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Calcineurin inhibitor immunosuppressant

Ciclosporin

Ciclosporin (cyclosporine) is a calcineurin inhibitor immunosuppressant derived from the fungus Tolypocladium inflatum. It is primarily used to prevent organ transplant rejection and treat severe autoimmune conditions. The most testable fact: ciclosporin causes dose-dependent nephrotoxicity and requires therapeutic drug monitoring.

Practice questionsHigh-yield facts
Drug classCalcineurin inhibitor immunosuppressant
MechanismInhibits calcineurin, blocking T-cell activation and IL-2 production
Main usesOrgan transplant rejection prophylaxis, severe autoimmune diseases
Key adverse effectNephrotoxicity with tubular damage and interstitial fibrosis
8 min readFor medical studentsUpdated 2026-10-14

Mechanism of action

Ciclosporin is a cyclic polypeptide that acts as a selective immunosuppressant by inhibiting T-lymphocyte activation. After entering T cells, ciclosporin binds to the intracellular protein cyclophilin to form a complex. This ciclosporin-cyclophilin complex then binds to and inhibits calcineurin, a calcium- and calmodulin-dependent serine-threonine phosphatase.

Calcineurin normally dephosphorylates the nuclear factor of activated T cells (NFAT), allowing NFAT to translocate to the nucleus and activate genes essential for T-cell function. By inhibiting calcineurin, ciclosporin prevents NFAT dephosphorylation and nuclear translocation, thereby blocking the transcription of interleukin-2 (IL-2) and other cytokines including IL-3, IL-4, interferon-gamma, and TNF-alpha.

IL-2 is critical for T-cell proliferation and activation. Without IL-2 production, T-cell-mediated immune responses are suppressed, including cell-mediated immunity and some antibody production. Importantly, ciclosporin is relatively selective for T cells and does not suppress the bone marrow to the same extent as cytotoxic agents, though it does affect other immune cells that depend on calcineurin signaling.

High-yield for exams
  • Ciclosporin inhibits calcineurin by forming a complex with cyclophilin, blocking IL-2 production and T-cell activation
  • Dose-limiting toxicity is nephrotoxicity: acute (reversible vasoconstriction) and chronic (irreversible striped interstitial fibrosis)
  • Extensively metabolized by CYP3A4; grapefruit juice and azole antifungals increase levels, rifampin decreases levels
  • Classic triad of side effects: nephrotoxicity, hypertension, and tremor; cosmetic effects include hirsutism and gingival hyperplasia
  • Requires therapeutic drug monitoring (trough levels); toxic and therapeutic ranges are narrow
  • PRES (posterior reversible encephalopathy syndrome) presents with seizures, confusion, visual changes, and hypertension
  • Hyperkalemia and hypomagnesemia are common metabolic effects; avoid potassium-sparing diuretics and NSAIDs
  • Increased risk of opportunistic infections (CMV, PCP) and malignancies (lymphoma, skin cancer) due to immunosuppression

Indications

Ciclosporin is approved for multiple transplant and autoimmune indications:

Transplantation

  • Solid organ transplant rejection prophylaxis: kidney, liver, heart, lung, pancreas, and combined transplants
  • Usually combined with corticosteroids and other immunosuppressants (mycophenolate, azathioprine)
  • Prevents acute and chronic rejection by suppressing T-cell responses to donor antigens

Autoimmune and inflammatory conditions

  • Severe rheumatoid arthritis: refractory to conventional disease-modifying antirheumatic drugs
  • Psoriasis: severe, recalcitrant plaque psoriasis in adults
  • Atopic dermatitis: severe cases unresponsive to topical therapy
  • Nephrotic syndrome: particularly steroid-resistant or steroid-dependent minimal change disease and focal segmental glomerulosclerosis
  • Aplastic anemia: as an alternative to bone marrow transplantation
  • Ulcerative colitis: severe refractory disease (off-label but established use)
  • Uveitis: sight-threatening posterior or intermediate uveitis

Ophthalmic formulation

  • Dry eye disease: topical ciclosporin ophthalmic emulsion increases tear production in patients with keratoconjunctivitis sicca

Dosing varies widely by indication and formulation, and therapeutic drug monitoring is essential for transplant patients.

