Rofecoxib

314.36

314.36

1806241-263-5

0QTW8Z7MCR

758705|720256

DTXSID2023567

C1832

White to off-white to light yellow powder

M - Musculo-skeletal system

2932209090

68.8

2.3

white to beige

1.333±0.06 g/cm3(Predicted)

207°C

577.6±50.0 °C(Predicted)

303.1±30.1 °C

1.619

H2O: Insoluble ;DMSO: soluble 5mg/mL, clear (warmed)

Refrigerator

3.2X10-9 mm Hg at 25 deg C /Estimated/

Henry's Law constant = 2.6X10-12 atm-cu m/mole at 25 °C /Estimated/

Hydroxyl radical reaction rate constant = 1.3X10-10 cu cm/ molecule-sec at 25 °C /Estimated/

NONH for all modes of transport

3

22

S24/25

LU5135000

Xn

P264, P270, P301+P312, P330, P501

H302

SRP: The most favorable course of action is to use an alternative chemical product with less inherent propensity for occupational exposure or environmental contamination. Recycle any unused portion of the material for its approved use or return it to the manufacturer or supplier. Ultimate disposal of the chemical must consider: the material's impact on air quality; potential migration in soil or water; effects on animal, aquatic, and plant life; and conformance with environmental and public health regulations.

Ahuja N et al; Rofecoxib: An Update on Physicochemical, Pharmaceutical, Pharmacodynamic and Pharmacokinetic Aspects; J Pharm Pharmacol 55 (7): 859-94 (2003)

|Warning|H302 (100%): Harmful if swallowed [Warning Acute toxicity, oral]|P264, P270, P301+P312, P330, and P501|Aggregated GHS information provided by 41 companies from 1 notifications to the ECHA C&L Inventory.

No overdoses of rofecoxib were reported during clinical trials. Administration of single doses of rofecoxib 1000 mg to 6 healthy volunteers and multiple doses of 250 mg/day for 14 days to 75 healthy volunteers did not result in serious toxicity.

In clinical studies involving several thousand patients treated for at least 3 months, the rate of serum aminotransferase enzyme elevations above three times the upper limit of the normal range was 1.8% in rofecoxib treated compared to 0.3% in placebo treated patients and 0.1-0.4% in patients receiving other common NSAIDs. Thus, ALT elevations due to rofecoxib were uncommon and usually of minimal clinical significance, resolving even with drug continuation.

Concurrent use /of rifampin/ with rofecoxib may decrease rofecoxib plasma concentrations by 50%; ... .|Rofecoxib 75 mg per day for 10 days increased plasma methotrexate concentrations by 23% in patients receiving methotrexate 7.5 to 15 mg/week; the effect of recommended doses of rofecoxib in unknown; therefore, monitoring for methotrexate toxicity is recommended.|Concurrent use /of aspirin/ with rofecoxib may increase the risk for gastrointestinal (GI) ulcerations or GI complications.|The administration of rofecoxib with calcium carbonate-, aluminum- or magnesium-containing antacids decreased the area under the plasma concentration-time curve (AUC) by 13% and 8%, respectively, in elderly patients; the peak plasma concentration of rofecoxib was decreased by approximately 20% for both antacids.|For more Interactions (Complete) data for ROFECOXIB (14 total), please visit the HSDB record page.

87%

For the treatment of osteoarthritis, rheumatoid arthritis, acute pain in adults, and primary dysmenorrhea, as well as acute treatment of migraine attacks with or without auras.|FDA Label

Rofecoxib is a nonsteroidal antiinflammatory drug (NSAID) that selectively inhibits cyclooxgenase-2 (Cox-2), which was used in the therapy of chronic arthritis and mild-to-moderate musculoskeletal pain. Rofecoxib was withdrawn in 2004 because of an association with an increase in cardiovascular events with its long term use. Rofecoxib had also been linked transient serum aminotransferase elevations during therapy and to rare instances of idiosyncratic drug induced liver disease.

