Usage
Ciclosporin is an immunosuppressant medication primarily used to prevent organ rejection after transplantation (kidney, liver, heart). It is also prescribed for the treatment of various autoimmune diseases, including severe rheumatoid arthritis, psoriasis, atopic dermatitis, nephrotic syndrome, and uveitis. Pharmacologically, ciclosporin is classified as a calcineurin inhibitor. It works by inhibiting the activation of T lymphocytes, crucial components of the immune system responsible for attacking foreign tissues or, in the case of autoimmune diseases, the body’s own tissues.
Alternate Names
Ciclosporin is also known as cyclosporine, cyclosporin A, and cyclosporine modified. Brand names include Neoral, Sandimmune, Gengraf, and Ikervis (ophthalmic).
How It Works
Pharmacodynamics: Ciclosporin exerts its immunosuppressive effects by selectively targeting T lymphocytes. It binds to cyclophilin, forming a complex that inhibits calcineurin. Calcineurin is essential for activating the transcription factor NFAT (nuclear factor of activated T cells), which promotes the expression of interleukin-2 (IL-2). IL-2 is a cytokine crucial for T cell proliferation and activation. By inhibiting IL-2 production, ciclosporin suppresses the immune response.
Pharmacokinetics:
- Absorption: Oral absorption is variable and incomplete, influenced by food intake and the specific formulation used (e.g., Neoral, Sandimmune). Modified formulations offer improved and more consistent absorption.
- Distribution: Ciclosporin is highly lipophilic and extensively distributes into tissues, including erythrocytes and lipoproteins.
- Metabolism: Extensively metabolized by the cytochrome P450 system, primarily CYP3A4, producing several metabolites, some of which possess immunosuppressive activity.
- Elimination: Primarily eliminated through biliary excretion into feces, with a small portion excreted in urine. The terminal half-life is highly variable (approximately 18 hours), and clearance is influenced by liver function.
Mode of Action: Ciclosporin inhibits the activation and proliferation of T lymphocytes by preventing the transcription of IL-2 and other cytokines involved in the immune response. It binds to cytosolic protein cyclophilin, forming a complex that then inhibits the phosphatase activity of calcineurin. This inhibition blocks the dephosphorylation and nuclear translocation of NFAT, thus preventing its binding to the IL-2 promoter region and reducing IL-2 production.
Elimination Pathways: Primarily biliary excretion via feces; hepatic metabolism by CYP3A4 enzymes plays a significant role. Minor renal excretion.
Dosage
Ciclosporin dosage is highly individualized based on the patient’s condition, age, weight, organ function, and other factors. Therapeutic drug monitoring is essential to ensure appropriate blood levels and minimize toxicity.
Standard Dosage
Adults: The initial dose varies depending on the indication. For organ transplantation, the initial oral dose is typically 15 mg/kg/day divided into two doses, starting 4-12 hours before transplantation. For autoimmune conditions, starting doses are lower, usually between 2.5 to 5 mg/kg/day divided twice daily. Maintenance doses are adjusted based on therapeutic drug monitoring.
Children: Pediatric dosing is weight-based and requires careful monitoring. For organ transplantation, initial doses are similar to adults, while autoimmune disease doses are lower and individualized. Higher doses per kg of body weight may be required in children than in adults.
Special Cases:
- Elderly Patients: Reduced doses may be necessary due to age-related decline in renal function. Close monitoring of renal function and blood pressure is crucial.
- Patients with Renal Impairment: Dosage adjustments are required based on the degree of renal impairment. Lower starting doses and careful monitoring are essential.
- Patients with Hepatic Dysfunction: Ciclosporin metabolism is mainly hepatic. Dosage adjustments may be necessary for patients with hepatic impairment, especially if they have significantly impaired liver function.
- Patients with Comorbid Conditions: Careful consideration should be given to patients with conditions like hypertension, diabetes, or other metabolic disorders as cyclosporine can exacerbate these conditions. Dosage adjustment and close monitoring might be necessary.
Clinical Use Cases
Ciclosporin dosages in specific clinical settings like intubation, surgical procedures, mechanical ventilation, ICU use, or emergency situations are determined by the underlying condition being treated (organ transplant rejection or autoimmune disease) and require individualization based on patient factors and therapeutic drug monitoring. No standard dosages exist specifically for these settings.
Dosage Adjustments
Dosage adjustments are frequently required based on blood trough levels, clinical response, and the occurrence of adverse effects. Patients with renal or hepatic impairment, metabolic disorders, or genetic polymorphisms affecting CYP3A4 activity require specific dose adjustments and close monitoring.
Side Effects
Common Side Effects:
- Nephrotoxicity (kidney damage)
- Hypertension (high blood pressure)
- Tremor
- Hirsutism (excessive hair growth)
- Gingival hyperplasia (gum overgrowth)
- Hyperlipidemia (high cholesterol)
- Gastrointestinal disturbances (nausea, vomiting, diarrhea)
- Headache
Rare but Serious Side Effects:
- Infections (due to immunosuppression)
- Seizures
- Hepatotoxicity (liver damage)
- Anaphylactic reactions
- Malignancies (increased risk of certain cancers)
- Posterior reversible encephalopathy syndrome (PRES)
Long-Term Effects:
- Chronic kidney disease
- Increased risk of cardiovascular disease
- Increased risk of skin cancer and other malignancies
Adverse Drug Reactions (ADR):
- Thrombotic microangiopathy (TMA)
- Hemolytic uremic syndrome (HUS)
- DRESS syndrome (drug reaction with eosinophilia and systemic symptoms)
Contraindications
- Hypersensitivity to ciclosporin
- Uncontrolled hypertension
- Uncontrolled infections
- Malignancy (except certain skin cancers)
- Concurrent use of specific medications (e.g., live attenuated vaccines, St. John’s Wort)
- Breastfeeding (generally contraindicated)
Drug Interactions
Ciclosporin has numerous clinically significant drug interactions. It is metabolized by CYP3A4 and can act as both a substrate and an inhibitor of this enzyme.