Pharmacokinetics

Ciclosporin has complex and variable pharmacokinetics that necessitate therapeutic drug monitoring.

Absorption: Oral bioavailability is variable (10-60%) and depends on the formulation. Two main oral formulations exist: the original formulation and a microemulsion formulation with more predictable absorption. Absorption is reduced by food high in fat, increased by grapefruit juice (CYP3A4 inhibition). Peak levels occur 1.5-2 hours after oral microemulsion dosing.

Distribution: Highly lipophilic with extensive tissue distribution. Volume of distribution is 3-5 L/kg. Approximately 90% is protein-bound, primarily to lipoproteins and erythrocytes. Only 1-2% circulates as free drug. Ciclosporin distributes into breast milk.

Metabolism: Extensively metabolized in the liver and gut wall by the cytochrome P450 3A4 (CYP3A4) enzyme system, producing more than 25 metabolites. The major metabolite is AM1, which has approximately 10% of the immunosuppressive activity of the parent compound. This extensive CYP3A4 metabolism is the basis for numerous clinically significant drug interactions.

Excretion: Primarily via bile into feces (90%), with only 6% excreted in urine. The elimination half-life is biphasic, with a terminal half-life of 8-24 hours (average 12-18 hours) in transplant recipients. Clearance is not significantly affected by renal impairment but may be reduced in hepatic dysfunction.

Therapeutic monitoring: Trough levels (C0) or 2-hour post-dose levels (C2) are monitored. Target ranges depend on the organ transplanted, time post-transplant, and concomitant immunosuppression, typically 100-400 ng/mL for trough levels in stable transplant patients.

Adverse effects

Ciclosporin has a characteristic adverse effect profile that students must recognize.

Renal toxicity (dose-limiting)

  • Nephrotoxicity: the most important adverse effect, occurring in up to 25-75% of transplant recipients
  • Acute: afferent arteriolar vasoconstriction leading to decreased GFR, usually reversible with dose reduction
  • Chronic: interstitial fibrosis, tubular atrophy, arteriolar hyalinosis ("striped fibrosis"), often irreversible
  • Presents with elevated creatinine, hypertension, hyperkalemia, hypomagnesemia
  • Requires therapeutic drug monitoring and dose adjustment

Cardiovascular

  • Hypertension: occurs in 25-50% of patients due to renal vasoconstriction and sodium retention
  • May require antihypertensive therapy (calcium channel blockers often preferred)

Neurological

  • Tremor (fine, dose-related)
  • Headache, paresthesias
  • Posterior reversible encephalopathy syndrome (PRES): rare but serious, presents with seizures, altered mental status, visual disturbances, hypertension; usually reversible

Metabolic

  • Hyperkalemia: reduced potassium excretion
  • Hypomagnesemia: increased renal magnesium wasting
  • Hyperuricemia and gout
  • Hyperlipidemia (hypertriglyceridemia and hypercholesterolemia)
  • Glucose intolerance (less than tacrolimus)

Cosmetic (important for patient adherence)

  • Gingival hyperplasia: in 25-30% of patients, more common in children, worsened by calcium channel blockers
  • Hirsutism: excessive hair growth, particularly distressing for female patients
  • Coarsening of facial features

Gastrointestinal

  • Nausea, vomiting, diarrhea
  • Hepatotoxicity (elevated liver enzymes)
  • Abdominal discomfort

Infectious and neoplastic

  • Increased susceptibility to bacterial, viral (CMV, HSV, EBV), fungal, and protozoal infections
  • Increased malignancy risk: lymphoproliferative disorders (especially post-transplant lymphoproliferative disorder associated with EBV), squamous cell carcinoma of skin

Other

  • Anemia, leukopenia (less than with cytotoxic agents)
  • Thrombocytopenia
  • Pancreatitis (rare)

Contraindications and warnings

Absolute contraindications

  • Hypersensitivity to ciclosporin or any component of the formulation
  • Hypersensitivity to polyoxyethylated castor oil (in the intravenous formulation)
  • For non-transplant indications: abnormal renal function, uncontrolled hypertension, malignancy (psoriasis/RA patients)

Warnings and precautions

Renal function: Monitor serum creatinine and BUN regularly. Dose reduction required if creatinine rises >25-30% above baseline. Chronic nephrotoxicity may be irreversible. Use with caution in patients with pre-existing renal impairment.

