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Rofecoxib

A Review of its Use in the Management of Osteoarthritis, Acute Pain and Rheumatoid Arthritis

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Summary

Abstract

Rofecoxib is a selective cyclo-oxygenase (COX)-2 inhibitor which has little or no effect on the COX-1 isoenzyme at doses up to 1000 mg/day. Rofecoxib has greater selectivity for COX-2 than celecoxib, meloxicam, diclofenac and indomethacin.

In well-controlled clinical trials, rofecoxib 12.5 to 500 mg/day has been evaluated for its efficacy in the treatment of osteoarthritis, acute pain and rheumatoid arthritis [lower dosages (5 to 125 mg/day) were generally used in the chronic pain indications]. In the treatment of patients with osteoarthritis, rofecoxib was more effective in providing symptomatic relief than placebo, paracetamol (acetaminophen) and celecoxib and was similar in efficacy to ibuprofen, diclofenac, naproxen and nabumetone. Overall, both the physician’s assessment of disease status and the patient’s assessment of response to therapy tended to favour rofecoxib. In patients with postsurgical dental pain, pain after spinal fusion or orthopaedic surgery, or primary dysmenorrhoea, rofecoxib provided more rapid and more sustained pain relief and reduced requirements for supplemental morphine use after surgery than placebo. Rofecoxib was more efficacious than celecoxib in patients with acute dental pain and pain after spinal fusion surgery, although celecoxib may have been used at a subtherapeutic dose. In comparison with traditional nonsteroidal anti-inflammatory drugs (NSAIDs) ibuprofen, diclofenac and naproxen sodium, rofecoxib was similar in efficacy in the treatment of acute pain. Although naproxen sodium provided more rapid pain relief than rofecoxib in patients with primary dysmenorrhoea, the reverse was true after orthopaedic surgery: rofecoxib provided more rapid pain relief and less supplemental morphine was needed. Rofecoxib was as effective as naproxen in providing symptomatic relief for over 8700 patients with rheumatoid arthritis.

Compared with traditional NSAID therapy, rofecoxib had a significantly lower incidence of endoscopically confirmed gastroduodenal ulceration and, in approximately 13 000 patients with osteoarthritis and rheumatoid arthritis, a lower incidence of gastrointestinal (GI) adverse events. Rofecoxib was generally well tolerated in all indications with an overall tolerability profile similar to traditional NSAIDs. The most common adverse events in rofecoxib recipients were nausea, dizziness and headache.

In conclusion, rofecoxib is at least as effective as traditional NSAID therapy in providing pain relief for both chronic and acute pain conditions. Rofecoxib provides an alternative treatment option to traditional NSAID therapy in the management of symptomatic pain relief in patients with osteoarthritis. Initial data from patients with primary dysmenorrhoea and postoperative pain are promising and further trials may confirm its place in the treatment of these indications. Rofecoxib has also shown promising results in patients with rheumatoid arthritis and is likely to become a valuable addition to current drug therapy for this patient population. Importantly, rofecoxib is associated with a lower incidence of GI adverse events than traditional NSAIDs making it a primary treatment option in patients at risk of developing GI complications or patients with chronic conditions requiring long term treatment.

Pharmacodynamic Profile

Rofecoxib is a selective and potent cyclo-oxygenase (COX)-2 inhibitor both in vitro and in vivo. In vitro, concentrations of rofecoxib required to inhibit COX-2 by 50% (IC50) were 0.018 to 0.046 µmol/L; there was no appreciable effect on the COX-1 isoenzyme. In 25 healthy volunteers, the IC50 value for inhibition of COX-2 activity by rofecoxib 25 to 1000mg was 0.77 µmol/L; in contrast, the IC50 value for indomethacin 5 to 75mg was 0.3 µmol/L. There was no significant inhibition of COX-1 with rofecoxib; the indomethacin IC50 for COX-1 was 0.09 µmol/L. In vitro rofecoxib has a higher selectivity ratio (COX-1 IC50/COX-2 IC50) for COX-2 inhibition than celecoxib, meloxicam, diclofenac and indomethacin.

