VIOXX™

rofecoxib

12.5mg, 25mg Tablets

12.5mg, 25mg Oral suspension

Presentation

VIOXX 12.5 mg tablet is a cream/off-white round shallow cup tablet engraved 'MSD 74' on one side and 'VIOXX' on the other. Each tablet contains 12.5 mg of rofecoxib.

VIOXX 25 mg tablet is a yellow round tablet engraved 'MSD 110' on one side and 'VIOXX' on the other. Each tablet contains 25 mg of rofecoxib.

VIOXX oral suspension comes in 2 strengths, both are opaque white to faint yellow suspensions. Each 5 mL dose contains either 12.5 mg or 25 mg of rofecoxib.

Therapeutic Class

VIOXX (rofecoxib), is a member of a new class of arthritis/analgesia medications called Coxibs. VIOXX is a cyclooxygenase-2 (COX-2) specific inhibitor .

Indications

VIOXX is indicated for:

Acute and chronic treatment of the signs and symptoms of osteoarthritis.

Relief of pain.

Treatment of primary dysmenorrhoea.

Dosage and Administration

VIOXX is administered orally.

Osteoarthritis

The recommended starting dose is 12.5mg once daily. Some patients may receive additional benefit by increasing the dose to 25mg once daily. The maximum recommended daily dose is 25mg.

For the Relief of Acute Pain and Treatment of Primary Dysmenorrhea

The recommended initial dose is 50mg once daily. Subsequent doses should be 25 to 50mg once daily. The maximum recommended daily dose is 50mg.

No dosage adjustment is necessary for elderly patients, for patients with mild-to-moderate renal insufficiency (creatinine clearance 30 to 80mL/min) or for patients with mild-to-moderate hepatic insufficiency (Child-Pugh score 5-9). There are no clinical data in patients with severe hepatic insufficiency (Child-Pugh score >9).

VIOXX may be taken with or without food.

Oral Suspension

VIOXX Oral Suspension 12.5 mg/5mL or 25 mg/5mL may be substituted for VIOXX Tablets 12.5 or 25mg, respectively, in any of the above indications.

Contraindications

VIOXX is contraindicated in patients with hypersensitivity to any component of this product.

Warnings and Precautions

In patients with advanced renal disease, treatment with VIOXX is not recommended. Clinical experience in patients with estimated creatinine clearance of <30 mL/min is not available. If therapy with VIOXX must be initiated in such patients, close monitoring of the patient's renal function is advisable.

Renal prostaglandins may play a compensatory role in the maintenance of renal perfusion. Therefore, under conditions of compromised renal perfusion, administration of VIOXX may cause a reduction in prostaglandin formation and, secondarily, in renal blood flow, and thereby impair renal function. Patients at greatest risk of this response are those with pre-existing significantly impaired renal function, uncompensated heart failure, or cirrhosis. Monitoring of renal function in such patients should be considered. As with other medicines known to inhibit prostaglandin synthesis, discontinuation of therapy with VIOXX would be expected to be followed by recovery to the pretreatment state.

Caution should be used when initiating treatment with VIOXX in patients with considerable dehydration. It is advisable to rehydrate patients prior to starting therapy with VIOXX.

As with other medicines known to inhibit prostaglandin synthesis, fluid retention and oedema have been observed in some patients taking VIOXX. In clinical studies, these episodes occurred at a similar rate to nonspecific cyclooxygenase inhibitors and generally were transient and did not require discontinuation of treatment. The possibility of fluid retention or oedema should be taken into consideration when VIOXX is used in patients with pre-existing oedema or heart failure.

Although clinical studies of VIOXX 25 or 50mg demonstrated similarity to placebo in the incidence of endoscopically detected ulcers at 12 weeks, and a combined analysis of eight trials (treatment with VIOXX 12.5, 25, or 50mg) showed a cumulative incidence of upper GI perforations, ulcers or bleeds (PUBs) significantly less than that in patients treated with nonspecific cyclooxygenase inhibitors for up to 12 months of treatment, ulcers and upper GI PUBs did occur in osteoarthritis (OA) patients treated with VIOXX or placebo. Therefore, physicians should be aware that individual patients may develop PUBs irrespective of treatment, but the risk is lower in patients treated with VIOXX than in patients treated with nonspecific cyclooxygenase inhibitors. Independent of treatment, patients with a prior history of a PUB and patients greater than 65 years of age appeared to be at higher risk for a PUB.

