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 approximay 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 received therapeutic doses of opioids.
Respiratory depression is the chief hazard from all opioid agonist preparations. Respiratory depression occurs most frequently in elderly or debilitated patients, usually following large initial doses in non-tolerant patients, or when opioids are given in conjunction with other agents that depress respiration. Oxycodone hydrochloride tablets should be used with extreme caution in patients with significant chronic obstructive pulmonary disease or cor pulmonale, and in patients having substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression. In such patients, even usual therapeutic doses of oxycodone hydrochloride tablets may decrease respiratory drive to the point of apnea. In these patients alternative non-opioid analgesics should be considered, and opioids should be employed only under careful medical supervision at the lowest effective dose.
3. Patients should be advised that oxycodone hydrochloride tablets may impair mental and/or physical ability required for the performance of potentially hazardous tasks (e.g., driving, operating heavy machinery).
Updated October 29, 2014.
Neuromuscular Blocking Agents: Oxycodone, as well as other opioid analgesics, may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression. CNS Depressants: Patients receiving narcotic analgesics, general anesthetics, phenothiazines, other tranquilizers, sedative-hypnotics or other CNS depressants (including alcohol) concomitantly with oxycodone hydrochloride tablets may exhibit an additive CNS depression. Interactive effects resulting in respiratory depression, hypotension, profound sedation, or coma may result if these drugs are taken in combination with the usual dosage of oxycodone hydrochloride tablets. When such combined therapy is contemplated, the dose of one or both agents should be reduced. Mixed Agonist/Antagonist Opioid Analgesics: Agonist/antagonist analgesics (i.e., pentazocine, nalbuphine, butorphanol and buprenorphine) should be administered with caution to patients who have received or are receiving a course of therapy with a pure opioid agonist analgesic such as oxycodone hydrochloride tablets. In this situation, mixed agonist/antagonist analgesics may reduce the analgesic effect of oxycodone hydrochloride tablets and/or may precipitate withdrawal symptoms in these patients. Monoamine Oxidase Inhibitors (MAOIs): MAOIs have been reported to intensify the effects of at least one opioid drug causing anxiety, confusion and significant depression of respiration or coma. The use of oxycodone hydrochloride tablets is not recommended for patients taking MAOIs or within 14 days of stopping such treatment.
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) AUC (72-84).
5. Women of childbearing potential who become, or are planning to become pregnant, should be advised to consult their physician regarding the effects of analgesics and other drug use during pregnancy on themselves and their unborn child.
If clinically advisable, patients (or their caregivers) receiving oxycodone hydrochloride tablets should be given the following information by the physician, nurse, pharmacist or caregiver:
6. Patients should be advised that oxycodone hydrochloride tablets are a potential drug of abuse. They should protect it from theft, and it should never be given to anyone other than the individual for whom it was prescribed.
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 T max (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 (V ss ) 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 ≤ 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.
Oxycodone is metabolized in part to oxymorphone via the cytochrome p450 isoenzyme CYP2D6. While this pathway may be blocked by a variety of drugs (e.g., certain cardiovascular drugs and antidepressants), such blockade has not yet been shown to be of clinical significance with this agent. However, clinicians should be aware of this possible interaction.
Oxycodone hydrochloride tablets are intended for use in patients who require oral pain therapy with an opioid agonist. As with any opioid analgesic, it is critical to adjust the dosing regimen individually for each patient (see DOSAGE AND ADMINISTRATION ). Selection of patients for treatment with oxycodone hydrochloride tablets should be governed by the same principles that apply to the use of other potent opioid analgesics. Opioid analgesics given on a fixed-dosage schedule have a narrow therapeutic index in certain patient populations, especially when combined with other drugs, and should be reserved for cases where the benefits of opioid analgesia outweigh the known risks of respiratory depression, altered mental state, and postural hypotension. Physicians should individualize treatment in every case, using nonopioid analgesics, prn opioids and/or combination products, and chronic opioid therapy with drugs such as oxycodone hydrochloride in a progressive plan of pain management such as outlined by the World Health Organization, the Agency for Health Care Policy and Research, and the American Pain Society. Use of oxycodone hydrochloride tablets is associated with increased potential risks and should be used only with caution in the following conditions: acute alcoholism; adrenocortical insufficiency (e.g., Addison's disease); convulsive disorders; CNS depression or coma; delirium tremens; debilitated patients; kyphoscoliosis associated with respiratory depression; myxedema or hypothyroidism; prostatic hypertrophy or urethral stricture; severe impairment of hepatic, pulmonary or renal function; and toxic psychosis. The administration of oxycodone hydrochloride tablets, like all opioid analgesics, may obscure the diagnosis or clinical course in patients with acute abdominal conditions. Oxycodone may aggravate convulsions in patients with convulsive disorders, and all opioids may induce or aggravate seizures in some clinical settings.
