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  • CLASSES

    Calcineurin Inhibitors
    Miscellaneous Ophthalmologicals for Dry Eye Disease

    BOXED WARNING

    Fungal infection, herpes infection, immunosuppression, infection, requires a specialized care setting, requires an experienced clinician, varicella, viral infection

    Increased susceptibility to infection may result from immunosuppression. 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. Cyclosporine therapy requires an experienced clinician who is knowledgeable in immunosuppressive therapy or organ transplantation. Cyclosporine administration requires a specialized care setting with facilities equipped and staffed with adequate laboratory and supportive medical services.

    Lymphoma, new primary malignancy, radiation therapy, skin cancer, sunlight (UV) exposure

    Patients receiving immunosuppressants such as oral or injectable cyclosporine are at increased risk for the development of a new primary malignancy, such as lymphoma or skin cancer. The increased risk appears related to the intensity and duration of immunosuppression rather than to the use of specific agents. In patients with psoriasis, the concomitant use of PUVA or UVB therapy, methotrexate or other immunosuppressive agents, coal tar, or radiation therapy is contraindicated because of the possibility of excessive immunosuppression and risk of malignancies. 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. Patients should also be warned to avoid excessive sunlight (UV) 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. The relative risk of malignancies is comparable to that observed in psoriasis patients treated with other immunosuppressive therapies. Skin lesions not typical of psoriasis should be biopsied before starting cyclosporine treatment.

    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; ophthalmic preparations used to increase tear production in patients with ocular inflammation associated with keratoconjunctivitis
    Microemulsion formulation (cyclosporine, USP (Modified)) has been introduced to improve the bioavailability

    COMMON BRAND NAMES

    Cequa, Gengraf, Neoral, Restasis, Sandimmune

    HOW SUPPLIED

    Cequa Ophthalmic Sol: 0.09%
    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 (ophthalmic emulsion)
    Adults

    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.

    Adolescents 16 to 17 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.

    Ophthalmic dosage (ophthalmic solution)
    Adults

    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.

    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

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

    Geriatric

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

    Adolescents

    16 to 17 years: 2 drops/day per affected eye for ophthalmic emulsion. For systemic formulations, the maximum dosage is dependent on indication, route of therapy, and cyclosporine serum concentrations. Safety and efficacy have not been established for the ophthalmic solution.
    13 to 16 years: For systemic formulations, the maximum dosage is dependent on indication, route of therapy, and cyclosporine serum concentrations. Safety and efficacy have not been established for the ophthalmic solution or emulsion.

    Children

    For systemic formulations, the maximum dosage is dependent on indication, route of therapy, and cyclosporine serum concentrations. Safety and efficacy have not been established for the ophthalmic solution or 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.
    If using the ophthalmic emulsion, invert the unit dose bottle a few times to obtain a uniform, white, opaque emulsion before using.
    To avoid contamination, advise patient to 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)
    Cequa:
    - Store at controlled room temperature (between 68 and 77 degrees F)
    - Store unused product in foil pouch
    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, requires a specialized care setting, requires an experienced clinician, varicella, viral infection

    Increased susceptibility to infection may result from immunosuppression. 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. Cyclosporine therapy requires an experienced clinician who is knowledgeable in immunosuppressive therapy or organ transplantation. Cyclosporine administration requires a specialized care setting with facilities equipped and staffed with adequate laboratory and supportive medical services.

    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.

    Lymphoma, new primary malignancy, radiation therapy, skin cancer, sunlight (UV) exposure

    Patients receiving immunosuppressants such as oral or injectable cyclosporine are at increased risk for the development of a new primary malignancy, such as lymphoma or skin cancer. The increased risk appears related to the intensity and duration of immunosuppression rather than to the use of specific agents. In patients with psoriasis, the concomitant use of PUVA or UVB therapy, methotrexate or other immunosuppressive agents, coal tar, or radiation therapy is contraindicated because of the possibility of excessive immunosuppression and risk of malignancies. 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. Patients should also be warned to avoid excessive sunlight (UV) 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. The relative risk of malignancies is comparable to that observed in psoriasis patients treated with other immunosuppressive therapies. Skin lesions not typical of psoriasis should be biopsied before starting cyclosporine treatment.

    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 solution and emulsion have not been established in pediatric patients younger than 18 years and 16 years of age, respectively.

    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% or more above baseline after 3 to 4 months of cyclosporine therapy. No overall differences in safety or effectiveness of cyclosporine ophthalmic solution or emulsion have 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 solution and 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 ophthalmic administration of cyclosporine.[36320] [63434]

