Action And Clinical Pharmacology: Oxycodone is a semisynthetic opioid analgesic which exerts an agonist effect at specific, saturable opioid receptors in the CNS and other tissues. In man, oxycodone produces a variety of effects including analgesia, constipation from decreased gastrointestinal motility, suppression of the cough reflex, respiratory depression from reduced responsiveness of the respiratory centre to CO2, nausea and vomiting via stimulation of the chemoreceptor trigger zone, changes in mood including euphoria and dysphoria, sedation, mental clouding, and alterations of the endocrine and autonomic nervous systems.
Oxycodone retains at least one-half of its analgesic activity when administered orally and with acute dosing is approximately twice as potent as orally administered morphine.
Studies with oxycodone controlled release in normal volunteers and patients demonstrate a consistent relationship between oxycodone dosage and plasma oxycodone concentrations as well as between concentration and pharmacodynamic effects. In a single dose analgesic assay, the peak effect of OxyContin (20 and 30 mg) was greater than that of 10 mg OxyContin and was equivalent to that of 2 tablets of oxycodone (5 mg) plus acetaminophen (325 mg), or 15 mg of immediate release oxycodone, but with a longer duration of action. In patients with cancer pain, OxyContin administered every 12 hours produced equivalent analgesia to immediate release oxycodone administered 4 times per day. In patients with pain due to osteoarthritis, OxyContin every 12 hours was more effective than placebo in decreasing pain and in improving quality of life, mood and sleep. In patients with low back pain, OxyContin every 12 hours was equally effective as immediate release oxycodone given 4 times per day. Titration to analgesic effect was achieved as easily with OxyContin as with immediate release oxycodone.
There is no intrinsic limit to the analgesic effect of oxycodone; like morphine, adequate doses will relieve even the most severe pain. Clinically however, dosage limitations are imposed by the adverse effects, primarily respiratory depression, nausea and vomiting, which can result from high doses.
Pharmacokinetics: After oral administration of oxycodone tablets, the drug is absorbed from the gastrointestinal tract and has a relatively high bioavailability of approximately 60 to 87%. Unlike morphine, oxycodone does not undergo high first pass metabolism, possibly due to the protective effect of a methoxy group in the 3- position which is a site of morphine glucuronidation. Oxycodone is metabolized in the liver by demethylation to noroxycodone and oxymorphone (via CYP2D6), and by conjugation, to a variety of glucuronide metabolites. Oxymorphone is known to possess analgesic activity, but concentrations in the plasma are very low and not as closely correlated to opioid effects as oxycodone concentrations. Although the AUC ratio of noroxycodone to oxycodone is about 0.6 following oral dosing, noroxycodone is reported to be a considerably weaker analgesic than oxycodone and is unlikely to contribute significantly to the analgesic effect of oxycodone. The analgesic activity profile of other metabolites is not known. The terminal elimination half-life after immediate release tablets is approximately 4 hours. The majority of metabolites and unchanged drug (conjugated 2.2%, unconjugated 5.5%) are excreted in the urine.
Pharmacokinetic studies of OxyContin in normal volunteers demonstrate that both AUC and Cmax increase in a dose proportional manner and that the 4 tablet strengths are bioequivalent. In single dose studies, OxyContin was absorbed to an equivalent extent as immediate release oxycodone but with a reduced maximum concentration (Cmax ratio approximately 50%) and prolonged (2.4´) time to maximum concentration (tmax approximately 2.8 hours).
In steady-state pharmacokinetic studies of OxyContin every 12 hours, maximum plasma concentrations (Cmax) of oxycodone were equivalent to those obtained with every 6 hours administration of oral immediate release preparations and were achieved approximately 3 hours after administration of OxyContin. Steady-state was achieved within 24 hours of initiation of dosing. The absorption of oxycodone from OxyContin tablets is not significantly influenced when administered in the presence of food.
