ROFEWAL

INDICATIONS
ROFEWAL is indicated for : ·
Relief of the signs and symptoms of osteoarthritis ·
Management of acute painful inflammatory conditions ·
Treatment of primary dysmenorrhoea.

COMPOSITION
ROFEWAL 25mg Tablet
Each tablet contains :
Rofecoxib ………………25mg
(Available in a Blister pack of 10 tablets)

DOSAGE AND ADMINISTRATION
Rofecoxib is administered orally. The lowest dose of Rofecoxib should be sought for each patient.

Osteoarthritis
The recommended starting dose of Rofecoxib 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.

Management of Acute Pain and Treatment of Primary Dysmenorrhoea
The recommended initial dose of Rofecoxib is 50mg once daily. Subsequent doses should be 50mg once daily as needed. Use of Rofecoxib for more than 5 days in management of pain has not been studied. Rofecoxib Tablets may be taken with or without food.

Advanced Renal Disease
No safety information is available regarding the use of Rofecoxib in patients with advanced kidney disease. Therefore, treatment with Rofecoxib is not recommended in these patients. If Rofecoxib therapy must be initiated, close monitoring of the patient's kidney function is advisable.

Pregnancy
In late pregnancy Rofecoxib should be avoided because it may cause premature closure of the ductus arteriosus.

CONTRAINDICATIONS
Rofecoxib is contraindicated in patients with known hypersensitivity to rofecoxib. Rofecoxib should not be given to patients who have experienced asthma, urticaria, or allergic - type reactions after taking aspirin or other NSAIDs.

PACKING & PRESENTATION
ROFEWAL 25mg Tablets : Strip of 10 tablets 10 strips in a carton

INTRODUCTION
Rofecoxib, a selective COX-2 inhibitor is a nonsteroidal anti-inflammatory drug that exhibits anti-inflammatory, analgesic, and antipyretic activities. The mechanism of action of Rofecoxib is believed to be due to inhibition of prostaglandin synthesis, via inhibition of cyclooxygenase - 2 (COX-2). At therapeutic concentrations in humans, Rofecoxib does not inhibit the cyclooxygenase - 1 (COX-1) isoenzyme.
In several in vivo rodent models, rofecoxib is a potent inhibitor of carrageenan - induced paw edema [ID50=1.5 mg/kg], carrageenan - induced paw hyperalgesia [ID50=1.0 mg/kg], lipopolysaccharide-induced pyresis [ID50=0.24 mg/kg], and adjuvant - induced arthritis [ID50=0.74 mg/kg/day]. Rofecoxib also has a protective effect on adjuvant - induced destruction of cartilage and bone structures in rats.

ROFECOXIB - A SELECTIVE AND POTENT COX-2 INHIBITOR
Rofecoxib is a novel COX-2 inhibitor with a biochemical and pharmacological profile clearly distinct from that of current nonsteroidal anti-inflammatory drugs and represents a new therapeutic class of anti-inflammatory agents for the treatment of the symptoms of osteoarthritis and rheumatoid arthritis with improved gastrointestinal tolerability.
Cyclooxygenase selectivity is reflected by the relative ratio of COX-2 IC50 to COX-1 IC50. Rofecoxib selectively inhibits cyclo-oxygenase -2 (COX-2) in a dose dependent manner in humans. No significant inhibition of cyclooxygenase -1 is observed with Rofecoxib up to dose of 1000mg.
Healthy volunteers were significantly less likely to develop gastrointestinal ulcers with rofecoxib than with ibuprofen or aspirin (p<0.001) administered for 7 days.
In double-blind, randomized study that measured fecal blood loss, rofecoxib (25 or 50 mg once daily) resulted in less fecal blood loss than ibuprofen (800 mg tid) and similar fecal blood loss to that observed in placebo in 67 healthy volunteers.
In clinical studies, a combined analysis of 8 clinical trials in patients with osteoarthritis (n=5435) demonstrated that significantly fewer upper gastrointestinal perforations, ulcers and bleeds occurred in patients receiving rofecoxib 12.5, 25 or 50mg than in those receiving ibuprofen 800mg, diclofenac 50mg or nabumetone 500mg three times daily.