    ADVERSE REACTIONS

    Severe

    bronchospasm / Rapid / 5.0-6.5
    lymphoma / Delayed / 0-6.0
    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
    skin cancer / Delayed / 1.0-3.0
    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
    nephrotoxicity / Delayed / Incidence not known
    renal tubular necrosis / Delayed / Incidence not known
    azotemia / 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
    new primary malignancy / Delayed / 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
    conjunctival hyperemia / Early / 0-6.0
    chest pain (unspecified) / Early / 1.0-6.0
    blurred vision / Early / 1.0-5.0
    blepharitis / Early / 1.0-5.0
    epiphora / 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
    immunosuppression / 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 / 1.0-25.0
    infection / Delayed / 0-24.7
    nausea / Early / 2.0-23.0
    ocular pain / Early / 0-22.0
    hypertrichosis / Delayed / 6.6-19.0
    ocular irritation / Rapid / 0-17.0
    abdominal pain / Early / 0-15.0
    diarrhea / Early / 3.0-13.0
    rash / 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 discharge / Delayed / 1.0-5.0
    ocular pruritus / Rapid / 1.0-5.0
    foreign body sensation / 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.
    Abemaciclib: (Moderate) Monitor for an increase in abemaciclib-related adverse reactions if coadministration with cyclosporine is necessary; consider reducing the dose of abemaciclib in 50-mg decrements if toxicities occur. Discontinue abemaciclib for patients unable to tolerate 50 mg twice daily. Abemaciclib is a CYP3A4 substrate and cyclosporine is a moderate CYP3A4 inhibitor. Coadministration with other moderate CYP3A4 inhibitors is predicted to increase the relative potency adjusted unbound AUC of abemaciclib plus its active metabolites (M2, M18, and M20) by approximately 1.6- to 2.4-fold.
    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. (Moderate) Concomitant use of codeine with cyclosporine may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of cyclosporine could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If cyclosporine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Cyclosporine is a moderate inhibitor of CYP3A4.
    Acetaminophen; Caffeine; Dihydrocodeine: (Moderate) Concomitant use of dihydrocodeine with cyclosporine may increase dihydrocodeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased dihydromorphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of dihydrocodeine until stable drug effects are achieved. Discontinuation of cyclosporine could decrease dihydrocodeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to dihydrocodeine. If cyclosporine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Cyclosporine is a moderate inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine.
    Acetaminophen; Codeine: (Moderate) Concomitant use of codeine with cyclosporine may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of cyclosporine could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If cyclosporine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Cyclosporine is a moderate inhibitor of CYP3A4.
    Acetaminophen; Hydrocodone: (Moderate) Concomitant use of hydrocodone with cyclosporine may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of cyclosporine could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If cyclosporine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Cyclosporine is a moderate inhibitor of CYP3A4.
    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: (Moderate) If the concomitant use of cyclosporine and afatinib is necessary, monitor for afatinib-related adverse reactions. If the original dose of afatinib is not tolerated, consider reducing the daily dose of afatinib by 10 mg; resume the previous dose of afatinib as tolerated after discontinuation of cyclosporine. 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. Afatinib is a P-glycoprotein (P-gp) substrate and cyclosporine is a P-gp inhibitor; coadministration may increase plasma concentrations of afatinib. Administration with another P-gp inhibitor, given 1 hour before a single dose of afatinib, increased afatinib exposure by 48%; there was no change in afatinib exposure when the P-gp inhibitor 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 the same P-gp inhibitor, and 111% and 105% when the inhibitor was administered 6 hours after afatinib.
    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. In addition, amlodipine is a weak inhibitor of CYP3A4; cyclosporine is a substrate with a narrow therapeutic index. 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. In addition, amlodipine is a weak inhibitor of CYP3A4; cyclosporine is a substrate with a narrow therapeutic index. 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; Metformin: (Moderate) Patients should be monitored for worsening glycemic control if therapy with cyclosporine is initiated in patients receiving antidiabetic agents. Cyclosporine has been reported to cause hyperglycemia or exacerbate diabetes mellitus; this effect appears to be dose-related and caused by direct beta-cell toxicity. Also, any drug that deteriorates the renal status of the patient is likely to alter metformin concentrations in the body, so renal function should be carefully monitored during the use of cyclosporine and metformin together.
    Alogliptin; Pioglitazone: (Moderate) Patients should be monitored for worsening glycemic control if therapy with cyclosporine is initiated in patients receiving antidiabetic agents. Cyclosporine has been reported to cause hyperglycemia or exacerbate diabetes mellitus; this effect appears to be dose-related and caused by direct beta-cell toxicity.
    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. In addition, amlodipine is a weak inhibitor of CYP3A4; cyclosporine is a substrate with a narrow therapeutic index. 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. In addition, amlodipine is a weak inhibitor of CYP3A4; cyclosporine is a substrate with a narrow therapeutic index. 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. In addition, amlodipine is a weak inhibitor of CYP3A4; cyclosporine is a substrate with a narrow therapeutic index. 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. In addition, amlodipine is a weak inhibitor of CYP3A4; cyclosporine is a substrate with a narrow therapeutic index. 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. In addition, amlodipine is a weak inhibitor of CYP3A4; cyclosporine is a substrate with a narrow therapeutic index. 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. In addition, amlodipine is a weak inhibitor of CYP3A4; cyclosporine is a substrate with a narrow therapeutic index. 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. In addition, amlodipine is a weak inhibitor of CYP3A4; cyclosporine is a substrate with a narrow therapeutic index. 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. In addition, amlodipine is a weak inhibitor of CYP3A4; cyclosporine is a substrate with a narrow therapeutic index. 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.
    Apalutamide: (Moderate) Closely monitor cyclosporine levels and adjust the dose of cyclosporine as appropriate if coadministration with apalutamide is necessary. Cyclosporine is extensively metabolized by CYP3A4 and has a narrow therapeutic index; apalutamide is a strong CYP3A4 inducer.
