Download Is there any evidence to support the use of enteric coated

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
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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
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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
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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
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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
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