Dr A. G. Lim, Updated 2004-06-13
Epsom & St Helier’s University Healthcare Trust
Guidelines for Ciclosporin in Severe Ulcerative Colitis
(Dr A. G. Lim, Consultant Gastroenterology)
Contents
1. Protocol for ciclosporin in severe ulcerative colitis
2. Background
3. Truelove and Witt criteria
4. Informed consent
5. Baseline studies
6. Contraindications
7. Drug interactions
8. Anaphylaxis
9. Patient monitoring
10. Clinical activity index
11. Drug monitoring
12. Side effects
13. Switching to oral ciclosporin
14. Concurrent treatment
15. Outpatient monitoring
References
Appendices
i. Patient Information Leaflet
ii. Nurse’s Guide for Ciclosporin Infusion
iii. Checklist for during Inpatient Ciclosporin infusion
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Dr A. G. Lim, Updated 2004-06-13
1. Protocol for Ciclosporin in severe Ulcerative Colitis (UC) refractory
to Corticosteroid and opposed to surgery
Confirmed diagnosis of UC
 3 or more Truelove & Witt criteria
 No response to IV Methyprednisolone after 5 – 7 days
Initiating ciclosporin use
 Informed consent
 Baseline studies
 Check for contraindications
 Check for drug interactions
Ciclosporin therapy as continuous infusion
 Dose = 2 mg/kg/day. [Extra caution with elderly or
patient with mild impaired creatinine clearance]
 Monitor of signs of allergy or anaphylaxis every 15
minutes in the first hour
 Discontinue and treat if signs of allergy develop
 If tolerating ciclosporin, continue infusion for 7 days
 Strict patient and drug monitoring
Treatment failure
 Refer for surgery
 Contact Stoma Nurse
Treatment success
 Switch to oral ciclosporin
 Outpatient monitoring
 Wean off ciclosporin
Concurrent Treatment
 Continue with IV Steroid, switch to oral if ciclosporin
treatment successful
 If on Azathioprine or 6-mercaptopurine, to stop and
restart 2-3 months in outpatient if ciclosporin
treatment successful
 Maintain aminosalicylates but not added to regime
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Dr A. G. Lim, Updated 2004-06-13
2. Background
Standard treatment of severe exacerbation of ulcerative colitis (UC) consists of
high dose intravenous corticosteroid and aminosalicylates (5-ASA) compounds.
Azathioprine is of limited use in the acute setting because of its slow onset of
action. Approximately 15% of patients with acute UC will require hospital
admissions for control of symptoms and up to 40% of these patients will need
colectomy.
Ciclosporin is a potent inhibitor of cell-mediated immunity. It acts mainly by
reversibly inhibiting T-lymphocyte function by inhibiting interleukin-2 production. It
does not interfere with stem cell activity. Ciclosporin is extracted from the fungus
Tolypocladium inflatum
There is evidence from controlled and uncontrolled studies that ciclosporin is
efficacious for UC. In a multicentre, double-blind, placebo-controlled trial of
intravenous and oral ciclosporin for the treatment of severe, steroid refractory UC,
achieving success in 80% of patients in the short term and maintaining success
in about two thirds of patients in the longer term. The short term outcome of
ciclosporin with a mean follow up period of 39 months was 91%. More than half
were found to avoid colectomy in the longer term.
Based on current evidence, ciclosporin appears to be a viable alternative to
emergency colectomy in severe UC in the short term.
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Dr A. G. Lim, Updated 2004-06-13
3. Truelove and Witt criteria

Passage of 6 or more stools per day

Temperature of > 37 degrees centigrade

Pulse rate > 90 bpm

Anaemia < 75% of normal HB

ESR > 30mm/hr after failing to respond to 5 – 10 days of IV Steroid
4. Informed consent

Inform patient that this treatment is unlicensed for inflammatory
bowel disease. It is offered as an alternative to surgery

Patients are also informed of the risks and benefits of colectomy by
surgical colleagues
5. Basline studies

History:
Detailed drug history
Seizure history
Cancer history
Menstrual history
Compliance

