CycloSPORINE (Systemic)

Drug class: Antineoplastic Agents

Usage of CycloSPORINE (Systemic)

Renal, Hepatic, and Cardiac Allotransplantation

Prevention of allograft rejection in kidney, liver, or heart transplant patients.

Treatment of chronic allograft rejection in patients previously treated with other immunosuppressive agents (e.g., azathioprine).

Manufacturers state that corticosteroid therapy should be used concomitantly with IV cyclosporine and conventional (nonmodified) oral formulations (Sandimmune) and be administered concomitantly, at least initially, with modified oral formulations (Gengraf or Neoral). Alternatively, some clinicians believe that routine concomitant use of corticosteroids during cyclosporine therapy is not necessary and that their use should be reserved for acute periods of allograft rejection.

Bone Marrow Allotransplantation

Prevention of acute graft-vs-host disease following bone marrow transplantation† [off-label].

Has been used for the treatment of moderate to severe, acute graft-vs-host disease† [off-label] following bone marrow transplantation.

Rheumatoid Arthritis

Management of the active stage of severe rheumatoid arthritis in selected adults who have an inadequate response to methotrexate; may be used in combination with methotrexate in those who do not respond adequately to methotrexate monotherapy.

Treatment of rheumatoid arthritis in adults who had an insufficient response to or did not tolerate NSAIAs† [off-label] and other DMARDs† [off-label].

Psoriasis

Treatment of immunocompetent adults with severe (i.e., extensive and/or disabling), recalcitrant plaque psoriasis that is not adequately responsive to ≥1 systemic therapy (e.g., retinoids, methotrexate, PUVA) or in patients for whom other systemic therapy is contraindicated or cannot be tolerated.

Crohn’s Disease

Has been used with some success in the management of refractory inflammatory, fistulizing, and chronically active Crohn’s disease† [off-label].

Relate drugs

How to use CycloSPORINE (Systemic)

General

Transplant Patients

  • Patients should be managed using a center experienced in the use and interpretation of cyclosporine concentrations and their application to dosage adjustment; however, if management with such a center is not possible, consult specialized references for general monitoring and dosing guidelines.
  • Frequency of monitoring blood cyclosporine concentrations depends in part on the time that has elapsed since transplantation, intercurrent illness, and concomitant drugs. Monitor concentrations whenever clinical manifestations suggest that dosage adjustment might be necessary.
  • Some clinicians monitor cyclosporine concentrations frequently (e.g., 3 or 4 times weekly to daily) during the early posttransplantation period, reducing monitoring to once monthly by 6–12 months after transplantation. (See Monitoring of Cyclosporine Concentrations under Cautions.)

    • Rheumatoid Arthritis

  • Therapeutic response generally is apparent after 4–8 weeks of cyclosporine therapy. If benefit is not apparent by week 16, discontinue the drug.
  • Prior to initiation of cyclosporine therapy, perform careful physical examination of the patient, including measurement of BP on ≥2 occasions and determination of Scr twice for a baseline.
  • Monitor BP and Scr every 2 weeks during the first 3 months of therapy; thereafter, monitor BP and Scr monthly in stable patients. Always monitor Scr and BP following modification of concomitant NSAIA therapy, either an increase in dosage and initiation of new NSAIA.
  • Monitor CBC and liver function at least monthly in patients receiving cyclosporine and methotrexate concomitantly.
  • Limited experience with long-term cyclosporine therapy for rheumatoid arthritis. Following discontinuance of the drug, control of the disease usually wanes within 4 weeks.

    • Psoriasis

  • Some improvement in clinical manifestations generally is observed after 2 weeks. Satisfactory control and stabilization of psoriasis may require 12–16 weeks of therapy.
  • Prior to initiation of cyclosporine therapy, perform careful dermatologic and physical examination of the patient, including measurement of BP on ≥2 occasions. Obtain baseline measurements for Scr (on 2 occasions), BUN, CBC, and serum concentrations of magnesium, potassium, uric acid, and lipids.
  • Evaluate BP every 2 weeks during the first 3 months of therapy; thereafter, evaluate BP monthly in stable patients or more frequently if dosage is adjusted.
  • Monitor Scr and BUN every 2 weeks during the first 3 months of therapy; thereafter, monitor these values monthly in stable patients.
  • Monitor CBC and serum concentrations of magnesium, potassium, uric acid, and lipids every 2 weeks during the first 3 months of therapy; thereafter, monitor these values monthly in stable patients or more frequently if dosage is adjusted.
  • Discontinuance generally results in relapse within several weeks.

    • Administration

    Administer orally as conventional (nonmodified) or modified formulations or by IV infusion.

