Oxycodone

1 INDICATIONS AND USAGE Oxycodone hydrochloride tablets are indicated for the management of pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate. Limitations of Use Because of the risks of addiction, abuse, misuse, overdose, and death, which can occur at any dosage or duration and persist over the course of therapy [see Warnings and Precautions (5.1)] , reserve opioid analgesics, including oxycodone hydrochloride tablets for use in patients for whom alternative treatment options are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain. Oxycodone hydrochloride is an opioid agonist indicated for the management of pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate. (1) Limitations of Use : Because of the risks of addiction, abuse, misuse, overdose, and death, which can occur at any dosage or duration and persist over the course of therapy, reserve opioid analgesics, including oxycodone hydrochloride for use in patients for whom alternative treatment options are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain. (1, 5.1)

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Oxycodone is a full opioid agonist and is relatively selective for the mu-opioid 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 for analgesia with 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 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 carbon dioxide 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 origins may produce similar findings). Marked mydriasis rather than miosis may be seen due to hypoxia in overdose situations. Effects on 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, transient elevations in serum amylase, and opioid-induced esophageal dysfunction (OIED). Effects on Cardiovascular System Oxycodone produces peripheral vasodilatation, which may result in orthostatic hypotension or syncope. Manifestations of histamine release and/or peripheral vasodilatation 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. Use of opioids for an extended period of time 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

2 DOSAGE AND ADMINISTRATION Oxycodone hydrochloride tablets should be prescribed only by healthcare professionals who are knowledgeable about the use of opioids and how to mitigate the associated risks. (2.1) Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals. Reserve titration to higher doses of oxycodone hydrochloride for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks. (2.1, 5) Many acute pain conditions (e.g., the pain that occurs with a number of surgical procedures or acute musculoskeletal injuries) require no more than a few days of an opioid analgesic. Clinical guidelines on opioid prescribing for some acute pain conditions are available. (2.1) Initiate the dosing regimen for each patient individually, taking into account the patient’s underlying case and severity of pain, prior analgesic treatment and response, and risk factors for addiction, abuse, and misuse. (2.1, 5.1) Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with oxycodone hydrochloride. Consider this risk when selecting an initial dose and when making dose adjustments. (2.1, 5.2) Discuss opioid overdose reversal agents and options for acquiring them with the patient and/or caregiver, both when initiating and renewing treatment with oxycodone hydrochloride, especially if the patient has additional risk factors for overdose, or close contacts at risk for exposure and overdose. (2.2, 5.1, 5.2, 5.3) Initiate treatment with oxycodone hydrochloride in a dosing range of 5 to 15 mg every 4 to 6 hours as needed for pain and at the lowest dose necessary to achieve adequate analgesia. Titrate the dose based upon the individual patient’s response to their initial dose of oxycodone hydrochloride. (2.3, 2.4) Periodically reassess patients receiving oxycodone hydrochloride to evaluate the continued need for opioid analgesics to maintain pain control, for the signs or symptoms of adverse reactions, and for the development of addiction, abuse, or misuse. (2.4) Do not rapidly reduce or abruptly discontinue oxycodone hydrochloride in a physically dependent patient because rapid reduction or abrupt discontinuation of opioid analgesics has resulted in serious withdrawal symptoms, uncontrolled pain, and suicide. (2.5, 5.1) 2.1 Important Dosage and Administration Instructions Oxycodone hydrochloride tablets should be prescribed only by healthcare professionals who are knowledgeable about the use of opioids and how to mitigate the associated risks. Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals [see Warnings and Precautions (5)]. Because the risk of overdose increases as opioid doses increase, reserve titration to higher doses of oxycodone hydrochloride tablets for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks. Many acute pain conditions (e.g., the pain that occurs with a number of surgical procedures or acute musculoskeletal injuries) require no more than a few days of an opioid analgesic. Clinical guidelines on opioid prescribing for some acute pain conditions are available. There is variability in the opioid analgesic dose and duration needed to adequately manage pain due both to the cause of pain and to individual patient factors. Initiate the dosing regimen for each patient individually, taking into account the patient’s underlying cause and severity of pain, prior analgesic treatment and response, and risk factors for addiction, abuse, and misuse [see Warnings and Precautions (5.1)]. Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with oxycodone hydrochloride tabl

