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    Calcineurin Inhibitors
    Miscellaneous Ophthalmologicals for Dry Eye Disease

    BOXED WARNING

    Fungal infection, herpes infection, immunosuppression, infection, lymphoma, neoplastic disease, psoriasis, requires a specialized care setting, requires an experienced clinician, varicella, viral infection

    Cyclosporine therapy requires an experienced clinician who is knowledgeable in immunosuppressive therapy or organ transplantation. Increased susceptibility to infection and possible development of neoplastic disease, especially lymphoma or skin malignancies, may result from immunosuppression. The increased risk appears related to the intensity and duration of immunosuppression rather than to the use of specific agents. Patients should not be treated concurrently with cyclosporine and PUVA or UVB, other radiation therapy, or other immunosuppressive agents because of the possibility of excessive immunosuppression and risk of malignancies. Patients should also be warned to avoid excessive sun exposure and wear sun protection. Patients should be evaluated before and during treatment for the presence of malignancies, and should be treated with cyclosporine only after complete resolution of suspicious lesions. Additionally, psoriasis patients with abnormal renal function, uncontrolled hypertension, or malignancies should not receive cyclosporine. Cyclosporine administration requires a specialized care setting with facilities equipped and staffed with adequate laboratory and supportive medical services. Bacterial, viral, protozoal, and fungal infection occur commonly during immunosuppressive therapy and can be fatal. Reactivation of a latent viral infection, especially herpes infection or varicella, can occur with immunosuppressive therapy. Patients should be instructed to report signs of infection promptly.

    Radiation therapy, skin cancer, sunlight (UV) exposure

    All patients taking cyclosporine need to avoid excess sunlight (UV) exposure because of an increased risk for skin malignancies. In patients with psoriasis treated with Neoral or Gengraf, the concomitant use of PUVA or UVB therapy, methotrexate or other immunosuppressive agents, coal tar, or radiation therapy is contraindicated. Also, psoriasis patients previously treated with PUVA and to a lesser extent, methotrexate or other immunosuppressive agents, UVB, coal tar, or radiation therapy are at increased risk of developing skin cancer when taking cyclosporine. The relative risk of malignancies is comparable to that observed in psoriasis patients treated with other immunosuppressive therapies. Patients should be thoroughly evaluated before and during cyclosporine treatment for the presence of skin cancer remembering that psoriatic plaques may hide malignant lesions. Skin lesions not typical of psoriasis should be biopsied before starting cyclosporine treatment. Patients should be treated with cyclosporine only after complete resolution of suspicious lesions and only if there are no other treatment options.

    Nephrotoxicity, renal disease, renal failure, renal impairment

    Cyclosporine in recommended dosages can cause nephrotoxicity. The risk of developing cyclosporine-induced nephrotoxicity increases with increasing doses of cyclosporine and duration of cyclosporine therapy. Neoral or Gengraf are contraindicated in patients with rheumatoid arthritis and psoriasis if abnormal renal function (such as renal disease, renal impairment, or renal failure) is present. All patients receiving nephrotoxic drugs concomitantly with systemic cyclosporine should be carefully monitored for worsening renal function. In all patients, serum creatinine should be monitored closely. It is not unusual for the serum creatinine and BUN to be elevated during systemic cyclosporine therapy for transplant rejection prophylaxis. The elevation of serum creatinine and BUN in renal transplant patients does not necessarily indicate rejection, and each patient must be fully evaluated before dosage adjustment is initiated. If patients are not monitored properly and doses are not adjusted correctly, systemic cyclosporine therapy can be associated with the occurrence of structural kidney damage and persistent renal dysfunction. In psoriasis and rheumatoid arthritis patients, serum creatinine and BUN should be monitored every 2 weeks during the initial 3 months of cyclosporine therapy and then monthly if the patient is stable. If the serum creatinine is >= 25% above the rheumatoid arthritis or psoriasis patient's baseline, the level should be repeated within 2 weeks. If the change remains >= 25% above baseline, the cyclosporine dose should be reduced by 25—50%. If at any time the serum creatinine increases by >= 50% above baseline, cyclosporine dosage should be reduced by 25—50%. Cyclosporine should be discontinued if reversibility (within 25% of baseline) of the serum creatinine is not achieved after two dosage reductions. It is recommended to monitor the serum creatinine after a dosage increase or addition of a NSAID during cyclosporine treatment.

    DEA CLASS

    Rx

    DESCRIPTION

    Immunosuppressive; cyclic polypeptide consisting of 11 amino acids; used to prevent organ rejection and in various autoimmune conditions; a microemulsion formulation (cyclosporine, USP (Modified)) has been introduced to improve the bioavailability; an ophthalmic preparation is available to increase tear production in patients with ocular inflammation associated with keratoconjunctivitis.

    COMMON BRAND NAMES

    Gengraf, Neoral, Restasis, Sandimmune

    HOW SUPPLIED

    Cyclosporine, Modified/Gengraf/Neoral/Sandimmune Oral Sol: 1mL, 100mg
    Cyclosporine/Cyclosporine, Modified/Gengraf/Neoral/Sandimmune Oral Cap: 25mg, 50mg, 100mg
    Cyclosporine/Sandimmune Intravenous Inj Sol: 1mL, 50mg
    Restasis Ophthalmic Emulsion: 0.05%

    DOSAGE & INDICATIONS

    For kidney transplant rejection prophylaxis.
    For kidney transplant rejection prophylaxis in combination with sirolimus and corticosteroids in patients who are considered low to moderate immunologic risk.
    Oral dosage
    Adults and Adolescents who weigh >= 40 kg and without a history of an acute allograft rejection episode or the presence of chronic allograft nephropathy on a renal biopsy

    Initially, up to 7 mg/kg/day PO in divided doses plus sirolimus load of 6 mg PO administered as soon as possible following transplantation, and then a maintenance dose of 2 mg PO once daily. Titrate the sirolimus dose to obtain a whole blood trough concentration of 16 to 24 ng/mL (chromatographic method) for the first year after transplantation; a target concentration of 12 to 20 ng/mL (chromatographic method) is recommended after year 1. Progressively withdraw cyclosporine over 4 to 8 weeks beginning 2 to 4 months following transplantation. Use of cyclosporine beyond 4 months should be considered only if the benefits outweigh the risks. According to renal transplant guidelines, use of sirolimus in combination with cyclosporine is effective in preventing rejection but is associated with enhanced nephrotoxicity and inferior outcomes, so significant reduction in the cyclosporine is advised.

    Adolescents who weigh < 40 kg and without a history of an acute allograft rejection episode or the presence of chronic allograft nephropathy on a renal biopsy

    Initially, up to 7 mg/kg/day PO in divided doses plus sirolimus load of 3 mg/m2 PO administered as soon as possible following transplantation, and then a maintenance dose of 1 mg/m2 PO once daily. Titrate the sirolimus dose to obtain a whole blood trough concentration of 16 to 24 ng/mL (chromatographic method) for the first year after transplantation; a target concentration of 12 to 20 ng/mL (chromatographic method) is recommended after year 1. Progressively withdraw cyclosporine over 4 to 8 weeks beginning 2 to 4 months following transplantation. Use of cyclosporine beyond 4 months should only be considered if the benefits outweigh the risks. According to renal transplant guidelines, use of sirolimus in combination with cyclosporine is effective in preventing rejection but is associated with enhanced nephrotoxicity and inferior outcomes, so significant reduction in the cyclosporine is advised.

    For kidney transplant rejection prophylaxis in combination with sirolimus and corticosteroids in patients who are considered high immunologic risk.
    NOTE: Black transplant recipients, repeat renal transplant recipients who lost a previous allograft for immunologic reason, or patients with high-panel reactive antibodies (PRA; peak PRA level greater than 80%) are considered high immunologic risk.
    NOTE: The protocol-specified target Cmin range for cyclosporine was 200 to 300 ng/mL up to week 2, 150 to 200 ng/mL for weeks 2 to 26, and 100 to 150 ng/mL for weeks 26 to 52, and for sirolimus was 10 to 15 ng/mL.
    Oral dosage
    Adults

    Initially, up to 7 mg/kg/day PO in divided doses plus sirolimus load of up to 15 mg PO administered on day 1 after transplantation, and then a maintenance dose of 5 mg PO once daily beginning on day 2; adjust the cyclosporine and sirolimus doses to achieve target whole blood trough concentrations. A minimum dose of 5 mg PO daily of prednisone is also needed, and antibody induction therapy may be used. According to renal transplant guidelines, use of sirolimus in combination with cyclosporine is effective in preventing rejection but is associated with enhanced nephrotoxicity and inferior outcomes, so significant reduction in the cyclosporine dosage is advised. Cyclosporine is indicated for use in combination with sirolimus and corticosteroids for the first year after transplantation. Safety and efficacy have not been established beyond 1 year. After 1 year, adjust the immunosuppression regimen as needed based on the patient's clinical status.

    Oral dosage
    Adults, Adolescents, and Children

    15 mg/kg PO as a single dose 4 to 12 hours before transplantation (this dosage can vary depending on the use of other immunosuppressives) in combination with corticosteroids. Doses of 10 to 14 mg/kg/day have been used, but according to Novartis, a 1994 survey in US transplant centers indicated a trend toward use of lower oral doses. Mean +/- SD initial doses were 9 +/- 3 mg/kg/day for renal transplant patients. In general, children may undergo the same dosing regimen as adults but often require and tolerate higher doses. Initial dosing of cyclosporine (Modified) can be given 4 to 12 hours before transplantation or postoperatively. In newly transplanted patients, the initial dosage of cyclosporine (Modified), is the same as the initial dosage of cyclosporine (Nonmodified). For maintenance therapy, the initial dosage can be continued, divided into 2 equal daily doses, and adjusted to achieve a predefined cyclosporine blood concentration. For cyclosporine (Nonmodified) a reduction of 5% weekly to 3 to 10 mg/kg/day is recommended after the first 1 to 2 weeks. Doses may be lower for cyclosporine (Modified). Cyclosporine blood concentration monitoring is necessary to appropriately monitor the patient. Renal transplant guidelines recommend a calcineurin inhibitor (CNI) such as cyclosporine and an antiproliferative agent such as mycophenolate with or without corticosteroids for initial maintenance immunosuppression. Of note, tacrolimus is suggested as the first-line CNI, and the CNI is suggested to be started before or at the time of transplantation rather than delayed until graft function onset. Guidelines also suggest that cyclosporine be continued rather than withdrawn during long-term maintenance therapy.

    Intravenous dosage
    Adults, Adolescents, and Children pre-transplantation

    5 to 6 mg/kg IV as a single dose 4 to 12 hours before transplantation. IV doses should be given as dilute solutions and administered by slow infusion over 2 to 6 hours. Renal transplant guidelines recommend a calcineurin inhibitor (CNI) such as cyclosporine and an antiproliferative agent plus or minus corticosteroids for initial maintenance immunosuppression. Of note, tacrolimus is suggested as the first-line CNI, and the CNI is suggested to be started before or at the time of transplantation rather than delayed until graft function onset.

    Adults, Adolescents, and Children posttransplantation

    5 to 6 mg/kg/day IV until able to tolerate and switch to PO dosage. Cyclosporine may be given as a continuous infusion during the immediate postoperative period.

    For the treatment of severe, plaque-type psoriasis in immunocompetent patients who failed to respond to at least one systemic therapy (e.g., PUVA, retinoids, methotrexate) or in patients for whom other systemic therapies are contraindicated or cannot be tolerated.
    Oral dosage (Cyclosporine, USP (Modified) FDA-approved)
    Adults

    The initial dose of cyclosporine (Modified), is 1.25 mg/kg PO twice daily (2.5 mg/kg/day PO). If significant clinical improvement is not observed after 4 weeks, the dose may be increased by 0.5 mg/kg/day PO every 2 weeks to a maximum of 4 mg/kg/day PO, administered as divided doses. However, according to the American Academy of Dermatology, doses up to 5 mg/kg/day PO are considered the customary maximum dose in psoriasis. Once a patient is adequately controlled and appears stable, the dose of cyclosporine should be reduced to the lowest dose that maintains an adequate response (plaques may not necessarily be totally cleared). If an adverse event occurs (e.g., hypertension, elevations in serum creatinine 25% above baseline, or other clinically significant laboratory abnormalities), a dosage reduction of 25% to 50% or, in some cases, discontinuation of therapy may be required. Patients generally show some improvement in clinical manifestations within 2 weeks. Satisfactory control and stabilization may take 12 to 16 weeks to achieve. Therapy should be discontinued if an adequate response is not observed after 6 weeks at 4 mg/kg/day or at the patient's maximum tolerated dose. In clinical trials, cyclosporine (Modified) doses at the lower end of the recommended dosage range were effective in maintaining a satisfactory response in 60% of patients. Doses below 2.5 mg/kg/day may also be effective. Continuous treatment for more than one year is not recommended. Upon stopping treatment with cyclosporine, relapse will occur in 50% of patients within 6 weeks. In the majority of patients, rebound disease does not occur after cessation of cyclosporine treatment; although, transformation of chronic plaque psoriasis to more severe forms of psoriasis has been reported.

    Oral dosage (Cyclosporine, USP (Nonmodified)†
    Adults

    In 1 study, eighty-one patients were randomly assigned to cyclosporine oral solution (Nonmodified) 3, 5, or 7.5 mg/kg/day PO or placebo for 16 weeks. Clinical response increased in a dose-related manner and all 3 doses of cyclosporine were statistically superior to the placebo vehicle. In another study, the ability of cyclosporine (CYA) to maintain remission was studied. Patients who demonstrated a decrease in body surface involvement of at least 70% on a dose of 5 mg/kg/day for 16 weeks were randomized to either placebo, CYA 1.5 mg/kg/day, or CYA 3 mg/kg/day for 24 weeks. By the end of the study, 42% of patients in the high-dose group experienced a relapse compared to 84% in the placebo group.

    For the treatment of severe rheumatoid arthritis (RA) in patients unresponsive to conventional therapy, alone or in combination with methotrexate when the disease has not adequately responded to methotrexate.
    For early rheumatoid arthritis (RA).
    Oral dosage
    Adults

    In a 42-month prospective study, 103 early RA patients (without prior use of disease-modifying drugs) were randomized to cyclosporine 2.5 mg/kg/day PO or methotrexate; all patients also received prednisone. Patients in both groups responded to therapy; however, no significant radiological worsening was found in patients treated with cyclosporine as compared to those treated with methotrexate. The authors concluded that cyclosporine may delay radiological disease progression and may inhibit joint damage in early RA patients.

    Oral dosage (Cyclosporine, USP (Modified) FDA-approved)
    Adults

    The initial dose of cyclosporine (Modified), is 1.25 mg/kg PO twice daily (2.5 mg/kg/day PO). Salicylates, NSAIDs, and oral corticosteroids may be continued. If insufficient benefit is seen and tolerability is good, the dose may be increased by 0.5 to 0.75 mg/kg/day PO after 8 weeks and again after 12 weeks to a maximum of 4 mg/kg/day. If an adverse event occurs (e.g., hypertension or elevations in serum creatinine 30% above baseline) a dosage reduction of 25% to 50% or, in some cases, discontinuation of therapy may be required. Discontinue therapy if no benefit is seen by 16 weeks. Cyclosporine has been shown to provide clinical benefit when used in combination with methotrexate in patients not responding to methotrexate monotherapy. Most patients can tolerate cyclosporine (Modified) at doses of less than 3 mg/kg/day PO when combined with methotrexate doses of up to 15 mg/week PO. A steroid-sparing effect as well as decreased doses of methotrexate are seen during combination therapy with cyclosporine for RA. Recurrence of RA disease activity is generally apparent within 4 weeks of stopping cyclosporine therapy. Cyclosporine (Nonmodified) has also been used in the treatment of RA at a similar dosage.

    For the treatment of xerophthalmia by increasing tear production in patients whose tear production is presumed to be suppressed due to ocular inflammation associated with keratoconjunctivitis sicca.
    Ophthalmic dosage
    Adults and Adolescents >= 16 years

    Instill 1 drop into affected eye(s) twice daily approximately 12 hours apart. Artificial tears may be used concurrently, allowing a 15-minute interval between administration of products. In clinical trials, administration of ophthalmic cyclosporine resulted in significant improvement in reducing objective (corneal staining and categorized Schirmer values) and subjective (i.e., blurred vision, need for concomitant artificial tears, and physician's evaluation) signs of dry eye disease. Benefit was shown across all severities of dry eye disease and was not associated with significant local or systemic toxicity. Increased tear production was not seen in patients currently taking topical anti-inflammatory drugs or using punctal plugs.

    For the treatment of heart transplant rejection prophylaxis, liver transplant rejection prophylaxis, and the treatment of acute and chronic graft-versus-host disease (GVHD)† and graft-versus-host disease (GVHD) prophylaxis†.
    NOTE: In general, children may undergo the same dosing regimen as adults but often require and tolerate higher doses.
    NOTE: In the prevention of organ transplant rejection, cyclosporine is intended to be used in combination with corticosteroid therapy.
    Oral dosage
    Adults, Adolescents, and Children

    15 mg/kg PO as a single dose 4 to 12 hours before transplantation (this dosage can vary depending on the transplanted organ and the use of other immunosuppressives). Doses of 14 to 18 mg/kg/day have been used, but according to Novartis, a 1994 survey in US transplant centers indicated a trend toward use of lower oral doses. Mean +/- SD initial doses were 8 +/- 4 mg/kg/day for liver transplant patients and 7 +/- 3 mg/kg/day for heart transplant patients. Initial dosing of cyclosporine (Modified) can be given 4 to 12 hours before transplantation or postoperatively. In newly transplanted patients, the initial dosage of cyclosporine (Modified), is the same as the initial dosage of cyclosporine (Nonmodified). For maintenance therapy, the initial dosage can be continued, divided into 2 equal daily doses and adjusted to achieve a predefined cyclosporine blood concentration. For cyclosporine (Nonmodified), a reduction of 5% weekly to 5 to 10 mg/kg/day is recommended after the first 1 or 2 weeks. Doses may be lower for cyclosporine (Modified). Cyclosporine blood concentration monitoring is necessary to appropriately monitor the patient. Heart transplant guidelines recommend use of the microemulsion formulation because of more favorable pharmacokinetic features as compared with the oil-based compound. Cyclosporine monotherapy with early corticosteroid withdrawal may be considered in highly selected patients. Also, seek lower cyclosporine concentrations when used with mycophenolate mofetil as compared with azathioprine because use of lower cyclosporine concentrations with mycophenolate mofetil is safe and is associated with lower rejection rates and improved renal function. Trial data suggest that tacrolimus-based regimens may be associated with lower rejection rates but not with superior survival as compared with cyclosporine-based regimens. Also, maintenance therapy for all pediatric heart transplant recipients should include a calcineurin inhibitor such as cyclosporine.

    For the treatment of severe atopic dermatitis†.
    Oral dosage
    Adults, Adolescents, and Children >= 2 years

    Several studies have demonstrated cyclosporine at doses of 5 mg/kg/day to be effective in the treatment of severe atopic dermatitis. It has generally been studied as short-term therapy (i.e., 6 to 8 weeks); however, there are reports describing long-term therapy in adults and multiple short courses (12-week cycles with at least 7 days between each course of therapy) vs. continuous therapy (therapy for 1 year) in children. The usefulness of cyclosporine is limited by side effects and rapid relapse of symptoms following discontinuation of therapy.

    For the treatment of severe aplastic anemia†.
    Oral dosage
    Adults and Children

    In appropriate patients (i.e., those not immediate candidates for bone marrow transplantation), the combination of cyclosporine (Nonmodified), at doses of 12 mg/kg/day PO in adults or 15 mg/kg/day PO in children and antithymocyte globulin (ATG) has become the standard of care treatment for aplastic anemia. While the response rate to combination therapy is good, relapses are common. Treatment regimens may also include corticosteroids, hematopoietic colony-stimulating factors, and/or cyclophosphamide. In a randomized trial, cyclosporine alone was compared to the combination of cyclosporine and ATG in patients with nonsevere aplastic anemia. In the cyclosporine group, the overall response rate was 46%, with 23% complete responses. A significantly higher response rate of 74% with 57% complete responses was seen with the combination treatment. A high-dose ATG regimen in combination with corticosteroids and cyclosporine resulted in a 78% response rate among patients who had not received previous therapy with ATG or cyclosporine. The cyclosporine regimen consisted of cyclosporine (Nonmodified) 12 mg/kg/day in adults or 15 mg/kg/day in children for 14 days, then cyclosporine doses were adjusted to maintain cyclosporine levels between 200 and 400 ng/mL. The majority of patients who relapsed responded to additional courses of immunosuppressive therapy. Actual survival at 1 and 2 years was 86% and 72%, respectively.

    For the treatment of chronic immune thrombocytopenia/idiopathic thrombocytopenic purpura (ITP)†.
    Oral dosage
    Adults

    A dosage of cyclosporine (Nonmodified) 1.25 to 2.5 mg/kg PO twice daily has been recommended. Cyclosporine should only be considered a last choice due to its long-term toxicity.

    For the treatment of myasthenia gravis† in patients who are poorly controlled with cholinesterase inhibitor therapy.
    Oral dosage
    Adults

    An initial dose of cyclosporine (Nonmodified), 5 mg/kg/day PO in 2 divided doses has been recommended. Increase as needed according to response and monitoring of trough cyclosporine concentrations.

    For the treatment of psoriatic arthritis†.
    Oral dosage
    Adults

    In a small prospective, randomized study, cyclosporine and methotrexate were compared for the treatment of psoriatic arthritis. Cyclosporine (Nonmodified) was initially given in a dose of 3 mg/kg/day PO. The dosage could be increased in increments of 1 mg/kg/day at monthly intervals (maximum dosage is 5 mg/kg/day). Conversely, the dosage was decreased by 1 mg/kg/day if azotemia, elevated hepatic enzymes, or hypertension was observed. Methotrexate was given orally in low doses in the comparative group. After 12 months of study, no differences were seen in the clinical response to either drug; however, only a total of 23 subjects were included in the 12-month evaluation. Hepatic transaminases were significantly higher in the methotrexate group.

    For the treatment of lupus nephritis† in patients with systemic lupus erythematosus (SLE) unresponsive to conventional therapy, or for the treatment of children with idiopathic nephrotic syndrome†.
    Oral dosage
    Adults

    2.5 mg/kg/day PO in 2 divided doses titrated to a blood trough of 80 to 150 ng/mL (Neoral) led to a complete response in 2 patients, a partial response in 4 patients, and no change in 3 patients with active lupus nephritis refractory to standard treatment with high-dose corticosteroids with or without immunosuppressive drugs. Cyclosporine is not a recommended induction agent, and consensus was not reached regarding the use of calcineurin inhibitors in patients whose nephritis fails to improve or worsens after 6 months of induction with cyclophosphamide, mycophenolate mofetil, or both. Cyclosporine may be a consideration if nephritis is worsening in patients treated for 3 months with glucocorticoids plus either cyclophosphamide or mycophenolate mofetil.]

    Children with steroid-dependent idiopathic nephrotic syndrome

    In a small series, 7 children with minimal change nephrotic syndrome (MCNS) and 7 children with focal segmental glomerulosclerosis (FSGS) were treated with cyclosporine (Nonmodified), 100 mg/m2/day PO divided into 2 doses. Doses were adjusted as necessary to achieve trough concentrations of 200 to 400 ng/mL. A satisfactory response was seen in MCNS, whereas the response in FSGS was poor. The authors concluded that the recommended dose of cyclosporine (nonmodified) for MCNS in children is 150 mg/m2/day PO.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    Maximum dosage for systemic formulations is dependent on indication, route of therapy, and cyclosporine serum concentrations; 2 drops/day per affected eye ophthalmic emulsion.

    Elderly

    Maximum dosage for systemic formulations is dependent on indication, route of therapy, and cyclosporine serum concentrations; 2 drops/day per affected eye ophthalmic emulsion.

    Adolescents

    >= 16 years: Maximum dosage for systemic formulations is dependent on indication, route of therapy, and cyclosporine serum concentrations; 2 drops/day per affected eye ophthalmic emulsion.
    < 16 years: Maximum dosage for systemic formulations is dependent on indication, route of therapy, and cyclosporine serum concentrations; safety and efficacy have not been established for the ophthalmic emulsion.

    Children

    Maximum dosage for systemic formulations is dependent on indication, route of therapy, and cyclosporine serum concentrations; safety and efficacy have not been established for the ophthalmic emulsion.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    While specific guidelines are not available, patients with hepatic impairment may require a dosage reduction of cyclosporine. Cyclosporine concentrations should be closely monitored in these patients.

    Renal Impairment

    Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

    ADMINISTRATION

    Oral Administration

    Administer on a consistent schedule with regard to time of day and in relation to meals.
    Cyclosporine, USP (Nonmodified) (Sandimmune) is not bioequivalent with cyclosporine, USP (Modified) (e.g., Neoral, Gengraf, SangCya). Cyclosporine, USP (Nonmodified) should not be used interchangeably with cyclosporine, USP (Modified) products without physician supervision.
    Oral solution and liquid-filled capsules of any one named brand are bioequivalent and direct conversions can be made between dosage forms of the brand used.

    Oral Solid Formulations

    Cyclosporine capsules, USP (Nonmodified), and Cyclosporine capsules, USP (Modified):
    Swallow capsules whole; do not crush or chew. Do not administer with grapefruit juice because grapefruit juice affects cyclosporine metabolism.

    Oral Liquid Formulations

    Cyclosporine oral solution, USP (Modified):
    Administer using calibrated measuring device supplied by the manufacturer for accurate measurement of the dose.
    To make more palatable, mix in orange or apple juice in a glass container, but be consistent in the diluents used. Do not administer with grapefruit juice because grapefruit juice affects cyclosporine metabolism. Neoral oral solution diluted with orange juice or apple juice is bioequivalent to Neoral oral solution diluted in water. The effect of milk on the bioavailability of cyclosporine (administered as Neoral oral solution) has not been evaluated.
    Stir well and administer immediately; do not allow diluted solutions to stand. Rinse the container with more fluid and administer to ensure total dose is given.
    Following use, dry the measuring device with a clean towel and replace protective cover; do not rinse the measuring device with water or other cleaning agents. If the syringe requires cleaning, it must be completely dry before resuming use.
     
    Cyclosporine oral solution, USP (Nonmodified):
    Administer using calibrated measuring device supplied by the manufacturer for accurate measurement of the dose.
    To make more palatable, mix with milk, chocolate milk, or orange juice in a glass container. The fluid should preferably be at room temperature when cyclosporine is added. Do not administer with grapefruit juice because grapefruit juice affects cyclosporine metabolism.
    Stir well and administer immediately. Rinse the container with more fluid and administer to ensure total dose is given. Following use, dry the measuring device with a clean towel and replace protective cover; do not rinse the measuring device with water or other cleaning agents.

    Injectable Administration

    Due to the risk of anaphylaxis, use intravenous route only in patients unable to take cyclosporine orally.
    Avoid use of polyvinyl chloride containers and administration sets during administration.
    Prior to administration, invert the bottle several times to ensure that cyclosporine is thoroughly dispersed and to avoid bolus administration.
    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.

    Intravenous Administration

    Dilution:
    Dilute the concentrate for injection by adding 1 mL (50 mg) of cyclosporine to 20—100 mL of 0.9% Sodium Chloride injection or 5% Dextrose injection. Prepare injections in glass containers to avoid possible leaching of diethylhexylphthalate (DEHP) from polyvinyl chloride (PVC) containers into the injection.
    Diluted solutions are stable for 24 hours.
     
    Intravenous (IV) infusion:
    Infuse IV slowly over 2—6 hours using an infusion pump. Infusion periods of up to 24 hours have been used. Do not administer rapidly as acute nephrotoxicity, flushing, and nausea may result.

    Ophthalmic Administration

    Use immediately after opening the single-use vial; discard any remaining contents after use.
    Invert the unit dose bottle a few times to obtain a uniform, white, opaque emulsion before using.
    To avoid contamination, advise patient not allow the tip of the vial to touch the eye or any surface. To avoid potential injury to the eye, advise patients not to touch the vial tip to their eye.
    Do not administer while wearing contact lenses. Remove contact lenses prior to administration. Lenses may be reinserted 15 minutes after administration.
    May be used concomitantly with artificial tears, allowing 15 minutes between administration of the products.

    STORAGE

    Generic:
    - Discard unused portion. Do not store for later use.
    - Protect from light
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Gengraf :
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    Neoral:
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    Restasis:
    - Store between 59 to 77 degrees F
    Sandimmune:
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    SangCya:
    - Avoid exposure to heat
    - Protect from freezing
    - Protect from moisture
    - Store at controlled room temperature (between 68 and 77 degrees F)
    - Store in original container

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Cyclosporine capsules and oral solution, USP (Modified), have increased bioavailability in comparison to cyclosporine capsules and oral solution, USP (Nonmodified); these products are not bioequivalent and cannot be used interchangeably without physician supervision. For a given trough concentration, cyclosporine exposure will be greater with the modified formulation than with the nonmodified formulation. If a patient who is receiving exceptionally high doses of cyclosporine nonmodified is converted to a cyclosporine modified formulation, particular caution should be exercised. Cyclosporine whole blood concentrations should be monitored in transplant and rheumatoid arthritis patients taking the cyclosporine modified formulation to avoid toxicity due to high concentrations. Cyclosporine whole blood concentrations do not correlate well with either response or incidence of renal dysfunction in psoriatic patients. Dose adjustments should be made in transplant patients to minimize possible organ rejection due to low cyclosporine levels. Comparison of blood concentrations in the published literature with blood concentrations obtained using current assay methods must be done with detailed knowledge of the assay methods employed.

    Fungal infection, herpes infection, immunosuppression, infection, lymphoma, neoplastic disease, psoriasis, requires a specialized care setting, requires an experienced clinician, varicella, viral infection

    Cyclosporine therapy requires an experienced clinician who is knowledgeable in immunosuppressive therapy or organ transplantation. Increased susceptibility to infection and possible development of neoplastic disease, especially lymphoma or skin malignancies, may result from immunosuppression. The increased risk appears related to the intensity and duration of immunosuppression rather than to the use of specific agents. Patients should not be treated concurrently with cyclosporine and PUVA or UVB, other radiation therapy, or other immunosuppressive agents because of the possibility of excessive immunosuppression and risk of malignancies. Patients should also be warned to avoid excessive sun exposure and wear sun protection. Patients should be evaluated before and during treatment for the presence of malignancies, and should be treated with cyclosporine only after complete resolution of suspicious lesions. Additionally, psoriasis patients with abnormal renal function, uncontrolled hypertension, or malignancies should not receive cyclosporine. Cyclosporine administration requires a specialized care setting with facilities equipped and staffed with adequate laboratory and supportive medical services. Bacterial, viral, protozoal, and fungal infection occur commonly during immunosuppressive therapy and can be fatal. Reactivation of a latent viral infection, especially herpes infection or varicella, can occur with immunosuppressive therapy. Patients should be instructed to report signs of infection promptly.

    Herpes simplex keratitis (dendritic keratitis), ocular infection

    Cyclosporine ophthalmic emulsion is contraindicated in patients with an active ocular infection. Cyclosporine ophthalmic emulsion has not been studied in patients with a history of herpes simplex keratitis (dendritic keratitis). No increase in the incidence of bacterial or fungal ocular infections was reported following the administration of cyclosporine ophthalmic emulsion.

    Radiation therapy, skin cancer, sunlight (UV) exposure

    All patients taking cyclosporine need to avoid excess sunlight (UV) exposure because of an increased risk for skin malignancies. In patients with psoriasis treated with Neoral or Gengraf, the concomitant use of PUVA or UVB therapy, methotrexate or other immunosuppressive agents, coal tar, or radiation therapy is contraindicated. Also, psoriasis patients previously treated with PUVA and to a lesser extent, methotrexate or other immunosuppressive agents, UVB, coal tar, or radiation therapy are at increased risk of developing skin cancer when taking cyclosporine. The relative risk of malignancies is comparable to that observed in psoriasis patients treated with other immunosuppressive therapies. Patients should be thoroughly evaluated before and during cyclosporine treatment for the presence of skin cancer remembering that psoriatic plaques may hide malignant lesions. Skin lesions not typical of psoriasis should be biopsied before starting cyclosporine treatment. Patients should be treated with cyclosporine only after complete resolution of suspicious lesions and only if there are no other treatment options.

    Nephrotoxicity, renal disease, renal failure, renal impairment

    Cyclosporine in recommended dosages can cause nephrotoxicity. The risk of developing cyclosporine-induced nephrotoxicity increases with increasing doses of cyclosporine and duration of cyclosporine therapy. Neoral or Gengraf are contraindicated in patients with rheumatoid arthritis and psoriasis if abnormal renal function (such as renal disease, renal impairment, or renal failure) is present. All patients receiving nephrotoxic drugs concomitantly with systemic cyclosporine should be carefully monitored for worsening renal function. In all patients, serum creatinine should be monitored closely. It is not unusual for the serum creatinine and BUN to be elevated during systemic cyclosporine therapy for transplant rejection prophylaxis. The elevation of serum creatinine and BUN in renal transplant patients does not necessarily indicate rejection, and each patient must be fully evaluated before dosage adjustment is initiated. If patients are not monitored properly and doses are not adjusted correctly, systemic cyclosporine therapy can be associated with the occurrence of structural kidney damage and persistent renal dysfunction. In psoriasis and rheumatoid arthritis patients, serum creatinine and BUN should be monitored every 2 weeks during the initial 3 months of cyclosporine therapy and then monthly if the patient is stable. If the serum creatinine is >= 25% above the rheumatoid arthritis or psoriasis patient's baseline, the level should be repeated within 2 weeks. If the change remains >= 25% above baseline, the cyclosporine dose should be reduced by 25—50%. If at any time the serum creatinine increases by >= 50% above baseline, cyclosporine dosage should be reduced by 25—50%. Cyclosporine should be discontinued if reversibility (within 25% of baseline) of the serum creatinine is not achieved after two dosage reductions. It is recommended to monitor the serum creatinine after a dosage increase or addition of a NSAID during cyclosporine treatment.

    Hyperkalemia, hypertension

    Systemic cyclosporine is contraindicated for use in patients with either psoriasis or rheumatoid arthritis who have uncontrolled hypertension. Because of its effects on the sympathetic nervous system, cyclosporine can elevate blood pressure. The risk of hypertension increases with increasing dose and duration of cyclosporine therapy. In any patient with treated hypertension prior to initiating systemic cyclosporine therapy, adjust the antihypertensive medication to control hypertension that may occur while receiving cyclosporine. Mild to moderate hypertension is more common than severe hypertension, and the incidence decreases over time. In renal, heart, or liver transplant patients treated with systemic cyclosporine, antihypertensive therapy may be required. However, since systemic cyclosporine may cause hyperkalemia, do not use potassium-sparing diuretics. Calcium-channel blockers, while effective treatment for cyclosporine-induced hypertension, may affect cyclosporine metabolism. Perform blood pressure measurements on at least two occasions to establish a baseline prior to beginning cyclosporine therapy in rheumatoid arthritis and psoriasis patients. After initiation of systemic cyclosporine treatment in rheumatoid arthritis and psoriasis patients, monitor blood pressure measurements every 2 weeks during the initial 3 months and then monthly once the patient is stable. In rheumatoid arthritis patients, it is recommended to monitor blood pressure after a dosage increase of NSAIDs. In psoriasis or rheumatoid arthritis patients, reduce the cyclosporine dosage by 25—50% if hypertension develops. If hypertension persists, further reduce the dose of cyclosporine or control blood pressure with antihypertensive agents. In most cases, blood pressure returns to baseline once cyclosporine is discontinued.

    Electrolyte imbalance

    Monitoring of serum electrolytes is recommended during systemic cyclosporine therapy due to electrolyte imbalance observed during therapy.

    Polyoxyethylated castor oil hypersensitivity

    Hypersensitivity reactions during therapy with cyclosporine, although infrequent, occasionally can be severe. Anaphylaxis has been reported following IV administration and is believed to be related to the polyoxyethylated vehicle (polyoxyl 35 castor oil, Cremophor EL). Patients with a history of hypersensitivity to IV phytonadione or IV teniposide should receive IV cyclosporine cautiously. All three of these parenteral agents contain polyoxyethylated fatty acid derivatives or polyoxyethylated castor oil (Cremophor EL). Patients with known polyoxyethylated castor oil hypersensitivity should not receive IV cyclosporine or should receive it cautiously with premedication.

    Children, infants

    Although no adequate and well-controlled trials have been completed in children and infants, transplant patients as young as one year of age have received systemic cyclosporine with no unusual adverse reactions. The safety and efficacy of systemic cyclosporine in children with juvenile rheumatoid arthritis or psoriasis below the age of 18 have not been established. The alcohol content of cyclosporine should be taken into account in pediatric patients: for a patient weighing 70 kg, the maximum daily oral dose delivers approximately 1 gram of alcohol (approximately 6% of the amount of alcohol contained in a standard drink), while the daily IV dose would deliver approximately 15% of the amount of alcohol contained in a standard drink. The safety and efficacy of cyclosporine ophthalmic emulsion have not been established in pediatric patients < 16 years of age.

    Pregnancy

    The oral and intravenous formulations of cyclosporine are classified as FDA pregnancy risk category C. Use of these systemic formulations during pregnancy should only be considered if the potential benefits to the mother justify the potential risks to the fetus; consider discontinuation of cyclosporine therapy in psoriasis patients. Prior to drug administration, females of childbearing age should be counseled about the potential risks of cyclosporine therapy and about appropriate contraceptive measures. Ophthalmic drops do not produce detectable concentrations of cyclosporine in the blood; thus maternal use of this formulation is not expected to result in fetal drug exposure. There are no adequate and well-controlled studies of cyclosporine during pregnancy. In animal models, cyclosporine has been shown to be embryotoxic and fetotoxic when given in maternally toxic doses. In pregnant transplant recipients who are being treated with immunosuppressants, the risk of premature births is increased. Outcomes of 116 pregnancies in women (mostly transplant patients) receiving cyclosporine throughout the entire gestational period showed premature birth (gestational period of 28 to 36 weeks) in 47% and low birth weight for gestational age in 28% of pregnancies. Sixteen fetal losses occurred. Most of the pregnancies were complicated by disorders including preeclampsia, eclampsia, premature labor, abruptio placentae, oligohydramnios, Rh incompatibility and fetoplacental dysfunction. Seven malformations were reported in 5 viable infants and in 2 cases of fetal loss. Neonatal complications occurred in 27%. A limited number of observations in children up to approximately 7 years of age exposed to cyclosporine in utero is available. Renal function and blood pressure in these children were normal. Additionally, for an adult weighing 70 kg, the maximum daily oral dose of cyclosporine would deliver about 1 gram of alcohol (approximately 6% of the amount of alcohol contained in a standard drink), while the daily IV dose would deliver approximately 15% of the amount of alcohol contained in a standard drink.

    Breast-feeding

    When administered systemically, cyclosporine is excreted into breast milk. The American Academy of Pediatrics considers cyclosporine a cytotoxic drug that may interfere with the cellular metabolism of a nursing infant. Cyclosporine preparations also contain ethanol, which will be present in human milk at levels similar to that found in maternal serum. After opthalmic administration of cyclosporine emulsion, blood concentrations are undetectable, making it unlikely that a clinically significant amount of drug would be excreted into breast milk. Consider the benefits of breast-feeding, the risk of infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    Geriatric

    Geriatric patients receiving systemic cyclosporine should be monitored with particular care. These patients are more likely to develop systolic hypertension and more likely to show elevated serum creatinine >= 50% above baseline after 3—4 months of cyclosporine therapy. No overall difference in safety or effectiveness of cyclosporine ophthalmic emulsion has been observed between elderly and younger patients.

    Alcoholism, biliary tract disease, hepatic disease, jaundice

    Hepatic disease can affect the elimination of cyclosporine and necessitate lower doses. In addition, cyclosporine can induce cholestasis and hyperbilirubinemia. Since bile salts are essential for the absorption of cyclosporine (Nonmodified), patients with biliary tract disease, jaundice, or patients who have recently received a liver transplant may have poor absorption of this formulation of cyclosporine. Cyclosporine (Modified) is not as dependent upon bile salts for absorption and may be beneficial in this patient population. Patients with hepatic disease, epilepsy, or alcoholism should be aware of the alcohol content of cyclosporine. For a patient weighing 70 kg, the maximum daily oral dose would deliver about 1 gram of alcohol (approximately 6% of the amount of alcohol contained in a standard drink); the daily intravenous dose would deliver approximately 15% of the amount of alcohol contained in a standard drink.

    Gout, hyperuricemia

    Hyperuricemia has occurred in 84% of renal allograft patients receiving systemic cyclosporine versus 30% of those receiving azathioprine. Gout developed in 7% of patients receiving systemic cyclosporine. Serum uric acid concentrations should be monitored carefully when cyclosporine therapy is initiated in patients with a known history of gout.

    Encephalopathy, hypomagnesemia

    Cyclosporine-induced encephalopathy has been associated with the following risk factors in many but not all cases: hypertension, hypomagnesemia, hypocholesterolemia, high-dose corticosteroids, high cyclosporine blood concentrations, and graft-versus-host disease. The changes in most cases have been reversible upon discontinuation of cyclosporine, and in some cases, improvement was noted after reduction of the dose. It appears patients receiving liver transplants are more susceptible to encephalopathy than those patients receiving kidney transplants.

    Vaccination

    Patients receiving any vaccination during cyclosporine therapy or in the 2 weeks prior to starting therapy should be considered unimmunized and should be revaccinated at least 3 months after discontinuation of therapy. Those undergoing immunosuppressive therapy should not be exposed to others who have recently received the oral poliovirus vaccine (OPV). Measles-mumps-rubella (MMR) vaccination is not contraindicated for the close contacts of immunocompromised patients, including health care professionals. Passive immunoprophylaxis with immune globulins may be indicated for immunocompromised persons instead of, or in addition to, vaccination. When exposed to a vaccine-preventable disease such as measles, severely immunocompromised children should be considered susceptible regardless of their vaccination history.

    Contact lenses

    Cyclosporine ophthalmic emulsion should not be administered while wearing contact lenses. Patients with decreased tear production typically should not wear contact lenses. If contact lenses are worn, they should be removed prior to administration of the drug. Lenses may be reinserted 15 minutes following administration of cyclosporine ophthalmic emulsion.

