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Home , Antipyretic, Celecoxib, Diclofenac, Diflunisal, Etodolac, Floctafenine

Nonsteroidal Anti-inflammatory Drugs (NSAIDs) (CPhA Monograph) https://myrxtx.ca/print/new/documents/MONOGRAPH/en/NSAIDsCPhA

Health Canada Advisories

New safety information for prescription-strength : Risk of heart attack and at high doses. (2015-04)

Nonsteroidal Anti-inflammatory Drugs (NSAIDs) ASA—— diethylamine—diclofenac potassium—diclofenac sodium———— —ibuprofen—indomethacin—— tromethamine—mefenamic ————naproxen sodium ————— Anti-inflammatory——— Aggregation Inhibitor

CPhA Monograph

Date of Revision: October 2014

This monograph has been compiled by CPhA and reviewed by experts. It may contain information different from that found in Health Canada– Approved Product Monographs. The reader is referred to the CPS Editorial Policy for more information.

For additional information regarding acetylsalicylic acid (ASA) please consult the ASA monograph.

Summary Product Information

Drug Strength

Celecoxib Oral 100 mg, 200 mg

Diclofenac diethylamine[a] Topical 1.16% (11.6 mg/g), 2.32% (23.2 mg/g)

Diclofenac potassium Oral 50 mg

Powder for oral solution 50 mg/packet

Diclofenac sodium[b] Ophthalmic Solution 0.1%

Oral Enteric-coated tablet 25 mg, 50 mg

Sustained-release tablet 75 mg, 100 mg

Rectal 50 mg, 100 mg

Topical Solution 1.5%

Diflunisal Oral Tablet 250 mg, 500 mg

Etodolac Oral Capsule 200 mg, 300 mg

Floctafenine Oral Tablet 200 mg, 400 mg

Flurbiprofen Oral Tablet 50 mg, 100 mg

Ibuprofen[b] Intravenous Solution 100 mg/mL[c]

Oral Capsule 200 mg,[a] 400 mg[a]

Suspension 100 mg/5 mL[a]

Suspension (drops) 200 mg/5 mL[a]

Tablet 200 mg,[a] 300 mg,[a] 400 mg,[a] 600 mg

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Drug Route of Administration Dosage Form Strength

Tablet (chewable) 50 mg,[a] 100 mg[a]

Indomethacin Oral Capsule 25 mg, 50 mg

Rectal Suppository 50 mg, 100 mg

Ketoprofen Oral Capsule 50 mg

Enteric-coated tablet 50 mg, 100 mg

Sustained-release tablet 200 mg

Ketorolac tromethamine Ophthalmic Solution 0.4%, 0.45%, 0.5%

Oral Tablet 10 mg

Parenteral (im) Solution 10 mg/mL, 30 mg/mL

Mefenamic acid Oral Capsule 250 mg

Meloxicam Oral Tablet 7.5 mg, 15 mg

Nabumetone Oral Tablet 500 mg

Naproxen[b] Oral Tablet 125 mg, 250 mg, 375 mg, 500 mg

Enteric-coated tablet 250 mg, 375 mg, 500 mg

Sustained-release tablet 750 mg

Suspension 25 mg/mL

Rectal Suppository 500 mg

Naproxen sodium Oral Capsule 220 mg[a]

Tablet 220 mg,[a] 275 mg, 550 mg

Nepafenac Ophthalmic Suspension 0.1%, 0.3%

Piroxicam Oral Capsule 10 mg, 20 mg

Sulindac Oral Tablet 150 mg, 200 mg

Tenoxicam Oral Tablet 20 mg

Tiaprofenic acid Oral Tablet 200 mg, 300 mg

[a] Available without a prescription. [b] Also available in combination products. Consult Health Canada's Drug Product Database [webprod5.hc-sc.gc.ca/dpd-bdpp/index-eng.jsp]. [c] Does not require a prescription but is generally prescribed by a medical practitioner.

Indications and Clinical Use

As anti-inflammatory, analgesic and antipyretic agents, NSAIDs provide symptomatic relief but do not cure the underlying disease. No NSAID has been proven superior for symptom relief. The choice of drug depends on individual risk factors such as NSAID toxicity, individual patient response, compliance potential, dosage forms, cost and available evidence. For compliance, drugs with a long half-life or available in dosage forms that allow once-daily dosing are preferred (diclofenac, ketoprofen, meloxicam, nabumetone, naproxen, tenoxicam).

Health Canada-approved Indications

Chronic treatment of inflammatory disorders including rheumatoid , and .

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Short-term treatment of mild to moderate associated with . NSAIDs are effective for musculoskeletal pain, such as muscle and joint pain, dental pain, post-operative pain, muscle strains and . For rapid pain relief, NSAIDs with a fast onset are preferred, while enteric-coated and sustained-release products are less suitable (see Table 7). Short-term treatment of pain due to . No NSAID has been shown to have superior efficacy in primary dysmenorrhea [Cochrane Database Syst Rev 2010;(1):CD001751]. Short-term treatment of . Agents with a fast onset are preferred (see Table 7). Diclofenac powder for oral solution is approved for treatment of acute attacks with or without aura. Indomethacin and sulindac are approved for the treatment of acute attacks of gouty arthritis. Ketorolac is approved for short-term treatment of severe pain following major . Diclofenac, ketorolac and nepafenac ophthalmic drops are approved for relief of pain and inflammation in surgery. Diclofenac and ketorolac are also approved for relief of pain and inflammation in ocular trauma.

Pediatrics

Only ibuprofen and naproxen are approved for use in children (see Table 1). Treatment of juvenile .

