CycloSPORINE (Systemic)

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Capsule, Oral:

Gengraf: 25 mg [contains cremophor el, fd&c blue #2 (indigotine)]

Gengraf: 50 mg [DSC] [contains alcohol, usp, fd&c blue #2 aluminum lake]

Gengraf: 100 mg [contains cremophor el, fd&c blue #2 (indigotine)]

Neoral: 25 mg, 100 mg [contains alcohol, usp]

SandIMMUNE: 25 mg, 100 mg

Generic: 25 mg, 50 mg, 100 mg

Solution, Intravenous:

SandIMMUNE: 50 mg/mL (5 mL) [contains alcohol, usp, cremophor el]

Generic: 50 mg/mL (5 mL)

Solution, Oral:

Gengraf: 100 mg/mL (50 mL) [contains propylene glycol]

Neoral: 100 mg/mL (50 mL) [contains alcohol, usp]

SandIMMUNE: 100 mg/mL (50 mL) [contains alcohol, usp]

Generic: 100 mg/mL (50 mL)

Pharmacology

Mechanism of Action

Inhibition of production and release of interleukin II and inhibits interleukin II-induced activation of resting T-lymphocytes.

Pharmacokinetics/Pharmacodynamics

Absorption

Oral:

Cyclosporine (non-modified): Erratic and incomplete; dependent on presence of food, bile acids, and GI motility; larger oral doses are needed in pediatrics due to shorter bowel length and limited intestinal absorption

Cyclosporine (modified): Erratic and incomplete; increased absorption, up to 30% when compared to cyclosporine (non-modified); less dependent on food, bile acids, or GI motility when compared to cyclosporine (non-modified)

Distribution

Widely distributed in tissues and body fluids including the liver, pancreas, and lungs

V_dss: 4-6 L/kg in renal, liver, and marrow transplant recipients (slightly lower values in cardiac transplant patients; children <10 years of age have higher values); ESRD: 3.49 L/kg

Metabolism

Extensively hepatic via CYP3A4; forms at least 25 metabolites; extensive first-pass effect following oral administration

Excretion

Primarily feces; urine (6%, 0.1% as unchanged drug and metabolites); clearance is more rapid in pediatric patients than in adults

Time to Peak

Serum: Oral:

Cyclosporine (non-modified): 2-6 hours; some patients have a second peak at 5-6 hours

Cyclosporine (modified): Renal transplant: 1.5-2 hours

Half-Life Elimination

Oral: May be prolonged with hepatic impairment and shorter in pediatric patients due to the higher metabolism rate

Cyclosporine (non-modified): Biphasic: Alpha: 1.4 hours; Terminal: 19 hours (range: 10-27 hours)

Cyclosporine (modified): Biphasic: Terminal: 8.4 hours (range: 5-18 hours)

Protein Binding

90% to 98% to lipoproteins

Use in Specific Populations

Special Populations: Renal Function Impairment

In a limited number of patients with end-stage renal disease (ESRD) (creatinine clearance <5 mL/minute), cyclosporine 3.5 mg/kg IV over 4 hours administered at the end of a hemodialysis session resulted in a mean volume of distribution of 3.49 L/kg and systemic clearance of 0.369 L/h/kg. This systemic clearance was approximately two-thirds the mean systemic clearance (0.56 L/h/kg) of cyclosporine in controls with normal renal function. In a small number of liver transplant patients, the mean clearance on and off hemodialysis was 463 mL/min and 398 mL/min, respectively. Less than 1% of the dose was recovered in the dialysate.

Special Populations: Hepatic Function Impairment

Severe hepatic impairment may result in significantly reduced clearance and increased cyclosporine exposures.

Use: Labeled Indications

Cyclosporine modified:

Transplant rejection prophylaxis: Prophylaxis of organ rejection in kidney, liver, and heart transplants (commonly used in combination with an antiproliferative immunosuppressive agent and corticosteroid).

Rheumatoid arthritis: Treatment of severe, active rheumatoid arthritis (RA) not responsive to methotrexate alone

Psoriasis: Treatment of severe, recalcitrant plaque psoriasis in non-immunocompromised adults unresponsive to or unable to tolerate other systemic therapy

Cyclosporine non-modified:

Transplant rejection (prophylaxis): Prophylaxis of organ rejection in kidney, liver, and heart transplants (commonly used in combination with an antiproliferative agent and a corticosteroid)

Transplant rejection, chronic (treatment): May be used for the treatment of chronic rejection (kidney, liver, and heart) in patients previously treated with other immunosuppressive agents. Note: While approved for the treatment of chronic organ rejection, other therapies are clinically preferred in this setting.

Use: Off Label

Acute graft-versus-host disease (prophylaxis)ayes

Based on the Prophylaxis and Treatment of GVHD: EBMT-ELN Working Group Recommendations for a Standardized Practice, cyclosporine as combination therapy given to prevent acute graft-versus-host disease (aGVHD) is effective and recommended in the management of this condition Ruutu 2014.

Data from a randomized study support the use of cyclosporine (in combination with methotrexate and prednisone) to prevent aGVHD following allogeneic hematopoietic stem cell transplantation Chao 1993. This combination was more effective than using cyclosporine and prednisone alone. Subsequently, data from a follow-up, prospective, randomized study demonstrated that the addition of prednisone did not have an impact on the incidence of acute or chronic GVHD; however, the addition of prednisone was associated with a somewhat lower incidence of early post-transplant complications Chao 2000. Further data suggest that the combination of cyclosporine and prednisone with or without methotrexate results in comparable chronic GVHD-free survival Ross 1999. A number of other trials support the use of cyclosporine (in combination with methotrexate) for this condition Ratanatharathorn 1998, Storb 1986a, Storb 1986b.

Chronic graft-versus-host disease (treatment)yes

Based on the American Society for Blood and Marrow Transplant (ASBMT) Consensus Conference on Clinical Practice in Chronic GVHD: Second-Line Treatment of Chronic Graft-versus-Host Disease, the use of calcineurin inhibitors (eg, cyclosporine) is effective and recommended for the treatment of patients with refractory chronic GVHD Wolff 2011.

Focal segmental glomerulosclerosisb

Data from a randomized controlled trial in patients with steroid-resistant focal segmental glomerulosclerosis (FSGS) treated with cyclosporine (in combination with low-dose prednisone) support the use of cyclosporine for this condition Cattran 1999. A meta-analysis of trials evaluating the use of various treatment strategies for adult patients with FSGS, demonstrated that treatment with cyclosporine (with or without prednisone) was more likely to achieve partial remission of nephrotic syndrome compared with symptomatic treatment or prednisone alone Braun 2008. Additional trials may be necessary to further define the role of cyclosporine for the treatment FSGS.

Immune thrombocytopenia, refractorycyes

Cyclosporine in the management of refractory or relapsed immune thrombocytopenia (ITP) has primarily been evaluated in noncontrolled settings and demonstrated beneficial results in at least half of the patients treated

Interstitial cystitis (bladder pain syndrome)cyes

Oral cyclosporine in the management of interstitial cystitis/bladder pain syndrome has been studied in controlled and noncontrolled trials demonstrating high efficacy rates. American Urological Association guidelines recommend oral cyclosporine as a fifth-line treatment option to be considered after other treatment modalities have failed. The guidelines also note that while sustained efficacy has been demonstrated, use of cyclosporine is limited by a high rate of adverse events and the potential for serious events (eg, immunosuppression, hypertension, nephrotoxicity).

Lung transplant (prevention of acute rejection)b

Data from a small, prospective, randomized controlled trial support the use of cyclosporine (in combination with other transplant immunosuppressants) for the prevention of acute rejection in lung transplant recipients Zuckermann 2003. However, based on a systematic review, tacrolimus may be preferred over cyclosporine for lung transplant immunosuppression Penninga 2013. Additional trials may be necessary to further define the role of cyclosporine in the treatment of this condition.

Lupus nephritisayes

Data from a multicenter, prospective, randomized, open-label, blinded-end point, controlled trial in patients with diffuse proliferative lupus nephritis treated with cyclosporine or azathioprine support the use of cyclosporine (in combination with corticosteroids) in the treatment of this condition Moroni 2006.

Although a consensus regarding the use of calcineurin inhibitors in the treatment of lupus nephritis was not reached by the American College of Rheumatology, evidence exists for use as an induction agent and during refractory disease Moroni 2006, Ogawa 2007.

Myasthenia graviscyes

Data in a limited number of clinical trials suggest that cyclosporine may be beneficial for the treatment of myasthenia gravis when used in combination with corticosteroids in patients who are not adequately controlled with pyridostigmine and corticosteroids Lavrnic 2005, Tindall 1993.

Based on the Myasthenia Gravis Foundation of America consensus-based guidance for the management of myasthenia gravis, cyclosporine may be used as an immunosuppressive agent in patients with myasthenia gravis who have not met treatment goals after an adequate trial of pyridostigmine. Cyclosporine may be added as monotherapy or in conjunction with glucocorticoids and/or pyridostigmine. Due to the risk for adverse effects and drug interactions with cyclosporine, other immunosuppressive agents may be preferred Lavrnic 2005, Sanders 2016.

Ulcerative colitis, severe refractoryayes

Data from a single center, randomized, double-blind, controlled trial and in patients with severe ulcerative colitis Van Assche 2003 and in patients with severe ulcerative colitis refractory to intravenous corticosteroid therapy Lichitiger 1994 support the use of intravenous cyclosporine for the treatment of this condition. Additional trials using oral cyclosporine in patients with severe, refractory ulcerative colitis supports the use of oral cyclosporine in the treatment of this condition De Saussure 2005, Weber 2006.

Based on the American College of Gastroenterology Ulcerative Colitis Guidelines in Adults, intravenous cyclosporine is effective and recommended for use when patients with severe ulcerative colitis fail to show significant improvement within 3 to 5 days with intravenous corticosteroid therapy. Restrict use to those who fail IV corticosteroid therapy or with contraindications or intolerance to corticosteroids.

Uveitisc

Results from controlled and noncontrolled studies demonstrate that cyclosporine is generally effective in treating noninfectious uveitis Mathews 2010, Murphy 2005, Ozdal 2002. However, limited prospective controlled clinical trials have been performed. Further data are needed to establish the efficacy, safety, optimal dosage, and length of cyclosporine therapy in the treatment of uveitis in adults. An expert review panel recommends cyclosporine as second-line treatment for noninfectious uveitis Díaz-Llopis 2009.

Contraindications

Hypersensitivity to cyclosporine or any component of the formulation. IV cyclosporine is contraindicated in hypersensitivity to polyoxyethylated castor oil (Cremophor EL).

