Cyclooxygenase-2 Enzyme Inhibitors: Place in Therapy



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Am Fam Physician. 2000 Jun 15;61(12):3669-3676.

  Related Editorial

Nonsteroidal anti-inflammatory drugs (NSAIDs) play a major role in the management of inflammation and pain caused by arthritis. A new class of NSAIDs that selectively inhibit the cyclooxygenase-2 (COX-2) enzyme has been developed. The first COX-2 inhibitors, celecoxib and rofecoxib, are said to provide therapeutic benefit with less toxicity than traditional NSAIDs. A third COX-2–selective inhibitor, meloxicam, has recently been introduced. COX-2 inhibitors and traditional NSAIDs do not appear to differ significantly in their effectiveness in alleviating pain or inflammation. They have similar gastrointestinal side effects, including abdominal pain, dyspepsia and diarrhea. However, short-term studies show fewer gastrointestinal ulcers in patients treated with COX-2 inhibitors compared with traditional NSAIDs. (Am Fam Physician 2000;61:3669–76.)

Celecoxib (Celebrex) and rofecoxib (Vioxx) are nonsteroidal anti-inflammatory drugs (NSAIDs), the first members of a new class of drugs that preferentially inhibit activity of the cyclooxygenase-2 (COX-2) enzyme. The COX-2 enzyme inhibitors were developed to treat the inflammation and pain of arthritis without the adverse side effects associated with previously available NSAIDs. In April 2000, a new COX-2 inhibitor, meloxicam (Mobic), was cleared by the U.S. Food and Drug Administration (FDA) for marketing in the United States.1

Although generally safe, “traditional” NSAIDs account for almost one fourth of all reported adverse drug events.2 Approximately 15 percent of NSAID users have gastrointestinal tract symptoms such as dyspepsia, heartburn, nausea or vomiting.3 Each year, 1 to 4 percent of NSAID users have serious gastrointestinal tract complications such as hemorrhage, with an estimated cost of $15,000 to $20,000 per hospitalization.3 An estimated 16,500 NSAID-related deaths occur annually among patients with osteoarthritis or rheumatoid arthritis.4 Medical costs of complications associated with NSAID use exceed $4 billion annually.5

Most patients who develop serious gastrointestinal tract complications associated with NSAIDs have no warning signs or symptoms.4 However, risk factors for these complications have been identified613  and are listed in Table 1.4 Factors such as the duration, dosage and type of NSAID independently affect the risk of developing gastroduodenal ulcers and complications. Although ulcer complications may occur at any time during NSAID therapy, the risk is highest during the first three months of use.6

TABLE 1.

Risk Factors for NSAID-Associated Gastrointestinal Ulcers

Established risk factors

Advanced age (risk increases with age)

History of ulcers

Concomitant use of corticosteroids

Use of higher NSAID dosages and more than one NSAID

Concomitant use of oral anticoagulants

Concomitant serious systemic disorder

Possible risk factors

Cigarette smoking

Alcohol consumption

Concomitant infection with Helicobacter pylori


NSAID = nonsteroidal anti-inflammatory drug.

Adapted with permission from Wolfe MM, Lichtenstein DR, Singh G. Gastrointestinal toxicity of non-steroidal antiinflammatory drugs. N Engl J Med 1999; 340:1888–99 [Published erratum appears in N Engl J Med 1999;341:548].

TABLE 1.   Risk Factors for NSAID-Associated Gastrointestinal Ulcers

View Table

TABLE 1.

Risk Factors for NSAID-Associated Gastrointestinal Ulcers

Established risk factors

Advanced age (risk increases with age)

History of ulcers

Concomitant use of corticosteroids

Use of higher NSAID dosages and more than one NSAID

Concomitant use of oral anticoagulants

Concomitant serious systemic disorder

Possible risk factors

Cigarette smoking

Alcohol consumption

Concomitant infection with Helicobacter pylori


NSAID = nonsteroidal anti-inflammatory drug.

Adapted with permission from Wolfe MM, Lichtenstein DR, Singh G. Gastrointestinal toxicity of non-steroidal antiinflammatory drugs. N Engl J Med 1999; 340:1888–99 [Published erratum appears in N Engl J Med 1999;341:548].

