Introduction and mechanism of action
Ciclosporin is a calcineurin inhibitor and blocks the transcription of cytokine genes in activated T cells. In particular, ciclosporin inhibits the transcription of interleukin 2. Ciclosporin through formation of a complex with cyclophilin inhibit the phosphatase activity of calcineurin, which regulates nuclear translocation and subsequent activation of NFAT transcription factors (nuclear factor of activated T-cells), which normally increases the transcription of genes for IL-2 and related cytokines.
Therapeutic indications - Considered off-label use in IBD
Ulcerative Colitis (UC): Intravenous ciclosporin is a rescue therapy for steroid refractory severe UC.
IV ciclosporin is also a useful option in patients with severe UC who should avoid steroids, such as those susceptible to steroid psychosis, patients with concomitant severe osteoporosis, or those with poorly controlled diabetes.
Crohn's Disease (CD): The calcineurin inhibitors are of limited value in CD as there are no randomized controlled studies of intravenous ciclosporin, and placebo-controlled trials have shown no efficacy of oral ciclosporin for treatment of CD.
Dosing, administration, and monitoring (ulcerative colitis)
The initial IV dosing is 2 mg/kg/day, thereafter adjusted daily based on serum concentration (trough concentrations should be 200-400 ng/mL).
The concentrate for solution for infusion should be diluted 1:20 to 1:100 with normal saline or 5% glucose and given as a slow intravenous infusion over 2 to 6 hours.
Response should be expected in up to 4 days of IV therapy, after which the drug can be administered orally.
IV ciclosporin therapy requires close monitoring for adverse effects. Baseline levels of electrolytes, creatinine, cholesterol and liver function should be measured. Ciclosporin should be avoided in patients with impaired creatinine clearance because of increased risk for nephrotoxicity. Patients with low cholesterol levels (below 120 mg/dL) should receive nutritional support to lower the risk of seizures. Creatinine levels and electrolytes should be measured every day or every other day during IV treatment, and dosing should be decreased if creatinine levels increases.
Ciclosporin is extensively metabolised by the liver. Dose reduction may be necessary in patients with severe liver impairment to maintain blood levels within the recommended target range.
In patients who respond to IV ciclosporin therapy, the route of administration can be changed to oral ciclosporin, 2 mg of oral agent for each 1 mg of IV ciclosporin, divided to 2 daily doses.
Drug monitoring during oral therapy
Weekly trough levels, weekly or biweekly electrolyte and creatinine levels. Oral ciclosporin can be continued up to 6 months, while waiting for surgery or for the effect of maintenance treatment with thiopurines. Patients receiving long term therapy with CsA should be given prophylaxis for Pneumocystis jirovecii (previously P. carinii) pneumonia.
Hypersensitivity to the active substance or to any of the drug contents.
Combination with products containing Hypericum perforatum (St John´s Wort).
Combination with medicines that are substrates for the multidrug efflux transporter P-glycoprotein or the organic anion transporter proteins (OATP) and for which elevated plasma concentrations are associated with serious and/or life-threatening events, e.g. bosentan, dabigatran etexilate and aliskiren.
Precautions and Adverse Effects
Lymphomas and other malignancies
Like other immunosuppressants, ciclosporin increases the risk of developing lymphomas and other malignancies, particularly those of the skin. The increased risk appears to be related to the degree and duration of immunosuppression.
Patients treated with ciclosporin should be warned to avoid excess unprotected sun exposure and should not receive concomitant ultraviolet B irradiation or PUVA photochemotherapy.
Like other immunosuppressants, ciclosporin predisposes patients to the development of a variety of bacterial, fungal, parasitic and viral infections, often with opportunistic pathogens.
A frequent and potentially serious complication of ciclosporin therapy is an increase in serum creatinine and urea. These functional changes are dose-dependent and are initially reversible, usually responding to dose reduction. Frequent monitoring of renal function is required.
Ciclosporin may cause dose-dependent, reversible increases in serum bilirubin and in liver enzymes. There have been solicited and spontaneous reports of hepatotoxicity and liver injury including cholestasis, jaundice, hepatitis and liver failure in patients treated with ciclosporin. Close monitoring of hepatic function is required and abnormal values may necessitate dose reduction.
Regular monitoring of blood pressure is required during ciclosporin therapy. If hypertension develops, appropriate antihypertensive treatment must be instituted.
Increase of Blood lipids
Ciclosporin has been reported to induce a reversible slight increase in blood lipids, it is advisable to perform lipid determinations before treatment and after the first month of therapy.
Ciclosporin enhances the risk of hyperkalemia, especially in patients with renal dysfunction. Caution is required when ciclosporin is co-administered with potassium-sparing drugs (e.g. potassium-sparing diuretics, angiotensin converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists) or potassium-containing medicinal products as well as in patients on a potassium rich diet.
Ciclosporin enhances the clearance of magnesium. This can lead to symptomatic hypomagnesemia. Control of serum magnesium levels is therefore recommended. If considered necessary, magnesium supplementation should be given.
Caution is required when treating patients with hyperuricemia.
During treatment with ciclosporin, vaccination may be less effective. The use of live attenuated vaccines should be avoided.
Interactions with other Drugs
Various agents are known to either increase or decrease plasma ciclosporin levels usually by inhibition or induction of enzymes involved in the metabolism of ciclosporin, in particular CYP3A4.
Ciclosporin is also an inhibitor of CYP3A4, the multidrug efflux transporter P-glycoprotein and organic anion transporter proteins (OATP) and may increase plasma levels of co-medications that are substrates of this enzyme and/or transporters.
Drugs that decrease ciclosporin levels
All inducers of CYP3A4 and/or P-glycoprotein are expected to decrease ciclosporin levels.
Examples of drugs that decrease ciclosporin levels: Barbiturates, carbamazepine, oxcarbazepine, phenytoin; nafcillin, intravenous sulfadimidine, probucol, orlistat, hypericum perforatum (St. John's wort), ticlopidine, sulfinpyrazone, terbinafine, bosentan, rifampicin, octreotide.
Drugs that increase ciclosporin levels
All inhibitors of CYP3A4 and/or P-glycoprotein may lead to increased levels of ciclosporine. Examples are: Nicardipine, metoclopramide, oral contraceptives, methylprednisolone (high dose), allopurinol, cholic acid and derivatives, protease inhibitors, imatinib, colchicine, nefazodone, macrolide antibiotics, azole antibiotic, verapamil, telaprevir, amiodarone, danazol, diltiazem, imatinib.
Animal studies have shown reproductive toxicity in rats and rabbits.
Experience with ciclosporin in pregnant women is limited. Pregnant women receiving immunosuppressive therapies after transplantation, including ciclosporin and ciclosporin-containing regimens, are at risk of premature delivery.
A limited number of observations in children exposed to ciclosporin in utero are available, up to an age of approximately 7 years. Renal function and blood pressure in these children were normal. However, there are no adequate and well-controlled studies in pregnant women and therefore ciclosporin should not be used during pregnancy unless the potential benefit to the mother justifies the potential risk to the foetus.
Ciclosporin passes into breast milk. Mothers receiving treatment with ciclosporin should not breast-feed because of the potential to cause serious adverse drug reactions in breast-fed newborns/infants. A decision should be made whether to abstain from breast-feeding or to abstain from using the medicinal drug, taking into account the importance of the medicinal product to the mother.
There is limited data on the effect of ciclosporin on human fertility.