Physical examination
Blood pressure
Infection
Abdominal examination

Laboratory data
FBC
U&E plus creatinine
creatinine is borderline
clearance
if
serum
difficile
toxin,
Magnesium
Cholesterol
ESR/CRP
Pregnancy test
Stool- MC&S, Clostridium
parasites and ova
AXR
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Dr A. G. Lim, Updated 2004-06-13
6. Contraindications

Septicaemia

Bowel perforation

Megacolon

Positive stool to MC&S/ Chlostridium difficile toxin/ parasites/ova

Uncontrolled hypertension

Creatinine > 33% above upper normal limit

Elevated LFT (>3times normal)

Uncorrected hypomagnesiumia (associated with an increased risk
of seizures)

Serum cholesterol <3.1 mmol/l (associated with an increased risk of
seizures)

Pregnancy / breast feeding

Maglinancy of any kind

Known hypersensitivity to ciclosporin / polyethoxylated castor oils
(in injection)
7. Drug interactions
Drugs that increase ciclosporin levels

Diltiazem

Nicardipine

Verapamil

Bromocriptine

Metoclopramide

Danazol

Ketoconazole

Fluconazole

Itraconazole

Erythromycin

Methylprednisolone

Oral Contraceptives
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Dr A. G. Lim, Updated 2004-06-13
Drugs that decrease ciclosporin levels

Rifampicin

Phenobarbital

Phenytoin

Carbamazipine
Other interactions

Grapefruit juice increases the blood levels of ciclosporin and
increases the risk of toxicity. Should not be consumed less than
one hour before or after and oral dose
8. Anaphylaxis

Monitor every 15 minutes for the first hour

Signs include hypotension, hives, wheezing, laryngeal spasm

Immediate discontinuation if such signs develop

Treat with chlorpheniramine/ adrenaline, as necessary, as with any
allergic reaction

The first infusion should not be started at night due to the risk of
anaphylaxis
9. Patient monitoring – Joint management with surgeons

Vital signs – pulse, blood pressure, temperature 4 times a day or more
often if deterioration

Daily physical examination for abdominal tenderness and distension

Daily review for adverse effects

Stool chart for bowel frequency, stool consistency, presence or
absence of blood

Blood tests – FBC, U&E, LFT, Mg, Cholesterol, ESR, CRP every 2nd
day (daily if abnormal)

Daily AXR if colonic atony or dilatation are detected; worrisome
findings include small bowel ileus and a continuous column of colonic
gas which may precede megacolon

Objective measure of clinical activity score (see table 1)
*Maximal score = 21
**Score of less than 10 on 2 consecutive days = indicate a clinical
response
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Dr A. G. Lim, Updated 2004-06-13
10. Table 1: Clinical activity index
Symptom
Diarrhoea (no of daily stools)
 0-2
 3 or 4
 5 or 6
 7-9
 10
Nocturnal diarrhoea
 No
 Yes
Visible blood in stools (% of movement)
 0
 <50
 >50
 100
Faecal incontinence
 No
 Yes
Abdominal pain or cramping
 None
 Mild
 Moderate
 Severe
General well-being
 Perfect
 Very good
 Good
 Average
 Poor
 Terrible
Abdominal tenderness
 None
 Mild and localized
 Mild to moderate and diffuse
 Severe or rebound
Need for antidiarrhoeal drugs
 No
 Yes
Score
0
1
2
3
4
0
1
0
1
2
3
0
1
0
1
2
3
4
0
1
2
3
4
5
0
1
2
3
0
1
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Dr A. G. Lim, Updated 2004-06-13
11. Drug monitoring and administration

Continuous infusion at dose of 2 mg/kg/day over 24 hours [ Caution
with elderly or in mild impaired creatinine clearance (ie 20-30%
reduction of estimated creatinine clearance)]

Drug only stable for 6 hours after mixing, therefore the infusion is split
into 4x 6 hours infusion pump.

E.g. 60kgs patient needs 120mg/24hours. Therefore, ciclosporin is
delivered at 30mgs/48ml N/Saline: 8ml/hr

Ciclosporin needs to be administered in the syringes and giving sets
that do not come in PVC. Giving sets used for heparin/GTN are
polyethylene based and can be used.

