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 treatment and may increase with duration of use.
Ketoprofen 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 greater risk for serious GI events.
Note: The enteric coated tablet and ER formulations are not recommended for the treatment of acute pain. Lower doses should be considered in small or debilitated patients.
Oral:
Ankylosing spondylitis (off-label): 100 mg twice daily (Dougados 2001).
Rheumatoid arthritis or osteoarthritis:
Immediate release: 50 mg 4 times daily or 75 mg 3 times daily; maximum: 300 mg/day.
Enteric coated [Canadian product]: Usual dose: 50 mg 3 or 4 times daily; up to 200 mg daily; twice daily regimen (eg, 100 mg twice daily) may be considered after maintenance dose is established; maximum: 300 mg/day.
Extended release: 200 mg once daily; maximum: 200 mg/day.
Dysmenorrhea, pain: Immediate release: 25 to 50 mg every 6 to 8 hours up to a maximum of 300 mg/day.
Rectal suppository [Canadian product]: Ankylosing spondylitis, osteoarthritis, or rheumatoid arthritis: Insert one suppository rectally in the morning and evening (twice daily) or at bedtime (once daily). May supplement with divided oral dosing up to a combined rectal/oral maximum of 200 mg daily; for severe rheumatic activity or an inadequate response to lower dosages, a combined rectal/oral dose up to 300 mg daily may be considered.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
In general, NSAIDs are not recommended for use in patients with advanced renal disease.
Manufacturer’s labeling:
GFR ≥25 mL/minute/1.73 m2: There are no specific dosage adjustments provided in the manufacturer’s labeling. In patients with mild impairment, the manufacturer’s labeling recommends a maximum dose of 150 mg/day.
GFR <25 mL/minute/1.73 m2: There are no specific dosage adjustments provided in the manufacturer’s labeling. Maximum dose: 100 mg/day
KDIGO 2012 guidelines provide the following recommendations for NSAIDs:
eGFR 30 to <60 mL/minute/1.73 m2: Temporarily discontinue in patients with intercurrent disease that increases risk of acute kidney injury. Prolonged therapy is not recommended.
eGFR <30 mL/minute/1.73 m2: Avoid use.
Hepatic impairment and serum albumin <3.5 g/dL: Maximum initial dose: 100 mg/day
Oral: An initial dose reduction of 33% to 50% has been recommended (Ketoprofen Canadian product labeling 2011); use with caution.
Rectal suppository [Canadian product]: There are no specific dosing adjustments provided in the manufacturer's labeling however an initial dose reduction is recommended.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product
Capsule, Oral:
Generic: 25 mg, 50 mg [DSC], 75 mg
Capsule Extended Release 24 Hour, Oral:
Generic: 200 mg
Yes
Active-Ketoprofen, Frotek, and Ketophene Rapidpaq creams are compounded from a kit. Refer to manufacturer’s labeling for compounding instructions.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product
Capsule, Oral:
Generic: 50 mg
Capsule Extended Release 24 Hour, Oral:
Generic: 200 mg [DSC]
Solution, Injection:
Anafen: 10 mg/mL ([DSC])
Suppository, Rectal:
Generic: 50 mg ([DSC]); 100 mg ([DSC])
Tablet, Oral:
Anafen: 5 mg [DSC], 20 mg [DSC]
Tablet Delayed Release, Oral:
Generic: 50 mg, 100 mg
Tablet Extended Release 24 Hour, Oral:
Generic: 200 mg
An FDA-approved patient medication guide, which is available with the product information and at http://www.fda.gov/downloads/Drugs/DrugSafety/UCM387559.pdf, must be dispensed with this medication.
Oral: Administer with food to reduce GI upset. Do not crush or break ER capsules.
Bariatric surgery: Capsule, extended release: Some institutions may have specific protocols that conflict with these recommendations; refer to institutional protocols as appropriate. Nonsteroidal anti-inflammatory drugs are not recommended for routine use after bariatric surgery. Where possible, cyclooxygenase-2 selective therapy should be used.
Rectal suppository [Canadian product]: Insert suppository rectally.