Elevations of ALT and/or AST (approximately three or more times the upper limit of normal) have been reported in approximately 1% of patients in clinical trials with VIOXX. The incidence of elevated AST and/or ALT in patients treated with VIOXX 12.5 and 25mg was similar to that of patients treated with ibuprofen, but notably less than the incidence in the diclofenac group. These elevations resolved in patients treated with VIOXX, with approximately half resolving while patients remained on therapy.

A patient with symptoms and/or signs suggesting liver dysfunction, or in whom an abnormal liver function test has occurred, should be evaluated for persistently abnormal liver function tests. If persistently abnormal liver function tests (three times the upper limit of normal) are detected, VIOXX should be discontinued.

VIOXX should be used with caution in patients who have previously experienced acute asthmatic attacks, urticaria, or rhinitis, which were precipitated by salicylates or non-specific cyclooxygenase inhibitors. Since the pathophysiology of these reactions is unknown, physicians should weigh the potential benefits of prescribing VIOXX versus the potential risks.

VIOXX may mask fever, which is a sign of infection. The physician should be aware of this when using VIOXX in patients being treated for infection.

Pregnancy

As with other medicines known to inhibit prostaglandin synthesis, use of VIOXX should be avoided in late pregnancy because it may cause premature closure of the ductus arteriosus.

In pregnant rats administered single doses of 3mg/kg of rofecoxib (>2 times the recommended daily human dose based on systemic exposure), there were treatment-related decreases in the diameter of the ductus arteriosus.

Reproductive studies conducted in rats and rabbits have demonstrated no evidence of developmental abnormalities at doses up to 50mg/kg/day (~29 times and ~2 times, respectively, the recommended daily human dose based on systemic exposure). However, animal reproduction studies are not always predictive of human response. There are no adequate and well-controlled studies in pregnant women. VIOXX should be used during the first two trimesters of pregnancy only if the potential benefit justifies the potential risk to the foetus.

Nursing Mothers

Rofecoxib is excreted in the milk of lactating rats. It is not known whether this medicine is excreted in human milk. Because many medicines are excreted in human milk and because of the possible adverse effects of medicines that inhibit prostaglandin synthesis on nursing infants, a decision should be made whether to discontinue nursing or to discontinue the medicine, taking into account the importance of the medicine to the mother.

Paediatric Use

Safety and effectiveness in paediatric patients have not been established.

Use in the Elderly

Pharmacokinetics in the elderly (65 years of age and older) are similar to those in the young. In clinical studies, no overall differences in safety or effectiveness were observed between elderly and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients.

In one of these studies (a six-week, double-blind, randomised clinical trial), VIOXX 12.5 or 25 mg once daily was administered to 341 osteoarthritis patients 80 years of age; one-third of these patients were low-dose (less than or equal to 325 mg daily) aspirin users. VIOXX had an adverse experience profile generally similar to placebo.

Effects on Ability to Drive and Use Machinery

There is no information to suggest that VIOXX affects a patient's ability to drive or operate machinery.

Animal Toxicology

In preclinical studies, rofecoxib has been demonstrated to be neither genotoxic, mutagenic, nor carcinogenic. Therapeutic safety margins established with VIOXX in repeated dose toxicity studies are substantially higher compared to nonspecific cyclooxygenase inhibitors. At high doses, exaggerated pharmacologically-mediated effects may be seen. See PREGNANCY for a discussion of reproductive effects.

Adverse Effects

In clinical trials, VIOXX was evaluated for safety in approximately 5400 individuals, including approximately 800 patients treated for one year or longer.

The following medicine-related adverse experiences were reported in clinical studies in patients treated for up to 6 months. These occurred in 2% of patients treated with VIOXX and at an incidence greater than placebo: lower extremity oedema, hypertension, heartburn, dyspepsia, epigastric discomfort, nausea, diarrhoea. In addition, oral ulcers were reported rarely.

The adverse experience profile was similar in patients treated with VIOXX for 1 year or longer.

Post-marketing experience

The following adverse reactions have been reported in post-marketing experience:

Body as a whole: Hypersensitivity reactions, including angioedema, pruritis, rash and urticaria

Interactions

In subjects stabilised on chronic warfarin therapy, the administration of VIOXX 25mg daily was associated with an approximate 8% increase in prothrombin time International Normalised Ratio (INR). In post-marketing experience there have been reports of increases in INR , some of which prompted reversal of anticoagulation, in patients taking VIOXX at clinical doses concurrently with warfarin. Standard monitoring of INR values should be conducted when therapy with VIOXX is initiated or changed, particularly in the first few days, in patients receiving warfarin or similar agents.