Plasma concentrations of oxycodone are increased by approximately 15% in elderly subjects receiving OxyContin; by 50 to 60% in patients with moderate degrees of renal impairment; and by approximately 2-fold in patients with hepatic cirrhosis.
Indications And Clinical Uses: For relief of moderate to severe pain, requiring the prolonged use of an opioid analgesic preparation.
Contra-Indications: Patients with hypersensitivity to opioid analgesics; acute asthma or other obstructive airway disease and acute respiratory depression; cor pulmonale; acute alcoholism; delirium tremens; severe CNS depression; convulsive disorders; increased cerebrospinal or intracranial pressure; head injury; suspected surgical abdomen; concomitant MAO inhibitors (or within 14 days of such therapy).
Manufacturers’ Warnings In Clinical States: Drug Dependence: As with other opioids, tolerance and physical dependence may develop upon repeated administration of oxycodone and there is a potential for development of psychological dependence. Oxycodone controlled release should therefore be prescribed and handled with the degree of caution appropriate to the use of a drug with abuse potential. Drug abuse is not a problem in patients with pain in whom oxycodone is appropriately indicated. Withdrawal symptoms may occur following abrupt discontinuation of therapy or upon administration of an opioid antagonist. Therefore, patients on prolonged therapy should be withdrawn gradually from the drug if it is no longer required for pain control.
CNS Depression: Oxycodone should be used with caution and in reduced dosage during concomitant administration of other opioid analgesics, general anesthetics, phenothiazines and other tranquilizers, sedative-hypnotics, tricyclic antidepressants and other CNS depressants, including alcohol. Respiratory depression, hypotension and profound sedation or coma may result.
Severe pain antagonizes the subjective and respiratory depressant actions of opioid analgesics. Should pain suddenly subside, these effects may rapidly become manifest. Patients who are scheduled for cordotomy or other interruption of pain transmission pathways should not receive oxycodone controlled release within 24 hours of the procedure.
Pregnancy: While animal reproduction studies have revealed no evidence of harm to the fetus due to oxycodone, safe use in pregnancy has not been established. Oxycodone controlled release should be given to pregnant patients only when the anticipated benefits outweigh the potential risks to the fetus.
Precautions: General: The respiratory depressant effects of oxycodone, and the capacity to elevate cerebrospinal fluid pressure, may be greatly increased in the presence of an already elevated intracranial pressure produced by trauma. Also, oxycodone may produce confusion, miosis, vomiting and other side effects which obscure the clinical course of patients with head injury. In such patients, oxycodone must be used with extreme caution and only if it is judged essential.
Oxycodone should be used with extreme caution in patients with substantially decreased respiratory reserve, pre-existing respiratory depression, hypoxia or hypercapnia. Such patients are often less sensitive to the stimulatory effects of carbon monoxide on the respiratory centre, and the respiratory depressant effects of oxycodone may reduce respiratory drive to the point of apnea.
Oxycodone administration may result in severe hypotension in patients whose ability to maintain adequate blood pressure is compromised by reduced blood volume, or concurrent administration of such drugs as phenothiazines or certain anesthetics.
Oxycodone may obscure the diagnosis or clinical course of patients with acute abdominal conditions.
Special Risk Groups: Oxycodone should be administered with caution, and in reduced dosages, to debilitated patients, to patients with severely reduced hepatic or renal function, and in patients with Addison’s disease, hypothyroidism, prostatic hypertrophy or urethral stricture.
Labor/Delivery and Lactation: In view of the potential for opioids to cross the placental barrier and to be excreted in breast milk, oxycodone should be used with caution in nursing mothers. Physical dependence or respiratory depression may occur in the infant if opioids are administered during labor.
Occupational Hazards: Driving and Operating Dangerous Machinery: Oxycodone may impair the mental and/or physical abilities needed for certain potentially hazardous activities such as driving a car or operating machinery. Patients should be cautioned accordingly.
Patients should also be cautioned about the combined effects of oxycodone with other CNS depressants, including other opioids, phenothiazines, sedative/hypnotics and alcohol.
