Health Canada has completed a safety review confirming that the use of nonsteroidal anti-inflammatory drugs (NSAIDs) starting from approximately 20 weeks of pregnancy or later may cause rare but serious kidney problems in an unborn baby. This can lead to low levels of amniotic fluid and possible complications, such as impaired lung maturation and limb contractures in the newborn baby. Health Canada is advising that pregnant women not use NSAIDs from approximately 20 to 28 weeks of pregnancy unless advised to do so by their health care provider. If a health care provider decides the use of NSAIDs between 20 and 28 weeks of pregnancy is necessary, Health Canada recommends that they use the lowest effective dose for the shortest duration possible and consider monitoring amniotic fluid levels via ultrasound if treatment extends beyond 48 hours. The use of NSAIDs remains contraindicated in the last trimester of pregnancy. The recommendations do not apply to the use of low-dose (81 mg) aspirin, pediatric-only formulations (those indicated only for children younger than 12 years), or ophthalmic formulations. Prescription and nonprescription NSAID product labels will be updated with this new information.
Further information is available at https://healthycanadians.gc.ca/recall-alert-rappel-avis/hc-sc/2021/75763a-eng.php.
Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction (MI), and stroke, which can be fatal. This risk may occur early in the treatment and may increase with duration of use.
Celecoxib is contraindicated in the setting of coronary artery bypass graft (CABG) surgery.
NSAIDs cause an increased risk of serious gastrointestinal (GI) adverse events, including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients and patients with a prior history of peptic ulcer disease and/or GI bleeding are at higher risk for serious GI events.
Note: Use the lowest effective dose for the shortest duration of time. Avoid or use with caution in patients at risk for or with existing cardiovascular disease, GI disease, kidney impairment, chronic liver disease, or a bleeding diathesis due to greater risk for adverse events. Consider administering in combination with a proton pump inhibitor in patients at risk for GI bleeding (eg, taking dual antiplatelet therapy or an anticoagulant, ≥60 years of age, high celecoxib doses) (ACCF/ACG/AHA [Abraham 2010]; ACCF/ACG/AHA [Bhatt 2008]).
Anti-inflammatory (eg, for arthritis associated with inflammatory rheumatic disease): Oral: Initial: 200 mg once daily or 100 mg twice daily; may increase to a maximum of 200 mg twice daily for several weeks during a disease flare until the flare resolves.
Dysmenorrhea: Oral: Initial: 400 mg, followed by an additional 200 mg approximately 12 hours later, if needed, on day 1; maintenance dose: 200 mg twice daily as needed; maximum daily maintenance dose: 400 mg/day. Begin at menses onset or 1 to 2 days prior to onset of menses for severe symptoms; usual duration: 1 to 5 days (Daniels 2009; Marjoribanks 2015; manufacturer's labeling).
Gout, treatment (acute flares) (off-label use):
Note: Some experts reserve use for patients who are not candidates for intra-articular glucocorticoids or when intra-articular glucocorticoid administration is not feasible (Gaffo 2022).
Oral: Initial: 400 mg, followed by 200 mg approximately 12 hours later on day 1, then continue 200 mg twice daily thereafter; maximum daily maintenance dose: 400 mg/day (Schumacher 2012; manufacturer's labeling). Begin within 24 to 48 hours of flare onset; discontinue 2 to 3 days after resolution of clinical signs; usual duration: 5 to 7 days (Gaffo 2022).
Osteoarthritis: Oral: 200 mg once daily or 100 mg twice daily.
Pain, acute (monotherapy or as an adjunctive agent): Oral: Initial: 400 mg, followed by 200 mg approximately 12 hours later, if needed, on day 1; thereafter, 200 mg twice daily as needed or scheduled; maximum daily maintenance dose: 400 mg/day (manufacturer's labeling). In select patients (eg, advanced age, comorbidity), some experts may initiate at 100 mg twice daily (Portenoy 2021).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
The renal dosing recommendations are based upon the best available evidence and clinical expertise. Senior Editorial Team: Bruce Mueller, PharmD, FCCP, FASN, FNKF; Jason A. Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC; Michael Heung, MD, MS.
Altered kidney function:
CrCl ≥60 mL/minute: No dosage adjustment necessary (<1% of the drug excreted in the urine) (Davies 2000; expert opinion).
CrCl >30 to <60 mL/minute: No dosage adjustment necessary (<1% of the drug excreted in the urine) (Davies 2000; expert opinion). However, use the lowest effective dose for the shortest duration possible. Use of analgesics other than nonsteroidal anti-inflammatory drugs (NSAIDs) or topical NSAIDs may be preferred. Avoid use in patients at high risk for acute kidney injury (ie, volume depleted, hypotensive, elderly, or taking concurrent nephrotoxic medications) (Baker 2020; KDIGO 2013; expert opinion).
CrCl ≤30 mL/minute: Avoid use due to increased risk of acute kidney injury (KDIGO 2013); Use of analgesics other than NSAIDs or topical NSAIDs are preferred. However, in select patients where alternatives are not effective, after careful assessment of risks versus benefits, use of celecoxib may be considered; use the lowest effective dose for the shortest duration possible with close monitoring of kidney function (expert opinion).
Hemodialysis, intermittent (thrice weekly): Unlikely to be significantly dialyzable (high protein binding, large Vd): Avoid use, as patients with end-stage kidney disease may be at increased risk for bleeding (eg, GI), cardiovascular adverse effects, and loss of residual kidney function (Kurella 2003; expert opinion). However, in select patients after careful assessment of risks versus benefits, use of celecoxib may be considered; use the lowest effective dose for the shortest duration possible (Koncicki 2017; expert opinion).
Peritoneal dialysis: Unlikely to be significantly dialyzable (high protein binding, large Vd): Avoid use, as patients with end-stage kidney disease may be at increased risk for bleeding (eg, GI), cardiovascular adverse effects, and loss of residual kidney function (Kurella 2003; expert opinion). However, in select patients after careful assessment of risks versus benefits, use of celecoxib may be considered; use the lowest effective dose for the shortest duration possible (Koncicki 2017; expert opinion).
