OXYCONTIN®

OXYCONTIN® (OXYCODONE HCl)

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OxyContin® (oxycodone hydrochloride controlled-release) Tablets are an opioid analgesic supplied in 10 mg, 20 mg, 40 mg, 80 mg, and 160 mg tablet strengths for oral administration.  The tablet strengths describe the amount of oxycodone per tablet as the hydrochloride salt.

C18 H21 NO4 • HCl     MW 351.83

The chemical formula is 4, 5α-epoxy-14-hydroxy-3-methoxy-17-methylmorphinan-6-one hydrochloride.

Oxycodone is a white, odorless crystalline powder derived from the opium alkaloid, thebaine. Oxycodone hydrochloride dissolves in water (1 g in 6 to 7 mL). It is slightly soluble in alcohol (octanol water partition coefficient 0.7).  The tablets contain the following inactive ingredients: ammonio methacrylate copolymer, hypromellose, lactose, magnesium stearate, polyethylene glycol 400, povidone, sodium hydroxide, sorbic acid, stearyl alcohol, talc, titanium dioxide, and triacetin. 

The 10 mg tablets also contain: hydroxypropyl cellulose.

The 20 mg tablets also contain: polysorbate 80 and red iron oxide.

The 40 mg tablets also contain: polysorbate 80 and yellow iron oxide.

The 80 mg tablets also contain:  FD&C blue No. 2, hydroxypropyl cellulose, and yellow iron oxide.

The 160 mg tablets also contain: FD&C blue No. 2 and polysorbate 80.

OXYCONTIN®
OxyContin’s long-acting formulation makes it popular but also prone to abuse.

Clinical pharmacology

Oxycodone is a pure agonist opioid whose principal therapeutic action is analgesia.  Other members of the class known as opioid agonists include substances such as morphine, hydromorphone, fentanyl, codeine, and hydrocodone.  Pharmacological effects of opioid agonists include anxiolysis, euphoria, feelings of relaxation, respiratory depression, constipation, miosis, and cough suppression, as well as analgesia.  Like all pure opioid agonist analgesics, with increasing doses there is increasing analgesia, unlike with mixed agonist/antagonists or non-opioid analgesics, where there is a limit to the analgesic effect with increasing doses. With pure opioid agonist analgesics, there is no defined maximum dose; the ceiling to analgesic effectiveness is imposed only by side effects, the more serious of which may include somnolence and respiratory depression.

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.

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 origin may produce similar findings).  Marked mydriasis rather than miosis may be seen with hypoxia in the setting of OxyContin® overdose

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 gastric, biliary and pancreatic secretions, spasm of sphincter of Oddi, and transient elevations in serum amylase.

Cardiovascular System

Oxycodone may produce release of histamine with or without associated peripheral vasodilation. Manifestations of histamine release and/or peripheral vasodilation may include pruritus, flushing, red eyes, sweating, and/or orthostatic hypotension.

Food Effects

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.

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.

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.

Drug-Drug Interactions 

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.

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Indications and usage

OxyContin Tablets are a controlled-release oral formulation of oxycodone hydrochloride indicated for the management of moderate to severe pain when a continuous, around-theclock analgesic is needed for an extended period of time.

OxyContin is NOT intended for use as a prn analgesic.

Physicians should individualize treatment in every case, initiating therapy at the appropriate point along a progression from non-opioid analgesics, such as non-steroidal anti-inflammatory drugs and acetaminophen to opioids in a plan of pain management such as outlined by the World Health Organization, the Agency for Healthcare Research and Quality (formerly known as the Agency for HealthCare Policy and Research), the Federation of State Medical Boards Model Guidelines, or the American Pain Society.

OxyContin is not indicated for pain in the immediate postoperative period (the first 12-24 hours following surgery), or if the pain is mild, or not expected to persist for an extended period of time. OxyContin is only indicated for postoperative use if the patient is already receiving the drug prior to surgery or if the postoperative pain is expected to be moderate to severe and persist for an extended period of time.  Physicians should individualize treatment, moving from parenteral to oral analgesics as appropriate.  (See American Pain Society guidelines.)

Contraindications

OxyContin® is 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.  OxyContin is contraindicated in any patient who has or is suspected of having paralytic ileus.

Misuse, Abuse and Diversion of Opioids Oxycodone is an opioid agonist of the morphine-type.  Such drugs are sought by drug abusers and people with addiction disorders and are subject to criminal diversion.

Oxycodone can be abused in a manner similar to other opioid agonists, legal or illicit.  This should be considered when prescribing or dispensing OxyContin in situations where the physician or pharmacist is concerned about an increased risk of misuse, abuse, or diversion.

OxyContin has been reported as being abused by crushing, chewing, snorting, or injecting the dissolved product.  These practices will result in the uncontrolled delivery of the opioid and pose a significant risk to the abuser that could result in overdose and death.

Use in Drug and Alcohol Addiction

OxyContin is an opioid with no approved use in the management of addictive disorders.  Its proper usage in individuals with drug or alcohol dependence, either active or in remission, is for the management of pain requiring opioid analgesia.

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 P450 2D6.  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.

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.

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