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Medicines Q&As Q&A 310.3 Is there any evidence to support the use of enteric coated (EC) over uncoated prednisolone tablets? Prepared by UK Medicines Information (UKMi) pharmacists for NHS healthcare professionals Before using this Q&A, read the disclaimer at www.ukmi.nhs.uk/activities/medicinesQAs/default.asp Date prepared: 11 June 2013 Background Data on this subject are sparse and the last overview, which was published in the Drug and Therapeutics Bulletin (DTB) 1987, concluded that uncertainty remains as to whether enteric coating decreases the tendency of steroids to cause ulcers (1). This was also the conclusion of the previous DTB on this subject in 1977, i.e. “there is no evidence that EC prednisolone is less likely than the plain tablets to cause peptic ulceration (PU) and the evidence that it is less likely to cause dyspepsia is not satisfactory (2). Since the DTB, a few more papers on this subject have been published but these are limited to pharmacokinetic studies and case reports. As the debate continues about whether the EC formulation provides gastro-protection compared with the uncoated tablets, in addition to the cost differential of the two products (three-fold difference at time of writing based on Drug Tariff June 2013), a summary of the findings of the DTB and an update of the literature with a focus on the implications of switching formulations are presented Answer According to the 1987 DTB, the limited data available suggest that corticosteroids appear to be weakly linked with PU; the link being most relevant in patients with diseases linked to PU, or history of PU, and any effect dependent on dose and duration. In addition, the risk of developing an ulcer is usually small compared with the prospective benefit from corticosteroid therapy. Furthermore, if steroids have a systemic ulcerogenic effect (rather than a local one) then enteric coatings will make no difference unless they reduce bioavailability and thus efficacy. It also noted that at the time of writing some commentators believed dyspepsia was less common with EC tablets, but its overall conclusion was that the use of EC prednisolone to decrease risk remains speculative and probably leads to a false sense of security (1). The literature on this topic remains sparse since the publication of the DTB. Most of the published pharmacokinetic studies have noted lower- and slower time topeak plasma concentration with EC than uncoated prednisolone tablets, though bioavailability was generally found to be similar. A small number of case reports have indicated problems with disease control with use of EC or with switch to EC from the uncoated formulation. From the limited available data, it would seem that EC tablets may be associated with less predictable absorption; and in certain clinical conditions where plasma levels of prednisolone need to be stable and predictable, some authors recommend the use of the uncoated tablets, particularly in the absence of robust evidence to suggest that enteric coating confers GI protection. The clinical implications of these reports may need to be considered in some cases when switching between formulations, but the evidence base is too limited to gauge the extent to which this could be problematic, and as with any therapeutic switching, additional monitoring of the patient may be required. Summary of published pharmacokinetic studies post DTB In a randomised, cross over assessment, 8 patients with COPD and 8 healthy volunteers received 30mg prednisolone as uncoated and EC tablets. Plasma prednisolone, cortisol and blood glucose were measured over 24 hours. Although absorption of prednisolone was considerably slower when administered as the EC, peak plasma concentrations and total AUC (0-24 hours) were equivalent for the two formulations, and malabsorption of prednisolone was not observed. EC administration was associated with less adrenal suppression than uncoated in volunteers but this difference did not reach statistical significance in the patient group. Plasma cortisol concentrations declined more slowly following administration of the EC to both groups. Plasma cortisol concentrations were lower at 24 hours in patients receiving the EC product in association with higher terminal prednisolone Available through NICE Evidence Search at www.evidence.nhs.uk 1 Medicines Q&As concentrations. Blood glucose concentrations increased over an 8 hour period in both groups; a lag in the increase of glucose following administration of the EC form was not observed. Eosinophil counts were reduced to an equal extent after administration of both formulations in both patients and volunteers. The researchers conclude that the pharmacokinetic differences between preparations of prednisolone were not reflected in pharmacodynamic changes in blood glucose or eosinophil count in this study. However, administration of the EC form resulted in a lag in the decline of plasma cortisol and, in volunteers, cortisol suppression was not as marked when EC was used (3) Prednisolone absorption and bioavailability of 10mg EC and uncoated tablets were investigated after fasting and heavy meals (EC only) in 7 healthy volunteers. The same volunteers also received 16 mg of IV prednisolone. In fasted