    Oral Administration

    Modified formulations of cyclosporine (Gengraf, Neoral), both as the solution and in the liquid-filled capsules, have increased oral bioavailability compared with the conventional oral solution and liquid-filled capsules of the drug (Sandimmune); conventional (nonmodified) and modified formulations are not bioequivalent. (See Pharmacokinetics.) Any change in the formulation of cyclosporine should be performed with caution and under the supervision of a clinician since dosage adjustment may be necessary.

    Conventional (nonmodified) capsules of Sandimmune are bioequivalent to Sandimmune oral solution.

    Modified oral capsules of Neoral are bioequivalent to Neoral oral solution. Modified oral capsules of Gengraf are bioequivalent to Gengraf oral solution. The Neoral and Gengraf modified oral formulations are bioequivalent to each other.

    Conventional (Nonmodified) Capsules (Sandimmune)

    Administer orally once daily on a consistent schedule with regard to time of day and in relation to meals.

    Modified Capsules (Gengraf and Neoral)

    Administer orally twice daily on a consistent schedule with regard to time of day and in relation to meals.

    Conventional (Nonmodified) Oral Solution (Sandimmune)

    Administer orally once daily on a consistent schedule with regard to time of day and in relation to meals.

    Measure dose carefully with the graduated dosing syringe provided by the manufacturer. Remove the protective cover of the dosing syringe and withdraw the prescribed dose from the bottle and transfer to a glass (not plastic) container of suitable beverage. Use of a glass container may minimize adherence of the drug to the container walls. Do not use styrofoam containers; they are porous and may absorb the drug.

    To increase palatability, mix the measured dose with milk, chocolate milk, or orange juice, preferably at room temperature but not hot. Avoid frequent changing of the diluting beverage. Stir well and administer immediately. After the initial diluted solution has been administered, rinse the container with additional diluent (e.g., juice) and administer the remaining mixture to ensure that the entire dose has been given.

    After use, dry the outside of the dosing syringe with a clean, dry towel and replace the protective cover. Do not rinse the dosing syringe with water, alcohol, or other cleaning agents. If the syringe requires cleaning, allow it to dry completely before reuse, since introduction of water into the product will cause variation in dose.

    Modified Oral Solution (Gengraf and Neoral)

    Administer orally twice daily on a consistent schedule with regard to time of day and in relation to meals.

    Prepare and administer Gengraf or Neoral modified oral solution in a similar manner to the conventional (nonmodified) oral solution; however, the dosing syringe for Gengraf does not have a protective cover.

    To increase palatability, mix the measured dose with orange or apple juice at room temperature; do not use milk for dilution, since the resultant mixture can be unpalatable.

    After use of Gengraf oral solution, dry the outside of the dosing syringe with a clean towel and store the syringe in a clean, dry place.

    IV Administration

    For solution and drug compatibility information, see Compatibility under Stability.

    Reserve IV administration for patients in whom oral administration is not tolerated or is contraindicated (due to risk of anaphylaxis with IV administration).

    Switch patients to an oral formulation as soon as possible after surgery.

    Cyclosporine concentrate for injection must be diluted prior to IV infusion.

    Dilution

    Dilute each mL of the injection concentrate in 20–100 mL of 0.9% sodium chloride or 5% dextrose injection immediately before administration. (See Parenteral under Storage.)

    Rate of Administration

    Transplant patients: Infuse over 2–6 hours.

    Crohn’s disease: Infuse over 24 hours.

    Dosage

    Individualize dosage of cyclosporine.

    Pediatric Patients

    Transplant Recipients Conventional Capsules and Oral Solution (Sandimmune) Oral

    Initially, 15 mg/kg administered as a single dose 4–12 hours before transplantation. Lower initial dosages (e.g., 10–14 mg/kg daily) may be preferred for renal allotransplantation.

    Postoperatively, continue initial dosage once daily for 1–2 weeks; then, taper by 5% per week (over about 6–8 weeks) to a maintenance dosage of 5–10 mg/kg daily. Maintenance dosages have been tapered to as low as 3 mg/kg daily in selected renal allograft recipients without an apparent increase in graft rejection rate.

    In several studies, pediatric patients have required and tolerated higher dosages.

    Modified Capsules and Oral Solution (Gengraf and Neoral) Oral

    Newly transplanted patients may receive the modified oral formulation at the same initial dose as for the conventional (nonmodified) oral formulation.

    Suggested initial dosages (based on a 1994 survey of average dosages of conventional formulations): 9 mg/kg for renal allograft recipients, 8 mg/kg for hepatic allograft recipients, and 7 mg/kg for cardiac allograft recipients administered in 2 equally divided doses daily. Give initial dose 4–12 hours before transplantation or postoperatively.