Rheumatoid arthritis and psoriasis patients with abnormal renal function, uncontrolled hypertension, or malignancies. Concomitant treatment with PUVA or UVB therapy, methotrexate, other immunosuppressive agents, coal tar, or radiation therapy are also contraindications for use in patients with psoriasis.

Canadian labeling: Additional contraindications (not in the US labeling): Concurrent use with bosentan; rheumatoid arthritis and psoriasis patients with primary or secondary immunodeficiency excluding autoimmune disease, uncontrolled infection, or malignancy (excluding non-melanoma skin cancer).

Dosage and Administration

Dosing: Adult

Neoral/Gengraf (cyclosporine modified) and Sandimmune (cyclosporine non-modified) are not bioequivalent and cannot be used interchangeably. Use caution when selecting, dispensing, and administrating cyclosporine products; in general, cyclosporine (modified) is more commonly used clinically.

Psoriasis: Oral: Cyclosporine (modified): Initial dose: 2.5 mg/kg/day in 2 divided doses.

Titration:

Increase by 0.5 mg/kg/day if insufficient response is seen after 4 weeks of treatment. Additional dosage increases may be made every 2 weeks if needed (maximum dose: 4 mg/kg/day).

Guideline recommended dosing: 2.5 to 5 mg/kg/day in 2 divided doses, adjust dose downward in 0.5 to 1 mg/kg increments when clearance of psoriasis is achieved or if hypertension or decreased renal function occur; interval therapy is preferred (Menter 2009).

Discontinue if no benefit is seen by 6 weeks of therapy at the maximum dose. Once patients are adequately controlled, the dose should be decreased to the lowest effective dose. Doses lower than 2.5 mg/kg/day may be effective. Treatment longer than 1 year is not recommended.

Note: Increase the frequency of blood pressure monitoring after each alteration in dosage of cyclosporine. Cyclosporine dosage should be decreased by 25% to 50% in patients with no history of hypertension who develop sustained hypertension during therapy and, if hypertension persists, treatment with cyclosporine should be discontinued.

Rheumatoid arthritis: Oral: Cyclosporine (modified): Initial dose: 2.5 mg/kg/day in 2 divided doses; salicylates, NSAIDs, and oral glucocorticoids may be continued (refer to Drug Interactions).

Titration: Dose may be increased by 0.5 to 0.75 mg/kg/day if insufficient response is seen after 8 weeks of treatment; additional dosage increases may be made again at 12 weeks (maximum dose: 4 mg/kg daily). Discontinue if no benefit is seen by 16 weeks of therapy.

Note: Increase the frequency of blood pressure monitoring after each alteration in dosage of cyclosporine. Cyclosporine dosage should be decreased by 25% to 50% in patients with no history of hypertension who develop sustained hypertension during therapy and, if hypertension persists, treatment with cyclosporine should be discontinued.

Solid organ transplant (newly transplanted patients): Cyclosporine is commonly used in combination with an antiproliferative immunosuppressive agent and a corticosteroid. Although cyclosporine may be initiated preoperatively, it is more frequently started postoperatively (depending on concomitant renal function); adjust dose to achieve desired plasma concentration.

Oral: Dose is dependent upon type of transplant and formulation; refer to institutional protocol for specific dosing:

Cyclosporine (modified): Manufacturer's labeling:

Renal: 9 ± 3 mg/kg/day in 2 divided doses.

Liver: 8 ± 4 mg/kg/day in 2 divided doses.

Heart: 7 ± 3 mg/kg/day in 2 divided doses.

Cyclosporine (non-modified): Refer to institutional protocol for specific dosing; dosing in clinical practice may differ greatly compared to the manufacturer's labeling.

Note: When using the non-modified formulation, cyclosporine levels may increase in liver transplant patients when the T-tube is closed; dose may need decreased.

IV: Cyclosporine (non-modified): Manufacturer's labeling: Initial dose: 5 to 6 mg/kg/day or one-third of the oral dose as a single dose, infused over 2 to 6 hours; use should be limited to patients unable to take capsules or oral solution; patients should be switched to an oral dosage form as soon as possible.

Note: Many transplant centers administer cyclosporine as "divided dose" infusions (in 2 doses daily) or as a continuous (24-hour) infusion; dosages range from 3 to 7.5 mg/kg/day. Specific institutional protocols should be consulted.

Note: Conversion to cyclosporine (modified) from cyclosporine (non-modified): Start with daily dose previously used and adjust to obtain preconversion cyclosporine trough concentration. Plasma concentrations should be monitored every 4 to 7 days and dose adjusted as necessary, until desired trough level is obtained. When transferring patients with previously poor absorption of cyclosporine (non-modified), monitor trough levels at least twice weekly (especially if initial dose exceeds 10 mg/kg daily); high plasma levels are likely to occur.

Acute graft versus host disease (aGVHD), prevention (off-label use): IV followed by oral:

Initial: IV: 3 mg/kg/day 1 day prior to transplant; may convert to oral therapy when tolerated; titrate dose to appropriate cyclosporine trough concentration (in combination with methotrexate); taper per protocol (refer to specific references and institutional protocols for tapering and target trough details); discontinue 6 months post-transplant in the absence of acute GVHD (Ratanatharathorn 1998; Ruutu 2014; Storb 1986a; Storb 1986b).

or

Initial: IV: 5 mg/kg/day (as a continuous infusion over 20 hours) for 6 days (loading dose) starting 2 days prior to transplant, then 3 mg/kg/day over 20 hours for 11 days starting on post-transplant day 4, then 3.75 mg/kg/day over 20 hours for 21 days starting on day 15, then oral (in 2 divided daily doses): 10 mg/kg/day days 36 to 83, then 8 mg/kg/day days 84 to 97, then 6 mg/kg/day days 98 to 119, then 4 mg/kg/day days 120 to 180, then discontinue (in combination with methotrexate +/- corticosteroid) (Chao 1993; Chao 2000).

Focal segmental glomerulosclerosis (off-label use): Oral: Initial: 3.5 to 5 mg/kg/day in 2 divided doses (every 12 hours; in combination with oral prednisone) (Braun 2008; Cattran 1999).

Immune thrombocytopenia, refractory (off-label use): Oral: 5 mg/kg/day in 2 divided doses (every 12 hours) for 6 days, followed by 2.5 to 3 mg/kg/day (titrate to serum levels of 100 to 200 ng/mL); time to response in clinical trials was ~3 to 4 weeks (Provan 2010). Additional studies have used initial doses of 2.5 to 5 mg/kg/day in 2 divided doses; maintenance doses were adjusted to maintain serum levels between 150 and 400 ng/mL (Choudhary 2008; Emilia 2002; Zver 2006).

Interstitial cystitis (bladder pain syndrome) (off-label use): Oral: Initial: 2 to 3 mg/kg/day in 2 divided doses (maximum of 300 mg daily). Once symptom relief is established, the dose can be tapered as tolerated (to as low as 1 mg/kg as a single daily dose) and in some cases can be stopped with continued benefit. Treatment duration was at least 6 months to more than 1 year in some patients (Forrest 2012; Sairanen 2004; Sairanen 2005; Sairanen 2008).

Lung transplant (prevention of acute rejection) (off-label use): IV followed by oral: Initial: 1 mg/kg/day IV beginning immediately after transplantation (in combination with other transplant immunosuppressants); convert to oral cyclosporine as soon as possible post extubation. Target cyclosporine levels were maintained between 250 and 350 ng/mL during the first month, and around 200 ng/mL thereafter (Zuckermann 2003).

Myasthenia gravis (off-label use): Patients who remain significantly symptomatic on pyridostigmine: Oral: Initial: 100 mg twice daily; increase slowly as needed to 3 to 6 mg/kg/day in 2 divided doses. May be added as monotherapy or in conjunction with glucocorticoids and/or pyridostigmine (Lavrnic 2005; Sanders 2016). Onset of clinical response to cyclosporine may take 1 to 3 months, with a maximum effect apparent at 7 months (Ciafaloni 2000).

Nephrotic syndrome (Canadian labeling): Oral: Cyclosporine (modified):

Initial: 3.5 mg/kg/day in 2 divided doses (every 12 hours); titrate for induction of remission and renal function. Adjunct therapy with low-dose oral corticosteroids is recommended for patients with an inadequate response to cyclosporine (particularly if steroid-resistant).

Maintenance: Dose is individualized based on proteinuria, serum creatinine, and tolerability but should be maintained at lowest effective dose; maximum dose: 5 mg/kg daily. Discontinue if no improvement is observed after 3 months.

Lupus nephritis (off-label use): Oral: Cyclosporine (modified): Initial: 4 mg/kg/day for 1 month (reduce dose if trough concentrations >200 ng/mL); reduce dose by 0.5 mg/kg every 2 weeks to a maintenance dose of 2.5 to 3 mg/kg/day (Moroni 2006).

Ulcerative colitis, severe (steroid-refractory) (off-label use):

IV: Cyclosporine (non-modified): 2 to 4 mg/kg/day, infused continuously over 24 hours. (Lichtiger 1994; Van Assche 2003). Note: Some studies suggest no therapeutic difference between low-dose (2 mg/kg) and high-dose (4 mg/kg) cyclosporine regimens; therefore, 2 mg/kg/day is the target treatment dose (ACG [Rubin 2019]; Van Assche 2003).

Oral: Cyclosporine (modified): 2.3 to 3 mg/kg every 12 hours (De Saussure 2005; Weber 2006).

Note: Patients responsive to IV therapy should be switched to oral therapy when possible.

Uveitis (off-label dose): Oral: 2.5 to 5 mg/kg/day in 2 divided doses; gradually decrease to maintenance dose; used alone or in conjunction with other corticosteroids (Isnard Bagnis 2002; Matthews 2010; Murphy 2005; Ozdal 2002; Zaghetto 2010). An expert panel recommends initial dose of 3 to 5 mg/kg/day; reducing dose, once inflammation was under control, to 2 to 3 mg/kg/day until a maintenance dose of 1 mg/kg/day is achieved (Diaz-Llopis 2009).

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Note: Cyclosporine (modified) (Gengraf, Neoral) and cyclosporine (non-modified) (Sandimmune) are not bioequivalent and cannot be used interchangeably. Adjust initial dose to achieve desired target cyclosporine concentration; specific institutional protocols should be consulted.

Hepatitis, autoimmune (induction of remission): Note: Guidelines recommend cyclosporine as second-line induction agent (AASLD [Manns 2010]; EASL 2015). Limited data available: Children ≥2 years and Adolescents: Oral: Initial: 3 to 5 mg/kg/day divided every 8 to 12 hours; titrate to targeted cyclosporine trough concentrations; concentrations reported in the literature range between 150 to 300 ng/mL for induction of remission with lower goals (100 to 200 ng/mL) following remission. Once remission has been sustained, usually at about 6 months of therapy, cyclosporine is slowly tapered off (~14 days) and maintenance therapy with a corticosteroid ± immunosuppressant is initiated (Alvarez 1999; Cuarterolo 2006; Debray 1999; Franulović 2012; Sciveres 2004).

