LUPKYNIS 7.9mg capsule me medication leaflet

Lupkynis 7.9 mg soft capsules

Each soft capsule contains 7.9 mg of voclosporin.

Each soft capsule contains 21.6 mg ethanol and 28.7 mg sorbitol.

Lupkynis may contain trace amounts of soya lecithin, see section 4.4.

For the full list of excipients, see section 6.1.

Soft capsule (capsule)

Pink/orange oval soft capsules measuring approximately 13 mm × 6 mm.

Lupkynis is indicated in combination with mycophenolate mofetil for the treatment of adult patientswith active class III, IV or V (including mixed class III/V and IV/V) lupus nephritis (LN).

Lupkynis treatment should be initiated and supervised by a qualified physician experienced in thediagnosis and treatment of lupus nephritis.

The recommended dose is 23.7 mg (three 7.9 mg soft capsules), twice daily.

It is recommended that Lupkynis is administered consistently as close to a 12-hour schedule aspossible and with a minimum of 8 hours between each dose. If a dose is missed, it should be taken assoon as possible within 4 hours after missing the dose; beyond the 4-hour time frame, the next regulardose should be taken at the usual scheduled time. The next dose should not be doubled.

Lupkynis should be used in combination with mycophenolate mofetil.

Physicians should evaluate the efficacy of treatment at a time point of at least 24 weeks and make anappropriate risk-benefit analysis for continuation of therapy.

Dose adjustment based on eGFR

It is recommended to establish a baseline estimated glomerular filtration rate (eGFR) before startingtreatment with voclosporin, and assess every two weeks for the first month, and every four weeksthereafter.

Dose adjustments are required for those individuals whose eGFR is confirmed to be reduced (i.e., twoconsecutive assessments within 48 hours) and below 60 mL/min/1.73 m2. If eGFR remains ≥ 60mL/min/1.73 m2 no dose modification is required (see table 1).

Table 1: Recommended dose adjustments based on eGFR

Confirmed eGFR Recommendationdecrease from baseline1≥ 30 % reduction Stop administration of voclosporin. Restart treatment upon eGFRrecovery at 7.9 mg (1 capsule) twice daily and increase as toleratedbased on renal function.

> 20 % and < 30 % Reduce dose of voclosporin by 7.9 mg (1 capsule) twice daily.reduction Retest within two weeks; if eGFR decrease has not recovered, reducedose by further 7.9 mg (one capsule) twice daily.≤ 20 % reduction Maintain current dose and monitor.

1 If eGFR remains ≥ 60 mL/min/1.73 m2 no action is required

It is recommended that patients requiring a reduction in dose are reassessed for eGFR recovery withintwo weeks. For patients that had a decrease in dose due to eGFR reduction, increasing the dose by 7.9mg twice a day for each eGFR measurement that is ≥ 80 % of baseline should be considered; thestarting dose should not be exceeded.

Co-administration with moderate CYP3A4 inhibitors

When co-administering Lupkynis with moderate cytochrome P450 (CYP)3A4 inhibitors (e.g.,verapamil, fluconazole, diltiazem), daily dose must be reduced to 15.8 mg in the morning and 7.9 mgin the evening (see section 4.5).

In patients with mild and moderate hepatic impairment (Child-Pugh Class A and B, respectively), therecommended starting dose is 15.8 mg twice daily. The effect of voclosporin in patients with severehepatic impairment (Child-Pugh Class C) has not been assessed and voclosporin is not recommendedin this patient population (see sections 4.4 and 5.2).

Careful monitoring of renal function is recommended (see table 1 and section 4.4). Limited data areavailable on the use of Lupkynis in patients with baseline eGFR 30 to < 45 mL/min/1.73 m2. It isrecommended to use Lupkynis in these patients, only if the benefit outweighs the risk, and at a startingdose of 23.7 mg twice daily.

Lupkynis has not been studied in patients with severe renal impairment (eGFR < 30 mL/min/1.73 m2)and is not recommended in these patients unless the benefit outweighs the risk. If used, therecommended starting dose is 15.8 mg twice daily (see section 5.2).

Data are limited in LN patients > 65 years, and there are no data in patients aged > 75 years. Lupkynisis not recommended in patients > 75 years of age (see section 5.2).

The safety and efficacy of Lupkynis in children and adolescents aged 5 to 18 years have not yet beenestablished. No data are available.

There is no relevant use of Lupkynis in children below the age of 5 years in lupus nephritis.

Oral use.

The soft capsules must be swallowed whole and can be taken with or without food.

It is recommended not to take Lupkynis with grapefruit or grapefruit juice (see section 4.5).

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Co-administration of voclosporin with strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole,clarithromycin) (see section 4.5).

