DISEASE MODIFYING DRUGS IN INFLAMMATORY BOWEL DISEASE                     Dr A.F. Muller DM FRCP                   Consult...
DISEASE MODIFYING DRUGS IN INFLAMMATORY BOWEL DISEASEThis document is designed to provide information for Gastroenterologi...
AZATHIOPRINE / 6 MERCAPTOPURINEThe purine analogues azathioprine and mercaptopurine are effective in inducing andmaintaini...
Limited evidence suggests the possibility of a slight increased risk of lymphoma; aslight but non significant increase in ...
3. Patient develops abnormal LFT’s – withdrawal of the drug usually leads to a        resolution of the abnormalities and ...
3. Lemann M. et al. Infliximab and azathioprine for steroid dependent Crohn’sdisease patients - a randomised placebo contr...
AZATHIOPRINE / 6-MERCAPTOPURINE TREATMENT FOR IBD                          PATIENTS                              INFORMATI...
• Full Blood Count (FBC)• Liver Function Test (LFT)• Some centres will also arrange a test to measure Thiopurine Methyl Tr...
CICLOSPORINIntroduction :The main role for ciclosporin is in the treatment of patients with severe steroidrefractory Ulcer...
blockers                    Increase ciclosporin levels   and make dose reductions-Diltiazem, Verapamil,                  ...
CICLOSPORIN TREATMENT FOR PATIENTS WITH IBD                          PATIENT INFORMATION SHEET This information leaflet is...
• You may feel a little sick in the early stages, possibly with some abdominal discomfort• Hot or burning sensations in th...
METHOTREXATEIntroduction :Methotrexate is an immunomodulator used to induce and maintain remission ofCrohn’s disease and U...
and CXR may be considered for some                                                           patients                     ...
The incidence of hepatotoxicity in patients with inflammatory bowel disease is verylow and particularly so, if the drug is...
•   Immunisation with live vaccines should be avoided (pneumoccocal and       Influenza vaccinations can be given)        ...
10. Kurnik D, Loebstein R, Fishbein E, Almog S, Halkin H, Bar-Meir S, Chowers Y.Bioavailability of oral vs. subcutaneous l...
METHOTREXATE TREATMENT FOR PATIENTS WITH IBD                   PATIENT INFORMATION LEAFLET This information leaflet is des...
Other rare side effects include : headache; acne; skin irritation and itching; increasedsensitivity to light; tingling / n...
DRUGS FOR INFLAMMATORY BOWEL DISEASE                   AMINOSALICYLATES (5-ASA)Included in this group of drugs are : Sulph...
Following dose changes                         Consider repeating bloods 1 month                                          ...
DRUGS FOR INFLAMMATORY BOWEL DISEASE             THE AMINOSALICYLATES (5-ASA)                   PATIENT INFORMATION       ...
5-ASAs are effective in the treatment of inflammatory bowel disease but canoccasionally be associated with some side effec...
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Disease Modifying Drugs in Inflammatory Bowel Disease (IBD)

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Disease Modifying Drugs in Inflammatory Bowel Disease (IBD)

  1. 1. 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 1
  2. 2. DISEASE MODIFYING DRUGS IN INFLAMMATORY BOWEL DISEASEThis document is designed to provide information for Gastroenterologists, PrimaryCare Clinicians and patients with IBD regarding the use of disease modifying drugs,their indications, side effects and guidelines for safe monitoring. This document doesnot 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 ofGastroenterology and Crohn’s and Colitis Association websites. INDEX 1. Azathioprine / 6 Mercaptopurine 2. Ciclosporin 3. Methotrexate 4. 5-Amino Salicylates 2
  3. 3. AZATHIOPRINE / 6 MERCAPTOPURINEThe purine analogues azathioprine and mercaptopurine are effective in inducing andmaintaining remission in patients with ulcerative colitis and Crohn’s disease.Azathioprine is a prodrug which is converted to mercaptopurine and then metabolisedto 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 riskof myelosuppression.The onset of action of these drugs is very variable and in many patients, the beneficialeffects may not be seen for 3 – 4 months, and in some cases even longer.DosageAzathioprine : A typical dose regimen may be 1mg/kg/day orally, increasing by slowtitration to a target dose of 2 – 2.5 mg/kg/day. This approach may minimise the risk ofdirect and indirect toxicity (see below).Some centres have access to the measurement of Thiopurine Methyl Transferasegenotyping or enzyme levels. About 1 in 300 of the population have no TPMT and thedrug should be avoided in this group. Similarly heterozygotes with intermediateTPMT levels should receive lower treatment doses (e.g 50% of standard doseregimen).Unfortunately the measurement of TPMT levels does not replace the need for carefulhaematochemical monitoring as only just over ¼ of cases of myelotoxicity will be dueto patients with TPMT mutations. In nearly ¾ of patients who develop neutropeniano reason will have been identified.Measurement of TPMT levels should be considered for patients prior to startingazathioprine if available locally.Mercaptopurine : A change from azathioprine to Mercaptopurine should lead to adose reduction of about 50%. Incremental dose increases (as with azathioprine) up toa maximum dose of 1.5 mg/kg orally. As with azathioprine, patients identified asbeing heterozygotes / intermediate TPMT levels should receive lower treatmentdoses.Direct Toxicity :Pancreatitis; bone marrow suppression; allergic reactions including nausea, swingingfevers); drug induced hepatitis.Indirect toxicity : Infections – bacterial and viral (including herpes zoster andsimplex, Epstein Barr virus (EBV); Cytomegalovirus (CMV). 3
  4. 4. Limited evidence suggests the possibility of a slight increased risk of lymphoma; aslight but non significant increase in cervical cancer and an increased risk of non-melanoma skin cancer (similar findings in the immunocompromised transplantpopulation).Kandiel et al (1) found a relative risk of 4 for the development of lymphoma inpatients taking azathioprine, but were unable to distinguish between whether this wasthe result of the medication, the severity of the underlying inflammatory boweldisease or a combination of the two.The recent reports of six cases of hepato-splenic lymphoma in young people oncombined thiopurine/infliximab therapy for Crohn’s disease is of concern. Therelative contribution of each drug is not clear.There are very few case reports of an association between cervical cancer and IBDpatients taking azathioprine, although there is more evidence available for patientswith rheumatoid arthritis or systemic lupus erythematosus. There are occasionalreports of IBD patients on immunosuppressive therapy developing skin tumours (2).Laboratory monitoringClose long term follow up of Full blood count (FBC) and LFT’s is required in allpatients taking AZA/MP. The risk of a patient developing a drug induced neutropeniamay not occur for many months after starting treatment and this is not accounted forby variations in TPMT levels. British Society of Gastroenterology Recommendation FBC, U&E, creatinine, LFT’s. Pre-treatment Consider TPMT genetic testing or enzyme assessment levels. Avoid treatment if TPMT homozygous recessive or low enzyme activity Immunisation with influenza and pneumovax recommended whilst on treatment Monitoring FBC & LFT’s weekly for 4 weeks or when 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 yearlyWhat 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 4