Hypertension: Monitor blood pressure regularly. Control hypertension before initiating therapy in non-transplant patients. May require antihypertensive medication.

Hepatic impairment: Reduced metabolism in severe liver disease may necessitate dose adjustment. Monitor liver function tests.

Infections and malignancy: Immunosuppression increases risk of opportunistic infections and lymphomas. Avoid live vaccines. Screen for latent tuberculosis. Patients require lifelong surveillance for skin cancers and lymphoproliferative disease. Consider prophylaxis for Pneumocystis jirovecii in high-risk patients.

Hyperkalemia: Monitor potassium levels, especially when combined with potassium-sparing diuretics, ACE inhibitors, ARBs, or potassium supplements. Avoid high-potassium diet.

Pregnancy and lactation: Pregnancy category C (US, historical classification). Not absolutely contraindicated in transplant patients where benefit outweighs risk, but associated with prematurity, low birth weight, and possible neonatal hyperkalemia and renal dysfunction. Excreted in breast milk; breastfeeding not recommended.

PRES: Discontinue if symptoms develop (seizures, altered consciousness, visual disturbances, hypertension).

Specific product formulations: The original and microemulsion formulations are not bioequivalent and cannot be used interchangeably without dose adjustment and monitoring. Always specify which formulation is being prescribed.

Drug interactions

Ciclosporin has extensive drug interactions, primarily through CYP3A4 metabolism and P-glycoprotein transport. These interactions can significantly alter ciclosporin levels, requiring dose adjustment and increased monitoring.

CYP3A4 inhibitors (increase ciclosporin levels)

  • Azole antifungals: ketoconazole, fluconazole, itraconazole, voriconazole
  • Macrolide antibiotics: erythromycin, clarithromycin (not azithromycin)
  • Calcium channel blockers: diltiazem, verapamil, nicardipine
  • HIV protease inhibitors: ritonavir, saquinavir, indinavir
  • Other: amiodarone, allopurinol, colchicine, grapefruit juice, metoclopramide
  • May require 25-50% ciclosporin dose reduction

CYP3A4 inducers (decrease ciclosporin levels)

  • Anticonvulsants: phenytoin, phenobarbital, carbamazepine
  • Antimicrobials: rifampin, rifabutin
  • Herbal: St. John's wort (contraindicated)
  • Other: nafcillin, octreotide
  • May lead to subtherapeutic levels and risk of organ rejection
  • May require ciclosporin dose increase

Nephrotoxic drugs (additive toxicity)

  • Aminoglycosides: gentamicin, tobramycin, amikacin
  • Amphotericin B
  • NSAIDs: avoid or use with extreme caution
  • Trimethoprim, vancomycin
  • Other calcineurin inhibitor: tacrolimus (never combine)
  • ACE inhibitors and ARBs (also increase hyperkalemia risk)

Drugs affecting potassium

  • Potassium-sparing diuretics (amiloride, spironolactone, triamterene)
  • ACE inhibitors and ARBs
  • Potassium supplements
  • All increase hyperkalemia risk; monitor closely

Statins

  • Increased risk of myopathy and rhabdomyolysis (ciclosporin inhibits statin metabolism)
  • Use lowest effective statin dose; pravastatin and fluvastatin preferred
  • Avoid simvastatin >10 mg/day

Other interactions

  • Digoxin: ciclosporin increases digoxin levels (P-glycoprotein inhibition)
  • Colchicine: increased colchicine toxicity, potentially life-threatening
  • Sirolimus/everolimus: ciclosporin increases levels of mTOR inhibitors; do not administer simultaneously
  • Methotrexate: increased methotrexate levels
  • Live vaccines: avoid due to immunosuppression

Always check for interactions when adding or discontinuing medications in patients on ciclosporin. Therapeutic drug monitoring is essential when any interacting drug is initiated or stopped.

