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CONTRAINDICATIONS AND WARNINGS
ARTHROTEC, because of the abortifacient property of the
misoprostol component, is contraindicated in women who
are pregnant.
PRECAUTIONS
Reports, primarily from Brazil, of congenital anomalies
and reports of fetal death subsequent to misuse of misoprostol
alone, as an abortifacient, have been received. Patients
must be advised of the abortifacient property and warned
not to give the drug to others. ARTHROTEC should not be
used in women of childbearing potential unless the patient
requires nonsteroidal anti-inflammatory drug (NSAID) therapy
and is at high risk of developing gastric or duodenal
ulceration or for developing complications from gastric
or duodenal ulcers associated with the use of the NSAID.
WARNINGS
In such patients, ARTHROTEC may be prescribed if the patient:
From Our Sponsors
Regarding misoprostol:
See CONTRAINDICATIONS AND WARNINGS
.
Regarding diclofenac:
Gastrointestinal (GI) effects risk of GI ulceration,
bleeding and perforation
Serious GI toxicity, such as inflammation, bleeding,
ulceration and perforation of the stomach, small intestine
or large intestine, can occur at any time, with or without
warning symptoms, in patients treated with NSAIDs. Minor
upper GI problems, such as dyspepsia, are common and may
also occur at any time during NSAID therapy. Therefore,
physicians and patients should remain alert for ulceration
and bleeding, even in the absence of previous GI tract
symptoms. Patients should be informed about the signs
and/or symptoms and the steps to take if they occur. The
utility of periodic laboratory monitoring has not been
demonstrated, nor has it been adequately assessed. Only
1 in 5 patients who develop a serious upper GI adverse
event on NSAID therapy is symptomatic. It has been demonstrated
that upper GI ulcers, gross bleeding, or perforation,
caused by NSAIDs, appear to occur in approximately 1%
of patients treated for 3-6 months, and in 2-4% of patients
treated for 1 year. These trends continue thus, increasing
the likelihood of developing a serious GI event at some
time during the course of therapy. However, even short-term
therapy has risk.
NSAIDs should be prescribed with extreme caution in those
with a prior history of ulcer disease or GI bleeding.
Most spontaneous reports of fatal GI events are in elderly
or debilitated patients and therefore special care should
be taken in treating this population. To minimize the
potential risk for an adverse event, the lowest effective
dose should be used for the shortest possible duration.
For very high-risk patients, alternate therapies that
do not involve NSAIDs should be considered.
Studies have shown that patients with a history of peptic
ulcer disease and/or GI bleeding, and who use NSAIDs,
have a greater than 10-fold risk for developing a GI bleed
than patients with neither of these risk factors. In addition
to a past history of ulcer disease, pharmacoepidemiological
studies have identified several other conditions or co-therapies
that may increase the risk for GI bleeding, such as: treatment
with oral corticosteroids, treatment with anticoagulants,
longer duration of NSAID therapy, older age, smoking,
alcoholism, poor general health and Helicobacter pylori
positive status.
Hepatic effects
Elevations of one or more liver tests may occur during
ARTHROTEC therapy. These laboratory abnormalities may
progress, may remain unchanged, or may be transient with
continued therapy. Borderline elevations (ie, less than
3 times the ULN [ULN = the upper limit of the normal range]),
or greater elevations of transaminases occurred in about
15% of diclofenac-treated patients. Of the hepatic enzymes,
ALT (SGPT) is the one recommended for the monitoring of
liver injury.
In clinical trials, meaningful elevations (ie, more than
3 times the ULN) of AST (SGOT) (ALT was not measured in
all studies) occurred in about 2% of approximately 5,700
patients at some time during diclofenac treatment. In
a large, open, controlled trial, meaningful elevations
of ALT and/or AST occurred in about 4% of 3,700 patients
treated for 2-6 months, including marked elevations (ie,
more than 8 times the ULN) in about 1% of the 3,700 patients.
