Included as part of the "PRECAUTIONS" Section
Cardiovascular Thrombotic Events
Clinical trials of several cyclooxygenase (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.
In a trial with celecoxib capsules, there was about a threefold increased risk of the composite endpoint of cardiovascular death, MI, or stroke for the celecoxib 400 mg twice daily and celecoxib 200 mg twice daily treatment arms compared to placebo. The increases in both celecoxib dose groups versus placebo-treated patients were mainly due to an increased incidence of myocardial infarction.
To minimize the potential risk for an adverse CV event in NSAID-treated patients, use ELYXYB for the fewest number of days per month as needed, based on individual treatment goals. 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 ELYXYB, 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 administered in the first 10 to 14 days following CABG surgery found an increased incidence of myocardial infarction and stroke. NSAIDs, including ELYXYB, 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 ELYXYB in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events. If ELYXYB is used in patients with a recent MI, monitor patients for signs of cardiac ischemia.
Gastrointestinal Bleeding, Ulceration And Perforation
NSAIDs, including ELYXYB, can 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 celecoxib. 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 to 6 months, and in about 2% to 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, antiplatelet drugs (such as 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 severe liver impairment and/or coagulopathy are at increased risk for GI bleeding.
Strategies To Minimize The GI Risks In NSAID-Treated Patients
- 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 ELYXYB 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, including ELYXYB.
In controlled clinical trials of celecoxib capsules, the incidence of borderline elevations (greater than or equal to 1.2 times and less than 3 times the upper limit of normal) of liver associated enzymes was 6% for celecoxib and 5% for placebo, and approximately 0.2% of patients taking celecoxib and 0.3% of patients taking placebo had notable elevations of ALT and AST.
If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., nausea, fatigue, pruritus, jaundice, right upper quadrant tenderness, and/or flu-like symptoms), discontinue ELYXYB immediately, and perform a clinical evaluation of the patient.
NSAIDs, including ELYXYB, can lead to new onset of hypertension or worsening of preexisting hypertension, either of which may contribute to the increased incidence of CV events. Use NSAIDS, including ELYXYB, with caution in patients with hypertension. Monitor blood pressure (BP) during the initiation of ELYXYB treatment and throughout the course of therapy.
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].
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, and death.
Additionally, fluid retention and edema have been observed in some patients treated with NSAIDs. Use of ELYXYB 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].
In a clinical study, the cumulative rates at 9 months of peripheral edema in patients on celecoxib capsules 400 mg twice daily, ibuprofen 800 mg three times daily, and diclofenac 75 mg twice daily were 4.5%, 6.9%, and 4.7%, respectively.
Avoid the use of ELYXYB in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure. If ELYXYB 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, including celecoxib, the active ingredient in ELYXYB, 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, ACE-inhibitors or the 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 celecoxib in patients with severe renal impairment. The renal effects of celecoxib may hasten the progression of renal dysfunction in patients with preexisting renal disease.
Correct volume status in dehydrated or hypovolemic patients prior to initiating ELYXYB. Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia during use of ELYXYB [see DRUG INTERACTIONS]. ELYXYB is not recommended in patients with severe renal impairment.
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.
Celecoxib has been associated with anaphylactic reactions in patients with and without known hypersensitivity to celecoxib and in patients with aspirin sensitive asthma. Celecoxib is a sulfonamide and both NSAIDs and sulfonamides may cause allergic type reactions including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people [see CONTRAINDICATIONS and Exacerbation Of Asthma Related To Aspirin Sensitivity].
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, ELYXYB is contraindicated in patients with this form of aspirin sensitivity [see CONTRAINDICATIONS]. When ELYXYB 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
Serious skin reactions have occurred following treatment with celecoxib, including erythema multiforme, exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP). These serious events may occur without warning and can be fatal.
Inform patients about the signs and symptoms of serious skin reactions, and to discontinue the use of ELYXYB at the first appearance of skin rash or any other sign of hypersensitivity. ELYXYB is contraindicated in patients with previous serious skin reactions to NSAIDs [see CONTRAINDICATIONS].
Medication Overuse Headache
Overuse of acute migraine drugs (e.g., ergotamine, triptans, opioids, nonsteroidal anti-inflammatory drugs or combination of these drugs for 10 or more days per month), including ELYXYB, may lead to exacerbation of headache (medication overuse headache). Medication overuse headache may present as migraine-like daily headaches or as a marked increase in frequency of migraine attacks. Detoxification of patients, including withdrawal of the overused drugs and treatment of withdrawal symptoms (which often includes a transient worsening of headache) may be necessary.