Drug Interactions: CNS depressants, such as other opioids, anesthetics, sedatives, hypnotics, barbiturates, phenothiazines, chloral hydrate and glutethimide may enhance the depressant effects of oxycodone. MAO inhibitors (including procarbazine HCl), pyrazolidone antihistamines, beta-blockers and alcohol may also enhance the depressant effect of oxycodone.
Adverse Reactions: Adverse effects of oxycodone controlled release are similar to those of other opioid analgesics, and represent an extension of pharmacological effects of the drug class. The major hazards of opioids include respiratory and CNS depression and to a lesser degree, circulatory depression, respiratory arrest, shock and cardiac arrest.
The most frequently observed adverse effects are constipation, nausea, somnolence, dizziness, vomiting, pruritus, headache, dry mouth, asthenia and sweating.
Sedation: Sedation is a common side effect of opioid analgesics, especially in opioid naive individuals. Sedation may also occur partly because patients often recuperate from prolonged fatigue after the relief of persistent pain. Most patients develop tolerance to the sedative effects of opioids within 3 to 5 days and, if the sedation is not severe, will not require any treatment except reassurance. If excessive sedation persists beyond a few days, the dose of the opioid should be reduced and alternate causes investigated. Some of these are: concurrent CNS depressant medication, hepatic or renal dysfunction, brain metastases, hypercalcemia and respiratory failure. If it is necessary to reduce the dose, it can be carefully increased again after 3 or 4 days if it is obvious that the pain is not being well controlled. Dizziness and unsteadiness may be caused by postural hypotension, particularly in elderly or debilitated patients, and may be alleviated if the patient lies down.
Nausea and Vomiting: Nausea is a common side effect on initiation of therapy with opioid analgesics and is thought to occur by activation of the chemoreceptor trigger zone, stimulation of the vestibular apparatus and through delayed gastric emptying. The prevalence of nausea declines following continued treatment with opioid analgesics. When instituting therapy with an opioid for chronic pain, the routine prescription of an antiemetic should be considered. In the cancer patient, investigation of nausea should include such causes as constipation, bowel obstruction, uremia, hypercalcemia, hepatomegaly, tumor invasion of celiac plexus and concurrent use of drugs with emetogenic properties. Persistent nausea which does not respond to dosage reduction may be caused by opioid-induced gastric stasis and may be accompanied by other symptoms including anorexia, early satiety, vomiting and abdominal fullness. These symptoms respond to chronic treatment with gastrointestinal prokinetic agents.
Constipation: Practically all patients become constipated while taking opioids on a persistent basis. In some patients, particularly the elderly or bedridden, fecal impaction may result. It is essential to caution the patients in this regard and to institute an appropriate regimen of bowel management at the start of prolonged opioid therapy. Stimulant laxatives, stool softeners, and other appropriate measures should be used as required.
The following adverse effects occur less frequently with opioid analgesics and include those reported in OxyContin clinical trials, whether related or not to oxycodone.
General and CNS: dysphoria, euphoria, anxiety, depression, depersonalization, nervousness, agitation, hyperkinesia, hypotonia, twitching, tremor, speech disorder, vision abnormalities, hypesthesia, paresthesia, thought abnormalities, abnormal dreams, hallucinations, confusion, abnormal gait, insomnia, vertigo and tinnitus.
Cardiovascular: tachycardia, palpitation, faintness, syncope, vasodilation, postural hypotension, chest pain, ST depression and migraine.
Respiratory: bronchospasm, pharyngitis and dyspnea.
Gastrointestinal: dysphagia, anorexia, taste alterations, abdominal pain, diarrhea, dyspepsia, eructation, flatulence, hiccups, gastritis, increased appetite and stomatitis.
Genitourinary: urinary retention or hesitancy, dysuria, polyuria, hematuria, antidiuretic effects and impotence.
