Oxycodone

7 DRUG INTERACTIONS Table 1 includes clinically significant drug interactions with oxycodone HCl. Table 1: Clinically Significant Drug Interactions with Oxycodone HCl Inhibitors of CYP3A4 and CYP2D6 Clinical Impact: The concomitant use of oxycodone HCl and CYP3A4 inhibitors can increase the plasma concentration of oxycodone, resulting in increased or prolonged opioid effects. These effects could be more pronounced with concomitant use of oxycodone HCl and CYP2D6 and CYP3A4 inhibitors, particularly when an inhibitor is added after a stable dose of oxycodone HCl is achieved [see Warnings and Precautions (5.3) ] . After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the oxycodone plasma concentration will decrease [see Clinical Pharmacology (12.3) ] , resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to oxycodone. Intervention: If concomitant use is necessary, consider dosage reduction of oxycodone HCl until stable drug effects are achieved. Evaluate patients at frequent intervals for respiratory depression and sedation. If a CYP3A4 inhibitor is discontinued, consider increasing the oxycodone HCl dosage until stable drug effects are achieved. Evaluate for signs of opioid withdrawal. Examples: Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), protease inhibitors (e.g., ritonavir). CYP3A4 Inducers Clinical Impact: The concomitant use of oxycodone HCl and CYP3A4 inducers can decrease the plasma concentration of oxycodone [see Clinical Pharmacology (12.3) ] , resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to oxycodone [see Warnings and Precautions (5.6) ] . After stopping a CYP3A4 inducer, as the effects of the inducer decline, the oxycodone plasma concentration will increase [see Clinical Pharmacology (12.3) ] , which could increase or prolong both the therapeutic effects and adverse reactions, and may cause serious respiratory depression. Intervention: If concomitant use is necessary, consider increasing the oxycodone HCl dosage until stable drug effects are achieved. Evaluate patients for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider oxycodone HCl dosage reduction and evaluate patients at frequent intervals for signs of respiratory depression and sedation. Examples: Rifampin, carbamazepine, phenytoin Benzodiazepines and Other Central Nervous System (CNS) Depressants Clinical Impact: Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death [see Warnings and Precautions (5.3) ] . Intervention: Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Inform patients and caregivers of this potential interaction and educate them on the signs and symptoms of respiratory depression (including sedation). If concomitant use is warranted, consider prescribing naloxone for the emergency treatment of opioid overdose [see Dosage and Administration (2.2) , Warnings and Precautions (5.1 , 5.2 , 5.3) ] . Examples: Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol. Serotonergic Drugs Clinical Impact: The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome [see Adverse Reactions (6.2) ] . Intervention: If concomitant use is warranted, frequently evaluate the patient, particularly during treatment initiation and dose adjustment. Discontinue oxycodone HCl if serotonin syndrome is suspected. Examples: Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). Monoamine Oxidase Inhibitors (MAOIs) Clinical Impact: MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions (5.2) ] . Intervention: The use of oxycodone HCl is not recommended for patients taking MAOIs or within 14 days of stopping such treatment. If urgent use of an opioid is necessary, use test doses and frequent titration of small doses to treat pain while closely monitoring blood pressure and signs and symptoms of CNS and respiratory depression. Examples: phenelzine, tranylcypromine, linezolid Mixed Agonist/Antagonist Opioid Analgesics Clinical Impact: May reduce the analgesic effect of oxycodone HCl and/or may precipitate withdrawal symptoms. Intervention: Avoid concomitant use Examples: Butorphanol, nalbuphine, pentazocine, buprenorphine Muscle Relaxants Clinical Impact: Oxycodone may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression. Intervention: Because respiratory depression may be greater than otherwise expected, decrease the dosage of oxycodone HCl and/or the muscle relaxant as necessary. Due to the risk of respiratory depression with concomitant use of skeletal muscle relaxants and opioids, consider prescribing naloxone for the emergency treatment of opioid overdose [see Dosage and Administration (2.2) , Warnings and Precautions (5.2 , 5.3) ] . Diuretics Clinical Impact: Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. Intervention: Evaluate patients for signs of dismissed diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed. Anticholinergic Drugs Clinical Impact: The concomitant risk of anticholinergic drugs may result in increased risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Intervention: Evaluate patients for signs of urinary retention or reduced gastric motility when oxycodone HCl is used concurrently with anticholinergic drugs. Serotonergic Drugs: Concomitant use may result in serotonin syndrome. Discontinue oxycodone HCl tablets if serotonin syndrome is suspected. ( 7 ) Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics: Avoid use with oxycodone HCl tablets because they may reduce analgesic effect of oxycodone HCl tablets or precipitate withdrawal symptoms. ( 7 ) Monoamine Oxidase Inhibitors (MAOIs): Can potentiate the effects of morphine. Avoid concomitant use in patients receiving MAOIs or within 14 days of stopping treatment with an MAOI. ( 7 )

Indicated for "management of pain severe enough to require daily, around-the-clock, long-term opioid treatment" in adults and opioid-tolerant pediatric patients ages 11+ already taking at least 20 mg daily oxycodone equivalent. Reserved for patients where "alternative treatment options are ineffective, not tolerated, or would be otherwise inadequate." Not for as-needed use.