    ADVERSE REACTIONS

    Severe

    bronchospasm / Rapid / 5.0-6.5
    seizures / Delayed / 1.0-5.0
    hyperkalemia / Delayed / 0-3.0
    eczema vaccinatum / Delayed / 0-3.0
    peptic ulcer / Delayed / 0-3.0
    angioedema / Rapid / 0-3.0
    heart failure / Delayed / 0-3.0
    myocardial infarction / Delayed / 0-3.0
    bone fractures / Delayed / 0-3.0
    hearing loss / Delayed / 0-2.0
    anaphylactoid reactions / Rapid / 0.1-0.1
    azotemia / Delayed / Incidence not known
    renal tubular necrosis / Delayed / Incidence not known
    hemolytic anemia / Delayed / Incidence not known
    hemolytic-uremic syndrome / Delayed / Incidence not known
    thrombosis / Delayed / Incidence not known
    hepatic failure / Delayed / Incidence not known
    papilledema / Delayed / Incidence not known
    visual impairment / Early / Incidence not known
    GI bleeding / Delayed / Incidence not known
    pancreatitis / Delayed / Incidence not known
    leukoencephalopathy / Delayed / Incidence not known
    acute respiratory distress syndrome (ARDS) / Early / Incidence not known
    pulmonary edema / Early / Incidence not known

    Moderate

    hypertension / Early / 8.0-53.0
    gingival hyperplasia / Delayed / 2.0-16.0
    hypertriglyceridemia / Delayed / 15.0-15.0
    edema / Delayed / 0-15.0
    elevated hepatic enzymes / Delayed / 4.0-7.0
    hyperbilirubinemia / Delayed / 1.0-7.0
    stomatitis / Delayed / 5.0-7.0
    dyspnea / Early / 1.0-6.5
    leukopenia / Delayed / 0-6.0
    hypomagnesemia / Delayed / 4.0-6.0
    depression / Delayed / 1.0-6.0
    secondary malignancy / Delayed / 0-6.0
    chest pain (unspecified) / Early / 1.0-6.0
    conjunctival hyperemia / Early / 1.0-5.0
    epiphora / Early / 1.0-5.0
    blurred vision / Early / 1.0-5.0
    hyperuricemia / Delayed / 0-3.0
    anemia / Delayed / 0-3.0
    lymphadenopathy / Delayed / 0-3.0
    bleeding / Early / 0-3.0
    hypercholesterolemia / Delayed / 0-3.0
    peripheral neuropathy / Delayed / 0-3.0
    confusion / Early / 0-3.0
    constipation / Delayed / 0-3.0
    gastritis / Delayed / 0-3.0
    esophagitis / Delayed / 0-3.0
    dysphagia / Delayed / 0-3.0
    glossitis / Early / 0-3.0
    hot flashes / Early / 0-3.0
    cataracts / Delayed / 0-3.0
    urinary incontinence / Early / 0-3.0
    hematuria / Delayed / 0-3.0
    diabetes mellitus / Delayed / 0-3.0
    hypoglycemia / Early / 0-3.0
    goiter / Delayed / 0-3.0
    migraine / Early / 0-3.0
    candidiasis / Delayed / 1.0-2.9
    conjunctivitis / Delayed / 0-2.0
    hyperglycemia / Delayed / 0-2.0
    skin ulcer / Delayed / 1.0-1.0
    bullous rash / Early / 1.0-1.0
    psoriasis / Delayed / 0-1.0
    dysuria / Early / 1.0-1.0
    hyperchloremic acidosis / Delayed / Incidence not known
    gout / Delayed / Incidence not known
    metabolic acidosis / Delayed / Incidence not known
    thrombocytopenia / Delayed / Incidence not known
    jaundice / Delayed / Incidence not known
    hepatitis / Delayed / Incidence not known
    cholestasis / Delayed / Incidence not known
    hyperlipidemia / Delayed / Incidence not known
    hyperesthesia / Delayed / Incidence not known
    ataxia / Delayed / Incidence not known
    encephalopathy / Delayed / Incidence not known
    dysarthria / Delayed / Incidence not known
    BK virus-associated nephropathy / Delayed / Incidence not known
    infertility / Delayed / Incidence not known
    hyperprolactinemia / Delayed / Incidence not known
    sinus tachycardia / Rapid / Incidence not known
    ocular inflammation / Early / Incidence not known
    wheezing / Rapid / Incidence not known

    Mild

    tremor / Early / 7.0-55.0
    hirsutism / Delayed / 21.0-45.0
    headache / Early / 2.0-25.0
    infection / Delayed / 0-24.7
    nausea / Early / 2.0-23.0
    hypertrichosis / Delayed / 6.6-19.0
    ocular irritation / Rapid / 17.0-17.0
    abdominal pain / Early / 0-15.0
    diarrhea / Early / 3.0-13.0
    rash (unspecified) / Early / 7.0-12.0
    dyspepsia / Early / 2.2-12.0
    muscle cramps / Delayed / 2.0-12.0
    paresthesias / Delayed / 1.0-11.0
    rhinitis / Early / 0-11.0
    vomiting / Early / 2.0-10.0
    influenza / Delayed / 0-9.9
    dizziness / Early / 1.0-8.0
    sinusitis / Delayed / 0-8.0
    cough / Delayed / 3.0-6.5
    acne vulgaris / Delayed / 1.0-6.0
    fatigue / Early / 3.0-6.0
    arthralgia / Delayed / 1.0-6.0
    flatulence / Early / 4.0-5.0
    pharyngitis / Delayed / 3.0-5.0
    flushing / Rapid / 0-5.0
    ocular pain / Early / 1.0-5.0
    ocular discharge / Delayed / 1.0-5.0
    foreign body sensation / Rapid / 1.0-5.0
    ocular pruritus / Rapid / 1.0-5.0
    arthropathy / Delayed / 4.0-5.0
    insomnia / Early / 1.0-4.0
    alopecia / Delayed / 3.0-4.0
    purpura / Delayed / 2.0-4.0
    gingivitis / Delayed / 1.0-4.0
    gynecomastia / Delayed / 0-4.0
    increased urinary frequency / Early / 1.0-4.0
    epistaxis / Delayed / 0-3.0
    anxiety / Delayed / 0-3.0
    libido decrease / Delayed / 0-3.0
    vertigo / Early / 0-3.0
    hypoesthesia / Delayed / 0-3.0
    libido increase / Delayed / 0-3.0
    emotional lability / Early / 0-3.0
    drowsiness / Early / 0-3.0
    urticaria / Rapid / 0-3.0
    pruritus / Rapid / 0-3.0
    xerosis / Delayed / 0-3.0
    appetite stimulation / Delayed / 0-3.0
    eructation / Early / 0-3.0
    xerostomia / Early / 0-3.0
    weight gain / Delayed / 0-3.0
    dysgeusia / Early / 0-3.0
    weight loss / Delayed / 0-3.0
    anorexia / Delayed / 0-3.0
    menstrual irregularity / Delayed / 1.0-3.0
    asthenia / Delayed / 0-3.0
    fever / Early / 1.0-3.0
    malaise / Early / 0-3.0
    myalgia / Early / 0-3.0
    tinnitus / Delayed / 0-3.0
    polyuria / Early / 0-3.0
    nocturia / Early / 0-3.0
    urinary urgency / Early / 0-3.0
    folliculitis / Delayed / 1.0-2.9
    hiccups / Early / 0-2.0
    musculoskeletal pain / Early / 0-2.0
    leukorrhea / Delayed / 1.0-1.0
    lethargy / Early / Incidence not known
    spermatogenesis inhibition / Delayed / Incidence not known
    night sweats / Early / Incidence not known
    weakness / Early / Incidence not known