CRRT: Avoid use (expert opinion).
PIRRT (eg, sustained, low-efficiency diafiltration): Avoid use (expert opinion).
Acute kidney injury while on celecoxib therapy: Discontinue use (expert opinion).
Mild impairment (Child-Pugh class A): No dosage adjustment necessary; AUC increased ~40% in mild hepatic impairment compared with healthy subjects.
Moderate impairment (Child-Pugh class B): Reduce dose by 50%.
Severe impairment (Child-Pugh class C): Use is not recommended.
Abnormal liver function tests (persistent or worsening): Discontinue use.
(For additional information see "Celecoxib: Pediatric drug information")
Juvenile idiopathic arthritis (JIA): Note: Use the lowest effective dose for the shortest duration of time, consistent with individual patient goals.
Children ≥2 years and Adolescents:
≥10 kg to ≤25 kg: Oral: 50 mg twice daily
>25 kg: Oral: 100 mg twice daily
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Dosing adjustment in poor metabolizers of CYP2C9 substrates: Use with caution in patients who are known or suspected poor metabolizers of cytochrome P450 isoenzyme 2C9 substrates.
Children ≥2 years and Adolescents: Consider alternate therapy in JIA patients who are poor metabolizers; experience in adult patients suggests dosing adjustment.
Children ≥2 years and Adolescents:
Baseline:
Mild or moderate impairment: There are no dosage adjustments provided in the manufacturer's labeling; however, since <1% of the drug is excreted in the urine, dosage adjustment is not necessary (Davies 2000). Based on unpublished data, AUC was ~40% lower in adult patients with chronic renal insufficiency (GFR 35 to 60 mL/minute) compared with subjects with normal renal function due to a higher apparent clearance.
Severe impairment: Use is not recommended.
Advanced renal disease: Use is not recommended; however, if celecoxib treatment cannot be avoided, monitor renal function closely.
During therapy: Abnormal renal function tests (persistent or worsening): Discontinue use.
Children ≥2 years and Adolescents:
Moderate hepatic impatient (Child-Pugh Class B): Reduce dose by 50%; monitor closely
Severe hepatic impairment (Child-Pugh Class C): Use is not recommended; has not been studied
Initiate at the lowest recommended dose. The AUC in elderly patients (especially females and patients weighing <50 kg) may be increased by 50% compared with younger subjects.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Capsule, Oral:
CeleBREX: 50 mg, 100 mg, 200 mg, 400 mg
Generic: 50 mg, 100 mg, 200 mg, 400 mg
Solution, Oral:
Elyxyb: 120 mg/4.8 mL (4.8 mL) [contains alcohol, usp, cremophor el, cremophor rh40, levomenthol]
May be product dependent
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Capsule, Oral:
CeleBREX: 100 mg, 200 mg
Generic: 100 mg, 200 mg
An FDA-approved patient medication guide, which is available with the product information and as follows, must be dispensed with this medication:
NSAIDs: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/020998s050lbl.pdf#page=21
May be administered without regard to meals. Capsules may be swallowed whole or the entire contents emptied onto a teaspoon of cool or room temperature applesauce and administered immediately with water. The contents of the capsules sprinkled onto applesauce may be stored under refrigeration for up to 6 hours.
Lower doses (up to 200 mg twice daily) may be administered without regard to meals (may administer with food to reduce GI upset); larger doses should be administered with food to improve absorption. Capsules may be swallowed whole or the entire contents emptied onto a teaspoon of cool or room temperature applesauce and ingested immediately with water. The sprinkled contents of the capsule on applesauce may be stored under refrigeration for up to 6 hours.
Anti-inflammatory: Relief of the signs/symptoms of ankylosing spondylitis or rheumatoid arthritis.
Dysmenorrhea: Treatment of primary dysmenorrhea.
Juvenile idiopathic arthritis: Relief of the signs/symptoms of juvenile idiopathic arthritis (JIA) in patients 2 years and older.
Osteoarthritis: Relief of the signs/symptoms of osteoarthritis.
Pain, acute: Management of acute pain.
Gout, treatment (acute flares)
CeleBREX may be confused with CeleXA, Cerebyx, Cervarix, Clarinex
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.
1% to 10%:
Cardiovascular: Acute myocardial infarction (<2%), angina pectoris (<2%), chest pain (<2%), coronary artery disease (<2%), edema (<2%), exacerbation of hypertension (<2%), facial edema (<2%), palpitations (<2%), peripheral edema (2%), tachycardia (<2%)
Dermatologic: Alopecia (<2%), cellulitis (<2%), contact dermatitis (<2%), dermatitis (<2%), diaphoresis (<2%), ecchymoses (<2%), erythematous rash (<2%), maculopapular rash (<2%), pruritus (<2%), skin changes (<2%), skin photosensitivity (<2%), urticaria (<2%), xeroderma (<2%)
Endocrine & metabolic: Albuminuria (<2%), hot flash (<2%), hypercholesterolemia (<2%), hyperglycemia (<2%), hypokalemia (<2%), increased nonprotein nitrogen (<2%), weight gain (<2%)
Gastrointestinal: Abdominal pain (4%), anorexia (<2%), constipation (<2%), diarrhea (6%), diverticulitis of the gastrointestinal tract (<2%), dyspepsia (9%), dysphagia (<2%), eructation (<2%), esophagitis (<2%), flatulence (2%), gastritis (<2%), gastroenteritis (<2%), gastroesophageal reflux disease (<2%), hemorrhoids (<2%), hiatal hernia (<2%), increased appetite (<2%), melena (<2%), stomatitis (<2%), tenesmus (<2%), vomiting (<2%), xerostomia (<2%)
Genitourinary: Cystitis (<2%), dysuria (<2%), hematuria (<2%), urinary frequency (<2%)
Hematologic & oncologic: Anemia (<2%), thrombocythemia (<2%)
Hepatic: Increased liver enzymes (<3x ULN: ≤6%), increased serum alkaline phosphatase (<2%)
