General
ARTHROTEC cannot be expected to substitute for corticosteroids or to treat 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 fever and inflammation may
diminish the utility of these diagnostic signs in detecting complications of presumed
noninfectious, painful conditions.
Hepatic Effects
See WARNINGS.
Hematological Effects
Anemia is sometimes seen in patients receiving NSAIDs, including ARTHROTEC. This
may be due to fluid retention, occult or gross 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.
NSAIDs inhibit platelet aggregation and have been shown to prolong bleeding time
in some patients. Unlike aspirin, their effect on platelet function is quantitatively
less, of shorter duration, and reversible. 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.
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 nonsteroidal anti-inflammatory drugs 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.
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.
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).
Information for patients: Women of childbearing potential using ARTHROTEC
to treat arthritis should be told that they must not be pregnant when therapy with
ARTHROTEC is initiated, and that they must use an effective contraception method
while taking ARTHROTEC. See boxed CONTRAINDICATIONS AND WARNINGS.
THE PATIENT SHOULD NOT GIVE ARTHROTEC TO ANYONE ELSE. ARTHROTEC has been
prescribed for the patient’s specific condition, may not be the correct treatment
for another person, and may be dangerous to the other person if she were to become
pregnant.
SPECIAL NOTE FOR WOMEN: ARTHROTEC contains diclofenac sodium and misoprostol. Misoprostol
may cause abortion (sometimes incomplete), premature labor, or birth defects if
given to pregnant women.
Patients should be informed of the following information before initiating therapy
with an NSAID and periodically during the course of ongoing therapy. Patients should
also be encouraged to read the NSAID Medication Guide that accompanies each prescription
dispensed.
- ARTHROTEC, like other NSAIDs, may cause serious side effects, such as MI or stroke,
which may result in hospitalization and even death. Although serious CV events can
occur without warning symptoms, patients should be alert for the signs and symptoms
of chest pain, shortness of breath, weakness, slurring of speech, and should ask
for medical advice when observing any indicative sign or symptoms. Patients should
be apprised of the importance of this follow-up (see WARNINGS, CARDIOVASCULAR EFFECTS).
- ARTHROTEC, like other NSAIDs, can cause GI discomfort and, rarely, serious GI side
effects, such as ulcers and bleeding, which may result in hospitalizations and even
death. Although serious GI tract ulcerations and bleeding can occur without warning
symptoms, patients should be alert for the signs and symptoms of ulceration and
bleeding, and should ask for medical advice when observing any indicative sign or
symptoms, including epigastric pain, dyspepsia, melena, and hematemesis. Patients
should be apprised of the importance of this follow-up (see WARNINGS, Gastrointestinal
Effects - Risk of Ulceration, Bleeding and Perforation).
- ARTHROTEC, like other NSAIDs, can cause serious skin side effects, such as exfoliative
dermatitis, SJS and TEN, which may result in hospitalization and even death. Although
serious skin reactions may occur without warning, patients should be alert for the
signs and symptoms of skin rash and blisters, fever, or other signs of hypersensitivity
such as itching, and should ask for medical advice when observing any indicative
sign or symptoms. Patients should be advised to stop the drug immediately if they
develop any type of rash and contact their physicians as soon as possible.
- Patients should promptly report signs or symptoms of unexplained weight gain or
edema to their physicians.
- Patients should be informed of the warning signs and symptoms of hepatotoxicity
(e.g., nausea, fatigue, lethargy, pruritus, jaundice, right upper quadrant tenderness
and "flu-like" symptoms). If these occur, patients should be instructed
to stop therapy and seek immediate medical attention.
- Patients should be informed of the signs of an anaphylactic reaction (e.g. difficulty
breathing, swelling of the face or throat). If these occur, patients should be instructed
to seek immediate emergency help (see WARNINGS, Anaphylactic reactions).
- In late pregnancy, as with other NSAIDs, ARTHROTEC should be avoided because it
may cause premature closure of the ductus arteriosus.
- Arthrotec should not be taken by nursing mothers.
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.
Laboratory tests
Because serious GI tract ulcerations and bleeding can occur without warning symptoms,
physicians should monitor for signs of symptoms of GI bleeding. 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 (e.g., 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
ACE-Inhibitors:
Reports suggest that NSAIDs may diminish the antihypertensive effect of ACE-inhibitors.
This interaction should be given consideration in patients taking NSAIDs concomitantly
with ACE-inhibitors.
Aspirin:
When ARTHROTEC is administered with aspirin, the protein binding of diclofenac is
reduced, although the clearance of the free ARTHROTEC is not altered. The clinical
significance of this interaction is not known; however, as with other NSAIDs, concomitant
administration of diclofenac sodium and aspirin is not generally recommended because
of the potential risk of increased adverse effects.
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.
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:
NSAIDs have been reported to competitively inhibit methotrexate
accumulation in rabbit kidney slices. This may indicate that they could enhance
the toxicity of methotrexate. Caution should be used when NSAIDs are administered
concomitantly with methotrexate.