    DRUG INTERACTIONS

    Abatacept: (Moderate) Concomitant use of immunosuppressives may potentially increase the risk of serious infection in abatacept treated patients. Advise patients taking abatacept to seek immediate medical advice if they develop signs and symptoms suggestive of infection.
    Acalabrutinib: (Major) Decrease the acalabrutinib dose to 100 mg PO once daily if coadministered with cyclosporine. Coadministration may result in increased acalabrutinib exposure and toxicity (e.g., infection, bleeding, and atrial arrhythmias). Acalabrutinib is a CYP3A4 substrate; cyclosporine is a moderate CYP3A4 inhibitor. In physiologically based pharmacokinetic (PBPK) simulations, the Cmax and AUC values of acalabrutinib were increased by 2- to almost 3-fold when acalabrutinib was coadministered with moderate CYP3A inhibitors.
    Acarbose: (Moderate) Cyclosporine has been reported to cause hyperglycemia; this effect appears to be dose-related and caused by direct beta-cell toxicity. Therefore, a pharmacodynamic interaction is possible. Monitor the blood glucose.
    Acetaminophen; Butalbital: (Major) Phenobarbital may induce cyclosporine metabolism, thereby increasing the clearance of cyclosporine. It is likely that other barbiturates would interact similarly with cyclosporine; however no supportive data are available. If phenobarbital is added to an existing cyclosporine regimen, monitor cyclosporine concentrations closely to avoid loss of clinical efficacy until a new steady-state concentration is achieved. Conversely, if phenobarbital is discontinued, cyclosporine concentrations could increase.
    Acetaminophen; Butalbital; Caffeine: (Major) Phenobarbital may induce cyclosporine metabolism, thereby increasing the clearance of cyclosporine. It is likely that other barbiturates would interact similarly with cyclosporine; however no supportive data are available. If phenobarbital is added to an existing cyclosporine regimen, monitor cyclosporine concentrations closely to avoid loss of clinical efficacy until a new steady-state concentration is achieved. Conversely, if phenobarbital is discontinued, cyclosporine concentrations could increase.
    Acetaminophen; Butalbital; Caffeine; Codeine: (Major) Phenobarbital may induce cyclosporine metabolism, thereby increasing the clearance of cyclosporine. It is likely that other barbiturates would interact similarly with cyclosporine; however no supportive data are available. If phenobarbital is added to an existing cyclosporine regimen, monitor cyclosporine concentrations closely to avoid loss of clinical efficacy until a new steady-state concentration is achieved. Conversely, if phenobarbital is discontinued, cyclosporine concentrations could increase.
    Acetazolamide: (Minor) Acetazolamide may increase serum cyclosporine concentrations. If cyclosporine and acetazolamide are to be coadministered, monitor the patient for cyclosporine toxicity.
    Acyclovir: (Moderate) Additive nephrotoxicity can occur if cyclosporine is administered with other nephrotoxic drugs such as acyclovir. Monitor renal function and fluid status carefully.
    Adalimumab: (Moderate) The safety and efficacy of adalimumab in patients with immunosuppression have not been evaluated. Patients receiving cyclosporine along with adalimumab may be at a greater risk of developing an infection.
    Adefovir: (Moderate) Chronic coadministration of adefovir with nephrotoxic drugs, such as cyclosporine, may increase the risk of developing nephrotoxicity, even in patients who have normal renal function. Cyclosporine itself can cause structural kidney damage. Monitor renal function and fluid status carefully during co-use.
    Afatinib: (Major) If the concomitant use of cyclosporine and afatinib is necessary, consider reducing the afatinib dose by 10 mg per day if the original dose is not tolerated; resume the previous dose of afatinib as tolerated after discontinuation of cyclosporine. Afatinib is a P-glycoprotein (P-gp) substrate and inhibitor in vitro, and cyclosporine is a P-gp inhibitor; coadministration may increase plasma concentrations of afatinib. Administration of another P-gp inhibitor, ritonavir (200 mg twice daily for 3 days), 1 hour before afatinib (single dose) increased the afatinib AUC and Cmax by 48% and 39%, respectively; there was no change in the afatinib AUC when ritonavir was administered at the same time as afatinib or 6 hours later. In healthy subjects, the relative bioavailability for AUC and Cmax of afatinib was 119% and 104%, respectively, when coadministered with ritonavir, and 111% and 105% when ritonavir was administered 6 hours after afatinib. The manufacturer of afatinib recommends permanent discontinuation of therapy for severe or intolerant adverse drug reactions at a dose of 20 mg per day, but does not address a minimum dose otherwise.
    Albiglutide: (Moderate) Cyclosporine has been reported to cause hyperglycemia. It may have direct beta-cell toxicity; the effects may be dose-related. Patients should be monitored for worsening of glycemic control if therapy with cyclosporine is initiated in patients receiving antidiabetic agents, including incretin mimetics.
    Aldesleukin, IL-2: (Moderate) Aldesleukin may cause nephrotoxicity. Concurrent administration of drugs possessing nephrotoxic effects with Aldesleukin, such as cyclosporine, may increase the risk of kidney dysfunction. In addition, reduced kidney function secondary to Aldesleukin treatment may delay elimination of concomitant medications and increase the risk of adverse events from those drugs.
    Alefacept: (Severe) Patients receiving other immunosuppressives should not receive concurrent therapy with alefacept; there is the possibility of excessive immunosuppression and subsequent risks of infection and other serious side effects. In clinical efficacy trials, concurrent treatment of alefacept with these types of agents did not occur. The duration of the period following treatment with alefacept that is appropriate before starting other immunosuppressive therapy has not been evaluated.
    Aliskiren: (Major) Concomitant use of aliskiren with cyclosporine is not recommended because of significantly increased aliskiren blood concentrations and an increase in the number and/or intensity of adverse events such as headache, hot flushes, nausea, vomiting, and somnolence. Cyclosporine is an inhibitor of CYP3A4 and P-glycoprotein (P-gp). Aliskiren is a substrate of CYP3A4 and P-gp. As compared with aliskiren monotherapy, the maximum serum concentration (Cmax) of aliskiren was increased approximately 2.5-fold, and the systemic exposure was increased approximately 4.3-fold after a single 75 mg dose was given with a single cyclosporine 200 mg dose to healthy patients. Also, as compared with aliskiren receipt alone, prolongation of the median aliskiren elimination half-life (43 to 45 hours versus 26 hours) and the time to the maximum serum concentration (1.5 to 2 hours versus 0.5 hours) were noted. The mean systemic exposure and Cmax of cyclosporine were comparable to reported literature values.
    Aliskiren; Amlodipine: (Major) Concomitant use of aliskiren with cyclosporine is not recommended because of significantly increased aliskiren blood concentrations and an increase in the number and/or intensity of adverse events such as headache, hot flushes, nausea, vomiting, and somnolence. Cyclosporine is an inhibitor of CYP3A4 and P-glycoprotein (P-gp). Aliskiren is a substrate of CYP3A4 and P-gp. As compared with aliskiren monotherapy, the maximum serum concentration (Cmax) of aliskiren was increased approximately 2.5-fold, and the systemic exposure was increased approximately 4.3-fold after a single 75 mg dose was given with a single cyclosporine 200 mg dose to healthy patients. Also, as compared with aliskiren receipt alone, prolongation of the median aliskiren elimination half-life (43 to 45 hours versus 26 hours) and the time to the maximum serum concentration (1.5 to 2 hours versus 0.5 hours) were noted. The mean systemic exposure and Cmax of cyclosporine were comparable to reported literature values. (Moderate) Caution should be used when cyclosporine is coadministered with amlodipine; therapeutic response should be monitored, including cyclosporine levels as necessary. Amlodipine may increase cyclosporine concentrations. In one study, whole blood cyclosporine trough concentrations increased from 140.2 +/- 18.2 to 200 +/- 21.9 mcg/L after amlodipine addition. In another study, the systemic exposure (AUC) of cyclosporine increased following the addition of amlodipine, and was decreased in the absence of the drug. The postulated mechanism is the inhibitory effect of amlodipine on the P-glycoprotein-mediated efflux of cyclosporine from intestinal epithelial cells. Also, amlodipine is a CYP3A4 substrate and theoretically, cyclosporine, may increase the plasma concentration of amlodipine via CYP3A4 inhibition; this effect might lead to hypotension in some individuals.
    Aliskiren; Amlodipine; Hydrochlorothiazide, HCTZ: (Major) Concomitant use of aliskiren with cyclosporine is not recommended because of significantly increased aliskiren blood concentrations and an increase in the number and/or intensity of adverse events such as headache, hot flushes, nausea, vomiting, and somnolence. Cyclosporine is an inhibitor of CYP3A4 and P-glycoprotein (P-gp). Aliskiren is a substrate of CYP3A4 and P-gp. As compared with aliskiren monotherapy, the maximum serum concentration (Cmax) of aliskiren was increased approximately 2.5-fold, and the systemic exposure was increased approximately 4.3-fold after a single 75 mg dose was given with a single cyclosporine 200 mg dose to healthy patients. Also, as compared with aliskiren receipt alone, prolongation of the median aliskiren elimination half-life (43 to 45 hours versus 26 hours) and the time to the maximum serum concentration (1.5 to 2 hours versus 0.5 hours) were noted. The mean systemic exposure and Cmax of cyclosporine were comparable to reported literature values. (Moderate) Caution should be used when cyclosporine is coadministered with amlodipine; therapeutic response should be monitored, including cyclosporine levels as necessary. Amlodipine may increase cyclosporine concentrations. In one study, whole blood cyclosporine trough concentrations increased from 140.2 +/- 18.2 to 200 +/- 21.9 mcg/L after amlodipine addition. In another study, the systemic exposure (AUC) of cyclosporine increased following the addition of amlodipine, and was decreased in the absence of the drug. The postulated mechanism is the inhibitory effect of amlodipine on the P-glycoprotein-mediated efflux of cyclosporine from intestinal epithelial cells. Also, amlodipine is a CYP3A4 substrate and theoretically, cyclosporine, may increase the plasma concentration of amlodipine via CYP3A4 inhibition; this effect might lead to hypotension in some individuals.
    Aliskiren; Hydrochlorothiazide, HCTZ: (Major) Concomitant use of aliskiren with cyclosporine is not recommended because of significantly increased aliskiren blood concentrations and an increase in the number and/or intensity of adverse events such as headache, hot flushes, nausea, vomiting, and somnolence. Cyclosporine is an inhibitor of CYP3A4 and P-glycoprotein (P-gp). Aliskiren is a substrate of CYP3A4 and P-gp. As compared with aliskiren monotherapy, the maximum serum concentration (Cmax) of aliskiren was increased approximately 2.5-fold, and the systemic exposure was increased approximately 4.3-fold after a single 75 mg dose was given with a single cyclosporine 200 mg dose to healthy patients. Also, as compared with aliskiren receipt alone, prolongation of the median aliskiren elimination half-life (43 to 45 hours versus 26 hours) and the time to the maximum serum concentration (1.5 to 2 hours versus 0.5 hours) were noted. The mean systemic exposure and Cmax of cyclosporine were comparable to reported literature values.
    Aliskiren; Valsartan: (Major) Concomitant use of aliskiren with cyclosporine is not recommended because of significantly increased aliskiren blood concentrations and an increase in the number and/or intensity of adverse events such as headache, hot flushes, nausea, vomiting, and somnolence. Cyclosporine is an inhibitor of CYP3A4 and P-glycoprotein (P-gp). Aliskiren is a substrate of CYP3A4 and P-gp. As compared with aliskiren monotherapy, the maximum serum concentration (Cmax) of aliskiren was increased approximately 2.5-fold, and the systemic exposure was increased approximately 4.3-fold after a single 75 mg dose was given with a single cyclosporine 200 mg dose to healthy patients. Also, as compared with aliskiren receipt alone, prolongation of the median aliskiren elimination half-life (43 to 45 hours versus 26 hours) and the time to the maximum serum concentration (1.5 to 2 hours versus 0.5 hours) were noted. The mean systemic exposure and Cmax of cyclosporine were comparable to reported literature values. (Moderate) Coadministration of cyclosporine and an angiotensin II receptor antagonist, like valsartan, may increase the risk of hyperkalemia and reduced renal function. In response to cyclosporine-induced renal afferent vasoconstriction and glomerular hypoperfusion, angiotensin II is required to maintain an adequate glomerular filtration rate. Inhibition of angiotensin-converting enzyme (ACE) could reduce renal function acutely. Several cases of acute renal failure have been associated with the addition of enalapril to cyclosporine therapy in renal transplant patients. Also, cyclosporine can cause hyperkalemia, and inhibition of angiotensin II leads to reduced aldosterone concentrations, which can increase the serum potassium concentration. Closely monitor renal function and serum potassium concentrations in patients receiving cyclosporine concurrently with valsartan. Additionally, valsartan is a substrate of the hepatic uptake transporter OATP1B1 and cyclosporine is an inhibitor of OATP. Coadministration may increase systemic exposure to valsartan. Patients should be monitored for adverse effects of valsartan.
    Allopurinol: (Minor) Allopurinol may increase concentrations of cyclosporine. Close monitoring of cyclosporine concentrations is required when allopurinol is given concurrently with cyclosporine.
    Alogliptin: (Moderate) Cyclosporine has been reported to cause hyperglycemia; it may have direct beta-cell toxicity with dose-related effects. Monitor for changes in glycemic control if therapy with cyclosporine is initiated in patients receiving alogliptin.
    Alogliptin; Metformin: (Moderate) Cyclosporine has been reported to cause hyperglycemia; it may have direct beta-cell toxicity with dose-related effects. Monitor for changes in glycemic control if therapy with cyclosporine is initiated in patients receiving alogliptin. (Moderate) Cyclosporine has been reported to cause hyperglycemia; this effect appears to be dose-related and caused by direct beta-cell toxicity. Therefore, a pharmacodynamic interaction is possible with all antidiabetic agents and cyclosporine. Patients should be monitored for worsening glycemic control if therapy with cyclosporine is initiated in patients receiving antidiabetic agents.
    Alogliptin; Pioglitazone: (Moderate) Cyclosporine has been reported to cause hyperglycemia; it may have direct beta-cell toxicity with dose-related effects. Monitor for changes in glycemic control if therapy with cyclosporine is initiated in patients receiving alogliptin. (Moderate) Cyclosporine has been reported to cause hyperglycemia; this effect appears to be dose-related and caused by direct beta-cell toxicity. Therefore, a pharmacodynamic interaction is possible with all antidiabetic agents and cyclosporine. Patients should be monitored for worsening glycemic control if therapy with cyclosporine is initiated in patients receiving antidiabetic agents.
    Alpha-glucosidase Inhibitors: (Moderate) Cyclosporine has been reported to cause hyperglycemia; this effect appears to be dose-related and caused by direct beta-cell toxicity. Therefore, a pharmacodynamic interaction is possible. Monitor the blood glucose.
    Alprazolam: (Moderate) In patients taking drugs that inhibit CYP3A isoenzymes, use alprazolam with caution and consider alprazolam dose reduction (up to 50% dose reduction may be needed). Other drugs that may theoretically inhibit CYP3A4 metabolism of alprazolam include cyclosporine.
    Alvimopan: (Moderate) Alvimopan is a substrate of P-glycoprotein (P-gp). Although the concomitant use of mild to moderate inhibitors of P-gp did not influence the pharmacokinetics of alvimopan, the concomitant use of strong P-gp inhibitors, such as cyclosporine, has not been studied. Coadministration of cyclosporine and alvimopan may result in elevated concentrations of alvimopan. If these drugs are coadministered, patients should be monitored for increased toxicity as well as increased therapeutic effect of alvimopan.
    Ambrisentan: (Major) When coadministering ambrisentan with cyclosporine, the ambrisentan dose should not be titrated to the recommended maximum daily dose. Limit the adult dose of ambrisentan to 5 mg once daily when coadministered with cyclosporine. Cyclosporine is a strong inhibitor of P-glycoprotein, OATP, and CYP3A4. In vitro data indicate ambrisentan is a substrate of P-glycoprotein, OATP, and CYP3A4. Cyclosporine twice daily (targeting a trough concentration of 150 - 200 ng/mL) and ambrisentan (5 mg once daily) were coadministered in a 14-day repeated dose study in healthy volunteers. The AUC and Cmax of ambrisentan increased approximately 2-fold and 1.5-fold, respectively.
    Amikacin: (Major) Additive nephrotoxicity can occur if cyclosporine is administered with other nephrotoxic drugs such as aminoglycosides.
    Amiloride: (Major) Cyclosporine can cause hyperkalemia. Simultaneous use of cyclosporine with potassium-sparing diuretics, such as amiloride, spironolactone or triamterene, can increase this risk, and is not recommended.
    Amiloride; Hydrochlorothiazide, HCTZ: (Major) Cyclosporine can cause hyperkalemia. Simultaneous use of cyclosporine with potassium-sparing diuretics, such as amiloride, spironolactone or triamterene, can increase this risk, and is not recommended.
    Amiodarone: (Moderate) Cyclosporine is a CYP3A4 substrate. Amiodarone is a CYP3A4 inhibitor and may decrease the clearance of cyclosporine, which may reduce cyclosporine dosage requirements or cause cyclosporine toxicity.
    Amlodipine: (Moderate) Caution should be used when cyclosporine is coadministered with amlodipine; therapeutic response should be monitored, including cyclosporine levels as necessary. Amlodipine may increase cyclosporine concentrations. In one study, whole blood cyclosporine trough concentrations increased from 140.2 +/- 18.2 to 200 +/- 21.9 mcg/L after amlodipine addition. In another study, the systemic exposure (AUC) of cyclosporine increased following the addition of amlodipine, and was decreased in the absence of the drug. The postulated mechanism is the inhibitory effect of amlodipine on the P-glycoprotein-mediated efflux of cyclosporine from intestinal epithelial cells. Also, amlodipine is a CYP3A4 substrate and theoretically, cyclosporine, may increase the plasma concentration of amlodipine via CYP3A4 inhibition; this effect might lead to hypotension in some individuals.
    Amlodipine; Atorvastatin: (Major) Avoid the coadministration of atorvastatin and cyclosporine because the risk of developing myopathy increases when these two drugs are given together. Atorvastatin is a substrate for OATP1B1 transporter; cyclosporine is an inhibitor of this transporter. Concomitant administration of atorvastatin 10 mg and cyclosporine 5.2 mg/kg/day resulted in a significantly higer atorvastatin AUC (8.7-fold higher) compared to that of atorvastatin alone. (Moderate) Caution should be used when cyclosporine is coadministered with amlodipine; therapeutic response should be monitored, including cyclosporine levels as necessary. Amlodipine may increase cyclosporine concentrations. In one study, whole blood cyclosporine trough concentrations increased from 140.2 +/- 18.2 to 200 +/- 21.9 mcg/L after amlodipine addition. In another study, the systemic exposure (AUC) of cyclosporine increased following the addition of amlodipine, and was decreased in the absence of the drug. The postulated mechanism is the inhibitory effect of amlodipine on the P-glycoprotein-mediated efflux of cyclosporine from intestinal epithelial cells. Also, amlodipine is a CYP3A4 substrate and theoretically, cyclosporine, may increase the plasma concentration of amlodipine via CYP3A4 inhibition; this effect might lead to hypotension in some individuals.
    Amlodipine; Benazepril: (Moderate) Caution should be used when cyclosporine is coadministered with amlodipine; therapeutic response should be monitored, including cyclosporine levels as necessary. Amlodipine may increase cyclosporine concentrations. In one study, whole blood cyclosporine trough concentrations increased from 140.2 +/- 18.2 to 200 +/- 21.9 mcg/L after amlodipine addition. In another study, the systemic exposure (AUC) of cyclosporine increased following the addition of amlodipine, and was decreased in the absence of the drug. The postulated mechanism is the inhibitory effect of amlodipine on the P-glycoprotein-mediated efflux of cyclosporine from intestinal epithelial cells. Also, amlodipine is a CYP3A4 substrate and theoretically, cyclosporine, may increase the plasma concentration of amlodipine via CYP3A4 inhibition; this effect might lead to hypotension in some individuals.
    Amlodipine; Hydrochlorothiazide, HCTZ; Olmesartan: (Moderate) Caution should be used when cyclosporine is coadministered with amlodipine; therapeutic response should be monitored, including cyclosporine levels as necessary. Amlodipine may increase cyclosporine concentrations. In one study, whole blood cyclosporine trough concentrations increased from 140.2 +/- 18.2 to 200 +/- 21.9 mcg/L after amlodipine addition. In another study, the systemic exposure (AUC) of cyclosporine increased following the addition of amlodipine, and was decreased in the absence of the drug. The postulated mechanism is the inhibitory effect of amlodipine on the P-glycoprotein-mediated efflux of cyclosporine from intestinal epithelial cells. Also, amlodipine is a CYP3A4 substrate and theoretically, cyclosporine, may increase the plasma concentration of amlodipine via CYP3A4 inhibition; this effect might lead to hypotension in some individuals. (Moderate) Coadministration of cyclosporine and an angiotensin II receptor antagonist, like olmesartan, may increase the risk of hyperkalemia and reduced renal function. In response to cyclosporine-induced renal afferent vasoconstriction and glomerular hypoperfusion, angiotensin II is required to maintain an adequate glomerular filtration rate. Inhibition of angiotensin-converting enzyme (ACE) could reduce renal function acutely. Several cases of acute renal failure have been associated with the addition of enalapril to cyclosporine therapy in renal transplant patients. Also, cyclosporine can cause hyperkalemia, and inhibition of angiotensin II leads to reduced aldosterone concentrations, which can increase the serum potassium concentration. Closely monitor renal function and serum potassium concentrations in patients receiving cyclosporine concurrently with olmesartan.
    Amlodipine; Hydrochlorothiazide, HCTZ; Valsartan: (Moderate) Caution should be used when cyclosporine is coadministered with amlodipine; therapeutic response should be monitored, including cyclosporine levels as necessary. Amlodipine may increase cyclosporine concentrations. In one study, whole blood cyclosporine trough concentrations increased from 140.2 +/- 18.2 to 200 +/- 21.9 mcg/L after amlodipine addition. In another study, the systemic exposure (AUC) of cyclosporine increased following the addition of amlodipine, and was decreased in the absence of the drug. The postulated mechanism is the inhibitory effect of amlodipine on the P-glycoprotein-mediated efflux of cyclosporine from intestinal epithelial cells. Also, amlodipine is a CYP3A4 substrate and theoretically, cyclosporine, may increase the plasma concentration of amlodipine via CYP3A4 inhibition; this effect might lead to hypotension in some individuals. (Moderate) Coadministration of cyclosporine and an angiotensin II receptor antagonist, like valsartan, may increase the risk of hyperkalemia and reduced renal function. In response to cyclosporine-induced renal afferent vasoconstriction and glomerular hypoperfusion, angiotensin II is required to maintain an adequate glomerular filtration rate. Inhibition of angiotensin-converting enzyme (ACE) could reduce renal function acutely. Several cases of acute renal failure have been associated with the addition of enalapril to cyclosporine therapy in renal transplant patients. Also, cyclosporine can cause hyperkalemia, and inhibition of angiotensin II leads to reduced aldosterone concentrations, which can increase the serum potassium concentration. Closely monitor renal function and serum potassium concentrations in patients receiving cyclosporine concurrently with valsartan. Additionally, valsartan is a substrate of the hepatic uptake transporter OATP1B1 and cyclosporine is an inhibitor of OATP. Coadministration may increase systemic exposure to valsartan. Patients should be monitored for adverse effects of valsartan.
    Amlodipine; Olmesartan: (Moderate) Caution should be used when cyclosporine is coadministered with amlodipine; therapeutic response should be monitored, including cyclosporine levels as necessary. Amlodipine may increase cyclosporine concentrations. In one study, whole blood cyclosporine trough concentrations increased from 140.2 +/- 18.2 to 200 +/- 21.9 mcg/L after amlodipine addition. In another study, the systemic exposure (AUC) of cyclosporine increased following the addition of amlodipine, and was decreased in the absence of the drug. The postulated mechanism is the inhibitory effect of amlodipine on the P-glycoprotein-mediated efflux of cyclosporine from intestinal epithelial cells. Also, amlodipine is a CYP3A4 substrate and theoretically, cyclosporine, may increase the plasma concentration of amlodipine via CYP3A4 inhibition; this effect might lead to hypotension in some individuals. (Moderate) Coadministration of cyclosporine and an angiotensin II receptor antagonist, like olmesartan, may increase the risk of hyperkalemia and reduced renal function. In response to cyclosporine-induced renal afferent vasoconstriction and glomerular hypoperfusion, angiotensin II is required to maintain an adequate glomerular filtration rate. Inhibition of angiotensin-converting enzyme (ACE) could reduce renal function acutely. Several cases of acute renal failure have been associated with the addition of enalapril to cyclosporine therapy in renal transplant patients. Also, cyclosporine can cause hyperkalemia, and inhibition of angiotensin II leads to reduced aldosterone concentrations, which can increase the serum potassium concentration. Closely monitor renal function and serum potassium concentrations in patients receiving cyclosporine concurrently with olmesartan.
    Amlodipine; Telmisartan: (Moderate) Caution should be used when cyclosporine is coadministered with amlodipine; therapeutic response should be monitored, including cyclosporine levels as necessary. Amlodipine may increase cyclosporine concentrations. In one study, whole blood cyclosporine trough concentrations increased from 140.2 +/- 18.2 to 200 +/- 21.9 mcg/L after amlodipine addition. In another study, the systemic exposure (AUC) of cyclosporine increased following the addition of amlodipine, and was decreased in the absence of the drug. The postulated mechanism is the inhibitory effect of amlodipine on the P-glycoprotein-mediated efflux of cyclosporine from intestinal epithelial cells. Also, amlodipine is a CYP3A4 substrate and theoretically, cyclosporine, may increase the plasma concentration of amlodipine via CYP3A4 inhibition; this effect might lead to hypotension in some individuals. (Moderate) Coadministration of cyclosporine and an angiotensin II receptor antagonist, like telmisartan, may increase the risk of hyperkalemia and reduced renal function. In response to cyclosporine-induced renal afferent vasoconstriction and glomerular hypoperfusion, angiotensin II is required to maintain an adequate glomerular filtration rate. Inhibition of angiotensin-converting enzyme (ACE) could reduce renal function acutely. Several cases of acute renal failure have been associated with the addition of enalapril to cyclosporine therapy in renal transplant patients. Also, cyclosporine can cause hyperkalemia, and inhibition of angiotensin II leads to reduced aldosterone concentrations, which can increase the serum potassium concentration. Closely monitor renal function and serum potassium concentrations in patients receiving cyclosporine concurrently with telmisartan.
    Amlodipine; Valsartan: (Moderate) Caution should be used when cyclosporine is coadministered with amlodipine; therapeutic response should be monitored, including cyclosporine levels as necessary. Amlodipine may increase cyclosporine concentrations. In one study, whole blood cyclosporine trough concentrations increased from 140.2 +/- 18.2 to 200 +/- 21.9 mcg/L after amlodipine addition. In another study, the systemic exposure (AUC) of cyclosporine increased following the addition of amlodipine, and was decreased in the absence of the drug. The postulated mechanism is the inhibitory effect of amlodipine on the P-glycoprotein-mediated efflux of cyclosporine from intestinal epithelial cells. Also, amlodipine is a CYP3A4 substrate and theoretically, cyclosporine, may increase the plasma concentration of amlodipine via CYP3A4 inhibition; this effect might lead to hypotension in some individuals. (Moderate) Coadministration of cyclosporine and an angiotensin II receptor antagonist, like valsartan, may increase the risk of hyperkalemia and reduced renal function. In response to cyclosporine-induced renal afferent vasoconstriction and glomerular hypoperfusion, angiotensin II is required to maintain an adequate glomerular filtration rate. Inhibition of angiotensin-converting enzyme (ACE) could reduce renal function acutely. Several cases of acute renal failure have been associated with the addition of enalapril to cyclosporine therapy in renal transplant patients. Also, cyclosporine can cause hyperkalemia, and inhibition of angiotensin II leads to reduced aldosterone concentrations, which can increase the serum potassium concentration. Closely monitor renal function and serum potassium concentrations in patients receiving cyclosporine concurrently with valsartan. Additionally, valsartan is a substrate of the hepatic uptake transporter OATP1B1 and cyclosporine is an inhibitor of OATP. Coadministration may increase systemic exposure to valsartan. Patients should be monitored for adverse effects of valsartan.
    Amobarbital: (Major) Phenobarbital may induce cyclosporine metabolism, thereby increasing the clearance of cyclosporine. It is likely that other barbiturates would interact similarly with cyclosporine; however no supportive data are available. If phenobarbital is added to an existing cyclosporine regimen, monitor cyclosporine concentrations closely to avoid loss of clinical efficacy until a new steady-state concentration is achieved. Conversely, if phenobarbital is discontinued, cyclosporine concentrations could increase.
    Amoxicillin; Clarithromycin; Lansoprazole: (Major) Clarithromycin may inhibit the metabolism of cyclosporine via inhibition of the CYP3A4 isoenzyme, thus increasing cyclosporine's effects and the potential for toxicity. Clarithromycin may also reduce the intestinal metabolism of cyclosporine. It has been recommended to avoid cyclosporine in combination with macrolide agents or reduce the cyclosporine dosage by 50% when it is necessary to give any macrolides concurrently. Increased cyclosporine concentrations may be seen with 2 days of beginning combination therapy. In managing potential interactions between macrolides and cyclosporine, appropriate monitoring of cyclosporine concentrations is critical to help avoid graft failure or drug-related toxicity.
    Amoxicillin; Clarithromycin; Omeprazole: (Major) Clarithromycin may inhibit the metabolism of cyclosporine via inhibition of the CYP3A4 isoenzyme, thus increasing cyclosporine's effects and the potential for toxicity. Clarithromycin may also reduce the intestinal metabolism of cyclosporine. It has been recommended to avoid cyclosporine in combination with macrolide agents or reduce the cyclosporine dosage by 50% when it is necessary to give any macrolides concurrently. Increased cyclosporine concentrations may be seen with 2 days of beginning combination therapy. In managing potential interactions between macrolides and cyclosporine, appropriate monitoring of cyclosporine concentrations is critical to help avoid graft failure or drug-related toxicity.
    Amphotericin B cholesteryl sulfate complex (ABCD): (Moderate) Cyclosporine should be used cautiously with nephrotoxic drugs, such as amphotericin B, as cyclosporine itself can cause structural kidney damage. Additive nephrotoxicity can occur if these drugs are administered together. Monitor renal function and fluid status carefully.
    Amphotericin B lipid complex (ABLC): (Moderate) Cyclosporine should be used cautiously with nephrotoxic drugs, such as amphotericin B, as cyclosporine itself can cause structural kidney damage. Additive nephrotoxicity can occur if these drugs are administered together. Monitor renal function and fluid status carefully.
    Amphotericin B liposomal (LAmB): (Moderate) Cyclosporine should be used cautiously with nephrotoxic drugs, such as amphotericin B, as cyclosporine itself can cause structural kidney damage. Additive nephrotoxicity can occur if these drugs are administered together. Monitor renal function and fluid status carefully.
    Amphotericin B: (Moderate) Cyclosporine should be used cautiously with nephrotoxic drugs, such as amphotericin B, as cyclosporine itself can cause structural kidney damage. Additive nephrotoxicity can occur if these drugs are administered together. Monitor renal function and fluid status carefully.
    Amprenavir: (Major) An interaction is anticipated to occur with all anti-retroviral protease inhibitors and cyclosporine, as all protease inhibitors inhibit CYP3A4. Cyclosporine toxicity, consisting of fatigue, headache, and GI distress, has been reported by a patient receiving cyclosporine and saquinavir. Prior to beginning saquinavir the patient had been receiving stable doses of cyclosporine resulting in trough concentrations of 150 to 200 mcg/ml. After receiving saquinavir for 3 days, the cyclosporine trough concentration increased to 580 mcg/ml. Dosages of both agents were decreased by 50% leading to resolution of symptoms. This interaction is probably due to CYP3A4 inhibition by saquinavir. Another possible mechanism is that both drugs have a high affinity for the drug efflux protein, P-glycoprotein, which may increase the absorption or decrease the clearance of the other drug.
    Angiotensin-converting enzyme inhibitors: (Moderate) Several cases of acute renal failure have been associated with the addition of angiotensin-converting enzyme (ACE) inhibitors to cyclosporine therapy in renal transplant patients. In response to cyclosporine-induced renal afferent vasoconstriction and glomerular hypoperfusion, angiotensin II is required to maintain an adequate glomerular filtration rate. Inhibition of ACE could reduce renal function acutely. Also, cyclosporine can cause hyperkalemia, and inhibition of angiotensin II leads to reduced aldosterone concentrations, which can increase the serum potassium concentration. Closely monitor renal function and serum potassium concentrations in patients receiving cyclosporine concurrently with ACE inhibitors or potassium salts.
    Apixaban: (Moderate) Use apixaban and cyclosporine together with caution in patients with significant renal dysfunction as risk of bleeding may be increased. Cyclosporine is a moderate CYP3A4 and P-glycoprotein (P-gp) inhibitor. Apixaban is a substrate of CYP3A4 and P-gp. In a pharmacokinetic study, apixaban Cmax and AUC increased by 31% and 40%, respectively, when given with another moderate CYP3A4 and P-gp inhibitor. Although serum concentrations of non-vitamin K oral anticoagulants have been increased in the presence of moderate inhibitors, one cohort study found that the risk of bleeding was not increased.
    Aprepitant, Fosaprepitant: (Moderate) Avoid the concomitant use of cyclosporine with aprepitant, fosaprepitant due to substantially increased exposure of aprepitant; cyclosporine levels may also be affected. If coadministration cannot be avoided, use caution and monitor cyclosporine levels, as well as watching for an increase in cyclosporine- and aprepitant-related adverse effects for several days after administration of a multi-day aprepitant regimen. Cyclosporine is a moderate CYP3A4 inhibitor and aprepitant is a CYP3A4 substrate. Coadministration of daily oral aprepitant (230 mg, or 1.8 times the recommended single dose) with a moderate CYP3A4 inhibitor, diltiazem, increased the aprepitant AUC 2-fold with a concomitant 1.7-fold increase in the diltiazem AUC; clinically meaningful changes in ECG, heart rate, or blood pressure beyond those induced by diltiazem alone did not occur. Cyclosporine is also a CYP3A4 substrate. Aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor and inducer and may additionally increase plasma concentrations of cyclosporine. For example, a 5-day oral aprepitant regimen increased the AUC of another CYP3A4 substrate, midazolam (single dose), by 2.3-fold on day 1 and by 3.3-fold on day 5. After a 3-day oral aprepitant regimen, the AUC of midazolam (given on days 1, 4, 8, and 15) increased by 25% on day 4, and then decreased by 19% and 4% on days 8 and 15, respectively. As a single 125 mg or 40 mg oral dose, the inhibitory effect of aprepitant on CYP3A4 is weak, with the AUC of midazolam increased by 1.5-fold and 1.2-fold, respectively. After administration, fosaprepitant is rapidly converted to aprepitant and shares many of the same drug interactions. However, as a single 150 mg intravenous dose, fosaprepitant only weakly inhibits CYP3A4 for a duration of 2 days; there is no evidence of CYP3A4 induction. Fosaprepitant 150 mg IV as a single dose increased the AUC of midazolam (given on days 1 and 4) by approximately 1.8-fold on day 1; there was no effect on day 4. Less than a 2-fold increase in the midazolam AUC is not considered clinically important.
    Aprotinin: (Moderate) The manufacturer recommends using aprotinin cautiously in patients that are receiving drugs that can affect renal function, such as cyclosporine, as the risk of renal impairment may be increased.
    Armodafinil: (Moderate) In vitro data indicate that armodafinil is an inducer of CYP3A4/5 isoenzymes. Therefore, armodafinil may induce the metabolism of medications which are substrates for CYP3A4 such as cyclosporine. Increased cyclosporine clearance and decreased cyclosporine concentrations can lead to loss of therapeutic effect. Cyclosporine concentrations should be monitored closely after the addition or discontinuation of armodafinil until a new steady-state level is achieved.
    Aspirin, ASA; Butalbital; Caffeine: (Major) Phenobarbital may induce cyclosporine metabolism, thereby increasing the clearance of cyclosporine. It is likely that other barbiturates would interact similarly with cyclosporine; however no supportive data are available. If phenobarbital is added to an existing cyclosporine regimen, monitor cyclosporine concentrations closely to avoid loss of clinical efficacy until a new steady-state concentration is achieved. Conversely, if phenobarbital is discontinued, cyclosporine concentrations could increase.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Major) Phenobarbital may induce cyclosporine metabolism, thereby increasing the clearance of cyclosporine. It is likely that other barbiturates would interact similarly with cyclosporine; however no supportive data are available. If phenobarbital is added to an existing cyclosporine regimen, monitor cyclosporine concentrations closely to avoid loss of clinical efficacy until a new steady-state concentration is achieved. Conversely, if phenobarbital is discontinued, cyclosporine concentrations could increase.
    Aspirin, ASA; Pravastatin: (Major) Concomitant administration of cyclosporine and pravastatin increases the risk of myopathy and rhabdomyolysis; limit pravastatin to 20 mg PO once daily when these agents are used together. During pharmacokinetic trials, a single dose of cyclosporine increased the AUC and Cmax of pravastatin by 282% and 327%, respectively. However, neither myopathy nor significant increases in CPK levels have been observed in 3 reports involving 100 post-transplant (cardiac or renal) patients treated for up to 2 years with pravastatin (10 to 40 mg) and cyclosporine. Some of these patients also received other concomitant immunosuppressive therapies.
    Atazanavir: (Major) An interaction is anticipated to occur with all anti-retroviral protease inhibitors and cyclosporine, as all protease inhibitors inhibit CYP3A4. Cyclosporine toxicity, consisting of fatigue, headache, and GI distress, has been reported by a patient receiving cyclosporine and saquinavir. Prior to beginning saquinavir the patient had been receiving stable doses of cyclosporine resulting in trough concentrations of 150 to 200 mcg/ml. After receiving saquinavir for 3 days, the cyclosporine trough concentration increased to 580 mcg/ml. Dosages of both agents were decreased by 50% leading to resolution of symptoms. This interaction is probably due to CYP3A4 inhibition by saquinavir. Another possible mechanism is that both drugs have a high affinity for the drug efflux protein, P-glycoprotein, which may increase the absorption or decrease the clearance of the other drug.
    Atazanavir; Cobicistat: (Major) An interaction is anticipated to occur with all anti-retroviral protease inhibitors and cyclosporine, as all protease inhibitors inhibit CYP3A4. Cyclosporine toxicity, consisting of fatigue, headache, and GI distress, has been reported by a patient receiving cyclosporine and saquinavir. Prior to beginning saquinavir the patient had been receiving stable doses of cyclosporine resulting in trough concentrations of 150 to 200 mcg/ml. After receiving saquinavir for 3 days, the cyclosporine trough concentration increased to 580 mcg/ml. Dosages of both agents were decreased by 50% leading to resolution of symptoms. This interaction is probably due to CYP3A4 inhibition by saquinavir. Another possible mechanism is that both drugs have a high affinity for the drug efflux protein, P-glycoprotein, which may increase the absorption or decrease the clearance of the other drug. (Moderate) Cyclosporine therapeutic drug monitoring is recommended when administered concurrently with cobicistat. Use of these medications together may result in elevated cyclosporine serum concentrations. Predictions regarding this interaction can be made based on the metabolic pathways of these drugs. Cobicistat is an inhibitor of CYP3A4, an isoenzyme responsible for the metabolism of cyclosporine. These drugs used in combination may result in elevated cyclosporine plasma concentrations, causing an increased risk for cyclosporine-related adverse events.
    Atorvastatin: (Major) Avoid the coadministration of atorvastatin and cyclosporine because the risk of developing myopathy increases when these two drugs are given together. Atorvastatin is a substrate for OATP1B1 transporter; cyclosporine is an inhibitor of this transporter. Concomitant administration of atorvastatin 10 mg and cyclosporine 5.2 mg/kg/day resulted in a significantly higer atorvastatin AUC (8.7-fold higher) compared to that of atorvastatin alone.
    Atorvastatin; Ezetimibe: (Major) Avoid the coadministration of atorvastatin and cyclosporine because the risk of developing myopathy increases when these two drugs are given together. Atorvastatin is a substrate for OATP1B1 transporter; cyclosporine is an inhibitor of this transporter. Concomitant administration of atorvastatin 10 mg and cyclosporine 5.2 mg/kg/day resulted in a significantly higer atorvastatin AUC (8.7-fold higher) compared to that of atorvastatin alone. (Major) Cyclosporine may significantly increase ezetimibe serum concentrations. In addition, ezetimibe can increase cyclosporine serum concentrations. In a study of twelve healthy subjects, daily administration of 20 mg ezetimibe for 8 days and a single dose of 100 mg cyclosporine on day 7 resulted in a mean 15% increase in cyclosporine AUC (up to 51%) compared to a single dose of 100 mg cyclosporine alone. In a study of eight post-renal transplant patients with mildly impaired or normal renal function (CrCl > 50 mL/min), stable doses of cyclosporine (75 to 150 mg twice daily) increased the mean AUC and Cmax values of total ezetimibe 3.4-fold (range 2.3-fold to 7.9-fold) and 3.9-fold (range 3-fold to 4.4-fold), respectively, compared to a historical healthy control population (n=17). In a different study, a renal transplant patient with severe renal insufficiency (creatinine clearance of 13.2 mL/min/1.73 m2) who was receiving multiple medications, including cyclosporine, demonstrated a 12-fold greater exposure to total ezetimibe compared to healthy subjects. The degree of increase in ezetimibe exposure may be greater in patients with severe renal insufficiency. In patients treated with cyclosporine, the potential effects of the increased exposure to ezetimibe from concomitant use should be carefully weighed against the antilipemic benefits provided by ezetimibe. Patients who take cyclosporine concurrently with ezetimibe should be closely monitored for serum cyclosporine concentrations and for potential adverse effects of ezetimibe and cyclosporine.
    Atracurium: (Moderate) Cyclosporine may potentiate the action of nondepolarizing neuromuscular blockers. Prolonged neuromuscular blockade has been reported in patients receiving cyclosporine who receive neuromuscular blockers as part of surgical anesthesia. Monitor patients for recurrent neuromuscular blockade and respiratory depression; extended ventilatory support may be required.
    Atropine; Hyoscyamine; Phenobarbital; Scopolamine: (Major) Phenobarbital may induce cyclosporine metabolism, thereby increasing the clearance of cyclosporine. It is likely that other barbiturates would interact similarly with cyclosporine; however no supportive data are available. If phenobarbital is added to an existing cyclosporine regimen, monitor cyclosporine concentrations closely to avoid loss of clinical efficacy until a new steady-state concentration is achieved. Conversely, if phenobarbital is discontinued, cyclosporine concentrations could increase.
    Axitinib: (Moderate) Use caution if coadministration of axitinib with cyclosporine is necessary, due to the risk of increased axitinib-related adverse reactions. Axitinib is a CYP3A4 substrate and cyclosporine is a moderate CYP3A4 inhibitor. Coadministration with a strong CYP3A4/5 inhibitor, ketoconazole, significantly increased the plasma exposure of axitinib in healthy volunteers. The manufacturer of axitinib recommends a dose reduction in patients receiving strong CYP3A4 inhibitors, but recommendations are not available for moderate or weak CYP3A4 inhibitors.
    Azilsartan: (Moderate) Coadministration of cyclosporine and an angiotensin II receptor antagonist, like azilsartan, may increase the risk of hyperkalemia and reduced renal function. In response to cyclosporine-induced renal afferent vasoconstriction and glomerular hypoperfusion, angiotensin II is required to maintain an adequate glomerular filtration rate. Inhibition of angiotensin-converting enzyme (ACE) could reduce renal function acutely. Several cases of acute renal failure have been associated with the addition of enalapril to cyclosporine therapy in renal transplant patients. Also, cyclosporine can cause hyperkalemia, and inhibition of angiotensin II leads to reduced aldosterone concentrations, which can increase the serum potassium concentration. Closely monitor renal function and serum potassium concentrations in patients receiving cyclosporine concurrently with azilsartan.
    Azilsartan; Chlorthalidone: (Moderate) Coadministration of cyclosporine and an angiotensin II receptor antagonist, like azilsartan, may increase the risk of hyperkalemia and reduced renal function. In response to cyclosporine-induced renal afferent vasoconstriction and glomerular hypoperfusion, angiotensin II is required to maintain an adequate glomerular filtration rate. Inhibition of angiotensin-converting enzyme (ACE) could reduce renal function acutely. Several cases of acute renal failure have been associated with the addition of enalapril to cyclosporine therapy in renal transplant patients. Also, cyclosporine can cause hyperkalemia, and inhibition of angiotensin II leads to reduced aldosterone concentrations, which can increase the serum potassium concentration. Closely monitor renal function and serum potassium concentrations in patients receiving cyclosporine concurrently with azilsartan.
    Azithromycin: (Moderate) Both cyclosporine and azithromycin are P-glycoprotein (P-gp) inhibitors and substrates; coadministration may lead to increased concentrations of either agent. Monitor patients for increased side effects if these drugs are given together. In a case report, one patient had increased cyclosporine concentrations after administration of azithromycin and decreased cyclosporine concentrations after azithromycin discontinuation.
    Bacillus Calmette-Guerin Vaccine, BCG: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Bacitracin: (Minor) Additive nephrotoxicity may occur with concurrent use of bacitracin and other nephrotoxic agents. When possible, avoid concomitant administration of systemic bacitracin and other nephrotoxic drugs such as cyclosporine. Use of topically administrated preparations containing bacitracin, especially when applied to large surface areas, may have additive nephrotoxic potential with cyclosporine.
    Barbiturates: (Major) Phenobarbital may induce cyclosporine metabolism, thereby increasing the clearance of cyclosporine. It is likely that other barbiturates would interact similarly with cyclosporine; however no supportive data are available. If phenobarbital is added to an existing cyclosporine regimen, monitor cyclosporine concentrations closely to avoid loss of clinical efficacy until a new steady-state concentration is achieved. Conversely, if phenobarbital is discontinued, cyclosporine concentrations could increase.
    Basiliximab: (Minor) Because basiliximab is an immunosuppressant, additive effects may be seen with other immunosuppressives.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Major) Phenobarbital may induce cyclosporine metabolism, thereby increasing the clearance of cyclosporine. It is likely that other barbiturates would interact similarly with cyclosporine; however no supportive data are available. If phenobarbital is added to an existing cyclosporine regimen, monitor cyclosporine concentrations closely to avoid loss of clinical efficacy until a new steady-state concentration is achieved. Conversely, if phenobarbital is discontinued, cyclosporine concentrations could increase.
    Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: (Major) Medications with significant alcohol content should not be ingested during therapy with metronidazole and should be avoided for 3 days after therapy is discontinued. Cyclosporine parenteral and oral solutions contain ethanol; liquid-filled capsules contain ethanol in lower percentages. Administration of ethanol-containing formulations of cyclosporine to patients receiving or who have recently received metronidazole may result in disulfiram-like reactions. A disulfiram reaction would not be expected to occur with non-ethanol containing formulations.
    Bismuth Subsalicylate; Metronidazole; Tetracycline: (Major) Medications with significant alcohol content should not be ingested during therapy with metronidazole and should be avoided for 3 days after therapy is discontinued. Cyclosporine parenteral and oral solutions contain ethanol; liquid-filled capsules contain ethanol in lower percentages. Administration of ethanol-containing formulations of cyclosporine to patients receiving or who have recently received metronidazole may result in disulfiram-like reactions. A disulfiram reaction would not be expected to occur with non-ethanol containing formulations.
    Bleomycin: (Minor) Previous treatment with nephrotoxic agents, like cyclosporine, may result in decreased bleomycin clearance if renal function has been impaired. Monitor for signs/symptoms of bleomycin toxicity in patients with concomittant or prior cyclosporine therapy.
    Blinatumomab: (Moderate) No drug interaction studies have been performed with blinatumomab. The drug may cause a transient release of cytokines leading to an inhibition of CYP450 enzymes. The interaction risk with CYP450 substrates is likely the highest during the first 9 days of the first cycle and the first 2 days of the second cycle. Monitor patients receiving concurrent CYP450 substrates that have a narrow therapeutic index (NTI) such as cyclosporine. The dose of the concomitant drug may need to be adjusted.
    Boceprevir: (Major) Close monitoring of cyclosporine serum concentrations and frequent assessments of renal function are advised when coadministering cyclosporine with boceprevir. Cyclosporine is a substrate of the hepatic isoenzyme CYP3A4; boceprevir inhibits this isoenzyme. Additionally, both cyclosporine and boceprevir are inhibitors and substrates of the drug efflux transporter P-glycoprotein (PGP). After a single 100 mg dose of cyclosporine, the mean AUC and Cmax of cyclosporine are increased approximately 2.7-fold and 2-fold, respectively, when administered in combination with boceprevir; thus, cyclosporine dose reductions and prolongation of the dosing interval are recommended to achieve desired cyclosporine concentrations. If cyclosporine dose adjustments are made, re-adjust the dose upon completion of boceprevir treatment.
    Bortezomib: (Minor) Monitor patients for the development of peripheral neuropathy when receiving bortezomib in combination with other drugs that can cause peripheral neuropathy like cyclosporine; the risk of peripheral neuropathy may be additive.
    Bosentan: (Severe) The concomitant administration of bosentan and cyclosporine A is contraindicated. During the first day of coadministration with cyclosporine, trough concentrations of bosentan are increased by about 30-fold. Steady-state, bosentan plasma concentrations are 3- to 4-fold higher with concurrent cyclosporine administration. In addition, coadministration of bosentan at higher than approved doses (500-1000 mg PO twice daily) decreases the plasma concentrations of cyclosporine A (CYP3A4 substrate) by approximately 50%. In the cyclosporine interaction study, clinical toxicity has been observed, including: severe headache, nausea, vomiting, mild decreases in blood pressure, and small increases in heart rate; no serious adverse effects were reported.
    Brigatinib: (Moderate) Monitor cyclosporine serum concentrations and watch for decreased efficacy of cyclosporine if coadministration with brigatinib is necessary. Cyclosporine is a CYP3A substrate and brigatinib induces CYP3A in vitro; plasma concentrations of cyclosporine may decrease.
    Brodalumab: (Moderate) Coadministration of brodalumab may result in altered exposure to cyclosporine. During chronic inflammation, increased levels of certain cytokines can alter the formation of CYP450 enzymes. Thus, the formation of CYP450 enzymes could be normalized during brodalumab administration. Clinically relevant drug interactions may occur with CYP450 substrates that have a narrow therapeutic index such as cyclosporine. Monitor cyclosporine concentrations if brodalumab is initiated or discontinued in a patient taking cyclosporine; cyclosporine dose adjustments may be needed.
    Bromocriptine: (Major) When bromocriptine is used for diabetes, do not exceed a dose of 1.6 mg once daily during concomitant use of cyclosporine. Use this combination with caution in patients receiving bromocriptine for other indications. Concurrent use may increase bromocriptine concentrations. Bromocriptine is extensively metabolized in the liver via CYP3A4; cyclosporine is a moderate inhibitor of CYP3A4. Administration of bromocriptine with a moderate inhibitor of CYP3A4 increased the bromocriptine mean AUC and Cmax by 3.7-fold and 4.6-fold, respectively.
    Bupivacaine; Lidocaine: (Moderate) Concomitant use of systemic lidocaine and cyclosporine may increase lidocaine plasma concentrations by decreasing lidocaine clearance and therefore prolonging the elimination half-life. Monitor for lidocaine toxicity if used together. Lidocaine is a CYP3A4 and CYP1A2 substrate; cyclosporine inhibits CYP3A4.
    Butabarbital: (Major) Phenobarbital may induce cyclosporine metabolism, thereby increasing the clearance of cyclosporine. It is likely that other barbiturates would interact similarly with cyclosporine; however no supportive data are available. If phenobarbital is added to an existing cyclosporine regimen, monitor cyclosporine concentrations closely to avoid loss of clinical efficacy until a new steady-state concentration is achieved. Conversely, if phenobarbital is discontinued, cyclosporine concentrations could increase.
    Cabazitaxel: (Minor) Cabazitaxel is a substrate for P-glycoprotein (Pgp). No formal drug interaction studies have been conducted with Pgp inhibitors, such as cyclosporine. Use caution when cabazitaxel is administered concomitantly with Pgp inhibitors.
    Cabozantinib: (Moderate) Monitor for an increase in cabozantinib- and cyclosporine-related adverse events if concomitant use of cabozantinib and cyclosporine is necessary; consider closer monitoring of cyclosporine serum concentrations. Cabozantinib is primarily metabolized by CYP3A4 and cyclosporine is a CYP3A4 inhibitor. Coadministration with a strong CYP3A4 inhibitor, ketoconazole (400 mg daily for 27 days), increased cabozantinib (single dose) exposure by 38%. The manufacturer of cabozantinib recommends a dose reduction when used with strong CYP3A4 inhibitors; however, recommendations are not available for concomitant use with a moderate inhibitor of CYP3A4. Cabozantinib is also a P-glycoprotein (P-gp) inhibitor and cyclosporine is a substrate of P-gp; plasma concentrations of cyclosporine may be increased. However, the clinical relevance of this finding is unknown.
    Canagliflozin: (Moderate) Cyclosporine has been reported to cause hyperglycemia. Cyclosporine may have direct beta-cell toxicity that may be dose-related. Canagliflozin did not meaningfully alter the pharmacokinetics of cyclosporine in pharmacokinetic studies. In addition, canagliflozin is a substrate/weak inhibitor of drug transporter P glycoprotein (P-gp). Cyclosporine is a PGP inhibitor/substrate in vitro. Patients should be monitored for changes in glycemic control if therapy with either of these immunosuppressant drugs is initiated in patients receiving canagliflozin.
    Canagliflozin; Metformin: (Moderate) Cyclosporine has been reported to cause hyperglycemia. Cyclosporine may have direct beta-cell toxicity that may be dose-related. Canagliflozin did not meaningfully alter the pharmacokinetics of cyclosporine in pharmacokinetic studies. In addition, canagliflozin is a substrate/weak inhibitor of drug transporter P glycoprotein (P-gp). Cyclosporine is a PGP inhibitor/substrate in vitro. Patients should be monitored for changes in glycemic control if therapy with either of these immunosuppressant drugs is initiated in patients receiving canagliflozin. (Moderate) Cyclosporine has been reported to cause hyperglycemia; this effect appears to be dose-related and caused by direct beta-cell toxicity. Therefore, a pharmacodynamic interaction is possible with all antidiabetic agents and cyclosporine. Patients should be monitored for worsening glycemic control if therapy with cyclosporine is initiated in patients receiving antidiabetic agents.
    Candesartan: (Moderate) Coadministration of cyclosporine and an angiotensin II receptor antagonist, like candesartan, may increase the risk of hyperkalemia and reduced renal function. In response to cyclosporine-induced renal afferent vasoconstriction and glomerular hypoperfusion, angiotensin II is required to maintain an adequate glomerular filtration rate. Inhibition of angiotensin-converting enzyme (ACE) could reduce renal function acutely. Several cases of acute renal failure have been associated with the addition of enalapril to cyclosporine therapy in renal transplant patients. Also, cyclosporine can cause hyperkalemia, and inhibition of angiotensin II leads to reduced aldosterone concentrations, which can increase the serum potassium concentration. Closely monitor renal function and serum potassium concentrations in patients receiving cyclosporine concurrently with candesartan.
