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DISEASE MODIFYING DRUGS IN INFLAMMATORY BOWEL DISEASE

By Cheryl Martin,2014-11-10 06:11
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DISEASE MODIFYING DRUGS IN INFLAMMATORY BOWEL DISEASE

DISEASE MODIFYING DRUGS IN INFLAMMATORY BOWEL DISEASE

    Dr A.F. Muller DM FRCP

    Consultant Gastroenterologist

    On behalf on the Inflammatory Bowel Disease Committee of the

    BRITISH SOCIETY OF GASTROENTEROLOGY

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DISEASE MODIFYING DRUGS IN INFLAMMATORY BOWEL DISEASE

    This document is designed to provide information for Gastroenterologists, Primary Care Clinicians and patients with IBD regarding the use of disease modifying drugs, their indications, side effects and guidelines for safe monitoring. This document does not cover the use of biological agents whose use is considered elsewhere. It is expected that this information will be made available on the British Society of Gastroenterology and Crohn’s and Colitis Association websites.

    INDEX

1. Azathioprine / 6 Mercaptopurine

2. Ciclosporin

3. Methotrexate

4. 5-Amino Salicylates

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    AZATHIOPRINE / 6 MERCAPTOPURINE

    The purine analogues azathioprine and mercaptopurine are effective in inducing and maintaining remission in patients with ulcerative colitis and Crohn’s disease.

    Azathioprine is a prodrug which is converted to mercaptopurine and then metabolised to the active metabolite 6-thioguanine. Thiopurine Methyl Transferase (TPMT) converts mercaptopurine to 6-methyl-mercaptopurine. When TPMT levels are low, higher levels of 6-thioguanine are produced and this is associated with a greater risk of myelosuppression.

    The onset of action of these drugs is very variable and in many patients, the beneficial effects may not be seen for 3 4 months, and in some cases even longer.

Dosage

    Azathioprine : A typical dose regimen may be 1mg/kg/day orally, increasing by slow titration to a target dose of 2 2.5 mg/kg/day. This approach may minimise the risk of

    direct and indirect toxicity (see below).

    Some centres have access to the measurement of Thiopurine Methyl Transferase genotyping or enzyme levels. About 1 in 300 of the population have no TPMT and the drug should be avoided in this group. Similarly heterozygotes with intermediate TPMT levels should receive lower treatment doses (e.g 50% of standard dose regimen).

    Unfortunately the measurement of TPMT levels does not replace the need for careful haematochemical monitoring as only just over ? of cases of myelotoxicity will be due to patients with TPMT mutations. In nearly ? of patients who develop neutropenia no reason will have been identified.

    Measurement of TPMT levels should be considered for patients prior to starting azathioprine if available locally.

    Mercaptopurine : A change from azathioprine to Mercaptopurine should lead to a dose reduction of about 50%. Incremental dose increases (as with azathioprine) up to a maximum dose of 1.5 mg/kg orally. As with azathioprine, patients identified as being heterozygotes / intermediate TPMT levels should receive lower treatment doses.

Direct Toxicity :

    Pancreatitis; bone marrow suppression; allergic reactions including nausea, swinging fevers); drug induced hepatitis.

Indirect toxicity : Infections bacterial and viral (including herpes zoster and

    simplex, Epstein Barr virus (EBV); Cytomegalovirus (CMV).

    Limited evidence suggests the possibility of a slight increased risk of lymphoma; a slight but non significant increase in cervical cancer and an increased risk of non-melanoma skin cancer (similar findings in the immunocompromised transplant population).

    Kandiel et al (1) found a relative risk of 4 for the development of lymphoma in patients taking azathioprine, but were unable to distinguish between whether this was

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    the result of the medication, the severity of the underlying inflammatory bowel disease or a combination of the two.

    The recent reports of six cases of hepato-splenic lymphoma in young people on combined thiopurine/infliximab therapy for Crohn’s disease is of concern. The

    relative contribution of each drug is not clear.

    There are very few case reports of an association between cervical cancer and IBD patients taking azathioprine, although there is more evidence available for patients with rheumatoid arthritis or systemic lupus erythematosus. There are occasional reports of IBD patients on immunosuppressive therapy developing skin tumours (2).

Laboratory monitoring

    Close long term follow up of Full blood count (FBC) and LFT’s is required in all patients taking AZA/MP. The risk of a patient developing a drug induced neutropenia may not occur for many months after starting treatment and this is not accounted for by variations in TPMT levels.

     British Society of Gastroenterology

    Recommendation

    FBC, U&E, creatinine, LFT’s.

