Version October 2024
Only health care providers experienced in the management of systemic immunosuppressive therapy for the indicated disease should prescribe cyclosporine. At doses used in solid organ transplantation, only health care providers experienced in immunosuppressive therapy and management of organ transplant recipients should prescribe cyclosporine. Patients receiving cyclosporine should be managed in facilities equipped and staffed with adequate laboratory and supportive medical resources. The health care provider responsible for maintenance therapy should have complete information requisite for the follow-up of the patient.
Cyclosporine may increase the susceptibility to infection and the development of neoplasia. In kidney, liver, and heart transplant patients, Gengraf and Neoral may be administered with other immunosuppressive agents. Increased susceptibility to infection and the possible development of lymphoma and other neoplasms may result from the increase in the degree of immunosuppression in transplant patients.
The absorption of Sandimmune capsules and oral solution during long-term administration was found to be erratic. It is recommended that patients taking Sandimmune capsules or oral solution over a period of time be monitored at repeated intervals for cyclosporine blood levels and that subsequent dose adjustments be made to avoid toxicity from high levels and possible organ rejection from low absorption of cyclosporine. This is of special importance in liver transplants. Numerous assays are being developed to measure blood levels of cyclosporine.
Sandimmune capsules and oral solution have decreased bioavailability in comparison with Gengraf and Neoral capsules and Gengraf and Neoral oral solution. Gengraf and Neoral have increased bioavailability compared to Sandimmune capsules and oral solution and are not bioequivalent to Sandimmune and cannot be used interchangeably without the supervision of a health care provider. For a given trough concentration, cyclosporine exposure will be greater with Neoral and Gengraf than with Sandimmune. If a patient who is receiving exceptionally high doses of Sandimmune is converted to Neoral or Gengraf, particular caution should be exercised. Cyclosporine blood concentrations should be monitored in transplant and rheumatoid arthritis (RA) patients taking Gengraf and Neoral to avoid toxicity due to high concentrations. Dose adjustments should be made in transplant patients to minimize possible organ rejection due to low concentrations. Comparison of blood concentrations in the published literature with blood concentrations obtained using current assays must be done with detailed knowledge of the assay methods employed.
Psoriasis patients previously treated with psoralens plus ultraviolet A (PUVA) and, to a lesser extent, methotrexate or other immunosuppressive agents, ultraviolet B (UVB), coal tar, or radiation therapy, are at an increased risk of developing skin malignancies when taking cyclosporine. Also see boxed warnings above.
Cyclosporine, in recommended doses, can cause systemic hypertension and nephrotoxicity. The risk increases with increasing dose and duration of cyclosporine therapy. Renal dysfunction, including structural kidney damage, is a potential consequence of cyclosporine and, therefore, renal function must be monitored during therapy.
Note: Cyclosporine (modified) (Gengraf, Neoral) and cyclosporine (non-modified) (Sandimmune) are not bioequivalent and cannot be used interchangeably. Initial dosing provided; adjust initial dose to achieve desired target cyclosporine concentration for indication; specific institutional protocols should be consulted.
Hepatitis, autoimmune, second-line therapy: Limited data available:
Children ≥2 years and Adolescents: Oral: Initial: 3 to 5 mg/kg/day in divided doses 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, and further reduced after 1 year of therapy to attain goals of 50 to 70 ng/mL. When clinically indicated, cyclosporine may be tapered off (over ~14 days) (Ref).
Graft-versus-host disease (GVHD), prevention: Limited data available, optimal regimen not established:
Infants, Children, and Adolescents: IV followed by oral: Initial: IV: 3 to 5 mg/kg/day in divided doses every 12 hours administered over 2 hours (Ref) beginning 1 day prior to transplant; 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); duration of therapy variable and dependent upon clinical parameters including underlying disease (malignant vs nonmalignant); in reports, 100 days post-hematopoietic stem-cell transplantation to 6 months has been reported (Ref). 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) (Ref).
Kawasaki disease, refractory; alternative therapy:
Note: Consider use in refractory Kawasaki disease when a second intravenous immune globulin (IVIG) infusion, infliximab, or a course of steroids has failed (Ref). Dose varies based on route of administration.
IV: Infants ≥2 months and Children: IV: 3 mg/kg/day in divided doses every 12 hours; adjust dose to achieve the following cyclosporine concentrations: 2-hour peak of 300 to 600 ng/mL and trough of 50 to 150 ng/mL. Transition to oral cyclosporine (modified) when clinically feasible (Ref).
Oral: Infants ≥2 months and Children: Cyclosporine (modified) (Gengraf, Neoral): Oral: 4 to 8 mg/kg/day in divided doses every 12 hours. Higher doses of 10 mg/kg/day have also been reported; adjust dose to achieve the following cyclosporine concentrations: 2-hour peak of 300 to 600 ng/mL and trough of 50 to 150 ng/mL. Once patient is afebrile, clinically improving, and C-reactive protein is ≤1 mg/dL or after 2 weeks of therapy (whichever is longer), taper by 10% every 3 days. May discontinue once dose is down to 1 mg/kg/day (Ref).
Lupus nephritis: Limited data available: Note: Cyclosporine may be considered as maintenance therapy in patients with Class I or II who are at risk for relapse, or as initial induction and subsequent maintenance therapy for use in patients with at least Class III lupus nephritis for whom cyclophosphamide or standard-dose mycophenolic acid analogs (MPAA) are not an option; use in combination with MPAA at a reduced doses and glucocorticoids (Ref).
Children and Adolescents: Oral: 3 to 5 mg/kg/day in divided doses; adjust dose to maintain patient-specific targeted trough concentration (eg, ~60 to 100 ng/mL); continue therapy for at least 1 to 2 years; some experts suggest a duration of >36 months for proliferative cases (Ref). 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 (Ref). A smaller trial of 7 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 (Ref). Case reports have suggested that lower doses (1.8 to 2.5 mg/kg/day) are effective to induce remission (Ref). 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 (Ref).
Nephrotic syndrome: Limited data available:
Frequently relapsing (with or without steroid dependency):
Weight-directed dosing: Children and Adolescents: Oral: 4 to 5 mg/kg/day in divided doses twice daily; titrate doses to achieve target trough concentration of 60 to 150 ng/mL. In children <6 years of age, daily dose may be divided 3 times daily to achieve goals (Ref). Doses as low as 3 mg/kg/day divided twice daily have also been recommended (Ref). Treatment should continue for at least 12 months to reduce risk of relapse (Ref).
BSA-directed dosing: Children ≥3 years and Adolescents: Cyclosporine (modified): Oral: 150 mg/m2/day in divided doses twice daily; titrate doses 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) (Ref). Note: KDIGO guidelines recommend goal trough concentration of 60 to 150 ng/mL (Ref).
Steroid resistant:
Weight-directed dosing: Cyclosporine: Children and Adolescents: Oral: 3 to 6 mg/kg/day in divided doses twice daily; to achieve target trough concentration of 60 to 150 ng/mL. After 6 months of therapy, assess continuation. If no remission (partial or complete), then discontinue therapy; if remission is achieved (partial or complete), then continue for a minimum of 12 months (Ref).
BSA-directed dosing: Cyclosporine (modified): Children and Adolescents: Oral: 150 mg/m2/day in divided doses twice daily; titrate doses to achieve a target trough concentration of 120 to 180 ng/mL; in one study, if remission was not achieved by 12 weeks, doses were increased to achieve a target trough concentration of 300 to 400 ng/mL (Ref). Note: KDIGO guidelines recommend goal trough concentration of 60 to 150 ng/mL (Ref).
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 (Ref)
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 (Ref)
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 recipients 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 recipients when the T-tube is closed; may need to decrease dose (Ref).
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:
Kidney: 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.
There are no pediatric-specific dosage adjustments provided in the manufacturer's labeling; based on experience in adult patients, monitor concentrations and adjust dose for increases in serum creatinine.
Nephrotic syndrome:
eGFR <30 mL/minute/1.73 m2: Reduce dose or discontinue therapy (Ref).
Mild to moderate impairment: There are no dosage adjustments provided in the manufacturer's labeling; monitor blood concentrations.
Severe impairment: There are no dosage adjustments provided in the manufacturer's labeling; however, metabolism is extensively hepatic (exposure is increased). Monitor blood concentrations; may require dose reduction.
(For additional information see "Cyclosporine (ciclosporin) (systemic): Drug information")
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.
Aplastic anemia (off-label use):
Severe: Oral: 5 mg/kg/day in 2 divided doses (in combination with antithymocyte globulin [equine] and eltrombopag) for a minimum of 12 months; begin tapering off cyclosporine over the next 12 months to discontinue by month 24 (Ref) or 10 mg/kg in 2 divided doses (every 12 hours) (in combination with antithymocyte globulin [equine]) for 6 months then tapered over 18 months; target cyclosporine trough levels were maintained between 200 to 400 ng/mL (Ref).
Non-severe: Oral: 2.5 mg/kg every 12 hours (with antithymocyte globulin [equine]) for at least 6 months or until blood cell count plateaus, followed by gradual taper; target cyclosporine trough levels were maintained between 75 to 200 ng/mL (Ref).
Focal segmental glomerulosclerosis (off-label use):
Note: Cyclosporine should be administered for at least 4 to 6 months before considering the disease to be resistant. To minimize relapse, continue cyclosporine for at least 12 months if there is an initial response, unless eGFR declines to <30 mL/minute/1.73 m2 (Ref).
Oral: Initial: 3 to 5 mg/kg/day in 2 divided doses (every 12 hours; with or without corticosteroids) (Ref). Target trough levels of 100 to 175 ng/mL are published but only used to verify adherence or to minimize toxicity; dose should be titrated to achieve a reduction in proteinuria. Reduce dose if serum creatinine increases to >30% of baseline; if serum creatinine fails to improve after dose reduction, discontinuation of therapy should be considered (Ref).
Graft-versus-host disease, acute, 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 oral intake is tolerated using an IV-to-oral ratio of ~1:2 to 1:4 (depending on protocol); 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 (Ref).
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) (Ref).
Graft-versus-host disease, chronic, treatment (off-label use): Oral: 6 mg/kg twice daily every other day (in combination with prednisone) until week 40, followed by a gradual cyclosporine taper (Ref).
Immune thrombocytopenia, refractory (off-label use): Oral: 2.5 to 3 mg/kg/day as monotherapy or in combination with other agents (eg, prednisone) (Ref).
Myasthenia gravis, chronic immunosuppressive therapy (alternative agent) (off-label use):
Note: For use as monotherapy or in combination with glucocorticoids in patients with glucocorticoid-resistant or glucocorticoid-dependent disease (Ref).
Oral: Initial: 2.5 mg/kg/day in 2 divided doses given every 12 hours; may increase total daily dose in increments of 0.5 mg/kg/day every 4 to 8 weeks to a maximum of 5 mg/kg/day based on tolerance, efficacy, and target trough concentration (maximum total dose is not established). Onset of clinical response to cyclosporine may take 1 to 3 months, with a maximum effect apparent at 7 months (Ref).
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.
Psoriasis: Oral: Cyclosporine (modified): Initial dose: 1 to 3 mg/kg/day in 2 divided doses (Ref).
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).
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. 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 (alternative agent):
Note: Although included as an FDA-approved use in the manufacturer’s prescribing information for the treatment of severe, active rheumatoid arthritis not responsive to methotrexate, current guidelines do not include recommendations for cyclosporine in the treatment of rheumatoid arthritis; other agents are preferred (Ref).
Oral: Cyclosporine (modified): Initial dose: 2.5 mg/kg/day in 2 divided doses; salicylates, nonsteroidal anti-inflammatory drugs, and oral glucocorticoids may be continued.
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/day). 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. Decrease cyclosporine dosage by 25% to 50% in patients with no history of hypertension who develop sustained hypertension during therapy; if hypertension persists, discontinue cyclosporine.
Solid organ transplantation: 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.
Note: Cyclosporine therapeutic drug monitoring in solid organ transplant recipients is frequently individualized based on disease, concurrent therapy, type of assay used, and institution-specific protocols. Trough concentrations are commonly used for convenience to facilitate dose adjustments for efficacy and toxicity; however, pharmacokinetic studies suggest that the 2-hour post dose level (C2) is a more consistent predictor of overall cyclosporine exposure and may be considered in some clinical scenarios (Ref).
Oral: Dose is dependent upon type of transplant and formulation; refer to institutional protocol for specific dosing:
Cyclosporine (modified): Manufacturer's labeling for newly transplanted patients:
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.
Lung (off label): Initial (conversion from IV post transplant): Usual dosage ranges from 2.5 to 5 mg/kg/day in 2 divided doses but is dependent on IV dose administered and cyclosporine plasma concentrations (Griffith 1994; Treede 2001; Zuckermann 2003).
Cyclosporine (nonmodified): Refer to institutional protocol for specific dosing; dosing in clinical practice may differ greatly compared to the manufacturer's labeling. Note: When using the nonmodified formulation, cyclosporine levels may increase in liver transplant recipients when the T-tube is closed; dose may need to be decreased.
IV: Cyclosporine (nonmodified):
Heart, liver, renal: Manufacturer's labeling for newly transplanted patients: 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.
Lung (off label): Initial: 1 to 2.5 mg/kg/day beginning immediately after transplantation (in combination with other transplant immunosuppressants); convert to oral cyclosporine with conversion dose based on blood C2 or trough levels as soon as possible post extubation (Griffith 1994; Treede 2001; Zuckermann 2003).
Note: Many transplant centers administer cyclosporine as "divided dose" infusions (in 2 doses daily) or as a continuous (24-hour) infusion. Specific institutional protocols should be consulted.