PHARMACOKINETICS
Absorption
The mean oral bioavailability of Rofecoxib at therapeutically recommended doses of 12.5, 25 and 50 mg is approximately 93%.
The area under the curve (AUC) and peak plasma level (Cmax ) following a single 25 mg dose were 3286 (+843) ng*hr/ml and 207 (+111) ng/ml, respectively. Both Cmax and AUC are roughly dose proportional across the clinical dose range. At doses greater than 50mg, there is a less than proportional increase in Cmax and AUC, which is thought to be due to the low solubility of the drug in aqueous media.

Pharmacokinetic Parameters of Rofecoxib

Pharmacokinetic Parameter Value
Dose 25mg/day
Cmax at steady state 321 ng/ml
Tmax 2 - 3 hrs
Terminal elimination half life (T ½ ) 17 hrs
AUC at steady state 4018 ng*hr/ml
Clearance 7.2 L/h

Food and other interactions
Food had no significant effect on either the peak plasma concentration (Cmax) or extent of absorption (AUC) of rofecoxib in tablet formulation.
Rofecoxib tablets can be administered without regard to timing of meals.
There was a 13% and 8% decrease in AUC when Rofecoxib was administered with calcium carbonate antacid and magnesium/aluminum antacid to elderly subjects, respectively. There was an approximate 20% decrease in Cmax of rofecoxib with either antacids.

Distribution
Rofecoxib is approximately 87% bound to human plasma protein over the range of concentrations of 0.05 to 25 T g/ml. The apparent volume of distribution at steady (Vdss) is approximately 91 L following a 12.5 mg dose and 86L following a 25mg dose.

Metabolism
Metabolism of Rofecoxib is primarily mediated through reduction by cytosolic enzymes. The principal metabolic products are the dihydro derivatives of rofecoxib, which account for nearly 56% of recovered radioactivity in the urine. An additional 8.8% of the dose was recovered as the glucuronide of the hydroxy derivative, a product of oxidative metabolism. These metabolites are inactive.
Cytochrome P450 plays a minor role in metabolism of rofecoxib.

Excretion
Rofecoxib is eliminated predominantly by hepatic metabolism with little (< 1%) unchanged drug recovered in the urine. Following a single radio labeled dose of 125 mg, approximately 72% of the dose was excreted into the urine as metabolites and 14% in the feces as unchanged drug.
The effective half-life (based on steady - state levels) was approximately 17 hours.

Elderly
Dosage adjustment in the elderly is not necessary; however, therapy with Rofecoxib should be initiated at the lowest recommended dose.

Pediatric
Efficacy and safety of Rofecoxib is not established in patients below 18 years of age.

Hepatic insufficiency
A pharmacokinetic study in mild insufficiency patients indicated that rofecoxib AUC was similar between these patients and healthy subjects. Limited data in patients with moderate hepatic insufficiency suggest a trend towards higher AUC (about 69%) of rofecoxib in these patients, but more data are needed to evaluate pharmacokinetics in these patients. Patients with severe hepatic insufficiency have not been studied.

Renal insufficiency
While renal insufficiency does not influence the pharmacokinetics of rofecoxib, use of Rofecoxib in advanced renal disease is not recommended at present because no safety information is available regarding the use of Rofecoxib in these patients.

