voclosporin (Rx)

Brand and Other Names:Lupkynis
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Dosing & Uses

AdultPediatric

Dosage Forms & Strengths

capsule

  • 7.9mg

Lupus Nephritis

Indicated in combination with a background immunosuppressive therapy regimen for active lupus nephritis (LN)

23.7 mg PO BID initially; modify dose based on eGFR

Use in combination with mycophenolate mofetil (MMF) and corticosteroids

Consider discontinuation if no therapeutic benefit by 24 weeks

Safety and efficacy not established >1 year; consider risks and benefits of longer durations of treatment in light of treatment response and risk of nephrotoxicity

Dosage Modifications

eGFR dosage adjustments

  • If eGFR <60 mL/min/1.73 m2 and reduced from baseline by >20 to <30%: Reduce by 7.9 mg BID; reassess within 2 weeks; if eGFR is still reduced from baseline by >20%, reduce dose again by 7.9 mg BID
  • If eGFR <60 mL/min/1.73 m2 and reduced from baseline by ≥30%: Discontinue; reassess within 2 weeks; consider restarting at lower dose (eg, 7.9 mg BID) only if eGFR returns to ≥80% of baseline
  • Dose reductions due to eGFR: Consider increasing dose by 7.9 mg BID for each eGFR ≥80% of baseline; do not exceed starting dose

Coadministration of CYP3A4 inhibitors/inducers

  • Strong CYP3A4 inhibitors: Contraindicated
  • Moderate CYP3A4 inhibitors: Reduce voclosporin to 15.8 mg qAM and 7.9 mg qPM
  • Mild CYP3A4 inhibitors: No dosage adjustment necessary
  • Strong CYP3A4 inducers: Avoid coadministration
  • Avoid any food or drink containing grapefruit

Renal impairment

  • Baseline eGFR ≤45 mL/min/1.73 m2: Use not recommended unless benefits outweigh risks; not studied If used in patients with severe renal impairment (eGFR <30 mL/min/1.73 m2) at baseline: Decrease starting dose to 15.8 mg PO BID
  • End-stage renal disease with or without hemodialysis: Pharmacokinetics are unknown

Hepatic impairment

  • Mild or moderate (Child-Pugh A or B): Reduce to 15.8 mg BID
  • Severe (Child-Pugh C): Not recommended

Dosing Considerations

Monitoring parameters

  • Before initiating therapy
    • Baseline parameters: eGFR and blood pressure (BP)
    • Use not recommended in patients with a baseline eGFR ≤45 mL/min/1.73 m2 unless benefits outweigh risks
    • Do not initiate in if BP >165/105 mmHg or with hypertensive emergency
  • During treatment
    • eGFR: Every 2 weeks for first month, and every 4 weeks thereafter
    • BP: Every 2 weeks for first month, and as clinically indicated thereafter

Limitation of use

  • Safety and efficacy not established in combination with cyclophosphamide; use not recommended

Safety and efficacy not established

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Interactions

Interaction Checker

and voclosporin

No Results

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    No Interactions Found
    Interactions Found

    Contraindicated

      Serious - Use Alternative

        Significant - Monitor Closely

          Minor

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            Adverse Effects

            >10%

            Glomerular filtration rate decreased (26%)

            Hypertension (19%)

            Diarrhea (19%)

            Headache (15%)

            Anemia (12%)

            Cough (11%)

            1-10%

            Urinary tract infection (10%)

            Upper abdominal pain (7%)

            Dyspepsia (6%)

            Alopecia (6%)

            Renal Impairment (6%)

            Abdominal pain (5%)

            Mouth ulceration (4%)

            Fatigue (4%)

            Tremor (3%)

            Acute kidney injury (3%)

            Decreased appetite (3%)

            Gingivitis (<3%)

            Hypertrichosis (<3%)

            Frequency Not Defined

            Upper respiratory tract infections (bacterial and viral)

