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| |  Long-Acting OxyContin Tablets Now Available To Relieve Pain NORWALK, Conn., May 31, 1996 -- For patients suffering from moderate to severe pain which requires treatment for more than a few days, such as the pain associated with arthritis, cancer, injuries, lower back problems, and other musculoskeletal conditions, now there is new OxyContin(TM) (oxycodone HCl controlled-release) Tablets C-II (Warning: May be habit forming) -- the first and only 12-hour oxycodone pain medicine. Purdue Pharma L.P., a leader in pain management, today announced that long-acting OxyContin Tablets (for the treatment of moderate to severe pain lasting more than a few days) is available in U.S. pharmacies with a doctor's prescription. OxyContin -- the first and only 12-hour oxycodone analgesic New OxyContin is a significant advance in the treatment of persistent pain. Millions of Americans suffer from moderate to severe chronic pain serious enough to have an impact on their lives. Among the most common causes of persistent, debilitating pain are arthritis, lower back conditions, injuries and cancer. For example, more than eight million Americans are permanently disabled by back pain -- with 65,000 new cases diagnosed each year. Cancer is diagnosed in over one million Americans each year. In advanced stages, nearly 75% of cancer patients have pain that is moderate, severe or very severe. In earlier stages, 30% to 45% of cancer patients experience moderate to severe pain. Unlike short-acting pain medications, which must be taken every 3 to 6 hours -- often on an "as needed" basis -- OxyContin Tablets are taken every 12 hours, providing smooth and sustained pain control all day and all night. Dosing with OxyContin Tablets on a regular schedule spares patients from anxious "clock-watching" when pain must be controlled over long periods. Twice-daily dosing simplifies and improves patients' lives "The importance of pain control with twice-daily dosing can't be stressed strongly enough," reported Paul D. Goldenheim, M.D., Vice President of Purdue Pharma. "Until now, patients with persistent pain had to take products such as Percocet(R), Vicodin(R), and Tylenol(R) with Codeine as often as six times a day. Now, with every twelve-hour OxyContin dose, many patients may experience pain relief and may enjoy daytime activities and nighttime rest without the inconvenience of taking tablets every four to six hours. Moreover, we've discovered that the simplicity and convenience of twice-daily dosing also enhances patient compliance with their doctor's instructions." Patient benefits demonstrated in clinical studies In clinical trials of OxyContin Tablets, involving more than 700 patients, key findings included: "Because of its effectiveness and good acceptability to patients, our studies suggest that OxyContin is an ideal choice in progressive pain management when around-the-clock therapy is indicated," added Dr. Goldenheim. OxyContin allows flexible dosing OxyContin is available in three tablet strengths (10 mg, 20 mg, 40 mg) -- ideal for long-term control over a broad range of pain. Small, color-coded tablets make the product easy to swallow and easy to identify. OxyContin Tablets are available by prescription only. OxyContin Tablets are to be taken whole. Taking broken, chewed or crushed tablets could lead to the rapid release and absorption of a potentially toxic dose of oxycodone. The most serious risk associated with opioids, including OxyContin, is respiratory depression. Common opioid side effects are constipation, nausea, sedation, dizziness, vomiting, pruritis, headache, dry mouth, sweating, and weakness. Headquartered in Norwalk, Connecticut, Purdue Pharma L.P. is a leader in the research and development of long-acting pharmaceuticals, with a special emphasis on pain relief. Through Partners Against Pain(R) and other programs, the company is also committed to providing effective professional and patient education services. Purdue Pharma, its international associated companies and affiliates distribute pharmaceuticals to more than 100 countries. Associated companies maintain production and research facilities in the United States, Canada, the United Kingdom, Germany and Israel, as well as marketing and distribution centers in Ireland, Austria and Switzerland. NOTE: Percocet is a registered trademark of the DuPont Merck Pharmaceutical Co. Vicodin is a registered trademark of Knoll Pharmaceutical Company. Tylenol with Codeine is a registered trademark of McNeil Pharmaceutical. Please see brief summary of prescribing information which follows the background information. BACKGROUND Persistent Pain Goes Largely Untreated Millions of Americans suffer from moderate to severe persistent pain. Arthritis, lower back conditions, cancer and injuries are among the most common causes of persistent, debilitating pain. Despite the availability of medications to control or alleviate pain, the underreporting and undertreatment of pain remains one of the most pressing issues affecting the quality of patient care today. Why is pain undertreated? The reasons why pain remains so inadequately managed are many, but several have been identified: 1) poor assessment by healthcare professionals, 2) underreporting by patients who accept pain as an inevitable consequence of disease, and 3) underuse of pain medications because of unwarranted fears of uncontrollable side effects and/or addiction by physicians and patients alike. In