Premature Closure Of Fetal Ductus Arteriosus
ELYXYB may cause premature closure of the ductus arteriosus. Avoid use of NSAIDs, including ELYXYB, 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 ELYXYB has any signs or symptoms of anemia, monitor hemoglobin or hematocrit.
In controlled clinical trials of celecoxib capsules, the incidence of anemia was 0.6% with celecoxib and 0.4% with placebo. Patients on long-term treatment with ELYXYB should have their hemoglobin or hematocrit checked if they exhibit any signs or symptoms of anemia or blood loss.
NSAIDs, including ELYXYB, may increase the risk of bleeding events. Co-morbid conditions such as coagulation disorders or concomitant use of warfarin, other anticoagulants, antiplatelet drugs (e.g., aspirin), 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 celecoxib 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, including ELYXYB, treatment with a CBC and a chemistry profile periodically [see Gastrointestinal Bleeding, Ulceration And Perforation, Hepatotoxicity, Renal Toxicity And Hyperkalemia].
In controlled clinical trials with celecoxib capsules, elevated BUN occurred more frequently in patients receiving celecoxib compared with patients on placebo. This laboratory abnormality was also seen in patients who received comparator NSAIDs in these studies. The clinical significance of this abnormality has not been established.
Disseminated Intravascular Coagulation (DIC)
ELYXYB is not indicated in pediatric patients or for the treatment of juvenile rheumatoid arthritis (JRA). Disseminated intravascular coagulation has occurred with use of celecoxib capsules in pediatric patients with systemic onset JRA, which required monitoring for signs and symptoms of abnormal clotting or bleeding.
Patient Counseling Information
Advise the patient to read the FDA-approved patient labeling (Medication Guide and Instructions for Use).
For patients who are prescribed the recommended dosage of 120 mg, instruct them to drink the entire amount of ELYXYB directly from the bottle.
For patients who are prescribed the reduced dosage (i.e., patients with moderate hepatic impairment or CYP2C9 poor metabolizers), instruct them to use an oral dosing syringe to correctly measure the prescribed amount of medication. Inform these patients that oral dosing syringes may be obtained from their pharmacy and that a household teaspoon is not an accurate measuring device. Instruct these patients to discard the unused portion of ELYXYB.
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 ELYXYB and seek immediate medical therapy [see WARNINGS AND PRECAUTIONS and Use In Specific Populations].
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 ELYXYB immediately if they develop any type of rash and to contact their healthcare provider as soon as possible [see WARNINGS AND PRECAUTIONS].
Medication Overuse Headache
Inform patients that use of acute migraine drugs for 10 or more days per month, including ELYXYB, may lead to an exacerbation of headache and encourage patients to record headache frequency and drug use (e.g., by keeping a headache diary). Instruct patients to contact their healthcare provider if the frequency of their migraines increases; withdrawal of ELYXYB may be necessary [see WARNINGS AND PRECAUTIONS].
Advise females of reproductive potential who desire pregnancy that NSAIDs, including ELYXYB, may be associated with a reversible delay in ovulation [see Use In Specific Populations].
Inform pregnant women to avoid use of ELYXYB and other NSAIDs starting at 30 weeks of 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 ELYXYB 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 ELYXYB until they talk to their healthcare provider [see DRUG INTERACTIONS].
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Celecoxib was not carcinogenic when administered orally for two years to rats at oral doses up to 200 mg/kg for males and 10 mg/kg for females (associated with plasma exposures (AUC) approximately 14 and 7 times, respectively, that in humans at the maximum recommended human dose (MRHD) of 120 mg/day) or in mice at oral doses up to 25 mg/kg for males and 50mg/kg for ho the females (associated with plasma AUCs approximately 4 times in humans at the MRHD.
Celecoxib was not mutagenic in an Ames test and a mutation assay in Chinese hamster ovary (CHO) cells, nor clastogenic in a chromosome aberration assay in CHO cells and an in vivo micronucleus test in rat bone marrow.
Impairment Of Fertility
Administration of celecoxib to male and female rats prior to and during mating and continuing in females through implantation had no effect on fertility or male reproductive function at oral doses up to 600 mg/kg/day, which were associated with plasma AUCs approximately 40 times that in humans at the MRHD. Increased implantation loss was observed at doses ≥50 mg/kg/day, which was associated with plasma AUC approximately 20 times that in humans at the MRHD.
Use In Specific Populations
Use of NSAIDs, including celecoxib, during the third trimester of pregnancy increases the risk of premature closure of the fetal ductus arteriosus. Avoid use of NSAIDs, including ELYXYB, in pregnant women starting at 30 weeks of gestation.