    Adjust dosage to attain a predefined blood cyclosporine concentration. Titrate dosage based on clinical evaluation of rejection and patient tolerability. Lower maintenance dosages may be possible with modified oral formulations compared with conventional (nonmodified) formulations.

    Conversion from Conventional Oral Formulations (Sandimmune) to Modified Oral Formulations (Gengraf, Neoral) Oral

    Initial dosage of the modified formulation should be the same as the previous dosage of the conventional (nonmodified) oral formulation (1:1 conversion). Adjust dosage to attain trough blood concentrations that are similar to those achieved with the conventional oral formulation; however, attainment of therapeutic trough concentrations will result in greater exposure (AUC) to cyclosporine than would occur with the conventional oral formulation.

    Monitor trough blood cyclosporine concentrations every 4–7 days until they are the same as they were with the conventional (nonmodified) oral formulation. Monitor patient safety by determining Scr and BP every 2 weeks for the first 2 months after the conversion. Adjust dosage if trough blood concentrations are outside of the desired range and/or measures of safety worsen. Dosage titration should be guided by trough blood concentrations, tolerability, and clinical response.

    Monitor trough blood concentrations closely following conversion from conventional (nonmodified) oral formulations to modified oral formulations in patients with suspected poor absorption of cyclosporine from the conventional formulations. Measure trough blood concentrations in these patients at least twice weekly (daily in patients receiving >10 mg/kg daily) until the trough blood cyclosporine concentration is maintained in the desired range, since higher bioavailability from the modified oral formulations may result in excessive trough concentrations after conversion to this formulation. Use caution with conversional dosages >10 mg/kg daily.

    Concentrate for Injection IV

    Initially, 5–6 mg/kg as a single dose 4–12 hours before transplantation. Postoperatively, 5–6 mg/kg once daily until the patient is able to tolerate oral administration. Pediatric patients may require higher dosages.

    In patients unable to take cyclosporine orally, may administer the drug by IV infusion at about one-third the recommended oral dosage.

    Adults

    Transplant Recipients Conventional Capsules and Oral Solution (Sandimmune) Oral

    Initially, 15 mg/kg administered as a single dose 4–12 hours before transplantation. Lower initial dosages (e.g., 10–14 mg/kg daily) may be preferred for renal allotransplantation.

    Postoperatively, continue initial dosage once daily for 1–2 weeks; then, taper by 5% per week (over about 6–8 weeks) to a maintenance dosage of 5–10 mg/kg daily. Maintenance dosages have been tapered to as low as 3 mg/kg daily in selected renal allograft recipients without an apparent increase in graft rejection rate.

    Modified Capsules and Oral Solution (Gengrafand Neoral) Oral

    Newly transplanted patients may receive the modified oral formulation at the same initial dose as for the conventional (nonmodified) oral formulation.

    Suggested initial dosages (based on a 1994 survey of average dosages of conventional formulations): 9 mg/kg for renal allograft recipients, 8 mg/kg for hepatic allograft recipients, and 7 mg/kg for cardiac allograft recipients administered in 2 equally divided doses daily. Give initial dose 4–12 hours before transplantation or postoperatively.

    Adjust dosage to attain a predefined blood cyclosporine concentration. Titrate dosage based on clinical evaluation of rejection and patient tolerability. Lower maintenance dosages may be possible with modified oral formulations compared with conventional (nonmodified) formulations.

    Conversion from Conventional Oral Formulations (Sandimmune) to Modified Oral Formulations (Gengraf, Neoral) Oral

    Initial dosage of the modified oral formulation should be the same as the previous dosage of the conventional (nonmodified) oral formulation (1:1 conversion). Adjust dosage to attain trough blood concentrations that are similar to those achieved with the conventional oral formulation; however, attainment of therapeutic trough concentrations will result in greater exposure (AUC) to cyclosporine than would occur with conventional oral formulation.

    Monitor trough blood cyclosporine concentrations every 4–7 days until they are the same as they were with the conventional (nonmodified) oral formulation. Monitor patient safety by determining Scr and BP every 2 weeks for the first 2 months after the conversion. Adjust dosage if trough blood concentrations are outside of the desired range and/or measures of safety worsen. Dosage titration should be guided by trough blood concentrations, tolerability, and clinical response.

    Monitor trough blood concentrations closely following conversion from conventional (nonmodified) oral formulations to modified oral formulations in patients with suspected poor absorption of cyclosporine from the conventional formulations. Measure trough blood concentrations in these patients at least twice weekly (daily in patients receiving >10 mg/kg daily) until the trough blood cyclosporine concentration is maintained in the desired range, since higher bioavailability from the modified oral formulations may result in excessive trough concentrations after conversion to this formulation. Use caution with conversional dosages >10 mg/kg daily.