    Consider TPMT genetic testing or enzyme Pre-treatment

    levels. assessment

    Avoid treatment if TPMT homozygous

    recessive or low enzyme activity

    Immunisation with influenza and pneumovax

    recommended whilst on treatment

    FBC & LFT’s weekly for 4 weeks or when Monitoring

    associated with dose increase

    Once the dose, disease and blood monitoring

    is stable reduce to 3 monthly

    U&E, Creatinine at 4, 12 & 26 weeks, then

    yearly

What to do if :

    1. Bone marrow suppression occurs : Mild (WCC > 2.5) reduce dose of

    azathioprine and repeat FBC regularly to confirm improvement; Moderate

    (WCC 1.5 2.5) stop azathioprine for 1 week, then consider restarting at

    much lower dosage with weekly FBC monitoring; Severe (WCC < 1.5)

    withdraw treatment. If patient pyrexial admit for intravenous antibiotics and

    consider use of granulocyte-colony stimulating factor (G-CSF).

    2. Patient develops pancreatitis : discontinue treatment

    3. Patient develops abnormal LFT’s – withdrawal of the drug usually leads to a

     resolution of the abnormalities and a liver biopsy is rarely required. Consider

     other causes of abnormal LFT’s.

    4. Pregnancy : there is no evidence that azathioprine is teratogenic so the

     treatment can be continued. Generally azathioprine should not be started

     during pregnancy.

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Recommendations

    - Advise patients to use sunscreens and protective covering to reduce sunlight

    exposure.

    - Immunisation with LIVE vaccines should be avoided. Influenza and

    pneumovax can be given.

    - Avoid in patients with hepatitis B/C or history of TB.

    - AZA / MP are partly metabolised by xanthine oxidase. Care should be taking

    in patients taking allopurinol, as the combination of these drugs may lead to

    enhanced effects and increased toxicity. Ideally, the combination of

    allopurinol and AZA / MP should be avoided. When the combination is

    necessary, the dose of AZA / MP should be reduced by 25% or more to avoid

    drug accumulation and toxicity.

    - The combination of AZA / MP with amino salicylates can occasionally

    increase the risk of neutropenia.

    The combination of azathioprine and infliximab treatment is superior to azathioprine alone for inducing and maintaining remission and complete steroid withdrawal in steroid dependent patients with active Crohn’s disease (3). However, clearly this

    approach carries implications with respect to the increased potential for drug-related toxicity.

    Clear recommendations as to the duration of therapy cannot be drawn from the available literature. In practice, most physicians now intend to continue therapy for 3-5 years, and discuss withdrawing azathioprine at this time with the patient. It should be made clear to patients that there is a degree of uncertainty with respect to long-term toxicity if treatment is continued beyond this time frame.

.

    1. Kandiel A et al : Increased risk of lymphoma among inflammatory bowel disease patients treated with azathioprine and mercaptopurine GUT 2005; 54 : 1121 5.

    2. Austin AS, Spiller RC. Inflammatory bowel disease, azathioprine and skin cancer : case report and review of the literature. Eur. J. Gastroenterol. Hepatol. 2001; 13 : 193-4.

    3. Lemann M. et al. Infliximab and azathioprine for steroid dependent Crohn’s

    disease patients - a randomised placebo controlled trial. Gastroenterology 2006; 130 : 1054 61.

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    AZATHIOPRINE / 6-MERCAPTOPURINE TREATMENT FOR IBD

    PATIENTS

    INFORMATION SHEET

    This information leaflet is designed to answer common questions patients ask about their medicine. Further information can be found in the information leaflet supplied

    by the manufacturer or from your pharmacist or doctor.

What are they ? • Azathioprine and 6-Mercaptopurine are immunosuppressant

    drugs used in the treatment of inflammatory bowel disease. They are often prescribed when steroids have proved insufficient in bringing the condition under control. They allow a reduction in the dose of steroids, but may take 12-16 weeks or more to become effective.

How is it taken?

    • In tablet form, daily. The dosage will be advised by your Gastroenterology specialist team.

Are there any side effects ?

    These drugs are an important part of the treatment of patients with inflammatory bowel disease, but a small number of patients may experience side effects that will prevent them from continuing with treatment. Should you develop symptoms that might be related to your treatment you should discuss them with your Doctor / Gastroenterologist / IBD nurse specialist. Side effects that you should look out for include :

    • Nausea / vomiting and loss of appetite

    • Abdominal pain should this develop, the drug should be stopped immediately • Hair loss

    • Adverse effects on the blood

    • Fever, weakness and fatigue (rare)

    • Unusual bleeding / bruising (rare)

    • Jaundice (rare)

    • Rashes (rare)

• There are no special problems for children taking these medicines.

