Sulindac
A yellow, odourless or almost odourless, polymorphic, crys
talline powder. Ph. Eur. solubilities are: very slightly soluble
in water and in ether; sparingly soluble in alcohol, soluble in
dichloromethane, dissolves in dilute solutions of alkali hy-
droxides. USP solubilities are: practically insoluble in water
and in petroleum spirit; slightly soluble in alcohol, in acetone.
in chloroform, and in methyl alcohol: very slightly soluble in
isopropyl alcohol and in ethyl acetate. Protect from light
Adverse Effects
As for NSAIDs in general.
Urine discoloration has occasionally been reported with sulindac.
Sulindac metabolites have been reported as major or
minor components in renal stones.
A report of 4 patients and a short review of 8 previously re
ported cases of serious adverse reactions to sulindac: reac-
tions included fever and skin, liver, CNS. lymph node, bone-
marrow, and lung involvement.
Effects on the blood, Agranulocytosis, thrombocytopenia
Nia, haemolytic anaemia and aplastic anemia have been
repotted in patients taking sulindac.
Effects on the CNS. Acute deterioration of parkinsonism
occurred in a patient following the introduction of suhndac
therapy.
See also under Hypersensitivity, below.
Effects on the endocrine system. Reversible gynaeco-
mastia associated with sulindac therapy has been reported
one patient. There has also been a report of reversible hy
pothyroidism in an elderly patient taking sulindac.
Effects on the gallbladder. A "sludge" composed of crys-
talline metabolites of sulindac has been found in the common
bile duct during surgery for biliary obstruction in patients
who had been taking sulindac.'
Effects on the kidneys. Sulindac-induced renal impair
ment, interstitial nephritis, and nephrotic syndrome have been
reported.
The ability of NSAIDs to inhibit renal prostaglandin synthe
sis is an important factor in the development of renal toxicity.
Generally, inhibition of prostaglandin synthesis has no signif-
icant effect on renal blood flow or glomerular filtration rate.
However, patients with reduced renal perfusion have in-
creased dependence on prostaglandin synthesis for renal
haemodynamic function. In these patients, inhibition of pros-
taglandin synthesis can produce deleterious effects on renal
blood flow and glomerular filtration rate. It has been suggest-
ed that sulindac, as a prodrug, may not inhibit renal prostag-
landin synthesis in therapeutic doses. However, this
potentially important therapeutic advantage has not been uni-
formly observed in short-term studies in patients with renal
dysfunction.
There have been reports of renal stones consisting of between
10 and 90% of sulindac metabolites developing in patients
treated with sulindac.
Effects on the liver. Hepatotoxicity reported in patients re-
ceiving sulindac includes hepatocellular injury and cholestat-
ic jaundice. Symptoms of hypersensitivity including rash,
fever, or eosinophilia have been reported in 35 lo 55% of pa
tienis with sulindac-induced liver damage.' in these patients
the liver damage occurred usually within 4 to 8 weeks of be-
ginning sulindac therapy. Her reference lo a report citing the
strongest evidence for an association of sulindac with liver
disease compared with other NSAIDs. see under NSAIDs.
Effects on the skin. Toxic epidermal necrolysis has
occurred in patients taking sulindac. In one patient toxic hep
titis and the Stevens-Johnson/toxic epidermal necrolysis
syndrome resulted in death.
An unusual pernio-like reaction affecting the toes and confermed
by rechallenge has also been reported.
Sulindac has also been reported to cause photosensitivity.
Hypersensitivity. Hypersensitivity reactions to sulindac
elude pneumonitis, generalised lymphadenopathy, aseptic
meningitis and anaphylactoid reaction.'
Precautions
As for NSAIDs in general.
Sulindac metabolites have been reported as major or
minor components in renal stones. It should there-
fore be used with caution in patients with a history
of renal stones and such patients should be kept well
hydrated while receiving sulindac.
The dose of sulindac may need to be reduced in pa-
tients with liver or renal function impairment.