Co-administration of VIOXX with rifampicin, a potent inducer of CYP enzymes, produced an approximate 50% decrease in rofecoxib plasma concentrations.Therefore, when VIOXX is coadministered with rifampicin, use of the highest recommended dose of VIOXX should be considered.

VIOXX 75mg (3 to 6 times higher than the recommended doses for osteoarthritis) administered once daily for 10 days increased plasma methotrexate concentrations (AUC(0-24hr)) by 23% in patients with rheumatoid arthritis receiving methotrexate 7.5 to 15mg/week. At 24 hours post-dose, a similar proportion of patients treated with methotrexate alone (94%) and subsequently treated with methotrexate co-administered with 75 mg of rofecoxib (88%) had methotrexate plasma concentrations below the measurable limit (5ng/mL).The effects of the recommended doses of VIOXX on plasma methotrexate levels are unknown. Adequate monitoring for methotrexate-related toxicity should be considered when VIOXX and methotrexate are administered concomitantly.

In patients with mild-to-moderate hypertension, administration of 25mg daily of VIOXX with an ACE inhibitor (benazepril, 10 to 40mg daily) for 4 weeks was associated with a small attenuation of the antihypertensive effect (average increase in mean Mean Arterial Pressure of 2.8mm Hg) compared to the ACE inhibitor alone. This interaction should be given consideration in patients taking VIOXX concomitantly with ACE inhibitors.

VIOXX can be used with low dose aspirin. At steady state, VIOXX 50mg once daily had no effect on the anti-platelet activity of low-dose (81mg once daily) aspirin. In a six-week clinical trial in 341 osteoarthritis patients 80 years of age, one-third of whom were low-dose (less than or equal to 325mg daily) aspirin users, VIOXX 12.5 or 25mg once daily had an adverse experience profile generally similar to placebo. Additionally, no clinically important differences were noted for aspirin users versus patients not using aspirin in the overall incidence of clinical adverse experiences. Because of its lack of platelet effects VIOXX is not a substitute for aspirin for cardiovascular prophylaxis.

In medicine-interaction studies, VIOXX did not have clinically important effects on the pharmacokinetics of the following medicines: prednisone/prednisolone, oral contraceptives (ethinyl estradiol/norethindrone 35/1), or digoxin.

Antacids, cimetidine, and ketoconazole did not have clinically important effects on the pharmacokinetics of rofecoxib.

Although additional specific interaction studies were not performed, in clinical studies, VIOXX was used concomitantly with a wide range of commonly prescribed drugs without evidence of clinical adverse interactions. These medications included antiarrhythmics, anticonvulsants, lithium, oral hypoglycaemics, agents known to cause QT prolongation, and xanthines.

Overdosage

No overdoses of VIOXX were reported during clinical trials.

In clinical studies, administration of VIOXX at single doses up to 1000mg and multiple doses up to 250mg/day for 14 days did not result in significant toxicity.

In the event of overdose, it is reasonable to employ the usual supportive measures, e.g., remove unabsorbed material from the gastrointestinal tract, employ clinical monitoring, and institute supportive therapy, if required.

Rofecoxib is not dialysable by haemodialysis; it is not known whether rofecoxib is dialysable by peritoneal-dialysis.

Actions

VIOXX is a potent, orally active cyclooxygenase-2 (COX-2) specific inhibitor within, and significantly above, the clinical dose range. Cyclooxygenase is responsible for the generation of prostaglandins, which are potent biological mediators involved in diverse physiologic functions as well as pathologic conditions. Two isoforms of cyclooxygenase have been identified: cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2). COX-1 is constitutively expressed and enzymatically active in various tissues, including the stomach, intestines, and kidneys, and in platelets. Evidence suggests that COX-1 is responsible for prostaglandin-mediated normal physiologic functions such as gastric cytoprotection and platelet aggregation, and is involved in renal function. Inhibition of COX-1 by nonspecific cyclooxygenase inhibitors (commonly known as NSAIDs) has been associated with gastric damage and renal toxicity, including renal papillary necrosis. In contrast, COX-2 is constitutively expressed in only a limited number of tissues, including the brain and kidney (glomeruli and renal vasculature), and is the inducible isoform of the enzyme that has been shown to be up-regulated by proinflammatory stimuli. Based on patterns of expression and localisation, COX-2 has been postulated to be primarily responsible for the synthesis of prostanoid mediators of pain, inflammation, and fever. Specific inhibition of COX-2 would, therefore, be expected to decrease these clinical signs and symptoms without influencing gastrointestinal integrity and with a decreased propensity for NSAID-associated renal papillary necrosis. The efficacy of VIOXX is due to its specific inhibition of COX-2.

