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Immunosuppressants: Cyclosporine, Methotrexate, Everolimus, Sirolimus, and Tacrolimus

Synonym/acronym: Cyclosporine (Sandimmune), methotrexate (MTX, amethopterin, Folex, Rheumatrex), methotrexate sodium (Mexate), everolimus (Afinitor, Certican, Zortress), sirolimus (Rapamycin), tacrolimus (Prograf).

Common use

To monitor appropriate drug dosage of immunosuppressant related to organ transplant maintenance.


Whole blood (1 mL) collected in lavender-top tube for cyclosporine, everolimus; sirolimus; tacrolimus. Serum (1 mL) collected in a red-top tube for methotrexate; specimen must be protected from light.
ImmunosuppressantRoute of AdministrationRecommended Collection Time
CyclosporineOral or intravenous12 hr after dose or immediately prior to next dose
MethotrexateOralVaries according to dosing protocol
IntramuscularVaries according to dosing protocol
EverolimusOralImmediately prior to next dose
SirolimusOralImmediately prior to next dose
TacrolimusOralImmediately prior to next dose
Leucovorin therapy, also called leucovorin rescue, is used in conjunction with administration of methotrexate. Leucovorin, a fast-acting form of folic acid, protects healthy cells from the toxic effects of methotrexate

Normal findings

(Method: Immunoassay for cyclosporine and methotrexate; liquid chromatography with tandem mass spectrometry for everolimus, sirolimus, and tacrolimus)
Therapeutic DoseHalf-Life (hr)Volume of Distribution (L/kg)Protein Binding (%)Excretion
Conventional UnitsSI Units (Conventional Units × 0.832)
Cyclosporine100–300 ng/mL renal transplant83–250 nmol/L8–244–690Renal
200–350 ng/mL cardiac, hepatic, pancreatic transplant166–291 nmol/L8–244–690Renal
100–300 ng/mL bone marrow transplant83–250 nmol/L8–244–690Renal
MethotrexateDependent on therapeutic approach5–90.4–150–70Renal
Low dose: 0.5–1 micromol/L
High dose: Less than 5 micromol/L at 24 h; less than 0.5 micromol/L at 48 h; less than 0.1 micromol/L at 72 h
Conventional UnitsSI Units (Conventional Units × 0.832)
EverolimusTransplant: 3–8 ng/mL18–35 (kidney); 30–35 (liver)128–58975Biliary
Oncology: 5–10 ng/mL18–35128–58975Biliary
SirolimusMaintenance phase: renal transplant: 4–12 ng/mL; liver transplant: 12–20 ng/mL46–784–2092Biliary
TacrolimusMaintenance phase: renal transplant: 6–12 ng/mL; liver transplant: 4–10 ng/mL; pancreas transplant: 10–18 ng/mL; bone marrow transplant: 10–20 ng/mL10–141.599Biliary
Therapeutic targets for the initial phase post-transplantation are slightly higher than during the maintenance phase and are influenced by the specific therapy chosen for each patient with respect to coordination of treatment for other conditions and corresponding therapies. Therapeutic ranges for everolimus, sirolimus, and tacrolimus assume concomitant administration of cyclosporine and steroids.


Cyclosporine is an immunosuppressive drug used in the management of organ rejection, especially rejection of heart, liver, pancreas, and kidney transplants. Its most serious side effect is renal impairment or renal failure. Cyclosporine is often administered in conjunction with corticosteroids (e.g., prednisone) for its anti-inflammatory or immune-suppres-sing properties and with other drugs (e.g., everolimus, sirolimus, tacrolimus) to reduce graft-versus-host disease. Methotrexate is a highly toxic drug that causes cell death by disrupting DNA synthesis. Methotrexate is also used in the treatment of rheumatoid arthritis, psoriasis, polymyositis, and Reiter’s syndrome. These drugs are metabolized by the cytochrome enzyme, CYP3A4 or CYP3A5, which is essential to achieve the desired therapeutic effect. Testing for specific CYP450 genotype defects can be performed in some laboratories on blood and buccal specimens. Counseling and informed written consent are generally required for genetic testing. Test results can identify poor and ultrasensitive drug metabolizers. This allows for the possibility of personalized adjustments to their medication regimen or decisions to seek alternative drugs which in turn results in safer, more effective treatment.

Many factors must be considered in effective dosing and monitoring of therapeutic drugs, including patient age; weight; interacting medications; electrolyte balance; protein levels; water balance; conditions that affect absorption and excretion; as well as foods, herbals, vitamins, and minerals that can either potentiate or inhibit the intended target concentration.

