Voclosporin (Monograph)

Brand name: Lupkynis ([Web]
Drug class: Immunosuppressive Agents
Chemical name: (3S,6S,9S,12R,15S,18S,21S,24S,30S,33S)-30-ethyl-33-[(1R,2R,4E)-1-hydroxy-2-methylhepta-4,6-dienyl]-1,4,7,10,12,15,19,25,28-nonamethyl-6,9,18,24-tetrakis(2-methylpropyl)-3,21-di(propan-2-yl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotritriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone
Molecular formula: C₆₃H₁₁₁N₁₁O₁₂
CAS number: 515814-00-3

Medically reviewed by Drugs.com on Dec 28, 2022. Written by ASHP.

Introduction

Calcineurin-inhibitor immunosuppressive agent.

Uses for Voclosporin

Active Lupus Nephritis

Treatment of adults with active lupus nephritis in combination with a background immunosuppressive therapy regimen.

The Kidney Disease: Improving Global Outcomes (KDIGO) guideline on management of glomerular diseases provides recommendations for the treatment of patients with systemic lupus erythematosus (SLE), including those with lupus nephritis. The guidelines state that voclosporin can be added to a mycophenolic acid analog and glucocorticoids as initial therapy for 1 year in patients with baseline eGFR ≥45 mL/minute per 1.73 m².

Safety and efficacy not established in combination with cyclophosphamide; use of voclosporin not recommended in this situation.

Voclosporin Dosage and Administration

General

Pretreatment Screening

• Determine baseline eGFR. Voclosporin is not recommended in patients with eGFR ≤45 mL/minute per 1.73 m² unless the benefit exceeds the risk.

• Measure BP; do not initiate voclosporin in patients with BP >165/105 mm Hg or with hypertensive emergency.

Patient Monitoring

• Monitor BP every 2 weeks for the first month after initiating voclosporin, and thereafter as clinically indicated. In patients with BP >165/105 mm Hg or with hypertensive emergency, discontinue voclosporin and initiate antihypertensive therapy.

• Monitor for the development of infection.

• Monitor eGFR every 2 weeks for the first month, and every 4 weeks thereafter. Consider dosage reduction or discontinuation if eGFR decreases from baseline. If eGFR remains persistently decreased, evaluate for chronic calcineurin-inhibitor nephrotoxicity.

• Monitor for neurologic symptoms and consider dosage reduction or discontinuation if neurotoxicity occurs.

• Monitor serum potassium levels periodically during treatment.

• Consider obtaining ECGs and monitoring electrolytes in patients at high risk of QT_c prolongation.

• Monitor patients for skin changes.

Administration

Oral Administration

Administer orally twice daily.

Swallow capsules whole on an empty stomach.

Administer consistently as close to a 12-hour schedule as possible, and with at least 8 hours between doses. A missed dose should be taken as soon as possible if no more than 4 hours have passed since the scheduled time. 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 grapefruit and grapefruit juice while taking voclosporin.

Dosage

Adults

Active Lupus Nephritis

Oral

Recommended starting dosages is 23.7 mg twice a day. Use in combination with mycophenolate mofetil and corticosteroids.

If no therapeutic benefit by 24 weeks, consider discontinuation of voclosporin.

Consider risks and benefits of voclosporin treatment beyond 1 year in light of treatment response and risk of worsening nephrotoxicity. Safety and efficacy not established beyond 1 year.

Dosage Modification for Changes in Estimated Glomerular Filtration Rate (eGFR)

Modify dosage of voclosporin based on eGFR. Assess eGFR every 2 weeks for the first month, and every 4 weeks thereafter.

If eGFR is <60 mL/minute per 1.73 m² and reduced from baseline by >20% and <30%, reduce dosage by 7.9 mg twice a day. Re-assess eGFR within 2 weeks; if eGFR is still reduced from baseline by >20%, reduce dose again by 7.9 mg twice a day.

If eGFR is <60 mL/minute per 1.73 m² and reduced from baseline by ≥30%, discontinue voclosporin. Re-assess eGFR within 2 weeks; consider re-initiating voclosporin at a lower dosage (7.9 mg twice a day) only if eGFR has returned to ≥80% of baseline.

