OXYCODONE HYDROCHLORIDE (oxycodone hydrochloride 10 mg) Dailymed

9 Drug Abuse And Dependence

9.1 Controlled Substance

Oxycodone HCl extended-release tablets contains oxycodone, a Schedule II controlled substance.

9.2 Abuse

Oxycodone HCl extended-release tablets contains oxycodone, a substance with a high potential for abuse similar to other opioids including fentanyl, hydrocodone, hydromorphone, methadone, morphine, oxymorphone, and tapentadol. Oxycodone HCl extended-release tablets can be abused and is subject to misuse, addiction, and criminal diversion [see Warnings and Precautions (5.1)].

The high drug content in extended-release formulations adds to the risk of adverse outcomes from abuse and misuse.

All patients treated with opioids require careful monitoring for signs of abuse and addiction, because use of opioid analgesic products carries the risk of addiction even under appropriate medical use.

Prescription drug abuse is the intentional non-therapeutic use of a prescription drug, even once, for its rewarding psychological or physiological effects. Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that develop after repeated substance use and includes: a strong desire to take the drug, difficulties in controlling its use, persisting in its use despite harmful consequences, a higher priority given to drug use than to other activities and obligations, increased tolerance, and sometimes a physical withdrawal.

"Drug-seeking" behavior is very common in persons with substance use disorders. Drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing or referral, repeated “loss” of prescriptions, tampering with prescriptions, and reluctance to provide prior medical records or contact information for other treating healthcare provider(s). “Doctor shopping” (visiting multiple prescribers to obtain additional prescriptions) is common among drug abusers and people suffering from untreated addiction.  Preoccupation with achieving adequate pain relief can be appropriate behavior in a patient with poor pain control.

Abuse and addiction are separate and distinct from physical dependence and tolerance. Healthcare providers should be aware that addiction may not be accompanied by concurrent tolerance and symptoms of physical dependence in all addicts. In addition, abuse of opioids can occur in the absence of true addiction.

Oxycodone HCl extended-release tablets, like other opioids, can be diverted for non-medical use into illicit channels of distribution. Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests, as required by state and federal law, is strongly advised.

Proper assessment of the patient, proper prescribing practices, periodic reevaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs.

Risks Specific to Abuse of Oxycodone HCl Extended-Release Tablets

Oxycodone HCl extended-release tablets are for oral use only. Abuse of oxycodone HCl extended-release tablets poses a risk of overdose and death. The risk is increased with concurrent use of oxycodone HCl extended-release tablets with alcohol and other central nervous system depressants.  Taking cut, broken, chewed, crushed, or dissolved oxycodone HCl extended-release tablets enhances drug release and increases the risk of overdose and death.

With parenteral abuse, the inactive ingredients in oxycodone HCl extended-release tablets can be expected to result in local tissue necrosis, infection, pulmonary granulomas, increased risk of endocarditis, valvular heart injury, embolism, and death. Cases of thrombotic microangiopathy (a condition characterized clinically by thrombocytopenia and microangiopathic hemolytic anemia) associated with parenteral abuse have been reported.

Parenteral drug abuse is commonly associated with transmission of infectious diseases, such as hepatitis and HIV.

Abuse Deterrence Studies

Oxycodone HCl extended-release tablets are formulated with inactive ingredients intended to make the tablet more difficult to manipulate for misuse and abuse. For the purposes of describing the results of studies of the abuse-deterrent characteristics of oxycodone HCl extended-release tablets resulting from a change in formulation, in this section, the original formulation of oxycodone HCl extended-release tablets, which is no longer marketed, will be referred to as “original OxyContin” and the reformulated, currently marketed product will be referred to as “oxycodone HCl extended-release tablets". 

In Vitro Testing

In vitro physical and chemical tablet manipulation studies were performed to evaluate the success of different extraction methods in defeating the extended-release formulation. Results support that, relative to original OxyContin, there is an increase in the ability of oxycodone HCl extended-release tablets to resist crushing, breaking, and dissolution using a variety of tools and solvents.  The results of these studies also support this finding for oxycodone HCl extended-release tablets relative to an immediate-release oxycodone. When subjected to an aqueous environment, oxycodone HCl extended-release tablets gradually forms a viscous hydrogel (i.e., a gelatinous mass) that resists passage through a needle. 