Nonsteroidal Antiinflammatory Drugs

/September 20, 2004/ Merck & Co., Inc. announced a voluntary withdrawal of Vioxx (rofecoxib) from the U.S. and worldwide market due to safety concerns of an increased risk of cardiovascular events (including heart attack and stroke) in patients on Vioxx. Vioxx is a prescription COX-2 selective, non-steroidal anti-inflammatory drug (NSAID) that was approved by FDA in May 1999 for the relief of the signs and symptoms of osteoarthritis, for the management of acute pain in adults, and for the treatment of menstrual symptoms, and was later approved for the relief of the signs and symptoms of rheumatoid arthritis in adults and children.|Anti-inflammatory.|Rofecoxib is indicated for the relief of the signs and symptoms of osteoarthritis. /Included in US product labeling/|Rofecoxib is indicated for short-term use (5 days) for relief of acute pain, especially when anti-inflammatory actions may be desired, such as following dental or orthopedic surgery. /Included in US product labeling/|Rofecoxib is indicated for short-term use (5 days) for relief of the pain and other symptoms of primary dysmenorrhea. /Included in US product labeling

/Merck & Co., Inc. announced a voluntary withdrawal of Vioxx (rofecoxib) from the U.S. and worldwide market/ due to safety concerns of an increased risk of cardiovascular events (including heart attack and stroke) in patients on Vioxx. Vioxx is a prescription COX-2 selective, non-steroidal anti-inflammatory drug (NSAID) that was approved by FDA in May 1999 for the relief of the signs and symptoms of osteoarthritis, for the management of acute pain in adults, and for the treatment of menstrual symptoms, and was later approved for the relief of the signs and symptoms of rheumatoid arthritis in adults and children.|There is controversy whether cyclooxygenase-2 (COX-2) specific inhibitors are associated with elevations in blood pressure requiring treatment in typical clinical practice. We examined the risk of new onset hypertension in a retrospective case-control study involving 17 844 subjects aged > or =65 years from 2 US states. Multivariable logistic models were examined to assess the relative risk of new onset hypertension requiring treatment in patients who used celecoxib or rofecoxib compared with patients taking either the other COX-2 specific inhibitor, a nonspecific NSAID, or no NSAID. During the 1999 to 2000 study period, 3915 patients were diagnosed and began treatment for hypertension; 4 controls were selected for every case. In no model was celecoxib significantly associated with the development of hypertension. Rofecoxib users were at a significantly increased relative risk of new onset hypertension compared with patients taking celecoxib (odds ratio (OR) 1.6; 95% confidence interval (CI), 1.2 to 2.1), taking a nonspecific NSAID (OR 1.4; 95% CI, 1.1 to 1.9), or taking no NSAID (OR 1.6; 95% CI, 1.3 to 2.0). There were no clear dosage or duration effects. In patients with a history of chronic renal disease, liver disease, or congestive heart failure, the relative risk of new onset hypertension was twice as high in those taking rofecoxib compared with celecoxib (OR 2.1; 95% CI, 1.0 to 4.3). In this retrospective case-control study of patients aged > or =65 years, rofecoxib use was associated with an increased relative risk of new onset hypertension; this was not seen in patients taking celecoxib.|In a double-blind study, 35 stable subjects on low-dose aspirin with > or = 2 previous acute coronary events and 2 of 2 screening CRP values >2.0 mg/L were randomized to the COX-2 inhibitor rofecoxib (25 mg) or placebo daily for 6 months. Serum CRP, interleukin-6 (IL-6), P-selectin, matrix metalloproteinase-9 (MMP-9), and brachial artery endothelial function were evaluated. In the placebo group, CRP (median) was 3.16 mg/L (25% and 75% quartiles, 1.90 and 5.78 mg/L) at baseline and 4.22 mg/L (25% and 75% quartiles, 2.04 and 6.25 mg/L) at 6 months; in the rofecoxib group, CRP was 3.45 mg/L (25% and 75% quartiles, 2.08 and 5.78 mg/L) at baseline and 1.41 mg/L (25% and 75% quartiles, 1.17 and 4.81 mg/L) at 6 months (P=0.03). Rofecoxib compared with placebo also lowered IL-6 at 6 months (P=0.0002). There was a significant off-drug effect on CRP and IL-6 levels in the rofecoxib group 3 months after treatment (P=0.005 and P=0.009, respectively). Rofecoxib did not significantly affect P-selectin, MMP-9, and brachial artery vasoreactivity. Prolonged COX-2 inhibition attenuates CRP and IL-6, does not modify P-selectin and MMP-9, and has no deleterious effect on endothelial function in stable patients with a history of recurrent acute coronary events and raised CRP. These results strengthen the rationale for evaluating the clinical benefit of COX-2 inhibition in patients with ischemic heart disease.|A 73-year-old woman was prescribed rofecoxib 25 mg/day for rheumatoid arthritis in addition to other medications on which the patient had been stabilized. Six months after initiation of rofecoxib, linear plaques over the infra-orbital and bitemporal areas of both eyes were observed. Several itchy violaceous papules also developed on her right wrist and dorsum of the left foot. She also had a hyperpigmented macule on her right buccal mucosa. As the skin rash was localized and the patient was initially unwilling to undergo skin biopsy, rofecoxib was continued and a topical steroid was started. One month later, the patient was seen in the dermatology clinic, and the improvement of her skin reaction was significant. A skin biopsy performed during this visit was consistent with LDE. On the next day, her rheumatologist decided to discontinue the offending drug, rofecoxib. Two months later, all skin lesions had completely resolved. No rechallenge with rofecoxib was attempted. LDE is a rare skin reaction that can be associated with several drugs. Rofecoxib, a cyclooxygenase-2 inhibitor, has never before been reported to cause LDE. An objective causality assessment indicates that rofecoxib was the probable cause of the skin reaction.|For more Drug Warnings (Complete) data for ROFECOXIB (31 total), please visit the HSDB record page.

Rofecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, is classified as a nonsteroidal anti-inflammatory drug (NSAID). Unlike celecoxib, rofecoxib lacks a sulfonamide chain and does not require CYP450 enzymes for metabolism. Like other NSAIDs, rofecoxib exhibits anti-inflammatory, analgesic, and antipyretic activity. NSAIDs appear to inhibit prostaglandin synthesis via the inhibition of cyclooxygenase (COX), which are responsible for catalyzing the formation of prostaglandins in the arachidonic acid pathyway. There are at least two isoenzymes, COX-1 and COX-2, that have been identified. Although the exact mechanisms have not been clearly established, NSAIDs exert their anti-inflammatory, analgesic, and antipyretic primarily through the inhibition of COX-2. The inhibition of COX-1 is principally responsible for the negative effects on the GI mucosa. As rofecoxib is selective for COX-2, it may be potentially associated with a decreased risk of certain adverse events, but more data is needed to fully evaulate the drug.

A subclass of cyclooxygenase inhibitors with specificity for CYCLOOXYGENASE-2. (See all compounds classified as Cyclooxygenase 2 Inhibitors.)

The mean oral bioavailability of rofecoxib at therapeutically recommended doses of 12.5, 25, and 50 mg is approximately 93%.|Approximately 72% and 14% of a radioactive rofecoxib dose is eliminated in the urine as metabolites and /in/ feces as unchanged drug, respectively.|Time to peak concentration: Approximately 2 to 3 hours.|At steady state, the apparent volume of distribution is about 91 and 86 L after a 12.5 and 25 mg dose, respectively.|At recommended doses, the mean oral bioavailability is 93%. The peak plasma concentration and area under the plasma concentration-time curve are roughly proportional across the clinical dose range.|For more Absorption, Distribution and Excretion (Complete) data for ROFECOXIB (11 total), please visit the HSDB record page.

Hepatic. Metabolism of rofecoxib is primarily mediated through reduction by cytosolic enzymes. The principal metabolic products are the cis-dihydro and trans-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. The biotransformation of rofecoxib and this metabolite is reversible in humans to a limited extent (< 5%). These metabolites are inactive as COX-1 or COX-2 inhibitors. Cytochrome P450 plays a minor role in metabolism of rofecoxib.|The metabolism of rofecoxib, a potent and selective inhibitor of cyclooxygenase-2, was examined in vitro using human liver subcellular fractions. The biotransformation of rofecoxib was highly dependent on the subcellular fraction and the redox system used. In liver microsomal incubations, NADPH-dependent oxidation of rofecoxib to 5-hydroxyrofecoxib predominated, whereas NADPH-dependent reduction of rofecoxib to the 3,4-dihydrohydroxy acid metabolites predominated in cytosolic incubations. In incubations with S9 fractions, metabolites resulting from both oxidative and reductive pathways were observed. In contrast to microsomes, the oxidation of rofecoxib to 5-hydroxyrofecoxib by S9 fractions followed two pathways, one NADPH-dependent and one NAD+-dependent (non-cytochrome P450), with the latter accounting for about 40% of total activity. The 5-hydroxyrofecoxib thus formed was found to undergo NADPH-dependent reduction ("back reduction") to rofecoxib in incubations with liver cytosolic fractions. In incubations with dialyzed liver cytosol, net hydration of rofecoxib to form 3,4-dihydro-5-hydroxyrofecoxib was observed, whereas the 3,4-dihydrohydroxy acid derivatives were formed when NADPH was present. Although 3,4-dihydro-5-hydroxyrofecoxib could be reduced to the 3,4-dihydrohydroxy acid by cytosol in the presence of NADPH, the former species does not appear to serve as an intermediate in the overall reductive pathway of rofecoxib metabolism. In incubations of greater than 2 h with S9 fractions, net reductive metabolism predominated over oxidative metabolism. These in vitro results are consistent with previous findings on the metabolism of rofecoxib in vivo in human and provide a valuable insight into mechanistic aspects of the complex metabolism of this drug.|Metabolism of rofecoxib is primarily mediated through reduction by cytosolic enzymes. The principal metabolic products are the cis-dihydro and trans-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. The biotransformation of rofecoxib and this metabolite is reversible in humans to a limited extent (<5%). Theses metabolites are inactive as COX-1 or COX-2 inhibitors.|Rofecoxib has known human metabolites that include 5-hydroxy-rofecoxib.