Table 1: Health Canada-approved Indications Anti-inflammatory/Analgesic Antipyretic

Moderate to Mild to Severe Moderate Pain Pain Including Accompanied After Rheumatoid Ankylosing by Major Drug Arthritis Osteoarthritis Spondylitis Ophthalmic Dysmenorrhea Inflammation Surgery Fever

Celecoxib Yes Yes Yes — — — Yes —

Diclofenac ————— Yes—— diethylamine

Diclofenac ————— Yes—— potassium

Diclofenac Yes Yes — Yes — — — — sodium

Diflunisal Yes Yes — — — Yes — —

Etodolac Yes Yes — — — — — —

Floctafenine — — — — — Yes — —

Flurbiprofen Yes Yes Yes — Yes Yes — —

Ibuprofen — — — — Yes Yes[a][b] Yes[c] Yes[a]

Indomethacin[d] Yes Yes Yes — — Yes — —

Ketoprofen Yes Yes Yes — Yes Yes — —

Ketorolac ———Yes— —Yes— tromethamine

Mefenamic ————YesYes—— acid

Meloxicam Yes Yes — — — — — —

Nabumetone Yes Yes — — — — — —

Naproxen Yes[a] Yes Yes — Yes Yes — —

Naproxen Yes[e] Yes[e] ——Yes[b][f] Yes[b][f] — Yes[b][f] sodium

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Anti-inflammatory/Analgesic Antipyretic

Moderate to Mild to Severe Moderate Pain Pain Including Accompanied After Rheumatoid Ankylosing by Major Drug Arthritis Osteoarthritis Spondylitis Ophthalmic Dysmenorrhea Inflammation Surgery Fever

Nepafenac — — — Yes — — — —

Piroxicam Yes Yes Yes — — — — —

Sulindac[d] Yes Yes Yes — — Yes — —

Tenoxicam Yes Yes Yes — — Yes — —

Tiaprofenic Yes Yes — — — — — — acid

[a] Approved in children for this indication. [b] Nonprescription product available for self-. [c] By iv infusion as adjunct to . [d] Also approved for gouty arthritis. [e] Only the controlled-release product is approved for this indication. [f] Controlled-release product is not approved for this indication.

Uses Without Health Canada Approval

Celecoxib may be effective for reducing the number of adenomatous colonic polyps in patients with familial adenomatous polyposis (FAP) [Cochrane Database Syst Rev 2004;(2):CD004079].

Pediatrics

Indomethacin is part of the treatment of Bartter syndrome [Pediatr Nephrol 2004;19(8):858-63]. Indomethacin iv has been used in premature neonates to close a patent . Indomethacin has also been used as a tocolytic to treat premature labor. There is conflicting evidence whether such use is associated with adverse fetal outcomes including constriction of the ductus arteriosus, impaired renal function and necrotizing enterocolitis [Obstet Gynecol 2005;106(1):173-9].

Ketorolac has been administered by iv and has been given im or iv to children 2 years of age and older.

Ibuprofen may slow the loss of lung function in children with cystic fibrosis who are ≥6 years and with a forced expiratory volume over 1 minute (FEV1) >60% [Am J Respir Crit Care Med 2007;176(10):957-69], [Cochrane Database Syst Rev 2013;(6):CD001501].

Contraindications

Hypersensitivity to the NSAID or to any ingredient in the formulation or component of the container. Perioperative setting of coronary artery bypass graft surgery (CABG) because of the risk of thrombotic events. The exception is low- dose ASA, which is recommended to reduce thrombotic events in the 2011 ACCF/AHA Guideline for Coronary Artery Bypass Graft Surgery [Circulation 2011;124(23):2610-42]. History of or allergic-type reactions after taking NSAIDs or ASA including ASA intolerance and the Triad (asthma, nasal polyps and ASA intolerance), since fatal anaphylactoid reactions are possible. Cross-reactivity among structurally different nonselective NSAIDs occurs. Third trimester of because of possible premature closure of the ductus arteriosus and possible prolonged parturition. Severe uncontrolled since exacerbations can occur. Active gastric, duodenal or peptic ulcers and inflammatory bowel disease, since NSAIDs (including low-dose ASA) can increase the risk of gastrointestinal , and ulceration. Cerebrovascular bleeding and other bleeding disorders because NSAIDs can increase bleeding. Severe impairment because most NSAIDs are metabolized in the liver. Severe renal impairment (ClCr <30 mL/minute) since NSAIDs can cause renal failure, especially in patients who have renal dysfunction. since NSAIDs can cause hyperkalemia. Risk of bleeding increases perioperatively; therefore, discontinue prior to surgery. The exception is low-dose ASA when used perioperatively for antithrombotic effects. Children, with the exceptions noted in Table 1.

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Celecoxib is contraindicated in patients who are allergic to sulfonamides due to its similar structure.

Warnings and Precautions

Serious Warnings and Precautions

NSAIDs have been associated with an increased risk of potentially fatal thrombotic events including and stroke [BMJ 2011;342:c7086]. Until further evidence is available use NSAIDs with caution in patients with pre-existing (except low-dose ASA). Gastrointestinal perforation, ulceration and bleeding, in some cases fatal, have been reported with all systemic NSAIDs. An anaphylactic-like reaction and aseptic meningitis have been reported with high-dose NSAID use in patients with systemic erythematosus.

General

Consider alternative in patients at high risk of gastrointestinal, renal or cardiovascular toxicity. All NSAIDs have the potential to cause similar cardiovascular, CNS, dermatologic, gastrointestinal, hepatic, , renal and reproductive adverse reactions, although the degree of risk may vary among agents. Risk increases with dose, duration and underlying risk factors. Topical and ophthalmic products have a low incidence of systemic effects.

