The safety profile, tolerability, and effective dose range of rofecoxib in the treatment of rheumatoid arthritis

doi:10.1016/S0149-2918(99)80048-4

Clinical Therapeutics

Volume 21, Issue 10, October 1999, Pages 1688-1702

https://doi.org/10.1016/S0149-2918(99)80048-4 Get rights and content

Abstract

Nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit both cyclooxygenase (COX)-1 and COX-2 isoenzymes and are effective in the treatment of inflammatory disorders. This 8-week, double-masked, placebo-controlled trial was undertaken to assess the safety profile, tolerability, and effective dose range of once-daily rofecoxib, a COX-2-specific inhibitor, in the treatment of rheumatoid arthritis (RA). After a 3- to 15-day washout of prior NSAID therapy, 658 patients were randomly allocated to receive placebo or rofecoxib 5 mg, 25 mg, or 50 mg once daily. Safety profile, tolerability, and efficacy were evaluated after 2, 4, and 8 weeks of therapy. Six hundred fifty-eight patients (168, 158, 171, and 161 in the placebo and 5-mg, 25-mg, and 50-mg rofecoxib groups, respectively) were enrolled at 79 clinical centers in the United States. Mean age was 55 years, mean duration of RA was 10 years, and 506 (77%) of the 658 patients were female. All groups had similar baseline demographic characteristics. Patients taking rofecoxib 25 and 50 mg showed significant clinical improvement compared with those taking placebo; 43.9% in the rofecoxib 25-mg group and 49.7% in the rofecoxib 50-mg group completed the treatment period and achieved an American College of Rheumatology 20 response (P = 0.025 and 0.001 vs placebo, respectively). The 5-mg dose of rofecoxib did not differ significantly from placebo. Patients in the rofecoxib 25- and 50-mg groups showed significant improvement in key individual efficacy measurements, including patient global assessment of pain, patient and investigator global assessment of disease activity, and Stanford Health Assessment Questionnaire Disability Index (P < 0.05 vs placebo). Compared with placebo, significantly fewer patients in the 25-mg and 50-mg rofecoxib groups discontinued therapy because of lack of efficacy (P = 0.02 and P = 0.032, respectively). Our results show that rofecoxib 25 and 50 mg once daily was effective and generally welltolerated in patients with RA.

References (51)

JonesDA et al.
Molecular cloning of human prostaglandin endoperoxide synthase type II and demonstration of expression in response to cytokines
J Biol Chem
(1993)
WalengaRW et al.
Constitutive expression of prostaglandin endoperoxide G/H synthetase (PGHS) -2 but not PGHS-1 in human tracheal epithelial cells in vitro
Prostaglandins
(1996)
Lyons-GiordanoB et al.
Interleukin-1 differentially modulates chondrocyte expression of cyclooxygenase-2 and phospholipase A2
Exp Cell Res
(1993)
BerenbaumF et al.
Synergistic effect of interleukin-1 β and tumor necrosis factor a or PGE2 production by articular chondrocytes does not involve PLA2 stimulation
Exp Cell Res
(1996)
MeadeEA et al.
Differential inhibition of prostaglandin endoperoxide synthase (cyclooxygenase) isozymes by aspirin and other non-steroidal anti-inflammatory drugs
J Biol Chem
(1993)
LangmanMJS et al.
Risks of bleeding peptic ulcer associated with individual non-steroidal anti-inflammatory drugs
Lancet
(1994)
HawkeyCJ
COX-2 inhibitors
Lancet
(1999)
SteinCM et al.
Placebo-controlled studies in rheumatoid arthritis: Ethical issues
Lancet
(1999)
RochonPA et al.
Are randomized control trial outcomes influenced by the inclusion of a placebo group? A systematic review of non-steroidal antiinflammatory drug trials for arthritis treatment
J Clin Epidemiol
(1999)
ACR Clinical Guidelines Committee
Guidelines for the management of rheumatoid arthritis
Arthritis Rheum
(1996)

VaneJR

Inhibition of prostaglandin synthesis as a mechanism of action of aspirin-like drugs

Nat New Biol

(1971)

SmithJB et al.

Aspirin selectivity inhibits prostaglandin production in human platelets

Nat New Biol

(1971)

SiriosJ et al.

