| Cyclosporin |
Introduction
Cyclosporin has Australian marketing approval for suppression of rejection of kidney, liver and heart transplants and treatment of a number of immune-mediated diseases. It also has a range of recognised off-label uses for treatment of other immune-mediated disorders including some autoimmune diseases.
In dermatology, cyclosporin is used in a wide variety of inflammatory conditions (eg psoriasis, atopic dermatitis, lichen planus) but the difficulties in its use, and the reversibility of benefit on ceasing administration markedly limit its usefulness.
In gastroenterology, it is used in patients with refractory ulcerative colitis that has not responded to other drugs such as corticosteroids.
For information on use in rheumatology, see below.
For information on use of cyclosporin in prevention of lung rejection, see Calcineurin inhibitors
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Cyclosporin is an immunosuppressant drug that works by inhibiting cytokine release from activated T cells. Its action is mediated by inhibition of calcineurin. Calcineurin inhibitors react in the cytoplasm of T-lymphocytes with cellular proteins to form a complex, which blocks the phosphorylase activity of calcineurin. This prevents the phosphorylation of nuclear transcription factors, which can then no longer move into the nucleus to activate transcription of growth factors and proinflammatory cytokines. T cells have limited amounts of calcineurin, but they are dependent upon it for their immune activation.
Oral absorption and bioavailability are quite variable, depending on timing of dose, patient population and formulation used. Different brands of oral cyclosporin have different bioavailability and doses are therefore not directly interchangeable between brands. When prescribing cyclosporin, refer to the specific brand. In general, it is not advisable to switch brands in a patient with a stable, well-controlled medical condition, but if undertaken should be accompanied by additional monitoring.
Cyclosporin is extensively metabolised by the liver with the multiple metabolites being eliminated primarily by biliary excretion. The half-life is highly variable, ranging from 6 to 20 hours.
Adverse effects
Cyclosporin is a potent immunosuppressant with a high potential for toxicity and adverse effects and should therefore be used only under the supervision of a specialist with expertise in its use. The main toxicity is reversible renal impairment and hypertension. Other common adverse effects include hirsutism, gingival hyperplasia, gastrointestinal disturbances, pancreatitis, weight gain, oedema, hepatic dysfunction, hyperlipidaemia, anaemia and other haematological abnormalities, central nervous system disturbances (eg tremor, fatigue, headache), and a burning sensation in the hands and feet. Hyperkalaemia, hypomagnesaemia and hyperuricaemia can occur. An increased rate of malignancies and infections has been reported.
For nontransplant indications, cyclosporin is contraindicated in patients with uncontrolled hypertension, uncontrolled infection, primary or secondary immunodeficiency, IgA deficiency and in patients with impaired baseline renal function.
Clinically significant drug interactions include increased cyclosporin levels with CYP3A4 inhibitors (such as diltiazem, ketoconazole, and erythromycin) and decreased cyclosporin levels with enzyme inducers (including phenytoin, rifampicin, and St John’s wort). The bioavailability of cyclosporin has been shown to increase when the drug is taken concomitantly with grapefruit juice.
Monitoring
Creatinine should be measured every two weeks until the dosage is stable, then monthly. A full blood count, liver function tests and potassium should be measured periodically. Blood pressure should be closely monitored. Routine cyclosporin level monitoring is generally not required when it is used for indications other than transplantation; however, use of high doses should be guided by monitoring of blood levels. Patients not responding may also benefit from therapeutic drug monitoring, to rule out absorption problems and noncompliance.
In the treatment of rheumatoid arthritis, the initial dose of cyclosporin is 2.5 to 3 mg/kg/day (in divided doses) for 6 weeks. Onset of effect is 2 to 4 months. In the absence of a clinical response, the dose can be increased every 1 to 2 months by 0.5 to 1 mg/kg/day to a maximum dose of 5 mg/kg/day. Once a patient has been stable for 3 months, an attempt should be made to reduce the dose to the lowest effective dose. If there is no response after 6 months, despite the maximum dose being given for 3 months, cyclosporin should be discontinued. The dose should be reduced if there is a 30% increase in the creatinine level, and cyclosporin should be ceased if the creatinine rises by 50%. Co-administration with fish oil can reduce the nephrotoxicity and hypertension.
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