call your healthcare provider right away if you have symptoms of an infection such as: • fever • cough or flu-like symptoms • warm, red, or painful areas on your • sweats or chills • muscle aches skin See “What are the possib

CLINICAL PHARMACOLOGY -

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).

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.

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 Tmax of 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, Cmax and AUC of voclosporin were reduced by 29% to 53% and 15% to 25%, respectively.

Distribution-                                                                                                                   The apparent volume of distribution (Vss/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 (CLss/F) of voclosporin is 63.6 L/h, and mean terminal half-life (t1/2) 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 Cmax and AUC were similar in volunteers with mild (CLCr 60 to 89 mL/min as estimated by Cockcroft-Gault) and moderate (CLCr 30 to 59 mL/min) renal impairment compared to volunteers with normal renal function (CLCr =90 mL/min).

The Cmax and AUC increased 1.5- and 1.7-fold, respectively, in volunteers with severe renal impairment (CLCr <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 Cmax and 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-                                                                          

• Moderate CYP3A inhibitors: Co-administration of multiple doses of fluconazole or diltiazem is predicted to increase voclosporin Cmax and AUC0-12 approximately 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 Cmax and AUC0-12.

• Moderate CYP3A inducers: Co-administration of multiple doses of efavirenz is predicted to decrease voclosporin Cmax and AUC0-12 by 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.

 USE IN SPECIFIC POPULATIONS

1. Pregnancy Risk Summary-

 Avoid use of LUPKYNIS in pregnant women due to the alcohol content of the drug formulation. The available data on the use of LUPKYNIS in pregnant patients are insufficient to determine whether there is a drug-associated risk for major birth defects, miscarriage, or adverse maternal or fetal outcomes.

There are risks to the mother and fetus associated with systemic lupus erythematosus (SLE) (see Clinical Considerations). LUPKYNIS may be used in combination with a background immunosuppressive therapy regimen that includes MMF. MMF used in pregnant women and men whose female partners are pregnant can cause fetal harm (major birth defects and miscarriage). .

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

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

2. Lactation Risk Summary-                                                                                      There are no available data on the presence of voclosporin in human milk, the effects on the breastfed infant, or the effects on milk production. Voclosporin is present in milk of lactating rats. When a drug is present in animal milk, it is likely that the drug will be present in human milk.

Given the serious adverse reactions seen in adult patients treated with LUPKYNIS such as increased risk of serious infections, advise patients that breastfeeding is not recommended during treatment and for at least 7 days after the last dose of LUPKYNIS (approximately 6 elimination half-lives).

3. Females and Males of Reproductive Potential-                                                    LUPKYNIS may be used in combination with a background immunosuppressive therapy regimen that includes MMF. If LUPKYNIS is administered with MMF, the information for MMF regarding pregnancy testing, contraception, and infertility also applies to this combination regimen.

4. Pediatric Use -                                                                                                            The safety and efficacy of LUPKYNIS in pediatric patients has not been established.

5. Geriatric Use-                                                                                                               Clinical studies of LUPKYNIS did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients.

In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

6. Renal Impairment-                                                                                                     Use of LUPKYNIS is not recommended in patients with a baseline eGFR =45 mL/min/1.73 m2 unless the benefit exceeds the risk. If used in patients with severe renal impairment at baseline,

LUPKYNIS should be used at a reduced dose . No dosage adjustment is recommended in patients with mild or moderate renal impairment at baseline.

Monitor eGFR closely. After initiating therapy, dosing adjustments should be made based on eGFR

7. Hepatic Impairment -                                                                                                       In patients with mild and moderate hepatic impairment (Child-Pugh A and Child-Pugh B), reduce the LUPKYNIS dosage 

Avoid LUPKYNIS in patients with severe hepatic impairment (Child-Pugh C) 

 OVERDOSAGE-                                                                                                                   Cases of accidental overdose have been reported with LUPKYNIS; symptoms may include tremor, headache, nausea and vomiting, infections, tachycardia, urticaria, lethargy, and increases in blood urea nitrogen, serum creatinine, and alanine aminotransferase levels. No specific antidote to LUPKYNIS therapy is available.

If overdose occurs, general supportive measures and symptomatic treatment should be conducted, including stopping treatment with LUPKYNIS and assessing blood urea nitrogen, serum creatinine, eGFR and alanine aminotransferase levels.

Consider contacting a poison center (1-800-221-2222) or medical toxicologist for advice and review of overdosage management recommendations.