Clinical pearls

  • Ciclosporin vs. tacrolimus: Both are calcineurin inhibitors, but tacrolimus binds to FKBP-12 (not cyclophilin) and is 10-100 times more potent. Tacrolimus has higher rates of diabetes and neurotoxicity; ciclosporin has more cosmetic effects (hirsutism, gingival hyperplasia) and hyperlipidemia. Nephrotoxicity occurs with both.
  • Therapeutic drug monitoring: Trough levels are standard but 2-hour post-dose (C2) monitoring may better predict rejection risk. Target ranges decrease over time post-transplant as rejection risk falls. Steady state is reached in 3-5 days.
  • Gingival hyperplasia management: Emphasize dental hygiene. The effect is potentiated by calcium channel blockers; consider alternative antihypertensive if possible. May regress with dose reduction or drug discontinuation.
  • Grapefruit juice: Contains furanocoumarins that irreversibly inhibit intestinal CYP3A4. A single glass can increase ciclosporin levels by 50-200%. Effect lasts 24 hours. Patients must avoid all grapefruit products.
  • PRES recognition: Presents with headache, confusion, seizures, visual disturbances, and hypertension. MRI shows posterior cerebral edema. Usually occurs with supratherapeutic levels or sudden BP elevation. The condition is typically reversible if ciclosporin is stopped promptly.
  • Microemulsion formulation: Neoral and generic microemulsion products have more predictable absorption than original Sandimmune formulation. Never switch formulations without careful monitoring and likely dose adjustment.
  • Striped fibrosis: Chronic ciclosporin nephrotoxicity produces a characteristic pathologic pattern of tubular atrophy with "striped" interstitial fibrosis on renal biopsy. This is distinct from acute rejection and indicates chronic drug toxicity, often irreversible.
  • Vaccination strategy: Give all routine vaccines before transplantation when possible. Post-transplant, avoid live vaccines (MMR, varicella, live influenza, yellow fever). Inactivated vaccines (influenza, pneumococcal, hepatitis B) are safe but may have reduced efficacy.
  • Ophthalmic formulation: Topical ciclosporin 0.05% or 0.09% emulsion for dry eye acts locally to reduce T-cell-mediated inflammation on the ocular surface. Systemic absorption is minimal. Onset of effect takes 3-6 months.
  • Pregnancy: While not absolutely contraindicated in transplant patients (where alternative is often graft loss), ciclosporin crosses the placenta. Registry data show increased prematurity and low birth weight but no clear pattern of congenital malformations. Maternal renal function and blood pressure require close monitoring.
Mnemonic

CYCLOSPORINE adverse effects: Convulsions (PRES), Ypertension (hypertension), Cyclophilin binding, Lymphoma risk, Oliguria (nephrotoxicity), Serum creatinine elevated, Potassium elevated, Oral gingival hyperplasia, Renal failure, Infection susceptibility, Neurotoxicity/tremor, Elevated BP

Practice questions

1. A 52-year-old man underwent kidney transplantation 6 months ago and has been maintained on ciclosporin, mycophenolate, and prednisone. He now presents with elevated serum creatinine (2.8 mg/dL, baseline 1.2 mg/dL) and hypertension (160/95 mmHg). He denies fever, dysuria, or allograft tenderness. Ciclosporin trough level is 450 ng/mL (target 100-300 ng/mL). Renal biopsy shows tubular atrophy with striped interstitial fibrosis and arteriolar hyalinosis. What is the most likely diagnosis?

Answer: C. Chronic ciclosporin nephrotoxicity is characterized by elevated creatinine, hypertension, supratherapeutic drug levels, and the pathognomonic finding of striped interstitial fibrosis with tubular atrophy on biopsy. Acute rejection would show lymphocytic infiltration and tubulitis. BK virus causes tubular epithelial viral inclusions. The absence of fever, stable graft, and characteristic histology point to drug toxicity.

2. A 45-year-old woman with a heart transplant on ciclosporin is started on clarithromycin for pneumonia. Three days later, she develops confusion, headache, visual blurring, and a generalized tonic-clonic seizure. Blood pressure is 180/110 mmHg. MRI shows bilateral posterior cerebral white matter edema. Ciclosporin level is 850 ng/mL. What is the most appropriate immediate management?