2 DOSAGE AND ADMINISTRATION Oxycodone HCl 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 HCl 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. (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 HCl tablets. Consider this risk when selecting an initial dose and when making dose adjustments. (2.1 , 5.2) Discuss availability of naloxone with the patient and caregiver and assess each patient’s need for access to naloxone, both when initiating and renewing treatment with oxycodone HCl tablets. Consider prescribing naloxone based on the patient’s risk factors for overdose. (2.2 , 5.1 , 5.2 , 5.3) Initiate treatment with oxycodone HCl 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 HCl tablets. (2.3 , 2.4) Do not abruptly discontinue oxycodone HCl in a physically dependent patient because rapid discontinuation of opioid analgesics has resulted in serious withdrawal symptoms, uncontrolled pain, and suicide. (2.5) 2.1 Important Dosage and Administration Instructions Oxycodone HCl 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 HCl 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 HCl tablets. Consider this risk when selecting an initial dose and when making dose adjustments [see Warnings and Precautions (5) ] . 2.2 Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose Discuss the availability of naloxone for the emergency treatment of opioid overdose with the patient and caregiver and assess the potential need for access to naloxone, both when initiating and renewing treatment with oxycodone HCl tablets [see Warnings and Precautions (5.3) ] . Inform patients and caregivers about the various ways to obtain naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (e.g., by prescription, directly from a pharmacist, or as part of a community-based program). Consider prescribing naloxone, based on the patient’s risk factors for overdose, such as concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose. The presence of risk factors for overdose should not prevent the proper management of pain in any given patient [see Warnings and Precautions (5.1 , 5.2 , 5.3) ] . Consider prescribing naloxone if the patient has household members (including children) or other close contacts at risk for accidental ingestion or overdose . 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 HCl 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 HCl Tablets as the First Opioid Analgesic Initiate treatment with oxycodone HCl 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 HCl tablets. Conversion from Other Opioids to Oxycodone HCl 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 HCl tablets. It is safer to underestimate a patient’s 24-hour oxycodone HCl tablets dosage than to overestimate the 24-hour oxycodone HCl tablets dosage and manage an adverse reaction due to overdose. If a patient has been receiving opioid-containing medications prior to taking oxycodone HCl 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 HCl tablets close observation and adjustment of dosage based upon the patient’s response to oxycodone HCl tablets are imperative. Administration of supplemental analgesia for breakthrough or incident pain and titration of the total daily dose of oxycodone HCl 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 dose of oxycodone HCl tablets in response to the level of analgesia and adverse effects afforded by the dosing regimen. If the non-opioid regimen is continued as a separate single entity agent, the starting dose oxycodone HCl tablets should be based upon the most recent dose of opioid as a baseline for further titration of oxycodone. Incremental increases should be gauged according to side effects to an acceptable level of analgesia. Conversion from Oxycodone HCl Immediate-Release Tablets to Extended-Release Oxycodone The relative bioavailability of oxycodone HCl immediate-release tablets compared to extended-release oxycodone is unknown, so conversion to extended-release oxycodone may lead to increased risk of excessive sedation and respiratory depression. 