    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. (Moderate) Concomitant use of codeine with cyclosporine may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of cyclosporine could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If cyclosporine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Cyclosporine is a moderate inhibitor of CYP3A4.
    Aspirin, ASA; Caffeine; Dihydrocodeine: (Moderate) Concomitant use of dihydrocodeine with cyclosporine may increase dihydrocodeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased dihydromorphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of dihydrocodeine until stable drug effects are achieved. Discontinuation of cyclosporine could decrease dihydrocodeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to dihydrocodeine. If cyclosporine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Cyclosporine is a moderate inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine.
    Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Concomitant use of codeine with cyclosporine may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of cyclosporine could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If cyclosporine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Cyclosporine is a moderate inhibitor of CYP3A4.
    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, causing an increased risk for cyclosporine-related adverse events. Predictions regarding this interaction can be made based on the metabolic pathways of these drugs. Cobicistat is a strong inhibitor of CYP3A4, an isoenzyme responsible for the metabolism of cyclosporine.
    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.
    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) Caution is warranted with the concomitant use of azithromycin and cyclosporine as increased cyclosporine concentrations may occur. Dose adjustment of cyclosporine may be necessary; monitor cyclosporine serum concentrations during use with azithromycin and after discontinuation of azithromycin.
    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.
    Baricitinib: (Major) Do not use baricitinib in combination with potent immunosuppressants such as cyclosporine. A risk of added immunosuppression exists when baricitinib is coadministered with potent immunosuppressives. Combined use of multiple-dose tofacitinib with potent immunosuppressives has not been studied in patients with rheumatoid arthritis.
    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.
    Betrixaban: (Major) Avoid betrixaban use in patients with severe renal impairment receiving cyclosporine. Reduce betrixaban dosage to 80 mg PO once followed by 40 mg PO once daily in all other patients receiving cyclosporine. Bleeding risk may be increased; monitor patients closely for signs and symptoms of bleeding. Betrixaban is a substrate of P-gp; cyclosporine inhibits P-gp.
    Bictegravir; 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.
    Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: (Major) Monitor serum concentrations of cyclosporine when coadministered with systemic metronidazole. Concomitant use with metronidazole may increase the serum concentrations of cyclosporine; thereby, increasing the risk of side effects. Also, medications with significant alcohol content should not be ingested during therapy with metronidazole and should be avoided for 3 days after metronidazole 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) Monitor serum concentrations of cyclosporine when coadministered with systemic metronidazole. Concomitant use with metronidazole may increase the serum concentrations of cyclosporine; thereby, increasing the risk of side effects. Also, medications with significant alcohol content should not be ingested during therapy with metronidazole and should be avoided for 3 days after metronidazole 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.
    Brompheniramine; Guaifenesin; Hydrocodone: (Moderate) Concomitant use of hydrocodone with cyclosporine may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of cyclosporine could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If cyclosporine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Cyclosporine is a moderate inhibitor of CYP3A4.
    Brompheniramine; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with cyclosporine may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of cyclosporine could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If cyclosporine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Cyclosporine is a moderate inhibitor of CYP3A4.
    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.
    Cabozantinib: (Minor) Monitor for an increase in cabozantinib- and cyclosporine-related adverse events if concomitant use of is necessary; consider closer monitoring of cyclosporine serum concentrations. Cabozantinib is a Multidrug Resistance Protein 2 (MRP2) substrate and cyclosporine is an MRP2 inhibitor. MRP2 inhibitors have the potential to increase plasma concentrations of cabozantinib; however, the clinical relevance of this interaction is unknown. Cabozantinib is also a P-glycoprotein (P-gp) inhibitor and has the potential to increase plasma concentrations of P-gp substrates such as cyclosporine; however, the clinical relevance of this finding is unknown.
    Canagliflozin; Metformin: (Moderate) Patients should be monitored for worsening glycemic control if therapy with cyclosporine is initiated in patients receiving antidiabetic agents. Cyclosporine has been reported to cause hyperglycemia or exacerbate diabetes mellitus; this effect appears to be dose-related and caused by direct beta-cell toxicity. Also, any drug that deteriorates the renal status of the patient is likely to alter metformin concentrations in the body, so renal function should be carefully monitored during the use of cyclosporine and metformin together.
    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.
    Cannabidiol: (Moderate) Consider a dose reduction of cannabidiol if coadministered with cyclosporine. Coadministration may increase cannabidiol plasma concentrations increasing the risk of adverse reactions. Cannabidiol is metabolized by CYP3A4; cyclosporine is a moderate inhibitor of CYP3A4.
    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.
    Carbinoxamine; Hydrocodone; Phenylephrine: (Moderate) Concomitant use of hydrocodone with cyclosporine may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of cyclosporine could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If cyclosporine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Cyclosporine is a moderate inhibitor of CYP3A4.
    Carbinoxamine; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with cyclosporine may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of cyclosporine could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If cyclosporine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Cyclosporine is a moderate inhibitor of CYP3A4.
    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.
    Chlorpheniramine; Codeine: (Moderate) Concomitant use of codeine with cyclosporine may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of cyclosporine could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If cyclosporine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Cyclosporine is a moderate inhibitor of CYP3A4.
    Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Moderate) Concomitant use of dihydrocodeine with cyclosporine may increase dihydrocodeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased dihydromorphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of dihydrocodeine until stable drug effects are achieved. Discontinuation of cyclosporine could decrease dihydrocodeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to dihydrocodeine. If cyclosporine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Cyclosporine is a moderate inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine.
    Chlorpheniramine; Dihydrocodeine; Pseudoephedrine: (Moderate) Concomitant use of dihydrocodeine with cyclosporine may increase dihydrocodeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased dihydromorphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of dihydrocodeine until stable drug effects are achieved. Discontinuation of cyclosporine could decrease dihydrocodeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to dihydrocodeine. If cyclosporine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Cyclosporine is a moderate inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine.
    Chlorpheniramine; Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with cyclosporine may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of cyclosporine could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If cyclosporine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Cyclosporine is a moderate inhibitor of CYP3A4.
    Chlorpheniramine; Hydrocodone: (Moderate) Concomitant use of hydrocodone with cyclosporine may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of cyclosporine could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If cyclosporine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Cyclosporine is a moderate inhibitor of CYP3A4.
    Chlorpheniramine; Hydrocodone; Phenylephrine: (Moderate) Concomitant use of hydrocodone with cyclosporine may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of cyclosporine could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If cyclosporine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Cyclosporine is a moderate inhibitor of CYP3A4.
    Chlorpheniramine; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with cyclosporine may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of cyclosporine could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If cyclosporine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Cyclosporine is a moderate inhibitor of CYP3A4.
    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, causing an increased risk for cyclosporine-related adverse events. Predictions regarding this interaction can be made based on the metabolic pathways of these drugs. Cobicistat is a strong inhibitor of CYP3A4, an isoenzyme responsible for the metabolism of cyclosporine.
    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, causing an increased risk for cyclosporine-related adverse events. Predictions regarding this interaction can be made based on the metabolic pathways of these drugs. Cobicistat is a strong inhibitor of CYP3A4, an isoenzyme responsible for the metabolism of cyclosporine. (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, causing an increased risk for cyclosporine-related adverse events. Predictions regarding this interaction can be made based on the metabolic pathways of these drugs. Cobicistat is a strong inhibitor of CYP3A4, an isoenzyme responsible for the metabolism of cyclosporine.
    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).
    Codeine: (Moderate) Concomitant use of codeine with cyclosporine may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of cyclosporine could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If cyclosporine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Cyclosporine is a moderate inhibitor of CYP3A4.
    Codeine; Guaifenesin: (Moderate) Concomitant use of codeine with cyclosporine may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of cyclosporine could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If cyclosporine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Cyclosporine is a moderate inhibitor of CYP3A4.
    Codeine; Phenylephrine; Promethazine: (Moderate) Concomitant use of codeine with cyclosporine may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of cyclosporine could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If cyclosporine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Cyclosporine is a moderate inhibitor of CYP3A4.
    Codeine; Promethazine: (Moderate) Concomitant use of codeine with cyclosporine may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of cyclosporine could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If cyclosporine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Cyclosporine is a moderate inhibitor of CYP3A4.
    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) Cyclosporine therapeutic drug monitoring is recommended when administered concurrently with crizotinib; additionally, monitor for an increase in crizotinib-related adverse reactions. Use of these medications together may result in elevated serum concentrations of both drugs, causing an increased risk for treatment-related adverse events. Crizotinib Is a CYP3A substrate and moderate inhibitor. Cyclosporine is a CYP3A4 substrate with a narrow therapeutic index and is also a moderate CYP3A4 inhibitor.
    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) Close monitoring of cyclosporine concentrations is required when danazol is given concurrently with cyclosporine. 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.
    Dapagliflozin; Metformin: (Moderate) Patients should be monitored for worsening glycemic control if therapy with cyclosporine is initiated in patients receiving antidiabetic agents. Cyclosporine has been reported to cause hyperglycemia or exacerbate diabetes mellitus; this effect appears to be dose-related and caused by direct beta-cell toxicity. Also, any drug that deteriorates the renal status of the patient is likely to alter metformin concentrations in the body, so renal function should be carefully monitored during the use of cyclosporine and metformin together.
    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, causing an increased risk for cyclosporine-related adverse events. Predictions regarding this interaction can be made based on the metabolic pathways of these drugs. Cobicistat is a strong inhibitor of CYP3A4, an isoenzyme responsible for the metabolism of cyclosporine.
    Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (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, causing an increased risk for cyclosporine-related adverse events. Predictions regarding this interaction can be made based on the metabolic pathways of these drugs. Cobicistat is a strong inhibitor of CYP3A4, an isoenzyme responsible for the metabolism of cyclosporine. (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.
    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.
    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.
    Dihydrocodeine; Guaifenesin; Pseudoephedrine: (Moderate) Concomitant use of dihydrocodeine with cyclosporine may increase dihydrocodeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased dihydromorphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of dihydrocodeine until stable drug effects are achieved. Discontinuation of cyclosporine could decrease dihydrocodeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to dihydrocodeine. If cyclosporine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Cyclosporine is a moderate inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine.
