Chemical formula: C₁₇H₁₉NO₄ Molecular mass: 301.337 g/mol PubChem compound: 5284604
Oxymorphone is a full opioid agonist and is relatively selective for the mu-opioid receptor, although it can bind to other opioid receptors at higher doses. The principal therapeutic action of oxymorphone is analgesia. Like all full opioid agonists, there is no ceiling effect for analgesia with oxymorphone. Clinically, dosage is titrated to provide adequate analgesia and may be limited by adverse reactions, including respiratory and CNS depression.
The precise mechanism of the analgesic action is unknown. However, specific CNS opioid receptors for endogenous compounds with opioid-like activity have been identified throughout the brain and spinal cord and are thought to play a role in the analgesic effects of this drug.
Oxymorphone produces respiratory depression by direct action on brain stem respiratory centers. The respiratory depression involves a reduction in the responsiveness of the brain stem respiratory centers to both increases in carbon dioxide tension and electrical stimulation.
Oxymorphone causes miosis, even in total darkness. Pinpoint pupils are a sign of opioid overdose but are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origins may produce similar findings). Marked mydriasis rather than miosis may be seen due to hypoxia in overdose situations.
Oxymorphone causes a reduction in motility associated with an increase in smooth muscle tone in the antrum of the stomach and duodenum. Digestion of food in the small intestine is delayed and propulsive contractions are decreased. Propulsive peristaltic waves in the colon are decreased, while tone may be increased to the point of spasm, resulting in constipation. Other opioid-induced effects may include a reduction in biliary and pancreatic secretions, spasm of sphincter of Oddi, and transient elevations in serum amylase.
Oxymorphone produces peripheral vasodilation which may result in orthostatic hypotension or syncope. Manifestations of histamine release and/or peripheral vasodilation may include pruritus, flushing, red eyes, sweating and/or orthostatic hypotension.
Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing hormone (LH) in humans. They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagon.
Chronic use of opioids may influence the hypothalamic-pituitary-gonadal axis, leading to androgen deficiency that may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility. The causal role of opioids in the clinical syndrome of hypogonadism is unknown because the various medical, physical, lifestyle, and psychological stressors that may influence gonadal hormone levels have not been adequately controlled for in studies conducted to date.
Opioids have been shown to have a variety of effects on components of the immune system in in vitro and animal models. The clinical significance of these findings is unknown. Overall, the effects of opioids appear to be modestly immunosuppressive.
The minimum effective analgesic concentration varies widely among patients, especially among patients who have been previously treated with potent agonist opioids. The minimum effective analgesic concentration of oxymorphone for any individual patient may increase over time due to an increase in pain, the development of a new pain syndrome and/or the development of analgesic tolerance.
There is a relationship between increasing oxymorphone plasma concentration and increasing frequency of dose-related opioid adverse reactions such as nausea, vomiting, CNS effects, and respiratory depression. In opioid-tolerant patients, the situation may be altered by the development of tolerance to opioid-related adverse reactions.
The absolute oral bioavailability of oxymorphone is approximately 10%. Studies in healthy volunteers reveal predictable relationships between oxymorphone hydrochloride tablets dosage and plasma oxymorphone concentrations.
Steady-state levels were achieved after three days of multiple dose administration. Under both single-dose and steady-state conditions, dose proportionality has been established for 5 mg, 10 mg and 20 mg doses of oxymorphone hydrochloride tablets, for both peak plasma levels (Cmax) and extent of absorption (AUC) (see table below).
Mean (± SD) Oxymorphone Hydrochloride Tablets Pharmacokinetic Parameters:
| Regimen | Dosage | Cmax (ng/mL) | ACU (ng·hr/mL) | T1/2 (hr) |
|---|---|---|---|---|
| Single Dose | 5 mg 10 mg 20 mg | 1.10 ± 0.55 1.93 ± 0.75 4.39 ± 1.72 | 4.48 ± 2.07 9.10 ± 3.40 20.07 ± 5.80 | 7.25 ± 4.40 7.78 ± 3.58 9.43 ± 3.36 |
| Multiple Dosea | 5 mg 10 mg 20 mg | 1.73 ± 0.62 3.51 ± 0.91 7.33 ± 2.93 | 4.63 ± 1.49 10.19 ± 3.34 21.10 ± 7.59 | NA NA NA |
NA = not applicable a Results after 5 days of every 6 hours dosing.
After oral dosing with 40 mg of oxymorphone hydrochloride tablets in healthy volunteers under fasting conditions or with a high-fat meal, the Cmax and AUC were increased by approximately 38% in fed subjects relative to fasted subjects. As a result, oxymorphone hydrochloride tablets should be dosed at least one hour prior to or two hours after eating.
Formal studies on the distribution of oxymorphone in various tissues have not been conducted.
Oxymorphone is not extensively bound to human plasma proteins; binding is in the range of 10% to 12%.