Lymphomas and other malignancies

Immunosuppressants increase the risk of developing lymphomas and other malignancies, particularlyof the skin. It is recommended that patients are advised to avoid or limit unprotected exposure tosunlight and UV light.

Immunosuppressants, including voclosporin, may increase the risk of developing bacterial, viral,fungal, and protozoal infections, including opportunistic infections which may be serious or fatal (seesection 4.8). Patients must be monitored closely for infections during treatment with voclosporin. If aninfection occurs, the benefit of continuing voclosporin should be assessed in consideration of the riskof continued administration.

Renal toxicity

As with other calcineurin-inhibitors, adverse reactions of acute worsening of renal function or eGFRdecreases have been seen in patients treated with voclosporin. In the first four weeks of treatment withvoclosporin, haemodynamic reductions in eGFR have been observed (see section 4.8). This can bemanaged by dose adjustments. Regular monitoring of eGFR levels is recommended (see section 4.2).

Pure red cell aplasia

Cases of pure red cell aplasia (PRCA) have been reported in patients treated with a differentcalcineurin inhibitor. All of these patients had risk factors for PRCA, such as a parvovirus B19infection, a primary disease or concomitant treatments associated with PRCA. The mechanism of

PRCA due to calcineurin inhibitors has not been clarified. If PRCA is diagnosed, discontinuation of

Lupkynis should be considered.

Hyperkalaemia, which may be serious and require treatment, has been reported with calcineurininhibitors, including voclosporin (see section 4.8). Concomitant use of medicinal products associatedwith hyperkalaemia (e.g., potassium-sparing diuretics, angiotensin converting enzyme (ACE)inhibitors, angiotensin receptor blockers (ARBs)) may increase the risk of hyperkalaemia. It isrecommended that patients are monitored for serum potassium levels periodically during treatment.

Voclosporin can cause or worsen systemic hypertension (see section 4.8). Blood pressure should bemonitored every two weeks for the first month after initiating voclosporin, and as clinically indicatedthereafter. In the event of clinically concerning elevated blood pressure, the recommendations in table2 should be followed.

Table 2: Recommendations for management of hypertension

Blood pressure Recommendation

Systolic pressure > 130 and ≤ 165 mmHg Antihypertensive therapy may beand initiated/adjusted

Diastolic pressure > 80 and ≤ 105 mmHg

Blood pressure > 165/105 mmHg, with Stop administration of voclosporin andsymptoms of hypertension initiate/adjust antihypertensive therapy

The use of voclosporin in combination with other medicinal products that are known to prolong QTcmay result in clinically significant QT prolongation. Certain circumstances may increase the risk ofthe occurrence of torsade de pointes and/or sudden death in association with the use of medicinalproducts that prolong the QTc interval, including bradycardia; hypokalaemia or hypomagnesaemia;concomitant use of other medicinal products that prolong the QTc interval; and the presence ofcongenital prolongation of the QT interval.

Neurotoxicity

Patients receiving immunosuppressive therapies, including voclosporin, are at increased risk ofneurotoxicity (see section 4.8). Patients should be monitored for new-onset or worsening ofneurological symptoms including seizures, tremors, or signs and symptoms suggestive of posteriorreversible encephalopathy syndrome (PRES) and reduction or discontinuation of voclosporin shouldbe considered if these occur.

Voclosporin has not been studied in patients with severe hepatic impairment (Child-Pugh Class C)and, therefore, it is not recommended for use in this patient population.

Immunosuppressants may affect the response to vaccination, and vaccination during treatment withvoclosporin may be less effective. The use of live attenuated vaccines should be avoided.

Co-administration of voclosporin with moderate or strong CYP3A4 inducers is not recommended (seesection 4.5).

The safety and efficacy of voclosporin have not been established in combination withcyclophosphamide.

This medicinal product contains 21.6 mg of alcohol (ethanol) in each soft capsule. Therefore, a dose of23.7 mg of Lupkynis contains 64.8 mg ethanol. The amount in each 23.7 mg dose of this medicinalproduct is equivalent to less than 2 mL beer or 1 mL wine. The small amount of alcohol in thismedicinal product will not have any noticeable effects.

Sorbitol

This medicinal product contains 28.7 mg of sorbitol in each soft capsule. The additive effect ofconcomitantly administered products containing sorbitol (or fructose) and dietary intake of sorbitol (orfructose) should be taken into account. The content of sorbitol in medicinal products for oral use mayaffect the bioavailability of other medicinal products for oral use administered concomitantly.

Soya lecithin (potential residue from manufacturing process)

This medicinal product may contain trace amounts of soya lecithin. Patients who have experiencedanaphylactic reactions to soya or peanut, must not use this medicinal product.

Voclosporin is metabolised by CYP3A4 and is an inhibitor of P-glycoprotein (P-gp) and organic-anion-transporting polypeptide (OATP)1B1 and OATP1B3.

