gantrisin
Generic Name: (
acetyl sulfisoxazole)
Dosage Type: suspension Organization: Roche Laboratories Inc.
DESCRIPTION
Gantrisin (sulfisoxazole) is an antibacterial sulfonamide
available as a pediatric suspension for oral administration. Each
teaspoonful (5 mL) of the pediatric suspension contains the equivalent
of approximately 0.5 gm sulfisoxazole in the form of acetyl sulfisoxazole
in a vehicle containing 0.3% alcohol, carboxymethylcellulose (sodium),
citric acid, methylcellulose, parabens (methyl and propyl), partial
invert sugar, sodium citrate, sorbitan monolaurate, sucrose, flavors
and water.
Acetyl sulfisoxazole, the tasteless
form of sulfisoxazole, is N1-acetyl sulfisoxazole and must be distinguished from N4-acetyl sulfisoxazole,
which is a metabolite of sulfisoxazole. Acetyl sulfisoxazole is a
white or slightly yellow, crystalline powder that is slightly soluble
in alcohol and practically insoluble in water. Acetyl sulfisoxazole
has a molecular weight of 309.34 and the following structural formula:
CLINICAL PHARMACOLOGY
Following oral administration, sulfisoxazole is
rapidly and completely absorbed; the small intestine is the major
site of absorption, but some of the drug is absorbed from the stomach.
Sulfonamides are present in the blood as free, conjugated (acetylated
and possibly other forms) and protein-bound forms. The amount present
as "free" drug is considered to be the therapeutically active form.
Approximately 85% of a dose of sulfisoxazole is bound to plasma proteins,
primarily to albumin; 65% to 72% of the unbound portion is in the
nonacetylated form.
Maximum plasma concentrations
of intact sulfisoxazole following a single 2-gm oral dose of sulfisoxazole
to healthy adult volunteers ranged from 127 to 211 mcg/mL (mean, 169
mcg/mL) and the time of peak plasma concentration ranged from 1 to
4 hours (mean, 2.5 hours). The elimination half-life of sulfisoxazole
ranged from 4.6 to 7.8 hours after oral administration. The elimination
of sulfisoxazole has been shown to be slower in elderly subjects (63
to 75 years) with diminished renal function (creatinine clearance,
37 to 68 mL/min).1 After multiple-dose oral administration
of 500 mg qid to healthy volunteers, the average steady-state plasma
concentrations of intact sulfisoxazole ranged from 49.9 to 88.8 mcg/mL
(mean, 63.4 mcg/mL).2
Wide variation
in blood levels may result following identical doses of a sulfonamide.
Blood levels should be measured in patients receiving sulfonamides
at the higher recommended doses or being treated for serious infections.
Free sulfonamide blood levels of 50 to 150 mcg/mL may be considered
therapeutically effective for most infections, with blood levels of
120 to 150 mcg/mL being optimal for serious infections. The maximum
sulfonamide level should not exceed 200 mcg/mL, since adverse reactions
occur more frequently above this concentration.
N1-acetyl sulfisoxazole
is metabolized to sulfisoxazole by digestive enzymes in the gastrointestinal
tract and is absorbed as sulfisoxazole. This enzymatic splitting is
presumed to be responsible for slower absorption and lower peak blood
concentrations than are attained following administration of an equal
oral dose of sulfisoxazole. With continued administration of acetyl
sulfisoxazole, blood concentrations approximate those of sulfisoxazole.
Following a single 4-gm dose of acetyl sulfisoxazole to healthy volunteers,
maximum plasma concentrations of sulfisoxazole ranged from 122 to
282 mcg/mL (mean, 181 mcg/mL) for the pediatric suspension and occurred
between 2 and 6 hours postadministration. The half-life of elimination
from plasma ranged from 5.4 to 7.4.
Sulfisoxazole
and its acetylated metabolites are excreted primarily by the kidneys
through glomerular filtration. Concentrations of sulfisoxazole are
considerably higher in the urine than in the blood. The mean urinary
excretion recovery following oral administration of sulfisoxazole
is 97% within 48 hours, of which 52% is intact drug, with the remaining
as the N4-acetylated
metabolite. Following administration of acetyl sulfisoxazole pediatric
suspension, approximately 58% is excreted in the urine as total drug
within 72 hours.
Sulfisoxazole is distributed
only in extracellular body fluid. It is excreted in human milk. It
readily crosses the placental barrier and enters into fetal circulation
and also crosses the blood-brain barrier. In healthy subjects, cerebrospinal
fluid concentrations of sulfisoxazole vary; in patients with meningitis,
however, concentrations of free drug in cerebrospinal fluid as high
as 94 mcg/mL have been reported.