Oxymorphone Hydrochloride Tablets half-life ranges from approximately 9-11 hours after a single oral dose (5-40 mg).
Oxymorphone is highly metabolized, principally in the liver, and undergoes reduction or conjugation with glucuronic acid to form both active and inactive products. The two major metabolites of oxymorphone are oxymorphone-3-glucuronide and 6-OH-oxymorphone. The mean plasma AUC for oxymorphone-3-glucuronide is approximately 90-fold higher than the parent compound. The pharmacologic activity of the glucuronide metabolite has not been evaluated. 6-OH-oxymorphone has been shown in animal studies to have analgesic bioactivity. The mean plasma 6-OH-oxymorphone AUC is approximately 70% of the oxymorphone AUC following single oral doses but is essentially equivalent to the parent compound at steady-state.
Because oxymorphone is extensively metabolized, <1% of the administered dose is excreted unchanged in the urine. On average, 33% to 38% of the administered dose is excreted in the urine as oxymorphone-3-glucuronide and 0.25% to 0.62% is excreted as 6-OH-oxymorphone in subjects with normal hepatic and renal function. In animals given radiolabeled oxymorphone, approximately 90% of the administered radioactivity was recovered within 5 days of dosing. The majority of oxymorphone-derived radioactivity was found in the urine and feces.
The plasma levels of oxymorphone administered as an extended-release tablet were about 40% higher in elderly (≥65 years of age) than in younger subjects.
The effect of sex on the pharmacokinetics of oxymorphone hydrochloride tablets has not been studied. In a study with an extended-release formulation of oxymorphone, there was a consistent tendency for female subjects to have slightly higher AUCss and Cmax values than male subjects. However, sex differences were not observed when AUCss and Cmax were adjusted by body weight.
The liver plays an important role in the pre-systemic clearance of orally administered oxymorphone. Accordingly, the bioavailability of orally administered oxymorphone may be markedly increased in patients with moderate to severe liver disease. The effect of hepatic impairment on the pharmacokinetics of oxymorphone hydrochloride tablets has not been studied. However, in a study with an extended-release formulation of oxymorphone, the disposition of oxymorphone was compared in 6 patients with mild, 5 patients with moderate, and one patient with severe hepatic impairment, and 12 subjects with normal hepatic function. The bioavailability of oxymorphone was increased by 1.6-fold in patients with mild hepatic impairment and by 3.7-fold in patients with moderate hepatic impairment. In one patient with severe hepatic impairment, the bioavailability was increased by 12.2-fold. The half-life of oxymorphone was not significantly affected by hepatic impairment.
The effect of renal impairment on the pharmacokinetics of oxymorphone hydrochloride tablets has not been studied. However, in a study with an extended-release formulation of oxymorphone, an increase of 26%, 57%, and 65% in oxymorphone bioavailability was observed in mild (creatinine clearance 51-80 mL/min; n=8), moderate (creatinine clearance 30-50 mL/min; n=8), and severe (creatinine clearance <30 mL/min; n=8) patients, respectively, compared to healthy controls.
In vitro studies revealed little to no biotransformation of oxymorphone to 6-OH-oxymorphone by any of the major cytochrome P450 (CYP P450) isoforms at therapeutically relevant oxymorphone plasma concentrations.
No inhibition of any of the major CYP P450 isoforms was observed when oxymorphone was incubated with human liver microsomes at concentrations of ≤50 µM. An inhibition of CYP 3A4 activity occurred at oxymorphone concentrations ≥150 µM. Therefore, it is not expected that oxymorphone, or its metabolites will act as inhibitors of any of the major CYP P450 enzymes in vivo.
Increases in the activity of the CYP 2C9 and CYP 3A4 isoforms occurred when oxymorphone was incubated with human hepatocytes. However, clinical drug interaction studies with Oxymorphone Hydrochloride Tablets ER showed no induction of CYP450 3A4 or 2C9 enzyme activity, indicating that no dose adjustment for CYP 3A4- or 2C9-mediated drug-drug interactions is required.
The effect of co-ingestion of alcohol with Oxymorphone Hydrochloride Tablets has not been evaluated. However, an in vivo study was performed to evaluate the effect of alcohol (40%, 20%, 4% and 0%) on the bioavailability of a single dose of 40 mg of extended-release oxymorphone tablets in healthy, fasted volunteers. Following concomitant administration of 240 mL of 40% ethanol the Cmax increased on average by 70% and up to 270% in individual subjects. Following the concomitant administration of 240 mL of 20% ethanol, the Cmax increased on average by 31% and up to 260% in individual subjects. In some individuals there was also a decrease in oxymorphone peak plasma concentrations. No effect on the release of oxymorphone from the extended-release tablet was noted in an in vitro alcohol interaction study. The mechanism of the in vivo interaction is unknown. Therefore, avoid co-administration of oxymorphone and ethanol.
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