Rofecoxib

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.

/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.

Drug-Induced Liver Injury Severity and Toxicity (DILIst)

ROFECOXIB

DILI Positive

Oral

DOI:10.1016/j.drudis.2019.09.022

/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ Rofecoxib was not carcinogenic in mice given oral doses up to 30 mg/kg (male) and 60 mg/kg (female) and in male and female rats given oral doses up to 8 mg/kg for two years.

/GENOTOXICITY/ Rofecoxib was not mutagenic in an Ames test or in a V-79 mammalian cell mutagenesis assay, nor clastogenic in a chromosome aberration assay in Chinese hamster ovary (CHO) cells, in an in vitro and an in vivo alkaline elution assay, or in an in vivo chromosomal aberration test in mouse bone marrow.

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Rofecoxib did not impair male fertility in rats at oral doses up to 100 mg/kg and rofecoxib had no effect on fertility in female rats at doses up to 30 mg/kg.

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Rofecoxib was not teratogenic in rats at doses up to 50 mg/kg/day. There was a slight, non-statistically significant increase in the overall incidence of vertebral malformations only in the rabbit at doses of 50 mg/kg/day.

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Rofecoxib produced peri-implantation and post-implantation losses and reduced embryo/fetal survival in rats and rabbits at oral doses >/=10 and >/=75 mg/kg/day, respectively. These changes are expected with inhibition of prostaglandin synthesis and are not the result of permanent alteration of female reproductive function. There was an increase in the incidence of postnatal pup mortality in rats at >/=5 mg/kg/day. In studies in pregnant rats administered single doses of rofecoxib, there was a treatment-related decrease in the diameter of the ductus arteriosus at all doses used. As with other drugs known to inhibit prostaglandin synthesis.

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.

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.