It has also demonstrated analgesic and antipyretic effects in 94 patients with fever caused by an upper respiratory tract infection (URTI) or suspected benign systemic viral infection. Single doses of rofecoxib 12.5 or 25mg or ibuprofen 400mg significantly reduced body temperature within 1 to 1.5 hours and 30 minutes of administration, respectively, compared with placebo. Similar results have been demonstrated in animal models of inflammation, pain and fever.

Rofecoxib treatment had less effect on the gastrointestinal (GI) mucosa than aspirin, naproxen, ibuprofen and indomethacin. In 24 healthy volunteers, gastric mucosal prostaglandin E2 (PGE2) synthesis was increased 18% by rofecoxib 50 mg/day and decreased 65% by naproxen 500mg twice daily; in turn, COX-2 dependent lipopolysaccharide PGE2 production was inhibited by approximately 80% for both. Serum thromboxane (TXB2) generation (a measure of COX-1 activity) was unaffected by rofecoxib and inhibited by 94% with naproxen. Intestinal permeability was 3-fold higher with indomethacin 150 mg/day than with rofecoxib 25 or 50 mg/day or placebo. GI microbleeding was associated with ibuprofen 2400 mg/day treatment resulting in a higher rate of faecal blood loss than with rofecoxib 25 or 50 mg/day (2 vs 1ml/day) in 67 healthy volunteers.

Rofecoxib had no effect on TXB2 inhibition or the anti-platelet activity of low-dose aspirin in an ex vivo study in 24 healthy volunteers. Likewise in vitro, rofecoxib had no effect on TXB2 production by calcium ionophore-challenged human platelets.

Pharmacokinetic Profile

After oral administration, single 12.5 or 25mg doses of rofecoxib are well absorbed, reaching maximum plasma concentrations (Cmax) of approximately 207 µg/L 2 to 3 hours after administration of rofecoxib 25mg. A steady-state Cmax of 321 µg/L was reached within 4 days. The mean oral bioavailability of a 12.5 to 50mg dose was 93%. If rofecoxib is administered with food, the time to reach Cmax is delayed by 1 to 2 hours.

At concentrations of 0.05 to 25 mg/L, rofecoxib is largely bound to plasma proteins (87%); tissue distribution has not yet been characterised in humans. Radioactively labelled rofecoxib is extensively metabolised within the liver to 2 inactive cis-dihydro and trans- dihydro metabolites which together account for approximately 56% of radioactivity recovered in the urine. The elimination half-life of rofecoxib is approximately 17 hours. Elimination occurs via hepatic metabolism with <1% of a rofecoxib dose excreted unchanged in the urine. Approximately 14% of a single 125mg radiolabelled dose of rofecoxib was excreted unchanged in the faeces.

In those aged ≥65 years, oral administration of rofecoxib 25mg results in a 34% increase in the area under the plasma concentration-time curve (AUC) compared with younger adults; while dosage adjustment is not necessary, treatment should be initiated at the lowest possible dose in these patients. Absorption is also decreased when rofecoxib is administered concurrently with calcium carbonate or magnesium/aluminium antacids in this patient group.

Limited data are available on the pharmacokinetics of rofecoxib in patients with renal or hepatic impairment. The AUC was increased by 69% in 4 individuals with moderate hepatic impairment compared with 4 healthy individuals. There are currently no data on patients with severe hepatic impairment. In 6 patients with end-stage renal failure undergoing dialysis 4 hours after the administration of rofecoxib, Cmax and AUC were decreased by 18 and 9%, respectively. To date there are no data on the effects of rofecoxib in advanced renal disease; therefore rofecoxib is not recommended in these patients.