Potential for other medicinal products to affect voclosporin exposure

Voclosporin is metabolised by CYP3A4. Concomitant use of medicinal products or herbal remediesknown to inhibit or induce CYP3A4 may affect the metabolism of voclosporin and thereby increase ordecrease voclosporin blood levels.

Voclosporin exposure was 18.6-fold higher in the presence of the strong CYP3A4 inhibitorketoconazole compared to voclosporin administered alone. Co-administration of voclosporin withstrong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin) is contraindicated (seesection 4.3).

Voclosporin exposure was 2.71-fold higher in the presence of the moderate CYP3A4 inhibitorverapamil compared to voclosporin administration alone. Reduce the dose to 15.8 mg in the morningand 7.9 mg in the evening when voclosporin is co-administered with moderate CYP3A4 inhibitors(e.g., verapamil, fluconazole, erythromycin, diltiazem, grapefruit and grapefruit juice, see section 4.2).

Mild CYP3A4 inhibitors may increase voclosporin exposure, but no in vivo study has been performed.

No dose adjustment is required when voclosporin is co-administered with mild CYP3A4 inhibitors butadditional monitoring of eGFR is recommended when initiating treatment with a mild CYP3A4inhibitor.

Voclosporin exposure was 87 % lower and maximum concentration (Cmax) was 68 % lower in thepresence of the strong CYP3A4 inducer rifampicin (600 mg once daily for 10 consecutive days)compared to voclosporin administration alone. Co-administration of multiple doses of moderate

CYP3A4 inducers are also expected to result in clinically relevant decreases of voclosporin exposure.

Strong and moderate CYP3A4 inducers (e.g., carbamazepine, phenobarbital, rifampicin, St John’s

Wort, efavirenz) are not recommended to be dosed concomitantly with voclosporin (see section 4.4).

Mild inducers of CYP3A4 may also result in decreased exposure and possibly a decreased effect, butthe clinical relevance is unknown.

Potential for voclosporin to affect exposure to other medicinal products

Voclosporin is an inhibitor of P-glycoprotein (P-gp). Concomitant administration of voclosporin withmultiple doses of digoxin increased digoxin Cmax and area under the curve (AUC) by 1.51-fold and1.25-fold, respectively. Caution must be exercised in case of co-administration of voclosporin withsensitive P-gp substrates, especially those with narrow therapeutic index (e.g., digoxin, dabigatranetexilate, fexofenadine) where patients should be appropriately monitored as outlined in respectiveproduct labelling.

OATP1B1/OATP1B3 substrates

Voclosporin is an inhibitor of OATP1B1 and OATP1B3 transporters. In one clinical study theconcomitant administration of a single 40 mg dose of simvastatin with 23.7 mg BID voclosporinincreased Cmax and AUC of the active metabolite simvastatin acid (a sensitive OATP1B1/OATP1B3substrate) by 3.1-fold and 1.8-fold, respectively. In the same study, exposure of the parent drugsimvastatin (which is also a BCRP substrate) was unaffected in terms of AUC while its Cmax increasedby 1.6-fold, which could potentially be attributed to an interaction between intestinal BCRP andvoclosporin. Patients should be monitored for adverse events such as myopathy and rhabdomyolysiswhen OATP1B1/OATP1B3 substrates (e.g., simvastatin, atorvastatin, pravastatin, rosuvastatin) areused concomitantly with voclosporin.

Voclosporin inhibits breast cancer resistance protein (BCRP) in vitro. A clinically relevant inhibitionof intestinal BCRP cannot be excluded and voclosporin may increase the concentration of thesesubstrates in vivo. Monitor use of BCRP substrates where small concentration changes may lead toserious toxicity (e.g., rosuvastatin) when used concomitantly with voclosporin.

MMF

Co-administration of voclosporin with mycophenolate mofetil (MMF) had no clinically significantimpact on mycophenolic acid (MPA) blood concentrations.

Multiple administrations of voclosporin orally (0.4 mg/kg twice daily) had no clinically relevant effecton the pharmacokinetics of the sensitive CYP3A4 substrate midazolam.

There are no or limited amount of data (less than 300 pregnancy outcomes) from the use ofvoclosporin in pregnant women. Animal studies have shown reproductive toxicity (see section 5.3).

Lupkynis is not recommended during pregnancy and in women of childbearing potential not usingcontraception.

In a study in 12 lactating subjects, the highest estimated voclosporin dose ingested by a fully breastfedinfant was 1.4% of maternal weight-adjusted dose (see section 5.2). The effect of voclosporin onnewborns/infants is unknown.

A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from

Lupkynis therapy taking into account the benefit of breast-feeding for the child and the benefit oftherapy for the woman.