    Candesartan; Hydrochlorothiazide, HCTZ: (Moderate) Coadministration of cyclosporine and an angiotensin II receptor antagonist, like candesartan, may increase the risk of hyperkalemia and reduced renal function. In response to cyclosporine-induced renal afferent vasoconstriction and glomerular hypoperfusion, angiotensin II is required to maintain an adequate glomerular filtration rate. Inhibition of angiotensin-converting enzyme (ACE) could reduce renal function acutely. Several cases of acute renal failure have been associated with the addition of enalapril to cyclosporine therapy in renal transplant patients. Also, cyclosporine can cause hyperkalemia, and inhibition of angiotensin II leads to reduced aldosterone concentrations, which can increase the serum potassium concentration. Closely monitor renal function and serum potassium concentrations in patients receiving cyclosporine concurrently with candesartan.
    Capreomycin: (Major) Since capreomycin is eliminated by the kidney, coadministration with other potentially nephrotoxic drugs, including cyclosporine, may increase serum concentrations of either drug. Theoretically, the chronic coadministration of these drugs may increase the risk of developing nephrotoxicity, even in patients who have normal renal function. Monitor patients for changes in renal function if these drugs are coadministered.
    Carbamazepine: (Moderate) Carbamazepine can increase the clearance of cyclosporine by inducing cyclosporine metabolism.
    Cardiac glycosides: (Major) Severe digitalis toxicity has been seen within days of starting cyclosporine in patients previously taking digoxin. Monitor serum digoxin concentrations if digoxin is used concomitantly with cyclosporine; a digoxin dosage reduction may be needed. Reduced clearance of digoxin has been observed when it is given concurrently with cyclosporine. Reduced clearance may be due to cyclosporine inhibition of P-glycoprotein (P-gp), an energy-dependent drug efflux pump. Inhibition of the P-gp-mediated renal tubular secretion of digoxin is the postulated mechanism for decreased renal clearance. A decrease in the apparent volume of distribution of digoxin has been reported after cyclosporine administration.
    Carvedilol: (Moderate) Modest increases in mean trough cyclosporine concentrations may occur following initiation of carvedilol treatment. It is recommended that cyclosporine serum concentrations be monitored to individualize dosage.
    Caspofungin: (Major) In two clinical studies, cyclosporine increased the systemic exposure (AUC) of caspofungin by approximately 35%. Cyclosporine concentrations are not altered by coadministration with caspofungin. Seven of 20 healthy subjects who received caspofungin (35 mg or 70 mg) in combination with cyclosporine (3 mg/kg or 4 mg/kg) developed transient elevations in alanine transaminase (ALT) up to 3 times the upper limit of normal. Elevations in aspartate transaminase (AST) paralleled ALT elevations but were of lesser magnitude. As determined retrospectively, 14 of 40 patients who received caspofungin and cyclosporine (1 to 290 days, median 17.5 days) had an ALT concentration elevation greater than 5 times the upper limit of normal or greater than 3 times the baseline value during concurrent therapy or the following 14 days. Five of the 14 cases and one case of elevated bilirubin were considered possibly related to concomitant therapy; no clinical evidence of hepatotoxicity or serious hepatic events occurred. The manufacturer recommends against the concomitant use of caspofungin with cyclosporine unless the potential benefit outweighs the risk. Monitor patients who develop abnormal liver enzyme concentrations; a risk versus benefit decision for therapy continuation is recommended.
    Ceftriaxone: (Moderate) Cyclosporine serum concentrations may be increased if ceftriaxone is added. Although data are limited, ceftriaxone should be used cautiously in patients currently stabilized on cyclosporine. Vigilant serum cyclosporine serum concentration monitoring is warranted. Two case reports suggest that cyclosporine serum concentrations may rise if ceftriaxone is added. No changes in renal or hepatic function were observed in the 2 renal transplant patients. The mechanism of the potential interaction is unknown.
    Celecoxib: (Moderate) Serum creatinine,potassium concentrations, and cyclosporine concentrations should be closely monitored when systemic cyclosporine is given with nonsteroidal antiinflammatory drugs (NSAIDs). Renal dysfunction associated with cyclosporine may be potentiated by concurrent usage of NSAIDs. The effects of NSAIDs on the production of renal prostaglandins may cause changes in the elimination of cyclosporine. Potentiation of renal dysfunction may especially occur in a dehydrated patient. Patients should be monitored for signs and symptoms of cyclosporine toxicity and infection, as NSAIDs may mask fever, pain, or swelling.
    Ceritinib: (Major) Avoid coadministration of ceritinib with cyclosporine due to increased cyclosporine exposure. If coadministration is unavoidable, monitor cyclosporine levels and watch for cyclosporine-related adverse reactions; a dosage adjustment may be necessary. Ceritinib is a CYP3A4 inhibitor and cyclosporine is a CYP3A4 substrate with a narrow therapeutic index.
    Certolizumab pegol: (Moderate) The safety and efficacy of certolizumab in patients with immunosuppression have not been evaluated. Patients receiving immunosuppressives along with certolizumab may be at a greater risk of developing an infection. Many of the serious infections occurred in patients on immunosuppressive therapy who received certolizumab.
    Chloramphenicol: (Moderate) Increased cyclosporine trough concentrations have been reported in patients receiving chloramphenicol increasing the risk for cyclosporine toxicity. Close monitoring of cyclosporine concentrations appears to be warranted; cyclosporine dosage adjustments may be necessary during concurrent therapy.
    Chloroquine: (Major) Close monitoring of serum cyclosporine concentrations is recommended during coadministration of chloroquine. Sudden increases in cyclosporine concentrations have been reported after the addition of chloroquine. Discontinue chloroquine if necessary.
    Chlorthalidone; Clonidine: (Minor) Clonidine can inhibit cyclosporine-induced glomerular vasoconstriction and has been shown to offset cyclosporine-induced nephrotoxicity. Clonidine may adversely affect cyclosporine pharmacokinetics; limited data suggest that cyclosporine concentrations increase - dramatically, in some cases - when clonidine is added. Until more data are available, clinicians should use clonidine cautiously in patients stabilized on cyclosporine.
    Cholic Acid: (Major) Avoid concomitant use of cholic acid and inhibitors of the bile salt efflux pump (BSEP) such as cyclosporine because there is a risk of increased accumulation of conjugated bile salts in the liver resulting in clinical symptoms. If concomitant use is unavoidable, then monitor serum transaminases and bilirubin closely.
    Cidofovir: (Severe) The administration of cidofovir with other potentially nephrotoxic agents, such as cyclosporine is contraindicated. Cyclosporine should be discontinued at least 7 days prior to beginning cidofovir. Monitor renal function and fluid status carefully during cyclosporine usage.
    Cimetidine: (Moderate) Additive nephrotoxicity can occur if cyclosporine is administered with other nephrotoxic drugs such as cimetidine.
    Ciprofloxacin: (Moderate) Monitor renal function during concomitant therapy. Cyclosporine serum concentrations should be monitored and suitable dosage adjustments made. Coadministration of ciprofloxacin and cyclosporine may result in elevated plasma cyclosporine concentrations. Cyclosporine is extensively metabolized by CYP3A4; ciprofloxacin is an inhibitor of CYP3A4. Additionally, some quinolones, including ciprofloxacin, have been associated with transient elevations in serum creatinine in patients receiving concomitant cyclosporine and ciprofloxacin therapy and may potentiate renal dysfunction. Cases of nephrotoxicity with and without increases in cyclosporine concentrations during concurrent cyclosporine and ciprofloxacin treatment have been reported.
    Cisapride: (Severe) Cisapride is metabolized by the hepatic cytochrome P450 enzyme system, specifically the CYP3A4 isoenzyme. QT prolongation and ventricular arrhythmias, including torsade de pointes and death, have occurred when inhibitors of CYP3A4 are coadministered with cisapride. Cyclosporine may have the potential to inhibit the metabolism of cisapride through CYP3A4 and thus, should not be used with cisapride
    Cisatracurium: (Moderate) Cyclosporine may potentiate the action of nondepolarizing neuromuscular blockers. Prolonged neuromuscular blockade has been reported in patients receiving cyclosporine who receive neuromuscular blockers as part of surgical anesthesia. Monitor patients for recurrent neuromuscular blockade and respiratory depression; extended ventilatory support may be required.
    Cisplatin: (Moderate) Additive nephrotoxicity can occur if cyclosporine is administered with other nephrotoxic drugs such as cisplatin. Use of cyclosporine can aggravate the nephrotoxicity and electrolyte loss seen with cisplatin if given concurrently or shortly after cisplatin therapy.
    Cladribine: (Minor) Concurrent use of purine analogs with other agents which cause bone marrow or immune suppression such as immunosuppressives may result in additive effects. A dosage reduction of the antineoplastic may be indicated when used in combination with other myelosuppressive chemotherapy.
    Clarithromycin: (Major) Clarithromycin may inhibit the metabolism of cyclosporine via inhibition of the CYP3A4 isoenzyme, thus increasing cyclosporine's effects and the potential for toxicity. Clarithromycin may also reduce the intestinal metabolism of cyclosporine. It has been recommended to avoid cyclosporine in combination with macrolide agents or reduce the cyclosporine dosage by 50% when it is necessary to give any macrolides concurrently. Increased cyclosporine concentrations may be seen with 2 days of beginning combination therapy. In managing potential interactions between macrolides and cyclosporine, appropriate monitoring of cyclosporine concentrations is critical to help avoid graft failure or drug-related toxicity.
    Clofarabine: (Moderate) Concomitant use of clofarabine, a substrate of OAT1 and OAT3, and cyclosporine, an inhibitor of OAT protein (OATP), may result in increased clofarabine levels. Therefore, monitor for signs of clofarabine toxicity such as gastrointestinal toxicity (e.g., nausea, vomiting, diarrhea, mucosal inflammation), hematologic toxicity, and skin toxicity (e.g. hand and foot syndrome, rash, pruritus) in patients also receiving OATP inhibitors.
    Clonidine: (Minor) Clonidine can inhibit cyclosporine-induced glomerular vasoconstriction and has been shown to offset cyclosporine-induced nephrotoxicity. Clonidine may adversely affect cyclosporine pharmacokinetics; limited data suggest that cyclosporine concentrations increase - dramatically, in some cases - when clonidine is added. Until more data are available, clinicians should use clonidine cautiously in patients stabilized on cyclosporine.
    Cobicistat: (Moderate) Cyclosporine therapeutic drug monitoring is recommended when administered concurrently with cobicistat. Use of these medications together may result in elevated cyclosporine serum concentrations. Predictions regarding this interaction can be made based on the metabolic pathways of these drugs. Cobicistat is an inhibitor of CYP3A4, an isoenzyme responsible for the metabolism of cyclosporine. These drugs used in combination may result in elevated cyclosporine plasma concentrations, causing an increased risk for cyclosporine-related adverse events.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Alafenamide: (Moderate) Cyclosporine therapeutic drug monitoring is recommended when administered concurrently with cobicistat. Use of these medications together may result in elevated cyclosporine serum concentrations. Predictions regarding this interaction can be made based on the metabolic pathways of these drugs. Cobicistat is an inhibitor of CYP3A4, an isoenzyme responsible for the metabolism of cyclosporine. These drugs used in combination may result in elevated cyclosporine plasma concentrations, causing an increased risk for cyclosporine-related adverse events. (Moderate) Cyclosporine therapeutic drug monitoring is recommended when administered concurrently with tenofovir alafenamide. Tenofovir-containing products should be avoided with concurrent or recent use of a nephrotoxic agent, such as cyclosporine. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir alafenamide with drugs that are eliminated by active tubular secretion may increase concentrations of tenofovir and/or the co-administered drug. Drugs that decrease renal function may also increase concentrations of tenofovir. Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Monitor patients receiving concomitant nephrotoxic agents for changes in serum creatinine and phosphorus, and urine glucose and protein. In addition, tenofovir alafenamide is a substrate of the drug transporters P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and the organic anion transport protein (OATP1B1 and 1B3); cyclosporine is an inhibitor of all three transporters. Inhibition of P-gp, BCRP, and OATP by cyclosporine may further increase tenofovir plasma concentrations. When tenofovir alafenamide is administered as part of a cobicistat-containing product, its availability is increased by cobicistat and a further increase of tenofovir alafenamide concentrations is not expected upon coadministration of an additional P-gp inhibitor.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Tenofovir should be avoided with concurrent or recent use of a nephrotoxic agent; patients receiving concomitant nephrotoxic agents, such as cyclosporine, should be carefully monitored for changes in serum creatinine and phosphorus. (Moderate) Cyclosporine therapeutic drug monitoring is recommended when administered concurrently with cobicistat. Use of these medications together may result in elevated cyclosporine serum concentrations. Predictions regarding this interaction can be made based on the metabolic pathways of these drugs. Cobicistat is an inhibitor of CYP3A4, an isoenzyme responsible for the metabolism of cyclosporine. These drugs used in combination may result in elevated cyclosporine plasma concentrations, causing an increased risk for cyclosporine-related adverse events.
    Cobimetinib: (Major) Avoid the concurrent use of cobimetinib with chronic cyclosporine therapy due to the risk of cobimetinib toxicity. If concurrent short-term (14 days or less) use of cyclosporine is unavoidable, reduce the dose of cobimetinib to 20 mg once daily for patients normally taking 60 mg daily; after discontinuation of cyclosporine, resume cobimetinib at the previous dose. Use an alternative to cyclosporine in patients who are already taking a reduced dose of cobimetinib (40 or 20 mg daily). Cobimetinib is a P-glycoprotein (P-gp) substrate as well as a CYP3A substrate in vitro; cyclosporine is a moderate inhibitor of CYP3A and P-gp. In healthy subjects (n = 15), coadministration of a single 10 mg dose of cobimetinib with itraconazole (200 mg once daily for 14 days), a strong CYP3A4 inhibitor, increased the mean cobimetinib AUC by 6.7-fold (90% CI, 5.6 to 8) and the mean Cmax by 3.2-fold (90% CI, 2.7 to 3.7).
    Colchicine: (Major) Due to the risk for serious colchicine toxicity including multi-organ failure and death, avoid coadministration of colchicine and cyclosporine in patients with normal renal and hepatic function unless the use of both agents is imperative. Coadministration is contraindicated in patients with renal or hepatic impairment because colchicine accumulation may be greater in these populations. Cyclosporine can inhibit colchicine's metabolism via P-glycoprotein (P-gp) and CYP3A4, resulting in increased colchicine exposure. If coadministration in patients with normal renal and hepatic function cannot be avoided, adjust the dose of colchicine by either reducing the daily dose or the dosage frequency, and carefully monitor for colchicine toxicity. Specific dosage adjustment recommendations are available for the Colcrys product for patients who have taken cyclosporine in the past 14 days or require concurrent use: for prophylaxis of gout flares, if the original dose is 0.6 mg twice daily, decrease to 0.3 mg once daily or if the original dose is 0.6 mg once daily, decrease to 0.3 mg once every other day; for treatment of gout flares, give 0.6 mg as a single dose, then 0.3 mg 1 hour later, and do not repeat for at least 3 days; for familial Mediterranean fever, do not exceed a 0.6 mg/day.
    Colesevelam: (Moderate) Colesevelam decreases the Cmax and AUC of cyclosporine by 44% and 34%, respectively. The manufacturer recommends administration of cyclosporine at least 4 hours before colesevelam. Additionally, cyclosporine serum concentrations should be monitored.
    Colistimethate, Colistin, Polymyxin E: (Major) Theoretically, chronic coadministration may increase the risk of developing nephrotoxicity, even in patients who have normal renal function. Monitor patients for changes in renal function during concurrent use. Since colistimethate sodium is eliminated by the kidney, coadministration with other potentially nephrotoxic drugs, including cyclosporine, may increase serum concentrations of either drug.
    Conivaptan: (Major) Avoid concomitant use of conivaptan, a CYP3A4/P-glycoprotein (P-gp) inhibitor and CYP3A4 substrate, and cyclosporine, a CYP3A4/P-gp substrate and CYP3A4 inhibitor. Coadministration may result in elevated concentrations of both conivaptan and cyclosporine. According to the manufacturer of conivaptan, concomitant use of conivaptan with CYP3A4 substrates, such as cyclosporine, should be avoided. Subsequent treatment with CYP3A substrates may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Crizotinib: (Moderate) Monitor cyclosporine serum concentrations if coadministration with crizotinib is necessary and monitor for treatment-related adverse reactions. Exposure to both drugs may increase; adjust the dose of cyclosporine as clinically appropriate. Both crizotinib and cyclosporine are CYP3A4 substrates and moderate inhibitors. Additionally, cyclosporine is a P-glycoprotein (P-gp) substrate. Crizotinib inhibits P-gp at clinically relevant concentrations and has the potential to increase plasma concentrations of drugs that are substrates of P-gp.
    Dabigatran: (Major) Avoid concomitant use of dabigatran and cyclosporine. Increased serum concentrations of dabigatran and an increased risk of bleeding are possible when dabigatran, a P-glycoprotein (P-gp) substrate, is coadministered with cyclosporine, a P-gp inhibitor. P-gp inhibition is a major independent factor that results in increased exposure to dabigatran.
    Daclizumab: (Minor) Because daclizumab is an immunosuppressant, additive effects may be seen with other immunosuppressives. While therapy is designed to take advantage of this effect, patients may be predisposed to over-immunosuppression.
    Dalfopristin; Quinupristin: (Moderate) As cyclosporine is a CYP3A4 substrate, use with a CYP3A4 inhibitor, such as streptogramins, may result in increased serum concentrations of cyclosporine. CYP3A4 inhibitors may decrease the clearance of cyclosporine, which may reduce cyclosporine dosage requirements or cause cyclosporine toxicity including nephrotoxicity, hepatotoxicity, or seizures.
    Danazol: (Major) Danazol has been reported to increase concentrations of cyclosporine. Danazol is an inhibitor of CYP3A4 while cyclosporine is a substrate of CYP3A4. In a patient stabilized on cyclosporine, the addition of danazol 200 mg every 8 hours yielded a 38% increase in the cyclosporine blood concentration and necessitated a cyclosporine dosage reduction from 250 mg twice daily to 200 mg twice daily. Close monitoring of cyclosporine concentrations is required when danazol is given concurrently with cyclosporine. Case reports suggest that methyltestosterone may also increase plasma concentrations of cyclosporine, potentially increasing the risk of nephrotoxicity. The mechanism has not been established but is thought to be due to inhibition of cyclosporine metabolism. No data are available to evaluate whether other androgens act similarly. Until further data are available, close monitoring of cyclosporine serum concentrations is prudent during coadministration with androgens.
    Dapagliflozin: (Moderate) Both cyclosporine and tacrolimus have been reported to cause hyperglycemia. Tacrolimus has been implicated in causing insulin-dependent diabetes mellitus in patients after renal transplantation. Both of these drugs may have direct beta-cell toxicity; the effects from cyclosporine may be dose-related. Patients should be monitored for changes in glycemic control if therapy with either of these immunosuppressant drugs is initiated in patients receiving dapagliflozin.
    Dapagliflozin; Metformin: (Moderate) Both cyclosporine and tacrolimus have been reported to cause hyperglycemia. Tacrolimus has been implicated in causing insulin-dependent diabetes mellitus in patients after renal transplantation. Both of these drugs may have direct beta-cell toxicity; the effects from cyclosporine may be dose-related. Patients should be monitored for changes in glycemic control if therapy with either of these immunosuppressant drugs is initiated in patients receiving dapagliflozin. (Moderate) Cyclosporine has been reported to cause hyperglycemia; this effect appears to be dose-related and caused by direct beta-cell toxicity. Therefore, a pharmacodynamic interaction is possible with all antidiabetic agents and cyclosporine. Patients should be monitored for worsening glycemic control if therapy with cyclosporine is initiated in patients receiving antidiabetic agents.
    Dapagliflozin; Saxagliptin: (Moderate) Both cyclosporine and tacrolimus have been reported to cause hyperglycemia. Tacrolimus has been implicated in causing insulin-dependent diabetes mellitus in patients after renal transplantation. Both of these drugs may have direct beta-cell toxicity; the effects from cyclosporine may be dose-related. Patients should be monitored for changes in glycemic control if therapy with either of these immunosuppressant drugs is initiated in patients receiving dapagliflozin. (Moderate) Cyclosporine has been reported to cause hyperglycemia. Patients should be monitored for changes in glycemic control if therapy with cyclosporine is initiated in patients receiving saxagliptin.
    Darunavir: (Major) An interaction is anticipated to occur with all anti-retroviral protease inhibitors and cyclosporine, as all protease inhibitors inhibit CYP3A4. Cyclosporine toxicity, consisting of fatigue, headache, and GI distress, has been reported by a patient receiving cyclosporine and saquinavir. Prior to beginning saquinavir the patient had been receiving stable doses of cyclosporine resulting in trough concentrations of 150 to 200 mcg/ml. After receiving saquinavir for 3 days, the cyclosporine trough concentration increased to 580 mcg/ml. Dosages of both agents were decreased by 50% leading to resolution of symptoms. This interaction is probably due to CYP3A4 inhibition by saquinavir. Another possible mechanism is that both drugs have a high affinity for the drug efflux protein, P-glycoprotein, which may increase the absorption or decrease the clearance of the other drug.
    Darunavir; Cobicistat: (Major) An interaction is anticipated to occur with all anti-retroviral protease inhibitors and cyclosporine, as all protease inhibitors inhibit CYP3A4. Cyclosporine toxicity, consisting of fatigue, headache, and GI distress, has been reported by a patient receiving cyclosporine and saquinavir. Prior to beginning saquinavir the patient had been receiving stable doses of cyclosporine resulting in trough concentrations of 150 to 200 mcg/ml. After receiving saquinavir for 3 days, the cyclosporine trough concentration increased to 580 mcg/ml. Dosages of both agents were decreased by 50% leading to resolution of symptoms. This interaction is probably due to CYP3A4 inhibition by saquinavir. Another possible mechanism is that both drugs have a high affinity for the drug efflux protein, P-glycoprotein, which may increase the absorption or decrease the clearance of the other drug. (Moderate) Cyclosporine therapeutic drug monitoring is recommended when administered concurrently with cobicistat. Use of these medications together may result in elevated cyclosporine serum concentrations. Predictions regarding this interaction can be made based on the metabolic pathways of these drugs. Cobicistat is an inhibitor of CYP3A4, an isoenzyme responsible for the metabolism of cyclosporine. These drugs used in combination may result in elevated cyclosporine plasma concentrations, causing an increased risk for cyclosporine-related adverse events.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Major) An interaction is anticipated to occur with all anti-retroviral protease inhibitors and cyclosporine, as all protease inhibitors inhibit CYP3A4. Cyclosporine toxicity, consisting of fatigue, headache, and GI distress, has been reported by a patient receiving cyclosporine and saquinavir. Prior to beginning saquinavir the patient had been receiving stable doses of cyclosporine resulting in trough concentrations of 150 to 200 mcg/ml. After receiving saquinavir for 3 days, the cyclosporine trough concentration increased to 580 mcg/ml. Dosages of both agents were decreased by 50% leading to resolution of symptoms. This interaction is probably due to CYP3A4 inhibition by saquinavir. Another possible mechanism is that both drugs have a high affinity for the drug efflux protein, P-glycoprotein, which may increase the absorption or decrease the clearance of the other drug. (Major) Reduce cyclosporine dose to one-fifth (1/5th) of the patients current cyclosporine dose when initiating treatment with dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir, as coadministration results in elevated cyclosporine blood concentrations. With subsequent doses, monitor cyclosporine blood concentrations to determine further dose adjustments. After completion of the 4-drug hepatitis C treatment regimen, the dose should be re-adjusted based on measured blood concentrations. Monitor for renal function and cyclosporine associated adverse reactions. (Major) Reduce cyclosporine dose to one-fifth (1/5th) of the patients current cyclosporine dose when initiating treatment with dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir, as coadministration results in elevated cyclosporine blood concentrations. With subsequent doses, monitor cyclosporine blood concentrations to determine further dose adjustments. After completion of thehepatitis C treatment regimen, the dose should be re-adjusted based on measured blood concentrations. Monitor for renal function and cyclosporine associated adverse reactions (Major) Reduce cyclosporine dose to one-fifth (1/5th) of the patients current cyclosporine dose when initiating treatment with dasabuvir; ombitasvir; paritaprevir; ritonavir, as coadministration results in elevated cyclosporine blood concentrations. With subsequent doses, monitor cyclosporine blood concentrations to determine further dose adjustments. After completion of the 4-drug hepatitis C treatment regimen, the dose should be re-adjusted based on measured blood concentrations. Monitor for renal function and cyclosporine associated adverse reactions.
    Dasatinib: (Moderate) Dasatinib inhibits CYP3A4. Therefore, caution is warranted when drugs that are metabolized by this enzyme, such as cyclosporine, are administered concurrently with dasatinib as increased adverse reactions may occur.
    Daunorubicin Liposomal: (Major) Concurrent use of daunorubicin with other agents which cause bone marrow or immune suppression such as other immunosuppressives may result in additive effects. In addition, high doses of cyclosporine (starting at 16 mg/kg/day IV) may increase exposure to anthracyclines (e.g. daunorubicin) in cancer patients. Cyclosporine is a substrate and inhibitor of P-glycoprotein, an energy-dependent drug efflux pump encoded for by the multidrug resistance gene-1 (MDR1). Overexpression of this protein has been described as a mechanism of resistance to naturally-occurring (non-synthetic) chemotherapy agents. Cyclosporine can block MDR1-mediated resistance when given at much higher doses than those used in transplantation and may also enhance the efficacy of daunorubicin by inhibiting this protein. Valspodar is a cyclosporine analog with less renal and immunosuppressive effects than cyclosporine while retaining effects on MDR. The addition of cyclosporine or valspodar to daunorubicin therapy may result in increases in AUC for both daunorubicin and daunorubincinol possibly due to a decrease in clearance of parent drug, a decrease in metabolism of daunorubincinol, or an increase in intracellular daunorubicin concentrations.
    Daunorubicin Liposomal; Cytarabine Liposomal: (Major) Concurrent use of daunorubicin with other agents which cause bone marrow or immune suppression such as other immunosuppressives may result in additive effects. In addition, high doses of cyclosporine (starting at 16 mg/kg/day IV) may increase exposure to anthracyclines (e.g. daunorubicin) in cancer patients. Cyclosporine is a substrate and inhibitor of P-glycoprotein, an energy-dependent drug efflux pump encoded for by the multidrug resistance gene-1 (MDR1). Overexpression of this protein has been described as a mechanism of resistance to naturally-occurring (non-synthetic) chemotherapy agents. Cyclosporine can block MDR1-mediated resistance when given at much higher doses than those used in transplantation and may also enhance the efficacy of daunorubicin by inhibiting this protein. Valspodar is a cyclosporine analog with less renal and immunosuppressive effects than cyclosporine while retaining effects on MDR. The addition of cyclosporine or valspodar to daunorubicin therapy may result in increases in AUC for both daunorubicin and daunorubincinol possibly due to a decrease in clearance of parent drug, a decrease in metabolism of daunorubincinol, or an increase in intracellular daunorubicin concentrations.
    Daunorubicin: (Major) Concurrent use of daunorubicin with other agents which cause bone marrow or immune suppression such as other immunosuppressives may result in additive effects. In addition, high doses of cyclosporine (starting at 16 mg/kg/day IV) may increase exposure to anthracyclines (e.g. daunorubicin) in cancer patients. Cyclosporine is a substrate and inhibitor of P-glycoprotein, an energy-dependent drug efflux pump encoded for by the multidrug resistance gene-1 (MDR1). Overexpression of this protein has been described as a mechanism of resistance to naturally-occurring (non-synthetic) chemotherapy agents. Cyclosporine can block MDR1-mediated resistance when given at much higher doses than those used in transplantation and may also enhance the efficacy of daunorubicin by inhibiting this protein. Valspodar is a cyclosporine analog with less renal and immunosuppressive effects than cyclosporine while retaining effects on MDR. The addition of cyclosporine or valspodar to daunorubicin therapy may result in increases in AUC for both daunorubicin and daunorubincinol possibly due to a decrease in clearance of parent drug, a decrease in metabolism of daunorubincinol, or an increase in intracellular daunorubicin concentrations.
    Deferasirox: (Moderate) The concomitant administratin of midazolam, a CYP3A4 substrate, and deferasirox resulted in a decrease in the peak serum concentration of midazolam by 23% and midazolam exposure by 17% in healthy volunteers. This effect may be even more pronounced in patients. Although not specifically studied, reduced serum concentrations may also occur in patients taking other CYP3A4 substrates such as cyclosporine. If these drugs are used together, monitor patients for a decrease in the effects of cyclosporine.
    Deferoxamine: (Moderate) Although not specifically studied, reduced serum concentrations of deferoxamine may occur in patients taking other CYP3A4 substrates such as cyclosporine. If these drugs are used together, monitor patients for a decrease in the effects of cyclosporine. In addition, coadministration of deferasirox with other potentially nephrotoxic drugs, including cyclosporine, may increase the risk of acute renal failure. Monitor serum creatinine and/or creatinine clearance in patients who are receiving deferasirox and cyclosporine concomitantly.
    Deflazacort: (Major) Decrease deflazacort dose to one third of the recommended dosage when coadministered with cyclosporine. Concurrent use may significantly increase concentrations of 21-desDFZ, the active metabolite of deflazacort, resulting in an increased risk of toxicity. Deflazacort is a CYP3A4 substrate; cyclosporine is a moderate inhibitor of CYP3A4. Administration of deflazacort with clarithromycin, a strong CYP3A4 inhibitor, increased total exposure to 21-desDFZ by about 3-fold.
    Delavirdine: (Moderate) Delavirdine is a potent inhibitor of the CYP3A4 and increased plasma concentrations of drugs extensively metabolized by this enzyme, such as cyclosporine, should be expected with concurrent use of delavirdine.
    Dichlorphenamide: (Moderate) Use dichlorphenamide and systemic cyclosporine together with caution as both drugs can cause metabolic acidosis. Concurrent use may increase the severity of metabolic acidosis. Measure sodium bicarbonate concentrations at baseline and periodically during dichlorphenamide treatment. If metabolic acidosis occurs or persists, consider reducing the dose or discontinuing dichlorphenamide therapy.
    Diclofenac: (Major) Significant interactions may occur between systemic cyclosporine and nonsteroidal antiinflammatory drugs (NSAIDs) such as diclofenac. Clinical status and serum creatinine and potassium concentrations should be closely monitored when cyclosporine is given with nonsteroidal antiinflammatory drugs (NSAIDs). Renal dysfunction associated with cyclosporine may be potentiated by concurrent usage of diclofenac, especially in a dehydrated patient. Although concomitant administration of diclofenac does not affect cyclosporine blood concentrations, a doubling of diclofenac blood concentrations and occasional reports of reversible decreases in renal function have been noted. Consequently, the dose of diclofenac should be in the lower end of the therapeutic range. The mechanism of the interaction may be inhibition of diclofenac metabolism, as diclofenac is a substrate for and cyclosporine an inhibitor of CYP3A4. NSAIDs may mask fever, pain, swelling and other signs and symptoms of an infection; use NSAIDs with caution in patients receiving immunosuppressants such as cyclosporine. Interactions with skin and eye products containing these drugs are not expected. Increased tear production was not seen in patients receiving ophthalmic NSAIDs or using punctual plugs concurrently with cyclosporine ophthalmic emulsion.
    Diclofenac; Misoprostol: (Major) Significant interactions may occur between systemic cyclosporine and nonsteroidal antiinflammatory drugs (NSAIDs) such as diclofenac. Clinical status and serum creatinine and potassium concentrations should be closely monitored when cyclosporine is given with nonsteroidal antiinflammatory drugs (NSAIDs). Renal dysfunction associated with cyclosporine may be potentiated by concurrent usage of diclofenac, especially in a dehydrated patient. Although concomitant administration of diclofenac does not affect cyclosporine blood concentrations, a doubling of diclofenac blood concentrations and occasional reports of reversible decreases in renal function have been noted. Consequently, the dose of diclofenac should be in the lower end of the therapeutic range. The mechanism of the interaction may be inhibition of diclofenac metabolism, as diclofenac is a substrate for and cyclosporine an inhibitor of CYP3A4. NSAIDs may mask fever, pain, swelling and other signs and symptoms of an infection; use NSAIDs with caution in patients receiving immunosuppressants such as cyclosporine. Interactions with skin and eye products containing these drugs are not expected. Increased tear production was not seen in patients receiving ophthalmic NSAIDs or using punctual plugs concurrently with cyclosporine ophthalmic emulsion.
    Diflunisal: (Moderate) Clinical status and serum creatinine and potassium concentrations should be closely monitored when cyclosporine is given with diflunisal, a nonsteroidal antiinflammatory drug (NSAID). Renal dysfunction associated with cyclosporine may be potentiated by concurrent usage of NSAIDs. Potentiation of renal dysfunction may especially occur in a dehydrated patient. Nonsteroidal antiinflammatory drugs (NSAIDs) may also mask fever, pain, swelling and other signs and symptoms of an infection; use NSAIDs with caution in patients receiving immunosuppressants such as cyclosporine.
    Digitoxin: (Major) Severe digitalis toxicity has been seen within days of starting cyclosporine in patients previously taking digoxin. Monitor serum digoxin concentrations if digoxin is used concomitantly with cyclosporine; a digoxin dosage reduction may be needed. Reduced clearance of digoxin has been observed when it is given concurrently with cyclosporine. Reduced clearance may be due to cyclosporine inhibition of P-glycoprotein (P-gp), an energy-dependent drug efflux pump. Inhibition of the P-gp-mediated renal tubular secretion of digoxin is the postulated mechanism for decreased renal clearance. A decrease in the apparent volume of distribution of digoxin has been reported after cyclosporine administration.
    Digoxin: (Major) Severe digitalis toxicity has been seen within days of starting cyclosporine in patients previously taking digoxin. Monitor serum digoxin concentrations if digoxin is used concomitantly with cyclosporine; a digoxin dosage reduction may be needed. Reduced clearance of digoxin has been observed when it is given concurrently with cyclosporine. Reduced clearance may be due to cyclosporine inhibition of P-glycoprotein (P-gp), an energy-dependent drug efflux pump. Inhibition of the P-gp-mediated renal tubular secretion of digoxin is the postulated mechanism for decreased renal clearance. A decrease in the apparent volume of distribution of digoxin has been reported after cyclosporine administration.
    Diltiazem: (Moderate) Diltiazem inhibits CYP3A4 metabolism and thereby increases cyclosporine serum concentrations. Cyclosporine dosage reduction (20 to 50%) may be required when diltiazem therapy is initiated to prevent cyclosporine toxicity.
    Diphenhydramine; Ibuprofen: (Moderate) Serum creatinine, potassium concentrations, and cyclosporine concentrations should be closely monitored when systemic cyclosporine is given with nonsteroidal antiinflammatory drugs (NSAIDs). Renal dysfunction associated with cyclosporine may be potentiated by concurrent usage of NSAIDs. The effects of NSAIDs on the production of renal prostaglandins may cause changes in the elimination of cyclosporine. Potentiation of renal dysfunction may especially occur in a dehydrated patient. Patients should be monitored for signs and symptoms of cyclosporine toxicity and infection, as NSAIDs may mask fever, pain, or swelling. Increased tear production was not seen in patients receiving ophthalmic NSAIDs or using punctual plugs concurrently with cyclosporine ophthalmic emulsion.
    Diphenhydramine; Naproxen: (Moderate) Serum creatinine ,potassium concentrations, and cyclosporine concentrations should be closely monitored when systemic cyclosporine is given with nonsteroidal antiinflammatory drugs (NSAIDs). Renal dysfunction associated with cyclosporine may be potentiated by concurrent usage of NSAIDs. The effects of NSAIDs on the production of renal prostaglandins may cause changes in the elimination of cyclosporine. Potentiation of renal dysfunction may especially occur in a dehydrated patient. Patients should be monitored for signs and symptoms of cyclosporine toxicity and infection, as NSAIDs may mask fever, pain, or swelling. Increased tear production was not seen in patients receiving ophthalmic NSAIDs or using punctual plugs concurrently with cyclosporine ophthalmic emulsion.
    Disulfiram: (Major) Cyclosporine parenteral and oral solutions contain ethanol; liquid-filled capsules contain ethanol in lower percentages. Administration of ethanol-containing formulations of cyclosporine to patients receiving or who have recently received disulfiram may result in disulfiram-like reactions. A disulfiram reaction would not be expected to occur with non-ethanol containing formulations.
    Docetaxel: (Major) Cyclosporine is a substrate and inhibitor of P-glycoprotein, an energy-dependent drug efflux pump encoded for by the multidrug resistance gene-1 (MDR1). Overexpression of this protein has been described as a mechanism of resistance to naturally-occurring (non-synthetic) chemotherapy agents. Cyclosporine may enhance the efficacy of the certain chemotherapy agents including docetaxel, paclitaxel, and vinca alkaloids by inhibiting this protein. Cyclosporine can block MDR1-mediated resistance when given at much higher doses than those used in transplantation. The addition of cyclosporine may also enhance the efficacy and/or toxicity of these chemotherapy regimens by other mechanisms. The addition of cyclosporine may increase the AUC values of these chemotherapy agents due to a decrease in either chemotherapy metabolism or clearance, or due to an increase in the intracellular concentrations of the chemotherapy agent.
    Doxacurium: (Moderate) Cyclosporine may potentiate the action of nondepolarizing neuromuscular blockers. Prolonged neuromuscular blockade has been reported in patients receiving cyclosporine who receive neuromuscular blockers as part of surgical anesthesia. Monitor patients for recurrent neuromuscular blockade and respiratory depression; extended ventilatory support may be required.
    Doxercalciferol: (Moderate) CYP450 enzyme inhibitors, like cyclosporine, may inhibit the 25-hydroxylation of doxercalciferol, thereby decreasing the formation of the active metabolite and thus, decreasing efficacy. Patients should be monitored for a decrease in efficacy if CYP450 inhibitors are coadministered with doxercalciferol.
    Doxorubicin: (Major) Concurrent use of doxorubicin with other agents which cause bone marrow or immune suppression such as other immunosuppressives may result in additive effects. In addition, high doses of cyclosporine (starting at 16 mg/kg/day IV) may increase exposure to anthracyclines (e.g. doxorubicin) in cancer patients. Cyclosporine is a substrate and inhibitor of P-glycoprotein, an energy-dependent drug efflux pump encoded for by the multidrug resistance gene-1 (MDR1). Overexpression of this protein has been described as a mechanism of resistance to naturally-occurring (non-synthetic) chemotherapy agents. Cyclosporine can block MDR1-mediated resistance when given at much higher doses than those used in transplantation and may also enhance the efficacy of doxorubicin by inhibiting this protein. Valspodar is a cyclosporine analog with less renal and immunosuppressive effects than cyclosporine while retaining effects on MDR. The addition of cyclosporine or valspodar to doxorubicin therapy may result in increases in AUC for both doxorubicin and doxorubicinol possibly due to a decrease in clearance of parent drug, a decrease in metabolism of doxorubicinol, or an increase in intracellular doxorubicin concentrations. Literature reports suggest that adding cyclosporine to doxorubicin results in more profound and prolonged hematologic toxicity than doxorubicin alone; coma and/or seizures have also been described.
    Dronabinol, THC: (Major) Use caution if coadministration of dronabinol with cyclosporine is necessary, and monitor for an increase in dronabinol-related adverse reactions (e.g., feeling high, dizziness, confusion, somnolence) as well as increased cyclosporine levels. Dronabinol is a CYP2C9 and 3A4 substrate; cyclosporine is a moderate inhibitor of CYP3A4. Concomitant use may result in elevated plasma concentrations of dronabinol. Dronabinol is also highly bound to plasma proteins and may displace and increase the free fraction of other concomitantly administered protein-bound drugs such as cyclosporine.
    Dronedarone: (Severe) The concomitant use of dronedarone and cyclosporine is contraindicated. Dronedarone is metabolized by CYP3A and is an inhibitor of CYP3A and P-gp. Cyclosporine is a substrate and strong inhibitor of CYP3A4 and is a substrate for P-gp. Repeated doses of ketoconazole, also a strong CYP3A4 inhibitor, increased dronedarone exposure 17-fold and increased dronedarone Cmax 9-fold. No data exist regarding the safe administration of dronedarone with strong CYP3A4 inhibitors; therefore, concomitant use is contraindicated. Also, the effects of dronedarone on the pharmacokinetics of cyclosporine have not been described, although an increase in cyclosporine serum concentrations is possible.
    Dulaglutide: (Moderate) Cyclosporine has been reported to cause hyperglycemia. It may have direct beta-cell toxicity; the effects may be dose-related. Patients should be monitored for worsening of glycemic control if therapy with cyclosporine is initiated in patients receiving antidiabetic agents, including incretin mimetics.
    Dupilumab: (Moderate) Coadministration of dupilumab may result in altered exposure to cyclosporine. During chronic inflammation, increased levels of certain cytokines can alter the formation of CYP450 enzymes. Thus, the formation of CYP450 enzymes could be normalized during dupilumab administration. Clinically relevant drug interactions may occur with CYP450 substrates that have a narrow therapeutic index such as cyclosporine. Monitor cyclosporine concentrations if dupilumab is initiated or discontinued in a patient taking cyclosporine; cyclosporine dose adjustments may be needed.
    Dutasteride; Tamsulosin: (Moderate) Use caution when administering tamsulosin with a moderate CYP3A4 inhibitor such as cyclosporine. Tamsulosin is extensively metabolized by CYP3A4 hepatic enzymes. In clinical evaluation, concomitant treatment with a strong CYP3A4 inhibitor resulted in significant increases in tamsulosin exposure; interactions with moderate CYP3A4 inhibitors have not been evaluated. If concomitant use in necessary, monitor patient closely for increased side effects.
    Echinacea: (Major) Echinacea possesses immunostimulatory activity and may theoretically reduce the response to immunosuppressant drugs like cyclosporine. Although documentation is lacking, coadministration of echinacea with immunosuppressants is not recommended by some resources. Furthermore, cyclosporine is metabolized by CYP3A4. The effects of echinacea on CYP3A4 are complex. In vitro data suggest that echinacea can inhibit the CYP3A4 isoenzyme; however, the clinical significance of these data are not yet known, as some authors have reported the in vivo activity in humans to be minor. Other limited in vivo data indicate that echinacea inhibits intestinal CYP3A4, but induces hepatic CYP3A4. While the overall effect on orally administered drugs that are substrates of CYP3A4 may be negligible, it may be prudent to monitor patients for changes in efficacy or toxicity until more data are available.
    Edoxaban: (Moderate) Coadministration of edoxaban and cyclosporine may result in increased concentrations of edoxaban. Edoxaban is a P-glycoprotein (P-gp) substrate and cyclosporine is a P-gp inhibitor. Increased concentrations of edoxaban may occur during concomitant use of cyclosporine; monitor for increased adverse effects of edoxaban. Dosage reduction may be considered for patients being treated for deep venous thrombosis (DVT) or pulmonary embolism.
    Efalizumab: (Major) The safety and efficacy of efalizumab in combination with other immunosuppressive agents have not been evaluated. Patients receiving immunosuppressives should not receive concurrent therapy with efalizumab because of the potential risk for serious infections and secondary malignancies. The risk is related to the intensity and duration of immunosuppression rather than the specific agents.
    Efavirenz: (Moderate) Efavirenz induces cytochrome P450 (CYP) 3A4 and may decrease serum concentrations of drugs metabolized by this enzyme. Caution is recommended when administering efavirenz with CYP3A4 substrates that have a narrow therapeutic range, such as cyclosporine. Monitoring of serum cyclosporine concentrations for at least 2 weeks is recommended when starting or stopping treatment with efavirenz.
    Efavirenz; Emtricitabine; Tenofovir: (Major) Tenofovir should be avoided with concurrent or recent use of a nephrotoxic agent; patients receiving concomitant nephrotoxic agents, such as cyclosporine, should be carefully monitored for changes in serum creatinine and phosphorus. (Moderate) Efavirenz induces cytochrome P450 (CYP) 3A4 and may decrease serum concentrations of drugs metabolized by this enzyme. Caution is recommended when administering efavirenz with CYP3A4 substrates that have a narrow therapeutic range, such as cyclosporine. Monitoring of serum cyclosporine concentrations for at least 2 weeks is recommended when starting or stopping treatment with efavirenz.
    Elbasvir; Grazoprevir: (Severe) Concurrent administration of elbasvir; grazoprevir with cyclosporine is contraindicated. Use of these drugs together is expected to significantly increase the plasma concentrations of elbasvir and grazoprevir, and may result in adverse effects (i.e., elevated ALT concentrations). Cyclosporine is an inhibitor of the hepatic enzyme CYP3A and the organic anion transporting protein (OATP1B1). Elbasvir and grazoprevir are metabolized by CYP3A, and grazoprevir is also a substrate of OATP1B1/3.
    Eletriptan: (Major) Eletriptan is contraindicated for use within 72 hours of usage of any drug that is a potent CYP3A4 inhibitor whereby the inhibition effect is described in the prescribing information for the potential interacting drug, such as cyclosporine.
    Eliglustat: (Major) In intermediate or poor CYP2D6 metabolizers (IMs or PMs), coadministration of cyclosporine and eliglustat is not recommended. In extensive CYP2D6 metabolizers (EMs), coadministration of cyclosporine and eliglustat requires dosage reduction of eliglustat to 84 mg PO once daily. Monitor therapeutic cyclosporine concentrations closely and adjust the dosage as necessary. The coadministration of eliglustat with both cyclosporine and a moderate or strong CYP2D6 inhibitor is contraindicated in all patients. Cyclosporine is a moderate CYP3A inhibitor and P-glycoprotein (P-gp) substrate; eliglustat is a CYP3A and CYP2D6 substrate and a P-gp inhibitor. Coadministration of eliglustat with CYP3A inhibitors, such as cyclosporine, may increase eliglustat exposure and the risk of serious adverse events (e.g., QT prolongation and cardiac arrhythmias); this risk is the highest in CYP2D6 IMs and PMs because a larger portion of the eliglustat dose is metabolized via CYP3A. In addition, coadministration of eliglustat with P-gp substrates (e.g., cyclosporine) may result in increased concentrations of the concomitant drug. Although specific recommendations are not available, when eliglustat is given in combination with digoxin, another narrow therapeutic index P-gp substrate, an empiric digoxin dosage reduction of 30% followed by careful monitoring is recommended.
    Eluxadoline: (Major) When administered concurrently with cyclosporine, the dose of eluxadoline must be reduced to 75 mg PO twice daily, and the patient should be closely monitored for adverse effects (i.e., decreased mental and physical acuity). Eluxadoline is a substrate of the organic anion-transporting peptide (OATP1B1); cyclosporine is an OATP inhibitor. Use of these drugs together results in a 4.4-fold increase in exposure (AUC) and a 6.2-fold increase in maximum plasma concentration of eluxadoline. In addition, because the effects of eluxadoline on CYP3A4 have not been established, the manufacturer recommends caution when administering eluxadoline concurrently with CYP3A4 substrates that have a narrow therapeutic index, such as cyclosporine. Closely monitor cyclosporine drug concentrations when initiating or discontinuing eluxadoline therapy. Advise patients against driving or operating machinery until the combine effects of these drugs on the individual patient is known.
    Empagliflozin: (Moderate) Cyclosporine has been reported to cause hyperglycemia. Cyclosporine may have direct beta-cell toxicity; the effects may be dose-related. Patients should be monitored for changes in glycemic control if therapy with cyclosporine is initiated in patients receiving empagliflozin.
    Empagliflozin; Linagliptin: (Moderate) Cyclosporine has been reported to cause hyperglycemia. Cyclosporine may have direct beta-cell toxicity; the effects from cyclosporine may be dose-related. Patients should be monitored for changes in glycemic control if therapy with either of these immunosuppressant drugs is initiated in patients receiving linagliptin. (Moderate) Cyclosporine has been reported to cause hyperglycemia. Cyclosporine may have direct beta-cell toxicity; the effects may be dose-related. Patients should be monitored for changes in glycemic control if therapy with cyclosporine is initiated in patients receiving empagliflozin.
    Empagliflozin; Metformin: (Moderate) Cyclosporine has been reported to cause hyperglycemia. Cyclosporine may have direct beta-cell toxicity; the effects may be dose-related. Patients should be monitored for changes in glycemic control if therapy with cyclosporine is initiated in patients receiving empagliflozin. (Moderate) Cyclosporine has been reported to cause hyperglycemia; this effect appears to be dose-related and caused by direct beta-cell toxicity. Therefore, a pharmacodynamic interaction is possible with all antidiabetic agents and cyclosporine. Patients should be monitored for worsening glycemic control if therapy with cyclosporine is initiated in patients receiving antidiabetic agents.
    Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Moderate) Cyclosporine therapeutic drug monitoring is recommended when administered concurrently with tenofovir alafenamide. Tenofovir-containing products should be avoided with concurrent or recent use of a nephrotoxic agent, such as cyclosporine. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir alafenamide with drugs that are eliminated by active tubular secretion may increase concentrations of tenofovir and/or the co-administered drug. Drugs that decrease renal function may also increase concentrations of tenofovir. Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Monitor patients receiving concomitant nephrotoxic agents for changes in serum creatinine and phosphorus, and urine glucose and protein. In addition, tenofovir alafenamide is a substrate of the drug transporters P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and the organic anion transport protein (OATP1B1 and 1B3); cyclosporine is an inhibitor of all three transporters. Inhibition of P-gp, BCRP, and OATP by cyclosporine may further increase tenofovir plasma concentrations. When tenofovir alafenamide is administered as part of a cobicistat-containing product, its availability is increased by cobicistat and a further increase of tenofovir alafenamide concentrations is not expected upon coadministration of an additional P-gp inhibitor.
    Emtricitabine; Rilpivirine; Tenofovir disoproxil fumarate: (Major) Tenofovir should be avoided with concurrent or recent use of a nephrotoxic agent; patients receiving concomitant nephrotoxic agents, such as cyclosporine, should be carefully monitored for changes in serum creatinine and phosphorus.
    Emtricitabine; Tenofovir alafenamide: (Moderate) Cyclosporine therapeutic drug monitoring is recommended when administered concurrently with tenofovir alafenamide. Tenofovir-containing products should be avoided with concurrent or recent use of a nephrotoxic agent, such as cyclosporine. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir alafenamide with drugs that are eliminated by active tubular secretion may increase concentrations of tenofovir and/or the co-administered drug. Drugs that decrease renal function may also increase concentrations of tenofovir. Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Monitor patients receiving concomitant nephrotoxic agents for changes in serum creatinine and phosphorus, and urine glucose and protein. In addition, tenofovir alafenamide is a substrate of the drug transporters P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and the organic anion transport protein (OATP1B1 and 1B3); cyclosporine is an inhibitor of all three transporters. Inhibition of P-gp, BCRP, and OATP by cyclosporine may further increase tenofovir plasma concentrations. When tenofovir alafenamide is administered as part of a cobicistat-containing product, its availability is increased by cobicistat and a further increase of tenofovir alafenamide concentrations is not expected upon coadministration of an additional P-gp inhibitor.
    Emtricitabine; Tenofovir disoproxil fumarate: (Major) Tenofovir should be avoided with concurrent or recent use of a nephrotoxic agent; patients receiving concomitant nephrotoxic agents, such as cyclosporine, should be carefully monitored for changes in serum creatinine and phosphorus.
    Enalapril; Felodipine: (Major) Cyclosporine may competitively inhibit the first-pass metabolism of felodipine by cytochrome P450 3A4 in the gut wall, resulting in an increased bioavailability of felodipine. The concomitant administration of cyclosporine and felodipine significantly increases the peak felodipine plasma concentration (151%) and AUC (58%). The combination resulted in a greater decrease in mean diastolic blood pressure over 24 hours than either drug alone. Patients should avoid taking felodipine with cyclosporine; separate doses by at least two hours. Patients receiving cyclosporine should be monitored for potential risk of felodipine dose-related adverse effects (e.g., flushing, edema). Felodipine has been shown to have minimal effects on cyclosporine blood concentrations.
    Entecavir: (Moderate) In a small pilot study of entecavir in HBV-infected liver transplant recipients on stable doses of cyclosporine, entecavir exposure was approximately 2-fold the exposure in healthy subjects with normal renal function. Altered renal function contributed to the increase in entecavir exposure in these patients. Monitor renal function.
    Enzalutamide: (Major) Closely monitor cyclosporine levels and adjust the dose of cyclosporine as appropriate if coadministration with enzalutamide is necessary. Cyclosporine is extensively metabolized by CYP3A4 and has a narrow therapeutic index; enzalutamide is a strong CYP3A4 inducer.
    Epirubicin: (Major) Concurrent use of epirubicin with other agents which cause bone marrow or immune suppression such as other immunosuppressives may result in additive effects. In addition, high doses of cyclosporine (starting at 16 mg/kg/day IV) may increase exposure to anthracyclines in cancer patients. Cyclosporine is a substrate and inhibitor of P-glycoprotein, an energy-dependent drug efflux pump encoded for by the multidrug resistance gene-1 (MDR1). Overexpression of this protein has been described as a mechanism of resistance to naturally-occurring (non-synthetic) chemotherapy agents. Cyclosporine can block MDR1-mediated resistance when given at much higher doses than those used in transplantation and may also enhance the efficacy of epirubicin by inhibiting this protein. Valspodar is a cyclosporine analog with less renal and immunosuppressive effects than cyclosporine while retaining effects on MDR. The addition of cyclosporine or valspodar to epirubicin therapy may result in increases in AUC for both epirubicin and epirubicinol possibly due to a decrease in clearance of parent drug, a decrease in metabolism of epirubicinol, or an increase in intracellular epirubicin concentrations.
    Eplerenone: (Major) Eplerenone is metabolized by the CYP3A4 pathway. Cyclosporine inhibits the hepatic CYP3A4 isoenzyme and therefore may increase the serum concentrations of eplerenone. Increased eplerenone concentrations may lead to a risk of developing hyperkalemia and hypotension. If these medications are given concurrently in post-myocardial infarction patients with heart failure, do not exceed an eplerenone dose of 25 mg PO once daily. If these medications are given concurrently, and eplerenone is used for hypertension, initiate eplerenone at 25 mg PO once daily. The dose may be increased to a maximum of 25 mg PO twice daily for inadequate blood pressure response.
    Eprosartan: (Moderate) Coadministration of cyclosporine and an angiotensin II receptor antagonist, like eprosartan, may increase the risk of hyperkalemia and reduced renal function. In response to cyclosporine-induced renal afferent vasoconstriction and glomerular hypoperfusion, angiotensin II is required to maintain an adequate glomerular filtration rate. Inhibition of angiotensin-converting enzyme (ACE) could reduce renal function acutely. Several cases of acute renal failure have been associated with the addition of enalapril to cyclosporine therapy in renal transplant patients. Also, cyclosporine can cause hyperkalemia, and inhibition of angiotensin II leads to reduced aldosterone concentrations, which can increase the serum potassium concentration. Closely monitor renal function and serum potassium concentrations in patients receiving cyclosporine concurrently with eprosartan.
