Oxycontin

[oxycodone hydrochloride]

In a study comparing 10 mg of OxyContin every 12 hours to 5 mg of immediate-release oxycodone every 6 hours, the two treatments were found to be equivalent for AUC and Cmax, and similar for Cmin (trough) concentrations. There was less fluctuation in plasma concentrations for the OxyContin Tablets than for the immediate-release formulation.

Hours From Dosing 0 1 2 3 4 5 6 7 89101112
Oxycodone
Concentration
(ng/ mL), Log Scale
1 10 100
XX X X X X X X X X XXX X X X X
X X X X
10 mg 20 mg 40 mg 160 mg Single Dose 10 mg q12h Steady-State X 80 mg
Plasma Oxycodone By Time
TABLE 1 Mean [% coefficient variation] Regimen Dosage Form AUC (ng . hr/ mL)* Cmax (ng/ mL) Tmax (hrs) Trough Conc. (ng/ mL)
Single Dose 10 mg OxyContin 100.7 [26. 6] 10. 6 [20.1] 2.7 [44.1] n. a. 20 mg OxyContin 207.5 [35. 9] 21. 4 [36.6] 3.2 [57.9] n. a. 40 mg OxyContin 423.1 [33. 3] 39. 3 [34.0] 3.1 [77.4] n. a. 80 mg OxyContin* 1085. 5 [32.3] 98. 5 [32.1] 2.1 [52.3] n. a.
Multiple Dose 10 mg OxyContin Tablets q12h 103.6 [38. 6] 15. 1 [31.0] 3.2 [69.5] 7.2 [48.1] 5 mg immediate-release q6h 99. 0 [36.2] 15. 5 [28.8] 1.6 [49.7] 7.4 [50.9]
TABLE 2 Mean [% coefficient variation] Regimen Dosage Form AUC . (ng . hr/ mL)* Cmax (ng/ mL) Tmax (hrs) Trough Conc. (ng/ mL) 6
6 Page 7 8
Single Dose 4 x 40 mg OxyContin* 1935.3 [34.7] 152.0 [28. 9] 2.56 [42.3] n. a. 2 x 80 mg OxyContin* 1859.3 [30.1] 153.4 [25. 1] 2.78 [69.3] n. a. 1 x 160 mg OxyContin* 1856.4 [30.5] 156.4 [24. 8] 2.54 [36.4] n. a. * for single-dose AUC = AUC0-inf; for multiple-dose AUC = AUC0-T * data obtained while volunteers received naltrexone which can enhance absorption OxyContin ® is NOT INDICATED FOR RECTAL ADMINISTRATION. Data from a study involving 21 normal volunteers show that OxyContin Tablets administered per rectum resulted in an AUC 39% greater and a Cmax 9% higher than tablets administered by mouth. Therefore, there is an increased risk of adverse events with rectal administration.

Food Effects

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Food has no significant effect on the extent of absorption of oxycodone from OxyContin. However, the peak plasma concentration of oxycodone increased by 25% when a OxyContin 160 mg Tablet was administered with a high-fat meal. Distribution Following intravenous administration, the volume of distribution (Vss) 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 PRECAUTIONS).

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. Noroxycodone is reported to be a considerably weaker analgesic than oxycodone.

Oxymorphone, although possessing analgesic activity, is present in the plasma only in low concentrations. The correlation between oxymorphone concentrations and opioid effects was much less than that seen with oxycodone plasma concentrations. The analgesic activity profile of other metabolites is not known. The formation of oxymorphone, but not noroxycodone, is mediated by cytochrome P450 2D6 and, as such, its formation can, in theory, be affected by other drugs (see Drug-Drug Interactions).

Excretion

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.

Special Populations

Elderly

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

Gender

Female subjects have, on average, plasma oxycodone concentrations up to 25% higher than males on a body weight adjusted basis. The reason for this difference is unknown.

Renal Impairment

Data from a pharmacokinetic study involving 13 patients with mild to severe renal dysfunction (creatinine clearance <60 mL/ min) show 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 is 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 t½ of elimination for oxycodone of only 1 hour (see PRECAUTIONS).

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 normal 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 t½ elimination for oxycodone increased by 2.3 hours (see PRECAUTIONS).

