4.1. Therapeutic indications

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

4.2. Posology and method of administration

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

Posology

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 as possible and with a minimum of 8 hours between each dose. If a dose is missed, it should be taken as soon as possible within 4 hours after missing the dose; beyond the 4-hour time frame, the next regular dose 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 an appropriate 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 starting treatment with voclosporin, and assess every two weeks for the first month, and every four weeks thereafter.

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

Table 1: Recommended dose adjustments based on eGFR

Confirmed eGFR decrease from baseline1

Recommendation

≥ 30 % reduction

Stop administration of voclosporin. Restart treatment upon eGFR recovery at 7.9 mg (1 capsule) twice daily and increase as tolerated based on renal function.

> 20 % and < 30 % reduction

Reduce dose of voclosporin by 7.9 mg (1 capsule) twice daily.

Retest within two weeks; if eGFR decrease has not recovered, reduce dose 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 within two weeks. For patients that had a decrease in dose due to eGFR reduction, increasing the dose by 7.9 mg twice a day for each eGFR measurement that is ≥ 80 % of baseline should be considered; the starting 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 mg in the evening (see section 4.5).

Hepatic impairment

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

Renal impairment

Careful monitoring of renal function is recommended (see table 1 and section 4.4). Limited data are available on the use of Lupkynis in patients with baseline eGFR 30 to < 45 mL/min/1.73 m2. It is recommended to use Lupkynis in these patients, only if the benefit outweighs the risk, and at a starting dose 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, the recommended starting dose is 15.8 mg twice daily (see section 5.2).

Elderly

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

Paediatric population

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

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

Method of administration

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).

4.3. Contraindications

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).

4.4. Special warnings and precautions for use

Lymphomas and other malignancies

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

Serious infections

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

Renal toxicity

As with other calcineurin-inhibitors, adverse reactions of acute worsening of renal function or eGFR decreases have been seen in patients treated with voclosporin. In the first four weeks of treatment with voclosporin, haemodynamic reductions in eGFR have been observed (see section 4.8). This can be managed 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 different calcineurin inhibitor. All of these patients had risk factors for PRCA, such as a parvovirus B19 infection, 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

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

Hypertension

Voclosporin can cause or worsen systemic hypertension (see section 4.8). Blood pressure should be monitored every two weeks for the first month after initiating voclosporin, and as clinically indicated thereafter. In the event of clinically concerning elevated blood pressure, the recommendations in table 2 should be followed.

Table 2: Recommendations for management of hypertension

Blood pressure

Recommendation

Systolic pressure > 130 and ≤ 165 mmHg

and

Diastolic pressure > 80 and ≤ 105 mmHg

Antihypertensive therapy may be initiated/adjusted

Blood pressure > 165/105 mmHg, with symptoms of hypertension

Stop administration of voclosporin and initiate/adjust antihypertensive therapy

QT prolongation

The use of voclosporin in combination with other medicinal products 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 medicinal products that prolong the QTc interval, including bradycardia; hypokalaemia or hypomagnesaemia; concomitant use of other medicinal products that prolong the QTc interval; and the presence of congenital prolongation of the QT interval.

Neurotoxicity

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

Hepatic impairment

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.

Vaccination

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

Concomitant use with other medicinal products

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

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

Excipients

Ethanol

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

Sorbitol

This medicinal product contains 28.7 mg of sorbitol in each soft capsule. The additive effect of concomitantly administered products containing sorbitol (or fructose) and dietary intake of sorbitol (or fructose) should be taken into account. The content of sorbitol in medicinal products for oral use may affect 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 experienced anaphylactic reactions to soya or peanut, must not use this medicinal product.

4.5. Interaction with other medicinal products and other forms of interaction

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 remedies known to inhibit or induce CYP3A4 may affect the metabolism of voclosporin and thereby increase or decrease voclosporin blood levels.

CYP3A4 inhibitors

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

Voclosporin exposure was 2.71-fold higher in the presence of the moderate CYP3A4 inhibitor verapamil compared to voclosporin administration alone. Reduce the dose to 15.8 mg in the morning and 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 but additional monitoring of eGFR is recommended when initiating treatment with a mild CYP3A4 inhibitor.

CYP3A4 inducers

Voclosporin exposure was 87 % lower and maximum concentration (Cmax) was 68 % lower in the presence 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, but the clinical relevance is unknown.

Potential for voclosporin to affect exposure to other medicinal products

P-gp substrates

Voclosporin is an inhibitor of P-glycoprotein (P-gp). Concomitant administration of voclosporin with multiple doses of digoxin increased digoxin Cmax and area under the curve (AUC) by 1.51-fold and 1.25-fold, respectively. Caution must be exercised in case of co-administration of voclosporin with sensitive P-gp substrates, especially those with narrow therapeutic index (e.g., digoxin, dabigatran etexilate, fexofenadine) where patients should be appropriately monitored as outlined in respective product labelling.