    Eprosartan; Hydrochlorothiazide, HCTZ: (Moderate) Coadministration of cyclosporine and an angiotensin II receptor antagonist, like eprosartan, may increase the risk of hyperkalemia and reduced renal function. In response to cyclosporine-induced renal afferent vasoconstriction and glomerular hypoperfusion, angiotensin II is required to maintain an adequate glomerular filtration rate. Inhibition of angiotensin-converting enzyme (ACE) could reduce renal function acutely. Several cases of acute renal failure have been associated with the addition of enalapril to cyclosporine therapy in renal transplant patients. Also, cyclosporine can cause hyperkalemia, and inhibition of angiotensin II leads to reduced aldosterone concentrations, which can increase the serum potassium concentration. Closely monitor renal function and serum potassium concentrations in patients receiving cyclosporine concurrently with eprosartan.
    Erlotinib: (Moderate) Use caution if coadministration of erlotinib with cyclosporine is necessary due to the risk of increased erlotinib-related adverse reactions, and avoid coadministration with erlotinib if the patient is additionally taking a CYP1A2 inhibitor. If the patient is taking both cyclosporine and a CYP1A2 inhibitor and severe reactions occur, reduce the dose of erlotinib by 50 mg decrements; the manufacturer of erlotinib makes the same recommendations for toxicity-related dose reductions in patients taking strong CYP3A4 inhibitors without concomitant CYP1A2 inhibitors. Cyclosporine is a moderate CYP3A4 inhibitor. Erlotinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Coadministration of erlotinib with ketoconazole, a strong CYP3A4 inhibitor, increased the erlotinib AUC by 67%. Coadministration of erlotinib with ciprofloxacin, a moderate inhibitor of CYP3A4 and CYP1A2, increased the erlotinib AUC by 39% and the Cmax by 17%; coadministration with cyclosporine may also increase erlotinib exposure.
    Erythromycin: (Major) Erythromycin may inhibit the metabolism of cyclosporine via inhibition of the CYP3A4 isoenzyme, thus increasing cyclosporine's effects and the potential for toxicity. Additionally, erythromycin has been associated with inhibition of P-glycoprotein, which leads to decreased intestinal metabolism and increased oral absorption of cyclosporine. It has been recommend to avoid cyclosporine in combination with macrolide agents or reduce the cyclosporine dosage by 50% when it is necessary to give any macrolide concurrently. Increased cyclosporine concentrations may be seen with 2 days of beginning combination therapy. In managing potential interactions between macrolides and cyclosporine, appropriate monitoring of cyclosporine concentrations is critical to help avoid graft failure or drug-related toxicity.
    Erythromycin; Sulfisoxazole: (Major) Erythromycin may inhibit the metabolism of cyclosporine via inhibition of the CYP3A4 isoenzyme, thus increasing cyclosporine's effects and the potential for toxicity. Additionally, erythromycin has been associated with inhibition of P-glycoprotein, which leads to decreased intestinal metabolism and increased oral absorption of cyclosporine. It has been recommend to avoid cyclosporine in combination with macrolide agents or reduce the cyclosporine dosage by 50% when it is necessary to give any macrolide concurrently. Increased cyclosporine concentrations may be seen with 2 days of beginning combination therapy. In managing potential interactions between macrolides and cyclosporine, appropriate monitoring of cyclosporine concentrations is critical to help avoid graft failure or drug-related toxicity.
    Eslicarbazepine: (Moderate) In vivo studies suggest eslicarbazepine is an inducer of CYP3A4. Coadministration of CYP3A4 substrates, such as cyclosporine, may result in decreased serum concentrations of the substrate. Cyclosporine concentrations should be monitored closely to avoid loss of clinical efficacy until a new steady-state cyclosporine concentration is achieved when eslicarbazepine is added to an existing cyclosporine regimen; conversely, if eslicarbazepine is discontinued, cyclosporine concentrations could increase.
    Esomeprazole; Naproxen: (Moderate) Serum creatinine ,potassium concentrations, and cyclosporine concentrations should be closely monitored when systemic cyclosporine is given with nonsteroidal antiinflammatory drugs (NSAIDs). Renal dysfunction associated with cyclosporine may be potentiated by concurrent usage of NSAIDs. The effects of NSAIDs on the production of renal prostaglandins may cause changes in the elimination of cyclosporine. Potentiation of renal dysfunction may especially occur in a dehydrated patient. Patients should be monitored for signs and symptoms of cyclosporine toxicity and infection, as NSAIDs may mask fever, pain, or swelling. Increased tear production was not seen in patients receiving ophthalmic NSAIDs or using punctual plugs concurrently with cyclosporine ophthalmic emulsion.
    Esterified Estrogens; Methyltestosterone: (Moderate) Androgens may increase concentrations of cyclosporine, potentially increasing the risk of nephrotoxicity. Until further data are available, close monitoring of cyclosporine serum concentrations is prudent during coadministration with androgens.
    Estrogens: (Moderate) Estrogens and/or progestins in oral contraceptives or non-oral combination contraceptives may inhibit the metabolism of cyclosporine. Delayed cyclosporine clearance and elevated cyclosporine concentrations can lead to seizures, nephrotoxicity and/or hepatotoxicity. Additionally, estrogens are metabolized by CYP3A4; cyclosporine may increase plasma concentrations of estrogens and cause estrogen-related side effects. If estrogens or progestins are initiated or discontinued, the patient's cyclosporine concentrations should be monitored closely. Additionally, patients should be monitored for estrogenic side effects if these drugs are used concomitantly.
    Ethanol: (Major) Although the effects probably do not involve the ethanol content of red wine, in vitro data suggest that red wine may increase the oral clearance of cyclosporine (Non-modified). It should be noted that these results may not extrapolate to cyclosporine (Modified) formulations.
    Ethinyl Estradiol; Etonogestrel: (Moderate) Coadministration may result in increased serum concentrations of cyclosporine or etonogestrel. There have been reports indicating the estrogens and/or progestins in oral contraceptives or non-oral combination contraceptives may inhibit the metabolism of cyclosporine. Delayed cyclosporine clearance and elevated cyclosporine concentrations can lead to seizures, nephrotoxicity, and/or hepatotoxicity. If etonogestrel is initiated or discontinued, the patient's cyclosporine concentrations should be monitored closely. In addition, coadministration of etonogestrel and moderate CYP3A4 inhibitors such as cyclosporine may increase the serum concentration of etonogestrel.
    Ethotoin: (Moderate) Hydantoin anticonvulsants (i.e, phenytoin, fosphenytoin, and ethotoin) can induce the hepatic cytochrome P-450 enzyme system, thus decreasing plasma concentrations of cyclosporine. If a hydantoin anticonvulsant is added to a cyclosporine-containing regimens, cyclosporine concentrations should be closely monitored and adjusted as needed until a new steady-state is achieved. Conversely, if the anticonvulsant is discontinued, cyclosporine concentrations could increase and result in toxicity.
    Etodolac: (Moderate) Pharmacodynamic interactions have been reported between cyclosporine and NSAIDs, consisting of additive decreases in renal function with concomitant use. NSAIDs should be used with caution in patients receiving immunosuppressives as they may mask fever, pain, swelling and other signs and symptoms of an infection.
    Etonogestrel: (Moderate) Coadministration may result in increased serum concentrations of cyclosporine or etonogestrel. There have been reports indicating the estrogens and/or progestins in oral contraceptives or non-oral combination contraceptives may inhibit the metabolism of cyclosporine. Delayed cyclosporine clearance and elevated cyclosporine concentrations can lead to seizures, nephrotoxicity, and/or hepatotoxicity. If etonogestrel is initiated or discontinued, the patient's cyclosporine concentrations should be monitored closely. In addition, coadministration of etonogestrel and moderate CYP3A4 inhibitors such as cyclosporine may increase the serum concentration of etonogestrel.
    Etoposide, VP-16: (Major) High-dose cyclosporine resulting in concentrations above 2000 ng/mL, when administered with oral etoposide, VP-16 has led to an 80% increase in etoposide exposure with a 38% decrease in total body clearance of etoposide compared to etoposide alone. This interaction has been clinically established, and may require etoposide dosage reduction. Cyclosporine blocks the multidrug resistance (MDR) p-glycoprotein, which is a mechanism of resistance to naturally occurring (non-synthetic) chemotherapy agents. Cyclosporine can be given to block MDR resistance in doses much higher than those used in transplantation; although cyclosporine doses of 5 to 21 mg/kg/day have been shown to affect etoposide pharmacokinetics.
    Etravirine: (Major) Coadministration with etravirine may result in altered cyclosporine concentrations. Coadminister these drugs with caution, carefully monitor cyclosporine concentrations and make dosage adjustments as needed.
    Everolimus: (Major) A dose adjustment of everolimus is necessary when prescribed with cyclosporine due to increased plasma concentrations of everolimus; increased exposure to cyclosporine may also occur. However, for some indications, everolimus is indicated to be administered in combination with cyclosporine. An increased incidence of nephrotoxicity may occur with concomitant use. For patients with breast cancer, neuroendocrine tumors, renal cell carcinoma, and renal angiolipoma with tubular sclerosis complex (TSC), reduce the dose of Afinitor to 2.5 mg once daily; consider increasing the dose to 5 mg based on patient tolerance. For patients with subependymal giant cell astrocytoma (SEGA) with TSC, the recommended starting dose of Afinitor/Afinitor Disperz is 2.5 mg/m2 once daily, rounded to the nearest tablet strength; subsequent dosing should be guided by therapeutic drug monitoring (TDM), with administration every other day if dose reduction is required for patients receiving the lowest available tablet strength. If cyclosporine is discontinued, increase everolimus to its original dose after a washout period of 2 to 3 days. Zortress dosing for prophylaxis of organ rejection should be guided by TDM. Monitor cyclosporine concentrations and adjust the dose as appropriate. The recommended cyclosporine therapeutic ranges when administered with everolimus (Zortress) are 100 to 200 ng/mL through Month 1 post-transplant, 75 to 150 ng/mL at Months 2 and 3 post-transplant, 50 to 100 ng/mL at Month 4 post-transplant, and 25 to 50 ng/mL from Month 6 through Month 12 post-transplant. Everolimus is a CYP3A4 and P-glycoprotein (P-gp) substrate, as well as a weak CYP3A4 inhibitor. Cyclosporine is a CYP3A4 and P-gp inhibitor, as well as a CYP3A4 substrate with a narrow therapeutic index. Coadministration with other moderate CYP3A4/P-gp inhibitors increased everolimus exposure by 3.5-fold to 4.4-fold. Everolimus (Zortress) had a clinically minor influence on cyclosporine pharmacokinetics in transplant patients receiving cyclosporine. Steady-state exposure to everolimus was significantly increased by coadministration of a single dose of cyclosporine.
    Exenatide: (Moderate) Cyclosporine has been reported to cause hyperglycemia. It may have direct beta-cell toxicity; the effects may be dose-related. Patients should be monitored for worsening of glycemic control if therapy with cyclosporine is initiated in patients receiving antidiabetic agents, including incretin mimetics.
    Ezetimibe: (Major) Cyclosporine may significantly increase ezetimibe serum concentrations. In addition, ezetimibe can increase cyclosporine serum concentrations. In a study of twelve healthy subjects, daily administration of 20 mg ezetimibe for 8 days and a single dose of 100 mg cyclosporine on day 7 resulted in a mean 15% increase in cyclosporine AUC (up to 51%) compared to a single dose of 100 mg cyclosporine alone. In a study of eight post-renal transplant patients with mildly impaired or normal renal function (CrCl > 50 mL/min), stable doses of cyclosporine (75 to 150 mg twice daily) increased the mean AUC and Cmax values of total ezetimibe 3.4-fold (range 2.3-fold to 7.9-fold) and 3.9-fold (range 3-fold to 4.4-fold), respectively, compared to a historical healthy control population (n=17). In a different study, a renal transplant patient with severe renal insufficiency (creatinine clearance of 13.2 mL/min/1.73 m2) who was receiving multiple medications, including cyclosporine, demonstrated a 12-fold greater exposure to total ezetimibe compared to healthy subjects. The degree of increase in ezetimibe exposure may be greater in patients with severe renal insufficiency. In patients treated with cyclosporine, the potential effects of the increased exposure to ezetimibe from concomitant use should be carefully weighed against the antilipemic benefits provided by ezetimibe. Patients who take cyclosporine concurrently with ezetimibe should be closely monitored for serum cyclosporine concentrations and for potential adverse effects of ezetimibe and cyclosporine.
    Ezetimibe; Simvastatin: (Severe) The use of simvastatin with is contraindicated due to an increased risk for myopathy and rhabdomyolysis. Cyclosporine increases the AUC of statins when administered concomitantly, and the risk for myopathy is increased by high levels of HMG-CoA reductase inhibitory activity in plasma. Although the mechanism is not fully understood, it is presumably due to inhibition of CYP3A4 and/or OAT1B1 by cyclosporine; simvastatin is a substrate of CYP3A4 and OAT1B1. (Major) Cyclosporine may significantly increase ezetimibe serum concentrations. In addition, ezetimibe can increase cyclosporine serum concentrations. In a study of twelve healthy subjects, daily administration of 20 mg ezetimibe for 8 days and a single dose of 100 mg cyclosporine on day 7 resulted in a mean 15% increase in cyclosporine AUC (up to 51%) compared to a single dose of 100 mg cyclosporine alone. In a study of eight post-renal transplant patients with mildly impaired or normal renal function (CrCl > 50 mL/min), stable doses of cyclosporine (75 to 150 mg twice daily) increased the mean AUC and Cmax values of total ezetimibe 3.4-fold (range 2.3-fold to 7.9-fold) and 3.9-fold (range 3-fold to 4.4-fold), respectively, compared to a historical healthy control population (n=17). In a different study, a renal transplant patient with severe renal insufficiency (creatinine clearance of 13.2 mL/min/1.73 m2) who was receiving multiple medications, including cyclosporine, demonstrated a 12-fold greater exposure to total ezetimibe compared to healthy subjects. The degree of increase in ezetimibe exposure may be greater in patients with severe renal insufficiency. In patients treated with cyclosporine, the potential effects of the increased exposure to ezetimibe from concomitant use should be carefully weighed against the antilipemic benefits provided by ezetimibe. Patients who take cyclosporine concurrently with ezetimibe should be closely monitored for serum cyclosporine concentrations and for potential adverse effects of ezetimibe and cyclosporine.
    Famotidine; Ibuprofen: (Moderate) Serum creatinine, potassium concentrations, and cyclosporine concentrations should be closely monitored when systemic cyclosporine is given with nonsteroidal antiinflammatory drugs (NSAIDs). Renal dysfunction associated with cyclosporine may be potentiated by concurrent usage of NSAIDs. The effects of NSAIDs on the production of renal prostaglandins may cause changes in the elimination of cyclosporine. Potentiation of renal dysfunction may especially occur in a dehydrated patient. Patients should be monitored for signs and symptoms of cyclosporine toxicity and infection, as NSAIDs may mask fever, pain, or swelling. Increased tear production was not seen in patients receiving ophthalmic NSAIDs or using punctual plugs concurrently with cyclosporine ophthalmic emulsion.
    Felodipine: (Major) Cyclosporine may competitively inhibit the first-pass metabolism of felodipine by cytochrome P450 3A4 in the gut wall, resulting in an increased bioavailability of felodipine. The concomitant administration of cyclosporine and felodipine significantly increases the peak felodipine plasma concentration (151%) and AUC (58%). The combination resulted in a greater decrease in mean diastolic blood pressure over 24 hours than either drug alone. Patients should avoid taking felodipine with cyclosporine; separate doses by at least two hours. Patients receiving cyclosporine should be monitored for potential risk of felodipine dose-related adverse effects (e.g., flushing, edema). Felodipine has been shown to have minimal effects on cyclosporine blood concentrations.
    Fenofibrate: (Moderate) The use of fibric acid derivatives, such as fenofibrate, may potentiate the risk for renal dysfunction with cyclosporine. During the concomitant use of a drug that may exhibit additive or synergistic renal impairment with cyclosporine, close monitoring of renal function (in particular serum creatinine) and cyclosporine levels should be performed. If a significant impairment of renal function occurs, the dosage of the coadministered drug should be reduced or an alternative treatment considered.
    Fenoprofen: (Moderate) Pharmacodynamic interactions consisting of additive decreases in renal function have been reported between cyclosporine and nonsteroidal anti-inflammatory drugs. Patients should be monitored for signs and symptoms of cyclosporine toxicity and infection, as NSAIDs may mask fever, pain, or swelling.
    Ferric Citrate: (Moderate) Although drug interaction studies have not been conducted, it may be prudent to separate the timing of administration of oral cyclosporine from ferric citrate. According to the manufacturer of ferric citrate, clinicians should consider separating the timing of administration of ferric citrate and drugs where a reduction in the bioavailability of would have a clinically significant effect on its safety or efficacy. Because cyclosporine has a narrow therapeutic index, consider monitoring clinical response and serum concentrations during concurrent use of ferric citrate.
    Fidaxomicin: (Minor) Cyclosporine, a P-glycoprotein (PGP) inhibitor, significantly increased the serum concentrations of fidaxomicin and its microbiologically active metabolite, OP-1118 (both PGP substrates); however, the serum concentrations of both fidaxomicin and OP-1118 were still in the ng/ml range. The manufacturer states a dosage adjustment is not necessary. The mean serum Cmax for fidaxomicin increased from 4.67 ng/ml when fidaxomicin was used alone to 19.4 ng/ml when administered with cyclosporine, while the mean AUC increased from 59.5 ng-h/ml for fidaxomicin alone to 114 ng-h/ml when administered with cyclosporine. The mean serum Cmax for OP-1118 increased from 10.6 ng/ml when fidaxomicin was used alone to 100 ng/ml when administered with cyclosporine, while the mean AUC increased from 106 ng-h/ml for fidaxomicin alone to 438 ng-h/ml when administered with cyclosporine. These concentrations are still well below the fecal concentrations demonstrated with a 10 day course of fidaxomicin.
    Flibanserin: (Severe) The concomitant use of flibanserin and moderate CYP3A4 inhibitors, such as cyclosporine, is contraindicated. Moderate CYP3A4 inhibitors can increase flibanserin concentrations, which can cause severe hypotension and syncope. If initiating flibanserin following use of a moderate CYP3A4 inhibitor, start flibanserin at least 2 weeks after the last dose of the CYP3A4 inhibitor. If initiating a moderate CYP3A4 inhibitor following flibanserin use, start the moderate CYP3A4 inhibitor at least 2 days after the last dose of flibanserin.
    Fluconazole: (Major) Fluconazole inhibits the CYP3A4 metabolism of cyclosporine, resulting in significant increases in cyclosporine plasma concentrations. If these drugs are used together, monitor serum creatinine and cyclosporine concentrations, and adjust cyclosporine dosage accordingly. Renal transplant patients stabilized on cyclosporine for at least 6 months and on a stable cyclosporine dose for at least 6 weeks received fluconazole 200 mg PO daily for 14 days. Cyclosporine AUC, Cmax, Cmin were increased by 92%, 60%, and 157%, respectively. In addition, the apparent cyclosporine clearance decreased by 45%.
    Fludarabine: (Minor) Concurrent use of purine analogs with other agents which cause bone marrow or immune suppression such as immunosuppressives may result in additive effects. A dosage reduction of the antineoplastic may be indicated when used in combination with other myelosuppressive chemotherapy.
    Fluoxetine: (Moderate) Fluoxetine is a CYP3A4 inhibitor and may decrease the clearance of cyclosporine, with the potential to cause cyclosporine toxicity, including nephrotoxicity or seizures, or require the downward dosage adjustment of cyclosporine.
    Fluoxetine; Olanzapine: (Moderate) Fluoxetine is a CYP3A4 inhibitor and may decrease the clearance of cyclosporine, with the potential to cause cyclosporine toxicity, including nephrotoxicity or seizures, or require the downward dosage adjustment of cyclosporine.
    Fluoxymesterone: (Moderate) Androgens may increase concentrations of cyclosporine, potentially increasing the risk of nephrotoxicity. Until further data are available, close monitoring of cyclosporine serum concentrations is prudent during coadministration with androgens.
    Flurbiprofen: (Moderate) Pharmacodynamic interactions have been reported between cyclosporine and NSAIDs, consisting of additive decreases in renal function with concomitant use. NSAIDs should be used with caution in patients receiving immunosuppressives as they may mask fever, pain, swelling and other signs and symptoms of an infection.
    Fluvastatin: (Major) Do not exceed 20 mg fluvastatin twice daily in adults when coadministered with cyclosporine. The risk of developing myopathy/rhabdomyolysis increases when fluvastatin is used concomitantly with cyclosporine. Monitor patients for any signs or symptoms of muscle pain, weakness, or tenderness. The serious risk of myopathy or rhabdomyolysis should be weighed carefully against the benefits of combined 'statin' and cyclosporine therapy; there is no assurance that periodic monitoring of CK will prevent the occurrence of severe myopathy and renal damage. Cyclosporine has been shown to increase the AUC of HMG-CoA reductase inhibitors, presumably due to CYP3A4 inhibition. The fluvastatin AUC was increased by 90% with the concomitant cyclosporine administration.
    Fluvoxamine: (Moderate) Fluvoxamine is a CYP3A4 inhibitor and may decrease the clearance of cyclosporine, with the potential to cause cyclosporine toxicity or require the downward dosage adjustment of cyclosporine. Until more data are available, cyclosporine concentrations should be monitored very carefully any time fluvoxamine is prescribed.
    Food: (Major) The oral bioavailability of non-modified cyclosporine is highly variable and food interactions are possible. Administration with high-fat content meals increases both bioavailability and clearance; however, the AUC does not change significantly. In general, food will decrease the absorption of modified cyclosporine. It is important to take cyclosporine consistently with or without food to ensure uniform cyclosporine concentrations.
    Fosamprenavir: (Major) An interaction is anticipated to occur with all anti-retroviral protease inhibitors and cyclosporine, as all protease inhibitors inhibit CYP3A4. Cyclosporine toxicity, consisting of fatigue, headache, and GI distress, has been reported by a patient receiving cyclosporine and saquinavir. Prior to beginning saquinavir the patient had been receiving stable doses of cyclosporine resulting in trough concentrations of 150 to 200 mcg/ml. After receiving saquinavir for 3 days, the cyclosporine trough concentration increased to 580 mcg/ml. Dosages of both agents were decreased by 50% leading to resolution of symptoms. This interaction is probably due to CYP3A4 inhibition by saquinavir. Another possible mechanism is that both drugs have a high affinity for the drug efflux protein, P-glycoprotein, which may increase the absorption or decrease the clearance of the other drug.
    Foscarnet: (Major) The risk of renal toxicity may be increased if foscarnet is used in conjunction with other nephrotoxic agents such as cyclosporine. Monitor renal function and fluid status carefully during cyclosporine usage.
    Fosphenytoin: (Moderate) Hydantoin anticonvulsants (i.e, phenytoin, fosphenytoin, and ethotoin) can induce the hepatic cytochrome P-450 enzyme system, thus decreasing plasma concentrations of cyclosporine. If a hydantoin anticonvulsant is added to a cyclosporine-containing regimens, cyclosporine concentrations should be closely monitored and adjusted as needed until a new steady-state is achieved. Conversely, if the anticonvulsant is discontinued, cyclosporine concentrations could increase and result in toxicity.
    Furosemide: (Moderate) Coadministration of furosemide and cyclosporine increases the risk of gouty arhtritis. This is a result of furosemide-induced hyperuricemia and the impairment of renal urate excretion by cyclosporine.
    Ganciclovir: (Moderate) Use caution and monitor renal function when ganciclovir is coadministered with cyclosporine because of the potential increase in serum creatinine. Acute renal failure may occur in patients concomitantly receiving potential nephrotoxic drugs.
    Gefitinib: (Major) Monitor for an increased incidence of gefitinib-related adverse effects if gefitinib and cyclosporine are used concomitantly. Gefitinib is metabolized significantly by CYP3A4 and cyclosporine is a moderate CYP3A4 inhibitor; coadministration may decrease the metabolism of gefitinib and increase gefitinib concentrations. While the manufacturer has provided no guidance regarding the use of gefitinib with mild or moderate CYP3A4 inhibitors, administration of a single 250 mg gefitinib dose with a strong CYP3A4 inhibitor (itraconazole) increased the mean AUC of gefitinib by 80%.
    Gemfibrozil: (Moderate) The use of fibric acid derivatives, such as gemfibrozil, may potentiate the risk for renal dysfunction with cyclosporine. During the concomitant use of a drug that may exhibit additive or synergistic renal impairment with cyclosporine, close monitoring of renal function (in particular serum creatinine) and cyclosporine levels should be performed. If a significant impairment of renal function occurs, the dosage of the coadministered drug should be reduced or an alternative treatment considered.
    Gentamicin: (Major) Additive nephrotoxicity can occur if cyclosporine is administered with other nephrotoxic drugs such as aminoglycosides.
    Glecaprevir; Pibrentasvir: (Major) Coadministration of glecaprevir in patients requiring stable cyclosporine doses more than 100 mg per day is not recommended as coadministration may increase serum concentrations of glecaprevir and increase the risk of adverse effects. Glecaprevir is partially metabolized by CYP3A4, and is a substrate of the drug transporters P-glycoprotein (P-gp), OATP1B1, and BCRP; cyclosporine is an inhibitor of CYP3A4, P-gp, OATP1B1, and BCRP. Additionally, cyclosporine is a P-gp substrate and glecaprevir is a P-gp inhibitor; concentrations of cyclosporine may also be increased. In drug interaction studies, coadministration of cyclosporine with glecaprevir resulted in an approximately 5-fold increase in the AUC of glecaprevir. (Major) Coadministration of pibrentasvir in patients requiring stable cyclosporine doses more than 100 mg per day is not recommended as coadministration may increase serum concentrations of pibrentasvir and increase the risk of adverse effects. Pibrentasvir is a substrate of the drug transporters P-glycoprotein (P-gp) and BCRP; cyclosporine is an inhibitor of P-gp and BCRP. Additionally, cyclosporine is a P-gp substrate and pibrentasvir is a P-gp inhibitor; concentrations of cyclosporine may also be increased. In drug interaction studies, coadministration of cyclosporine with pibrentasvir resulted in an approximately 2-fold increase in the AUC of pibrentasvir.
    Glimepiride; Pioglitazone: (Moderate) Cyclosporine has been reported to cause hyperglycemia; this effect appears to be dose-related and caused by direct beta-cell toxicity. Therefore, a pharmacodynamic interaction is possible with all antidiabetic agents and cyclosporine. Patients should be monitored for worsening glycemic control if therapy with cyclosporine is initiated in patients receiving antidiabetic agents.
    Glimepiride; Rosiglitazone: (Moderate) Cyclosporine has been reported to cause hyperglycemia; this effect appears to be dose-related and caused by direct beta-cell toxicity. Therefore, a pharmacodynamic interaction is possible with all antidiabetic agents and cyclosporine. Patients should be monitored for worsening glycemic control if therapy with cyclosporine is initiated in patients receiving antidiabetic agents.
    Glipizide; Metformin: (Moderate) Cyclosporine has been reported to cause hyperglycemia; this effect appears to be dose-related and caused by direct beta-cell toxicity. Therefore, a pharmacodynamic interaction is possible with all antidiabetic agents and cyclosporine. Patients should be monitored for worsening glycemic control if therapy with cyclosporine is initiated in patients receiving antidiabetic agents.
    Glyburide; Metformin: (Moderate) Cyclosporine has been reported to cause hyperglycemia; this effect appears to be dose-related and caused by direct beta-cell toxicity. Therefore, a pharmacodynamic interaction is possible with all antidiabetic agents and cyclosporine. Patients should be monitored for worsening glycemic control if therapy with cyclosporine is initiated in patients receiving antidiabetic agents.
    Glycerol Phenylbutyrate: (Moderate) Concomitant use of glycerol phenylbutyrate and cyclosporine may result in decreased exposure of cyclosporine. Cyclosporine is a CYP3A substrate; glycerol phenylbutyrate is a weak inducer of CYP3A4. Monitor for decreased efficacy of cyclosporine during coadministration.
    Golimumab: (Moderate) The formation of CYP450 enzymes may be suppressed by increased concentrations of cytokines (e.g., TNF-alpha) during chronic inflammation. Thus, it is expected that the formation of CYP450 enzymes could be normalized during golimumab receipt. Clinically relevant drug interactions may occur with CYP450 substrates that have a narrow therapeutic index such as cyclosporine. If golimumab is initiated or discontinued in a patient taking cyclosporine, monitor the cyclosporine concentration; cyclosporine dose adjustment may be needed. In addition, the safety and efficacy of golimumab in patients with immunosuppression have not been evaluated. Patients receiving immunosuppressives along with golimumab may be at a greater risk of developing an infection.
    Grapefruit juice: (Major) Grapefruit juice inhibits the enterocyte CYP3A4 isoenzyme and increases cyclosporine serum concentrations. Thus, grapefruit and grapefruit juice consumption by patients receiving cyclosporine should be avoided. Grapefruit juice contains compounds that can inhibit P-450 isozymes and the p-glycoproteins lining the intestinal wall. Administration of either formulation of cyclosporine with grapefruit juice significantly increased cyclosporine concentrations and AUC compared to administration with either orange juice or water. Separating dose of grapefruit juice from cyclosporine may not eliminate the interaction completely, as the inhibitory effect of grapefruit juice can last for several hours. Patients stabilized on cyclosporine should avoid large changes (i.e., either increases or decreases) in their daily intake of grapefruit juice. Do not mix cyclosporine oral solution with grapefruit juice.
    Griseofulvin: (Moderate) Griseofulvin has been reported to reduce cyclosporine serum concentrations. Although very few reports of this interaction are known, the sequelae from this combination are significant. Closely monitor cyclosporine levels during concurrent treatment with griseofulvin. An increase in cyclosporine dose may be necessary if griseofulvin is added. The cyclosporine dosage may need to decreased if griseofulvin is discontinued.
    Guanfacine: (Major) Cyclosporine may significantly increase guanfacine plasma concentrations. FDA-approved labeling for extended-release (ER) guanfacine recommends that, if these agents are taken together, the guanfacine dosage should be decreased to half of the recommended dose. Specific recommendations for immediate-release (IR) guanfacine are not available. Monitor patients closely for alpha-adrenergic effects including hypotension, drowsiness, lethargy, and bradycardia. Upon cyclosporine discontinuation, the guanfacine ER dosage should be increased back to the recommended dose. Guanfacine is primarily metabolized by CYP3A4, and cyclosporine is a moderate CYP3A4 inhibitor.
    Hyaluronidase, Recombinant; Immune Globulin: (Moderate) Immune Globulin (IG) products have been reported to be associated with renal dysfunction, acute renal failure, osmotic nephrosis, and death. Patients predisposed to acute renal failure include patients receiving known nephrotoxic drugs like cyclosporine. Coadminister IG products at the minimum concentration available and the minimum rate of infusion practicable. Also, closely monitor renal function.
    Hydantoins: (Moderate) Hydantoin anticonvulsants (i.e, phenytoin, fosphenytoin, and ethotoin) can induce the hepatic cytochrome P-450 enzyme system, thus decreasing plasma concentrations of cyclosporine. If a hydantoin anticonvulsant is added to a cyclosporine-containing regimens, cyclosporine concentrations should be closely monitored and adjusted as needed until a new steady-state is achieved. Conversely, if the anticonvulsant is discontinued, cyclosporine concentrations could increase and result in toxicity.
    Hydrochlorothiazide, HCTZ; Irbesartan: (Moderate) Coadministration of cyclosporine and an angiotensin II receptor antagonist, like irbesartan, may increase the risk of hyperkalemia and reduced renal function. In response to cyclosporine-induced renal afferent vasoconstriction and glomerular hypoperfusion, angiotensin II is required to maintain an adequate glomerular filtration rate. Inhibition of angiotensin-converting enzyme (ACE) could reduce renal function acutely. Several cases of acute renal failure have been associated with the addition of enalapril to cyclosporine therapy in renal transplant patients. Also, cyclosporine can cause hyperkalemia, and inhibition of angiotensin II leads to reduced aldosterone concentrations, which can increase the serum potassium concentration. Closely monitor renal function and serum potassium concentrations in patients receiving cyclosporine concurrently with irbesartan.
    Hydrochlorothiazide, HCTZ; Losartan: (Moderate) Coadministration of cyclosporine and an angiotensin II receptor antagonist, like losartan, may increase the risk of hyperkalemia and reduced renal function. In response to cyclosporine-induced renal afferent vasoconstriction and glomerular hypoperfusion, angiotensin II is required to maintain an adequate glomerular filtration rate. Inhibition of angiotensin-converting enzyme (ACE) could reduce renal function acutely. Several cases of acute renal failure have been associated with the addition of enalapril to cyclosporine therapy in renal transplant patients. Also, cyclosporine can cause hyperkalemia, and inhibition of angiotensin II leads to reduced aldosterone concentrations, which can increase the serum potassium concentration. Closely monitor renal function and serum potassium concentrations in patients receiving cyclosporine concurrently with losartan.
    Hydrochlorothiazide, HCTZ; Olmesartan: (Moderate) Coadministration of cyclosporine and an angiotensin II receptor antagonist, like olmesartan, may increase the risk of hyperkalemia and reduced renal function. In response to cyclosporine-induced renal afferent vasoconstriction and glomerular hypoperfusion, angiotensin II is required to maintain an adequate glomerular filtration rate. Inhibition of angiotensin-converting enzyme (ACE) could reduce renal function acutely. Several cases of acute renal failure have been associated with the addition of enalapril to cyclosporine therapy in renal transplant patients. Also, cyclosporine can cause hyperkalemia, and inhibition of angiotensin II leads to reduced aldosterone concentrations, which can increase the serum potassium concentration. Closely monitor renal function and serum potassium concentrations in patients receiving cyclosporine concurrently with olmesartan.
    Hydrochlorothiazide, HCTZ; Spironolactone: (Major) Cyclosporine can cause hyperkalemia. Simultaneous use of cyclosporine with potassium-sparing diuretics, such as amiloride, spironolactone or triamterene, can increase this risk, and is not recommended.
    Hydrochlorothiazide, HCTZ; Telmisartan: (Moderate) Coadministration of cyclosporine and an angiotensin II receptor antagonist, like telmisartan, may increase the risk of hyperkalemia and reduced renal function. In response to cyclosporine-induced renal afferent vasoconstriction and glomerular hypoperfusion, angiotensin II is required to maintain an adequate glomerular filtration rate. Inhibition of angiotensin-converting enzyme (ACE) could reduce renal function acutely. Several cases of acute renal failure have been associated with the addition of enalapril to cyclosporine therapy in renal transplant patients. Also, cyclosporine can cause hyperkalemia, and inhibition of angiotensin II leads to reduced aldosterone concentrations, which can increase the serum potassium concentration. Closely monitor renal function and serum potassium concentrations in patients receiving cyclosporine concurrently with telmisartan.
    Hydrochlorothiazide, HCTZ; Triamterene: (Major) Cyclosporine can cause hyperkalemia. Simultaneous use of cyclosporine with potassium-sparing diuretics, such as amiloride, spironolactone or triamterene, can increase this risk, and is not recommended.
    Hydrochlorothiazide, HCTZ; Valsartan: (Moderate) Coadministration of cyclosporine and an angiotensin II receptor antagonist, like valsartan, may increase the risk of hyperkalemia and reduced renal function. In response to cyclosporine-induced renal afferent vasoconstriction and glomerular hypoperfusion, angiotensin II is required to maintain an adequate glomerular filtration rate. Inhibition of angiotensin-converting enzyme (ACE) could reduce renal function acutely. Several cases of acute renal failure have been associated with the addition of enalapril to cyclosporine therapy in renal transplant patients. Also, cyclosporine can cause hyperkalemia, and inhibition of angiotensin II leads to reduced aldosterone concentrations, which can increase the serum potassium concentration. Closely monitor renal function and serum potassium concentrations in patients receiving cyclosporine concurrently with valsartan. Additionally, valsartan is a substrate of the hepatic uptake transporter OATP1B1 and cyclosporine is an inhibitor of OATP. Coadministration may increase systemic exposure to valsartan. Patients should be monitored for adverse effects of valsartan.
    Hydrocodone; Ibuprofen: (Moderate) Serum creatinine, potassium concentrations, and cyclosporine concentrations should be closely monitored when systemic cyclosporine is given with nonsteroidal antiinflammatory drugs (NSAIDs). Renal dysfunction associated with cyclosporine may be potentiated by concurrent usage of NSAIDs. The effects of NSAIDs on the production of renal prostaglandins may cause changes in the elimination of cyclosporine. Potentiation of renal dysfunction may especially occur in a dehydrated patient. Patients should be monitored for signs and symptoms of cyclosporine toxicity and infection, as NSAIDs may mask fever, pain, or swelling. Increased tear production was not seen in patients receiving ophthalmic NSAIDs or using punctual plugs concurrently with cyclosporine ophthalmic emulsion.
    Hydroxychloroquine: (Moderate) Use caution with the coadministration of hydroxychloroquine and cyclosporine as increased serum concentrations of cyclosporine have been noted. Monitoring cyclosporine concentrations after starting or stopping hydroxychloroquine therapy may be necessary. Monitor patients for cyclosporine-related adverse events such as nephrotoxicity or hepatic toxicity.
    Ibandronate: (Moderate) Theoretically, coadministration of intravenous ibandronate with other potentially nephrotoxic drugs like cyclosporine may increase the risk of developing nephrotoxicity.
    Ibritumomab Tiuxetan: (Moderate) Use potassium phosphates cautiously with cyclosporine, as both drugs increase serum potassium concentrations. Concurrent use can cause hyperkalemia, especially in elderly patients or patients with impaired renal function. Patients should have serum potassium concentration determinations at periodic intervals.
    Ibrutinib: (Major) The concomitant use of ibrutinib and cyclosporine may result in increased plasma concentrations of ibrutinib or cyclosporine. If coadministered with cyclosporine, initiate ibrutinib therapy at a reduced dose of 140 mg/day PO for the treatment of B-cell malignancy or 420 mg/day PO for the treatment of chronic graft-versus-host disease; monitor patients more frequently for ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection). Monitor cyclosporine levels and observe patients for symptoms of cyclosporine toxicity. Ibrutinib is a 3A4 substrate and a P-glycoprotein (P-gp) inhibitor in vitro; cyclosporine is a CYP3A4 inhibitor and a P-gp substrate with a narrow therapeutic index. When ibrutinib was administered with multiple doses of another moderate CYP3A4 inhibitor, the Cmax and AUC values of ibrutinib were increased by 3.4-fold and 3-fold, respectively.
    Ibuprofen: (Moderate) Serum creatinine, potassium concentrations, and cyclosporine concentrations should be closely monitored when systemic cyclosporine is given with nonsteroidal antiinflammatory drugs (NSAIDs). Renal dysfunction associated with cyclosporine may be potentiated by concurrent usage of NSAIDs. The effects of NSAIDs on the production of renal prostaglandins may cause changes in the elimination of cyclosporine. Potentiation of renal dysfunction may especially occur in a dehydrated patient. Patients should be monitored for signs and symptoms of cyclosporine toxicity and infection, as NSAIDs may mask fever, pain, or swelling. Increased tear production was not seen in patients receiving ophthalmic NSAIDs or using punctual plugs concurrently with cyclosporine ophthalmic emulsion.
    Ibuprofen; Oxycodone: (Moderate) Serum creatinine, potassium concentrations, and cyclosporine concentrations should be closely monitored when systemic cyclosporine is given with nonsteroidal antiinflammatory drugs (NSAIDs). Renal dysfunction associated with cyclosporine may be potentiated by concurrent usage of NSAIDs. The effects of NSAIDs on the production of renal prostaglandins may cause changes in the elimination of cyclosporine. Potentiation of renal dysfunction may especially occur in a dehydrated patient. Patients should be monitored for signs and symptoms of cyclosporine toxicity and infection, as NSAIDs may mask fever, pain, or swelling. Increased tear production was not seen in patients receiving ophthalmic NSAIDs or using punctual plugs concurrently with cyclosporine ophthalmic emulsion.
    Ibuprofen; Pseudoephedrine: (Moderate) Serum creatinine, potassium concentrations, and cyclosporine concentrations should be closely monitored when systemic cyclosporine is given with nonsteroidal antiinflammatory drugs (NSAIDs). Renal dysfunction associated with cyclosporine may be potentiated by concurrent usage of NSAIDs. The effects of NSAIDs on the production of renal prostaglandins may cause changes in the elimination of cyclosporine. Potentiation of renal dysfunction may especially occur in a dehydrated patient. Patients should be monitored for signs and symptoms of cyclosporine toxicity and infection, as NSAIDs may mask fever, pain, or swelling. Increased tear production was not seen in patients receiving ophthalmic NSAIDs or using punctual plugs concurrently with cyclosporine ophthalmic emulsion.
    Idarubicin: (Major) Concurrent use of idarubicin with other agents which cause bone marrow or immune suppression such as cyclosporine may result in additive effects.
    Idelalisib: (Major) Avoid concomitant use of idelalisib, a strong CYP3A inhibitor, with cyclosporine, a CYP3A substrate, as cyclosporine toxicities may be significantly increased. The AUC of a sensitive CYP3A substrate was increased 5.4-fold when coadministered with idelalisib.
    Ifosfamide: (Moderate) Delayed renal clearance, and additive nephrotoxicity may occur in patients who have received or who are currently receiving nephrotoxic drugs and are now receiving ifosfamide. These drugs include cyclosporine. Damaged kidney tubules may be less likely to convert mesna to its active kidney protecting form, which may contribute to the potential for increased ifosfamide toxicity. Immunosuppressive effects may also be additive from this combination. Clinicians should be alert for an increased risk of ifosfamide toxicity which may include neurotoxicity, kidney toxicity, and bone marrow suppression.
    Imatinib: (Major) Imatinib, STI-571 is a potent inhibitor of cytochrome P450 3A4 and may increase concentrations of other drugs metabolized by this enzyme. Concurrent administration of cyclosporine and imatinib may result in increased concentrations of cyclosporine due to decreased metabolism. Monitoring of cyclosporine concentrations is warranted.
    Immune Globulin IV, IVIG, IGIV: (Moderate) Immune Globulin (IG) products have been reported to be associated with renal dysfunction, acute renal failure, osmotic nephrosis, and death. Patients predisposed to acute renal failure include patients receiving known nephrotoxic drugs like cyclosporine. Coadminister IG products at the minimum concentration available and the minimum rate of infusion practicable. Also, closely monitor renal function.
    Incretin Mimetics: (Moderate) Cyclosporine has been reported to cause hyperglycemia. It may have direct beta-cell toxicity; the effects may be dose-related. Patients should be monitored for worsening of glycemic control if therapy with cyclosporine is initiated in patients receiving antidiabetic agents, including incretin mimetics.
    Indinavir: (Major) An interaction is anticipated to occur with all anti-retroviral protease inhibitors and cyclosporine, as all protease inhibitors inhibit CYP3A4. Cyclosporine toxicity, consisting of fatigue, headache, and GI distress, has been reported by a patient receiving cyclosporine and saquinavir. Prior to beginning saquinavir the patient had been receiving stable doses of cyclosporine resulting in trough concentrations of 150 to 200 mcg/ml. After receiving saquinavir for 3 days, the cyclosporine trough concentration increased to 580 mcg/ml. Dosages of both agents were decreased by 50% leading to resolution of symptoms. This interaction is probably due to CYP3A4 inhibition by saquinavir. Another possible mechanism is that both drugs have a high affinity for the drug efflux protein, P-glycoprotein, which may increase the absorption or decrease the clearance of the other drug.
    Indomethacin: (Moderate) Additive decreases in renal function have been reported between cyclosporine and nonsteroidal anti-inflammatory drugs. Patients should be monitored for signs and symptoms of cyclosporine toxicity and infection, as NSAIDs may mask fever, pain, or swelling.
    Infliximab: (Moderate) The formation of CYP450 enzymes may be suppressed by increased concentrations of cytokines (e.g., TNF-alpha) during chronic inflammation. Thus, it is expected that the formation of CYP450 enzymes could be normalized during infliximab receipt. Clinically relevant drug interactions may occur with CYP450 substrates that have a narrow therapeutic index such as cyclosporine. If infliximab is initiated or discontinued in a patient taking cyclosporine, monitor the cyclosporine concentration; cyclosporine dose adjustment may be needed.
    Insulin Degludec; Liraglutide: (Moderate) Cyclosporine has been reported to cause hyperglycemia. It may have direct beta-cell toxicity; the effects may be dose-related. Patients should be monitored for worsening of glycemic control if therapy with cyclosporine is initiated in patients receiving antidiabetic agents, including incretin mimetics.
    Insulin Glargine; Lixisenatide: (Moderate) Cyclosporine has been reported to cause hyperglycemia. It may have direct beta-cell toxicity; the effects may be dose-related. Patients should be monitored for worsening of glycemic control if therapy with cyclosporine is initiated in patients receiving antidiabetic agents, including incretin mimetics.
    Insulins: (Moderate) Cyclosporine may cause hyperglycemia. Patients should be monitored for worsening of glycemic control if therapy with cyclosporine is initiated in patients receiving insulin.
    Intranasal Influenza Vaccine: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Irbesartan: (Moderate) Coadministration of cyclosporine and an angiotensin II receptor antagonist, like irbesartan, may increase the risk of hyperkalemia and reduced renal function. In response to cyclosporine-induced renal afferent vasoconstriction and glomerular hypoperfusion, angiotensin II is required to maintain an adequate glomerular filtration rate. Inhibition of angiotensin-converting enzyme (ACE) could reduce renal function acutely. Several cases of acute renal failure have been associated with the addition of enalapril to cyclosporine therapy in renal transplant patients. Also, cyclosporine can cause hyperkalemia, and inhibition of angiotensin II leads to reduced aldosterone concentrations, which can increase the serum potassium concentration. Closely monitor renal function and serum potassium concentrations in patients receiving cyclosporine concurrently with irbesartan.
    Irinotecan Liposomal: (Moderate) Use caution if irinotecan liposomal is coadministered with cyclosporine, a CYP3A4 inhibitor, due to increased risk of irinotecan-related toxicity. The metabolism of liposomal irinotecan has not been evaluated; however, coadministration of ketoconazole, a strong CYP3A4 and UGT1A1 inhibitor, with non-liposomal irinotecan HCl resulted in increased exposure to both irinotecan and its active metabolite, SN-38.
    Irinotecan: (Moderate) Cyclosporine is a moderate inhibitor of both CYP3A4 and P-glycoprotein (P-gp); irinotecan is a CYP3A4 and P-gp substrate. Coadministration may result in increased irinotecan exposure. Use caution if concomitant use is necessary and monitor for increased irinotecan side effects, including diarrhea, nausea, vomiting, and myelosuppression.
    Isavuconazonium: (Moderate) Use caution and closely monitor cyclosporine serum concentrations when administered concurrently with isavuconazonium. Use of these drugs together results in elevated cyclosporine serum concentrations and an increased risk for adverse reactions, such as renal toxicity. Cyclosporine dose adjustments may be necessary and should be guided by serum concentrations during coadministration. Isavuconazole, the active moiety of isavuconazonium, is an inhibitor of hepatic isoenzyme CYP3A4 as well as the drug transporter P-glycoprotein (P-gp); cyclosporine is a substrate of CYP3A4 and P-gp. Additionally, isavuconazole is a sensitive substrate of CYP3A4 while cyclosporine is an inhibitor of this enzyme; elevated isavuconazole serum concentrations may also occur.
    Isoniazid, INH: (Minor) Cyclosporine is a CYP3A4 substrate. Coadministration with a CYP3A4 inhibitor, such as isoniazid, may decrease the metabolism and clearance of cyclosporine, resulting in increased serum concentrations and, thus, potentially causing cyclosporine toxicity (e.g., nephrotoxicity, hepatotoxicity, or seizures). Reduced cyclosporine dosage requirements may be needed. Conversely, if isoniazid is discontinued, cyclosporine concentrations could decrease. Monitor serum cyclosporine concentrations carefully if isoniazid is used concomitantly and upon discontinuation.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Rifampin, rifabutin, or rifapentine can increase the clearance of cyclosporine by inducing cyclosporine metabolism. All are inducers of CYP3A4 metabolism. Thus, dosage adjustments of cyclosporine may be necessary if used with rifampin, rifapentine, or rifabutin. Induction of enzyme activities occurred within 4 days after the first rifapentine dose. Enzyme activities returned to baseline levels 14 days after rifapentine discontinuation. The magnitude of enzyme induction is dose and dosing frequency dependent. For example, less enzyme induction occurred with 600 mg every 72 hours as compared with daily usage. In vitro and in vivo enzyme induction studies have suggested less enzyme induction potential with rifapentine as compared with rifampin and more enzyme induction potential with rifapentine as compared with rifabutin. (Minor) Cyclosporine is a CYP3A4 substrate. Coadministration with a CYP3A4 inhibitor, such as isoniazid, may decrease the metabolism and clearance of cyclosporine, resulting in increased serum concentrations and, thus, potentially causing cyclosporine toxicity (e.g., nephrotoxicity, hepatotoxicity, or seizures). Reduced cyclosporine dosage requirements may be needed. Conversely, if isoniazid is discontinued, cyclosporine concentrations could decrease. Monitor serum cyclosporine concentrations carefully if isoniazid is used concomitantly and upon discontinuation.
    Isoniazid, INH; Rifampin: (Major) Rifampin, rifabutin, or rifapentine can increase the clearance of cyclosporine by inducing cyclosporine metabolism. All are inducers of CYP3A4 metabolism. Thus, dosage adjustments of cyclosporine may be necessary if used with rifampin, rifapentine, or rifabutin. Induction of enzyme activities occurred within 4 days after the first rifapentine dose. Enzyme activities returned to baseline levels 14 days after rifapentine discontinuation. The magnitude of enzyme induction is dose and dosing frequency dependent. For example, less enzyme induction occurred with 600 mg every 72 hours as compared with daily usage. In vitro and in vivo enzyme induction studies have suggested less enzyme induction potential with rifapentine as compared with rifampin and more enzyme induction potential with rifapentine as compared with rifabutin. (Minor) Cyclosporine is a CYP3A4 substrate. Coadministration with a CYP3A4 inhibitor, such as isoniazid, may decrease the metabolism and clearance of cyclosporine, resulting in increased serum concentrations and, thus, potentially causing cyclosporine toxicity (e.g., nephrotoxicity, hepatotoxicity, or seizures). Reduced cyclosporine dosage requirements may be needed. Conversely, if isoniazid is discontinued, cyclosporine concentrations could decrease. Monitor serum cyclosporine concentrations carefully if isoniazid is used concomitantly and upon discontinuation.
    Itraconazole: (Major) Monitor cyclosporine serum concentrations and adjust dose as needed if coadministration of itraconazole is necessary. Cyclosporine concentrations may be significantly increased in the presence of itraconazole. Itraconazole is a strong CYP3A4 and P-glycoprotein(P-gp) inhibitor; cyclosporine is a CYP3A4/P-gp substrate.
    Ivabradine: (Major) Avoid coadministration of ivabradine and cyclosporine as increased concentrations of ivabradine are possible. Ivabradine is primarily metabolized by CYP3A4; cyclosporine inhibits CYP3A4. Increased ivabradine concentrations may result in bradycardia exacerbation and conduction disturbances.
    Ivacaftor: (Major) Use caution when administering ivacaftor and cyclosporine concurrently. Ivacaftor is a substrate of CYP3A, and an inhibitor of CYP3A and P-glycoprotein (P-gp). Cyclosporine is a CYP3A and P-glycoprotein (P-gp) substrate and inhibitor. If these agents are given together, the manufacturer of ivacaftor recommends administering ivacaftor at the usual recommended dose but reducing the frequency to once daily (e.g., if the usual dosage is 150 mg twice daily, reduce to 150 mg once daily). Coadministration of ivacaftor with fluconazole, a moderate CYP3A inhibitor, increased ivacaftor exposure by 3-fold. In addition, coadministration of ivacaftor with CYP3A and P-gp substrates, such as cyclosporine, can increase cyclosporine exposure leading to increased or prolonged therapeutic effects and adverse events. More careful monitoring of cyclosporine blood concentrations may be warranted.
    Ixabepilone: (Major) Ixabepilone is a CYP3A4 substrate, and concomitant use of ixabepilone with strong CYP3A4 inhibitors such as cyclosporine should be avoided. Alternative therapies that do not inhibit the CYP3A4 isoenzyme should be considered. If concurrent treatment with a strong CYP3A4 inhibitor is necessary, strongly consider an ixabepilone dose reduction. Closely monitor patients for ixabepilone-related toxicities. If a strong CYP3A4 inhibitor is discontinued, allow 7 days to elapse before increasing the ixabepilone dose
    Ixekizumab: (Moderate) The formation of CYP450 enzymes may be altered by increased concentrations of cytokines during chronic inflammation. Thus, the formation of CYP450 enzymes could be normalized during ixekizumab administration. Clinically relevant drug interactions may occur with CYP450 substrates that have a narrow therapeutic index such as cyclosporine. If ixekizumab is initiated or discontinued in a patient taking cyclosporine, monitor cyclosporine concentrations; cyclosporine dose adjustments may be needed.
    Kanamycin: (Major) Kanamycin is a nephrotoxic drug. Additive nephrotoxicity is possible if kanamycin is administered with other nephrotoxic medications such as cyclosporine. The manufacturer of kanamycin indicates that such combinations should be avoided.
    Ketoconazole: (Major) The interactions between cyclosporine and systemic azole antifungals (e.g., ketoconazole) can be significant. Ketoconazole may inhibit cyclosporine CYP3A4-mediated metabolism, which may result in increased cyclosporine blood concentrations. Cyclosporine concentrations may increase within 1 to 3 days after starting azole antifungal therapy, and may persist for > 1 week after discontinuing antifungal treatment. Of the azoles, ketoconazole is the most potent CYP3A4 inhibitor; it also inhibits p-glycoprotein. Ketoconazole can increase cyclosporine concentrations up to 3-fold within days of addition of ketoconazole to cyclosporine therapy. It takes about 7 to 10 days for cyclosporine concentrations to normalize after stopping ketoconazole. Ketoconazole has been documented to lower the daily maintenance dosage of cyclosporine, thus reducing the overall cost of therapy; however, this approach is not routinely used. Ketoconazole may also potentiate renal dysfunction associated with cyclosporine. In all cases, renal function in these patients should be carefully monitored. Close monitoring of cyclosporine concentrations is required when given in combination with systemic azole antifungals; a 50% reduction in cyclosporine dosage may be required.
    Ketoprofen: (Moderate) Additive decreases in renal function have been reported between cyclosporine and nonsteroidal anti-inflammatory drugs. Patients should be monitored for signs and symptoms of cyclosporine toxicity and infection, as NSAIDs may mask fever, pain, or swelling.
    Ketorolac: (Moderate) Additive decreases in renal function have been reported between cyclosporine and nonsteroidal anti-inflammatory drugs. Patients should be monitored for signs and symptoms of cyclosporine toxicity and infection, as NSAIDs may mask fever, pain, or swelling.
    Lanreotide: (Moderate) Monitor cyclosporine levels if coadministration of cyclosporine with lanreotide is necessary; adjust the dose of cyclosporine as necessary to maintain therapeutic drug concentrations. Concomitant administration of lanreotide with cyclosporine may decrease the absorption of cyclosporine.
    Lansoprazole; Naproxen: (Moderate) Serum creatinine ,potassium concentrations, and cyclosporine concentrations should be closely monitored when systemic cyclosporine is given with nonsteroidal antiinflammatory drugs (NSAIDs). Renal dysfunction associated with cyclosporine may be potentiated by concurrent usage of NSAIDs. The effects of NSAIDs on the production of renal prostaglandins may cause changes in the elimination of cyclosporine. Potentiation of renal dysfunction may especially occur in a dehydrated patient. Patients should be monitored for signs and symptoms of cyclosporine toxicity and infection, as NSAIDs may mask fever, pain, or swelling. Increased tear production was not seen in patients receiving ophthalmic NSAIDs or using punctual plugs concurrently with cyclosporine ophthalmic emulsion.