In that open-label study, a higher incidence of borderline
(less than 3 times the ULN), moderate (3-8 times the ULN),
and marked (>8 times the ULN) elevations of ALT or
AST was observed in patients receiving diclofenac when
compared to other NSAIDs. Transaminase elevations were
seen more frequently in patients with osteoarthritis than
in those with rheumatoid arthritis.
In addition to enzyme elevations seen in clinical trials,
post-marketing surveillance has found rare cases of severe
hepatic reactions, including liver necrosis, jaundice,
and fulminant fatal hepatitis with and without jaundice.
Some of these rare reported cases underwent liver transplantation.
Physicians should measure transaminases periodically
in patients receiving long-term therapy with diclofenac,
because severe hepatotoxicity may develop without a prodrome
of distinguishing symptoms. The optimum times for making
the first and subsequent transaminase measurements are
not known. In the largest U.S. trial (open-label) that
involved 3,700 patients monitored first at 8 weeks and
1,200 patients monitored again at 24 weeks, almost all
meaningful elevations in transaminases were detected before
patients became symptomatic. In 42 of the 51 patients
in all trials who developed marked transaminase elevations,
abnormal tests occurred during the first 2 months of therapy
with diclofenac. Postmarketing experience has shown severe
hepatic reactions can occur at any time during treatment
with diclofenac. Cases of drug-induced hepatotoxicity
have been reported in the first month, and in some cases,
the first 2 months of therapy. Based on these experiences,
transaminases should be monitored within 4 to 8 weeks
after initiating treatment with diclofenac (see
PRECAUTIONS
Laboratory tests ).
In clinical trials with ARTHROTEC, meaningful elevation
of ALT (SGPT, more than 3 times the ULN) occurred in 1.6%
of 2,184 patients treated with ARTHROTEC, and in 1.4%
of 1,691 patients treated with diclofenac sodium. These
increases were generally transient, and enzyme levels
returned to within the normal range upon discontinuation
of ARTHROTEC therapy. The misoprostol component of ARTHROTEC
does not appear to exacerbate the hepatic effects caused
by the diclofenac sodium component. As with other NSAID
containing products, if abnormal liver tests persist or
worsen, if clinical signs and/or symptoms consistent with
liver disease develop, or if systemic manifestations occur
(eg, eosinophilia, rash, etc), ARTHROTEC should be discontinued
immediately.
To minimize the possibility that hepatic injury will
become severe between transaminase measurements, physicians
should inform patients of the warning signs and symptoms
of hepatotoxicity (eg, nausea, fatigue, lethargy, pruritus,
jaundice, right upper quadrant tenderness, and "flu-like"
symptoms), and the appropriate action patients should
take if these signs and symptoms appear.
Anaphylactoid reactions
As with other NSAID containing products, anaphylactoid
reactions may occur in patients without known prior exposure
to ARTHROTEC or its components. ARTHROTEC should not be
given to patients with the aspirin triad. The triad typically
occurs in asthmatic patients who experience rhinitis with
or without nasal polyps, or who exhibit severe, potentially
fatal bronchospasm after taking aspirin or other NSAIDs
(see CONTRAINDICATIONS and
PRECAUTIONS
Preexisting asthma ). Emergency help should be sought
in cases where an anaphylactoid reaction occurs. Allergic
reactions have been reported by less than 0.1% of patients
who received ARTHROTEC in clinical trials, and there have
been rare reports of anaphylaxis in the marketed use of
ARTHROTEC outside of the United States.
Advanced renal disease
In patients with advanced kidney disease, treatment with
ARTHROTEC is not recommended. If NSAID therapy must be
initiated however, close monitoring of the patient's kidney
function is advisable (see
PRECAUTIONS
Renal effects ).
PRECAUTIONS
Information for patients
See PATIENT INFORMATION at the end of this labeling for
important information to discuss with the patient.
ARTHROTEC is available only as a unit-of-use package
that includes a leaflet containing patient information.