Important note: These medications are metabolized and excreted by the kidneys and are therefore contra-indicated in patients with renal disease and cautiously advised in patients with renal impairment. Information regarding medications must be clearly and accurately communicated to avoid misunderstanding of the dose time in relation to the collection time. Miscommunication between the individual administering the medication and the individual collecting the specimen is the most frequent cause of subtherapeutic levels, toxic levels, and misleading information used in the calculation of future doses. Some pharmacies use a computerized pharma-cokinetics approach to dosing that eliminates the need to be concerned about peak and trough collections; random specimens are adequate. If administration of the drug is delayed, notify the appropriate department(s) to reschedule the blood draw and notify the requesting health-care provider (HCP) if the delay has caused any real or perceived therapeutic harm.

This procedure is contraindicated for



    Cyclosporine, Sirolimus, Tacrolimus

  • Assist in the management of treatments to prevent organ rejection
  • Monitor for toxicity
  • Everolimus

  • Assist in the management of treatments to prevent organ rejection
  • Assist in the management of treatments for subependymal giant cell astrocytoma
  • Monitor effectiveness of treatment of renal cell carcinoma
  • Monitor for toxicity
  • Methotrexate

  • Monitor effectiveness of treatment of cancer and some autoimmune disorders
  • Monitor for toxicity

Potential diagnosis

Normal levelsTherapeutic effect
Toxic levelsAdjust dose as indicated
 CyclosporineRenal impairment
 MethotrexateRenal impairment
 Everolimus, sirolimus, tacrolimusHepatic impairment

Critical findings

  • It is important to note the adverse effects of toxic and subtherapeutic levels. Care must be taken to investigate signs and symptoms of too little and too much medication.

  • Note and immediately report to the health-care provider (HCP) any critically increased or decreased values and related symptoms.

  • It is essential that a critical finding be communicated immediately to the requesting health-care provider (HCP). A listing of these findings varies among facilities.

  • Timely notification of a critical finding for lab or diagnostic studies is a role expectation of the professional nurse. Notification processes will vary among facilities. Upon receipt of the critical value the information should be read back to the caller to verify accuracy. Most policies require immediate notification of the primary HCP, Hospitalist, or on-call HCP. Reported information includes the patient’s name, unique identifiers, critical value, name of the person giving the report, and name of the person receiving the report. Documentation of notification should be made in the medical record with the name of the HCP notified, time and date of notification, and any orders received. Any delay in a timely report of a critical finding may require completion of a notification form with review by Risk Management.

  • Cyclosporine: Greater Than 500 ng/mL (SI: Greater Than 416 nmol/L)

  • Signs and symptoms of cyclosporine toxicity include increased severity of expected side effects, which include nausea, stomatitis, vomiting, anorexia, hypertension, infection, fluid retention, hypercalcemic metabolic acidosis, tremor, seizures, headache, and flushing. Possible interventions include close monitoring of blood levels to make dosing adjustments, inducing emesis (if orally ingested), performing gastric lavage (if orally ingested), withholding the drug, and initiating alternative therapy for a short time until the patient is stabilized.

  • Methotrexate: Greater Than 1 micromol/L After 48 Hr With High-Dose Therapy; Greater Than 0.02 micromol/L After 48 Hr With Low-Dose Therapy

  • Signs and symptoms of methotrexate toxicity include increased severity of expected side effects, which include nausea, stomatitis, vomiting, anorexia, bleeding, infection, bone marrow depression, and, over a prolonged period of use, hepatotoxicity. The effect of methotrexate on normal cells can be reversed by administration of 5-formyltetrahydrofolate (citrovorum or leucovorin). 5-Formyltetrahydrofolate allows higher doses of methotrexate to be given.

  • Everolimus: Greater Than 15 ng/mL (SI: Greater than 15 mcg/L)

  • Signs and symptoms of everolimus pulmonary toxicity include hypoxia, pleural effusion, cough, and dyspnea. Possible interventions include dosing adjustments, administration of corticosteroids, and monitoring of pulmonary function with chest x-ray. Use of everolimus is contraindicated in patients with severe hepatic impairment. Concomitant administration of strong CYP3A4 inhibitors may significantly increase everolimus levels.

  • Sirolimus: Greater Than 25 ng/mL (SI: Greater than 25 mcg/L)

  • Signs and symptoms of sirolimus pulmonary toxicity include cough, shortness of breath, chest pain, and rapid heart rate. Possible interventions include dosing adjustments, administration of corticosteroids, and monitoring of pulmonary function with chest x-ray.