Conversion to cyclosporine (modified) from cyclosporine (nonmodified): Until the blood trough concentration attains the preconversion value, it is strongly recommended that the cyclosporine blood-trough concentration be monitored every 4 to 7 days after conversion. In addition, monitor clinical safety parameters, such as serum creatinine and BP, every 2 weeks during the first 2 months after conversion. If the blood trough concentrations are outside the desired range and/or if the clinical safety parameters worsen, adjust the dosage accordingly.
T-cell large granular lymphocytic leukemia, symptomatic (off-label use): Oral: 5 to 10 mg/kg/day (in 2 divided doses), adjust dose to maintain therapeutic level of 200 to 400 ng/mL; after 3 months, slowly taper to cyclosporine dose required to maintain response; discontinue if no response or if relapse occurs (Ref) or 1 to 6.7 mg/kg/day (in 2 divided doses), adjust dose to maintain level of ≤250 ng/mL; continue indefinitely in the absence of toxicity (Ref).
Ulcerative colitis, severe, steroid-refractory (off-label use):
IV: Cyclosporine (non-modified): 2 to 4 mg/kg/day, infused continuously over 24 hours (Ref). 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 (Ref).
Oral: Cyclosporine (modified): 2.3 to 3 mg/kg every 12 hours (Ref).
Note: Patients responsive to IV therapy should be switched to oral therapy when possible.
Uveitis (off-label use): 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 (Ref). 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 (Ref).
The renal dosing recommendations are based upon the best available evidence and clinical expertise. Senior Editorial Team: Bruce Mueller, PharmD, FCCP, FASN, FNKF; Jason A. Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC; Michael Heung, MD, MS.
Note: Kidney impairment does not significantly alter the pharmacokinetics of cyclosporine (Ref); however, cyclosporine may cause acute or chronic kidney dysfunction. Routine monitoring of cyclosporine concentrations should be considered when therapeutic drug monitoring guidance is available; consider targeting the lower end of the therapeutic range in patients with preexisting kidney impairment (eg, CrCl <60 mL/minute) and avoid concurrent nephrotoxins (eg, nonsteroidal anti-inflammatory drugs) when possible (Ref).
Oral, IV:
Kidney impairment prior to treatment initiation:
Altered kidney function:
CrCl ≥60 mL/minute: No dosage adjustment necessary.
CrCl <60 mL/minute: No dosage adjustment necessary (0.1% excreted in the urine unchanged) (Ref). For nontransplant indications (eg, autoimmune disease), the manufacturer's labeling states use is contraindicated in patients with abnormal renal function (not defined); however, when potential benefits outweigh the risks, may consider cautious use with frequent monitoring of kidney function, or consider use of an alternative agent due to increased risk of worsening kidney function, especially for patients with more severe impairment (Ref).
Hemodialysis, intermittent (thrice weekly): Not dialyzable (Ref): No supplemental dose or dosage adjustment necessary (Ref). For nontransplant indications (eg, autoimmune disease) the manufacturer's labeling states use is contraindicated in patients with abnormal renal function (not defined); however, may use with extreme caution if benefits outweigh risks, or consider use of an alternative agent, especially if the patient has residual kidney function (Ref).
Peritoneal dialysis: Unlikely to be significantly dialyzable (large Vd): No dosage adjustment necessary (Ref). For nontransplant indications (eg, autoimmune disease) the manufacturer's labeling states use is contraindicated in patients with abnormal renal function (not defined); however, may use with extreme caution if benefits outweigh risks, or consider use of an alternative agent, especially if patient has residual kidney function (Ref).
CRRT: No dosage adjustment necessary (Ref). However, cyclosporine can potentially worsen acute kidney injury; therefore, avoid use unless benefits outweigh the risks. Monitor kidney function closely (Ref).
PIRRT (eg, sustained, low-efficiency diafiltration): No dosage adjustment necessary (Ref). However, cyclosporine can potentially worsen acute kidney injury; therefore, avoid use unless benefits outweigh the risks. Monitor kidney function closely (Ref).
Nephrotoxicity or acute kidney injury during treatment:
Altered kidney function:
Nontransplant indications (eg, autoimmune disease): The following general recommendations may be considered; individualize therapy according to risks/benefits and institutional protocols, when available:
If serum creatinine increases 25% to 30% above baseline (measured on 2 separate occasions at least 2 weeks apart), or by ≥50% at any time during therapy, reduce dose by 25% to 50% and monitor serum creatinine every 2 weeks for 1 month. If serum creatinine does not decrease to within 25% to 30% of baseline, further reduce dose by 25% to 50% and monitor serum creatinine every 2 weeks for 1 month. If serum creatinine does not decrease to within 25% to 30% of baseline, discontinue cyclosporine (Ref).
Transplant indications: There are no specific dosage adjustments recommended; therapy should be individualized by the patient's transplant team (Ref).
Patients receiving renal replacement therapies (eg, hemodialysis, peritoneal dialysis, CRRT):
Nontransplant indications (eg, autoimmune disease): Consider temporary interruption of therapy or switching to an alternative agent to help promote renal recovery and preserve residual kidney function if other factors (eg, concurrent nephrotoxins, dehydration) contributing to decreased kidney function cannot be mitigated. Continued use should only be considered if benefits outweigh risks of further kidney injury (Ref).
Transplant indications: There are no specific dosage adjustments recommended; therapy should be individualized by the patient's transplant team (Ref).
Mild-to-moderate impairment: There are no dosage adjustments provided in the manufacturer’s labeling; monitor blood concentrations.
Severe impairment: There are no dosage adjustments provided in the manufacturer’s labeling; however, metabolism is extensively hepatic (exposure is increased). Monitor blood concentrations; may require dose reduction.
In general, there is an increased risk for the development of diabetes mellitus following transplantation (also known as post-transplant diabetes mellitus [PTDM]) (Ref). The cause of PTDM is multifactorial, of which one modifiable risk factor is the use of calcineurin inhibitors (CNI) (eg, cyclosporine, tacrolimus) (Ref). When compared to tacrolimus, cyclosporine may have a lower incidence of new-onset diabetes and/or impaired fasting glucose (Ref); however, dosing strategies employed in early trials comparing the two CNIs may not reflect contemporary practice (ie, CNI-minimization or avoidance strategies) (Ref). While the impact of CNIs on pancreatic beta cells may be reversible (Ref), the risk of graft rejection must be considered when adjusting immunosuppressants in transplant recipients (Ref). Clinicians should note that PTDM is different than the hyperglycemia that is often seen in first few weeks following transplant.
Mechanism: Time-related; exact mechanism has not been fully elucidated. Potential mechanisms include beta cell dysfunction and increased insulin resistance (Ref). Clinicians should note that the cause of PTDM is multifactorial; the use of a CNI is one factor.
Onset: Varied; PTDM may develop early (ie, ≤3 months) or years after transplantation (Ref).
Risk factors:
• Presence of other risk factors for type 2 diabetes
• Black or Hispanic kidney transplant recipients (Ref)
• Hepatitis C virus infection (Ref)
Cyclosporine is a common cause of drug-induced gingival overgrowth (GO) (ie, gingival hyperplasia). Overgrowth may initially occur on the labial gingiva and in between the teeth; as overgrowth progresses, papillae appear to coalesce and patients may go on to experience swelling, bleeding, and difficulties with chewing and speech (Ref). Cyclosporine-induced GO may be reversible upon discontinuation of therapy (Ref); recurrence is likely when cyclosporine cannot be discontinued (Ref). Tacrolimus is less likely to result in GO as compared to cyclosporine (Ref).
Mechanism: Dose-related (Ref); exact mechanism not clearly established.
Onset: Delayed. Most cases occur within 3 months of treatment initiation; however, cases have been reported as early as 1 month following initiation (Ref)
Risk factors:
• Greater exposure to cyclosporine (ie, higher doses, increased serum concentrations [≥400 ng/mL]) (Ref)
• Concomitant use of other medications known to increase the risk of gingival hyperplasia (eg, calcium channel blockers, phenytoin) (Ref)
• Poor oral hygiene (eg, preexisting gingival inflammation (Ref); preexisting plaque accumulation (Ref)) (Ref)
• Prior history of gingival hyperplasia (Ref)
• The impact of human leukocyte antigen (HLA) types and matching on the risk of gingival overgrowth vary:
- HLA-DR1 expression has been associated with a decreased risk (Ref)
- HLA-A mismatching between donor and host following kidney transplant was found to be protective (Ref)
- No association with risk and HLA haplotype was detected in kidney transplant recipients (Ref)
Cyclosporine use may cause drug-induced thrombotic microangiopathy (DITMA) which can result in microangiopathic hemolytic anemia with thrombocytopenia (MAHA), microvascular thrombosis with vessel wall abnormalities (Ref). Patients generally present with kidney impairment and hypertension (Ref); however, other organ systems may also be impacted by cyclosporine-related DITMA (eg, pulmonary, dermatologic, musculoskeletal, hepatic, gastrointestinal) (Ref). Graft failure may or may not occur (Ref). Resolution can be achieved with early detection of the syndrome, cyclosporine discontinuation or dosage reduction, and initiation of syndrome-specific supportive treatment; however, kidney impairment may persist (Ref).
Mechanism: Dose- and time-dependent; secondary to endothelial dysfunction and increased platelet aggregation (Ref).
Onset: Varied; characterized by a gradual onset of kidney failure that occurs over weeks or months (Ref).
Risk factors:
• In general, risk factors for thrombotic microangiopathy include (Ref):
- Ischemia-reperfusion endothelial injury
- Kidney infections
- Vascular rejection
- Anticardiolipin antibodies
- Malignancies
- Concomitant use of other drugs known to cause DITMA (eg, mTOR inhibitors, antiviral agents)
Hepatotoxicity, characterized by hyperbilirubinemia, mild to moderate transaminase elevations, and biliary tract disease (eg, cholelithiasis) may occur in pediatric and adult patients (Ref). Liver injury, including cholestasis, jaundice, hepatitis, and hepatic failure, has also been reported. Improvement may be seen following dosage reduction (Ref)
Mechanism: Dose-related; related to the pharmacologic action (impaired bile acid flow resulting in intrahepatic cholestasis) (Ref)
Onset: Varied. May occur 2 to 8 weeks post transplant; however, later onset (>1 year post transplant) has been described (Ref)().
Risk factors:
• Greater exposure to cyclosporine (ie, higher doses, increased serum concentrations (Ref))
• Comorbid infection (eg, hepatitis C virus (Ref))
• Concomitant use of other potentially hepatotoxic medications
• Patients receiving total parenteral nutrition (Ref)
Mild to severe hyperkalemia may occur in patients who receive a calcineurin inhibitor (CNI), including cyclosporine; one retrospective trial described less severe as well as a shorter duration of hyperkalemia in patients treated with cyclosporine as compared to patients who received tacrolimus (Ref). CNI-induced hyperkalemia is commonly associated with hypertension, hyperchloremia, metabolic acidosis, and hypercalciuria (Ref).
Mechanism: Dose-related. CNIs may cause a hyporeninemic hypoaldosteronism (type 4 renal tubular acidosis) which is a result of tubular insensitivity to aldosterone and a subsequent decrease in the activity of the renin-angiotensin-aldosterone system (Ref). In addition, CNIs directly impact the ability to excrete potassium, in part via inhibition of the renal outer medullary potassium channel and Na+/K+-ATPase and activation of the chloride shunt mechanism (Ref). Consideration should also be made for the impact of kidney transplantation (eg, delayed graft function) and concomitant drugs (eg, trimethoprim) on potassium balance (Ref).
Onset: Varied; may occur soon after transplant or later during the course of therapy (Ref)
Risk factors:
• Concomitant use of other drugs that may cause hyperkalemia (eg, potassium-sparing diuretics, angiotensin-converting enzyme inhibitors, trimethoprim/sulfamethoxazole)
In general, there is an increased risk for the development of hypertension following kidney transplantation (Ref). The cause of post-transplant hypertension is multifactorial, of which one modifiable risk factor is the use of calcineurin inhibitors (CNI) (eg, cyclosporine, tacrolimus) (Ref). Cyclosporine-based regimens may be associated with a higher incidence of hypertension as compared to tacrolimus-based regimens (Ref); however, the risk of graft rejection must be considered when adjusting immunosuppressants in transplant recipients (Ref). Hypertension may lead to adverse short-term and long-term allograft outcomes as well as increased cardiovascular morbidity and mortality (Ref).
Mechanism: Dose-dependent (Ref); exact mechanism is unknown. Multiple mechanisms may contribute including tubular salt reabsorption, peripheral vasoconstriction, and the sympathetic nervous system (Ref). Vasoconstriction is caused by an increase of vasoconstrictor mediators (eg, sympathetic tone, renin-angiotensin system, and endothelin-1) and a decrease of vasodilator mediators (eg, prostaglandins, nitric oxide) (Ref). Cyclosporine may activate the sodium chloride cotransporter in the kidney; this effect appears to be mediated, in part, by the kinases WNK4 and SPAK (Ref). Clinicians should note that the cause of post-transplant hypertension is multifactorial; the use of a CNI is one factor.
Onset: Varied; may occur soon after transplant or later during the course of therapy (Ref).
Risk factors:
• Increasing dose (Ref)
• Longer duration
• In general, demographic and transplant-specific risk factors for post-transplant hypertension include (Ref):
- Preexisting hypertension
- Elevated body max index
- Males
- Black patients
- Older donor age
- Delayed graft function
- Glucocorticoid use
- Recurrent disease
- Acute rejection
- Post-transplant proteinuria
Cyclosporine is an immunosuppressant; therefore, use may result in infection including bacterial infection, viral infection, fungal infection, and protozoal infections, including opportunistic infections. Infections may be severe and potentially fatal.