The anti-inflammatory effects of VIOXX were demonstrated in standard animal models used to evaluate nonspecific cyclooxygenase inhibitors. Administered orally, VIOXX reversed swelling and hyperalgesia caused by intraplantar carrageenan injection in rats. Further VIOXX inhibited swelling associated with adjuvant-induced arthritis in rats. In these studies, the anti-inflammatory effect of VIOXX was similar to indomethacin.

In ex vivo human whole blood assays, serum thromboxane B2 (TXB2) concentration and lipopolysaccharide (LPS) induced prostaglandin E2 (PGE2) generation were used to measure COX-1 and COX-2 activity, respectively. In subjects receiving doses of VIOXX 12.5 and 25mg/day or clinically recommended doses of several nonspecific cyclooxygenase inhibitors, including nabumetone, etodolac, meloxicam, ibuprofen, diclofenac, and naproxen, LPS-induced PGE2 generation (COX-2) was inhibited by approximately 50% or more. However, at these doses of VIOXX and even with multiple doses up to 375mg daily (15 to 30-fold the clinical dose for osteoarthritis) and single doses up to 1000mg (40 to 80-fold the clinical dose for osteoarthritis), there was no dose-dependent inhibition of COX-1 compared with placebo. In contrast, nonspecific cyclooxygenase inhibitors at the clinically recommended doses significantly inhibited COX-1 (~40-95%).

In addition, urinary excretion of 11-dehydro TXB2 was used as a measure of in vivo COX-1 activity. VIOXX 12.5, 25, and 50mg daily did not inhibit COX-1 activity based on the absence of any significant reduction in the urinary excretion of 11-dehydro TXB2 compared with placebo. In contrast, three nonspecific cyclooxygenase inhibitors, i.e., meloxicam, diclofenac, and indomethacin substantially decreased the urinary excretion of 11-dehydro TXB2 compared with placebo.

The influence on gastroprotective COX-1 activity was also assessed in a clinical study where prostaglandin synthesis was measured in gastric biopsy samples from subjects administered either VIOXX 25mg daily, naproxen 500mg twice daily, or placebo. VIOXX did not inhibit gastric prostaglandin synthesis. In contrast, naproxen inhibited gastric prostaglandin synthesis by >70% compared with placebo. These data, together with the whole blood and urinary prostanoid biochemical assays, support the COX-2 specificity of VIOXX.

Platelet Function

Multiple doses of VIOXX 12.5, 25, and up to 375mg administered daily had no effect on bleeding time relative to placebo. Similarly, bleeding time was not altered in a single dose study with 500 or 1000mg of VIOXX. There was no inhibition of ex vivo arachidonic acid- or collagen-induced platelet aggregation with 12.5, 25, and 50mg of VIOXX. These findings are consistent with the COX-2 specificity of VIOXX.

Aspirin

At steady-state, VIOXX 50mg once daily had no effect on the anti-platelet activity of low-dose (81mg once daily) aspirin, as assessed by ex vivo platelet aggregation and serum TXB2 generated in clotting blood (a biochemical marker of platelet activation).

Pharmacokinetics

Absorption

Orally administered VIOXX is well absorbed at the therapeutically recommended doses of 12.5, 25, and 50mg. The mean oral bioavailability is approximately 93%. Following 25mg once daily dosing to steady-state, the peak plasma concentration (geometric mean Cmax = 0.305mcg/mL) was observed at approximately 2 hours (Tmax) after administration to fasted adults. The geometric mean area under the curve (AUC24hr) was 3.87mcg•hr/mL. VIOXX Tablets and VIOXX Oral Suspension are bioequivalent.

A standard meal had no clinically meaningful effect on the extent or rate of absorption of a 25mg dose of VIOXX. In clinical trials, VIOXX was administered without regard to food.

The pharmacokinetics of rofecoxib in 12 healthy subjects were similar (within approximately 30%) when administered alone, with a magnesium/aluminium hydroxide antacid, or a calcium carbonate antacid (approximately 50mEq acid neutralising capacity).