Hypersensitivity: Hypersensitivity reaction (<2%)
Nervous system: Anxiety (<2%), depression (<2%), drowsiness (<2%), fatigue (<2%), hypertonia (<2%), hypoesthesia (<2%), migraine (<2%), nervousness (<2%), pain (<2%), paresthesia (<2%), peripheral pain (<2%), vertigo (<2%)
Neuromuscular & skeletal: Arthralgia (<2%), increased creatine phosphokinase in blood specimen (<2%), lower limb cramp (<2%), myalgia (<2%), osteoarthritis (<2%), synovitis (<2%), tendinopathy (<2%)
Otic: Deafness (<2%), tinnitus (<2%)
Renal: Increased blood urea nitrogen (<2%), increased serum creatinine (<2%), nephrolithiasis (<2%)
Respiratory: Aggravated bronchospasm (<2%), bronchitis (<2%), bronchospasm (<2%), cough (<2%), dyspnea (<2%), epistaxis (<2%), flu-like symptoms (<2%), laryngitis (<2%), pharyngitis (2%), pneumonia (<2%), rhinitis (2%), sinusitis (2%), upper respiratory tract infection (8%)
Miscellaneous: Cyst (<2%), fever (<2%)
<1%:
Cardiovascular: Cardiac failure, cerebrovascular accident, pulmonary embolism, syncope, thrombophlebitis, ventricular fibrillation
Dermatologic: Gangrene of skin and/or subcutaneous tissue
Gastrointestinal: Cholelithiasis, esophageal perforation, gastrointestinal hemorrhage, hemorrhagic colitis, intestinal obstruction, intestinal perforation, pancreatitis
Hematologic: Thrombocytopenia
Infection: Sepsis
Nervous system: Ataxia, suicidal tendencies
Renal: Acute kidney injury
Frequency not defined:
Cardiovascular: Coronary thrombosis
Dermatologic: Acute generalized exanthematous pustulosis, erythema multiforme, exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis
Gastrointestinal: Gastrointestinal inflammation, gastrointestinal perforation, gastrointestinal ulcer
Hypersensitivity: Anaphylaxis
Immunologic: Drug reaction with eosinophilia and systemic symptoms
Respiratory: Alveolar osteitis (post oral surgery patients)
Postmarketing:
Cardiovascular: Deep vein thrombosis, vasculitis
Endocrine & metabolic: Hypoglycemia, hyponatremia
Gastrointestinal: Ageusia
Hematologic: Agranulocytosis, aplastic anemia, leukopenia, pancytopenia
Hepatic: Hepatic failure, hepatic necrosis, hepatitis, jaundice
Hypersensitivity: Angioedema, nonimmune anaphylaxis
Nervous system: Anosmia, aseptic meningitis, intracranial hemorrhage
Renal: Interstitial nephritis
Hypersensitivity to celecoxib, sulfonamides, aspirin, other NSAIDs, or any component of the formulation; patients who have experienced asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs; use in the setting of CABG surgery.
Note: Although the FDA-approved product labeling states this medication is contraindicated in patients with hypersensitivity to sulfonamide-containing drugs, the scientific basis of this cross-sensitivity has been challenged. See “Warnings/Precautions” for more detail.
Canadian labeling: Additional contraindications (not in US labeling): Pregnancy (third trimester); women who are breast-feeding; severe, uncontrolled heart failure; active gastrointestinal ulcer (gastric, duodenal, peptic); active gastrointestinal bleeding; inflammatory bowel disease; cerebrovascular bleeding; severe liver impairment or active hepatic disease; severe renal impairment (CrCl <30 mL/minute) or deteriorating renal disease; known hyperkalemia; use in patients <18 years of age
Concerns related to adverse effects:
• Anaphylactoid reactions: Even in patients without prior exposure, anaphylactic reactions and angioedema may occur; patients with "aspirin triad" (bronchial asthma, aspirin intolerance, rhinitis) may be at increased risk. Contraindicated in patients who have experienced an anaphylactic reaction with nonsteroidal anti-inflammatory drugs (NSAIDs) or aspirin therapy.
• Cardiovascular events: [US Boxed Warning]: NSAIDs cause an increased risk of serious (and potentially fatal) adverse cardiovascular thrombotic events, including MI and stroke. Risk may occur early during treatment and may increase with duration of use. Relative risk appears to be similar in those with and without known cardiovascular disease or risk factors for cardiovascular disease; however, absolute incidence of cardiovascular events (which may occur early during treatment) was higher in patients with known cardiovascular disease or risk factors. New-onset hypertension or exacerbation of hypertension may occur (NSAIDs may also impair response to angiotensin-converting enzyme [ACE] inhibitors, thiazide diuretics, or loop diuretics) and contribute to cardiovascular events; monitor BP; use with caution in patients with hypertension. May cause sodium and fluid retention, use with caution in patients with edema. Avoid use in patients with heart failure (ACCF/AHA [Yancy 2013]). Avoid use in patients with recent MI unless benefits outweigh risk of cardiovascular thrombotic events. Long-term cardiovascular risk in children has not been evaluated. Use the lowest effective dose for the shortest duration of time, consistent with individual patient goals, to reduce risk of cardiovascular events; alternate therapies should be considered for patients at high risk.
• Drug reaction with eosinophilia and systemic symptoms: Potentially serious, sometimes fatal, drug reaction with eosinophilia and systemic symptoms (DRESS), also known as multiorgan hypersensitivity reactions, has been reported with NSAIDs. Monitor for signs and symptoms (eg, fever, rash, lymphadenopathy, eosinophilia) in association with other organ system involvement (eg, hepatitis, nephritis, hematological abnormalities, myocarditis, myositis). Early symptoms of hypersensitivity reaction (eg, lymphadenopathy, fever) may occur without rash; discontinue therapy and further evaluate if DRESS is suspected.