Since reductions in fever can mask serious infections, warn patients to seek medical attention if fever is persistent. Use with caution in acute soft-tissue sports injuries such as tendonitis, since pain relief can lead patients to continue exercising and cause further damage.

Cardiovascular

NSAID use has been associated with an increase in the risk of cardiovascular mortality, myocardial infarction and stroke. Risk increases with dose and duration of use; risk does not decrease with time elapsed since myocardial infarction. Evidence suggests that compared to other NSAIDs, celecoxib. diclofenac and high-dose ibuprofen (2400 mg/day) are associated with more vascular risk and naproxen is associated with the least risk. Use caution when prescribing any NSAID in patients with cardiovascular disease, risk factors for cardiovascular disease, or heart failure (NYHA II-IV). The exception is low-dose ASA when used to prevent thrombotic events.

All NSAIDs can increase blood pressure and worsen pre-existing . All NSAIDs can cause sodium and water retention leading to exacerbation of pre-existing heart failure.

Central Nervous System

Headache and CNS depression can occur with any NSAID. has been reported with most NSAIDs. With ASA, tinnitus is often an early warning sign of excessive use.

Regular use of NSAIDs and acetaminophen (≥2 times per week) may increase the risk of hearing loss in both men and women [Am J Epidemiol 2012;176(6):544-54]. Further study is warranted.

Dependence/Tolerance

Dependence and tolerance do not develop with NSAIDs, in contrast to opioid analgesics.

Dermatologic

Topical products commonly produce local irritation. Serious skin reactions such as Stevens-Johnson syndrome are rare but have been reported for most NSAIDs. Photosensitivity can occur with most NSAIDs, including celecoxib, diclofenac, diflunisal, etodolac, flurbiprofen, ibuprofen, indomethacin, ketoprofen, , meloxicam, nabumetone, naproxen, piroxicam, sulindac, tenoxicam and tiaprofenic acid.

Gastrointestinal

Gastrointestinal toxicity can occur with any NSAID administered by any route at any time during therapy. However, reports of gastrointestinal bleeds are rare with topical products and associated with long-term treatment. Both upper and lower parts of the may be involved. Events can occur without warning, since most patients with serious gastrointestinal events have no symptoms.

The risk of toxicity increases with dose and duration of therapy. Most fatal GI events occur in elderly patients and debilitated patients, and patients with a prior history of peptic ulcers or gastrointestinal bleeding also have a high risk of serious events. Other risk factors include H. pylori infection, use, smoking, the use of multiple NSAIDs and other drug combinations (see Table 3).

To minimize risk, use the lowest effective dose for the shortest possible duration and consider alternative in high-risk patients.

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The risk of serious upper gastrointestinal toxicity may be lower with celecoxib and lower doses of ASA; however, toxicity is reduced but not eliminated. Enteric coating and administration with food do not reduce the risk of upper gastrointestinal bleeds although they may improve tolerance. NSAIDs are commonly combined with gastroprotective agents such as proton pump inhibitors in high-risk patients.

Hematologic

NSAIDs inhibit platelet aggregation and can increase bleeding risk. Use them with caution in patients with platelet disorders or hemophilia or who take drugs (see Table 3). Celecoxib does not inhibit platelet aggregation or prolong bleeding time at usual recommended doses, but serious bleeding has occurred when it has been used in patients taking anticoagulant drugs. Meloxicam does not inhibit platelet aggregation at the recommended dose of 7.5–15 mg daily.

Hepatic/Biliary/Pancreatic

Minor elevations in liver can occur with any NSAID. These may not affect liver function and may resolve despite continued treatment. There have been rare reports of more serious liver damage with all NSAIDs, including fulminant and .

Immune

The risk of aseptic meningitis associated with high-dose NSAIDs may be increased in patients with autoimmune disorders such as systemic lupus erythematosus.

Ophthalmologic

Reversible blurred vision may occur with NSAIDs, including (COX)-2 inhibitors. Use of ophthalmic NSAIDs may lead to keratitis; if patients exhibit corneal epithelial breakdown discontinue and monitor for improvement. The risk of corneal adverse reactions may be increased in some patient populations and with prolonged use of ophthalmic NSAIDs; see individual product monographs for more information.

Renal

Acute renal failure, sodium and potassium retention, renal papillary necrosis and interstitial nephritis have been reported with all NSAIDs. Acute renal failure occurs mainly when renal actively maintain renal function during decreased renal perfusion. Patients at risk include those with hypovolemia, dehydration, , hemorrhage, cirrhosis, heart failure, sodium depletion, pre-existing renal impairment (GFR <60 mL/minute) and those taking certain drugs concurrently (see Table 3). These conditions are more likely to be found in elderly patients. Onset of renal failure may be rapid but is usually reversible if the NSAID is discontinued. Renal function impairment appears to be associated with dose and duration.

Hyperkalemia is probably dose-dependent. Patients at risk for clinical consequences are those with an underlying predisposition to potassium retention such as renal impairment, or who are being co-administered certain drugs (see Table 3).

Respiratory

Nonselective NSAIDs display cross-reactivity in patients with aspirin-induced asthma. Celecoxib has not displayed similar cross- reactivity.

Sensitivity/Resistance

Some NSAID products contain lactose (see individual product monographs). Pennsaid (diclofenac sodium) contains dimethylsulfoxide (DMSO); use with caution in patients with a DMSO . Piroxicam cross-reacts with thimerosal. Celecoxib may cause an allergic reaction in patients with hypersensitivity to sulfonamides.

Sexual Function/Reproduction

Women trying to conceive should be cautious in their use of NSAIDs. synthesis via COX-2 is involved in ovulation, and animal studies indicate a disruption of blastocyst implantation.