    Concentrate for Injection IV

    Initially, 5–6 mg/kg as a single dose 4–12 hours before transplantation. Postoperatively, 5–6 mg/kg once daily until the patient is able to tolerate oral administration.

    In patients unable to take cyclosporine orally, may administer the drug by IV infusion at about one-third the recommended oral dosage.

    Rheumatoid Arthritis Modified Capsules and Oral Solution (Gengraf and Neoral) Oral

    Initially, 2.5 mg/kg daily in 2 divided doses. If response is insufficient but tolerance to the drug is good (including Scr <30% above baseline), may increase dosage by 0.5–0.75 mg/kg daily after 8 weeks and, again, after 12 weeks (maximum 4 mg/kg daily).

    Reduce dosage by 25–50% to control adverse effects (e.g., hypertension, clinically important laboratory abnormalities) that occur. Manage persistent hypertension by further reduction of cyclosporine dosage or use of antihypertensive agents. Discontinue if adverse effects are severe or do not respond to dosage reduction.

    Psoriasis Modified Capsules and Oral Solution (Gengraf and Neoral) Oral

    Initially, 1.25 mg/kg twice daily. Continue for ≥4 weeks unless prohibited by adverse effects. If initial dosage does not produce substantial clinical improvement within 4 weeks, increase dosage by approximately 0.5 mg/kg daily once every 2 weeks (maximum 4 mg/kg daily) based on the patient’s tolerance and response.

    Use lowest dosage that maintains an adequate response (not necessarily total clearance of psoriasis). Dosages <2.5 mg/kg daily may be equally effective.

    Decrease dosage by 25–50% to control adverse effects (e.g., hypertension, clinically important laboratory test abnormalities) that occur. Discontinue if adverse effects are severe or do not respond to dosage reduction.

    Crohn’s Disease Conventional (Nonmodified) Capsules (Sandimmune) Oral

    3.8–8 mg/kg daily has been used.

    Concentrate for Injection IV

    Initially, 4 mg/kg daily for about 2–10 days has been used. Patients who respond to initial IV regimen may be switched to oral therapy.

    Prescribing Limits

    Adults

    Rheumatoid Arthritis Modified Capsules and Oral Solution (Gengraf and Neoral) Oral

    Maximum 4 mg/kg daily.

    Psoriasis Modified Capsules and Oral Solution (Gengraf and Neoral) Oral

    Maximum 4 mg/kg daily.

    Special Populations

    Renal Impairment

    Monitor renal function closely; frequent dosage adjustments may be necessary.

    Contraindicated in rheumatoid arthritis or psoriasis patients with abnormal renal function.

    Warnings

    Contraindications

  • Known hypersensitivity to cyclosporine or to any ingredient in the formulation.
  • Rheumatoid arthritis or psoriasis patients with abnormal renal function, uncontrolled hypertension, or malignancies.
  • Concurrent therapy with methotrexate or other immunosuppressive agents, coal tar, PUVA, UVB, or other radiation in the management of psoriasis.

    • Warnings/Precautions

    Warnings

    Renal Effects

    Possible nephrotoxicity; elevations of BUN and Scr appear to be dose related, may be associated with high trough concentrations of the drug, and usually are reversible upon discontinuance of the drug.

    In patients with psoriasis, nephrotoxicity may occur at recommended dosages, with increasing risk as dosage and duration of therapy increase.

    Risk of nephrotoxicity may be increased in patients receiving other potentially nephrotoxic agents. (See Interactions.)

    Monitor renal function carefully. Potential for structural kidney damage and permanent renal dysfunction in the absence of appropriate monitoring and dosage adjustment.

    Carefully evaluate renal allograft recipients who develop increased BUN and Scr before adjusting cyclosporine dosage; these increases do not necessarily indicate the occurrence of organ rejection. If elevations of BUN and Scr are persistently high and unresponsive to adjustment of cyclosporine dosage, consider switching to other immunosuppressive therapy. If severe, intractable renal allograft rejection occurs and does not respond to rescue therapy with corticosteroids and monoclonal antibodies, it may be preferable to switch to alternative immunosuppressive therapy or to allow the kidney to be rejected and removed rather than to increase the cyclosporine dosage to an excessive level in an attempt to reverse the rejection episode.

    Possible hyperkalemia (may be associated with hyperchloremic metabolic acidosis), hypomagnesemia, decreased serum bicarbonate concentration, and hyperuricemia.

    Monitoring of Cyclosporine Concentrations

    Results obtained with various assay methods and biologic fluids (blood versus plasma or serum) are not interchangeable; consult specialized references and/or the assay manufacturer’s labeling for interpretative guidelines.