    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; Hydrocodone; Phenylephrine: (Moderate) Concomitant use of hydrocodone with cyclosporine may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of cyclosporine could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If cyclosporine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Cyclosporine is a moderate inhibitor of CYP3A4.
    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.
    Doravirine; Lamivudine; 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.
    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: (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.
    Duvelisib: (Moderate) Monitor for increased toxicity of duvelisib and cyclosporine during coadministration. Coadministration may increase the exposure of both drugs. Duvelisib is a substrate and moderate inhibitor of CYP3A; cyclosporine is also a substrate and moderate inhibitor of CYP3A.
    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.
    Efavirenz; Lamivudine; 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) 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.
    Elagolix: (Severe) Concomitant use of elagolix and strong organic anion transporting polypeptide (OATP) 1B1 inhibitors such as cyclosporine is contraindicated. Use of elagolix with drugs that inhibit OATP1B1 may increase elagolix plasma concentrations. Elagolix is a substrate of CYP3A, P-gp, and OATP1B1. Cyclosporine inhibits both OATP1B1 and P-gp. Another OATP1B1 potent inhibitor increased elagolix AUC in the range of 2- to 5.58-fold. Increased elagolix concentrations increase the risk for dose-related side effects, including loss of bone mineral density.
    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: (Moderate) Monitor for increased eletriptan-related adverse effects if coadministered with cyclosporine. Systemic concentrations of eletriptan may be increased. Eletriptan is a substrate for CYP3A4, and cyclosporine is a moderate CYP3A4 inhibitor. Coadministration of other moderate CYP3A4 inhibitors increased the eletriptan AUC by 2 to 4-fold.
    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. Advise patients against driving or operating machinery until the combine effects of these drugs on the individual patient is known.
    Empagliflozin; Metformin: (Moderate) Patients should be monitored for worsening glycemic control if therapy with cyclosporine is initiated in patients receiving antidiabetic agents. Cyclosporine has been reported to cause hyperglycemia or exacerbate diabetes mellitus; this effect appears to be dose-related and caused by direct beta-cell toxicity. Also, any drug that deteriorates the renal status of the patient is likely to alter metformin concentrations in the body, so renal function should be carefully monitored during the use of cyclosporine and metformin together.
    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.
    Encorafenib: (Major) Avoid coadministration of encorafenib and cyclosporine due to increased encorafenib exposure. If concurrent use cannot be avoided, reduce the encorafenib dose to one-half of the dose used prior to the addition of cyclosporine. If cyclosporine is discontinued, the original encorafenib dose may be resumed after 3 to 5 elimination half-lives of cyclosporine. Encorafenib is a CYP3A4 substrate; cyclosporine is a moderate CYP3A4 inhibitor. Coadministration of a moderate CYP3A4 inhibitor with a single 50 mg dose of encorafenib (0.1 times the recommended dose) increased the encorafenib AUC and Cmax by 2-fold and 45%, respectively.
    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.
    Eplerenone: (Major) Do not exceed an eplerenone dose of 25 mg PO once daily if given concurrently with a CYP3A4 inhibitor in a post-myocardial infarction patient with heart failure. In patients with hypertension receiving a concurrent CYP3A4 inhibitor, 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. In addition, measure serum creatinine and serum potassium within 3 to 7 days of initiating a CYP3A4 inhibitor and periodically thereafter. Eplerenone is a CYP3A4 substrate. Cyclosporine is a CYP3A4 inhibitor. Coadministration with moderate CYP3A4 inhibitors increased eplerenone exposure by 100% to 190%. Increased eplerenone concentrations may lead to a risk of developing hyperkalemia and hypotension.
    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.
    Ertugliflozin; Metformin: (Moderate) Patients should be monitored for worsening glycemic control if therapy with cyclosporine is initiated in patients receiving antidiabetic agents. Cyclosporine has been reported to cause hyperglycemia or exacerbate diabetes mellitus; this effect appears to be dose-related and caused by direct beta-cell toxicity. Also, any drug that deteriorates the renal status of the patient is likely to alter metformin concentrations in the body, so renal function should be carefully monitored during the use of cyclosporine and metformin together.
    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. If cyclosporine is discontinued, increase everolimus to its original dose after 3 days. For patients with subependymal giant cell astrocytoma (SEGA) with TSC or TSC-associated partial-onset seizures, reduce the daily dose by 50%. Change to every other day dosing if the reduced dose is lower than the lowest available strength. If cyclosporine is discontinued, increase everolimus to its original dose after 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.
    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.
    Gallium Ga 68 Dotatate: (Major) Avoid use of mannitol and cyclosporine, if possible. Concomitant administration of nephrotoxic drugs, such as cyclosporine, increases the risk of renal failure after administration of mannitol.
    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.
    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) Patients should be monitored for worsening glycemic control if therapy with cyclosporine is initiated in patients receiving antidiabetic agents. Cyclosporine has been reported to cause hyperglycemia or exacerbate diabetes mellitus; this effect appears to be dose-related and caused by direct beta-cell toxicity.
    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) Patients should be monitored for worsening glycemic control if therapy with cyclosporine is initiated in patients receiving antidiabetic agents. Cyclosporine has been reported to cause hyperglycemia or exacerbate diabetes mellitus; this effect appears to be dose-related and caused by direct beta-cell toxicity. Also, any drug that deteriorates the renal status of the patient is likely to alter metformin concentrations in the body, so renal function should be carefully monitored during the use of cyclosporine and metformin together.
    Glyburide; Metformin: (Moderate) Patients should be monitored for worsening glycemic control if therapy with cyclosporine is initiated in patients receiving antidiabetic agents. Cyclosporine has been reported to cause hyperglycemia or exacerbate diabetes mellitus; this effect appears to be dose-related and caused by direct beta-cell toxicity. Also, any drug that deteriorates the renal status of the patient is likely to alter metformin concentrations in the body, so renal function should be carefully monitored during the use of cyclosporine and metformin together.