Special Populations

Pregnant Women

NSAIDs may be safe for short-term use in the first and second trimester. In the third trimester, all NSAIDs are contraindicated because prostaglandin synthesis inhibition can cause premature closure of the ductus arteriosus, resulting in pulmonary hypertension of the newborn. As well, prostaglandin synthesis inhibition close to delivery can delay and prolong labor by inhibiting uterine contractions. Hemorrhage and impaired fetal renal function are other concerns.

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Nursing Women

Most NSAIDs are known or likely to be excreted in breast milk in small amounts. Preference should be given to NSAIDs considered by the American Academy of Pediatrics and other authorities to be safe for use in lactation: diclofenac (excluding powder for oral solution), flurbiprofen, ibuprofen, indomethacin, ketoprofen, mefenamic acid, naproxen and piroxicam. Agents with a short half-life are preferred.

Pediatrics

Exposure to NSAIDs increases risk of acute injury, even with normal doses [J Pediatr 2013 Jan 26. doi: 10.1016/j.jpeds.2012.11.069. Epub ahead of print]. Ensure proper hydration status of children when on NSAID therapy.

Geriatrics

Elderly patients are more likely to have risk factors for NSAID toxicity and are less able to tolerate adverse reactions if they occur.

Monitoring and Laboratory Tests

In patients on long-term therapy or at risk due to underlying disease or concurrent drugs, monitor at baseline and periodically:

blood pressure in patients with hypertension or the elderly electrolytes and in patients with heart failure and the elderly INR in patients taking hemoglobin in patients at high risk of gastrointestinal toxicity liver enzymes

Occupational Hazards

Patients should avoid driving and operating dangerous machinery if they experience any or drowsiness.

Adverse Reactions

Adverse Drug Reactions Overview

The most common adverse reactions involve gastrointestinal damage, ranging from patient discomfort to potentially fatal gastrointestinal ulceration, bleeding and perforation. Less common but serious cardiovascular, dermatologic, hypersensitivity and renal reactions may occur. COX-2 selectivity does not fully predict the safety profile. Individual patient risk factors (age, disease history) and dosage as well as duration of therapy strongly influence the incidence of NSAID adverse reactions (see Table 2).

Table 2: Adverse Drug Reactions[a] Body System Effect Incidence Clinical Comment

Cardiovascular Myocardial infarction, stroke Up to Risk increases with dose and duration of use. Risk of 1%/person- myocardial infarction and stroke may be higher with year[b] celecoxib, diclofenac and high-dose ibuprofen (2400 mg/day), and lower with naproxen. Hypertension 0.7–3%

Edema 2–9%

Worsening of heart failure <1%

Central Nervous Headache, drowsiness, 1–10% Indomethacin most commonly associated. System dizziness

Tinnitus 1–10% ASA most commonly associated.

Dermatologic 1–10%

Stevens-Johnson syndrome, <1% epidermal necrolysis, erythema multiforme

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Body System Effect Incidence Clinical Comment

Photosensitivity <1%

Gastrointestinal , dyspepsia, 1–14% , anorexia,

Perforation, ulceration, 2–4% per bleeding in upper and lower year GI tract

Hematologic Prolonged bleeding time, ≤10% Chronic blood loss can lead to anemia. Inhibition of anemia platelet aggregation is not reported with celecoxib and meloxicam.

Blood dyscrasias <1–3%

Hepatic/Biliary Elevated liver enzymes 1% Diclofenac most commonly associated with hepatic /Pancreatic (over 3 times ULN) adverse drug reactions.

Hepatitis, liver failure <1%

Hypersensitivity Anaphylactoid reactions, <1% bronchospasm

Neurologic Aseptic meningitis <1% Reported with celecoxib, diclofenac, flurbiprofen, ibuprofen, ketoprofen, mefenamic acid, naproxen, piroxicam and sulindac.

Ophthalmologic Blurred vision <1%

Renal Decreased renal function, <1% acute renal failure

Hyperkalemia >1%

Renal papillary necrosis, <1% interstitial nephritis

Cystitis <2% Increased risk with tiaprofenic acid.

Sexual Function/ Reversible female infertility Rare Reproduction

[a] Incidence depends on dose, duration of therapy, concurrent drug therapy and individual patient characteristics. [b] Person-years refers to the product of the number of years of treatment times the number of members of a population who have been affected by a certain condition. Legend: Abbreviations: ULN=upper limit of normal.

Drug

Drug-Drug Interactions

See Table 3.

Table 3: Drug-Drug Interactions Interacting Drug Effect Clinical Comment

ACE Inhibitors and Decreased antihypertensive effect since Monitor BP, potassium levels and renal function. II NSAIDs can increase BP. Blockers Additive risk of hyperkalemia. NSAID- induced inhibition of renal prostaglandins decreases potassium and maintenance of renal blood flow.

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Interacting Drug Effect Clinical Comment

Additive risk of and renal failure, especially in patients with poor renal perfusion or if are used concurrently.

Beta-adrenergic Blockers Decreased antihypertensive effect since Monitor BP. NSAIDs can increase BP.

Cholestyramine Decreased oral absorption of NSAID. Space doses or avoid. Spacing doses will not prevent the with NSAIDs that undergo enterohepatic recirculation (indomethacin, meloxicam, piroxicam, sulindac).

Corticosteroids Increased risk of gastrointestinal bleeding. Consider gastroprotection in patients at risk. Concomitant ophthalmic administration of Monitor patient during concomitant use of these NSAIDs and may increase agents. the risk of healing complications.

Cyclosporine Additive risk of renal failure. Monitor renal function.

