Pharmacology:
The analgesic ingredient, oxycodone, is a semi-synthetic narcotic
with multiple actions qualitatively similar to those of morphine; the most
prominent of these involves the central nervous system and organs composed of
smooth muscle.
Oxycodone, as the hydrochloride salt, is a pure agonist opioid whose
principal therapeutic action is analgesia and has been in clinical use since
1917. Like all pure opioid agonists, there is no ceiling effect to analgesia,
such as is seen with partial agonists or non-opioid analgesics. Based upon a
single-dose, relative-potency study conducted in humans with cancer pain, 10 to
15 mg of oxycodone given intramuscularly produced an analgesic effect similar to
10 mg of morphine given intramuscularly. Both drugs have a 3 to 4 hour duration
of action. Oxycodone retains approximately one half of its analgesic activity
when administered orally.
Effects on Central Nervous
System: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 play a
role in the analgesic effects of this drug. A significant feature of
opioid-induced analgesia is that it occurs without loss of consciousness. The
relief of pain by morphine-like opioids is relatively selective, in that other
sensory modalities, (e.g., touch, vibrations, vision, hearing, etc.) are not
obtunded.
Oxycodone produces respiratory depression by direct action on brain stem
respiratory centers. The respiratory depression involves both a reduction in the
responsiveness of the brain stem respiratory centers to increases in carbon
dioxide tension and to electrical stimulation.
Oxycodone depresses the cough reflex by direct effect on the cough center in
the medulla. Antitussive effects may occur with doses lower than those usually
required for analgesia. Oxycodone 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.
Effects on Gastrointestinal
Tract and Other Smooth Muscle:Oxycodone, like other opioid analgesics, produces some degree of
nausea and vomiting which is caused by direct stimulation of the chemoreceptor
trigger zone (CTZ) located in the medulla. The frequency and severity of emesis
gradually diminishes with time.
Oxycodone may cause a decrease in the secretion of hydrochloric acid in the
stomach that reduces motility while increasing the tone of the antrum, 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.
Effects on Cardiovascular
System:Oxycodone, in therapeutic doses, produces peripheral
vasodilatation (arteriolar and venous), decreased peripheral resistance, and
inhibits baroreceptor reflexes. Manifestations of histamine release and/or
peripheral vasodilatation may include pruritus, flushing, red eyes, sweating,
and/or orthostatic hypotension.
Caution should be used in hypovolemic patients, such as those suffering acute
myocardial infarction, because oxycodone may cause or further aggravate their
hypotension. Caution should also be used in patients with cor pulmonale who have
received therapeutic doses of opioids.
Pharmacodynamics:
The relationship between the plasma level of oxycodone and the
analgesic response will depend on the patient's age, state of health, medical
condition and extent of previous opioid treatment.
The minimum effective plasma concentration of oxycodone to achieve analgesia
will vary widely among patients, especially among patients who have been
previously treated with potent agonist opioids. Thus, patients need to be
treated with individualized titration of dosage to the desired effect. The
minimum effective analgesic concentration of oxycodone for any individual
patient may increase with repeated dosing due to an increase in pain and/or
development of tolerance.
Pharmacokinetics:
The activity of oxycodone hydrochloride tablets is primarily due
to the parent drug oxycodone. Oxycodone hydrochloride tablets are designed to
provide immediate release of oxycodone.
Table 1 Pharmacokinetic Parameters (Mean±SD)| Dose/Parameters | AUC
(ngxhr/mL) | Cmax
(ng/mL) | Tmax
(hr) | Cmin
(ng/mL) | Cavg
(ng/mL) | Half-Life
(hr) |
Single Dose
Pharmacokinetics | | | | | | |
oxycodone hydrochloride tablets
5 mg
tabs x 3 | 133.2±33 | 22.3±8.2 | 1.8±1.8 | n/a | n/a | 3.73±0.9 |
oxycodone hydrochloride tablets
15 mg
tab | 128.2±35.1 | 22.2±7.6 | 1.4±0.7 | n/a | n/a | 3.55±1.0 |
oxycodone hydrochloride oral
concentrate
solution
15 mg oral solution | 130.6±34.7 | 21.1±6.1 | 1.9±1.5 | n/a | n/a | 3.71±0.8 |
oxycodone hydrochloride tablets
30 mg
tab | 268.2±60.7 | 39.3±14.0 | 2.6±3.0 | n/a | n/a | 3.85±1.3 |
Food-Effect,
Single
Dose | | | | | | |
oxycodone hydrochloride oral
solution,
USP
10 mg/10 mL
oral sol'n (fasted) | 105±6.2 | 19.0±3.7 | 1.25±0.5 | n/a | n/a | 2.9±0.4 |
oxycodone hydrochloride oral
solution,
USP
10 mg/10 mL
oral sol'n (fed) | 133±25.2 | 17.7±3.0 | 2.54±1.2 | n/a | n/a | 3.3±0.5 |
Multiple-Dose
Studies | AUC(72-84) |
|
| | | |
