Prescription Drug Name:
Oxycodone Hydrochloride Tablets, USP CII
ID:
5176403a-4709-4fc6-b1a9-72198e35bff5
Code:
34391-3
DESCRIPTION
id: ba10447b-b69e-4e87-9833-f4c5e8e455cf
displayName: Description Section
FDA Article Code: 34089-3
Each tablet for oral administration contains 5 mg, 15 mg or 30 mg of oxycodone hydrochloride USP.
Oxycodone hydrochloride USP 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).
Chemically, oxycodone hydrochloride is 4, 5α-epoxy-14-hydroxy-3-methoxy-17-methylmorphinan-6-one hydrochloride and has the following structural formula:
The 5 mg, 15 mg and 30 mg tablets contain the equivalent of 4.5 mg, 13.5 mg and 27 mg, respectively, of oxycodone free base.
CLINICAL PHARMACOLOGY
id: cfb80df7-4f0d-4244-a519-e365136d7ea6
displayName: Clinical Pharmacology Section
FDA Article Code: 34090-1
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.
| Dose\Parameters | AUC (ngxhr/mL) |
Cmax
(ng/mL) |
Tmax
(hr) |
Cmin
(ng/mL) |
Cavg
(ng/mL) |
Half-Life (hr) |
|
|---|---|---|---|---|---|---|---|
|
|
|||||||
| Oxycodone hydrochloride 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 15 mg tab |
128.2±35.1 | 22.2±7.6 | 1.4±0.7 | n/a | n/a | 3.55±1 | |
| Oxycodone hydrochloride Liquid Concentrate 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 30 mg tab |
268.2±60.7 | 39.3±14 | 2.6±3 | n/a | n/a | 3.85±1.3 | |
|
|
|||||||
| Oxycodone hydrochloride 10 mg/10 mL oral sol’n (fasted) |
105±6.2 | 19±3.7 | 1.25±0.5 | n/a | n/a | 2.9±0.4 | |
| Oxycodone hydrochloride 10 mg/10 mL oral sol’n (fed) |
133±25.2 | 17.7±3 | 2.54±1.2 | n/a | n/a | 3.3±0.5 | |
|
|
AUC(72-84) | ||||||
| Oxycodone hydrochloride 5 mg tabs q 6 h x 14 doses |
113.3±24 | 15.7±3.2 | 1.3±0.3 | 7.4±1.8 | 9.4±2 | n/a | |
| Oxycodone hydrochloride 3.33 mg (3.33 mL) oral sol’n. q 4 h x 21 doses |
99±24.8 | 12.9±3.1 | 1±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 tablets 15 mg and 30 mg, 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 5 mg oxycodone hydrochloride tablets (see Table 1 for pharmacokinetic parameters). Dose proportionality of oxycodone has been established using the oxycodone hydrochloride tablets 5 mg 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.
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
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
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.
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
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 < 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.
INDICATIONS AND USAGE
id: c85555df-990d-4c39-9dfc-e511948af845
displayName: Indications & Usage Section
FDA Article Code: 34067-9
CONTRAINDICATIONS
id: ed49ddca-d072-4714-9508-d66958acb1b4
displayName: Contraindications Section
FDA Article Code: 34070-3
WARNINGS
id: caccfb95-38e7-4cf5-8f56-e144dae8e0fa
displayName: Warnings Section
FDA Article Code: 34071-1
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.
Hypotensive Effect
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.
Head Injury and Increased Intracranial Pressure
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.
ADVERSE REACTIONS
id: 16b24f16-fd15-450a-81b2-53a12418402b
displayName: Adverse Reactions Section
FDA Article Code: 34084-4
Serious adverse reactions that may be associated with oxycodone hydrochloride tablets therapy in clinical use are those observed with other opioid analgesics and include: respiratory depression, respiratory arrest, circulatory depression, cardiac arrest, hypotension, and/or shock (see
The less severe adverse events seen on initiation of therapy with oxycodone hydrochloride tablets are also typical opioid side effects. These events are dose dependent, and their frequency depends on the clinical setting, the patient’s level of opioid tolerance, and host factors specific to the individual. They should be expected and managed as a part of opioid analgesia. The most frequent of these include nausea, constipation, vomiting, headache, and pruritus.
In many cases the frequency of adverse events during initiation of opioid therapy may be minimized by careful individualization of starting dosage, slow titration and the avoidance of large rapid swings in plasma concentration of the opioid. Many of these adverse events will abate as therapy is continued and some degree of tolerance is developed, but others may be expected to remain throughout therapy.
In all patients for whom dosing information was available (n=191) from the open-label and double-blind studies involving oxycodone hydrochloride tablets, the following adverse events were recorded in oxycodone hydrochloride tablets treated patients with an incidence ≥ 3%. In descending order of frequency they were: nausea, constipation, vomiting, headache, pruritus, insomnia, dizziness, asthenia, and somnolence.
The following adverse experiences occurred in less than 3% of patients involved in clinical trials with oxycodone:
Body as a Whole: abdominal pain, accidental injury, allergic reaction, back pain, chills and fever, fever, flu syndrome, infection, neck pain, pain, photosensitivity reaction, and sepsis.
Cardiovascular: deep thrombophlebitis, heart failure, hemorrhage, hypotension, migraine, palpitation, and tachycardia.
Digestive: anorexia, diarrhea, dyspepsia, dysphagia, gingivitis, glossitis, nausea, and vomiting.
Hemic and Lymphatic: anemia and leukopenia.
Metabolic and Nutritional: edema, gout, hyperglycemia, iron deficiency anemia, and peripheral edema.
Musculoskeletal: arthralgia, arthritis, bone pain, myalgia, and pathological fracture.
Nervous: agitation, anxiety, confusion, dry mouth, hypertonia, hypesthesia, nervousness, neuralgia, personality disorder, tremor, and vasodilation.
Respiratory: bronchitis, cough increased, dyspnea, epistaxis, laryngismus, lung disorder, pharyngitis, rhinitis, and sinusitis.
Skin and Appendages: herpes simplex, rash, sweating, and urticaria.
Special Senses: amblyopia.
Urogenital: urinary tract infection.
OVERDOSAGE
id: e33cb71e-a0b4-498d-b11e-18d3f798f447
displayName: Overdosage Section
FDA Article Code: 34088-5
Acute overdose with oxycodone hydrochloride tablets can be manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, bradycardia, hypotension, and death.
Treatment
To treat oxycodone hydrochloride tablets overdose, primary attention should be given to the re-establishment of a patent airway and institution of assisted or controlled ventilation. Supportive measures (including oxygen and vasopressors) should be employed in the management of circulatory shock and pulmonary edema accompanying overdose as indicated. Cardiac arrest or arrhythmias may require cardiac massage or defibrillation.
The narcotic antagonists, naloxone or nalmefene, are specific antidotes for opioid overdose. Opioid antagonists should not be administered in the absence of clinically significant respiratory or circulatory depression secondary to oxycodone hydrochloride tablets overdose. If needed the appropriate dose of naloxone hydrochloride or nalmefene should be administered simultaneously with efforts at respiratory resuscitation (see package insert for each drug for the details). Since the duration of action of oxycodone may exceed that of the antagonist, the patient should be kept under continued surveillance and repeated doses of the antagonist should be administered as needed to maintain adequate respiration. Gastric emptying may be useful in removing unabsorbed drug.
Opioid antagonists should be administered cautiously to persons who are suspected to be physically dependent on any opioid agonist, including oxycodone (see
Opioid-Tolerant Individuals
In an individual physically dependent on opioids, administration of a usual dose of antagonist will precipitate an acute withdrawal. The severity of the withdrawal syndrome produced will depend on the degree of physical dependence and the dose of the antagonist administered. Use of an opioid antagonist should be reserved for cases where such treatment is clearly needed. If it is necessary to treat serious respiratory depression in the physically dependent patient, administration of the antagonist should be begun with care and by titration with smaller than usual doses.
DOSAGE AND ADMINISTRATION
id: c1d47d60-8809-4c30-9529-5479af26be13
displayName: Dosage & Administration Section
FDA Article Code: 34068-7
Patients who have not been receiving opioid analgesics should be started on oxycodone hydrochloride tablets in a dosing range of 5 to 15 mg every 4 to 6 hours as needed for pain. The dose should be titrated based upon the individual patient’s response to their initial dose of oxycodone hydrochloride tablets. Patients with chronic pain should have their dosage given on an around-the-clock basis to prevent the reoccurrence of pain rather than treating the pain after it has occurred. This dose can then be adjusted to an acceptable level of analgesia taking into account side effects experienced by the patient.
For control of severe chronic pain, oxycodone hydrochloride tablets should be administered on a regularly scheduled basis, every 4 to 6 hours, at the lowest dosage level that will achieve adequate analgesia.
As with any potent opioid, it is critical to adjust the dosing regimen for each patient individually, taking into account the patient’s prior analgesic treatment experience. Although it is not possible to list every condition that is important to the selection of the initial dose of oxycodone hydrochloride tablets, attention should be given to: 1) the daily dose, potency, and characteristics of a pure agonist or mixed agonist/antagonist the patient has been taking previously, 2) the reliability of the relative potency estimate to calculate the dose of oxycodone needed, 3) the degree of opioid tolerance, 4) the general condition and medical status of the patient, and 5) the balance between pain control and adverse experiences.
Conversion from Fixed-Ratio Opioid/Acetaminophen, Opioid/Aspirin, or Opioid/Nonsteroidal Combination Drugs
When converting patients from fixed ratio opioid/non-opioid drug regimens a decision should be made whether or not to continue the non-opioid analgesic. If a decision is made to discontinue the use of non-opioid analgesic, it may be necessary to titrate the dose of oxycodone hydrochloride tablets in response to the level of analgesia and adverse effects afforded by the dosing regimen. If the non-opioid regimen is continued as a separate single entity agent, the starting dose oxycodone hydrochloride tablets should be based upon the most recent dose of opioid as a baseline for further titration of oxycodone. Incremental increases should be gauged according to side effects to an acceptable level of analgesia.
Patients Currently on Opioid Therapy
If a patient has been receiving opioid-containing medications prior to taking oxycodone hydrochloride tablets, the potency of the prior opioid relative to oxycodone should be factored into the selection of the total daily dose (TDD) of oxycodone.
In converting patients from other opioids to oxycodone hydrochloride tablets close observation and adjustment of dosage based upon the patient’s response to oxycodone hydrochloride tablets are imperative. Administration of supplemental analgesia for breakthrough or incident pain and titration of the total daily dose of oxycodone hydrochloride tablets may be necessary, especially in patients who have disease states that are changing rapidly.
Maintenance of Therapy
Continual re-evaluation of the patient receiving oxycodone hydrochloride tablets are important, with special attention to the maintenance of pain control and the relative incidence of side effects associated with therapy. If the level of pain increases, effort should be made to identify the source of increased pain, while adjusting the dose as described above to decrease the level of pain.
During chronic therapy, especially for non-cancer-related pain (or pain associated with other terminal illnesses), the continued need for the use of opioid analgesics should be re-assessed as appropriate.
HOW SUPPLIED
id: 329e74da-d335-4501-9f8c-b203f1eccbff
displayName: How Supplied Section
FDA Article Code: 34069-5
White to off white, round tablets, debossed with “U22” on one side and breakline on the other side.
Bottles of 30 NDC 13107-055-30
Bottles of 100 NDC 13107-055-01
Bottles of 1000 NDC 13107-055-99
Light green to green, round tablets, debossed with “U23” on one side and breakline on the other side.
Bottles of 30 NDC 13107-056-30
Bottles of 100 NDC 13107-056-01
Bottles of 1000 NDC 13107-056-99
Light blue to blue, round tablets, debossed with “U24” on one side and breakline on the other side.
Bottles of 30 NDC 13107-057-30
Bottles of 100 NDC 13107-057-01
Bottles of 1000 NDC 13107-057-99
DEA Order Form Required
Dispense in a tight, light-resistant container. Protect from moisture.
Manufactured by:
Dayton, NJ 08810
Manufactured for:
Dayton, NJ 08810
Revised: 08/2011
To request medical information or to report suspected adverse reactions, contact Aurobindo Pharma USA, Inc. at 1-866-850-2876 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
PACKAGE LABEL-PRINCIPAL DISPLAY PANEL – 5 mg (100 Tablet Bottle)
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displayName: PACKAGE LABEL.PRINCIPAL DISPLAY PANEL
FDA Article Code: 51945-4
PACKAGE LABEL-PRINCIPAL DISPLAY PANEL – 15 mg (100 Tablet Bottle)
id: 8ca9a0d6-0b9a-42c5-a645-362690c4a137
displayName: PACKAGE LABEL.PRINCIPAL DISPLAY PANEL
FDA Article Code: 51945-4
PACKAGE LABEL-PRINCIPAL DISPLAY PANEL – 30 mg (100 Tablet Bottle)
id: 4c8a8016-98c6-4461-8fbf-59a73fc68f55
displayName: PACKAGE LABEL.PRINCIPAL DISPLAY PANEL
FDA Article Code: 51945-4
30 mg