Cyclosporine:
ARTHROTEC, like other NSAID containing products, may
affect renal prostaglandins and increase the toxicity of certain drugs. Ingestion
of ARTHROTEC may increase cyclosporine nephrotoxicity. Patients who begin taking
ARTHROTEC or who increase their dose of ARTHROTEC while taking cyclosporine may
develop toxicity characteristic for clyclosporine. 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:
Clinical studies, as well as post marketing observations, have shown that ARTHROTEC
can reduce the natriuretic effect of furosemide and thiazides in some patients.
This response has been attributed to inhibition of renal prostaglandin synthesis.
During concomitant therapy with NSAIDs, the patient should be observed closely for
signs of renal failure (see WARNINGS, Renal Effects), as well as to assure
diuretic efficacy. 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.
Animal toxicology
A reversible increase in the number of normal surface gastric epithelial cells occurred
in the dog, rat, and mouse during long-term toxicology studies with misoprostol.
No such increase has been observed in humans administered misoprostol for up to
1 year. An apparent response of the female mouse to misoprostol in long-term studies
at 100 to 1000 times the human dose was hyperostosis, mainly of the medulla of sternebrae.
Hyperostosis did not occur in long-term studies in the dog and rat and has not been
seen in humans treated with misoprostol.
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/m²/day, 24 times the recommended maximum human dose of 0.6 mg/m²/day) was
not tumorigenic. In a 21-month mouse carcinogenicity study, oral misoprostol at
doses up to 16 mg/kg/day (48 mg/m²/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/m²/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/m²/day) was not tumorigenic. For a 50-kg person of average height (1.46m²
body surface area), this dose represents 0.08 times the recommended maximum human
dose (148 mg/m²) 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/m²/day, 0.006
times the recommended maximum human dose based on body surface area) in males and
1 mg/kg/day (3 mg/m²/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/m²/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 boxed CONTRAINDICATIONS AND WARNINGS
regarding misoprostol.
Non-teratogenic effects
See boxed CONTRAINDICATIONS AND WARNINGS. Misoprostol may endanger pregnancy
(may cause abortion) and thereby cause harm to the fetus when administered to a
pregnant woman. Misoprostol may produce uterine contractions, uterine bleeding,
and expulsion of the products of conception. Misoprostol has been used to ripen
the cervix, to induce labor, and to treat postpartum hemorrhage, outside of its
approved indication. A major adverse effect of these uses is hyperstimulation of
the uterus. Uterine rupture, amniotic fluid embolism, severe genital bleeding, shock,
fetal bradycardia, and fetal and material death have been reported. Higher doses
of misoprostol, including the 100 mcg tablet, may increase the risk of complications
from uterine hyperstimulation. ARTHROTEC, which contains 200 mcg of misoprostol,
is likely to have a greater risk of uterine hyperstimulation than the 100 mcg tablet
of misoprostol. Abortions caused by misoprostol may be incomplete. 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.
Cases of amniotic fluid embolism, which resulted in maternal and fetal death, have
been reported with use of misoprostol during pregnancy. Severe vaginal bleeding,
retained placenta, shock, fetal bradycardia, and pelvic pain have also been reported.
These women were administered misoprostol vaginally and/or orally over a range of
doses.
Additionally, because of the known effects of nonsteroidal anti-inflammatory drugs
including the diclofenac sodium component of ARTHROTEC, on the fetal cardiovascular
system (closure of ductus arteriosus), use during pregnancy (particularly late pregnancy)
should be avoided.
Teratogenic effects
See boxed CONTRAINDICATIONS and WARNINGS. Congenital anomalies sometimes
associated with fetal death have been reported subsequent to the unsuccessful use
of misoprostol as an abortifacient, but the drug’s teratogenic mechanism has not
been demonstrated. Several reports in the literature associate the use of misoprostol
during the first trimester of pregnancy with skull defects, cranial nerve palsies,
facial malformations, and limb defects.
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/m²/day, 0.8 times the
recommended maximum human dose based on body surface area) and 0.04 mg/kg/day misoprostol
(0.48 mg/m²/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/m²/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/m²/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/m²/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/m²/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/m²/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.
However, animal reproduction studies are not always predictive
of human response. There are no adequate and well-controlled studies in pregnant
women.
Nursing mothers
Diclofenac sodium has been found in the milk of nursing mothers. Misoprostol is rapidly
metabolised in the mother to misoprostol acid, which is biologically active and is excreted
in breast milk. There are no published reports of adverse effects of misoprostol in
breast-feeding infants of mothers taking misoprostol. Caution should be exercised when
ARTHROTEC is administered to a nursing woman.
Labor and Delivery
In rat studies with NSAIDs, as with other drugs known to inhibit prostaglandin synthesis,
an increased incidence of dystocia, delayed parturition, and decreased pup survival
occurred.
Pediatric use
Safety and effectiveness of ARTHROTEC in pediatric patients have not been established.
Geriatric use
As with any NSAIDs, caution should be exercised in treating the elderly (65 years
and older). Of the more than 2,100 subjects in clinical studies with ARTHROTEC,
25% were 65 and over, while 6% were 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 responses between the elderly and younger
patients, but greater sensitivity of some older individuals cannot be ruled out.
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 WARNINGS—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.