The information below is based on the summary of product characteristics approved by regulatory authorities and updated ECCO Guidelines. For full details from the SmPC please click here:
https://www.medicines.org.uk/emc/product/1036/smpc#gref
Additional related ECCO e-Learning resources can be found under IBD Curriculum Topic 6.1-6.11
Introduction and mechanism of action
Ciclosporin (CsA) 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 inhibits the phosphatase activity of calcineurin, which regulates nuclear translocation and subsequent activation of NFAT transcription factors (nuclear factor of activated T-cells), These factors are the ones that normally increase the transcription of genes for IL-2 and related cytokines.
All available evidence suggests that ciclosporin acts specifically and reversibly on lymphocytes. Unlike cytostatic agents, it does not depress haemopoiesis and has no effect on the function of phagocytic cells.
Therapeutic indications - Considered off-label use in IBD
Ulcerative Colitis (UC): Intravenous CsA is a rescue therapy for steroid refractory acute severe UC (ASUC) that require hospitalisation.
IV ciclosporin is also an 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.
IV ciclosporin should be quickly converted to oral administration after discharge and can be continued up to 6 months, while waiting for the effect of maintenance treatment with thiopurines (or another maintenance treatment such as vedolizumab or ustekinumab).
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)
Intravenous administration
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) and low magnesium 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.
Regular full physical examination and measurement of blood pressure are also necessary.
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 addition, experience with IV CsA in the elderly is limited; thus, dose selection should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of comorbidities, interactions with other drugs and increased susceptibility for infections.
Oral administration
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 the effect of maintenance treatment with thiopurines (or another maintenance treatment such as vedolizumab or ustekinumab). Patients receiving long term therapy with CsA should be given prophylaxis for Pneumocystis jirovecii (previously P. carinii) pneumonia, particularly when triple immunosuppression occurs (e.g., CsA, steroids and thioupurines).
Contraindications
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
Anaphylactoid reactions
Available ciclosporine concentrate for infusion contains polyoxyl castor oil, which can cause anaphylactoid reactions following intravenous administration. Symptoms of this reactions may present with flushing of the face and upper thorax, and non-cardiogenic pulmonary oedema (with acute respiratory distress, dyspnoea, wheezing), blood pressure changes and tachycardia. Special caution is therefore necessary in patients who have previously received preparations containing polyoxyl castor oil (e.g., a preparation containing Cremophor® EL) by intravenous injection or infusion, and in patients with an allergic predisposition. With these premises, it is cautious to continuously observe patients receiving IV ciclosporin infusion for at least the first 30 minutes of the infusion and at frequent intervals thereafter. If anaphylaxis occurs, the infusion should be discontinued and adequate measures undertaken. An aqueous solution of adrenaline 1:1000 and a source of oxygen should be available by the bedside. Prophylactic administration of an antihistamine (H1 + H2 blocker) prior to the infusion has also been successfully employed to prevent the occurrence of anaphylactoid reactions.
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.
Infections
Like other immunosuppressants, ciclosporin predisposes patients to the development of a variety of bacterial, fungal, parasitic and viral infections, often with opportunistic pathogens. Activation of latent polyomavirus infections that may lead to polyomavirus associated nephropathy (PVAN), or to JC virus associated progressive multifocal leukoencephalopathy (PML), have been observed in patients receiving ciclosporin. These conditions are often related to a high total immunosuppressive burden and should be considered in the differential diagnosis in immunosuppressed patients with deteriorating renal function or neurological symptoms. Effective pre-emptive and therapeutic strategies should be employed, particularly in patients on multiple long-term immunosuppressive therapy.
Renal toxicity
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. Additional care should be taken when when using ciclosporin together with other active substances that exhibit nephrotoxic synergy.
Hepatotoxicity
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. Also, the pharmacokinetics of ciclosporin may be impacted by changes in liver function during DAA therapy, related to clearance of HCV virus. A close monitoring and potential dose adjustment of ciclosporin is warranted to ensure continued efficacy.
Hypertension
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.
Hyperkalemia
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.
Hypomagnesemia
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.
Hyperuricemia
Caution is required when treating patients with hyperuricemia.
Vaccines
During treatment with ciclosporin, vaccination may be less effective. The use of live attenuated vaccines should be avoided.
Effects on ability to drive and use machines
Ciclosporin may cause neurological and visual disturbances, which may have a moderate influence on the ability to drive and use machines. Caution should be exercised when driving a motor vehicle or operating machines. However, no direct studies on the effects of Sandimmun on the ability to drive and use machines have been performed.
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.
Food interaction
The concomitant intake of grapefruit and grapefruit juice has been reported to increase the bioavailability of ciclosporin.
Combinations with increased risk for nephrotoxicity
Care should be taken when using ciclosporin together with other active substances that exhibit nephrotoxic synergy, including but not limited to: aminoglycosides (including gentamycin, tobramycin), amphotericin B, ciprofloxacin, vancomycin, trimethoprim (+ sulfamethoxazole); fibric acid derivatives (e.g., bezafibrate, fenofibrate); NSAIDs (including diclofenac, naproxen, sulindac); melphalan histamine H2-receptor antagonists (e.g., cimetidine, ranitidine); methotrexate.
During the concomitant use of a drug that may exhibit nephrotoxic synergy, close monitoring of renal function should be performed. If a significant impairment of renal function occurs, the dosage of the co-administered medicinal product should be reduced, or alternative treatment considered.
Concomitant use of ciclosporin and tacrolimus should be avoided due to the risk for nephrotoxicity and pharmacokinetic interaction via CYP3A4 and/or P-gp.
Impact of DAA (Direct-Acting Antiviral) therapy
The pharmacokinetics of ciclosporin may be impacted by changes in liver function during DAA therapy, related to clearance of HCV virus. A close monitoring and potential dose adjustment of ciclosporin is warranted to ensure continued efficacy.
Special situations
Pregnancy
There are no adequate or well-controlled clinical studies in pregnant women using ciclosporin. There is a moderate amount of data on the use of ciclosporin in pregnant patients from postmarketing experience, including transplantation registries and published literature with majority of cases available from transplant recipients. Pregnant women receiving immunosuppressive therapies after transplantation, including ciclosporin and ciclosporin-containing regimens, are at risk of premature delivery (<37 weeks).
Embryo-foetal developmental studies in rats and rabbits with ciclosporin have shown embryofoetal toxicity at dose levels below the maximum recommended human dose (MRHD) based on body surface area.
Therefore, ciclosporin should not be used during pregnancy unless the potential benefit to the mother outweighs the potential risk to the foetus.
Published data from the National Transplantation Pregnancy Registry (NTPR), described pregnancy outcomes in female kidney (482), liver (97), and heart (43) transplant recipients receiving ciclosporin. The data indicated successful pregnancies with a live birth rate of 76% and 76.9%, and 64% in kidney, liver, and heart transplant recipients, respectively. Premature delivery (< 37 weeks) was reported in 52%, 35%, and 35% of kidney, liver, and heart transplant recipients, respectively.
The rates of miscarriages and major birth defects were reported to be comparable to the rates observed in the general population. A potential direct effect of ciclosporin on maternal hypertension, preeclampsia, infections or diabetes could not be excluded given the limitations inherent to registries and postmarketing safety reporting.
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.
Breast-feeding
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.
No adverse effects on fertility were observed in male and female rats up to 15 mg/kg/day.
Fertility
There is limited data on the effect of ciclosporin on human fertility.