• GI events: [US Boxed Warning]: NSAIDs cause an increased risk of serious gastrointestinal inflammation, ulceration, bleeding, and perforation (may be fatal); elderly patients and patients with history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events. These events may occur at any time during therapy and without warning. Avoid use in patients with active GI bleeding. Use caution with a history of GI ulcers, concurrent therapy known to increase the risk of GI bleeding (eg, aspirin, anticoagulants and/or corticosteroids, selective serotonin reuptake inhibitors), smoking, use of alcohol, or in elderly or debilitated patients. Use the lowest effective dose for the shortest duration of time, consistent with individual patient goals, to reduce risk of GI adverse events; alternate therapies should be considered for patients at high risk. When used concomitantly with aspirin, a substantial increase in the risk of gastrointestinal complications (eg, ulcer) occurs; concomitant gastroprotective therapy (eg, proton pump inhibitors) is recommended (ACCF/ACG/AHA [Bhatt 2008]).
• Hematologic effects: Anemia may occur; monitor hemoglobin or hematocrit in patients on long-term treatment. Celecoxib does not usually affect PT, PTT or platelet counts; does not inhibit platelet aggregation at approved doses.
• Skin reactions: NSAIDs may cause serious skin adverse events, including exfoliative dermatitis, Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN); may occur without warning and in patients without prior known sulfa allergy; discontinue use at first sign of rash (or any other hypersensitivity).
• Sulfonamide ("sulfa") allergy: The FDA-approved product labeling for many medications containing a sulfonamide chemical group includes a broad contraindication in patients with a prior allergic reaction to sulfonamides. There is a potential for cross-reactivity between members of a specific class (eg, two antibiotic sulfonamides). However, concerns for cross-reactivity have previously extended to all compounds containing the sulfonamide structure (SO2NH2). An expanded understanding of allergic mechanisms indicates cross-reactivity between antibiotic sulfonamides and nonantibiotic sulfonamides may not occur or at the very least this potential is extremely low (Brackett 2004; Johnson 2005; Slatore 2004; Tornero 2004). In particular, mechanisms of cross-reaction due to antibody production (anaphylaxis) are unlikely to occur with nonantibiotic sulfonamides. T-cell-mediated (type IV) reactions (eg, maculopapular rash) are less well understood and it is not possible to completely exclude this potential based on current insights. In cases where prior reactions were severe (SJS/TEN), some clinicians choose to avoid exposure to these classes.
Disease-related concerns:
• Asthma: The manufacturer’s labeling states to not administer to patients with aspirin-sensitive asthma due to severe and potentially fatal bronchospasm that has been reported in such patients having received aspirin and the potential for cross reactivity with other NSAIDs. The manufacturer also states to use with caution in patients with other forms of asthma. However, in patients with known aspirin-exacerbated respiratory disease (AERD), the use of celecoxib initiated at a low dose with gradual titration in patients with stable, mild to moderate persistent asthma has been used without incident (Morales 2013).
• Bariatric surgery: Gastric ulceration: Avoid chronic use of oral nonselective NSAIDs after bariatric surgery; development of anastomotic ulcerations/perforations may occur (Bhangu 2014; Mechanick 2013). Short-term use of celecoxib or IV ketorolac are recommended as part of a multimodal pain management strategy for postoperative pain (Chou 2016; Horsley 2019; Thorell 2016).
• Coronary artery bypass graft surgery: [US Boxed Warning]: Celecoxib is contraindicated in the setting of coronary artery bypass graft surgery (CABG). Risk of MI and stroke may be increased with use following CABG surgery.
• Cytochrome P450 isoenzyme 2C9 deficiency: Use with caution in patients with known or suspected deficiency of cytochrome P450 isoenzyme 2C9 (CYP 2C9*3/*3); poor metabolizers may have higher plasma levels due to reduced metabolism; consider reduced initial doses (initiate therapy with 25% to 50% of the lowest starting dose [eg, 50% to 75% dose reduction]) (CPIC [Theken 2020]). Alternate therapies should be considered in patients with juvenile idiopathic arthritis (JIA) who are poor metabolizers of CYP2C9.
• Hepatic impairment: Use with caution in patients with moderate hepatic impairment; dosage adjustment recommended. Not recommended for patients with severe hepatic impairment. Transaminase elevations have been reported with use; closely monitor patients with any abnormal LFT. Rare (sometimes fatal), severe hepatic reactions (eg, fulminant hepatitis, hepatic necrosis, hepatic failure) have occurred with NSAID use; discontinue if signs or symptoms of liver disease develop, if systemic manifestations occur, or with persistent or worsening abnormal hepatic function tests.
• Renal impairment: NSAID use may compromise existing renal function. Dose-dependent decreases in prostaglandin synthesis may result from NSAID use, causing a reduction in renal blood flow which may cause renal decompensation (usually reversible). Patients with impaired renal function, dehydration, hypovolemia, heart failure, liver dysfunction, those taking diuretics, ACE inhibitors, angiotensin II receptor blockers, and the elderly are at greater risk for renal toxicity. Rehydrate patient before starting therapy; monitor renal function closely. Avoid use in patients with advanced renal disease; discontinue use with persistent or worsening abnormal renal function tests. Long-term NSAID use may result in renal papillary necrosis.
Special populations:
• Pediatric: Use with caution in pediatric patients with systemic-onset JIA; serious adverse reactions, including disseminated intravascular coagulation, may occur.
Consider alternate therapy in JIA patients who are identified to be CYP2C9 poor metabolizers. In a small pediatric study (n=4), the AUC of celecoxib was ~10 times higher in a child who was homozygous for CYP2C9*3, compared to children who were homozygous for the *1 allele (n=2) or who had the CYP2C9*1/*2 genotype; further studies are needed to determine if carriers of the CYP2C9*3 allele are at increased risk for cardiovascular toxicity or dose related adverse effects of celecoxib, especially with long-term, high-dose use of the drug (Stempak 2005). Long-term (>6 months) cardiovascular toxicity in children and adolescents has not been studied.
Substrate of CYP2C9 (major), CYP3A4 (minor); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential; Inhibits CYP2D6 (weak)
5-Aminosalicylic Acid Derivatives: Nonsteroidal Anti-Inflammatory Agents may enhance the nephrotoxic effect of 5-Aminosalicylic Acid Derivatives. Risk C: Monitor therapy
Acemetacin: May enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents. Risk X: Avoid combination
Ajmaline: Sulfonamides may enhance the adverse/toxic effect of Ajmaline. Specifically, the risk for cholestasis may be increased. Risk C: Monitor therapy
Alcohol (Ethyl): May enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents. Specifically, the risk of GI bleeding may be increased with this combination. Risk C: Monitor therapy
Aliskiren: Nonsteroidal Anti-Inflammatory Agents may diminish the antihypertensive effect of Aliskiren. Nonsteroidal Anti-Inflammatory Agents may enhance the nephrotoxic effect of Aliskiren. Risk C: Monitor therapy
Alpelisib: May decrease the serum concentration of CYP2C9 Substrates (High risk with Inducers). Risk C: Monitor therapy
Aminoglycosides: Nonsteroidal Anti-Inflammatory Agents may decrease the excretion of Aminoglycosides. Data only in premature infants. Risk C: Monitor therapy
Aminolevulinic Acid (Systemic): Photosensitizing Agents may enhance the photosensitizing effect of Aminolevulinic Acid (Systemic). Risk X: Avoid combination
Aminolevulinic Acid (Topical): Photosensitizing Agents may enhance the photosensitizing effect of Aminolevulinic Acid (Topical). Risk C: Monitor therapy
Angiotensin II Receptor Blockers: May enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents. Specifically, the combination may result in a significant decrease in renal function. Nonsteroidal Anti-Inflammatory Agents may diminish the therapeutic effect of Angiotensin II Receptor Blockers. The combination of these two agents may also significantly decrease glomerular filtration and renal function. Risk C: Monitor therapy
Angiotensin-Converting Enzyme Inhibitors: May enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents. Specifically, the combination may result in a significant decrease in renal function. Nonsteroidal Anti-Inflammatory Agents may diminish the antihypertensive effect of Angiotensin-Converting Enzyme Inhibitors. Risk C: Monitor therapy
Anticoagulants: Nonsteroidal Anti-Inflammatory Agents (COX-2 Selective) may enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy
Aspirin: May enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents (COX-2 Selective). Management: Concurrent use of aspirin at doses beyond cardioprotective levels is not recommended. While concurrent use of low-dose aspirin with a COX-2 inhibitor is permissable, patients should be monitored closely for signs/symptoms of GI ulceration/bleeding. Risk D: Consider therapy modification
Bemiparin: Nonsteroidal Anti-Inflammatory Agents may enhance the anticoagulant effect of Bemiparin. Management: Avoid concomitant use of bemiparin and nonsteroidal anti-inflammatory agents (NSAIDs) due to the increased risk of bleeding. If concomitant use is unavoidable, monitor closely for signs and symptoms of bleeding. Risk D: Consider therapy modification
Beta-Blockers: Nonsteroidal Anti-Inflammatory Agents may diminish the antihypertensive effect of Beta-Blockers. Risk C: Monitor therapy
Bile Acid Sequestrants: May decrease the absorption of Nonsteroidal Anti-Inflammatory Agents. Risk C: Monitor therapy
Bisphosphonate Derivatives: Nonsteroidal Anti-Inflammatory Agents may enhance the adverse/toxic effect of Bisphosphonate Derivatives. Both an increased risk of gastrointestinal ulceration and an increased risk of nephrotoxicity are of concern. Risk C: Monitor therapy
Corticosteroids (Systemic): May enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents (COX-2 Selective). Risk C: Monitor therapy
CycloSPORINE (Systemic): Nonsteroidal Anti-Inflammatory Agents may enhance the nephrotoxic effect of CycloSPORINE (Systemic). Nonsteroidal Anti-Inflammatory Agents may increase the serum concentration of CycloSPORINE (Systemic). CycloSPORINE (Systemic) may increase the serum concentration of Nonsteroidal Anti-Inflammatory Agents. Management: Consider alternatives to nonsteroidal anti-inflammatory agents (NSAIDs). Monitor for evidence of nephrotoxicity, as well as increased serum cyclosporine concentrations and systemic effects (eg, hypertension) during concomitant therapy with NSAIDs. Risk D: Consider therapy modification
CYP2C9 Inducers (Moderate): May decrease the serum concentration of Celecoxib. Risk C: Monitor therapy
CYP2C9 Inhibitors (Moderate): May increase the serum concentration of Celecoxib. Risk C: Monitor therapy
Dapsone (Topical): May enhance the adverse/toxic effect of Methemoglobinemia Associated Agents. Risk C: Monitor therapy
Deferasirox: Nonsteroidal Anti-Inflammatory Agents may enhance the adverse/toxic effect of Deferasirox. Specifically, the risk for GI ulceration/irritation or GI bleeding may be increased. Risk C: Monitor therapy
Desmopressin: Nonsteroidal Anti-Inflammatory Agents may enhance the hyponatremic effect of Desmopressin. Risk C: Monitor therapy
Digoxin: Nonsteroidal Anti-Inflammatory Agents may increase the serum concentration of Digoxin. Risk C: Monitor therapy
Drospirenone-Containing Products: May enhance the hyperkalemic effect of Nonsteroidal Anti-Inflammatory Agents. Risk C: Monitor therapy
Enoxaparin: Nonsteroidal Anti-Inflammatory Agents may enhance the anticoagulant effect of Enoxaparin. Management: Discontinue nonsteroidal anti-inflammatory agents (NSAIDs) prior to initiating enoxaparin whenever possible. If concomitant administration is unavoidable, monitor closely for signs and symptoms of bleeding. Risk D: Consider therapy modification