Graft versus host disease (GVHD), prevention: Limited data available: Infants, Children, and Adolescents: IV followed by oral: Initial: IV: 3 to 5 mg/kg/day divided every 12 hours administered over 2 hours or as a single daily dose administered over 8 hours (Lanino 2009; Martin 2003; Storb 1986) or 3 mg/kg/day as a continuous infusion (Nash 2000) beginning one day prior to transplant; may be given with or without methotrexate; may convert to oral therapy when tolerating oral intake; titrate dose to appropriate cyclosporine trough concentration, reported doses ranged from 6 to 12.5 mg/kg/day in divided doses every 12 hours; taper per protocol (refer to specific references for tapering and target trough details); discontinue 6 months post-transplant in the absence of acute GVHD (Lanino 2009; Martin 2003; Storb 1986). Lower doses of 1 mg/kg/day divided every 12 hours have also been reported; a study of 59 pediatric patients (median age: 8 years; range: 1 to 18 years) with acute leukemia compared low-dose IV cyclosporine (1 mg/kg/day divided every 12 hours) with standard IV dose (3 mg/kg/day divided every 12 hours); although patients receiving the lower initial IV dose experienced a higher incidence of GVHD there was a statistically significant decrease in the rate of leukemia relapse (15% vs 41% in the standard dose group) (Locatelli 2000)

Kawasaki disease, refractory: Cyclosporine (modified): Limited data available; optimal regimen not defined: Infants ≥2 months and Children: Oral: Initial: 4 mg/kg/day divided every 12 hours, titrate to target trough concentration; maximum daily dose: 8 mg/kg/day. Dosing based on a prospective trial of 28 pediatric patients (4 months to 5 years) who failed two doses of immune globulin therapy, cyclosporine treatment was continued until patients were afebrile and CRP <0.3 mg/dL or a maximum duration of 3 weeks reached (Suzuki 2011). In a case series of 10 patients (ages: 2 months to 11 years) who failed to respond to multiple therapies, some of whom received infliximab, patients received an initial loading dose of 3 mg/kg/day IV divided every 12 hours; followed by oral cyclosporine (modified) (Neoral) 10 mg/kg/day divided every 12 hours once patient was afebrile for >24 hours; dose was adjusted to achieve a target concentration of 50 to 150 ng/mL; dose was tapered by 10% every 3 days over 1 month once patient was afebrile, clinically improving and had a CRP ≤1 mg/dL or after 2 weeks of therapy, whichever was longer (Tremoulet 2012).

Lupus nephritis: Limited data available: Children and Adolescents: Oral: 3 to 5 mg/kg/day in divided doses for 1 to 2 years (KDIGO 2012). Reported range from trials: 2 to 5 mg/kg/day divided every 12 hours adjusted to maintain targeted trough concentrations. In one trial of 40 children and adolescents (age range: 9 to 14 years), a dosage range of 3.5 to 5 mg/kg/day was shown to effectively decrease proteinuria and allow for reduction of steroid dose; study duration 1 year (Fu 1998). A smaller trial of seven adolescents (14 to 18 years) used an initial dose of 1.5 to 3 mg/kg/day and adjusted to clinical response; after 1 year of therapy, final dosage range was 2 to 4 mg/kg/day (Baca 2006). Case reports have suggested that lower doses (1.8 to 2.5 mg/kg/day) are effective to induce remission (Kawasaki 2008; Suzuki 2006). In a small trial (n=13; age: 4 to 16 years), combination therapy with mycophenolate for induction of severe disease has been reported using cyclosporine 3 to 6 mg/kg/day in 2 to 3 divided doses (Aragon 2010).

Nephrotic syndrome:

Frequently relapsing:

BSA-based dosing: Children ≥3 years and Adolescents: Cyclosporine (modified): Oral: 150 mg/m²/day divided twice daily; doses were titrated as necessary to achieve a target trough concentration of 80 to 100 ng/mL; dose based on a randomized, open-label, crossover study of 60 pediatric patients (age range: 3 to 18 years) (Gellermann 2013)

Weight-based dosing: Children and Adolescents: Oral: 4 to 5 mg/kg/day divided twice daily for at least 12 months (KDIGO 2012); doses as low as 3 mg/kg/day divided twice daily have also been recommended (Gipson 2009)

Steroid-dependent (for steroid sparing effect): Children and Adolescents: Oral: 4 to 5 mg/kg/day divided twice daily for at least 12 months (KDIGO 2012); doses as low as 3 mg/kg/day divided twice daily have also been recommended (Gipson 2009)

Steroid resistant:

BSA-based dosing: Cyclosporine (modified): Children and Adolescents: Oral: 150 mg/m²/day divided twice daily; doses were titrated as necessary to achieve a target trough concentration of 120 to 180 ng/mL; if remission was not achieved by 12 weeks, doses were increased to achieve a target trough concentration of 300 to 400 ng/mL; dose based on a randomized, controlled open-label trial of 32 patients (Cyclosporine group: n=15; age: 6.99 ± 5.48 years; age range: 1.67 to 15.5 years) (Plank 2008)

Weight-based dosing: Cyclosporine (modified): Children and Adolescents: Oral: 5 to 6 mg/kg/day divided twice daily before meals; dose based on two randomized trials in children (Combined total n=92); target trough concentrations ranged from 100 to 250 ng/mL; lower concentrations were accepted if patients were in remission or if toxicity occurred (Choudhry 2009; Gipson 2011). Cyclosporine has been used for 6 or 12 months in trials, optimal duration has not been defined (Lombel 2013); guidelines recommend a minimum duration of 6 months; if no remission (partial or complete) is achieved after at least 6 months of therapy then discontinue; if remission is achieved (partial or complete) by 6 months then continue for a minimum of 12 months (KDIGO 2012).

Solid organ transplantation, rejection prophylaxis:

IV: Cyclosporine (nonmodified): Note: Limit parenteral use to patients unable to take capsules or oral solution; patients should be switched to an oral dosage form as soon as possible.

Intermittent IV infusion:

Manufacturer’s labeling: Infants ≥6 months, Children, and Adolescents: Initial: 5 to 6 mg/kg/day or one-third (¹/₃) of the oral dose as a single daily dose over 2 to 6 hours; administer 4 to 12 hours prior to organ transplantation or may be given postoperatively

Alternate dosing: Limited data available: Infants ≥3 months, Children, and Adolescents: 2 to 6 mg/kg/day in divided doses every 8 to 12 hours (Burckart 1985; Burckart 1986b; McDiamid 1995; Tzakis 1991)

Continuous IV infusion: Limited data available: Children and Adolescents: 2 to 4 mg/kg/day; doses as high as 4.5 mg/kg/day have been used in patients ≥6 years old (Al-Uzri 1994; Alvarez 2000; Benfield 2005; Clardy 1988; Kahan 1987)

Oral: Note: Dose is dependent upon type of transplant and formulation. Adjust dose to achieve desired target cyclosporine concentration; specific institutional protocols should be consulted.

Cyclosporine (nonmodified): Infants ≥6 months, Children, and Adolescents: Initial: 10 to 14 mg/kg/day has been used for renal transplants (the manufacturer’s labeling includes dosing from initial clinical trials of 15 mg/kg/day [range: 14 to 18 mg/kg/day]); administer 4 to 12 hours prior to organ transplantation. Continue initial dose daily for 1 to 2 weeks; taper by 5% per week to a maintenance dose of 5 to 10 mg/kg/day; some renal transplant patients may be dosed as low as 3 mg/kg/day to achieve target concentrations.

Note: When using nonmodified formulation, cyclosporine concentrations may increase in liver transplant patients when the T-tube is closed; may need to decrease dose (Burckart 1986b).

Cyclosporine (modified): Dose differs based on type of transplant, consult institution protocol: Dosage below is the mean (±SD) of initial doses used in a 1994 survey.

Initial dose:

Renal: 9 ± 3 mg/kg/day divided every 12 hours

Liver: 8 ± 4 mg/kg/day divided every 12 hours

Heart: 7 ± 3 mg/kg/day divided every 12 hours

Conversion to cyclosporine (modified) from cyclosporine (nonmodified): Start with daily dose previously used and adjust to obtain preconversion cyclosporine trough concentration. Plasma concentrations should be monitored every 4 to 7 days and dose adjusted as necessary, until desired trough concentration is obtained. When transferring patients with previously poor absorption of cyclosporine (nonmodified), monitor trough concentrations at least twice weekly (especially if initial dose exceeds 10 mg/kg daily); high plasma concentrations are likely to occur due to improved bioavailability.

Reconstitution

Injection: To minimize leaching of DEHP, non-PVC containers and sets should be used for preparation and administration.

Sandimmune injection: Injection should be further diluted (1 mL [50 mg] of concentrate in 20-100 mL of D5W or NS) for administration by intravenous infusion.

Oral solution: Should be mixed in glass containers (not in plastic).

Administration

Oral solution: Do not administer liquid from plastic or styrofoam cup. May dilute Neoral oral solution with room temperature orange juice or apple juice. May dilute Sandimmune oral solution with milk, chocolate milk, or orange juice. Avoid changing diluents frequently. Mix thoroughly and drink at once. Use syringe provided to measure dose. Mix in a glass container and rinse container with more diluent to ensure total dose is taken. Do not rinse syringe before or after use (may cause dose variation).

Administer this medication consistently with relation to time of day and meals.

Combination therapy with renal or heart transplantation:

Everolimus: May administer cyclosporine at the same time as everolimus

Sirolimus: Must administer cyclosporine 4 hours separate from sirolimus

IV: The manufacturer recommends that following dilution, intravenous admixture be administered over 2 to 6 hours. However, many transplant centers administer as divided doses (2 doses/day) or as a 24-hour continuous infusion. Anaphylaxis has been reported with IV use; reserve for patients who cannot take oral form. Patients should be under continuous observation for at least the first 30 minutes of the infusion, and should be monitored frequently thereafter. Maintain patent airway; other supportive measures and agents for treating anaphylaxis should be present when IV drug is given. To minimize leaching of DEHP, non-PVC sets should be used for administration.

Dietary Considerations

Avoid grapefruit juice with oral cyclosporine use.

Storage

Capsules (modified): Store in the original unit-dose container at 20°C to 25°C (68°F to 77°F).

Capsules (non-modified): Store at 25°C (77°F); excursions are permitted between 15°C and 30°C (59°F and 86°F). An odor may be detected upon opening the unit-dose container, which will dissipate shortly thereafter. This odor does not affect the quality of the product.

