PROBENECID
DESCRIPTION:
BENCID* (Probenecid) is a uricosuric and renal tubular transport blocking
agent.
Probenecid is the generic name for 4-((dipropylamino) sulfonyl) benzoic acid
(molecular weight 285.36).
Probenecid is a white or nearly white, fine, crystalline powder. Probenecid is
soluble in dilute alkali, in alcohol, in chloroform, and in acetone; it is
practically insoluble in water and in dilute acids.
Each tablet contains 0.5 g probenecid and the following inactive ingredients:
calcium stearate, D&C Yellow 10, gelatin, hydroxypropyl methylcellulose, iron
oxide, magnesium carbonate, polyethylene glycol, starch, talc, and titanium
dioxide.
ACTIONS/CLINICAL PHARMACOLOGY:
BENCID is a uricosuric and renal tubular blocking agent. It inhibits the
tubular reabsorption of urate, thus increasing the urinary excretion of uric
acid and decreasing serum urate levels. Effective uricosuria reduces the
miscible urate pool, retards urate deposition, and promotes resorption of urate
deposits.
BENCID inhibits the tubular secretion of penicillin and usually increases
penicillin plasma levels by any route the antibiotic is given. A 2-fold to 4-
fold elevation has been demonstrated for various penicillins.
BENCID also has been reported to inhibit the renal transport of many other
compounds including aminohippuric acid (PAH), aminosalicylic acid (PAS),
indomethacin, sodium iodomethamate and related iodinated organic acids, 17-
ketosteroids, pantothenic acid, phenolsulfonphthalein (PSP), sulfonamides, and
sulfonylureas. See also DRUG INTERACTIONS.
BENCID decreases both hepatic and renal excretion of sulfobromophthalein (BSP).
The tubular reabsorption of phosphorus is inhibited in hypoparathyroid but not
in euparathyroid individuals.
BENCID does not influence plasma concentrations of salicylates, nor the
excretion of streptomycin, chloramphenicol, chlortetracycline, oxytetracycline,
or neomycin.
INDICATIONS AND USAGE:
For treatment of the hyperuricemia associated with gout and gouty arthritis.
As an adjuvant to therapy with penicillin or with ampicillin, methicillin,
oxacillin, cloxacillin, or nafcillin, for elevation and prolongation of plasma
levels by whatever route the antibiotic is given.
CONTRAINDICATIONS:
Hypersensitivity to this product.
Children under 2 years of age.
Not recommended in persons with known blood dyscrasias or uric acid kidney
stones.
Therapy with BENCID should not be started until an acute gouty attack has
subsided.
WARNINGS:
Exacerbation of gout following therapy with BENCID may occur; in such cases
colchicine or other appropriate therapy is advisable.
BENCID increases plasma concentrations of methotrexate in both animals and
humans. In animal studies, increased methotrexate toxicity has been reported. If
BENCID is given with methotrexate, the dosage of methotrexate should be reduced
and serum levels may need to be monitored.
In patients on BENCID the use of salicylates in either small or large doses is
contraindicated because it antagonizes the uricosuric action of BENCID. The
biphasic action of salicylates in the renal tubules accounts for the so-called
"paradoxical effect" of uricosuric agents. In patients on BENCID who require a
mild analgesic agent the use of acetaminophen rather than small doses of
salicylates would be preferred.
Rarely, severe allergic reactions and anaphylaxis have been reported with the
use of BENCID. Most of these have been reported to occur within several hours
after readministration following prior usage of the drug.
The appearance of hypersensitivity reactions requires cessation of therapy with
BENCID.
Use In Pregnancy: BENCID crosses the placental barrier and appears in cord
blood. The use of any drug in women of childbearing potential requires that the
anticipated benefit be weighed against possible hazards.
PRECAUTIONS:
General
Hematuria, renal colic, costovertebral pain, and formation of uric acid stones
associated with the use of BENCID in gouty patients may be prevented by
alkalization of the urine and a liberal fluid intake (See DOSAGE AND
ADMINISTRATION). In these cases when alkali is administered, the acid-base
balance of the patient should be watched.
