Valdecoxib

Valdecoxib is an orally administered, highly selective cyclo-oxygenase (C0X)-2 inhibitor with anti-inflammatory and analgesic properties.

In well designed trials, valdecoxib demonstrated efficacy versus placebo in patients with osteoarthritis (OA), rheumatoid arthritis (RA), primary dysmenor-rhoea and postoperative pain. Initial results in patients with migraine headache were promising. The efficacy of valdecoxib appears dose dependent up to 40 mg/ day.

Valdecoxib 10 mg/day was as effective as naproxen and rofecoxib in improving signs and symptoms of OA. The American College of Rheumatology 20% response rate was similar in recipients of valdecoxib, naproxen and diclofenac in patients with RA. In patients with dysmenorrhoea, valdecoxib 20 or 40mg up to twice daily provided as effective pain relief as naproxen sodium 550mg twice daily.

In acute post-surgical pain, single-dose valdecoxib 40mg had a rapid onset of action, provided similar analgesia to oxycodone 10mg plus paracetamol (acetaminophen) 1000mg and provided a longer time to rescue medication than rofecoxib or oxycodone/paracetamol after oral surgery. Pre-emptive administration of valdecoxib 10–80mg was particularly effective in dental pain. Valdecoxib had opioid-sparing effects after hip or knee arthroplasty and reduced pain after laparoscopic cholecystectomy.

Valdecoxib is generally well tolerated. The incidence of gastroduodenal ulcers was generally lower than with nonselective NSAIDs (i.e. NSAIDs not specifically developed as selective COX-2 inhibitors). With concomitant aspirin, the ulcer rate in valdecoxib recipients increased significantly, but was still lower than that in recipients of aspirin plus nonselective NSAIDs.

In conclusion, valdecoxib, a COX-2-selective inhibitor, is as efficacious in pain relief as nonselective NSAIDs, with better gastrointestinal tolerability. It was as effective in RA, OA and primary dysmenorrhoea (the approved indications) as nonselective NSAIDs and as effective as rofecoxib in RA flare. In acute post-surgical pain, valdecoxib provided similar pain relief to oxycodone/paracetamol, had a long duration of action, a rapid onset of analgesia and was opioid-sparing. Valdecoxib provides a valuable alternative in the treatment of chronic arthritis pain and acute pain.

Valdecoxib (a ‘coxib’) is a highly selective inhibitor of cyclo-oxygenäse (C0X)-2 with anti-inflammatory and analgesic properties. This selectivity is the likely mechanism conferring the better gastrointestinal (GI) tolerability profile of coxibs relative to NSAIDs not specifically developed as selective COX-2 inhibitors (referred to here as nonselective NSAIDs). In an in vitro study, the valdecoxib concentration required to inhibit 50% of enzyme activity was 0.005 μmol/L for COX-2, but was 140 μmol/L for COX-1. Binding of valdecoxib to COX-2 is reversible and inhibited by nonselective NSAIDs. An in vitro study found valdecoxib only weakly antagonised the anti-platelet effect of aspirin.

In healthy male volunteers, valdecoxib 10 mg/day was rapidly absorbed, reaching a steady-state mean maximum plasma concentration (C_max) of 161 ng/mL after a mean 2.25 hours (t_max). A single dose of valdecoxib 50mg reached a mean C_max of 1040 ng/mL at a tmax of 1.7 hours. Absorption may be delayed by up to 2 hours by food. The elimination half-life of valdecoxib was ≈7–8 hours; this increased in elderly patients, with overall exposure to valdecoxib increasing by 30–40%. In patients with moderate hepatic impairment, exposure to valdecoxib is increased by 130%.

Valdecoxib is extensively metabolised via cytochrome P450 (CYP) isoenzymes, especially CYP3A4 and CYP2C9, and interacts with some drugs metabolised by CYP isoenzymes (e.g. fluconazole, dextromethorphan and omeprazole). Excretion is mainly renal (76% of a radiolabelled valdecoxib dose) and metabolites are mostly excreted via the kidney.

In healthy volunteers, coadministration of valdecoxib and warfarin significantly increased the international normalised ratio and its variability. Exposure to lithium, or ethinylestradiol/norethisterone (norethindrone) 35μg/1μg increased with coadministration of valdecoxib.

Oral valdecoxib was more effective than placebo (p < 0.05) and similar in efficacy to nonselective NSAIDs in patients with osteoarthritis (OA), rheumatoid arthritis (RA), primary dysmenorrhoea, acute postoperative pain and migraine headache in randomised, double-blind trials. ]In 12-week studies in patients with OA of the hip or knee, valdecoxib 10 or 20 mg/day generally improved global assessments (e.g. composite arthritis index scores) by 27–37% from baseline and pain assessments (e.g. patient’s perception of arthritis pain) by 26–45%, to a significantly greater extent than placebo (10–30% and 12–36%, respectively). Valdecoxib 10 or 20 mg/day had similar efficacy to naproxen 500mg twice daily (stable OA) and valdecoxib 10 mg/day was similar to rofecoxib 25 mg/day in reducing pain intensity in a 2-week study in patients with a flare of OA of the knee.

In patients with stable RA, American College of Rheumatology 20% (ACR-20) response rates and improvements in ACR-20 components were similar (32–36%) in patients receiving valdecoxib 20 or 40 mg/day or diclofenac slow release 75mg twice daily for 26 weeks. In patients experiencing an RA flare, valdecoxib 10–40 mg/day had similar efficacy to naproxen 500mg twice daily for 12 weeks and resulted in significantly better outcomes, including ACR-20 response rates (46–49%), than placebo (32%).