Role of COX-2 Enzyme Inhibitors

NSAIDs exert anti-inflammatory and analgesic effects through the inhibition of prostaglandin synthesis, by blocking COX activity. In the early 1990s, COX was discovered to have two isoforms: COX-1 and COX-2.14

COX-1, described as a “housekeeping” enzyme, is normally expressed in the gastrointestinal tract, kidneys and platelets. It appears to be responsible for mediating the production of thromboxane A2 and prostaglandins. Under the influence of COX-1, prostaglandins maintain the integrity of the gastric mucosa, mediate normal platelet function and regulate renal blood flow.15

The isoenzyme COX-2 is primarily associated with inflammation. Cytokines and growth factors increase the expression of COX-2, mainly at inflammatory sites, producing prostaglandins that mediate inflammation, pain and fever.15

Traditional NSAIDs in varying degrees inhibit prostaglandin formation through the inhibition of both COX isoforms (Table 2).16,17 Inhibition of COX-1 is not necessary for anti-inflammatory and analgesic effects but is thought to account for much of the toxicity of traditional NSAIDs.18

TABLE 2.

COX Enzyme Isoform Selectivity of Some Traditional NSAIDs and COX-2 Inhibitors*

Nonselective NSAIDs

Aspirin

Diclofenac (Voltaren)

Fenoprofen (Nalfon)

Ibuprofen (e.g., Advil, Motrin)

Indomethacin (Indocin)

Ketoprofen (Orudis)

Ketorolac (Toradol)

Naproxen (Naprosyn)

Nabumetone (Relafen)

Oxaprozin (Daypro)

Piroxicam (Feldene)

Tolmetin (Tolectin)

Relatively COX-2–selective NSAIDs†

Etodolac (Lodine)

Meloxicam (Mobic)

Highly COX-2–selective NSAIDs

Celecoxib (Celebrex)

Rofecoxib (Vioxx)


COX = cyclooxygenase; NSAID = nonsteroidal anti-inflammatory drug.

*—Based on in vitro data using the ratio of the IC50 values, which is defined as the concentration of a drug that inhibits enzyme activity by 50 percent. 16 In vitro comparison may not translate into clinical practice. 17

†—Preferential inhibition of COX-2 selectivity is diminished at higher dosages.

‡—COX-2 selectivity is not diminished at higher dosages.

TABLE 2.   COX Enzyme Isoform Selectivity of Some Traditional NSAIDs and COX-2 Inhibitors*

View Table

TABLE 2.

COX Enzyme Isoform Selectivity of Some Traditional NSAIDs and COX-2 Inhibitors*

Nonselective NSAIDs

Aspirin

Diclofenac (Voltaren)

Fenoprofen (Nalfon)

Ibuprofen (e.g., Advil, Motrin)

Indomethacin (Indocin)

Ketoprofen (Orudis)

Ketorolac (Toradol)

Naproxen (Naprosyn)

Nabumetone (Relafen)

Oxaprozin (Daypro)

Piroxicam (Feldene)

Tolmetin (Tolectin)

Relatively COX-2–selective NSAIDs†

Etodolac (Lodine)

Meloxicam (Mobic)

Highly COX-2–selective NSAIDs

Celecoxib (Celebrex)

Rofecoxib (Vioxx)


COX = cyclooxygenase; NSAID = nonsteroidal anti-inflammatory drug.

*—Based on in vitro data using the ratio of the IC50 values, which is defined as the concentration of a drug that inhibits enzyme activity by 50 percent. 16 In vitro comparison may not translate into clinical practice. 17

†—Preferential inhibition of COX-2 selectivity is diminished at higher dosages.

‡—COX-2 selectivity is not diminished at higher dosages.