    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) If golimumab is initiated or discontinued in a patient taking cyclosporine, monitor the cyclosporine concentration; cyclosporine dose adjustment may be needed. Monitor closely for additive immunosuppression and for infection. Patients receiving immunosuppressives along with golimumab may be at a greater risk of developing an infection. 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.
    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.
    Guaifenesin; Hydrocodone: (Moderate) Concomitant use of hydrocodone with cyclosporine may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of cyclosporine could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If cyclosporine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Cyclosporine is a moderate inhibitor of CYP3A4.
    Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with cyclosporine may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of cyclosporine could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If cyclosporine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Cyclosporine is a moderate inhibitor of CYP3A4.
    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.
    Homatropine; Hydrocodone: (Moderate) Concomitant use of hydrocodone with cyclosporine may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of cyclosporine could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If cyclosporine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Cyclosporine is a moderate inhibitor of CYP3A4.
    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: (Moderate) Concomitant use of hydrocodone with cyclosporine may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of cyclosporine could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If cyclosporine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Cyclosporine is a moderate inhibitor of CYP3A4.
    Hydrocodone; Ibuprofen: (Moderate) Concomitant use of hydrocodone with cyclosporine may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of cyclosporine could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If cyclosporine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Cyclosporine is a moderate inhibitor of CYP3A4. (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.
    Hydrocodone; Phenylephrine: (Moderate) Concomitant use of hydrocodone with cyclosporine may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of cyclosporine could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If cyclosporine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Cyclosporine is a moderate inhibitor of CYP3A4.
    Hydrocodone; Potassium Guaiacolsulfonate: (Moderate) Concomitant use of hydrocodone with cyclosporine may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of cyclosporine could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If cyclosporine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Cyclosporine is a moderate inhibitor of CYP3A4.
    Hydrocodone; Potassium Guaiacolsulfonate; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with cyclosporine may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of cyclosporine could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If cyclosporine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Cyclosporine is a moderate inhibitor of CYP3A4.
    Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with cyclosporine may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of cyclosporine could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If cyclosporine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Cyclosporine is a moderate inhibitor of CYP3A4.
    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) If coadministered with cyclosporine, reduce the ibrutinib dose to 280 mg/day PO for the treatment of B-cell malignancies. Resume ibrutinib at the previous dose if cyclosporine is discontinued. Initiate ibrutinib at the recommended dose of 420 mg/day PO for the treatment of chronic graft-versus-host disease. Monitor patients for ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection); interruption of ibrutinib therapy or a dose reduction may be necessary in patients who develop severe toxicity. 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.
    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.
    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.
    Inotersen: (Moderate) Use caution with concomitant use of inotersen and cyclosporine due to the risk of glomerulonephritis and nephrotoxicity.
    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.
    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) If cyclosporine and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to once daily. Coadministration may increase exposure to both drugs leading to increased or prolonged therapeutic effects and adverse events. More careful monitoring of cyclosporine blood concentrations may be warranted. Ivacaftor is a CYP3A substrate and cyclosporine is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased ivacaftor exposure by 3-fold. In addition, ivacaftor is an inhibitor of CYP3A and P-glycoprotein (P-gp); cyclosporine is a sensitive CYP3A and P-gp substrate.
    Ivosidenib: (Major) Avoid coadministration of ivosidenib with cyclosporine due to increased plasma concentrations of ivosidenib, which increases the risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. Ivosidenib is a CYP3A4 substrate and cyclosporine is a moderate CYP3A4 inhibitor. Coadministration with another moderate CYP3A4 inhibitor is predicted to increase the ivosidenib single-dose AUC to 173% of control based on physiologically-based pharmacokinetic modeling, with no change in Cmax. Multiple doses of the moderate CYP3A4 inhibitor are predicted to increase the ivosidenib steady-state AUC to 152% of control and AUC to 190% of control.
    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.
    Lamivudine; 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.
    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.
    Larotrectinib: (Moderate) Cyclosporine therapeutic drug monitoring is recommended when administered concurrently with larotrectinib. Use of these medications together may result in elevated cyclosporine serum concentrations, causing an increased risk for cyclosporine-related adverse events. Larotrectinib is a weak inhibitor of CYP3A4, an isoenzyme responsible for the metabolism of cyclosporine.
    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.
    Letermovir: (Major) Decrease the dose of letermovir to 240 mg once daily if coadministered with cyclosporine. Frequently monitor cyclosporine whole blood concentrations during treatment and after discontinuation of letermovir and adjust the dose of cyclosporine accordingly. Coadministration result in increased exposure to both drugs. If cyclosporine is initiated after starting letermovir, decrease the next dose of letermovir to 240 mg once daily. If cyclosporine is discontinued after starting letermovir, increase the next dose of letermovir to 480 mg once daily. If cyclosporine dosing is interrupted due to high cyclosporine concentrations, no dose adjustment of letermovir is needed.
    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.
    Levothyroxine; Liothyronine (Porcine): (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.