There are no adequate and well-controlled studies of celecoxib 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 animal studies, administration of celecoxib during pregnancy resulted in adverse effects on development, including increases in embryonic death and fetal malformations, at doses or maternal plasma drug exposures greater than those used clinically [see Data]. 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 celecoxib, resulted in increased pre-and post-implantation loss.
In the general U.S. population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown.
Labor or Delivery
There are no studies on the effects of celecoxib during labor or delivery. In animal studies, NSAIDs, including celecoxib, inhibit prostaglandin synthesis, cause delayed parturition, and increase the incidence of stillbirth.
The available data do not establish the presence or absence of developmental toxicity related to the use of celecoxib.
Published literature reports that the use of NSAIDs during the third trimester of pregnancy may cause premature closure of the fetal ductus arteriosus.
Administration of celecoxib to rats during early embryonic development resulted in increased pre-and postimplantation loss at oral doses ≥50 mg/kg/day, which was associated with plasma exposure (AUC) approximately 20 times that in humans at the maximum recommended dose (MRHD) of 120 mg/day.
Administration of celecoxib to pregnant rats throughout the period of organogenesis resulted in increased incidences of a specific fetal malformation (diaphragmatic hernia) at oral doses ≥30 mg/kg/day, associated with plasma exposure (AUC) approximately 20 times that in humans at the MRHD.
Administration of celecoxib to pregnant rabbits throughout organogenesis produced increased incidences of fetal visceral (ventricular septal defects) and skeletal malformations at oral doses ≥150 mg/kg/day, associated with maternal plasma AUC approximately 7 times that in humans at the MRHD.
Celecoxib produced no evidence of delayed labor or parturition in rats at oral doses up to 100 mg/kg/day, which was associated with maternal plasma AUC approximately 25 times that in humans at the MRHD.
Limited data from 3 published reports that included a total of 12 breastfeeding women showed low levels of celecoxib in breast milk. The calculated average daily infant dose was 10 to 40 mcg/kg/day, less than 1% of the weight-based therapeutic dose for a two-year old-child. A report of two breastfed infants who were 17 and 22 months of age did not show any adverse events. There is no information available regarding the effects of celecoxib on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for ELYXYB and any potential adverse effects on the breastfed infant from the celecoxib or from the underlying maternal condition.
Females And Males Of Reproductive Potential
Based on the mechanism of action, the use of prostaglandin-mediated NSAIDs, including ELYXYB, 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 ELYXYB, in women who have difficulties conceiving or who are undergoing investigation of infertility.
Safety and effectiveness in pediatric patients have not been established. Disseminated intravascular coagulation has occurred in pediatric patients [see WARNINGS AND PRECAUTIONS].
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, treat for the fewest number of days per month, as needed, and monitor patients for adverse effects [see WARNINGS AND PRECAUTIONS].
In the controlled clinical trials for migraine, approximately 70 patients were ≥ 65 years of age. Of the total number of patients who received celecoxib (for indications other than migraine) in pre-approval clinical trials, more than 3,300 were 65-74 years of age, while approximately 1,300 additional patients were 75 years and over. No substantial differences in effectiveness were observed between these subjects and younger subjects. In clinical studies comparing renal function as measured by the GFR, BUN and creatinine, and platelet function as measured by bleeding time and platelet aggregation, the results were not different between elderly and young volunteers.
However, as with other NSAIDs, including those that selectively inhibit COX-2, there have been more spontaneous postmarketing reports of fatal GI events and acute renal failure in the elderly than in younger patients [see WARNINGS AND PRECAUTIONS].
No dosage adjustment is needed for patients with mild hepatic impairment (Child-Pugh Class A). Reduce the dose of ELYXYB in patients with moderate hepatic impairment (Child-Pugh Class B) [see DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY]. The use of ELYXYB in patients with severe hepatic impairment (Child-Pugh Class C) is not recommended.
No dosage adjustment is needed for patients with mild or moderate renal impairment. ELYXYB is not recommended in patients with severe renal impairment [see WARNINGS AND PRECAUTIONS and CLINICAL PHARMACOLOGY].
Poor Metabolizers Of CYP2C9 Substrates
In patients who are known or suspected to be poor CYP2C9 metabolizers (i.e., CYP2C9*3/*3), based on genotype or previous history/experience with other CYP2C9 substrates (e.g., warfarin, phenytoin) reduce the dose of ELYXYB [see DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY].