Cyclosporine

Cyclosporine is a potent immunosuppressant widely used to prevent organ transplant rejection and treat autoimmune diseases such as rheumatoid arthritis and psoriasis. 

As a calcineurin inhibitor, it suppresses T-cell activation and cytokine production, requiring careful therapeutic monitoring due to its narrow therapeutic index and potential for nephrotoxicity, hypertension, and drug interactions.

What is Cyclosporine?

Cyclosporine is an immunosuppressive drug originally derived from a fungus first isolated from a soil sample in Norway, Tolypocladium inflatum gams. 

Cyclosporine is a calcineurin inhibitor used primarily to prevent organ rejection in kidney, liver, and heart transplants. It also treats autoimmune diseases such as rheumatoid arthritis, psoriasis, and graft-versus-host disease (GVHD). 

Its narrow therapeutic index necessitates careful monitoring due to risks of rejection, nephrotoxicity, and drug interactions.

Mechanism of Action

• Inhibits calcineurin, blocking IL-2 production and suppressing T-cell activation.
• Metabolized in the liver (CYP3A4) and excreted primarily in bile/feces.
• Half-life: 8.4–27 hours.

Indications & Dosing

Organ Transplant (Kidney, Liver, Heart):

• Oral: 15 mg/kg before transplant, tapering to 5–10 mg/kg/day in divided doses (BID).
• IV: 5–6 mg/kg/day until the patient can tolerate oral dosing.

Rheumatoid Arthritis: 2.5 mg/kg/day (max 4 mg/kg/day).

Severe Psoriasis: 2.5–4 mg/kg/day (taper if no response after six weeks).

Focal Segmental Glomerulosclerosis (FSGS): 3 mg/kg/day in two divided doses.

Off-Label Uses: GVHD, autoimmune hepatitis, ulcerative colitis, Crohn’s disease, and posterior uveitis.

Brand and Generic Names of Cyclosporine

Brand Name (Modified Cyclosporine, Microemulsion Formulation)

• Neoral® (Novartis)
• Gengraf® (Abbott)

Brand Name (Non-Modified Cyclosporine, Original Formulation)

• Sandimmune® (Novartis)

Generic Cyclosporine (Various Manufacturers)

• Cyclosporine Modified Capsules (Sandoz)
• Cyclosporine Modified Capsules (Pliva)
• Cyclosporine Modified Capsules (Ivax)
• Cyclosporine Modified Capsules (Morton Grove)
• Cyclosporine Solution (Generic Sandimmune) (Apotex, Morton Grove)

Important Note Regarding Formulation Changes

Generic and brand-name cyclosporine formulations are not interchangeable due to differences in bioavailability and absorption. 

Brand-name Neoral (a microemulsion formulation) provides more consistent and predictable drug levels compared to non-modified Sandimmune and some generics. 

While FDA AB-rated generics fall within 80–125% bioequivalence, small variations in drug exposure may have serious clinical consequences for transplant patients, requiring therapeutic drug monitoring (TDM) to ensure safe conversion. 

Some studies report that 18–20% of patients need dose adjustments when switching between formulations, increasing the risk of graft rejection or toxicity. Until more long-term data is available, clinicians should carefully supervise any formulation changes and ensure close patient-provider communication.

Administration Guidelines

Administration guidelines for cyclosporine include:

Key Differences Between Formulations

Sandimmune (Non-Modified): Poor bioavailability; absorption depends on bile.

Neoral/Gengraf (Modified): Improved absorption; NOT interchangeable with Sandimmune.

Routes of Administration

Cyclosporine routes of administration include: 

Oral: capsule or solution

IV: dilute in D5W or NS; infuse over 2-6 hours

Best Practices for Administration

• Take at the same time each day, consistently in relation to meals.
• Oral Solution: Mix with juice (NOT in plastic cups) to improve palatability.
• AVOID grapefruit juice – it interferes with CYP3A4 metabolism, affecting drug levels.

Monitoring Guidelines

Target Drug Levels (Trough, ng/mL):

• Kidney transplant: 200–400 (first week), 75–160 (1 year).
• Heart/Liver transplant: 250–350 (first 6 months), then 100–200.

Labs to Monitor:

The following labs should be regularly monitored in patients receiving cyclosporine:

• Renal: Creatinine, BUN (risk of nephrotoxicity).
• Liver: AST, ALT, bilirubin.
• Electrolytes: Hyperkalemia, hypomagnesemia risk.
• Blood Pressure: Hypertension common.
• Lipids, CBC: infection, anemia risk.

