A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Tolectin Warnings, Precautions, Pregnancy, Nursing, Abuse - Tolmetin
Tolectin Warnings, Precautions, Pregnancy, Nursing, Abuse - Tolmetin
WARNINGS
Risk of GI Ulceration, Bleeding and Perforation with NSAID Therapy:
Serious gastrointestinal toxicity such as bleeding, ulceration, and perforation,
can occur at any time, with or without symptoms, in patients treated chronically
with NSAID (Nonsteroidal Anti-Inflammatory Drug) therapy. Although minor upper
gastrointestinal problems, such as dyspepsia, are common, usually developng
early in therapy, physicians should remain alert for ulceration and bleeding
in patients treated chronically with NSAID's even in the absence of previous
GI tract symptoms. In patients observed in clinical trials of several months
to two years duration, symptomatic upper GI ulcers, gross bleeding or perforation
appear to occur in approximately 1% of patients treated for 3-6 months, and
in about 2-4% of patients treated for one year. Physicians should inform patients
about the signs and/or symptoms of serious GI toxicity and what steps to take
if they occur.
Studies to date have not identified any subset of patients not at risk of developing
peptic ulceration and bleeding. Except for a prior history of serious GI events
and other risk factors known to be associated with peptic ulcer disease, such
as alcoholism, smoking, etc., no risk factors (e.g., age, sex) have been associated
with increased risk. Elderly or debilitated patients seem to tolerate ulceration
or bleeding less well than other individuals and most spontaneous reports of
fatal GI events are in this population. Studies to date are inconclusive concerning
the relative risk of various NSAID's in causing such reactions. High doses of
any NSAID probably carry a greater risk of these reactions, although controlled
clinical trials showing this do not exist in most cases. In considering the
use of relatively large doses (within the recommended dosage range), sufficient
benefit should be anticipated to offset the potential increased risk of GI toxicity.
PRECAUTIONS
General
Because of ocular changes observed in animals and reports of adverse eye findings
with nonsteroidal anti-inflammatory agents, it is recommended that patients
who develop visual disturbances during treatment with TOLECTIN have ophthalmologic
evaluations.
As with other nonsteroidal anti-inflammatory drugs, long-term administration
of tolmetin to animals has resulted in renal papillary necrosis and other abnormal
renal pathology. In humans, there have been reports of acute interstitial nephritis
with hematuria, proteinuria, and occasionally nephrotic syndrome.
A second form of renal toxicity has been seen in patients with prerenal conditions
leading to a reduction in renal blood flow or blood volume, where the renal
prostaglandins have a supportive role in the maintenance of renal perfusion.
In these patients administration of an NSAID may cause a dose dependent reduction
in prostaglandin formation and may precipitate overt renal decompensation. Patients
at greatest risk of this reaction are those with heart failure, liver dysfunction,
those taking diuretics, and the elderly. Discontinuation of NSAID therapy is
typically followed by recovery to the pretreatment state.
Since TOLECTIN and its metabolites are eliminated primarily by the kidneys,
patients with impaired renal function should be closely monitored, and it should
be anticipated that they will require lower doses.
TOLECTIN prolongs bleeding time. Patients who may be adversely affected by
prolongation of bleeding time should be carefully observed when TOLECTIN is
administered.
In patients receiving concomitant TOLECTIN-steroid therapy, any reduction in
steroid dosage should be gradual to avoid the possible complications of sudden
steroid withdrawal.
Peripheral edema has been reported in some patients receiving TOLECTIN therapy.
Therefore, as with other nonsteroidal anti-inflammatory drugs, TOLECTIN should
be used with caution in patients with compromised cardiac function, hypertension,
or other conditions predisposing to fluid retention.
The antipyretic and anti-inflammatory activities of the drug may reduce fever
and inflammation, thus diminishing their utility as diagnostic signs in detecting
complications of presumed non-infectious, non-inflammatory painful conditions.
As with other nonsteroidal anti-inflammatory drugs, borderline elevations of
one or more liver tests may occur in up to 15% of patients. These abnormalities
may progress, may remain essentially unchanged, or may be transient with continued
therapy. The SGPT (ALT) test is probably the most sensitive indicator of liver
dysfunction. Meaningful (3 times the upper limit of normal) elevations of SGPT
or SGOT (AST) occurred in controlled clinical trials in less than 1% of patients.
A patient with symptoms and/or signs suggesting liver dysfunction, or in whom
an abnormal liver test has occurred, should be evaluated for evidence of the
development of more severe hepatic reaction while on therapy with TOLECTIN.