Osteoarthritis: Management of the signs and symptoms of osteoarthritis
Pain (immediate release only): Management of pain
Primary dysmenorrhea (immediate release only): Treatment of primary dysmenorrhea
Rheumatoid arthritis: Management of the signs and symptoms of rheumatoid arthritis
Ankylosing spondylitis
Ketoprofen may be confused with ketotifen
Beers Criteria: Ketoprofen is identified in the Beers Criteria as a potentially inappropriate medication to be avoided for chronic use in patients 65 years and older (unless alternative agents ineffective and patient can receive concomitant gastroprotective agent) due to increased risk of GI bleeding and peptic ulcer disease in older adults in high risk category (eg, older than 75 years of age or receiving concomitant oral/parenteral corticosteroids, anticoagulants, or antiplatelet agents) (Beers Criteria [AGS 2019]).
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.
>10%:
Gastrointestinal: Dyspepsia (11%)
Hepatic: Abnormal hepatic function tests (≤15%)
1% to 10%:
Dermatologic: Skin rash (>1%)
Gastrointestinal: Abdominal pain (3% to 9%), anorexia (>1%), constipation (3% to 9%), diarrhea (3% to 9%), flatulence (3% to 9%), nausea (3% to 9%), stomatitis (>1%), vomiting (>1%)
Genitourinary: Urinary tract irritation (>1%)
Nervous system: Abnormal dreams, depression, dizziness (>1%), drowsiness, headache (3% to 9%), insomnia, malaise, nervousness
Ophthalmic: Visual disturbance (>1%)
Otic: Tinnitus (>1%)
Renal: Renal insufficiency (3% to 9%; including increased blood urea nitrogen)
<1%:
Cardiovascular: Acute myocardial infarction, cardiac arrhythmia, cardiac failure, edema, facial edema, hypertension, palpitations, peripheral vascular disease, shock, tachycardia, vasodilation
Dermatologic: Alopecia, bullous rash, diaphoresis, eczema, erythema multiforme, exfoliative dermatitis, onycholysis, pruritus, skin discoloration, skin photosensitivity, Stevens-Johnson syndrome, toxic epidermal necrolysis, urticaria
Endocrine & metabolic: Change in libido, exacerbation of diabetes mellitus, gynecomastia, hyponatremia, increased thirst, microvesicular steatosis, weight gain, weight loss
Gastrointestinal: Buccal necrosis, dysgeusia, eructation, gastritis, gastrointestinal hemorrhage, gastrointestinal perforation, gastrointestinal ulcer, hematemesis, increased appetite, melena, occult blood in stools, pancreatitis, peptic ulcer, salivation, ulcerative colitis, xerostomia
Genitourinary: Hematuria, impotence, nephrotic syndrome, uterine hemorrhage
Hematologic & oncologic: Agranulocytosis, anemia, disorder of hemostatic components of blood, hemolysis, purpuric disease, purpuric rash, rectal hemorrhage, thrombocytopenia
Hepatitis: Cholestatic hepatitis, hepatitis, jaundice
Hypersensitivity: Anaphylaxis, hypersensitivity reaction
Infection: Infection, septicemia
Nervous system: Amnesia, aseptic meningitis, chills, confusion, dysphoria, hallucination, migraine, nightmares, paresthesia, personality disorder, vertigo
Neuromuscular & skeletal: Myalgia
Ophthalmic: Conjunctivitis, dry eye syndrome, eye pain, retinal hemorrhage, retinal pigment changes
Otic: Auditory impairment
Renal: Acute renal tubular disease, interstitial nephritis, renal failure syndrome
Respiratory: Bronchospasm, dyspnea, epistaxis, hemoptysis, laryngeal edema, pharyngitis, rhinitis
Frequency not defined:
Cardiovascular: Cerebrovascular accident, coronary thrombosis
Gastrointestinal: Gastrointestinal inflammation
Postmarketing:
Hepatic: Hepatotoxicity (idiosyncratic) (Chalasani 2014)
Immunologic: Drug rash with eosinophilia and systemic symptoms
Hypersensitivity to ketoprofen or any component of the formulation; history of asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs; use in the setting of CABG surgery
Canadian labeling: Additional contraindications (not in US labeling): Active peptic ulcer or active inflammatory disease of the GI tract; inflammatory lesions or recent bleeding of the rectum or anus (suppository only)
Concerns related to adverse effects:
• Anaphylactoid reactions: Even in patients without prior exposure anaphylactoid reactions may occur; patients with "aspirin triad" (bronchial asthma, aspirin intolerance, rhinitis) may be at increased risk. Contraindicated in patients who experience bronchospasm, asthma, rhinitis, or urticaria with nonsteroidal anti-inflammatory drug (NSAID) 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 serious cardiovascular thrombotic events (which may occur early during treatment) was higher in patients with known cardiovascular disease or risk factors and in those receiving higher doses. New onset hypertension or exacerbation of hypertension may occur (NSAIDs may also impair response to ACE inhibitors, thiazide diuretics, or loop diuretics); may contribute to cardiovascular events; monitor blood pressure; use with caution in patients with hypertension. May cause sodium and fluid retention, use with caution in patients with edema. Avoid use in heart failure (ACCF/AHA [Yancy 2013]). Avoid use in patients with a recent MI unless benefits outweigh risk of cardiovascular thrombotic events. 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.
