Neoral

Approved Indications:

Transplantation:

• Prophylaxis of Organ Rejection in:
• Kidney transplantation
• Liver transplantation
• Heart transplantation
• Lung, pancreas, or bone marrow transplantation (off-label in some countries)

Autoimmune Diseases:

• Rheumatoid Arthritis (RA) (severe, active cases unresponsive to methotrexate)
• Psoriasis (severe, recalcitrant, non-immunosuppressive therapy-resistant)
• Nephrotic Syndrome (steroid-dependent or steroid-resistant cases)

Ophthalmic Use:

• Chronic Dry Eye Syndrome (moderate to severe keratoconjunctivitis sicca not improved by artificial tears)
• Topical ophthalmic formulation (e.g., cyclosporine 0.05% ophthalmic emulsion)

Clinically Accepted Off-label Uses:

• Atopic Dermatitis (moderate to severe, short-term use)
• Systemic Lupus Erythematosus (SLE) – especially lupus nephritis
• Inflammatory Bowel Disease (refractory ulcerative colitis)
• Myasthenia Gravis
• Behçet’s Disease
• Autoimmune uveitis
• Aplastic anemia (in combination with antithymocyte globulin)

Route of Administration: Oral (capsules/solution), Intravenous (IV), Ophthalmic (topical)

Transplantation (Adults and Children):

• Oral (initial):
  5–6 mg/kg/day in 2 divided doses, started 12 hours before transplant
• Maintenance dose:
  2–5 mg/kg/day in divided doses, adjusted per blood trough levels (C0 or C2 monitoring)

IV Dose (when oral route not possible):

• Initial: 3–5 mg/kg/day by continuous infusion over 2–6 hours
• IV to oral conversion ratio: 1:3 (IV dose ≈ 1/3 oral dose)

Rheumatoid Arthritis:

• Adults:
  Start at 2.5 mg/kg/day orally in 2 divided doses; may increase to max 4 mg/kg/day based on response

Psoriasis:

• Adults:
  2.5–5 mg/kg/day orally in 2 divided doses; usually for short-term use (<1 year)

Nephrotic Syndrome:

• Adults & Children:
  5–6 mg/kg/day orally (children) or 2.5–5 mg/kg/day (adults); adjust based on renal function and blood levels

Dry Eye Disease (Ophthalmic):

• Instill 1 drop of 0.05% cyclosporine ophthalmic emulsion into each eye twice daily

Special Populations:

• Elderly: Use lowest effective dose; monitor renal function
• Hepatic Impairment: May require dose reduction; monitor trough levels
• Renal Impairment: Avoid high doses; monitor serum creatinine and adjust dose as needed

Cyclosporine selectively inhibits the activity of calcineurin, a calcium/calmodulin-dependent serine/threonine phosphatase crucial for T-cell activation. It binds to cyclophilin, forming a complex that inhibits calcineurin, thereby blocking the dephosphorylation and nuclear translocation of NFAT (nuclear factor of activated T-cells). This prevents the transcription of interleukin-2 (IL-2) and other cytokines, suppressing the activation, proliferation, and differentiation of T-lymphocytes. The result is potent immunosuppressive activity without significant bone marrow suppression.

• Absorption: Variable; enhanced by microemulsion formulations (e.g., Neoral)
• Bioavailability:
• Conventional (Sandimmune): 20–50%
• Microemulsion (Neoral): 30–60%
• Onset of Action: Within 4–8 hours for IV; 1–2 days for oral
• Peak Plasma Time: 1.5–2 hours (oral)
• Distribution: Widely distributed; 90% protein-bound; large volume of distribution
• Metabolism: Extensively metabolized in liver by CYP3A4 and P-glycoprotein
• Active Metabolites: None with significant immunosuppressive activity
• Elimination: Primarily via bile; <6% in urine
• Half-life:
• Adults: 6–27 hours (depending on formulation and liver function)
• Children: Shorter half-life (~4–8 hours)

• Pregnancy:
  FDA Category C. Evidence of fetal toxicity in animals; however, human data (transplant patients) show no consistent pattern of malformations. May be used if benefits outweigh risks.
• Lactation:
  Excreted in breast milk. Breastfeeding is not recommended due to potential immunosuppression, nephrotoxicity, and hepatotoxicity in infants.
• Recommendation:
  Use in pregnancy only when clearly needed. Avoid during breastfeeding.