Drug-Drug Interactions (see PRECAUTIONS)

Oxycodone is metabolized in part by cytochrome P450 2D6 to oxymorphone which represents less than 15% of the total administered dose. This route of elimination may be blocked by a variety of drugs (e. g., certain cardiovascular drugs including amiodarone and quinidine as well as polycyclic anti-depressants). However, in a study involving 10 subjects using quinidine, a known inhibitor of cytochrome P450 2D6, the pharmacodynamic effects of oxycodone were unchanged.

Pharmacodynamics

A single-dose, double-blind, placebo-and dose-controlled study was conducted using OxyContin ® (10, 20, and 30 mg) in an analgesic pain model involving 182 patients with moderate to severe pain. Twenty and 30 mg of OxyContin were superior in reducing pain compared with placebo, and this difference was statistically significant. The onset analgesic action with OxyContin occurred within 1 hour in most patients following oral administration.

CLINICAL TRIALS

A double-blind placebo-controlled, fixed-dose, parallel group, two-week study was conducted in 133 patients with chronic, moderate to severe pain, who were judged as having inadequate pain control with their current therapy. In this study, 20 mg OxyContin q12h but not 10 mg OxyContin q12h decreased pain compared with placebo, and this difference was statistically significant.

DRUG ABUSE AND ADDICTION

OxyContin ® is a mu-agonist opioid with an abuse liability similar to morphine and is a Schedule II controlled substance. Oxycodone, like morphine and other opioids used in analgesia, can be abused and is subject to criminal diversion.

Drug addiction is characterized by compulsive use, use for non-medical purposes, and continued use despite harm or risk of harm. Drug addiction is a treatable disease, utilizing a multi-disciplinary approach, but relapse is common. "Drug-seeking" behavior is very common in addicts and drug abusers. 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 physician( s). "Doctor shopping" to obtain additional prescriptions is common among drug abusers and people suffering from untreated addiction.

Abuse and addiction are separate and distinct from physical dependence and tolerance. Physicians 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 and is characterized by misuse for non-medical purposes, often in combination with other psychoactive substances. OxyContin, like other opioids, has been diverted for non-medical use.

Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests is strongly advised. Proper assessment of the patient, proper prescribing practices, periodic re-evaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs. OxyContin consists of a dual-polymer matrix, intended for oral use only. Abuse of the crushed tablet poses a hazard of overdose and death. This risk is increased with concurrent abuse of alcohol and other substances. With parenteral abuse, the tablet excipients, especially talc, can be expected to result in local tissue necrosis, infection, pulmonary granulomas, and increased risk of endocarditis and valvular heart injury. Parenteral drug abuse is commonly associated with transmission of infectious diseases such as hepatitis and HIV.

Respiratory Depression

Respiratory depression is the chief hazard from oxycodone, the active ingredient in OxyContin ® , as with all opioid agonists. Respiratory depression is a particular problem 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 should be used with extreme caution in patients with significant chronic obstructive pulmonary disease or cor pulmonale, and in patients having a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression. In such patients, even usual therapeutic doses of oxycodone 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.

Head Injury

The respiratory depressant effects of opioids include carbon dioxide retention and secondary elevation of cerebrospinal fluid pressure, and may be markedly exaggerated in the presence of head injury, intracranial lesions, or other sources of pre-existing increased intracranial pressure. Oxycodone produces effects on pupillary response and consciousness which may obscure neurologic signs of further increases in intracranial pressure in patients with head injuries.

Hypotensive Effect

OxyContin may cause severe hypotension. There is an added risk to individuals 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 may produce orthostatic hypotension in ambulatory patients. Oxycodone, like all opioid analgesics of the morphine-type, should be administered with caution to patients in circulatory shock, since vasodilation produced by the drug may further reduce cardiac output and blood pressure.

Drug-Drug Interactions

Opioid analgesics, including OxyContin ® , may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.