Concurrent administration of rofecoxib and oral prednisone or intravenous prednisolone had no clinically significant effects on the pharmacokinetics of prednisone or prednisolone. Likewise, serum concentrations of digoxin, ethinylestradiol and norethindrone were unaffected by coadministration of rofecoxib. In patients with rheumatoid arthritis, the addition of rofecoxib 12.5, 25 or 50mg to a stable methotrexate regimen (7.5 to 15 mg/week) had no clinically significant effect on methotrexate plasma concentrations. The plasma concentration of rofecoxib 75 mg/day was increased and the renal clearance of methotrexate 7.5 to 15 mg/week was decreased when these drugs were coadministered at these dosages. When rofecoxib is coadministered with either warfarin or rifampicin, patients should be monitored for potential interactions.

Therapeutic Efficacy

Rofecoxib is more effective than placebo, paracetamol (acetaminophen), nabumetone or celecoxib and is generally as effective as the traditional NSAIDs ibuprofen, naproxen (or naproxen sodium) or diclofenac in the treatment of osteoarthritis or acute pain. It has shown promising results compared with naproxen in patients with rheumatoid arthritis.

Osteoarthritis. In the treatment of osteoarthritis, rofecoxib 12.5 to 125 mg/day for 6 weeks was significantly more effective than placebo in improving pain compared with baseline values as assessed by the Western Ontario McMasters Universities Osteoarthritis Index (WOMAC) and the patient’s assessment of arthritic pain.

In comparative trials with other NSAIDs, pain when walking showed a significantly greater improvement with rofecoxib 12.5 or 25 mg/day than with celecoxib 200 mg/day or paracetamol 1000 mg/day. Furthermore, rofecoxib was similar in efficacy when compared with ibuprofen 2400 mg/day, diclofenac 150 mg/day or naproxen 1000 mg/day. Patient assessment of response to therapy, physician global assessment of disease status and the WOMAC pain subscale scores were also similar for rofecoxib and diclofenac but the 2 former scales showed slightly greater improvement with rofecoxib compared with ibuprofen; reaching significance in 1 study. Data from 1 study show that diclofenac was significantly better than rofecoxib for patient assessment of response to therapy, physician global assessment of disease status and patient global assessment of disease status. Joint space narrowing, signifying disease progression, decreased in over 700 patients receiving rofecoxib 12.5 or 50 mg/day and diclofenac in two 1-year trials.

Postsurgical dental pain. Postsurgical dental pain was relieved more rapidly, and at 8 hours after administration of the study drug, total pain relief was greater, with single doses of rofecoxib 12.5 to 500mg than with either placebo or a single dose of celecoxib 200mg. Single doses of rofecoxib and ibuprofen 400mg had similar effects on these measures. A longer duration of analgesic effect and less need for rescue medication 24 hours after drug administration was also seen with rofecoxib recipients compared with placebo, ibuprofen or celecoxib. Single 50 and 500mg doses of rofecoxib were not significantly different with respect to total pain relief scores at 8 hours, although rofecoxib 50mg showed significantly better efficacy than 12.5 but not 25mg. However, comparisons between rofecoxib and celecoxib must be interpreted cautiously because celecoxib was given at doses recommended for osteoarthritis, which may have been subtherapeutic in this indication.

Postoperative surgical pain. Rofecoxib 50mg was effective in relieving acute pain in patients who had spinal fusion or orthopaedic surgery. Compared with celecoxib 200mg and placebo, rofecoxib recipients who had spinal fusion surgery had significantly lower verbal analogue pain scores (VbAS) at 12 and 16 hours postoperatively (p < 0.03). Rofecoxib VbAS scores remained numerically lower than placebo or celecoxib recipients up to 20 hours postoperatively. In addition, rofecoxib recipients required significantly less supplemental morphine than celecoxib or placebo recipients. Again, caution must be exercised in interpreting comparative data for rofecoxib and celecoxib, since subtherapeutic doses may have been used. In the treatment of 218 patients who underwent orthopaedic surgery, rofecoxib 50mg provided significantly greater pain relief up to 8 hours postoperatively than placebo and similar pain relief compared with naproxen sodium 550mg. However, compared with both naproxen sodium and placebo, rofecoxib provided a more rapid onset of pain relief and less supplemental morphine was required. There were no differences between rofecoxib 50mg and placebo in terms of visual analogue scale scores, patient assessment of overall pain relief or supplemental morphine use in the treatment of radical prostectomy in a small study.