Microbiology
The sulfonamides are bacteriostatic agents and the
spectrum of activity is similar for all. Sulfonamides inhibit bacterial
synthesis of dihydrofolic acid by preventing the condensation of the
pteridine with aminobenzoic acid through competitive inhibition of
the enzyme dihydropteroate synthetase. Resistant strains have altered
dihydropteroate synthetase with reduced affinity for sulfonamides
or produce increased quantities of aminobenzoic acid.
Susceptibility Tests
Diffusion Techniques
Quantitative methods that require measurement of
zone diameters give the most precise estimate of the susceptibility
of bacteria to antimicrobial agents. One such standard procedure3 which has been recommended for use with disks to test susceptibility
of organisms to sulfisoxazole uses the 250- or 300-mcg sulfisoxazole
disk. Interpretation involves the correlation of the diameter obtained
in the disk test with the minimum inhibitory concentration (MIC) for
sulfisoxazole.
Reports from the laboratory
giving results of the standard single-disk susceptibility test with
a 250- or 300-mcg sulfisoxazole disk should be interpreted according
to the following criteria:
| Zone Diameter (mm) |
Interpretation |
|---|
| = 17 |
Susceptible |
| 13-16 |
Moderately susceptible |
| = 12 |
Resistant |
A report of "susceptible" indicates that the pathogen
is likely to be inhibited by generally achievable blood levels. A
report of "moderately susceptible" suggests that the organism would
be susceptible if high dosage is used or if the infection is confined
to tissues and fluids in which high antimicrobial levels are attained.
A report of "resistant" indicates that achievable concentrations are
unlikely to be inhibitory, and other therapy should be selected.
Standardized procedures require the use of laboratory
control organisms. The 250- or 300-mcg sulfisoxazole disk should give
the following zone diameters:
|
|
Organism |
Zone Diameter (mm) |
|
|---|
|
|
E. coli |
18-26 mm |
|
|
|
ATCC 25922 |
|
|
|
|
S. aureus |
24-34 mm |
|
|
|
ATCC 25923 |
|
|
Dilution Techniques
Use a standardized dilution method4 (broth,
agar, microdilution) or equivalent with sulfisoxazole powder. The
MIC values obtained should be interpreted according to the following
criteria:
| MIC (mcg/mL) |
Interpretation |
|---|
| =256 |
Susceptible |
| =512 |
Resistant |
As with standard diffusion techniques, dilution
methods require the use of laboratory control organisms. Dilutions
of standard sulfisoxazole powder should provide the following MIC
values:
|
|
Organism |
MIC (mcg/mL) |
|
|---|
|
|
S. aureus |
32-128 |
|
|
|
ATCC 29213 |
|
|
|
|
E. faecalis |
32-128 |
|
|
|
ATCC 29212 |
|
|
|
|
E. coli |
8-32 |
|
|
|
ATCC 25922 |
|
|
INDICATIONS AND USAGE
Acute, recurrent or chronic urinary tract infections
(primarily pyelonephritis, pyelitis and cystitis) due to susceptible
organisms (usually Escherichia coli,
Klebsiella-Enterobacter, staphylococcus, Proteus mirabilis and, less frequently, Proteus vulgaris) in the absence of
obstructive uropathy or foreign bodies.
Meningococcal
meningitis where the organism has been demonstrated to be susceptible. Haemophilus influenzae meningitis as
adjunctive therapy with parenteral streptomycin.
Meningococcal meningitis prophylaxis when sulfonamide-sensitive group
A strains are known to prevail in family groups or larger closed populations.
(The prophylactic usefulness of sulfonamides when group B or C infections
are prevalent has not been proven and in closed population groups
may be harmful.)
Acute otitis media due to Haemophilus influenzae when used concomitantly
with adequate doses of penicillin or erythromycin (see appropriate
labeling for prescribing information).
Trachoma.
Inclusion conjunctivitis. Nocardiosis. Chancroid. Toxoplasmosis as
adjunctive therapy with pyrimethamine. Malaria due to chloroquine-resistant
strains of Plasmodium falciparum, when used as adjunctive therapy.
Currently,
the increasing frequency of resistant organisms is a limitation of
the usefulness of antibacterial agents including the sulfonamides,
especially in the treatment of chronic and recurrent urinary tract
infections.