response to these concerns, new guidelines for the treatment of acute pain and cancer pain were published in the December 20, 1995 issue of Journal of the American Medical Association (JAMA), encouraging patients to become more active in managing their personal pain. Patients must communicate with physicians/nurses The fear of addiction is exaggerated One cause of patient resistance to appropriate pain treatment -- the fear of addiction -- is largely unfounded. According to Dr. Max, "Experts agree that most pain caused by surgery or cancer can be relieved, primarily by carefully adjusting the dose of opioid (narcotic) pain reliever to each patient's need, and that there is very little risk of addiction from the proper uses of these Paul D. Goldenheim, M.D., Vice President of Purdue Pharma L.P. in Norwalk, Connecticut, agrees with this assessment. "Proper use of medication is an essential weapon in the battle against persistent pain. But too often fear, misinformation and poor communication stand in the way of their legitimate use." Brief summary on q12h OxyContin(TM) Before prescribing, see complete prescribing information, including DOSAGE AND ADMINISTRATION. For the management of moderate to severe pain where use of an opioid analgesic is appropriate for more than a few days. 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. Oxycontin TABLETS ARE TO BE SWALLOWED WHOLE, AND ARE NOT TO BE BROKEN, CHEWED OR CRUSHED. TAKING BROKEN, CHEWED OR CRUSHED. Respiratory Depression Respiratory depression, the chief hazard from all opioid agonist preparations, 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 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 preexisting 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. 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 preexisting increased intracranial pressure. Oxycodone produces effects which may obscure neurologic signs of further increases in intracranial pressure in patients with head injuries. Hypotensive Effect OxyContin, 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. OxyContin may produce orthostatic hypotension in ambulatory patients. OxyContin, like all opioid analgesics, should be administered with caution to patients in circulatory shock, since vasodilation produced by the drug may further reduce cardiac output and blood pressure. PRECAUTIONS: General -- OxyContin tablets are intended for use in patients who require oral pain therapy with an opioid agonist of more than a few days duration. As with any opioid analgesic, it is critical to adjust the dosing regimen individually for each patient. Selection of patients for treatment with OxyContin should be governed by the same principles that apply to the use of similar controlled-release opioid analgesics. Opioid analgesics given on a fixed-dosage schedule have a narrow therapeutic index in certain patient populations, especially when combined with other drugs, and should be reserved for cases where the benefits of opioid analgesia outweigh the known risks of respiratory depression, altered mental state, and postural hypotension. Physicians should individualize treatment in every case, using non-opioid analgesics, prn opioids and/or combination products, and chronic opioid therapy with drugs such as OxyContin in a progressive plan of pain management such as outlined by the World Health Organization, the Agency for Health Care Policy and Research, and the American Pain Society. Use of OxyContin is associated with increased potential risks and should be used only with caution in the following conditions: acute alcoholism; adrenocortical insufficiency (e.g., Addison's disease); CNS depression or coma; delirium tremens; debilitated patients; kyphoscoliosis associated with respiratory depression; myxedema or hypothyroidism; prostatic hypertrophy or urethral stricture; severe impairment of hepatic, pulmonary or renal function; and toxic psychosis. The administration of oxycodone, like all opioid analgesics, may obscure the diagnosis or clinical course in patients with acute abdominal conditions. Oxycodone may aggravate convulsions in patients with convulsive disorders, and all opioids may induce or aggravate seizures in some clinical settings. Interactions with other CNS Depressants OxyContin, like all opioid analgesics, should be used with caution and started in a reduced dosage (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, other tranquilizers and alcohol. Interactive effects resulting in respiratory depression, hypotension, profound sedation or coma may result if these drugs are taken in combination with the usual doses of OxyContin. Interactions with Mixed Agonist/Antagonist Opioid Analgesics Agonist/antagonist analgesics (i.e., pentazocine, nalbuphine, butorphanol and buprenorphine) should be administered with caution to a patient who has received or is receiving a course of therapy with a pure opioid agonist analgesic such as oxycodone. In this situation, mixed agonist/antagonist analgesics may reduce the analgesic effect of oxycodone and/or may precipitate withdrawal symptoms in these patients. Ambulatory Surgery OxyContin is not recommended pre-operatively (preemptive analgesia) or for the management of pain in the immediate post-operative period (the first 12 to 24 hours following surgery) for patients not previously taking the drug, because its safety in this setting has not been established. Patients who are already receiving OxyContin tablets as part of ongoing analgesic therapy may be