2.4 Titration and Maintenance of Therapy Individually titrate oxycodone HCl tablets to a dose that provides adequate analgesia and minimizes adverse reactions. Continually reevaluate patients receiving oxycodone HCl tablets to assess the maintenance of pain control, signs and symptoms of opioid withdrawal, and other adverse reactions, as well as to reassess for the development of addiction, abuse, or misuse [see Warnings and Precautions (5.1 , 5.14) ] . Frequent communication is important among the prescriber, other members of the healthcare team, the patient, and the caregiver/family during periods of changing analgesic requirements, including initial titration. If the level of pain increases after dosage stabilization, attempt to identify the source of increased pain before increasing the oxycodone HCl tablets dosage. If after increasing the dosage, unacceptable opioid-related adverse reactions are observed (including an increase in pain after a dosage increase), consider reducing the dosage [see Warnings and Precautions (5) ] . Adjust the dosage to obtain an appropriate balance between management of pain and opioid-related adverse reactions. 2.5 Safe Reduction or Discontinuation of Oxycodone HCl Tablets Do not abruptly discontinue oxycodone HCl in patients who may be physically dependent on opioids. Rapid discontinuation of opioid analgesics in patients who are physically dependent on opioids has resulted in serious withdrawal symptoms, uncontrolled pain, and suicide. Rapid discontinuation has also been associated with attempts to find other sources of opioid analgesics, which may be confused with drug-seeking for abuse. Patients may also attempt to treat their pain or withdrawal symptoms with illicit opioids, such as heroin, and other substances. When a decision has been made to decrease the dose or discontinue therapy in an opioid-dependent patient taking oxycodone HCl, there are a variety of factors that should be considered, including the total daily dose of opioid (including oxycodone HCl tablets) the patient has been taking, the duration of treatment, the type of pain being treated, and the physical and psychological attributes of the patient. It is important to ensure ongoing care of the patient and to agree on an appropriate tapering schedule and follow-up plan so that patient and provider goals and expectations are clear and realistic. When opioid analgesics are being discontinued due to a suspected substance use disorder, evaluate and treat the patient, or refer for evaluation and treatment of the substance use disorder. Treatment should include evidence-based approaches, such as medication assisted treatment of opioid use disorder. Complex patients with comorbid pain and substance use disorders may benefit from referral to a specialist. There are no standard opioid tapering schedules that are suitable for all patients. Good clinical practice dictates a patient-specific plan to taper the dose of the opioid gradually. For patients on oxycodone HCl who are physically opioid-dependent, initiate the taper by a small enough increment (e.g., no greater than 10% to 25% of the total daily dose) to avoid withdrawal symptoms, and proceed with dose-lowering at an interval of every 2 to 4 weeks. Patients who have been taking opioids for briefer periods of time may tolerate a more rapid taper. It may be necessary to provide the patient with lower dosage strengths to accomplish a successful taper. Reassess the patient frequently to manage pain and withdrawal symptoms, should they emerge. Common withdrawal symptoms include restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Other signs and 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 withdrawal symptoms arise, it may be necessary to pause the taper for a period of time or raise the dose of the opioid analgesic to the previous dose, and then proceed with a slower taper. In addition, evaluate patients for any changes in mood, emergence of suicidal thoughts, or use of other substances. When managing patients taking opioid analgesics, particularly those who have been treated for an extended period of time, and/or with high doses for chronic pain, ensure that a multimodal approach to pain management, including mental health support (if needed), is in place prior to initiating an opioid analgesic taper. A multimodal approach to pain management may optimize the treatment of chronic pain, as well as assist with the successful tapering of the opioid analgesic [see Warnings and Precautions (5.14) , Drug Abuse and Dependence (9.3) ] .

Incidence >5%: constipation (23%), nausea (23%), somnolence (23%), dizziness (13%), pruritus (13%), vomiting (12%), headache (7%), dry mouth (6%), weakness (6%), sweating (5%). Pediatric patients (11-16 years): vomiting (21%), nausea (15%), headache (14%), fever (11%), dizziness (9%).