Clinical Studies

In a randomized, double-blind, placebo-controlled 5-period crossover pharmacodynamic study, 30 recreational opioid users with a history of intranasal drug abuse received intranasally administered active and placebo drug treatments. The five treatment arms were finely crushed oxycodone HCl extended-release tablets 30 mg tablets, coarsely crushed oxycodone HCl extended-release tablets 30 mg tablets, finely crushed original OxyContin 30 mg tablets, powdered oxycodone HCl 30 mg, and placebo. Data for finely crushed oxycodone HCl extended-release tablets, finely crushed original OxyContin, and powdered oxycodone HCl are described below.

Drug liking was measured on a bipolar drug liking scale of 0 to 100 where 50 represents a neutral response of neither liking nor disliking, 0 represents maximum disliking and 100 represents maximum liking. Response to whether the subject would take the study drug again was also measured on a bipolar scale of 0 to 100 where 50 represents a neutral response, 0 represents the strongest negative response (“definitely would not take drug again”) and 100 represents the strongest positive response (“definitely would take drug again”). 

Twenty-seven of the subjects completed the study. Incomplete dosing due to granules falling from the subjects’ nostrils occurred in 34% (n = 10) of subjects with finely crushed oxycodone HCl extended-release tablets, compared with 7% (n = 2) of subjects with finely crushed original OxyContin and no subjects with powdered oxycodone HCl.

The intranasal administration of finely crushed oxycodone HCl extended-release tablets was associated with a numerically lower mean and median drug liking score and a lower mean and median score for take drug again, compared to finely crushed original OxyContin or powdered oxycodone HCl as summarized in Table 5.

Table 5: Summary of Maximum Drug Liking (E_max) Data Following Intranasal Administration

VAS Scale (100 mm)*		Oxycodone HCl extended-release tablets (finely crushed)	Original OxyContin (finely crushed)	Oxycodone HCl (powdered)
Drug Liking	Mean (SE)	80.4 (3.9)	94.0 (2.7)	89.3 (3.1)
	Median (Range)	88 (36-100)	100 (51-100)	100 (50-100)
Take Drug Again	Mean (SE)	64.0 (7.1)	89.6 (3.9)	86.6 (4.4)
	Median (Range)	78 (0-100)	100 (20-100)	100 (0-100)
* Bipolar scales (0 = maximum negative response, 50 = neutral response, 100 = maximum positive response)

Figure 1 demonstrates a comparison of drug liking for finely crushed oxycodone HCl extended-release tablets compared to powdered oxycodone HCl in subjects who received both treatments.  The Y-axis represents the percent of subjects attaining a percent reduction in drug liking for oxycodone HCl extended-release tablets vs. oxycodone HCl powder greater than or equal to the value on the X-axis.  Approximately 44% (n = 12) had no reduction in liking with oxycodone HCl extended-release tablets relative to oxycodone HCl.  Approximately 56% (n = 15) of subjects had some reduction in drug liking with oxycodone HCl extended-release tablets relative to oxycodone HCl. Thirty-three percent (n = 9) of subjects had a reduction of at least 30% in drug liking with oxycodone HCl extended-release tablets compared to oxycodone HCl, and approximately 22% (n = 6) of subjects had a reduction of at least 50% in drug liking with oxycodone HCl extended-release tablets compared to oxycodone HCl.

Figure 1: Percent Reduction Profiles for E_max of Drug Liking VAS for Oxycodone HCl Extended-Release Tablets vs. Oxycodone HCl, N=27 Following Intranasal Administration



The results of a similar analysis of drug liking for finely crushed oxycodone HCl extended-release tablets relative to finely crushed original OxyContin were comparable to the results of finely crushed oxycodone HCl extended-release tablets relative to powdered oxycodone HCl. Approximately 43% (n = 12) of subjects had no reduction in liking with oxycodone HCl extended-release tablets relative to original OxyContin.  Approximately 57% (n = 16) of subjects had some reduction in drug liking, 36% (n = 10) of subjects had a reduction of at least 30% in drug liking, and approximately 29% (n = 8) of subjects had a reduction of at least 50% in drug liking with oxycodone HCl extended-release tablets compared to original OxyContin.

Summary

The in vitro data demonstrate that oxycodone HCl extended-release tablets have physicochemical properties expected to make abuse via injection difficult. The data from the clinical study, along with support from the in vitro data, also indicate that oxycodone HCl extended-release tablets have physicochemical properties that are expected to reduce abuse via the intranasal route. However, abuse of oxycodone HCl extended-release tablets by these routes, as well as by the oral route, is still possible.

Additional data, including epidemiological data, when available, may provide further information on the impact of the current formulation of oxycodone HCl extended-release tablets on the abuse liability of the drug. Accordingly, this section may be updated in the future as appropriate.

Oxycodone HCl extended-release tablets contain oxycodone, an opioid agonist and Schedule II controlled substance with an abuse liability similar to other opioid agonists, legal or illicit, including fentanyl, hydromorphone, methadone, morphine, and oxymorphone. Oxycodone HCl extended-release tablets can be abused and is subject to misuse, addiction, and criminal diversion [see Warnings and Precautions (5.1) and Drug Abuse and Dependence (9.1)] .

9.3 Dependence

Both tolerance and physical dependence can develop during chronic opioid therapy. Tolerance is the need for increasing doses of opioids to maintain a defined effect such as analgesia (in the absence of disease progression or other external factors). Tolerance may occur to both the desired and undesired effects of drugs, and may develop at different rates for different effects.

Physical dependence results in withdrawal symptoms after abrupt discontinuation or a significant dosage reduction of a drug. Withdrawal also may be precipitated through the administration of drugs with opioid antagonist activity (e.g., naloxone, nalmefene), mixed agonist/antagonist analgesics (e.g., pentazocine, butorphanol, nalbuphine), or partial agonists (e.g., buprenorphine). Physical dependence may not occur to a clinically significant degree until after several days to weeks of continued opioid usage.

Oxycodone HCl extended-release tablets should not be abruptly discontinued [see Dosage and Administration (2.9)]. If oxycodone HCl extended-release tablets are abruptly discontinued in a physically-dependent patient, a withdrawal syndrome may occur. Some or all of the following can characterize this syndrome: restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Other signs and symptoms also may develop, including irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate.

Infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal signs [see Use in Specific Populations (8.1)].

12.1 Mechanism of Action

Oxycodone is a full opioid agonist and is relatively selective for the mu receptor, although it can bind to other opioid receptors at higher doses. The principal therapeutic action of oxycodone is analgesia. Like all full opioid agonists, there is no ceiling effect to analgesia for oxycodone. Clinically, dosage is titrated to provide adequate analgesia and may be limited by adverse reactions, including respiratory and CNS depression.

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 are thought to play a role in the analgesic effects of this drug.

12.2 Pharmacodynamics

Effects on the Central Nervous System

Oxycodone produces respiratory depression by direct action on brain stem respiratory centers. The respiratory depression involves a reduction in the responsiveness of the brain stem respiratory centers to both increases in CO₂ tension and electrical stimulation.

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 origin may produce similar findings).  Marked mydriasis rather than miosis may be seen with hypoxia in overdose situations [see Overdosage (10)].

Effects on the Gastrointestinal Tract and Other Smooth Muscle

Oxycodone causes a reduction in motility associated with an increase in smooth muscle tone in the antrum of the 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 the Cardiovascular System

Oxycodone produces peripheral vasodilation which may result in orthostatic hypotension or syncope.  Manifestations of histamine release and/or peripheral vasodilation may include pruritus, flushing, red eyes, sweating, and/or orthostatic hypotension.

Effects on the Endocrine System

Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing hormone (LH) in humans [see Adverse Reactions (6.2)]. They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagon.

Chronic use of opioids may influence the hypothalamic-pituitary-gonadal axis, leading to androgen deficiency that may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility. The causal role of opioids in the clinical syndrome of hypogonadism is unknown because the various medical, physical, lifestyle, and psychological stressors that may influence gonadal hormone levels have not been adequately controlled for in studies conducted to date [see Adverse Reactions (6.2)].

Effects on the Immune System 

Opioids have been shown to have a variety of effects on components of the immune system in in vitro and animal models. The clinical significance of these findings is unknown. Overall, the effects of opioids appear to be modestly immunosuppressive.

Concentration –Efficacy Relationships

Studies in normal volunteers and patients reveal predictable relationships between oxycodone dosage and plasma oxycodone concentrations, as well as between concentration and certain expected opioid effects, such as pupillary constriction, sedation, overall subjective “drug effect”, analgesia and feelings of relaxation.

The minimum effective analgesic concentration will vary widely among patients, especially among patients who have been previously treated with potent agonist opioids. The minimum effective analgesic concentration of oxycodone for any individual patient may increase over time due to an increase in pain, the development of a new pain syndrome, and/or the development of analgesic tolerance [see Dosage and Administration (2.1, 2.5)].

Concentration –Adverse Reaction Relationships

There is a relationship between increasing oxycodone plasma concentration and increasing frequency of dose-related opioid adverse reactions such as nausea, vomiting, CNS effects, and respiratory depression.  In opioid-tolerant patients, the situation may be altered by the development of tolerance to opioid-related adverse reactions [see Dosage and Administration (2.1 , 2.5) ].

12.3 Pharmacokinetics

The activity of oxycodone HCl extended-release tablets is primarily due to the parent drug oxycodone.  Oxycodone HCl extended-release tablets are designed to provide delivery of oxycodone over 12 hours.

Cutting, breaking, chewing, crushing or dissolving oxycodone HCl extended-release tablets impairs the controlled-release delivery mechanism and results in the rapid release and absorption of a potentially fatal dose of oxycodone.

Oxycodone release from oxycodone HCl extended-release tablets is pH independent.  The oral bioavailability of oxycodone is 60% to 87%.  The relative oral bioavailability of oxycodone from oxycodone HCl extended-release tablets to that from immediate-release oral dosage forms is 100%.  Upon repeated dosing with oxycodone HCl extended-release tablets in healthy subjects in pharmacokinetic studies, steady-state levels were achieved within 24 to 36 hours. Oxycodone is extensively metabolized and eliminated primarily in the urine as both conjugated and unconjugated metabolites.  The apparent elimination half-life (t_½) of oxycodone following the administration of oxycodone HCl extended-release tablets was 4.5 hours compared to 3.2 hours for immediate-release oxycodone.

Absorption

About 60% to 87% of an oral dose of oxycodone reaches the central compartment in comparison to a parenteral dose.  This high oral bioavailability is due to low pre-systemic and/or first-pass metabolism. 

Plasma Oxycodone Concentration over Time

Dose proportionality has been established for oxycodone HCl extended-release tablets 10 mg, 15 mg, 20 mg, 30 mg, 40 mg, 60 mg, and 80 mg tablet strengths for both peak plasma concentrations (C_max) and extent of absorption (AUC) (see Table 6).  Given the short elimination t_½ of oxycodone, steady-state plasma concentrations of oxycodone are achieved within 24 to 36 hours of initiation of dosing with oxycodone HCl extended-release tablets. In a study comparing 10 mg of oxycodone HCl extended-release tablets every 12 hours to 5 mg of immediate-release oxycodone every 6 hours, the two treatments were found to be equivalent for AUC and C_max, and similar for C_min (trough) concentrations.

Table: 6 Mean [% coefficient of variation]

Regimen	Dosage Form	AUC (ng · hr/mL)*	Cmax (ng/mL)	Tmax (hr)
Single Dose†	10 mg	136 [27]	11.5 [27]	5.11 [21]
	15 mg	196 [28]	16.8 [29]	4.59 [19]
	20 mg	248 [25]	22.7 [25]	4.63 [22]
	30 mg	377 [24]	34.6 [21]	4.61 [19]
	40 mg	497 [27]	47.4 [30]	4.40 [22]
	60 mg	705 [22]	64.6 [24]	4.15 [26]
	80 mg	908 [21]	87.1 [29]	4.27 [26]
* for single-dose AUC = AUC0-inf †data obtained while subjects received naltrexone, which can enhance absorption

Food Effects

Food has no significant effect on the extent of absorption of oxycodone from oxycodone HCl extended-release tablets. 

Distribution

Following intravenous administration, the steady-state volume of distribution (V_ss) for oxycodone was 2.6 L/kg. Oxycodone binding to plasma protein at 37°C and a pH of 7.4 was about 45%.  Once absorbed, oxycodone is distributed to skeletal muscle, liver, intestinal tract, lungs, spleen, and brain. Oxycodone has been found in breast milk [see Use in Specific Populations (8.4)].