There are no data on the effect of voclosporin on human fertility. In animal studies, voclosporin-related changes in the male reproductive tract were observed (see section 5.3).

Lupkynis has no or negligible influence on the ability to drive and use machines.

The most frequently reported adverse reactions with use of voclosporin are decreased eGFR (26.2 %)and hypertension (19.1 %).

The most frequently reported serious adverse reactions with use of voclosporin were infections (10.1%), acute kidney injury (3 %) and hypertension (1.9 %).

In the first 4 weeks of treatment with voclosporin, haemodynamic reductions in eGFR are commonlyexperienced, which subsequently stabilise, even if treatment is continued (see section 4.4).

Adverse reactions that occurred in patients with LN receiving the recommended dose of voclosporinwith a median treatment duration of 1 year in two placebo-controlled clinical studies and/or post-marketing use are summarised in table 3.

All adverse reactions are listed by system organ class (SOC) and frequency: very common (≥ 1/10),common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), veryrare (< 1/10,000) and not known (cannot be estimated from the available data).

Table 3: Adverse reactions

System organ class Very common Common Not known

Infections and infestations Upper respiratory Pneumoniatract infection1 Influenza

Herpes zoster

Gastroenteritis

Blood and lymphatic system Anaemiadisorders

Immune system disorders Hypersensitivity

Metabolism and nutrition Hyperkalaemiadisorders Decreased appetite

Nervous system disorders Headache Seizure

Tremor

Vascular disorders Hypertension2

Respiratory, thoracic and Coughmediastinal disorders

Gastrointestinal disorders Diarrhoea Nausea

Abdominal pain3 Gingival hyperplasia4

Dyspepsia

Mouth ulceration

Skin and subcutaneous tissue Alopeciadisorders Hypertrichosis5

Renal and urinary disorders Glomerular Acute kidney disease6filtration rate Acute kidney injury6decreased6,71 Includes the following Preferred Terms (PTs): viral upper respiratory tract infection and upper respiratorytract infection bacterial2 Includes the following PTs: blood pressure increased, blood pressure diastolic increased, diastolichypertension3 Includes the following PTs: abdominal pain upper, abdominal discomfort4 Includes the following PTs: gingivitis, gingival bleeding, gingival hypertrophy, gingival swelling5 Includes the following PTs: hypertrichosis, hirsutism6 Includes the PT renal impairment7 Includes the PT blood creatinine increased

The overall incidence of infections was 62.2 % in the voclosporin group and 54.9 % in the placebogroup. Infections occurring in at least 5 % of patients receiving voclosporin and at least 1 % morefrequently than patients receiving placebo were urinary tract infection, viral upper respiratory tractinfection, herpes zoster and gastroenteritis. Serious infections occurred in 10.1 % of voclosporin and10.2 % of placebo patients; the most common were pneumonia (voclosporin 4.1 %, placebo 3.8 %),gastroenteritis (voclosporin 1.5 %, placebo 0.4 %) and urinary tract infection (voclosporin 1.1 %,placebo 0.4 %). Serious opportunistic infections occurred in 1.1 % of voclosporin patients and 0.8 %of placebo patients. Fatal infections occurred in 0.7 % of patients receiving voclosporin and in 0.8 %of patients receiving placebo (see section 4.4).

Renal toxicity

Adverse reactions suggestive of renal toxicity which occurred at a frequency of ≥ 1 % higher invoclosporin compared to placebo were decreased eGFR (26.2 % vs. 9.4 %), renal impairment (5.6 %vs. 2.6 %), acute kidney injury (3.4 % vs. 0.8 %), and hyperkalaemia (1.9 % vs. 0.8 %). Seriousadverse reactions were reported in 5.2 % of voclosporin patients and 3.4 % of placebo patients.

The most common adverse reactions leading to dose modification (reduction in dose or temporarydiscontinuation) were decreased eGFR (voclosporin 23.6 %, placebo 6.8 %), renal impairment(voclosporin 3.0 %, placebo 0.8 %) and acute kidney injury (voclosporin 0.7 %, placebo 0). The mostcommon adverse reactions leading to permanent medicinal product discontinuation were eGFRdecreases (voclosporin 3.7 %, placebo 1.9 %) and renal impairment (voclosporin 1.9 %, placebo 1.5%). Following a decrease in eGFR, the median time to recovery was 49 days for patients onvoclosporin with an eGFR decrease ≥ 20 %. Similarly for patients with an eGFR decrease of ≥ 30 %,the median time to recovery was 102 days on voclosporin.

Hypertension was reported in 19.1 % of voclosporin patients and 8.6 % of placebo patients. Theincidence of hypertension was highest in the first 4 weeks of treatment with voclosporin and declinedthereafter. Hypertension was severe in 1.1 % of voclosporin patients and 0.8 % of placebo patients.