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CYP450 Interactions: Drugs that inhibit CYP3A4 (e.g., azole antifungals, macrolide antibiotics, calcium channel blockers) can increase ciclosporin levels, leading to toxicity. Drugs that induce CYP3A4 (e.g., rifampin, anticonvulsants) can decrease ciclosporin levels, reducing efficacy.
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Other Interactions:
- Nephrotoxic drugs (e.g., aminoglycosides, NSAIDs): increased risk of nephrotoxicity.
- Potassium-sparing diuretics: increased risk of hyperkalemia.
- Statins: increased risk of myopathy.
- Grapefruit juice: inhibits CYP3A4, increasing ciclosporin levels.
Pregnancy and Breastfeeding
- Pregnancy Safety Category: C (FDA). Ciclosporin can cross the placenta and is associated with an increased risk of prematurity and low birth weight. Use only if the potential benefit outweighs the potential risk to the fetus.
- Breastfeeding: Ciclosporin is excreted into breast milk. Breastfeeding is generally contraindicated during ciclosporin therapy due to the potential for immunosuppression and other adverse effects in the infant.
Drug Profile Summary
- Mechanism of Action: Calcineurin inhibitor; suppresses T lymphocyte activation and IL-2 production.
- Side Effects: Nephrotoxicity, hypertension, tremor, hirsutism, gingival hyperplasia, infections.
- Contraindications: Hypersensitivity, uncontrolled hypertension, infections, malignancy, breastfeeding.
- Drug Interactions: Numerous, primarily CYP3A4-mediated; nephrotoxic drugs, potassium-sparing diuretics.
- Pregnancy & Breastfeeding: Category C; generally contraindicated during breastfeeding.
- Dosage: Highly individualized; typically 2.5-15 mg/kg/day divided twice daily depending on indication.
- Monitoring Parameters: Ciclosporin blood trough levels, renal function (serum creatinine, BUN), liver function tests, blood pressure, electrolyte levels.
Popular Combinations
Ciclosporin is often used in combination with other immunosuppressants, such as corticosteroids (e.g., prednisone) and mycophenolate mofetil, to prevent organ rejection. In rheumatoid arthritis, it may be combined with methotrexate.
Precautions
- General Precautions: Monitor renal function, liver function, blood pressure, and electrolyte levels regularly. Screen for infections.
- Specific Populations: Dose adjustments are essential for elderly patients and those with renal or hepatic impairment.
- Pregnant Women: Use with caution; monitor closely.
- Breastfeeding Mothers: Avoid breastfeeding.
- Children & Elderly: Close monitoring is required due to differences in pharmacokinetics.
- Lifestyle Considerations: Limit alcohol intake; avoid grapefruit juice.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Ciclosporin?
A: Ciclosporin dosage is highly individualized. For organ transplantation, the initial oral dose is typically 15 mg/kg/day divided twice daily, then adjusted based on blood levels. For autoimmune conditions, the initial dose is usually lower, in the range of 2.5-5mg/kg/day divided twice daily.
A: Primarily metabolized by CYP3A4 in the liver.
Q3: What are the most serious side effects of Ciclosporin?
A: Nephrotoxicity, infections, hypertension, neurotoxicity (including seizures), hepatotoxicity, and malignancies.
Q4: What are the main drug interactions with Ciclosporin?
A: Drugs that inhibit or induce CYP3A4 (e.g., azole antifungals, macrolide antibiotics, rifampin), nephrotoxic drugs (e.g., NSAIDs, aminoglycosides), and potassium-sparing diuretics.
Q5: Can Ciclosporin be used during pregnancy?
A: It can be used if the potential benefits outweigh the risks, but it’s categorized as Pregnancy Category C due to the potential for fetal harm.
Q6: Is it safe to breastfeed while taking Ciclosporin?
A: Generally contraindicated due to the drug’s excretion in breast milk and potential adverse effects on the infant.
Q7: How should Ciclosporin be monitored?
A: Regular monitoring of ciclosporin blood trough levels, renal function tests (serum creatinine, BUN), liver function tests, blood pressure, and electrolyte levels are crucial.
Q8: What is the mechanism of action of Ciclosporin?
A: Ciclosporin inhibits calcineurin, which ultimately blocks the activation of T lymphocytes and the production of interleukin-2 (IL-2), suppressing the immune response.
Q9: What are the common indications for using Ciclosporin?
A: Prevention of organ rejection after transplantation and treatment of autoimmune diseases like rheumatoid arthritis, psoriasis, atopic dermatitis, nephrotic syndrome and uveitis.
A: Yes, different formulations exist, including Neoral, Sandimmune, Gengraf, and Ikervis (ophthalmic). Some formulations offer improved bioavailability and consistency of absorption.