  5. 5. 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.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 azathioprinealone for inducing and maintaining remission and complete steroid withdrawal insteroid dependent patients with active Crohn’s disease (3). However, clearly thisapproach carries implications with respect to the increased potential for drug-relatedtoxicity.Clear recommendations as to the duration of therapy cannot be drawn from theavailable literature. In practice, most physicians now intend to continue therapy for3-5 years, and discuss withdrawing azathioprine at this time with the patient. It shouldbe 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 diseasepatients 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. 5
  6. 6. 3. Lemann M. et al. Infliximab and azathioprine for steroid dependent Crohn’sdisease patients - a randomised placebo controlled trial. Gastroenterology 2006;130 : 1054 – 61. 6
  7. 7. 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 immunosuppressantdrugs used in the treatment of inflammatory bowel disease. They are often prescribedwhen steroids have proved insufficient in bringing the condition under control. Theyallow a reduction in the dose of steroids, but may take 12-16 weeks or more tobecome effective.How is it taken?• In tablet form, daily. The dosage will be advised by your Gastroenterology specialistteam.Are there any side effects ?These drugs are an important part of the treatment of patients with inflammatorybowel disease, but a small number of patients may experience side effects that willprevent them from continuing with treatment. Should you develop symptoms thatmight be related to your treatment you should discuss them with your Doctor /Gastroenterologist / IBD nurse specialist. Side effects that you should look out forinclude :• 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 maybe 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 monitoringWhilst taking this treatment, you will need regular blood tests. Once the dose oftreatment is stable, the frequency of blood testing will be reduced. The testing will besupervised by your Gastroenterology specialist team or in a shared care arrangementwith your General Practitioner. 7
  8. 8. • 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, thenmonthly for two months and three monthly thereafter if the results are stable. Anychange in dosage will require similar monitoring. You may also be asked to have testsof kidney function from time to time.Other information :• Immunisation with LIVE vaccines should be avoided. (Influenza and pneumovaxcan be given). Please discuss with your General Practitioner or Hospital specialistteam.• Sunscreens and or protective clothing should be encouraged to reduce sunlightexposure.• Other medicines that you are prescribed may interact with azathioprine orMercaptopurine. These include drugs used to treat gout (Allopurinol), the bloodthinning 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 prematurebirth 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 ofMercaptopurine is not recommended during pregnancy.The literature with respect to the safety of thiopurines in men whose partners are planning toconceive 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. 8
  9. 9. CICLOSPORINIntroduction :The main role for ciclosporin is in the treatment of patients with severe steroidrefractory Ulcerative Colitis. The study by Lichtiger1 demonstrated an 80% responserate in this group to intravenous ciclosporin. After conversion to oral treatment about2/3rds of patients were maintained in remission without steroids, with the remaining1/3 rd proceeding to colectomy.Response rates are improved by the addition of azathioprine or Mercaptopurine 2,3, andciclosporin can be used as a bridge for maintenance therapy having a slow onset ofaction.Ciclosporin is of little benefit in Crohn’s disease and should be avoided4.Ciclosporin may be given either intravenously (2mg/kg/day) or orally in amicroemusion 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 / sepsisMonitoringOral : Trough (immediately before next dose) ciclosporin levels should be measuredweekly and dosages adjusted accordingly (liase with Clinical Biochemist / Renal Unitfor local therapeutic ranges); Initially, twice weekly – weekly creatinine (and / orestimated glomerular filtration rate {eGFR}levels. The dose of ciclosporin should bereduced if creatinine levels increase by more than 20% from baseline.Ciclosporin levels are affected by many drugs, particularly antibiotics. More frequentmonitoring should take place when new drugs are introduced.Intravenous : Facilities should be available to monitor ciclosporin and creatinine andelectrolyte levels daily.Agents likely to increase Ciclopsorin levels Drug Effect ActionCalcium channel Monitor ciclosporin levels 9
