ELYXYB Dailymed

The following adverse reactions are discussed in greater detail in other sections of the labeling:

• Cardiovascular Thrombotic Events [see Warnings and Precautions (5.1)]
• GI Bleeding, Ulceration and Perforation [see Warnings and Precautions (5.2)]
• Hepatotoxicity [see Warnings and Precautions (5.3)]
• Hypertension [see Warnings and Precautions (5.4)]
• Heart Failure and Edema [see Warnings and Precautions (5.5)]
• Renal Toxicity and Hyperkalemia [see Warnings and Precautions (5.6)]
• Anaphylactic Reactions [see Warnings and Precautions (5.7)]
• Exacerbation of Asthma Related to Aspirin Sensitivity [see Warnings and Precautions (5.8)]
• Serious Skin Reactions [see Warnings and Precautions (5.9)]
• Medication Overuse Headache [see Warnings and Precautions (5.10)]
• Premature Closure of Fetal Ductus Arteriosus [see Warnings and Precautions (5.11)]
• Hematologic Toxicity [see Warnings and Precautions (5.12)]

Most common adverse reaction (at least 3% and greater than placebo) is dysgeusia (6.1).

To report SUSPECTED ADVERSE REACTIONS, contact Promius Pharma, LLC. at 1-888-966-8766 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to the rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety of ELYXYB was evaluated in 815 patients who received at least one dose of ELYXYB in two, randomized, double-blind, placebo-controlled trials (Study 1 and 2) in adult patients with migraine [see Clinical Studies (14)].

 The most common (at least 2% of patients who received ELYXYB and greater than placebo) adverse reaction in Study 1 and Study 2 was dysgeusia, which occurred in 3% of patients who received ELYXB compared to 1% of patients who received placebo.

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of celecoxib. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relation ship to drug exposure.

Cardiovascular: Vasculitis, deep venous thrombosis

General: Anaphylactic reaction, angioedema

Liver and biliary: Liver necrosis, hepatitis, jaundice, hepatic failure

Hemic and lymphatic: Agranulocytosis, aplastic anemia, pancytopenia, leucopenia

Metabolic: Hypoglycemia, hyponatremia

Nervous: Aseptic meningitis, ageusia, anosmia, fatal intracranial hemorrhage

Renal: Interstitial nephritis

7. Drug Interactions

See Table 1 for clinically significant drug interactions with celecoxib.