Injection: Store below 30°C (86°F) or at controlled room temperature (product dependent). Protect from light. The manufacturer recommends discarding diluted infusion solutions in D5W or NS after 24 hours.

Oral solution (modified): Store in the original container at 20°C to 25°C (68°F to 77°F). Do not store in the refrigerator. Once opened, use within 2 months. At temperatures below 20°C (68°F), the solution may gel; light flocculation or the formation of a light sediment also may occur. There is no impact on product performance or dosing using the syringe provided. Allow to warm to room temperature (25°C [77°F]) to reverse these changes.

Oral solution (non-modified): Store in the original container at temperatures below 30°C (86°F). Do not store in the refrigerator. Protect from freezing. Once opened, use within 2 months.

Drug Interactions

AcetaZOLAMIDE: May increase the serum concentration of CycloSPORINE (Systemic). Monitor therapy

Adalimumab: May decrease the serum concentration of CycloSPORINE (Systemic). Monitor therapy

Afatinib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Afatinib. Management: Reduce afatinib by 10 mg if not tolerated. Some non-US labeling recommends avoiding combination if possible. If used, administer the P-gp inhibitor simultaneously with or after the dose of afatinib. Consider therapy modification

Aliskiren: CycloSPORINE (Systemic) may increase the serum concentration of Aliskiren. Avoid combination

Allopurinol: May increase the serum concentration of CycloSPORINE (Systemic). Monitor therapy

Alpelisib: BCRP/ABCG2 Inhibitors may increase the serum concentration of Alpelisib. Management: Avoid coadministration of BCRP/ABCG2 inhibitors and alpelisib due to the potential for increased alpelisib concentrations and toxicities. If coadministration cannot be avoided, closely monitor for increased alpelisib adverse reactions. Consider therapy modification

Ambrisentan: CycloSPORINE (Systemic) may increase the serum concentration of Ambrisentan. Management: Limit ambrisentan dose to 5 mg/day and monitor for ambrisentan adverse reactions in patients receiving systemic cyclosporine. Consider therapy modification

Aminoglycosides: May enhance the nephrotoxic effect of CycloSPORINE (Systemic). Monitor therapy

Amiodarone: May increase the serum concentration of CycloSPORINE (Systemic). Management: Monitor for increased serum concentrations and/or toxicity of cyclosporine if combined with amiodarone. A reduction in cyclosporine dosage will likely be needed. Consider therapy modification

Amphotericin B: May enhance the nephrotoxic effect of CycloSPORINE (Systemic). Monitor therapy

Androgens: May enhance the hepatotoxic effect of CycloSPORINE (Systemic). Androgens may increase the serum concentration of CycloSPORINE (Systemic). Consider therapy modification

Angiotensin II Receptor Blockers: May enhance the hyperkalemic effect of CycloSPORINE (Systemic). Monitor therapy

Antifungal Agents (Azole Derivatives, Systemic): May decrease the metabolism of CycloSPORINE (Systemic). Fluconazole and isavuconazonium considerations are addressed in separate monographs. Exceptions: Fluconazole; Isavuconazonium Sulfate. Consider therapy modification

Aprepitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

ARIPiprazole: CYP3A4 Inhibitors (Weak) may increase the serum concentration of ARIPiprazole. Management: Monitor for increased aripiprazole pharmacologic effects. Aripiprazole dose adjustments may or may not be required based on concomitant therapy and/or indication. Consult full interaction monograph for specific recommendations. Monitor therapy

Armodafinil: May decrease the serum concentration of CycloSPORINE (Systemic). Monitor therapy

Ascorbic Acid: May decrease the serum concentration of CycloSPORINE (Systemic). Monitor therapy

Asunaprevir: OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase the serum concentration of Asunaprevir. Avoid combination

AtorvaSTATin: CycloSPORINE (Systemic) may increase the serum concentration of AtorvaSTATin. Avoid combination

Azithromycin (Systemic): May increase the serum concentration of CycloSPORINE (Systemic). Monitor therapy

Barbiturates: May increase the metabolism of CycloSPORINE (Systemic). Consider therapy modification

Baricitinib: Immunosuppressants may enhance the immunosuppressive effect of Baricitinib. Management: Use of baricitinib in combination with potent immunosuppressants such as azathioprine or cyclosporine is not recommended. Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted. Consider therapy modification

BCG (Intravesical): Immunosuppressants may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

Betrixaban: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Betrixaban. Management: Decrease the adult betrixaban dose to an initial single dose of 80 mg followed by 40 mg once daily if combined with a P-glycoprotein inhibitor. Consider therapy modification

Bilastine: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Bilastine. Management: Consider alternatives when possible; bilastine should be avoided in patients with moderate to severe renal insufficiency who are receiving p-glycoprotein inhibitors. Consider therapy modification

Bosentan: CycloSPORINE (Systemic) may increase the serum concentration of Bosentan. Bosentan may decrease the serum concentration of CycloSPORINE (Systemic). Avoid combination

Brentuximab Vedotin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Brentuximab Vedotin. Specifically, concentrations of the active monomethyl auristatin E (MMAE) component may be increased. Monitor therapy

Calcium Channel Blockers (Dihydropyridine): May increase the serum concentration of CycloSPORINE (Systemic). CycloSPORINE (Systemic) may increase the serum concentration of Calcium Channel Blockers (Dihydropyridine). Exceptions: Clevidipine. Monitor therapy

Calcium Channel Blockers (Nondihydropyridine): May decrease the metabolism of CycloSPORINE (Systemic). CycloSPORINE (Systemic) may decrease the metabolism of Calcium Channel Blockers (Nondihydropyridine). Consider therapy modification

CarBAMazepine: May decrease the serum concentration of CycloSPORINE (Systemic). Management: Monitor frequently for decreased serum concentrations and therapeutic effects of cyclosporine if combined with carbamazepine. Increased cyclosporine doses will likely be needed to maintain adequate serum concentrations. Consider therapy modification

Carvedilol: May increase the serum concentration of CycloSPORINE (Systemic). Consider therapy modification

Caspofungin: CycloSPORINE (Systemic) may enhance the adverse/toxic effect of Caspofungin. CycloSPORINE (Systemic) may increase the serum concentration of Caspofungin. Caspofungin may increase the serum concentration of CycloSPORINE (Systemic). Management: Weigh potential benefits of caspofungin against a possible elevated risk of hepatotoxicity. Monitor liver function and re-evaluate treatment in patients with abnormal values. Mild transaminase elevations may occur relatively commonly. Consider therapy modification

Celiprolol: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Celiprolol. Monitor therapy

Chloramphenicol (Systemic): May increase the serum concentration of CycloSPORINE (Systemic). Management: Cyclosporine dose reductions will likely be required with initiation of concurrent chloramphenicol. Monitor cyclosporine concentrations and response closely following initiation and/or discontinuation of chloramphenicol. Consider therapy modification

Cholic Acid: BSEP/ABCB11 Inhibitors may decrease the excretion of Cholic Acid. Avoid combination

Cladribine: May enhance the immunosuppressive effect of Immunosuppressants. Avoid combination

Clarithromycin: May increase the serum concentration of CycloSPORINE (Systemic). Monitor therapy

Clofazimine: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Coccidioides immitis Skin Test: Immunosuppressants may diminish the diagnostic effect of Coccidioides immitis Skin Test. Monitor therapy

Colchicine: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Colchicine. Colchicine distribution into certain tissues (e.g., brain) may also be increased. Management: Colchicine is contraindicated in patients with impaired renal or hepatic function who are also receiving a p-glycoprotein inhibitor. In those with normal renal and hepatic function, reduce colchicine dose as directed. See full monograph for details. Consider therapy modification

Colesevelam: May decrease the serum concentration of CycloSPORINE (Systemic). Management: Administer cyclosporine at least 4 hours prior to colesevelam. Monitor for decreased cyclosporine concentrations during concomitant colesevelam therapy. Consider therapy modification

Conivaptan: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

Crizotinib: May increase the serum concentration of CycloSPORINE (Systemic). Avoid combination

Cyclophosphamide: May decrease the serum concentration of CycloSPORINE (Systemic). Monitor therapy

CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates (High risk with Inducers). Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

CYP3A4 Inhibitors (Moderate): May decrease the metabolism of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

CYP3A4 Inhibitors (Strong): May increase the serum concentration of CycloSPORINE (Systemic). Consider therapy modification

Dabigatran Etexilate: P-glycoprotein/ABCB1 Inhibitors may increase serum concentrations of the active metabolite(s) of Dabigatran Etexilate. Monitor therapy

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Denosumab: May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased. Monitor therapy

DexAMETHasone (Systemic): May decrease the serum concentration of CycloSPORINE (Systemic). DexAMETHasone (Systemic) may increase the serum concentration of CycloSPORINE (Systemic). CycloSPORINE (Systemic) may increase the serum concentration of DexAMETHasone (Systemic). Monitor therapy

Digoxin: CycloSPORINE (Systemic) may increase the serum concentration of Digoxin. Monitor therapy

Dofetilide: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Dofetilide. Monitor therapy

DOXOrubicin (Conventional): CycloSPORINE (Systemic) may increase the serum concentration of DOXOrubicin (Conventional). Management: Consider a doxorubicin dose reduction, as clinically appropriate, when used with cyclosporine. Use this combination with caution; increase monitoring for toxic effects of doxorubicin. Consider therapy modification

Dronabinol: May increase the serum concentration of CycloSPORINE (Systemic). Specifically, dronabinol may displace cyclosporine from its protein-binding sites, leading to an increased concentration of active, unbound drug. Monitor therapy

Dronedarone: CycloSPORINE (Systemic) may increase the serum concentration of Dronedarone. Avoid combination

Duvelisib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Echinacea: May diminish the therapeutic effect of Immunosuppressants. Consider therapy modification

Edoxaban: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Edoxaban. Management: See full monograph for details. Reduced doses are recommended for patients receiving edoxaban for venous thromboembolism in combination with certain P-gp inhibitors. Similar dose adjustment is not recommended for edoxaban use in atrial fibrillation. Consider therapy modification

Efavirenz: May decrease the serum concentration of CycloSPORINE (Systemic). Management: Increase monitoring of cyclosporine concentrations when starting, stopping, or adjusting doses of concurrent efavirenz, particularly within the first 2 weeks. Cyclosporine dose adjustment may be required. Consider therapy modification

Elagolix: OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase the serum concentration of Elagolix. Avoid combination

Eltrombopag: CycloSPORINE (Systemic) may decrease the serum concentration of Eltrombopag. Monitor therapy

Eluxadoline: CycloSPORINE (Systemic) may increase the serum concentration of Eluxadoline. Management: Decrease the eluxadoline dose to 75 mg twice daily if combined with cyclosporine and monitor patients for increased eluxadoline effects/toxicities. Consider therapy modification