    Monitor trough (predose) cyclosporine concentrations. Standardize the sampling time for each patient; consider the effect of once- versus twice-daily dosing and the time for pharmacokinetic reequilibration to steady state following dosage changes.

    Monitor predose cyclosporine concentrations periodically in patients receiving conventional (nonmodified) oral formulations (Sandimmune capsules or solution), since absorption is reportedly erratic during long-term therapy.

    Monitoring may be especially important in hepatic allograft recipients, since absorption of the drug in these patients may be erratic, especially during the first few weeks following transplantation (because of surgical techniques [e.g., bile duct management] or surgically induced liver dysfunction).

    Routinely monitor blood or plasma concentrations in allograft recipients receiving the modified oral formulations (Gengraf, Neoral) and periodically in patients with rheumatoid arthritis being treated with these preparations (to avoid toxicity secondary to high cyclosporine concentrations). In studies in psoriasis patients, cyclosporine concentrations did not correlate well with clinical improvement or adverse effects.

    Monitor cyclosporine concentrations carefully following conversion from conventional (nonmodified) oral formulations to modified formulations. (See Conversion from Conventional Oral Formulations [Sandimmune] to Modified Oral Formulations [Gengraf, Neoral)] under Dosage and Administration.)

    Adjust dosage to avoid toxicity resulting from high blood or plasma concentrations of the drug or to prevent possible organ rejection resulting from low concentrations.

    Hepatic Effects

    Hepatotoxicity reported in patients with kidney, heart, or liver allografts, usually during the first month of therapy when higher dosages are used. Usually reversible following dosage reduction.

    Lymphomas and Other Malignancies

    Possible increased development of lymphoma.

    Manufacturer cautions that although cyclosporine should be administered with corticosteroids, conventional (nonmodified) oral formulations of the drug (Sandimmune) and the concentrate for injection should not be administered concomitantly with other immunosuppressive agents, since increased risk of lymphoma may result. However, the manufacturers state that modified oral formulations of cyclosporine (Gengraf and Neoral) may be administered with other immunosuppressive agents, although the degree of immunosuppression produced may result in an increased risk of lymphoma and other neoplasms.

    Evaluate patients thoroughly for the presence of malignancies before initiating cyclosporine therapy for rheumatoid arthritis, as well as during the treatment course. Concurrent use of cyclosporine and other immunosuppressive agents may increase the risk of malignancies through induction of excessive immunosuppression.

    Possible increased risk of developing malignancies of the skin and lymphoproliferative disorders in patients receiving cyclosporine to treat psoriasis. Evaluate such patients thoroughly before initiating cyclosporine therapy, as well as during the treatment course, for the presence of malignancies; consider that psoriatic plaques may obscure malignant lesions. Avoid concomitant therapy with methotrexate or other immunosuppressive agents, coal tar, PUVA, UVB, or other radiation, due to potential for excessive immunosuppression and increased risk of malignancies. Limit exposure to sunlight or other UV light during cyclosporine therapy.

    Infectious Complications

    Possible increased susceptibility to infection.

    Evaluate psoriasis patients for presence of occult infection prior to and throughout therapy.

    Manufacturer cautions that although cyclosporine should be administered with corticosteroids, conventional (nonmodified) oral formulations of the drug (Sandimmune) and the concentrate for injection should not be administered concomitantly with other immunosuppressive agents, since increased susceptibility to infection may result. However, the manufacturers state that modified oral formulations (Gengraf and Neoral) may be administered with other immunosuppressives, although the degree of immunosuppression produced may result in increased susceptibility to infection.

    Latent Viral Infections

    Increased risk of reactivation of latent viral infections, including BK virus-associated nephropathy (BKVN). Principally observed in renal transplant patients (usually within the first year posttransplantation); may result in severe allograft dysfunction and/or graft loss. Risk appears to correlate with degree of overall immunosuppression rather than use of specific immunosuppressant. Monitor closely for signs of BKVN (e.g., deterioration of renal function); if BKVN develops, institute early treatment, and consider reducing immunosuppressive therapy.

    Bioequivalency of Formulations

    Modified oral formulations of cyclosporine (Gengraf and Neoral liquid-filled capsules and solution) have increased oral bioavailability compared with conventional (nonmodified) oral formulations (Sandimmune liquid-filled capsules and solution); therefore, the modified and conventional (nonmodified) formulations are not bioequivalent and cannot be used interchangeably without appropriate medical supervision. (See Conversion from Conventional Oral Formulations [Sandimmune] to Modified Oral Formulations [Gengraf, Neoral] under Dosage and Administration.)

    For a given trough concentration, cyclosporine exposure will be greater with Gengraf and Neoral preparations than with Sandimmune preparations.