  10. 10. blockers Increase ciclosporin levels and make dose reductions-Diltiazem, Verapamil, as necessaryNifedipine, AmlodipineGrapefruit juice May increase Ciclosporin Avoid concurrent use levelsMacrolides Markedly increase 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 courseMetoclopramide Increases ciclosporin Avoid concurrent use if levels possible – where concurrent use essential, monitor ciclosporin levels and examine pt for signs of toxicityOral contraceptives Marked increase in If used in combination,- 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.Tacrolimus Increases ciclosporin 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. 10
  11. 11. 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 ofsevere ulcerative colitis. It is used when patients have not responded to standard treatment forinflammatory bowel disease, including steroids. The use of ciclosporin has been demonstratedto reduce the need for a surgical operation to remove the large bowel (called a colectomy). Itis also used in other groups of patients including those with organ transplants, rheumatoidarthritis 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 capsulesize. The total dose is usually in the range of 5.5 – 6.5 mg/Kg per day, given in divided dosesabout 12 hours apart. The dose may be adjusted according to response and blood levels of thedrug.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 aliquid if you have problems swallowing the capsules.Neoral is taken twice a day. Ideally the two doses should be taken 12 hours apart at 8.00amand 8.00pm. This is because blood levels are checked and it is important that the drug hasbeen taken at a known time beforehand. It is very important that when blood is taken tomeasure 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. Wholegrapefruit and grapefruit juice should not be taken for at least one hour before you take thecapsules 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 isa problem.• Shakiness of the hands. 11
  12. 12. • You may feel a little sick in the early stages, possibly with some abdominal discomfort• Hot or burning sensations in the hands and feet. This normally lessens after a couple ofweeks.• Metallic taste in the mouth• Cramps and painful periods. Some women may notice that their periods cease whilst theyare on ciclosporin.Do I need any special checks while on ciclosporin ?Ciclosporin can raise your blood pressure and affect the kidneys. We recommend that yourblood pressure, blood count and kidney function are checked every 2-4 weeks for 2 monthsthen at 1-2 monthly intervals thereafter as appropriate.What do I do if I experience side effects ?If you feel unwell, develop a sore throat or any infections or are unsure about a certainreaction contact your doctor / IBD nurse specialist or pharmacist.What happens if I forget to take a dose ?If you forget to take a dose, take another one as soon as you remember, unless it is almosttime for your next dose. Do not double the dose. If you take too much ciclosporin tell yourdoctor immediately.Does ciclosporin interfere with my other medicines ?Ciclosporin can interact with other medicines including non-steroidal anti-inflammatorydrugs e.g ibuprofen, St John’s Wort and erythromycin. Always check with your doctor orpharmacist first.It is safe to drink alcohol in moderation whilst on ciclosporin. Avoid binge drinking as thiscan seriously affect blood levels of the drug.You should avoid having ‘live’ vaccines such as polio. Most travel vaccines and flu vaccinesare, however, acceptable. Discuss with your doctor or pharmacist first.Is ciclosporin OK in pregnancy and breast feeding ?If you are planning to become pregnant whilst on ciclosporin you should discuss with yourdoctor first. You should not breast feed if you are taking ciclosporin.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. 12