Distribution

Rofecoxib is approximately 85% bound to human plasma protein over the range of concentrations of 0.05 to 25 mcg/mL. The volume of distribution (Vdss) is approximately 100 L in humans.

Rofecoxib crosses the placenta in rats and rabbits, and the blood-brain barrier in rats.

Metabolism

Rofecoxib is extensively and hepatically metabolised. The main metabolic pathway is reduction to produce cis - and trans -dihydro rofecoxib (as hydroxy acids) Cytochrome P450 (CYP) enzymes are not the dominant pathways for rofecoxib metabolism.

Six metabolites have been identified in man. The principal metabolites are cis - and trans -dihydro rofecoxib (as hydroxy acids)and the 5-hydroxy glucuronide metabolite, These principal metabolites either demonstrate no measurable activity as cyclooxygenase inhibitors or are only weakly active as COX-2 inhibitors. None of these metabolites inhibit COX-1.

Elimination

Following administration of a 125mg radiolabeled oral dose of rofecoxib to healthy subjects, 72% of radioactivity was recovered in urine and 14% in faeces.

Elimination of rofecoxib occurs almost exclusively through metabolism followed by renal excretion. Steady-state concentrations of rofecoxib are reached within 4 days of once-daily administration of 25mg, with an accumulation ratio of approximately 1.7, corresponding to an accumulation half-life of ~17 hours. The plasma clearance is estimated to be approximately 120mL/min for a 25mg dose.

Characteristics in Patients (Special Populations)

Gender

The pharmacokinetics of rofecoxib are comparable in men and women.

Elderly

Pharmacokinetics in the elderly (65 years of age and older) are similar to those in the young. There is modestly greater systemic exposure (~30% greater AUC) in the elderly than in the young; the difference is not clinically meaningful. Extent and rate of absorption do not appear to be influenced by age. No dosage adjustment is necessary for elderly patients, (see Dosage and Administration).

Race

There is no clinically important effect of race on the pharmacokinetics of VIOXX.

Hepatic Insufficiency

Patients with mild-to-moderate hepatic insufficiency (Child-Pugh score 5-9) administered a single 25mg dose of VIOXX had an approximately 30% higher mean AUC than healthy subjects given the same dose. No dosage adjustment is required in patients with mild-to-moderate hepatic insufficiency. There are no clinical or pharmacokinetic data in patients with severe hepatic insufficiency (Child-Pugh score >9).

Renal Insufficiency

The pharmacokinetics of a single 50mg dose of VIOXX in patients with end-stage renal disease on haemodialysis were not significantly different from those in healthy subjects. Haemodialysis contributed negligibly to elimination (dialysis clearance approximately 40mL/min).

Paediatric Patients

The pharmacokinetics of rofecoxib in paediatric patients have not been studied.

Pharmaceutical Precautions

Tablets: Store below 30°C .

Oral Suspension: Shake well before using. Store below 30°C .

Medicine Classification

Prescription Medicine.

Package Quantities

Packages of 10 and 30 tablets are available for 25mg tablets and packages of 30 tablets are available for 12.5mg tablets.

Oral suspension is available in amber glass bottles containing 150 mL.

Further Information

Chemistry

VIOXX tablets and oral suspension contain rofecoxib, which is described chemically as 4-[4-(methylsulfonyl)phenyl]-3-phenyl-2(5 H)- furanone.

The empirical formula is C17H14O4S. The molecular weight is 314.36. The structural formula is:

Rofecoxib is a white to off-white to light yellow powder. Rofecoxib is sparingly soluble in acetone, slightly soluble in methanol and isopropyl acetate, very slightly soluble in ethanol, practically insoluble in octanol, and insoluble in water.

Composition

Active Ingredients:

Each tablet of VIOXX for oral administration contains either 12.5 or 25 mg of rofecoxib.

Each 5 mL of the oral suspension contains either 12.5 or 25 mg of rofecoxib.

Inactive Ingredients:

Each tablet contains lactose, microcrystalline cellulose, hydroxypropyl cellulose, croscarmellose sodium, magnesium stearate, and yellow ferric oxide.

Each 5 mL of oral suspension contains xanthan gum, sorbitol solution, sodium citrate (dihydrate), citric acid (monohydrate), strawberry flavour, and purified water. Added as preservatives are sodium methylparaben 0.13% and sodium propylparaben 0.02%