ome and/or potential development of analgesic tolerance.
Concentration-Adverse Experience Relationships
There is a general relationship between increasing opioid plasma concentration and increasing frequency of adverse experiences such as nausea, vomiting, CNS effects, and respiratory depression.
CNS Depressant/Alcohol Interaction
Additive pharmacodynamic effects may be expected when OPANA ER is used in conjunction with alcohol, other opioids, or illicit drugs that cause central nervous system depression.
12.3 Pharmacokinetics
Absorption
The absolute oral bioavailability of oxymorphone is approximately 10%.
Steady-state levels are achieved after three days of multiple dose administration. Under both single-dose and steady-state conditions, dose proportionality has been established for the 5 mg, 10 mg, 20 mg, and 40 mg doses of oxymorphone hydrochloride extended-release tablets, for both peak plasma levels (Cmax) and extent of absorption (AUC) (see Table 4).
Table 4: Mean (±SD) Oxymorphone Hydrochloride Extended-Release Tablets Pharmacokinetic Parameters
Regimen
Dosage
Cmax
(ng/mL)
AUC
(ng·hr/mL)
T ½
(hr)
Single Dose
5 mg
10 mg
20 mg
40 mg
0.27±0.13
0.65±0.29
1.21±0.77
2.59±1.65
4.54±2.04
8.94±4.16
17.81±7.22
37.90±16.20
11.30±10.81
9.83±5.68
9.89±3.21
9.35±2.94
Multiple Dosea
5 mg
10 mg
20 mg
40 mg
0.70±0.55
1.24±0.56
2.54±1.35
4.47±1.91
5.60±3.87
9.77±3.52
19.28±8.32
36.98±13.53
NA
NA
NA
NA
NA = not applicable
a Results after 5 days of q12h dosing.
Food EffectTwo studies examined the effect of food on the bioavailability of single doses of 20 and 40 mg of oxymorphone hydrochloride extended-release tablets in healthy volunteers. In both studies, after the administration of oxymorphone hydrochloride extended-release tablets, the Cmax was increased by approximately 50% in fed subjects compared to fasted subjects. A similar increase in Cmax was also observed with oxymorphone solution.
The AUC was unchanged in one study and increased by approximately 18% in the other study in fed subjects following the administration of oxymorphone hydrochloride extended-release tablets. Examination of the AUC suggests that most of the difference between fed and fasting conditions occurs in the first four hours after dose administration. After oral dosing with a single dose of 40 mg, a peak oxymorphone plasma level of 2.8 ng/ml is achieved at 1hour in fasted subjects and a peak of 4.25 ng/ml is achieved at 2 hours in fed subjects and that beyond the 12 hour time point, there is very little difference in the curves. As a result, OPANA ER should be dosed at least one hour prior to or two hours after eating [see Dosage and Administration (2.1, 2.2)].
DistributionFormal 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%.
MetabolismOxymorphone is highly metabolized, principally in the liver, and undergoes reduction or conjugation with glucuronic acid to form both active and inactive metabolites. The two major metaboli |
