Ciclosporin & Tacrolimus

IBD Curriculum Topic 6.1-6.11

T-cell inhibiting calcineurin inhibitors are of limited value in Crohn’s disease, and are mainly used to induce remission in acute severe UC in those intolerant or refractory to corticosteroids.

Active disease

Ciclosporin

  • Only 1 of 4 trials has demonstrated efficacy for oral CYA for luminal disease, therefore it is not indicated
  • 3 small case series demonstrated efficacy for IV CYA
  • Case series demonstrate benefit in perianal disease, though response is rapidly lost on drug withdrawal

Oral tacrolimus

  • Oral tacrolimus for luminal disease has only been reported in uncontrolled studies or case reports and cannot be recommended

Maintaining remission

Ciclosporin and tacrolimus cannot be recommended for maintaining remission in CD patients.

IBD Curriculum Topic 6.1-6.11

T-cell inhibiting calcineurin inhibitors are mainly used to induce remission in acute severe UC in those intolerant or refractory to corticosteroids.

Active disease

Ciclosporin

  • Ciclosporin is mainly used to induce remission in acute severe UC in those intolerant or refractory to corticosteroids. 76% to 85% respond by 8 days, with median response at 4 days; i.e. ≈10% require early colectomy.

Tacrolimus

  • About 70% (10% placebo) who achieve therapeutic levels respond by 2 weeks.
ECCO statement 11G (UC 2017)

Initial recommended treatment for severe active ulcerative colitis is intravenous steroids [EL1]. Monotherapy with intravenous ciclosporin [EL2] is an alternative especially in cases of serious adverse events due to steroids. All patients should receive adequate volume of intravenous fluids, and low-molecular-weight heparin for thromboprophylaxis; electrolyte abnormalities and anaemia should be corrected, if needed [EL5]. Patients are best cared for jointly by a gastroenterologist and a colorectal surgeon [EL5]

Maintaining remission

  • Ciclosporin is rarely used for maintenance therapy, but usually used to “bridge” to thiopurines. About 60-90% require colectomy over 7y (20% by 3 months), reduced in those naïve and then treated with thiopurines (e.g. by 18 months, colectomy in 10% started on thiopurines vs. 30% continuing thiopurines vs. 50% not provided thiopurines).
  • Similarly tacrolimus is rarely used for maintenance therapy although in one study was associated with partial response in ≈50% over 3-4 yrs.

Prevention of post-surgical recurrence

Not enough data to support its use.

Dosing, administration and monitoring

Before treatment

  • Ensure tests for microbial immunity and latency have been checked (Evaluation for opportunistic infections according to ECCO Checklist)
  • Complete blood count, liver enzymes, urea, creatinine, magnesium, cholesterol, blood pressure
  • National Formulary should be consulted to review adverse drug reactions and drug interactions.

Dosing

  • Ciclosporin
    • 2mg/kg/day by pump-controlled IV infusion over 24 hours.
    • 24h after start measuring blood levels daily
    • Adjust blood levels to 150-250 ng/ml
    • Usual dosing period 3-4 days but may continue for 7 days before switching to oral dosing given in 2 divided doses (4-8mg/kg/day) for maximum 4-6 months total (the total daily dose is divided in two doses every 12 h).
    • Consider adjunctive topical therapy if tolerated.
    • Check inpatient trough levels alternate daily, aim for 150-250 ng/ml (2 h post-dose peak of 700 ng/ml optimal according to pharmacokinetic data, though rarely used).
    • Avoid IV dosing with low Mg++ or low cholesterol (correct former and provide oral formulation for latter).
  • Tacrolimus
    • Initially provide 0.01-0.02 mg/kg/d IV or 0.025 mg/kg bd PO, aiming for a trough level ≈10ng/L.
    • Consider co-trimoxazole prophylaxis if patient on calcineurin inhibitors and 2 other immunosuppressants.

Follow-up

  • Measure FBC, LFT’s, U+E’s, Mg++, blood pressure, and ciclosporin levels daily until discharge (trough level, target 150-250 mcg/L). Treat hypokalaemia and hypomagnesaemia. Post discharge, measure same parameters every 2 weeks for 3 months, then monthly.
  • Take full drug history and check for drug interactions as CsA levels can be affected by concomitant therapies.
  • Monitor according to the drug indication and co-medication. Emphasise: blood pressure, peripheral paraesthesiae, creatinine, magnesium, potassium
  • For oral ciclosporin users assess monthly for clinical status, potential adverse events, blood pressure, creatinine, electrolytes, and ciclosporin levels
  • The duration of oral ciclosporin treatment should be approximately 3-4 months
  • After a flare of severe UC, transition of oral ciclosporin to thiopurines (in thiopurine-naïve patients) should be better done after cessation of steroids and one month before stopping

Red flag interactions

  • Patients should be warned to avoid grapefruit or its juice as it can affect absorption.
  • Contraindicated in uncontrolled hypertension, renal or liver failure, severe electrolyte disturbance or suspected systemic infection / sepsis. IV preparation should be avoided if cholesterol is < 3 mmol/L (oral ciclosporin can be used in this situation) or Mg++ is < 1.5 (provide IV Mg++).
  • Monitor blood pressure and creatinine (reduce dosage if there is a >20% change compared with baseline)
  • Monitor blood levels of ciclosporin

Adverse effects

  • Ciclosporin and infliximab have a similar incidence and range of side effects, although ciclosporin has the advantage of a short half life.
  • Both have similar side effects comprising nephrotoxicity, neurotoxicity, hypertension, metabolic abnormalities, infections, skin cancer and lymphoma.
  • Tremor, headache. Low Mg++, renal impairment or GI upset occur in ≈50%. Tacrolimus can induce diabetes. 3 patients died from infections in a series of 86 patients.

Special situations

  • Avoid live vaccines and follow Guidelines for Opportunistic Infections
  • Caution is required in hypertensive patients, those receiving potassium-sparing diuretics and patients with malignancies
  • Do not take within an hour of grapefruit juice consumption
  • Co-trimoxazole for Pneumocystis jiroveci (carini) pneumonia prophylaxis should be given in patients on triple immunosuppression. It should also be considered when double immunosuppression is used, especially if one of the immune-modulators is a calcineurin inhibitor

Pregnancy

  • Higher rates of complications occur in pregnant women taking CsA (but not tacrolimus) for rheumatological or post-transplant conditions.
  • Small case series of CsA in IBD also report adverse outcomes.
  • For ciclosporin, a meta-analysis of 15 studies with 410 pregnant patients did not find an increased rate of congenital malformations. Similar, but fewer, data exist for tacrolimus.

Breastfeeding

  • Limited data suggest that infant exposure to tacrolimus via breast milk is low and therefore this should be discussed. There are no data to support the use of ciclosporin in breastfeeding because therapeutic blood concentrations in the breastfed infant are described

Surgery

  • Ciclosporin is safe prior and after surgery.

Paediatrics

Not enough data

Elderly

Not enough data

ECCO statement 11G (UC 2017)

Initial recommended treatment for severe active ulcerative colitis is intravenous steroids [EL1]. Monotherapy with intravenous ciclosporin [EL2] is an alternative especially in cases of serious adverse events due to steroids. All patients should receive adequate volume of intravenous fluids, and low-molecular-weight heparin for thromboprophylaxis; electrolyte abnormalities and anaemia should be corrected, if needed [EL5]. Patients are best cared for jointly by a gastroenterologist and a colorectal surgeon [EL5]

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