Serious hypertension occurred in 1.9 % of voclosporin patients and 0.4 % of placebo patients.

Long term exposure (up to 36 months)

The pattern of adverse reactions with continued treatment (from 12 to 36 months) was consistent withthat seen in the first year of treatment; however, the incidences of the vast majority of events werelower in subsequent years. The overall incidence of infections was 49.1 % in the voclosporin groupand 43.0% in the placebo group. Infections occurring in at least 5 % of patients receiving voclosporinand at least 1 % more frequently than patients receiving placebo were urinary tract infection, upperrespiratory tract infection, viral upper respiratory tract infection and gastroenteritis. Serious infectionsoccurred in 6.9 % of voclosporin and 8.0 % of placebo patients; the most common were corona virusinfection (voclosporin 1.7 %, placebo 5.0 %) and pneumonia viral (voclosporin 1.7 %, placebo 0 %).

Adverse reactions suggestive of renal toxicity which occurred at a higher frequency in voclosporincompared to placebo were decreased eGFR (10.3 % vs. 5.0 %) and renal impairment (3.4 % vs. 2.0%). Hypertension was reported in 8.6 % of voclosporin patients and 7.0 % of placebo patients.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Cases of accidental overdose have been reported with voclosporin; symptoms included tremor andtachycardia. In an interaction study in healthy volunteers, co-administration of ketoconazole andvoclosporin resulted in an 18.6-fold increase in voclosporin exposure and increases in serumcreatinine, decreases in serum magnesium and increases in blood pressure were observed. Symptomsof overdose with other calcineurin inhibitors (but not observed with voclosporin) include headache,nausea and vomiting, infections, urticaria, lethargy, changes in electrolyte levels and increases inblood urea nitrogen, and alanine aminotransferase.

No specific antidote to voclosporin therapy is available. If overdose occurs, general supportivemeasures and symptomatic treatment should be conducted, including temporarily stopping treatmentwith voclosporin and assessing blood urea nitrogen, serum creatinine, eGFR and alanineaminotransferase levels.

Pharmacotherapeutic group: Immunosuppressants, calcineurin inhibitors, ATC code: L04AD03

Voclosporin is a calcineurin-inhibitor immunosuppressant that inhibits calcineurin in a dose-dependentmanner up to a maximum dose of 1.0 mg/kg. Activation of lymphocytes involves an increase inintracellular calcium concentrations. Calcineurin is a calcium/calmodulin-dependent phosphatasewhose activity is required for the induction of T-cell lymphokine production and proliferation. Theimmunosuppressant activity results in inhibition of lymphocyte proliferation, T-cell cytokineproduction, and expression of T-cell activation surface antigens.

In a randomised, placebo- and active-controlled (moxifloxacin 400 mg), single dose study withparallel study design, dose-dependent QT prolonging effect was detected with voclosporin in the doserange of 0.5 mg/kg to 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 hours to 6hours post-dose across different dose levels. The maximum mean placebo-adjusted changes of QTcFfrom baseline after voclosporin 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, randomised, placebo-controlled, crossover study in 31 healthy subjects, an absence oflarge mean increases (i.e., > 20 msec) was observed following 7 days of treatment with voclosporin at0.3 mg/kg, 0.5 mg/kg and 1.5 mg/kg twice daily (approximately 6-fold coverage of the therapeuticexposure). The mechanism for the QT prolonging effect as observed in the single-dose and multiple-dose studies is unknown.

Based on data in LN patients receiving voclosporin 23.7 mg or 39.5 mg twice daily, a regressionanalysis of placebo corrected QTcF change from baseline showed a minimal negative slope(−0.065344 msec/ng/mL), not statistically different from a slope of 0 (p = 0.1042).

The safety and efficacy of voclosporin were investigated in two placebo-controlled clinical trials(AURORA 1 and AURA-LV) in patients with LN of Class III or IV (alone or in combination with

Class V) or pure Class V. All patients received background therapy of MMF (2 g/day) andcorticosteroids (up to a total of 1 g of intravenous (IV) methylprednisolone over days 1 and 2 followedby a starting dose of oral corticosteroids of 25 mg/day (or 20 mg/day if body weight was < 45 kg),tapered down to 2.5 mg/day by week 16.

Patients that completed the AURORA 1 study could continue in a 2-year continuation study(AURORA 2).

Phase 3 AURORA 1

The AURORA 1 study was a phase 3, prospective, randomised, double-blind, study comparing 23.7mg (corresponding to a 0.37 mg/kg dose) twice daily of voclosporin (n = 179) vs. placebo (n = 178)over a 52-week treatment period. The demographic characteristics of patients in the study were wellbalanced across the two treatment arms. The mean age was 33 years (range 18 years to 72 years) andthe majority of patients were female (87.7 %), of which 81.8 % were of childbearing potential.