Valdecoxib 20 or 40mg twice daily as required for 3 days provided significant pain relief and reduced pain intensity (time weighted total of pain relief [TOTPAR] and time weighted sum of pain intensity difference) compared with placebo 8 and 12 hours after the first dose in patients with primary dysmenor-rhoea, with some dose-dependent effects evident. Naproxen sodium 550mg had similar efficacy.

In postoperative dental pain, valdecoxib 20 or 40mg (mostly single doses) was significantly better than placebo, based on onset of analgesia, 6- and 24-hour TOTPAR scores and time to rescue medication.

Preoperative valdecoxib administration was particularly effective. Postoperative pain intensity was significantly reduced versus placebo with valdecoxib 40 and 80mg administered before bunionectomy, and with parecoxib administered before laparoscopic cholecystectomy. Use of opioids reduced by 16–43% relative to placebo, and pain intensity significantly reduced in patients receiving valdecoxib 20 or 40mg twice daily following knee or hip arthroplasty.

Valdecoxib 40mg showed some advantages over rofecoxib 50mg; in one study, valdecoxib recipients had a faster onset of analgesia (<30 minutes) and, in another, had significantly higher TOTPAR scores and a significantly longer time to rescue medication. In two studies, valdecoxib 40mg was associated with significantly higher 24-hour TOTPAR scores and a significantly longer time to rescue medication than oxycodone/paracetamol.

Preliminary reports found a single dose of valdecoxib 40mg to be better than placebo in patients with moderate-to-severe migraine headache pain (resulting in mild or no pain in 48% vs 30% and relief of associated symptoms like nausea and phonophobia at 2 hours postdose). Valdecoxib 40–60mg was effective in up to three consecutive headaches and valdecoxib 20mg also significantly improved migraine pain and some other symptoms relative to placebo.

Valdecoxib was generally well tolerated in clinical trials. The incidence of headache, dizziness and fever was generally similar in recipients of valdecoxib and placebo.

GI symptoms other than ulcers had a similar incidence in valdecoxib and placebo recipients in most large, well designed trials, and the incidence of individual and total GI symptoms was similar in valdecoxib and placebo groups in a large pooled analysis. Exceptions were a higher incidence of total GI symptoms with valdecoxib 10 (but not 20) mg/day, ibuprofen and diclofenac than with placebo in a trial in patients with OA and, in patients with RA receiving a supratherapeutic dose of valdecoxib 40 mg/day for 12 weeks, significantly more dyspepsia than in those receiving placebo.

In patients with OA or RA, the incidence of endoscopically-proven gastric and gastroduodenal ulcers was significantly lower with valdecoxib 5–40 mg/day than with diclofenac, ibuprofen or naproxen (although in one trial there was no significant difference between valdecoxib 20 mg/day and naproxen).

The incidence of duodenal ulcers was significantly lower with valdecoxib 20 and 40 mg/day than with diclofenac 75mg twice daily in two studies, although no significant differences were seen between valdecoxib and other nonselective NSAIDs in the incidence of duodenal ulcers. The incidence of gastroduodenal ulcers was significantly greater in valdecoxib recipients who also used aspirin than in those who did not, although the incidence in valdecoxib plus aspirin recipients was still lower than that in nonselective NSAID plus aspirin recipients.

In a pooled analysis of eight 12- to 26-week trials in patients with OA or RA, the incidence of ulcer complications (perforation, obstruction or bleeding) was significantly lower with valdecoxib 5–80 mg/day than with nonselective NSAIDs.

In individual trials, no renal adverse effects occurred significantly more frequently in valdecoxib recipients than in other treatment groups or placebo recipients. However, a pooled analysis of almost 1000 patients with arthritis found a significantly increased incidence of renal events (mostly oedema or deterioration in blood pressure control) in patients receiving valdecoxib 10 mg/day (3%, similar to that with nonselective NSAIDs, vs 1% with placebo).

Pooled analyses of 6- to 52-week trials in >7900 arthritic patients found no difference in the incidence of thrombotic events between recipients of valdecoxib, other NSAIDs (ibuprofen, diclofenac or naproxen) and placebo.

Valdecoxib is approved in the US and some countries in the EU for the treatment of the signs and symptoms of OA and adult RA and for primary dysmenorrhoea. Dosage recommendations, contraindications and cautions differ between the EU and the US.

In the US, the approved dosage of oral valdecoxib for the treatment of arthritis is 10mg once daily, with no dosage adjustment required in patients aged >65 years. For primary dysmenorrhoea, the approved dosage is 20mg twice daily as required. In the EU countries in which valdecoxib is approved, the dosage for arthritis is 10mg once daily up to 20mg once daily if needed; treatment should be initiated at the lower dosage in patients aged >65 years. For primary dysmenorrhoea, the approved dosage is 40mg up to twice daily on day 1 and once daily on subsequent days. p ]Clinically significant drug interactions have occurred with drugs which are metabolised by CYP isoenzymes, including CYP2D6. Caution is recommended with concomitant administration of valdecoxib and other CYP2D6 substrates that have a narrow therapeutic index (e.g. flecainide, propafenone and metoprolol). Interactions with ACE inhibitors, reducing their antihypertensive effects, and with furosemide and thiazide diuretics, reducing their natriuretic effect, may also occur.