Eplerenone: Nonsteroidal Anti-Inflammatory Agents may diminish the antihypertensive effect of Eplerenone. Nonsteroidal Anti-Inflammatory Agents may enhance the hyperkalemic effect of Eplerenone. Risk C: Monitor therapy
Estrogen Derivatives: Nonsteroidal Anti-Inflammatory Agents (COX-2 Selective) may enhance the thrombogenic effect of Estrogen Derivatives. Nonsteroidal Anti-Inflammatory Agents (COX-2 Selective) may increase the serum concentration of Estrogen Derivatives. Risk C: Monitor therapy
Heparin: Nonsteroidal Anti-Inflammatory Agents may enhance the anticoagulant effect of Heparin. Management: Decrease the dose of heparin or nonsteroidal anti-inflammatory agents (NSAIDs) if coadministration is required. Risk D: Consider therapy modification
Herbal Products with Anticoagulant/Antiplatelet Effects (eg, Alfalfa, Anise, Bilberry): May enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents. Bleeding may occur. Risk C: Monitor therapy
HydrALAZINE: Nonsteroidal Anti-Inflammatory Agents may diminish the antihypertensive effect of HydrALAZINE. Risk C: Monitor therapy
Ketorolac (Nasal): May enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents. Risk X: Avoid combination
Ketorolac (Systemic): Nonsteroidal Anti-Inflammatory Agents may enhance the adverse/toxic effect of Ketorolac (Systemic). Risk X: Avoid combination
Lithium: Nonsteroidal Anti-Inflammatory Agents may increase the serum concentration of Lithium. Management: Consider reducing the lithium dose when initiating a NSAID. Monitor for increased lithium therapeutic/toxic effects if a NSAID is initiated/dose increased, or decreased effects if a NSAID is discontinued/dose decreased. Risk D: Consider therapy modification
Local Anesthetics: Methemoglobinemia Associated Agents may enhance the adverse/toxic effect of Local Anesthetics. Specifically, the risk for methemoglobinemia may be increased. Risk C: Monitor therapy
Loop Diuretics: Nonsteroidal Anti-Inflammatory Agents may diminish the diuretic effect of Loop Diuretics. Loop Diuretics may enhance the nephrotoxic effect of Nonsteroidal Anti-Inflammatory Agents. Management: Monitor for evidence of kidney injury or decreased therapeutic effects of loop diuretics with concurrent use of an NSAID. Consider avoiding concurrent use in CHF or cirrhosis. Concomitant use of bumetanide with indomethacin is not recommended. Risk D: Consider therapy modification
Lumacaftor and Ivacaftor: May decrease the serum concentration of CYP2C9 Substrates (High Risk with Inhibitors or Inducers). Lumacaftor and Ivacaftor may increase the serum concentration of CYP2C9 Substrates (High Risk with Inhibitors or Inducers). Risk C: Monitor therapy
Macimorelin: Nonsteroidal Anti-Inflammatory Agents may diminish the diagnostic effect of Macimorelin. Risk X: Avoid combination
Mecamylamine: Sulfonamides may enhance the adverse/toxic effect of Mecamylamine. Risk X: Avoid combination
MetFORMIN: Nonsteroidal Anti-Inflammatory Agents may enhance the adverse/toxic effect of MetFORMIN. Risk C: Monitor therapy
Methotrexate: Nonsteroidal Anti-Inflammatory Agents may increase the serum concentration of Methotrexate. Management: Avoid coadministration of higher dose methotrexate (such as that used for the treatment of oncologic conditions) and NSAIDs. Use caution if coadministering lower dose methotrexate and NSAIDs. Risk D: Consider therapy modification
Methoxsalen (Systemic): Photosensitizing Agents may enhance the photosensitizing effect of Methoxsalen (Systemic). Risk C: Monitor therapy
Mifamurtide: Nonsteroidal Anti-Inflammatory Agents may diminish the therapeutic effect of Mifamurtide. Risk X: Avoid combination
Naftazone: May enhance the antiplatelet effect of Nonsteroidal Anti-Inflammatory Agents. Risk C: Monitor therapy
Nitric Oxide: May enhance the adverse/toxic effect of Methemoglobinemia Associated Agents. Combinations of these agents may increase the likelihood of significant methemoglobinemia. Risk C: Monitor therapy
Nonsteroidal Anti-Inflammatory Agents: May enhance the adverse/toxic effect of other Nonsteroidal Anti-Inflammatory Agents. Specifically, the risk for gastrointestinal toxicity is increased. Risk X: Avoid combination
Nonsteroidal Anti-Inflammatory Agents (Topical): May enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents. Specifically, the risk of gastrointestinal (GI) toxicity is increased. Management: Coadministration of systemic nonsteroidal anti-inflammatory drugs (NSAIDs) and topical NSAIDs is not recommended. If systemic NSAIDs and topical NSAIDs, ensure the benefits outweigh the risks and monitor for increased NSAID toxicities. Risk D: Consider therapy modification
Omacetaxine: Nonsteroidal Anti-Inflammatory Agents may enhance the adverse/toxic effect of Omacetaxine. Specifically, the risk for bleeding-related events may be increased. Risk C: Monitor therapy
Phenylbutazone: May enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents. Risk X: Avoid combination
Porfimer: Photosensitizing Agents may enhance the photosensitizing effect of Porfimer. Risk C: Monitor therapy
Potassium Salts: Nonsteroidal Anti-Inflammatory Agents may enhance the hyperkalemic effect of Potassium Salts. Risk C: Monitor therapy
Potassium-Sparing Diuretics: Nonsteroidal Anti-Inflammatory Agents may diminish the antihypertensive effect of Potassium-Sparing Diuretics. Nonsteroidal Anti-Inflammatory Agents may enhance the hyperkalemic effect of Potassium-Sparing Diuretics. Risk C: Monitor therapy
PRALAtrexate: Nonsteroidal Anti-Inflammatory Agents may increase the serum concentration of PRALAtrexate. More specifically, NSAIDS may decrease the renal excretion of pralatrexate. Management: Avoid coadministration of pralatrexate with nonsteroidal anti-inflammatory drugs (NSAIDs). If coadministration cannot be avoided, closely monitor for increased pralatrexate serum levels or toxicity. Risk D: Consider therapy modification