The patient should read the leaflet before taking ARTHROTEC
and each time the prescription is renewed because the
leaflet may have been revised. Keep ARTHROTEC out of the
reach of children.
General
ARTHROTEC cannot be used to substitute for corticosteroids
or to treat for corticosteroid insufficiency. Abrupt discontinuation
of corticosteroids may lead to disease exacerbation. Patients
on prolonged corticosteroid therapy should have their
therapy tapered slowly if a decision is made to discontinue
corticosteroids.
The pharmacological activity of ARTHROTEC in reducing
inflammation may diminish the utility of this diagnostic
sign in detecting complications of presumed noninfectious,
painful conditions.
Renal effects
Caution should be used when initiating treatment with
ARTHROTEC in patients with considerable dehydration. It
is advisable to rehydrate patients first and then start
therapy with ARTHROTEC. Caution is also recommended in
patients with preexisting kidney disease (see
WARNINGS
Advanced renal disease ).
As with other NSAIDs, long-term administration of diclofenac
has resulted in renal papillary necrosis and other renal
medullary changes. Renal toxicity has also been seen in
patients in which renal prostaglandins have a compensatory
role in the maintenance of renal perfusion. In these patients,
administration of an NSAID may cause a dose-dependent
reduction in prostaglandin formation and, secondarily,
in renal blood flow, which may precipitate overt renal
decompensation. Patients at greatest risk of this reaction
are those with impaired renal function, heart failure,
or liver dysfunction, those taking diuretics and ACE inhibitors,
and the elderly. Discontinuation of NSAID therapy is usually
followed by recovery to the pretreatment state.
Diclofenac metabolites are eliminated primarily by the
kidneys. The extent to which the metabolites may accumulate
in patients with renal failure has not been studied. As
with other NSAIDs, metabolites of which are excreted by
the kidney, patients with significantly impaired renal
function should be more closely monitored.
Hematologic effects
Anemia is sometimes seen in patients receiving diclofenac
or other NSAIDs. This may be due to fluid retention, GI
blood loss, or an incompletely described effect upon erythropoiesis.
Patients on long-term treatment with NSAIDs, including
ARTHROTEC, should have their hemoglobin or hematocrit
checked if they exhibit any signs or symptoms of anemia.
All drugs that inhibit the biosynthesis of prostaglandins
may interfere to some extent with platelet function and
vascular responses to bleeding.
NSAIDs inhibit platelet aggregation and, unlike aspirin,
their effect on platelet function is reversible, quantitatively
less, and of shorter duration. ARTHROTEC does not generally
affect platelet counts, prothrombin time (PT), or partial
thromboplastin time (PTT). Patients receiving ARTHROTEC
who may be adversely affected by alterations in platelet
function, such as those with coagulation disorders or
patients receiving anticoagulants, should be carefully
monitored.
Aseptic meningitis
As with other NSAIDs, aseptic meningitis with fever and
coma has been observed on rare occasions in patients on
diclofenac therapy. Although it is probably more likely
to occur in patients with systemic lupus and related connective
tissue diseases, it has been reported in patients who
do not have an underlying chronic disease. If signs or
symptoms of meningitis develop in a patient on diclofenac,
the possibility of its being related to diclofenac should
be considered.
Fluid retention and edema
Fluid retention and edema have been observed in some patients
taking NSAID containing products, including ARTHROTEC.
Therefore, as with other NSAID containing products, ARTHROTEC
should be used with caution in patients with a history
of cardiac decompensation, hypertension, or other conditions
predisposing to fluid retention.
Preexisting asthma
Patients with asthma may have aspirin-sensitive asthma.
The use of aspirin in patients with aspirin-sensitive
asthma has been associated with severe bronchospasm, which
can be fatal. Since cross-reactivity, including bronchospasm,
between aspirin and other NSAIDs has been reported in
such aspirin-sensitive patients. ARTHROTEC should not
be administered to patients with this form of aspirin
sensitivity and should be used with caution in patients
with preexisting asthma.