Viral infections reported with use of cyclosporine include polyomavirus infection (which may result in polyomavirus-associated nephropathy [PVAN]), JC virus infection-associated progressive multifocal leukoencephalopathy, cytomegalovirus disease (CMV), and reactivation of hepatitis B virus or hepatitis C virus (Ref). PVAN, primarily from activation of BK virus, may lead to the deterioration of kidney function and/or kidney graft loss, especially in kidney transplant recipients (Ref). Risk of infectious complications in transplant recipients may be higher with calcineurin inhibitors, including cyclosporine, as compared to mTOR inhibitors (eg, sirolimus or everolimus) (Ref); cyclosporine may be associated with a lower risk of infections as compared to glucocorticoids or other immunosuppressants (eg, cyclophosphamide) when used for the treatment of idiopathic membranous nephropathy (Ref).
Mechanism: Exact mechanism unknown; related to pharmacologic action. Cyclosporine inhibits T-lymphocyte activation by interacting with an intracellular protein, FKBP-12 and calcineurin-dependent proteins to inhibit calcineurin phosphatase activity (Ref).
Onset: Varied; in general, the onset of infections following solid organ transplant varies greatly; the majority of clinically important infections occur within the first 180 days (Ref).
Risk factors:
• Concomitant use of other immunosuppressive agents or preexisting immune function impairment
• Increased cyclosporine exposure
• CMV infection: Transplant recipients that are CMV seronegative at the time of transplant who receive a graft from a CMV seropositive donor (Ref)
In general, use of immunosuppressive agents may result in an increased risk of lymphoproliferative disorders and/or neoplasms (including skin carcinoma) (Ref). The risk of malignant lymphoma may be lower in transplant recipients who receive cyclosporine as compared to tacrolimus (Ref); however, not all studies have observed this pattern (Ref).
Mechanism: Dose- and time-related; related to the pharmacologic action. Cyclosporine inhibits T-lymphocyte activation by interacting with an intracellular protein, FKBP-12 and calcineurin-dependent proteins to inhibit calcineurin phosphatase activity.
Onset: Delayed. Post-transplant lymphoproliferative disorders (PTLD) and non-skin–non-lymphoma malignancies generally occur during the first year after transplant when immunosuppressive therapy is most aggressive; however, the incidence of skin malignancies increase more linearly with time (Ref).
Risk factors:
• Intensity of immunosuppression (Ref)
• Concomitant use of other immunosuppressive agents or preexisting immune function impairment
• Epstein-Barr virus (EBV) seronegative transplant recipients (Ref)
- Note: In general, pediatric transplant recipients are at a higher risk of PTLD as these patients are more likely to be EBV seronegative at transplantation (Ref)
- Note: Clinicians may also consider the role that EBV acute infection and/or reactivation may play in the risk of EBV-associated lymphoma in patients receiving immunosuppressive therapies; risk not well defined (Ref)
• Pretransplant malignancy (Ref)
• Fewer human leukocyte antigen matches (Ref)
• History of at least 1 prior rejection episode (Ref)
• Age <25 years or >60 years (Ref)
• Skin carcinoma:
- Exposure to sunlight/UV light
- Patients with psoriasis with prior use of psoralen plus ultraviolet A photochemotherapy and possibly methotrexate or other immunosuppressants, UVB, coal tar, or radiation.
Use of calcineurin inhibitors (CNIs), including cyclosporine, may result in acute or chronic nephrotoxicity. Cyclosporine is thought to have a higher nephrotoxicity potential as compared to tacrolimus; however, not all studies have observed this pattern (Ref).
Acute CNI nephrotoxicity: Considered to be acute, functional, dose-dependent, and generally reversible after dose reduction or discontinuation; characterized by moderate increased serum creatinine concentrations unexplained by other causes for acute kidney injury (AKI) with a concomitant increase in cyclosporine trough concentrations (Ref). Kidney biopsy may or may not reveal an acute arteriolopathy and/or tubular vacuolization (Ref). Acute microvascular toxicity may also occur and is differentiated by the presence of glomerular capillary thrombosis as well as thrombi in the arterioles; presentation may range from asymptomatic to hemolytic uremic syndrome (Ref).
Chronic CNI nephrotoxicity: Considered to be chronic, structural, progressive, and irreversible; all three compartments of the kidney (vessels, tubulo-interstitium, glomeruli) may be involved (Ref). Nodular hyaline deposits in the media of afferent arterioles is considered a hallmark; kidney biopsy may reveal arteriolar hyalinosis, tubular atrophy and interstitial fibrosis ("striped fibrosis"), glomerular capsular fibrosis, global and focal segmental glomerulosclerosis, juxtaglomerular apparatus hyperplasia, and/or tubular microcalcifications (Ref). Additional extra-renal symptoms may be present due to tubular functional alterations and ion homeostasis (eg, hyperkalemia, hypomagnesemia, hyperchloremic metabolic acidosis, hyperuricemia); hypertension may also occur (Ref).
Mechanism: Exact mechanism has not been fully elucidated; however, the main mechanisms are changes in glomerular and tubular function with the main targets being tubular epithelial cells, vascular endothelial cells, and arteriolar myocytes (Ref).
Acute CNI nephrotoxicity: Dose-related (Ref); secondary to vasoconstriction of the afferent and efferent glomerular arterioles and reductions in renal blood flow and GFR resulting in hypoperfusion and parenchymal ischemia. Vasoconstriction is caused by an increase of vasoconstrictor mediators (eg, sympathetic tone, renin-angiotensin system, and endothelin-1) and a decrease of vasodilator mediators (eg, prostaglandins, nitric oxide) (Ref).
Chronic CNI nephrotoxicity : Dose- and time-related; exact mechanism is unknown; a combination of hemodynamic changes and direct toxic effects on tubular epithelial cells is thought to play a role (Ref). Nodular hyaline deposits may cause narrowing of the vascular lumen which contributes to the development of interstitial fibrosis, tubular atrophy, and glomerular sclerosis. In addition, renal vasoconstriction may result in local hypoxia or ischemia and subsequent cellular injury. Upregulation of TGF-β and activation of the renin-angiotensin system may also contribute to the tubular-interstitial effects seen in patients with chronic CNI nephrotoxicity (Ref). Furthermore, CNIs may be directly toxic to tubular and interstitial cells as well cause a decrease in the excretion of other endogenous toxic substances via inhibition of P-glycoprotein (multidrug resistance protein 1 [MR1] or ATP-binding cassette subfamily B, member 1 [ABCB1]) (Ref).
Onset: Varied; in one trial, the acute phase of CNI nephrotoxicity occurred with a median onset of 6 months post transplantation, whereas the chronic phase occurred at a median onset of 3 years (Ref).
Risk factors:
• Systemic overexposure to cyclosporine (Ref)
• Increased local exposure to cyclosporine (eg, due to ABCB1 genotype or expression in renal tubular epithelial cells or drug interactions) (Ref)
• Increased exposure to metabolites of tacrolimus (eg, due to CYP3A4/5 genotype or expression in the renal tubular epithelial cells or drug interactions) (Ref)
• Older kidney age (Ref)
• Concomitant use of other nephrotoxic drugs, particularly nonsteroidal anti-inflammatory drugs (Ref)
• Genetic polymorphisms of other genes (eg, TGF-β, ACE) (Ref)
• Patients receiving cyclosporine for the treatment of steroid-dependent nephrotic syndrome as compared to patients with steroid-sensitive nephrotic syndrome (Ref)
Dose-related neurotoxicity may occur with use of calcineurin inhibitors (CNIs), including cyclosporine. Neurotoxicity may be less common with cyclosporine as compared to tacrolimus (Ref).
Mild symptoms may include tremor, neuralgia, peripheral neuropathy, headache, mood changes (agitation, anxiety), and insomnia (Ref). Tremor is a common manifestation and generally involves the upper extremities, especially upon extension (Ref). Headaches are often described as migrainous, occipital, and frequent (eg, weekly) (Ref).
More severe symptoms of neurotoxicity may occur less frequently and include seizure, visual disturbance (including cortical blindness), severe psychomotor disturbance, stupor, coma, delusions, psychosis, hallucinations, cerebellar ataxia, or asthenia (Ref).
Reversible posterior leukoencephalopathy syndrome (RPLS) has been rarely reported (Ref); symptoms (mental status changes, headache, hypertension, seizures, and visual disturbances) are reversible with dose reduction or discontinuation of therapy.
Mechanism: Dose-related; exact mechanism is unknown. Cyclosporine-induced neurotoxicity may be related to the ability of CNIs to increase the permeability of the blood brain barrier via multiple mechanisms; once within the CNS, cyclosporine may cause neurotoxicity via calcineurin inhibition (Ref).
Onset: Varied; CNI-induced neurotoxicity may occur within weeks after transplantation (Ref). Onset of RPLS has been described days to years post transplant; onset may differ depending on the transplanted organ (Ref).
Risk factors:
• Increased cyclosporine exposure; including dosing strategies that result in high peak concentrations (eg, IV administration) or alterations in clearance or metabolism (eg, advanced liver failure, drug interactions) (Ref)
• Increased donor age (Ref)
• Prior history of hepatic encephalopathy in liver transplant recipients (Ref)
• Concomitant use of high-dose corticosteroids
• RPLS: Risk is increased in patients with significant fluid overload, elevated blood pressure, hypomagnesemia, hypocholesterolemia, concomitant use of high-dose corticosteroids, graft-versus-host disease, or impaired kidney function (Ref)
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. 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.
Kidney, liver, and heart transplant:
>10%:
Cardiovascular: Hypertension (13% to 53%) (table 1)
|
Drug (Cyclosporine) |
Comparator (Azathioprine) |
Indication |
Number of Patients (Cyclosporine) |
Number of Patients (Azathioprine) |
|---|---|---|---|---|
|
53% |
N/A |
Heart transplant |
112 |
N/A |
|
26% |
18% |
Kidney transplant |
227 |
228 |
|
13% |
N/A |
Kidney transplant |
705 |
N/A |
|
27% |
N/A |
Liver transplant |
75 |
N/A |
Endocrine & metabolic: Hirsutism (21% to 45%)
Gastrointestinal: Gingival hyperplasia (4% to 16%) (table 2)
|
Drug (Cyclosporine) |
Comparator (Azathioprine) |
Indication |
Number of Patients (Cyclosporine) |
Number of Patients (Azathioprine) |
|---|---|---|---|---|
|
5% |
N/A |
Heart transplant |
112 |
N/A |
|
9% |
N/A |
Kidney transplant |
705 |
N/A |
|
4% |
0% |
Kidney transplant |
227 |
228 |
|
16% |
N/A |
Liver transplant |
75 |
N/A |
Genitourinary: Urinary tract infection (21%)
Infection: Viral infection (16%) (table 3)
|
Drug (Cyclosporine) |
Comparator (Azathioprine with Steroids) |
Indication |
Number of Patients (Cyclosporine) |
Number of Patients (Azathioprine with Steroids) |
|---|---|---|---|---|
|
16% |
18% |
Kidney transplant |
227 |
228 |
Nervous system: Headache (2% to 15%) (table 4)
|
Drug (Cyclosporine) |
Comparator (Azathioprine) |
Indication |
Number of Patients (Cyclosporine) |
Number of Patients (Azathioprine) |
|---|---|---|---|---|
|
15% |
N/A |
Heart transplant |
112 |
N/A |
|
2% |
<1% |
Kidney transplant |
227 |
228 |
|
2% |
N/A |
Kidney transplant |
705 |
N/A |
|
4% |
N/A |
Liver transplant |
75 |
N/A |
Neuromuscular & skeletal: Tremor (21% to 55%) (table 5)
|
Drug (Cyclosporine) |
Comparator (Azathioprine) |
Indication |
Number of Patients (Cyclosporine) |
Number of Patients (Azathioprine) |
|---|---|---|---|---|
|
31% |
N/A |
Heart transplant |
112 |
N/A |
|
21% |
N/A |
Kidney transplant |
705 |
N/A |
|
12% |
0% |
Kidney transplant |
227 |
228 |
|
55% |
N/A |
Liver transplant |
75 |
N/A |
Renal: Nephrotoxicity (25% to 38%) (table 6)
|
Drug (Cyclosporine) |
Comparator (Azathioprine) |
Indication |
Number of Patients (Cyclosporine) |
Number of Patients (Azathioprine) |
|---|---|---|---|---|
|
38% |
N/A |
Heart transplant |
112 |
N/A |
|
32% |
6% |
Kidney transplant |
227 |
228 |
|
25% |
N/A |
Kidney transplant |
705 |
N/A |
|
37% |
N/A |
Liver transplant |
75 |
N/A |
1% to 10%:
Cardiovascular: Chest pain (≤4%), edema (≤2%), flushing (≤4%)
Dermatologic: Acne vulgaris (1% to 6%), nail disease (brittle fingernails) (≤2%), skin infection (≤7%)
Endocrine & metabolic: Gynecomastia (≤4%), hyperglycemia (≤2%)
Gastrointestinal: Abdominal distress (≤7%), anorexia (≤2%), diarrhea (3% to 8%), gastritis (≤2%), hiccups (≤2%), nausea and vomiting (4% to 10%), peptic ulcer (≤2%)
Hematologic & oncologic: Anemia (≤2%), leukopenia (≤6%), malignant lymphoma (≤6%) (table 7), thrombocytopenia (≤2%)
|
Drug (Cyclosporine) |
Comparator (Azathioprine) |
Indication |
Number of Patients (Cyclosporine) |
Number of Patients (Azathioprine) |
|---|---|---|---|---|
|
6% |
N/A |
Heart transplant |
112 |
N/A |
|
1% |
N/A |
Kidney transplant |
705 |
N/A |
|
<1% |
0% |
Kidney transplant |
227 |
228 |
|
1% |
N/A |
Liver transplant |
75 |
N/A |
Hepatic: Hepatotoxicity (≤7%)
Hypersensitivity: Hypersensitivity reaction (≤2%)
Infection: Abscess (4%), cytomegalovirus disease (5%) (table 8), fungal infection (systemic: 2%) (table 9), localized fungal infection (8%) (table 10), septicemia (5%), wound infection (≤7%)
|
Drug (Cyclosporine) |
Comparator (Azathioprine with Steroids) |
Indication |
Number of Patients (Cyclosporine) |
Number of Patients (Azathioprine with Steroids) |
|---|---|---|---|---|
|
5% |
12% |
Kidney transplant |
227 |
228 |
|
Drug (Cyclosporine) |
Comparator (Azathioprine with Steroids) |
Indication |
Number of Patients (Cyclosporine) |
Number of Patients (Azathioprine with Steroids) |
Comments |
|---|---|---|---|---|---|
|
2% |
4% |
Kidney transplant |
227 |
228 |
Systemic fungal infection |
|
Drug (Cyclosporine) |
Comparator (Azathioprine with Steroids) |
Indication |
Number of Patients (Cyclosporine) |
Number of Patients (Azathioprine with Steroids) |
|---|---|---|---|---|
|
8% |
10% |
Kidney transplant |
227 |
228 |
Nervous system: Confusion (≤2%), paresthesia (1% to 3%), seizure (1% to 5%) (table 11)
|
Drug (Cyclosporine) |
Comparator (Azathioprine) |
Indication |
Number of Patients (Cyclosporine) |
Number of Patients (Azathioprine) |
|---|---|---|---|---|
|
4% |
N/A |
Heart transplant |
112 |
N/A |
|
3% |
1% |
Kidney transplant |
227 |
228 |
|
1% |
N/A |
Kidney transplant |
705 |
N/A |
|
5% |
N/A |
Liver transplant |
75 |
N/A |
Neuromuscular & skeletal: Myalgia (≤2%)
Ophthalmic: Conjunctivitis (≤2%)
Otic: Hearing loss (≤2%), tinnitus (≤2%)
Respiratory: Pneumonia (6%), sinusitis (≤7%)
Miscellaneous: Fever (≤2%)
<1%:
Cardiovascular: Acute myocardial infarction
Dermatologic: Night sweats, pruritus, trichorrhexis
Endocrine & metabolic: Weight loss
Gastrointestinal: Aphthous stomatitis, constipation, dysphagia, pancreatitis
Genitourinary: Hematuria
Hematologic & oncologic: Upper gastrointestinal hemorrhage
Nervous system: Anxiety, depression, lethargy, tingling sensation
Neuromuscular & skeletal: Arthralgia, asthenia
Ophthalmic: Visual disturbance
Psoriasis or rheumatoid arthritis (RA):
Incidence reported for RA unless otherwise noted.
