oxycodone hydrochloride 7.5 MG Oral Tablet

INDICATIONS AND USAGE Oxycodone Hydrochloride Oral Solution is indicated in adults for the management of pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate. Oxycodone Hydrochloride Oral Solution 100 mg per 5 mL (20 mg/mL) is indicated for the relief of pain in opioid-tolerant adults. Limitations of Use Because of the risks of addiction, abuse, and misuse with opioids, which can occur at any dosage or duration [see Warnings and Precautions ( 5.2 )] , reserve Oxycodone Hydrochloride Oral Solution for use in patients for whom alternative treatment options (e.g., non-opioid analgesics or opioid combination products): Have not been tolerated or are not expected to be tolerated Have not provided adequate analgesia or are not expected to provide adequate analgesia Oxycodone Hydrochloride Oral Solution should not be used for an extended period of time unless the pain remains severe enough to require an opioid analgesic and for which alternative treatment options continue to be inadequate. Oxycodone Hydrochloride Oral Solution is an opioid agonist indicated in adults for the management of pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate. ( 1 ) Oxycodone Hydrochloride Oral Solution 100 mg per 5 mL (20 mg/mL) is indicated for the relief of pain in opioid-tolerant adults. Limitations of Use ( 1 ) Because of the risks of addiction, abuse, and misuse with opioids, which can occur at any dosage or duration ( 5.2 ), reserve Oxycodone Hydrochloride Oral Solution for use in patients for whom alternative treatment options (e.g., non-opioid analgesics or opioid combination products): Have not been tolerated or are not expected to be tolerated, Have not provided adequate analgesia or are not expected to provide adequate analgesia. Oxycodone Hydrochloride Oral Solution should not be used for an extended period of time unless the pain remains severe enough to require an opioid analgesic and for which alternative treatment options continue to be inadequate.

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 tablets. Consider this risk when selecting an initial dose and when making dose adjustments [see Warnings and Precautions (5)]. 2.2 Patient Access to an Opioid Overdose Reversal Agent for the Emergency Treatment of Opioid Overdose Inform patients and caregivers about opioid overdose reversal agents (e.g., naloxone, nalmefene). Discuss the importance of having access to an opioid overdose reversal agent, especially if the patient has risk factors for overdose (e.g., concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose) or if there are household members (including children) or other close contacts at risk for accidental ingestion or opioid overdose. The presence of risk factors for overdose should not prevent the management of pain in any patient [see Warnings and Precautions (5.1, 5.2, 5.3)] . Discuss the options for obtaining an opioid overdose reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program) [see Warnings and Precautions (5.2)] . There are important differences among the opioid overdose reversal agents, such as route of administration, product strength, approved patient age range, and pharmacokinetics. Be familiar with these differences, as outlined in the approved labeling for those products, prior to recommending or prescribing such an agent. 2.3 Initial Dosage Although it is not possible to list every condition that is important to the selection of the initial dose of oxycodone hydrochloride tablets, attention must be given to: the daily dose, potency and characteristics of a full agonist or mixed agonist/antagonist the patient has been taking previously. the reliability of the relative potency estimate to calculate the dose of oxycodone HCl needed. the degree of opioid tolerance. the general condition and medical status of the patient, including the patient’s weight and age. the balance between pain management and adverse reactions. the type and severity of the patient’s pain. risk factors for abuse or addiction, including a prior history of abuse or addiction. Use of Oxycodone Hydrochloride Tablets as the First Opioid Analgesic Initiate treatment with oxycodone hydrochloride tablets 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. Conversion from Other Opioids to Oxycodone Hydrochloride Tablets There is inter-patient variability in the potency of opioid drugs and opioid formulations. Therefore, a conservative approach is advised when determining the total daily dosage of oxycodone hydrochloride tablets. It is safer to underestimate a patient’s 24-hour oxycodone hydrochloride tablets dosage than to overestimate the 24-hour oxycodone hydrochloride tablets dosage and manage an adverse reaction due to overdose. If a patient has been receiving opioid-containing medications prior to taking oxycodone hydrochloride tablets, the potency of the prior opioid relative to oxycodone should be factored into the selection of the total daily dose (TDD) of oxycodone. In converting patients from other opioids to oxycodone hydrochloride tablets close observation and adjustment of dosage based upon the patient’s response to oxycodone hydrochloride tablets is imperative. Administration of supplemental analgesia for breakthrough or incident pain and titration of the total daily dose of oxycodone hydrochloride tablets may be necessary, especially in patients who have disease states that are changing rapidly. Conversion from Fixed-Ratio Opioid/Acetaminophen, Opioid/Aspirin, or Opioid/Nonsteroidal Combination Drugs When converting patients from fixed ratio opioid/non-opioid drug regimens a decision should be made whether or not to continue the non-opioid analgesic. If a decision is made to discontinue the use of non-opioid analgesic, it may be necessary to titrate the dos