OATP1B1/OATP1B3 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 Cmax and AUC of the active metabolite simvastatin acid (a sensitive OATP1B1/OATP1B3 substrate) by 3.1-fold and 1.8-fold, respectively. In the same study, exposure of the parent drug simvastatin (which is also a BCRP substrate) was unaffected in terms of AUC while its Cmax increased by 1.6-fold, which could potentially be attributed to an interaction between intestinal BCRP and voclosporin. Patients should be monitored for adverse events such as myopathy and rhabdomyolysis when OATP1B1/OATP1B3 substrates (e.g., simvastatin, atorvastatin, pravastatin, rosuvastatin) are used concomitantly with voclosporin.

BCRP substrates

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

MMF

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

CYP3A4 substrates

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

4.6. Fertility, pregnancy and lactation

Pregnancy

There are no or limited amount of data (less than 300 pregnancy outcomes) from the use of voclosporin 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 using contraception.

Breast-feeding

In a study in 12 lactating subjects, the highest estimated voclosporin dose ingested by a fully breastfed infant was 1.4% of maternal weight-adjusted dose (see section 5.2). The effect of voclosporin on newborns/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 of therapy for the woman.

Fertility

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).

4.7. Effects on ability to drive and use machines

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

4.8. Undesirable effects

Summary of the safety profile

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 commonly experienced, which subsequently stabilise, even if treatment is continued (see section 4.4).

Tabulated list of adverse reactions

Adverse reactions that occurred in patients with LN receiving the recommended dose of voclosporin with 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), very rare (< 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 tract infection1

Pneumonia

Influenza

Herpes zoster

Gastroenteritis

Urinary tract infection

Blood and lymphatic system disorders

Anaemia

Immune system disorders

Hypersensitivity

Metabolism and nutrition disorders

Hyperkalaemia

Decreased appetite

Nervous system disorders

Headache

Seizure

Tremor

Vascular disorders

Hypertension2

Respiratory, thoracic and mediastinal disorders

Cough

Gastrointestinal disorders

Diarrhoea

Abdominal pain3

Nausea

Gingival hyperplasia4

Dyspepsia

Mouth ulceration

Skin and subcutaneous tissue disorders

Alopecia

Hypertrichosis5

Renal and urinary disorders

Glomerular filtration rate decreased6,7

Acute kidney disease6

Acute kidney injury6

General disorders and administration site conditions

Fatigue

1 Includes the following Preferred Terms (PTs): viral upper respiratory tract infection and upper respiratory tract infection bacterial

2 Includes the following PTs: blood pressure increased, blood pressure diastolic increased, diastolic hypertension

3 Includes the following PTs: abdominal pain upper, abdominal discomfort

4 Includes the following PTs: gingivitis, gingival bleeding, gingival hypertrophy, gingival swelling

5 Includes the following PTs: hypertrichosis, hirsutism

6 Includes the PT renal impairment

7 Includes the PT blood creatinine increased

Description of selected adverse reactions

Infections

The overall incidence of infections was 62.2 % in the voclosporin group and 54.9 % in the placebo group. Infections occurring in at least 5 % of patients receiving voclosporin and at least 1 % more frequently than patients receiving placebo were urinary tract infection, viral upper respiratory tract infection, herpes zoster and gastroenteritis. Serious infections occurred in 10.1 % of voclosporin and 10.2 % 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 in voclosporin 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 %). Serious adverse 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 temporary discontinuation) 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 most common adverse reactions leading to permanent medicinal product discontinuation were eGFR decreases (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 on voclosporin 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

Hypertension was reported in 19.1 % of voclosporin patients and 8.6 % of placebo patients. The incidence of hypertension was highest in the first 4 weeks of treatment with voclosporin and declined thereafter. 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 with that seen in the first year of treatment; however, the incidences of the vast majority of events were lower in subsequent years. The overall incidence of infections was 49.1 % in the voclosporin group and 43.0% in the placebo group. Infections occurring in at least 5 % of patients receiving voclosporin and at least 1 % more frequently than patients receiving placebo were urinary tract infection, upper respiratory tract infection, viral upper respiratory tract infection and gastroenteritis. Serious infections occurred in 6.9 % of voclosporin and 8.0 % of placebo patients; the most common were corona virus infection (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 voclosporin compared 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 of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

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

No specific antidote to voclosporin therapy is available. If overdose occurs, general supportive measures and symptomatic treatment should be conducted, including temporarily stopping treatment with voclosporin and assessing blood urea nitrogen, serum creatinine, eGFR and alanine aminotransferase levels.