Answer: C. This patient has posterior reversible encephalopathy syndrome (PRES), a serious complication of ciclosporin toxicity presenting with seizures, hypertension, confusion, and visual changes with posterior cerebral edema on MRI. Clarithromycin (a CYP3A4 inhibitor) increased ciclosporin levels precipitating PRES. Immediate ciclosporin discontinuation and blood pressure control are essential; PRES is usually reversible if detected early. Continuing ciclosporin or increasing the dose would worsen toxicity.

3. A 38-year-old man with severe psoriasis is started on ciclosporin. Which of the following laboratory abnormalities is most likely to occur as a direct result of ciclosporin therapy?

Answer: B. Ciclosporin characteristically causes hyperkalemia (due to decreased renal potassium excretion) and hypomagnesemia (due to increased renal magnesium wasting). This combination is a classic adverse effect that requires monitoring. Potassium-sparing diuretics and potassium supplements should be avoided. Ciclosporin does not typically cause hypokalemia or magnesium retention, making the other options incorrect.

Frequently asked questions

How does ciclosporin work?

Ciclosporin binds to the intracellular protein cyclophilin, and this complex inhibits calcineurin, a phosphatase required for T-cell activation. By blocking calcineurin, ciclosporin prevents the production of interleukin-2 (IL-2) and other cytokines, thereby suppressing T-cell-mediated immune responses. This mechanism makes it highly effective for preventing organ transplant rejection and treating autoimmune diseases driven by T-cell activity.

What are the side effects of ciclosporin?

The most serious side effect is nephrotoxicity, which can be acute (reversible) or chronic (irreversible interstitial fibrosis). Other major side effects include hypertension, tremor, hyperkalemia, hypomagnesemia, increased infection risk, and higher cancer risk (lymphoma and skin cancer). Cosmetic effects like hirsutism (excess hair growth) and gingival hyperplasia (gum overgrowth) are common and particularly troublesome for patients. Gastrointestinal upset, hepatotoxicity, and hyperlipidemia also occur.

What is the difference between ciclosporin and tacrolimus?

Both are calcineurin inhibitors used for transplant immunosuppression, but they bind different intracellular proteins: ciclosporin binds cyclophilin while tacrolimus binds FKBP-12. Tacrolimus is more potent and has higher rates of new-onset diabetes and neurotoxicity, whereas ciclosporin causes more cosmetic side effects (hirsutism, gingival hyperplasia) and hyperlipidemia. Both cause nephrotoxicity and hypertension. The choice between them depends on individual patient factors, side effect profile, and transplant center protocols.

Why does ciclosporin require therapeutic drug monitoring?

Ciclosporin has a narrow therapeutic index, meaning the difference between effective and toxic doses is small. It also has highly variable oral bioavailability (10-60%) and extensive drug interactions through CYP3A4 metabolism. Subtherapeutic levels risk organ rejection or disease flare, while toxic levels cause nephrotoxicity and other serious adverse effects. Trough blood levels are monitored regularly to ensure patients remain in the therapeutic range, with adjustments made based on clinical response, time since transplant, and concomitant medications.

Can you drink grapefruit juice while taking ciclosporin?

No, grapefruit juice is contraindicated with ciclosporin. Grapefruit contains compounds that irreversibly inhibit CYP3A4 enzymes in the intestinal wall, dramatically increasing ciclosporin absorption and blood levels by 50-200%. Even a single glass can cause this effect, which lasts up to 24 hours. Elevated ciclosporin levels increase the risk of serious toxicity, particularly nephrotoxicity and neurotoxicity. Patients must avoid all grapefruit products including juice, fresh fruit, and grapefruit-containing foods.

Conditions it is used for

Organ transplant rejectionRheumatoid arthritisPsoriasisAtopic dermatitisNephrotic syndromeAplastic anemiaUlcerative colitisUveitis
tacrolimussirolimuseverolimusmycophenolateazathioprinebelataceptbasiliximabprednisone

Sources and further reading

DailyMed (FDA labels)StatPearls (NCBI Bookshelf)MedlinePlusWHO ATC/DDD index: L04AD01WHO ATC/DDD index: S01XA18

Educational content for medical students, prepared by the WhiteCoat Pro editorial team with AI assistance; every page is reviewed by a second AI model for factual errors. It is not medical advice and does not replace the product label, local guidelines or a clinician.