OXAYDO- oxycodone hydrochloride tablet

OXAYDO by

Drug Labeling and Warnings

OXAYDO by is a Prescription medication manufactured, distributed, or labeled by Zyla Life Sciences US Inc.. Drug facts, warnings, and ingredients follow.

Drug Details [pdf]

  • BOXED WARNING (What is this?)

    WARNING: ADDICTION, ABUSE, AND MISUSE: RISK EVALUATION AND MITIGATION STRATEGY (REMS); LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; NEONATAL OPIOID WITHDRAWAL SYNDROME; CYTOCHROME P450 3A4 INTERACTION; and RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS

    Addiction, Abuse, and Misuse

    OXAYDO exposes patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death. Assess each patient’s risk prior to prescribing OXAYDO, and monitor all patients regularly for the development of these behaviors and conditions [see Warnings and Precautions (5.1)].

    Opioid Analgesic Risk Evaluation and Mitigation Strategy (REMS):

    To ensure that the benefits of opioid analgesics outweigh the risks of addiction, abuse, and misuse, the Food and Drug Administration (FDA) has required a REMS for these products [see Warnings and Precautions (5.2)]. Under the requirements of the REMS, drug companies with approved opioid analgesic products must make REMS-compliant education programs available to healthcare providers. Healthcare providers are strongly encouraged to

    • complete a REMS-compliant education program,
    • counsel patients and/or their caregivers, with every prescription, on safe use, serious risks, storage, and disposal of these products,
    • emphasize to patients and their caregivers the importance of reading the Medication Guide every time it is provided by their pharmacist, and
    • consider other tools to improve patient, household, and community safety.

    Life-Threatening Respiratory Depression

    Serious, life-threatening, or fatal respiratory depression may occur with use of OXAYDO. Monitor for respiratory depression, especially during initiation of OXAYDO or following a dose increase [see Warnings and Precautions (5.3)].

    Accidental Ingestion

    Accidental ingestion of even one dose of OXAYDO, especially by children, can result in a fatal overdose of oxycodone [see Warnings and Precautions (5.3)].

    Neonatal Opioid Withdrawal Syndrome

    Prolonged use of OXAYDO during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [see Warnings and Precautions (5.4)].

    Cytochrome P450 3A4 Interaction

    The concomitant use of OXAYDO with all cytochrome P450 3A4 inhibitors may result in an increase in oxycodone plasma concentrations, which could increase or prolong adverse reactions and may cause potentially fatal respiratory depression. In addition, discontinuation of a concomitantly used cytochrome P450 3A4 inducer may result in an increase in oxycodone plasma concentration. Monitor patients receiving OXAYDO and any CYP3A4 inhibitor or inducer [see Warnings and Precautions (5.5), Drug Interactions (7), Clinical Pharmacology (12.3)].

    Risks From Concomitant Use With Benzodiazepines Or Other CNS Depressants

    Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death [see Warnings and Precautions (5.6), Drug Interactions (7)].

    • Reserve concomitant prescribing of OXAYDO and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate.
    • Limit dosages and durations to the minimum required.
    • Follow patients for signs and symptoms of respiratory depression and sedation.
  • 1 INDICATIONS AND USAGE

    OXAYDO is indicated for the management of acute and chronic 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, and misuse with opioids, even at recommended doses [see Warnings and Precautions (5.1)], reserve OXAYDO 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.
  • 2 DOSAGE AND ADMINISTRATION

    2.1 Important Dosage and Administration Instructions

    Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals [see Warnings and Precautions (5)].

    Initiate the dosing regimen for each patient individually, taking into account the patient's severity of pain, patient response, prior analgesic treatment experience, and risk factors for addiction, abuse, and misuse [see Warnings and Precautions (5.1)].

    Monitor patients closely for respiratory depression, especially within the first 24-72 hours of initiating therapy and following dosage increases with OXAYDO and adjust the dosage accordingly [see Warnings and Precautions (5.3)].

    OXAYDO must be swallowed whole. Take each tablet with enough water to ensure complete swallowing immediately after placing in the mouth [see Patient Counseling Information (17)]. OXAYDO is not amenable to crushing and dissolution. Do not administer OXAYDO via nasogastric, gastric or other feeding tubes as it may cause obstruction of feeding tubes.

    2.2 Initial Dosage

    Although it is not possible to list every condition that is important to the selection of the initial dose of OXAYDO, attention must be given to:

    1. the daily dose, potency and characteristics of a full agonist or mixed agonist/antagonist the patient has been taking previously
    2. the reliability of the relative potency estimate to calculate the dose of oxycodone HCl needed
    3. the degree of opioid tolerance
    4. the general condition and medical status of the patient, including the patient’s weight and age
    5. the balance between pain management and adverse reactions
    6. the type and severity of the patient’s pain
    7. risk factors for abuse or addiction, including a prior history of abuse or addiction

    Use of OXAYDO as the First Opioid Analgesic

    Initiate treatment with OXAYDO in a dosing range of 5 mg to 15 mg every 4 to 6 hours as needed for pain. Titrate the dose based upon the individual patient’s response to their initial dose of OXAYDO. Patients with chronic pain should have their dosage given on an around-the-clock basis to prevent the reoccurrence of pain rather than treating the pain after it has occurred. This dose can then be adjusted to an acceptable level of analgesia taking into account side effects experienced by the patient.