Dermatologic: urticaria, exfoliative dermatitis, other skin rashes and edema.
Other: lymphadenopathy, malaise, chills, fever, dehydration and thirst.
Withdrawal (Abstinence) Syndrome: Physical dependence with or without psychological dependence tends to occur on chronic administration. An abstinence syndrome may be precipitated when opioid administration is discontinued or opioid antagonists administered. The following withdrawal symptoms may be observed after opioids are discontinued: body aches, diarrhea, gooseflesh, loss of appetite, nervousness or restlessness, runny nose, sneezing, tremors or shivering, stomach cramps, nausea, trouble with sleeping, unusual increase in sweating and yawning, weakness, tachycardia and unexplained fever. In patients who are appropriately treated with opioid analgesics and who undergo gradual withdrawal from the drug, these symptoms are usually mild.
Symptoms And Treatment Of Overdose: Symptoms: Serious overdosage with oxycodone may be characterized by respiratory depression (a decrease in respiratory rate and/or tidal volume, Cheyne-Stokes respiration, cyanosis), extreme somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, and sometimes bradycardia and hypotension. Severe overdosage may result in apnea, circulatory collapse, cardiac arrest and death.
Treatment: Primary attention should be given to the establishment of adequate respiratory exchange through the provision of a patent airway and controlled or assisted ventilation. The opioid antagonist naloxone HCl is a specific antidote against respiratory depression due to overdosage or as a result of unusual sensitivity to oxycodone. An appropriate dose of an opioid antagonist should therefore be administered, preferably by the i.v. route. The usual initial i.v. adult dose of naloxone is 0.4 mg or higher. Concomitant efforts at respiratory resuscitation should be carried out. Since the duration of action of oxycodone, particularly sustained release formulations, may exceed that of the antagonist, the patient should be under continued surveillance and doses of the antagonist should be repeated as needed to maintain adequate respiration.
An antagonist should not be administered in the absence of clinically significant respiratory or cardiovascular depression. Oxygen, i.v. fluids, vasopressors and other supportive measures should be used as indicated.
In individuals physically dependent on opioids, the administration of the usual dose of opioid antagonist will precipitate an acute withdrawal syndrome. The severity of this syndrome will depend on the degree of physical dependence and the dose of antagonist administered. The use of opioid antagonists in such individuals should be avoided if possible. If an opioid antagonist must be used to treat serious respiratory depression in the physically dependent patient, the antagonist should be administered with extreme care by using dosage titration, commencing with 10 to 20% of the usual recommended initial dose.
Evacuation of gastric contents may be useful in removing unabsorbed drug, particularly when a sustained release formulation has been taken.
Dosage And Administration: Adults: Individual dosing requirements vary considerably based on each patient’s age, weight, severity and cause of pain, and medical and analgesic history.
Patients currently receiving other oral oxycodone formulations may be transferred to OxyContin at the same total daily oxycodone dosage, equally divided into two 12 hourly OxyContin doses.
For patients who are receiving an alternate opioid, the “oral oxycodone equivalent” of the analgesic presently being used should be determined. Having determined the total daily dosage of the present analgesic, Table I can be used to calculate the approximate daily oral oxycodone dosage that should provide equivalent analgesia. This total daily oral oxycodone dose should then be equally divided into two 12 hourly OxyContin doses. It is usually appropriate to treat a patient with only one opioid at a time. Patients who are receiving 1 to 5 tablets or capsules/day of a fixed-dose combination opioid/nonopioid containing 5 mg of oxycodone or 30 mg codeine should be started on 10 to 20 mg OxyContin every 12 hours. For patients receiving 6 to 9 tablets or capsules/day of a fixed-dose combination opioid/nonopioid containing 5 mg of oxycodone or 30 mg codeine, a starting dose of 20 to 30 mg every 12 hours should be used and for patients receiving 10 to 12 tablets or capsules/day of a fixed-dose combination opioid/nonopioid containing 5 mg of oxycodone or 30 mg codeine, a starting dose of 30 to 40 mg every 12 hours is suggested. For those receiving >12 tablets or capsules/day of a fixed-dose combination opioid/nonopioid containing 5 mg of oxycodone or 30 mg codeine, conversions should be based on the total daily opioid dose. Patients who have not previously received opioid analgesics should be initiated on OxyContin 10 mg every 12 hours.