6 ADVERSE REACTIONS The following serious adverse reactions are described, or described in greater detail, in other sections: Addiction, Abuse, and Misuse [see Warnings and Precautions (5.1)] Life-Threatening Respiratory Depression [see Warnings and Precautions (5.2)] Interactions with Benzodiazepines or Other CNS Depressants [see Warnings and Precautions (5.3)] Neonatal Opioid Withdrawal Syndrome [see Warnings and Precautions (5.4)] Opioid-Induce Hyperalgesia and Allodynia [see Warnings and Precautions (5.7)] Adrenal Insufficiency [see Warnings and Precautions (5.9)] Severe Hypotension [see Warnings and Precautions (5.10)] Gastrointestinal Adverse Reactions [see Warnings and Precautions (5.12)] Seizures [see Warnings and Precautions (5.13)] Withdrawal [see Warnings and Precautions (5.14)] Most common adverse reactions (≥3%) were nausea, constipation, vomiting, headache, pruritus, insomnia, dizziness, asthenia, and somnolence. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Camber Pharmaceuticals Inc., at 1-866-495-8330 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Oxycodone hydrochloride tablets have been evaluated in open label clinical trials in patients with cancer and nonmalignant pain. Oxycodone hydrochloride tablets are associated with adverse experiences similar to those seen with other opioids. Serious adverse reactions associated with oxycodone hydrochloride use included: respiratory depression, respiratory arrest, circulatory depression, cardiac arrest, hypotension, and/or shock. The common adverse reactions seen on initiation of therapy with oxycodone hydrochloride are dose related and are typical opioid-related adverse reactions. The most frequent of these included nausea, constipation, vomiting, headache, pruritus, insomnia, dizziness, asthenia, and somnolence. The frequency of these reactions depended on several factors, including clinical setting, the patient’s level of opioid tolerance, and host factors specific to the individual. In all patients for whom dosing information was available (n=191) from the open-label and double-blind studies involving oxycodone hydrochloride, the following adverse events were recorded in oxycodone hydrochloride treated patients with an incidence ≥ 3%. In descending order of frequency they were: nausea, constipation, vomiting, headache, pruritus, insomnia, dizziness, asthenia, and somnolence. Other less frequently observed adverse reactions from opioid analgesics, including oxycodone hydrochloride included: Blood and lymphatic system disorders : anemia, leukopenia Cardiac disorders : cardiac failure, palpitation, tachycardia Gastrointestinal disorders : abdominal pain, dry mouth, diarrhea, dyspepsia, dysphagia, glossitis, nausea, vomiting. General disorders and administration site conditions : chills, edema, edema peripheral, pain, pyrexia Immune system disorders : hypersensitivity Infections and infestations : bronchitis, gingivitis, infection, pharyngitis, rhinitis, sepsis, sinusitis, urinary tract infection Injury, poisoning and procedural complications : injury Metabolism and nutrition disorders : decreased appetite, gout, hyperglycemia Musculoskeletal and connective tissue disorders : arthralgia, arthritis, back pain, bone pain, myalgia, neck pain, pathological fracture Nervous system disorders : hypertonia, hypoesthesia, migraine, neuralgia, tremor, vasodilation Psychiatric disorders : agitation, anxiety, confusional state, nervousness, personality disorder Respiratory, thoracic and mediastinal disorders : cough, dyspnea, epistaxis, laryngospasm, lung disorder Skin and subcutaneous tissue disorders : photosensitivity reaction, rash, hyperhidrosis, urticaria Vascular disorders