Important
Note: In vitro sulfonamide susceptibility tests are not
always reliable. The test must be carefully coordinated with bacteriologic
and clinical response. When the patient is already taking sulfonamides,
follow-up cultures should have aminobenzoic acid added to the culture
media.
CONTRAINDICATIONS
Gantrisin is contraindicated in the following patient
populations: patients with a known hypersensitivity to sulfonamides;
infants less than 2 months of age (except in the treatment of congenital
toxoplasmosis as adjunctive therapy with pyrimethamine); pregnant
women at term; and mothers
nursing infants less than 2 months of age.
Use in pregnant women at term, in infants less than 2 months of age
and in mothers nursing infants less than 2 months of age is contraindicated
because sulfonamides may promote kernicterus in the newborn by displacing
bilirubin from plasma proteins.
WARNINGS
FATALITIES ASSOCIATED WITH THE ADMINISTRATION OF
SULFONAMIDES, ALTHOUGH RARE, HAVE OCCURRED DUE TO SEVERE REACTIONS,
INCLUDING STEVENS-JOHNSON SYNDROME, TOXIC EPIDERMAL NECROLYSIS, FULMINANT
HEPATIC NECROSIS, AGRANULOCYTOSIS, APLASTIC ANEMIA AND OTHER BLOOD
DYSCRASIAS.
SULFONAMIDES, INCLUDING SULFISOXAZOLE,
SHOULD BE DISCONTINUED AT THE FIRST APPEARANCE OF SKIN RASH OR ANY
SIGN OF AN ADVERSE REACTION. In rare instances, a skin rash may be
followed by more severe reactions such as Stevens-Johnson syndrome,
toxic epidermal necrolysis, hepatic necrosis and serious blood disorders
(see PRECAUTIONS).
Clinical signs such as rash, sore throat, fever, arthralgia,
pallor, purpura or jaundice may be early indications of serious reactions.
Cough, shortness of breath and pulmonary infiltrates
are hypersensitivity reactions of the respiratory tract that have
been reported in association with sulfonamide treatment.
The sulfonamides should not be used for the treatment
of group A beta-hemolytic streptococcal infections. In an established
infection, they will not eradicate the streptococcus and, therefore,
will not prevent sequelae such as rheumatic fever.
Pseudomembranous colitis has been reported with nearly all antibacterial
agents, including sulfisoxazole, and may range in severity from mild
to life-threatening. Therefore, it is important to consider this diagnosis
in patients who present with diarrhea subsequent to the administration
of antibacterial agents.
Treatment with antibacterial
agents alters the normal flora of the colon and may permit overgrowth
of clostridia. Studies indicate that toxin produced by Clostridium difficile is one primary
cause of "antibiotic-associated colitis."
After
the diagnosis of pseudomembranous colitis has been established, therapeutic
measures should be initiated. Mild cases of pseudomembranous colitis
usually respond to drug discontinuation alone. In moderate to severe
cases, consideration should be given to management with fluids and
electrolytes, protein supplementation, and treatment with an antibacterial
drug clinically effective against C.
difficile colitis.
PRECAUTIONS
General
Sulfonamides should be given with caution to patients
with impaired renal or hepatic function and to those with severe allergy
or bronchial asthma. In glucose-6-phosphate dehydrogenase-deficient
individuals, hemolysis may occur; this reaction is frequently dose-related.
The frequency of resistant organisms limits the usefulness
of antibacterial agents, including the sulfonamides, as sole therapy
in the treatment of urinary tract infections. Since sulfonamides are
bacteriostatic and not bactericidal, a complete course of therapy
is needed to prevent immediate regrowth and the development of resistant
uropathogens.
Information for Patients
Patients should maintain an adequate fluid intake
to prevent crystalluria and stone formation.
Laboratory Tests
Complete blood counts should be done frequently
in patients receiving sulfonamides. If a significant reduction in
the count of any formed blood element is noted, sulfonamide therapy
should be discontinued. Urinalyses with careful microscopic examination
and renal function tests should be performed during therapy, particularly
for those patients with impaired renal function. Blood levels should
be measured in patients receiving a sulfonamide for serious infections
(see INDICATIONS AND USAGE).
Drug Interactions
It has been reported that sulfisoxazole may prolong
the prothrombin time in patients who are receiving anticoagulants,
including warfarin. This interaction should be kept in mind when Gantrisin
is given to patients already on anticoagulant therapy, and prothrombin
time or other suitable coagulation test should be monitored.