    Lapatinib: (Major) Lapatinib is a CYP3A4 substrate and a CYP3A4 inhibitor at clinically relevant concentrations in vitro. Cyclosporine is a P-glycoprotein inhibitor, a CYP3A4 substrate, and a CYP3A4 inhibitor. Concomitant use of lapatinib with strong CYP3A4 inhibitors should generally be avoided. Furthermore, because lapatinib inhibits CYP3A4, exercise caution and consider cyclosporine dose reduction; careful monitoring of cyclosporine serum concentrations may be advisable. Lastly, concurrent administration of lapatinib with a P-glycoprotein inhibitor such as cyclosporine is likely to cause elevated serum lapatinib concentrations, and caution is recommended.
    Ledipasvir; Sofosbuvir: (Moderate) Caution and close monitoring of adverse reactions is advised with concomitant administration of cyclosporine and ledipasvir. Both ledipasvir and cyclosporine are substrates and inhibitors of the drug transporter P-glycoprotein (P-gp). In addition, cyclosporine is a breast cancer resistance protein (BCRP) inhibitor; ledipasivr is a BCRP substrate. Taking these drugs together may increase plasma concentrations of both drugs. According to the manufacturer, no significant interactions were observed when these medications were administered concurrently during drug interaction studies.
    Lesinurad; Allopurinol: (Minor) Allopurinol may increase concentrations of cyclosporine. Close monitoring of cyclosporine concentrations is required when allopurinol is given concurrently with cyclosporine.
    Levofloxacin: (Moderate) Concomitant use of levofloxacin can result in increased serum concentrations of cyclosporine. In a clinical study involving healthy volunteers, levofloxacin did not significantly affect the pharmacokinetic disposition of cyclosporine. However, in renal transplant patients stabilized on cyclosporine microemulsion, the addition of levofloxacin resulted in reduced metabolism of cyclosporine. Higher cyclosporine AUC values were observed, but increased adverse reactions and supratherapeutic serum concentrations were not noted. Serum concentrations of cyclosporine should be monitored and dosage changes made only if adverse effects or supratherapeutic concentrations occur. In the study of healthy volunteers, cyclosporine caused a slight increase in the half-life of levofloxacin and a slight decrease in the maximum serum concentration of levofloxacin; these changes were considered to be clinically unimportant.
    Levothyroxine: (Moderate) Serum trough cyclosporine concentrations appear to be reduced by concurrent oral cyclosporine and levothyroxine use. Claosely monitor cyclosporine concentrations with concomitant levothyroxine therapy. Among 10 patients who took cyclosporine (Neoral) capsules twice daily for at least a year and oral levothyroxine 100 mcg daily for at least 3 months, the trough serum cyclosporine concentration was significantly lower as compared with values from 30 patients who only took cyclosporine. The mechanism of the interaction may be decreased oral cyclosporine absorption. Cyclosporine is a substrate of P-glycoprotein (P-gp), and levothyroxine appears to be an inducer of intestinal P-gp.
    Lidocaine: (Moderate) Concomitant use of systemic lidocaine and cyclosporine may increase lidocaine plasma concentrations by decreasing lidocaine clearance and therefore prolonging the elimination half-life. Monitor for lidocaine toxicity if used together. Lidocaine is a CYP3A4 and CYP1A2 substrate; cyclosporine inhibits CYP3A4.
    Linagliptin: (Moderate) Cyclosporine has been reported to cause hyperglycemia. Cyclosporine may have direct beta-cell toxicity; the effects from cyclosporine may be dose-related. Patients should be monitored for changes in glycemic control if therapy with either of these immunosuppressant drugs is initiated in patients receiving linagliptin.
    Linagliptin; Metformin: (Moderate) Cyclosporine has been reported to cause hyperglycemia. Cyclosporine may have direct beta-cell toxicity; the effects from cyclosporine may be dose-related. Patients should be monitored for changes in glycemic control if therapy with either of these immunosuppressant drugs is initiated in patients receiving linagliptin. (Moderate) Cyclosporine has been reported to cause hyperglycemia; this effect appears to be dose-related and caused by direct beta-cell toxicity. Therefore, a pharmacodynamic interaction is possible with all antidiabetic agents and cyclosporine. Patients should be monitored for worsening glycemic control if therapy with cyclosporine is initiated in patients receiving antidiabetic agents.
    Lincosamides: (Moderate) Cyclosporine dosage adjustments may be required in patients receiving concurrent clindamycin. Close monitoring of cyclosporine serum concentrations is warranted before, during, and after concurrent clindamycin usage. Two lung transplant patients receiving clindamycin for Staphylococcus aureus infections required increasing doses of cyclosporine to maintain target cyclosporine serum concentrations. When clindamycin treatment was stopped, the dose of cyclosporine was reduced to the regimen used prior to clindamycin therapy. The mechanism of the interaction is unknown.
    Liotrix: (Moderate) Serum trough cyclosporine concentrations appear to be reduced by concurrent oral cyclosporine and levothyroxine use. Claosely monitor cyclosporine concentrations with concomitant levothyroxine therapy. Among 10 patients who took cyclosporine (Neoral) capsules twice daily for at least a year and oral levothyroxine 100 mcg daily for at least 3 months, the trough serum cyclosporine concentration was significantly lower as compared with values from 30 patients who only took cyclosporine. The mechanism of the interaction may be decreased oral cyclosporine absorption. Cyclosporine is a substrate of P-glycoprotein (P-gp), and levothyroxine appears to be an inducer of intestinal P-gp.
    Liraglutide: (Moderate) Cyclosporine has been reported to cause hyperglycemia. It may have direct beta-cell toxicity; the effects may be dose-related. Patients should be monitored for worsening of glycemic control if therapy with cyclosporine is initiated in patients receiving antidiabetic agents, including incretin mimetics.
    Live Vaccines: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Lixisenatide: (Moderate) Cyclosporine has been reported to cause hyperglycemia. It may have direct beta-cell toxicity; the effects may be dose-related. Patients should be monitored for worsening of glycemic control if therapy with cyclosporine is initiated in patients receiving antidiabetic agents, including incretin mimetics.
    Lomefloxacin: (Moderate) Concomitant administration of other quinolones and cyclosporine has resulted in elevated cyclosporine serum concentrations.
    Lomitapide: (Major) Concomitant use of lomitapide and cyclosporine may significantly increase the serum concentration of lomitapide. Therefore, the lomitapide dose should not exceed 30 mg/day PO during concurrent use. Cyclosporine is a weak CYP3A4 inhibitor; the exposure to lomitapide is increased by approximately 2-fold in the presence of weak CYP3A4 inhibitors.
    Loperamide: (Moderate) The plasma concentration of loperamide, a CYP3A4 and P-glycoprotein (P-gp) substrate, may be increased when administered concurrently with cyclosporine, a CYP3A4 and P-gp inhibitor. If these drugs are used together, monitor for loperamide-associated adverse reactions, such as CNS effects and cardiac toxicities (i.e., syncope, ventricular tachycardia, QT prolongation, torsade de pointes, cardiac arrest).
    Loperamide; Simethicone: (Moderate) The plasma concentration of loperamide, a CYP3A4 and P-glycoprotein (P-gp) substrate, may be increased when administered concurrently with cyclosporine, a CYP3A4 and P-gp inhibitor. If these drugs are used together, monitor for loperamide-associated adverse reactions, such as CNS effects and cardiac toxicities (i.e., syncope, ventricular tachycardia, QT prolongation, torsade de pointes, cardiac arrest).
    Lopinavir; Ritonavir: (Major) An interaction is anticipated to occur with all anti-retroviral protease inhibitors and cyclosporine, as all protease inhibitors inhibit CYP3A4. Cyclosporine toxicity, consisting of fatigue, headache, and GI distress, has been reported by a patient receiving cyclosporine and saquinavir. Prior to beginning saquinavir the patient had been receiving stable doses of cyclosporine resulting in trough concentrations of 150 to 200 mcg/ml. After receiving saquinavir for 3 days, the cyclosporine trough concentration increased to 580 mcg/ml. Dosages of both agents were decreased by 50% leading to resolution of symptoms. This interaction is probably due to CYP3A4 inhibition by saquinavir. Another possible mechanism is that both drugs have a high affinity for the drug efflux protein, P-glycoprotein, which may increase the absorption or decrease the clearance of the other drug.
    Losartan: (Moderate) Coadministration of cyclosporine and an angiotensin II receptor antagonist, like losartan, may increase the risk of hyperkalemia and reduced renal function. In response to cyclosporine-induced renal afferent vasoconstriction and glomerular hypoperfusion, angiotensin II is required to maintain an adequate glomerular filtration rate. Inhibition of angiotensin-converting enzyme (ACE) could reduce renal function acutely. Several cases of acute renal failure have been associated with the addition of enalapril to cyclosporine therapy in renal transplant patients. Also, cyclosporine can cause hyperkalemia, and inhibition of angiotensin II leads to reduced aldosterone concentrations, which can increase the serum potassium concentration. Closely monitor renal function and serum potassium concentrations in patients receiving cyclosporine concurrently with losartan.
    Lovastatin: (Major) Avoid the concurrent use of cyclosporine and lovastatin. Cyclosporine may increase the risk of myopathy, rhabdomyolysis and acute renal failure in patients taking lovastatin. In uncontrolled clinical studies of lovastatin, myopathy was reported more frequently in patients receiving concomitant therapy with cyclosporine. Cyclosporine may reduce the clearance of the HMG-CoA reductase inhibitors (statins), Cyclosporine has been shown to increase the AUC of HMG-CoA reductase inhibitors, presumably due to CYP3A4 inhibition.
    Lovastatin; Niacin: (Major) Avoid the concurrent use of cyclosporine and lovastatin. Cyclosporine may increase the risk of myopathy, rhabdomyolysis and acute renal failure in patients taking lovastatin. In uncontrolled clinical studies of lovastatin, myopathy was reported more frequently in patients receiving concomitant therapy with cyclosporine. Cyclosporine may reduce the clearance of the HMG-CoA reductase inhibitors (statins), Cyclosporine has been shown to increase the AUC of HMG-CoA reductase inhibitors, presumably due to CYP3A4 inhibition.
    Lumacaftor; Ivacaftor: (Major) Concomitant use of cyclosporine and lumacaftor; ivacaftor is not recommended. If concurrent use cannot be avoided, monitor cyclosporine serum concentrations closely and adjust the dose accordingly. Lumacaftor; ivacaftor may decrease the systemic exposure of cyclosporine. In return, cyclosporine may increase ivacaftor exposure, although the clinical significance of this interaction is unclear. Cyclosporine is a substrate and moderate inhibitor of CYP3A. Lumacaftor is a strong inducer of CYP3A, and ivacaftor is CYP3A substrate. In addition, the exposure of cyclosporine may be altered via P-glycoprotein (P-gp) transport. Cyclosporine is P-gp substrate; in vitro studies suggest lumacaftor; ivacaftor has the potential to induce and inhibit P-gp.
    Lumacaftor; Ivacaftor: (Major) Use caution when administering ivacaftor and cyclosporine concurrently. Ivacaftor is a substrate of CYP3A, and an inhibitor of CYP3A and P-glycoprotein (P-gp). Cyclosporine is a CYP3A and P-glycoprotein (P-gp) substrate and inhibitor. If these agents are given together, the manufacturer of ivacaftor recommends administering ivacaftor at the usual recommended dose but reducing the frequency to once daily (e.g., if the usual dosage is 150 mg twice daily, reduce to 150 mg once daily). Coadministration of ivacaftor with fluconazole, a moderate CYP3A inhibitor, increased ivacaftor exposure by 3-fold. In addition, coadministration of ivacaftor with CYP3A and P-gp substrates, such as cyclosporine, can increase cyclosporine exposure leading to increased or prolonged therapeutic effects and adverse events. More careful monitoring of cyclosporine blood concentrations may be warranted.
    Maraviroc: (Moderate) Use caution if coadministration of maraviroc with cyclosporine is necessary, due to a possible increase in maraviroc exposure. Maraviroc is a CYP3A/P-glycoprotein (P-gp) substrate and cyclosporine is a CYP3A4/P-gp inhibitor. Monitor for an increase in adverse effects with concomitant use.
    Measles Virus; Mumps Virus; Rubella Virus; Varicella Virus Vaccine, Live: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Measles/Mumps/Rubella Vaccines, MMR: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Meclofenamate Sodium: (Moderate) Additive decreases in renal function have been reported between cyclosporine and NSAIDs. Patients should be monitored for signs and symptoms of cyclosporine toxicity and infection, as NSAIDs may mask fever, pain, or swelling.
    Mefenamic Acid: (Moderate) Additive decreases in renal function have been reported between cyclosporine and NSAIDs. Patients should be monitored for signs and symptoms of cyclosporine toxicity and infection, as NSAIDs may mask fever, pain, or swelling.
    Mefloquine: (Moderate) Mefloquine is metabolized by CYP3A4. Cyclosporine is an inhibitor of this enzyme and may decrease the clearance of mefloquine and increase mefloquine systemic exposure.
    Meloxicam: (Moderate) Serum creatinine ,potassium concentrations, and cyclosporine concentrations should be closely monitored when systemic cyclosporine is given with nonsteroidal antiinflammatory drugs (NSAIDs). Renal dysfunction associated with cyclosporine may be potentiated by concurrent usage of NSAIDs. The effects of NSAIDs on the production of renal prostaglandins may cause changes in the elimination of cyclosporine. Potentiation of renal dysfunction may especially occur in a dehydrated patient. Patients should be monitored for signs and symptoms of cyclosporine toxicity and infection, as NSAIDs may mask fever, pain, or swelling. Increased tear production was not seen in patients receiving ophthalmic NSAIDs or using punctual plugs concurrently with cyclosporine ophthalmic emulsion.
    Melphalan: (Minor) Additive nephrotoxicity can occur if cyclosporine is administered with other nephrotoxic drugs such as melphalan. Monitor renal function and fluid status carefully during cyclosporine usage.
    Mephobarbital: (Major) Phenobarbital may induce cyclosporine metabolism, thereby increasing the clearance of cyclosporine. It is likely that other barbiturates would interact similarly with cyclosporine; however no supportive data are available. If phenobarbital is added to an existing cyclosporine regimen, monitor cyclosporine concentrations closely to avoid loss of clinical efficacy until a new steady-state concentration is achieved. Conversely, if phenobarbital is discontinued, cyclosporine concentrations could increase.
    Mercaptopurine, 6-MP: (Minor) Concurrent use of purine analogs with other agents which cause bone marrow or immune suppression such as immunosuppressives may result in additive effects. A dosage reduction of the antineoplastic may be indicated when used in combination with other myelosuppressive chemotherapy.
    Metformin: (Moderate) Cyclosporine has been reported to cause hyperglycemia; this effect appears to be dose-related and caused by direct beta-cell toxicity. Therefore, a pharmacodynamic interaction is possible with all antidiabetic agents and cyclosporine. Patients should be monitored for worsening glycemic control if therapy with cyclosporine is initiated in patients receiving antidiabetic agents.
    Metformin; Pioglitazone: (Moderate) Cyclosporine has been reported to cause hyperglycemia; this effect appears to be dose-related and caused by direct beta-cell toxicity. Therefore, a pharmacodynamic interaction is possible with all antidiabetic agents and cyclosporine. Patients should be monitored for worsening glycemic control if therapy with cyclosporine is initiated in patients receiving antidiabetic agents. (Moderate) Cyclosporine has been reported to cause hyperglycemia; this effect appears to be dose-related and caused by direct beta-cell toxicity. Therefore, a pharmacodynamic interaction is possible with all antidiabetic agents and cyclosporine. Patients should be monitored for worsening glycemic control if therapy with cyclosporine is initiated in patients receiving antidiabetic agents.
    Metformin; Repaglinide: (Major) Cyclosporine appears to inhibit the metabolism of repaglinide by inhibiting CYP3A4. Cyclosporine also appears to inhibit the uptake of repaglinide into the liver by inhibiting the organic anion transporting protein OATP1B1, which is an active hepatic uptake transporter. Increased repaglinide concentrations were noted among healthy patients who took oral cyclosporine 100 mg daily for 2 days. After a single 0.25 mg repaglinide dose, the mean area under the plasma concentration-time curve for repaglinide increased 244% (range, 119 to 533%) as compared with data from placebo recipients. In addition to a pharmacokinetic interaction, cyclosporine has been reported to cause hyperglycemia. Cyclosporine may have direct beta-cell toxicity; the effects from cyclosporine may be dose-related. Monitor patients glycemic control if cyclosporine is started or stopped in patients receiving repaglinide. (Moderate) Cyclosporine has been reported to cause hyperglycemia; this effect appears to be dose-related and caused by direct beta-cell toxicity. Therefore, a pharmacodynamic interaction is possible with all antidiabetic agents and cyclosporine. Patients should be monitored for worsening glycemic control if therapy with cyclosporine is initiated in patients receiving antidiabetic agents.
    Metformin; Rosiglitazone: (Moderate) Cyclosporine has been reported to cause hyperglycemia; this effect appears to be dose-related and caused by direct beta-cell toxicity. Therefore, a pharmacodynamic interaction is possible with all antidiabetic agents and cyclosporine. Patients should be monitored for worsening glycemic control if therapy with cyclosporine is initiated in patients receiving antidiabetic agents. (Moderate) Cyclosporine has been reported to cause hyperglycemia; this effect appears to be dose-related and caused by direct beta-cell toxicity. Therefore, a pharmacodynamic interaction is possible with all antidiabetic agents and cyclosporine. Patients should be monitored for worsening glycemic control if therapy with cyclosporine is initiated in patients receiving antidiabetic agents.
    Metformin; Saxagliptin: (Moderate) Cyclosporine has been reported to cause hyperglycemia. Patients should be monitored for changes in glycemic control if therapy with cyclosporine is initiated in patients receiving saxagliptin. (Moderate) Cyclosporine has been reported to cause hyperglycemia; this effect appears to be dose-related and caused by direct beta-cell toxicity. Therefore, a pharmacodynamic interaction is possible with all antidiabetic agents and cyclosporine. Patients should be monitored for worsening glycemic control if therapy with cyclosporine is initiated in patients receiving antidiabetic agents.
    Metformin; Sitagliptin: (Moderate) Cyclosporine has been reported to cause hyperglycemia. Patients should be monitored for changes in glycemic control if therapy with cyclosporine is initiated in patients receiving sitagliptin. (Moderate) Cyclosporine has been reported to cause hyperglycemia; this effect appears to be dose-related and caused by direct beta-cell toxicity. Therefore, a pharmacodynamic interaction is possible with all antidiabetic agents and cyclosporine. Patients should be monitored for worsening glycemic control if therapy with cyclosporine is initiated in patients receiving antidiabetic agents.
    Methazolamide: (Minor) Acetazolamide may increase serum cyclosporine concentrations. Data are not available regarding an interaction between cyclosporine and other carbonic anhydrase inhibitors (e.g., methazolamide), although monitoring is warranted.
    Methohexital: (Major) Phenobarbital may induce cyclosporine metabolism, thereby increasing the clearance of cyclosporine. It is likely that other barbiturates would interact similarly with cyclosporine; however no supportive data are available. If phenobarbital is added to an existing cyclosporine regimen, monitor cyclosporine concentrations closely to avoid loss of clinical efficacy until a new steady-state concentration is achieved. Conversely, if phenobarbital is discontinued, cyclosporine concentrations could increase.
    Methotrexate: (Moderate) Cyclosporine should be used cautiously with nephrotoxic drugs, such as methotrexate, as cyclosporine itself can cause structural kidney damage. Additive nephrotoxicity can occur if these drugs are administered together. Monitor renal function and fluid status carefully. Additionally, concurrent administration of methotrexate and cyclosporine in patients with rheumatoid arthritis can elevate methotrexate concentrations and decrease the levels of the 7-hydroxy-methotrexate metabolite. Of 20 patients with rheumatoid arthritis that received methotrexate and cyclosporine, the mean peak methotrexate concentration increased 26%, the mean methotrexate AUC increased 18%, and the AUC of the 7-hydroxy-methotrexate metabolite decreased 80% as compared with patients that received methotrexate alone. Cyclosporine concentrations do not appear to be altered, but data is from only 6 patients. Monitoring of methotrexate and cyclosporine concentrations during concurrent cyclosporine therapy is recommended.
    Methylprednisolone: (Moderate) Convulsions have been reported during concurrent use of cyclosporine and high dose methylprednisolone. In addition, mutual inhibition of metabolism occurs with concurrent use of cyclosporine and methylprednisolone; therefore, the potential for adverse events associated with either drug may be increased. Coadministration should be approached with caution.
    Methyltestosterone: (Moderate) Androgens may increase concentrations of cyclosporine, potentially increasing the risk of nephrotoxicity. Until further data are available, close monitoring of cyclosporine serum concentrations is prudent during coadministration with androgens.
    Metoclopramide: (Moderate) Oral metoclopramide has been shown to increase the mean bioavailability of oral cyclosporine by roughly 30%, probably due to decreased GI motility. Until more data are available, cyclosporine serum concentrations should be monitored carefully if metoclopramide is added.
    Metreleptin: (Moderate) Upon initiation or discontinuation of metreleptin in a patient receiving cyclosporine, drug concentration monitoring should be performed and the cyclosporine dosage adjusted as needed. Leptin is a cytokine and may have the potential to alter the formation of cytochrome P450 (CYP450) enzymes. The effect of metreleptin on CYP450 enzymes may be clinically relevant for CYP450 substrates with a narrow therapeutic index, such as cyclosporine.
    Metronidazole: (Major) Medications with significant alcohol content should not be ingested during therapy with metronidazole and should be avoided for 3 days after therapy is discontinued. Cyclosporine parenteral and oral solutions contain ethanol; liquid-filled capsules contain ethanol in lower percentages. Administration of ethanol-containing formulations of cyclosporine to patients receiving or who have recently received metronidazole may result in disulfiram-like reactions. A disulfiram reaction would not be expected to occur with non-ethanol containing formulations.
    Micafungin: (Moderate) Leukopenia, neutropenia, anemia, and thrombocytopenia have been associated with micafungin. In theory, patients who are taking immunosuppressive agents such as cyclosporine concomitantly with micafungin may have additive risks for infection or other side effects. However, the manufacturer has listed no particular precautions for co-use of micafungin with cyclosporine. Concurrent administration of micafungin and cyclosporinel did not alter the pharmacokinetic parameters of micafungin. Furthermore, there was no effect of a single or multiple doses of micafungin on cyclosporine pharmacokinetic parameters.
    Mifepristone, RU-486: (Severe) Mifepristone, RU-486 inhibits CYP3A4 in vitro. Coadministration of mifepristone may lead to an increase in serum concentrations of drugs that are CYP3A4 substrates and that have a narrow therapeutic index, such as cyclosporine. Coadministration is contraindicated when the drug is used chronically, such as in the treatment of Cushing's syndrome. Due to the slow elimination of mifepristone from the body, such interactions may be observed for a prolonged period after mifepristone administration. In addition, the CYP3A4 metabolism of mifepristone could be theoretically inhibited by cyclosporine.
    Miglitol: (Moderate) Cyclosporine has been reported to cause hyperglycemia; this effect appears to be dose-related and caused by direct beta-cell toxicity. Therefore, a pharmacodynamic interaction is possible. Monitor the blood glucose.
    Mitotane: (Major) Use caution if mitotane and cyclosporineare used concomitantly, and monitor cyclosporine levels; adjust cyclosporine doses as appropriate. Mitotane is a strong CYP3A4 inducer and cyclosporine is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of cyclosporine. When administered with the CYP3A4 inducer, rifapentine, induction of enzyme activities occurred within 4 days after the first rifapentine dose; enzyme activities returned to baseline levels 14 days after rifapentine discontinuation. The magnitude of enzyme induction is dose and dosing frequency dependent. In vitro and in vivo enzyme induction studies have suggested less enzyme induction potential with rifapentine as compared with rifampin, another strong CYP3A4 inducer.
    Mitoxantrone: (Major) Concurrent use of mitoxantrone with other agents which cause bone marrow or immune suppression such as other immunosuppressives may result in additive effects. In addition, high doses of cyclosporine (starting at 16 mg/kg/day IV) may increase exposure to anthracyclines in cancer patients. Cyclosporine is a substrate and inhibitor of P-glycoprotein, an energy-dependent drug efflux pump encoded for by the multidrug resistance gene-1 (MDR1). Overexpression of this protein has been described as a mechanism of resistance to naturally-occurring (non-synthetic) chemotherapy agents. Cyclosporine can block MDR1-mediated resistance when given at much higher doses than those used in transplantation and may also enhance the efficacy of mitoxantrone by inhibiting this protein. Valspodar is a cyclosporine analog with less renal and immunosuppressive effects than cyclosporine while retaining effects on MDR. The addition of cyclosporine or valspodar to mitoxantrone therapy may increase the intracellular concentrations of mitoxantrone leading to increased efficacy and side effects.
    Mivacurium: (Moderate) Cyclosporine may potentiate the action of nondepolarizing neuromuscular blockers. Prolonged neuromuscular blockade has been reported in patients receiving cyclosporine who receive neuromuscular blockers as part of surgical anesthesia. Monitor patients for recurrent neuromuscular blockade and respiratory depression; extended ventilatory support may be required.
    Modafinil: (Moderate) Modafinil can increase the clearance of cyclosporine by inducing cyclosporine metabolism. Increased cyclosporine clearance and decreased cyclosporine concentrations can lead to loss of therapeutic effect or organ rejection. Cyclosporine concentrations should be monitored closely after the addition of modafinil until a new steady-state level is achieved.
    Muromonab-CD3: (Major) Because cyclosporine is an immunosuppressant, additive affects may be seen with other immunosuppressives or antineoplastic agents. While therapy is designed to take advantage of this effect, patients may be predisposed to over-immunosuppression resulting in an increased risk for the development of severe infections, malignancies including lymphoma and leukemia, myelodysplastic syndromes, and lymphoproliferative disorders. The risk is related to the intensity and duration of immunosuppression rather than the specific agents. If cyclosporine is given concurrently with muromonab-CD3, there may be a greater incidence of seizures, encephalopathy, infections, neoplasms, and thrombotic events. Early detection of lymphoproliferative disorders with subsequent reduction of total immunosuppression may result in regression of some lymphoproliferative disorders. To reduce the potential for malignancy and infections, dosages of cyclosporine should be reduced to the lowest level compatible with an effective therapeutic response if used with muromonab-CD3. Maintenance immunosuppression should be resumed 3 days prior to the cessation of muromonab-CD3 therapy.
    Mycophenolate: (Moderate) Because mycophenolate mofetil is an immunosuppressant, additive affects may be seen with other immunosuppressives, such as cyclosporine.
    Nabumetone: (Moderate) Serum creatinine ,potassium concentrations, and cyclosporine concentrations should be closely monitored when systemic cyclosporine is given with nonsteroidal antiinflammatory drugs (NSAIDs). Renal dysfunction associated with cyclosporine may be potentiated by concurrent usage of NSAIDs. The effects of NSAIDs on the production of renal prostaglandins may cause changes in the elimination of cyclosporine. Potentiation of renal dysfunction may especially occur in a dehydrated patient. Patients should be monitored for signs and symptoms of cyclosporine toxicity and infection, as NSAIDs may mask fever, pain, or swelling. Increased tear production was not seen in patients receiving ophthalmic NSAIDs or using punctual plugs concurrently with cyclosporine ophthalmic emulsion.
    Nafcillin: (Moderate) Nafcillin can increase the clearance of cyclosporine by inducing cyclosporine metabolism. Cyclosporine concentrations should be monitored closely to avoid loss of clinical efficacy until a new steady-state cyclosporine concentration is achieved when nafcillin is added to an existing cyclosporine regimen.
    Naldemedine: (Major) Monitor for potential naldemedine-related adverse reactions if coadministered with cyclosporine. The plasma concentrations of naldemedine may be increased during concurrent use. Naldemedine is a substrate of CYP3A4 and P-gp; cyclosporine is a moderate P-gp inhibitor and a moderate CYP3A4 inhibitor.
    Nandrolone Decanoate: (Moderate) Androgens may increase concentrations of cyclosporine, potentially increasing the risk of nephrotoxicity. Until further data are available, close monitoring of cyclosporine serum concentrations is prudent during coadministration with androgens.
    Nanoparticle Albumin-Bound Paclitaxel: (Major) In vitro, the metabolism of paclitaxel is inhibited by cyclosporine, but cyclosporine concentrations used exceeded those found in vivo following normal therapeutic doses used. Additionally, cyclosporine and valspodar (PSC-833), a cyclosporine analog, block the multidrug resistance (MDR) P-glycoprotein, which is a mechanism of resistance to naturally occurring (non-synthetic) chemotherapy agents. These agents could enhance paclitaxel's activity and toxicity.
    Naproxen: (Moderate) Serum creatinine ,potassium concentrations, and cyclosporine concentrations should be closely monitored when systemic cyclosporine is given with nonsteroidal antiinflammatory drugs (NSAIDs). Renal dysfunction associated with cyclosporine may be potentiated by concurrent usage of NSAIDs. The effects of NSAIDs on the production of renal prostaglandins may cause changes in the elimination of cyclosporine. Potentiation of renal dysfunction may especially occur in a dehydrated patient. Patients should be monitored for signs and symptoms of cyclosporine toxicity and infection, as NSAIDs may mask fever, pain, or swelling. Increased tear production was not seen in patients receiving ophthalmic NSAIDs or using punctual plugs concurrently with cyclosporine ophthalmic emulsion.
    Naproxen; Pseudoephedrine: (Moderate) Serum creatinine ,potassium concentrations, and cyclosporine concentrations should be closely monitored when systemic cyclosporine is given with nonsteroidal antiinflammatory drugs (NSAIDs). Renal dysfunction associated with cyclosporine may be potentiated by concurrent usage of NSAIDs. The effects of NSAIDs on the production of renal prostaglandins may cause changes in the elimination of cyclosporine. Potentiation of renal dysfunction may especially occur in a dehydrated patient. Patients should be monitored for signs and symptoms of cyclosporine toxicity and infection, as NSAIDs may mask fever, pain, or swelling. Increased tear production was not seen in patients receiving ophthalmic NSAIDs or using punctual plugs concurrently with cyclosporine ophthalmic emulsion.
    Naproxen; Sumatriptan: (Moderate) Serum creatinine ,potassium concentrations, and cyclosporine concentrations should be closely monitored when systemic cyclosporine is given with nonsteroidal antiinflammatory drugs (NSAIDs). Renal dysfunction associated with cyclosporine may be potentiated by concurrent usage of NSAIDs. The effects of NSAIDs on the production of renal prostaglandins may cause changes in the elimination of cyclosporine. Potentiation of renal dysfunction may especially occur in a dehydrated patient. Patients should be monitored for signs and symptoms of cyclosporine toxicity and infection, as NSAIDs may mask fever, pain, or swelling. Increased tear production was not seen in patients receiving ophthalmic NSAIDs or using punctual plugs concurrently with cyclosporine ophthalmic emulsion.
    Natalizumab: (Major) The concomitant use of natalizumab and immunosuppressives may further increase the risk of infections, including progressive multifocal leukoencephalopathy (PML), over the risk observed with use of natalizumab alone. Prior treatment with an immunosuppressant is also a risk factor for PML. The safety and efficacy of natalizumab in combination with immunosuppressants has not been evaluated. Multiple sclerosis (MS) patients receiving chronic immunosuppressant therapy should not ordinarily be treated with natalizumab. Also, natalizumab for Crohn's disease should not be used in combination with cyclosporine.
    Nateglinide: (Moderate) Cyclosporine has been reported to cause hyperglycemia. Patients should be monitored for worsening of glycemic control if therapy with cyclosporine is initiated in patients receiving nateglinide.
    Nebivolol; Valsartan: (Moderate) Coadministration of cyclosporine and an angiotensin II receptor antagonist, like valsartan, may increase the risk of hyperkalemia and reduced renal function. In response to cyclosporine-induced renal afferent vasoconstriction and glomerular hypoperfusion, angiotensin II is required to maintain an adequate glomerular filtration rate. Inhibition of angiotensin-converting enzyme (ACE) could reduce renal function acutely. Several cases of acute renal failure have been associated with the addition of enalapril to cyclosporine therapy in renal transplant patients. Also, cyclosporine can cause hyperkalemia, and inhibition of angiotensin II leads to reduced aldosterone concentrations, which can increase the serum potassium concentration. Closely monitor renal function and serum potassium concentrations in patients receiving cyclosporine concurrently with valsartan. Additionally, valsartan is a substrate of the hepatic uptake transporter OATP1B1 and cyclosporine is an inhibitor of OATP. Coadministration may increase systemic exposure to valsartan. Patients should be monitored for adverse effects of valsartan.
    Nefazodone: (Major) Both nefazodone and cyclosporine are substrates and inhibitors of CYP3A4. Nefazodone is known to increase cyclosporine serum concentrations by inhibiting cyclosporine metabolism. A single case report is noted of increasing cyclosporine concentrations after the addition of nefazodone; the cyclosporine concentration returned to previous levels after the discontinuation of nefazodone. The manufacturer has also received reports of this interaction. In some cases cyclosporine levels have been seven-times their baseline after nefazodone administration. Because of the potential toxicity of cyclosporine, nefazodone should be used cautiously, if at all, in patients receiving cyclosporine. Monitoring of serum cyclosporine concentrations is recommended.
    Nelfinavir: (Major) An interaction is anticipated to occur with all anti-retroviral protease inhibitors and cyclosporine, as all protease inhibitors inhibit CYP3A4. Cyclosporine toxicity, consisting of fatigue, headache, and GI distress, has been reported by a patient receiving cyclosporine and saquinavir. Prior to beginning saquinavir the patient had been receiving stable doses of cyclosporine resulting in trough concentrations of 150 to 200 mcg/ml. After receiving saquinavir for 3 days, the cyclosporine trough concentration increased to 580 mcg/ml. Dosages of both agents were decreased by 50% leading to resolution of symptoms. This interaction is probably due to CYP3A4 inhibition by saquinavir. Another possible mechanism is that both drugs have a high affinity for the drug efflux protein, P-glycoprotein, which may increase the absorption or decrease the clearance of the other drug.
    Neomycin: (Minor) Because the systemic absorption of neomycin is minimal, the risk of this interaction is expected to be low; however, the combined use of cyclosporine and systemic neomycin may increase the risk of nephrotoxicity or ototoxicity.
    Neratinib: (Major) Avoid concomitant use of cyclosporine with neratinib due to an increased risk of neratinib-related toxicity. Neratinib is a CYP3A4 substrate and cyclosporine is a moderate CYP3A4 inhibitor. The effect of moderate CYP3A4 inhibition on neratinib concentrations has not been studied; however, coadministration with a strong CYP3A4 inhibitor increased neratinib exposure by 481%. Because of the significant impact on neratinib exposure from strong CYP3A4 inhibition, the potential impact on neratinib safety from concomitant use with moderate CYP3A4 inhibitors should be considered as they may also significantly increase neratinib exposure.
    Neuromuscular blockers: (Moderate) Cyclosporine may potentiate the action of nondepolarizing neuromuscular blockers. Prolonged neuromuscular blockade has been reported in patients receiving cyclosporine who receive neuromuscular blockers as part of surgical anesthesia. Monitor patients for recurrent neuromuscular blockade and respiratory depression; extended ventilatory support may be required.
    Nevirapine: (Major) Nevirapine may induce cyclosporine metabolism, thereby increasing the clearance of cyclosporine. If nevirapine is added to an existing cyclosporine regimen, monitor cyclosporine concentrations closely to avoid loss of clinical efficacy until a new steady-state concentration is achieved. Conversely, if nevirapine is discontinued, cyclosporine concentrations could increase.
    Niacin; Simvastatin: (Severe) The use of simvastatin with is contraindicated due to an increased risk for myopathy and rhabdomyolysis. Cyclosporine increases the AUC of statins when administered concomitantly, and the risk for myopathy is increased by high levels of HMG-CoA reductase inhibitory activity in plasma. Although the mechanism is not fully understood, it is presumably due to inhibition of CYP3A4 and/or OAT1B1 by cyclosporine; simvastatin is a substrate of CYP3A4 and OAT1B1.
    Nicardipine: (Moderate) Coadministration of nicardipine and cyclosporine may result in elevated plasma cyclosporine concentrations. Monitor plasma concentrations of cyclosporine closely, and adjust the dose as necessary. Cyclosporine is extensively metabolized by CYP3A4 and is a substrate of the P-glycloprotein (P-gp) drug transporter; nicardipine is an inhibitor of both CYP3A4 and P-gp.
    Nifedipine: (Moderate) Cyclosporine may increase nifedipine blood concentrations when given concomitantly. Concurrent use of cyclosporine and nifedipine has been associated with increased severity and frequency of gingival hyperplasia; patients receiving these drugs together should be instructed to follow strict oral hygiene. Patients with severe gingival hyperplasia should be promptly referred for evaluation. Nifedipine has been shown to have minimal effects on cyclosporine blood concentrations.
    Nilotinib: (Major) Concomitant use of nilotinib, a substrate and inhibitor of CYP3A4 and P-glycoprotein (P-gp), and cyclosporine, a CYP3A4 and P-gp substrate and inhibitor with a narrow therapeutic range, may result in increased nilotinib and/or cyclosporine levels. A dose reduction of either agent may be necessary if these drugs are used together; monitor patients for nilotinib and cyclosporine toxicity (e.g., cyclosporine concentrations to help avoid graft failure or drug-related toxicity and QT interval prolongation).
    Nintedanib: (Moderate) Cyclosporine is a moderate inhibitor of both P-glycoprotein (P-gp) and CYP3A4; nintedanib is a P-gp substrate as well as a minor substrate of CYP3A4. Coadministration may increase the concentration and clinical effect of nintedanib. If concomitant use of cyclosporine and nintedanib is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of therapy may be necessary.
    Non-Ionic Contrast Media: (Moderate) Because the use of other nephrotoxic drugs, including cyclosporine, is an additive risk factor for nephrotoxicity in patients receiving radiopaque contrast agents, when possible, cyclosporine should be withheld during radiopaque contrast agent administration.
    Norfloxacin: (Moderate) Norfloxacin appears to increase cyclosporine concentrations. The mechanism of the interaction appears to be inhibition of CYP3A4 by norfloxacin. Close monitoring of cyclosporine concentrations is required when norfloxacin is given concurrently with cyclosporine and suitable dosage adjustments made.
    Octreotide: (Major) Octreotide may induce cyclosporine metabolism, thereby increasing the clearance of cyclosprone. In addition, administration of octreotide to patients receiving oral cyclosporine has been shown to decrease the oral bioavailability of cyclosporine. Since oral cyclosporine is administered in an olive oil vehicle, the mechanism of this interaction is thought to be due to the decreased absorption of fat by octreotide. If octreotide is added to an existing cyclosporine regimen, monitor cyclosporine concentrations closely to avoid loss of clinical efficacy until a new steady-state concentration is achieved. Conversely, if octreotide is discontinued, cyclosporine concentrations could increase.
    Olaparib: (Major) Avoid coadministration of olaparib with cyclosporine and consider alternative agents with less CYP3A4 inhibition due to increased olaparib exposure. If concomitant use is unavoidable, reduce the dose of olaparib tablets to 150 mg twice daily; reduce the dose of olaparib capsules to 200 mg twice daily. Olaparib is a CYP3A4/5 substrate and cyclosporine is a moderate CYP3A4 inhibitor.
    Olmesartan: (Moderate) Coadministration of cyclosporine and an angiotensin II receptor antagonist, like olmesartan, may increase the risk of hyperkalemia and reduced renal function. In response to cyclosporine-induced renal afferent vasoconstriction and glomerular hypoperfusion, angiotensin II is required to maintain an adequate glomerular filtration rate. Inhibition of angiotensin-converting enzyme (ACE) could reduce renal function acutely. Several cases of acute renal failure have been associated with the addition of enalapril to cyclosporine therapy in renal transplant patients. Also, cyclosporine can cause hyperkalemia, and inhibition of angiotensin II leads to reduced aldosterone concentrations, which can increase the serum potassium concentration. Closely monitor renal function and serum potassium concentrations in patients receiving cyclosporine concurrently with olmesartan.
    Ombitasvir; Paritaprevir; Ritonavir: (Major) An interaction is anticipated to occur with all anti-retroviral protease inhibitors and cyclosporine, as all protease inhibitors inhibit CYP3A4. Cyclosporine toxicity, consisting of fatigue, headache, and GI distress, has been reported by a patient receiving cyclosporine and saquinavir. Prior to beginning saquinavir the patient had been receiving stable doses of cyclosporine resulting in trough concentrations of 150 to 200 mcg/ml. After receiving saquinavir for 3 days, the cyclosporine trough concentration increased to 580 mcg/ml. Dosages of both agents were decreased by 50% leading to resolution of symptoms. This interaction is probably due to CYP3A4 inhibition by saquinavir. Another possible mechanism is that both drugs have a high affinity for the drug efflux protein, P-glycoprotein, which may increase the absorption or decrease the clearance of the other drug. (Major) Reduce cyclosporine dose to one-fifth (1/5th) of the patients current cyclosporine dose when initiating treatment with dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir, as coadministration results in elevated cyclosporine blood concentrations. With subsequent doses, monitor cyclosporine blood concentrations to determine further dose adjustments. After completion of the 4-drug hepatitis C treatment regimen, the dose should be re-adjusted based on measured blood concentrations. Monitor for renal function and cyclosporine associated adverse reactions. (Major) Reduce cyclosporine dose to one-fifth (1/5th) of the patients current cyclosporine dose when initiating treatment with dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir, as coadministration results in elevated cyclosporine blood concentrations. With subsequent doses, monitor cyclosporine blood concentrations to determine further dose adjustments. After completion of thehepatitis C treatment regimen, the dose should be re-adjusted based on measured blood concentrations. Monitor for renal function and cyclosporine associated adverse reactions
    Oritavancin: (Moderate) Avoid use of oritavancin with drugs that have a narrow therapeutic window, such as cyclosporine. Cyclosporine is metabolized by CYP3A4; oritavancin is a weak CYP3A4 inducer. Plasma concentrations and efficacy of cyclosporine may be reduced if these drugs are administered concurrently. Monitor for lack of cyclosporine efficacy.
    Orlistat: (Major) Orlistat decreases the absorption of fat by inhibiting gastrointestinal lipases and as cyclosporine is dependent on lipid absorption, especially the Sandimmune formulation, the absorption of cyclosporine is inhibited. Caution is advised with the concomitant use of orlistat and cyclosporine therapy. More frequent cyclosporine concentration monitoring may be needed. To reduce the chance of a drug-drug interaction, cyclosporine should be administered at least 2 hours before or after orlistat in patients taking both drugs; although, as noted, separation of administration times may not always alter the course of the interaction.
    Oxandrolone: (Moderate) Androgens may increase concentrations of cyclosporine, potentially increasing the risk of nephrotoxicity. Until further data are available, close monitoring of cyclosporine serum concentrations is prudent during coadministration with androgens.
    Oxaprozin: (Moderate) Additive decreases in renal function have been reported between cyclosporine and NSAIDs. Patients should be monitored for signs and symptoms of cyclosporine toxicity and infection, as NSAIDs may mask fever, pain, or swelling.
    Oxcarbazepine: (Moderate) Oxcarbazepine and its active metabolite, MHD, are dose-dependent inducers of the hepatic CYP3A4/5 isoenzymes thereby having the potential to lower the plasma levels of medications metabolized through these pathways, including cyclosporine.
    Oxymetholone: (Moderate) Androgens may increase concentrations of cyclosporine, potentially increasing the risk of nephrotoxicity. Until further data are available, close monitoring of cyclosporine serum concentrations is prudent during coadministration with androgens.
    Paclitaxel: (Major) In vitro, the metabolism of paclitaxel is inhibited by cyclosporine, but cyclosporine concentrations used exceeded those found in vivo following normal therapeutic doses used in transplantation. Additionally, cyclosporine blocks the multidrug resistance (MDR) P-glycoprotein, which is a mechanism of resistance to naturally occurring (non-synthetic) chemotherapy agents. These agents could enhance paclitaxel's activity and toxicity. Paclitaxel has poor oral availability due to its high affinity for P-glycoprotein present in high levels in the GI tract. In clinical studies, oral paclitaxel has been given in combination with cyclosporine to improve the bioavailability of paclitaxel, due to cyclosporine-induced blockade of P-glycoprotein located in the in GI tract. The bioavailability of oral paclitaxel was 8-fold higher when given in combination with cyclosporine than after oral paclitaxel alone. Therapeutic concentrations were achieved within 7.4 hours, comparable to an equivalent IV dose.
    Palbociclib: (Major) Monitor for an increase in palbociclib-related adverse reactions if coadministration with cyclosporine is necessary. Concentrations of cyclosporine may also increase; monitor cyclosporine levels and adjust the dose as necessary. Palbociclib is primarily metabolized by CYP3A4 and cyclosporine is a moderate CYP3A4 inhibitor. In a drug interaction trial, coadministration with a strong CYP3A4 inhibitor increased the AUC and Cmax of palbociclib by 87% and 34%, respectively; moderate inhibitors may also increase palbociclib exposure. Palbociclib is also a weak time-dependent inhibitor of CYP3A while cyclosporine is a CYP3A4 substrate with a narrow therapeutic index. In a drug interaction trial in healthy subjects (n = 26), coadministration with palbociclib increased the AUC and Cmax of a sensitive CYP3A4 substrate by 61% and 37%, respectively.
    Pamidronate: (Moderate) Coadministration of pamidronate with other nephrotoxic drugs, including cyclosporine, may increase the risk of developing nephrotoxicity following pamidronate administration, even in patients who have normal renal function.
    Pancuronium: (Moderate) Cyclosporine may potentiate the action of nondepolarizing neuromuscular blockers. Prolonged neuromuscular blockade has been reported in patients receiving cyclosporine who receive neuromuscular blockers as part of surgical anesthesia. Monitor patients for recurrent neuromuscular blockade and respiratory depression; extended ventilatory support may be required.
    Paromomycin: (Minor) Because the systemic absorption of oral paromomycin is minimal, the risk of this interaction is expected to be low; however, the combined use of cyclosporine and paromomycin may increase the risk of nephrotoxicity or ototoxicity.
    Pasireotide: (Major) Pasireotide and cyclosporine coadministration may decrease the relative bioavailability of cyclosporine. Patients taking both of these drugs should have their cyclosporine concentrations monitored; if needed, adjust the cyclosporine dosage to maintain therapeutic concentrations.
    Pazopanib: (Major) Avoid administering pazopanib with strong breast cancer resistance protein (BCRP) inhibitors, such as cyclosporine. The concomitant use of pazopanib, a weak CYP3A4 inhibitor and a CYP3A4, P-glycoprotein (P-gp), and BCRP substrate, and cyclosporine, a CYP3A4, P-gp, and BCRP inhibitor and CYP3A4 substrate, may result in altered pazopanib and/or cyclosporine concentrations.
    Peginterferon Alfa-2b: (Moderate) Concomitant use of immunosuppressive agents, such as cyclosporine, with peginterferon alfa-2b warrants the therapeutic monitoring of the immunosuppressant in appropriate populations as the effect on immunosuppressant concentrations is unknown.
    Pentamidine: (Moderate) Additive nephrotoxicity may be seen with the combination of pentamidine and other agents that cause nephrotoxicity, including cyclosporine.
    Pentobarbital: (Major) Phenobarbital may induce cyclosporine metabolism, thereby increasing the clearance of cyclosporine. It is likely that other barbiturates would interact similarly with cyclosporine; however no supportive data are available. If phenobarbital is added to an existing cyclosporine regimen, monitor cyclosporine concentrations closely to avoid loss of clinical efficacy until a new steady-state concentration is achieved. Conversely, if phenobarbital is discontinued, cyclosporine concentrations could increase.
    Pentostatin: (Minor) Concurrent use of purine analogs with other agents which cause bone marrow or immune suppression such as immunosuppressives may result in additive effects. A dosage reduction of the antineoplastic may be indicated when used in combination with other myelosuppressive chemotherapy.
    Perindopril; Amlodipine: (Moderate) Caution should be used when cyclosporine is coadministered with amlodipine; therapeutic response should be monitored, including cyclosporine levels as necessary. Amlodipine may increase cyclosporine concentrations. In one study, whole blood cyclosporine trough concentrations increased from 140.2 +/- 18.2 to 200 +/- 21.9 mcg/L after amlodipine addition. In another study, the systemic exposure (AUC) of cyclosporine increased following the addition of amlodipine, and was decreased in the absence of the drug. The postulated mechanism is the inhibitory effect of amlodipine on the P-glycoprotein-mediated efflux of cyclosporine from intestinal epithelial cells. Also, amlodipine is a CYP3A4 substrate and theoretically, cyclosporine, may increase the plasma concentration of amlodipine via CYP3A4 inhibition; this effect might lead to hypotension in some individuals.
    Phenobarbital: (Major) Phenobarbital may induce cyclosporine metabolism, thereby increasing the clearance of cyclosporine. It is likely that other barbiturates would interact similarly with cyclosporine; however no supportive data are available. If phenobarbital is added to an existing cyclosporine regimen, monitor cyclosporine concentrations closely to avoid loss of clinical efficacy until a new steady-state concentration is achieved. Conversely, if phenobarbital is discontinued, cyclosporine concentrations could increase.
    Phenytoin: (Moderate) Hydantoin anticonvulsants (i.e, phenytoin, fosphenytoin, and ethotoin) can induce the hepatic cytochrome P-450 enzyme system, thus decreasing plasma concentrations of cyclosporine. If a hydantoin anticonvulsant is added to a cyclosporine-containing regimens, cyclosporine concentrations should be closely monitored and adjusted as needed until a new steady-state is achieved. Conversely, if the anticonvulsant is discontinued, cyclosporine concentrations could increase and result in toxicity.
    Phosphorus Salts: (Moderate) Use potassium phosphates cautiously with cyclosporine, as both drugs increase serum potassium concentrations. Concurrent use can cause hyperkalemia, especially in elderly patients or patients with impaired renal function. Patients should have serum potassium concentration determinations at periodic intervals.
    Pioglitazone: (Moderate) Cyclosporine has been reported to cause hyperglycemia; this effect appears to be dose-related and caused by direct beta-cell toxicity. Therefore, a pharmacodynamic interaction is possible with all antidiabetic agents and cyclosporine. Patients should be monitored for worsening glycemic control if therapy with cyclosporine is initiated in patients receiving antidiabetic agents.
    Piroxicam: (Moderate) Additive decreases in renal function have been reported between cyclosporine and NSAIDs. Patients should be monitored for signs and symptoms of cyclosporine toxicity and infection, as NSAIDs may mask fever, pain, or swelling.
    Polymyxin B: (Moderate) Cyclosporine should be used cautiously with nephrotoxic drugs, as cyclosporine itself can cause structural kidney damage and there is potential for additive nephrotoxicity. Systemic polymyxin B should generally not be used concurrently or sequentially with other drugs that have the potential for nephrotoxicity or neurotoxicity. Monitor renal function and fluid status carefully during co-use.
    Polymyxins: (Major) Theoretically, chronic coadministration may increase the risk of developing nephrotoxicity, even in patients who have normal renal function. Monitor patients for changes in renal function during concurrent use. Since colistimethate sodium is eliminated by the kidney, coadministration with other potentially nephrotoxic drugs, including cyclosporine, may increase serum concentrations of either drug.
    Posaconazole: (Major) The interactions between cyclosporine and systemic azole antifungals can be significant. Posaconazole may inhibit cyclosporine CYP3A4-mediated metabolism, which may result in increased cyclosporine blood concentrations. Cyclosporine concentrations may increase within 1 to 3 days after starting azole antifungal therapy, and may persist for > 1 week after discontinuing antifungal treatment. Posaconazole appears to inhibit cyclosporine metabolism in a dose-dependent fashion; higher doses result in greater inhibition of cyclosporine metabolism than do lower doses. Increased cyclosporine serum concentrations occurred when posaconazole was given to patients stabilized on cyclosporine. Reduce cyclosporine doses to three-fourths the original dose when initiating therapy with posaconazole. In all cases, renal function in these patients should be carefully monitored. Close monitoring of cyclosporine concentrations is required when given in combination with systemic azole antifungals; a 50% reduction in cyclosporine dosage may be required.
    Potassium Phosphate; Sodium Phosphate: (Moderate) Use potassium phosphates cautiously with cyclosporine, as both drugs increase serum potassium concentrations. Concurrent use can cause hyperkalemia, especially in elderly patients or patients with impaired renal function. Patients should have serum potassium concentration determinations at periodic intervals.
    Potassium: (Moderate) Potassium salts should be used with caution in patients taking drugs that may increase serum potassium concentrations, such as cyclosporine. Concurrent use can cause severe and potentially fatal hyperkalemia, especially in patients with other risk factors for hyperkalemia (i.e., severe renal impairment). Monitor potassium concentrations during concurrent therapy.
    Potassium-sparing diuretics: (Major) Cyclosporine can cause hyperkalemia. Simultaneous use of cyclosporine with potassium-sparing diuretics, such as amiloride, spironolactone or triamterene, can increase this risk, and is not recommended.
    Pramlintide: (Moderate) Cyclosporine has been reported to cause hyperglycemia. Patients should be monitored for worsening of glycemic control if therapy with cyclosporine is initiated in patients receiving pramlintide.
    Prasterone, Dehydroepiandrosterone, DHEA (Dietary Supplements): (Moderate) Androgens may increase concentrations of cyclosporine, potentially increasing the risk of nephrotoxicity. Until further data are available, close monitoring of cyclosporine serum concentrations is prudent during coadministration with androgens.
    Prasterone, Dehydroepiandrosterone, DHEA (FDA-approved): (Moderate) Androgens may increase concentrations of cyclosporine, potentially increasing the risk of nephrotoxicity. Until further data are available, close monitoring of cyclosporine serum concentrations is prudent during coadministration with androgens.
    Pravastatin: (Major) Concomitant administration of cyclosporine and pravastatin increases the risk of myopathy and rhabdomyolysis; limit pravastatin to 20 mg PO once daily when these agents are used together. During pharmacokinetic trials, a single dose of cyclosporine increased the AUC and Cmax of pravastatin by 282% and 327%, respectively. However, neither myopathy nor significant increases in CPK levels have been observed in 3 reports involving 100 post-transplant (cardiac or renal) patients treated for up to 2 years with pravastatin (10 to 40 mg) and cyclosporine. Some of these patients also received other concomitant immunosuppressive therapies.
    Primidone: (Major) Phenobarbital may induce cyclosporine metabolism, thereby increasing the clearance of cyclosporine. It is likely that other barbiturates would interact similarly with cyclosporine; however no supportive data are available. If phenobarbital is added to an existing cyclosporine regimen, monitor cyclosporine concentrations closely to avoid loss of clinical efficacy until a new steady-state concentration is achieved. Conversely, if phenobarbital is discontinued, cyclosporine concentrations could increase.