    For control of severe chronic pain, OXAYDO should be administered on a regularly scheduled basis, every 4 to 6 hours, at the lowest dosage level that will achieve adequate analgesia.

    Conversion from Other Opioids to OXAYDO

    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 OXAYDO. It is safer to underestimate a patient’s 24-hour OXAYDO dosage than to overestimate the 24-hour OXAYDO dosage and manage an adverse reaction due to overdose. If a patient has been receiving opioid-containing medications prior to taking OXAYDO, 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 OXAYDO, close observation and adjustment of dosage based upon the patient’s response to OXAYDO is imperative. Administration of supplemental analgesia for breakthrough or incident pain and titration of the total daily dose of OXAYDO may be necessary, especially in patients who have disease states that are changing rapidly.

    Conversion from Fixed-Ratio Oral Opioid/Non-Opioid Combinations

    When converting patients from fixed-ratio opioid/non-opioid drug regimens to OXAYDO, determine whether or not to continue the non-opioid analgesic. Titrate the dose of OXAYDO in response to the level of analgesia and adverse reactions afforded by the dosing regimen regardless of whether the non-opioid is continued.

    Conversion from Other Oral Opioid Therapy to OXAYDO

    If a patient has been receiving opioid-containing medications prior to taking OXAYDO, factor the potency of the prior opioid relative to oxycodone into the selection of the total daily dose of oxycodone.

    In converting patients from other opioids to OXAYDO, close observation and adjustment of dosage based upon the patient's response to OXAYDO is imperative.

    Conversion from OXAYDO to Extended-Release Oxycodone

    The relative bioavailability of OXAYDO compared to extended-release oxycodone is unknown, so conversion to extended-release tablets must be accompanied by close observation for signs of excessive sedation and respiratory depression.

    2.3 Titration and Maintenance of Therapy

    Individually titrate OXAYDO to a dose that provides adequate analgesia and minimizes adverse reactions. Continually reevaluate patients receiving OXAYDO to assess the maintenance of pain control and the relative incidence of adverse reactions, as well as monitoring for the development of addiction, abuse, or misuse [see Warnings and Precautions (5.1)]. 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 dosage of OXAYDO. If unacceptable opioid-related adverse reactions are observed, consider reducing the dosage. Adjust the dosage to obtain an appropriate balance between management of pain and opioid-related adverse reactions.

    2.4 Safe Reduction or Discontinuation of OXAYDO

    Do not abruptly discontinue OXAYDO 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 OXAYDO, there are a variety of factors that should be considered, including the dose of OXAYDO 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 OXAYDO 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, monitor 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 a long duration 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 (5.13), Drug Abuse and Dependence (9.3)].

  • 3 DOSAGE FORMS AND STRENGTHS

    Tablets: 5 mg and 7.5 mg of oxycodone HCl, USP:

    StrengthDescription
    5 mg   Round, convex, white tablet, debossed “5” on one side, letter “O” on other side.
    7.5 mg   Round, convex, white tablet, debossed “7.5” on one side, letter “O” on other side.
  • 4 CONTRAINDICATIONS

    OXAYDO 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 [see Warnings and Precautions (5.7)]
    • Known or suspected gastrointestinal obstruction, including paralytic ileus [see Warnings and Precautions (5.11)]
    • Hypersensitivity to oxycodone, oxycodone salts, or any components of the product (e.g., anaphylaxis) [see Adverse Reactions (6.2)]
  • 5 WARNINGS AND PRECAUTIONS

    5.1 Addiction, Abuse, and Misuse

    OXAYDO contains oxycodone, a Schedule II controlled substance. As an opioid, OXAYDO 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 OXAYDO. Addiction can occur at recommended dosages and if the drug is misused or abused.

    Assess each patient’s risk for opioid addiction, abuse, or misuse prior to prescribing OXAYDO, and monitor all patients receiving OXAYDO 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 OXAYDO, but use in such patients necessitates intensive counseling about the risks and proper use of OXAYDO along with intensive monitoring for signs of addiction, abuse, and misuse.

