Cyclosporine
- Article Author:
- Carolina Tapia
- Article Author:
- Trevor Nessel
- Article Editor:
- Patrick Zito
- Updated:
- 9/29/2020 4:16:56 PM
- For CME on this topic:
- Cyclosporine CME
- PubMed Link:
- Cyclosporine
Indications
Cyclosporine is an immunosuppressive agent used to treat organ rejection post-transplant. It also has uses in certain other autoimmune diseases.[1][2][3][4][5]
FDA approved indications include:
- In solid organ transplantation, it has clinical use for the treatment of organ rejection in kidney, liver, and heart allogeneic transplants.
- In patients with rheumatoid arthritis, it is indicated when the disease has not adequately responded to methotrexate.
- For psoriasis, indications include the treatment of adult, nonimmunocompromised patients with severe, recalcitrant, plaque psoriasis who have not responded to at least one systemic therapy.
- In patients with amyotrophic lateral sclerosis (ALS or Lou Gehrig disease), cyclosporin has the approval to treat amyotrophic lateral sclerosis and its variants.
- In nephrotic syndrome, it is indicated to treat focal segmental glomerulosclerosis not responding to corticosteroids.
- In individuals with graft vs. host disease (GVHD), it prevents and treats the disease.
- In the case of uveitis, cyclosporin is indicated for refractory posterior uveitis and Behcet disease.
Non-FDA approved indications include:
- Allergic conjunctivitis, keratoconjunctivitis, Langerhans cells histiocytosis, ocular graft vs. host disease, autoimmune hepatitis, Duchenne muscular dystrophy, ulcerative colitis, pure red cell aplasia, Henoch Schonlein purpura nephritis
Mechanism of Action
Cyclosporine has demonstrated to suppress cell-mediated immune reactions. Research has detected no effects on phagocytic function in animals, and it does not cause bone marrow suppression in animal or human models.[6][7]
The mechanism of action of cyclosporine is a calcineurin inhibitor, a cytochrome P450 3A4 inhibitor, and a P-glycoprotein inhibitor. Cyclosporin A (CsA) inhibits the synthesis of interleukins (IL), including IL-2, which is essential for self-activation T lymphocytes (LT) and their differentiation. Cyclosporine is effective due to specific and reversible inhibition of immunocompetent lymphocytes in the G0- and G1-phase of the cell cycle. The T-helper cell is the primary target, although it may also suppress T-suppressor cells. The LT-B-lymphocyte (LB) co-operation is essential for activation of LB; the latter also gets inhibited. Research has demonstrated that CsA had an inhibiting effect on CD4+ CD25+ Tregs, which might block the host immune tolerance potentiality
Metabolism: Via hepatic CYP3A4undergoes metabolism into a pair of hydroxylated derivatives (AM1 and AM9), and one N-methylated derivative (AM4N).
Enzymes inhibited: CYP3A4 and P-glycoprotein
Half-Life: 8.4 to 27 hours: The time to peak blood cyclosporine concentrations (Tmax) ranges from 1.5 to 2 hours following oral administration of Cyclosporine Oral Solution USP MODIFIED.
Clearance: 5 to 7 mL/min/kg in patients recipients of renal or liver allografts, appears to be somewhat slower in cardiac transplant patients.
Excretion: Mainly bile and feces
Factors that are known to influence absorption: time post-transplant, bile flow, dietary composition, gastrointestinal state, liver function, small bowel length, vehicle.
Administration
Dosing for Organ Transplant in Adults
Oral
- Four to 12 hours pre-transplant: 14 to 18 mg/kg by mouth for one dose
- One to two weeks post-transplant: 5 to 15 mg/kg per day by mouth divided twice a day
- Reduce the dose by 5% per week until 5 to 10 mg/kg per day by mouth divided twice per day
Intravenous (IV) (maximum concentration 2.5 mg/dL)
- Four to 12 hours pre-transplant IV: 5 to 6 mg/kg IV for one dose over 2 to 6 hours
- Post-transplant, until the patient can tolerate oral therapy: 2 to 10 mg/kg IV once per day
Focal Segmental Glomerulosclerosis: Oral 3 mg/kg/day every 12 hours
Rheumatoid Arthritis: Oral (modified): Initially: 2.5 mg /kg per day every 12 hrs, increase 0.5 to 0.75 mg /kg per day after eight weeks if the response has not been effective. Maximum dose: 4 mg/kg per day
Psoriasis: Oral (modified): Initially: 2.5 mg/kg per day every 12 hours, increase 0.5 mg/kg per day after four weeks if the response has not been effective. Maximum dose: 4 mg/kg per day
Adjust dosage according to trough levels.
Adverse Effects
Adverse effects include[8][9][10]:
- Cardiovascular: hypertension, arrhythmia
- Renal System: Decreases glomerular filtration rate (GFR) due to an increased tone of the glomerular afferent arterioles. Serum creatinine concentration rises and decreases creatinine clearance. The undesirable effects correlate with the duration of treatment and dose.