    Levothyroxine; Liothyronine (Synthetic): (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; Metformin: (Moderate) Patients should be monitored for worsening glycemic control if therapy with cyclosporine is initiated in patients receiving antidiabetic agents. Cyclosporine has been reported to cause hyperglycemia or exacerbate diabetes mellitus; this effect appears to be dose-related and caused by direct beta-cell toxicity. Also, any drug that deteriorates the renal status of the patient is likely to alter metformin concentrations in the body, so renal function should be carefully monitored during the use of cyclosporine and metformin together.
    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.
    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.
    Lorlatinib: (Moderate) Closely monitor cyclosporine levels and adjust the dose of cyclosporine as appropriate if coadministration with lorlatinib is necessary. Cyclosporine is extensively metabolized by CYP3A4 and has a narrow therapeutic index; lorlatinib is a moderate CYP3A4 inducer.
    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) If cyclosporine and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to once daily. Coadministration may increase exposure to both drugs leading to increased or prolonged therapeutic effects and adverse events. More careful monitoring of cyclosporine blood concentrations may be warranted. Ivacaftor is a CYP3A substrate and cyclosporine is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased ivacaftor exposure by 3-fold. In addition, ivacaftor is an inhibitor of CYP3A and P-glycoprotein (P-gp); cyclosporine is a sensitive CYP3A and P-gp substrate.
    Mannitol: (Major) Avoid use of mannitol and cyclosporine, if possible. Concomitant administration of nephrotoxic drugs, such as cyclosporine, increases the risk of renal failure after administration of mannitol.
    Maraviroc: (Moderate) Use caution and closely monitor for increased adverse effects during concurrent administration of maraviroc and cyclosporine as increased maraviroc concentrations may occur. Maraviroc is a substrate of CYP3A, P-glycoprotein (P-gp), organic anion-transporting polypeptide (OATP1B), and multidrug resistance-associated protein (MRP2). Cyclosporine is a CYP3A4, P-gp, OATP1B1, and MRP2 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) Patients should be monitored for worsening glycemic control if therapy with cyclosporine is initiated in patients receiving antidiabetic agents. Cyclosporine has been reported to cause hyperglycemia or exacerbate diabetes mellitus; this effect appears to be dose-related and caused by direct beta-cell toxicity. Also, any drug that deteriorates the renal status of the patient is likely to alter metformin concentrations in the body, so renal function should be carefully monitored during the use of cyclosporine and metformin together.
    Metformin; Pioglitazone: (Moderate) Patients should be monitored for worsening glycemic control if therapy with cyclosporine is initiated in patients receiving antidiabetic agents. Cyclosporine has been reported to cause hyperglycemia or exacerbate diabetes mellitus; this effect appears to be dose-related and caused by direct beta-cell toxicity. (Moderate) Patients should be monitored for worsening glycemic control if therapy with cyclosporine is initiated in patients receiving antidiabetic agents. Cyclosporine has been reported to cause hyperglycemia or exacerbate diabetes mellitus; this effect appears to be dose-related and caused by direct beta-cell toxicity. Also, any drug that deteriorates the renal status of the patient is likely to alter metformin concentrations in the body, so renal function should be carefully monitored during the use of cyclosporine and metformin together.
    Metformin; Repaglinide: (Major) Use of cyclosporine with repaglinide results in increased repaglinide exposure and an increased risk for hypoglycemia. Limit the repaglinide daily dose to 6 mg/day and increase the frequency of glucose monitoring. Cyclosporine has additionally been associated with hyperglycemia and may independently alter blood glucose, via a directe effect on beta cells in the pancreas. Monitor closely for alterations in glycemic control. Cyclosporine inhibits the metabolism of repaglinide by inhibiting the drug transporter OATP1B1, which is an active hepatic uptake transporter, and also inhibits CYP3A4. In a drug interaction study, cyclosporine increased low-dose repaglinide exposures by 2.5 fold. Increased repaglinide concentrations were also noted among healthy patients who took oral cyclosporine 100 mg daily for 2 days; after a single 0.25 mg repaglinide dose, the mean AUC for repaglinide increased 244% (range, 119% to 533%) as compared with control data. (Moderate) Patients should be monitored for worsening glycemic control if therapy with cyclosporine is initiated in patients receiving antidiabetic agents. Cyclosporine has been reported to cause hyperglycemia or exacerbate diabetes mellitus; this effect appears to be dose-related and caused by direct beta-cell toxicity. Also, any drug that deteriorates the renal status of the patient is likely to alter metformin concentrations in the body, so renal function should be carefully monitored during the use of cyclosporine and metformin together.
    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) Patients should be monitored for worsening glycemic control if therapy with cyclosporine is initiated in patients receiving antidiabetic agents. Cyclosporine has been reported to cause hyperglycemia or exacerbate diabetes mellitus; this effect appears to be dose-related and caused by direct beta-cell toxicity. Also, any drug that deteriorates the renal status of the patient is likely to alter metformin concentrations in the body, so renal function should be carefully monitored during the use of cyclosporine and metformin together.
    Metformin; Saxagliptin: (Moderate) Patients should be monitored for worsening glycemic control if therapy with cyclosporine is initiated in patients receiving antidiabetic agents. Cyclosporine has been reported to cause hyperglycemia or exacerbate diabetes mellitus; this effect appears to be dose-related and caused by direct beta-cell toxicity. Also, any drug that deteriorates the renal status of the patient is likely to alter metformin concentrations in the body, so renal function should be carefully monitored during the use of cyclosporine and metformin together.
    Metformin; Sitagliptin: (Moderate) Patients should be monitored for worsening glycemic control if therapy with cyclosporine is initiated in patients receiving antidiabetic agents. Cyclosporine has been reported to cause hyperglycemia or exacerbate diabetes mellitus; this effect appears to be dose-related and caused by direct beta-cell toxicity. Also, any drug that deteriorates the renal status of the patient is likely to alter metformin concentrations in the body, so renal function should be carefully monitored during the use of cyclosporine and metformin together.