5 WARNINGS AND PRECAUTIONS Opioid-Induced Hyperalgesia and Allodynia : Opioid-Induced Hyperalgesia (OIH) occurs when opioid analgesic paradoxically causes an increase in pain, or an increase in sensitivity to pain. If OIH is suspected, carefully consider appropriately decreasing the dose of the current opioid analgesic, or opioid rotation. (5.7) Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients : Regularly evaluate closely, particularly during initiation and titration. (5.8) Adrenal Insufficiency : If diagnosed, treat with physiologic replacement of corticosteroids, and wean patient off of the opioid. (5.9) Severe Hypotension : Regularly evaluate during dosage initiation and titration. Avoid use of oxycodone hydrochloride in patients with circulatory shock. (5.10) Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness : Monitor for sedation and respiratory depression. Avoid use of oxycodone hydrochloride in patients with impaired consciousness or coma. (5.11) 5.1 Addiction, Abuse, and Misuse Oxycodone hydrochloride tablets contains oxycodone, a Schedule II controlled substance. As an opioid, oxycodone hydrochloride exposes users to the risks of addiction, abuse, and misuse [see Drug Abuse and Dependence (9)] . Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed oxycodone hydrochloride. Addiction can occur at recommended dosages and if the drug is misused or abused. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. In postmarketing studies, addiction, abuse, misuse, and fatal and non-fatal opioid overdose were observed in patients with long-term opioid use [see Adverse Reactions (6.2)]. Assess each patient’s risk for opioid addiction, abuse, or misuse prior to prescribing oxycodone hydrochloride, and reassess all patients receiving oxycodone hydrochloride for the development of these behaviors and conditions. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). The potential for these risks should not, however, prevent the proper management of pain in any given patient. Patients at increased risk may be prescribed opioids such as oxycodone hydrochloride, but use in such patients necessitates intensive counseling about the risks and proper use of oxycodone hydrochloride along with frequent reevaluation for signs of addiction, abuse, and misuse. Consider recommending or prescribing an opioid overdose reversal agent [see Dosage and Administration (2.2), Warnings and Precautions (5.2)]. Opioids are sought for nonmedical use and are subject to diversion from legitimate prescribed use. Consider these risks when prescribing or dispensing oxycodone hydrochloride. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on careful storage of the drug during the course of treatment and on the proper disposal of unused drugs. Contact local state professional licensing board or state-controlled substances authority for information on how to prevent and detect abuse or diversion of this product. 5.2 Life-Threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid overdose reversal agents (e.g., naloxone, nalmefene), depending on the patient’s clinical status [see Overdosage (10)] . Carbon dioxide (CO 2 ) retention from opioid-induced res

4 CONTRAINDICATIONS Oxycodone hydrochloride is contraindicated in patients with: Significant respiratory depression [see Warnings and Precautions (5.2)]. Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment or hypercarbia [see Warnings and Precautions (5.8)]. Known or suspected gastrointestinal obstruction, including paralytic ileus [see Warnings and Precautions (5.12)] . Known hypersensitivity (e.g., anaphylaxis) to oxycodone [see Adverse Reactions (6.2)]. Significant respiratory depression (4) Acute or severe bronchial asthma in an unmonitored setting or in absence of resuscitative equipment (4) Known or suspected gastrointestinal obstruction, including paralytic ileus (4) Hypersensitivity to oxycodone (4)

10 OVERDOSAGE Clinical Presentation Acute overdose with oxycodone can be manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and in some cases, pulmonary edema, bradycardia, hypotension, hypoglycemia, partial or complete airway obstruction, atypical snoring, and death. Marked mydriasis rather than miosis may be seen with hypoxia in overdose situations [see Clinical Pharmacology (12.2)] . Toxic leukoencephalopathy has been reported after opioid overdose and can present hours, days, or weeks after apparent recovery from the initial intoxication. Treatment of Overdose In case of overdose, priorities are the re-establishment of a patent and protected airway and institution of assisted or controlled ventilation, if needed. Employ other supportive measures (including oxygen and vasopressors) in the management of circulatory shock and pulmonary edema as indicated. Cardiac arrest or arrhythmias will require advanced life-support measures. For clinically significant respiratory or circulatory depression secondary to opioid overdose, administer an opioid overdose reversal agent such as naloxone or nalmefene. Because the duration of opioid reversal is expected to be less than the duration of action of oxycodone in oxycodone hydrochloride, carefully monitor the patient until spontaneous respiration is reliably reestablished. If the response to an opioid overdose reversal agent is suboptimal or only brief in nature, administer additional reversal agent as directed by the product’s prescribing information. In an individual physically dependent on opioids, administration of the recommended usual dosage of the overdose reversal agent will precipitate an acute withdrawal syndrome. The severity of the withdrawal symptoms experienced will depend on the degree of physical dependence and the dose of the reversal agent administered. If a decision is made to treat serious respiratory depression in the physically dependent patient, administration of the reversal agent should be initiated with care and by titration with smaller than usual doses of the reversal agent.