oxycodone hydrochloride tablets
5 mg
tabs
q6h x 14 doses | 113.3±24.0 | 15.7±3.2 | 1.3±0.3 | 7.4±1.8 | 9.4±2.0 | n/a |
oxycodone hydrochloride oral
solution,
USP
3.33 mg (3.33 mL)
oral sol'n q4h x 21 doses | 99.0±24.8 | 12.9±3.1 | 1.0±0.3 | 7.2±2.3 | 9.7±2.6 | n/a |
Absorption:About 60% to 87% of an oral dose of oxycodone reaches the
systemic circulation in comparison to a parenteral dose. This high oral
bioavailability (compared to other oral opioids) is due to lower pre-systemic
and/or first-pass metabolism of oxycodone. The relative oral bioavailability of
oxycodone hydrochloride tablets 15 mg and 30 mg tablets, compared to the 5 mg
oxycodone hydrochloride tablets, is 96% and 101% respectively. Oxycodone
hydrochloride tablets, 15 mg and 30 mg are bioequivalent to the oxycodone
hydrochloride tablets, 5 mg (see Table 1 for pharmacokinetic parameters). Dose
proportionality of oxycodone has been established using the oxycodone
hydrochloride tablets 5 mg tablets at doses of 5 mg, 15 mg (three 5 mg tablets)
and 30 mg (six 5 mg tablets) based on extent of absorption (AUC) (see Figure 1).
It takes approximately 18 to 24 hours to reach steady-state plasma
concentrations of oxycodone with oxycodone hydrochloride tablets.
Food Effect:A single-dose food effect study was conducted in normal
volunteers using the 5 mg/5 mL solution. The concurrent intake of a high fat
meal was shown to enhance the extent (27% increase in AUC), but not the rate of
oxycodone absorption from the oral solution (see Table 1). In addition, food
caused a delay in Tmax (1.25 to 2.54 hour). Similar effects of food are expected
with the 15 mg and 30 mg tablets.
Distribution:Following intravenous administration, the volume of distribution
(Vss) for oxycodone was 2.6 L/kg. Plasma protein binding
of oxycodone at 37°C and a pH of 7.4 was about 45%. Oxycodone has been found in
breast milk (see PRECAUTIONS-Nursing
Mothers).
Metabolism:Oxycodone hydrochloride is extensively metabolized to
noroxycodone, oxymorphone, and their glucuronides. The major circulating
metabolite is noroxycodone with an AUC ratio of 0.6 relative to that of
oxycodone. Oxymorphone is present in the plasma only in low concentrations. The
analgesic activity profile of other metabolites is not known at present.
The formation of oxymorphone, but not noroxycodone, is mediated by CYP2D6 and
as such its formation can, in theory, be affected by other drugs (see PRECAUTIONS-Drug
Interactions).
Elimination:Oxycodone and its metabolites are excreted primarily via the
kidney. The amounts measured in the urine have been reported as follows: free
oxycodone up to 19%; conjugated oxycodone up to 50%; free oxymorphone 0%;
conjugated oxymorphone less than or equal to 14%; both free and conjugated noroxycodone have been
found in the urine but not quantified. The total plasma clearance was 0.8 L/min
for adults. Apparent elimination half-life of oxycodone following the
administration of oxycodone hydrochloride tablets was 3.5 to 4 hours.
Special
Populations:Geriatric:
Population pharmacokinetic studies conducted with oxycodone
hydrochloride tablets, indicated that the plasma concentrations of oxycodone did
not appear to be increased in patients over the age of 65.
Gender:
Population pharmacokinetic analyses performed in the clinical
study support the lack of gender effect on the pharmacokinetics of oxycodone
from oxycodone hydrochloride tablets.
Race:
Population pharmacokinetic analyses support the lack of race effect on oxycodone pharmacokinetics after
administration of oxycodone hydrochloride tablets, but these data should be interpreted conservatively, since the majority
of patients enrolled into the studies were Caucasians (94%).
Renal Insufficiency:
In a clinical trial supporting the development of oxycodone
hydrochloride tablets, too few patients with decreased renal function were
evaluated to study these potential differences. In previous studies, patients
with renal impairment (defined as a creatinine clearance less than 60 mL/min) had
concentrations of oxycodone in the plasma that were higher than in subjects with
normal renal function. Based on information available on the metabolism and
excretion of oxycodone, dose initiation in patients with renal impairment should
follow a conservative approach. Dosages should be adjusted according to the
clinical situation.
Hepatic Failure:
In a clinical trial supporting the development of oxycodone
hydrochloride tablets, too few patients with decreased hepatic function were
evaluated to study these potential differences. However, since oxycodone is
extensively metabolized, its clearance may decrease in hepatic failure patients.
Dose initiation in patients with hepatic impairment should follow a conservative
approach. Dosages should be adjusted according to the clinical situation.
