SULPHASALAZINE
DESCRIPTION:
Salazopyrin Tablets contain sulfasalazine, 500 mg, for oral administration.
Salazopyrin Tablets are film coated with cellulose acetate phthalate to
retard disintegration of the tablet in the stomach and reduce potential
irritation of the gastric mucosa.
THERAPEUTIC CLASSIFICATION: Anti-inflammatory agent and/or immunomodulatory
agent.
CHEMICAL DESIGNATION:
5-((p-(2-pyridylsulfamoyl)phenyl)azo) salicylic acid.
Molecular Formula C18H14N4O5S
ACTIONS/CLINICAL PHARMACOLOGY:
PHARMACODYNAMICS
The mode of action of sulfasalazine (SSZ) or its metabolites, 5-aminosalicylic
acid (5-ASA) and sulfapyridine (SP), is still under investigation, but may be
related to the anti-inflammatory and/or immunomodulatory properties that have
been observed in animal and In Vitro models, to its affinity for connective
tissue, and/or to the relatively high concentration it reaches in serous fluids,
the liver and intestinal walls, as demonstrated in autoradiographic studies in
animals. In ulcerative colitis, clinical studies utilizing rectal administration
of SSZ, SP, and 5-ASA have indicated that the major therapeutic action may
reside in the 5-ASA moiety. The relative contribution of the parent drug and the
major metabolites in rheumatoid arthritis remains under investigation.
PHARMACOKINETICS
In Vivo studies have indicated that the absolute bioavailability of orally
administered SSZ is less than 15% for parent drug. In the intestine SSZ is
metabolized by intestinal bacteria to SP and 5-ASA. Of the two species, SP is
relatively well absorbed from the intestine and highly metabolized, while 5-ASA
is much less well absorbed.
ABSORPTION: Following oral administration of 1 g of SSZ to 9 healthy males,
less than 15% of a dose of SSZ is absorbed as parent drug. Detectable serum
concentrations of SSZ have been found in healthy subjects within 90 minutes
after the ingestion. Maximum concentrations of SSZ occur between 3 and 12 hours
post-ingestion, with the mean peak concentration (6 Mu-g/mL) occurring at 6
hours.
In comparison, peak plasma levels of both SP and 5-ASA occur approximately 10
hrs after dosing. This longer time to peak is indicative of gastrointestinal
transit to the lower intestine where bacteria mediated metabolism occurs. SP
apparently is well absorbed from the colon with an estimated bioavailability of
60%. In this same study, 5-ASA is much less well absorbed from the GI tract with
an estimated bioavailability of from 10 to 30%.
DISTRIBUTION: Following intravenous injection, the calculated volume of
distribution (Vdss) for SSZ was 7.5 +/- 1.6 L. SSZ is highly bound to albumin
(>99.3%) while SP is only about 70% bound to albumin. Acetylsulfapyridine
(AcSP), the principal metabolite of SP, is approximately 90% bound to plasma
proteins.
METABOLISM: As mentioned above, SSZ is metabolized by intestinal bacteria to SP
and 5-ASA. Approximately 15% of a dose of SSZ is absorbed as parent and is
metabolized to some extent in the liver to the same two species. The observed
plasma half-life for intravenous sulfasalazine is 7.6 +/- 3.4 hours. The primary
route of metabolism of SP is via acetylation to form AcSP. The rate of
metabolism of SP to AcSP is dependent upon acetylator phenotype. In fast
acetylators the mean plasma half-life of SP is 10.4 hrs while in slow
acetylators it is 14.8 hrs. SP can also be metabolized to 5-hydroxy-
sulfapyridine (SPOH) and N-acetyl-5-hydroxy- sulfapyridine. 5-ASA is primarily
metabolized in both the liver and intestine to N-acetyl- 5-aminosalicylic acid
via a non-acetylation phenotype dependent route. Due to low plasma levels
produced by 5-ASA after oral administration, reliable estimates of plasma half-
life are not possible.