Most patients were White (36.1 %) or Asian (30.5 %), and approximately one third of the studypopulation was Hispanic or Latino. The mean weight was 66.5 kg (range 36 kg to 142 kg). Themedian time since systemic lupus erythematosus (SLE) diagnosis was 5.0 years and the median timesince LN diagnosis was 2.0 years.

Before entering the AURORA 1 study, most patients (98 %) had received treatment for LN in the past,with approximately 55 % of patients taking MMF at screening. The proportion of LN treatment naïvepatients was very low (2 %).

More patients in the voclosporin arm than the placebo arm achieved the primary endpoint of renalresponse (table 4).

Table 4: AURORA 1 - Summary of key efficacy endpoints

Voclosporin Placebo Odds ratio p-value(n = 179) (n = 178) vs. placebon (%) n (%) (95 % CI)73 40 2.65

Renal response at week 52 < 0.001(40.8) (22.5) (1.64, 4.27)58 35 2.23

Renal response at week 24 = 0.002(32.4) (19.7) (1.34, 3.72)126 89 2.43

Partial renal response* at week 24 < 0.001(70.4) (50.0) (1.56, 3.79)125 92 2.26

Partial renal response* at week 52 < 0.001(69.8) (51.7) (1.45, 3.51)

* Partial renal response defined as a 50 % reduction in UPCR.

Notes: CI = Confidence interval; UPCR = Urine protein to creatinine ratio

The overall proportion of patients that achieved each of the components assessed for the primaryendpoint at 52 weeks in the voclosporin vs placebo arm were:

- urine protein to creatinine ratio (UPCR) ≤ 0.5 mg/mg: 45.3 % vs 23.0 %

- with normal, stable renal function (defined as eGFR ≥ 60 mL/min/1.73 m2or no confirmed decrease from baseline in eGFR of > 20 %): 82.1 % vs. 75.8 %

- in the presence of sustained, low-dose steroids (not more than 10 mg for ≥3 consecutive days or for ≥ 7 days in total during weeks 44 to 52): 87.2 % vs. 85.4 %

- and received no rescue medication for LN: 91.1 % vs. 86.5 %

More patients in the voclosporin arm than the placebo arm achieved UPCR ≤ 0.5 mg/mg (64.8 % vs.43.8 %) and the time to UPCR ≤ 0.5 mg/mg was significantly shorter for voclosporin treatment(median time: 169 days vs. 372 days for placebo treatment; hazard ratio (HR) 2.02; 95 % CI: 1.51,2.70; p < 0.001).

Figure 1: Kaplan-Meier curve of time (days) to UPCR ≤ 0.5 mg/mg

The time taken to reach a 50 % reduction in UPCR was significantly shorter for the voclosporin armthan the placebo arm (HR 2.05; 95 % CI: 1.62, 2.60; p < 0.001). Median time to 50 % reduction in

UPCR was 29 days for voclosporin vs. 63 days for placebo (figure 2).

Figure 2: Kaplan-Meier curve of time (days) to 50 % reduction in UPCR from baseline

Over 80 % of patients in the AURORA 1 study achieved a reduction in dose of oral corticosteroid to ≤2.5 mg/day at week 24 and this dose was maintained by over 75 % of patients at week 52.

Phase 3 AURORA 2

The AURORA 2 study was a continuation study to evaluate the long-term safety and efficacy ofvoclosporin in patients that completed treatment in the AURORA 1 study. Patients stayed on the sametreatment and dose of voclosporin (n = 116) or placebo (n = 100) as at the end of AURORA 1 andcontinued treatment for up to a further 2 years. Over 85 % of patients completed the study(voclosporin: 87.1 %, placebo 85.0 %); 79.3 % of voclosporin patients and 73 % of placebo patientswere still on study treatment at the end of study.

The proportion of patients in renal response at month 36 was 33 % (59/179) in the voclosporin groupand 22 % (39/178) in the placebo group (ITT, AURORA 1) and 51 % (59/116) in the voclosporingroup and 39 % (39/100) in the placebo group (ITT, AURORA 2).

The European Medicines Agency has deferred the obligation to submit the results of studies with

Lupkynis in one or more subsets of the paediatric population, in LN (see section 4.2 for informationon paediatric use).

Following oral administration (voclosporin 23.7 mg twice daily) the median time to reach maximumwhole blood concentrations (Cmax) is 1.5 hours (range: 0.75 hour to 2 hours). With a twice daily dosingregimen, voclosporin steady state is achieved after 6 days and voclosporin accumulates approximately2-fold relative to a single dose. At steady state, the whole blood mean Cmax and pre-dose trough valuesfor voclosporin were 120 ng/mL (32 % CV) and 15.0 ng/mL (49 % CV), respectively. In vitro datainvestigating if voclosporin is a substrate of the efflux transporters P-gp or BCRP are inconclusive, butclinically relevant effects of P-gp/BCRP inhibitors are not expected.