>10%:
Cardiovascular: Edema (5% to 14%), hypertension (psoriasis, RA: 8% to 28%) (table 12)
|
Drug (Cyclosporine) |
Placebo |
Indication |
Number of Patients (Cyclosporine) |
Number of Patients (Placebo) |
Comments |
|---|---|---|---|---|---|
|
28% |
N/A |
Psoriasis |
182 |
N/A |
Neoral |
|
25% |
N/A |
Psoriasis |
185 |
N/A |
Sandimmune |
|
26% |
N/A |
Rheumatoid arthritis |
155 |
N/A |
Sandimmune |
|
25% |
N/A |
Rheumatoid arthritis |
143 |
N/A |
Neoral |
|
8% |
2% |
Rheumatoid arthritis |
269 |
201 |
Sandimmune |
Dermatologic: Hypertrichosis (psoriasis: 5% to 7%; RA: 15% to 19%, skin rash (psoriasis: 1% to 3%; RA: 12%)
Endocrine & metabolic: Increased nonprotein nitrogen (18% to 19%), increased serum triglycerides (psoriasis: ≤15%)
Gastrointestinal: Abdominal pain (psoriasis: 3% to 6%; RA: 15%), diarrhea (psoriasis: 5% to 6%; RA: 12% to 13%), dyspepsia (psoriasis: 2% to 3%; RA: 8% to 12%), nausea (psoriasis: 6%; RA: 18% to 23%)
Genitourinary: Female genital tract disease (psoriasis: 9% to 12%)
Infection: Infection (psoriasis: 24% to 25%; RA: 1% to 3%)
Nervous system: Headache (psoriasis, RA: 14% to 25%) (table 13), pain (psoriasis: 3% to 4%; RA: 6% to 13%), paresthesia (psoriasis, RA: 5% to 11%)
|
Drug (Cyclosporine) |
Placebo |
Indication |
Number of Patients (Cyclosporine) |
Number of Patients (Placebo) |
Comments |
|---|---|---|---|---|---|
|
16% |
N/A |
Psoriasis |
182 |
N/A |
Neoral |
|
14% |
N/A |
Psoriasis |
185 |
N/A |
Sandimmune |
|
25% |
N/A |
Rheumatoid arthritis |
143 |
N/A |
Neoral |
|
23% |
N/A |
Rheumatoid arthritis |
155 |
N/A |
Sandimmune |
|
17% |
9% |
Rheumatoid arthritis |
269 |
201 |
Sandimmune |
Neuromuscular & skeletal: Lower limb cramp (2% to 12%), tremor (7% to 13%) (table 14)
|
Drug (Cyclosporine) |
Placebo |
Indication |
Number of Patients (Cyclosporine) |
Number of Patients (Placebo) |
Comments |
|---|---|---|---|---|---|
|
13% |
N/A |
Rheumatoid arthritis |
143 |
N/A |
Neoral |
|
8% |
4% |
Rheumatoid arthritis |
269 |
201 |
Sandimmune |
|
7% |
N/A |
Rheumatoid arthritis |
155 |
N/A |
Sandimmune |
Renal: Increased serum creatinine (psoriasis: 16% to 20%; RA: ≥30%: 39% to 48%; RA: ≥50%: 18% to 24%) (table 15), nephrotoxicity (psoriasis: 21%; RA: 10%)
|
Drug (Cyclosporine) |
Placebo |
Indication |
Number of Patients (Cyclosporine) |
Number of Patients (Placebo) |
Comments |
|---|---|---|---|---|---|
|
20% |
N/A |
Psoriasis |
182 |
N/A |
Neoral |
|
16% |
N/A |
Psoriasis |
185 |
N/A |
Sandimmune |
|
48% |
N/A |
Rheumatoid arthritis |
143 |
N/A |
Neoral; creatinine elevations ≥30% |
|
43% |
13% |
Rheumatoid arthritis |
269 |
201 |
Sandimmune; creatinine elevations ≥30% |
|
39% |
N/A |
Rheumatoid arthritis |
155 |
N/A |
Sandimmune; creatinine elevations ≥30% |
|
24% |
3% |
Rheumatoid arthritis |
269 |
201 |
Sandimmune; creatinine elevations ≥50% |
|
18% |
N/A |
Rheumatoid arthritis |
155 |
N/A |
Sandimmune; creatinine elevations ≥50% |
|
18% |
N/A |
Rheumatoid arthritis |
143 |
N/A |
Neoral; creatinine elevations ≥50% |
Respiratory: Flu-like symptoms (psoriasis: 8% to 19%; RA: 3%), upper respiratory tract infection (psoriasis, RA: 8% to 14%)
1% to 10%:
Cardiovascular: Abnormal heart sounds (1% to 3%), acute myocardial infarction (1% to 3%), cardiac arrhythmia (2% to 5%), cardiac failure (1% to 3%), chest pain (psoriasis, RA: 1% to 6%), flushing (psoriasis, RA: 1% to 3%), peripheral ischemia (1% to 3%)
Dermatologic: Acne vulgaris (psoriasis: 1% to 3%), cellulitis (1% to 3%), dermatitis (1% to 3%), diaphoresis (1% to 3%), dyschromia (1% to 3%), eczema (1% to 3%), enanthema (1% to 3%), folliculitis (psoriasis, RA: 1% to 3%), hyperkeratosis (psoriasis: 1% to 3%), nail disease (1% to 3%), pruritus (psoriasis, RA: 1% to 3%), urticaria (1% to 3%), xeroderma (psoriasis, RA: 1% to 3%)
Endocrine & metabolic: Decreased libido (1% to 3%), diabetes mellitus (1% to 3%), goiter (1% to 3%), hot flash (psoriasis, RA: 1% to 3%), hyperkalemia (1% to 3%), hyperuricemia (1% to 3%), hypoglycemia (1% to 3%), hypomagnesemia (4% to 6%), increased libido (1% to 3%), increased serum cholesterol (psoriasis: <3%), menstrual disease (3%), weight gain (1% to 3%), weight loss (1% to 3%)
Gastrointestinal: Abdominal distention (psoriasis: 1% to 3%), constipation (psoriasis, RA: 1% to 3%), dysgeusia (1% to 3%), dysphagia (1% to 3%), enlargement of salivary glands (1% to 3%), eructation (1% to 3%), esophagitis (1% to 3%), flatulence (4% to 5%), gastric ulcer (1% to 3%), gastritis (1% to 3%), gastroenteritis (1% to 3%), gingival hemorrhage (psoriasis, RA: 1% to 3%), gingival hyperplasia (psoriasis, RA: 2% to 6%) (table 16), gingivitis (3% to 4%), glossitis (1% to 3%), increased appetite (psoriasis: 1% to 3%), peptic ulcer (1% to 3%), tongue disease (1% to 3%), vomiting (6% to 9%), xerostomia (1% to 3%)
|
Drug (Cyclosporine) |
Placebo |
Indication |
Number of Patients (Cyclosporine) |
Number of Patients (Placebo) |
Comments |
|---|---|---|---|---|---|
|
6% |
N/A |
Psoriasis |
185 |
N/A |
Sandimmune |
|
4% |
N/A |
Psoriasis |
182 |
N/A |
Neoral |
|
4% |
N/A |
Rheumatoid arthritis |
155 |
N/A |
Sandimmune |
|
4% |
N/A |
Rheumatoid arthritis |
143 |
N/A |
Neoral |
|
2% |
1% |
Rheumatoid arthritis |
269 |
201 |
Sandimmune |
Genitourinary: Breast fibroadenosis (1% to 3%), hematuria (1% to 3%), leukorrhea (1%), mastalgia (1% to 3%), nocturia (1% to 3%), urinary frequency (psoriasis, RA: 1% to 4%), urinary incontinence (1% to 3%), urinary tract infection (3%), urinary urgency (1% to 3%), urine abnormality (1% to 3%), uterine hemorrhage (1% to 3%)
Hematologic & oncologic: Abnormal erythrocytes (psoriasis: 1% to 3%), anemia (1% to 3%), bleeding tendency disorder (psoriasis: 1% to 3%), carcinoma (1% to 3%), disorder of hemostatic components of blood (psoriasis: 1% to 3%), leukopenia (1% to 3%), lymphadenopathy (1% to 3%), malignant neoplasm of skin (psoriasis: 1% to 3%), purpuric disease (2% to 4%), qualitative disorder of platelet function (psoriasis: 1% to 3%), rectal hemorrhage (3%)
Hepatic: Hyperbilirubinemia (psoriasis, RA: 1% to 3%)
Hypersensitivity: Angioedema (1% to 3%)
Infection: Abscess (including renal; 1% to 3%), bacterial infection (1% to 3%), candidiasis (1% to 3%), fungal infection (1% to 3%), herpes simplex infection (1% to 3%), herpes zoster infection (1% to 3%), viral infection (1% to 3%)
Nervous system: Anxiety (1% to 3%), confusion (1% to 3%), depression (3% to 6%), dizziness (psoriasis: 1% to 3%; RA: 6% to 8%), drowsiness (1% to 3%), emotional lability (1% to 3%), hypoesthesia (1% to 3%), insomnia (psoriasis, RA: 1% to 4%) (table 17), lack of concentration (1% to 3%), malaise (1% to 3%), migraine (2% to 3%), nervousness (psoriasis, RA: 1% to 3%), neuropathy (1% to 3%), paranoid ideation (1% to 3%), psychiatric disturbance (psoriasis: 4% to 5%), rigors (3%), vertigo (psoriasis, RA: 1% to 3%)
|
Drug (Cyclosporine) |
Placebo |
Indication |
Number of Patients (Cyclosporine) |
Number of Patients (Placebo) |
Comments |
|---|---|---|---|---|---|
|
4% |
2% |
Rheumatoid arthritis |
269 |
201 |
Sandimmune |
|
3% |
N/A |
Rheumatoid arthritis |
143 |
N/A |
Neoral |
|
1% |
N/A |
Rheumatoid arthritis |
155 |
N/A |
Sandimmune |
Neuromuscular & skeletal: Arthralgia (psoriasis, RA: 1% to 6%), arthropathy (4%), asthenia (1% to 3%), bone fracture (1% to 3%), bursitis (1% to 3%), dislocation (1% to 3%), muscle spasm (≤4%), myalgia (1% to 3%), stiffness (1% to 3%), synovial cyst (1% to 3%), tendinopathy (1% to 3%)
Ophthalmic: Cataract (1% to 3%), conjunctivitis (1% to 3%), eye pain (1% to 3%), visual disturbance (psoriasis, RA: 1% to 3%)
Otic: Deafness (1% to 3%), tinnitus (1% to 3%), vestibular disturbance (1% to 3%)
Renal: Increased blood urea nitrogen (1% to 3%), polyuria (1% to 3%), pyelonephritis (1% to 3%)
Respiratory: Abnormal breath sounds (1% to 3%), bronchospasm (psoriasis, RA: ≤5%), cough (psoriasis, RA: ≤5%), dyspnea (psoriasis, RA: ≤5%), epistaxis (1% to 3%), pharyngitis (5%), respiratory tract infection (psoriasis: 1% to 3%), rhinitis (psoriasis, RA: ≤5%), sinusitis (4%), tonsillitis (1% to 3%)
Miscellaneous: Fever (psoriasis: 1% to 3%)
<1%: Hematologic & oncologic: Basal cell carcinoma of skin (psoriasis), malignant lymphoma, squamous cell carcinoma of skin (psoriasis)
Frequency not defined (any indication):
Cardiovascular: Glomerular capillary thrombosis
Hematologic & oncologic: Lymphoproliferative disorder
Renal: Renal tubular necrosis
Postmarketing (any indication):
Dermatologic: Exacerbation of psoriasis
Endocrine & metabolic: Gout (Clive 2000), hyperkalemia (Farouk 2020), hyperuricemia (Clive 2000)
Gastrointestinal: Cholestasis (Gbur 1991)
Hematologic & oncologic: Hemolytic-uremic syndrome (Chiurchiu 2002, Remuzzi 1989), malignant neoplasm (Varga 1991), microangiopathic hemolytic anemia with thrombocytopenia (Ödek 2014), thrombotic microangiopathy (Al Nouri 2014)
Hepatic: Hepatic failure, hepatitis, jaundice
Hypersensitivity: Anaphylaxis (including nonimmune anaphylaxis; possibly associated with Cremophor EL vehicle in injection formulation) (Moeinian 2018)
Immunologic: Graft complications
Infection: Increased susceptibility to infection (including JC virus infection, BK virus, polyomavirus infection, and polyomavirus associated nephropathy) (Bansal 2008)
Nervous system: Central nervous system toxicity, encephalopathy (Yamamoto 2002), fatigue (Mathews 2010), idiopathic intracranial hypertension (Morente 2015), migraine (Maghrabi 1998), progressive multifocal leukoencephalopathy (Aksamit 1995), reversible posterior leukoencephalopathy syndrome (Sood 2003)
Neuromuscular & skeletal: Lower extremity pain (possibly a manifestation of Calcineurin-inhibitor induced pain syndrome) (Lawson 2003), myopathy (Ding 2019)
Ophthalmic: Papilledema (Yu 2019)
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.
Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
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).
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.
Special populations:
• Patients with systemic lupus erythematosus (SLE) undergoing hip or knee replacement surgery: Patients with severe SLE (referring to patients with severe organ manifestations such as nephritis) should not interrupt therapy when undergoing hip or knee replacement surgery. For patients with SLE withoutsevere disease, hold cyclosporine for at least 1 week prior to surgery to reduce infection risk; therapy can be restarted once surgical wound shows evidence of healing (eg, no swelling, erythema, or drainage), sutures/staples are removed, and no ongoing nonsurgical site infections (typically ~14 days to reduce infection risk) (ACR/AAHKS [Goodman 2022]).
• Transplant recipients: Make dose adjustments based on blood concentrations; dependent on organ transplanted, time after transplant, organ function, and CsA toxicity.
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 patients who are pregnant or breastfeeding, patients with liver disease, seizure disorders, alcohol dependency, or pediatric patients.
• Modified/nonmodified forms: 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 with 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).
• Vaccines: Live, attenuated vaccines may be less effective; vaccination should be avoided.
Some dosage forms may contain propylene glycol; in neonates large amounts of propylene glycol delivered orally, intravenously (eg, >3,000 mg/day), or topically have been associated with potentially fatal toxicities which can include metabolic acidosis, seizures, renal failure, and CNS depression; toxicities have also been reported in children and adults including hyperosmolality, lactic acidosis, seizures and respiratory depression; use caution (AAP 1997; Shehab 2009).
Cyclosporine injection contains polyoxyethylated castor oil (Cremophor EL)
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Capsule, Oral, (Modified):
Gengraf: 25 mg, 100 mg [contains fd&c blue #2 (indigotine,indigo carmine), polyoxyl/peg-35 castor oil(cremophor el)]
Neoral: 25 mg, 100 mg [contains alcohol, usp]
Generic: 25 mg, 50 mg, 100 mg
Capsule, Oral, (Non-Modified):
SandIMMUNE: 25 mg, 100 mg
Generic: 25 mg, 100 mg
Solution, Intravenous:
SandIMMUNE: 50 mg/mL (5 mL) [contains alcohol, usp, polyoxyl/peg-35 castor oil(cremophor el)]
Generic: 50 mg/mL (5 mL)
Solution, Oral, (Modified):
Gengraf: 100 mg/mL (50 mL) [contains propylene glycol]
Neoral: 100 mg/mL (50 mL) [contains alcohol, usp]
Generic: 100 mg/mL (50 mL)
Solution, Oral, (Non-Modified):
SandIMMUNE: 100 mg/mL (50 mL) [contains alcohol, usp]
Yes
Capsules (cycloSPORINE Modified Oral)
25 mg (per each): $1.38
50 mg (per each): $2.74
100 mg (per each): $5.50
Capsules (cycloSPORINE Oral)
25 mg (per each): $3.85
100 mg (per each): $15.35 - $17.35
Capsules (Gengraf Oral)
25 mg (per each): $2.10
100 mg (per each): $8.40
Capsules (Neoral Oral)
25 mg (per each): $3.24
100 mg (per each): $12.86
Capsules (SandIMMUNE Oral)
25 mg (per each): $5.23
100 mg (per each): $20.68
Solution (cycloSPORINE Intravenous)
50 mg/mL (per mL): $9.39
Solution (cycloSPORINE Modified Oral)
100 mg/mL (per mL): $5.99
Solution (Gengraf Oral)
100 mg/mL (per mL): $9.49
Solution (Neoral Oral)
100 mg/mL (per mL): $14.00
Solution (SandIMMUNE Intravenous)
50 mg/mL (per mL): $16.10
Solution (SandIMMUNE Oral)
100 mg/mL (per mL): $20.05
Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Capsule, Oral:
Neoral: 10 mg [contains alcohol, usp]
Capsule, Oral, (Modified):
Neoral: 25 mg [contains alcohol, usp]
Neoral: 50 mg [contains alcohol, usp, fd&c blue #2 (indigo carm) aluminum lake]
Neoral: 100 mg [contains alcohol, usp]
Generic: 25 mg, 50 mg, 100 mg
Solution, Intravenous:
SandIMMUNE IV: 50 mg/mL (1 mL, 5 mL) [contains alcohol, usp, polyoxyl/peg-35 castor oil(cremophor el)]
Solution, Oral, (Modified):
Neoral: 100 mg/mL (50 mL) [contains alcohol, usp, propylene glycol]
Oral: Administer consistently with relation to time of day and meals.
Oral solution: Use syringe provided to measure dose. Administer with oral syringe, glass dropper, or glass container (not plastic or styrofoam cup); to improve palatability, may mix Sandimmune oral solution with milk, chocolate milk, or orange juice that is at room temperature. May mix Neoral with orange juice or apple juice that is at room temperature; avoid mixing with grapefruit juice; Neoral mixed with milk can be unpalatable; mix in a glass container, stir well and drink at once; do not allow to stand before drinking; rinse container with more diluent to ensure that the total dose is taken. After use, dry outside of dosing syringe; do not rinse with water or other cleaning agents; if dosage syringe requires cleaning it must be completely dry before resuming use; introduction of water into the product will cause dose variations.
Parenteral: To minimize leaching of DEHP, non-PVC containers and sets should be used for administration. May administer by IV intermittent infusion or continuous infusion; for intermittent infusion, administer over 2 to 6 hours. Anaphylaxis has been reported with IV use. Patients should be continuously monitored for at least the first 30 minutes of the infusion and should be monitored frequently thereafter.
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: The manufacturer recommends administering sirolimus 4 hours after cyclosporine. If given concurrently to facilitate adherence, additional monitoring may be required with initiation or dose adjustment of either agent.
IV: The manufacturer recommends that following dilution, IV 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.
Product is formulated in a vehicle known as polyoxyl 35/polyoxyethylated castor oil (Cremophor EL), which has been found to leach the plasticizer di(2- ethylhexyl) phthalate (DEHP) from PVC infusion bags or administration sets; to eliminate leaching of DEHP, use DEHP-free or non–PVC-lined (eg, polyethylene- or polypropylene-lined sets) IV administration sets.
Cyclosporine levels should not be drawn from the infusion line in which cyclosporine is infused, as falsely elevated cyclosporine levels may occur if used for therapeutic drug monitoring; once a line is used for a cyclosporine IV infusion, it should be considered contaminated (Ref).
Hazardous agent (NIOSH 2016 [group 2]).
Use appropriate precautions for receiving, handling, storage, preparation, dispensing, transporting, administration, and disposal. Follow NIOSH and USP 800 recommendations and institution-specific policies/procedures for appropriate containment strategy (NIOSH 2016; USP-NF 2020).
Note: Facilities may perform risk assessment of some hazardous drugs to determine if appropriate for alternative handling and containment strategies (USP-NF 2020). Refer to institution-specific handling policies/procedures.
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.
Cyclosporine modified (Gengraf, Neoral): Prophylaxis of organ rejection in kidney, liver, and heart transplants as part of combination therapy (FDA approved in ages ≥1 year and adults); treatment of severe, active rheumatoid arthritis (RA) not responsive to methotrexate alone (FDA approved in adults); treatment of severe, recalcitrant plaque psoriasis in nonimmunocompromised patients unresponsive to or unable to tolerate other systemic therapy (FDA approved in adults).
Cyclosporine nonmodified (Sandimmune): Prophylaxis of organ rejection in kidney, liver, and heart transplants in combination with corticosteroids; treatment of chronic organ rejection in patients previously treated with other immunosuppressive (All indications: FDA approved in ages ≥6 months and adults).
Has also been used to treat nephrotic syndrome, lupus nephritis, refractory Kawasaki disease, autoimmune hepatitis, and prevention and treatment of graft-versus-host disease in bone marrow transplant recipients.
Note: Although included as an FDA-approved use in the manufacturer's prescribing information for treatment in adults with severe, active rheumatoid arthritis not responsive to methotrexate, current guidelines do not include recommendations for cyclosporine in the treatment of rheumatoid arthritis; other agents are preferred (ACR [Fraenkel 2021]; EULAR [Smolen 2020]).
CycloSPORINE may be confused with cycloPHOSphamide, Cyklokapron, cycloSERINE, voclosporin
CycloSPORINE modified (Neoral, Gengraf) may be confused with cycloSPORINE non-modified (SandIMMUNE)
Gengraf may be confused with Prograf
Neoral may be confused with Neurontin, Nizoral
SandIMMUNE may be confused with SandoSTATIN
The Institute for Safe Medication Practices (ISMP) includes this medication among its list of drug classes (immunosuppressant agent, parenteral and oral) which have a heightened risk of causing significant patient harm when used in error (High-Alert Medications in Community/Ambulatory Care and Long-Term Care Settings).
Substrate of CYP3A4 (major), P-glycoprotein/ABCB1 (major); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential; Inhibits BCRP/ABCG2, BSEP/ABCB11, CYP2C9 (weak), CYP3A4 (weak), OATP1B1/1B3 (SLCO1B1/1B3), P-glycoprotein/ABCB1
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the drug interactions program by clicking on the “Launch drug interactions program” link above.
