Included as part of the "PRECAUTIONS" Section
Cardiovascular Thrombotic Events
Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an
increased risk of serious cardiovascular (CV) thrombotic events, including myocardial infarction (MI), and
stroke, which can be fatal. Based on available data, it is unclear that the risk for CV thrombotic events is similar
for all NSAIDs. The relative increase in serious CV thrombotic events over baseline conferred by NSAID use
appears to be similar in those with and without known CV disease or risk factors for CV disease. However,
patients with known CV disease or risk factors had a higher absolute incidence of excess serious CV thrombotic
events, due to their increased baseline rate. Some observational studies found that this increased risk of
serious CV thrombotic events began as early as the first weeks of treatment. The increase in CV thrombotic risk
has been observed most consistently at higher doses.
To minimize the potential risk for an adverse CV event in NSAID-treated patients, use the lowest effective dose
for the shortest duration possible. Physicians and patients should remain alert for the development of such
events, throughout the entire treatment course, even in the absence of previous CV symptoms. Patients should
be informed about the symptoms of serious CV events and the steps to take if they occur.
There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV
thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID, such as piroxicam,
increases the risk of serious gastrointestinal (GI) events [see Gastrointestinal Bleeding, Ulceration, And Perforation].
Status Post Coronary Artery Bypass Graft (CABG) Surgery
Two large, controlled clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10–14 days
following CABG surgery found an increased incidence of myocardial infarction and stroke. NSAIDs are
contraindicated in the setting of CABG [see CONTRAINDICATIONS].
Observational studies conducted in the Danish National Registry have demonstrated that patients treated with
NSAIDs in the post-MI period were at increased risk of reinfarction, CV-related death, and all-cause mortality
beginning in the first week of treatment. In this same cohort, the incidence of death in the first year post-MI
was 20 per 100 person years in NSAID-treated patients compared to 12 per 100 person years in non-NSAID
exposed patients. Although the absolute rate of death declined somewhat after the first year post-MI, the
increased relative risk of death in NSAID users persisted over at least the next four years of follow-up.
Avoid the use of FELDENE in patients with a recent MI unless the benefits are expected to outweigh the risk of
recurrent CV thrombotic events. If FELDENE is used in patients with a recent MI, monitor patients for signs of
Gastrointestinal Bleeding, Ulceration, And Perforation
NSAIDs, including FELDENE, cause serious gastrointestinal (GI) adverse events including inflammation,
bleeding, ulceration, and perforation of the esophagus, stomach, small intestine, or large intestine, which can
be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients
treated with NSAIDs. Only one in five patients who develop a serious upper GI adverse event on NSAID therapy
is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occurred in approximately
1% of patients treated for 3–6 months, and in about 2%–4% of patients treated for one year. However, even
short-term NSAID therapy is not without risk.
Risk Factors For GI Bleeding, Ulceration, And Perforation
Patients with a prior history of peptic ulcer disease and/or GI bleeding who used NSAIDs had a greater than 10-
fold increased risk for developing a GI bleed compared to patients without these risk factors. Other factors that
increase the risk of GI bleeding in patients treated with NSAIDs include longer duration of NSAID therapy;
concomitant use of oral corticosteroids, aspirin, anticoagulants, or selective serotonin reuptake inhibitors
(SSRIs); smoking; use of alcohol; older age; and poor general health status. Most postmarketing reports of fatal
GI events occurred in elderly or debilitated patients. Additionally, patients with advanced liver disease and/or
coagulopathy are at increased risk for GI bleeding.
Strategies to Minimize the GI Risks in NSAID-treated patients
- Use the lowest effective dosage for the shortest possible duration.
- Avoid administration of more than one NSAID at a time.
- Avoid use in patients at higher risk unless benefits are expected to outweigh the increased risk of bleeding.
For such patients, as well as those with active GI bleeding, consider alternate therapies other than NSAIDs.
- Remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy.
- If a serious GI adverse event is suspected, promptly initiate evaluation and treatment, and discontinue
FELDENE until a serious GI adverse event is ruled out.
- In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, monitor patients more closely
for evidence of GI bleeding [see DRUG INTERACTIONS].
Elevations of ALT or AST (three or more times the upper limit of normal [ULN]) have been reported in
approximately 1% of NSAID-treated patients in clinical trials. In addition, rare, sometimes fatal, cases of severe
hepatic injury, including fulminant hepatitis, liver necrosis, and hepatic failure have been reported.