    Protease inhibitors: (Major) An interaction is anticipated to occur with all anti-retroviral protease inhibitors and cyclosporine, as all protease inhibitors inhibit CYP3A4. Cyclosporine toxicity, consisting of fatigue, headache, and GI distress, has been reported by a patient receiving cyclosporine and saquinavir. Prior to beginning saquinavir the patient had been receiving stable doses of cyclosporine resulting in trough concentrations of 150 to 200 mcg/ml. After receiving saquinavir for 3 days, the cyclosporine trough concentration increased to 580 mcg/ml. Dosages of both agents were decreased by 50% leading to resolution of symptoms. This interaction is probably due to CYP3A4 inhibition by saquinavir. Another possible mechanism is that both drugs have a high affinity for the drug efflux protein, P-glycoprotein, which may increase the absorption or decrease the clearance of the other drug.
    Purine analogs: (Minor) Concurrent use of purine analogs with other agents which cause bone marrow or immune suppression such as immunosuppressives may result in additive effects. A dosage reduction of the antineoplastic may be indicated when used in combination with other myelosuppressive chemotherapy.
    Pyrimidine analogs: (Minor) Additive immunosuppressant affects may be seen when cyclosporine is coadministered with other immunosuppressives like antineoplastic agents. Patients may be predisposed to increased immunosuppression and myelosuppression, resulting in an increased risk of infection or other side effects.
    Quinine: (Moderate) Quinine is a substrate of P-glycoprotein (PGP), and cyclosporine is a PGP substrate and inhibitor. Therefore, quinine concentrations could be increased with coadministration. Monitor patients for increased side effects of quinine if these drugs are given together.
    Rabeprazole: (Minor) Rabeprazole may inhibit the metabolism of cyclosporine, a CYP3A4 substrate.
    Ramelteon: (Moderate) Coadministration of ramelteon with inhibitors of CYP3A4, such as cyclosporine, may lead to increases in the serum concentrations of ramelteon.
    Ranitidine: (Minor) Although data are conflicting, cautious use of ranitidine and cyclosporine is warranted; cyclosporine can cause nephrotoxicity, and ranitidine is substantially excreted by the kidney. The risk of toxic reactions to ranitidine may be greater in patients with impaired renal function; ranitidine dose reduction is needed for renal impairment.
    Ranolazine: (Severe) Cyclosporine inhibits the cytochrome P450 3A4 (CYP3A4) isoenzyme. Moderate or potent CYP3A4 inhibitors are contraindicated for use with ranolazine, a CYP3A4 substrate. Inhibition of ranolazine metabolism by cyclosporine could lead to increased ranolazine plasma concentrations. In addition, ranolazine is a substrate of P-glycoprotein (P-gp); inhibitors of P-gp may increase the absorption of ranolazine and should be coadministered with caution. When possible, it is prudent to avoid coadministration of ranolazine with cyclosporine due to the potential for increased plasma concentrations of ranolazine, which may result in QT prolongation and increase the risk for proarrhythmias. If necessary to coadminister these drugs, it is prudent to monitor the individual patient response to ranolazine therapy closely, including an evaluation of the ECG effects and antianginal benefits during coadministration.
    Rapacuronium: (Moderate) Cyclosporine may potentiate the action of nondepolarizing neuromuscular blockers. Prolonged neuromuscular blockade has been reported in patients receiving cyclosporine who receive neuromuscular blockers as part of surgical anesthesia. Monitor patients for recurrent neuromuscular blockade and respiratory depression; extended ventilatory support may be required.
    Red Yeast Rice: (Severe) Since compounds in red yeast rice are chemically similar to and possess actions similar to lovastatin, patients should avoid this dietary supplement if they currently take cyclosporine, a drug known to increase the risk of myopathy when coadministered with HMG-CoA reductase inhibitors.
    Repaglinide: (Major) Cyclosporine appears to inhibit the metabolism of repaglinide by inhibiting CYP3A4. Cyclosporine also appears to inhibit the uptake of repaglinide into the liver by inhibiting the organic anion transporting protein OATP1B1, which is an active hepatic uptake transporter. Increased repaglinide concentrations were noted among healthy patients who took oral cyclosporine 100 mg daily for 2 days. After a single 0.25 mg repaglinide dose, the mean area under the plasma concentration-time curve for repaglinide increased 244% (range, 119 to 533%) as compared with data from placebo recipients. In addition to a pharmacokinetic interaction, cyclosporine has been reported to cause hyperglycemia. Cyclosporine may have direct beta-cell toxicity; the effects from cyclosporine may be dose-related. Monitor patients glycemic control if cyclosporine is started or stopped in patients receiving repaglinide.
    Ribociclib: (Moderate) Use caution if coadministration of ribociclib with cyclosporine is necessary, as the systemic exposure of both drugs may be increased resulting in an increase in treatment-related adverse reactions including neutropenia and QT prolongation. Monitor cyclosporine concentrations and adjust the dose of cyclosporine if necessary. Ribociclib is extensively metabolized by CYP3A4 and is a moderate CYP3A4 inhibitor; cyclosporine is a moderate CYP3A4 inhibitor and a CYP3A4 substrate with a narrow therapeutic window. .
    Ribociclib; Letrozole: (Moderate) Use caution if coadministration of ribociclib with cyclosporine is necessary, as the systemic exposure of both drugs may be increased resulting in an increase in treatment-related adverse reactions including neutropenia and QT prolongation. Monitor cyclosporine concentrations and adjust the dose of cyclosporine if necessary. Ribociclib is extensively metabolized by CYP3A4 and is a moderate CYP3A4 inhibitor; cyclosporine is a moderate CYP3A4 inhibitor and a CYP3A4 substrate with a narrow therapeutic window. .
    Rifabutin: (Major) Rifampin, rifabutin, or rifapentine can increase the clearance of cyclosporine by inducing cyclosporine metabolism. All are inducers of CYP3A4 metabolism. Thus, dosage adjustments of cyclosporine may be necessary if used with rifampin, rifapentine, or rifabutin. Induction of enzyme activities occurred within 4 days after the first rifapentine dose. Enzyme activities returned to baseline levels 14 days after rifapentine discontinuation. The magnitude of enzyme induction is dose and dosing frequency dependent. For example, less enzyme induction occurred with 600 mg every 72 hours as compared with daily usage. In vitro and in vivo enzyme induction studies have suggested less enzyme induction potential with rifapentine as compared with rifampin and more enzyme induction potential with rifapentine as compared with rifabutin.
    Rifampin: (Major) Rifampin, rifabutin, or rifapentine can increase the clearance of cyclosporine by inducing cyclosporine metabolism. All are inducers of CYP3A4 metabolism. Thus, dosage adjustments of cyclosporine may be necessary if used with rifampin, rifapentine, or rifabutin. Induction of enzyme activities occurred within 4 days after the first rifapentine dose. Enzyme activities returned to baseline levels 14 days after rifapentine discontinuation. The magnitude of enzyme induction is dose and dosing frequency dependent. For example, less enzyme induction occurred with 600 mg every 72 hours as compared with daily usage. In vitro and in vivo enzyme induction studies have suggested less enzyme induction potential with rifapentine as compared with rifampin and more enzyme induction potential with rifapentine as compared with rifabutin.
    Rifamycins: (Major) Rifampin, rifabutin, or rifapentine can increase the clearance of cyclosporine by inducing cyclosporine metabolism. All are inducers of CYP3A4 metabolism. Thus, dosage adjustments of cyclosporine may be necessary if used with rifampin, rifapentine, or rifabutin. Induction of enzyme activities occurred within 4 days after the first rifapentine dose. Enzyme activities returned to baseline levels 14 days after rifapentine discontinuation. The magnitude of enzyme induction is dose and dosing frequency dependent. For example, less enzyme induction occurred with 600 mg every 72 hours as compared with daily usage. In vitro and in vivo enzyme induction studies have suggested less enzyme induction potential with rifapentine as compared with rifampin and more enzyme induction potential with rifapentine as compared with rifabutin.
    Rifapentine: (Major) Rifampin, rifabutin, or rifapentine can increase the clearance of cyclosporine by inducing cyclosporine metabolism. All are inducers of CYP3A4 metabolism. Thus, dosage adjustments of cyclosporine may be necessary if used with rifampin, rifapentine, or rifabutin. Induction of enzyme activities occurred within 4 days after the first rifapentine dose. Enzyme activities returned to baseline levels 14 days after rifapentine discontinuation. The magnitude of enzyme induction is dose and dosing frequency dependent. For example, less enzyme induction occurred with 600 mg every 72 hours as compared with daily usage. In vitro and in vivo enzyme induction studies have suggested less enzyme induction potential with rifapentine as compared with rifampin and more enzyme induction potential with rifapentine as compared with rifabutin.
    Rifaximin: (Moderate) Concurrent use of rifaximin, a P-glycoprotein (P-gp) and organic anion-transporting polypeptide (OATP1A1/1B1/1B3) substrate, with cyclosporine, a P-gp and OATP inhibitor, increases the systemic exposure and maximum plasma concentration to rifaximin by 83- and 124-fold, respectively. The clinical significance of this increase in systemic exposure is unknown; thus, caution and close monitoring for adverse reactions is advised if these drugs must be administered together.
    Rilonacept: (Moderate) Patients receiving immunosuppressives along with rilonacept may be at a greater risk of developing an infection.
    Ritonavir: (Major) An interaction is anticipated to occur with all anti-retroviral protease inhibitors and cyclosporine, as all protease inhibitors inhibit CYP3A4. Cyclosporine toxicity, consisting of fatigue, headache, and GI distress, has been reported by a patient receiving cyclosporine and saquinavir. Prior to beginning saquinavir the patient had been receiving stable doses of cyclosporine resulting in trough concentrations of 150 to 200 mcg/ml. After receiving saquinavir for 3 days, the cyclosporine trough concentration increased to 580 mcg/ml. Dosages of both agents were decreased by 50% leading to resolution of symptoms. This interaction is probably due to CYP3A4 inhibition by saquinavir. Another possible mechanism is that both drugs have a high affinity for the drug efflux protein, P-glycoprotein, which may increase the absorption or decrease the clearance of the other drug.
    Rivaroxaban: (Minor) The coadministration of rivaroxaban and cyclosporine should be undertaken with caution in patients with renal impairment; it is unclear whether a clinically significant interaction occurs when these drugs are coadministered to patients with normal renal function. Cyclosporine is a combined mild CYP3A4 inhibitor and P-glycoprotein (P-gp) inhibitor. Rivaroxaban is a substrate of CYP3A4/5 and the P-gp transporter. Coadministration in patients with renal impairment may result in increased exposure to rivaroxaban compared with patients with normal renal function and no inhibitor use since both pathways of elimination are affected. While an increase in exposure to rivaroxaban may be expected, results from an analysis of the ROCKET-AF trial which allowed concomitant administration of rivaroxaban and a combined P-gp inhibitor and weak or moderate CYP3A4 inhibitor did not show an increased risk of bleeding in patients with CrCl 30 to < 50 mL/minute [HR (95% CI): 1.05 (0.77, 1.42)].
    Rocuronium: (Moderate) Cyclosporine may potentiate the action of nondepolarizing neuromuscular blockers. Prolonged neuromuscular blockade has been reported in patients receiving cyclosporine who receive neuromuscular blockers as part of surgical anesthesia. Monitor patients for recurrent neuromuscular blockade and respiratory depression; extended ventilatory support may be required.
    Rofecoxib: (Moderate) Additive decreases in renal function may occur with coadministration of cyclosporine and NSAIDs. NSAIDs should be used with caution in patients receiving immunosuppressives as they may mask fever, pain, swelling and other signs and symptoms of an infection.
    Rolapitant: (Major) Avoid the concurrent use of cyclosporine and rolapitant if possible; if coadministration is necessary, monitor cyclosporine levels and watch for cyclosporine-related adverse effects. Cyclosporine is a P-glycoprotein (P-gp) substrate, where an increase in exposure may significantly increase adverse effects; rolapitant is a P-gp inhibitor. When rolapitant was administered with another P-gp substrate, digoxin, the day 1 Cmax and AUC were increased by 70% and 30%, respectively; the Cmax and AUC on day 8 were not studied. Additionally, cyclosporine is an inhibitor of CYP3A4 and rolapitant is a CYP3A4 substrate. Theoretically this could increase rolapitant concentrations, but this effect is not expected to be clinically relevant.
    Romidepsin: (Moderate) Romidepsin is a substrate for P-glycoprotein (P-gp). Cyclosporine is an inhibitor of P-gp. Concurrent administration of romidepsin with an inhibitor of P-gp may cause an increase in systemic romidepsin concentrations. Use caution when concomitant administration of these agents is necessary.
    Rosiglitazone: (Moderate) Cyclosporine has been reported to cause hyperglycemia; this effect appears to be dose-related and caused by direct beta-cell toxicity. Therefore, a pharmacodynamic interaction is possible with all antidiabetic agents and cyclosporine. Patients should be monitored for worsening glycemic control if therapy with cyclosporine is initiated in patients receiving antidiabetic agents.
    Rosuvastatin: (Major) It would be prudent to avoid concurrent use of rosuvastatin and cyclosporine when possible. Consider an alternative HMG-CoA reductase inhibitor (e.g., pravastatin) with less propensity to interact with cyclosporine, and one that has been studied more extensively in transplant patients receiving cyclosporine. If rosuvastatin must be used concurrently with cyclosporine, limit the rosuvastatin dosage to 5 mg/day in adults. Combination therapy with HMG-CoA reductase inhibitors and cyclosporine has been associated with myopathy and rhabdomyolysis. When rosuvastatin is coadministered with cyclosporine in heart transplant patients, the Cmax and AUC of rosuvastatin are increased 11-fold and 7-fold, respectively, compared with historical data with normal volunteers
    Rotavirus Vaccine: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Rubella Virus Vaccine Live: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Rufinamide: (Minor) Rufinamide is not metabolized through hepatic CYP isozymes; however, it is a weak inducer of CYP3A4. In theory, decreased exposure of drugs that are extensively metabolized by CYP3A4, such as cyclosporine, may occur during concurrent use with rufinamide.
    Sacubitril; Valsartan: (Moderate) Coadministration of cyclosporine and an angiotensin II receptor antagonist, like valsartan, may increase the risk of hyperkalemia and reduced renal function. In response to cyclosporine-induced renal afferent vasoconstriction and glomerular hypoperfusion, angiotensin II is required to maintain an adequate glomerular filtration rate. Inhibition of angiotensin-converting enzyme (ACE) could reduce renal function acutely. Several cases of acute renal failure have been associated with the addition of enalapril to cyclosporine therapy in renal transplant patients. Also, cyclosporine can cause hyperkalemia, and inhibition of angiotensin II leads to reduced aldosterone concentrations, which can increase the serum potassium concentration. Closely monitor renal function and serum potassium concentrations in patients receiving cyclosporine concurrently with valsartan. Additionally, valsartan is a substrate of the hepatic uptake transporter OATP1B1 and cyclosporine is an inhibitor of OATP. Coadministration may increase systemic exposure to valsartan. Patients should be monitored for adverse effects of valsartan.
    Salicylates: (Minor) Due to the inhibition of renal prostaglandins by salicylates, concurrent use of salicylates and other nephrotoxic agents like cyclosporine may lead to additive nephrotoxicity.
    Sapropterin: (Moderate) Caution is advised with the concomitant use of sapropterin and cyclosporine as coadministration may result in increased systemic exposure of cyclosporine. Cyclosporine is a substrate for the drug transporter P-glycoprotein (P-gp); in vitro data show that sapropterin may inhibit P-gp. If these drugs are used together, closely monitor for increased side effects of cyclosporine.
    Saquinavir: (Major) An interaction is anticipated to occur with all anti-retroviral protease inhibitors and cyclosporine, as all protease inhibitors inhibit CYP3A4. Cyclosporine toxicity, consisting of fatigue, headache, and GI distress, has been reported by a patient receiving cyclosporine and saquinavir. Prior to beginning saquinavir the patient had been receiving stable doses of cyclosporine resulting in trough concentrations of 150 to 200 mcg/ml. After receiving saquinavir for 3 days, the cyclosporine trough concentration increased to 580 mcg/ml. Dosages of both agents were decreased by 50% leading to resolution of symptoms. This interaction is probably due to CYP3A4 inhibition by saquinavir. Another possible mechanism is that both drugs have a high affinity for the drug efflux protein, P-glycoprotein, which may increase the absorption or decrease the clearance of the other drug.
    Saxagliptin: (Moderate) Cyclosporine has been reported to cause hyperglycemia. Patients should be monitored for changes in glycemic control if therapy with cyclosporine is initiated in patients receiving saxagliptin.
    Secobarbital: (Major) Phenobarbital may induce cyclosporine metabolism, thereby increasing the clearance of cyclosporine. It is likely that other barbiturates would interact similarly with cyclosporine; however no supportive data are available. If phenobarbital is added to an existing cyclosporine regimen, monitor cyclosporine concentrations closely to avoid loss of clinical efficacy until a new steady-state concentration is achieved. Conversely, if phenobarbital is discontinued, cyclosporine concentrations could increase.
    Secukinumab: (Moderate) The formation of CYP450 enzymes may be altered by increased concentrations of cytokines during chronic inflammation. Thus, the formation of CYP450 enzymes could be normalized during secukinumab administration. Clinically relevant drug interactions may occur with CYP450 substrates that have a narrow therapeutic index such as cyclosporine. If secukinumab is initiated or discontinued in a patient taking cyclosporine, monitor cyclosporine concentrations; cyclosporine dose adjustments may be needed.
    Sertraline: (Moderate) Although a causal relationship has not been established, the combination of cyclosporine and sertraline is suspected of causing serotonin syndrome in a renal transplant patient. Sertraline serum concentrations may have increased due to possible CYP3A4 inhibition by cyclosporine.
    Sevelamer: (Moderate) Although drug interaction studies have not been conducted, it may be prudent to separate the timing of administration of cyclosporine from sevelamer. According to the manufacturer of sevelamer, clinicians should consider separating the timing of administration of sevelamer and drugs where a reduction in the bioavailability of would have a clinically significant effect on its safety or efficacy. The duration of separation should be based on the absorption characteristics of the coadministered drug. Because cyclosporine has a narrow therapeutic index, consider monitoring clinical response and serum concentrations during concurrent use of sevelamer.
    Silodosin: (Major) In vitro data indicate that silodosin is a P-glycoprotein substrate. The manufacturer of silodosin recommends against concurrent use of silodosin and potent P-gp inhibitors such as cyclosporine.
    Siltuximab: (Moderate) Use siltuximab and cyclosporine together with caution; monitor cyclosporine levels and adjust the dose of cyclosporine as necessary. Inhibition of IL-6 signaling by siltuximab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates as compared to metabolism prior to treatment. Therefore, CYP450 substrates with a narrow therapeutic index, such as cyclosporine, may have fluctuations in drug levels and therapeutic effect when siltuximab therapy is started or discontinued. This effect on CYP450 enzyme activity may persist for several weeks after stopping siltuximab.
    Simeprevir: (Major) Avoid concurrent use of simeprevir and cyclosporine. Inhibition of the hepatic isoenzyme CYP3A4 and the drug transporters OATP1B1 and P-glycoprotein (P-gp) by cyclosporine causes significant increases in the plasma concentrations of simeprevir. Similarly, the plasma concentrations of cyclosporine are increased when administered with simeprevir. Use of these drugs together may increase the potential for adverse events.
    Simvastatin: (Severe) The use of simvastatin with is contraindicated due to an increased risk for myopathy and rhabdomyolysis. Cyclosporine increases the AUC of statins when administered concomitantly, and the risk for myopathy is increased by high levels of HMG-CoA reductase inhibitory activity in plasma. Although the mechanism is not fully understood, it is presumably due to inhibition of CYP3A4 and/or OAT1B1 by cyclosporine; simvastatin is a substrate of CYP3A4 and OAT1B1.
    Simvastatin; Sitagliptin: (Severe) The use of simvastatin with is contraindicated due to an increased risk for myopathy and rhabdomyolysis. Cyclosporine increases the AUC of statins when administered concomitantly, and the risk for myopathy is increased by high levels of HMG-CoA reductase inhibitory activity in plasma. Although the mechanism is not fully understood, it is presumably due to inhibition of CYP3A4 and/or OAT1B1 by cyclosporine; simvastatin is a substrate of CYP3A4 and OAT1B1. (Moderate) Cyclosporine has been reported to cause hyperglycemia. Patients should be monitored for changes in glycemic control if therapy with cyclosporine is initiated in patients receiving sitagliptin.
    Sipuleucel-T: (Major) Concomitant use of sipuleucel-T and immunosuppressives should be avoided. Concurrent administration of immunosuppressives with the leukapheresis procedure that occurs prior to sipuleucel-T infusion has not been studied. Sipuleucel-T stimulates the immune system and patients receiving immunosuppressives may have a diminished response to sipuleucel-T. When appropriate, consider discontinuing or reducing the dose of immunosuppressives prior to initiating therapy with sipuleucel-T.
    Sirolimus: (Major) Administer sirolimus 4 hours after oral cyclosporine due to an increase in sirolimus concentrations when coadministered with cyclosporine. Use therapeutic drug monitoring to maintain sirolimus target concentrations, and monitor renal function closely during coadministration. If cyclosporine is discontinued, higher doses of sirolimus are necessary to maintain the target sirolimus trough concentration. Long-term administration of the combination has been associated with deterioration of renal function. Sirolimus is a substrate for CYP3A4 and P-gp, and cyclosporine is an inhibitor of CYP3A4 and P-gp. Simultaneous administration of sirolimus 10 mg and cyclosporine 300 mg increased sirolimus Cmax and AUC by 116% to 512% and 148% to 230%, respectively; Cmax and AUC increased by 33% to 37% and 33% to 80% when sirolimus was given 4 hours after cyclosporine.
    Sitagliptin: (Moderate) Cyclosporine has been reported to cause hyperglycemia. Patients should be monitored for changes in glycemic control if therapy with cyclosporine is initiated in patients receiving sitagliptin.
    Smallpox Vaccine, Vaccinia Vaccine: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Sofosbuvir; Velpatasvir: (Moderate) Use caution when administering velpatasvir with cyclosporine. Taking these medications together may increase the plasma concentrations of both drugs, potentially resulting in adverse events. Both drugs are substrates and inhibitors of the drug transporter P-glycoprotein (P-gp). Velpatasvir is also a substrate for the Breast Cancer Resistance Protein (BCRP). Cyclosporine is a BCRP inhibitor. In addition, cyclosporine is an inhibitor of the hepatic enzyme CYP3A4. Velpatasvir is a CYP3A4 substrate.
    Sofosbuvir; Velpatasvir; Voxilaprevir: (Major) Avoid concurrent administration of voxilaprevir and cyclosporine. Taking these medications together may increase the plasma concentrations of both drugs, potentially resulting in adverse events. Both drugs are substrates and inhibitors of the drug transporter P-glycoprotein (P-gp). Cyclosporine is also an inhibitor of the Organic Anion Transporting Polypeptides 1B1 (OATP1B1 ), Breast Cancer Resistance Protein (BCRP), and CYP3A4; voxilaprevir is a substrate of OATP1B1, BCRP, and CYP3A4. (Moderate) Use caution when administering velpatasvir with cyclosporine. Taking these medications together may increase the plasma concentrations of both drugs, potentially resulting in adverse events. Both drugs are substrates and inhibitors of the drug transporter P-glycoprotein (P-gp). Velpatasvir is also a substrate for the Breast Cancer Resistance Protein (BCRP). Cyclosporine is a BCRP inhibitor. In addition, cyclosporine is an inhibitor of the hepatic enzyme CYP3A4. Velpatasvir is a CYP3A4 substrate.
    Somatropin, rh-GH: (Moderate) Somatropin may increase the activity of cytochrome-mediated metabolism of cyclosporine clearance.
    Spironolactone: (Major) Cyclosporine can cause hyperkalemia. Simultaneous use of cyclosporine with potassium-sparing diuretics, such as amiloride, spironolactone or triamterene, can increase this risk, and is not recommended.
    St. John's Wort, Hypericum perforatum: (Severe) Clinical interactions between cyclosporine and St. John's wort, Hypericum perforatum have been reported. It appears that St. John's wort may increase the metabolism of cyclosporine through induction of the hepatic CYP3A4 isoenzyme. Clinically, decreased cyclosporine concentrations resulting from the concurrent administration of St. John's wort have led to reports of acute heart transplant rejection. A similar report of subtherapeutic cyclosporine concentrations has been noted in a kidney-pancreas transplant patient who self-medicated with St. John's wort. Graft loss has occurred. St. John's wort in all forms, including teas, should be avoided in patients treated with cyclosporine.
    Streptogramins: (Moderate) As cyclosporine is a CYP3A4 substrate, use with a CYP3A4 inhibitor, such as streptogramins, may result in increased serum concentrations of cyclosporine. CYP3A4 inhibitors may decrease the clearance of cyclosporine, which may reduce cyclosporine dosage requirements or cause cyclosporine toxicity including nephrotoxicity, hepatotoxicity, or seizures.
    Streptomycin: (Major) Cyclosporine should be used cautiously with nephrotoxic drugs, as cyclosporine itself can cause structural kidney damage. Additive nephrotoxicity can occur if cyclosporine is administered with other nephrotoxic drugs such as streptomycin. Monitor renal function and fluid status carefully during cyclosporine usage.
    Succinylcholine: (Moderate) Cyclosporine may potentiate the action of nondepolarizing neuromuscular blockers. Prolonged neuromuscular blockade has been reported in patients receiving cyclosporine who receive neuromuscular blockers as part of surgical anesthesia. Monitor patients for recurrent neuromuscular blockade and respiratory depression; extended ventilatory support may be required.
    Sulfadiazine: (Moderate) Use caution and closely monitor cyclosporine serum concentrations when administered concurrently with sulfadiazine. Use of these drugs together may result in decreased cyclosporine serum concentrations and the potential for decreased efficacy. Cyclosporine dose adjustments may be necessary and should be guided by serum concentrations during coadministration.
    Sulfamethoxazole; Trimethoprim, SMX-TMP, Cotrimoxazole: (Major) Avoid the concomitant use of sulfamethoxazole; trimethoprim and cyclosporine. There have been reports of significant, but reversible nephrotoxicity with coadministration in renal transplant patients. In addition, there are case reports of reduced exposure to cyclosporine in patients receiving concomitant sulfonamides. Monitor renal function and cyclosporine concentrations if concomitant use is required.
    Sulfasalazine: (Moderate) Use caution and closely monitor cyclosporine serum concentrations when administered concurrently with sulfasalazine. Use of these drugs together may result in decreased cyclosporine serum concentrations and the potential for decreased efficacy. Cyclosporine dose adjustments may be necessary and should be guided by serum concentrations during coadministration.
    Sulfinpyrazone: (Major) Sulfinpyrazone may decrease the serum concentration of cyclosporine. Sulfinpyrazone may increase the metabolism of cyclosporine through induction of the hepatic CYP3A4 isoenzyme. Cyclosporine concentrations should be monitored closely to avoid loss of clinical efficacy.
    Sulfonylureas: (Moderate) Sulfonylureas may increase concentrations of cyclosporine. Retrospective data from 6 adults with post-renal transplant diabetes mellitus and normal hepatic and renal function before and after glyburide initiation were examined. The mean plasma cyclosporine concentration from 5 months of data before glyburide use was 212.3 +/- 66.4 ng/ml. In contrast, the mean plasma cyclosporine concentration from 5 months of data during glyburide use was 334.8 +/- 65.8 ng/ml. Until more data are available, when glyburide is added to cyclosporine therapy, monitor cyclosporine concentrations and adjust cyclosporine dosage as necessary. Also, monitor patients for increased cyclosporine toxicity (renal dysfunction, neurotoxicity). In addition, cyclosporine has been reported to cause hyperglycemia. Cyclosporine may have direct beta-cell toxicity, the effects of which may be dose-related. Patients should be monitored for worsening of glycemic control if cyclosporine is initiated in patients receiving antidiabetic agents.
    Sulindac: (Moderate) Renal dysfunction associated with cyclosporine may be potentiated by concurrent usage of sulindac. Patients should be monitored for signs and symptoms of cyclosporine toxicity and infection, as NSAIDs may mask fever, pain, or swelling.
    Sunitinib: (Moderate) Concurrent administration of sunitinib with inhibitors of CYP3A4 such as cyclosporine results in increased concentrations of sunitinib and its primary active metabolite. Whenever possible selection of an alternative concomitant medication with no or minimal enzyme inhibition potential is recommended. If an alternative therapy is not available, monitor patients closely for increased adverse reactions to sunitinib; a reduction in the dose of sunitinib may be required
    Tacrolimus: (Severe) Concurrent use of cyclosporine and tacrolimus may increase the risk of nephrotoxicity due to synergistic or additive effects. Concomitant tacrolimus and cyclosporine usage is not recommended. When switching patients from cyclosporine to tacrolimus, wait at least 24 hours after the last dose of cyclosporine before beginning tacrolimus therapy. In the presence of elevated tacrolimus or cyclosporine concentrations, dosing with the other drug usually should be delayed until the concentration falls into the normal range.
    Tamoxifen: (Major) Cyclosporine is a CYP3A4 inhibitor. Tamoxifen is metabolized by CYP3A4, CYP2D6, and to a lesser extent, CYP2C9 and CYP2C19, to other potent active metabolites including endoxifen, which are then inactivated by sulfotransferase 1A1 (SULT1A1). Cyclosporine may inhibit the metabolism of tamoxifen to these metabolites, which have up to 33 times more affinity for the estrogen receptor than tamoxifen. Additionally, cyclosporine is a substrate of CYP3A4 and P-glycoprotein (P-gp); tamoxifen inhibits both CYP3A4 and P-gp. Concomitant use of cyclosporine and tamoxifen may result in increased cyclosporine exposure and decreased concentrations of the active metabolites of tamoxifen, which can compromise efficacy. If it is not possible to avoid concomitant use, monitor patients for increased serum concentrations of cyclosporine and changes in the therapeutic efficacy of tamoxifen.
    Tamsulosin: (Moderate) Use caution when administering tamsulosin with a moderate CYP3A4 inhibitor such as cyclosporine. Tamsulosin is extensively metabolized by CYP3A4 hepatic enzymes. In clinical evaluation, concomitant treatment with a strong CYP3A4 inhibitor resulted in significant increases in tamsulosin exposure; interactions with moderate CYP3A4 inhibitors have not been evaluated. If concomitant use in necessary, monitor patient closely for increased side effects.
    Teduglutide: (Moderate) Teduglutide may increase absorption of cyclosporine because of it's pharmacodynamic effect of improving intestinal absorption. Careful monitoring and possible dose adjustment of cyclosporine is recommended.
    Telaprevir: (Major) Close monitoring of cyclosporine serum concentrations and frequent assessments of renal function are advised when coadministering cyclosporine with telaprevir. Cyclosporine is a substrate of the hepatic isoenzyme CYP3A4; telaprevir inhibits this isoenzyme. Additionally, both cyclosporine and telaprevir are inhibitors and substrates of the drug efflux transporter P-glycoprotein (PGP). After a single 100 mg dose of cyclosporine, the mean AUC and Cmax of cyclosporine are increased approximately 4.5-fold and 1.3-fold, respectively, when administered in combination with telaprevir; thus, cyclosporine dose reductions and prolongation of the dosing interval are recommended to achieve desired cyclosporine concentrations. If cyclosporine dose adjustments are made, re-adjust the dose upon completion of telaprevir treatment.
    Telavancin: (Minor) Concurrent or sequential use of telavancin with other potentially nephrotoxic drugs such as cyclosporine may lead to additive nephrotoxicity. Closely monitor renal function and adjust telavancin doses based on calculated creatinine clearance.
    Telbivudine: (Moderate) Monitor renal function before and during telbivudine treatment, and also monitor for myopathy, especially when prescribed with other drugs that may affect renal function or cause myopathy. Cyclosporine may alter renal function and it may alter telbivudine plasma concentrations because telbivudine is eliminated primarily by renal excretion. Additionally, it is not known if the risk of myopathy during treatment with telbivudine is increased with concurrent administration of other drugs associated with myopathy such as cyclosporine. Physicians considering concomitant treatment with these or other agents associated with myopathy should weigh carefully the potential benefits and risks and should monitor patients for any signs or symptoms of unexplained muscle pain, tenderness, or weakness, particularly during periods of upward dosage titration.
    Telithromycin: (Moderate) Telithromycin is a competitive substrate and inhibitor of CYP3A4. Coadministration of telithromycin with other drugs metabolized by CYP3A4, including cyclosporine, may result in increased plasma concentrations of cyclosporine that could increase or prolong both the therapeutic and adverse effects.
    Telmisartan: (Moderate) Coadministration of cyclosporine and an angiotensin II receptor antagonist, like telmisartan, may increase the risk of hyperkalemia and reduced renal function. In response to cyclosporine-induced renal afferent vasoconstriction and glomerular hypoperfusion, angiotensin II is required to maintain an adequate glomerular filtration rate. Inhibition of angiotensin-converting enzyme (ACE) could reduce renal function acutely. Several cases of acute renal failure have been associated with the addition of enalapril to cyclosporine therapy in renal transplant patients. Also, cyclosporine can cause hyperkalemia, and inhibition of angiotensin II leads to reduced aldosterone concentrations, which can increase the serum potassium concentration. Closely monitor renal function and serum potassium concentrations in patients receiving cyclosporine concurrently with telmisartan.
    Telotristat Ethyl: (Major) Use caution if coadministration of telotristat ethyl and cyclosporine is necessary, as the systemic exposure of cyclosporine may be decreased resulting in reduced efficacy; exposure to telotristat ethyl may also be increased. If these drugs are used together, monitor patients for suboptimal efficacy of cyclosporine as well as an increase in adverse reactions related to telotristat ethyl. Consider increasing the dose of cyclosporine if necessary. Cyclosporine is a CYP3A4 substrate. The mean Cmax and AUC of another sensitive CYP3A4 substrate was decreased by 25% and 48%, respectively, when coadministered with telotristat ethyl; the mechanism of this interaction appears to be that telotristat ethyl increases the glucuronidation of the CYP3A4 substrate. Additionally, the active metabolite of telotristat ethyl, telotristat, is a substrate of P-glycoprotein (P-gp) and cyclosporine is a P-gp inhibitor. Exposure to telotristat ethyl may increase.
    Temozolomide: (Minor) Myelosuppression, primarily neutropenia and thrombocytopenia, is the dose-limiting toxicity of temozolomide. Concurrent use of temozolomide with other agents that cause bone marrow or immune suppression such as other antineoplastic agents or immunosuppressives may result in additive effects.
    Temsirolimus: (Moderate) Use caution if coadministration of temsirolimus with cyclosporine is necessary, and monitor for an increase in temsirolimus- and cyclosporine-related adverse reactions. Temsirolimus is a CYP3A4 substrate, as well as a P-glycoprotein (P-gp) substrate/inhibitor in vitro. Cyclosporine is a CYP3A4 inhibitor, and also a P-gp substrate/inhibitor. The manufacturer of temsirolimus recommends a dose reduction if coadministered with a strong CYP3A4 inhibitor, but recommendations are not available for concomitant use of moderate CYP3A4 inhibitors or P-gp inhibitors / substrates. Coadministration of temsirolimus with ketoconazole, a strong CYP3A4 inhibitor, had no significant effect on the AUC or Cmax of temsirolimus, but increased the sirolimus AUC and Cmax by 3.1-fold and 2.2-fold, respectively. Coadministration of cyclosporine with sirolimus significantly increased blood levels of sirolimus, the active metabolite of temsirolimus.
    Teniposide: (Minor) Concurrent use of teniposide or etoposide with other agents which cause bone marrow or immune suppression such as other antineoplastic agents or immunosuppressives may result in additive effects.
    Tenofovir Alafenamide: (Moderate) Cyclosporine therapeutic drug monitoring is recommended when administered concurrently with tenofovir alafenamide. Tenofovir-containing products should be avoided with concurrent or recent use of a nephrotoxic agent, such as cyclosporine. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir alafenamide with drugs that are eliminated by active tubular secretion may increase concentrations of tenofovir and/or the co-administered drug. Drugs that decrease renal function may also increase concentrations of tenofovir. Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Monitor patients receiving concomitant nephrotoxic agents for changes in serum creatinine and phosphorus, and urine glucose and protein. In addition, tenofovir alafenamide is a substrate of the drug transporters P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and the organic anion transport protein (OATP1B1 and 1B3); cyclosporine is an inhibitor of all three transporters. Inhibition of P-gp, BCRP, and OATP by cyclosporine may further increase tenofovir plasma concentrations. When tenofovir alafenamide is administered as part of a cobicistat-containing product, its availability is increased by cobicistat and a further increase of tenofovir alafenamide concentrations is not expected upon coadministration of an additional P-gp inhibitor.
    Tenofovir Alafenamide: (Moderate) Cyclosporine therapeutic drug monitoring is recommended when administered concurrently with tenofovir alafenamide. Tenofovir-containing products should be avoided with concurrent or recent use of a nephrotoxic agent, such as cyclosporine. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir alafenamide with drugs that are eliminated by active tubular secretion may increase concentrations of tenofovir and/or the co-administered drug. Drugs that decrease renal function may also increase concentrations of tenofovir. Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Monitor patients receiving concomitant nephrotoxic agents for changes in serum creatinine and phosphorus, and urine glucose and protein. In addition, tenofovir alafenamide is a substrate of the drug transporters P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and the organic anion transport protein (OATP1B1 and 1B3); cyclosporine is an inhibitor of all three transporters. Inhibition of P-gp, BCRP, and OATP by cyclosporine may further increase tenofovir plasma concentrations. When tenofovir alafenamide is administered as part of a cobicistat-containing product, its availability is increased by cobicistat and a further increase of tenofovir alafenamide concentrations is not expected upon coadministration of an additional P-gp inhibitor.
    Tenofovir, PMPA: (Major) Tenofovir should be avoided with concurrent or recent use of a nephrotoxic agent; patients receiving concomitant nephrotoxic agents, such as cyclosporine, should be carefully monitored for changes in serum creatinine and phosphorus.
    Terbinafine: (Moderate) Terbinafine has been found to increase the clearance of cyclosporine. As decreased cyclosporine serum concentrations and thus, an increased risk of organ rejection are possible, monitoring of cyclosporine concentrations is recommended during terbinafine use.
    Testolactone: (Moderate) Androgens may increase concentrations of cyclosporine, potentially increasing the risk of nephrotoxicity. Until further data are available, close monitoring of cyclosporine serum concentrations is prudent during coadministration with androgens.
    Testosterone: (Moderate) Androgens may increase concentrations of cyclosporine, potentially increasing the risk of nephrotoxicity. Until further data are available, close monitoring of cyclosporine serum concentrations is prudent during coadministration with androgens.
    Thioguanine, 6-TG: (Minor) Concurrent use of purine analogs with other agents which cause bone marrow or immune suppression such as immunosuppressives may result in additive effects. A dosage reduction of the antineoplastic may be indicated when used in combination with other myelosuppressive chemotherapy.
    Thiopental: (Major) Phenobarbital may induce cyclosporine metabolism, thereby increasing the clearance of cyclosporine. It is likely that other barbiturates would interact similarly with cyclosporine; however no supportive data are available. If phenobarbital is added to an existing cyclosporine regimen, monitor cyclosporine concentrations closely to avoid loss of clinical efficacy until a new steady-state concentration is achieved. Conversely, if phenobarbital is discontinued, cyclosporine concentrations could increase.
    Ticagrelor: (Moderate) Coadministration of ticagrelor and cyclosporine results in increased exposure to ticagrelor which may increase the bleeding risk. Ticagrelor is a P-glycoprotein (P-gp) substrate and cyclosporine is a P-gp inhibitor. No dose adjustment is recommended by the manufacturer of ticagrelor. Use combination with caution and monitor for evidence of bleeding.
    Ticlopidine: (Moderate) Ticlopidine decreases cyclosporine concentrations. It is prudent to monitor cyclosporine concentrations if ticlopidine therapy is initiated or discontinued.
    Tinidazole: (Minor) Tinidazole may increase cyclosporine serum concentrations when administered concomitantly. Although this interaction has not been studied, a similar interaction has been reported with the concomitant use of metronidazole (a chemically similar nitroimidazole) and cyclosporine. Patients should be monitored for signs of toxicity during coadministration.
    Tipranavir: (Major) An interaction is anticipated to occur with all anti-retroviral protease inhibitors and cyclosporine, as all protease inhibitors inhibit CYP3A4. Cyclosporine toxicity, consisting of fatigue, headache, and GI distress, has been reported by a patient receiving cyclosporine and saquinavir. Prior to beginning saquinavir the patient had been receiving stable doses of cyclosporine resulting in trough concentrations of 150 to 200 mcg/ml. After receiving saquinavir for 3 days, the cyclosporine trough concentration increased to 580 mcg/ml. Dosages of both agents were decreased by 50% leading to resolution of symptoms. This interaction is probably due to CYP3A4 inhibition by saquinavir. Another possible mechanism is that both drugs have a high affinity for the drug efflux protein, P-glycoprotein, which may increase the absorption or decrease the clearance of the other drug.
    Tobramycin: (Major) Additive nephrotoxicity can occur if cyclosporine is administered with other nephrotoxic drugs such as aminoglycosides.
    Tocilizumab: (Moderate) Closely observe patients for signs of infection, altered clinical response, or drug toxicity. Most patients taking tocilizumab who developed serious infections were taking concomitant immunosuppressives. Tocilizumab has the potential to affect expression of multiple CYP enzymes including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Clinically relevant drug interactions may occur with CYP450 substrates that have a narrow therapeutic index such as cyclosporine. If tocilizumab is initiated or discontinued in a patient taking cyclosporine, check the drug concentration; cyclosporine dose adjustment may be needed.
    Tofacitinib: (Severe) Do not use tofacitinib in combination with potent immunosuppressants such as cyclosporine. A risk of added immunosuppression exists when tofacitinib is coadministered with potent immunosuppressives. Cyclosporine is also an inhibitor of CYP3A4, and tofacitinib is a CYP3A4 substrate. Increased systemic exposure of tofacitinib has been noted with concurrent cyclosporine administration. Combined use of multiple-dose tofacitinib with potent immunosuppressives has not been studied in patients with rheumatoid arthritis.
    Tolmetin: (Moderate) Additive decreases in renal function may occur with coadministration of NSAIDs and cyclosporine. NSAIDs should be used with caution in patients receiving immunosuppressives as they may mask fever, pain, swelling and other signs and symptoms of an infection.
    Tolvaptan: (Major) Tolvaptan is a substrate for P-gp. Cyclosporine is an inhibitor of P-gp. Coadministration may result in increased exposure of tolvaptan. If tolvaptan and cyclosporine are coadministered, a reduction in the dose of tolvaptan may be required.
    Topotecan: (Major) Avoid the concomitant use of cyclosporine, a P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP) inhibitor, with oral topotecan, a P-gp and BCRP substrate; P-gp inhibitors have less of an effect on intravenous topotecan and these may be coadministered with caution. If coadministration of cyclosporine and oral topotecan is necessary, carefully monitor for increased toxicity of topotecan, including severe myelosuppression and diarrhea. Administration of oral cyclosporine (15 mg/kg) within 4 hours of oral topotecan increased exposure of topotecan lactone and total topotecan by 2 to 3 fold compared with control. Concurrent administration of 1 mg/m2 intravenous topotecan and oral elacridar, an inhibitor of P-gp and BCRP, led to significantly increased total topotecan AUC and systemic clearance as compared with values obtained without concomitant elacridar. Specifically, the mean clearance of total topotecan decreased 10% from 24.8 +/- 8 L/hr to 22.3 +/- 5.8 L/hr, and the mean systemic exposure increased 18% from 82.2 +/-32.5 mcghr/L to 96.3 +/- 31.6 mcghr/L. Concomitant use had no significant effect on the maximum plasma concentration and terminal half-life of total topotecan or of topotecan lactone. If intravenous topotecan is administered with a drug known to inhibit P-gp, carefully monitor patients for topotecan-related adverse reactions.
    Toremifene: (Moderate) Metabolism of toremifene may be inhibited by drugs known to inhibit CYP3A4 hepatic enzymes, including cyclosporine.
    Trabectedin: (Moderate) Use caution if coadministration of trabectedin and cyclosporine is necessary, due to the risk of increased trabectedin exposure. Trabectedin is a CYP3A substrate and cyclosporine is a moderate CYP3A inhibitor. Coadministration with ketoconazole (200 mg twice daily for 7.5 days), a strong CYP3A inhibitor, increased the systemic exposure of a single dose of trabectedin (0.58 mg/m2 IV) by 66% and the Cmax by 22% compared to a single dose of trabectedin (1.3 mg/m2) given alone. The manufacturer of trabectedin recommends avoidance of strong CYP3A inhibitors within 1 day before and 1 week after trabectedin administration; there are no recommendations for concomitant use of moderate or weak CYP3A inhibitors.
    Trandolapril; Verapamil: (Moderate) Coadministration of verapamil with cyclosporine can lead to increased cyclosporine concentrations and toxicity. Verapamil inhibits CYP3A4 metabolism and thereby can increase the serum concentrations of cyclosporine. Verapamil should be used cautiously in patients stabilized on cyclosporine; cyclosporine dosage reduction may be required.
    Tretinoin, ATRA: (Moderate) Cyclosporine may decrease the CYP450 metabolism of tretinoin, ATRA, potentially resulting in increased plasma concentrations of tretinoin, ATRA. No specific studies have been done with oral tretinoin and cyclosporine, however, patients should be closely monitored for tretinoin toxicity while receiving concomitant therapy.
    Triamterene: (Major) Cyclosporine can cause hyperkalemia. Simultaneous use of cyclosporine with potassium-sparing diuretics, such as amiloride, spironolactone or triamterene, can increase this risk, and is not recommended.
    Tubocurarine: (Moderate) Cyclosporine may potentiate the action of nondepolarizing neuromuscular blockers. Prolonged neuromuscular blockade has been reported in patients receiving cyclosporine who receive neuromuscular blockers as part of surgical anesthesia. Monitor patients for recurrent neuromuscular blockade and respiratory depression; extended ventilatory support may be required.
    Typhoid Vaccine: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Ulipristal: (Minor) In vitro data indicate that ulipristal may be an inhibitor of P-glycoprotein (P-gp) at clinically relevant concentrations. Thus, co-administration of ulipristal and P-gp substrates such as cyclosporine may increase the cyclosporine concentrations; use caution. In the absence of clinical data, co-administration of ulipristal (when given daily) and P-gp substrates is not recommended.
    Ustekinumab: (Moderate) The formation of CYP450 enzymes may be altered during chronic inflammation; the formation of CYP450 enzymes could be normalized during ustekinumab receipt. For CYP450 substrates that have a narrow therapeutic index such as cyclosporine, consider monitoring the cyclosporine concentration if ustekinumab is initiated or discontinued; cyclosporine dose adjustment may be needed. In addition, the safety and efficacy of ustekinumab in patients with immunosuppression have not been evaluated. Patients receiving immunosuppressives along with ustekinumab may be at a greater risk of developing an infection or malignancy.
    Valdecoxib: (Moderate) Clinical status and serum creatinine and potassium levels should be closely monitored when cyclosporine is given with NSAIDs. Pharmacodynamic interactions have been reported between cyclosporine and NSAIDs, consisting of additive decreases in renal function with concomitant use. NSAIDs should be used with caution in patients receiving immunosuppressives as they may mask fever, pain, swelling and other signs and symptoms of an infection.
    Valganciclovir: (Moderate) Use caution and monitor renal function when valganciclovir is coadministered with cyclosporine because of the potential increase in serum creatinine. Acute renal failure may occur in patients concomitantly receiving potential nephrotoxic drugs.
    Valsartan: (Moderate) Coadministration of cyclosporine and an angiotensin II receptor antagonist, like valsartan, may increase the risk of hyperkalemia and reduced renal function. In response to cyclosporine-induced renal afferent vasoconstriction and glomerular hypoperfusion, angiotensin II is required to maintain an adequate glomerular filtration rate. Inhibition of angiotensin-converting enzyme (ACE) could reduce renal function acutely. Several cases of acute renal failure have been associated with the addition of enalapril to cyclosporine therapy in renal transplant patients. Also, cyclosporine can cause hyperkalemia, and inhibition of angiotensin II leads to reduced aldosterone concentrations, which can increase the serum potassium concentration. Closely monitor renal function and serum potassium concentrations in patients receiving cyclosporine concurrently with valsartan. Additionally, valsartan is a substrate of the hepatic uptake transporter OATP1B1 and cyclosporine is an inhibitor of OATP. Coadministration may increase systemic exposure to valsartan. Patients should be monitored for adverse effects of valsartan.
    Vancomycin: (Minor) Additive nephrotoxicity can occur if cyclosporine is administered with other nephrotoxic drugs such as vancomycin. Renal function should be monitored closely and vancomycin doses should be adjusted according to vancomycin serum concentrations.
    Vandetanib: (Major) Use caution and monitor cyclosporine levels if coadministration of vandetanib with cyclosporine is necessary, due to a possible increase in cyclosporine-related adverse reactions. Cyclosporine is partially a substrate of P-glycoprotein (P-gp). Coadministration with vandetanib increased the Cmax and AUC of digoxin, another P-gp substrate, by 29% and 23%, respectively. Cyclosporine is also a moderate CYP3A4 inhibitor. While strong CYP3A4 inducers affect serum concentrations of both vandetanib and its active metabolite, N-desmethyl-vandetanib, cyclosporine is not expected to affect vandetanib exposure based on a crossover study (n = 14) in which no clinically significant interaction was noted between vandetanib and the strong CYP3A4 inhibitor itraconazole.
    Varicella-Zoster Virus Vaccine, Live: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Vecuronium: (Moderate) Cyclosporine may potentiate the action of nondepolarizing neuromuscular blockers. Prolonged neuromuscular blockade has been reported in patients receiving cyclosporine who receive neuromuscular blockers as part of surgical anesthesia. Monitor patients for recurrent neuromuscular blockade and respiratory depression; extended ventilatory support may be required.
    Vemurafenib: (Moderate) Concomitant use of vemurafenib and cyclosporine may result in altered concentrations of cyclosporine and increased concentrations vemurafenib. Vemurafenib is a substrate/inducer of CYP3A4 and a substrate/inhibitor of P-glycoprotein (PGP). Budesonide is a substrate of CYP3A4 and a substrate/inhibitor of PGP. Use caution and monitor patients for toxicity and efficacy.
    Venetoclax: (Major) Avoid the concomitant use of venetoclax and cyclosporine; venetoclax is a substrate of CYP3A4, P-glycoprotein (P-gp), and Breast Cancer Resistance Protein (BCRP) and cyclosporine is an inhibitor of CYP3A4 (moderate), P-gp, and BCRP. Consider alternative agents. If concomitant use of these drugs is required, reduce the venetoclax dosage by at least 50% (maximum dose of 200 mg/day). If cyclosporine is discontinued, wait 2 to 3 days and then resume the recommended venetoclax dosage (or prior dosage if less). Monitor patients for signs and symptoms of venetoclax toxicity such as hematologic toxicity, GI toxicity, and tumor lysis syndrome. In a drug interaction study (n = 11), the venetoclax Cmax and AUC values were increased by 106% and 78%, respectively, when a P-gp inhibitor was co-administered in healthy subjects.
    Verapamil: (Moderate) Coadministration of verapamil with cyclosporine can lead to increased cyclosporine concentrations and toxicity. Verapamil inhibits CYP3A4 metabolism and thereby can increase the serum concentrations of cyclosporine. Verapamil should be used cautiously in patients stabilized on cyclosporine; cyclosporine dosage reduction may be required.
    Vinblastine: (Moderate) Use vinblastine and cyclosporine together with caution; concomitant use may result in increased vinblastine plasma concentrations and increased vinblastine toxicity. Cyclosporine is a CYP3A4 and P-glycoprotein (P-gp) inhibitor and vinblastine is a CYP3A4 and P-gp substrate.
    Vincristine Liposomal: (Moderate) Use cyclosporine and vincristine together with caution; concomitant use may result in increased vincristine plasma concentrations and increased vincristine toxicity. Cyclosporine is a CYP3A4 and P-glycoprotein (P-gp) inhibitor and vincristine is a CYP3A4 and P-gp substrate. Early onset and/or increased severity of neuromuscular adverse events have been reported when vincristine was administered with a strong CYP3A4 and P-gp inhibitor.
    Vincristine: (Moderate) Use cyclosporine and vincristine together with caution; concomitant use may result in increased vincristine plasma concentrations and increased vincristine toxicity. Cyclosporine is a CYP3A4 and P-glycoprotein (P-gp) inhibitor and vincristine is a CYP3A4 and P-gp substrate. Early onset and/or increased severity of neuromuscular adverse events have been reported when vincristine was administered with a strong CYP3A4 and P-gp inhibitor.
    Vinorelbine: (Moderate) Caution is warranted when cyclosporine is administered with vinorelbine as there is a potential for elevated vinorelbine concentrations. Monitor patients for an earlier onset and/or an increased severity of adverse effects including neurotoxicity and myelosuppression. Vinorelbine is a substrate of CYP3A4 and P-glycoprotein (P-gp). Cyclosporine is an inhibitor of CYP3A4 and P-gp.
    Vorapaxar: (Moderate) Use caution during concurrent use of vorapaxar and cyclosporine. Increased serum concentrations of vorapaxar are possible when vorapaxar, a CYP3A4 substrate, is coadministered with cyclosporine, a mild CYP3A inhibitor. Increased exposure to vorapaxar may increase the risk of bleeding complications.
    Voriconazole: (Major) The interactions between cyclosporine and systemic azole antifungals, including voriconazole, can be significant. Voriconazole may inhibit the metabolism and lead to increased concentrations of cyclosporine. Plasma cyclosporine concentrations should be monitored closely if voriconazole is added. Reduce cyclosporine doses by one-half when initiating therapy with voriconazole due to voriconazole-induced inhibition of CYP3A4. When voriconazole is discontinued, cyclosporine concentrations should be carefully monitored and the dose increased as needed. In all cases, renal function in these patients should be carefully monitored. Close monitoring of cyclosporine concentrations is required when given in combination with systemic azole antifungals; a 50% reduction in cyclosporine dosage may be required.
    Warfarin: (Moderate) Cyclosporine, when given systemically, may increase the effect of warfarin by inhibiting warfarin metabolism via CYP3A4. Two reports are noted in the literature of a severe interaction between cyclosporine and warfarin. Patients taking warfarin should have their INR monitored closely during and after concomitant cyclosporine usage.
    Yellow Fever Vaccine, Live: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Zafirlukast: (Minor) As cyclosporine is a CYP3A4 substrate, use with a CYP3A4 inhibitor, such as cyclosporine, may result in increased serum concentrations of cyclosporine. Monitor serum cyclosporin concentrations carefully if a CYP3A4 inhibitor is used concomitantly. Conversely, if a CYP3A4 inhibitor is discontinued, cyclosporine concentrations could decrease.
    Zileuton: (Minor) Zileuton is a CYP3A4 inhibitor and may decrease the clearance of cyclosporine, with the potential to reduce cyclosporine dosage requirements or cause cyclosporine toxicity. This potential interaction may result in increased serum concentrations of cyclosporine.
    Zoledronic Acid: (Moderate) Since zoledronic acid is eliminated by the kidney, coadministration of zoledronic acid with other nephrotoxic drugs, such as cyclosporine, may increase serum concentrations of either zoledronic acid and/or these coadministered drugs.
    Zonisamide: (Minor) Zonisamide is a weak inhibitor of P-glycoprotein (P-gp), and cyclosporine is a substrate of P-gp. There is theoretical potential for zonisamide to affect the pharmacokinetics of drugs that are P-gp substrates. Use caution when starting or stopping zonisamide or changing the zonisamide dosage in patients also receiving drugs which are P-gp substrates.