    Opioids are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Consider these risks when prescribing or dispensing OXAYDO. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on the proper disposal of unused drug [see Patient Counseling Information (17)]. Contact the 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 Opioid Analgesic Risk Evaluation and Mitigation Strategy (REMS)

    To ensure that the benefits of opioid analgesics outweigh the risks of addiction, abuse, and misuse, the Food and Drug Administration (FDA) has required a Risk Evaluation and Mitigation Strategy (REMS) for these products. Under the requirements of the REMS, drug companies with approved opioid analgesic products must make REMS-compliant education programs available to healthcare providers. Healthcare providers are strongly encouraged to do all of the following:

    • Complete a REMS-compliant education program offered by an accredited provider of continuing education (CE) or another education program that includes all the elements of the FDA Education Blueprint for Health Care Providers Involved in the Management or Support of Patients with Pain.
    • Discuss the safe use, serious risks, and proper storage and disposal of opioid analgesics with patients and/or their caregivers every time these medicines are prescribed. The Patient Counseling Guide (PCG) can be obtained at this link: www.fda.gov/OpioidAnalgesicREMSPCG.
    • Emphasize to patients and their caregivers the importance of reading the Medication Guide that they will receive from their pharmacist every time an opioid analgesic is dispensed to them.
    • Consider using other tools to improve patient, household, and community safety, such as patient- prescriber agreements that reinforce patient-prescriber responsibilities.

    To obtain further information on the opioid analgesic REMS and for a list of accredited REMS CME/CE, call 1-800-503-0784, or log on to www.opioidanalgesicrems.com. The FDA Blueprint can be found at www.fda.gov/OpioidAnalgesicREMSBlueprint.

    5.3 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 antagonists, depending on the patient’s clinical status [see Overdosage (10)]. Carbon dioxide (CO2) 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 OXAYDO, the risk is greatest during the initiation of therapy or following a dosage increase. Monitor patients closely for respiratory depression, especially within the first 24-72 hours of initiating therapy with and following dosage increases of OXAYDO.

    To reduce the risk of respiratory depression, proper dosing and titration of OXAYDO are essential [see Dosage and Administration (2)]. Overestimating the OXAYDO dosage when converting patients from another opioid product can result in a fatal overdose with the first dose.

    Accidental ingestion of even one dose of OXAYDO, especially by children, can result in respiratory depression and death due to an overdose of oxycodone.

    5.4 Neonatal Opioid Withdrawal Syndrome

    Prolonged use of OXAYDO during pregnancy can result in withdrawal in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly. Advise pregnant women using opioids for a prolonged period of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [see Use in Specific Populations (8.1), Patient Counseling Information (17)].

    5.5 Risks of Concomitant Use or Discontinuation of Cytochrome P450 3A4 Inhibitors and Inducers

    Concomitant use of OXAYDO with a CYP3A4 inhibitor, such as macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), and protease inhibitors (e.g., ritonavir), may increase plasma concentrations of oxycodone and prolong opioid adverse reactions, which may cause potentially fatal respiratory depression [see Warnings and Precautions (5.3)], particularly when an inhibitor is added after a stable dose of OXAYDO is achieved. Similarly, discontinuation of a CYP3A4 inducer, such as rifampin, carbamazepine, and phenytoin, in OXAYDO-treated patients may increase oxycodone plasma concentrations and prolong opioid adverse reactions. When using OXAYDO with CYP3A4 inhibitors or discontinuing CYP3A4 inducers in OXAYDO-treated patients, monitor patients closely at frequent intervals and consider dosage reduction of OXAYDO until stable drug effects are achieved [see Drug Interactions (7)].

    Concomitant use of OXAYDO with CYP3A4 inducers or discontinuation of a CYP3A4 inhibitor could decrease oxycodone plasma concentrations, decrease opioid efficacy or, possibly, lead to a withdrawal syndrome in a patient who had developed physical dependence to oxycodone. When using OXAYDO with CYP3A4 inducers or discontinuing CYP3A4 inhibitors, monitor patients closely at frequent intervals and consider increasing the opioid dosage if needed to maintain adequate analgesia or if symptoms of opioid withdrawal occur [see Drug Interactions (7)].

    5.6 Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants

    Profound sedation, respiratory depression, coma, and death may result from the concomitant use of OXAYDO with benzodiazepines or other CNS depressants (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol). 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 the lowest effective dosages and minimum durations of concomitant use. In patients already receiving an opioid analgesic, prescribe a lower initial dose of the benzodiazepine or other CNS depressant than indicated in the absence of an opioid, and titrate based on clinical response. If an opioid analgesic is initiated in a patient already taking a benzodiazepine or other CNS depressant, prescribe a lower initial dose of the opioid analgesic, and titrate based on clinical response. Follow patients closely for signs and symptoms of respiratory depression and sedation.

    Advise both patients and caregivers about the risks of respiratory depression and sedation when OXAYDO is used with benzodiazepines or other CNS depressants (including alcohol and illicit drugs). Advise patients not to drive or operate heavy machinery until the effects of concomitant use of the benzodiazepine or other CNS depressant have been determined. Screen patients for risk of substance use disorders, including opioid abuse and misuse, and warn them of the risk for overdose and death associated with the use of additional CNS depressants including alcohol and illicit drugs [see Drug Interactions (7) and Patient Counseling Information (17)].

    5.7 Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients

    The use of OXAYDO in patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment is contraindicated.

    Patients with Chronic Pulmonary Disease: OXAYDO-treated patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression are at increased risk of decreased respiratory drive including apnea, even at recommended dosages of OXAYDO [see Warnings and Precautions (5.3)].

    Elderly, Cachectic, or Debilitated Patients: Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients because they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients [see Warnings and Precautions (5.3)].