Elevations of ALT or AST (less than three times ULN) may occur in up to 15% of patients treated with NSAIDs
Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, diarrhea,
pruritus, jaundice, right upper quadrant tenderness, and "flu-like" symptoms). If clinical signs and symptoms
consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.),
discontinue FELDENE immediately, and perform a clinical evaluation of the patient.
NSAIDs, including FELDENE, can lead to new onset of hypertension or worsening of preexisting hypertension,
either of which may contribute to the increased incidence of CV events. Patients taking angiotensin converting
enzyme (ACE) inhibitors, thiazide diuretics, or loop diuretics may have impaired response to these therapies
when taking NSAIDs [see DRUG INTERACTIONS].
Monitor blood pressure (BP) during the initiation of NSAID treatment and throughout the course of therapy.
Heart Failure And Edema
The Coxib and traditional NSAID Trialists’ Collaboration meta-analysis of randomized controlled trials
demonstrated an approximately two-fold increase in hospitalizations for heart failure in COX-2 selective-treated
patients and nonselective NSAID-treated patients compared to placebo-treated patients. In a Danish National
Registry study of patients with heart failure, NSAID use increased the risk of MI, hospitalization for heart failure,
Additionally, fluid retention and edema have been observed in some patients treated with NSAIDs. Use of
piroxicam may blunt the CV effects of several therapeutic agents used to treat these medical conditions (e.g.,
diuretics, ACE inhibitors, or angiotensin receptor blockers [ARBs]) [see DRUG INTERACTIONS].
Avoid the use of FELDENE in patients with severe heart failure unless the benefits are expected to outweigh the
risk of worsening heart failure. If FELDENE is used in patients with severe heart failure, monitor patients for
signs of worsening heart failure.
Renal Toxicity And Hyperkalemia
Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury.
Renal toxicity has also been seen in patients in whom 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, dehydration,
hypovolemia, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors or ARBs, and the elderly.
Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state.
No information is available from controlled clinical studies regarding the use of FELDENE in patients with
advanced renal disease. The renal effects of FELDENE may hasten the progression of renal dysfunction in
patients with preexisting renal disease.
Correct volume status in dehydrated or hypovolemic patients prior to initiating FELDENE. Monitor renal function
in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia during use of FELDENE
[see DRUG INTERACTIONS]. Avoid the use of FELDENE in patients with advanced renal disease unless the
benefits are expected to outweigh the risk of worsening renal function. If FELDENE is used in patients with
advanced renal disease, monitor patients for signs of worsening renal function.
Increases in serum potassium concentration, including hyperkalemia, have been reported with use of NSAIDs,
even in some patients without renal impairment. In patients with normal renal function, these effects have been
attributed to a hyporeninemic-hypoaldosteronism state.
Piroxicam has been associated with anaphylactic reactions in patients with and without known hypersensitivity
to piroxicam and in patients with aspirin-sensitive asthma [see CONTRAINDICATIONS and Exacerbation Of Asthma Related To Aspirin Sensitivity].
Seek emergency help if an anaphylactic reaction occurs.
Exacerbation Of Asthma Related To Aspirin Sensitivity
A subpopulation of patients with asthma may have aspirin-sensitive asthma which may include chronic
rhinosinusitis complicated by nasal polyps; severe, potentially fatal bronchospasm; and/or intolerance to aspirin
and other NSAIDs. Because cross-reactivity between aspirin and other NSAIDs has been reported in such
aspirin-sensitive patients, FELDENE is contraindicated in patients with this form of aspirin sensitivity [see CONTRAINDICATIONS]. When FELDENE is used in patients with preexisting asthma (without known aspirin
sensitivity), monitor patients for changes in the signs and symptoms of asthma.
Serious Skin Reactions
NSAIDs, including piroxicam, can cause serious skin adverse reactions such as exfoliative dermatitis, Stevens-
Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. These serious events may
occur without warning. Inform patients about the signs and symptoms of serious skin reactions, and to
discontinue the use of FELDENE at the first appearance of skin rash or any other sign of hypersensitivity.
FELDENE is contraindicated in patients with previous serious skin reactions to NSAIDs [see CONTRAINDICATIONS].
Premature Closure Of Fetal Ductus Arteriosus
Piroxicam may cause premature closure of the fetal ductus arteriosus. Avoid use of NSAIDs, including FELDENE,
in pregnant women starting at 30 weeks of gestation (third trimester) [see Use In Specific Populations].