The discovery of the COX-2 isoenzyme led to the theory that COX-2–selective inhibition would provide the potent anti-inflammatory and analgesic effects of traditional NSAIDs without influencing COX-1.19 Preservation of COX-1 would maintain the prostaglandins that are important for normal platelet function and protection of the gastrointestinal mucosa, whereas inhibition of COX-2 would affect the prostaglandins that mediate inflammation and other pathologic processes.15

Indications and Dosages

The FDA has labeled celecoxib, in oral dosages of 100 mg twice daily and 200 mg once daily, for the treatment of osteoarthritis. This drug is also labeled, in an oral dosage of 100 to 200 mg twice daily, for the treatment of rheumatoid arthritis in adults.20

The FDA has labeled rofecoxib for the treatment of primary dysmenorrhea, the management of acute pain in adults and the relief of signs and symptoms of osteoarthritis. For osteoarthritis therapy, the recommended oral dosage of rofecoxib is 12.5 to 25 mg once daily. For acute pain and primary dysmenorrhea, the recommended dosage is 50 mg once daily, taken as needed.20

The FDA recommends that celecoxib and rofecoxib be used in the lowest effective dosage for the shortest duration possible.20

Meloxicam, the newest COX-2 inhibitor, has been labeled by the FDA for the treatment of osteoarthritis. The starting and maintenance dosage of this drug is 7.5 mg per day.1

Efficacy

In general, traditional and selective NSAIDs possess equivalent efficacy, although only a few comparative studies are available.2026 Therefore, the role of COX-2 inhibitors is not related to any increased efficacy in treating pain or inflammation compared with traditional NSAIDs. Rather, the advantage of COX-2 inhibitors is the result of their more favorable side effect profile.26

Pharmacokinetics

Celecoxib and rofecoxib are well absorbed and reach peak concentrations about three hours after administration. These drugs can be administered without regard to meals, although a high-fat meal can delay absorption. Plasma protein binding, primarily to albumin, accounts for 97 percent of the binding of celecoxib and 87 percent of the binding of rofecoxib.20

The drugs are metabolized hepatically. Celecoxib is metabolized through the cytochrome P450-2C9 system. Drugs that inhibit cytochrome P450-2C9 have the potential to increase serum concentrations of celecoxib. Potential also exists for increased concentrations of drugs metabolized by the cytochrome P450-2D6 isoenzyme, which can be directly inhibited by celecoxib.

The hepatic cytochrome P450 system has a minor role in the metabolism of rofecoxib. The metabolism of this drug is primarily through reduction by cytosolic enzymes in the liver.20

Selected potential drug interactions for celecoxib are listed in Table 3.20  Known drug interactions for celecoxib and rofecoxib are listed in Table 4.20

TABLE 3.

Celecoxib (Celebrex): Selected Potential Drug Interactions

Cytochrome P450-2C9 inhibitors that may increase serum concentrations of celecoxib

Amiodarone (Cordarone)

Chloramphenicol (Chloromycetin)

Cimetidine (Tagamet)

Fluconazole (Diflucan)

Fluvastatin (Lescol)

Omeprazole (Prilosec)

Zafirlukast (Accolate)

Drugs metabolized by cytochrome P450-2D6 whose serum concentrations may be increased by celecoxib

Antiarrhythmics: flecainide (Tambocor), encainide (Enkaid), mexiletine (Mexitil)

Antidepressants:

Selective serotonin reuptake inhibitors: fluoxetine (Prozac), paroxetine (Paxil), sertraline (Zoloft)

Tricyclic antidepressants: amitriptyline (Elavil), imipramine (Tofranil), nortriptyline (Pamelor)

Venlafaxine (Effexor)

Antipsychotics: haloperidol (Haldol), perphenazine (Trilafon), risperidone (Risperdal)

Beta blockers: metoprolol tartrate (Lopressor), propranolol (Inderal), timolol (Betimol)

Opiates: codeine, dextromethorphan


Information from McEboy GK, ed. AHFS drug information 2000. Bethesda, Md.: American Society of Health-System Pharmacists, 2000.

TABLE 3.   Celecoxib (Celebrex): Selected Potential Drug Interactions

View Table

TABLE 3.

Celecoxib (Celebrex): Selected Potential Drug Interactions

Cytochrome P450-2C9 inhibitors that may increase serum concentrations of celecoxib

Amiodarone (Cordarone)

Chloramphenicol (Chloromycetin)

Cimetidine (Tagamet)

Fluconazole (Diflucan)

Fluvastatin (Lescol)

Omeprazole (Prilosec)

Zafirlukast (Accolate)

Drugs metabolized by cytochrome P450-2D6 whose serum concentrations may be increased by celecoxib

Antiarrhythmics: flecainide (Tambocor), encainide (Enkaid), mexiletine (Mexitil)

Antidepressants:

Selective serotonin reuptake inhibitors: fluoxetine (Prozac), paroxetine (Paxil), sertraline (Zoloft)

Tricyclic antidepressants: amitriptyline (Elavil), imipramine (Tofranil), nortriptyline (Pamelor)

Venlafaxine (Effexor)

Antipsychotics: haloperidol (Haldol), perphenazine (Trilafon), risperidone (Risperdal)

Beta blockers: metoprolol tartrate (Lopressor), propranolol (Inderal), timolol (Betimol)

Opiates: codeine, dextromethorphan


Information from McEboy GK, ed. AHFS drug information 2000. Bethesda, Md.: American Society of Health-System Pharmacists, 2000.

TABLE 4.

Celecoxib (Celebrex) and Rofecoxib (Vioxx): Documented Drug Interactions

Interacting drug Celecoxib Rofecoxib

Methotrexate (Rheumatrex)

No

Yes*

Warfarin (Coumadin)

No

Yes†

Ketoconazole (Nizoral)

No

No

Lithium

Yes‡

NA

Fluconazole (Diflucan)

Yes§

NA

Glyburide (Micronase)

No

NA

Phenytoin (Dilantin)

No

NA

Tolbutamide (Orinase)

No

NA

Rifampin (Rifadin)

NA

Yes∥

Digoxin (Lanoxin)

NA

No

Oral contraceptives

NA

No


NA = not available (studies not conducted).

*—At higher than recommended dosages of rofecoxib (75 mg per day).

†—International Normalized Ratio (INR) increased 8 to 11 percent in patients treated with rofecoxib (25 to 50 mg doses).

‡—A 17 percent increase in lithium in area under the serum concentration-versus-time curve.

§—A twofold increase in celecoxib in area under the serum concentration-versus-time curve.

∥—Approximately 50 percent decrease in rofecoxib serum concentrations.

Information from McEboy GK, ed. AHFS drug information 2000. Bethesda, Md.: American Society of Health-System Pharmacists, 2000.

TABLE 4.   Celecoxib (Celebrex) and Rofecoxib (Vioxx): Documented Drug Interactions

View Table

TABLE 4.

Celecoxib (Celebrex) and Rofecoxib (Vioxx): Documented Drug Interactions

Interacting drug Celecoxib Rofecoxib

Methotrexate (Rheumatrex)

No

Yes*

Warfarin (Coumadin)

No

Yes†

Ketoconazole (Nizoral)

No

No

Lithium

Yes‡

NA

Fluconazole (Diflucan)

Yes§

NA

Glyburide (Micronase)

No

NA

Phenytoin (Dilantin)

No

NA

Tolbutamide (Orinase)

No

NA

Rifampin (Rifadin)

NA

Yes∥

Digoxin (Lanoxin)

NA

No

Oral contraceptives

NA

No


NA = not available (studies not conducted).

*—At higher than recommended dosages of rofecoxib (75 mg per day).

†—International Normalized Ratio (INR) increased 8 to 11 percent in patients treated with rofecoxib (25 to 50 mg doses).

‡—A 17 percent increase in lithium in area under the serum concentration-versus-time curve.

§—A twofold increase in celecoxib in area under the serum concentration-versus-time curve.

∥—Approximately 50 percent decrease in rofecoxib serum concentrations.

Information from McEboy GK, ed. AHFS drug information 2000. Bethesda, Md.: American Society of Health-System Pharmacists, 2000.

Rofecoxib is not recommended for use in patients with moderate to severe hepatic insufficiency. Patients with moderate hepatic impairment should be started on a reduced dosage of celecoxib, and the drug should not be used in patients with severe hepatic impairment. Hepatic enzymes should be monitored if liver dysfunction is suspected.20

Celecoxib has been shown to cause no change in the glomerular filtration rate in patients at risk for NSAID-induced renal effects. Chronic renal insufficiency (glomerular filtration rate of 35 to 60 mL per minute) has not been found to significantly influence the pharmacokinetics of celecoxib or rofecoxib. Because of unanswered questions about safety, these drugs are not recommended for use in patients with advanced renal disease.20

Severely dehydrated patients need to be treated before celecoxib or rofecoxib therapy is initiated. Renal function should be monitored in elderly patients and in patients with chronic renal insufficiency or congestive heart failure. Renal function should also be monitored in patients who are concurrently taking an NSAID and a diuretic or an angiotensin-converting enzyme inhibitor.20

Safety

SPECIAL POPULATIONS

With COX-2 inhibitors, dosage adjustments generally are not required in elderly patients, but use of the lowest dosage is recommended. Because these agents have not been studied in patients younger than 18 years, they are not recommended for use in children and adolescents.