    Monitor such patients closely, particularly when initiating and titrating OXAYDO and when OXAYDO is given concomitantly with other drugs that depress respiration [see Warnings and Precautions (5.3)]. Alternatively, consider the use of non-opioid analgesics in these patients.

    5.8 Adrenal Insufficiency

    Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Presentation of adrenal insufficiency may include non-specific symptoms and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. If adrenal insufficiency is suspected, confirm the diagnosis with diagnostic testing as soon as possible. If adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids. Wean the patient off of the opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers. Other opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency. The information available does not identify any particular opioids as being more likely to be associated with adrenal insufficiency.

    5.9 Severe Hypotension

    OXAYDO may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients. There is increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs (e.g., phenothiazines or general anesthetics) [see Drug Interactions (7)]. Monitor these patients for signs of hypotension after initiating or titrating the dosage of OXAYDO. In patients with circulatory shock, OXAYDO may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of OXAYDO in patients with circulatory shock.

    5.10 Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness

    In patients who may be susceptible to the intracranial effects of CO2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors), OXAYDO may reduce respiratory drive, and the resultant CO2 retention can further increase intracranial pressure. Monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy with OXAYDO.

    Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of OXAYDO in patients with impaired consciousness or coma.

    5.11 Risks of Use in Patients with Gastrointestinal Conditions

    OXAYDO is contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus.

    The oxycodone in OXAYDO may cause spasm of the sphincter of Oddi. Opioids may cause increases in serum amylase. Monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms.

    5.12 Increased Risk of Seizures in Patients with Seizure Disorders

    The oxycodone in OXAYDO may increase the frequency of seizures in patients with seizure disorders, and may increase the risk of seizures occurring in other clinical settings associated with seizures. Monitor patients with a history of seizure disorders for worsened seizure control during OXAYDO therapy.

    5.13 Withdrawal

    Do not abruptly discontinue OXAYDO in a patient physically dependent on opioids. When discontinuing OXAYDO in a physically dependent patient, gradually taper the dosage. Rapid tapering of OXAYDO in a patient physically dependent on opioids may lead to a withdrawal syndrome and return of pain [see Dosage and Administration (2.4), Drug Abuse and Dependence (9.3)].

    Additionally, avoid the use of mixed agonist/antagonist (e.g, pentazocine, nalbuphine, and butorphanol) or partial agonist (e.g., buprenorphine) analgesics in patients who are receiving a full opioid agonist analgesic, including OXAYDO. In these patients, mixed agonist/antagonist and partial agonist analgesics may reduce the analgesic effect and/or precipitate withdrawal symptoms [see Drug Interactions (7)].

    5.14 Risks of Driving and Operating Machinery

    OXAYDO may impair the mental or physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery. Warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects of OXAYDO and know how they will react to the medication [see Patient Counseling Information (17)].

  • 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 (5.3)]
    • Neonatal Opioid Withdrawal Syndrome [see Warnings and Precautions (5.4)]
    • Interactions with Benzodiazepines or Other CNS Depressants [see Warnings and Precautions (5.6)]
    • Adrenal Insufficiency [see Warnings and Precautions (5.8)]
    • Severe Hypotension [see Warnings and Precautions (5.9)]
    • Gastrointestinal Adverse Reactions [see Warnings and Precautions (5.11)]
    • Seizures [see Warnings and Precautions (5.12)]
    • Withdrawal [see Warnings and Precautions (5.13)]

    6.1 Clinical Trials Experience

    Because clinical trials are conducted under widely varying conditions, the 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 clinical practice.

    Serious adverse reactions that may be associated with OXAYDO include: respiratory depression, respiratory arrest, circulatory depression, cardiac arrest, hypotension, and/or shock [see Warnings and Precautions (5) and Overdosage (10)].

    The common adverse reactions seen on initiation of therapy with OXAYDO are dose-dependent, and their frequency depends on 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 therapy. The most frequent of the adverse reactions include nausea, constipation, vomiting, headache, and pruritus.

    The frequency of adverse reactions during initiation of opioid therapy may be minimized by careful individualization of starting dosage, slow titration and the avoidance of large rapid swings in plasma concentration of the opioid. Many of these adverse reactions will abate as therapy is continued and some degree of tolerance is developed, but others may be expected to remain throughout therapy.

    In all patients for whom dosing information was available (n=191) from open-label and double-blind studies involving oxycodone, the following adverse reactions were recorded in oxycodone-treated patients with an incidence of ≥3%. In descending order of frequency they were: nausea, constipation, vomiting, headache, pruritus, insomnia, dizziness, asthenia, and somnolence.

    The following adverse reactions occurred in less than 3% of patients involved in clinical trials with oxycodone:

    Body as a Whole: abdominal pain, accidental injury, allergic reaction, back pain, chills and fever, fever, flu syndrome, infection, neck pain, pain, photosensitivity reaction, and sepsis.

    Cardiovascular: deep vein thrombophlebitis, heart failure, hemorrhage, hypotension, migraine, palpitation, and tachycardia.