Use with caution in patients with a history of peptic ulcer.
BENCID has been used in patients with some renal impairment but dosage
requirements may be increased. BENCID may not be effective in chronic renal
insufficiency particularly when the glomerular filtration rate is 30 mL/minute
or less. Because of its mechanism of action, BENCID is not recommended in
conjunction with a penicillin in the presence of Known renal impairment.
A reducing substance may appear in the urine of patients receiving BENCID. This
disappears with discontinuance of therapy. Suspected glycosuria should be
confirmed by using a test specific for glucose.
Drug Interactions
When BENCID is used to elevate plasma concentrations of penicillin or other
beta- lactams, or when such drugs are given to patients taking BENCID
therapeutically, high plasma concentrations of the other drug may increase the
incidence of adverse reactions associated with that drug. In the case of
penicillin or other beta-lactams, psychic disturbances have been reported.
The use of salicylates antagonizes the uricosuric action of BENCID (See
WARNINGS). The uricosuric action of BENCID is also antagonized by pyrazinamide.
BENCID produces an insignificant increase in free sulfonamide plasma
concentrations but a significant increase in total sulfonamide plasma levels.
Since BENCID decreases the renal excretion of conjugated sulfonamides, plasma
concentrations of the latter should be determined from time to time when a
sulfonamide and BENCID are coadministered for prolonged periods. BENCID may
prolong or enhance the action of oral sulfonylureas and thereby increase the
risk of hypoglycemia.
It has been reported that patients receiving BENCID require significantly less
thiopental for induction of anesthesia. In addition, ketamine and thiopental
anesthesia were significantly prolonged in rats receiving probenecid.
The concomitant administration of probenecid increases the mean plasma
elimination half-life of a number of drugs which can lead to increased plasma
concentrations. These include agents such as indomethacin, acetaminophen,
naproxen, ketoprofen, meclofenamate, lorazepam, and rifampin. Although the
clinical significance of this observation has not been established, a lower
dosage of the drug may be required to produce a therapeutic effect, and
increases in dosage of the drug in question should be made cautiously and in
small increments when probenecid is being co-administered. Although specific
instances of toxicity due to this potential interaction have not been observed
to date physicians should be alert to this possibility.
Probenecid given concomitantly with sulindac had only a slight effect on plasma
sulfide levels, while plasma levels of sulindac and sulfone were increased.
Sulindac was shown to produce a modest reduction in the uricosuric action of
probenecid, which probably is not significant under most circumstances.
In animals and in humans, BENCID has been reported to increase plasma
concentrations of methotrexate (See WARNINGS).
Falsely high readings for theophylline have been reported in an In Vitro study,
using the Schack and Waxler technic, when therapeutic concentrations of
theophylline and BENCID were added to human plasma.
DRUG INTERACTIONS:
When BENCID is used to elevate plasma concentrations of penicillin or other
beta- lactams, or when such drugs are given to patients taking BENCID
therapeutically, high plasma concentrations of the other drug may increase the
incidence of adverse reactions associated with that drug. In the case of
penicillin or other beta-lactams, psychic disturbances have been reported.
The use of salicylates antagonizes the uricosuric action of BENCID (See
WARNINGS). The uricosuric action of BENCID is also antagonized by pyrazinamide.
BENCID produces an insignificant increase in free sulfonamide plasma
concentrations but a significant increase in total sulfonamide plasma levels.
Since BENCID decreases the renal excretion of conjugated sulfonamides, plasma
concentrations of the latter should be determined from time to time when a
sulfonamide and BENCID are coadministered for prolonged periods. BENCID may
prolong or enhance the action of oral sulfonylureas and thereby increase the
risk of hypoglycemia.