EXCRETION: Absorbed SP and 5-ASA and their metabolites are primarily eliminated
in the urine either as free metabolites or as glucuronide conjugates. The
majority of 5-ASA stays within the colonic lumen and is excreted as 5-ASA and
acetyl-5-ASA with the feces. The calculated clearance of SSZ following
intravenous administration was 1 L/hr. Renal clearance was estimated to account
for 37% of total clearance.
SPECIAL POPULATIONS
ELDERLY: Elderly patients with rheumatoid arthritis showed a prolonged plasma
half-life for SSZ, SP, and their metabolites. The clinical impact of this is
unknown.
ACETYLATOR STATUS: The metabolism of SP to AcSP is mediated by polymorphic
enzymes such that two distinct populations of slow and fast metabolizers exist.
Approximately 60% of the Caucasian population can be classified as belonging to
the slow acetylator phenotype. These subjects will display a prolonged plasma
half- life for SP (14.8 hrs vs. 10.4 hrs) and an accumulation of higher plasma
levels of SP than fast acetylators. The clinical implication of this is unclear;
however, in a small pharmacokinetic trial where acetylator status was
determined, subjects that were slow acetylators of SP showed a higher incidence
of adverse events.
GENDER: Gender appears not to have an effect on either the rate or the pattern
of metabolites of SSZ, SP, or 5-ASA.
INDICATIONS AND USAGE:
Salazopyrin Tablets are indicated:
a) in the treatment of mild to moderate ulcerative colitis, and as adjunctive
therapy in severe ulcerative colitis;
b) for the prolongation of the remission period between acute attacks of
ulcerative colitis; and
c) in the treatment of patients with rheumatoid arthritis who have responded
inadequately to salicylates or other non-steroidal anti- inflammatory drugs.
Salazopyrin is particularly indicated in patients with ulcerative colitis
who cannot take uncoated sulfasalazine tablets because of gastrointestinal
intolerance, and in whom there is evidence that this intolerance is not
primarily the result of high blood levels of sulfapyridine and its metabolites,
e.g., patients experiencing nausea and vomiting with the first few doses of the
drug, or patients in whom a reduction in dosage does not alleviate the adverse
gastrointestinal effects.
Salazopyrin is recommended in the management of adults with active,
classic and definitive rheumatoid arthritis who have had an insufficient
therapeutic response to or are intolerant of an adequate trial of full doses of
one or more non-steroidal anti-inflammatory drugs. In rheumatoid arthritis,
concurrent treatment with analgesics and/or non-steroidal anti-inflammatory
drugs is recommended at least until the effect of Salazopyrin is
apparent. Rest and physiotherapy as indicated should be continued. Unlike anti-
inflammatory drugs, Salazopyrin does not produce an immediate response.
CONTRAINDICATIONS:
Salazopyrin Tablets are contraindicated in:
Pediatric patients under two years of age,
Patients with intestinal or urinary obstruction,
Patients with porphyria,
Patients hypersensitive to sulfasalazine, its metabolites, sulfonamides, or
salicylates.
WARNINGS:
Only after critical appraisal should Salazopyrin Tablets be given to
patients with hepatic or renal damage or blood dyscrasias. Deaths associated
with the administration of sulfasalazine have been reported from
hypersensitivity reactions, agranulocytosis, aplastic anemia, other blood
dyscrasias, renal and liver damage, irreversible neuromuscular and CNS changes,
and fibrosing alveolitis. The presence of clinical signs such as sore throat,
fever, pallor, purpura or jaundice may be indications of serious blood
disorders. Complete blood counts, as well as urinalysis with careful microscopic
examination, should be done frequently in patients receiving AZULFIDINE EN- tabs
(see Laboratory Tests). Oligospermia and infertility have been observed in men
treated with sulfasalazine. Withdrawal of the drug appears to reverse these
effects.
PRECAUTIONS:
GENERAL:
Salazopyrin Tablets should be given with caution to patients with severe
allergy or bronchial asthma. Adequate fluid intake must be maintained in order
to prevent crystalluria and stone formation. Patients with glucose- 6-phosphate
dehydrogenase deficiency should be observed closely for signs of hemolytic
anemia. This reaction is frequently dose related. If toxic or hypersensitivity
reactions occur, Salazopyrin should be discontinued immediately.