  • Tacrolimus: Greater Than 25 ng/mL (SI: Greater than 25 mcg/L)

  • Signs and symptoms of tacrolimus toxicity include tremors, seizures, headache, high blood pressure, hyperkalemia, tinnitus, nausea, and vomiting. Possible interventions include treatment of hypertension, administration of antiemetics for nausea and vomiting, and dosing adjustments.

Interfering factors

  • Numerous drugs interact with cyclosporine and either increase cyclosporine levels or increase the risk of toxicity. These drugs include acyclovir, aminoglycosides, amiodarone, amphotericin B, anabolic steroids, cephalosporins, cimetidine, danazol, erythromycin, furosemide, ketoconazole, melphalan, methylprednisolone, miconazole, NSAIDs, oral contraceptives, and trimethoprim- sulfamethoxazole.
  • Drugs that may decrease cyclosporine levels include carbamazepine, ethotoin, mephenytoin, phenobarbital, phenytoin, primidone, and rifampin.
  • Drugs that may increase methotrexate levels or increase the risk of toxicity include NSAIDs, probenecid, salicylate, and sulfonamides.
  • Antibiotics may decrease the absorption of methotrexate.
  • Drugs and foods that may increase everolimus levels include ketoconazole, amprenavir, aprepitant, atazanavir, clarithromycin, delavirdine, diltiazem, erythromycin, fluconazole, fosamprenavir, grapefruit juice, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, verapamil, and voriconazole.
  • Drugs and herbs that may decrease everolimus levels include carbamazepine, dexamethasone, phenobarbital, phenytoin, rifabutin, rifampin, and St. John’s Wort.
  • Drugs and foods that may increase sirolimus levels include bromocriptine, cimetidine, cisapride, clotrimazole, danazol, diltiazem, fluconazole, indinavir, metoclopramide, nicardipine, ritonavir, troleandomycin, and verapamil.
  • Drugs and herbs that may increase sirolimus levels include carbamazepine, phenobarbital, phenytoin, rifapentine, and St. John’s Wort.
  • Drugs and foods that may increase tacrolimus levels include bromocriptine, chloramphenicol, cimetidine, cisapride, clarithromycin, clotrimazole, cyclosporine, danazol, diltiazem, erythromycin, fluconazole, grapefruit juice, itraconazole, ketoconazole, methylprednisolone, metoclopramide, nelfinavir, nicardipine, nifedipine, torinavir, troleandomycin, verapamil, and voriconazole.
  • Drugs and herbs that may decrease tacrolimus levels include carbamazepine, ethotoin, mephenytoin, octreotide, phenobarbital, primidone, rifabutin, rifampin, sirolimus, and St. John’s Wort.

Nursing Implications and Procedure


  • Positively identify the patient using at least two unique identifiers before providing care, treatment, or services.
  • Patient Teaching: Inform the patient this test can assess in monitoring therapeutic and toxic drug levels.
  • Obtain a history of the patient’s complaints, including a list of known allergens, especially allergies or sensitivities to latex.
  • Obtain a history of the patient’s genitourinary and immune systems, symptoms, and results of previously performed laboratory tests and diagnostic and surgical procedures. Some considerations prior to medication administration include documentation of adequate renal function with creatinine and BUN levels, documentation of adequate hepatic function with alanine aminotransferase (ALT) and bilirubin levels, and documentation of adequate hematological and immune function with platelet and white blood cell (WBC) count. Patients receiving methotrexate must be well hydrated and, depending on the therapy, may be treated with sodium bicarbonate for urinary alkalinization to enhance drug excretion. Leucovorin calcium rescue therapy may also be part of the protocol.
  • Obtain a list of the patient’s current medications, including herbs, nutritional supplements, and nutraceuticals (see Effects of Natural Products on Laboratory Values online at DavisPlus).
  • Review the procedure with the patient. Inform the patient that specimen collection takes approximately 5 to 10 min. Address concerns about pain and explain that there may be some discomfort during the venipuncture.
  • Sensitivity to social and cultural issues, as well as concern for modesty, is important in providing psychological support before, during, and after the procedure.
  • Note that there are no food, fluid, or medication restrictions unless by medical direction.


  • Potential complications:
  • Note that lack of consideration for the proper collection time in relation to the dosing schedule can provide misleading information that may result in an erroneous interpretation of levels, creating the potential for a medication-error-related injury to the patient.