    Conversion from Gengraf or Neoral to Sandimmune preparations using a 1:1 ratio may result in lower blood concentrations; increase monitoring to avoid the potential of underdosing.

    Hematologic Effects

    Possible leukopenia, anemia, and thrombocytopenia.

    Risk of developing syndrome of thrombocytopenia and microangiopathic hemolytic anemia (pathologically similar to hemolytic uremic syndrome); may result in graft failure. Manifestations include thrombosis of renal microvasculature with platelet-fibrin thrombi occluding glomerular capillaries and afferent arterioles, microangiopathic hemolytic anemia, thrombocytopenia, and decreased renal function. Such findings are generalizable to other immunosuppressive agents used after transplantation. Neither the pathogenesis nor optimal management is clear.

    CNS Effects

    Potential for seizures, particularly when used in combination with high-dose corticosteroids.

    Encephalopathy, manifested by impaired consciousness, seizures, visual changes (e.g., blindness), loss of motor function, movement disorders, and psychiatric disturbances, described in patients receiving cyclosporine; in many cases, such manifestations accompanied by white-matter changes. May be associated with high blood or plasma concentrations of the drug, concurrent high-dose corticosteroid therapy, hypertension, and/or hypomagnesemia. May be reversible upon discontinuance of the drug or following dosage reduction.

    Optic disc edema with possible visual impairment reported rarely; occurred more frequently in transplant recipients.

    Sensitivity Reactions

    Anaphylaxis

    Risk of anaphylaxis with IV cyclosporine; reserve for patients unable to tolerate oral formulations of the drug.

    Continuously observe patients for ≥30 minutes following initiation of the IV infusion; closely monitor at frequent intervals thereafter for possible allergic manifestations. Appropriate equipment for maintenance of an adequate airway and other supportive measures and agents for the treatment of anaphylactic reactions (e.g., epinephrine, oxygen) should be readily available.

    If anaphylaxis occurs, discontinue IV infusion immediately and administer appropriate therapy (e.g., epinephrine, oxygen) as indicated.

    General Precautions

    Hypertension

    Mild to moderate hypertension occurs in about 50% of renal transplant recipients and most cardiac transplant patients receiving the drug. Hypertension reported in about 28% of psoriasis patients and systolic hypertension reported in about 33% of rheumatoid arthritis patients receiving the drug.

    Generally develops within a few weeks after beginning cyclosporine therapy and affects both SBP and DBP.

    May respond to dosage reduction and/or antihypertensive therapy, but response to antihypertensive therapy may be variable. Elevated DBP may be more resistant to treatment than elevated SBP.

    Contraindicated in rheumatoid arthritis and psoriasis patients with uncontrolled hypertension.

    Malabsorption Syndromes

    Patients with malabsorption may have difficulty achieving therapeutic concentrations of cyclosporine with conventional (nonmodified) oral formulations (Sandimmune).

    Specific Populations

    Pregnancy

    Category C.

    Lactation

    Distributed into milk; women should not breast-feed infants while receiving the drug.

    Pediatric Use

    No adequate and controlled studies to date; however, cyclosporine has been used in children ≥6 months of age without unusual adverse effects. Modified oral formulations (Gengraf and Neoral) used in children ≥1 year of age.

    Consider the possibility that serious nephrotoxicity, hypertension, and/or seizures may occur.

    Safety and efficacy of cyclosporine for the management of juvenile rheumatoid arthritis or psoriasis in children <18 years of age not established.

    Geriatric Use

    Assess renal function with particular care, due to greater frequency of decreased renal function observed in geriatric patients.

    Patients ≥65 years of age were more likely to develop systolic hypertension while receiving cyclosporine to treat rheumatoid arthritis in clinical studies and also were more likely to have Scr elevations of ≥50% above baseline after 3–4 months of therapy.

    Renal Impairment

    Use with caution; assess renal function prior to and periodically during prolonged therapy. Dosage adjustment may be necessary depending on degree of renal impairment.

    Carefully evaluate renal allograft recipients who develop increased BUN and Scr before initiating adjustment of cyclosporine dosage, since these increases do not necessarily indicate the occurrence of organ rejection.

    Contraindicated in rheumatoid arthritis or psoriasis patients with abnormal renal function.

    Common Adverse Effects

    Transplant recipients: Renal impairment, tremor, hirsutism, hypertension, gum hyperplasia.

    Rheumatoid arthritis: Renal impairment, hypertension, headache, GI disturbances, hirsutism/hypertrichosis.

    Psoriasis: Renal impairment, headache, hypertension, hypertriglyceridemia, hirsutism/hypertrichosis, paresthesia or hyperesthesia, flu-like symptoms, nausea/vomiting, diarrhea, abdominal discomfort, lethargy, musculoskeletal or joint pain.