7. Patients should be advised that if they have been receiving treatment with oxycodone hydrochloride tablets for more than a few weeks and cessation of therapy is indicated, it may be appropriate to taper the oxycodone hydrochloride tablets dose, rather than abruptly discontinue it, due to the risk of precipitating withdrawal symptoms. Their physician can provide a dose schedule to accomplish a gradual discontinuation of the medication.
Oxycodone hydrochloride tablets are contraindicated in patients with known hypersensitivity to oxycodone, or in any situation where opioids are contraindicated. This includes patients with significant respiratory depression (in unmonitored settings or the absence of resuscitative equipment) and patients with acute or severe bronchial asthma or hypercarbia. Oxycodone hydrochloride tablets are contraindicated in any patient who has or is suspected of having paralytic ileus.
Physical dependence and tolerance are not unusual during chronic opioid therapy. Significant tolerance should not occur in most patients treated with the lowest doses of oxycodone. It should be expected, however, that a fraction of patients will develop some degree of tolerance and require progressively higher dosages of oxycodone hydrochloride tablets to maintain pain control during chronic treatment. The dosage should be selected according to the patient's individual analgesic response and ability to tolerate side effects. Tolerance to the analgesic effects of opioids is usually paralleled by tolerance to side effects except for constipation. Physical dependence results in withdrawal symptoms in patients who abruptly discontinue the drug or may be precipitated through the administration of drugs with opioid antagonist activity. If oxycodone hydrochloride tablets are abruptly discontinued in a physically dependent patient, an abstinence syndrome may occur (see DRUG ABUSE AND DEPENDENCE ). If signs and symptoms of withdrawal occur, patients should be treated by reinstitution of opioid therapy followed by gradual tapered dose reduction of oxycodone hydrochloride tablets combined with symptomatic support (see DOSAGE AND ADMINISTRATION: Cessation of Therapy ).
Oxycodone hydrochloride tablets, USP are an immediate-release oral formulation of oxycodone hydrochloride indicated for the management of moderate to severe pain where the use of an opioid analgesic is appropriate.
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 presystemic 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 tablet (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 approximay 18 to 24 hours to reach steady-state plasma concentrations of oxycodone with oxycodone hydrochloride tablets.
1. Patients should be advised to report episodes of breakthrough pain and adverse experiences occurring during therapy. Individualization of dosage is essential to make optimal use of this medication.
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4. Patients should not combine oxycodone hydrochloride tablets with alcohol or other central nervous system depressants (sleep aids, tranquilizers) except by the orders of the prescribing physician, because additive effects may occur.
Oxycodone hydrochloride tablets, like all opioid analgesics, may cause severe hypotension in an individual whose ability to maintain blood pressure has been compromised by a depleted blood volume, or after concurrent administration with drugs such as phenothiazines or other agents which compromise vasomotor tone. Oxycodone hydrochloride tablets may produce orthostatic hypotension in ambulatory patients. Oxycodone hydrochloride tablets, like all opioid analgesics, should be administered with caution to patients in circulatory shock, since vasodilatation produced by the drug may further reduce cardiac output and blood pressure.
Oxycodone hydrochloride tablets may cause spasm of the sphincter of Oddi and should be used with caution in patients with biliary tract disease, including acute pancreatitis. Opioids like oxycodone hydrochloride tablets may cause increases in the serum amylase level.
The respiratory depressant effects of narcotics and their capacity to elevate cerebrospinal fluid pressure may be markedly exaggerated in the presence of head injury, other intracranial lesions or a pre-existing increase in intracranial pressure. Furthermore, narcotics produce adverse reactions which may obscure the clinical course of patients with head injuries.
2. Patients should be advised not to adjust the dose of oxycodone hydrochloride tablets without consulting the prescribing professional.
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 < 60mL/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.
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 tablets contain the following inactive ingredients: lactose monohydrate, magnesium stearate, microcrystalline cellulose, sodium starch glycolate and stearic acid. Colors: 15 mg tablets contain FD&C Blue # 2 Aluminum Lake and D&C Yellow # 10 Aluminum Lake 30 mg tablets contain FD&C Blue # 2 Aluminum Lake The 5 mg, 15 mg and 30 mg tablets contain the equivalent of 4.5 mg, 13.5 mg and 27.0 mg, respectively, of oxycodone free base.
Oxycodone hydrochloride tablets, USP is an opioid analgesic. Each tablet for oral administration contains 5 mg, 15 mg or 30 mg of oxycodone hydrochloride, USP. Oxycodone hydrochloride is a white to off white, 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). Chemically, oxycodone hydrochloride is 4, 5α-epoxy-14-hydroxy-3-methoxy-17-methylmorphinan-6-one hydrochloride and has the following structural formula:Oxycodone hydrochloride