  • Avoid the use of equipment containing latex if the patient has a history of allergic reaction to latex.
  • Instruct the patient to cooperate fully and to follow directions. Direct the patient to breathe normally and to avoid unnecessary movement.
  • Observe standard precautions, and follow the general guidelines in Patient Preparation and Specimen Collection. Consider recommended collection time in relation to the dosing schedule. Positively identify the patient, and label the appropriate specimen container with the corresponding patient demographics, initials of the person collecting the specimen, date, and time of collection, noting the last dose of medication taken. Perform a venipuncture.
  • Remove the needle and apply direct pressure with dry gauze to stop bleeding. Observe/assess venipuncture site for bleeding or hematoma formation and secure gauze with adhesive bandage.
  • Promptly transport the specimen to the laboratory for processing and analysis.


  • Inform the patient that a report of the results will be made available to the requesting HCP, who will discuss the results with the patient.
  • Nutritional Considerations: Patients taking immunosuppressant therapy tend to have decreased appetites due to the side effects of the medication. Instruct patients to consume a variety of foods within the basic food groups, maintain a healthy weight, be physically active, limit salt intake, limit alcohol intake, and be a nonsmoker.
  • Recognize anxiety related to test results, and offer support. Patients receiving these drugs usually have conditions that can be intermittently moderately to severely debilitating, resulting in significant lifestyle changes. Educate the patient regarding access to counseling services, as appropriate.
  • Reinforce information given by the patient’s HCP regarding further testing, treatment, or referral to another HCP. Explain to the patient the importance of following the medication regimen and give instructions regarding drug interactions. Answer any questions or address any concerns voiced by the patient or family.
  • Instruct the patient to be prepared to provide the pharmacist with a list of other medications he or she is already taking in the event that the requesting HCP prescribes a medication.
  • Depending on the results of this procedure, additional testing may be performed to evaluate or monitor progression of the disease process and determine the need for a change in therapy. Evaluate test results in relation to the patient’s symptoms and other tests performed.

Related Monographs

  • Related tests include ALT, AST, bilirubin, BUN, CBC platelet count, CBC WBC count and differential, and creatinine.
  • Refer to the Genitourinary and Immune systems tables at the end of the book for related tests by body system.


Drugs that prevent or reduce the immune response. They are used in the treatment of a variety of severe inflammations such as uveitis, scleritis, keratoconjunctivitis sicca, Behçet's syndrome, sympathetic ophthalmia, and to prevent corneal graft rejection. They include the corticosteroids (e.g. prednisolone), ciclosporin (cyclosporine), tacrolimus, and cytotoxic agents (e.g. azathioprine, chlorambucil, cyclophosphamide, methotrexate). It must be noted that immunosuppressants render the patient more susceptible to infection because immunity is reduced.
References in periodicals archive ?
To determine if the drugs will work, the researchers observed how HIV infection would be affected by immunosuppressant drugs in 91 patients who were followed for a median of 3.
and Europe of HUMIRA for inducing and sustaining clinical remission in adult patients with moderately to severely active UC who demonstrated an inadequate response to immunosuppressant therapy,' said John Medich, Ph.
These results suggest that using analogs as internal standards to quantify immunosuppressants and other analytes can be appropriate in the clinical laboratory; however, given the ion suppression differences between analyte and internal standard for cyclosporin A, isotope-labeled internal standards may be of advantage.
The study findings further suggest that in patients who do not achieve complete endoscopic healing at that time, the early introduction of more aggressive treatments, such as immunosuppressants, may be warranted.
A subgroup of 7,415 IBD patients filled two or more prescriptions for immunosuppressant medications during the study.
The specific goals of the trial are to establish the impact of immunosuppression on patient survival and on the progression of HIV disease, establish the impact of HIV infection on graft survival, and better describe the interactions that occur between immunosuppressant drugs and antiretroviral drugs.
The mechanism of action of sirolimus is distinct from that of other commonly used immunosuppressants.
These results suggest that Zenapax may be a promising addition to current immunosuppressant therapy for cardiac transplant recipients, further reducing the incidence of rejection," said Donna Mancini, MD, Lead Researcher, Medical Director of Cardiac Transplantation at the Columbia Presbyterian Center of New York Presbyterian Hospital and Associate Professor of Medicine at the Columbia University College of Physicians & Surgeons.
One of them takes no other drug, while the other receives extremely low doses of immunosuppressants.
Contract notice: Supply of reagents and consumables for the assay immunosuppressants, with provision of a controller.
Current treatments of these diseases generally utilize non-specific immunosuppressants or immunomodulatory compounds or cytokines.