COLCHICINE
DESCRIPTION:
Colchicine is an alkaloid obtained from various species of Colchicum. The
chemical name for colchicine is (S)-N-(5,6,7,9-tetrahydro- 1,2,3,10-
tetramethoxy-9-oxobenzo (a) heptalen- 7-yl) acetamide (molecular weight 399.43).
Colchicine consists of pale yellow scales or powder; it darkens on exposure to
light. Colchicine is soluble in water, freely soluble in alcohol and in
chloroform, and slightly soluble in ether.
Each tablet contains 0.5 g probenecid and 0.5 mg colchicine and the following
inactive ingredients: calcium stearate, gelatin, magnesium carbonate, starch.
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ACTIONS/CLINICAL PHARMACOLOGY:
The mode of action of colchicine in gout is unknown. It is not an analgesic,
though it relieves pain in acute attacks of gout. It is not a uricosuric agent
and will not prevent progression of gout to chronic gouty arthritis. It does
have a prophylactic, suppressive effect that helps to reduce the incidence of
acute attacks and to relieve the residual pain and mild discomfort that patients
with gout occasionally feel.
In man and certain other animals, colchicine can produce a temporary leukopenia
that is followed by leukocytosis.
Colchicine has other pharmacologic actions in animals: It alters neuromuscular
function, intensifies gastrointestinal activity by neurogenic stimulation,
increases sensitivity to central depressants, heightens response to
sympathomimetic compounds, depresses the respiratory center, constricts blood
vessels, causes hypertension by central vasomotor stimulation, and lowers body
temperature.
INDICATIONS AND USAGE:
For the treatment of chronic gouty arthritis when complicated by frequent,
recurrent acute attacks of gout.
CONTRAINDICATIONS:
Hypersensitivity to this product or to probenecid or colchicine.
Children under 2 years of age.
Not recommended in persons with known blood dyscrasias or uric acid kidney
stones.
Therapy with ColBENEMID should not be started until an acute gouty attack has
subsided.
Pregnancy: Probenecid crosses the placental barrier and appears in cord blood.
Colchicine can arrest cell division in animals and plants. In certain species of
animal under certain conditions, colchicine has produced teratogenic effects.
The possibility of such effects in humans also has been reported. Because of the
colchicine component, ColBENEMID is contraindicated in pregnant patients. The
use of any drug in women of childbearing potential requires that the anticipated
benefit be weighed against possible hazards.
WARNINGS:
Exacerbation of gout following therapy with ColBENEMID may occur; in such cases
additional colchicine or other appropriate therapy is advisable.
Probenecid increases plasma concentrations of methotrexate in both animals and
humans. In animal studies, increased methotrexate toxicity has been reported. If
ColBENEMID is given with methotrexate, the dosage of methotrexate should be
reduced and serum levels may need to be monitored.
In patients on ColBENEMID the use of salicylates in either small or large doses
is contraindicated because it antagonizes the uricosuric action of probenecid.
The biphasic action of salicylates in the renal tubules accounts for the so-
called "paradoxical effect" of uricosuric agents. In patients on ColBENEMID 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 ColBENEMID. 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
ColBENEMID.
Colchicine has been reported to adversely affect spermatogenesis in animals.
Reversible azoospermia has been reported in one patient.
PRECAUTIONS:
General
Hematuria, renal colic, costovertebral pain, and formation of uric acid stones
associated with the use of ColBENEMID 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.
ColBENEMID has been used in patients with some renal impairment but dosage
requirements may be increased. ColBENEMID may not be effective in chronic renal
insufficiency particularly when the glomerular filtration rate is 30 mL/minute
or less.
A reducing substance may appear in the urine of patients receiving probenecid.
This disappears with discontinuance of therapy. Suspected glycosuria should be
confirmed by using a test specific for glucose.
Adequate animal studies have not been conducted to determine the carcinogenicity
potential of probenecid or this drug combination. Since colchicine is an
established mutagen, its ability to act as a carcinogen must be suspected and
administration of ColBENEMID should involve a weighing of the benefit-vs-risk
when long-term administration is contemplated.
Drug Interactions
When probenecid is used to elevate plasma concentrations of penicillin, or other
beta- lactams, or when such drugs are given to patients taking probenecid
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 probenecid (See
WARNINGS). The uricosuric action of probenecid is also antagonized by
pyrazinamide.
Probenecid produces an insignificant increase in free sulfonamide plasma
concentrations but a significant increase in total sulfonamide plasma levels.
Since probenecid decreases the renal excretion of conjugated sulfonamides,
plasma concentrations of the latter should be determined from time to time when
a sulfonamide and ColBENEMID are coadministered for prolonged periods.
Probenecid may prolong or enhance the action of oral sulfonylureas and thereby
increase the risk of hypoglycemia.
It has been reported that patients receiving probenecid 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-administrated. 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, probenecid 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 probenecid were added to human plasma.
DRUG INTERACTIONS:
When probenecid is used to elevate plasma concentrations of penicillin, or other
beta- lactams, or when such drugs are given to patients taking probenecid
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 probenecid (See
WARNINGS). The uricosuric action of probenecid is also antagonized by
pyrazinamide.
Probenecid produces an insignificant increase in free sulfonamide plasma
concentrations but a significant increase in total sulfonamide plasma levels.
Since probenecid decreases the renal excretion of conjugated sulfonamides,
plasma concentrations of the latter should be determined from time to time when
a sulfonamide and ColBENEMID are coadministered for prolonged periods.
Probenecid may prolong or enhance the action of oral sulfonylureas and thereby
increase the risk of hypoglycemia.
It has been reported that patients receiving probenecid 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-administrated. 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, probenecid 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 probenecid 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.
Probenecid
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.
Colchicine
Side effects due to colchicine appear to be a function of dosage. The
possibility of increased colchicine toxicity in the presence of hepatic
dysfunction should be considered. The appearance of any of the following
symptoms may require reduction of dosage or discontinuance of the drug.
Central Nervous System: peripheral neuritis.
Musculoskeletal: muscular weakness.
Gastrointestinal: nausea, vomiting, abdominal pain, or diarrhea may be
particularly troublesome in the presence of peptic ulcer or spastic colon.
Hypersensitivity: urticaria.
Hematologic: aplastic anemia, agranulocytosis.
Integumentary: dermatitis, purpura, alopecia.
At toxic doses, colchicine may cause severe diarrhea, generalized vascular
damage, and renal damage with hematuria and oliguria.
DOSAGE AND ADMINISTRATION:
Therapy with ColBENEMID should not be Started until an acute gouty attack has
subsided. However, if an acute attack is precipitated During therapy, ColBENEMID
may be continued without changing the dosage, and additional colchicine or other
appropriate therapy should be given to control the acute attack.
The recommended adult dosage is 1 tablet of ColBENEMID daily for one week,
followed by 1 tablet twice a day thereafter.
Some degree of renal impairment may be present in patients with gout. A daily
dosage of 2 tablets may be adequate. However, if necessary, the daily dosage may
be increased by 1 tablet every four weeks within tolerance (and usually not
above 4 tablets per day) if symptoms of gouty arthritis are not controlled or
the 24 hour uric acid excretion is not above 700 mg. As noted, probenecid 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.
ColBENEMID (or probenecid) should be continued at the dosage that will maintain
normal serum urate levels. When acute attacks have been absent for six months or
more and serum urate levels remain within normal limits, the daily dosage of
ColBENEMID may be decreased by 1 tablet every six months. The maintenance dosage
should not be reduced to the point where serum urate levels tend to rise.