Primary dysmenorrhoea. In patients with primary dysmenorrhoea, rofecoxib 25 or 50mg was similar in efficacy to naproxen sodium 550mg and significantly better than placebo for providing pain relief up to 8 hours after the onset of moderate to severe pain. Patient evaluation of the study drug favoured rofecoxib when compared with placebo (p ≤ 0.006); patient preference was similar for rofecoxib and naproxen sodium. However, time to actual pain intensity difference relative to baseline was shortest for naproxen sodium (1 hour vs 1.5 hours for rofecoxib and placebo (p ≤ 0.006). A significantly greater proportion of placebo than either rofecoxib or naproxen sodium recipients required rescue medication and took extra doses of study medication within 12 hours of pain onset (p ≤ 0.006).

Rheumatoid arthritis. After a median of 9 months, rofecoxib 50mg once daily had similar efficacy compared with naproxen 500mg twice daily for improvements in global disease activity and investigator assessment of efficacy in over 8000 patients with rheumatoid arthritis. There were no statistically or clinically significant differences between rofecoxib and naproxen in the improvement in the Modified Health Assessment Questionnaire score compared with baseline. In a smaller study (n = 658), rofecoxib 25 and 50mg were significantly better than placebo in achieving a 20% improvement in various American College of Rheumatology parameters after 8 weeks of therapy. The results held for individual efficacy measurements and were maintained 1 year after the initiation of therapy. Co-administration of methotrexate had no significant effect on either treatment.

Tolerability

GI Adverse Events. The incidence of withdrawal because of a GI adverse event (perforations, ulcerations and bleeding; PUB) was lower for rofecoxib (3.5%) than for traditional NSAIDs ibuprofen, diclofenac or nabumetone (4.8%), according to the results of a meta-analysis of 8 double-blind randomised studies including a total of over 5000 patients with osteoarthritis. Furthermore, a significant difference between rofecoxib and the traditional NSAIDs in the incidence of PUBs was evident as early as 6 weeks (p = 0.004). At 12 months, the rate per 100 patient-years for GI adverse events was significantly lower with rofecoxib (p = 0.01). Endoscopy confirmed the lower incidence of GI ulceration ≥3mm and ≥5mm with rofecoxib treatment 25 or 50 mg/day than with ibuprofen 2400 mg/day (p < 0.001).

A lower overall incidence of confirmed upper GI events was reported with rofecoxib (1.4%) than with naproxen (3%) in over 8000 patients with rheumatoid arthritis enrolled in the VIGOR (VIOXX Gastrointestinal Outcomes Research) study. The relative risk (RR) of a confirmed upper GI event for rofecoxib versus naproxen was 0.5 (p < 0.001). The RR of a complicated confirmed upper GI event was 0.4 (p = 0.005). Similarly the RR of complicated upper GI bleeding and bleeding beyond the duodenum was 0.4 (p = 0.004) and 0.5 (p = 0.03), respectively.

Cardiovascular Adverse Events. In the VIGOR study, the mortality rates in over 8000 patients with rheumatoid arthritis were comparable with rofecoxib and naproxen (0.5 vs 0.4%). The mortality rate from cardiovascular causes was 0.2% for both treatment groups. However, the incidence of myocardial infarctions was higher for rofecoxib (0.4 vs 0.1% with naproxen); within this group, 38% of those who had a myocardial infarction were eligible for aspirin as a secondary prophylaxis but were not receiving this therapy. When these patients were excluded from the analysis, the incidence of myocardial infarction was 0.2% for rofecoxib and 0.1% for naproxen. A lower incidence of thromboembolic cardiovascular events was reported with rofecoxib 12.5 and 25mg than with diclofenac 150 mg/day in a 1-year study of 784 patients with osteoarthritis.