    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) Monitor serum concentrations of cyclosporine when coadministered with systemic metronidazole. Concomitant use with metronidazole may increase the serum concentrations of cyclosporine; thereby, increasing the risk of side effects. Also, medications with significant alcohol content should not be ingested during therapy with metronidazole and should be avoided for 3 days after metronidazole 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: (Severe) Coadministration of cyclosporine is contraindicated when mifepristone is used chronically, such as in the treatment of Cushing's syndrome. Mifepristone, a CYP3A4 inhibitor, is likely to increase cyclosporine concentrations and adverse effects, since cyclosporine is a CYP3A4 substrate with a narrow therapeutic index. Due to the slow elimination of mifepristone from the body, such interactions may be observed for a prolonged period after mifepristone administration.
    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.
    Naloxegol: (Major) Avoid concomitant administration of naloxegol and cyclosporine due to the potential for increased naloxegol exposure. If coadministration cannot be avoided, decrease the naloxegol dosage to 12.5 mg once daily and monitor for adverse reactions including opioid withdrawal symptoms such as hyperhidrosis, chills, diarrhea, abdominal pain, anxiety, irritability, and yawning. Naloxegol is a CYP3A4 substrate; cyclosporine is a moderate CYP3A4 inhibitor. Coadministration with another moderate CYP3A4 inhibitor increased naloxegol exposure by approximately 3.4-fold.
    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) Patients should be monitored for worsening glycemic control if therapy with cyclosporine is initiated in patients receiving antidiabetic agents. Cyclosporine has been reported to cause hyperglycemia or exacerbate diabetes mellitus; this effect appears to be dose-related and caused by direct beta-cell toxicity.
    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; nicardipine is an inhibitor of CYP3A4.
    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 cyclosporine, a CYP3A4 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) Dual inhibitors of P-glycoprotein (P-gp) and CYP3A4, such as cyclosporine, are expected to increase the exposure and clinical effect of nintedanib. If use together is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity (nausea, vomiting, diarrhea, abdominal pain, loss of appetite), headache, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of nintedanib therapy may be necessary. Cyclosporine is a moderate inhibitor of both P-gp and CYP3A4; nintedanib is a P-gp substrate and a minor CYP3A4 substrate. In drug interactions studies, administration of nintedanib with a dual P-gp and CYP3A4 inhibitor increased nintedanib AUC by 60%.
    Nisoldipine: (Major) Avoid coadministration of nisoldipine with cyclosporine due to increased plasma concentrations of nisoldipine. If coadministration is unavoidable, monitor blood pressure closely during concurrent use of these medications. Nisoldipine is a CYP3A4 substrate and cyclosporine is a CYP3A4 inhibitor.
    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.
    Obeticholic Acid: (Major) Avoid coadministration of obeticholic acid, an inhibitor of the bile salt efflux pump (BSEP) with other BSEP inhibitors, such as cyclosporine; if coadministration is necessary, monitor serum transaminases and bilirubin. Concomitant medications that inhibit canalicular membrane bile acid transporters such as the BSEP may exacerbate accumulation of conjugated bile salts including taurine conjugate of obeticholic acid in the liver and result in clinical symptoms.
    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.
    Osimertinib: (Moderate) Monitor cyclosporine levels if coadministration with osimertinib is necessary; adjust the dose of cyclosporine if clinically appropriate. Cyclosporine is a P-glycoprotein (P-gp) substrate and osimertinib is a P-gp inhibitor. Concomitant use may increase cyclosporine exposure.
    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: (Moderate) Monitor cyclosporine levels and watch for cyclosporine-related adverse reactions if coadministration with palbociclib is necessary. Palbociclib is a weak time-dependent inhibitor of CYP3A while cyclosporine is a CYP3A4 substrate with narrow therapeutic index.
    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. In addition, amlodipine is a weak inhibitor of CYP3A4; cyclosporine is a substrate with a narrow therapeutic index. 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.
    Pioglitazone: (Moderate) Patients should be monitored for worsening glycemic control if therapy with cyclosporine is initiated in patients receiving antidiabetic agents. Cyclosporine has been reported to cause hyperglycemia or exacerbate diabetes mellitus; this effect appears to be dose-related and caused by direct beta-cell toxicity.
    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.
    Pitavastatin: (Severe) Coadministration of pitavastatin and cyclosporine is contraindicated due to significantly increased pitavastatin exposure and risk for myopathy or rhabdomyolysis. In a drug interaction study, concurrent use of cyclosporine increased the pitavastatin Cmax and AUC by 6.6- and 4.6-fold, respectively.
    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: (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 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) Patients should be monitored for worsening glycemic control if therapy with cyclosporine is initiated in patients receiving antidiabetic agents. Cyclosporine has been reported to cause hyperglycemia or exacerbate diabetes mellitus; this effect appears to be dose-related and caused by direct beta-cell toxicity.
    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.
    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) Use of cyclosporine with repaglinide results in increased repaglinide exposure and an increased risk for hypoglycemia. Limit the repaglinide daily dose to 6 mg/day and increase the frequency of glucose monitoring. Cyclosporine has additionally been associated with hyperglycemia and may independently alter blood glucose, via a directe effect on beta cells in the pancreas. Monitor closely for alterations in glycemic control. Cyclosporine inhibits the metabolism of repaglinide by inhibiting the drug transporter OATP1B1, which is an active hepatic uptake transporter, and also inhibits CYP3A4. In a drug interaction study, cyclosporine increased low-dose repaglinide exposures by 2.5 fold. Increased repaglinide concentrations were also noted among healthy patients who took oral cyclosporine 100 mg daily for 2 days; after a single 0.25 mg repaglinide dose, the mean AUC for repaglinide increased 244% (range, 119% to 533%) as compared with control data.
    Revefenacin: (Major) Coadministration of revefenacin with cyclosporine is not recommended because it could lead to an increase in systemic exposure of the active metabolite of revefenacin and an increased potential for anticholinergic adverse effects. The active metabolite of revefenacin is a substrate of OATP1B1 and OATP1B3; cyclosporine is an inhibitor of OATP1B1/1B3.
    Ribociclib: (Moderate) Monitor cyclosporine concentrations if coadministration with ribociclib is necessary; adjust the dose of cyclosporine if necessary. Cyclosporine is a CYP3A4 substrate with a narrow therapeutic index and ribociclib is a strong CYP3A4 inhibitor.
    Ribociclib; Letrozole: (Moderate) Monitor cyclosporine concentrations if coadministration with ribociclib is necessary; adjust the dose of cyclosporine if necessary. Cyclosporine is a CYP3A4 substrate with a narrow therapeutic index and ribociclib is a strong CYP3A4 inhibitor.
    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