safely continued on the drug if appropriate dosage adjustments are made considering the procedure, other drugs given and the temporary changes in physiology caused by the surgical intervention (see PRECAUTIONS: Drug-Drug Interactions). Use in Pancreatic/Biliary Tract Disease Oxycodone may cause spasm of the sphincter of Oddi and should be used with caution in patients with biliary tract disease, including acute pancreatitis. Opioids like oxycodone may cause increases in the serum amylase level. Tolerance and Physical Dependence 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). Physical dependence is the occurrence of withdrawal symptoms after abrupt discontinuation of a drug or upon administration of an antagonist. Physical dependence and tolerance are not unusual during chronic opioid therapy. Significant tolerance should not occur in most of the patients treated with the lowest doses of oxycodone. It should be expected, however, that a fraction of cancer patients will develop some degree of tolerance and require progressively higher dosages of OxyContin to maintain pain control during chronic treatment. Regardless of whether this occurs as a result of increased pain secondary to disease progression or pharmacological tolerance, dosages can usually be increased safely by adjusting the patient's dose to maintain an acceptable balance between pain relief and side effects. The dosage should be selected according to the patient's individual analgesic response and ability to tolerate side effects. Tolerance to the analgesic effect of opioids is usually paralleled by tolerance to side effects, except for constipation. Physical dependence results in withdrawal symptoms in patients who abruptly discontinue the drug or may be precipitated through the administration of drugs with opioid antagonist activity (see OVERDOSAGE). If OxyContin is abruptly discontinued in a physically dependent patient, an abstinence syndrome may occur. This is characterized by some or all of the following: restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia and mydriasis. Other 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. If signs and symptoms of withdrawal occur, patients should be treated by reinstitution of opioid therapy followed by a gradual, tapered dose reduction of OxyContin combined with symptomatic support. Information for Patients/Caregivers If clinically advisable, patients receiving OxyContin should be given the following information by the physician: 1. OxyContin tablets were designed to work properly only if swallowed whole. They may release all their contents at once if broken, chewed or crushed, resulting in a risk of overdose. 2. Report episodes of breakthrough pain and adverse experiences occurring during therapy. Individualization of dosage is essential to make optimal use of this medication. 3. Do not adjust the dose of OxyContin without consulting the prescribing professional. 4. OxyContin may impair mental and/or physical ability required for the performance of potentially hazardous tasks (e.g., driving, operating heavy machinery). 5. Do not combine OxyContin with alcohol or other central nervous system depressants (sleep aids, tranquilizers) except by the orders of the prescribing physician, because additive effects may occur. 6. Women of childbearing potential who become, or are planning to become, pregnant should consult their physician regarding the effects of analgesics and other drug use during pregnancy on themselves and their unborn child. 7. OxyContin is a potential drug of abuse. Patients should protect it from theft, and it should never be given to anyone other than the individual for whom it was prescribed. 8. Patients may pass empty matrix "ghosts" (tablets) via colostomy or in the stool; this is of no concern since the active medication has already been absorbed. 9. If patients have been receiving treatment with OxyContin for more than a few weeks and cessation of therapy is indicated, it may be appropriate to taper the OxyContin dose, rather than abruptly discontinue it, due to the risk of precipitating withdrawal symptoms. Their physician can provide a dose schedule to accomplish a gradual discontinuation of the medication. 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. Oxycodone may be expected to have additive effects when used in conjunction with alcohol, other opioids or illicit drugs which cause central nervous system depression. 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. 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. Mutagenicity Studies of oxycodone in animals to evaluate its carcinogenic and mutagenic potential have not been conducted owing to the length of clinical experience with the drug substance. Pregnancy Teratogenic Effects -- Category B: Reproduction studies have been performed in rats and rabbits by oral administration at doses up to 8 mg/kg (48 mg/m2) and 125 mg/kg (1375 mg/m2), respectively. These doses are 4 and 60 times a human dose of 120 mg/day (74 mg/m2), based on mg/kg of a 60 kg adult (0.7 and 19 times this human dose based upon mg/m2). 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. Nonteratogenic Effects -- Neonates whose mothers have been taking oxycodone chronically may exhibit respiratory depression and/or withdrawal symptoms, either at birth and/or in the nursery. 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. 