COX-2 inhibitors are classified as pregnancy category C medications. They should not be used in lactating women or in women in the third trimester of pregnancy (because of possible premature closure of the ductus arteriosus).

CONTRAINDICATIONS

Treatment with COX-2 inhibitors is contraindicated in patients who have hypersensitivity to these drugs, asthma, urticaria or previous anaphylactic reactions after taking aspirin or NSAIDs. Celecoxib contains a sulfonamide group. Patients with a demonstrated allergic reaction to sulfonamides should not take this drug.20

ADVERSE EFFECTS AND PRECAUTIONS

Like traditional NSAIDs, the COX-2 inhibitors commonly cause abdominal pain, dyspepsia and diarrhea. Because of potential aggravation of hypertension and lower extremity edema, caution should be exercised in prescribing COX-2 inhibitors to patients with congestive heart failure, fluid retention or hypertension.20

PLATELET EFFECTS AND BLEEDING TIME

Aspirin and traditional NSAIDs exert their antiplatelet effect by inhibiting COX, and thereby inhibiting the formation of thromboxane A2. Systemic bleeding tendencies associated with the use of aspirin and traditional NSAIDs are attributable to inhibition of platelet COX-1.

COX-2–specific inhibitors retain some platelet thromboxane A2 inhibitory properties, but their antiplatelet potency is far less than that of traditional NSAIDs.27 Patients who have coagulation abnormalities or are concurrently using COX-2 inhibitors and alcohol or anticoagulants are at increased risk for bleeding.28

COX-2 inhibitors do not increase bleeding time. Studies on these agents administered in normal and higher than normal dosages for seven to 12 days found no effect on platelet aggregation and bleeding time.18 Therefore, these drugs are not a substitute for aspirin for cardiovascular protection, and they can be used with low-dose aspirin therapy. However, concomitant use of a COX-2 inhibitor and aspirin may increase the risk of gastrointestinal adverse events, because aspirin dosages as low as 10 mg are capable of suppressing prostaglandin synthesis in the gastric mucosa.29

Rofecoxib and celecoxib have been shown to cause a slight elevation of prothrombin time in patients who are taking warfarin (Coumadin). Thus, the International Normalized Ratio (INR) should be monitored when celecoxib or rofecoxib is initiated or the dosage of one of these drugs is changed in patients who are receiving concomitant warfarin therapy.

NSAID GASTROPATHY

Under normal circumstances, prostaglandins protect the lining of the gastric mucosa and limit the output of gastric acid. The risk of ulcer development is increased by approximately 15 to 20 percent in patients with rheumatoid arthritis or osteoarthritis who are taking traditional NSAIDs.6 If first-line acetaminophen therapy is ineffective, treatment with COX-2 inhibitors may be considered in patients with osteoarthritis who are at high risk for gastrointestinal tract ulceration. Treatment with COX-2 inhibitors should also be considered in patients with rheumatoid arthritis who are at high risk for ulcers and in other at-risk patients who require NSAID therapy.

Celecoxib and rofecoxib have been found to cause fewer gastrointestinal ulcers than traditional NSAIDs.20 In six 12- to 24-week randomized, controlled trials involving more than 4,500 patients, endoscopic examinations demonstrated a statistically significant lower incidence of ulcers with celecoxib than with naproxen, ibuprofen or diclofenac. How this translates in terms of clinically significant upper gastrointestinal tract events remains to be demonstrated.30 In eight randomized trials of rofecoxib, the combined incidence of upper gastrointestinal tract perforations, symptomatic gastroduodenal ulcers and upper gastrointestinal tract bleeding over 12 months was significantly lower in patients who received rofecoxib than in those treated with traditional NSAIDs.25

Acute gastrointestinal bleeding is more likely to occur more often in elderly and debilitated patients. Extreme caution should be used in prescribing any NSAID to patients with a history of peptic ulcer disease or gastrointestinal tract bleeding.