Oxycodone is metabolized in part to oxymorphone via cytochrome P4502D6. While this pathway may be blocked by a variety of drugs (e. g., certain cardiovascular drugs including amiodarone and quinidine as well as polycyclic antidepressants), such blockade has not yet been shown to be of clinical significance with this agent. Clinicians should be aware of this possible interaction, however. Use with CNS Depressants OxyContin, like all opioid analgesics, should be started at 1/ 3 to 1/ 2 of the usual dosage in patients who are concurrently receiving other central nervous system depressants including sedatives or hypnotics, general anesthetics, phenothiazines, centrally acting anti-emetics, tranquilizers, and alcohol because respiratory depression, hypotension, and profound sedation or coma may result. No specific interaction between oxycodone and monoamine oxidase inhibitors has been observed, but caution in the use of any opioid in patients taking this class of drugs is appropriate.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Studies of oxycodone to evaluate its carcinogenic potential have not been conducted. Oxycodone was not mutagenic in the following assays: Ames Salmonella and E. coli test with and without metabolic activation at doses of up to 5000 µg, chromosomal aberration test in human lymphocytes in the absence of metabolic activation at doses of up to 1500 µg/ mL and with activation 48 hours after exposure at doses of up to 5000 µg/ mL, and in the in vivo bone marrow micronucleus test in mice (at plasma levels of up to 48 µg/ mL). Oxycodone was clastogenic in the human lymphocyte chromosomal assay in the presence of metabolic activation in the human chromosomal aberration test (at greater than or equal to 1250 µg/ mL) at 24 but not 48 hours of exposure and in the mouse lymphoma assay at doses of 50 µg/ mL or greater with metabolic activation and at 400 µg/ mL or greater without metabolic activation.

Pregnancy Teratogenic Effects

-Category B

Reproduction studies have been performed in rats and rabbits by oral administration at doses up to 8 mg/ kg and 125 mg/ kg, respectively. These doses are 3 and 46 times a human dose of 160 mg/ day, based on mg/ kg basis. The results did not reveal evidence of harm to the fetus due to oxycodone. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Labor and Delivery OxyContin ® is not recommended for use in women during and immediately prior to labor and delivery because oral opioids may cause respiratory depression in the newborn.

Neonates whose mothers have been taking oxycodone chronically may exhibit respiratory depression and/ or withdrawal symptoms, either at birth and/ or in the nursery.

Nursing Mothers

Low concentrations of oxycodone have been detected in breast milk. Withdrawal symptoms can occur in breast-feeding infants when maternal administration of an opioid analgesic is stopped. Ordinarily, nursing should not be undertaken while a patient is receiving OxyContin because of the possibility of sedation and/ or respiratory depression in the infant.

Pediatric Use

Safety and effectiveness of OxyContin have not been established in pediatric patients below the age of 18. It must be remembered that OxyContin Tablets cannot be crushed or divided for administration.

Geriatric Use

In controlled pharmacokinetic studies in elderly subjects (greater than 65 years) the clearance of oxycodone appeared to be slightly reduced. Compared to young adults, the plasma concentrations of oxycodone were increased approximately 15% (see PHARMACOKINETICS AND METABOLISM). Of the total number of subjects (445) in clinical studies of OxyContin, 148 (33.3%) were age 65 and older (including those age 75 and older) while 40 (9.0%) were age 75 and older. In clinical trials with appropriate initiation of therapy and dose titration, no untoward or unexpected side effects were seen in the elderly patients who received OxyContin. Thus, the usual doses and dosing intervals are appropriate for these patients. As with all opioids, the starting dose should be reduced to 1/ 3 to 1/ 2 of the usual dosage in debilitated, non-tolerant patients.

Respiratory depression is the chief hazard 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.

Laboratory Monitoring

Due to the broad range of plasma concentrations seen in clinical populations, the varying degrees of pain, and the development of tolerance, plasma oxycodone measurements are usually not helpful in clinical management. Plasma concentrations of the active drug substance may be of value in selected, unusual or complex cases.

Hepatic Impairment

A study of OxyContin in patients with hepatic impairment indicates greater plasma concentrations than those with normal function. The initiation of therapy at 1/ 3 to 1/ 2 the usual doses and careful dose titration is warranted. Renal Impairment In patients with renal impairment, as evidenced by decreased creatinine clearance (< 60 mL/ min), the concentrations of oxycodone in the plasma are approximately 50% higher than in subjects with normal renal function. Dose initiation should follow a conservative approach. Dosages should be adjusted according to the clinical situation.

Gender Differences

In pharmacokinetic studies, opioid-naive females demonstrate up to 25% higher average plasma concentrations and greater frequency of typical opioid adverse events than males, even after adjustment for body weight. The clinical relevance of a difference of this magnitude is low for a drug intended for chronic usage at individualized dosages, and there was no male/ female difference detected for efficacy or adverse events in clinical trials.

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