  13. 13. METHOTREXATEIntroduction :Methotrexate is an immunomodulator used to induce and maintain remission ofCrohn’s disease and Ulcerative colitis in patients who have steroid dependent orrefractory disease, or who have been intolerant of either azathioprine or 6-Mercaptopurine. Methotrexate inhibits the enzyme dihydrofolate reductase, essentialfor the synthesis of purines and pyrimidines. Although unlicensed to treatinflammatory bowel disease, methotrexate is widely used in Crohn’s disease (BNFsection 1.5) and less commonly in ulcerative colitis.Dose and mode of administration :Much of the evidence for the beneficial effects for methotrexate has been with theintramuscular route of administration. The evidence for the efficacy andbioavailability of oral methotrexate is limited in Crohn’s disease, although there isvery good evidence for its efficacy in the treatment of Rheumatoid Arthritis for over50 years. Many Gastroenterologists are now recommending oral therapy as it is moreconvenient for the patient and easier to supervise.Intramuscular route : 25mg once per week for up to 16 weeks, then reduced to 15mgonce a week.Oral route : Intially 15mg once per week as a single dose, increasing to 20mg onceper week after 2 weeks and up to a maximum of 25mg once a week after a further 2weeks as tolerated and according to response.A lower starting dose may be required for the elderly or frail or those with renalimpairment. Clinical response is usually evident in 4-6 weeks.Folic acid treatment : Folic acid reduces the toxicity of methotrexate treatment andimproves continuation of therapy and compliance. Folic acid should be taken ONCEweekly, but SHOULD NOT be taken on the same day as the methotrexate.Recommended monitoring and precautions / interactionsMonitoring Schedule : British Society of Gastroenterology recommendation Avoid use in patients with known liverPre-treatment assessment disease (including fatty liver), alcohol excess, obesity, diabetes or women trying to conceive. FBC, U&E, LFT’s Pre-treatment Pulmonary Function Tests 13
  14. 14. and CXR may be considered for some patients FBC, U&E, LFT’S every 2 weeks afterMonitoring the last dose change; thereafter monthly until stabilised. Monitoring frequency every 2-3 months if patients results remain stableAction to be taken : Withold treatment and recheck in 1 weekWBC < 3.5 x 109/l Discuss with Specialist team Withold treatment and recheck in 1 weekNeutrophils < 2.0 x 109/l Discuss with Specialist team Withold treatment and recheck in 1 weekPlatelets < 150 x 109/l Discuss with Specialist teamMCV > 105fl Check serum B12, folate & TFT and Discuss with Specialist team Consider for liver biopsy when persistentAST, ALT > 2 fold rise (from the upper elevation occurs.limit of the reference range) Discontinue treatment in patients with abnormal LFT’s who decline liver biopsyAlbumin – Unexplained fall in the Monitor closely and consider need forabsence of active disease liver biopsy Nausea occurs commonly & may beNausea reduced by changing timing of dose (before bedtime), ensure adequate intake of folic acid, & consider antiemetic at time of weekly doseRashes or oral ulceration, vomiting & Withold treatment and recheck in 1 weekdiarrhoea Discuss with Specialist teamRenal function – significantdeterioration compared to baseline or Withold treatment and recheck resultsupper limit of normal of reference Discuss with Specialist teamrange Immediate FBC and withhold until theSevere sore throat, abnormal bruising result of FBC is availableNew or increasing dyspnoea or dry Withold treatment; CXR & pulmonarycough function tests; Discuss with Specialist team 14
  15. 15. The incidence of hepatotoxicity in patients with inflammatory bowel disease is verylow and particularly so, if the drug is only given to carefully selected patients –avoiding its use in : • In patients suspected of alcohol abuse; • The Obese • Patients with previously demonstrated fatty liver, pre-treatment abnormalities of liver function and those with pre-existing liver diseaseLiver biopsy should be considered when there is a persistent elevation of thetransaminases above baseline or a decrease in the albumin level below the referencerange when the inflammatory disease is inactive.Methotrexate is contraindicated in patients with significant renal impairment becausethe primary mode of excretion of the drug is via the kidneys. Renal toxicity occursrarely with methotrexate treatment, but cases of nephrotic syndrome and renal failurehave been described.Pneumonitis has very rarely been reported in patients with IBD taking methotrexatetreatment. If respiratory symptoms develop whilst a patient is receiving methotrexatetreatment, a CXR and pulmonary function tests should be arranged urgently and thedrug discontinued.Bone marrow suppression may occur as a result of methotrexate treatment. The risk isgreatest in the elderly and those with significant renal impairment. When a significantfall in the indices has occurred the following should be arranged immediately : • Stop Methotrexate therapy • Give Folinic Acid Rescue – The initial dose should be at least 20mg given intravenously. Subsequent doses of 15mg given orally at 6 hourly intervals until the haematological abnormalities have improved (usually not more than 2 – 8 doses. • Consider immediate discussion with Supervising Specialist