ELYXYB - celecoxib

1 INDICATIONS AND USAGE ELYXYB is indicated for the acute treatment of migraine with or without aura in adults. Limitations of Use ELYXYB is not indicated for the preventive treatment of migraine. ELYXYB is a nonsteroidal anti-inflammatory drug indicated for the acute treatment of migraine with or without aura in adults ( 1 ) Limitations of Use ELYXYB is not indicated for the preventive treatment of migraine. ( 1 )

2 DOSAGE AND ADMINISTRATION The recommended dose of ELYXYB is 120 mg taken orally, with or without food ( 2.1 ) The maximum dosage in a 24-hour period is 120 mg ( 2.1 ) Use ELYXYB for the fewest number of days per month, as needed ( 2.1 ) Hepatic Impairment: The recommended and maximum dose is 60 mg (2.4 mL) in patients with moderate hepatic impairment (Child-Pugh Class B) ( 2.2 , 8.6 , 12.3 ) Poor Metabolizers of CYP2C9 Substrates: The recommended and maximum dose is 60 mg (2.4 mL) in patients who are known or suspected to be CYP2C9 poor metabolizers ( 2.3 , 8.8 , 12.5 ) 2.1 Recommended Dosage The recommended dose of ELYXYB is 120 mg taken orally, with or without food [see Clinical Pharmacology ( 12.3 ) ] . The maximum dosage in a 24-hour period is 120 mg. The safety and effectiveness of a second dose in a 24-hour period have not been established. Use ELYXYB for the fewest number of days per month, as needed. 2.2 Dosage Modification in Patients with Hepatic Impairment The recommended and maximum dose in patients with moderate hepatic impairment (Child- Pugh Class B) is 60 mg (2.4 mL) [see Use in Specific Populations ( 8.6 ) and Clinical Pharmacology ( 12.3 )]. A calibrated measuring device is recommended to measure and deliver the prescribed dose accurately. A household teaspoon or tablespoon is not an adequate measuring device. Use of ELYXYB in patients with severe hepatic impairment is not recommended. 2.3 Dosage Modification in CYP2C9 Poor Metabolizers The recommended and maximum dose in patients who are known or suspected to be CYP2C9 poor metabolizers is 60 mg (2.4 mL) [see Use in Specific Populations ( 8.8 ) and Clinical Pharmacology ( 12.5 )]. A calibrated measuring device is recommended to measure and deliver the prescribed dose accurately. A household teaspoon or tablespoon is not an adequate measuring device.

5 WARNINGS AND PRECAUTIONS Hepatotoxicity : Inform patients of warning signs and symptoms of hepatotoxicity. Discontinue if abnormal liver tests persist or worsen or if clinical signs and symptoms of liver disease develop ( 5.3 ) Hypertension : Patients taking some antihypertensive medications may have impaired response to these therapies when taking NSAIDs. Monitor blood pressure ( 5.4 , 7 ) Heart Failure and Edema : Avoid use of ELYXYB in patients with severe heart failure unless benefits are expected to outweigh risk of worsening heart failure ( 5.5 ) Renal Toxicity : Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia. Avoid use of ELYXYB in patients with severe renal impairment unless benefits are expected to outweigh risk of worsening renal function ( 5.6 ) Anaphylactic Reactions : Seek emergency help if an anaphylactic reaction occurs ( 5.7 ) Exacerbation of Asthma Related to Aspirin Sensitivity : ELYXYB is contraindicated in patients with aspirin-sensitive asthma. Monitor patients with preexisting asthma (without aspirin sensitivity) ( 5.8 ) Serious Skin Reactions : Discontinue ELYXYB at first appearance of skin rash or other signs of hypersensitivity ( 5.9 ) Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) : Discontinue and evaluate clinically ( 5.10 ) Medication Overuse Headache : Detoxification may be necessary ( 5.11 ) Fetal Toxicity : Limit use of NSAIDs, including ELYXYB, between about 20 to 30 weeks in pregnancy due to the risk of oligohydramnios/fetal renal dysfunction. Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy due to the risks of oligohydramnios/fetal renal dysfunction and premature closure of the fetal ductus arteriosus ( 5.12 , 8.1 ) Hematologic Toxicity : Monitor hemoglobin or hematocrit in patients with any signs or symptoms of anemia ( 5.13 , 7 ) 5.1 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…