If a nonopioid analgesic is being provided, it may be continued. If the nonopioid is discontinued, consideration should be given to increasing the opioid dose to compensate for the nonopioid analgesic. Oxycodone controlled release can be safely used concomitantly with usual doses of other nonopioid analgesics.
OxyContin tablets should not be broken, chewed or crushed.
Dose Titration: Dose titration is the key to success with opioid analgesic therapy. Proper optimization of doses scaled to the relief of the individual’s pain should aim at the regular administration of the lowest dose which will maintain the patient free of pain at all times. Dosage adjustments should be based on the patient’s clinical response. In patients receiving oxycodone controlled release chronically, the dose may be titrated at intervals of 24 hours to that which provides satisfactory pain relief without unmanageable side effects. Oxycodone controlled release is designed to allow 12 hourly dosing. If breakthrough pain repeatedly occurs at the end of the dosing interval it is generally an indication for a dosage increase rather than more frequent administration.
Adjustment or Reduction of Dosage: Following successful relief of pain, periodic attempts to re-assess the opioid analgesic requirements should be made. If treatment discontinuation is required, the dose of opioid may be decreased as follows: one-half of the previous daily dose given every 12 hours for the first 2 days, followed thereafter by a 25% reduction every 2 days.
Opioid analgesics may only be partially effective in relieving dysesthetic pain, postherpetic neuralgia, stabbing pains, activity-related pain and some forms of headache. That is not to say that patients with these types of pain should not be given an adequate trial of opioid analgesics, but it may be necessary to refer such patients at an early time to other forms of pain therapy.
Availability And Storage: 10 mg: Each round, unscored, white, biconvex, controlled release tablet, imprinted with OC on one side and the mg strength on the other, contains: oxycodone HCl 10 mg. Nonmedicinal ingredients: hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose, magnesium stearate, polyethylene glycol, polymethyl acrylate, povidone, stearyl alcohol, talc, triacetin and titanium dioxide. Polyethylene bottles of 50.
20 mg: Each round, unscored, pink, biconvex, controlled release tablet, imprinted with OC on one side and the mg strength on the other, contains: oxycodone HCl 20 mg. Nonmedicinal ingredients: hydroxypropyl methylcellulose, lactose, magnesium stearate, iron oxide, polyethylene glycol, polymethyl acrylate, polysorbate 80, povidone, stearyl alcohol, talc, triacetin and titanium dioxide. Polyethylene bottles of 50.
40 mg: Each round, unscored, yellow, biconvex, controlled release tablet, imprinted with OC on one side and the mg strength on the other, contains: oxycodone HCl 40 mg. Nonmedicinal ingredients: hydroxypropyl methylcellulose, iron oxide, lactose, magnesium stearate, polyethylene glycol, polymethyl acrylate, polysorbate 80, povidone, stearyl alcohol, talc, triacetin and titanium dioxide. Polyethylene bottles of 50.
80 mg: Each round, unscored, green, biconvex, controlled release tablet, imprinted with OC on one side and the mg strength on the other, contains: oxycodone HCl 80 mg. Polyethylene bottles of 50. Nonmedicinal ingredients: FD&C Blue No. 2 aluminum lake, hydroxypropyl methylcellulose, hydroxypropyl cellulose, iron oxide, lactose, magnesium stearate, polyethylene glycol, polymethyl acrylate, povidone, stearyl alcohol, talc, triacetin and titanium dioxide.
Store at 15 to 30°C.
OXYCONTIN® Purdue Frederick Oxycodone HCl Opioid Analgesic