RENAL EFFECTS

NSAID inhibition of compensatory renal prostaglandins can worsen renal function in certain patient populations. At particular risk are patients with reduced renal perfusion as a result of congestive heart failure, diabetes mellitus, dehydration or aging.31 Renal prostaglandins influence total renal blood flow, sodium and water reabsorption, and renin release. COX-1 activity accounts for most of these functions. COX-2 is expressed in the kidney and is involved in its function.31

Unanswered Questions

Potential concerns and clinical applications of COX-2 inhibitors are currently under investigation.16,3234 The COX-2 enzyme is being studied because of its normal expression in the kidney and brain and its role in the development of these organs. COX-2 is also thought to be involved in the development of colon tumors and adenomas. The FDA has recently labeled celecoxib, in a dosage of 400 mg twice daily, for use in reducing the number of adenomatous colorectal polyps in patients with familial adenomatous polyposis.34 COX-2 inhibitors may also have potential application in the prevention of Alzheimer's disease.16,32,33

Recommendations

Studies suggest that COX-2 inhibitors are as efficacious as traditional NSAIDs in treating inflammatory disease.2026 COX-2 inhibitors also have a theoretically more favorable side effect profile than traditional NSAIDs. However, the differences between traditional NSAIDs and COX-2 inhibitors have been small and clinically modest.26 The decision to use the more expensive COX-2 inhibitors should be based on the individual patient's risk of gastrointestinal tract hemorrhage.

Based on a number-needed-to treat analysis, it has been suggested that the prevention of adverse effects may justify prescribing COX-2 agents to high-risk patients, such as those 75 years or older, who have a history of gastrointestinal tract bleeding.26 Cost favors the use of generic, traditional NSAIDs in patients who are not at high risk for bleeding.26  The costs of various NSAIDs are presented in Table 5.

TABLE 5.

Costs of Some Common Nonsteroidal Anti-inflammatory Drugs

Drug Usual dosage for adults* Formulations Cost per pill (generic)†

Acetic acids

Diclofenac potassium (Cataflam)

100 to 200 mg daily

50 mg

$1.81 (1.53)

Diclofenac sodium

Immediate-release (Voltaren)

100 to 200 mg daily

25 mg

0.66 (0.44 to 0.47)

50 mg

1.29 (0.86 to 1.06)

75 mg

1.56 (1.06 to 1.28)

Delayed-release (Voltaren XR)

100 to 200 mg daily

100 mg

3.12

With misoprostol (Arthrotec)

50 mg three times daily 50 mg three or four times daily for rheumatoid arthritis

50 mg diclofenac sodium with 200 μg misoprostol 75 mg diclofenac sodium with 200 μg misoprostol

1.47

1.54

Etodolac

Immediate-release (Lodine)

600 to 1,000 mg daily given in two divided doses

200 mg

1.37 (1.11)

300 mg

1.55 (1.25 to 1.26)

400 mg

1.64 (1.26 to 1.40)

500 mg

1.65 (1.46)

Extended-release (Lodine XL)

400 to 1,000 mg daily

400 mg

1.50

500 mg

1.57

600 mg

2.85

Sulindac (Clinoril)

150 mg twice daily (maximum dosage: 400 mg daily)

150 mg

1.12 (0.90 to 1.15)

200 mg

1.38 (0.75 to 0.91)

Propionic acids

Flurbiprofen (Ansaid)

200 to 300 mg daily given in two to four divided doses

50 mg

1.15 (0.60 to 0.72)

100 mg

1.80 (1.08 to 1.23)

Ibuprofen (Motrin)

400 to 800 mg three or four times daily (maximum dosage: 3,200 mg daily)

200 mg

0.21 (0.10 to 0.13)

400 mg

0.24 (0.08 to 0.20)

600 mg

0.35 (0.04 to 0.21)

800 mg

0.45 (0.06 to 0.38)

Ketoprofen

Immediate-release (Orudis)

150 to 300 mg daily given in three to four divided doses

25 mg

0.96 (0.74)

50 mg

1.17 (0.90 to 0.92)

75 mg

1.30 (0.98 to 1.02)

Extended-release (Orvail)

