Mesalazine (mesalamine or 5-aminosalicylic acid)
Light tan to pink needle-shaped crystals, odourless or with
slight characteristic odour. The colour may darken on expo
sure to air. Slightly soluble in water: very slightly soluble ii
dehydrated alcohol, acetone, and methyl alcohol; practically
insoluble in chloroform, ether, butyl alcohol, ethyl acetate, n
hexane, dichloromethane, and propyl alcohol, soluble in di
lute hydrochloric acid and in dilute alkali hydroxides.
Adverse Effects and Precautions
Headache, gastro-intestinal disturbances, such a;
nausea, diarrhoea, and abdominal pain, or hypersen
sitivity reactions may occasionally occur. Some pa
tients may experience exacerbation of symptoms o
colitis. There are some reports of nephrotoxicity
pulmonary symptoms, hepatitis, aplastic anaemia
agranulocytosis,, leucopenia, neutropenia, thrombo
cytopenia, myocarditis, pancreatitis, and peripheral
neuropathy. A lupus-like syndrome has occurred.
It has been recommended that mesalazine should
not be given to patients with impaired renal function
or salicylate hypersensitivity, and should be used
with caution in the elderly. It is contra-indicated in
children under 2 years of age. If a blood dyscrasia is
suspected treatment should be stopped immediately
and a blood count performed. Patients or their carers
should be told how to recognise signs of blood tox-
icity and should be advised to seek immediate med-
ical attention if symptoms such as fever, sore throat,
mouth ulcers, bruising, or bleeding develops.
Many of the adverse effects associated with sulphasalazine
therapy have been attributed to the sulphapyridine moiety and
most patients unable to tolerate sulphasalazine because of hy-
persensitivity or adverse reactions can be transferred to me-
salazine without adverse effects occurring. However, a
small number of patients also experience adverse effects
whilst taking mesalazine and these are often very similar to
those seen with sulphasalazine. They may include nausea.
abdominal discomfort or pain. exacerbation of diarrhoea,
headache, fever, and rashes: mesalazine is not associated with
sulphasalazine's adverse effects on sperm.
Mesalazine therapy should be initiated cautiously in patients
with a history of sulphasalazine hypersensitivity and it
should
be withdrawn if signs of sensitivity develop or if there is
diarrhoea or rectal bleeding. It has been suggested2 that
patients with a history of sulphasalazine hypersensitivity
should be given test doses of mesalazine before starting a
full course.
Effects on the blood. Although uncommon, mesalazine-
associated adverse effects on the blood have been reported.
including thrombocytopenia. neutropenia, and fatal aplastic
anaemia.3 In July 1995 the Committee on Safety of Medicines
in the UK stated that it had been notified of 49 haematological
reactions suspected to be associated with mesalazine. includ-
ing 5 reports of aplastic anaemia. I of agranulocytosis, 11 of
leucopenia. and 17 of thrombocytopenia. There had been 3
fatalities. They recommended a blood count and immediate
withdrawal of the drug if a dyscrasia was suspected. Antilym-
phocyte immunoglobulin may be useful in the management
of mesalazine-associated aplastic anaemia.
Effects on the cardiovascular system. Myocarditis asso-
ciated with chest pain and ECG abnormalities has been
rported in 2 patients taking mesalazine: 1 patient died in
cardiogenic shock. It was suggested that mesalazine or sul-
phasalazine should be replaced by glucocorticoids if cardiac
symptoms arise during treatment. Pericarditis, together
with fever, rash. dyspnoea, pleural and pericardial effusions.
and arthritis, has also been described, and is considered to
constitute a drug-induced lupus-like syndrome.
mesalazine Lancet 1990: 3351 605.
Effects on fertility. For a review of the effects of sul-
phasalazine on male fertility and reversal of these effects on
changing therapy to mesalazine, see Sulphasalazine, p. 1215.
Effect on the hair. Accelerated hair loss from the scalp
occurred in 2 patients receiving mesalazine enemas' in whom
this reaction did not occur during sulphasalazine treatment.
There have been case reports of sulphasala7.ine causing hair
loss as well as improvement in alopecia.
Effects on the kidneys. The risk of nephrotoxicity may be
low for mesalazine and the related compounds like sulphasalazin
and olsalazine Even so adverse effects on the kidneys have
occured and between February 1988 and December 1990 the
UK Committee on Safety of Medicines received 9 reports of
serious nephrotoxic reactions associated with the use of Asa-
col. a modified-release mesalazine preparation. The reactions
included 4 cases of interstitial nephritis, 3 of severe renal
failure and 2 cases of nephrotic syndrome. A subsequent case
report' indicated that by September 1998 the number of such
reports for mesalazine totalled 104. including 35 cases of in-
terstitial nephritis. The authors considered that monitoring of
renal function was required in patients receiving mesalazine.
The nephrotic svndrome3 and interstitial nephritis have also
been reported with sulphasalazine.
Effects on the nervous System. A report of peripheral
neuropathy predominantly affecting the legs. associated
with mesalazine treatment. The symptoms resolved on dis-
continuing the drug. Mononcuritis multiplex was part of the
presentation of an eosinophilic reaction attributed to mesala-
zine in an asthmatic patient:- Churg-Strauss syndrome developed
after withdrawal of mesalazine. but the patient subsequently
recovered without sequelae.