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the drug interactions program
Abrocitinib: May enhance the immunosuppressive effect of Immunosuppressants (Therapeutic Immunosuppressant Agents). Risk X: Avoid combination
AcetaZOLAMIDE: May increase the serum concentration of CycloSPORINE (Systemic). Risk C: Monitor therapy
Adalimumab: May decrease the serum concentration of CycloSPORINE (Systemic). Risk C: Monitor therapy
Afatinib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Afatinib. Management: If combined, administer the P-gp inhibitor simultaneously with, or after, the dose of afatinib. Monitor closely for signs and symptoms of afatinib toxicity and if the combination is not tolerated, reduce the afatinib dose by 10 mg. Risk D: Consider therapy modification
Aldesleukin: May increase the serum concentration of CYP Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor therapy
Aliskiren: CycloSPORINE (Systemic) may increase the serum concentration of Aliskiren. Risk X: Avoid combination
Allopurinol: May increase the serum concentration of CycloSPORINE (Systemic). Risk C: 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. Risk D: Consider therapy modification
ALPRAZolam: CYP3A4 Inhibitors (Weak) may increase the serum concentration of ALPRAZolam. Risk C: Monitor therapy
Ambrisentan: CycloSPORINE (Systemic) may increase the serum concentration of Ambrisentan. Management: Limit ambrisentan dose to 5 mg daily and monitor for ambrisentan adverse reactions in patients receiving cyclosporine. Risk D: Consider therapy modification
Aminoglycosides: May enhance the nephrotoxic effect of CycloSPORINE (Systemic). Risk C: Monitor therapy
Amphotericin B: May enhance the nephrotoxic effect of CycloSPORINE (Systemic). Amphotericin B may increase the serum concentration of CycloSPORINE (Systemic). Risk C: Monitor therapy
Androgens: May enhance the hepatotoxic effect of CycloSPORINE (Systemic). Androgens may increase the serum concentration of CycloSPORINE (Systemic). Management: Consider avoiding concomitant use of androgens and cyclosporine. If concomitant use is unavoidable, monitor serum cyclosporine concentrations and for signs and symptoms of hepatotoxicity. Cyclosporine dose reductions may be required. Risk D: Consider therapy modification
Antifungal Agents (Azole Derivatives, Systemic): May decrease the metabolism of CycloSPORINE (Systemic). Fluconazole and isavuconazonium considerations are addressed in separate monographs. Management: Consider reducing cyclosporine doses by 50% to 80% during coadministration with ketoconazole, 50% with voriconazole or itraconazole, and 25% with posaconazole. Cyclosporine dose reductions may be required with other azoles. Risk D: Consider therapy modification
Antithymocyte Globulin (Equine): Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the adverse/toxic effect of Antithymocyte Globulin (Equine). Specifically, these effects may be unmasked if the dose of immunosuppressive therapy is reduced. Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Antithymocyte Globulin (Equine). Specifically, infections may occur with greater severity and/or atypical presentations. Risk C: Monitor therapy
Armodafinil: May decrease the serum concentration of CycloSPORINE (Systemic). Risk C: Monitor therapy
Asciminib: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor therapy
Ascorbic Acid: May decrease the serum concentration of CycloSPORINE (Systemic). Risk C: Monitor therapy
Atogepant: OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase the serum concentration of Atogepant. Management: For episodic migraine, the recommended atogepant dose is 10 mg or 30 mg once daily if given with OATP1B1/1B3 inhibitors. For chronic migraine, the recommended atogepant dose is 30 mg once daily with OATP1B1/1B3 inhibitors. Risk D: Consider therapy modification
Atorvastatin: CycloSPORINE (Systemic) may increase the serum concentration of Atorvastatin. Risk X: Avoid combination
Azithromycin (Systemic): May increase the serum concentration of CycloSPORINE (Systemic). Risk C: Monitor therapy
Baricitinib: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Baricitinib. Risk X: Avoid combination
BCG Products: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the adverse/toxic effect of BCG Products. Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of BCG Products. Risk X: Avoid combination
Berberine-Containing Products: May increase the serum concentration of CycloSPORINE (Systemic). Risk C: Monitor therapy
Berotralstat: CycloSPORINE (Systemic) may increase the serum concentration of Berotralstat. Berotralstat may increase the serum concentration of CycloSPORINE (Systemic). Management: Decrease the berotralstat dose to 110 mg daily when combined with cyclosporine. Additionally, monitor for increased cyclosporine concentrations and toxicities when these agents are combined. Risk D: Consider therapy modification
Bilastine: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Bilastine. Risk X: Avoid combination
Bosentan: CycloSPORINE (Systemic) may increase the serum concentration of Bosentan. Bosentan may decrease the serum concentration of CycloSPORINE (Systemic). Risk X: Avoid combination
Brincidofovir: OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase the serum concentration of Brincidofovir. Management: Consider alternatives to OATP1B/1B3 inhibitors in patients treated with brincidofovir. If coadministration is required, administer OATP1B1/1B3 inhibitors at least 3 hours after brincidofovir and increase monitoring for brincidofovir adverse reactions. Risk D: Consider therapy modification
Brivudine: May enhance the adverse/toxic effect of Immunosuppressants (Therapeutic Immunosuppressant Agents). Risk X: Avoid combination
Bulevirtide: CycloSPORINE (Systemic) may diminish the therapeutic effect of Bulevirtide. Risk X: Avoid combination
Calcium Channel Blockers (Dihydropyridine): May increase the serum concentration of CycloSPORINE (Systemic). CycloSPORINE (Systemic) may increase the serum concentration of Calcium Channel Blockers (Dihydropyridine). Risk C: Monitor therapy
Calcium Channel Blockers (Nondihydropyridine): May decrease the metabolism of CycloSPORINE (Systemic). CycloSPORINE (Systemic) may decrease the metabolism of Calcium Channel Blockers (Nondihydropyridine). Risk C: Monitor therapy
Cannabidiol: May increase the serum concentration of CycloSPORINE (Systemic). Cannabidiol may decrease the serum concentration of CycloSPORINE (Systemic). Risk C: Monitor therapy
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. Risk D: Consider therapy modification
Celiprolol: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Celiprolol. Risk C: Monitor therapy
Chikungunya Vaccine (Live): Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the adverse/toxic effect of Chikungunya Vaccine (Live). Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Chikungunya Vaccine (Live). Risk X: Avoid combination
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. Risk D: Consider therapy modification
Chloroquine: May increase the serum concentration of CycloSPORINE (Systemic). Risk C: Monitor therapy
Cholic Acid: BSEP/ABCB11 Inhibitors may decrease the excretion of Cholic Acid. Management: Avoid the use of bile salt efflux pump inhibitors with cholic acid. If such a combination cannot be avoided, monitor serum transaminases (eg, AST, ALT) and bilirubin closely. Risk D: Consider therapy modification
Ciprofloxacin (Systemic): May enhance the nephrotoxic effect of CycloSPORINE (Systemic). Risk C: Monitor therapy
Cladribine: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Cladribine. Risk X: Avoid combination
Clarithromycin: May increase the serum concentration of CycloSPORINE (Systemic). Management: Monitor for increased serum concentrations/toxic effects of cyclosporine if combined with clarithromycin. Cyclosporine dose reductions and/or prolongation of the dosing interval will likely be required. Risk D: Consider therapy modification
Clofazimine: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk C: Monitor therapy
Coccidioides immitis Skin Test: Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the diagnostic effect of Coccidioides immitis Skin Test. Management: Consider discontinuing therapeutic immunosuppressants several weeks prior to coccidioides immitis skin antigen testing to increase the likelihood of accurate diagnostic results. Risk D: Consider therapy modification
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: This combination is often contraindicated, but combined use may be permitted with dose adjustment and monitoring. Recommendations vary based on brand, indication, use of CYP3A4 inhibitors, and hepatic/renal function. See interaction monograph for details. Risk D: 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. Risk D: Consider therapy modification
COVID-19 Vaccines: Calcineurin Inhibitors (Systemic) may diminish the therapeutic effect of COVID-19 Vaccines. Management: Rheumatology guidelines recommend holding calcineurin inhibitors for 1 to 2 weeks after each vaccine dose as permitted by the underlying disease. This is specific to the use of calcineurin inhibitors for rheumatologic or musculoskeletal disease. Risk D: Consider therapy modification
CycloPHOSphamide: May decrease the serum concentration of CycloSPORINE (Systemic). Risk C: Monitor therapy
CYP3A4 Inducers (Moderate): May decrease the serum concentration of CycloSPORINE (Systemic). Risk C: Monitor therapy
CYP3A4 Inducers (Strong): May decrease the serum concentration of CycloSPORINE (Systemic). Management: Monitor closely for reduced cyclosporine concentrations when combined with strong CYP3A4 inducers. Cyclosporine dose increases will likely be required to maintain adequate serum concentrations. Risk D: Consider therapy modification
CYP3A4 Inhibitors (Moderate): May increase the serum concentration of CycloSPORINE (Systemic). Risk C: Monitor therapy
CYP3A4 Inhibitors (Strong): May increase the serum concentration of CycloSPORINE (Systemic). Management: Monitor cyclosporine serum concentrations and clinical cyclosporine closely with concurrent use of any strong CYP3A4 inhibitor. Cyclosporine dose reductions and/or prolongation of the dosing interval will likely be required. Risk D: Consider therapy modification
CYP3A4 Inhibitors (Weak): May increase the serum concentration of CycloSPORINE (Systemic). Risk C: Monitor therapy
Dabigatran Etexilate: P-glycoprotein/ABCB1 Inhibitors may increase serum concentrations of the active metabolite(s) of Dabigatran Etexilate. Risk C: Monitor therapy
Dengue Tetravalent Vaccine (Live): Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the adverse/toxic effect of Dengue Tetravalent Vaccine (Live). Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Dengue Tetravalent Vaccine (Live). Risk X: Avoid combination
Denosumab: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Denosumab. Management: Consider the risk of serious infections versus the potential benefits of coadministration of denosumab and immunosuppressants. If combined, monitor for signs/symptoms of serious infections. Risk D: Consider therapy modification
Deucravacitinib: May enhance the immunosuppressive effect of Immunosuppressants (Therapeutic Immunosuppressant Agents). Risk X: Avoid combination
Digoxin: CycloSPORINE (Systemic) may increase the serum concentration of Digoxin. Risk C: Monitor therapy
Dinutuximab Beta: May increase the serum concentration of CYP Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor therapy
Disulfiram: May enhance the adverse/toxic effect of Products Containing Ethanol. Management: Do not use disulfiram with dosage forms that contain ethanol. Risk X: Avoid combination
Dofetilide: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Dofetilide. Risk C: Monitor therapy
DOXOrubicin (Conventional): P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of DOXOrubicin (Conventional). Risk X: Avoid combination
DOXOrubicin (Liposomal): P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of DOXOrubicin (Liposomal). Risk C: Monitor therapy
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. Risk C: Monitor therapy
Dronedarone: CycloSPORINE (Systemic) may increase the serum concentration of Dronedarone. Risk X: Avoid combination
Edoxaban: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Edoxaban. Risk C: Monitor therapy
Elacestrant: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor therapy
Elagolix: OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase the serum concentration of Elagolix. Risk X: Avoid combination
Elagolix, Estradiol, and Norethindrone: OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase the serum concentration of Elagolix, Estradiol, and Norethindrone. Specifically, concentrations of elagolix may be increased. Risk X: Avoid combination
Elbasvir and Grazoprevir: OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase the serum concentration of Elbasvir and Grazoprevir. Risk X: Avoid combination
Elranatamab: May increase the serum concentration of CYP Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor therapy
Eltrombopag: CycloSPORINE (Systemic) may decrease the serum concentration of Eltrombopag. Risk C: Monitor therapy
Eluxadoline: OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase the serum concentration of Eluxadoline. Management: Decrease the eluxadoline dose to 75 mg twice daily if combined with OATP1B1/1B3 inhibitors and monitor patients for increased eluxadoline effects/toxicities. Risk D: Consider therapy modification
Enoxacin: May increase the serum concentration of CycloSPORINE (Systemic). Risk C: Monitor therapy
Epcoritamab: May increase the serum concentration of CYP Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor therapy
Erdafitinib: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Management: If coadministration with these narrow therapeutic index/sensitive P-gp substrates is unavoidable, separate erdafitinib administration by at least 6 hours before or after administration of these P-gp substrates. Risk D: Consider therapy modification
Erythromycin (Systemic): May increase the serum concentration of CycloSPORINE (Systemic). Risk C: Monitor therapy
Ethinyl Estradiol-Containing Products: May increase the serum concentration of CycloSPORINE (Systemic). Risk C: 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. Risk D: 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. Management: Consider empiric etoposide phosphate dose reductions of at least 50% in patients receiving, or who have recently received, cyclosporine. Monitor closely for increased toxicity of etoposide phosphate if cyclosporine is initiated or dose changed. Risk D: Consider therapy modification
Etrasimod: May enhance the immunosuppressive effect of Immunosuppressants (Therapeutic Immunosuppressant Agents). Risk X: Avoid combination
Everolimus: CycloSPORINE (Systemic) may increase the serum concentration of Everolimus. Management: When everolimus is used as a post-transplant immunosuppressant (Zortress brand), lower cyclosporine doses and lower target serum cyclosporine concentrations must be used. Monitor both everolimus and cyclosporine serum concentrations closely when combined. Risk D: Consider therapy modification
Ezetimibe: May increase the serum concentration of CycloSPORINE (Systemic). CycloSPORINE (Systemic) may increase the serum concentration of Ezetimibe. Risk C: Monitor therapy
Fexinidazole: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination
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. Risk D: Consider therapy modification
Filgotinib: May enhance the immunosuppressive effect of Immunosuppressants (Therapeutic Immunosuppressant Agents). Risk X: Avoid combination
Fimasartan: CycloSPORINE (Systemic) may increase the serum concentration of Fimasartan. Risk C: Monitor therapy
Finerenone: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Finerenone. Risk C: Monitor therapy
Flibanserin: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Flibanserin. Risk C: Monitor therapy
Fluconazole: May increase the serum concentration of CycloSPORINE (Systemic). Risk C: Monitor therapy
Fluvastatin: CycloSPORINE (Systemic) may increase the serum concentration of Fluvastatin. Management: Limit fluvastatin to 20 mg twice daily and avoid use of fluvastatin extended-release tablets in patients who are also receiving cyclosporine and monitor for fluvastatin toxicities (eg, myalgia, myopathy, rhabdomyolysis). Risk D: Consider therapy modification
Foscarnet: May enhance the nephrotoxic effect of CycloSPORINE (Systemic). Risk X: Avoid combination
Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Consider avoiding this combination if possible. If required, monitor patients closely for increased adverse effects of the CYP3A4 substrate. Risk D: Consider therapy modification
Futibatinib: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor therapy
Ganciclovir-Valganciclovir: May enhance the nephrotoxic effect of CycloSPORINE (Systemic). Risk C: Monitor therapy
Gilteritinib: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor therapy
Givinostat: May increase the serum concentration of CYP3A4 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor therapy
Glecaprevir and Pibrentasvir: CycloSPORINE (Systemic) may increase the serum concentration of Glecaprevir and Pibrentasvir. Management: Glecaprevir/pibrentasvir is not recommended for use in patients requiring stable doses of cyclosporine greater than 100 mg per day. If combined with lower doses of cyclosporine, monitor for increased glecaprevir/pibrentasvir toxicities. Risk D: Consider therapy modification
Glofitamab: May increase the serum concentration of CYP Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor therapy
GlyBURIDE: CycloSPORINE (Systemic) may diminish the therapeutic effect of GlyBURIDE. GlyBURIDE may increase the serum concentration of CycloSPORINE (Systemic). Risk C: Monitor therapy
Grape Juice, Purple: May decrease the serum concentration of CycloSPORINE (Systemic). Risk C: 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. Risk X: Avoid combination
Griseofulvin: May decrease the serum concentration of CycloSPORINE (Systemic). Risk C: Monitor therapy
Hydroxychloroquine: May increase the serum concentration of CycloSPORINE (Systemic). Risk C: Monitor therapy
Ilaprazole: May increase the serum concentration of CycloSPORINE (Systemic). Risk C: Monitor therapy
Imipenem: May enhance the neurotoxic effect of CycloSPORINE (Systemic). Risk C: Monitor therapy
Inebilizumab: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Inebilizumab. Risk C: Monitor therapy
Influenza Virus Vaccines: Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Influenza Virus Vaccines. Management: Administer influenza vaccines at least 2 weeks prior to initiating immunosuppressants if possible. If vaccination occurs less than 2 weeks prior to or during therapy, revaccinate 2 to 3 months after therapy discontinued if immune competence restored. Risk D: Consider therapy modification
Interleukin-6 (IL-6) Inhibiting Therapies: May decrease the serum concentration of CycloSPORINE (Systemic). Risk C: Monitor therapy
Ixabepilone: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Ixabepilone. Risk C: Monitor therapy
Lapatinib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Lapatinib. Risk C: Monitor therapy
Larotrectinib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Larotrectinib. Risk C: Monitor therapy
Lasmiditan: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk X: 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. Risk D: Consider therapy modification
Leflunomide: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Leflunomide. Management: Increase the frequency of chronic monitoring of platelet, white blood cell count, and hemoglobin or hematocrit to monthly, instead of every 6 to 8 weeks, if leflunomide is coadministered with immunosuppressive agents. Risk D: 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. Risk D: Consider therapy modification
Lercanidipine: May increase the serum concentration of CycloSPORINE (Systemic). CycloSPORINE (Systemic) may increase the serum concentration of Lercanidipine. Risk X: 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. If starting letermovir doses are less than 480 mg (ie, in pediatric patients) decreasing the letermovir dose 50% when combined with cyclosporine may also be appropriate. Risk D: Consider therapy modification
Linezolid: CycloSPORINE (Systemic) may increase the serum concentration of Linezolid. Risk C: Monitor therapy
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. Risk D: Consider therapy modification
Loop Diuretics: CycloSPORINE (Systemic) may enhance the adverse/toxic effect of Loop Diuretics. Specifically, the risk for hyperuricemia and gout may be increased. Risk C: Monitor therapy
Lovastatin: CycloSPORINE (Systemic) may increase the serum concentration of Lovastatin. Risk X: Avoid combination
Lumateperone: CycloSPORINE (Systemic) may increase the serum concentration of Lumateperone. Risk C: Monitor therapy
Maribavir: May increase the serum concentration of CycloSPORINE (Systemic). Risk C: Monitor therapy
Mavorixafor: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Mavorixafor. Risk C: Monitor therapy
Melphalan: May enhance the nephrotoxic effect of CycloSPORINE (Systemic). Risk C: 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. Risk C: Monitor therapy
Methotrimeprazine: Products Containing Ethanol may enhance the adverse/toxic effect of Methotrimeprazine. Specifically, a disulfiram-like reaction may occur and CNS depressant effects may be increased. Management: Avoid products containing alcohol in patients treated with methotrimeprazine. Risk X: Avoid combination
MethylPREDNISolone: CycloSPORINE (Systemic) may enhance the neuroexcitatory and/or seizure-potentiating effect of MethylPREDNISolone. MethylPREDNISolone may decrease the serum concentration of CycloSPORINE (Systemic). Risk C: Monitor therapy
Metoclopramide: May increase the serum concentration of CycloSPORINE (Systemic). Risk C: Monitor therapy
Midazolam: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Midazolam. Risk C: Monitor therapy
Mifamurtide: CycloSPORINE (Systemic) may diminish the therapeutic effect of Mifamurtide. Risk X: Avoid combination
MiFEPRIStone: May increase the serum concentration of CycloSPORINE (Systemic). Risk X: Avoid combination
Minoxidil (Systemic): CycloSPORINE (Systemic) may enhance the adverse/toxic effect of Minoxidil (Systemic). Severe hypertrichosis has been reported with this combination. Risk C: Monitor therapy
Mitapivat: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor therapy
MitoXANTRONE: CycloSPORINE (Systemic) may increase the serum concentration of MitoXANTRONE. Risk C: Monitor therapy
Momelotinib: OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase the serum concentration of Momelotinib. Risk C: Monitor therapy
Morphine (Systemic): P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Morphine (Systemic). Risk C: Monitor therapy
Mosunetuzumab: May increase the serum concentration of CYP Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor therapy
Multivitamins/Fluoride (with ADE): May increase the serum concentration of CycloSPORINE (Systemic). Multivitamins/Fluoride (with ADE) may decrease the serum concentration of CycloSPORINE (Systemic). Risk C: Monitor therapy
Multivitamins/Minerals (with ADEK, Folate, Iron): May increase the serum concentration of CycloSPORINE (Systemic). Multivitamins/Minerals (with ADEK, Folate, Iron) may decrease the serum concentration of CycloSPORINE (Systemic). Risk C: Monitor therapy
Multivitamins/Minerals (with AE, No Iron): May increase the serum concentration of CycloSPORINE (Systemic). Multivitamins/Minerals (with AE, No Iron) may decrease the serum concentration of CycloSPORINE (Systemic). Risk C: Monitor therapy
Mumps- Rubella- or Varicella-Containing Live Vaccines: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the adverse/toxic effect of Mumps- Rubella- or Varicella-Containing Live Vaccines. Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Mumps- Rubella- or Varicella-Containing Live Vaccines. Risk X: Avoid combination
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). Risk D: Consider therapy modification
Nadofaragene Firadenovec: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the adverse/toxic effect of Nadofaragene Firadenovec. Specifically, the risk of disseminated adenovirus infection may be increased. Risk X: Avoid combination
Nadolol: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Nadolol. Risk C: Monitor therapy
Naldemedine: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Naldemedine. Risk C: Monitor therapy
Naloxegol: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Naloxegol. Risk C: Monitor therapy
Natalizumab: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Natalizumab. Risk X: Avoid combination
Neuromuscular-Blocking Agents: CycloSPORINE (Systemic) may enhance the neuromuscular-blocking effect of Neuromuscular-Blocking Agents. Risk C: Monitor therapy
NiMODipine: CYP3A4 Inhibitors (Weak) may increase the serum concentration of NiMODipine. Risk C: Monitor therapy
Nirmatrelvir and Ritonavir: May increase the serum concentration of CycloSPORINE (Systemic). Management: Consider avoiding this combination if possible and using alternative anti-COVID-19 therapy if appropriate. If coadministration is required, consider reducing cyclosporine dose by 80% and monitoring cyclosporine concentrations closely. Risk D: 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. Risk D: Consider therapy modification
Nonsteroidal Anti-Inflammatory Agents (Topical): May enhance the adverse/toxic effect of CycloSPORINE (Systemic). Specifically, the nephrotoxicity of cyclosporine (systemic) may be increased. Risk C: Monitor therapy
Norethindrone: May increase the serum concentration of CycloSPORINE (Systemic). Risk C: Monitor therapy
Norfloxacin: May increase the serum concentration of CycloSPORINE (Systemic). Risk C: 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. Risk D: Consider therapy modification
Ocrelizumab: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Ocrelizumab. Risk C: Monitor therapy
Ofatumumab: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Ofatumumab. Risk C: 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. Risk D: 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. Risk D: Consider therapy modification
Omeprazole: May increase the serum concentration of CycloSPORINE (Systemic). Risk C: Monitor therapy
Orlistat: May decrease the serum concentration of CycloSPORINE (Systemic). Management: Administer oral cyclosporine 3 hours after orlistat. Monitor for decreased serum concentrations of oral cyclosporine, even with the recommended dose separation. Risk D: Consider therapy modification
Ornidazole: May enhance the adverse/toxic effect of Products Containing Ethanol. Specifically, a disulfiram-like reaction may occur. Risk X: Avoid combination
Pacritinib: May increase the serum concentration of CYP3A4 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk X: Avoid combination
Pacritinib: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk X: Avoid combination
PAZOPanib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of PAZOPanib. Risk X: Avoid combination
PAZOPanib: BCRP/ABCG2 Inhibitors may increase the serum concentration of PAZOPanib. Risk X: Avoid combination
P-glycoprotein/ABCB1 Inducers: May decrease the serum concentration of CycloSPORINE (Systemic). Risk C: Monitor therapy
P-glycoprotein/ABCB1 Inhibitors: May increase the serum concentration of CycloSPORINE (Systemic). Risk C: Monitor therapy
Pidotimod: Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Pidotimod. Risk C: Monitor therapy
Pimecrolimus: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Pimecrolimus. Risk X: Avoid combination
Pimozide: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Pimozide. Risk X: Avoid combination
Pitavastatin: CycloSPORINE (Systemic) may increase the serum concentration of Pitavastatin. Risk X: Avoid combination
Pneumococcal Vaccines: Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Pneumococcal Vaccines. Risk C: Monitor therapy
Poliovirus Vaccine (Live/Trivalent/Oral): Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the adverse/toxic effect of Poliovirus Vaccine (Live/Trivalent/Oral). Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Poliovirus Vaccine (Live/Trivalent/Oral). Risk X: Avoid combination
Polymethylmethacrylate: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the potential for allergic or hypersensitivity reactions to Polymethylmethacrylate. Management: Use caution when considering use of bovine collagen-containing implants such as the polymethylmethacrylate-based Bellafill brand implant in patients who are receiving immunosuppressants. Consider use of additional skin tests prior to administration. Risk D: Consider therapy modification
Potassium-Sparing Diuretics: May enhance the hyperkalemic effect of CycloSPORINE (Systemic). Risk X: Avoid combination
Pralsetinib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Pralsetinib. Management: If this combo cannot be avoided, decrease pralsetinib dose from 400 mg daily to 300 mg daily; from 300 mg daily to 200 mg daily; and from 200 mg daily to 100 mg daily. Risk D: Consider therapy modification
Pravastatin: CycloSPORINE (Systemic) may increase the serum concentration of Pravastatin. Pravastatin may increase the serum concentration of CycloSPORINE (Systemic). Management: Initiate pravastatin dose at 10 mg daily and limit the maximum pravastatin dose to 20 mg daily in patients who are also receiving cyclosporine. Monitor for pravastatin toxicities (eg, myalgia, myopathy, rhabdomyolysis) if combined. Risk D: Consider therapy modification
PrednisoLONE (Systemic): CycloSPORINE (Systemic) may enhance the neuroexcitatory and/or seizure-potentiating effect of PrednisoLONE (Systemic). PrednisoLONE (Systemic) may decrease the serum concentration of CycloSPORINE (Systemic). CycloSPORINE (Systemic) may increase the serum concentration of PrednisoLONE (Systemic). Risk C: Monitor therapy
PredniSONE: CycloSPORINE (Systemic) may enhance the neuroexcitatory and/or seizure-potentiating effect of PredniSONE. CycloSPORINE (Systemic) may increase serum concentrations of the active metabolite(s) of PredniSONE. PredniSONE may decrease the serum concentration of CycloSPORINE (Systemic). Risk C: Monitor therapy
Pretomanid: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor therapy
Probucol: May decrease the serum concentration of CycloSPORINE (Systemic). Risk C: Monitor therapy
Pyrazinamide: May enhance the myopathic (rhabdomyolysis) effect of CycloSPORINE (Systemic). Pyrazinamide may decrease the serum concentration of CycloSPORINE (Systemic). Risk C: Monitor therapy
Quercetin: May increase the serum concentration of CycloSPORINE (Systemic). Risk C: Monitor therapy
Quinupristin and Dalfopristin: May increase the serum concentration of CycloSPORINE (Systemic). Risk C: Monitor therapy
Rabies Vaccine: Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Rabies Vaccine. Management: Complete rabies vaccination at least 2 weeks before initiation of immunosuppressant therapy if possible. If combined, check for rabies antibody titers, and if vaccination is for post exposure prophylaxis, administer a 5th dose of the vaccine. Risk D: Consider therapy modification
Ranolazine: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Ranolazine. Risk C: Monitor therapy
Red Yeast Rice: CycloSPORINE (Systemic) may increase the serum concentration of Red Yeast Rice. Risk X: Avoid combination
Relugolix: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Relugolix. Management: Avoid coadministration of relugolix with oral P-gp inhibitors whenever possible. If combined, take relugolix at least 6 hours prior to the P-gp inhibitor and monitor patients more frequently for adverse reactions. Risk D: Consider therapy modification
Relugolix, Estradiol, and Norethindrone: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Relugolix, Estradiol, and Norethindrone. Management: Avoid use of relugolix/estradiol/norethindrone with P-glycoprotein (P-gp) inhibitors. If concomitant use is unavoidable, relugolix/estradiol/norethindrone should be administered at least 6 hours before the P-gp inhibitor. Risk D: Consider therapy modification
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. Risk D: Consider therapy modification
Repotrectinib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Repotrectinib. Risk X: Avoid combination
Resmetirom: OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase the serum concentration of Resmetirom. Risk X: Avoid combination
Revefenacin: OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase serum concentrations of the active metabolite(s) of Revefenacin. Risk X: Avoid combination
RifAXIMin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of RifAXIMin. Risk C: Monitor therapy
Rimegepant: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Rimegepant. Management: Avoid administration of another dose of rimegepant within 48 hours if given concomitantly with a P-glycoprotein (P-gp) inhibitor. Risk D: Consider therapy modification