Hormonal regulation of messenger ribonucleic acid encoding a novel isoform of prostaglandin endoperoxide H synthase in rat preovulatory follicles. Induction in vivo and in vitro

J. Biol Chem

(1992)

KujubuDA et al.

TIS10, a phorbol ester tumor promoterinducible mRNA from Swiss 3T3 cells, encodes a novel prostaglandin synthase/cyclooxygenase homologue

J Biol Chem

(1991)

XieWL et al.

Expression of a mitogen-responsive gene encoding prostaglandin synthase is regulated by mRNA splicing

O'BanionMK et al.

cDNA cloning and functional activity of a glucocorticoid-regulated inflammatory cyclooxygenase

LuongC et al.

Flexibility of the NSAID binding site in the structure of human cyclooxygenase-2

Nat Struct Biol

(1996)

KurumbailRG et al.

Structural basis for selective inhibition of cyclooxygenase-2 by anti-inflammatory agents

Nature

(1996)

VaneJR et al.

Anti-inflammatory drugs and their mechanism of action

Inflamm Res

(1998)

WhittleBJR et al.

Selective inhibition of prostaglandin production in inflammatory exudates and gastric mucosa

Nature

(1980)

MoncadaS et al.

An enzyme isolated from arteries transforms prostaglandin endoperoxides to an unstable substance that inhibits platelet aggregation

Nature

(1976)

AkarasereenontP et al.

Involvement of tyrosine kinase in the induction of cyclo-oxygenase and nitric oxide synthase by endotoxin in cultured cells

Br J Pharmacol

(1994)

BlancoA et al.

Involvement of tyrosine kinases in the induction of cyclo-oxygenase-2 in human endothelial cells

Biochem J

(1995)

MitchellJA et al.

Selectivity of nonsteroidal anti-inflammatory drugs as inhibitors of constitutive and inducible cyclo-oxygenase

SiegleI et al.

Expression of cyclooxygenase 1 and cyclooxygenase 2 in human synovial tissue: Differential elevation of cyclooxygenase 2 in inflammatory joint diseases

Arthritis Rheum

(1998)

