Voclosporin

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.

Voclosporin is an inhibitor of OATP1B1 and OATP1B3 transporters. In one clinical study the concomitant administration of a single 40 mg dose of simvastatin with 23.7 mg BID voclosporin increased C_max and AUC of the active metabolite simvastatin acid (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 C_max 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.

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.

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.

Voclosporin exposure was 87% lower and maximum concentration (C_max) 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. Mild inducers of CYP3A4 may also result in decreased exposure and possibly a decreased effect, but the clinical relevance is unknown.

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.

Voclosporin is an inhibitor of P-glycoprotein (P-gp). Concomitant administration of voclosporin with multiple doses of digoxin increased digoxin C_max 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.

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).

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.

Careful monitoring of renal function is recommended. Limited data are available on the use of voclosporin in patients with baseline eGFR 30 to <45 mL/min/1.73 m². It is recommended to use voclosporin in these patients, only if the benefit outweighs the risk, and at a starting dose of 23.7 mg twice daily.

Voclosporin 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.

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.

Recommended dose adjustments based on eGFR:

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.

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.

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.

Voclosporin is not recommended during pregnancy and in women of childbearing potential not using contraception.

It is unknown whether voclosporin/metabolites are excreted in human milk. Available pharmacodynamic/toxicological data in animals have shown excretion of voclosporin/metabolites in milk. A risk to the newborns/infants cannot be excluded.

A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from voclosporin 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, voclosporinrelated changes in the male reproductive tract were observed.

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

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.

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 are summarised in the table below.

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).

Adverse reactions:

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.

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.