- Endocrinological and metabolic: Dyslipidemia (predisposing factors such as hypertension), hypomagnesemia, hyperkalemia, gynecomastia hypertrichosis.
- Neurotoxicity: There have been reports of convulsions, especially in combination with high dose methylprednisolone, encephalopathy, anxiety, headache, and fever.
- Others: There is an increased risk for the development of skin and lymphoproliferative malignancies in cyclosporine-treated psoriasis patients.
- Increase in the occurrence of malignant lymphomas.
- Increase the level of inflammatory cytokines such as TNF-alfa.
- Increase the infection risk.
Contraindications
Contraindications to cyclosporin include:
- Drugs: amphotericin B deoxycholate, atorvastatin, bosentan, cidofovir, elbasvir/grazoprevir, flibanserin, lomitapide, mifepristone, neomycin oral, pitavastatin, saquinavir, simvastatin, sitaxentan, tacrolimus
- BCG
- Attenuated vaccine
- Hypersensitivity to cyclosporine or any of the ingredients of the formulation (such as polyoxyethylated castor oil).
- Active infection
- Patients with impaired renal function
- Asthma
- History of blood dyscrasias
- Uncontrolled hypertension
- In the case of psoriasis: Concomitant PUVA therapy, ultraviolet B (UVB) radiation, coal tar, methotrexate, other immunosuppressants
Monitoring
Patient BUN/SCr, Mg++, and blood pressure require monitoring while on therapy. Uric acid monitoring is debatable.
Therapeutic monitoring of cyclosporine in transplant patients is a valuable tool in adjusting drug dosage to prevent acute rejection, nephrotoxicity, and predictable dose-dependent adverse reactions.
The ideal therapeutic range of cyclosporine in whole blood as follows:
Kidney transplant: 200 to 400 ng/ml in the first week of post-transplantation; 125 to 275 ng/ml in the second week to the sixth month of post-transplantation; 100 to 150 ng/ml in the seventh to twelfth month of post-transplantation; and 75 to 160 ng/ml 1 year after post-transplantation (residual concentration predose)
Heart transplant: 250 to 350 ng/mL on the first 6 months; 100 to 200 ng/mL in 6 months to 1 year after post-transplantation (residual concentration predose)
Liver transplant: 250 to 350 ng/mL for the first 6 months; 100-200 ng/mL in the sixth month to 1 year after post-transplantation (residual concentration predose)
The range between effective cyclosporine concentrations and the concentrations associated with serious toxicity is fairly narrow.
Sub-optimal doses or concentrations can lead to therapeutic failure or severe toxicity.
Cyclosporine is subject to therapeutic monitoring based on pharmacokinetics measures.
Cyclosporine has low-to-moderate within-subject variability.
Toxicity
In the event of toxicity, establishing a patent airway is a priority. Watch for signs of respiratory insufficiency and provide ventilation assistance if needed. Monitor for shock and treat if necessary. Anticipate seizures and treat if necessary, and initiate supportive and symptomatic treatment. When overdosage occurs in patients prescribed cyclosporine therapy, the clinician may withhold the drug for a few days, or alternate-day therapy initiated until the patient stabilizes.
Hemodialysis only eliminates 1% of the dose.
Monitoring serum CsA levels is mandatory, and patients may need multiple dose adjustments during the treatment period. The CVC (central venous catheter) line not used to infuse CsA can be safely used to collect blood samples for serum CsA levels. The procedure can be performed immediately after interrupting the infusion if using the appropriate technique for discarding 5 mL of blood.
Drugs that can decrease CsA levels: rifampicin, rifabutin, isoniazid, barbiturates, phenytoin, carbamazepine, IV trimethoprim, IV sulfadimidine, imipenem, cephalosporins, terbinafine, ciprofloxacin, ticlopidine, octreotide, and nefazodone.
Drugs that can increase CsA levels: verapamil, diltiazem, amlodipine, nicardipine, ketoconazole, fluconazole, itraconazole, erythromycin, clarithromycin, azithromycin, saquinavir, indinavir, nelfinavir, ritonavir, methylprednisolone.
Enhancing Healthcare Team Outcomes
Cyclosporine is a widely used immunosuppressive drug, especially in transplant patients. The majority of patients on cyclosporine can be followed as outpatients by the nurse practitioner, primary care provider, an internist, and the specialist. The clinical staff must obtain cyclosporine levels regularly to prevent acute rejection, nephrotoxicity, and predictable dose-dependent adverse reactions.
Further, the pharmacist and nurse should educate the patient on potential complications of the drug and the need to follow up. Pharmacists should verify dosing, and also given the extensive drug-drug interaction list for cyclosporine, thorough medication reconciliation is in order, with any red flags reported promptly to the rest of the healthcare team. Nursing can monitor both for treatment effectiveness as well as for adverse effects of the medication, alerting the treating physician to any concerns. Finally, patients on cyclosporine are at a slight risk of lymphoproliferative malignancies and infections; thus, a thorough history and physical exam are vital at each clinic visit.
Cyclosporine therapy has a much higher opportunity for patient success with the communication and collaboration of an interprofessional healthcare team approach. [Level V]