            Herpes zoster

            Pneumonia

            Gastroenteritis

            Urinary tract infections

            Cytomegalovirus chorioretinitis

            Cytomegalovirus infection

            Herpes zoster cutaneous disseminated

            Blood creatinine increased

            Azotemia

            Renal failure

            Oliguria

            Proteinuria

            Hyperkalemia

            QT prolongation

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            Warnings

            Black Box Warnings

            Malignancies and serious infections

            • Increased risk for developing malignancies and serious infections with voclosporin or other immunosuppressants that may lead to hospitalization or death

            Contraindications

            Coadministration of strong CYP3A4 inhibitors (eg, ketoconazole, itraconazole, clarithromycin)

            Serious or severe hypersensitivity reactions to voclosporin or any of its excipients

            Cautions

            Hypertension is a common adverse reaction and may require antihypertensive therapy; monitor relevant drug interactions

            May cause a spectrum of neurotoxicities, which may include posterior reversible encephalopathy syndrome, delirium, seizure, coma, tremors, paresthesia, headache, mental status changes, and changes in motor and sensory functions; monitor for neurologic abnormalities; reduce dosage or discontinue therapy

            Hyperkalemia reported with calcineurin inhibitors; risk may be increased if coadministered with other agents associated with hyperkalemia (eg, potassium-sparing diuretics, ACE inhibitors, angiotensin receptor blockers); monitor serum potassium levels

            Cases of pure red cell aplasia (PRCA) reported in patients treated with another calcineurin-inhibitor immunosuppressant; reported risk factors were parvovirus B19 infection, underlying disease, or concomitant medications associated with PRCA; if diagnosed, consider discontinuation

            Lymphoma and other malignancies

            • Immunosuppressants, including voclosporin, increase risk of developing lymphomas and other malignancies, particularly of the skin
            • Risk may be related to intensity and duration of immunosuppression
            • Examine for skin changes
            • Avoid or limit sun exposure and avoid artificial UV light (tanning beds, sun lamps) by wearing protective clothing and using a broad-spectrum sunscreen with a high protection factor (SPF ≥30)

            Serious infections

            • Immunosuppressants, including voclosporin, increase the risk of developing bacterial, viral, fungal, and protozoal infections, including opportunistic infections
            • Infections may lead to serious, including fatal, outcomes
            • Viral infections reported include cytomegalovirus and herpes zoster infections
            • Monitor for any developing infection
            • Consider benefits and risks; use the lowest effective dose needed to maintain response

            Nephrotoxicity

            • Nephrotoxicity reported; may cause acute and/or chronic nephrotoxicity
            • Monitor renal function; consider dosage reduction or discontinuation at baseline
            • Safety and efficacy not established >1 year; consider risks and benefits of longer durations of treatment in light of treatment response and risk of nephrotoxicity
            • Concomitant nephrotoxic drugs may increase risk of nephrotoxicity

            Drug interaction overview

            • Sensitive CYP3A4 substrate; P-gp inhibitor; OATP1B1 inhibitor
            • CYP3A4 inhibitors
              • Coadministration with strong or moderate CYP3A4 inhibitors increases voclosporin effects and risk of adverse reactions
              • Use contraindicated for strong CYP3A4 inhibitors; reduce voclosporin dose for moderate CYP3A4 inhibitors; avoid food or drink containing grapefruit during treatment
            • CYP3A4 inducers
              • Coadministration with strong or moderate CYP3A4 inducers decreases voclosporin effects and efficacy
              • Avoid coadministration of strong and moderate CYP3A4 inducers
            • P-gp substrates
              • Coadministration of voclosporin increases effects and risk of adverse reactions of P-gp substrates; reduce dose of P-gp substrates with a narrow therapeutic window, if needed
            • OATP1B substrates
              • Effects on OATP1B1 substrates (eg, statins) has not been studied clinically; information suggests voclosporin may increase concentration of OATP1B1 substrates; monitor for adverse reactions of OATP1B1 substrates when concomitantly used
            • Vaccines
              • Live attenuated vaccines during treatment: Avoid use
              • Inactivated vaccines: Noted safe for administration; however, may not be sufficiently immunogenic during treatment
            • QT prolongation
              • Prolongs QTc interval in a dose-dependent manner after single-dose administration at a dose higher than the recommended therapeutic dose
              • Use in combination with other drugs that are known to prolong QTc may result in clinically significant QT prolongation
              • Consider obtaining electrocardiograms and monitoring electrolytes in patients at high risk
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            Pregnancy & Lactation