    Digestive: anorexia, diarrhea, dyspepsia, dysphagia, gingivitis, glossitis, and nausea and vomiting.

    Hematopoietic and Lymphatic: anemia and leukopenia.

    Metabolism and Nutrition: edema, gout, hyperglycemia, iron deficiency anemia, and peripheral edema.

    Musculoskeletal: arthralgia, arthritis, bone pain, myalgia, and pathological fracture.

    Nervous System: agitation, anxiety, confusion, dry mouth, hypertonia, hypesthesia, nervousness, neuralgia, personality disorder, tremor, and vasodilation.

    Respiratory: bronchitis, cough increased, dyspnea, epistaxis, laryngismus, lung disorder, pharyngitis, rhinitis, and sinusitis.

    Skin and Appendages: herpes simplex, rash, sweating, and urticaria.

    Special Senses: amblyopia.

    Urogenital: urinary tract infection.

    6.2 Postmarketing Experience

    The following adverse reactions have been identified during post approval use of oxycodone. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These events include:

    Serotonin syndrome: Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of opioids with serotonergic drugs.

    Adrenal insufficiency: Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use.

    Anaphylaxis: Anaphylaxis has been reported with ingredients contained in OXAYDO.

    Androgen deficiency: Cases of androgen deficiency have occurred with chronic use of opioids [see Clinical Pharmacology (12.2)].

  • 7 DRUG INTERACTIONS

    Table 1 includes clinically significant drug interactions with OXAYDO.

    Table 1: Clinically Significant Drug Interactions with OXAYDO
    Inhibitors of CYP3A4 and CYP2D6
    Clinical Impact:

    The concomitant use of OXAYDO 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 OXAYDO and CYP2D6 and CYP3A4 inhibitors, particularly when an inhibitor is added after a stable dose of OXAYDO is achieved [see Warnings and Precautions (5.5)].

    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 OXAYDO until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals.

    If a CYP3A4 inhibitor is discontinued, consider increasing the OXAYDO dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal.
    ExamplesMacrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), protease inhibitors (e.g., ritonavir)
    CYP3A4 Inducers
    Clinical Impact:

    The concomitant use of OXAYDO 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 (5.5)].

    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 OXAYDO dosage until stable drug effects are achieved [see Dosage and Administration (2.3)]. Monitor for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider OXAYDO dosage reduction and monitor for signs of respiratory depression.
    ExamplesRifampin, 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, increases the risk of respiratory depression, profound sedation, coma, and death.
    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. Follow patients closely for signs of respiratory depression and sedation [see Warnings and Precautions (5.6)].
    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.
    Intervention:If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue OXAYDO 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), 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 (5.3)].
    Intervention:

    The use of OXAYDO 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 and Partial Agonist Opioid Analgesics
    Clinical Impact:May reduce the analgesic effect of OXAYDO and/or 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:Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of OXAYDO and/or the muscle relaxant as necessary.
    Diuretics
    Clinical Impact:Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
    Intervention:Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.
    Anticholinergic Drugs
    Clinical Impact:The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
    Intervention:Monitor patients for signs of urinary retention or reduced gastric motility when OXAYDO is used concomitantly with anticholinergic drugs.
  • 8 USE IN SPECIFIC POPULATIONS

    8.1 Pregnancy

    Risk Summary

    Prolonged use of opioid analgesics during pregnancy may cause neonatal opioid withdrawal syndrome [see Warnings and Precautions (5.4)]. There are no available data with OXAYDO in pregnant women to inform a drug-associated risk for major birth defects and miscarriage.

    In animal reproduction studies with oral administrations of oxycodone HCl in rats and rabbits during the period of organogenesis at doses 2.6 and 8.1 times, respectively, the human dose of 60 mg/day did not reveal evidence of teratogenicity or embryo-fetal toxicity. In several published studies, treatment of pregnant rats with oxycodone at clinically relevant doses and below resulted in neurobehavioral effects in offspring [see Data]. Based on animal data, advise pregnant women of the potential risk to a fetus.

    The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

    Clinical Considerations

    •   Fetal/Neonatal Adverse Reactions
    •   Prolonged use of opioid analgesics during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth.
    •   Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea, and failure to gain weight. The onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination of the drug by the newborn. Observe newborns for symptoms of neonatal opioid withdrawal syndrome and manage accordingly [see Warnings and Precautions (5.4)].
    •   Labor or Delivery
    •   Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. An opioid antagonist, such as naloxone, must be available for reversal of opioid-induced respiratory depression in the neonate. OXAYDO is not recommended for use in pregnant women during or immediately prior to labor, when other analgesic techniques are more appropriate. Opioid analgesics, including OXAYDO, can prolong labor through actions which temporarily reduce the strength, duration, and frequency of uterine contractions. However, this effect is not consistent and may be offset by an increased rate of cervical dilation, which tends to shorten labor. Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression.

