Cyclooxygenase-2 Enzyme Inhibitors: Place in Therapy

Cyclooxygenase-2 Enzyme Inhibitors: Place in Therapy – for arthritis pain care

Sara L. Noble

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 ssociated 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 identified(6-13) 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)

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)

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.(20-26) 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)

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.(16,32-34) 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.(20-26) 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.

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 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.

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.

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.

REFERENCES

(1.) Mobic tablets approved by U.S. FDA for osteoarthritis 04/14/2000. Retrieved April 19, 2000, from the World Wide Web: http://pharmacology.about. com/health/pharmacology/library/0daily/00news/.

(2.) Non-steroidal anti-inflammatory drugs and serious gastrointestinal adverse reactions. Br Med J [Clin Res] 1986;292:614.

(3.) Singh G. Recent considerations in nonsteroidal anti-inflammatory drug gastropathy. Am J Med 1998;105:31S-8S.

(4.) Wolfe MM, Lichtenstein DR, Singh G. Gastrointestinal toxicity of nonsteroidal anti-inflammatory drugs. N Engl J Med 1999;340:1888-99 [Published erratum appears in N Engl J Med 1999;341:548].

(5.) Kendall BJ, Peura DA. NSAID-associated gastrointestinal damage and the elderly. GI disease in the elderly series: article five in the series. Pract Gastroenterol 1993;17(11):13-20,29.

(6.) Lanza FL. A guideline for the treatment and prevention of NSAID-induced ulcers. Members of the Ad Hoc Committee on Practice Parameters of the American College of Gastroenterology. Am J Gastroenterol 1998;92:2037-46.

(7.) Lichtenstein DR, Syngal S, Wolfe MM. Nonsteroidal anti-inflammatory drugs and the gastrointestinal tract. The double-edged sword. Arthritis Rheum 1995;38:5-18.

(8.) Fries JF. NSAID gastropathy: the second most deadly rheumatic disease? Epidemiology and risk appraisal. J Rheumatol Suppl 1991;28:6-10.

(9.) Silverstein FE, Graham DY, Senior JR, Davies HW, Struthers BJ, Bittman RM, et al. Misoprostol reduces serious gastrointestinal complications in patients with rheumatoid arthritis receiving nonsteroidal anti-inflammatory drugs. A randomized, double-blind, placebo-controlled trial. Ann Intern Med 1995;123:241-9.

(10.) Simon LS, Hatoum HT, Bittman RM, Archambault, WT, Polisson RP. Risk factors for serious nonsteroidal-induced gastrointestinal complications: regression analysis of the MUCOSA trial. Fam Med 1996;28:204-10.

(11.) Griffin MR. Epidemiology of nonsteroidal anti-inflammatory drug-associated gastrointestinal injury. Am J Med 1998;104:23S-9S.

(12.) Singh G, Rosen Ramey D. NSAID induced gastrointestinal complications: the ARAMIS perspective–1997. Arthritis, Rheumatism, and Aging Medical Information System. J Rheumatol Suppl 1998;51:8-16.

(13.) Gabriel SE, Jaakkimainen L, Bombardier C. Risk for serious gastrointestinal complications related to use of nonsteroidal anti-inflammatory drugs. A meta-analysis. Ann Intern Med 1991;115:787-96.

(14.) Fu JY, Masferrer JL, Seibert K, Raz A, Needleman P. The induction and suppression of prostaglandin H2 synthase (cyclooxygenase) in human monocytes. J Biol Chem 1990;265(28):16737-40.

(15.) Crofford LJ. COX-1 and COX-2 tissue expression: implications and predictions. J Rheumatol 1997; 24(suppl 49):15-9.

(16.) Vane JR, Bakhle YS, Botting RM. Cyclooxygenases 1 and 2. Annu Rev Pharmacol Toxicol 1998;38:97-120.

(17.) Gierse JK, Koboldt CM, Walker MC, Seibert K, Isakson PC. Kinetic basis for selective inhibition of cyclo-oxygenases. Biochem J 1999;339(part 3):607-14.

(18.) Lipsky PE, Isakson PC. Outcome of specific COX-2 inhibition in rheumatoid arthritis. J Rheumatol 1997;24(suppl 49):9-14.

(19.) Needleman P, Isakson P. The discovery and function of COX-2. J Rheumatol 1997;24(suppl 49):6-8.

(20.) McEboy GK, ed. AHFS Drug information 2000. Bethesda, Md.: American Society of Health-System Pharmacists, 2000.

(21.) Celecoxib for arthritis. Med Lett Drugs Ther 1999; 41:11-2.

(22.) Ehrich EW, Dallob A, De Lepeleire I, Van Hecken A, Riendeau D, Yuan W, et al. Characterization of rofecoxib as a cyclooxygenase-2 isoform inhibitor and demonstration of analgesia in the dental pain model. Clin Pharmacol Ther 1999;65:336-47.