4 CONTRAINDICATIONS ELYXYB is contraindicated in the following patients: Known hypersensitivity (e.g., anaphylactic reactions and serious skin reactions) to celecoxib, any components of the drug product [see Warnings and Precautions ( 5.7 , 5.9 )]. History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs. Severe, sometimes fatal, anaphylactic reactions to NSAIDs have been reported in such patients [see Warnings and Precautions ( 5.7 , 5.8 )]. In the setting of coronary artery bypass graft (CABG) surgery [see Warnings and Precautions ( 5.1 )]. In patients who have demonstrated allergic-type reactions to sulfonamides [see Warnings and Precautions ( 5.7 )]. Known hypersensitivity to celecoxib, any components of the drug product, or sulfonamides ( 4 ) History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs ( 4 ) In the setting of CABG surgery ( 4 )

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 ( 5.13 )]. 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 325mg). 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 ( 5.13 )]. 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 us…

8.1 Pregnancy Risk Summary Use of NSAIDs, including ELYXYB, can cause premature closure of the fetal ductus arteriosus and fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. Because of these risks, limit dose and duration of ELYXYB use between about 20 and 30 weeks of gestation, and avoid ELYXYB use at about 30 weeks of gestation and later in pregnancy ( see Clinical Considerations , Data ). Premature Closure of Fetal Ductus Arteriosus Use of NSAIDs, including ELYXYB, at about 30 weeks gestation or later in pregnancy increases the risk of premature closure of the fetal ductus arteriosus. Oligohydramnios/Neonatal Renal Impairment Use of NSAIDs at about 20 weeks gestation or later in pregnancy has been associated with cases of fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. Data from observational studies regarding other potential embryofetal risks of NSAID use in women in the first or second trimesters of pregnancy are inconclusive. In animal reproduction 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. Prostaglandins also have been shown to have an important role in fetal kidney development. In published animal studies, prostaglandin synthesis inhibitors have been reported to impair kidney development when administered at clinically relevant doses. All pregnancies have a background risk of birth defects, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. The reported rate of major birth defects among deliveries to women with migraine ranged from 2.2% to 2.9% and the reported rate of miscarriage was 17%, which were similar to rates reported in women without migraine. Clinical Considerations Fetal/Neonatal Adverse Reactions Premature Closure of Fetal Ductus Arteriosus: Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy, because NSAIDs, including ELYXYB, can cause premature closure of the fetal ductus arteriosus (see Data ). Oligohydramnios/Neonatal Renal Impairment If an NSAID is necessary at about 20 weeks gestation or later in pregnancy, limit the use to the lowest effective dose and shortest duration possible. If ELYXYB treatment extends beyond 48 hours, consider monitoring with ultrasound for oligohydramnios. If oligohydramnios occurs, discontinue ELYXYB and follow up according to clinical practice ( see Data ). 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 Premature Closure of Fetal Ductus Arteriosus: Published literature reports that the use of NSAIDs at about 30 weeks of gestation and later in pregnancy may cause premature closure of the fetal ductus arteriosus. Oligohydramnios/Neonatal Renal Impairment: Published studies and postmarketing reports describe maternal NSAID use at about 20 weeks gestation or later in pregnancy associated with fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. In many cases, but not…

12.5 Pharmacogenomics CYP2C9 activity is reduced in individuals with genetic polymorphisms that lead to reduced enzyme activity, such as those homozygous for the CYP2C9*2 and CYP2C9*3 polymorphisms. Limited data from 4 published reports that included a total of 8 subjects with the homozygous CYP2C9*3/*3 genotype showed celecoxib systemic levels that were 3- to 7-fold higher in these subjects compared to subjects with CYP2C9*1/*1 or *I/*3 genotypes. The pharmacokinetics of celecoxib have not been evaluated in subjects with other CYP2C9 polymorphisms, such as *2, *5, *6, *9, and *11. It is estimated that the frequency of the homozygous *3/*3 genotype is 0.3% to 1.0% in various ethnic groups [see Dosage and Administration ( 2.3 ) and Use in Specific Populations ( 8.8 )].

6 ADVERSE REACTIONS 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 )] Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) [see Warnings and Precautions ( 5.10 )] Medication Overuse Headache [see Warnings and Precautions ( 5.11 )] Fetal Toxicity [see Warnings and Precautions ( 5.12 )] Hematologic Toxicity [see Warnings and Precautions ( 5.13 )] Most common adverse reaction (at least 3% and greater than placebo) is dysgeusia ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact SCILEX Pharmaceuticals Inc. at 1-866-SCILEX3 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 ELYXYB 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 relationship 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 Skin and Appendages : Erythema multiforme, exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), acute generalized exanthematous pustulosis (AGEP), and fixed drug eruption (FDE) [ see Warnings and Precautions ( 5.9 ) ].