    Data

    •   Animal Data
    •   In embryo-fetal development studies in rats and rabbits, pregnant animals received oral doses of oxycodone HCl administered during the period of organogenesis up to 16 mg/kg/day and up 25 mg/kg/day, respectively. These studies revealed no evidence of teratogenicity or embryo-fetal toxicity due to oxycodone. The highest doses tested in rats and rabbits were equivalent to approximately 2.6 and 8.1 times an adult human dose of 60 mg/day, respectively, on a mg/m2 basis. In published studies, offspring of pregnant rats administered oxycodone during gestation have been reported to exhibit neurobehavioral effects including altered stress responses, increased anxiety-like behavior (2 mg/kg/day IV from Gestation Day 8 to 21 and Postnatal Day 1, 3, and 5; 0.3-times an adult human dose of 60 mg/day, on a mg/m2 basis) and altered learning and memory (15 mg/kg/day orally from breeding through parturition; 2.4 times an adult human dose of 60 mg/day, on a mg/m2 basis).

    8.2 Lactation

    Risk Summary

    Oxycodone is present in breast milk. Published lactation studies report variable concentrations of oxycodone in breast milk with administration of immediate-release oxycodone to nursing mothers in the early postpartum period. The lactation studies did not assess breastfed infants for potential adverse reactions. Lactation studies have not been conducted with OXAYDO, and no information is available on the effects of the drug on the breastfed infant or the effects of the drug on milk production. Because of the potential for serious adverse reactions, including excess sedation and respiratory depression in a breastfed infant, advise patients that breastfeeding is not recommended during treatment with OXAYDO.

    Clinical Considerations

    Monitor infants exposed to OXAYDO through breast milk for excess sedation and respiratory depression. Withdrawal symptoms can occur in breastfed infants when maternal administration of an opioid analgesic is stopped or when breastfeeding is stopped.

    8.3 Females and Males of Reproductive Potential

    Infertility

    Chronic use of opioids may cause reduced fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible [see Adverse Reactions (6.2)].

    8.4 Pediatric Use

    The safety, effectiveness, and pharmacokinetics of OXAYDO in pediatric patients below the age of 18 have not been established.

    8.5 Geriatric Use

    Elderly patients (aged 65 years or older) may have increased sensitivity to oxycodone. In general, use caution when selecting a dosage for an elderly patient, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy.

    Respiratory depression is the chief risk for elderly patients treated with opioids, and has occurred after large initial doses were administered to patients who were not opioid-tolerant or when opioids were co-administered with other agents that depress respiration. Titrate the dosage of OXAYDO slowly in geriatric patients and monitor closely for signs of central nervous system and respiratory depression [see Warnings and Precautions (5.7)].

    Oxycodone is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

    8.6 Hepatic Impairment

    Since oxycodone is extensively metabolized in the liver, its clearance may decrease in patients with hepatic impairment. Follow a conservative approach to initiate dosing in patients with hepatic impairment. Monitor patients closely and adjust the dose based on clinical response [see Dosage and Administration (2.2)].

    8.7 Renal Impairment

    Information from oxycodone HCl indicates that patients with renal impairment had higher plasma concentrations of oxycodone than subjects with normal renal function. Use a conservative approach to initiate dosing in patients with renal impairment. Monitor patients closely and adjust the dose based on clinical response [see Dosage and Administration (2.2)].

  • 9 DRUG ABUSE AND DEPENDENCE

    9.1 Controlled Substance

    OXAYDO contains oxycodone, a Schedule II controlled substance.

    9.2 Abuse

    OXAYDO contains oxycodone, a substance with a high potential for abuse similar to other opioids including fentanyl, hydrocodone, hydromorphone, methadone, morphine, oxymorphone, and tapentadol. OXAYDO can be abused and is subject to misuse, addiction, and criminal diversion [see Warnings and Precautions (5.1)].

    All patients treated with opioids require careful monitoring for signs of abuse and addiction, because use of opioid analgesic products carries the risk of addiction even under appropriate medical use.

    Prescription drug abuse is the intentional non-therapeutic use of a prescription drug, even once, for its rewarding psychological or physiological effects.

    Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that develop after repeated substance use and includes: a strong desire to take the drug, difficulties in controlling its use, persisting in its use despite harmful consequences, a higher priority given to drug use than to other activities and obligations, increased tolerance, and sometimes a physical withdrawal.

    “Drug-seeking” behavior is very common in persons with substance abuse disorders. Drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing or referral, repeated “loss” of prescriptions, tampering with prescriptions, and reluctance to provide prior medical records or contact information for other treating healthcare provider(s). “Doctor shopping” (visiting multiple prescribers to obtain additional prescriptions) is common among drug abusers and people suffering from untreated addiction. Preoccupation with achieving adequate pain relief can be appropriate behavior in a patient with poor pain control.

    Abuse and addiction are separate and distinct from physical dependence and tolerance. Healthcare providers should be aware that addiction may not be accompanied by concurrent tolerance and symptoms of physical dependence in all addicts. In addition, abuse of opioids can occur in the absence of true addiction.

    OXAYDO, like other opioids, can be diverted for non-medical use into illicit channels of distribution. Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests, as required by state and federal law, is strongly advised.