Enzalutamide: May decrease the serum concentration of CycloSPORINE (Systemic). Avoid combination

Eplerenone: May enhance the hyperkalemic effect of CycloSPORINE (Systemic). Avoid combination

Erdafitinib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Erdafitinib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Erdafitinib: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. Monitor therapy

Erythromycin (Systemic): May increase the serum concentration of CycloSPORINE (Systemic). Monitor therapy

Etoposide: CycloSPORINE (Systemic) may decrease the metabolism of Etoposide. Management: Consider reducing the dose of etoposide by 50% if the patient is receiving, or has recently received, cyclosporine. Monitor for increased toxic effects of etoposide if cyclosporine is initiated, the dose is increased, or it has been recently discontinued. Consider therapy modification

Etoposide Phosphate: CycloSPORINE (Systemic) may increase the serum concentration of Etoposide Phosphate. CycloSPORINE may decrease the metabolism, via CYP isoenzymes, and decrease the p-glycoprotein-mediated elimination of Etoposide Phosphate. Consider therapy modification

Everolimus: CycloSPORINE (Systemic) may increase the serum concentration of Everolimus. Management: When using everolimus for renal cell carcinoma, avoid concurrent cyclosporine. When using everolimus as post-transplant immunosuppression, concurrent cyclosporine should be used at lower doses and with lower target serum cyclosporine concentrations. Consider therapy modification

Ezetimibe: May increase the serum concentration of CycloSPORINE (Systemic). CycloSPORINE (Systemic) may increase the serum concentration of Ezetimibe. Monitor therapy

Fibric Acid Derivatives: CycloSPORINE (Systemic) may enhance the nephrotoxic effect of Fibric Acid Derivatives. Fibric Acid Derivatives may decrease the serum concentration of CycloSPORINE (Systemic). Management: Careful consideration of the risks and benefits should be undertaken prior to use of this combination; extra monitoring of renal function and cyclosporine concentrations will likely be required. Adjustment of cyclosporine dose may be necessary. Consider therapy modification

Fimasartan: CycloSPORINE (Systemic) may increase the serum concentration of Fimasartan. Monitor therapy

Fingolimod: Immunosuppressants may enhance the immunosuppressive effect of Fingolimod. Management: Avoid the concomitant use of fingolimod and other immunosuppressants when possible. If combined, monitor patients closely for additive immunosuppressant effects (eg, infections). Consider therapy modification

Flibanserin: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Flibanserin. Monitor therapy

Fluconazole: May increase the serum concentration of CycloSPORINE (Systemic). Monitor therapy

Fluvastatin: CycloSPORINE (Systemic) may increase the serum concentration of Fluvastatin. Management: Limit fluvastatin to 20 mg twice daily in patients who are also receiving cyclosporine. Consider therapy modification

Fosaprepitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Foscarnet: May enhance the nephrotoxic effect of CycloSPORINE (Systemic). Avoid combination

Fosnetupitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Fosphenytoin: May decrease the serum concentration of CycloSPORINE (Systemic). Consider therapy modification

Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

Ganciclovir-Valganciclovir: May enhance the nephrotoxic effect of CycloSPORINE (Systemic). Monitor therapy

Glecaprevir and Pibrentasvir: CycloSPORINE (Systemic) may increase the serum concentration of Glecaprevir and Pibrentasvir. Avoid combination

GlyBURIDE: CycloSPORINE (Systemic) may diminish the therapeutic effect of GlyBURIDE. GlyBURIDE may increase the serum concentration of CycloSPORINE (Systemic). Monitor therapy

Grapefruit Juice: May decrease the metabolism of CycloSPORINE (Systemic). Management: Monitor for altered cyclosporine concentrations/effects if grapefruit intake is increased/decreased. Advise patients to not alter their pattern of grapefruit/grapefruit juice intake without consulting their healthcare provider. Avoid combination

Grazoprevir: CycloSPORINE (Systemic) may increase the serum concentration of Grazoprevir. Avoid combination

Griseofulvin: May decrease the serum concentration of CycloSPORINE (Systemic). Monitor therapy

Idelalisib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

Imatinib: May increase the serum concentration of CycloSPORINE (Systemic). Monitor therapy

Imipenem: CycloSPORINE (Systemic) may enhance the neurotoxic effect of Imipenem. Imipenem may decrease the serum concentration of CycloSPORINE (Systemic). Imipenem may increase the serum concentration of CycloSPORINE (Systemic). Monitor therapy

Isavuconazonium Sulfate: May increase the serum concentration of CycloSPORINE (Systemic). Monitor therapy

Ivacaftor: May increase the serum concentration of CycloSPORINE (Systemic). Monitor therapy

Ivosidenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Larotrectinib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Larotrectinib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Larotrectinib. Monitor therapy

Lasmiditan: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. Avoid combination

Lefamulin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Lefamulin. Management: Avoid concomitant use of lefamulin tablets with P-glycoprotein/ABCB1 inhibitors. If concomitant use is required, monitor for lefamulin adverse effects. Consider therapy modification

Leflunomide: Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants. Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly. Consider therapy modification

Lemborexant: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Lemborexant. Management: The maximum recommended dosage of lemborexant is 5 mg, no more than once per night, when coadministered with weak CYP3A4 inhibitors. Consider therapy modification

Lercanidipine: May increase the serum concentration of CycloSPORINE (Systemic). CycloSPORINE (Systemic) may increase the serum concentration of Lercanidipine. Avoid combination

Letermovir: May increase the serum concentration of CycloSPORINE (Systemic). CycloSPORINE (Systemic) may increase the serum concentration of Letermovir. Management: Decrease the letermovir dose to 240 mg daily when combined with cyclosporine. Additionally, monitor for increased cyclosporine concentrations and toxicities when combined with letermovir. Consider therapy modification

Lomitapide: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Lomitapide. Management: Patients on lomitapide 5 mg/day may continue that dose. Patients taking lomitapide 10 mg/day or more should decrease the lomitapide dose by half. The lomitapide dose may then be titrated up to a max adult dose of 30 mg/day. Consider therapy modification

Loop Diuretics: CycloSPORINE (Systemic) may enhance the adverse/toxic effect of Loop Diuretics. Monitor therapy

Lorlatinib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Avoid concurrent use of lorlatinib with any CYP3A4 substrates for which a minimal decrease in serum concentrations of the CYP3A4 substrate could lead to therapeutic failure and serious clinical consequences. Consider therapy modification

Lovastatin: CycloSPORINE (Systemic) may increase the serum concentration of Lovastatin. Avoid combination

Lumacaftor and Ivacaftor: May increase the serum concentration of CycloSPORINE (Systemic). Avoid combination

Lumateperone: CycloSPORINE (Systemic) may increase the serum concentration of Lumateperone. Monitor therapy

Melphalan: May enhance the nephrotoxic effect of CycloSPORINE (Systemic). Monitor therapy

Methotrexate: CycloSPORINE (Systemic) may increase the serum concentration of Methotrexate. This may result in nausea, vomiting, oral ulcers, hepatotoxicity and/or nephrotoxicity. Methotrexate may increase the serum concentration of CycloSPORINE (Systemic). This may result in nephrotoxicity. Consider therapy modification

MethylPREDNISolone: CycloSPORINE (Systemic) may increase the serum concentration of MethylPREDNISolone. MethylPREDNISolone may increase the serum concentration of CycloSPORINE (Systemic). MethylPREDNISolone may decrease the serum concentration of CycloSPORINE (Systemic). Monitor therapy

Metoclopramide: May increase the absorption of CycloSPORINE (Systemic). Monitor therapy

Metreleptin: May decrease the serum concentration of CycloSPORINE (Systemic). Metreleptin may increase the serum concentration of CycloSPORINE (Systemic). Monitor therapy

Mifamurtide: CycloSPORINE (Systemic) may diminish the therapeutic effect of Mifamurtide. Avoid combination

MiFEPRIStone: May increase the serum concentration of CycloSPORINE (Systemic). Management: Avoid cyclosporine during and 2 weeks following mifepristone for treatment of hyperglycemia in Cushing's syndrome. The interaction magnitude could be lower with single doses used to terminate pregnancy, but neither effect has been studied clinically. Avoid combination

Minoxidil (Systemic): CycloSPORINE (Systemic) may enhance the adverse/toxic effect of Minoxidil (Systemic). Severe hypertrichosis has been reported. Monitor therapy

Minoxidil (Topical): CycloSPORINE (Systemic) may enhance the adverse/toxic effect of Minoxidil (Topical). Specifically, hypertrichosis risk may be increased. Monitor therapy

Mitotane: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Doses of CYP3A4 substrates may need to be adjusted substantially when used in patients being treated with mitotane. Consider therapy modification

MitoXANTRONE: CycloSPORINE (Systemic) may increase the serum concentration of MitoXANTRONE. Management: Consider mitoxantrone dose reduction, as clinically appropriate, when used with cyclosporine. Use this combination with caution and monitor closely for toxic effects of mitoxantrone. Consider therapy modification

Modafinil: May decrease the serum concentration of CycloSPORINE (Systemic). Monitor therapy

Multivitamins/Fluoride (with ADE): May decrease the serum concentration of CycloSPORINE (Systemic). Monitor therapy

Multivitamins/Minerals (with ADEK, Folate, Iron): May decrease the serum concentration of CycloSPORINE (Systemic). Monitor therapy

Multivitamins/Minerals (with AE, No Iron): May decrease the serum concentration of CycloSPORINE (Systemic). Monitor therapy

Mycophenolate: CycloSPORINE (Systemic) may decrease the serum concentration of Mycophenolate. Specifically, cyclosporine may decrease concentrations of the active metabolite mycophenolic acid. Management: Mycophenolate requirements may be greater in patients receiving cyclosporine. Monitor mycophenolate dosing and response to therapy particularly closely when adjusting concurrent cyclosporine (starting, stopping, or changing dose). Consider therapy modification

Nafcillin: May increase the metabolism of CycloSPORINE (Systemic). Monitor therapy

Naldemedine: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Naldemedine. Monitor therapy

Naloxegol: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Naloxegol. Monitor therapy

Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Avoid combination

Neratinib: CycloSPORINE (Systemic) may increase the serum concentration of Neratinib. Management: Avoid concomitant use of neratinib and cyclosporine if possible. If combined, monitor for increased neratinib effects/toxicities. Consider therapy modification

Netupitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Neuromuscular-Blocking Agents: CycloSPORINE (Systemic) may enhance the neuromuscular-blocking effect of Neuromuscular-Blocking Agents. Monitor therapy

NiMODipine: CYP3A4 Inhibitors (Weak) may increase the serum concentration of NiMODipine. Monitor therapy