It has been proposed that sulfisoxazole competes with
thiopental for plasma protein binding. In one study involving 48 patients,
intravenous sulfisoxazole resulted in a decrease in the amount of
thiopental required for anesthesia and in a shortening of the awakening
time. It is not known whether chronic oral doses of sulfisoxazole
would have a similar effect. Until more is known about this interaction,
physicians should be aware that patients receiving sulfisoxazole might
require less thiopental for anesthesia.
Sulfonamides
can displace methotrexate from plasma protein-binding sites, thusincreasing free methotrexate concentrations. Studies in man have shown
sulfisoxazole infusions to decrease plasma protein-bound methotrexate
by one-fourth.
Sulfisoxazole can also potentiate
the blood sugar lowering activity of sulfonylureas, as well as cause
hypoglycemia by itself.
Carcinogenesis, Mutagenesis and Impairment of Fertility
Carcinogenesis
Sulfisoxazole was not carcinogenic to mice in either
sex when administered by gavage for 103 weeks at dosages up to approximately
18 times the highest recommended human daily dose or to rats at 4
times the highest recommended human daily dose. Rats appear to be
especially susceptible to the goitrogenic effects of sulfonamides
and long-term administration of sulfonamides has resulted in thyroid
malignancies in this species.
Mutagenesis
There are no studies available that adequately evaluate
the mutagenic potential of Gantrisin. Ames mutagenic assays have not
been performed with sulfisoxazole. However, sulfisoxazole was not
observed to be mutagenic in E. coli Sd-4-73 when tested in the absence of a metabolic activating system.
Impairment of Fertility
Gantrisin has not undergone adequate trials relating
to impairment of fertility. In a reproduction study in rats given
7 times the highest recommended human dose per day of sulfisoxazole,
no effects were observed regarding mating behavior, conception rate
or fertility index (percent pregnant).
Pregnancy
Teratogenic Effects
Pregnancy Category C. At dosages 7 times the highest
recommended human daily dose, sulfisoxazole was not teratogenic in
either rats or rabbits. However, in two other teratogenicity studies,
cleft palates developed in both rats and mice, and skeletal defects
were also observed in rats after administration of 9 times the highest
recommended human daily dose of sulfisoxazole.
There are no adequate and well-controlled studies of Gantrisin in
pregnant women. It is not known whether Gantrisin can cause fetal
harm when administered to a pregnant woman prior to term or can affect
reproduction capacity. Gantrisin should be used during pregnancy only
if the potential benefit justifies the potential risk to the fetus.
Nonteratogenic Effects
Kernicterus may occur in the newborn as a result
of treatment of a pregnant woman at term with sulfonamides (see CONTRAINDICATIONS).
Nursing Mothers
Gantrisin is excreted in human milk. Because of
the potential for the development of kernicterus in neonates due to
the displacement of bilirubin from plasma proteins by sulfisoxazole,
a decision should be made whether to discontinue nursing or discontinue
the drug taking into account the importance of the drug to the mother
(see CONTRAINDICATIONS).
Pediatric Use
Gantrisin is not recommended for use in infants
less than 2 months of age except in the treatment of congenital toxoplasmosis
as adjunctive therapy with pyrimethamine (see CONTRAINDICATIONS).
ADVERSE REACTIONS
The listing that follows includes adverse reactions
both that have been reported with Gantrisin and some which have not
been reported with this specific drug; however, the pharmacologic
similarities among the sulfonamides require that each of the reactions
be considered with the administration of Gantrisin.
Allergic/Dermatologic: Anaphylaxis,
erythema multiforme (Stevens-Johnson syndrome), toxic epidermal necrolysis,
exfoliative dermatitis, angioedema, arteritis and vasculitis, allergic
myocarditis, serum sickness, rash, urticaria, pruritus, photosensitivity,
and conjunctival and scleral injection, generalized allergic reactions
and generalized skin eruptions. In addition, periarteritis nodosa
and systemic lupus erythematosus have been reported (see WARNINGS).
Cardiovascular: Tachycardia, palpitations,
syncope, cyanosis.
Endocrine: The sulfonamides bear certain chemical similarities
to some goitrogens, diuretics (acetazolamide and thiazides) and oral
hypoglycemia agents. Cross-sensitivity may exist with these agents.
Development of goiter, diuresis and hypoglycemia have occurred rarely
in patients receiving sulfonamides.
Gastrointestinal: Hepatitis, hepatocellular
necrosis, jaundice, pseudomembranous colitis, nausea, emesis, anorexia,
abdominal pain, diarrhea, gastrointestinal hemorrhage, melena, flatulence,
glossitis, stomatitis, salivary gland enlargement, pancreatitis.