17 hours|Approximately 17 hours.

The anti-inflammatory, analgesic, and antipyretic effects of NSAIDs appear to result from the inhibition of prostaglandin synthesis. Although the exact mechanism of action has not been determined, these effects appear to be mediated through the inhibition of the COX-2 isoenzyme at the sites of inflammation with subsequent reduction in the synthesis of certain prostaglandins from their arachidonic acid precursors. Rofecoxib selectively inhibits the cyclooxygenase-2 (COX-2) enzyme, which is important for the mediation of inflammation and pain. Unlike non-selective NSAIDs, rofecoxib does not inhibit platelet aggregation. It also has little to no affinity for COX-1.|Rofecoxib is a nonsteroidal anti-inflammatory drug (NSAID) with anti-inflammatory, analgesic, and antipyretic therapeutic effects. It has been proposed that rofecoxib inhibits the activity of the enzyme cyclooxygenase-2 (COX-2), resulting in a decreased formation of precursors of prostaglandins. Rofecoxib does not inhibit cyclooxygenase-1 (COX-1) isoenzyme in humans at therapeutic concentrations.

In an overdose, remove unabsorbed drug from GI tract, monitor patient, and provide supportive therapy as needed. Hemodialysis doesn't't remove it.

/CASE REPORTS/ A 77-year old mildly hypertensive woman with no underlying renal disease who was admitted to the Emergency Department (ED) in a comatose state with fever. The patient had been on low dose enalapril and a potassium rich diet. Five days before admission, rofecoxib, a new selective COX-2 inhibitor nonsteroidal anti-inflammatory drug (NSAID), was added for leg pain. She was found to have severe hyperkalemia and died 90 min after her arrival. A cannot absolutely determine whether the COX-2 inhibitor was the dominant contributor to the development of hyperkalemia or the combination itself, with an intercurrent infection and some degree of dehydration. Physicians should be aware of this possible complication and only prescribe NSAIDs, including the new COX-2 drugs, to the elderly under close monitoring of kidney function and electrolyte tests.|/CASE REPORTS/ Angioedema is a recognised side effect of rofecoxib, a cyclo-oxygenase-2 (COX-2) inhibitor. But death resulting from a hemorrhagic pulmonary edema after its ingestion has not been recorded. The case of a 60 year old man who died from hemorrhagic pulmonary edema in the presence of angioedema after the ingestion of two doses of 12.5 mg of rofecoxib is reported.

MK 0966

Vioxx|Oral: Tablets: 12.5 mg Vioxx (Merck); 25 mg Vioxx (Merck); 50 mg Vioxx (Merck). Oral Suspension: 12.5 mg/5 mL Vioxx (Merck); 25 mg/5 mL Vioxx (Merck).

/Merck & Co., Inc. announced a voluntary withdrawal of Vioxx (rofecoxib) from the U.S. and worldwide market/ due to safety concerns of an increased risk of cardiovascular events (including heart attack and stroke) in patients on Vioxx. Vioxx is a prescription COX-2 selective, non-steroidal anti-inflammatory drug (NSAID) that was approved by FDA in May 1999 for the relief of the signs and symptoms of osteoarthritis, for the management of acute pain in adults, and for the treatment of menstrual symptoms, and was later approved for the relief of the signs and symptoms of rheumatoid arthritis in adults and children.|Information available in 2004 indicated that Rofecoxib was used in the manufacture of pharmaceutical preparations in the following countries: Argentina, Australia, Austria, Belgium, Brazil, Canada, Chile, Colombia, Costa Rica, Croatia, Denmark, Ecuador, El Salvador, Finland, France, Germany, Greece, Guatemala, Honduras, Hong Kong, Hungary, India, Indonesia, Ireland, Israel, Italy, Malaysia, Mexico, Netherlands, New Zealand, Nicaragua, Norway, Panama, Poland, Portugal, Romania, Singapore, Slovenia, South Africa, Spain, Sweden, Switzerland, Thailand, Turkey, United Kingdom, USA, Yugoslavia (1,2)

Human Drugs -> FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) -> Active Ingredients|Pharmaceuticals