General Tolerability Profile. Rofecoxib was generally well tolerated in the clinical trials of patients with osteoarthritis, acute pain or rheumatoid arthritis. In patients with osteoarthritis, adverse events reported with a higher incidence with rofecoxib 25 or 125 mg/day than with placebo, included URTI (9.6 and 13.5% for rofecoxib 25 and 125mg vs 5.6% for placebo) headache (5.5 and 12.2 vs 6.9%), viral syndrome (6.8 and 4.1 vs 1.4%) and sinusitis (4.1 for both rofecoxib doses vs 2.8%). Likewise URTI, sinusitis and heartburn were reported with a higher incidence with rofecoxib 12.5 or 25 mg/day than with diclofenac 150 mg/day, although these differences were not significant. However, a lower incidence of URTI (2.9 for rofecoxib vs 5% for diclofenac/misoprostol), abdominal pain (8.7 vs 13.3%), diarrhoea (6.2 vs 19.9%), dyspepsia (2.9 vs 10.8%), epigastric discomfort (3.7 vs 11.2%), headache (5.8 vs 9.5%) and nausea (8.3 vs 10.4%) were associated with rofecoxib 12.5 mg/day than with diclofenac/misoprostol (50mg/200µg twice daily). A lower incidence of epigastric discomfort and a similar incidence of diarrhoea were reported with rofecoxib 12.5 or 25 mg/day compared with ibuprofen 800mg 3 times daily. However, a higher incidence of nausea was associated with rofecoxib 25mg.

In the treatment of postsurgical dental pain, rofecoxib 50 mg/day was generally associated with a lower incidence of nausea, headache and vomiting compared with placebo, ibuprofen 400 mg/day and celecoxib 200 mg/day.

In patients with postoperative surgical pain, constipation, nausea and fever were the most commonly reported adverse events with rofecoxib 25 or 50mg therapy. Rofecoxib 25 or 50 mg/day was associated with a lower incidence of constipation than either placebo or naproxen sodium 550 mg/day; a higher incidence of nausea was noted with rofecoxib 50 mg/day than with naproxen sodium or placebo and there was a higher incidence of fever with rofecoxib 50 mg/day compared with naproxen.

Nausea and dry mouth were the most commonly reported adverse effects associated with rofecoxib 25 or 50mg in the treatment of primary dysmenorrhoea. In these patients a higher proportion of rofecoxib recipients experienced an adverse event compared with placebo or naproxen sodium 550mg recipients.

The most common adverse events occurring in patients with rheumatoid arthritis were diarrhoea, headache, fatigue and dizziness. The incidences of headache and fatigue were lower with rofecoxib than placebo. The incidences of lower extremity oedema were low and were similar between the treatment groups.

Pharmacoeconomic Considerations

There are few formal data on the pharmacoeconomics of rofecoxib. In patients with osteoarthritis, rofecoxib has a slightly higher acquisition cost per patient than other commonly used NSAIDs ($1.60 vs 1.67 per day, Canadian (Can) dollars), leading to an incremental annual cost of $24.45 per patient using rofecoxib. Higher costs may be attributed to patients using rofecoxib in the treatment of acute pain, because higher dosages are generally used for this indication. On the other hand, however, rofecoxib is associated with a reduction of 0.0109 PUBs per patient per year which translates into costs per PUB averted of $Can2247.

In patients with rheumatoid arthritis and a high risk of developing NSAID-induced GI complications, 40 patients would need to be treated with rofecoxib to prevent 1 ulcer complication (assuming rofecoxib reduced the risk by 50%); this equates to a yearly incremental cost of $US30 000 based on 1999 US data comparing rofecoxib 25 mg/day with a generic NSAID such as naproxen. More than 500 patients with rheumatoid arthritis and a low risk of developing an NSAID-induced GI complication would need to be treated to prevent 1 ulcer (based on similar assumptions) at a yearly incremental cost of $US400 000.