• CNS effects: May cause drowsiness, dizziness, blurred vision, and other neurologic effects which may impair physical or mental abilities; patients must be cautioned about performing tasks which require mental alertness (eg, operating machinery or driving).
• 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 increased risk of serious GI 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 of serious GI events. These events may occur at any time during therapy and without warning. Avoid use in patients with active GI bleeding. In patients with a history of acute lower GI bleeding, avoid use of non-aspirin NSAIDs, especially if due to angioectasia or diverticulosis (Strate 2016). 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), advanced hepatic disease, coagulopathy, 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 GI complications (eg, ulcer) occurs; concomitant gastroprotective therapy (eg, proton pump inhibitors) is recommended (Bhatt 2008).
• Hematologic effects: Platelet adhesion and aggregation may be decreased; may prolong bleeding time; patients with coagulation disorders or who are receiving anticoagulants should be monitored closely. Anemia may occur; patients on long-term NSAID therapy should be monitored for anemia. Rarely, NSAID use has been associated with potentially severe blood dyscrasias (eg, agranulocytosis, thrombocytopenia, aplastic anemia).
• Hepatic effects: 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 immediately if signs or symptoms of hepatic disease develop or if systemic manifestations occur.
• Hyperkalemia: NSAID use may increase the risk of hyperkalemia, particularly in the elderly, diabetics, renal disease, and with concomitant use of other agents capable of inducing hyperkalemia (eg, ACE-inhibitors). Monitor potassium closely.
• Ophthalmic events: Blurred/diminished vision has been reported; discontinue therapy and refer for ophthalmologic evaluation if symptoms occur. Periodic ophthalmic exams may be necessary with prolonged use.
• Renal effects: NSAID use may compromise existing renal function; dose-dependent decreases in prostaglandin synthesis may result from NSAID use, reducing renal blood flow which may cause renal decompensation (usually reversible). Patients with impaired renal function, dehydration, hypovolemia, heart failure, hepatic impairment, those taking diuretics, and ACE inhibitors, and the elderly are at greater risk of renal toxicity. Rehydrate patient before starting therapy; monitor renal function closely. Long-term NSAID use may result in renal papillary necrosis and other renal injury.
• Skin reactions: NSAIDs may cause potentially fatal serious skin adverse events including exfoliative dermatitis, Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN); may occur without warning; discontinue use at first sign of skin rash (or any other hypersensitivity).
Disease-related concerns:
• Aseptic meningitis: May increase the risk of aseptic meningitis, especially in patients with systemic lupus erythematosus (SLE) and mixed connective tissue disorders.
• Asthma: Contraindicated in patients with aspirin-sensitive asthma; severe and potentially fatal bronchospasm may occur. Use caution in patients with other forms of asthma.
• 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]: Use is contraindicated in the setting of coronary artery bypass graft (CABG) surgery. Risk of MI and stroke may be increased with use following CABG surgery.
• Hepatic impairment: Use with caution in patients with hepatic impairment; patients with advanced hepatic disease are at an increased risk of GI bleeding with NSAIDs. Systemic exposure may be increased in patients with chronic disease and/or hypoalbuminemia. Closely monitor patients with any abnormal liver function test (LFT).