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 respiratory depression can exacerbate the sedating effects of opioids. While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of oxycodone hydrochloride, the risk is greatest during the initiation of therapy or following a dosage increase. To reduce the risk of respiratory depression, proper dosing and titration of oxycodone hydrochloride are essential [see Dosage and Administration (2)] . Overestimating the oxycodone hydrochloride dosage when converting patients from another opioid product can result in fatal overdose with the first dose. Accidental ingestion of even one dose of oxycodone hydrochloride, especially by children, can result in respiratory depression and death due to an overdose of oxycodone. Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help right away in the event of a known or suspected overdose . Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the opioid dosage using best practices for opioid taper [see Dosage and Administration (2.5)] . Patient Access to an Opioid Overdose Reversal Agent for the Emergency Treatment of Opioid Overdose Inform patients and caregivers about opioid overdose reversal agents (e.g., naloxone, nalmefene). Discuss the importance of having access to an opioid overdose reversal agent, especially if the patient has risk factors for overdose (e.g., concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose) or if there are household members (including children) or other close contacts at risk for accidental ingestion or opioid overdose. The presence of risk factors for overdose should not prevent the management of pain in any patient [see Warnings and Precautions (5.1, 5.3)]. Discuss the options for obtaining an opioid overdose reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program). There are important differences among the opioid overdose reversal agents, such as route of administration, product strength, approved patient age range, and pharmacokinetics. Be familiar with these differences, as outlined in the approved labeling for those products, prior to recommending or prescribing such an agent. Educate patients and caregivers on how to recognize respiratory depression, and how to use an opioid overdose reversal agent for the emergency treatment of opioid overdose. Emphasize the importance of calling 911 or getting emergency medical help, even if an opioid overdose reversal agent is administered [see Dosage and Administration (2.2), Warnings and Precautions (5.1, 5.3), Overdosage (10)]. 5.3 Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants Profound sedation, respiratory depression, coma, and death may result from the concomitant use of oxycodone hydrochloride with benzodiazepines and/or other CNS depressants, including alcohol (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, gabapentinoids [gabapentin or pregabalin], and other opioids). Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioid analgesics alone. Because of similar pharmacological properties, it is reasonable to expect similar risk with the concomitant use of other CNS depressant drugs with opioid analgesics [see Drug Interactions (7)] . If the decision is made to prescribe a benzodiazepine or other CNS depressant concomitantly with an opioid analgesic, prescribe

CONTRAINDICATIONS Oxycodone Hydrochloride Tablets is contraindicated in patients with: • Significant respiratory depression [see Warnings and Precautions ( 5.3 )]. • Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment or hypercarbia [see Warnings and Precautions ( 5.7 )]. • Known or suspected gastrointestinal obstruction, including paralytic ileus [see Warnings and Precautions ( 5.11 )]. • 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 )