CYP2C9 Inhibitors Increased levels and toxicity of NSAIDs Many NSAIDs are metabolized by CYP2C9 (see (, voriconazole) that are metabolized by CYP2C9. Table 7). Reduce dose of NSAID.

CYP2D6 Substrates Inhibition of CYP2D6 (celecoxib only). Consider alternate therapy or monitor for altered (, , response/adverse effects. metoprolol)

Digoxin Increased digoxin levels with some Diclofenac, etodolac, ibuprofen and indomethacin NSAIDs. may interact with digoxin. Lack of interaction has been found with ketoprofen, meloxicam, piroxicam and tenoxicam.

Diuretics (loop, and Antagonism of therapeutic effect of Monitor BP and potassium levels. potassium-sparing) and increased risk of renal failure; additive risk of hyperkalemia with potassium-sparing diuretics. Mechanism involves sodium and water retention by NSAIDs plus decreased potassium excretion.

Drugs that increase the risk Additive bleeding risk: NSAIDs inhibit Monitor INR in patients taking anticoagulants, of bleeding (anticoagulants, platelet aggregation. Severe bleeding and although bleeding has occurred without a change antiplatelet drugs, heparin, increased PT have been reported when in INR. ASA has a prolonged effect on platelet low-molecular-weight NSAIDs, including celecoxib, have been aggregation, and high doses should be avoided heparins and SSRIs) combined with anticoagulants. with anticoagulants. Low-dose ASA is used with for therapeutic effect.

Lithium Increased levels possibly due to Most NSAIDs can increase lithium levels. ASA decreased renal . does not interact. Monitor lithium levels when starting and stopping NSAIDs other than ASA.

Methotrexate Increased levels and toxicity Avoid combining antineoplastic doses of with antineoplastic doses, possibly due to methotrexate with NSAIDs if possible. Monitor decreased renal tubular secretion. renal function and CBC. Risk is considered less with low methotrexate doses used for arthritis.

NSAIDs Additive risk of toxicity when multiple Avoid combining 2 NSAIDs. Risk of NSAIDs are administered. gastrointestinal bleeding increases, even when low doses of ASA are combined with other NSAIDs. Ibuprofen, naproxen and mefenamic acid may decrease the cardioprotective effect of ASA by binding to the active site on COX; give ASA 2 h before NSAIDs.

Potassium Supplements Additive risk of hyperkalemia. Monitor potassium levels.

Probenecid Increased levels of some NSAIDs. Diflunisal, indomethacin, ketoprofen, ketorolac, naproxen and tenoxicam interact. Monitor for NSAID toxicity.

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Legend: Abbreviations: BP = blood pressure.

Drug-Food Interactions

Oral NSAIDs should be administered with food to reduce gastric irritation.

Drug-Herb Interactions

Ginkgo may cause bleeding and increase the risk of gastrointestinal bleeding with NSAIDs.

Drug-Laboratory Interactions

NSAIDs can increase bleeding time and cause gastrointestinal bleeding with chronic use, which may interfere with the interpretation of fecal occult blood tests.

Table 4: Drug-Laboratory Interactions Interacting Drug Effect

Diflunisal False positive serum salicylate levels

Etodolac False positive reaction for urinary bilirubin

Indomethacin False negatives in the suppression test

Ketoprofen Interference with urine tests for bile salts, albumin, 17-ketosteroids and 17-hydroxycorticosteroids

Mefenamic acid False positive reaction for urinary bilirubin, using the diazo tablet test

Naproxen Interference with urinary tests for 5-hydroxy indoleacetic acid (5HIAA) and urinary analyses of 17-ketogenic

Dosage and Administration

Dosing Considerations

Use the lowest effective dose for the shortest time to reduce risk of gastrointestinal and cardiovascular events. In rheumatoid arthritis, patient response varies among the different NSAIDs. Gradually increase the dose over the first 1–2 weeks. If there is inadequate response or poor tolerance after 4 weeks, switch to a different NSAID. If gastric intolerance occurs, an enteric-coated dosage form may be preferred.

Recommended Dose and Dosage Adjustment

Adults

See Table 5.

Table 5: Dose in Adult Patients Drug Indication Route Usual Dose Maximum Dose

Celecoxib Osteoarthritis or Oral 200 mg daily as a single dose 200 mg daily ankylosing spondylitis or in 2 divided doses

Rheumatoid arthritis Oral 100–200 mg BID 400 mg daily

Acute pain Oral 400 mg single dose on the 400 mg first day, then 100–200 mg Maximum duration: 1 wk daily prn

Familial adenomatous Oral 400 mg BID polyposis

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Drug Indication Route Usual Dose Maximum Dose

(not an approved use in Canada)

Diclofenac Acute joint or muscle Topical 2–4 g applied TID–QID Maximum duration: 1 wk diethylamine pain

Diclofenac Acute pain Oral Usual dose: 50 mg Q6–8H 100 mg daily potassium prn Maximum duration: 1 wk

Acute treatment of Powder for 50 mg (one packet) of One packet per attack. migraine attacks with or oral powder (single dose) Safety of a second dose without aura solution has not been evaluated

Primary Dysmenorrhea Oral Loading dose of 100 mg 200 mg/day on day 1; 100 followed by 50 mg Q6–8H mg/day on days 2–7 prn Maximum duration: 1 wk

Diclofenac sodium Rheumatoid arthritis and Oral Initiate therapy with enteric- 100 mg daily osteoarthritis enteric- coated tablets: 75 mg daily in To minimize the risk of coated 3 divided doses cardiovascular adverse tablet events the lowest effective dose should be used for Oral For maintenance therapy the shortest duration sustained- only: 75 mg or 100 mg daily possible release in the morning or evening tablet

Rectal 50 mg or 100 mg daily suppository Substitute for last oral dose of the day

