Ciclosporin

Discuss the indication for ciclosporin?

Acute severe colitis not responding to steroids

  • Rescue therapy with ciclosporin could be considered on the third day of intensive treatment if predictive factors are poor (>8 bloody stools, or 3-8 bloody stools and CRP>45).
  • Ciclosporin is suitable for patients with persistent severe colitis after 7 days of intravenous steroids who do not need immediate colectomy

Discuss the mechanism of action of ciclosporin?

It is a lipophilic 11-amino acid cyclic peptide of fungal origin with strong immunosuppressive actions thatacts primarily through inhibition of T-helper cells by binding to cyclophilin (cytosolic protein). This ciclosporin-cyclophilin complex binds to and inhibits calcineurin, a calcium dependent protein phosphatase required for the activation of transcription factors used in early cytokine production. In particular interleukin 2 (IL-2), a cytokine required for T cell activation and proliferation is blocked

Discuss the dose of ciclosporin?

2mg/kg/day by continuous IV infusion (continue up to 7 days depending on the response).
Some centres use oral ciclosporin 5-8mg/kg/day in 2 divided doses with small studies suggesting that oral ciclosporin has the same efficacy and toxicity as the intravenous form.

Discuss the contraindications for ciclosporin use?

  • Moderate to severe renal impairment (creatinine > 130 micromol/litre or 20-30% reduction in eGFR)
  • Current malignancy (previous malignancies may also be a contraindication).
  • Current infection.
  • Uncontrolled hypertension
  • Immunodeficiency

Discuss the tests needed before using ciclosporin?

Check the renal function, LFTs, magnesium and cholesterol.

Discuss magnesium and cholesterol?

The risk of seizures is increased in patients with a low cholesterol (<3.0 mmol/l) or magnesium (<0.50 mmol/l). Oral therapy is an alternative in these circumstances. Microemulsion ciclosporin does not contain the chromophore present in intravenous ciclosporin that has been associated with neurotoxicity causing seizures in patients with hypocholesterolaemia or hypomagnesaemia.

  • Monitoring
  • Check ciclosporin levels on day 2 and then every 3 days (aim for trough levels of 150-250 ng/ml).
  • Monitor U&E, LFT, Mg and Cholesterol on alternate days.
  • Reduce the ciclosporin dose by 25% if any of these occur
    • serum creatinine rises by more than 30% from baseline
    • SBP is > 150mm Hg or DBP exceeds 90 mm Hg despite antihypertensive treatment.
    • Serum liver enzymes double
    • Hypertension is treated with a calcium channel blocker such as nifedepine, because it may offer protection against ciclosporin induced nephrotoxicity. However the use of calcium channel blockers can lead to a rise in serum ciclosporin levels, so careful drug level monitoring is essential.

Discuss conversion to oral ciclosporin?

Once response occurs IV ciclosporin is converted to oral ciclosporin in 2 divided doses. An oral dose of 5mg/kg/day is equivalent to 2mg/kg/day intravenous dose since the oral bioavailability of neural (ciclosporin) is 30-40%. However the blood levels need to be monitored and the dose titrated accordingly. For patients who are not on an immunomodulator (azathioprine or 6-mercaptopurine) oral ciclosporin should be continued for 3 months whilst an immunomodulator is introduced.

Discuss ciclosporin levels?

The levels could be done at anytime during the 24 hr infusion. Trough levels are needed once the patient is on oral ciclosporin. Aim for ciclosporin levels of 150-250 ng/ml.

Discuss PCP prophylaxis?

PCP prophylaxis with Co-trimoxazole (960mg 1 tab administered three times per week) should be considered especially with triple immunosuppression (steroids, azathiopurine and ciclosporin)

Discuss the side effects?

  • Nephrotoxicity — acute renal failure. It is largely reversible with dose reduction. Other renal effects of ciclosporin include tubular dysfunction and rarely a haemolytic syndrome
  • Hypertension — is caused by renal vasoconstriction and sodium retention. It responds to dose reduction. Calcium channel blockers, particularly diltiazem are usually considered the drugs of choice if antihypertensive therapy is needed in the setting of ciclosporin therapy.
  • Neurotoxicity —severe headache, visual abnormalities, seizures, tremor.
    Other neuropsychiatric neurologic symptoms such as headache, psychosis, seizures, speech apraxia, dysesthesias, anxiety and sleep disturbances, are rare. The neurologic side effects are usually reversible following change to an oral preparation, lowering the drug dose, or drug discontinuation.
  • Metabolic abnormalities — Glucose intolerance, hyperuricemia, hyperkalaemia (via effects on renal function)
  • Infections — Bacterial, viral (most often cytomegalovirus), and fungal infections.
  • Risk of malignancy — Long term use associated an increased risk of squamous cell skin cancer and benign or malignant lymphoproliferative disorders.
  • Other side effects — anorexia, nausea and vomiting, diarrhea, abdominal discomfort. gingival hyperplasia, hirsutism and abnormal liver function.

Author: Dr Simon Chan
Editor: Dr Rakesh Shah

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