Nivolumab: Immunosuppressants may diminish the therapeutic effect of Nivolumab. Consider therapy modification

Nonsteroidal Anti-Inflammatory Agents: May enhance the nephrotoxic effect of CycloSPORINE (Systemic). Nonsteroidal Anti-Inflammatory Agents may increase the serum concentration of CycloSPORINE (Systemic). CycloSPORINE (Systemic) may increase the serum concentration of Nonsteroidal Anti-Inflammatory Agents. Management: Consider alternatives to nonsteroidal anti-inflammatory agents (NSAIDs). Monitor for evidence of nephrotoxicity, as well as increased serum cyclosporine concentrations and systemic effects (eg, hypertension) during concomitant therapy with NSAIDs. Consider therapy modification

Norfloxacin: May decrease the metabolism of CycloSPORINE (Systemic). Monitor therapy

Obeticholic Acid: BSEP/ABCB11 Inhibitors may increase serum concentrations of the active metabolite(s) of Obeticholic Acid. Management: Avoid concomitant use of obeticholic acid and bile salt efflux pump (BSEP) inhibitors if possible. If concomitant therapy is necessary, monitor patients for elevated liver transaminases and elevated bilirubin. Consider therapy modification

Ocrelizumab: May enhance the immunosuppressive effect of Immunosuppressants. Monitor therapy

Ombitasvir, Paritaprevir, and Ritonavir: May increase the serum concentration of CycloSPORINE (Systemic). Management: Reduce cyclosporine dose by 80% when initiating therapy with ombitasvir/paritaprevir/ritonavir and monitor cyclosporine blood levels closely. Consider therapy modification

Ombitasvir, Paritaprevir, Ritonavir, and Dasabuvir: May increase the serum concentration of CycloSPORINE (Systemic). Management: Reduce cyclosporine dose 80% when initiating therapy with ombitasvir/paritaprevir/ritonavir/dasabuvir and monitor cyclosporine blood levels closely. Consider therapy modification

Omeprazole: May increase the serum concentration of CycloSPORINE (Systemic). Monitor therapy

Orlistat: May decrease the serum concentration of CycloSPORINE (Systemic). Management: Administer orlistat at least 3 hours before or after oral cyclosporine. Monitor for decreased serum concentrations of oral cyclosporine, even with the recommended dose separation. Consider therapy modification

Palbociclib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

PAZOPanib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of PAZOPanib. Avoid combination

PAZOPanib: BCRP/ABCG2 Inhibitors may increase the serum concentration of PAZOPanib. Avoid combination

P-glycoprotein/ABCB1 Inhibitors: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. P-glycoprotein inhibitors may also enhance the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Monitor therapy

P-glycoprotein/ABCB1 Substrates: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of P-glycoprotein/ABCB1 Substrates. P-glycoprotein inhibitors may also enhance the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Exceptions: Loperamide. Monitor therapy

Phenytoin: May increase the metabolism of CycloSPORINE (Systemic). Consider therapy modification

Pidotimod: Immunosuppressants may diminish the therapeutic effect of Pidotimod. Monitor therapy

Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Pimozide: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Pimozide. Avoid combination

Pitavastatin: CycloSPORINE (Systemic) may increase the serum concentration of Pitavastatin. Avoid combination

Potassium-Sparing Diuretics: May enhance the hyperkalemic effect of CycloSPORINE (Systemic). Avoid combination

Pravastatin: CycloSPORINE (Systemic) may increase the serum concentration of Pravastatin. Pravastatin may increase the serum concentration of CycloSPORINE (Systemic). Management: Limit pravastatin to 20 mg/day in patients who are also receiving cyclosporine. Consider therapy modification

PrednisoLONE (Systemic): May decrease the serum concentration of CycloSPORINE (Systemic). CycloSPORINE (Systemic) may increase the serum concentration of PrednisoLONE (Systemic). PrednisoLONE (Systemic) may increase the serum concentration of CycloSPORINE (Systemic). Monitor therapy

PredniSONE: CycloSPORINE (Systemic) may increase serum concentrations of the active metabolite(s) of PredniSONE. PredniSONE may decrease the serum concentration of CycloSPORINE (Systemic). PredniSONE may increase the serum concentration of CycloSPORINE (Systemic). Monitor therapy

Probucol: May decrease the serum concentration of CycloSPORINE (Systemic). Monitor therapy

Protease Inhibitors: May increase the serum concentration of CycloSPORINE (Systemic). CycloSPORINE (Systemic) may increase the serum concentration of Protease Inhibitors. Consider therapy modification

Prucalopride: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Prucalopride. Monitor therapy

Pyrazinamide: May decrease the serum concentration of CycloSPORINE (Systemic). Monitor therapy

Quinupristin: May increase the serum concentration of CycloSPORINE (Systemic). Monitor therapy

Ranolazine: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Ranolazine. Monitor therapy

Ranolazine: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. Monitor therapy

Repaglinide: CycloSPORINE (Systemic) may increase the serum concentration of Repaglinide. Management: Limit the daily repaglinide dose to a maximum of 6 mg with concurrent use of cyclosporine, and monitor closely for increased repaglinide effects. Consider therapy modification

Revefenacin: OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase serum concentrations of the active metabolite(s) of Revefenacin. Avoid combination

Rifamycin Derivatives: May increase the metabolism of CycloSPORINE (Systemic). Consider therapy modification

RifAXIMin: CycloSPORINE (Systemic) may increase the serum concentration of RifAXIMin. Monitor therapy

Ritonavir: May increase the serum concentration of CycloSPORINE (Systemic). Management: Consider empiric cyclosporine dose reductions and monitor cyclosporine serum concentrations closely if ritonavir is initiated. Consider therapy modification

Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. Consider therapy modification

Rosuvastatin: CycloSPORINE (Systemic) may increase the serum concentration of Rosuvastatin. Management: Limit rosuvastatin to 5 mg/day in patients who are also receiving cyclosporine. Canadian labeling contraindicates concomitant use of rosuvastatin with cyclosporine. Consider therapy modification

Sarilumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Sevelamer: May decrease the serum concentration of CycloSPORINE (Systemic). Monitor therapy

Silodosin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Silodosin. Monitor therapy

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Simeprevir: May increase the serum concentration of CycloSPORINE (Systemic). CycloSPORINE (Systemic) may increase the serum concentration of Simeprevir. Avoid combination

Simvastatin: CycloSPORINE (Systemic) may increase the serum concentration of Simvastatin. Avoid combination

Siponimod: Immunosuppressants may enhance the immunosuppressive effect of Siponimod. Monitor therapy

Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Management: Evaluate patients to see if it is medically appropriate to reduce or discontinue therapy with immunosuppressants prior to initiating sipuleucel-T therapy. Consider therapy modification

Sirolimus: May enhance the adverse/toxic effect of CycloSPORINE (Systemic). An increased risk of calcineurin inhibitor-induced hemolytic uremic syndrome/thrombotic thrombocytopenic purpura/thrombotic microangiopathy (HUS/TTP/TMA) has been described. CycloSPORINE (Systemic) may increase the serum concentration of Sirolimus. This is of specific concern with cyclosporine [MODIFIED]. Management: Administer oral doses of sirolimus 4 hours after doses of cyclosporine. Monitor for toxic effects of sirolimus if used with cyclosporine. Consider therapy modification

Smallpox and Monkeypox Vaccine (Live): Immunosuppressants may diminish the therapeutic effect of Smallpox and Monkeypox Vaccine (Live). Monitor therapy

Somatostatin Analogs: May decrease the serum concentration of CycloSPORINE (Systemic). Consider therapy modification

St John's Wort: May decrease the serum concentration of CycloSPORINE (Systemic). Management: Consider alternatives to St. John's wort (SJW). If the combination cannot be avoided, monitor for decreased cyclosporine concentrations/effects. Monitor for increased cyclosporine concentrations/effects following SJW discontinuation. Consider therapy modification

Stiripentol: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Use of stiripentol with CYP3A4 substrates that are considered to have a narrow therapeutic index should be avoided due to the increased risk for adverse effects and toxicity. Any CYP3A4 substrate used with stiripentol requires closer monitoring. Consider therapy modification

Sulfinpyrazone: May decrease the serum concentration of CycloSPORINE (Systemic). Monitor therapy

Sulfonamide Antibiotics: May enhance the nephrotoxic effect of CycloSPORINE (Systemic). Sulfonamide Antibiotics may decrease the serum concentration of CycloSPORINE (Systemic). Monitor therapy

Tacrolimus (Systemic): CycloSPORINE (Systemic) may enhance the nephrotoxic effect of Tacrolimus (Systemic). Tacrolimus (Systemic) may enhance the nephrotoxic effect of CycloSPORINE (Systemic). Tacrolimus (Systemic) may increase the serum concentration of CycloSPORINE (Systemic). CycloSPORINE (Systemic) may increase the serum concentration of Tacrolimus (Systemic). Avoid combination

Tacrolimus (Topical): CycloSPORINE (Systemic) may enhance the nephrotoxic effect of Tacrolimus (Topical). Tacrolimus (Topical) may enhance the nephrotoxic effect of CycloSPORINE (Systemic). Tacrolimus (Topical) may increase the serum concentration of CycloSPORINE (Systemic). CycloSPORINE (Systemic) may increase the serum concentration of Tacrolimus (Topical). Avoid combination

Talazoparib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Talazoparib. Management: These listed exceptions are discussed in detail in separate interaction monographs. Monitor therapy

Talazoparib: BCRP/ABCG2 Inhibitors may increase the serum concentration of Talazoparib. Monitor therapy

Tegaserod: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Tegaserod. Monitor therapy

Telithromycin: May increase the serum concentration of CycloSPORINE (Systemic). Monitor therapy

Temsirolimus: May enhance the adverse/toxic effect of CycloSPORINE (Systemic). An increased risk of calcineurin inhibitor-induced hemolytic uremic syndrome/thrombotic thrombocytopenic purpura/thrombotic microangiopathy (HUS/TTP/TMA) has been described with concomitant sirolimus use. Consider therapy modification

Tertomotide: Immunosuppressants may diminish the therapeutic effect of Tertomotide. Monitor therapy

Ticagrelor: CycloSPORINE (Systemic) may increase the serum concentration of Ticagrelor. Monitor therapy

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Tofacitinib: Immunosuppressants may enhance the immunosuppressive effect of Tofacitinib. Management: Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted, and this warning seems particularly focused on more potent immunosuppressants. Consider therapy modification

Topotecan: BCRP/ABCG2 Inhibitors may increase the serum concentration of Topotecan. Avoid combination

Topotecan: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Topotecan. Avoid combination

Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Monitor therapy

Triazolam: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Triazolam. Management: Consider triazolam dose reduction in patients receiving concomitant weak CYP3A4 inhibitors. Consider therapy modification