Isolated instances have been reported when Salazopyrin Tablets have
passed undisintegrated. If this is observed, the administration of AZULFIDINE
EN-tabs should be discontinued immediately.
INFORMATION FOR PATIENTS:
Patients should be informed of the possibility of adverse effects and of the
need for careful medical supervision. The occurrence of sore throat, fever,
pallor, purpura, or jaundice may indicate a serious blood disorder. Should any
of these occur, the patients should seek medical advice. Patients should be
instructed to take Salazopyrin in evenly divided doses, preferably after
meals, and to swallow the tablets whole. Additionally, patients should be
adivised that sulfasalazine may produce an orange-yellow discoloration of the
urine or skin.
ULCERATIVE COLITIS: Patients with ulcerative colitis should be made aware that
ulcerative colitis rarely remits completely, and that the risk of relapse can be
substantially reduced by continued administration of Salazopyrin at a
maintenance dosage.
RHEUMATOID ARTHRITIS: Rheumatoid arthritis rarely remits. Therefore, continued
administration of Salazopyrin may be needed.
LABORATORY TESTS:
Complete blood counts, including differ-ential white cell count and liver
function tests, should be performed before starting Salazopyrin and every
second week during the first three months of therapy. During the second three
months, the same tests should be done once monthly and thereafter once every
three months, and as clinically indicated. Urinalysis and an assessment of renal
function should also be done periodically during treatment with AZULFIDINE EN-
tabs.
The determination of serum sulfapyridine levels may be useful since
concentrations greater than 50 Mu-g/mL appear to be associated with an increased
incidence of adverse reactions.
DRUG INTERACTIONS:
Reduced absorption of folic acid and digoxin have been reported when those
agents were administered concomitantly with sulfasalazine.
DRUG/LABORATORY TEST INTERACTIONS:
The presence of sulfasalazine or its metabolites in body fluids has not been
reported to interfere with laboratory test procedures.
CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY:
Two-year oral carcinogenicity studies were conducted in male and female F344/N
rats and B6C3F1 mice. Sulfasalazine was tested at 84 (496 mg/m(squared)), 168
(991 mg/m(squared)), and 337.5 (1991 mg/m(squared)) mg/kg/day doses in rats. A
statistically significant increase in the incidence of urinary bladder
transitional cell papillomas was observed in male rats. In female rats, two (4%)
of the 337.5 mg/kg rats had transitional cell papilloma of the kidney. The
increased incidence of neoplasms in the urinary bladder and kidney of rats was
also associated with an increase in the renal calculi formation and hyperplasia
of transitional cell epithelium. For the mouse study, sulfasalazine was tested
at 675 (2025 mg/m(squared)), 1350 (4050 mg/m(squared)), and 2700 (8100
mg/m(squared)) mg/kg/day. The incidence of hepatocellular adenoma or carcinoma
in male and female mice was significantly greater than the control at all doses
tested.
Sulfasalazine did not show mutagenicity in the bacterial reverse mutation assay
(Ames test) and in L51784 mouse lymphoma cell assay at the HGPRT gene. However,
sulfasalazine showed equivocal mutagenic response in the micronucleus assay of
mouse and rat bone marrow and mouse peripheral RBC and in the sister chromatid
exchange, chromosomal aberration, and micronucleus assays in lymphocytes
obtained from humans.
Impairment of male fertility was observed in reproductive studies performed in
rats and rabbits. Oligospermia and infertility have been described in men
treated with sulfasalazine. Withdrawal of the drug appears to reverse these
effects.
PREGNANCY:
TERATOGENIC EFFECTS: PREGNANCY CATEGORY B.