subjects, the absolute bioavailability fraction (as normalised for IV doses, of prednisolone) from uncoated tablets was 1.055 and from EC tablets 0.996. Peak concentrations after uncoated and EC tablets were 309 and 249ng/ml attained at 0.98 and 5.14 hours, respectively. Mean plasma elimination half-lives following uncoated, EC and IV administration in fasting conditions were 3.73, 3.89 and 3.78 hours, respectively. Food interfered with both the absorption and pharmacokinetics of EC prednisolone resulting in variability in its plasma levels; in some cases absorption of prednisolone was delayed for 12 hours and remained at a measurable level for 24 hours, and in other cases, a normal absorption pattern was observed. This inter-and intrasubject variability of the effect of food appears to be related to its quantity, constituents and also the subject’s physiological characteristics. It was concluded that EC prednisolone tablets should be administered at least 2 hours between meals. However, for more predictable corticosteroid absorption (perhaps thus avoiding therapeutic failure), the authors suggest that uncoated prednisolone tablets are preferable (4). Summary of cases of failure to respond to EC prednisolone 13 year old, with active Crohn's was initially treated with prednisolone 40mg/d with good relief of his symptoms. As an outpatient he was re-prescribed EC prednisolone by his GP instead of the uncoated tablets prescribed in clinic. On the same dose as before his symptoms (abdominal pain and diarrhoea) recurred. Non-EC prednisolone was re-prescribed and he improved. The authors note that this is not an isolated occurrence in their unit and that the absorption of drugs in Crohn's disease is known to be erratic, and EC prednisolone is likely to be less well absorbed. They add that there are other reports in the literature of adults with Crohn's disease who have failed to respond to EC prednisolone and responded to the non EC formulation. Therefore they advocate the use of non-EC prednisolone in the treatment of Crohn's disease and suggest that in any condition where there is a rapid transit time or diarrhoea, EC prednisolone should be used with caution (5). 11 year-old with cystic fibrosis (CF) and allergic bronchopulmonary aspergillosis was treated with 2 weeks’ of antibiotics and EC prednisolone 60mg/d, but there was negligible improvement in radiological appearance. He had no signs of steroid therapy (e.g. little weight gain and no facial redness or fullness) and no signs of becoming cushingoid. Antibiotics were discontinued and steroid therapy changed to uncoated prednisolone 40mg/d. Two weeks later, the chest X-ray had cleared almost completely and the patient was notably cushingoid, suggesting improved absorption of prednisolone. The authors note that the pH in the jejunum (where prednisolone absorption takes place) in CF is <5 for prolonged periods, however, prednisolone is released from the EC preparation at pH 6-8 and it is therefore unlikely to be available at pH 5. They suggest that in CF, the bioavailability of all EC preparations should be questioned, and there may be good theoretical reasons to advise that non-EC prednisolone be specified for this patient group (6). 40-year-old woman presented with a three-day history of anorexia, nausea, and vomiting. During preceding fortnight she had felt generally weak and had noticed postural dizziness and cold hands and feet. She was taking prednisolone (2.5mg EC tablets QDS) for SLE. She was diagnosed with acute adrenal insufficiency and treated with fluids and full doses of parenteral hydrocortisone and fludrocortisone. Over the next 2 weeks she improved and was discharged on prednisolone 10mg bd (as plain tablets). During her convalescence, absorption of prednisolone was studied by oral administration of 10mg prednisolone as plain tablets and EC Available through NICE Evidence Search at www.evidence.nhs.uk 2 Medicines Q&As tablets or as the solution of prednisolone sodium phosphate used for IV infusion in the fasted state. A further patient with an ileostomy was also studied. In both patients, the absorption of prednisolone from plain tablets was comparable with results in other studies in terms of peak plasma concentrations and AUC. The absorption from solution was slightly better. In neither patient, however, was there much absorption of prednisolone from the EC tablets. The lag time produced by EC of prednisolone tablets is between 2 to 2.5 hours. These tests show that in both these patients with an ileostomy, there was negligible absorption of prednisolone from an EC preparation that was bioequivalent to plain tablets in normal subjects. Because such bio-inequivalence may manifest clinically as corticosteroid insufficiency, as in the first patient, the author suggests that EC prednisolone preparations have little place in the treatment of patients with an ileostomy (7). 