Effects on the pancreas. Reports of pancreatitis. with ab-
dominal pain and raised serum amylase activity, in 2 patients
taking rnesalanne. The reaction was confirmed by rechal-
lenee in both patients and symptoms resolved on withdrawal
of mesalazine. The Committee on Safety of Medicines in the
UK had received 15 reports of pancreatitis associated with
mesalazine therapy at February 1994.
Effects on the respiratory system. Pulmonary complica-
tions occur rarely with sulphasalazine . It is not
known which component of sulphasalazine is responsible al-
though. following a report of alveolitis in a patient with ulcer
ative colitis given mesalazine. It was concluded that both
sulphasalazine and 5-aminosalicylate (mesalazine) could in-
duce hypersensitivity lung disease. Similar cases have since
been reported and pulmonary symptoms may also manifest
as part of a broader lupus-like syndrome (see Effects on the
Cardiovascular System, above).
Pregnancy. Renal insufficiency in a neonate whose mother
received mesalazine during pregnancy was suggested to be
due to the drug, although the proposed mechanism, inhibi-
tion of prostaglandin synthesis in the neonatal kidney, has
been questioned.
Interactions
Preparations in which the formulation is designed to
release mesalazine in the colon should not be given
with lactulose or similar drugs which lower pH
thereby preventing the release of mesalazine.
Mesalazine may inhibit the metabolism of thiopu-
rine antineoplastics such as azathioprine or mercap-
topurine .
Pharmacokinetics
Following oral administration of conventional for-
Mulations, mesalazine would be extensively ab-
sorbed from the upper gastro-intestinal tract, with
little of the drug reaching the colon. Oral prepara-
tions are therefore generally formulated to release
the drug in the terminal ileum and colon, where it is
thought to exert a mainly local action. The specific
release characteristics differ somewhat between for-
mulations and this, together with interindividual
variation, makes comparison of pharmacokinetic
data between studies difficult. Some 20 to 50% of an
oral rinse is thought to be lost to absorption in
healthy subjects, but absorption is lower in
patients with active inflammatory bowel disease. Absorption
from rectal dosage forms has also varied widely,
with factors such as the dose. the formulation, and
the pH also playing a role. but mean absorption of
around 10 to 20% of a rectal dose has been reported
in several studies.
The absorbed portion of mesalazine is almost com-
pletely acetylated in the gut wall and in the liver, and
the rate of acetylation, and hence the concentration
of parent drug and metabolite in the systemic circu-
lation. is independent of the acetylator status. It has
been suggested that the metabolite. acetyl-5-
aminosalicylic acid. may itself have some activity.
The acetylated metabolite is excreted mainly in
urine by tubular secretion, together with traces of
the parent compound: a clearance of about 3 to 4 mL
per minute per kg has been reported for the former.
The elimination half-life of mesalazine is reported
to be about I hour and it is 40 to 50% bound to plas-
ma proteins; the acetylated metabolite has a half-life
up to 10 hours and is about 80% bound to plasma
proteins.
Only negligible quantities of mesalazine cross the
placenta. Amounts distributed into breast milk are
very small.
Reviews.
Distribution into breast milk. The concentrations of me-
salazine in maternal plasma and breast milk in a lactating
woman taking 500 mg three times daily, were 410 and 1 10 ng
per mL respectively. Although it was considered that the
amount of mesalazine excreted in breast milk was small and
that it was sate during breast feeding, maternal use of me-
salazine 500 mg suppositories twice daily has been associated
with watery diarrhoea in a breast-fed infant.
Uses and Administration
Mesalazine is an anti-inflammatory drug structural-
ly related to the salicylates and active in inflamma-
tory bowel disease : it is considered to be
the active moiety of sulphasalazine . Its
mode of action is uncertain, but may be due. at least
in part. to its ability to inhibit local prostaglandin
and leukotriene synthesis in the gastro-intestinal
mucosa.
Mesalazine is given by mouth or rectally in the man-
agement of mi Id to moderate acute ulcerative colitis
or the maintenance of remission, particularly in pa-
tients who tolerate sulphasalazine poorly. An oral
dose of 400 mg of mesalazine is theoretically equiv-
alent to I g of sulphasalazine.
There are several differently formulated oral prepa-
rations of mesalazine available, and dosage recom-
mendations vary. For some UK enteric-coated
tablets (Asacol and Coltec EC) the usual initial adult
dose is 2.4 g daily in divided doses followed by 1.2
to 2.4 g in divided doses daily for maintenance of
remission. The dose of another enteric-coated tablet
(Salofalk) is 1.5 g daily in divided doses, followed
by 0.75 to 1.5 g daily in divided doses for mainte-
nance of remission. Yet another formulation (Penta-
sa Slow Release tablets) is given in doses of up to
4 g daily in divided doses; for maintenance therapy
the dose is adjusted individually from an initial dose
of 1.5 g daily.
When given rectally, the suggested dose is 0.75 to
3 g daily in divided doses as suppositories. In the
UK. I or 2 g has been given daily as an enema for-
mutation, but in the USA an enema containing 4 g of
mesalazine has been given.
Administration. Because the release characteristics of dif-
ferent formulations of mesalazine vary, they should not be re-
garded as interchangeable. This applies even to those
formulations (such as Asacol and Coltec EC) where the dos-
age is apparently similar.
Behcet's syndrome. A topical aqueous suspension of me-
salazine produced healing of oral and vaginal ulcers in a pa-
tient with BehCet's syndrome,