Co-administration of voclosporin with food decreased both the rate and extent of absorption. Cmax and

AUC of voclosporin were reduced by 53 % and 25 % when given with high-fat food and by 29 % and15 % when given with low-fat food. These changes were not considered to be clinically relevant.

Therefore, voclosporin can be taken with or without food.

Voclosporin is 97 % bound to plasma proteins. Voclosporin partitions extensively into red blood cellsand distribution between whole blood and plasma is concentration- and temperature-dependent. Apopulation pharmacokinetic analysis in patients resulted in an apparent volume of distribution (Vss/F)of 2,154 L.

Voclosporin is extensively metabolised, predominantly by CYP3A4 to form oxidative metabolites.

Voclosporin is the major circulating component following a single dose of [14C]-voclosporin. Onemajor metabolite was observed in human whole blood and represented 16.7 % of total exposure. Themajor metabolite is not expected to contribute to the pharmacological activity of voclosporin since itwas reported as about 8-fold less potent in a lymphocyte proliferation assay and has lower exposurethan voclosporin.

The mean apparent clearance at steady state (CLss/F) after voclosporin 23.7 mg twice daily is 63.6 L/h(37.5 % CV). The mean terminal half-life (t½) at steady state is approximately 30 hours (range: 24.9hours to 36.5 hours).

Following single oral administration of 70 mg [14C]-voclosporin, 94.8 % of the radioactivity wasrecovered by 168 hours post dose: 92.7 % was recovered in faeces (including 5 % as unchangedvoclosporin), and 2.1 % was recovered in urine (including 0.25 % as unchanged voclosporin).

In healthy volunteers, a non-linearity between dose and exposure was observed at the lower end of thedose range studied (0.25 mg/kg to 1.5 mg/kg twice daily), which had a relatively minor effect on thepharmacokinetics. The dose-proportionality factor was always less than 1.5. This non-linearity has notbeen detected over the dose range studied in LN patients.

In clinical studies, kidney function was monitored by eGFR and doses were adjusted based on a pre-defined dose adjustment protocol. Enrolled LN patients had a baseline eGFR > 45 mL/min/1.73 m2.

Dosing adjustments have to follow the recommendations outlined in table 1.

A dedicated renal impairment study revealed that after single and multiple doses of voclosporin, Cmaxand AUC were similar in volunteers with mild (creatinine clearance (CLCr) 60 mL/min to 89 mL/minas estimated by Cockcroft Gault) and moderate (CLCr 30 mL/min to 59 mL/min) renal impairmentcompared to volunteers with normal renal function (CLCr ≥ 90 mL/min). After a single dose ofvoclosporin in volunteers with severe renal impairment (CLCr < 30 mL/min), Cmax and AUC increased1.5-fold and 1.7-fold, respectively. The effect of end-stage renal disease (ESRD) with or withouthaemodialysis on the pharmacokinetics of voclosporin is unknown (see section 4.2).

A dedicated hepatic impairment study compared systemic exposure of voclosporin in patients withmild or moderate hepatic impairment (Child-Pugh A and B, respectively) vs. healthy controls withnormal hepatic function. In patients with mild and moderate hepatic impairment, voclosporin Cmax and

AUC0-48 increased by 1.5-fold and approximately 2-fold, respectively (see section 4.2). Voclosporinhas not been evaluated in patients with severe hepatic impairment (Child-Pugh C) and its use in thesepatients is not recommended (see section 4.4).

Age, sex, race and body weight

A population pharmacokinetic analysis assessing the effects of age, sex, race and body weight did notsuggest any clinically significant impact of these covariates on voclosporin exposures.

Following a single 23.7 mg dose of voclosporin in lactating volunteers (see section 4.6), an average of0.00472 mg voclosporin was excreted in breast milk in 48h, with 80% being excreted within 12h. Datashowed that the voclosporin milk to maternal blood exposure ratio was in the range of 0.42 to 0.95.

For a breastmilk intake of 200 mL/kg/day, the highest relative infant dose was 1.4% of maternalweight-adjusted dose.

Adverse reactions not observed in clinical studies, but seen in animals at exposure levels similar toclinical exposure levels and with possible relevance to clinical use were as follows:

Repeated-dose animal studies have shown neuro-histological findings of gliosis and perivascularinfiltrates in the brain and spinal cord in rats, but not in dogs or monkeys. These findings were notobserved at doses approximately 0.3-times the maximum recommended human dose (MRHD) of 23.7mg voclosporin twice a day on medicinal product exposure (AUC) basis.