            Pregnancy

            Avoid use in pregnant females; formulation contains alcohol (21.6 mg of dehydrated ethanol per capsule for a dose of 129.4 mg/day); studies have demonstrated that alcohol is associated with fetal harm (eg, central nervous system abnormalities, behavioral disorders, impaired intellectual development)

            Insufficient data available on use in pregnant females to determine drug-associated risks for major birth defects, miscarriage, or adverse maternal or fetal outcomes

            May be used in combination with a immunosuppressive therapy regimen that includes MMF; information for MMF regarding pregnancy, pregnancy testing, contraception, and infertility also applies to this combination regimen; refer to MMF prescribing information for more information

            There are risks (eg, worsening of the underlying disease, premature birth, miscarriage, intrauterine growth restriction) to mother and fetus associated with systemic lupus erythematosus

            Animal data

            • Oral administration of either voclosporin or a 50:50 mixture of voclosporin and its cis-isomer was embryocidal and feticidal in rats and rabbits at doses 15x and 1x, respectively, the maximum recommended human dose (MRHD) of 23.7 mg BID, based on drug exposure AUC
            • Reduced placental and fetal body weights occurred in rabbits at 0.1x-0.3x the MRHD and in rats at higher drug exposures
            • Crosses the placenta in pregnant rats
            • Dystocia was evident in a prenatal and postnatal study in rats

            Lactation

            No available data on presence in human milk, effects on breastfed infants, or effects on milk production

            Present in milk of lactating rats; therefore, drug is likely to be present in human milk

            Breastfeeding is not recommended during treatment and for at least 7 days after last dose (~6 elimination half-lives)

            Pregnancy Categories

            A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

            B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

            C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

            D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

            X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

            NA: Information not available.

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            Pharmacology

            Mechanism of Action

            Calcineurin-inhibitor immunosuppressant

            Mechanism of voclosporin suppression of calcineurin has not been fully established

            Activation of lymphocytes involves an increase in intracellular calcium concentrations that bind to calcineurin regulatory site and activate calmodulin binding catalytic subunit and through dephosphorylation activates the transcription factor, Nuclear Factor of Activated T-Cell Cytoplasmic

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

            Absorption

            Peak plasma time: 1.5 hr (empty stomach)

            Steady-state reached at 6 days

            Effects of food

            • Coadministration with either low- or high-fat meals decreased both rate and extent of absorption
            • Plasma concentration and AUC of voclosporin were reduced by 29% to 53% and 15% to 25%

            Distribution

            Vd (steady-state): 2,154 L

            Protein bound: 97%

            Metabolism

            Predominately metabolized by CYP3A4

            Metabolite in human whole blood represented 16.7% of total exposure and is about 8-fold less potent than parent molecule

            Elimination

            Clearance (steady-state): 63.6 L/hr

            Half-life: ~30 hr

            Excretion (single 70-mg dose): Feces (92.7% [5% unchanged]); urine (2.1% [0.25% unchanged])

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            Administration

            Oral Administration

            Swallow capsule whole on an empty stomach

            Do not open, crush, or divide capsule

            Administer at a consistent 12-hr schedule as close as possible and with at least 8 hr between doses

            Avoid eating grapefruit or drinking grapefruit juice

            Missed dose

            • ≤4 hr after missed dose: Take as soon as possible
            • >4 hr after missed dose: Wait until next scheduled dose; do NOT double dose

            Storage

            Store at room temperature (20-25ºC [68-77ºF]); excursions permitted to 15-30ºC (59- 86ºF)

            Do not put in another container

            Keep in original packaging until ready to be taken

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            Formulary

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            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
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