It has been reported that patients receiving BENCID require significantly less
thiopental for induction of anesthesia. In addition, ketamine and thiopental
anesthesia were significantly prolonged in rats receiving probenecid.
The concomitant administration of probenecid increases the mean plasma
elimination half-life of a number of drugs which can lead to increased plasma
concentrations. These include agents such as indomethacin, acetaminophen,
naproxen, ketoprofen, meclofenamate, lorazepam, and rifampin. Although the
clinical significance of this observation has not been established, a lower
dosage of the drug may be required to produce a therapeutic effect, and
increases in dosage of the drug in question should be made cautiously and in
small increments when probenecid is being co-administered. Although specific
instances of toxicity due to this potential interaction have not been observed
to date physicians should be alert to this possibility.
Probenecid given concomitantly with sulindac had only a slight effect on plasma
sulfide levels, while plasma levels of sulindac and sulfone were increased.
Sulindac was shown to produce a modest reduction in the uricosuric action of
probenecid, which probably is not significant under most circumstances.
In animals and in humans, BENCID has been reported to increase plasma
concentrations of methotrexate (See WARNINGS).
Falsely high readings for theophylline have been reported in an In Vitro study,
using the Schack and Waxler technic, when therapeutic concentrations of
theophylline and BENCID were added to human plasma.
(See Also PRECAUTIONS)
ADVERSE REACTIONS:
The following adverse reactions have been observed and within each category are
listed in order of decreasing severity.
Central Nervous System: headache, dizziness.
Metabolic: precipitation of acute gouty arthritis.
Gastrointestinal: hepatic necrosis, vomiting, nausea, anorexia, sore gums.
Genitourinary: nephrotic syndrome, uric acid stones with or without hematuria,
renal colic, costovertebral pain, urinary frequency.
Hypersensitivity: anaphylaxis, fever, urticaria, pruritus.
Hematologic: aplastic anemia, leukopenia, hemolytic anemia which in some
patients could be related to genetic deficiency of glucose -6- phosphate
dehydrogenase in red blood cells, anemia.
Integumentary: dermatitis, alopecia, flushing.
DOSAGE AND ADMINISTRATION:
Gout
Therapy with BENCID should not be Started until an acute gouty attack has
subsided. However, if an acute attack is precipitated During therapy, BENCID
may be continued without changing the dosage, and full therapeutic dosage of
colchicine or other appropriate therapy should be given to control the acute
attack.
The recommended adult dosage is 0.25 g (1/2 tablet of BENCID) twice a day for
one week, followed by 0.5 g (1 tablet) twice a day thereafter.
Some degree of renal impairment may be present in patients with gout. A daily
dosage of 1 g may be adequate. However, if necessary, the daily dosage may be
increased by 0.5 g increments every 4 weeks within tolerance (and usually not
above 2 g per day) if symptoms of gouty arthritis are not controlled or the 24
hour uric acid excretion is not above 700 mg. As noted, BENCID may not be
effective in chronic renal insufficiency particularly when the glomerular
filtration rate is 30 mL/minute or less.
Gastric intolerance may be indicative of overdosage, and may be corrected by
decreasing the dosage.
As uric acid tends to crystallize out of an acid urine, a liberal fluid intake
is recommended, as well as sufficient sodium bicarbonate (3 to 7.5 g daily) or
potassium citrate (7.5 g daily) to maintain an alkaline urine (See PRECAUTIONS).
Alkalization of the urine is recommended until the serum urate level returns to
normal limits and tophaceous deposits disappear, i.e., during the period when
urinary excretion of uric acid is at a high level. Thereafter, alkalization of
the urine and the usual restriction of purine- producing foods may be somewhat
relaxed.
BENCID should be continued at the dosage that will maintain normal serum urate
levels. When acute attacks have been absent for 6 months or more and serum urate
levels remain within normal limits, the daily dosage may be decreased by 0.5 g
every 6 months. The maintenance dosage should not be reduced to the point where
serum urate levels tend to rise.