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 may influence gonadal hormone levels have not been adequately controlled for in studies conducted to date [see Adverse Reactions (6.2)] . Effects on the Immune System Opioids have been shown to have a variety of effects on components of the immune system in in vitro and animal models. The clinical significance of these findings is unknown. Overall, the effects of opioids appear to be modestly immunosuppressive. Concentration-Efficacy Relationships The minimum effective analgesic concentration will vary widely among patients, especially among patients who have been previously treated with opioid agonists. The minimum effective analgesic concentration of oxycodone for any individual patient may increase over time due to an increase in pain, the development of a new pain syndrome, and/or the development of analgesic tolerance [see Dosage and Administration (2.1, 2.3)] . Concentration-Adverse Reaction Relationships There is a relationship between increasing oxycodone plasma concentration and increasing frequency of dose-related opioid adverse reactions such as nausea, vomiting, CNS effects, and respiratory depression. In opioid-tolerant patients, the situation may be altered by the development of tolerance to opioid-related adverse reactions [see Dosage and Administration (2.1, 2.3)] . 12.3 Pharmacokinetics The activity of oxycodone hydrochloride tablets is primarily due to the parent drug oxycodone. Oxycodone hydrochloride tablets are designed to provide immediate release of oxycodone. Table 2: Pharmacokinetic Parameters (Mean±SD) Dose\Parameters AUC (ngxhr/mL) C max (ng/mL) T max (hr) C min (ng/mL) C avg (ng/mL) Half-Life (hr) Single Dose Pharmacokinetics Oxycodone Hydrochloride 5 mg tabs x 3 133.2±33 22.3±8.2 1.8±1.8 n/a n/a 3.73±0.9 Oxycodone Hydrochloride 15 mg tab 128.2±35.1 22.2±7.6 1.4±0.7 n/a n/a 3.55±1.0 Oxycodone Hydrochloride Liquid Concentrate 15 mg oral solution 130.6±34.7 21.1±6.1 1.9±1.5 n/a n/a 3.71±0.8 Oxycodone Hydrochloride 30 mg tab 268.2±60.7 39.3±14.0 2.6±3.0 n/a n/a 3.85±1.3 Food-Effect, Single Dose Oxycodone Hydrochloride 10 mg/10 mL oral sol’n (fasted) 105±6.2 19.0±3.7 1.25±0.5 n/a n/a 2.9±0.4 Oxycodone Hydrochloride 10 mg/10 mL oral sol’n (fed) 133±25.2 17.7±3.0 2.54±1.2 n/a n/a 3.3±0.5 Multiple-Dose Studies AUC (72-84) Oxycodone Hydrochloride 5 mg tabs q6h x 14 doses 113.3±24.0 15.7±3.2 1.3±0.3 7.4±1.8 9.4±2.0 n/a Oxycodone Hydrochloride 3.33 mg (3.33 mL) oral sol’n. q4h x 21 doses 99.0±24.8 12.9±3.1 1.0±0.3 7.2±2.3 9.7±2.6 n/a Absorption About 60% to 87% of an oral dose of oxycodone reaches the systemic circulation in comparison to a parenteral dose. This high oral bioavailability (compared to other oral opioids) is due to lower presystemic and/or first-pass metabolism of oxycodone. The relative oral bioavailability of oxycodone hydrochloride 15 mg and 30 mg tablets, compared to the 5 mg oxycodone hydrochloride tablets, is 96% and 101% respectively. Oxycodone hydrochloride 15 mg tablets and 30 mg tablets are bioequivalent to the 5 mg oxycodone hydrochloride tablet ( see Table 2 for pharmacokinetic parameters). Dose proportionality of oxycodone has been established using the oxycodone hydrochloride 5 mg tablets at doses of 5 mg, 15 mg (three 5 mg tablets) and 30 mg (six 5 mg tablets) based on extent of absorption (AUC) ( see Figure 1). It takes approximately 18 to 24 hours to reach steady-state plasma concentrations of oxycodone with oxycodone hydrochloride. Food Effect A single-dose food effect study was conducted in normal volunteers using the 5 mg/5 mL solution. The concurrent intake of a high fat meal was shown to enhance the extent (27% increase in AUC), but not the rate of oxycodone absorption from the oral solution ( see Table 2). In addition, food caused a delay in T max (1.25 to 2.54 hour). Similar effects of food are expected with the 15 mg and 30 mg tablets. Distribution Following intravenous administration, the volume of distribution (V ss ) for oxycodone was 2.6 L/kg. Plasma protein binding of oxycodone at 37°C and a pH of 7.4 was about 45%. Oxycodone has been found in breast milk [see Special Populations (8.2)] . Elimination Metabolism A high portion of oxycodone is N-dealkylated to noroxycodone during first-pass metabolism, and is catalyzed by CYP3A4. Oxymorphone is formed by the O-demethylation of oxycodone. The metabolism of oxycodone to oxymorphone is catalyzed by CYP2D6 [see Drug Interactions (7)] . Free and conjugated noroxycodone, free and conjugated oxycodone, and oxymorphone are excreted in human urine following a single oral dose of oxycodone. The major circulating metabolite is noroxycodone with an AUC ratio of 0.6 relative to that of oxycodone. Oxymorphone is present in the plasma only in low concentrations. The analgesic activity profile of other metabolites is not known at present. 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