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

Dosage Modification for Drug Interactions

If coadministered with moderate CYP3A4 inhibitors, reduce voclosporin daily dosage to 15.8 mg in the morning and 7.9 mg in the evening. No dosage adjustment recommended when voclosporin is coadministered with mild CYP3A4 inhibitors. Concomitant use with strong CYP3A4 inhibitors is contraindicated.

Special Populations

Hepatic Impairment

Mild or moderate hepatic impairment (Child-Pugh A or Child-Pugh B): Recommended dosage is 15.8 mg twice daily.

Severe hepatic impairment (Child-Pugh C): Use not recommended.

Renal Impairment

Not recommended in patients with a baseline eGFR ≤45 mL/minute per 1.73 m² unless benefit exceeds risk.

If used in patients with severe renal impairment, recommended dosage is 15.8 mg twice daily.

Geriatric 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.

Cautions for Voclosporin

Contraindications

• Concomitant use of strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin). These drugs can significantly increase exposure to voclosporin, which may increase risk of acute and/or chronic nephrotoxicity.

• Known serious or severe hypersensitivity reaction to voclosporin or any excipients.

Warnings/Precautions

Warnings

Lymphoma and Other Malignancies

Voclosporin increases the risk of developing lymphomas and other malignancies, particularly of the skin. (See Boxed Warning.) This risk may be related to the intensity and duration of immunosuppression rather than to the use of any specific agent.

Monitor patients for skin changes and advise them to avoid or limit sun exposure and to avoid artificial UV light (e.g., tanning beds, sun lamps) by wearing protective clothing and using a broad-spectrum sunscreen with a high protection factor (SPF 30 or higher).

Serious Infections

Voclosporin, like other immunosuppressants, increases the risk of developing bacterial, viral, fungal, and protozoal infections, including opportunistic infections. (See Boxed Warning.) These infections may lead to serious outcomes, including death. Reported viral infections include cytomegalovirus and herpes zoster infections.

Monitor for the development of infection. Consider benefits and risks for the individual patient, and use the lowest effective dosage needed to maintain response.

Other Warnings and Precautions

Nephrotoxicity

Voclosporin can cause acute and/or chronic nephrotoxicity. Monitor eGFR regularly during treatment, and consider dose reduction or discontinuation in patients who experience decreases in eGFR from baseline. Evaluate persistent decreases in eGFR for chronic calcineurin inhibitor nephrotoxicity.

Consider benefits and risks of voclosporin, including the risk of worsening nephrotoxicity, when the drug is used for durations of longer than 1 year since efficacy and safety of voclosporin have not been established beyond 1 year, Also consider benefits and risks of treatment when voclosporin is co-administered with drugs associated with nephrotoxicity.

Hypertension

Hypertension commonly reported; may require antihypertensive therapy. Some antihypertensive drugs can increase risk for hyperkalemia, and certain calcium-channel blocking agents (verapamil and diltiazem) may increase voclosporin blood concentrations and require dosage reduction of voclosporin.

Monitor BP regularly and treat hypertension as appropriate. Consider discontinuation of voclosporin in patients who experience increases in BP that cannot be managed with dose reduction of voclosporin or other appropriate medical intervention.

Neurotoxicity

May cause neurotoxicities. The most severe neurotoxicities include posterior reversible encephalopathy syndrome (PRES), delirium, seizure, and coma; others include tremors, paresthesias, headache, mental status changes, and changes in motor and sensory functions. Monitor for neurologic symptoms and consider dosage reduction or discontinuation of voclosporin if neurotoxicity occurs.

Hyperkalemia

Hyperkalemia, including serious cases requiring treatment, reported. The risk of hyperkalemia may be increased with concomitant use of agents associated with hyperkalemia. Monitor serum potassium concentrations periodically during treatment.

QTc Prolongation

Clinically significant QT prolongation may occur if used in combination with other drugs that prolong the QT_c interval. Risk of torsades de pointes and/or sudden death with use of drugs that prolong the QT_c interval may be increased in patients with bradycardia, hypokalemia or hypomagnesemia, with concomitant use of other drugs that prolong the QT_c interval, and in the presence of congenital prolongation of the QT interval.

Immunizations

Avoid live attenuated vaccines. May interfere with usual response to immunizations.

Inactivated vaccines noted to be safe for administration may not be sufficiently immunogenic during treatment with voclosporin.