Reproduction studies have been performed in rats and rabbits at doses up to 6
times the human dose and have revealed no evidence of impaired female fertility
or harm to the fetus due to sulfasalazine. There are, however, no adequate and
well-controlled studies in pregnant women. Because animal reproduction studies
are not always predictive of human response, this drug should be used during
pregnancy only if clearly needed.
A national survey evaluated the outcome of pregnancies associated with
inflammatory bowel disease (IBD). In 186 pregnancies in women treated with
sulfasalazine alone or sulfasalazine and concomitant steroid therapy, the
incidence of fetal morbidity and mortality was comparable both to that of 245
untreated IBD pregnancies, as well as to pregnancies in the general
population.(REF. 1)
A study of 1,455 pregnancies associated with exposure to sulfonamides including
sulfasalazine, indicated that this group of drugs did not appear to be
associated with fetal malformation.(REF. 2) A review of the medical literature
covering 1,155 pregnancies in women with ulcerative colitis suggested that the
outcome was similar to that expected in the general population.(REF. 3)
No clinical studies have been performed to evaluate the effect of sulfasalazine
on the growth development and functional maturation of children whose mothers
received the drug during pregnancy.
NONTERATOGENIC EFFECTS: Sulfasalazine and sulfapyridine pass the placental
barrier. Although sulfapyridine has been shown to have poor bilirubin displacing
capacity, the potential for kernicterus in newborns should be kept in mind.
A case of agranulocytosis has been reported in an infant whose mother was taking
both sulfasalazine and prednisone throughout pregnancy.
NURSING MOTHERS:
Caution should be exercised when AZULFIDINE EN- tabs is administered to a
nursing mother. Sulfonamides are excreted in the milk. In the newborn, they
compete with bilirubin for binding sites on the plasma proteins and may cause
kernicterus. Insignificant amounts of uncleaved sulfasalazine have been found in
milk, whereas the sulfapyridine levels in milk are about 30 to 60 percent of
those in the maternal serum. Sulfapyridine has been shown to have a poor
bilirubin displacing capacity.
PEDIATRIC USE:
The safety and effectiveness of AZULFIDINE EN- tabs in pediatric patients below
the age of two years with ulcerative colitis has not been established. The
safety and effectiveness in juvenile rheumatoid arthritis has not been
established. It has been reported that the frequency of adverse events in
patients with systemic onset of juvenile arthritis is high.(REF. 4)
DRUG INTERACTIONS:
Reduced absorption of folic acid and digoxin have been reported when those
agents were administered concomitantly with sulfasalazine.
ADVERSE REACTIONS:
Clinical experience to date has indicated that patients with rheumatoid
arthritis treated with Salazopyrin Tablets appear to have a similar
profile and incidence of adverse effects to patients with ulcerative colitis.
There are no known adverse effects that are specific to patients with rheumatoid
arthritis treated with sulfasalazine with the possible exception of skin rash,
which was seen in 13% of patients in rheumatoid arthritis clinical trials but in
about one in thirty patients or less in ulcerative colitis studies. The
estimated incidence of adverse effects other than skin rash in patients treated
with sulfasalazine is as follows for both ulcerative colitis and rheumatoid
arthritis:
The most common adverse reactions associated with sulfasalazine are anorexia,
headache, nausea, vomiting, gastric distress, and apparently reversible
oligospermia. These occur in about one-third of the patients. Less frequent
adverse reactions are pruritus, urticaria, fever, Heinz body anemia, hemolytic
anemia and cyanosis, which may occur at a frequency of one in every thirty
patients or less. Experience suggests that with a daily dosage of 4 g or more,
or total serum sulfapyridine levels above 50 Mu-g/mL, the incidence of adverse
reactions tends to increase.
Although the listing which follows includes a few adverse reactions which have
not been reported with this specific drug, the pharmacological similarities
among the sulfonamides require that each of these reactions be considered when
Salazopyrin is administered.
Other adverse reactions which occur rarely, in approximately 1 in 1000 patients
or less are:
BLOOD DYSCRASIAS: aplastic anemia, agranulocytosis, leukopenia, megaloblastic
(macrocytic) anemia, purpura, thrombocytopenia, hypoprothrombinemia,
methemoglobinemia, congenital neutropenia, and myelodysplastic syndrome.