Elimination

Metabolism

Oxycodone is extensively metabolized by multiple metabolic pathways to produce noroxycodone, oxymorphone and noroxymorphone, which are subsequently glucuronidated.  Noroxycodone and noroxymorphone are the major circulating metabolites. CYP3A mediated N-demethylation to noroxycodone is the primary metabolic pathway of oxycodone with a lower contribution from CYP2D6 mediated O-demethylation to oxymorphone. Therefore, the formation of these and related metabolites can, in theory, be affected by other drugs [see Drug Interactions (7)].

Noroxycodone exhibits very weak anti-nociceptive potency compared to oxycodone, however, it undergoes further oxidation to produce noroxymorphone, which is active at opioid receptors.  Although noroxymorphone is an active metabolite and present at relatively high concentrations in circulation, it does not appear to cross the blood-brain barrier to a significant extent.  Oxymorphone is present in the plasma only at low concentrations and undergoes further metabolism to form its glucuronide and noroxymorphone.  Oxymorphone has been shown to be active and possessing analgesic activity but its contribution to analgesia following oxycodone administration is thought to be clinically insignificant.  Other metabolites (α- and ß-oxycodol, noroxycodol and oxymorphol) may be present at very low concentrations and demonstrate limited penetration into the brain as compared to oxycodone.  The enzymes responsible for keto-reduction and glucuronidation pathways in oxycodone metabolism have not been established.

Excretion

Oxycodone and its metabolites are excreted primarily via the kidney.  The amounts measured in the urine have been reported as follows: free and conjugated oxycodone 8.9%, free noroxycodone 23%, free oxymorphone less than 1%, conjugated oxymorphone 10%, free and conjugated noroxymorphone 14%, reduced free and conjugated metabolites up to 18%.  The total plasma clearance was approximately 1.4 L/min in adults.

Specific Populations

Age: Geriatric Population

The plasma concentrations of oxycodone are only nominally affected by age, being 15% greater in elderly as compared to young subjects (age 21 to 45).

Age: Pediatric Population

In the pediatric age group of 11 years of age and older, systemic exposure of oxycodone is expected to be similar to adults at any given dose of oxycodone HCl extended-release tablets.

Sex

Across individual pharmacokinetic studies, average plasma oxycodone concentrations for female subjects were up to 25% higher than for male subjects on a body weight-adjusted basis. The reason for this difference is unknown [see Use in Specific Populations (8.8)].

Hepatic Impairment

Data from a study involving 24 patients with mild to moderate hepatic dysfunction show peak plasma oxycodone and noroxycodone concentrations 50% and 20% higher, respectively, than healthy subjects.  AUC values are 95% and 65% higher, respectively.  Oxymorphone peak plasma concentrations and AUC values are lower by 30% and 40%.  These differences are accompanied by increases in some, but not other, drug effects. The mean elimination t_½ for oxycodone increased by 2.3 hours.

Renal Impairment

Data from a pharmacokinetic study involving 13 patients with mild to severe renal dysfunction (creatinine clearance <60 mL/min) showed peak plasma oxycodone and noroxycodone concentrations 50% and 20% higher, respectively, and AUC values for oxycodone, noroxycodone, and oxymorphone 60%, 50%, and 40% higher than normal subjects, respectively. This was accompanied by an increase in sedation but not by differences in respiratory rate, pupillary constriction, or several other measures of drug effect. There was an increase in mean elimination t_½ for oxycodone of 1 hour.

Drug Interaction Studies

CYP3A4 Inhibitors

CYP3A4 is the major isoenzyme involved in noroxycodone formation. Co-administration of oxycodone HCl extended-release tablets (10 mg single dose) and the CYP3A4 inhibitor ketoconazole (200 mg BID) increased oxycodone AUC and C_max by 170% and 100%, respectively [see Drug Interactions (7)].

CYP3A4 Inducers

A published study showed that the co-administration of rifampin, a drug metabolizing enzyme inducer, decreased oxycodone AUC and C_max values by 86% and 63%, respectively [see Drug Interactions (7)].

CYP2D6 Inhibitors

Oxycodone is metabolized in part to oxymorphone via CYP2D6. While this pathway may be blocked by a variety of drugs such as certain cardiovascular drugs (e.g., quinidine) and antidepressants (e.g., fluoxetine), such blockade has not been shown to be of clinical significance with oxycodone HCl extended-release tablets [see Drug Interactions (7)].