Pure Red Cell Aplasia

Pure red cell aplasia (PRCA) reported in patients treated with another calcineurin-inhibitor immunosuppressant; all of these patients reported risk factors for PRCA. If PRCA is diagnosed, consider discontinuation of voclosporin.

Specific Populations

Pregnancy

Insufficient data to determine risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Avoid use in pregnant women because the formulation of voclosporin contains alcohol, which is associated with fetal harm. There are risks to the mother and fetus associated with systemic lupus erythematosus (SLE).

In animal studies, embryocidal and fetocidal effects observed. There were no treatment-related fetal malformations or variations.

Lactation

No available data on the presence of voclosporin in human milk, the effects on the breastfed infant, or the effects on milk production. Distributed into milk of lactating rats and likely to be present in human milk. Breastfeeding not recommended during treatment and for ≥7 days after last dose of voclosporin.

Females and Males of Reproductive Potential

Voclosporin may be used in combination with mycophenolate mofetil, which can cause major birth defects and miscarriage when used in pregnant women and men whose female partners are pregnant. Refer to the mycophenolate mofetil prescribing information for more information on its use during pregnancy. If voclosporin is administered with mycophenolate mofetil, the information for mycophenolate mofetil regarding pregnancy testing, contraception, and infertility also applies to this combination regimen.

Pediatric Use

Safety and efficacy not established.

Geriatric Use

Insufficient data to determine whether geriatric patients respond differently from 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.

Hepatic Impairment

In mild and moderate hepatic impairment (Child-Pugh A and Child-Pugh B), reduce dosage. Avoid voclosporin in severe hepatic impairment (Child-Pugh C). In mild or moderate hepatic impairment, peak plasma concentration and AUC are increased approximately 1.5- to 2.0-fold. Effect of severe hepatic impairment on pharmacokinetics of voclosporin is unknown.

Renal Impairment

Not recommended in patients with a baseline eGFR ≤45 mL/minute per 1.73 m² unless benefit exceeds risk. If used in patients with severe renal impairment at baseline, administer at a reduced dosage. Peak plasma concentrations and AUC increased 1.5- and 1.7-fold, respectively, in severe renal impairment. Effect of end-stage renal disease with or without hemodialysis on pharmacokinetics of voclosporin is unknown.

No dosage adjustment recommended in mild or moderate renal impairment at baseline. Peak plasma concentrations and AUC not affected by mild and moderate renal impairment. Monitor eGFR closely, and perform dosing adjustments based on eGFR as directed.

Common Adverse Effects

Adverse reactions (≥3%): decreased glomerular filtration rate, hypertension, diarrhea, headache, anemia, cough, urinary tract infection, upper abdominal pain, dyspepsia, alopecia, renal impairment, abdominal pain, mouth ulceration, fatigue, tremor, acute kidney injury, decreased appetite.

Interactions for Voclosporin

Sensitive substrate of CYP3A4. Does not inhibit breast cancer resistance protein (BCRP), CYP1A2, 2B6, 2C8, 2C9, 2C19, or 2D6; does not induce CYP1A2, 2B6, or 3A4.

Weak inhibitor of P-gp; inhibitor of organic anion transporting polypeptides (OATP) 1B1 and 1B3. Not a substrate for BCRP, OATP1B1, or OATP1B3.

Drugs Affecting or Affected by Hepatic Microsomal Enzymes

Strong and moderate inhibitors of CYP3A4: Voclosporin exposure increased with coadministration of strong or moderate CYP3A4 inhibitors; this may increase risk of adverse reactions to voclosporin. Coadministration with strong CYP3A4 inhibitors contraindicated. Reduce dosage of voclosporin when coadministered with moderate CYP3A4 inhibitors and avoid food or drink containing grapefruit during treatment with voclosporin.

Strong and moderate inducers of CYP3A4: Voclosporin exposure decreased with coadministration of strong or moderate CYP3A4 inducers; this may decrease efficacy of voclosporin. Avoid coadministration with strong or moderate CYP3A4 inducers.

Drugs Affecting or Affected by Transport Systems

P-glycoprotein substrates: When coadministered with voclosporin, exposure of P-gp substrates and risk of adverse reactions may be increased. If used with certain P-gp substrates with a narrow therapeutic window, reduce dosage of the substrate as recommended in its prescribing information, if needed.