Severe hepatic reactions, including jaundice and fatal hepatitis, have been
reported with TOLECTIN as with other nonsteroidal anti-inflammatory drugs. Although
such reactions are rare, if abnormal liver tests persist or worsen, if clinical
signs and symptoms consistent with liver disease develop, or if systemic manifestations
occur (e.g. eosinophilia, rash, etc.), TOLECTIN should be discontinued.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Tolmetin sodium did not possess any carcinogenic liability in the following
long-term studies: a 24-month study in rats at doses as high as 75 mg/kg/day,
and an 18-month study in mice at doses as high as 50 mg/kg/day.
No mutagenic potential of tolmetin sodium was found in the Ames Salmonella-Microsomal
Activation Test.
Reproductive studies revealed no impairment of fertility in animals. Effects
on parturition have been shown, however, as with other prostaglandin inhibitors.
This information is detailed in the Pregnancy section below.
Pregnancy
Pregnancy Category C. Reproduction studies in rats and rabbits at doses up
to 50 mg/kg (1.5 times the maximum clinical dose based on a body weight of 60
kg) revealed no evidence of teratogenesis or impaired fertility due to TOLECTIN.
However, TOLECTIN is an inhibitor of prostaglandin synthetase. Drugs in this
class have known effects on the fetal cardiovascular system which may cause
constriction of the ductus arteriosus in utero during the third trimester
of pregnancy, which may result in persistent pulmonary hypertension of the newborn.
There are no adequate and well-controlled studies in pregnant women. TOLECTIN
should be used during pregnancy only if the potential benefit justifies the
potential risk to the fetus.
Non-Teratogenic Effects
Prostaglandin inhibitors have also been shown to increase the incidence of
dystocia and delayed parturition in animals.
Nursing Mothers
TOLECTIN has been shown to be secreted in human milk. Because of the possible
adverse effects of prostaglandin inhibiting drugs on neonates, use in nursing
mothers should be avoided.
Pediatric Use
The safety and effectiveness of TOLECTIN in children under 2 years of age have
not been established.
Drug Interactions
The in vitro binding of warfarin to human plasma proteins is unaffected
by tolmetin, and tolmetin does not alter the prothrombin time of normal volunteers.
However, increased prothrombin time and bleeding have been reported in patients
on concomitant TOLECTIN and warfarin therapy. Therefore, caution should be exercised
when administering TOLECTIN to patients on anticoagulants.
In adult diabetic patients under treatment with either sulfonylureas or insulin
there is no change in the clinical effects of either TOLECTIN or the hypoglycemic
agents.
Caution should be used if TOLECTIN is administered concomitantly with methotrexate.
TOLECTIN and other nonsteroidal anti-inflammatory drugs have been reported to
reduce the tubular secretion of methotrexate in an animal model, possibly enhancing
the toxicity of methotrexate.
Laboratory Tests
Because serious GI tract ulceration and bleeding can occur without warning
symptoms, physicians should follow chronically treated patients for the signs
and symptoms of ulceration and bleeding and should inform them of the importance
of this follow-up (see WARNINGS
Risk of GI Ulceration, Bleeding and Perforation
with NSAID Therapy ).
Drug/Laboratory Test Interaction
The metabolites of tolmetin sodium in urine have been found to give positive
tests for proteinuria using tests which rely on acid precipitation as their
endpoint (e.g. sulfosalicylic acid). No interference is seen in the tests for
proteinuria using dye-impregnated commercially available reagent strips (e.g.,
Albustix®, Uristix®, etc.).
Drug-Food Interaction
In a controlled single dose study, administration of TOLECTIN with milk had
no effect on peak plasma tolmetin concentrations, but decreased total tolmetin
bioavailability by 16%. When TOLECTIN was taken immediately after a meal, peak
plasma tolmetin concentrations were reduced by 50% while total bioavailability
was again decreased by 16%.
Information for Patients
TOLECTIN, like other drugs of its class, is not free of side effects. The side
effects of these drugs can cause discomfort and, rarely, there are more serious
side effects, such as gastrointestinal bleeding, which may result in hospitalization
and even fatal outcomes.
NSAID's (Nonsteroidal Anti-Inflammatory Drugs) are often essential agents in
the management of arthritis, but they also may be commonly employed for conditions
which are less serious.
Physicians may wish to discuss with their patients the potential risks (see
WARNINGS
, PRECAUTIONS
, and ADVERSE REACTIONS sections) and likely benefits
of NSAID treatment, particularly when the drugs are used for less serious conditions
where treatment without NSAID's may represent an acceptable alternative to both
the patient and physician.
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