team / Medical On Call team or the local Haematologist.Pregnancy & Breast feeding :Methotrexate is both teratogenic and is an abortofacient. Methotrexate may also betoxic to sperm. Adequate birth control is therefore essential for both men and women.Contraception (for both sexes) should be continued for at least 3 months afterstopping methotrexate therapy.Methotrexate may be excreted in breast milk so breast feeding is contraindicated.Should an inadvertent pregnancy occur, referral should me made to an Obstetrician.Cautions : • Patients with clinically significant renal impairment from any cause • Localised or systemic infection including hepatitis B & C and past history of TB • Unexplained anaemia or cytopenia associated with bone marrow failure 15
  16. 16. • Immunisation with live vaccines should be avoided (pneumoccocal and Influenza vaccinations can be given) Drug interactions : o Phenytoin, Co-trimoxazole, Trimethoprim – the antifolate effect of methotrexate is increased o Probenacid, Penicillin, Azapropazone, NSAID’s – Methotrexate excretion is reduced (but a clinically significant interaction between methotrexate and NSAID’s is rare o Tolbutamide – serum concentrations of methotrexate may be increasedDuration of treatmentAs for azathioprine, the duration for continuing treatment with MTX cannot berecommended from current literature alone. If well-tolerated, the drug may becontinued for several years, under appropriate supervision. Hepatic fibrosis nowseems relatively uncommom in these IBD patients, and liver biopsy is no longerroutinely recommended after 1.5g intake. Serum markers of fibrosis are available inspcialist centres, if needed. Again, informed discussion with the patient as to theuncertainties of long-term toxicity are necessary, if therapy continues beyond 3-5years without attempted withdrawal of the drug. REFERENCES1. Feagan.BG, Rochon.J. et al .Methotrexate for the treatment of Crohn’s disease. TheNorth American Crohn’s study group Investigations.N.Engl.J.Med.1995;332:292-297.2.Feagan.BG, Fedorak.R et al. A comparison of methotrexate with placebo for themaintenance of remission in crohn’s disease.N.Engl.J.Med. 2000; 342: 1627-1632.3. Alfadhli AA, McDonald JW, Feagan BG. Methotrexate for induction of remissionin refractory Crohn’s disease. Cochrane Database Syst. Rev. 2005; (1) : CD003459.4. Hawthorne AB. Methotrexate : a useful alternative in Crohn’s disease ? Gut 2001;49 : 9-10.5. Rampton DS. Methotrexate in Crohn’s disease. Gut 2001; 48 : 790-1.6.Fraser AG, Morton D, McGovern D, Travis S, Jewell DP. The efficacy ofmethotrexate for maintaining remission in inflammatory bowel disease. Aliiment.Pharmacol. Ther. 2002; 16 : 693-7.7. Aberra FN, Lichtenstein GR. Review article : monitoring of immunomodulatorsin inflammatory bowel disease. Aliment. Pharmacol. Ther. 2005; 21 : 307-19.8. Siegel CA, Sands BE. Review article : practical management of inflammatorybowel disease patients taking immunomodulators. Aliment. Pharmacol. Ther. 2005;22 : 1-16.9. Sun JH, Das KM. Low-dose oral methotrexate for maintaining Crohn’s diseaseremission : where we stand. J. Clin. Gastroenterol. 2005; 39 : 751-6. 16
  17. 17. 10. Kurnik D, Loebstein R, Fishbein E, Almog S, Halkin H, Bar-Meir S, Chowers Y.Bioavailability of oral vs. subcutaneous low dose methotrexate in patients withCrohn’s disease. Aliment. Pharmacol. Ther. 2003; 18 : 57-63. 17
  18. 18. METHOTREXATE TREATMENT FOR PATIENTS WITH IBD PATIENT INFORMATION LEAFLET 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 ?• Methotrexate is a medicine used to induce and maintain remission of Crohn’sdisease and Ulcerative colitis in patients who have steroid dependent or refractorydisease, or who have been intolerant of either azathioprine or 6-Mercaptopurine.How is it taken ?• In tablet form, weekly or by Intra Muscular injection.Your Gastroenterology team will decide on the appropriate dose for you as well asorganizing regular blood tests.To reduce the risk of side effects from methotrexate, you will also be asked to take avitamin called Folic Acid once a week (that will also be prescribed for you), but youshould NOT take this on the same day as the methotrexate treatment.How does it work ?Methotrexatesuppresses inflammation and dampens down the body’s immune system.How long does it take to work ?The benefits of methotrexate treatment often take quite a number of weeks to occur.How long will I be taking it ?Patients who respond to methotrexate usually remain on it for many months and perhapsseveral years as long as the blood test monitoring remains satisfactory.Do not stop taking your medicine unless your doctor tells you to, however well you feel.What are the