58-year-old man with a cadaveric renal transplant was started on EC prednisolone tablets and azathioprine. A few days later he showed evidence of a rejection and was given conventional treatment with pulsed methylprednisolone. However, 24 hours later he developed classical signs of an acute intestinal obstruction. An abdominal x-ray showed aggregation of the EC tablets which had not been absorbed and were causing the obstruction. Parenteral prednisolone and azathioprine were commenced and 3 days later the patient had relief of the intestinal obstruction and was able to take fluids orally. His medication was then changed to normal prednisolone and azathioprine. The authors note this case illustrates that, although in some patients EC tablets are absorbed, in others they may be passed unabsorbed into the small intestine. They suggest that in conditions in which the plasma levels of prednisolone need to be stable and predictable, their use is unsatisfactory. They were also of the opinion that it is doubtful whether the coating of the prednisolone tablet prevents peptic ulceration and suggest that this effect may be due to non-absorption of the medication, with potentially dangerous effects (8). Summary When this topic was reviewed in the two DTBs several decades ago, no convincing evidence was found to support the claim that EC prednisolone reduces the risk of PU. Since these publications, the literature has remained sparse on this topic. Most of the published pharmacokinetic studies have noted lower- and slower time to- peak plasma concentration with EC than uncoated prednisolone tablets, though bioavailability was generally found to be similar. A small number of case reports have indicated problems with disease control with use of EC or with switch to EC from the uncoated formulation. From the limited available data, it would seem that EC tablets may be associated with less predictable absorption; and in certain clinical conditions where plasma levels of prednisolone need to be stable and predictable, some authors recommend the use of the uncoated tablets, particularly in the absence of robust evidence to suggest that enteric coating confers GI protection. There may be theoretical clinical implications to consider when switching between formulations but the evidence base is too limited to gauge the extent to which this could be problematic, and thus patient monitoring may be required when switching. In the absence of supporting published data, the conclusion of the DTB on this subject from 1987 that uncertainty remains as to whether enteric coating decreases the tendency of steroids to cause ulcers, remains unchanged. This is reflected in the BNF which states there is no conclusive evidence that the use of EC preparations of prednisolone reduces the risk of PU (9). Limitations No recent data are available and the most recent overview was published over 20 years ago in the DTB. The literature since the DTBs is limited to pharmacokinetic studies and case reports. No published data were identified that compared use of proton pump inhibitor plus uncoated prednisolone with EC prednisolone Available through NICE Evidence Search at www.evidence.nhs.uk 3 Medicines Q&As References 1. Anon. Do corticosteroids cause peptic ulcers? Drug Ther Bull 1987; 25: 41-3 2. Anon. What use is enteric-coated prednisolone? Drug & Therapeutics Bulletin, October 1977; 15 (21): 83-4 3. Adair C.G, McCallion O, McElnay J.C, et al. A pharmacokinetic and pharmacodynamic comparison of plain and enteric-coated prednisolone tablets. BJCP 1992; 33: 495-499 4. Al-Habet SMH, Rogers HJ. Effect of food on the absorption and pharmacokinetics of prednisolone from enteric-coated tablets. Eur J Clin Pharmacol 1989; 37/4: 423-426 5. Beattie RM, Walker-Smith JA. Use of enteric coated prednisolone in Crohn's disease. Archives of Disease in Childhood 1994; 71: 282 6. Gilbert J, Littlewood JM. Enteric-coated prednisolone in cystic fibrosis. Lancet 1986; 2 (8516): 1167-8 7. Al-Habet S, Kinsella HC, Rogers HJ, Trounce JR. Malabsorption of prednisolone from entericcoated tablets after ileostomy. BMJ 1980; 281: 843-4 8. Fernando ON, Moorhead J. Absorption of enteric-coated prednisolone. BMJ 1979; 1 (6180): 9. BNF 65 (March- September 2013): https://www.evidence.nhs.uk/formulary/bnf/current/6endocrine-system/63-corticosteroids/632-glucocorticoid-therapy/side-effects-of-corticosteroids Quality Assurance Prepared by Yuet Wan, London and South East Regional Medicines Information, Guy’s Hospital Date Prepared January 25th 2010, updated 11 June 2013 Checked by David Erskine, London and South East Regional Medicines Information, Guy’s Hospital Date of check 12 June 2013 Search strategy Date 01/12/2009 1. EMBASE; exp PREDNISOLONE/; 57883 results. 2. EMBASE; exp ENTERIC COATED TABLET/; 1321 results. 3. EMBASE; 1 AND 2; 51 results. 4. EMBASE; 3 [Limit to: Human and English Language]; 44 results. 5. MEDLINE; exp PREDNISOLONE/; 39666 results. 6. MEDLINE; exp TABLETS, ENTERIC-COATED/; 1879 results. 7. MEDLINE; 5 AND 6; 41 results. 8. MEDLINE; 7 [Limit to: Humans and English Language]; 34 results. 9. EMBASE, MEDLINE; Duplicate filtered: [3 [Limit to: Human and English Language]], [7 [Limit to: Humans and English Language]]; 78 results. Alliance Pharmaceuticals (Medical Information, 01/12/2009: personal communication) Websites: NeLM, Cochrane Library, CKS, NPC Date 25/01/2010 Above search repeated- no new data identified Date 11/06/2013 Above search repeated but only limited to publication date from 2009 to current - no new data identified- nothing from search of NHS Evidence (enteric prednisolone) but have included BNF statement (ref 9) Available through NICE Evidence Search at www.evidence.nhs.uk 4