    What other drugs will affect CycloSPORINE (Systemic)

    Extensively metabolized by CYP3A.

    Drugs Affecting Hepatic Microsomal Enzymes

    CYP3A inhibitors: Potential pharmacokinetic interaction (increased cyclosporine concentrations in biologic fluid).

    CYP3A inducers: Potential pharmacokinetic interaction (decreased cyclosporine concentrations in biologic fluid).

    Nephrotoxic Drugs

    Potentiation of renal dysfunction well substantiated; may be related to nephrotoxic potential of the interacting drug or to accumulation of cyclosporine induced by the interacting drug. Use with caution.

    Specific Drugs and Foods

    Drug or Food

    Interaction

    Comments

    ACE inhibitors

    Possible hyperkalemia

    Caution advised and control of potassium concentrations recommended

    Allopurinol

    Increased plasma or blood concentrations of cyclosporine

    Monitor concentration of cyclosporine; adjust cyclosporine dosage accordingly

    Amiodarone

    Increased plasma or blood concentrations of cyclosporine

    Monitor concentration of cyclosporine; adjust cyclosporine dosage accordingly

    Aminoglycosides (gentamicin, tobramycin)

    Possible additive nephrotoxic effects

    Possible increased risk of acute tubular necrosis in renal allograft recipients

    Use with caution

    Avoid concomitant use in renal allograft recipients

    Amphotericin B

    Possible additive nephrotoxic effects

    If concomitant therapy is necessary, temporarily withhold cyclosporine until trough serum cyclosporine concentration (determined by RIA) is <150 ng/mL; adjust subsequent dosage accordingly

    Angiotensin II receptor blockers

    Possible hyperkalemia

    Caution advised and control of potassium concentrations recommended

    Anticonvulsants (carbamazepine, oxcarbazepine, phenobarbital, phenytoin)

    Decreased plasma or blood concentrations of cyclosporine

    Monitor concentration of cyclosporine; adjust cyclosporine dosage accordingly

    Antifungals, azoles (fluconazole, itraconazole, ketoconazole, voriconazole)

    Increased plasma or blood concentrations of cyclosporine

    Carefully monitor concentration of cyclosporine; adjust cyclosporine dosage accordingly

    Bosentan

    Decreased plasma concentrations of cyclosporine; increased plasma bosentan concentrations

    Concomitant use contraindicated

    Bromocriptine

    Increased plasma or blood concentrations of cyclosporine

    Monitor concentration of cyclosporine; adjust cyclosporine dosage accordingly

    Calcium-channel blocking agents

    Diltiazem, nicardipine, verapamil: Increased plasma or blood concentrations of cyclosporine

    Nifedipine: Frequent gingival hyperplasia

    Diltiazem, nicardipine, verapamil: Monitor concentration of cyclosporine; adjust cyclosporine dosage accordingly

    Ciprofloxacin

    Possible additive nephrotoxic effects

    Use with caution

    Colchicine

    Possible additive nephrotoxic effects; increased plasma or blood concentrations of cyclosporine

    Possible decreased clearance of colchicine increasing the potential for enhanced colchicine toxicity (myopathy, neuropathy)

    Monitor concentration of cyclosporine; adjust cyclosporine dosage accordingly

    Monitor closely for colchicine toxicity; adjust colchicine dosage or discontinue drug as indicated

    Contraceptives, oral

    Increased plasma or blood concentrations of cyclosporine

    Monitor concentration of cyclosporine; adjust cyclosporine dosage accordingly

    Corticosteroids (methylprednisolone, prednisolone)

    Increased plasma or blood concentrations of cyclosporine; possible decreased clearance of prednisolone; seizures reported with combined cyclosporine and high-dose corticosteroid therapy

    Monitor concentration of cyclosporine; adjust cyclosporine dosage accordingly

    Co-trimoxazole

    Possible additive nephrotoxic effects

    Use with caution

    Danazol

    Increased plasma or blood concentrations of cyclosporine

    Monitor concentration of cyclosporine; adjust cyclosporine dosage accordingly

    Digoxin

    Possible decreased volume of distribution and clearance of digoxin; digoxin toxicity reported

    Monitor closely for digoxin toxicity; adjust digoxin dosage accordingly

    Diuretics, potassium-sparing

    Possible hyperkalemia

    Concomitant use not recommended

    Fibric acid derivatives

    Possible additive nephrotoxic effects

    Use with caution

    Grapefruit juice

    Increased oral bioavailability of cyclosporine

    Avoid concomitant use

    Histamine H2-receptor antagonists (cimetidine, ranitidine)

    Possible additive nephrotoxic effects

    HIV protease inhibitors (indinavir, nelfinavir, ritonavir, saquinavir)