Dosage and Administration

In the US, rofecoxib is approved for the treatment of osteoarthritis and acute pain including dental pain, postsurgical pain and primary dysmenorrhoea in adults. It is available in tablet form 12.5 or 25mg or as a suspension 12.5 or 25mg in 5ml. For patients with osteoarthritis, the recommended initial dose is 12.5 mg/day; this dose may be increased up to a maximum of 25 mg/day. For the treatment of acute pain, the recommended initial daily dosage is 50mg and 50mg may be given on subsequent days as needed. Doses of up to 1000mg have been evaluated in clinical trials; however, there are few tolerability data at this dose level. Rofecoxib can be administered with or without food.

Physicians and patients should be alert for ulceration and bleeding even in the absence of previous GI symptoms. Rofecoxib is not recommended in patients with moderate or severe hepatic impairment, advanced kidney disease, pre-existing asthma, aspirin-sensitive asthma, hypersensitivity to rofecoxib or at a late stage in pregnancy. Patients using rofecoxib long term should be monitored for the development of hypertension and oedema and have their haemoglobin or haematocrit checked if they exhibit signs or symptoms of anaemia or blood loss. Caution should be used in patients with hypertension or heart failure.

Caution should be used when coadministering rofecoxib with ACE inhibitors, rifampicin, warfarin, methotrexate, lithium and aspirin. Coadministration of rofecoxib with either cimetidine or ketoconazole did not have any clinically significant effect on the pharmacokinetics of rofecoxib.

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Notes

  1. Aggregate of commonly usedNSAIDs inOntario,Canada.

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Authors and Affiliations

  1. Adis International Limited, 41 Centorian Drive, Private Bag 65901, Mairangi Bay, Auckland 10, New Zealand

    Anna J. Matheson & David P. Figgitt

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  1. Anna J. Matheson
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Correspondence to Anna J. Matheson.

Additional information

Various sections of the manuscript reviewed by: B. Bannwarth, Laboratoire de Thérapeutique, Université Victor Segalen Bordeaux, Bordeaux, Cedex, France; W. Bolten, Rheumatologie, Klaus-Miehlke-Klinik, Weisbaden, Germany; G. Cannon, University of Utah College of Medicine, Salt Lake City, Utah, USA; G. de Pouvourville, Centre de Recherche en Gestion, Ecole Polytechnique, Paris, France; T. Schnitzer, The Office of Clinical Research and Training, Northwestern University School of Medicine, Chicago, Illinois, USA.

Data Selection

Sources: Medical literature published in any language since 1983 on rofecoxib, identified using Medline and EMBASE, supplemented by AdisBase (a proprietary database of Adis International, Auckland, New Zealand). Additional references were identified from the reference lists of published articles. Bibliographical information, including contributory unpublished data, was also requested from the company developing the drug.

Search strategy: Medline search terms were ‘rofecoxib’ or ‘MK 966’. EMBASE search terms were ‘rofecoxib’ or ‘MK 966’. AdisBase search terms were ‘rofecoxib’ or ‘MK-966’. Searches were last updated 4/04/2001.

Selection: Studies in patients with osteoarthritis, rheumatoid arthritis, postoperative dental pain, postoperative surgical pain or primary dysmenorrhoea who received rofecoxib. Inclusion of studies was based mainly on the methods section of the trials. When available, large, well controlled trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic and pharmacokinetic data are also included.

Index terms: rofecoxib, osteoarthritis, rheumatoid arthritis, postoperative dental pain, postoperative surgical pain, primary dysmenorrhoea, pharmacodynamics, pharmacokinetics, therapeutic use.

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Matheson, A.J., Figgitt, D.P. Rofecoxib. Drugs 61, 833–865 (2001). https://doi.org/10.2165/00003495-200161060-00019

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