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 since oxycodone may be excreted in the milk. Pediatric Use Safety and effectiveness in pediatric patients below the age of 18 have not been established with this dosage form of oxycodone. However, oxycodone has been used extensively in the pediatric population in other dosage forms, as have the excipients used in this formulation. No specific increased risk is expected from the use of this form of oxycodone in pediatric patients old enough to safely take tablets if dosing is adjusted for the patient's weight. 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%. In clinical trials with appropriate initiation of therapy and dose titration, no untoward or unexpected side effects were seen based on age, and the usual doses and dosing intervals are appropriate for the geriatric patient. 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. 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 (less than 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. 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 ADVERSE REACTIONS: Serious adverse reactions which may be associated with OxyContin tablet therapy in clinical use are those observed with other opioid analgesics, including: respiratory depression, apnea, respiratory arrest, and (to an even lesser degree) circulatory depression, hypotension or shock (see OVERDOSE). The non-serious adverse events seen on initiation of therapy with OxyContin are typical opioid side effects. These events are dose- dependent, and their frequency depends upon the dose, 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 (more than 5%) include constipation, nausea, somnolence, dizziness, vomiting, pruritus, headache, dry mouth, sweating and asthenia. In many cases the frequency of these events during initiation of therapy may be minimized by careful individualization of starting dosage, slow titration, and the avoidance of large swings in the plasma concentrations of the opioid. Many of these adverse events will cease or decrease in intensity as OxyContin therapy is continued and some degree of tolerance is developed. In clinical trials comparing OxyContin with immediate-release oxycodone and placebo, the most common adverse events (more than 5%) reported by patients (pts) at least once during therapy were:
The following adverse experiences were reported in OxyContin treated patients with an incidence between 1% and 5%. In descending order of frequency they were anorexia, nervousness, insomnia, fever, confusion, diarrhea, abdominal pain, dyspepsia, rash, anxiety, euphoria, dyspnea, postural hypotension, chills, twitching, gastritis, abnormal dreams, thought abnormalities, and hiccups. The following adverse reactions occurred in less than 1% of patients involved in clinical trials: General: accidental injury, chest pain, facial edema, malaise, neck pain, pain Cardiovascular: migraine, syncope, vasodilation, ST depression Digestive: dysphagia, eructation, flatulence, gastrointestinal disorder, increased appetite, nausea and vomiting, stomatitis Hemic and Lymphatic: lymphadenopathy Metabolic and Nutritional: dehydration, edema, peripheral edema, thirst Nervous: abnormal gait, agitation, amnesia, depersonalization, depression, emotional lability, hallucination, hyperkinesia, hypesthesia, hypotonia, malaise, paresthesia, speech disorder, stupor, tinnitus, tremor, vertigo, withdrawal syndrome Respiratory: cough increased, pharyngitis, voice alteration Skin: dry skin, exfoliative dermatitis Special Senses: abnormal vision, taste perversion Urogenital: dysuria, hematuria, impotence, polyuria, urinary retention, urination impaired DRUG ABUSE AND DEPENDENCE (Addiction): OxyContin is a mu-agonist opioid with an abuse liability similar to morphine and is a Schedule II controlled substance. Oxycodone products are common targets for both drug abusers and drug addicts. Delayed absorption, as provided by OxyContin tablets, is believed to reduce the abuse liability of a drug. OVERDOSAGE: Acute overdosage with oxycodone 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. In the treatment of oxycodone overdosage, 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 pure opioid antagonists such as naloxone or nalmefene are specific antidotes against respiratory depression from opioid overdose. Opioid antagonists should not be administered in the absence ofclinically significant respiratory or circulatory depression secondary to oxycodone overdose. They should be administered cautiously to persons who are known, or suspected to be, physically dependent on any opioid agonist including OxyContin. In such cases, an abrupt or complete reversal of opioid effects may precipitate an acute abstinence syndrome. The severity of the withdrawal syndrome produced will depend on the degree of physical dependence and the dose of the antagonist administered. Please see the prescribing information for the specific opioid antagonist for details of their proper use. SAFETY AND HANDLING: OxyContin tablets are solid dosage forms that pose no known health risk to health-care providers beyond that of any controlled substance. As with all such drugs, care should be taken to prevent diversion or abuse by proper handling. CAUTION: DEA Order Form Required. Federal law prohibits dispensing without prescription. Manufactured by The PF Laboratories, Inc., Totowa, N.J. 07512. Distributed by Purdue Pharma L.P., Norwalk, CT 06850-3590 Copyright 1995, Purdue Pharma L.P. U.S. Patent Numbers 4,861,598; 4,970,075; and 5,266,331 - December 5, 1995, A4909-BS
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