HYPERSENSITIVITY REACTIONS: erythema multiforme (Stevens-Johnson syndrome),
exfoliative dermatitis, epidermal necrolysis (Lyell's syndrome) with corneal
damage, anaphylaxis, serum sickness syndrome, pneumonitis with or without
eosinophilia, vasculitis, fibrosing alveolitis, pleuritis, pericarditis with or
without tamponade, allergic myocarditis, polyarteritis nodosa, lupus
erythematosus-like syndrome, hepatitis and hepatic necrosis with or without
immune complexes, parapsoriasis varioliformis acuta (Mucha-Haberman syndrome),
rhabdomyolysis, photosensitization, arthralgia, periorbital edema, conjunctival
and scleral injection and alopecia.
GASTROINTESTINAL REACTIONS: hepatitis, pancreatitis, bloody diarrhea, impaired
folic acid absorption, impaired digoxin absorption, stomatitis, diarrhea,
abdominal pains, and neutropenic enterocolitis.
CNS REACTIONS: transverse myelitis, convulsions, meningitis, transient lesions
of the posterior spinal column, cauda equina syndrome, Guillain- Barre syndrome,
peripheral neuropathy, mental depression, vertigo, hearing loss, insomnia,
ataxia, hallucinations, tinnitus and drowsiness.
RENAL REACTIONS: toxic nephrosis with oliguria and anuria, nephritis, nephrotic
syndrome, hematuria, crystalluria, proteinuria, and hemolytic-uremic syndrome.
OTHER REACTIONS: urine discoloration and skin discoloration.
The sulfonamides bear certain chemical similarities to some goitrogens,
diuretics (acetazolamide and the thiazides), and oral hypoglycemic agents.
Goiter production, diuresis and hypoglycemia have occurred rarely in patients
receiving sulfonamides. Cross-sensitivity may exist with these agents. Rats
appear to be especially susceptible to the goitrogenic effects of sulfonamides
and long-term administration has produced thyroid malignancies in this species.
DRUG ABUSE AND DEPENDENCE:
None reported.
OVERDOSAGE:
There is evidence that the incidence and severity of toxicity following
overdosage is directly related to the total serum sulfapyridine concentration.
Symptoms of overdosage may include nausea, vomiting, gastric distress and
abdominal pains. In more advanced cases, central nervous system symptoms such as
drowsiness, convulsions, etc. may be observed. Serum sulfapyridine
concentrations may be used to monitor the progress of recovery from overdosage.
There are no documented reports of deaths due to ingestion of large single doses
of sulfasalazine.
It has not been possible to determine the LD50 in laboratory animals such as
mice, since the highest oral daily dose of sulfasalazine which can be given (12
g/kg) is not lethal. Doses of regular sulfasalazine tablets of 16 g per day have
been given to patients without mortality.
INSTRUCTIONS FOR OVERDOSAGE:
Gastric lavage or emesis plus catharsis as indicated. Alkalinize urine. If
kidney function is normal, force fluids. If anuria is present, restrict fluids
and salt, and treat appropriately. Catheterization of the ureters may be
indicated for complete renal blockage by crystals. The low molecular weight of
sulfasalazine and its metabolites may facilitate their removal by dialysis. For
agranulocytosis, discontinue the drug immediately, hospitalize the patient, and
institute appropriate therapy. For hypersensitivity reactions, discontinue
treatment immediately. Such reactions may be controlled with antihistamines and,
if necessary, systemic corticosteroids. When, in the physician's opinion,
reinstitution of Salazopyrin Tablets is warranted, regimens modeled upon
recommended desensitization procedures may be attempted approximately two weeks
after treatment has been discontinued and symptoms have disappeared (see DOSAGE
AND ADMINISTRATION).