common side effects ?Fortunately many patients do not suffer any side effects with this treatment. Some ofthe common side effects can be reduced by simple measures :• Nausea / vomiting – this is perhaps the commonest side effect likely to occur. Thesesymptoms can often be reduced by taking the drug at a different time of the day – egon retiring to bed; by ensuring that you are taking the vitamin supplement called Folicacid; for some patients, your Specialist will give you a prescription for an anti-sickness medication to take about an hour before your weekly dose of methotrexate.Other common side effects include : mouth and nasal ulcers; diarrhoea; abdominalpain and bloating; fatigue; symptoms of a cold / flu like illness; joint pain; insomnia;facial flushing; eye irritation; dizziness; mild hair loss; loss of libido / impotence;decreased fertility (reversible on completion of treatment). 18
  19. 19. Other rare side effects include : headache; acne; skin irritation and itching; increasedsensitivity to light; tingling / numbness; dry cough and / or shortness of breath.Should you develop any of these troublesome symptoms you should report them toyour specialist Gastroenterology team.Special monitoringYou will need to undertake a pre treatment screening. The results of which will ensuresuitability. Blood tests will be taken at regular intervals throughout administration ofthe drug.• Do not receive any live vaccines (rubella, polio).• Avoid contact with people who have infections.• Avoid pregnancy.• Contraception is strongly recommended.• If breastfeeding, this should be stopped as methotrexate passes into breast milk.• In certain patients, liver biopsy may be required if treatment is ongoing.Methotrexate and pregnancyDo not become pregnant whilst taking methotrexate treatment. Because methotrexatemay damage sperm, adequate birth control is essential for both men and women.Contraception (for both sexes) should be continued for at least 3 months afterstopping methotrexate treatment.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. 19
  20. 20. DRUGS FOR INFLAMMATORY BOWEL DISEASE AMINOSALICYLATES (5-ASA)Included in this group of drugs are : Sulphasalazine, Mesalazine, Olsalazine andBalsalazide. Comment of mode of action is required ?Route of administration :Oral as tablets, granules and suspensions (sulphasalazine only).Rectally as suppositories or enemas.Cautions / Contraindications :Sulphasalazine :Glucose 6 phosphate dehydrogenase deficiency – may cause haemolysis.Pregnancy / breast feeding :Sulphasalazine may be associated with transient reversible oligospermia in men ofchild bearing potential.Folic acid supplements should be prescribed to those trying to conceive and duringpregnancy.Small amounts of the drug are excreted in breast milk although this is not thought tobe a risk to healthy infants.Contraindicated in patients with hypersensitivity to sulphonamides / co-trimoxazole.All 5-ASA’sUse with caution in patients with renal impairment – and discuss with Nephrologyteam & monitor renal function regularly whilst on treatment.Avoid in patients with severe renal failure.There is a possible increased risk of haematological toxicity (leucopenia, unexplainedbleeding / bruising and purpura) when patients are taking azathioprine or 6 –Mercaptopurine – monitor blood tests more frequently.British Society of Gastroenterology (BSG) recommended monitoring schedule : BSG Guidelines :Pre-treatment assessment FBC, U&E, Creatinine, LFT’sMonitoring FBC & LFT’s at 1 month FBC, U&E, Creatinine, LFT’s at 3 months If results stable repeat above blood tests about once yearly 20
  21. 21. Following dose changes Consider repeating bloods 1 month after increaseActions to be taken :Nausea, dizziness, headache, worsening If troublesome, reduce or stop treatmentdiarrhoea and consider alternative Monitor carefully – if WBC continues toWBC < 4.0 x 109/l fall, withhold until discussed with Gastroenterology specialist team Monitor carefully – if neutrophil countNeutrophils < 2.0 x 109/l continues to fall, withhold until discussed with Gastroenterology specialist team Monitor carefully – if platelet countPlatelets < 150 fl continues to fall, withhold until discussed with Gastroenterology specialist team Check amylase level; consider ultrasoundSevere abdominal pain or CT scanning> 2 fold rise above upper limit of normal Withold until discussed with specialistreference range for ALT / AST team; Ultrasound liver.Rise of creatinine level above the normal Withold until discussed with specialistrange (or rise of > 20% compared to team; Urinalysis for proteinuria etc; renalbaseline) ultrasound; nephrology opinion. Check FBC immediately and withholdAbnormal bruising or severe sore throat until result available. discuss with Gastroenterology specialist teamUnexplained acute widespread rash Withold; seek urgent specialist (preferably Dermatological) advice 1. Ransford RA, Langman MJ. Sulphasalazine and mesalazine : serious adverse reactions re-evaluated on the basis of suspected adverse reaction reports to the Committee on Safety of Medicines. Gut 2002; 51 : 536-9. 