150 to 300 mg daily given in three or four divided doses

100 mg

2.19

150 mg

2.67

200 mg

3.01 (2.49)

Over-the-counter (Orudis KT)

12.5 mg every 4 to 6 hours

12.5 mg

0.09

Naproxen

Immediate-release (Naprosyn)

250 to 500 mg twice daily

250 mg

1.18 (0.12)

375 mg

1.46 (0.21)

500 mg

1.88 (0.18)

Delayed-release (EC Naprosyn)

750 or 1,000 mg daily

375 mg

1.77

500 mg

2.03

Naproxen sodium

Immediate-release (Anaprox, Anaprox DS)

275 or 550 mg twice daily

275 mg

0.84 (0.67 to 0.74)

550 mg

1.31 (1.04 to 1.15)

Extended-release (Naprelan)

750 or 1,000 mg daily

375 mg

1.27

500 mg

1.56

Over-the-counter (Aleve)

220 mg every 8 to 12 hours

220 mg

0.14 (0.06 to 0.14)

Oxaprozin (Daypro)

1,200 mg daily

600 mg

1.53

Nonacidic agents

Nabumetone (Relafen)

1,000 to 2,000 mg given once daily or twice daily in divided doses

500 mg

1.21

750 mg

1.43

Cyclooxygenase-2 inhibitors

Celecoxib (Celebrex)

100 mg twice daily or 200 mg daily for osteoarthritis 100 to 200 mg twice daily for rheumatoid arthritis

100 mg 200 mg

1.43

2.42

Rofecoxib (Vioxx)

12.5 to 25 mg daily for osteoarthritis

12.5 mg

2.42

25 mg

2.42

50 mg daily for primar dysmenorrhea and acute pain

50 mg

3.54

12.5 or 25 mg in 5-mL suspension

3.60 for 12.5 or 25 mg per 5-mL suspension


*—Dosages given are those used in the treatment of patients with osteoarthritis or rheumatoid arthritis.

†—Estimated cost to the pharmacist based on average wholesale prices in Red book. Montvale, N.J.: Medical Economics Data, 2000. Cost to the patient will be higher, depending on prescription filling fee.

TABLE 5.   Costs of Some Common Nonsteroidal Anti-inflammatory Drugs

View Table

TABLE 5.

Costs of Some Common Nonsteroidal Anti-inflammatory Drugs

Drug Usual dosage for adults* Formulations Cost per pill (generic)†

Acetic acids

Diclofenac potassium (Cataflam)

100 to 200 mg daily

50 mg

$1.81 (1.53)

Diclofenac sodium

Immediate-release (Voltaren)

100 to 200 mg daily

25 mg

0.66 (0.44 to 0.47)

50 mg

1.29 (0.86 to 1.06)

75 mg

1.56 (1.06 to 1.28)

Delayed-release (Voltaren XR)

100 to 200 mg daily

100 mg

3.12

With misoprostol (Arthrotec)

50 mg three times daily 50 mg three or four times daily for rheumatoid arthritis

50 mg diclofenac sodium with 200 μg misoprostol 75 mg diclofenac sodium with 200 μg misoprostol

1.47

1.54

Etodolac

Immediate-release (Lodine)

600 to 1,000 mg daily given in two divided doses

200 mg

1.37 (1.11)

300 mg

1.55 (1.25 to 1.26)

400 mg

1.64 (1.26 to 1.40)

500 mg

1.65 (1.46)

Extended-release (Lodine XL)

400 to 1,000 mg daily

400 mg

1.50

500 mg

1.57

600 mg

2.85

Sulindac (Clinoril)

150 mg twice daily (maximum dosage: 400 mg daily)

150 mg

1.12 (0.90 to 1.15)

200 mg

1.38 (0.75 to 0.91)

Propionic acids

Flurbiprofen (Ansaid)

200 to 300 mg daily given in two to four divided doses

50 mg

1.15 (0.60 to 0.72)

100 mg

1.80 (1.08 to 1.23)

Ibuprofen (Motrin)

400 to 800 mg three or four times daily (maximum dosage: 3,200 mg daily)

200 mg

0.21 (0.10 to 0.13)

400 mg

0.24 (0.08 to 0.20)

600 mg

0.35 (0.04 to 0.21)

800 mg

0.45 (0.06 to 0.38)