DOSAGE AND ADMINISTRATION:
The dosage of Salazopyrin Tablets should be adjusted to each individual's
response and tolerance. The drug should be given in evenly divided doses over
each 24-hour period, intervals between nighttime doses should not exceed 8 hours
with administration after meals recommended when feasible. Experience suggests
that with daily dosages of 4 g or more, the incidence of adverse effects tends
to increase; hence, patients receiving these dosages should be instructed about
and carefully observed for the appearance of adverse effects.
Some patients may be sensitive to treatment with sulfasalazine. Various
desensitization-like regimens have been reported to be effective in 34 of 53
patients,(REF. 5) 7 of 8 patients,(REF.6) and 19 of 20 patients.(REF. 7) These
regimens suggest starting with a total daily dose of 50 to 250 mg sulfasalazine
initially, and doubling it every 4 to 7 days until the desired therapeutic
level is achieved. If the symptoms of sensitivity recur, Salazopyrin
should be discontinued. Desensitization should not be attempted in patients who
have a history of agranulocytosis, or who have experienced an anaphylactoid
reaction while previously receiving sulfasalazine.
USUAL DOSAGE
Patients should be instructed to take Salazopyrin in evenly divided
doses, preferably after meals, and to swallow the tablets whole.
ULCERATIVE COLITIS
INITIAL THERAPY
ADULTS: 3 to 4 g daily in evenly divided doses. It may be advisable to initiate
therapy with a lower dosage, e.g., 1 to 2 g daily, to reduce possible
gastrointestinal intolerance. If daily doses exceeding 4 g are required to
achieve the desired therapeutic effect, the increased risk of toxicity should be
kept in mind.
CHILDREN, TWO YEARS OF AGE AND OLDER: 40 to 60 mg per kg of body weight in each
24-hour period, divided into 3 to 6 doses.
MAINTENANCE THERAPY:
ADULTS: 2 g daily.
CHILDREN, TWO YEARS OF AGE AND OLDER: 30 mg per kg of body weight in each 24-
hour period, divided into 4 doses.
The response of acute ulcerative colitis to Salazopyrin can be evaluated
by clinical criteria, including the presence of fever, weight changes, and
degree and frequency of diarrhea and bleeding, as well as by sigmoidoscopy and
the evaluation of biopsy samples. It is often necessary to continue medication
even when clinical symptoms, including diarrhea, have been controlled. When
endoscopic examination confirms satisfactory improvement, dosage of AZULFIDINE
EN-tabs is reduced to a maintenance level. If diarrhea recurs, dosage should be
increased to previously effective levels.
Salazopyrin is particularly indicated in patients who cannot take
uncoated sulfasalazine tablets because of gastrointestinal intolerance (e.g.,
anorexia, nausea). If symptoms of gastric intolerance (anorexia, nausea,
vomiting, etc.) occur after the first few doses of AZULFIDINE EN- tabs, they are
probably due to increased serum levels of total sulfapyridine, and may be
alleviated by halving the daily dose of Salazopyrin and subsequently
increasing it gradually over several days. If gastric intolerance continues, the
drug should be stopped for 5 to 7 days, then reintroduced at a lower daily dose.
RHEUMATOID ARTHRITIS: ADULTS: 2 g daily in evenly divided doses. It is advisable
to initiate therapy with a lower dosage of AZULFIDINE EN- tabs, e.g., 0.5 to 1.0
g daily, to reduce possible gastrointestinal intolerance. A suggested dosing
schedule is given below.
In rheumatoid arthritis, the effect of Salazopyrin can be assessed by the
degree of improvement in the number and extent of actively inflamed joints. A
therapeutic response has been observed as early as four weeks after starting
treatment with Salazopyrin, but treatment for 12 weeks may be required in
some patients before clinical benefit is noted. Consideration can be given to
increasing the daily dose of Salazopyrin to 3 g if the clinical response
after 12 weeks is inadequate. Careful monitoring is recommended for doses over 2
g per day.
Suggested Dosing Schedule:
Number of Salazopyrin
-------------------------------------------------------------------------
Week of Treatment Morning Evening
----------------- ------------------- -----------------
1 - One
2 One One
3 One Two
4 Two Two
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