2. Van Staa TP, Travis S, Leufkens HG, Logan RF. 5-aminosalicylic acids and the risk of renal disease : a large British epidemiological study. Gastroenterology 2004; 126 : 1733 – 9. 3. Muller AF, Stevens P, McIntyre AS, Ellison H, Logan RF. Experience of 5- aminosalicylate nephrotoxicity in the United Kingdom. Aliment. Pharmacol. Ther. 2005; 21 : 1217 – 1224. 21
  22. 22. DRUGS FOR INFLAMMATORY BOWEL DISEASE THE AMINOSALICYLATES (5-ASA) 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.If you have been diagnosed with Inflammatory Bowel Disease (Crohn’s disease orUlcerative Colitis) you may be prescribed an aminosalicylate sometimes called 5-ASA (or mesalazine, olsalazine, basalazide, or sulphasalazine). These drugs have amajor role in maintaining remission of ulcerative colitis. Crohn’s disease patientsmay also benefit from treatment with these drugs and they are often used to helpreduce the chances of Crohn’s disease recurring after operations.What are 5-ASA’s ?They are a group of drugs that work by minimising the degree of inflammation in theintestine, giving the damaged lining time to heal.There are several slightly different drugs in this group that all are designed to treatdifferent areas of the intestine. Your doctor will start you on the one that will give youthe most benefit. It is important that you stick to the same unless your doctor tells youotherwise.How are 5-ASA’s given ?These drugs can be given by mouth (tablets, capsules and granules). For patientswhose colitis is limited to the distal part of the colon, these treatments may prove veryeffective when given through the anus by inserting a suppository or enema.How long will it take to work ?These drugs do not work straight away. In order to remain in remission, you mustcontinue to take your mesalazine even if you feel well.Do I need to take 5-ASAs long term ?To keep the bowel condition under control and to reduce the risk of flare ups, patientsare usually advised to take these treatments long term.The risk of bowel cancer in inflammatory bowel disease is slightly increased, butsome studies have suggested that this risk may be reduced by long-term use of 5-aminosalicylates.What dose of 5-ASAs will I be given ?The dose will be decided by your doctor, and usually depends on how active thedisease is and may be increased or decreased accordingly.You will usually remain on a dose to help keep your disease under control, this isknown as a maintenance dose.What are the common side effects ? 22
  23. 23. 5-ASAs are effective in the treatment of inflammatory bowel disease but canoccasionally be associated with some side effects, which are usually mild such asdiarrhoea, nausea, vomiting, headaches, and rashes.Generally however, these drugs are very well tolerated with 90% of patientsexperiencing no side- effects.Very rarely, these drugs can affect the blood, kidneys, liver and pancreas. Rarelysome patients can be allergic or particularly sensitive to 5-ASAs and so it is importantto report any unexplained bleeding, bruising, skin rash, prolonged sore throat or fever.If this happens sometimes the drug has to be stopped or changed.Do I need to have blood tests ?Because these drugs very rarely can cause blood disorders, your Doctor or NurseSpecialist will arrange for you to have occasional blood checks – these wouldnormally be done at least once per year but usually sooner (e.g. between 1 - 3 months)if you have recently started on the drug.Can I have immunisations whilst taking 5-ASA’s ?It is safe to have Vaccinations whilst on 5-ASAs.Can I drink alcohol whilst taking 5-ASA’s ?There is no reason to avoid alcohol (in moderation) whilst taking 5-ASAs, but it cansometimes aggravate nausea.Do 5-ASA’s affect fertility or pregnancy ?There is one drug called Salazopyrin (sulphasalazine) that is associated with areversible reduction of male fertility. Salazopyrin is used less frequently nowadays asthe newer drugs may have fewer side effects. Other 5-ASAs do not affect fertility andall can be safely taken in pregnancy.Do these drugs interfere with my other medicines ?Most drugs can be taken safely, however always check with your doctor or pharmacistfirst. 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. 23
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