Anemia has occurred in NSAID-treated patients. This may be due to occult or gross blood loss, fluid retention, or
an incompletely described effect on erythropoiesis. If a patient treated with FELDENE has any signs or
symptoms of anemia, monitor hemoglobin or hematocrit.
NSAIDs, including FELDENE, may increase the risk of bleeding events. Co-morbid conditions such as coagulation
disorders, concomitant use of warfarin, other anticoagulants, antiplatelet agents (e.g., aspirin), serotonin
reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) may increase this risk.
Monitor these patients for signs of bleeding [see DRUG INTERACTIONS].
Masking Of Inflammation And Fever
The pharmacological activity of FELDENE in reducing inflammation, and possibly fever, may diminish the utility
of diagnostic signs in detecting infections.
Because serious GI bleeding, hepatotoxicity, and renal injury can occur without warning symptoms or signs,
consider monitoring patients on long-term NSAID treatment with a CBC and a chemistry profile periodically [see Gastrointestinal Bleeding, Ulceration, And Perforation, Hepatotoxicity, Renal Toxicity And Hyperkalemia] .
Because of reports of adverse eye findings with nonsteroidal anti-inflammatory agents, it is recommended that
patients who develop visual complaints during treatment with FELDENE have ophthalmic evaluations.
Patient Counseling Information
Advise the patient to read the FDA-approved patient labeling (Medication Guide) that accompanies each
prescription dispensed. Inform patients, families, or their caregivers of the following information before
initiating therapy with FELDENE and periodically during the course of ongoing therapy.
Cardiovascular Thrombotic Events
Advise patients to be alert for the symptoms of cardiovascular thrombotic events, including chest pain,
shortness of breath, weakness, or slurring of speech, and to report any of these symptoms to their health care
provider immediately [see WARNINGS AND PRECAUTIONS].
Gastrointestinal Bleeding, Ulceration, And Perforation
Advise patients to report symptoms of ulcerations and bleeding, including epigastric pain, dyspepsia, melena,
and hematemesis to their health care provider. In the setting of concomitant use of low-dose aspirin for cardiac
prophylaxis, inform patients of the increased risk for and the signs and symptoms of GI bleeding [see WARNINGS AND PRECAUTIONS].
Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus,
diarrhea, jaundice, right upper quadrant tenderness, and "flu-like" symptoms). If these occur, instruct patients
to stop FELDENE and seek immediate medical therapy [see WARNINGS AND PRECAUTIONS].
Heart Failure And Edema
Advise patients to be alert for the symptoms of congestive heart failure including shortness of breath,
unexplained weight gain, or edema and to contact their healthcare provider if such symptoms occur [see WARNINGS AND PRECAUTIONS].
Inform patients of the signs of an anaphylactic reaction (e.g., difficulty breathing, swelling of the face or throat).
Instruct patients to seek immediate emergency help if these occur [see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS].
Serious Skin Reactions
Advise patients to stop FELDENE immediately if they develop any type of rash and to contact their healthcare
provider as soon as possible [see WARNINGS AND PRECAUTIONS].
Advise females of reproductive potential who desire pregnancy that NSAIDs, including FELDENE, may be
associated with a reversible delay in ovulation [see Use In Specific Populations].
Inform pregnant women to avoid use of FELDENE and other NSAIDs starting at 30 weeks gestation because of
the risk of the premature closing of the fetal ductus arteriosus [see WARNINGS AND PRECAUTIONS and Use In Specific Populations].
Avoid Concomitant Use Of NSAIDs
Inform patients that the concomitant use of FELDENE with other NSAIDs or salicylates (e.g., diflunisal, salsalate)
is not recommended due to the increased risk of gastrointestinal toxicity, and little or no increase in efficacy
[see WARNINGS AND PRECAUTIONS and DRUG INTERACTIONS]. Alert patients that NSAIDs may be present in
"over the counter" medications for treatment of colds, fever, or insomnia.
Use Of NSAIDS And Low-Dose Aspirin
Inform patients not to use low-dose aspirin concomitantly with FELDENE until they talk to their healthcare
provider [see DRUG INTERACTIONS].
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Long-term animal studies have not been conducted to characterize the carcinogenic potential of piroxicam.
Piroxicam was not mutagenic in an Ames bacterial reverse mutation assay, or in a dominant lethal mutation
assay in mice, and was not clastogenic in an in vivo chromosome aberration assay in mice.
Impairment Of Fertility
Reproductive studies in which rats were administered piroxicam at doses of 2, 5, or 10 mg/kg/day (up to 5
times the maximum recommended human dose [MRHD] of 20 mg based on mg/m2 body surface area [BSA])
revealed no impairment of male or female fertility.