    PREGNANCY AND LACTATION

    Pregnancy

    The oral and intravenous formulations of cyclosporine are classified as FDA pregnancy risk category C. Use of these systemic formulations during pregnancy should only be considered if the potential benefits to the mother justify the potential risks to the fetus; consider discontinuation of cyclosporine therapy in psoriasis patients. Prior to drug administration, females of childbearing age should be counseled about the potential risks of cyclosporine therapy and about appropriate contraceptive measures. Ophthalmic drops do not produce detectable concentrations of cyclosporine in the blood; thus maternal use of this formulation is not expected to result in fetal drug exposure. There are no adequate and well-controlled studies of cyclosporine during pregnancy. In animal models, cyclosporine has been shown to be embryotoxic and fetotoxic when given in maternally toxic doses. In pregnant transplant recipients who are being treated with immunosuppressants, the risk of premature births is increased. Outcomes of 116 pregnancies in women (mostly transplant patients) receiving cyclosporine throughout the entire gestational period showed premature birth (gestational period of 28 to 36 weeks) in 47% and low birth weight for gestational age in 28% of pregnancies. Sixteen fetal losses occurred. Most of the pregnancies were complicated by disorders including preeclampsia, eclampsia, premature labor, abruptio placentae, oligohydramnios, Rh incompatibility and fetoplacental dysfunction. Seven malformations were reported in 5 viable infants and in 2 cases of fetal loss. Neonatal complications occurred in 27%. A limited number of observations in children up to approximately 7 years of age exposed to cyclosporine in utero is available. Renal function and blood pressure in these children were normal. Additionally, for an adult weighing 70 kg, the maximum daily oral dose of cyclosporine would deliver about 1 gram of alcohol (approximately 6% of the amount of alcohol contained in a standard drink), while the daily IV dose would deliver approximately 15% of the amount of alcohol contained in a standard drink.

    When administered systemically, cyclosporine is excreted into breast milk. The American Academy of Pediatrics considers cyclosporine a cytotoxic drug that may interfere with the cellular metabolism of a nursing infant. Cyclosporine preparations also contain ethanol, which will be present in human milk at levels similar to that found in maternal serum. After opthalmic administration of cyclosporine emulsion, blood concentrations are undetectable, making it unlikely that a clinically significant amount of drug would be excreted into breast milk. Consider the benefits of breast-feeding, the risk of infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    MECHANISM OF ACTION

    Cyclosporine induces immunosuppression by inhibiting the first phase of T-cell activation. The first phase of T-cell activation causes transcriptional activation of immediate and early gene products (e.g., interleukins - IL-2, IL-3, and IL-4, tumor necrosis factor alpha, and interferon gamma) that allow T-cells to progress from the G0 to G1 phases. Cyclosporine binds to an immunophilin termed cyclophilin. Immunophilins (e.g., cyclophilin and FK binding proteins) are immunosuppressant-binding proteins that are distributed in all cellular compartments and play an important role in protein regulation. The cyclosporine-cyclophilin complex then binds to and inhibits the calcium-calmodulin activated phosphatase calcineurin. The calcineurin enzyme catalyzes critical dephosphorylation reactions necessary for early lymphokine gene transcription, and subsequent early activation of T-cells. Calcineurin inhibition results in blockade of signal transduction of the nuclear factor of activated T-cells (NF-AT). The blockade of signal transduction results in failure to activate NF-AT regulated genes. NF-AT activated genes include those required for B-cell activation including interleukin (IL)-4 and CD40 ligand and those required for T-cell activation including IL-2 and interferon gamma. Cyclosporine does not affect suppressor T-cells or T-cell independent, antibody-mediated immunity.
     
    In patients whose tear production is suppressed due to inflammation associated with keratoconjunctivitis sicca, ophthalmic cyclosporine is thought to act as a partial immunomodulator. The exact mechanism of action is unknown. In dry eye syndrome, lymphocytes can aggregate and damage the lacrimal gland causing fibrosis and loss of tear production. Cyclosporine is thought to reverse this process by causing apoptosis of lymphocytes allowing for tear production.

    PHARMACOKINETICS

    Cyclosporine is administered orally, intravenously, or ophthalmically. Cyclosporine is extremely hydrophobic. First-pass metabolism, mode of administration, formulation, and drug interactions all affect cyclosporine absorption.
     
    Cyclosporine is a substrate and inhibitor of P-glycoprotein, which is an energy-dependent drug-efflux pump located in intestinal epithelium and the blood brain barrier. There appears to be overlap between inhibitors and/or substrates of cytochrome P450 (CYP) 3A4 and P-glycoprotein. The P-glycoprotein efflux of cyclosporine from intestinal cells back into the gut lumen allows for CYP3A4 metabolism prior to absorption, thus limiting cyclosporine availability. When cyclosporine is administered with inhibitors of both CYP3A4 and P-glycoprotein (e.g., diltiazem, erythromycin, or ketoconazole) increased cyclosporine bioavailability leads to increased cyclosporine concentrations.
     
    Cyclosporine is distributed widely throughout the body, crosses the placenta, and is found in breast milk. Preferential uptake of cyclosporine occurs in the liver, pancreas, and adipose tissue, while it penetrates the CNS poorly. In blood, the distribution of cyclosporine is concentration dependent; as the hemocrit rises, the cyclosporine concentration in plasma decreases. Approximately 22—47% of cyclosporine is found in plasma, 4—9% in lymphocytes, 5—12% in granulocytes, and 41—58% in erythrocytes. At high drug concentrations the binding to lymphocytes and erythrocytes becomes saturated. In plasma, cyclosporine is approximately 90% bound to lipoproteins. In addition, binding to erythrocytes and lipoproteins is temperature dependent. As the temperature increases, binding to lipoproteins increases; however, binding to erythrocytes increases as the temperature decreases. Other medications that may affect the binding of cyclosporine to lipoproteins may modify the clinical response to cyclosporine. Cyclosporine is metabolized extensively by the CYP3A enzyme system in the liver and to a lesser extent in the gastrointestinal tract and kidney. Agents that affect the CYP3A system may significantly alter the metabolism of cyclosporine. At least 25 metabolites of cyclosporine have been identified, some of which are biologically active. Although most cyclosporine metabolites show only 10—20% of the immunosuppressive activity of the parent drug, they do contribute to toxicity. The major metabolites of cyclosporine are M1, M9, and M4N, resulting from oxidation at the 1-beta, 9-gamma, and 4-N-desmethylated positions. The percentage of dose present as M1, M9, or M4N is similar when either cyclosporine (Modified) or cyclosporine (Nonmodified) is administered. At steady state, concentrations and AUCs of cyclosporine metabolites may exceed that of cyclosporine. Mean AUCs for blood concentrations of these metabolites are 70%, 21%, and 7.5% respectively, of blood cyclosporine concentrations. The elimination half-life of cyclosporine is highly variable. In patients with normal hepatic function the average half-life ranges from 16—27 hours, but can vary from 10—40 hours. Elimination of cyclosporine and its metabolites is principally through the bile and feces. Cyclosporine undergoes enterohepatic recycling. Only 6% of the cyclosporine dose is excreted renally, of which 0.1% is excreted as unchanged cyclosporine. Although cyclosporine blood levels are widely used to assist dosing, accurate interpretation is hampered by variation in absorption, variation in protein binding, sampling error, type of assay, cross-reactivity of metabolites, enterohepatic recycling of drug, and drug interactions.

    Oral Route

    Because of the unpredictability of cyclosporine oral absorption, it is difficult to convert between oral and parenteral doses. Most clinicians use a 3:1 ratio when converting between oral and parenteral routes (e.g., 30 mg IV is roughly equivalent to 90 mg orally).
     
    Oral absorption of Cyclosporine, USP (Nonmodified): The absolute bioavailability of cyclosporine administered as cyclosporine (Nonmodified) is highly variable; the bioavailability is estimated to be < 10% in liver transplant patients and can range from 7.4—92.2% in renal transplant patients. The oral absorption of cyclosporine (Nonmodified) is limited by the relatively narrow window for absorption in the proximal small intestine, the potential for pre-systemic metabolism in the gut, reliance on pancreatic enzymes and bile in the gut to achieve adequate dispersion, and the variable affects of food. The time to maximum concentration varies widely, both within-patient and between patients; in a study of renal transplant patients, the Tmax ranged from 1.5—22 hours. In general, absorption of cyclosporine (Nonmodified) is not affected by a light meal, but may be increased with a high-fat meal or grapefruit juice. The status of the GI tract may decrease absorption as well; conditions associated with decreased absorption include diarrhea, decreased small bowel length, and concurrent administration of drugs that increase GI motility. Due to the large differences in bioavailability in cyclosporine (Nonmodified), patients titrated to the same trough levels could be exposed to different amounts of the cyclosporine as measured by area under the time-concentration curve (AUC).
     
    Oral absorption of Cyclosporine, USP (Modified): Cyclosporine (Modified) formulations are not bioequivalent to cyclosporine (Nonmodified) formulations; these products cannot be interchanged without physician supervision. The physical properties of the cyclosporine (Modified) formulation (i.e., microemulsion) make the absorption of cyclosporine less dependent on bile, food, and other factors that assist dispersion and subsequent absorption of lipophilic substances from the GI tract. Although, agents which influence pre-systemic metabolism (e.g., grapefruit juice) may still influence cyclosporine (Modified) absorption. The absolute bioavailability of cyclosporine (Modified) has not been determined in adults. In studies of renal transplant, rheumatoid arthritis, and psoriasis patients, the mean cyclosporine AUC was approximately 20—50% greater and the blood Cmax was approximately 40—106% greater following administration of cyclosporine (Modified) compared to cyclosporine (Nonmodified). In liver transplant patients, the dose normalized AUC was 50% greater and Cmax 90% greater in patients administered cyclosporine (Modified) versus cyclosporine (Nonmodified). Although the AUC and Cmax values are higher on cyclosporine (Modified) relative to cyclosporine (Nonmodified), the predose trough levels are similar for the two formulations. Following oral administration, the Tmax for cyclosporine (Modified) ranges from 1.5—2 hours. Food decreases the absorption of cyclosporine (Modified). As compared to cyclosporine (Nonmodified), the AUC of cyclosporine (Modified) is linear within the therapeutic dosage range. Intersubject variability of cyclosporine exposure (AUC) ranges from about 20—50% when administered as cyclosporine (Modified) or cyclosporine (Nonmodified). There is less intrasubject variation in AUC with cyclosporine (Modified), despite random changes in food intake, bile secretion, or time of trough concentration measurement. Intrasubject variability of AUC in renal transplant patients is 9—21% for cyclosporine (Modified) and 19—26% for cyclosporine (Nonmodified). In these same studies, the intrasubject variation in trough concentrations was similar for the two formulations.

    Intravenous Route

    Because of the unpredictability of cyclosporine oral absorption, it is difficult to convert between oral and parenteral doses. Most clinicians use a 3:1 ratio when converting between oral and parenteral routes (e.g., 30 mg IV is roughly equivalent to 90 mg orally).

    Other Route(s)

    Ophthalmic Route
    Following ophthalmic administration, blood concentrations of cyclosporine were below the quantitation limit of 0.1 ng/mL. There was no detectable drug accumulation in blood during 12 months of treatment with cyclosporine ophthalmic emulsion.