Organic anion transporting polypeptides (OATP) 1B1 substrates: Voclosporin is an inhibitor of OATP1B1 in vitro; however, clinical effect of this interaction not studied. Concentration of OATP1B1 substrates may be increased when coadministered with voclosporin. Monitor for adverse reactions of OATP1B1 substrates when coadministered with voclosporin.

Vaccines

Avoid live vaccines.

Specific Drugs and Foods

Voclosporin Pharmacokinetics

Absorption

Bioavailability

Following oral administration on an empty stomach, peak plasma concentrations reached in 1–4 hours (median 1.5 hours).

Food

Coadministration with food decreases peak plasma concentrations by 29–53% and AUC by 15–25%.

Special Populations

Severe renal impairment (Cl_cr below 30 mL/minute): Peak plasma concentrations and AUC increased 1.5- and 1.7-fold, respectively. Effect of end-stage renal disease with or without hemodialysis on pharmacokinetics is unknown.

Mild and moderate hepatic impairment (Child-Pugh A or B): Peak plasma concentrations and AUC increased approximately 1.5- to 2.0-fold. Effect of severe hepatic impairment (Child-Pugh C) on pharmacokinetics is unknown.

Pharmacokinetics not affected by age, sex, race, or body weight.

Distribution

Distributed into milk in rats; likely to be present in human milk.

Plasma Protein Binding

97% protein-bound.

Elimination

Metabolism

Metabolized predominantly by CYP3A4.

Elimination Route

92.7% recovered in feces (including 5% as unchanged voclosporin); 2.1% recovered in urine (including 0.25% as unchanged voclosporin).

Half-life

Mean 30 hours.

Stability

Storage

Oral

Capsules

Store at 20–25ºC (excursions permitted to 15–30ºC) in original packaging.

Actions

• Calcineurin-inhibitor immunosuppressant and an analog of cyclosporine; mechanism in suppression of calcineurin is not fully established. Calcineurin, a T-cell activator, promotes inflammation and costimulation of B cells, as well as detrimental effects on podocyte cytoskeleton and function.

• Activation of lymphocytes involves an increase in concentrations of intracellular calcium, which binds to the calcineurin regulatory site and activates calmodulin binding catalytic subunit and through dephosphorylation activates the transcription factor, nuclear factor of activated T-cell cytoplasmic (NFATc).

• Immunosuppressant activity results in inhibition of lymphocyte proliferation, T-cell cytokine production, and expression of T-cell activation surface antigens.

• Studies in animal models suggest voclosporin has a non-immunological role for calcineurin inhibition in kidney function through stabilization of actin cytoskeleton and stress fibers in podocytes, leading to increased podocyte integrity in glomeruli.

Advice to Patients

• Advise the patient to read the FDA-approved patient labeling (medication guide).

• Advise patients to swallow voclosporin capsules whole, and not to open, crush, or divide the capsules.

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

• Advise patients that if a dose is missed, to 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.

• Advise patients to avoid eating grapefruit or drinking grapefruit juice while taking voclosporin.

• 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.

• 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.

• Inform patients that voclosporin 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.

• Inform patients that voclosporin can cause high blood pressure, which may require treatment with antihypertensive therapy. Advise patients to monitor their blood pressure.

• Inform patients that they are at risk of developing adverse neurologic effects including seizure, altered mental status, and tremor. Advise patients to contact their clinician should they develop vision changes, delirium, or tremors.

• 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 voclosporin, and other CYP3A4 enzyme-modulating drugs can alter voclosporin exposure.

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

• Inform female patients of the potential risk to a fetus and to avoid use of voclosporin during pregnancy. When voclosporin is administered in combination with mycophenolate mofetil, refer patients to the mycophenolate medication guide. Advise females to inform their healthcare provider if they are pregnant or become pregnant.

• Advise females not to breastfeed during treatment with voclosporin and for 7 days after the last dose of voclosporin.

• Inform patients that voclosporin can interfere with the usual response to immunizations and that they should avoid live vaccines.

• Advise patients to inform their clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.

• Advise patients to inform their clinician of other important precautionary information.

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Voclosporin can only be obtained through specialty pharmacies. Consult the manufacturer's website ([Web]) for additional information.

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