OXYCODONE HYDROCHLORIDE — oxycodone hydrochloride tablet
Physicians Total Care, Inc.
Oxycodone hydrochloride tablet, USP, is an opioid analgesic.
Each tablet for oral administration contains 5 mg, 10 mg, 15 mg, 20 mg or 30 mg of oxycodone hydrochloride, USP.
Oxycodone hydrochloride is a white, odorless crystalline powder derived from the opium alkaloid, thebaine. Oxycodone hydrochloride dissolves in water (1 g in 6 to 7 mL) and is considered slightly soluble in alcohol (octanol water partition coefficient is 0.7).
The tablets contain the following inactive ingredients: magnesium stearate, microcrystalline cellulose, silicon dioxide, and stearic acid. The 5 mg tablet also contains D&C Red No. 30 aluminum lake, D&C Yellow No. 10 aluminum lake, and hydrated alumina. The 10 mg tablet also contains D&C Red No. 27 aluminum lake, D&C Red No. 30 aluminum lake, and hydrated alumina. The 15 mg tablet also contains D&C Yellow No. 10 aluminum lake and hydrated alumina. The 20 mg tablet also contains FD&C Blue No. 1 aluminum lake, FD&C Blue No. 2 aluminum lake, FD&C Red No. 40 aluminum lake, FD&C Yellow No. 6 aluminum lake, and hydrated alumina.
The 5 mg, 10 mg, 15 mg. 20 mg, and 30 mg tablets contain the equivalent of 4.5 mg, 9.0 mg. 13.5 mg, 18.0 mg, and 27.0 mg, respectively, of oxycodone free base.
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.
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.
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 reducing 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.
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.
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.
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.
|Dose/Parameters||AUC(ng x hr/mL)||Cmax (ng/mL)||Tmax (hr)||Cmin (ng/mL)||Cavg (ng/mL)||Half-Life(hr)|
|OxycodoneHCl 5 mgtablets x 3||133.2 ± 33||22.3 ± 8.2||1.8 ± 1.8||n/a||n/a||3.73 ± 0.9|
|OxycodoneHCl 15 mgtablet||128.2 ± 35.1||22.2 ± 7.6||1.4 ± 0.7||n/a||n/a||3.55 ± 1.0|
|OxycodoneHCl 15 mgoral solution||130.6 ± 30.7||21.1 ± 6.1||1.9 ± 1.5||n/a||n/a||3.71 ± 0.8|
|OxycodoneHCl 30 mgtablet||268.2 ± 60.7||39.3 ± 14.0||2.6 ± 3.0||n/a||n/a||3.85± 1.3|
|Food-Effect, Single Dose|
|OxycodoneHCl 10 mg/10 mL oralSolution(fasted)||105 ± 6.2||19.0 ± 3.7||1.25 ± 0.5||n/a||n/a||2.9 ± 0.4|
|OxycodoneHCl 10 mg/10 mL oralSolution(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)|
|OxycodoneHCl 5 mgtablets q6hx 14 doses||113.3 ± 24.0||15.7 ± 3.2||1.3 ± 0.3||7.4 ± 1.8||9.4 ± 2.0||n/a|
|OxycodoneHCl 3.33 mg(3.33 mL)oral solutionq4h x 21doses||99.0 ± 24.8||12.9 ± 3.1||1.0 ± 0.3||7.2 ± 2.3||9.7 ± 2.6||n/a|
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 15 mg and 30 mg tablets, compared to the 5 mg oxycodone hydrochloride tablets, is 96% and 101%, respectively. Oxycodone hydrochloride 15 mg tablets and 30 mg tablets are bioequivalent to the 5 mg oxycodone hydrochloride tablets (see Table 1 for pharmacokinetic parameters). Dose proportionality of oxycodone has been established using the oxycodone hydrochloride 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.
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.
Following intravenous administration, the volume of distribution (V s) 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).
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 CYP206 and as such its formation can, in theory, be affected by other drugs (see PRECAUTIONS, Drug Interactions).
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 514%; 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.
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.
Population pharmacokinetic analyses performed in the clinical study support the lack of gender effect on the pharmacokinetics of oxycodone from oxycodone hydrochloride tablets.
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%).
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.
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.
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