Usage
Cyclosporine is an immunosuppressant prescribed for the prevention of organ rejection following allogeneic transplantation of kidney, liver, and heart. It is also used in the treatment of severe, active rheumatoid arthritis unresponsive to methotrexate and severe, recalcitrant plaque psoriasis in patients who have failed to respond to other systemic therapies. Its pharmacological classification is immunosuppressant. Cyclosporine’s mechanism of action involves inhibiting calcineurin, a phosphatase necessary for T-cell activation. This inhibition prevents the production of cytokines, particularly interleukin-2, reducing the immune response.
Alternate Names
Cyclosporine is also known as ciclosporin and cyclosporin A. Brand names include Neoral, Sandimmune, and Gengraf.
How It Works
Pharmacodynamics: Cyclosporine primarily acts on T lymphocytes, inhibiting their activation and proliferation. It reduces the production of inflammatory cytokines, leading to immunosuppression.
Pharmacokinetics:
- Absorption: Oral absorption is incomplete and variable. Modified formulations (Neoral, Gengraf) have improved bioavailability compared to Sandimmune.
- Metabolism: Extensively metabolized by the liver, primarily by CYP3A4 enzymes.
- Elimination: Primarily eliminated through bile and feces, with minor renal excretion.
Mode of Action: Cyclosporine binds to cyclophilin, forming a complex that inhibits calcineurin. This inhibition blocks the dephosphorylation of the nuclear factor of activated T-cells (NFAT), preventing its translocation to the nucleus and reducing the transcription of cytokine genes.
Elimination Pathways: Predominantly biliary excretion, with a small amount excreted in the urine. Metabolism occurs mainly through hepatic CYP3A4 enzymes.
Dosage
Standard Dosage
Adults:
- Organ Transplantation: Initial oral dose: 15 mg/kg (Sandimmune) or 7-9 mg/kg (modified formulations) divided twice daily. Dose adjustments are based on blood levels and clinical response, targeting trough levels for specific organs.
- Rheumatoid Arthritis: Initial oral dose: 2.5 mg/kg/day of a modified formulation divided twice daily. Can increase by 0.5-0.75 mg/kg/day every 8-12 weeks, not to exceed 4 mg/kg/day.
- Psoriasis: Initial oral dose: 2.5 mg/kg/day of a modified formulation divided twice daily. Can increase by 0.5 mg/kg/day every 4 weeks, not to exceed 4 mg/kg/day.
Children: Dosage is determined by the child’s weight, the transplanted organ, and concomitant medications. Pediatric use requires careful monitoring due to increased clearance and potential for nephrotoxicity.
Special Cases:
- Elderly Patients: Initiate with lower doses and monitor closely for adverse effects, particularly nephrotoxicity and hypertension.
- Patients with Renal Impairment: Dose reduction is necessary, guided by renal function and trough levels.
- Patients with Hepatic Dysfunction: Dose adjustment may be required. Close monitoring of liver function tests and cyclosporine levels is essential.
- Patients with Comorbid Conditions: Individualized dosing based on the specific comorbidity, e.g., dose adjustments may be necessary for patients with diabetes, hypertension, or other conditions.
Clinical Use Cases
Cyclosporine dosing in these settings is generally consistent with the standard dosage guidelines for transplantation, focusing on achieving therapeutic blood levels and minimizing toxicity. Dosage adjustments may be needed based on patient response and tolerability.
- Intubation: Not specifically indicated.
- Surgical Procedures: Peri-operative dosing in transplant surgery follows established protocols.
- Mechanical Ventilation: Not specifically indicated.
- Intensive Care Unit (ICU) Use: Dosage adjustments may be necessary in critically ill patients based on organ function and drug clearance.
- Emergency Situations: Not typically used.
Dosage Adjustments:
Dosage adjustments are based on blood trough concentrations, clinical response, and adverse events. Renal and hepatic function should be monitored closely, and dose adjustments may be needed in patients with impairment. Drug interactions, especially with CYP3A4 inhibitors or inducers, necessitate dosage modification. Genetic polymorphisms affecting drug metabolism may also require individualized dosing strategies.
Side Effects
Common Side Effects: Hypertension, nephrotoxicity, tremor, hirsutism, gingival hyperplasia, hyperlipidemia, gastrointestinal disturbances.