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2008, Seminars in Arthritis and Rheumatism
To assess the efficacy of cyclooxygenase-2 selective inhibitors (coxibs) in osteoarthritis (OA) and their gastrointestinal, cardiovascular, renovascular, and hepatic side effects compared with traditional nonsteroidal antiinflammatory drugs (NSAIDs) and acetaminophen.
Bibliographic database searches for randomized controlled trials, meta-analyses, and literature reviews.
Coxibs are comparable to traditional NSAIDs, providing moderate benefit for OA patients in pain and function versus placebo. NSAIDs, including coxibs, are superior to acetaminophen for OA, particularly in patients with moderate to severe pain. Coxibs decrease gastroduodenal ulcers (74% relative risk reduction) and ulcer complications (61% reduction) versus traditional NSAIDs. Meta-analysis of randomized trials indicates that coxibs increase the risk of myocardial infarctions approximately twofold versus placebo and versus naproxen, but do not increase the risk versus nonnaproxen NSAIDs. NSAIDs, including coxibs, commonly cause fluid retention and increase blood pressure and uncommonly induce congestive heart failure or significant renal dysfunction; risk factors include advanced age, hypertension, and heart or kidney disease. NSAIDs are a rare cause of clinical hepatotoxicity (<1 liver-related death per 100,000 NSAID users in clinical studies). Increased rates of aminotransferase elevations occur with rofecoxib (2%) and high-dose lumiracoxib (3%), and postmarketing cases of clinical liver injury with lumiracoxib have been reported recently.
Coxibs are as effective as traditional NSAIDs and superior to acetaminophen for the treatment of OA. Coxibs cause fewer gastrointestinal complications than traditional NSAIDs. Coxibs increase cardiovascular risk versus placebo and naproxen—but probably not versus nonnaproxen NSAIDs. Blood pressure commonly increases after initiation of selective or nonselective NSAIDs, especially in hypertensive patients.
Gastrointestinal Safety of Cyclooxygenase-2 Inhibitors: A Cochrane Collaboration Systematic Review
2007, Clinical Gastroenterology and Hepatology
Background & Aims: Nonselective non-steroidal anti-inflammatory drugs (NSAIDs) and cyclooxygenase-2 inhibitors (COX-2s) are used to treat a variety of arthritic and inflammatory conditions. The aim of this study was to assess the upper gastrointestinal (GI) harms of the long-term use of COX-2s, compared with nonselective NSAIDs and placebo, in arthritis sufferers. Methods: A systematic review of randomized controlled trials (RCTs) was conducted. Searches were conducted in (1) Cochrane Central Register of Controlled Trials (CENTRAL), (2) the Cochrane Collaboration Library (2005), (3) MEDLINE (to December 2006), and (4) Excerpta Medica Database (EMBASE) (to June 2005). Reference lists from trials and abstracts of conference proceedings were searched by hand, and experts were contacted to identify further relevant trials. RCTs of celecoxib, rofecoxib, etoricoxib, valdecoxib, and lumiracoxib were included if they reported on endoscopic ulcers, clinically important ulcer complications, or adverse gastrointestinal (GI) symptoms with the use of these COX-2s, compared with placebo or with nonselective NSAIDs. Study selection and data extraction were performed in duplicate by independent reviewers. Data were analyzed by using Review Manager 4.2 in accordance with accepted meta-analysis techniques. Results: Compared with nonselective NSAIDs, COX-2s produced significantly fewer gastroduodenal ulcers (relative risk, 0.26; 95% confidence interval, 0.23–0.30) and clinically important ulcer complications (relative risk, 0.39; 95% confidence interval, 0.31–0.50), as well as fewer treatment withdrawals caused by GI symptoms. The co-administration of acetylsalicylic acid appears to reduce the GI safety of COX-2s in subgroup analyses. Conclusions: COX-2s appear to offer greater upper GI safety and are better tolerated than nonselective NSAIDs. The co-administration of acetylsalicylic acid might reduce the safety advantage of COX-2s over that of nonselective NSAIDs.
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The safety profile, tolerability, and effective dose range of rofecoxib in the treatment of rheumatoid arthritis

Abstract

J Biol Chem

Prostaglandins

Exp Cell Res

Exp Cell Res

J Biol Chem

Lancet

Lancet

Lancet

J Clin Epidemiol

Guidelines for the management of rheumatoid arthritis

Arthritis Rheum

Inhibition of prostaglandin synthesis as a mechanism of action of aspirin-like drugs

Nat New Biol

Aspirin selectivity inhibits prostaglandin production in human platelets

Nat New Biol

Hormonal regulation of messenger ribonucleic acid encoding a novel isoform of prostaglandin endoperoxide H synthase in rat preovulatory follicles. Induction in vivo and in vitro

J. Biol Chem

TIS10, a phorbol ester tumor promoterinducible mRNA from Swiss 3T3 cells, encodes a novel prostaglandin synthase/cyclooxygenase homologue

J Biol Chem

Expression of a mitogen-responsive gene encoding prostaglandin synthase is regulated by mRNA splicing

cDNA cloning and functional activity of a glucocorticoid-regulated inflammatory cyclooxygenase

Flexibility of the NSAID binding site in the structure of human cyclooxygenase-2

Nat Struct Biol

Structural basis for selective inhibition of cyclooxygenase-2 by anti-inflammatory agents

Nature

Anti-inflammatory drugs and their mechanism of action

Inflamm Res

Selective inhibition of prostaglandin production in inflammatory exudates and gastric mucosa

Nature

An enzyme isolated from arteries transforms prostaglandin endoperoxides to an unstable substance that inhibits platelet aggregation

Nature

Involvement of tyrosine kinase in the induction of cyclo-oxygenase and nitric oxide synthase by endotoxin in cultured cells

Br J Pharmacol

Involvement of tyrosine kinases in the induction of cyclo-oxygenase-2 in human endothelial cells

Biochem J

Selectivity of nonsteroidal anti-inflammatory drugs as inhibitors of constitutive and inducible cyclo-oxygenase

Expression of cyclooxygenase 1 and cyclooxygenase 2 in human synovial tissue: Differential elevation of cyclooxygenase 2 in inflammatory joint diseases

Arthritis Rheum