Porphyria
The use of ARTHROTEC in patients with hepatic porphyria
should be avoided. To date, one patient has been described
in whom diclofenac sodium probably triggered a clinical
attack of porphyria. The postulated mechanism, demonstrated
in rats, for causing such attacks by diclofenac sodium,
as well as some other NSAIDs, is through stimulation of
the porphyrin precursor delta-aminolevulinic acid (ALA).
Laboratory tests
Patients on long-term treatment with NSAIDs should have
their CBC and a chemistry profile checked periodically.
If clinical signs and symptoms consistent with liver or
renal disease develop, systemic manifestations occur (eg,
eosinophilia, rash, etc) or if abnormal liver tests persist
or worsen, ARTHROTEC should be discontinued.
Effect on blood coagulation:
Diclofenac sodium impairs platelet aggregation but does
not affect bleeding time, plasma thrombin clotting time,
plasma fibrinogen, or factors V and VII to XII. Statistically
significant changes in prothrombin and partial thromboplastin
times have been reported in normal volunteers. The mean
changes were observed to be less than 1 second in both
instances, however, and are unlikely to be clinically
important. Diclofenac sodium is a prostaglandin synthetase
inhibitor, however, and all drugs that inhibit prostaglandin
synthesis interfere with platelet function to some degree;
therefore, patients who may be adversely affected by such
an action should be carefully observed. Misoprostol has
not been shown to exacerbate the effects of diclofenac
on platelet activity.
Drug interactions
Aspirin: Concomitant administration
of ARTHROTEC and aspirin is not recommended because diclofenac
sodium is displaced from its binding sites by aspirin,
resulting in lower plasma concentrations, peak plasma
levels and AUC values.
Digoxin: Elevated digoxin levels
have been reported in patients receiving digoxin and diclofenac
sodium. Patients receiving digoxin and ARTHROTEC should
be monitored for possible digoxin toxicity.
Antihypertensive agents: NSAIDs
can inhibit the activity of antihypertensives, including
ACE inhibitors. Thus, caution should be taken when administering
ARTHROTEC with such agents.
Warfarin: The effects of warfarin
and NSAIDs on GI bleeding are synergistic, such that users
of both drugs together have a risk of serious bleeding
greater than users of either drug alone.
Oral hypoglycemics: Diclofenac
sodium does not alter glucose metabolism in healthy people
nor does it alter the effects of oral hypoglycemic agents.
There are rare reports, however, from marketing experience,
of changes in effects of insulin or oral hypoglycemic
agents in the presence of diclofenac sodium that necessitated
change in the doses of such agents. Both hypo- and hyperglycemic
effects have been reported. A direct causal relationship
has not been established, but physicians should consider
the possibility that diclofenac sodium may alter a diabetic
patient's response to insulin or oral hypoglycemic agents.
Methotrexate and cyclosporine:
ARTHROTEC, like other NSAID containing products, may affect
renal prostaglandins and increase the toxicity of certain
drugs. Ingestion of ARTHROTEC may increase serum concentrations
of methotrexate and increase cyclosporine nephrotoxicity.
Patients who begin taking ARTHROTEC or who increase their
dose of ARTHROTEC or any other NSAID containing product
while taking methotrexate or cyclosporine may develop
toxicity characteristic for these drugs. They should be
observed closely, particularly if renal function is impaired.
Lithium: NSAIDs have produced
an elevation of plasma lithium levels and a reduction
in renal lithium clearance. The mean minimum lithium concentration
increased 15% and the renal clearance was decreased by
approximately 20%. These effects have been attributed
to inhibition of renal prostaglandin synthesis by the
NSAID. Thus, when NSAIDs and lithium are administered
concurrently, subjects should be observed carefully for
signs of lithium toxicity.
Antacids: Antacids reduce the
bioavailability of misoprostol acid. Antacids may also
delay absorption of diclofenac sodium. Magnesium-containing
antacids exacerbate misoprostol-associated diarrhea. Thus,
it is not recommended that ARTHROTEC be coadministered
with magnesium-containing antacids.
Diuretics: The diclofenac sodium
component of ARTHROTEC, like other NSAIDs, can inhibit
the activity of diuretics. Concomitant therapy with potassium-sparing
diuretics may be associated with increased serum potassium
levels.
Other drugs: In small groups
of patients (7-10 patients/interaction study), the concomitant
administration of azathioprine, gold, chloroquine, D-penicillamine,
prednisolone, doxycycline or digitoxin did not significantly
affect the peak levels and AUC levels of diclofenac sodium.
Phenobarbital toxicity has been reported to have occurred
in a patient on chronic phenobarbital treatment following
the initiation of diclofenac therapy. In vitro , diclofenac
interferes minimally with the protein binding of prednisolone
(10% decrease in binding). Benzylpenicillin, ampicillin,
oxacillin, chlortetracycline, doxycycline, cephalothin,
erythromycin, and sulfamethoxazole have no influence,
in vitro , on the protein binding of diclofenac in human
serum.
Carcinogenesis, mutagenesis, impairment of fertility
Long-term animal studies to evaluate the potential for
carcinogenesis and animal studies to evaluate the effects
on fertility have been performed with each component of
ARTHROTEC given alone. ARTHROTEC itself (diclofenac sodium
and misoprostol combinations in 250:1 ratio) was not genotoxic
in the Ames test, the Chinese hamster ovary cell (CHO/HGPRT)
forward mutation test, the rat lymphocyte chromosome aberration
test or the mouse micronucleus test.
In a 24-month rat carcinogenicity study, oral misoprostol
at doses up to 2.4 mg/kg/day (14.4 mg/m 2 /day, 24 times
the recommended maximum human dose of 0.6 mg/m 2 /day)
was not tumorigenic. In a 21-month mouse carcinogenicity
study, oral misoprostol at doses up to 16 mg/kg/day (48
mg/m 2 /day), 80 times the recommended maximum human dose
based on body surface area, was not tumorigenic. Misoprostol,
when administered to male and female breeding rats in
an oral dose-range of 0.1 to 10 mg/kg/day (0.6 to 60 mg/m
2 /day, 1 to 100 times the recommended maximum human dose
based on body surface area) produced dose-related pre-
and post-implantation losses and a significant decrease
in the number of live pups born at the highest dose. These
findings suggest the possibility of a general adverse
effect on fertility in males and females.
In a 24-month rat carcinogenicity study, oral diclofenac
sodium up to 2 mg/kg/day (12 mg/m 2 /day) was not tumorigenic.
For a 50-kg person of average height (1.46m 2 body surface
area), this dose represents 0.08 times the recommended
maximum human dose (148 mg/m 2 ) on a body surface area
basis. In a 24-month mouse carcinogenicity study, oral
diclofenac sodium at doses up to 0.3 mg/kg/day (0.9 mg/m
2 /day, 0.006 times the recommended maximum human dose
based on body surface area) in males and 1 mg/kg/day (3
mg/m 2 /day, 0.02 times the recommended maximum human
dose based on body surface area) in females was not tumorigenic.
Diclofenac sodium at oral doses up to 4 mg/kg/day (24
mg/m 2 /day, 0.16 times the recommended maximum human
dose based on body surface area) was found to have no
effect on fertility and reproductive performance of male
and female rats.
Pregnancy
Pregnancy category X: See CONTRAINDICATIONS AND
WARNINGS
regarding misoprostol. ARTHROTEC is contraindicated in
pregnancy.
Non-teratogenic effects
Misoprostol may endanger pregnancy (may cause miscarriage)
and thereby cause harm to the fetus when administered
to a pregnant woman. Misoprostol produces uterine contractions,
uterine bleeding, and expulsion of the products of conception.
Miscarriages caused by misoprostol may be incomplete.
In studies in women undergoing elective termination of
pregnancy during the first trimester, misoprostol caused
partial or complete expulsion of the products of conception
in 11% of the subjects and increased uterine bleeding
in 41%.
Reports, primarily from Brazil, of congenital anomalies
and reports of fetal death subsequent to misuse of misoprostol
alone, as an abortifacient, have been received (see CONTRAINDICATIONS
AND
WARNINGS
). If a woman is or becomes pregnant while taking this
drug, the drug should be discontinued and the patient
apprised of the potential hazard to the fetus.
The diclofenac sodium component of ARTHROTEC, like other
NSAIDs which are prostaglandin-inhibiting drugs, may affect
the fetal cardiovascular system causing premature closure
of the ductus arteriosus. NSAIDs may also inhibit uterine
contractions.
Teratogenic effects
An oral teratology study has been performed in pregnant
rabbits at dose combinations (250:1 ratio) up to 10 mg/kg/day
diclofenac sodium (120 mg/m 2 /day, 0.8 times the recommended
maximum human dose based on body surface area) and 0.04
mg/kg/day misoprostol (0.48 mg/m 2 /day, 0.8 times the
recommended maximum human dose based on body surface area)
and has revealed no evidence of teratogenic potential
for ARTHROTEC.
Oral teratology studies have been performed in pregnant
rats at doses up to 1.6 mg/kg/day (9.6 mg/m 2 /day, 16
times the recommended maximum human dose based on body
surface area) and pregnant rabbits at doses up to 1.0
mg/kg/day (12 mg/m 2 /day, 20 times the recommended maximum
human dose based on body surface area) and have revealed
no evidence of teratogenic potential for misoprostol.
Oral teratology studies have been performed in pregnant
mice at doses up to 20 mg/kg/day (60 mg/m 2 /day, 0.4
times the recommended maximum human dose based on body
surface area), pregnant rats at doses up to 10 mg/kg/day
(60 mg/m 2 /day. 0.4 times the recommended maximum human
dose based on body surface area) and pregnant rabbits
at doses up to 10 mg/kg/day (120 mg/m 2 /day, 0.8 times
the recommended maximum human dose based on body surface
area) and have revealed no evidence of teratogenic potential
for diclofenac sodium.
Nursing mothers
Diclofenac sodium has been found in the milk of nursing
mothers. It is unlikely that misoprostol is excreted into
milk since the drug is rapidly metabolized throughout
the body.
Excretion of the active metabolite (misoprostol acid)
into milk is possible, but has not been studied. Because
of the potential for serious adverse reactions in nursing
infants, ARTHROTEC is not recommended for use by nursing
mothers.
Pediatric use
Safety and effectiveness of ARTHROTEC in pediatric patients
have not been established.
Geriatric use
Of the more than 2100 subjects in clinical studies with
ARTHROTEC, 25% were 65 and over, while 6% wre 75 and over.
In studies with diclofenac, 31% of subjects were 65 and
over. No overall differences in safety or effectiveness
were observed between these subjects and younger subjects,
and other reported clinical experience has not identified
differences in repsonses between the elderly and younger
patients, but greater sensitivity of some older individuals
cannot be ruled out. As with any NSAID, the elderly are
likely to tolerate adverse events less well than younger
patients
Diclofenac is known to be substantially excreted by the
kidney, and the risk of toxic reactions to ARTHROTEC may
be greater in patients with impaired renal function. Because
elderly patients are more likely to have decreased renal
function, care should be taken in dose selection, and
it may be useful to monitor renal function (See
PRECAUTIONS
Renal Effects ).
Based on studies in the elderly, no adjustment of the
dose of ARTHROTEC is necessary in the elderly for pharmacokinetic
reasons. (See Pharmacokinetics of ARTHROTEC Special populations
), although many elderly may need to receive a reduced
dose because of low body weight or disorders associated
with aging.
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has had a negative serum pregnancy test within 2 weeks
prior to beginning therapy. 