Prilocaine: Methemoglobinemia Associated Agents may enhance the adverse/toxic effect of Prilocaine. Combinations of these agents may increase the likelihood of significant methemoglobinemia. Management: Monitor patients for signs of methemoglobinemia (e.g., hypoxia, cyanosis) when prilocaine is used in combination with other agents associated with development of methemoglobinemia. Avoid lidocaine/prilocaine in infants receiving such agents. Risk C: Monitor therapy
Probenecid: May increase the serum concentration of Nonsteroidal Anti-Inflammatory Agents. Risk C: Monitor therapy
Prostaglandins (Ophthalmic): Nonsteroidal Anti-Inflammatory Agents may diminish the therapeutic effect of Prostaglandins (Ophthalmic). Nonsteroidal Anti-Inflammatory Agents may also enhance the therapeutic effects of Prostaglandins (Ophthalmic). Risk C: Monitor therapy
Quinolones: Nonsteroidal Anti-Inflammatory Agents may enhance the neuroexcitatory and/or seizure-potentiating effect of Quinolones. Nonsteroidal Anti-Inflammatory Agents may increase the serum concentration of Quinolones. Risk C: Monitor therapy
Rifapentine: May decrease the serum concentration of CYP2C9 Substrates (High risk with Inducers). Risk C: Monitor therapy
Selective Serotonin Reuptake Inhibitors: May enhance the antiplatelet effect of Nonsteroidal Anti-Inflammatory Agents (COX-2 Selective). Nonsteroidal Anti-Inflammatory Agents (COX-2 Selective) may diminish the therapeutic effect of Selective Serotonin Reuptake Inhibitors. Risk C: Monitor therapy
Sincalide: Drugs that Affect Gallbladder Function may diminish the therapeutic effect of Sincalide. Management: Consider discontinuing drugs that may affect gallbladder motility prior to the use of sincalide to stimulate gallbladder contraction. Risk D: Consider therapy modification
Sodium Nitrite: Methemoglobinemia Associated Agents may enhance the adverse/toxic effect of Sodium Nitrite. Combinations of these agents may increase the likelihood of significant methemoglobinemia. Risk C: Monitor therapy
Sodium Phosphates: May enhance the nephrotoxic effect of Nonsteroidal Anti-Inflammatory Agents. Specifically, the risk of acute phosphate nephropathy may be enhanced. Management: Consider avoiding this combination by temporarily suspending treatment with NSAIDs, or seeking alternatives to oral sodium phosphate bowel preparation. If the combination cannot be avoided, maintain adequate hydration and monitor renal function closely. Risk D: Consider therapy modification
Tacrolimus (Systemic): Nonsteroidal Anti-Inflammatory Agents may enhance the nephrotoxic effect of Tacrolimus (Systemic). Risk C: Monitor therapy
Tenofovir Products: Nonsteroidal Anti-Inflammatory Agents may enhance the nephrotoxic effect of Tenofovir Products. Management: Seek alternatives to these combinations whenever possible. Avoid use of tenofovir with multiple NSAIDs or any NSAID given at a high dose due to a potential risk of acute renal failure. Diclofenac appears to confer the most risk. Risk D: Consider therapy modification
Tenoxicam: May enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents. Risk X: Avoid combination
Thiazide and Thiazide-Like Diuretics: May enhance the nephrotoxic effect of Nonsteroidal Anti-Inflammatory Agents. Nonsteroidal Anti-Inflammatory Agents may diminish the therapeutic effect of Thiazide and Thiazide-Like Diuretics. Risk C: Monitor therapy
Thioridazine: CYP2D6 Inhibitors (Weak) may increase the serum concentration of Thioridazine. Management: Consider avoiding concomitant use of thioridazine and weak CYP2D6 inhibitors. If combined, monitor closely for QTc interval prolongation and arrhythmias. Some weak CYP2D6 inhibitors list use with thioridazine as a contraindication. Risk D: Consider therapy modification
Tolperisone: Nonsteroidal Anti-Inflammatory Agents may enhance the adverse/toxic effect of Tolperisone. Specifically, the risk of hypersensitivity reactions may be increased. Tolperisone may enhance the therapeutic effect of Nonsteroidal Anti-Inflammatory Agents. Risk C: Monitor therapy
Tricyclic Antidepressants (Tertiary Amine): May enhance the antiplatelet effect of Nonsteroidal Anti-Inflammatory Agents (COX-2 Selective). Risk C: Monitor therapy
Triflusal: Nonsteroidal Anti-Inflammatory Agents may decrease the protein binding of Triflusal. Specifically, NSAIDs may decrease protein binding of the active Triflusal metabolite. Triflusal may decrease the protein binding of Nonsteroidal Anti-Inflammatory Agents. Risk C: Monitor therapy
Vancomycin: Nonsteroidal Anti-Inflammatory Agents may increase the serum concentration of Vancomycin. Risk C: Monitor therapy
Verteporfin: Photosensitizing Agents may enhance the photosensitizing effect of Verteporfin. Risk C: Monitor therapy
Peak concentrations are delayed and AUC is increased by 10% to 20% when taken with a high-fat meal. Management: Administer without regard to meals.
Nonsteroidal anti-inflammatory drugs (NSAIDs) may delay or prevent rupture of ovarian follicles. This may be associated with infertility that is reversible upon discontinuation of the medication. Consider discontinuing use in patients having difficulty conceiving or those undergoing investigation of fertility.
Based on available information, NSAIDs can be continued in males with rheumatic and musculoskeletal diseases who are planning to father a child (ACR [Sammaritano 2020]).
The use of nonsteroidal anti-inflammatory drugs (NSAIDs) close to conception may be associated with an increased risk of miscarriage due to cyclooxygenase-2 inhibition interfering with implantation (Bermas 2014; Bloor 2013).