Table 1: Clinically Significant Drug Interactions with Celecoxib

Drugs That Interfere with Hemostasis
Clinical Impact	Celecoxib and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of celecoxib and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention	Monitor patients with concomitant use of ELYXYB with anticoagulants (e.g., warfarin), antiplatelet drugs (e.g., aspirin), SSRIs, and SNRIs for signs of bleeding [see Warnings and Precautions (5.12) ].
Aspirin
Clinical Impact	In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions (5.2)]. In two studies in healthy volunteers and in patients with established heart disease respectively, celecoxib (200 mg to 400 mg daily) has demonstrated a lack of interference with the cardioprotective antiplatelet effect of aspirin (100 mg to 325 mg).
Intervention	Concomitant use of ELYXYB and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.12)].ELYXYB is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact	NSAIDs may diminish the antihypertensive effect of ACE inhibiters, ARBs, or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention	During concomitant use of ELYXYB and ACE inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of ELYXYB and ACE inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.6) ].When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact	Clinical studies, as well as postmarketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention	During concomitant use of ELYXYB with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions (5.6)].
Digoxin
Clinical Impact	The concomitant use of celecoxib with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention	During concomitant use of ELYXYB and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact	NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention	During concomitant use of ELYXYB and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact	Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). Celecoxib has no effect on methotrexate pharmacokinetics.
Intervention	During concomitant use of ELYXYB and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact	Concomitant use of celecoxib and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention	During concomitant use of ELYXYB and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact	Concomitant use of celecoxib with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity [see Warnings and Precautions (5.2)].
Intervention	The concomitant use of ELYXYB with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact	Concomitant use of celecoxib and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention	During concomitant use of ELYXYB and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal, and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
CYP2C9 Inhibitors or inducers
Clinical Impact	Celecoxib metabolism is predominantly mediated via cytochrome P450 (CYP) 2C9 in the liver. Co-administration of ELYXYB with drugs that are known to inhibit CYP2C9 (e.g., fluconazole) may enhance the exposure and toxicity of celecoxib whereas co-administration with CYP2C9 inducers (e.g., rifampin) may lead to compromised efficacy of ELYXYB.
Intervention	Evaluate each patient's medical history when consideration is given to prescribing ELYXYB. A dosage adjustment may be warranted when ELYXYB is administered with CYP2C9 inhibitors or inducers.
CYP2D6 substrates
Clinical Impact	In vitro studies indicate that celecoxib, although not a substrate, is an inhibitor of CYP2D6. Therefore, there is a potential for an in vivo drug interaction with drugs that are metabolized by CYP2D6 (e.g., atomoxetine), and celecoxib may enhance the exposure and toxicity of these drugs.
Intervention	Evaluate each patient's medical history when consideration is given to prescribing ELYXYB. A dosage adjustment may be warranted when ELYXYB is administered with CYP2D6 substrates.
Corticosteroids
Clinical Impact	Concomitant use of corticosteroids with celecoxib may increase the risk of GI ulceration or bleeding.
Intervention	Monitor patients with concomitant use of ELYXYB with corticosteroids for signs of bleeding [see Warnings and Precautions (5.2) ].

• Drugs that Interfere with Hemostasis (e.g., warfarin, aspirin, SSRIs/SNRIs): Monitor patients for bleeding who are concomitantly taking ELYXYB with drugs that interfere with hemostasis. Concomitant use of ELYXYB and analgesic doses of aspirin is not generally recommended (7)
• ACE Inhibitors, Angiotensin Receptor Blockers (ARB), or Beta-Blockers: Concomitant use with ELYXYB may diminish the antihypertensive effect of these drugs. Monitor blood pressure (7)
• ACE Inhibitors and ARBs: Concomitant use with ELYXYB in elderly, volume depleted, or those with renal impairment may result in deterioration of renal function. In such high-risk patients, monitor for signs of worsening renal function (7)
• Diuretics: NSAIDs can reduce natriuretic effect of furosemide and thiazide diuretics. Monitor patients to assure diuretic efficacy including antihypertensive effects (7)
• Digoxin: Concomitant use with ELYXYB can increase serum concentration and prolong half-life of digoxin. Monitor serum digoxin levels (7)

8. Use In Specific Populations

• Pregnancy: Use of NSAIDs during the third trimester of pregnancy increases the risk of premature closure of the fetal ductus arteriosus. Avoid use of NSAIDs in pregnant women starting at 30 weeks of gestation (5.11, 8.1)
• Infertility: NSAIDs are associated with reversible infertility. Consider withdrawal of ELYXYB in women who have difficulties conceiving (8.3)

8.1 Pregnancy

Risk Summary

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.

Clinical Considerations

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.

Data

Human Data

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.

Animal data

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.

8.2 Lactation

Risk Summary

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.

8.3 Females and Males of Reproductive Potential

Infertility

Females

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.

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established. Disseminated intravascular coagulation has occurred in pediatric patients [see Warnings and Precautions (5.15)].

8.5 Geriatric Use

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 Warning and Precautions (5.1, 5.2, 5.3, 5.6, 5.14)].

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 (5.4, 5.6)].

8.6 Hepatic Impairment

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 (2.2) and Clinical Pharmacology (12.3)]. The use of ELYXYB in patients with severe hepatic impairment (Child-Pugh Class C) is not recommended.

8.7 Renal Impairment

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 (5.6) and Clinical Pharmacology (12.3)].

8.8 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 ( 2.3) and Clinical Pharmacology (12.5)].