General
DAYPRO 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 DAYPRO in reducing fever and inflammation may
diminish the utility of these diagnostic signs in detecting complications of
presumed noninfectious, painful conditions.
Hepatic Effects
Borderline elevations of one or more liver tests may occur in up to 15% of
patients taking NSAIDs including DAYPRO. These laboratory abnormalities may
progress, remain unchanged, or may be transient with continued therapy. Notable
elevations of ALT or AST (approximately three or more times the upper limit
of normal) have been reported in approximately 1% of patients in clinical trials
with NSAIDs. In addition, rare cases of severe hepatic reactions, including
jaundice and fatal fulminate hepatitis, liver necrosis and hepatic failure,
some of them with fatal outcomes have been reported.
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 a more severe hepatic reaction while on therapy with DAYPRO.
If clinical signs and symptoms consistent with liver disease develop, or if
systemic manifestations occur (e.g., eosinophilia, rash, etc.), DAYPRO should
be discontinued.
Photosensitivity: Oxaprozin has been associated with rash and/or
mild photosensitivity in dermatologic testing. An increased incidence of rash
on sun-exposed skin was seen in some patients in the clinical trials.
Hematological effects
Anemia is sometimes seen in patients receiving NSAIDs, including DAYPRO. This may be due to fluid retention, occult or gross GI blood loss, or an incompletely described effect upon erythrogenesis. Patients on long-term treatment with DAYPRO should have their hemoglobin or hematocrit values determined 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 DAYPRO 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 the 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, DAYPRO should not be administered to patients
with this form of aspirin sensitivity and should be used with caution in patients
with preexisting asthma.
Information for patients
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.
- DAYPRO, like other NSAIDs, may cause CV 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).
- DAYPRO, like other NSAIDs, can cause GI discomfort and, rarely, serious
GI side effects, such as ulcers and bleeding, which may result in hospitalization
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 ulcerations 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).
- DAYPRO, 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 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 therapy.
- Patients should be informed of the signs of an anaphylactoid 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, Anaphylactoid
reactions).
- In late pregnancy, as with other NSAIDs, DAYPRO should be avoided because
it may cause premature closure of the ductus arteriosus.
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, DAYPRO should be discontinued.
Carcinogenesis, Mutagenesis, Impairment of Fertility
In oncogenicity studies, oxaprozin administration for 2 years was associated with the exacerbation of liver neoplasms (hepatic adenomas and carcinomas) in male CD mice, but not in female CD mice or rats. The significance of this species-specific finding to man is unknown.
Oxaprozin did not display mutagenic potential. Results from the Ames test, forward mutation in yeast and Chinese hamster ovary (CHO) cells, DNA repair testing in CHO cells, micronucleus testing in mouse bone marrow, chromosomal aberration testing in human lymphocytes, and cell transformation testing in mouse fibroblast all showed no evidence of genetic toxicity or cell-transforming ability.
Oxaprozin administration was not associated with impairment of fertility in
male and female rats at oral doses up to 200 mg/kg/day (1180 mg/m2);
the usual human dose is 17 mg/kg/day (629 mg/m2). However, testicular
degeneration was observed in beagle dogs treated with 37.5 to 150 mg/kg/day
(750 to 3000 mg/m2) of oxaprozin for 6 months, or 37.5 mg/kg/day
for 42 days, a finding not confirmed in other species. The clinical relevance
of this finding is not known.
Pregnancy
Teratogenic effects-Pregnancy Category C
Teratology studies with oxaprozin were performed in mice, rats, and rabbits.
In mice and rats, no drug-related developmental abnormalities were observed
at 50 to 200 mg/kg/day of oxaprozin (225 to 900 mg/m2). However,
in rabbits, infrequent malformed fetuses were observed in dams treated with
7.5 to 30 mg/kg/day of oxaprozin (the usual human dosage range). Animal reproductive
studies are not always predictive of human response. There are no adequate or
well-controlled studies in pregnant women. Oxaprozin should be used during pregnancy
only if the potential benefits justify the potential risks to the fetus.
Nonteratogenic effects
Because of the known effects of nonsteroidal anti-inflammatory drugs on the fetal cardiovascular system (closure of ductus arteriosus), use during pregnancy (particularly late pregnancy) should be avoided.
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. The effects of DAYPRO on labor and delivery in pregnant women are unknown.
Nursing mothers
It is not known whether this drug is excreted in human milk; however, oxaprozin was found in the milk of lactating rats. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from DAYPRO, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
Pediatric use
Safety and effectiveness in pediatric patients below the age of 6 years of age have not been established. The effectiveness of DAYPRO for the treatment of the signs and symptoms of juvenile rheumatoid arthritis (JRA) in pediatric patients aged 6-16 years is supported by evidence from adequate and well controlled studies in adult rheumatoid arthritis patients, and is based on an extrapolation of the demonstrated efficacy of DAYPRO in adults with rheumatoid arthritis and the similarity in the course of the disease and the drug's mechanism of effect between these two patient populations. Use of DAYPRO in JRA patients 6-16 years of age is also supported by the following pediatric studies.
The pharmacokinetic profile and tolerability of oxaprozin were assessed in
JRA patients relative to adult rheumatoid arthritis patients in a 14 day multiple
dose pharmacokinetic study. Apparent clearance of unbound oxaprozin in JRA patients
was reduced compared to adult rheumatoid arthritis patients, but this reduction
could be accounted for by differences in body weight (see Pharmacokinetics,
Pediatric patients) . No pharmacokinetic data are available for pediatric
patients under 6 years. Adverse events were reported by approximately 45% of
JRA patients versus an approximate 30% incidence of adverse events in the adult
rheumatoid arthritis patient cohort. Most of the adverse events were related
to the gastrointestinal tract and were mild to moderate.
In a 3 month open label study, 10-20 mg/kg/day of oxaprozin were administered
to 59 JRA patients. Adverse events were reported by 58% of JRA patients. Most
of those reported were generally mild to moderate, tolerated by the patients,
and did not interfere with continuing treatment. Gastrointestinal symptoms were
the most frequently reported adverse effects and occurred at a higher incidence
than those historically seen in controlled studies in adults. Fifty-two patients
completed 3 months of treatment with a mean daily dose of 20 mg/kg. Of 30 patients
who continued treatment (19-48 week range total treatment duration), nine (30%)
experienced rash on sun-exposed areas of the skin and 5 of those discontinued
treatment. Controlled clinical trials with oxaprozin in pediatric patients have
not been conducted.
Geriatric use
No adjustment of the dose of DAYPRO is necessary in the elderly for pharmacokinetic
reasons, although many elderly may need to receive a reduced dose because
of low body weight or disorders associated with aging. No significant differences
in the pharmacokinetic profile for oxaprozin were seen in studies in the healthy
elderly (see CLINICAL PHARMACOLOGY, Special populations).
Of the total number of subjects evaluated in four placebo controlled clinical studies of oxaprozin, 39% were 65 and over, and 11% were 75 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.
Although selected elderly patients in controlled clinical trials tolerated as well as younger patients, caution should be exercised in treating the elderly, and extra care should be taken when choosing a dose. As with any NSAID, the elderly are likely to tolerate adverse reactions less well than younger patients.
DAYPRO is substantially excreted by the kidney, and the risk of toxic reactions
to DAYPRO 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 use- ful to monitor renal function (see WARNINGS,
Renal effects) .
Last updated on RxList: 4/17/2008