Interactions
For interactions associated with NSAIDs.
Dimethyl sulphoxide reduces plasma concentrations
of the active metabolite of sulindac and concomitant
administration of the two drugs has also resulted in
peripheral neuropathy. Diflunisal and aspirin are re
ported to reduce the plasma concentration of the ac-
tive metabolite of sulindac. Unlike other NSAIDs.
sulindac is reported not to reduce the antihyperten-
sive effects of drugs such as thiazide diuretics, but
nevertheless the manufacturers recommend that
blood pressure be closely monitored in patients tak
ing antihypenensives and sulindac together.
Pharmacokinetics
Sulindac is absorbed from the gastro-intestinal tract.
It is metabolised by reversible reduction to the sul-
phide metabolite, which appears to be the biologi-
cally active form, and by irreversible oxidation to
the sulphone metabolite. Peak plasma concentra-
tions of the sulphide metabolite are achieved in
about 2 hours. The mean elimination half-life of
sulindac is about 7 to 8 hours and of the sulphide
metabolite about 16 to 18 hours. Sulindac and its
metabolites are highly bound to plasma protein.
About 50% is excreted in the urine mainly as the sul-
phone metabolite and its glucuronide conjugate.
wnh smaller amounts of sulindac and its glucuro
nide conjugate. Sulindac and its metabolites are also
excreted in bile and undergo extensive enterohepatic
circulation.
Uses and Administration
Sulindac is an NSAID. It is structurally relat
ed to indomethacin; its biological activity ap
pears to be due to its sulphide metabolite. Sulindac
is used in musculoskeletal and joint disorders such
as ankylosing spondylitis, osteoarthritis, and rheu
matoid arthritis, and also in the short-tern manage
ment of acute gout and peri-articular conditions
such as bursitis and tendinitis. It is also used to re
duce fever.
A usual dose of sulindac by mouth is initially 150 or
200 mg twice daily reduced according to response.
The maximum recommended daily dose is 400 mg.
The UK manufacturers recommend that the treat-
ment of peri-articular disorders should be limited to
7 to 10 days; for acute gout, 7 days of therapy is usu
ally adequate. The dose may need to be reduced in
patients with liver or renal function impairment.
Sulindac sodium has been given by rectal supposito
ry in doses of 200 to 400 mg daily.
Gastro-intestinal disorders. In placebo-controlled
studiesl2 sulindac 150 to 200 mg twice daily for 6 to 9
months has reduced the number and size of polyps in patients
with familial adenomatous polyposis but the effect may be
incomplete and in one study only polyps less than 2 mm in
size regressed. The size and number of polyps has been
reported to increase on discontinuation of treatment and
long-term therapy is therefore being studied. However, some
workers have observed diminution of sulindac's effective
ness with long term treatment although others have reported that they have managed recurrences by adjustment of the
maintenance dosage used: it appeared that there were individ-
ual variations in sensitivity to sulindac with respect to preven
tion of polyps recurrence although 200 mg daily appeared to
be an average maintenance dose needed. Whether sulindac
prevents malignant degeneration is unknown but there has
been a report of a patient who developed rectal cancer during
ling-term therapy for familial adenomatous polyposis. Some
consider that sulindac is unlikely to replace surgery as prima-
ry therapy for familial adenomatous polyposis.
Sulindac has also been reported to have produced beneficial
effects in a patient with duodenal polyps associated with
Gardner's syndrome but a placebo-controlled study has sug-
gested that it may not be effective against sporadic type co
lonic polyps.
Premature labour. The most common approach lo post-
poning premature labour with drugs is with a selective
beta agonist. However, as prostaglandins have a role in uter-
ine contraction and cervical ripening and dilatation, prostag-
landin synthetase inhibitors such as indomethacin have also
been used. Sulindac has also been tried as an alternative to
indomethacin as ii appears to have little placental transfer and
may therefore have fewer fetal side-effects.