Osteoarthritis of the Topical 50 drops per knee, TID or 40 knee(s) drops per knee, QID

Cataract surgery Ophthalmic Pre-operatively: instill 1 drop Space instillation of eye up to 5 times during the 3 h drops by at least 5-minute preceding surgery intervals

Post-operatively: instill 1 drop 15, 30 and 45 minutes following surgery, then 3–5 times daily for up to 4 wk

Ocular inflammation Ophthalmic Instill 1 drop 4–5 times daily Space instillation of eye drops by at least 5-minute intervals

Diflunisal Osteoarthritis and Oral 500–1000 mg daily in 2 1000 mg daily rheumatoid arthritis divided doses

Mild to moderate pain Oral 500 mg Q12H

Etodolac Osteoarthritis and Oral 200–300 mg BID 1000 mg daily rheumatoid arthritis If tolerated, 400 mg or 600 mg once daily in the evening

Floctafenine Short-term management Oral 200–400 mg Q6–8H prn 1200 mg daily of acute mild to moderate pain

Flurbiprofen Anti-inflammatory Oral 200 mg daily in 2–3 divided 300 mg daily only for short doses exacerbations

Dysmenorrhea Oral 50 mg QID

Mild to moderate pain Oral 50 mg Q4–6H prn

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Drug Indication Route Usual Dose Maximum Dose

Ibuprofen Analgesic, antipyretic Oral Nonprescription: 200–400 mg 1200 mg daily Q4H prn

IV 400–800 mg Q6H prn 2400 mg daily[a] for fever (3200 mg daily[a] for pain). Must be diluted before use as iv infusion. Do not administer as iv bolus or im

Osteoarthritis and Oral 1200 mg daily in divided 2400 mg daily[a] rheumatoid arthritis doses

Indomethacin Anti-inflammatory Oral or Initially 25 mg BID–TID. 200 mg daily rectal Increase dose by 25 or 50 mg at weekly intervals

Acute gouty arthritis Oral or 50 mg TID 200 mg daily rectal

Acute painful shoulder Oral or 25–50 mg TID 200 mg daily rectal Discontinue after symptoms have been controlled for several days

Patent ductus arteriosus IV[b] Initially 10 mg/kg followed by (not an approved use in 2 doses of 5 mg/kg at 12 or Canada) 24 h intervals

Ketoprofen Osteoarthritis, Oral Initially capsules or enteric- May be switched to rheumatoid arthritis and coated tablets: 150–250 mg sustained-release tablets ankylosing spondylitis daily in 3–4 divided doses 200 mg once daily in the Usual dose: 100 mg BID morning. Total oral doses should not exceed 300 mg daily

Primary dysmenorrhea Oral 25 or 50 mg TID–QID prn 50 mg per dose, 300 mg and mild to moderate daily pain

Ketorolac Analgesic Oral 10 mg Q4–6H prn 40 mg daily tromethamine Maximum: 5 days post- surgical (7 days for musculoskeletal pain) Total dose of oral plus im should not exceed 120 mg daily

IM 10–30 mg Q4–6H prn. 120 mg daily, maximum 2 Patient weight <50 kg: initially days 10 mg per dose Patient weight <50 kg: maximum 60 mg daily

Mefenamic acid Acute pain Oral 500 mg loading dose, then Maximum: 1 wk 250 mg Q6H prn

Dysmenorrhea Oral 500 mg loading dose, then Usually taken for 2–3 days 250 mg Q6H Start at the onset of menses and continue for 48–72 h

Meloxicam Osteoarthritis Oral Initially 7.5 mg once daily 15 mg daily Usual dose: 7.5–15 mg once daily

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Drug Indication Route Usual Dose Maximum Dose

Rheumatoid arthritis Oral Initially 15 mg (7.5 mg once daily if high risk of ADRs) Usual dose: 7.5–15 mg once daily

Nabumetone Osteoarthritis and Oral 1000 mg once daily 2000 mg daily in 1 dose or rheumatoid arthritis Adjust doses at 1-wk 2 divided doses intervals

Naproxen Osteoarthritis, Oral or 500–1000 mg daily as a 1000 mg daily. 1500 mg rheumatoid arthritis and rectal single dose or in divided daily may be used for ankylosing spondylitis doses limited periods

Other painful conditions Oral or 500 mg loading dose, then 1250 mg on the first day, rectal 250 mg Q6–8H 1000 mg daily thereafter

Acute Oral or 750 mg loading dose, then 1000 mg daily rectal 250 mg Q8H

Dysmenorrhea Oral 500 mg loading dose, then 1000 mg daily except for 250 mg (immediate-release) limited periods of 1250 mg Q6–8H, or 500 mg BID prn daily

Naproxen sodium Osteoarthritis and Oral, 750–1000 mg once daily 1500 mg daily may be rheumatoid arthritis controlled- used for limited periods release tablet[c]

Self-medication of fever Oral[d] Nonprescription: 220 mg 440 mg per day. and mild- moderate pain Q8–12H Maximum: 5 days for pain and 3 days for fever

Mild-moderate pain Oral[d] 550 mg loading dose, then 1375 mg daily accompanied by 275 mg Q6–8H, or 500 mg inflammation BID prn

Dysmenorrhea Oral[d] 550 mg loading dose, then 1375 mg daily 275 mg Q6–8H, or 500 mg BID prn

Nepafenac Cataract surgery Ophthalmic 0.1%: Instill 1 drop TID Shake well before use. 0.3%: Instill 1 drop once daily Space instillation of eye Start 1 day prior to surgery drops by at least 5-minute and continue × 2 wk intervals postoperatively