• Renal impairment: Avoid use in patients with advanced renal disease; discontinue use with persistent or worsening abnormal renal function tests.
Special populations:
• Elderly: Elderly patients are at greater risk for serious GI, cardiovascular, and/or renal adverse events; use with caution.
Other warnings/precautions:
• Surgical/dental procedures: Withhold for at least 4 to 6 half-lives prior to surgical or dental procedures.
Substrate of OAT1/3; Inhibits OAT1/3
5-Aminosalicylic Acid Derivatives: Nonsteroidal Anti-Inflammatory Agents may enhance the nephrotoxic effect of 5-Aminosalicylic Acid Derivatives. Risk C: Monitor therapy
Abrocitinib: Agents with Antiplatelet Properties may enhance the antiplatelet effect of Abrocitinib. Management: Do not use antiplatelet drugs with abrocitinib during the first 3 months of abrocitinib therapy. The abrocitinib prescribing information lists this combination as contraindicated. This does not apply to low dose aspirin (81 mg/day or less). Risk X: Avoid combination
Acalabrutinib: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy
Acemetacin: May enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents. Risk X: Avoid combination
Agents with Antiplatelet Properties (e.g., P2Y12 inhibitors, NSAIDs, SSRIs, etc.): May enhance the antiplatelet effect of other Agents with Antiplatelet Properties. 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
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: Agents with Antiplatelet Properties may enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy
Apixaban: Nonsteroidal Anti-Inflammatory Agents (Nonselective) may enhance the adverse/toxic effect of Apixaban. Specifically, the risk of bleeding may be increased. Management: A comprehensive risk to benefit assessment should be done for all patients before any concurrent use of apixaban and nonsteroidal anti-inflammatory drugs (NSAIDs). If combined, monitor patients extra closely for signs and symptoms of 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
Bemiparin: Agents with Antiplatelet Properties may enhance the anticoagulant effect of Bemiparin. Management: Avoid concomitant use of bemiparin with antiplatelet agents. 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
Cephalothin: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Cephalothin. Specifically, the risk for bleeding may be increased. Risk C: Monitor therapy
Collagenase (Systemic): Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Collagenase (Systemic). Specifically, the risk of injection site bruising and or bleeding may be increased. Risk C: Monitor therapy
Corticosteroids (Systemic): May enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents (Nonselective). 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
Dabigatran Etexilate: Nonsteroidal Anti-Inflammatory Agents (Nonselective) may enhance the adverse/toxic effect of Dabigatran Etexilate. Specifically, the risk of bleeding may be increased. Management: A comprehensive risk to benefit assessment should be done for all patients before any concurrent use of dabigatran and nonsteroidal anti-inflammatory drugs (NSAIDs). If combined, monitor patients extra closely for signs and symptoms of bleeding. Risk D: Consider therapy modification
Dasatinib: May enhance the anticoagulant effect of Agents with Antiplatelet Properties. 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
Deoxycholic Acid: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Deoxycholic Acid. Specifically, the risk for bleeding or bruising in the treatment area may be increased. Risk C: Monitor therapy
Desmopressin: Nonsteroidal Anti-Inflammatory Agents may enhance the hyponatremic effect of Desmopressin. Risk C: Monitor therapy
Dichlorphenamide: OAT1/3 Inhibitors may increase the serum concentration of Dichlorphenamide. 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
Edoxaban: Nonsteroidal Anti-Inflammatory Agents (Nonselective) may enhance the adverse/toxic effect of Edoxaban. Specifically, the risk of bleeding may be increased. Management: A comprehensive risk to benefit assessment should be done for all patients before any concurrent use of edoxaban and nonsteroidal anti-inflammatory drugs (NSAIDs). If combined, monitor patients extra closely for signs and symptoms of bleeding. Risk D: Consider therapy modification
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
Enoxaparin: Agents with Antiplatelet Properties may enhance the anticoagulant effect of Enoxaparin. Management: Discontinue antiplatelet agents 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
Fexinidazole: May increase the serum concentration of OAT1/3 Substrates (Clinically Relevant). Management: Avoid use of fexinidazole with OAT1/3 substrates when possible. If combined, monitor for increased OAT1/3 substrate toxicities. Risk D: Consider therapy modification
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
Heparin: Agents with Antiplatelet Properties may enhance the anticoagulant effect of Heparin. Management: Decrease the dose of heparin or agents with antiplatelet properties 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 Agents with Antiplatelet Properties. Bleeding may occur. Risk C: Monitor therapy
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
Ibritumomab Tiuxetan: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Ibritumomab Tiuxetan. Both agents may contribute to impaired platelet function and an increased risk of bleeding. Risk C: Monitor therapy
Ibrutinib: May enhance the adverse/toxic effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy
Icosapent Ethyl: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy
Inotersen: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. 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
Limaprost: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy
Lipid Emulsion (Fish Oil Based): May enhance the adverse/toxic effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy
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
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
Macimorelin: Nonsteroidal Anti-Inflammatory Agents may diminish the diagnostic effect of Macimorelin. 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
Multivitamins/Fluoride (with ADE): May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy
Multivitamins/Minerals (with ADEK, Folate, Iron): May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy
Multivitamins/Minerals (with AE, No Iron): May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy
Naftazone: May enhance the antiplatelet effect of Nonsteroidal Anti-Inflammatory Agents. Risk C: Monitor therapy
Nitisinone: May increase the serum concentration of OAT1/3 Substrates (Clinically Relevant). 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
Obinutuzumab: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Obinutuzumab. Specifically, the risk of serious bleeding-related events may be increased. Risk C: Monitor therapy
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
Omega-3 Fatty Acids: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy
Pentosan Polysulfate Sodium: May enhance the adverse/toxic effect of Agents with Antiplatelet Properties. Specifically, the risk of bleeding may be increased by concurrent use of these agents. Risk C: Monitor therapy
Pentoxifylline: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. 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
Pretomanid: May increase the serum concentration of OAT1/3 Substrates (Clinically Relevant). Risk C: Monitor therapy
Probenecid: May increase the serum concentration of Ketoprofen. Risk C: Monitor therapy
Prostacyclin Analogues: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. 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
Rivaroxaban: Nonsteroidal Anti-Inflammatory Agents (Nonselective) may enhance the adverse/toxic effect of Rivaroxaban. Specifically, the risk of bleeding may be increased. Management: A comprehensive risk to benefit assessment should be done for all patients before any concurrent use of rivaroxaban and nonsteroidal anti-inflammatory drugs (NSAIDs). If combined, monitor patients extra closely for signs and symptoms of bleeding. Risk D: Consider therapy modification
Salicylates: Nonsteroidal Anti-Inflammatory Agents (Nonselective) may enhance the adverse/toxic effect of Salicylates. An increased risk of bleeding may be associated with use of this combination. Nonsteroidal Anti-Inflammatory Agents (Nonselective) may diminish the cardioprotective effect of Salicylates. Salicylates may decrease the serum concentration of Nonsteroidal Anti-Inflammatory Agents (Nonselective). Management: Nonselective NSAIDs may reduce aspirin's cardioprotective effects. Administer ibuprofen 30-120 minutes after immediate-release aspirin, 2 to 4 hours after extended-release aspirin, or 8 hours before aspirin. Risk D: Consider therapy modification
Selective Serotonin Reuptake Inhibitors: May enhance the antiplatelet effect of Nonsteroidal Anti-Inflammatory Agents (Nonselective). Nonsteroidal Anti-Inflammatory Agents (Nonselective) may diminish the therapeutic effect of Selective Serotonin Reuptake Inhibitors. Management: Consider alternatives to NSAIDs. Monitor for evidence of bleeding and diminished antidepressant effects. It is unclear whether COX-2-selective NSAIDs reduce risk. Risk D: Consider therapy modification
Selumetinib: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy
Serotonin/Norepinephrine Reuptake Inhibitors: May enhance the antiplatelet effect of Nonsteroidal Anti-Inflammatory Agents (Nonselective). 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 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
Teriflunomide: May increase the serum concentration of OAT1/3 Substrates (Clinically Relevant). Risk C: Monitor therapy
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
Thrombolytic Agents: Agents with Antiplatelet Properties may enhance the anticoagulant effect of Thrombolytic Agents. Risk C: Monitor therapy
Tipranavir: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy
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 adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents (Nonselective). Specifically, the risk of major adverse cardiovascular events may be increased. Tricyclic Antidepressants (Tertiary Amine) may enhance the antiplatelet effect of Nonsteroidal Anti-Inflammatory Agents (Nonselective). Risk C: Monitor therapy
Urokinase: Agents with Antiplatelet Properties may enhance the anticoagulant effect of Urokinase. Risk X: Avoid combination
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
Vitamin E (Systemic): May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy
Vitamin K Antagonists (eg, warfarin): Nonsteroidal Anti-Inflammatory Agents (Nonselective) may enhance the anticoagulant effect of Vitamin K Antagonists. Management: Consider alternatives to this combination when possible. If the combination must be used, monitor coagulation status closely and advise patients to promptly report any evidence of bleeding or bruising. Risk D: Consider therapy modification
Zanubrutinib: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy
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 (Matyas 2015; Micu 2011).