Rare but Serious Side Effects: Infections, malignancies (lymphoma, skin cancer), seizures, hepatotoxicity, thrombotic microangiopathy.
Long-Term Effects: Chronic nephrotoxicity, increased risk of malignancies, hypertension, hyperlipidemia.
Adverse Drug Reactions (ADR): Anaphylaxis, Stevens-Johnson syndrome, angioedema, posterior reversible encephalopathy syndrome.
Contraindications
Absolute contraindications include hypersensitivity to cyclosporine. Relative contraindications include uncontrolled hypertension, significant renal dysfunction, certain malignancies, and concurrent use of nephrotoxic drugs or live vaccines.
Drug Interactions
Cyclosporine interacts with numerous drugs, particularly those metabolized by CYP3A4. Inhibitors of CYP3A4 (e.g., azole antifungals, macrolide antibiotics, grapefruit juice) increase cyclosporine levels, while inducers (e.g., rifampin, anticonvulsants) decrease levels. Other significant interactions include nonsteroidal anti-inflammatory drugs (NSAIDs), which can exacerbate nephrotoxicity.
Pregnancy and Breastfeeding
Cyclosporine is classified as Pregnancy Category C. It can cross the placenta and is present in breast milk. It should be used during pregnancy and breastfeeding only if the potential benefit justifies the potential risk to the fetus or infant.
Drug Profile Summary
- Mechanism of Action: Calcineurin inhibitor, blocks T-cell activation.
- Side Effects: Nephrotoxicity, hypertension, tremor, hirsutism.
- Contraindications: Hypersensitivity.
- Drug Interactions: CYP3A4 inhibitors/inducers, nephrotoxic drugs.
- Pregnancy & Breastfeeding: Use with caution, potential fetal/infant risks.
- Dosage: Varies based on indication and formulation. Requires therapeutic drug monitoring.
- Monitoring Parameters: Cyclosporine blood levels, renal function, blood pressure, liver function tests.
Popular Combinations
Cyclosporine is often used in combination with other immunosuppressants, such as corticosteroids and azathioprine, in transplant recipients. In rheumatoid arthritis, it may be combined with methotrexate.
Precautions
Monitor renal function, blood pressure, and cyclosporine blood levels closely. Pre-screening for infections and malignancies is essential. Avoid grapefruit juice and other CYP3A4 inhibitors. Vaccination with live attenuated vaccines is contraindicated.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Cyclosporine?
A: The dosage varies depending on the indication, formulation, and patient-specific factors. Therapeutic drug monitoring is crucial for optimizing dosage.
Q2: How should Cyclosporine be administered?
A: Orally in two divided doses, preferably 12 hours apart. Modified formulations (Neoral, Gengraf) improve bioavailability. Intravenous administration is used in specific situations, like pre-transplant or when oral administration is not feasible.
Q3: What are the major side effects of Cyclosporine?
A: Nephrotoxicity, hypertension, tremor, hirsutism, and increased risk of infections.
Q4: What are the key drug interactions with Cyclosporine?
A: Drugs that inhibit or induce CYP3A4 enzymes, nephrotoxic agents, and certain antifungals and antibiotics.
Q5: Can Cyclosporine be used during pregnancy or breastfeeding?
A: Use with caution. It’s essential to weigh the potential benefits against the potential risks to the fetus or infant.
A: Primarily by hepatic CYP3A4 enzymes.
Q7: What monitoring parameters are essential for patients on Cyclosporine?
A: Cyclosporine trough levels, blood pressure, renal function (serum creatinine, creatinine clearance), liver function tests, and signs of infection.
Q8: What are the contraindications to using Cyclosporine?
A: Hypersensitivity to cyclosporine, uncontrolled hypertension, and certain malignancies.
Q9: What is the role of therapeutic drug monitoring in Cyclosporine therapy?
A: Crucial for optimizing efficacy and minimizing toxicity, particularly nephrotoxicity. Trough levels are commonly measured to guide dose adjustments.
Q10: What patient education points are important for those prescribed Cyclosporine?
A: Adherence to the prescribed regimen, awareness of potential side effects, importance of regular monitoring, and avoidance of grapefruit juice and other interacting substances. Also, education regarding infection prevention measures is essential.