    Possible increased plasma or blood concentrations of cyclosporine

    Avoid concomitant use

    Use concomitantly with caution

    HMG CoA reductase inhibitors (statins)(atorvastatin, fluvastatin, lovastatin, pravastatin, simvastatin)

    Decreased clearance of the statin; possible myositis, myolysis, or rhabdomyolysis

    Reduce statin dosage; temporarily withhold or discontinue statin therapy in those with signs/symptoms of myopathy or risk factors predisposing to severe renal injury secondary to rhabdomyolysis

    Imatinib

    Increased plasma or blood concentrations of cyclosporine

    Monitor concentration of cyclosporine; adjust cyclosporine dosage accordingly

    Immunosuppressive agents

    Increased risk of lymphoma and susceptibility to infection

    Avoid concomitant use of conventional (nonmodified) oral formulations or the concentrate for injection with other immunosuppressive agents (except for corticosteroids)

    Modified oral formulations (Gengraf, Neoral) may be administered with other immunosuppressives, although the degree of immunosuppression produced may result in an increased risk of lymphoma and other neoplasms and in susceptibility to infection

    Patients with psoriasis should not receive cyclosporine concomitantly with other immunosuppressive agents since excessive immunosuppression may result

    Macrolides (azithromycin, clarithromycin, erythromycin)

    Increased plasma or blood concentrations of cyclosporine

    Monitor concentration of cyclosporine; adjust cyclosporine dosage accordingly

    Melphalan

    Possible additive nephrotoxic effects

    Use with caution

    Metoclopramide

    Increased plasma or blood concentrations of cyclosporine

    Monitor concentration of cyclosporine; adjust cyclosporine dosage accordingly

    Methotrexate

    Possible increased plasma concentrations of methotrexate and decreased plasma concentrations of 7-hydroxymethotrexate; no apparent effect on blood concentrations of cyclosporine

    Initiate cyclosporine at same initial dosage and range of adjustment as when administered alone

    Generally administer modified formulations of cyclosporine (Gengraf, Neoral) at ≤3 mg/kg daily in patients receiving methotrexate ≤15 mg weekly

    Nafcillin

    Decreased plasma or blood concentrations of cyclosporine

    Monitor concentration of cyclosporine; adjust cyclosporine dosage accordingly

    NSAIAs (diclofenac, naproxen, sulindac)

    Possible additive nephrotoxic effects; possible increased BP and/or serum potassium concentrations

    Increased diclofenac AUC

    Monitor Scr following modification of concomitant NSAIA therapy (increase in NSAIA dosage or initiation of new NSAIA)

    Select diclofenac dosage at lower end of the recommended dosage range

    Octreotide

    Decreased plasma or blood concentrations of cyclosporine

    Monitor concentration of cyclosporine; adjust cyclosporine dosage accordingly

    Orlistat

    Decreased absorption of cyclosporine

    Avoid concomitant use

    Potassium-sparing or -containing drugs

    Possible hyperkalemia

    Caution advised; control of potassium concentrations recommended

    Quinupristin/dalfopristin

    Increased plasma or blood concentrations of cyclosporine

    Monitor concentration of cyclosporine; adjust cyclosporine dosage accordingly

    Rifabutin

    Possible increased metabolism of cyclosporine

    Use with caution

    Rifampin

    Decreased plasma or blood concentrations of cyclosporine

    Monitor concentration of cyclosporine; adjust cyclosporine dosage accordingly

    St. John’s wort

    Marked decrease in blood concentrations of cyclosporine, resulting in subtherapeutic levels, rejection of transplanted organs, and graft loss

    Avoid concomitant use

    Sirolimus

    Increased Scr with concomitant sirolimus and full-dose cyclosporine therapy

    Increased blood sirolimus concentrations with concomitant administration

    Increase in Scr generally is reversible with cyclosporine dosage reduction

    Administer sirolimus 4 hours after cyclosporine to minimize effect on sirolimus concentrations

    Sulfinpyrazone

    Decreased plasma or blood concentrations of cyclosporine

    Monitor concentration of cyclosporine; adjust cyclosporine dosage accordingly

    Tacrolimus

    Possible additive nephrotoxic effects

    Avoid concomitant use

    Terbinafine

    Decreased plasma or blood concentrations of cyclosporine

    Monitor concentration of cyclosporine; adjust cyclosporine dosage accordingly

    Ticlopidine

    Decreased plasma or blood concentrations of cyclosporine

    Monitor concentration of cyclosporine; adjust cyclosporine dosage accordingly

    Vaccines

    Possible decreased immune response to vaccination

    Avoid administration of live vaccines during cyclosporine therapy

    Vancomycin

    Possible additive nephrotoxic effects

    Use with caution

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