(23.) Rofecoxib for osteoarthritis and pain. Med Lett Drugs Ther 1999;41:59-61.

(24.) Simon LS, Weaver AL, Graham DY, Kivitz AJ, Lipsky PE, Hubbard RC, et al. Anti-inflammatory and upper gastrointestinal effects of celecoxib in rheumatoid arthritis: a randomized controlled trial. JAMA 1999;282:1921-8.

(25.) Langman MJ, Jensen DM, Watson DJ, Harper SE, Zhao PL, Quan H, et al. Adverse upper gastrointestinal effects of rofecoxib compared with NSAIDs. JAMA 1999;282:1929-33.

(26.) Peterson WL, Cryer BC. COX-1 sparing NSAIDs–is the enthusiasm justified? [Editorial] JAMA 1999; 282:1961-3.

(27.) McAdam BF, Catella-Lawson F, Mardini IA, Kapoor S, Lawson JA, FitzGerald GA. Systemic biosynthesis of prostacyclin by cyclooxygenase (COX)-2: the human pharmacology of a selective inhibitor of COX-2. Proc Natl Acad Sci U S A 1999;96:272-7 [Published erratum appears in Proc Natl Acad Sci U S A 1999;96:5890].

(28.) Schafer AI. Effects of nonsteroidal anti-inflammatory therapy on platelets. Am J Med 1999;106:25S-36S.

(29.) Cryer B, Feldman M. Effects of very low dose daily, long-term aspirin therapy on gastric, duodenal, and rectal prostaglandin levels and on mucosal injury in healthy humans. Gastroenterology 1999;117:17-25.

(30.) Nightingale SL. From the Food and Drug Administration. JAMA 1999;281:786.

(31.) Whelton A. Nephrotoxicity of nonsteroidal anti-inflammatory drugs: physiologic foundations and clinical implications. Am J Med 1999;106:13S-24S.

(32.) Lipsky PE. The clinical potential of cyclooxygenase-2-specific inhibitors. Am J Med 1999;106:51S-7S.

(33.) Hawkey CJ. COX-2 inhibitors. Lancet 1999;353: 307-14.

(34.) Sheehan KM, Sheahan K, O’Donoghue DP, MacSweeney F, Conroy RM, Fitzgerald DJ, et al. The relationship between cyclooxygenase-2 expression and colorectal cancer. JAMA 1999;282:1254-7.

(35.) Goldstein JL, Agrawal N, Silverstein F, Burr A, Maurath CJ, Verburg KM, et al. Celecoxib is associated with a low rate of clinically significant upper GI events: a two-year open label trial [Abstract]. Am J Gastroenterol 1999;94:2752.

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 nonsteroidal

antiinflammatory drugs. N Engl J Med 1999; 340:1888-99

[Published erratum appears in N Engl J Med 1999;341:548].

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 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[sections] 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.

[sections]–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 5

Costs of Some Common Nonsteroidal Anti-inflammatory Drugs

Drug Usual dosage for adults[*]

Acetic acids

Diclofenac potassium (Cataflam) 100 to 200 mg daily

Diclofenac sodium

Immediate-release (Voltaren) 100 to 200 mg daily

Delayed-release (Voltaren XR) 100 to 200 mg daily

With misoprostol (Arthrotec) 50 mg three times daily

50 mg three or four times

daily for rheumatoid

arthritis

Etodolac

Immediate-release (Lodine) 600 to 1,000 mg daily given

in two divided doses

Extended-release (Lodine XL) 400 to 1,000 mg daily

Sulindac (Clinoril) 150 mg twice daily (maximum

dosage: 400 mg daily)

Propionic acids

Flurbiprofen (Ansaid) 200 to 300 mg daily given in

two to four divided doses

Ibuprofen (Motrin) 400 to 800 mg three or four

times daily (maximum

dosage: 3,200 mg daily)

Ketoprofen

Immediate-release (Orudis) 150 to 300 mg daily given in

three to four divided doses

Extended-release (Orvail) 150 to 300 mg daily given in

three or four divided doses

Over-the-counter (Orudis KT) 12.5 mg every 4 to 6 hours

Naproxen

Immediate-release (Naprosyn) 250 to 500 mg twice daily

Delayed-release (EC Naprosyn) 750 or 1,000 mg daily

Naproxen sodium

Immediate-release (Anaprox, 275 or 550 mg twice daily

Anaprox DS)