Ubrogepant: CycloSPORINE (Systemic) may increase the serum concentration of Ubrogepant. Management: Use an initial ubrogepant dose of 50 mg and consider avoiding a second dose for 24 hours when used with cyclosporine. Consider therapy modification

Upadacitinib: Immunosuppressants may enhance the immunosuppressive effect of Upadacitinib. Avoid combination

Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Management: Vaccine efficacy may be reduced. Complete all age-appropriate vaccinations at least 2 weeks prior to starting an immunosuppressant. If vaccinated during immunosuppressant therapy, revaccinate at least 3 months after immunosuppressant discontinuation. Consider therapy modification

Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Immunosuppressants may diminish the therapeutic effect of Vaccines (Live). Management: Avoid use of live organism vaccines with immunosuppressants; live-attenuated vaccines should not be given for at least 3 months after immunosuppressants. Exceptions: Smallpox and Monkeypox Vaccine (Live). Avoid combination

Venetoclax: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Venetoclax. Management: Consider a venetoclax dose reduction by at least 50% in patients requiring concomitant treatment with P-glycoprotein (P-gp) inhibitors. Consider therapy modification

VinCRIStine (Liposomal): P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of VinCRIStine (Liposomal). Avoid combination

Vitamin E (Systemic): May decrease the serum concentration of CycloSPORINE (Systemic). Monitor therapy

Voxilaprevir: OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase the serum concentration of Voxilaprevir. Avoid combination

Test Interactions

Specific whole blood assay for cyclosporine may be falsely elevated if sample is drawn from the same central venous line through which dose was administered (even if flush has been administered and/or dose was given hours before); cyclosporine metabolites cross-react with radioimmunoassay and fluorescence polarization immunoassay

Adverse Reactions

Adverse reactions reported with systemic use, including rheumatoid arthritis, psoriasis, and transplantation (kidney, liver, and heart). Percentages noted include the highest frequency regardless of indication/dosage. Frequencies may vary for specific conditions or formulation.

>10%:

Cardiovascular: Hypertension (8% to 53%), edema (5% to 14%)

Central nervous system: Headache (2% to 25%), paresthesia (1% to 11%)

Dermatologic: Hypertrichosis (5% to 19%)

Endocrine & metabolic: Hirsutism (21% to 45%), increased serum triglycerides (15%), female genital tract disease (9% to 11%)

Gastrointestinal: Nausea (2% to 23%), diarrhea (3% to 13%), gingival hyperplasia (2% to 16%), abdominal distress (<1% to 15%), dyspepsia (2% to 12%)

Genitourinary: Urinary tract infection (kidney transplant: 21%)

Infection: Increased susceptibility to infection (3% to 25%), viral infection (kidney transplant: 16%)

Neuromuscular & skeletal: Tremor (7% to 55%), leg cramps (2% to 12%)

Renal: Increased serum creatinine (16% to ≥50%), renal insufficiency (10% to 38%)

Respiratory: Upper respiratory tract infection (1% to 14%)

Kidney, liver, and heart transplant only (≤2% unless otherwise noted):

Cardiovascular: Chest pain (≤4%), flushing (<1% to 4%), glomerular capillary thrombosis, myocardial infarction

Central nervous system: Convulsions (1% to 5%), anxiety, confusion, lethargy, tingling sensation

Dermatologic: Skin infection (7%), acne vulgaris (1% to 6%), nail disease (brittle fingernails), hair breakage, night sweats, pruritus

Endocrine & metabolic: Gynecomastia (<1% to 4%), hyperglycemia, hypomagnesemia, weight loss

Gastrointestinal: Vomiting (2% to 10%), anorexia, aphthous stomatitis, constipation, dysphagia, gastritis, hiccups, pancreatitis

Genitourinary: Hematuria

Hematologic & oncologic: Leukopenia (<1% to 6%), lymphoma (<1% to 6%), anemia, thrombocytopenia, upper gastrointestinal hemorrhage

Hepatic: Hepatotoxicity (<1% to 7%)

Infection: Localized fungal infection (8%), cytomegalovirus disease (5%), septicemia (5%), abscess (4%), fungal infection (systemic: 2%)

Neuromuscular & skeletal: Arthralgia, myalgia, weakness

Ophthalmic: Conjunctivitis, visual disturbance

Otic: Hearing loss, tinnitus

Respiratory: Sinusitis (<1% to 7%), pneumonia (6%)

Miscellaneous: Fever

Rheumatoid arthritis only (1% to <3% unless otherwise noted):

Cardiovascular: Chest pain (4%), cardiac arrhythmia (2%), abnormal heart sounds, cardiac failure, myocardial infarction, peripheral ischemia

Central nervous system: Dizziness (8%), pain (6%), insomnia (4%), depression (3%), migraine (2% to 3%), anxiety, drowsiness, emotional lability, hypoesthesia, lack of concentration, malaise, neuropathy, nervousness, paranoia, vertigo

Dermatologic: Cellulitis, dermatological reaction, dermatitis, diaphoresis, dyschromia, eczema, enanthema, folliculitis, nail disease, pruritus, urticaria, xeroderma

Endocrine & metabolic: Menstrual disease (3%), decreased libido, diabetes mellitus, goiter, hot flash, hyperkalemia, hyperuricemia, hypoglycemia, increased libido, weight gain, weight loss

Gastrointestinal: Vomiting (9%), flatulence (5%), gingivitis (4%), constipation, dysgeusia, dysphagia, enlargement of salivary glands, eructation, esophagitis, gastric ulcer, gastritis, gastroenteritis, gingival hemorrhage, glossitis, peptic ulcer, tongue disease, xerostomia

Genitourinary: Leukorrhea (1%), breast fibroadenosis, hematuria, mastalgia, nocturia, urine abnormality, urinary incontinence, urinary urgency, uterine hemorrhage

Hematologic & oncologic: Purpura (3% to 4%), anemia, carcinoma, leukopenia, lymphadenopathy

Hepatic: Hyperbilirubinemia

Infection: Abscess (including renal), bacterial infection, candidiasis, fungal infection, herpes simplex infection, herpes zoster, viral infection

Neuromuscular & skeletal: Arthralgia, bone fracture, dislocation, myalgia, stiffness, synovial cyst, tendon disease, weakness

Ophthalmic: Cataract, conjunctivitis, eye pain, visual disturbance

Otic: Tinnitus, deafness, vestibular disturbance

Renal: Abscess (renal), increased blood urea nitrogen, polyuria, pyelonephritis

Respiratory: Cough (5%), dyspnea (5%), sinusitis (4%), abnormal breath sounds, bronchospasm, epistaxis, tonsillitis

Psoriasis only (1% to <3% unless otherwise noted):

Cardiovascular: Chest pain, flushing

Central nervous system: Psychiatric disturbance (4% to 5%), pain (3% to 4%), dizziness, insomnia, nervousness, vertigo

Dermatologic: Acne vulgaris, folliculitis, hyperkeratosis, pruritus, skin rash, xeroderma

Endocrine & metabolic: Hot flash

Gastrointestinal: Abdominal distention, constipation, gingival hemorrhage, increased appetite

Genitourinary: Urinary frequency

Hematologic & oncologic: Abnormal erythrocytes, altered platelet function, blood coagulation disorder, carcinoma, hemorrhagic diathesis

Hepatic: Hyperbilirubinemia

Neuromuscular & skeletal: Arthralgia (1% to 6%)

Ophthalmic: Visual disturbance

Respiratory: Flu-like symptoms (8% to 10%), bronchospasm (5%), cough (5%), dyspnea (5%), rhinitis (5%), respiratory tract infection

Miscellaneous: Fever

Postmarketing and/or case reports (any indication): Anaphylaxis/anaphylactoid reaction (possibly associated with Cremophor EL vehicle in injection formulation), brain disease, central nervous system toxicity, cholestasis, cholesterol increased, exacerbation of psoriasis (transformation to erythrodermic or pustular psoriasis), fatigue, gout, haemolytic uremic syndrome, hepatic insufficiency, hepatitis, hyperbilirubinemia, hyperkalemia, hyperlipidemia, hypertrichosis, hyperuricemia, hypomagnesemia, impaired consciousness, increased susceptibility to infection (including JC virus and BK virus), jaundice, leg pain (possibly a manifestation of Calcineurin-Inhibitor Induced Pain Syndrome), malignant lymphoma, migraine, myalgia, myopathy, myositis, papilledema, progressive multifocal leukoencephalopathy, pseudotumor cerebri, pulmonary edema (noncardiogenic), renal disease (polyoma virus-associated), reversible posterior leukoencephalopathy syndrome, rhabdomyolysis, thrombotic microangiopathy

Warnings/Precautions

Concerns related to adverse effects:

• Gingival hyperplasia: Gingival hyperplasia may occur; avoid concomitant nifedipine in patients who develop gingival hyperplasia (may increase frequency of hyperplasia).
• Hepatotoxicity: Hepatotoxicity (transaminase and bilirubin elevations) and liver injury (including cholestasis, jaundice, hepatitis, and liver failure) have been reported. These events were mainly in patients with confounding factors including infections, coadministration with other potentially hepatotoxic medications, underlying conditions, and significant comorbidities. Fatalities have also been reported rarely, primarily in transplant patients. Increased hepatic enzymes and bilirubin have occurred, usually in the first month and when used at high doses; improvement is usually seen with dosage reduction.
• Hyperkalemia: Significant hyperkalemia, with or without hyperchloremic metabolic acidosis, has been reported.
• Hypertension: [US Boxed Warning]: May cause hypertension; risk is increased with increasing doses/duration.
• Hyperuricemia: Significant hyperuricemia has been reported.
• Infections: [US Boxed Warning]: Increased risk of infection with use; fatal infections have been reported. Bacterial, viral, fungal, and protozoal infections (including opportunistic infections) have occurred. Polyoma virus infections, such as the JC virus and BK virus, may result in serious and sometimes fatal outcomes. The JC virus is associated with progressive multifocal leukoencephalopathy (PML), and PML has been reported in patients receiving cyclosporine. PML may be fatal and presents with hemiparesis, apathy, confusion, cognitive deficiencies, and ataxia; consider neurologic consultation as indicated. The BK virus is associated with nephropathy, and polyoma virus-associated nephropathy (PVAN) has been reported in patients receiving cyclosporine. PVAN is associated with serious adverse effects including renal dysfunction and renal graft loss. If PML or PVAN occur in transplant patients, consider reducing immunosuppression therapy as well as the risk that reduced immunosuppression poses to grafts.
• Malignancy: [US Boxed Warning]: Increased risk of lymphomas and other malignancies (including fatal outcomes), particularly skin cancers; risk is related to intensity/duration of therapy and the use of more than one immunosuppressive agent; all patients should avoid excessive sun/UV light exposure.
• Nephrotoxicity: [US Boxed Warning]: Renal impairment, including structural kidney damage has occurred (when used at high doses); risk is increased with increasing doses/duration; monitor renal function closely. Use caution with other potentially nephrotoxic drugs (eg, acyclovir, aminoglycoside antibiotics, amphotericin B, ciprofloxacin); monitor renal function closely with concomitant use. If significant renal impairment occurs, reduce the dose of the coadministered medication or consider alternative treatment. Elevations in serum creatinine and BUN associated with nephrotoxicity generally respond to dosage reductions. In renal transplant patients with rapidly rising BUN and creatinine, carefully evaluate to differentiate between cyclosporine-associated nephrotoxicity and renal rejection episodes. In cases of severe rejection that fail to respond to pulse steroids and monoclonal antibodies, switching to an alternative immunosuppressant agent may be preferred to increasing cyclosporine to excessive blood concentrations.
• Neurotoxicity: May cause seizures, particularly if used with high-dose corticosteroids. Encephalopathy (including posterior reversible encephalopathy syndrome [PRES]) has also been reported; predisposing factors include hypertension, hypomagnesemia, hypocholesterolemia, high-dose corticosteroids, high cyclosporine serum concentration, and graft-versus-host disease (GVHD). Encephalopathy may be more common in patients with liver transplant compared to kidney transplant. Other neurotoxic events, such as optic disc edema (including papilloedema and potential visual impairment), have been rarely reported primarily in transplant patients.
• Skin cancer: [US Boxed Warning]: Risk of skin cancer may be increased in psoriasis patients with a history of PUVA and possibly methotrexate or other immunosuppressants, UVB, coal tar, or radiation; increased risk of skin cancer has also been established in transplant patients; risk is related to intensity/duration of therapy and the use of more than one immunosuppressive agent; all patients should avoid excessive sun/UV light exposure.
• Thrombotic microangiopathy: In transplant patients, syndromes of microangiopathic hemolytic anemia and thrombocytopenia have occurred and may result in graft failure; it is accompanied by platelet consumption within the graft. Syndrome may occur without graft rejection. Although management of the syndrome is unclear, discontinuation or reduction of cyclosporine, in addition to streptokinase and heparin administration or plasmapheresis, has been associated with syndrome resolution. However, resolution seems to be dependent upon early detection of the syndrome via indium 111 labeled platelet scans.

Disease-related concerns:

• Hepatic impairment: Cyclosporine has extensive hepatic metabolism and exposure is increased in patients with severe hepatic impairment. May require dose reduction.
• Psoriasis: Appropriate use: If receiving other immunosuppressive agents, radiation or UV therapy, concurrent use of cyclosporine is not recommended.

Concurrent drug therapy issues:

• Cyclosporine combination therapy in renal transplant: Due to the increased risk for nephrotoxicity in renal transplantation, avoid using standard doses of cyclosporine in combination with everolimus; reduced cyclosporine doses are recommended; monitor cyclosporine concentrations closely. Cyclosporine and everolimus combination therapy may increase the risk for proteinuria. Cyclosporine combined with either everolimus or sirolimus may increase the risk for thrombotic microangiopathy/thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TMA/TTP/HUS).
• Drug-drug/drug-food interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Transplant patients: To be used initially with corticosteroids. Make dose adjustments based on cyclosporine blood concentrations. Anaphylaxis has been reported with IV use; reserve for patients who cannot take oral form.

Dosage form specific issues:

• Corn oil: Product may contain corn oil.
• Ethanol: Products may contain ethanol. The alcohol content should be considered in certain patient populations, including pregnant or breast-feeding women, patients with liver disease, seizure disorders, alcohol dependency, or pediatric patients.
• Non-interchangeability of modified/non-modified forms: [US Boxed Warning]: The modified/non-modified formulations are not bioequivalent; cyclosporine (modified) has increased bioavailability as compared to cyclosporine (non-modified) and the products cannot be used interchangeably without close monitoring. Cyclosporine (modified) refers to the oral solution and capsule dosage formulations of cyclosporine in an aqueous dispersion (previously referred to as “microemulsion”).
• Polyoxyethylated castor oil: Cyclosporine for injection contains the vehicle polyoxyethylated castor oil (Cremophor EL), which is associated with hypersensitivity (anaphylactic) reactions. Due to the risk for anaphylaxis, IV cyclosporine should be reserved for use in patients unable to take an oral formulation.
• Propylene glycol: Some dosage forms may contain propylene glycol; large amounts are potentially toxic and have been associated hyperosmolality, lactic acidosis, seizures, and respiratory depression; use caution (AAP 1997; Zar 2007).

Other warnings/precautions:

• Discontinuation of therapy: Myasthenia gravis: Abrupt cessation of this or any immunosuppressant, especially in clinically unstable individuals, may result in rapid deterioration of myasthenic symptoms and possibly myasthenic crisis (Melzer 2016).
• Experienced physician: [US Boxed Warning]: Prescribing and dosage adjustment should only be under the direct supervision of an experienced physician. Adequate laboratory/medical resources and follow-up are necessary.
• Monitoring of concentrations: Monitor cyclosporine concentrations closely following the addition, modification, or deletion of other medications. [US Boxed Warning]: Cyclosporine non-modified absorption is erratic; monitor blood concentrations closely.
• Vaccines: Live, attenuated vaccines may be less effective; vaccination should be avoided.

Monitoring Parameters

Monitor plasma concentrations, renal function (serum creatinine and BUN), and blood pressure periodically and following the addition, modification, or deletion of other medications. Monitor for hypersensitivity reactions (IV cyclosporine). Monitor for signs/symptoms of hepatotoxicity, secondary malignancy, diabetes mellitus, infection. Monitor for progressive cognitive or motor deficits; magnetic resonance imaging may be required for diagnosis of posterior reversible encephalopathy syndrome (PRES).

Nephrotic syndrome (Canadian labeling): Baseline blood pressure (2 readings within 2 weeks), fasting serum creatinine (at least 3 levels within 2 weeks), creatinine clearance, urinalysis, CBC, liver function, serum uric acid, serum potassium, and malignancy screening (eg, skin, mouth, lymph nodes). Biweekly monitoring of blood pressure for initial 3 months and then monthly thereafter, frequent monitoring of renal function and periodic cyclosporine trough levels are recommended during therapy. Consider renal biopsy in patients with steroid-dependent minimal change neuropathy who have been maintained on therapy >1 year.

Transplant patients: Cyclosporine trough levels, serum electrolytes, renal function, hepatic function, blood pressure, lipid profile, blood sugar, and HbA1c

Psoriasis therapy: Baseline blood pressure, serum creatinine (2 levels each), BUN, CBC, serum magnesium, potassium, uric acid, lipid profile. Every other week monitoring of blood pressure, complete blood count, serum creatinine, and levels of BUN, uric acid, potassium, lipids, and magnesium during the first 3 months of treatment for psoriasis. Monthly monitoring is recommended after this initial period. (Note: The Canadian labeling recommends bimonthly monitoring of serum creatinine after the initial period if serum creatinine remains stable and cyclosporine dose is ≤2.5 mg/kg daily, and monthly monitoring for higher doses). Also evaluate any atypical skin lesions prior to therapy. Increase the frequency of blood pressure monitoring after each alteration in dosage of cyclosporine.

Rheumatoid arthritis: Baseline blood pressure, and serum creatinine (2 levels each); serum creatinine every 2 weeks for first 3 months, then monthly if patient is stable. Increase the frequency of blood pressure monitoring after each alteration in dosage of cyclosporine. Additional Canadian labeling recommendations include CBC, hepatic function, urinalysis, serum potassium and uric acid (baseline and periodic thereafter).

Pregnancy

Pregnancy Considerations

Cyclosporine crosses the placenta; maternal concentrations do not correlate with those found in the umbilical cord. Cyclosporine may be detected in the serum of newborns for several days after birth (Claris 1993). Based on clinical use, premature births and low birth weight were consistently observed in pregnant transplant patients (additional pregnancy complications also present). Formulations may contain alcohol; the alcohol content should be taken into consideration in pregnant women.

The pharmacokinetics of cyclosporine may be influenced by pregnancy (Grimer 2007). Cyclosporine may be used in pregnant renal, liver, or heart transplant patients (Cowan 2012; EBPG Expert Group on Renal Transplantation 2002; McGuire 2009; Parhar 2012). If therapy is needed for psoriasis, other agents are preferred; however, cyclosporine may be used as an alternative agent along with close clinical monitoring; use should be avoided during the first trimester if possible (Bae 2012). If treatment is needed for lupus nephritis, other agents are recommended to be used in pregnant women (Hahn 2012).

Following transplant, normal menstruation and fertility may be restored within months; however, appropriate contraception is recommended to prevent pregnancy until 1-2 years following the transplant to improve pregnancy outcomes (Cowan 2012; EBPG Expert Group on Renal Transplantation 2002; McGuire 2009; Parhar 2012).

The Transplant Pregnancy Registry International (TPR) is a registry that follows pregnancies that occur in maternal transplant recipients or those fathered by male transplant recipients. The TPR encourages reporting of pregnancies following solid organ transplant by contacting them at 1-877-955-6877 or https://www.transplantpregnancyregistry.org.

Patient Education

What is this drug used for?

• It is used to keep the body from harming the organ after an organ transplant.
• It is used to treat rheumatoid arthritis.
• It is used to treat very bad psoriasis.
• It may be given to you for other reasons. Talk with the doctor.

Frequently reported side effects of this drug

• Diarrhea
• Hair growth
• Acne
• Flushing
• Common cold symptoms
• Joint pain
• Leg cramps
• Abdominal pain
• Vomiting
• Nausea

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Infection
• Bruising
• Bleeding
• Severe loss of strength and energy
• Gum changes
• Burning or numbness feeling
• Chest pain
• Fast heartbeat
• Mole changes
• Skin growth
• Lump in armpit, groin, or neck
• Hearing loss
• Shortness of breath
• Tremors
• Swelling
• Severe headache
• Severe dizziness
• Passing out
• Vision changes
• Kidney problems like not able to pass urine, blood in the urine, change in amount of urine passed, or weight gain
• Liver problems like dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin
• Posterior reversible encephalopathy syndrome like confusion, not alert, vision changes, seizures, or severe headache
• Electrolyte problems like mood changes, confusion, muscle pain or weakness, abnormal heartbeat, seizures, lack of appetite, or severe nausea or vomiting
• Progressive multifocal leukoencephalopathy like confusion, depression, trouble with memory, behavioral changes, change in strength on one side is greater than the other, trouble speaking, change in balance, or vision changes.
• Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.