    • Lower doses of these drugs may be used in patients aged over 60 years, as there may be a slight increased risk of side effects.

    • Avoid driving and hazardous work until you have learned how azathioprine / Mercaptopurine affects you as these drugs occasionally can cause dizziness. • No known problems with alcohol.

Special monitoring

    Whilst taking this treatment, you will need regular blood tests. Once the dose of treatment is stable, the frequency of blood testing will be reduced. The testing will be supervised by your Gastroenterology specialist team or in a shared care arrangement with your General Practitioner.

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• Full Blood Count (FBC)

    • Liver Function Test (LFT)

    • Some centres will also arrange a test to measure Thiopurine Methyl Transferase (TPMT).

    FBC and LFT will be checked weekly for four weeks post commencement, then monthly for two months and three monthly thereafter if the results are stable. Any change in dosage will require similar monitoring. You may also be asked to have tests of kidney function from time to time.

Other information :

    • Immunisation with LIVE vaccines should be avoided. (Influenza and pneumovax

    can be given). Please discuss with your General Practitioner or Hospital specialist team.

    • Sunscreens and or protective clothing should be encouraged to reduce sunlight

    exposure.

    • Other medicines that you are prescribed may interact with azathioprine or Mercaptopurine. These include drugs used to treat gout (Allopurinol), the blood thinning treatment warfarin and certain antibiotics (co-trimoxazole and trimethoprim). You should discuss these with your Doctor.

Azathioprine / Mercaptopurine in pregnancy and breast feeding ?

    Azathioprine is safe to take in pregnancy, although there are reports of premature birth and low birth-weight babies in mothers taking this treatment. Women receiving azathioprine treatment ideally should avoid breast feeding. Although Azathioprine is broken down by the body into Mercaptopurine, the use of Mercaptopurine is not recommended during pregnancy.

    The literature with respect to the safety of thiopurines in men whose partners are planning to conceive is mixed. Data and clinical experience suggest that the drug is safe in this context, although an increased risk of malformations have been reported in other series.

    Keep all medicines out of the reach of children. Never give any medication prescribed for you

    to anyone else. It may harm them even if their symptoms are the same as yours.

    For further information you can contact your IBD Nurse Specialist or

    Gastroenterology specialist.

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    CICLOSPORIN

Introduction :

    The main role for ciclosporin is in the treatment of patients with severe steroid 1 demonstrated an 80% response refractory Ulcerative Colitis. The study by Lichtiger

    rate in this group to intravenous ciclosporin. After conversion to oral treatment about 2/3rds of patients were maintained in remission without steroids, with the remaining 1/3 rd proceeding to colectomy. 2,3Response rates are improved by the addition of azathioprine or Mercaptopurine, and

    ciclosporin can be used as a bridge for maintenance therapy having a slow onset of action. 4Ciclosporin is of little benefit in Crohn’s disease and should be avoided.

    Ciclosporin may be given either intravenously (2mg/kg/day) or orally in a microemusion formula (Neoral) in doses between 4.6 7.5 mg kg/day.

Cautions :

    1. Uncontrolled hypertension

    2. Use of potassium sparing diuretics

    3. Immunisation with live vaccines should be avoided (Influenza and

    pneumovax can be given).

    4. Pregnancy and lactation

    5. Grape fruit juice to be avoided within one hour of ingestion

    6. Malignancy such as lymphoma etc

    7. Drug interactions : Many drugs interact with ciclosporin (the most important

    of which are included below), but refer to BNF / data sheet or your own

    Hospital drug information service.

Contraindications :

    1. Uncontrolled hypertension

    2. Renal and liver failure

    3. Severe electrolyte disturbance i.e. hyperkalaemia

    4. Suspected systemic infection / sepsis

Monitoring

    Oral : Trough (immediately before next dose) ciclosporin levels should be measured weekly and dosages adjusted accordingly (liase with Clinical Biochemist / Renal Unit for local therapeutic ranges); Initially, twice weekly weekly creatinine (and / or

    estimated glomerular filtration rate {eGFR}levels. The dose of ciclosporin should be reduced if creatinine levels increase by more than 20% from baseline.

    Ciclosporin levels are affected by many drugs, particularly antibiotics. More frequent monitoring should take place when new drugs are introduced.

    Intravenous : Facilities should be available to monitor ciclosporin and creatinine and electrolyte levels daily.