BENCID And Penicillin Therapy (General)
Adults:
The recommended dosage is 2 g (4 tablets of BENCID) daily in divided doses.
This dosage should be reduced in older patients in whom renal impairment may be
present.
Children 2-14 Years Of Age:
Initial dose: 25 mg/kg body weight (or 0.7 g/square meter body surface).
Maintenance dose: 40 mg/kg body weight (or 1.2 g/square meter body surface) per
day, divided into 4 doses.
For children weighing more than 50 kg (110 lb) the adult dosage is recommended.
BENCID is contraindicated in children under 2 years of age.
The PSP excretion test may be used to determine the effectiveness of BENCID in
retarding penicillin excretion and maintaining therapeutic levels. The renal
clearance of PSP is reduced to about one-fifth the normal rate when dosage of
BENCID is adequate.
Penicillin Therapy (Gonorrhea)
BENCID(R) (PROBENECID) PENICILLIN THERAPY (GONORRHEA)*
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RECOMMENDED REGIMENS** REMARKS
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Uncomplicated 4.8 million units of aqueous Follow-up: Obtain urethral and
gonococcal procaine penicillin G*/* I.M., other appropriate cultures
infection in at least 2 doses injected from men, and cervical, anal,
in men and at different sites at one and other appropriate cultures
women visit + 1 g of BENCID from women, 7 to 14 days after
(urethral, (Probenecid) orally completion of treatment.
cervical, just before injections Treatment of sexual partners:
rectal) Persons with known recent
exposure to gonorrhea should
receive same treatment as
Or those known to have gonorrhea.
Examination and treatment of
male sex partners of persons
with gonorrhea are essential
because of high prevalence of
3.5 g of ampicillin*/* nonsymptomatic urethral
orally + 1 g of BENCID gonococcal infection in such
orally given simultaneously. men.
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Pharyngeal 4.8 million units of aqueous Pharyngeal gonococcal
gonococcal procaine penicillin G*/* I.M., infections may be more
infection in at least 2 doses injected difficult to treat than
in men and at different sites at one anogenital gonorrhea.
women visit + 1 g of BENCID orally Posttreatment cultures
just before injections are essential.
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Uncomplicated 4.8 million units of aqueous
gonorrhea in procaine penicillin G*/* I.M.,
pregnant in at least 2 doses injected
patients at different sites at one
visit Or 3.5 g of ampicillin*/*
orally
+
1 g of BENCID orally given
simultaneously
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Acute Outpatients: Aqueous procaine Follow-up of patients with acute
gonococcal penicillin G*/* or salpingitis is essential. All
salpingitis ampicillin*/* with BENCID as patients should receive repeat
for gonorrhea in pregnancy, pelvic examinations and cultures
followed by 500 mg of for Neisseria Gonorrhoeae after
ampicillin 4 times a day treatment. Examination and
for 10 days appropriate treatment of male
sex partners are essential
because of high prevalence of
Hospitalized Patients: See nonsymptomatic urethral
details in CDC recommendations gonorrhea in such men.
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Disseminated 10 million units of aqueous
gonococcal crystalline penicillin G*/*
infection I.V. a day for 3 days or till
(arthritis- significant clinical improvement
dermatitis occurs. May be followed with
syndrome) 500 mg of ampicillin*/* 4 times
a day orally to complete 7 days
of treatment
Or
3.5 g of ampicillin*/* orally with
1 g of BENCID, followed by
500 mg of ampicillin*/* 4 times
a day for at least 7 days
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Gonococcal For postpubertal children See CDC recommendations for
infection and/or those weighing over detailed information
in children 45 kg (100 lb) use the dosage about prevention and treatment
regimens given above for of neonatal gonococcal
adults infection and gonococcal
ophthalmia.
Uncomplicated vulvovaginitis
and urethritis: aqueous
procaine penicillin G*/*
75,000-100,000 units/kg I.M.,
with BENCID 23 mg/kg orally
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