Birth defects have been observed following in utero NSAID exposure in some studies; however, data are conflicting (Bloor 2013). Nonteratogenic effects, including prenatal constriction of the ductus arteriosus, persistent pulmonary hypertension of the newborn, oligohydramnios, necrotizing enterocolitis, renal dysfunction or failure, and intracranial hemorrhage have been observed in the fetus/neonate following in utero NSAID exposure (Bermas 2014; Bloor 2013). Maternal NSAID use may cause fetal renal dysfunction leading to oligohydramnios. Although rare, this may occur as early as 20 weeks' gestation and is more likely to occur with prolonged maternal use. Oligohydramnios may be reversible following discontinuation of the NSAID (Dathe 2019; FDA 2020). In addition, nonclosure of the ductus arteriosus postnatally may occur and be resistant to medical management (Bermas 2014; Bloor 2013).
Maternal use of NSAIDs should be avoided beginning at 20 weeks' gestation. If NSAID use is necessary between 20 and 30 weeks' gestation, limit use to the lowest effective dose and shortest duration possible; consider ultrasound monitoring of amniotic fluid if treatment extends beyond 48 hours and discontinue the NSAID if oligohydramnios is found (FDA 2020). Because NSAIDs may cause premature closure of the ductus arteriosus, product labeling for celecoxib specifically states use should be avoided starting at 30 weeks' gestation.
Based on available information, NSAIDs can be continued during the first 2 trimesters of pregnancy in patients with rheumatic and musculoskeletal diseases; use in the third trimester is not recommended (ACR [Sammaritano 2020]).
NSAIDs may be used as part of a multimodal approach to pain relief following cesarean delivery (ACOG 2019).
Celecoxib is present in breast milk.
The relative infant dose (RID) of celecoxib is 1.7% when calculated using the highest breast milk concentration located and compared to a weight-adjusted maternal dose of 200 mg/day.
In general, breastfeeding is considered acceptable when the RID of a medication is <10% (Anderson 2016; Ito 2000).
The RID of celecoxib was calculated using a milk concentration of 330 ng/mL, providing an estimated infant dose via breast milk of 0.05 mg/kg/day. This milk concentration was obtained following maternal administration of celecoxib 200 mg as a single oral dose to 6 postpartum women (Gardiner 2006). In 1 study, the half-life of celecoxib in breast milk was calculated to be 4 to 6.5 hours (Knoppert 2003). Peak breast milk concentrations occurred between 2 and 4 hours after the maternal dose (Gardner 2006; Hale 2004).
Adverse events were not observed in 2 breastfeeding infants 17 and 22 months of age (Hale 2004).
Nonopioid analgesics, including nonsteroidal anti-inflammatory drugs (NSAIDs), are preferred for breastfeeding patients who require pain control peripartum or for surgery outside of the postpartum period (ABM [Martin 2018]; ABM [Reece-Stremtan 2017]) and short-term use of celecoxib is considered acceptable (ABM [Reece-Stremtan 2017]). NSAIDs are considered compatible for the treatment of rheumatic and musculoskeletal diseases in lactating patients; agents with a short half-life and established safety data in infants may be preferred (ACR [Sammaritano 2020]).
According to the manufacturer, the decision to breastfeed during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and benefits of treatment to the mother. Maternal use of NSAIDs should be avoided if the breastfeeding infant has platelet dysfunction, thrombocytopenia, or a ductal-dependent cardiac lesion (ABM [Martin 2018]; ABM [Reece-Stremtan 2017]; Bloor 2013).
CBC; hemoglobin/hematocrit (anemic patients); basic metabolic panel; occult blood loss and periodic liver function tests; monitor renal function (urine output, serum BUN and creatinine); monitor response (pain, range of motion, grip strength, mobility, ADL function), inflammation; blood pressure (baseline and during treatment); observe for weight gain, edema; observe for bleeding, bruising; evaluate gastrointestinal effects (abdominal pain, bleeding, dyspepsia)
JIA: Monitor for development of abnormal coagulation tests with systemic onset JIA
Inhibits prostaglandin synthesis by decreasing the activity of the enzyme, cyclooxygenase-2 (COX-2), which results in decreased formation of prostaglandin precursors; has antipyretic, analgesic, and anti-inflammatory properties. Celecoxib does not inhibit cyclooxygenase-1 (COX-1) at therapeutic concentrations.
Absorption: Prolonged due to low solubility
Distribution: Vd (apparent): Children and Adolescents ~7-16 years (steady-state): 8.3 ± 5.8 L/kg (Stempak 2002); Adults: ~400 L
Protein binding: ~97% primarily to albumin; binds to alpha1-acid glycoprotein to a lesser extent
Metabolism: Hepatic via CYP2C9; forms inactive metabolites (a primary alcohol, corresponding carboxylic acid, and its glucuronide conjugate)
Bioavailability: Absolute: Unknown
Half-life elimination: Children and Adolescents ~7-16 years (steady-state): 6 ± 2.7 hours (range: 3-10 hours) (Stempak 2002); Adults: ~11 hours (fasted)
Time to peak: Children: Median: 3 hours (range: 1-5.8 hours) (Stempak 2002); Adults: ~3 hours
Excretion: Feces (~57% as metabolites, <3% as unchanged drug); urine (27% as metabolites, <3% as unchanged drug); primary metabolites in feces and urine: Carboxylic acid metabolite (73% of dose); low amounts of glucuronide metabolite appear in urine
Renal function impairment: AUC is approximately 40% lower in patients with a CrCl of 35 to 60 mL/minute.
Hepatic function impairment: AUC is increased approximately 40% in patients with mild impairment and 180% in patients with moderate impairment.
Pediatric: The AUC and Cmax following administration of a capsule contents sprinkled on applesauce were reported to be similar as administration of an intact capsule (Krishnaswami 2012).
Geriatric: Cmax is 40% higher and AUC is 50% higher.
Race: AUC is approximately 40% higher in black compared with white patients.
Capsules (CeleBREX Oral)
50 mg (per each): $4.76
100 mg (per each): $10.19
200 mg (per each): $16.72
400 mg (per each): $25.08
Capsules (Celecoxib Oral)
50 mg (per each): $2.14 - $2.16
100 mg (per each): $4.37 - $4.62
200 mg (per each): $0.33 - $7.58
400 mg (per each): $11.07 - $11.37
Solution (Elyxyb Oral)
120MG/4.8ML (per mL): $33.75
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