Trough ciclosporin levels every 2 days

To achieve levels of 300-400 ng/ml

Dose of ciclosporin reduced if –
levels >500 ng/ml for 2 consecutive days
serum creatinine increases by 30% over baseline
serum liver enzymes double
diastolic blood pressure exceeds 90mmHg or
systolic blood pressure exceeds 150 mmHg despite
antihypertensive treatment

Ciclosporin doses can be reduced by 25% at least

Discuss ciclosporin monitoring with renal physicians (contact at Renal
Unit, St Helier Hospital)
12. Side effects

Seizures

Hypertension – treat with calcium channel blocker but this can lead to
a rise in ciclosporin level

Renal toxicity

Liver toxicity

Hyperkalaemia

Increased susceptibility to infection

Hyperlipidaemia

Anaphylaxis

Irritation at cannula injection site – care of cannula site essential
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Dr A. G. Lim, Updated 2004-06-13

Flushing

Tremor

Fatigue

Headaches

Gastrointestinal disturbances

Paraethesia (burning sensation in hands and feet)

Gingival hyperplasia (long term treatment only)

Hypertricosis (long term treatment only)
13. Switching to oral ciclosporin

If patient has demonstrated a decisive clinical improvement

Intravenous ciclosporin is discontinued at 8pm on that evening

Ciclosporin level is checked at 8am the following morning, immediately
preceding the first oral dose

Oral dose = 4-5 mg/kg/day ciclosporin (Neoral) given in 2 divided
doses

To achieve trough level of 150 – 300ng/ml
14. Concurrent treatment

Tail-off IV steroid (IV methylprednisolone) 60mg/24hrs to zero during
the 1st 3 days of ciclosporin use

On switching to oral ciclosporin, IV steroid can be discontinued and
switched to oral prednisolone 60mg. 5-ASA drug can be continued

Consider Septrin during time when patient on both IV steroid and
ciclosporin
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Dr A. G. Lim, Updated 2004-06-13
15. Outpatient monitoring
Clinic visit and review for adverse
effects
Weekly x 4 then, biweekly x 2 then,
every 3-4 weeks
Ciclosporin levels, FBC, ESR, CRP,
U&E, LFT, Mg, Cholesterol
With each visit as above and within 1
week after any dose change
Hypomagnesium
Often require parenteral
supplementation as oral
supplementation can exacerbate
diarrhoea
Prednisolone
Reduce by 10mg each week until 30mg
is reached and then by 5 mg weekly or
every other week as tolerated
At 15-20 mg of daily prednisolone,
smaller reductions may be required
Patients who cannot be maintained on
20mg of prednisolone daily are
considered ciclosporin failure and
should be referred for surgery
All patients should be weaned off within
6 months of hospital discharge
Ciclosporin
Once weaned off prednisolone,
ciclosporin dose is reduced by 50% for
2 weeks, followed by complete
ciclosporin withdrawal
Azathioprine or 6-mercaptopurine
Initiate at about 2-3 months after
discharge to allow onset of action
before ciclosporin is stopped
5-ASA
Maintenance dose
Endoscopy
Flexible sigmoidoscopy after 6-8 weeks
Rx
Colonoscopy at 4-6 months
Pregnancy
Ensure that contraception is used
during the period of ciclosporin
treatment. Safety of ciclosporin in
human pregnancy has not been fully
established
Breastfeeding
Ciclosporin passes into breast milk and
mothers receiving treatment should not
breast feed their infants
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Dr A. G. Lim, Updated 2004-06-13
Appendix 1
CICLOSPORIN – in treatment for severe ulcerative colitis
PATIENT INFORMATION LEAFLET
Background
Ciclosporin is an immune suppressing medication. It is used in patients with
severe exacerbation of ulcerative colitis (UC), who have not responded to high
dose intravenous steroids after 5-10 days. It is a relatively new in the treatment
for UC. However, it has been used for many years in preventing organ transplant
rejection.
It has been shown that approximately 15% of patients with acute UC will require
hospital admissions for control of symptoms and up to 40% of these patients will
need surgery e.g. bowel resection. There is preliminary research evidence shown
that ciclosporin is effective for treating severe UC. It has shown to achieve
success in 80% - 91% of patients in the short term and maintaining success in
about two thirds of patients in the longer term as in avoiding surgery.
Based on current evidence, ciclosporin appears to be a viable alternative to
emergency surgery in severe UC in the short term.
How is Ciclosporin given?
Ciclosporin is administered as a continuous infusion over 24hours via a pump.
The medication dose is split into 4 infusion bags or syringes.
Intravenous steroid is continued while you are having intravenous ciclosporin.
The steroid infusion is gradually tailed off and eventually discontinued.
You will be monitored closely when you are having the ciclosporin infusion. A
nurse will be caring out observation on blood pressure and pulse and any sign of
allergic reaction every 15 minutes during the first hour of the infusion.
Observation on blood pressure, pulse and temperature is gradually decreased to
4 hourly.
If you are already on Azathioprine or 6-mercaptopurine, this medication is
stopped temporarily to avoid excessive suppression of immune system.
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Dr A. G. Lim, Updated 2004-06-13
How long do I have the infusion?
The ciclosporin infusion is administered for 5 – 10 days.
If your condition improved after 5 – 10 days, then you will be prescribed oral
ciclosporin twice daily. (Please note: Grapefruit juice interact with ciclosporin, so
it should only be consumed less than one hour before and after an ORAL dose.)
Azathioprine or 6-mercaptopurine may be restarted once you are on oral
ciclosporin medication.
What are the side effects?
Ciclosporin is generally well tolerated.
Side-effects from ciclosporin are: headaches, flushing, tremor, fatigue,
gastrointestinal disturbances, burning sensation in hands and feet, seizures,
kidney impairment, liver toxicity, susceptibility to infections, irritation to cannula’s
site and anaphylaxis.
Regular blood tests will be carried to monitor your kidney and liver function.
Do I take ciclosporin for life?
No. You will be slowly weaned off ciclosporin until complete withdrawal.
You will be seen in the clinic weekly on the first month after you leave the
hospital, then every 2 weeks for 4 weeks, then every 3 – 4 weeks.
We will continue to monitor the ciclosporin level to prevent toxicity and your liver
and kidney function closely.
I hope this information has been helpful. Please do not hesitate to ask your
doctor if you need more information.
Dr A. G. Lim
Consultant Gastroenterology
Epsom and St Helier University Healthcare Trust
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Dr A. G. Lim, Updated 2004-06-13
Appendix ii
NURSE’S GUIDE FOR CICLOSPORIN INFUSION