ROFECOXIB : GI TOLERABILITY
Nonsteroidal anti-inflammatory drug (NSAID) induced gastrointestinal (GI) toxic effects, such as upper GI tract perforations, symptomatic gastroduodenal ulcers, and upper GI tract bleeding (PUBs), are thought to be attributable to cyclooxygenase - 1 (COX-1) inhibition. Rofecoxib specifically inhibits COX - 2 and has demonstrated a low potential for causing upper GI injury.
Compared with currently available NSAIDs (which inhibit COX-1 and COX - 2 isoforms of cyclooxygenase), Rofecoxib (a specific COX-2 inhibitor) is expected to cause less gastrointestinal toxicity.
A clinical trial was conducted to compare the effect on the upper gastrointestinal mucosa of a high dose of Rofecoxib with that of conventional doses of ibuprofen and aspirin.
In this acute short-term endoscopic study, Rofecoxib 250mg q.d. (a dose at least 10 times higher than that demonstrated to reduce the signs and symptoms of osteoarthritis) produced significantly less gastrointestinal mucosal damage than either ibuprofen 800 mg t.d.s. or aspirin 650 mg q.d.s. and was comparable to placebo in this regard.
Treatment with Rofecoxib 25mg daily or 50mg daily was associated with a significantly lower percentage of patients with endoscopic gastroduodenal ulcers than treatment with ibuprofen 2400mg daily.
Endoscopic Gastroduodenal Ulcers at 12 weeks Multinational Study

Treatment Group No. of Patients with ulcer Cumulative Incidence Rate
Placebo 5/182 5.1 %
Rofecoxib 25mg 9/187 5.3 %
Rofecoxib 50mg 15/182 8.8 %
Ibuprofen 49/187 29.2 %

GI side effects with Rofecoxib - A Meta-analysis
A combined analysis of 8 clinical trials in patients with osteoarthritis (n=5435) demonstrated that significantly fewer upper G.I. perforation, ulcers and bleed (PUBs) occurred in patients receiving Rofecoxib 12.5, 25 or 50 mg than those receiving ibuprofen 800mg, diclofenac 50mg or nabumetone 500mg 3 times daily (1.5 Vs 2.68%; p=0.006).

Effect on Platelets
Multiple doses of Rofecoxib 12.5, 25, and up to 375 mg administered daily upto 12 days had no effect on bleeding time relative to placebo. Similarly, bleeding time was not altered in a single dose study with 500 or 1000 mg of Rofecoxib.

SAFETY PROFILE
Rofecoxib is generally well tolerated and the most commonly reported adverse events are diarrhoea, headache, nausea and upper respiratory infections.
The following table of adverse experiences lists all adverse events, regardless of causality, occurring in at least 2% of patients receiving Rofecoxib in nine controlled studies of 6 week to 6 month duration conducted in patients with osteoarthritis at the therapeutically recommended doses (12.5 and 25mg), which included a placebo and/or positive control group.
The general safety profile of Rofecoxib 50mg OD in OA clinical trials of upto 6 months (476 patients) was similar to that of Rofecoxib at the recommended OA doses of 12.5 and 25mg OD, except for a higher incidence of gastrointestinal symptoms (abdominal pain, epigastric pain, heartburn, nausea and vomiting), lower extremity edema (6.3%) and hypertension (8.2%).

Clinical adverse events occurring in > 2.0% of patients treated with Rofecoxib

Placebo(N = 783) Rofecoxib12.5/25mg
(N = 2829) Ibuprofen2400mg
(N = 847) Diclofenac150mg
(N = 498)
Abdominal pain 4.1 3.4 4.6 5.8
Asthenia/Fatigue 1.0 2.2 2.0 2.6
Dizziness 2.2 3.0 2.7 3.4
Influenza - Like 3.1 2.9 1.5 3.2
Lower ExtremityEdema 1.1 3.7 3.8 3.4
URTI 7.8 8.5 5.8 8.2
Cardiovascular System
Hypertension 1.3 3.5 3.0 1.6
Digestive System
Diarrhea 6.8 6.5 7.1 10.6
Dyspepsia 2.7 3.5 4.7 4.0
Epigastric Discomfort 2.8 3.8 9.2 5.4
Heartburn 3.6 4.2 5.2 4.6
Nausea 2.9 5.2 7.1 7.4
Eyes, Ears, Nose, and Throat
Sinusitis 2.0 2.7 1.8 2.4
Musculoskeletal System
Back Pain 1.9 2.5 1.4 2.8
Nervous System
Headache 7.5 4.7 6.1 8.0
Respiratory System
Bronchitis 0.8 2.0 1.4 3.2
Urogenital system
Urinary Tract Infection 2.7 2.8 2.5 3.6