Use In Specific Populations
Use of NSAIDs, including FELDENE, during the third trimester of pregnancy increases the risk of premature
closure of the fetal ductus arteriosus. Avoid use of NSAIDs, including FELDENE, in pregnant women starting at
30 weeks of gestation (third trimester).
There are no adequate and well-controlled studies of FELDENE in pregnant women.
Data from observational studies regarding potential embryofetal risks of NSAID use in women in the first or
second trimesters of pregnancy are inconclusive. In the general U.S. population, all clinically recognized
pregnancies, regardless of drug exposure, have a background rate of 2–4% for major malformations, and 15–
20% for pregnancy loss.
In animal reproduction studies in rats and rabbits, there was no evidence of teratogenicity at exposures up to 5
and 10 times the MRHD, respectively. In rat studies with piroxicam, fetotoxicity (postimplantation loss) was
observed at exposures 2 times the MRHD, and delayed parturition and an increased incidence of stillbirth were
noted at doses equivalent to the MRHD of piroxicam. Based on animal data, prostaglandins have been shown to
have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization. In
animal studies, administration of prostaglandin synthesis inhibitors such as piroxicam, resulted in increased
pre- and post-implantation loss.
Labor or Delivery
There are no studies on the effects of FELDENE during labor or delivery. In animal studies, NSAIDS, including
piroxicam inhibit prostaglandin synthesis, cause delayed parturition, and increase the incidence of stillbirth.
Pregnant rats administered piroxicam at 2, 5, or 10 mg/kg/day during the period of organogenesis (Gestation
Days 6 to 15) demonstrated increased post-implantation losses with 5 and 10 mg/kg/day of piroxicam
(equivalent to 2 and 5 times the maximum recommended human dose [MRHD], of 20 mg respectively, based
on a mg/m2 body surface area [BSA]). There were no drug-related developmental abnormalities noted in
offspring. Gastrointestinal tract toxicity was increased in pregnant rats in the last trimester of pregnancy
compared to non-pregnant rats or rats in earlier trimesters of pregnancy. Pregnant rabbits administered
piroxicam at 2, 5, or 10 mg/kg/day during the period of organogenesis (Gestation Days 7 to 18) demonstrated
no drug-related developmental abnormalities in offspring (up to 10 times the MRHD based on a mg/m2 BSA).
In a pre- and post-natal development study in which pregnant rats were administered piroxicam at 2, 5, or 10
mg/kg/day on Gestation Day 15 through delivery and weaning of offspring, reduced weight gain and death were
observed in dams at 10 mg/kg/day (5 times the MRHD based on a mg/m2 BSA) starting on Gestation Day 20.
Treated dams revealed peritonitis, adhesions, gastric bleeding, hemorrhagic enteritis and dead fetuses in utero.
Parturition was delayed and there was an increased incidence of stillbirth in all piroxicam-treated groups (at
doses equivalent to the MRHD). Postnatal development could not be reliably assessed due to the absence of
maternal care secondary to severe maternal toxicity.
Limited data from 2 published reports that included a total of 6 breastfeeding women and 2 infants showed
piroxicam is excreted in human milk at approximately 1% to 3% of the maternal concentration. No
accumulation of piroxicam occurred in milk relative to that in maternal plasma during treatment. The
developmental and health benefits of breastfeeding should be considered along with the mother's clinical need
for FELDENE and any potential adverse effects on the breastfed infant from the FELDENE or from the underlying
Females And Males Of Reproductive Potential
Based on the mechanism of action, the use of prostaglandin-mediated NSAIDs, including FELDENE, may delay
or prevent rupture of ovarian follicles, which has been associated with reversible infertility in some women.
Published animal studies have shown that administration of prostaglandin synthesis inhibitors has the potential
to disrupt prostaglandin-mediated follicular rupture required for ovulation. Small studies in women treated with
NSAIDs have also shown a reversible delay in ovulation. Consider withdrawal of NSAIDs, including FELDENE, in
women who have difficulties conceiving or who are undergoing investigation of infertility.
FELDENE has not been investigated in pediatric patients. The safety and effectiveness of FELDENE have not
Elderly patients, compared to younger patients, are at greater risk for NSAID-associated serious cardiovascular,
gastrointestinal, and/or renal adverse reactions. If the anticipated benefit for the elderly patient outweighs
these potential risks, start dosing at the low end of the dosing range, and monitor patients for adverse effects
[see WARNINGS AND PRECAUTIONS].