    Proper assessment of the patient, proper prescribing practices, periodic re-evaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs.

    Risks Specific to Abuse of OXAYDO

    OXAYDO is intended for oral use only. Abuse of OXAYDO poses a risk of overdose and death. The risk of overdose and death is increased with concurrent abuse of alcohol or other central nervous system depressants. Parenteral drug abuse is commonly associated with transmission of infectious diseases such as hepatitis and HIV.

    In a double-blind, active-comparator, crossover study in 40 non-dependent recreational opioid users, “drug liking” responses and single-dose safety of crushed OXAYDO tablets were compared with crushed immediate-release oxycodone tablets when subjects self-administered the drug intranasally. The presence of sequence effects resulted in questionable reliability of the second period data. First period data demonstrated small numeric differences in the median and mean drug liking scores, lower in response to OXAYDO than immediate-release oxycodone. Thirty percent of subjects exposed to OXAYDO responded that they would not take the drug again compared to 5% of subjects exposed to immediate-release oxycodone. Study subjects self-administering OXAYDO reported a higher incidence of nasopharyngeal and facial adverse events and a decreased ability to completely insufflate two crushed tablets within a fixed time period (21 of 40 subjects). The clinical significance of the difference in drug liking and difference in response to taking the drug again reported in this study has not yet been established. There is no evidence that OXAYDO has a reduced abuse liability compared to immediate-release oxycodone.

    9.3 Dependence

    Both tolerance and physical dependence can develop during chronic opioid therapy. 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). Tolerance may occur to both the desired and undesired effects of drugs, and may develop at different rates for different effects.

    Physical dependence results in withdrawal symptoms after abrupt discontinuation or a significant dosage reduction of a drug. Withdrawal also may be precipitated through the administration of drugs with opioid antagonist activity (e.g., naloxone, nalmefene), mixed agonist/antagonist analgesics (e.g., pentazocine, butorphanol, nalbuphine), or partial agonists (e.g., buprenorphine). Physical dependence may not occur to a clinically significant degree until after several days to weeks of continued opioid usage.

    OXAYDO should not be abruptly discontinued in a physically-dependent patient [see Dosage and Administration (2.4)]. If OXAYDO is abruptly discontinued in a physically-dependent patient, a withdrawal syndrome may occur. Some or all of the following can characterize this syndrome: 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.

    Infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal signs [see Use in Specific Populations (8.1)].

  • 10 OVERDOSAGE

    Clinical Presentation

    Acute overdose with OXAYDO 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, 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)].

    Treatment of Overdose

    In case of overdose, priorities are the reestablishment 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 may require advanced life-support techniques.

    The opioid antagonists, naloxone or nalmefene, are specific antidotes to respiratory depression resulting from opioid overdose. For clinically significant respiratory or circulatory depression secondary to oxycodone overdose, administer an opioid antagonist. Opioid antagonists should not be administered in the absence of clinically significant respiratory or circulatory depression secondary to oxycodone overdose.

    Because the duration of opioid reversal is expected to be less than the duration of action of oxycodone in OXAYDO, carefully monitor the patient until spontaneous respiration is reliably reestablished. If the response to an opioid antagonist is suboptimal or only brief in nature, administer additional antagonist as directed by the product’s prescribing information.

    In an individual physically dependent on opioids, administration of the recommended usual dosage of the antagonist 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 antagonist administered. If a decision is made to treat serious respiratory depression in the physically dependent patient, administration of the antagonist should be initiated with care and by titration with smaller than usual doses of the antagonist.

  • 11 DESCRIPTION

    OXAYDO (oxycodone HCl) 5 mg and 7.5 mg tablets are an immediate-release opioid agonist intended for oral administration only.

    Chemically, oxycodone HCl is 4,5α-epoxy-14-hydroxy-3-methoxy-17-methylmorphinan-6-one HCl, a white, odorless crystalline powder. Oxycodone HCl is soluble in water (1 g in 6 to 7 mL). The molecular weight of oxycodone HCl is 351.82. The molecular formula for oxycodone HCl is C18H21NO4HCl, and the structure is:

    Oxado Chemical structure

    The inactive ingredients in OXAYDO include: colloidal silicon dioxide NF; crospovidone NF; magnesium stearate NF; microcrystalline cellulose NF; polyethylene oxide NF; and sodium lauryl sulfate NF.

    The tablets are round, convex, white and debossed with the strength (5 or 7.5) on one side and the letter “O” on the other side.

  • 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 the Central Nervous System

    Oxycodone produces respiratory depression by direct action on brainstem 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 the 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, and transient elevations in serum amylase.

    Effects on the Cardiovascular System

    Oxycodone produces peripheral vasodilation which may result in orthostatic hypotension or syncope. Manifestations of histamine release and/or peripheral vasodilation may include pruritus, flushing, red eyes and 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.

    Chronic use of opioids 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 potent agonist opioids. 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)].

    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, 2.2, 2.3)].