Agents likely to increase Ciclopsorin levels

    Drug Effect Action

     Monitor ciclosporin levels Calcium channel

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    Increase ciclosporin levels and make dose reductions blockers

    -Diltiazem, Verapamil, as necessary

    Nifedipine, Amlodipine

    May increase Ciclosporin Avoid concurrent use Grapefruit juice

    levels

    Markedly increase Macrolides Avoid if possible

    - Clarithromycin ciclosporin levels. If concurrent use essential,

    - Erythromycin Potentially serious monitor ciclosporin levels

    closely and reduce dose by

    1/3 for duration of

    macrolide course

    Increases ciclosporin Avoid concurrent use if Metoclopramide

    levels possible where

    concurrent use essential,

    monitor ciclosporin levels

    and examine pt for signs of

    toxicity

    Marked increase in If used in combination, Oral contraceptives

    - Danazol ciclosporin levels with monitor ciclosporin levels

    some oral contraceptives, more frequently, look for

    particularly Danazol signs of ciclosporin or

    hepatotoxicity. Adjust

    dosages levels as

    necessary.

    Increases ciclosporin Tacrolimus Avoid concomitant use

    levels & increased risk of

    renal failure

1. Lichtiger S, Present DH, Kornbluth A. et al. Cyclosporine in severe ulcerative

    colitis refractory to steroid therapy. N. Eng. J. Med. 1994; 330 : 1841-5. 2. Cohen RD, Stein R, Hanauer SB. Intravenous cyclosporin in ulcerative

    colitis : a five year experience. Am. J. Gastroenterol. 1999; 94 : 1587-92. 3. Fernandes-Banares F, Bertran X, Esteve-Comas M et al. Azathioprine is

    useful in maintaining long-term remission induced by intravenous

    cyclosporine in steroid-refractory severe ulcerative colitis. Am. J.

    Gastroenterol. 1996; 91 : 2498-9.

    4. McDonald JW et al. Cyclosporine for induction of remission in Crohn’s

    disease. Cochrane Database Syst Rev. 2005; 18 : CD000297.

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    CICLOSPORIN TREATMENT FOR PATIENTS WITH IBD

    PATIENT INFORMATION SHEET

    This information leaflet is designed to answer common questions patients ask about their medicine. Further information can be found in the information leaflet supplied

    by the manufacturer or from your pharmacist or doctor.

Why have I been started on this medicine ?

    Ciclosporin (cyclosporin, also known as Neoral) is generally reserved for the treatment of severe ulcerative colitis. It is used when patients have not responded to standard treatment for inflammatory bowel disease, including steroids. The use of ciclosporin has been demonstrated to reduce the need for a surgical operation to remove the large bowel (called a colectomy). It is also used in other groups of patients including those with organ transplants, rheumatoid arthritis and psoriasis.

How does it work ?

    Ciclosporin suppresses inflammation and dampens down the body’s immune system.

How long does it take to work ?

    The benefits of ciclosporin are often seen quite quickly.

What dose do I take ?

    The dose of ciclosporin is initially based on weight and rounded up to the nearest capsule size. The total dose is usually in the range of 5.5 6.5 mg/Kg per day, given in divided doses about

    12 hours apart. The dose may be adjusted according to response and blood levels of the drug.

    Some patients in hospital may be started on ciclosporin given intravenously (into a vein) first, as absorption of capsules could be erratic if your gut is very inflamed.

How do I take it ?

    Neoral.(ciclosporin) comes as a gel-filled capsule and is available in four different strengths

    100mg (grey), 50mg (white) 25mg (grey) and 10mg (white). Neoral is also available as a liquid if you have problems swallowing the capsules.

    Neoral is taken twice a day. Ideally the two doses should be taken 12 hours apart at 8.00am and 8.00pm. This is because blood levels are checked and it is important that the drug has been taken at a known time beforehand. It is very important that when blood is taken to measure drug levels that you take your dose of ciclosporin after blood has been taken.

    The capsules should be taken with a mouthful of water and swallowed whole. Whole

    grapefruit and grapefruit juice should not be taken for at least one hour before you take the

    capsules as grapefruit juice can increase ciclosporin levels in the blood.

How long will I be taking it ?

    Patients who respond to ciclosporin usually remain on it for about 3 months.

    Do not stop taking your medicine unless your doctor tells you to, however well you feel.

What are the common side effects ?

    Some of the side effects you may experience are:

    Increased hair growth. This can be removed or coloured if troublesome.

    Slightly enlarged or sore gums. Your dentist will be able to suggest treatment for this if it is a problem.

    Shakiness of the hands.

    You may feel a little sick in the early stages, possibly with some abdominal discomfort

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