1. Clinical Overview
Ciclosporin is a potent, lipophilic, cyclic undecapeptide immunosuppressant agent derived from the fungus Tolypocladium inflatum. It is a cornerstone drug in solid organ transplantation and autoimmune diseases. It acts primarily by selectively inhibiting T-lymphocyte activation and proliferation, thereby suppressing cell-mediated immunity. In the Indian context, it is widely used for renal, liver, and cardiac transplants, as well as for severe autoimmune conditions like psoriasis and rheumatoid arthritis, where conventional therapy has failed. It requires meticulous therapeutic drug monitoring (TDM) due to its narrow therapeutic index and significant inter- and intra-patient pharmacokinetic variability.
| Onset | Duration | Bioavailability |
|---|---|---|
| Immunosuppressive effects begin within hours of administration, but clinical response (e.g., in psoriasis) may take 2-4 weeks. | Variable; immunosuppression is maintained as long as therapeutic blood levels are sustained. Effects are reversible upon discontinuation. | Highly variable (10-60%), with a mean of approximately 30% for the conventional oral formulation (Sandimmun). Microemulsion formulations (Neoral) have more consistent and slightly higher bioavailability (~20-50%). |
2. Mechanism of Action
Ciclosporin is a calcineurin inhibitor. It forms a complex with the intracellular immunophilin, cyclophilin. This drug-cyclophilin complex binds to and inhibits the calcium/calmodulin-dependent serine-threonine phosphatase, calcineurin. Inhibition of calcineurin prevents the dephosphorylation and subsequent nuclear translocation of the cytosolic component of the nuclear factor of activated T-cells (NF-AT). This blocks the transcription of early T-cell activation genes, including those for interleukin-2 (IL-2), interferon-gamma, and other cytokines.
3. Indications & Uses
- Prophylaxis of organ rejection in kidney, liver, and heart allogeneic transplants
- Severe, active rheumatoid arthritis not responsive to methotrexate alone
- Severe psoriasis in adults unresponsive to conventional systemic therapy
- Prophylaxis of graft-versus-host disease (GvHD) following bone marrow transplantation
4. Dosage & Administration
Adult Dosage: HIGHLY INDICATION-SPECIFIC AND MUST BE INDIVIDUALIZED. Initial doses: Transplant: 10-15 mg/kg/day orally, 1-2 days pre-transplant, then tapered. Rheumatoid Arthritis: 2.5-5 mg/kg/day in two divided doses. Psoriasis: 2.5-5 mg/kg/day in two divided doses. Dose adjustments are based on TDM and clinical response.
Administration: Administer in two divided doses, 12 hours apart. Take consistently with respect to meals (either always with food or always on an empty stomach) to minimize variability. The microemulsion formulation (Neoral) is less affected by food. Swallow capsule whole with a full glass of water. Do not crush or chew. Grapefruit juice must be avoided.
5. Side Effects
Common side effects may include:
- Hypertension
- Tremor
- Hirsutism
- Gingival hyperplasia
- Hypertrichosis
- Headache
- Nausea
- Diarrhea
- Hyperlipidemia (increased cholesterol & triglycerides)
- Hyperuricemia
- Hypomagnesemia
- Hyperkalemia
6. Drug Interactions
| Drug | Effect | Severity |
|---|---|---|
| Ketoconazole, Fluconazole, Itraconazole, Voriconazole | Inhibit CYP3A4, markedly INCREASE ciclosporin levels (up to 5-fold). Risk of severe toxicity. | Major |
| Rifampicin, Rifabutin, Phenytoin, Carbamazepine, Phenobarbital | Induce CYP3A4, DECREASE ciclosporin levels significantly. Risk of graft rejection. | Major |
| NSAIDs (e.g., Diclofenac, Ibuprofen), Aminoglycosides, Amphotericin B | Additive nephrotoxicity. | Major |
| Potassium-sparing diuretics (Spironolactone), ACE Inhibitors (Ramipril) | Increased risk of hyperkalemia. | Moderate |
| Statins (Atorvastatin, Simvastatin) | Increased risk of myopathy/rhabdomyolysis. | Moderate |
| Digoxin | Increased digoxin levels (reduced renal clearance). | Moderate |
| Metoclopramide | May increase absorption of ciclosporin. | Moderate |
7. Patient Counselling
- DO take the medication at the same times each day, 12 hours apart.
- DO have regular blood tests for drug levels, kidney function, liver function, lipids, and magnesium.
- DO maintain good oral hygiene to minimize gingival hyperplasia.
- DO use effective sun protection (sunscreen, protective clothing) due to increased skin cancer risk.
- DO inform all your doctors and dentists you are taking ciclosporin.
- DON'T stop taking the medication suddenly.
- DON'T change brands without consulting your doctor.
- DON'T consume grapefruit, grapefruit juice, or Seville oranges.
- DON'T take any new prescription, over-the-counter, or herbal medicine (especially St. John's Wort) without checking with your doctor or pharmacist.
- DON'T receive live vaccines (e.g., MMR, Yellow Fever) without explicit approval from your specialist.
8. Toxicology & Storage
Overdose: Symptoms are extensions of its adverse effects: severe nausea, vomiting, drowsiness, headache, tachycardia, severe renal impairment, hepatotoxicity, hyperkalemia, seizures, and potentially fatal infections due to profound immunosuppression.
Storage: Store at room temperature (15-30°C). Protect from light and moisture. Keep in the original container, tightly closed. Do not freeze. Keep out of reach of children.