Piroxicam Osteoarthritis, Oral or 10–20 mg/day in 1 or 2 20 mg daily rheumatoid arthritis and rectal divided doses ankylosing spondylitis

Sulindac Osteoarthritis, Oral 150 mg BID 400 mg daily rheumatoid arthritis and ankylosing spondylitis

Acute painful shoulder Oral 200 mg BID 400 mg daily. Usual and acute gouty arthritis Lower dose when response duration of therapy 7–14 is obtained days for painful shoulder, 7 days for acute gouty arthritis

Tenoxicam Osteoarthritis and Oral 10–20 mg once daily 20 mg daily rheumatoid arthritis

Tiaprofenic acid Osteoarthritis and Oral 600 mg daily in 2–3 divided 600 mg daily rheumatoid arthritis doses

[a] Doses ≥2400 mg/day should not be used in patients with a history of heart disease or stroke, or who have risk factors for cardiovascular

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disease. [b] IV formulation only available though Special Access Programme as Indocid 1 mg/vial. [c] Tablet strength of controlled-release product (Naprelan) is expressed as naproxen base: 375 mg tablet = 375 mg naproxen base (412.5 mg naproxen sodium); 500 mg tablet = 500 mg naproxen base (550 mg naproxen sodium). [d] Strength of oral tablets and capsules (immediate-release) is expressed as naproxen sodium: 220 mg tablet = 200 mg naproxen base; 275 mg tablet = 250 mg naproxen base; 550 mg tablet = 500 mg naproxen base.

Geriatrics

Consider lower doses due to an increased potential for toxicity. For the following NSAIDs, lower doses are also recommended due to altered in the elderly: indomethacin, ketoprofen, nabumetone, and piroxicam (see Table 7).

Pediatrics

See Table 6.

Table 6: Dose in Pediatric Patients Initial and Maximum Dose and Drug Indication Usual Dose Clinical Comment

Ibuprofen, Analgesic, antipyretic 5–10 mg/kg Q6–8H prn Maximum: 40 mg/kg daily. nonprescription Maximum: 3 days for fever and 5 days for pain without seeing a physician

Ibuprofen, Cystic fibrosis 20–30 mg/kg BID Maximum: 1600 mg BID. Adjust to prescription peak serum ibuprofen 50–100 µg/mL. Serum levels must be closely monitored

Indomethacin Juvenile rheumatoid arthritis Initially 1–2 mg/kg/day in Maximum: 4 mg/kg/day or 150–200 (not an approved use in divided doses mg daily, whichever is less Canada) Usual dose: 2–4 mg/kg/day

Closure of patent ductus IV: 3 doses of 0.1 mg/kg to arteriosus in preterm neonates 0.25 mg/kg at 12–24 h [a] (not an approved use in intervals Canada)

Naproxen Juvenile rheumatoid arthritis Oral: 10 mg/kg/day in 2 divided doses

Naproxen sodium Headache in children Oral: Age >2 y: 5–7 (not an approved use in mg/kg/dose Q8–12H Canada)

[a] IV formulation only available though Special Access Programme as Indocid 1 mg/vial.

Renal Impairment

All NSAIDs are contraindicated in patients with severe renal impairment (ClCr <30 mL/minute). Consider lower doses in patients with mild to moderate renal impairment due to the increased risk of renal toxicity (see Warnings and Precautions, Renal). When NSAIDs are administered in the eye, systemic exposure is very low and no dose adjustment is required.

Hepatic Impairment

NSAIDs are highly metabolized; therefore, dosage reductions should be considered in patients with hepatic impairment. When NSAIDs are administered in the eye, systemic exposure is very low and no dose adjustment is required.

Genetic Polymorphism

Many NSAIDs are highly metabolized by CYP2C9, a polymorphic (see Table 7). For these NSAIDs, consider dosage reduction in poor CYP2C9 metabolizers. These patients are at lower risk for drug-drug interactions with CYP2C9 inhibitor drugs (see Table 3). Some NSAIDs (diclofenac, ibuprofen) are metabolized by the polymorphic enzyme CYP2C8 and caution is advised for poor CYP2C8 metabolizers.

Administration

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Oral NSAIDs are administered with food to reduce gastrointestinal irritation. Enteric-coated and sustained-release products should be swallowed whole, not crushed or chewed. Reconstitute diclofenac powder for oral solution with 30–60 mL of water; do not mix with any other liquid and drink immediately after reconstitution. The preservative in some ophthalmic preparations can discolour soft contact lenses and may cause irritation of the eye; see individual product monographs for more information.

Overdosage

For management of a suspected drug overdose, contact your regional Poison Control Centre. See the eCPS Directory section for a list of Poison Control Centres.

For nonsalicylate NSAIDs, the most common symptoms are gastrointestinal irritation and CNS depression. COX-2 selectivity is lost at high doses, therefore symptoms and management will be similar for COX-2 selective NSAIDs and nonselective NSAIDs. Management of NSAID overdoses is symptomatic and supportive. There is no specific antidote. Due to high , hemodialysis is usually not effective. ASA is the only NSAID that is removable by hemodialysis.

Action and Clinical

Mechanism of Action

The analgesic, anti-inflammatory, antipyretic and antithrombotic properties of NSAIDs are produced by inhibiting the action of COX enzymes, thereby inhibiting the synthesis of prostaglandins and A2 (TXA2). ASA binds irreversibly to COX enzymes, while other NSAIDs bind in a reversible manner.

COX enzymes exist in two forms, COX-1 and COX-2. COX-1 is constantly synthesized in most tissues, where it produces homeostatic prostaglandins involved in immune responses, gastric protection, vascular hemostasis and platelet aggregation, renal perfusion and the female reproductive system. In contrast, COX-2 is mainly produced in response to inflammation, although it is constantly synthesized in some areas such as the vascular endothelium, vascular smooth muscle, brain and kidney.