Extended-release (Naprelan) 750 or 1,000 mg daily

Over-the-counter (Aleve) 220 mg every 8 to 12 hours

Oxaprozin (Daypro) 1,200 mg daily

Nonacidic agents

Nabumetone (Relafen) 1,000 to 2,000 mg given once daily

or twice daily in divided doses

Cyclooxygenase-2 inhibitors

Celecoxib (Celebrex) 100 mg twice daily or 200 mg

daily for osteoarthritis

100 to 200 mg twice daily

for rheumatoid arthritis

Rofecoxib (Vioxx) 12.5 to 25 mg daily for

osteoarthritis

50 mg daily for primary

dysmenorrhea and acute pain

Usual dosage for adults[*] Formulations

100 to 200 mg daily 50 mg

100 to 200 mg daily 25 mg

50 mg

75 mg

100 to 200 mg daily 100 mg

50 mg three times daily 50 mg diclofenac sodium

50 mg three or four times with 200 [micro]g misoprostol

daily for rheumatoid 75 mg diclofenac sodium

arthritis with 200 [micro]g misoprostol

600 to 1,000 mg daily given 200 mg

in two divided doses 300 mg

400 mg

500 mg

400 to 1,000 mg daily 400 mg

500 mg

600 mg

150 mg twice daily (maximum 150 mg

dosage: 400 mg daily) 200 mg

200 to 300 mg daily given in 50 mg

two to four divided doses 100 mg

400 to 800 mg three or four 200 mg

times daily (maximum 400 mg

dosage: 3,200 mg daily) 600 mg

800 mg

150 to 300 mg daily given in 25 mg

three to four divided doses 50 mg

75 mg

150 to 300 mg daily given in 100 mg

three or four divided doses 150 mg

200 mg

12.5 mg every 4 to 6 hours 12.5 mg

250 to 500 mg twice daily 250 mg

375 mg

500 mg

750 or 1,000 mg daily 375 mg

500 mg

275 or 550 mg twice daily 275 mg

550 mg

750 or 1,000 mg daily 375 mg

500 mg

220 mg every 8 to 12 hours 220 mg

1,200 mg daily 600 mg

1,000 to 2,000 mg given once daily 500 mg

or twice daily in divided doses 750 mg

100 mg twice daily or 200 mg 100 mg

daily for osteoarthritis 200 mg

100 to 200 mg twice daily

for rheumatoid arthritis

12.5 to 25 mg daily for 12.5 mg

osteoarthritis 25 mg

50 mg daily for primary 50 mg

dysmenorrhea and acute pain 12.5 or 25 mg in 5-mL

suspension

Usual dosage for adults[*] Cost per pill (generic)[]

100 to 200 mg daily $1.81 (1.53)

100 to 200 mg daily 0.66 (0.44 to 0.47)

1.29 (0.86 to 1.06)

1.56 (1.06 to 1.28)

100 to 200 mg daily 3.12

50 mg three times daily 1.47

50 mg three or four times

daily for rheumatoid 1.54

arthritis

600 to 1,000 mg daily given 1.37 (1.11)

in two divided doses 1.55 (1.25 to 1.26)

1.64 (1.26 to 1.40)

1.65 (1.46)

400 to 1,000 mg daily 1.50

1.57

2.85

150 mg twice daily (maximum 1.12 (0.90 to 1.15)

dosage: 400 mg daily) 1.38 (0.75 to 0.91)

200 to 300 mg daily given in 1.15 (0.60 to 0.72)

two to four divided doses 1.80 (1.08 to 1.23)

400 to 800 mg three or four 0.21 (0.10 to 0.13)

times daily (maximum 0.24 (0.08 to 0.20)

dosage: 3,200 mg daily) 0.35 (0.04 to 0.21)

0.45 (0.06 to 0.38)

150 to 300 mg daily given in 0.96 (0.74)

three to four divided doses 1.17 (0.90 to 0.92)

1.30 (0.98 to 1.02)

150 to 300 mg daily given in 2.19

three or four divided doses 2.67

3.01 (2.49)

12.5 mg every 4 to 6 hours 0.09

250 to 500 mg twice daily 1.18 (0.12)

1.46 (0.21)

1.88 (0.18)

750 or 1,000 mg daily 1.77

2.03

275 or 550 mg twice daily 0.84 (0.67 to 0.74)

1.31 (1.04 to 1.15)

750 or 1,000 mg daily 1.27

1.56

220 mg every 8 to 12 hours 0.14 (0.06 to 0.14)

1,200 mg daily 1.53

1,000 to 2,000 mg given once daily 1.21

or twice daily in divided doses 1.43

100 mg twice daily or 200 mg 1.43

daily for osteoarthritis 2.42

100 to 200 mg twice daily —

for rheumatoid arthritis

12.5 to 25 mg daily for 2.42

osteoarthritis 2.42

50 mg daily for primary 3.54

dysmenorrhea and acute pain 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.

COPYRIGHT 2000 American Academy of Family Physicians

COPYRIGHT 2000 Gale Group