Ketoprofen

Immediate-release (Orudis)

150 to 300 mg daily given in three to four divided doses

25 mg

0.96 (0.74)

50 mg

1.17 (0.90 to 0.92)

75 mg

1.30 (0.98 to 1.02)

Extended-release (Orvail)

150 to 300 mg daily given in three or four divided doses

100 mg

2.19

150 mg

2.67

200 mg

3.01 (2.49)

Over-the-counter (Orudis KT)

12.5 mg every 4 to 6 hours

12.5 mg

0.09

Naproxen

Immediate-release (Naprosyn)

250 to 500 mg twice daily

250 mg

1.18 (0.12)

375 mg

1.46 (0.21)

500 mg

1.88 (0.18)

Delayed-release (EC Naprosyn)

750 or 1,000 mg daily

375 mg

1.77

500 mg

2.03

Naproxen sodium

Immediate-release (Anaprox, Anaprox DS)

275 or 550 mg twice daily

275 mg

0.84 (0.67 to 0.74)

550 mg

1.31 (1.04 to 1.15)

Extended-release (Naprelan)

750 or 1,000 mg daily

375 mg

1.27

500 mg

1.56

Over-the-counter (Aleve)

220 mg every 8 to 12 hours

220 mg

0.14 (0.06 to 0.14)

Oxaprozin (Daypro)

1,200 mg daily

600 mg

1.53

Nonacidic agents

Nabumetone (Relafen)

1,000 to 2,000 mg given once daily or twice daily in divided doses

500 mg

1.21

750 mg

1.43

Cyclooxygenase-2 inhibitors

Celecoxib (Celebrex)

100 mg twice daily or 200 mg daily for osteoarthritis 100 to 200 mg twice daily for rheumatoid arthritis

100 mg 200 mg

1.43

2.42

Rofecoxib (Vioxx)

12.5 to 25 mg daily for osteoarthritis

12.5 mg

2.42

25 mg

2.42

50 mg daily for primar dysmenorrhea and acute pain

50 mg

3.54

12.5 or 25 mg in 5-mL suspension

3.60 for 12.5 or 25 mg per 5-mL suspension


*—Dosages given are those used in the treatment of patients with osteoarthritis or rheumatoid arthritis.

†—Estimated cost to the pharmacist based on average wholesale prices in Red book. Montvale, N.J.: Medical Economics Data, 2000. Cost to the patient will be higher, depending on prescription filling fee.

Direct comparisons of the COX-2 inhibitors are lacking. Long-term studies of the chronic administration of these drugs on rates of perforation ulcers and bleeds are currently underway.35 Detailed information on meloxicam will become available over time.

The Authors

SARA L. NOBLE, PHARM.D., is associate professor of family medicine at the University of Mississippi School of Medicine, Jackson. Dr. Noble received her doctor of pharmacy degree from the University of Mississippi School of Pharmacy.

DEBORAH S. KING, PHARM.D., is assistant professor of clinical pharmacy practice at the University of Mississippi School of Pharmacy. Dr. King received her doctor of pharmacy degree from the University of Mississippi School of Pharmacy.

JOYCE I. OLUTADE, M.D., is assistant professor of family medicine at the University of Mississippi School of Medicine. Dr. Olutade received her medical degree from the University of Ibadan College of Medicine, Nigeria, and completed a family practice residency at Morehouse School of Medicine, Atlanta.

Address correspondence to Sara L. Noble, Pharm.D., Department of Family Medicine, University of Mississippi Medical Center, 2500 N. State St., Jackson, MS 39216. Reprints are not available from the authors.

The authors thank William H. Replogle, Ph.D., and T. Kristopher Harrell, Pharm.D., University of Mississippi, Jackson, for reviewing the manuscript.

Dr. Noble has conducted research funded by Merck & Co., Inc., and has received an honorarium from Pfizer Inc. Dr. King has been involved in studies for Merck & Co, Inc., and G.D. Searle & Co., and has received an honorarium from Pfizer Inc.

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Richard W. Sloan, M.D., R.Ph., coordinator of this series, is chairman and residency program director of the Department of Family Medicine at York (Pa.) Hospital and clinical associate professor in family and community medicine at the Milton S. Hershey Medical Center, Pennsylvania State University, Hershey, Pa.



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