In a 39-week oral toxicology study with cynomolgus monkeys, malignant lymphomas occurred at adose of 150 mg/kg/day (approximately 4-times and 7-times above the MRHD based on medicinalproduct exposure (AUC), for male and female animals, respectively). At this dose, monkeysexperienced high levels of immunosuppression as indicated by maximum calcineurin inhibition levels(Emax) of greater than 80 %. The no-observed-adverse-effect level (NOAEL) for this finding was 75mg/kg/day (approximately 4-times the MRHD, on medicinal product exposure (AUC) basis, for maleand female animals).

No mutagenic or genotoxic effects of voclosporin were observed in conventional genotoxicity studies.

In a 2-year mouse carcinogenicity study with oral voclosporin, an increased incidence of malignantlymphoma was observed at the highest dose tested (30 mg/kg/day; approximately 7.5-times the

MRHD on a medicinal product exposure (AUC) basis). This result is considered secondary tovoclosporin-related immune suppression. The NOAEL was 10 mg/kg/day (approximately 1-times the

MRHD on medicinal product exposure (AUC) basis).

In a rat fertility study with a 50:50 mixture of voclosporin and its cis-isomer, decreases in malereproductive organ weights, including the cauda epididymis, epididymis, seminal vesicles, prostate,and testes were noted at a dose of 25 mg/kg/day. The NOAEL for these findings was 10 mg/kg/day(approximately 5-times the MRHD on medicinal product exposure (AUC) basis). Mating and fertilityparameters, sperm motility, count and density, number of estrous stages per 14 days, and caesareansectioning parameters were not affected. Decreases in prostate and testes weights were also observedin the 13-week and 26-week repeat-dose toxicity studies with oral 50:50 mixture of voclosporin and itscis-isomer at doses of 25 mg/kg/day and 10 mg/kg/day, or 18-times and 7-times the MRHD, onmedicinal product exposure (AUC) basis. The NOAEL for these effects in the 26-week repeat-dosestudy was 2.5 mg/kg/day (approximately 1-times the MRHD on medicinal product exposure (AUC)basis).

Embryo-foetal development studies were conducted with the 50:50 mixture of voclosporin and its cis-isomer in both rats and rabbits and with voclosporin in rabbits. Embryo-foetal toxicity was onlyobserved at doses that were associated with maternal toxicity (at doses approximately 15-times and 1-times the MRHD, based upon medicinal product exposure (AUC), for rats and rabbits, respectively).

The maternal effects included changes in body weight and/or swollen mammary glands while thefoetal effects consisted of a slight reduction in body weight and related skeletal developmentalvariations. No malformative effects were noted in the studies. The NOAELs were 10 mg/kg/day in ratsand 1 mg/kg/day in rabbits (approximately 7-times and 0.01-times the MRHD, based on medicinalproduct exposure (AUC), for rats and rabbits, respectively).

In a pre- and post-natal developmental study in rats, maternal toxicity at a dose of 25 mg/kg/day 50:50mixture of voclosporin and its cis-isomer (approximately 17 times the MRHD on medicinal productexposure (AUC) basis) delayed parturition (dystocia) that resulted in reductions in the mean number oftotal pups delivered and surviving pups per litter. This dose was associated with maternal toxicitybased on decreased body weight gain. No adverse effects on dams or their pups were observed atdoses approximately 3-times the MRHD and lower (based on medicinal product exposure (AUC) witha maternal oral NOAEL dose of 10 mg/kg/day). There were no effects on behavioural and physicaldevelopment, or the reproductive performance of male or female pups. The no effect dose for deliveryand pup survival was 10 mg/kg/day.

Medicinal product-derived radioactivity was rapidly distributed to milk following the oraladministration of [14C]-voclosporin to lactating rats. When a medicinal product is present in animalmilk, it is likely that it will also be present in human milk.

Vitamin E (E307) polyethylene glycol succinate (tocofersolan)

Polysorbate 40

Medium-chain triglycerides

Gelatin

Sorbitol

Glycerin

Purified water

Titanium dioxide (E171)

Iron oxide, red (E172)

Iron oxide, yellow (E172)

Processing aids

Soya lecithin

Not applicable

4 years

Store in the original blister in order to protect from moisture.

Soft capsules are available in cold-formed aluminium blisters, laminated backing and lidding materialsthat are thermo-sealed together. Each blister contains 18 soft capsules. One carton contains 180 or 576soft capsules.

Not all pack sizes may be marketed.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Otsuka Pharmaceutical Netherlands B.V.

Herikerbergweg 2921101 CT Amsterdam

Netherlands

EU/1/22/1678/001 (180 soft capsules)

EU/1/22/1678/002 (576 soft capsules)

Date of first authorisation: 15 September 2022

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.