RisperiDONE: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of RisperiDONE. Risk C: Monitor therapy
Ritlecitinib: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Ritlecitinib. Risk X: Avoid combination
RomiDEPsin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of RomiDEPsin. Risk C: Monitor therapy
Rosuvastatin: CycloSPORINE (Systemic) may increase the serum concentration of Rosuvastatin. Management: Limit rosuvastatin to 5 mg daily in patients who are also receiving cyclosporine, and monitor patients for increased rosuvastatin toxicities. Canadian labeling contraindicates concomitant use of rosuvastatin with cyclosporine. Risk D: Consider therapy modification
Ruxolitinib (Topical): Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Ruxolitinib (Topical). Risk X: Avoid combination
Secnidazole: Products Containing Ethanol may enhance the adverse/toxic effect of Secnidazole. Risk X: Avoid combination
Sevelamer: May decrease the serum concentration of CycloSPORINE (Systemic). Risk C: Monitor therapy
Silodosin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Silodosin. Risk C: Monitor therapy
Simeprevir: May increase the serum concentration of CycloSPORINE (Systemic). CycloSPORINE (Systemic) may increase the serum concentration of Simeprevir. Risk X: Avoid combination
Simvastatin: CycloSPORINE (Systemic) may increase the serum concentration of Simvastatin. Risk X: Avoid combination
Sipuleucel-T: Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Sipuleucel-T. Management: Consider reducing the dose or discontinuing the use of immunosuppressants prior to initiating sipuleucel-T therapy. Risk D: Consider therapy modification
Sirolimus (Conventional): 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 (Conventional). 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. Risk D: Consider therapy modification
Sirolimus (Protein Bound): P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Sirolimus (Protein Bound). Risk X: Avoid combination
Somatostatin Analogs: May decrease the serum concentration of CycloSPORINE (Systemic). Risk C: Monitor therapy
Sparsentan: May increase the serum concentration of CycloSPORINE (Systemic). CycloSPORINE (Systemic) may increase the serum concentration of Sparsentan. Risk X: Avoid combination
Sphingosine 1-Phosphate (S1P) Receptor Modulator: May enhance the immunosuppressive effect of Immunosuppressants (Therapeutic Immunosuppressant Agents). Risk C: Monitor therapy
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. Risk D: Consider therapy modification
Sulfinpyrazone: May decrease the serum concentration of CycloSPORINE (Systemic). Risk C: Monitor therapy
Sulfonamide Antibiotics: May enhance the nephrotoxic effect of CycloSPORINE (Systemic). Sulfonamide Antibiotics may decrease the serum concentration of CycloSPORINE (Systemic). Risk C: Monitor therapy
Tacrolimus (Systemic): May enhance the nephrotoxic effect of CycloSPORINE (Systemic). CycloSPORINE (Systemic) may enhance the nephrotoxic effect of Tacrolimus (Systemic). Tacrolimus (Systemic) may increase the serum concentration of CycloSPORINE (Systemic). CycloSPORINE (Systemic) may increase the serum concentration of Tacrolimus (Systemic). Risk X: Avoid combination
Tacrolimus (Topical): Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Tacrolimus (Topical). Risk X: Avoid combination
Talazoparib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Talazoparib. Risk C: Monitor therapy
Talazoparib: BCRP/ABCG2 Inhibitors may increase the serum concentration of Talazoparib. Risk C: Monitor therapy
Talimogene Laherparepvec: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the adverse/toxic effect of Talimogene Laherparepvec. Specifically, the risk of infection from the live, attenuated herpes simplex virus contained in talimogene laherparepvec may be increased. Risk X: Avoid combination
Talquetamab: May increase the serum concentration of CYP Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor therapy
Taurursodiol: OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase the serum concentration of Taurursodiol. Risk X: Avoid combination
Taurursodiol: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk X: Avoid combination
Teclistamab: May increase the serum concentration of CYP Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor therapy
Tegaserod (Withdrawn from US Market): P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Tegaserod (Withdrawn from US Market). Risk C: 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. Risk C: Monitor therapy
Teniposide: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Teniposide. Risk C: Monitor therapy
Tenofovir Disoproxil Fumarate: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Tenofovir Disoproxil Fumarate. Risk C: Monitor therapy
Terbinafine (Systemic): May decrease the serum concentration of CycloSPORINE (Systemic). Risk C: Monitor therapy
Tertomotide: Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Tertomotide. Risk X: Avoid combination
Ticagrelor: CycloSPORINE (Systemic) may increase the serum concentration of Ticagrelor. Risk C: Monitor therapy
Ticlopidine: May decrease the serum concentration of CycloSPORINE (Systemic). Risk C: Monitor therapy
Tofacitinib: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Tofacitinib. Management: Coadministration of tofacitinib with potent immunosuppressants is not recommended. Use with non-biologic disease-modifying antirheumatic drugs (DMARDs) was permitted in psoriatic arthritis clinical trials. Risk X: Avoid combination
TOLBUTamide: CYP2C9 Inhibitors (Weak) may increase the serum concentration of TOLBUTamide. Risk C: Monitor therapy
Topotecan: BCRP/ABCG2 Inhibitors may increase the serum concentration of Topotecan. Risk X: Avoid combination
Topotecan: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Topotecan. Risk X: Avoid combination
Treosulfan: May increase the serum concentration of CYP3A4 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk X: Avoid combination
Triazolam: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Triazolam. Risk C: Monitor therapy
Trofinetide: May increase the serum concentration of CYP3A4 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor therapy
Typhoid Vaccine: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the adverse/toxic effect of Typhoid Vaccine. Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Typhoid Vaccine. Risk X: Avoid combination
Ublituximab: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Ublituximab. Risk C: Monitor therapy
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. Risk D: Consider therapy modification
Upadacitinib: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Upadacitinib. Risk X: Avoid combination
Vaccines (Live): Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the adverse/toxic effect of Vaccines (Live). Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Vaccines (Live). Risk X: Avoid combination
Vaccines (Non-Live/Inactivated/Non-Replicating): Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Vaccines (Non-Live/Inactivated/Non-Replicating). Management: Give non-live/inactivated/non-replicating vaccines at least 2 weeks prior to starting immunosuppressants when possible. Patients vaccinated less than 14 days before or during therapy should be revaccinated at least 2 to 3 months after therapy is complete. Risk D: Consider therapy modification
Venetoclax: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Venetoclax. Management: Reduce the venetoclax dose by at least 50% in patients requiring concomitant treatment with P-glycoprotein (P-gp) inhibitors. Resume the previous venetoclax dose 2 to 3 days after discontinuation of a P-gp inhibitor. Risk D: Consider therapy modification
VinCRIStine (Liposomal): P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of VinCRIStine (Liposomal). Risk X: Avoid combination
Vitamin E (Systemic): May increase the serum concentration of CycloSPORINE (Systemic). Vitamin E (Systemic) may decrease the serum concentration of CycloSPORINE (Systemic). Risk C: Monitor therapy
Voxilaprevir: OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase the serum concentration of Voxilaprevir. Risk X: Avoid combination
Wine: May decrease the serum concentration of CycloSPORINE (Systemic). Risk C: Monitor therapy
Yellow Fever Vaccine: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the adverse/toxic effect of Yellow Fever Vaccine. Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Yellow Fever Vaccine. Risk X: Avoid combination
Zavegepant: OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase the serum concentration of Zavegepant. Risk X: Avoid combination
Grapefruit juice increases cyclosporine serum concentrations. Management: Avoid grapefruit juice with concomitant oral cyclosporine use.
Avoid grapefruit juice with oral cyclosporine use.
Cyclosporine is an acceptable immunosuppressant for use in kidney (EBPG 2002; KDIGO 2009; López 2014), liver (AASLD [Lucey 2013]), or heart (ISHLT [Velleca 2022]) transplant recipients planning a pregnancy. Conception may be considered for patients on a stable/low maintenance dose for ≥1 year following transplant (AASLD [Lucey 2013]; EBPG 2002; ISHLT [Velleca 2022]; López 2014).
Cyclosporine is considered acceptable for use in patients with rheumatic and musculoskeletal diseases who are planning to become pregnant and are not able to use alternative therapies; however, blood pressure monitoring is recommended. Conception should be planned during a period of quiescent/low disease activity (ACR [Sammaritano 2020]). Patients treated with cyclosporine for lupus nephritis should continue treatment while planning to become pregnant; conception may be considered after 6 months of inactive disease (EULAR/ERA-EDTA [Bertsias 2012]).
Data related to paternal use of cyclosporine are limited. However, available data have not shown cyclosporine adversely impacts male fertility or increases the risk of adverse pregnancy outcomes when used prior to conception (Mouyis 2019). Potential effects on fertility are associated with higher doses; conception can be attempted once lower serum levels can be maintained and the allograft is functioning (Georgiou 2016). Erectile dysfunction was found to occur more frequently with cyclosporine than other immunosuppressants in a study of renal transplant recipients; consider screening patients with risk factors prior to use (Zakhem 2019). Cyclosporine is considered acceptable for use in patients with rheumatic and musculoskeletal diseases who are planning to father a child (ACR [Sammaritano 2020])
Cyclosporine crosses the placenta (Claris 1993).
In a study of 15 pregnant patients, maternal concentrations did not correlate with those found in the umbilical cord (n=14). Cyclosporine was detected in the serum of one newborn for several days after birth (Claris 1993).
Cyclosporine is not associated with specific teratogenic effects, but maternal use may be associated with an increased risk of intrauterine growth restriction, small for gestational age babies, maternal hypertension, and preeclampsia (EBPG 2002). Premature births and low birth weight were consistently observed in pregnant transplant recipients (additional pregnancy complications also present). In utero exposure to cyclosporine has not been found to influence renal function or blood pressure in children followed up to 7 years of age (limited data).
Some formulations may contain alcohol; the alcohol content should be taken into consideration prior to prescribing to patients who are pregnant.
Cyclosporine levels decline during pregnancy (KDIGO 2009) and increased monitoring is recommended (AASLD [Lucey 2013]; EBPG 2002; ISHLT [Velleca 2022]; López 2014).
Cyclosporine is an acceptable immunosuppressant for use in patients who become pregnant following a kidney (EBPG 2002; López 2014) or heart transplant (ISHLT [Velleca 2022]). Cyclosporine may also be used when needed in pregnant patients following a liver transplant (AASLD [Lucey 2013]).
For other indications, cyclosporine is not a preferred agent. Cyclosporine is considered acceptable for the treatment of myasthenia gravis in pregnant patients who are not controlled with or unable to tolerate corticosteroids (Sanders 2016). If therapy is needed for psoriasis, other agents are preferred; however, if cyclosporine is used, limit to shortest duration and lowest possible dose (Kaushik 2019). Cyclosporine can be used during pregnancy for refractory cases of lupus nephritis (EULAR/ERA-EDTA [Berstias 2012]) and other rheumatic and musculoskeletal diseases in patients who are not able to use alternative therapies; however, close monitoring of blood pressure is recommended (ACR [Sammaritano 2020]). Cyclosporine may be useful for the treatment of immune thrombocytopenia in pregnant patients who are refractory to preferred agents (Provan 2019). Use of cyclosporine for inflammatory bowel disease is limited to salvage therapy in patients who are pregnant (AGA [Mahadevan 2019]).
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.
Monitor plasma concentrations periodically and following the addition, modification, or deletion of other medications. Monitor renal function (serum creatinine and BUN) after any cyclosporine dosage changes or addition, modification, or deletion of other medications. Monitor blood pressure after any cyclosporine dosage changes or addition, modification, or deletion of other medications. Monitor for hypersensitivity reactions (IV cyclosporine). Monitor for signs/symptoms of hepatotoxicity, secondary malignancy, infection.
Transplant recipients: Cyclosporine trough concentrations, serum electrolytes, renal function, hepatic function, blood pressure, lipid profile.
Psoriasis therapy: Baseline blood pressure, serum creatinine (2 levels each), BUN, CBC, serum magnesium, potassium, uric acid, lipid profile. Biweekly 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. 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).
Reference ranges are method- and specimen-dependent; use the same analytical method consistently; trough concentrations should be obtained:
Oral: 12 to 18 hours after dose (chronic usage).
IV: 12 hours after dose or immediately prior to next dose.
Therapeutic concentrations: Refer to indication specific ranges. Not well-defined; dependent on organ transplanted, time after transplant, organ function, and cyclosporine toxicity; refer to institution specific protocols. General range: 100 to 400 ng/mL (SI: 83.2 to 332.8 nmol/L).
Toxic concentration: Not well defined, nephrotoxicity may occur at any level.
Inhibition of production and release of interleukin II and inhibits interleukin II-induced activation of resting T-lymphocytes.
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 in tissues and body fluids including the liver, pancreas, and lungs
Vdss: 4-6 L/kg in renal, liver, and marrow transplant recipients (slightly lower values in cardiac transplant recipients; children <10 years have higher values); ESRD: 3.49 L/kg
Protein binding: 90% to 98% to lipoproteins
Metabolism: Extensively hepatic via CYP3A4; forms at least 25 metabolites; extensive first-pass effect following oral administration
Bioavailability: Oral:
Cyclosporine (non-modified): Dependent on patient population and transplant type (<10% in adult liver transplant recipients and as high as 89% in renal transplant recipients); bioavailability of Sandimmune capsules and oral solution are equivalent; bioavailability of oral solution is ~30% of the IV solution
Children: 28% (range: 17% to 42%); gut dysfunction common in BMT patients and oral bioavailability is further reduced
Cyclosporine (modified): Bioavailability of Neoral capsules and oral solution are equivalent:
Children: 43% (range: 30% to 68%)
Adults: 23% greater than with cyclosporine (non-modified) in renal transplant recipients; 50% greater in liver transplant recipients.
Half-life elimination: Oral: May be prolonged in patients 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)
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
Excretion: Primarily feces; urine (6%, 0.1% as unchanged drug and metabolites); clearance is more rapid in pediatric patients than in adults
Altered kidney function: 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 recipients, 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.
Hepatic function impairment: Severe hepatic impairment may result in significantly reduced clearance and increased cyclosporine exposures.
آیا می خواهید مدیلیب را به صفحه اصلی خود اضافه کنید؟