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]).
Ketoprofen crosses the placenta (Bannwarth 1999).
Birth defects have been observed following in utero nonsteroidal anti-inflammatory drug (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, prescribing information for ketoprofen 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).
Ketoprofen is present in breast milk (Jacqz-Aigrain 2007).
One case each of esophageal ulcer, erosive gastritis, meningeal hemorrhage, and renal insufficiency following ketoprofen exposure via breast milk were spontaneously reported to the French Pharmacoviligance Database between 1984 and 2011 (Soussan 2014).
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]). 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]).
Breastfeeding is not recommended by the manufacturer. 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).
To minimize gastrointestinal effects, administer with food or milk.
CBC (periodically during long-term therapy or if develop signs/symptoms of anemia); chemistry profile (periodically during long-term therapy); weight gain or edema in patients with predisposing conditions, such as heart failure; signs of bleeding (occult or gross blood loss); periodic liver function tests; renal function (urine output, serum BUN, creatinine); blood pressure; periodic ophthalmic exams in patients receiving prolonged therapy
Reversibly inhibits cyclooxygenase-1 and 2 (COX-1 and 2) enzymes, which results in decreased formation of prostaglandin precursors; has antipyretic, analgesic, and anti-inflammatory properties
Other proposed mechanisms not fully elucidated (and possibly contributing to the anti-inflammatory effect to varying degrees), include inhibiting chemotaxis, altering lymphocyte activity, inhibiting neutrophil aggregation/activation, and decreasing proinflammatory cytokine levels.
Onset of action: Regular release: <30 minutes
Duration: Regular release: Up to 6 hours
Absorption: Almost complete
Distribution: 0.1 L/kg
Protein binding: >99%, primarily to albumin; Hepatic impairment: Unbound fraction is approximately doubled
Metabolism: Hepatic via glucuronidation; metabolite (inactive) can be converted back to parent compound; may have enterohepatic recirculation
Bioavailability: ~90%
Half-life elimination:
Regular release: 2 to 4 hours; Renal impairment: Mild: 3 hours; moderate to severe: 5 to 9 hours
Enteric coated tablet [Canadian product]: 2 hours
Extended release: ~3 to 7.5 hours
Rectal suppository [Canadian product]: ~2 to 2.5 hours
Time to peak, serum:
Regular release: 0.5 to 2 hours
Enteric coated tablet [Canadian product]: 1 to 2 hours
Extended release capsule: 6 to 7 hours; Extended release tablet [Canadian product]: 5 to 6 hours
Rectal suppository [Canadian product]: ~1 hour
Excretion: Urine (~80%, primarily as glucuronide conjugates)
Renal function impairment: Clearance is decreased and half-life is prolonged.
Hepatic function impairment: Unbound fraction is approximately doubled, probably due to hypoalbuminemia.
Geriatric: Plasma and renal clearance are reduced and the unbound fraction increases.
Capsule ER 24 Hour Therapy Pack (Ketoprofen ER Oral)
200 mg (per each): $10.82
Capsules (Ketoprofen Oral)
25 mg (per each): $14.96
75 mg (per each): $1.60
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