Onset of pseudomembranous colitis symptoms may occur
during or after treatment with sulfisoxazole (see WARNINGS).
Sulfisoxazole
has been reported to cause increased elevations of liver-associated
enzymes in patients with hepatitis.
Genitourinary: Crystalluria, hematuria,
BUN and creatinine elevations, nephritis and toxic nephrosis with
oliguria and anuria. Acute renal failure and urinary retention have
also been reported. The frequency of renal complications, commonly
associated with some sulfonamides, is lower in patients receiving
the more soluble sulfonamides such as sulfisoxazole.
Hematologic: Leukopenia,
agranulocytosis, aplastic anemia, thrombocytopenia, purpura, hemolyticanemia,
anemia, eosinophilia, clotting disorders including hypoprothrombinemia,
and hypofibrinogenemia, sulfhemoglobinemia, methemoglobinemia.
Musculoskeletal: Arthralgia, myalgia.
Neurologic: Headache, dizziness, peripheral
neuritis, paresthesia, convulsions, tinnitus, vertigo, ataxia, intracranial
hypertension.
Psychiatric: Psychosis, hallucination, disorientation,
depression, anxiety, apathy.
Respiratory: Cough, shortness of breath,
pulmonary infiltrates (see WARNINGS).
Vascular: Angioedema, arteritis, vasculitis.
Miscellaneous: Edema (including periorbital),
pyrexia, drowsiness, weakness, fatigue, lassitude, rigors, flushing,
hearing loss, insomnia, pneumonitis, chills.
OVERDOSAGE
The amount of a single dose of sulfisoxazole that
is associated with symptoms of overdosage or is likely to be life-threatening
has not been reported. Signs and symptoms of overdosage reported with
sulfonamides include anorexia, colic, nausea, vomiting, dizziness,
headache, drowsiness and unconsciousness. Pyrexia, hematuria and crystalluria
may be noted. Blood dyscrasias and jaundice are potential late manifestations
of overdosage.
General principles of treatment
include the immediate discontinuation of the drug; institution of
gastric lavage or emesis; forcing oral fluids; and the administration
of intravenous fluids if urine output is low and renal function is
normal. The patient should be monitored with blood counts and appropriate
blood chemistries, including electrolytes. If the patient becomes
cyanotic, the possibility of methemoglobinemia should be considered
and, if present, the condition should be treated appropriately with
intravenous 1% methylene blue. If a significant blood dyscrasia or
jaundice occurs, specific therapy should be instituted for these complications.
Peritoneal dialysis is not effective and hemodialysis
is only moderately effective in eliminating sulfonamides.
DOSAGE AND ADMINISTRATION
Systemic sulfonamides
are contraindicated in infants less than 2 months of age, except in the treatment of congenital toxoplasmosis as adjunctive
therapy with pyrimethamine.
Usual Dose for Pediatric Patients Over 2 Months of Age
Initial dose: One half of the 24-hour dose. Maintenance
dose: 150 mg/kg/24 hours or 4 gm/M2/24 hours — dose
to be divided into 4 to 6 doses/24 hours. The maximum dose should
not exceed 6 gm/24 hours.
HOW SUPPLIED
Pediatric Suspension (raspberry flavored), containing acetyl sulfisoxazole equivalent
to approximately 0.5 gm sulfisoxazole per teaspoonful (5 mL) —
bottles of 16 oz (1 pint) (NDC 0004-1003-28).
REFERENCES
- Boisvert A, Barbeau G, Belanger PM. Pharmacokinetics of sulfisoxazole
in young and elderly subjects. Gerontology. 1984; 30:125-131.
- Oie S, Gambertoglio JG, Fleckenstein L. Comparison of the disposition
of total and unbound sulfisoxazole after single and multiple dosing. J Pharmacokinet Biopharm. 1982; 10:157-172.
- National Committee for Clinical Laboratory Standards. Performance Standards for Antimicrobial Disk Susceptibility
Tests. 4th ed. Villanova, PA: April 1990. Approved Standard
NCCLS Document M2-A4, Vol. 10, No. 7 NCCLS.
- National Committee for Clinical Laboratory Standards. Methods for Dilution Antimicrobial Susceptibility
Tests for Bacteria that Grow Aerobically. 2nd ed. Villanova,
PA: April 1990. Approved Standard NCCLS Document M7-A2, Vol. 10, No.
8 NCCLS.
27898941
Rev: November 1997
Printed in USA
Copyright ©
1997 by Roche Laboratories Inc. All rights reserved.
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Revised: 03/2007Roche Laboratories Inc.