• Primary Class: Immunosuppressant
• Subclass: Calcineurin Inhibitor (CNI)

• Known hypersensitivity to cyclosporine or any component of the formulation
• Uncontrolled hypertension
• Malignancies or pre-malignant skin disorders (e.g., psoriasis patients with history of PUVA/UVB)
• Concomitant use with other nephrotoxic or hepatotoxic agents
• Abnormal renal function (e.g., serum creatinine >2.0 mg/dL in non-transplant indications)
• Ophthalmic use: Active eye infections (viral, bacterial, fungal)

• Nephrotoxicity: Dose-dependent; occurs in 25–38% of patients; monitor serum creatinine closely
• Hypertension: Common; may require antihypertensives (avoid calcium channel blockers like diltiazem/verapamil)
• Neurotoxicity: May manifest as tremor, paresthesia, seizures, or encephalopathy (especially at high doses)
• Hepatotoxicity: Elevations in liver enzymes; monitor LFTs regularly
• Malignancies: Increased risk of lymphomas and skin cancers, especially with long-term use
• Infection risk: Immunosuppression increases susceptibility to viral, bacterial, fungal infections
• Gingival hyperplasia and hirsutism: Common cosmetic side effects
• Avoid live vaccines: May be ineffective or unsafe
• Monitoring Required:
• Trough levels (C0 or C2)
• Serum creatinine, potassium, magnesium
• Liver function tests
• Blood pressure

Common:

• Renal: Increased serum creatinine, nephrotoxicity
• Cardiovascular: Hypertension
• Neurological: Tremor, headache, paresthesia
• Gastrointestinal: Nausea, diarrhea, abdominal discomfort
• Dermatologic: Hirsutism, acne, gingival hyperplasia
• Electrolyte Imbalance: Hyperkalemia, hypomagnesemia

Serious/Rare:

• Progressive multifocal leukoencephalopathy (PML)
• Posterior reversible encephalopathy syndrome (PRES)
• Hepatotoxicity
• Opportunistic infections (e.g., CMV, BK virus)
• Malignancies (especially lymphoma and skin cancer)

Ophthalmic (topical):

• Burning, stinging, foreign body sensation
• Rare: Eye pain, visual disturbance

Major Interactions:

• CYP3A4 inhibitors (↑ cyclosporine levels):
• Erythromycin, ketoconazole, fluconazole, diltiazem, verapamil, grapefruit juice
• CYP3A4 inducers (↓ cyclosporine levels):
• Rifampin, phenytoin, carbamazepine, St. John's Wort
• Nephrotoxic agents: Additive nephrotoxicity with NSAIDs, aminoglycosides, amphotericin B, tacrolimus
• Statins: Increased risk of rhabdomyolysis (especially simvastatin, lovastatin)
• Potassium-sparing diuretics or ACE inhibitors: Hyperkalemia risk
• Live vaccines: Reduced efficacy; avoid

Enzyme Systems Involved:
CYP3A4, P-glycoprotein substrate

• Updated KDIGO 2021 guidelines for nephrotic syndrome continue to recommend cyclosporine as an alternative to corticosteroids in steroid-resistant cases
• Recent transplant protocols emphasize individualized C0/C2 level targeting over fixed dosing
• In dermatology, updated consensus recommends limiting cyclosporine duration to ≤1 year for psoriasis and atopic dermatitis due to long-term risks
• FDA approved newer formulations (e.g., cyclosporine ophthalmic 0.1%) for dry eye in some regions

Oral Capsules/Solution:

• Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15–30°C
• Protect from light and moisture
• Do not refrigerate oral solution – may cause precipitation
• After opening, oral solution is stable for 2 months

IV Concentrate:

• Store at 15°C to 30°C
• Diluted solution must be used within 24 hours at room temperature

Ophthalmic Emulsion (0.05% or 0.1%):

• Store at 15°C to 25°C
• Protect from freezing
• Discard opened single-use vials after one-time use