Adverse Effects

The following adverse effects are relatively common with regular use of cyclosporine:

• Renal: Nephrotoxicity (elevated creatinine, reduced GFR).
• Cardiovascular: Hypertension and arrhythmias.
• Neurologic: Seizures, encephalopathy, tremors, and headaches.
• Metabolic/Endocrine: Hyperlipidemia, hyperkalemia, hypomagnesemia, and gynecomastia.
• Hematologic: Increased risk of infections, lymphoma, and skin cancer.
• Gastrointestinal: Nausea, diarrhea, hepatotoxicity.
• Other: Gingival hyperplasia, hirsutism, and progressive multifocal leukoencephalopathy (PML, rare).

Contraindications

The following are contraindications to cyclosporine use in patients:

Absolute Contraindications

Absolute contraindications include hypersensitivity, severe renal impairment, uncontrolled hypertension, and active infection.

Relative Contraindications

Relative contraindications include liver disease, pregnancy, and breastfeeding.

Drug Interactions

The following drug interactions may occur with cyclosporine and other medications: 

Increased Cyclosporine Levels (Toxicity Risk): Macrolides, azoles, calcium channel blockers, and grapefruit juice.

Decreased Cyclosporine Levels (Rejection Risk): Rifampin, anticonvulsants, and St. John’s Wort.

Increased Nephrotoxicity Risk: NSAIDs, aminoglycosides, and amphotericin B.

Serious Interaction: Sirolimus should be administered 4 hours apart from cyclosporine.

Black Box Warnings

Cyclosporine has certain black box warnings associated with its use:

⚠ High Risk of Malignancies & Serious Infections

⚠ Monitor Drug Levels to Prevent Toxicity or Rejection

⚠ Sandimmune ≠ Neoral – Do not interchange without physician approval

Toxicity & Overdose Management

Symptoms of cyclosporine toxicity include vomiting, drowsiness, hypertension, hepatotoxicity, and edema.

Management for cyclosporine toxicity includes:

• Airway support, seizure precautions.
• Dose reduction or cessation based on serum levels.
• Limited dialysis removal.

Patient Counseling Points

• Adherence is critical to prevent rejection.
• Monitor for infections, malignancies, and nephrotoxicity.
• Avoid grapefruit, NSAIDs, and unapproved medication substitutions.
• Report any formulation switches to the prescribing physician.

How Are Cyclosporine Levels Measured?

Cyclosporine levels are typically assessed through blood tests, with monitoring methods including:

Whole Blood Immunoassays: This should be done via a specific monoclonal immunoassay.

Chromatographic Techniques: High-performance liquid chromatography (HPLC) and liquid chromatography-tandem mass spectrometry (LC-MS/MS) offer precise quantification of cyclosporine and its metabolites.

Trough Level Testing: whole blood samples (not serum or plasma) are collected just before the next dose to determine the lowest concentration in circulation, guiding dose adjustments.

Peak Level Monitoring: In some cases, post-dose blood draws assess peak concentrations to evaluate absorption and metabolism, although samples obtained 2 hours post-dose may be more clinically relevant than general peak testing.

What Do High Cyclosporine Levels Mean?

Elevated cyclosporine levels increase the risk of toxicity, which can manifest as:

Nephrotoxicity: Cyclosporine-induced kidney damage can lead to reduced glomerular filtration rate (GFR), electrolyte imbalances, and potential kidney failure.

Hypertension: Increased blood pressure is a common side effect associated with high drug levels.

Neurotoxicity: Symptoms such as tremors, confusion, and seizures can indicate excessive immunosuppression.

Infection Susceptibility: Over-suppression of the immune system increases vulnerability to opportunistic infections.

Possible Causes of Elevated Levels: Drug interactions (e.g., with azole antifungals or macrolide antibiotics), impaired liver function, and decreased cytochrome P450 metabolism can contribute to high cyclosporine levels.

What Do Low Cyclosporine Levels Mean?

Subtherapeutic cyclosporine levels can lead to inadequate immunosuppression, increasing the risk of:

Organ Rejection: Insufficient levels in transplant patients may trigger immune-mediated graft rejection.

Autoimmune Disease Flare-ups: In patients with conditions like rheumatoid arthritis or psoriasis, inadequate dosing may result in symptom relapse.

Possible Causes of Decreased Levels: Poor drug absorption, gastrointestinal conditions, genetic polymorphisms affecting metabolism, and drug interactions (e.g., with anticonvulsants or rifampin) can lower cyclosporine concentrations.