NSAIDs differ in their selectivity for COX-1 and COX-2. Celecoxib is considered COX-2 selective and does not inhibit COX-1 when given at usual therapeutic doses. While experimental results vary depending on methodology, there is evidence to suggest some preferential COX-2 inhibition by diclofenac, etodolac, mefenamic acid, meloxicam and nabumetone. The remaining NSAIDs are considered nonselective and inhibit COX-1 and COX-2.

Inflammation is reduced by NSAIDs through inhibition of prostaglandin-mediated vasodilation, which increases local blood flow and results in redness and . NSAIDs reduce inflammatory pain by inhibiting the sensitization of peripheral pain receptors by prostaglandins, as well as through central actions. Dysmenorrhea pain is reduced by inhibition of the synthesis of endometrial prostaglandins that produce uterine contractions. Fever is reduced by inhibiting the prostaglandin-induced increase in the hypothalamic set point for body temperature that occurs during illness. NSAIDs do not reduce body temperature related to the environment or exercise. The antithrombotic effects of ASA result from inhibition of platelet aggregation via irreversible inhibition of COX-1-dependent TXA2 formation. ASA inhibits platelet aggregation for the lifetime of the platelet (7–10 days). Since mature human express COX-1 but not COX-2, NSAIDs that do not inhibit COX-1 at usual doses, such as celecoxib, do not inhibit platelet function.

The adverse effects of NSAIDs are derived from inhibition of COX-1 and COX-2, as described in Table 2.

Pharmacokinetics

NSAIDs share many similar pharmacokinetic properties but have clinically important differences in time to peak concentration and half- life. See Table 7.

Adults

Absorption

NSAIDs are well absorbed orally and rectally, with the exception of rectal ASA. Small amounts are absorbed topically. Naproxen sodium is more rapidly absorbed than naproxen.

Distribution

NSAIDs are highly bound to plasma proteins (>90%).

Metabolism

Most NSAIDs are extensively metabolized in the liver, often by CYP2C9, to mainly inactive metabolites.

Excretion

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NSAIDs are mainly eliminated in the urine as metabolites, with some excretion in feces.

Table 7: Pharmacokinetics Time to Peak Plasma Primary Metabolizing Elimination Half-life Drug Concentration (hours) Enzyme(s) (hours)

Celecoxib 3 CYP2C9 (minor CYP3A4) 11

Diclofenac potassium Tablet: 0.33–1 CYP2C9 (minor CYP2C8, Oral: 1.8 Powder for oral solution: CYP3A4, CYP2C18, Topical solution: 79 0.17–0.25 CYP2C19 and CYP2B6,CYP3A4) Active metabolites: 1–3

Diclofenac sodium Enteric-coated tablet: 2 Rectal suppository: 1 Sustained-release tablet: 4 Topical solution: 24–48

Diflunisal 2–3 8–12

Etodolac 2 CYP2C9 7

Floctafenine 1–2 Hydrolysis followed by 8[a][b] hydroxylation

Flurbiprofen 0.5–4 CYP2C9 7

Ibuprofen Liquid gel capsule: 0.66–0.7 CYP2C9 (minor CYP2C8) 2–3 Suspension: 1 Tablet, chewable tablet: 1–2

Indomethacin Oral: 2 CYP2C9 4.5[b]

Ketoprofen Capsule: 0.5–2 Glucuronidation Capsule: 2 Enteric-coated tablet: 1.5–4 Sustained-release tablet: [a][b] Sustained-release tablet: 5–6 3–4

Ketorolac tromethamine 1 Hydroxylation and 4–6 glucuronidation

Mefenamic acid 1–2 CYP2C9 2–3.5

Meloxicam 4–5 h; second peak at 12–14 h CYP2C9 15–20 (minor CYP3A4)

Nabumetone 2.5–3 Rapidly metabolized by 23 (6-MNA)[b] Active metabolite: 2.5–4 CYP1A2 to the active metabolite 6-MNA which is then metabolized by CYP2C9

Naproxen Enteric-coated tablet: 4 CYP2C9 (minor CYP1A2 and 15–17 Oral and rectal: 2–4 CYP2C8) Sustained-release tablet: 8

Naproxen sodium Capsule, tablet: 1–2 Controlled-release tablet (Naprelan): onset 0.5 h, peak 5 h

Piroxicam Oral: 4 CYP2C9 50[b] Rectal: 10

Sulindac 2 (active sulfide) Metabolized to the active 16 (active sulfide) sulfide form

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Time to Peak Plasma Primary Metabolizing Elimination Half-life Drug Concentration (hours) Enzyme(s) (hours)

Tenoxicam 0.5–6 CYP2C9 72

Tiaprofenic acid 0.5–1.5 Not established 2

[a] Increased half-life in renal impairment. [b] Increased half-life in the elderly.

Special Populations

Geriatrics

The pharmacokinetics of most NSAIDs do not change in elderly patients, with the exceptions noted in Table 7.

Storage and Stability

Store all dosage forms at room temperature (15–30°C).

CPhA Monographs are written by CPhA editors and are reviewed by expert physicians and pharmacists. CPhA recommends the full monograph be used. Partial monographs should not be provided to patients or anyone else and are for use only by clients at their own risk. CPhA assumes no responsibility for or liability in connection with the use of this monograph. Once printed, there is no guarantee the information is up-to-date. [Printed on: 03-17-2020 08:32 AM] RxTx, Compendium of Pharmaceuticals and Specialties © Canadian Pharmacists Association, 2020. All rights reserved

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