PRE INFUSION
1. Baseline vital sign of temperature, blood pressure and pulse

HOW TO ADMINISTER
1. DO NOT start the first infusion at night due to risk of anaphylaxis
2. Use polyethylene based giving sets and NOT PVC e.g. use the
giving sets that used for heparin/ GTN infusion
3. Administer infusion in N/Saline
4. Ciclosporin is given as continuous infusion. However, the infusion is
only stable for 6 hrs, therefore infusion is split into 4 pumps/ 24
hours
5. For example:
-> A 60kgs patient – needs 120mg/24hrs
-> Dilute 30mgs Ciclosporin in 48mls N/Saline
-> Run the pump rate at 8mls/hour (48mls in 6hrs)

DURING INFUSION
1. Monitor BP & P every 15 minutes for the first hour. Then 30
minutes for 2 hours. Observations gradually decreased to 4 hourly
or QDS daily
2. Observe for sign of anaphylactic shock – stop the infusion
immediately and treat appropriately and inform doctor
3. Other side-effects - see Guidelines pg 8-9
4. Monitor temperature 4 hourly
5. Monitor stool chart – note frequency, stool consistency, presence or
absence of blood
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Dr A. G. Lim, Updated 2004-06-13
Appendix iii
CHECKLIST FOR DURING INPATIENT CICLOSPORIN INFUSION

See Protocol pre-infusion

Daily review of adverse effects

Daily physical examination

Daily AXR

Blood test : FBC, U&E, LFT, Mg, Cholesterol, ESR, CRP every 2nd day
(daily if abnormal)

Ciclosporin levels every 2 days (to achieve levels of 300 – 400ng/l)
Alert EGH pathlab to send blood sample to St Helier (St Helier lab tel no
for result: 721 2662/ 3421)

Objective measure of clinical activity score (see table 1)

Wean off IV methyprednisolone to zero during 1st 3 days of Ciclosporin

Consider Septrin during time when patient is having both IV Steroids and
Ciclosporin
14