    12.3 Pharmacokinetics

    The analgesic activity of OXAYDO is primarily due to the parent drug oxycodone.

    The pharmacokinetics of oxycodone after OXAYDO administration are characterized by peak plasma concentrations occurring on average within 1.2 to 1.4 hours of the first dose under fasted conditions. Thereafter, oxycodone concentrations fall with an average terminal half-life ranging between 3-4 hours. OXAYDO is bioequivalent with oxycodone immediate-release tablets in the fasted state, with no differences identified in the time to peak exposure (Tmax) and terminal elimination half-life (T½) of oxycodone between administration of OXAYDO and oxycodone immediate-release tablets. Dose proportionality was established for OXAYDO at doses of 5 mg, 10 mg, and 15 mg (oxycodone HCl) based on proportional increases in oxycodone Cmax and AUC exposure levels.

    Absorption

    The oral bioavailability of oxycodone is 60% to 87%. The high oral bioavailability of oxycodone (compared to other oral opioids) is due to lower pre-systemic and/or first-pass metabolism of oxycodone compared to other oral opioids.

    Food Effect

    When administered with a high fat meal, mean AUC values are increased by 21% and peak concentrations are decreased by 14%. Food causes a delay in Tmax from 1.25 to 3.00 hours. These changes in oxycodone pharmacokinetics are not considered clinically relevant; therefore, OXAYDO can be taken without regard to food.

    Distribution

    Following intravenous administration, the volume of distribution for oxycodone was 2.6 L/kg. Plasma protein binding of oxycodone at 37°C and a pH of 7.4 was approximately 45%. Oxycodone has been found in breast milk [see Use in Specific Populations (8.2)].

    Elimination

    The total plasma clearance of oxycodone is 0.8 L/min for adults. Apparent elimination half-life of oxycodone following the administration of oxycodone was 3.5 to 4 hours.

    Metabolism

    Oxycodone HCl is extensively metabolized by multiple metabolic pathways to noroxycodone, oxymorphone, and noroxymorphone, which are subsequently glucuronidated. CYP3A4 mediated N-demethylation to noroxycodone is the primary metabolic pathway of oxycodone with less contribution from CYP2D6 mediated O-demethylation to oxymorphone. Therefore, the formation of these and related metabolites can, in theory, be affected by other drugs. The major circulating metabolite is noroxycodone with an AUC ratio of 0.6 relative to that of oxycodone. Noroxycodone is reported to be a considerably weaker analgesic than oxycodone. Oxymorphone, although possessing analgesic activity, is present in the plasma only in low concentrations. The correlation between oxymorphone concentrations and opioid effects was much less than that seen with oxycodone plasma concentrations. The analgesic activity profile of other metabolites is not known.

    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 oxycodone up to 50%; free oxymorphone 0%; and conjugated oxymorphone ≤14%. Both free and conjugated noroxycodone have been found in urine but not quantified.

    Specific Populations

    Age: Geriatric Population

    Information obtained for oxycodone indicates that the plasma concentrations of oxycodone did not appear to be increased in patients over the age of 65.

    Sex

    Information obtained for oxycodone support the lack of sex effect on the pharmacokinetics of oxycodone.

    Renal Impairment

    Information obtained for oxycodone indicates that patients with renal impairment had higher plasma concentrations of oxycodone than subjects with normal renal function [see Use in Specific Populations (8.7)].

    Hepatic Impairment

    Since oxycodone is extensively metabolized in the liver, its clearance may decrease in patients with hepatic impairment [see Use in Specific Populations (8.6)].

    Drug Interaction Studies

    CYP3A4 Inhibitors

    CYP3A4 is the major enzyme involved in noroxycodone formation. A published study showed that the coadministration of voriconazole, a CYP3A4 inhibitor, increased oxycodone AUC and Cmax by 3.6 and 1.7 fold, respectively [see Warnings and Precautions (5.5) and Drug Interactions (7)].

    CYP3A4 Inducers

    A published study showed that the co-administration of rifampin, a drug metabolizing enzyme inducer, decreased oxycodone AUC and Cmax values by 86% and 63%, respectively [see Warnings and Precautions (5.5) and Drug Interactions (7)].

    CYP2D6 Inhibitors

    Oxycodone is metabolized in part to oxymorphone via the cytochrome p450 isoenzyme CYP2D6. While this pathway may be blocked by a variety of drugs (e.g., certain cardiovascular drugs and antidepressants), such blockade has not yet been shown to be of clinical significance with OXAYDO.

  • 13 NONCLINICAL TOXICOLOGY

    13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

    Carcinogenesis

    Long-term studies in animals to evaluate its carcinogenic potential of oxycodone have not been conducted.

    Mutagenesis

    Oxycodone was genotoxic in an in vitro mouse lymphoma assay in the presence of metabolic activation. There was no evidence of genotoxic potential in an in vitro bacterial reverse mutation assay (Salmonella typhimurium and Escherichia coli) and in an assay for chromosomal aberrations (in vivo mouse bone marrow micronucleus assay).

    Impairment of Fertility

    Studies in animals to evaluate the potential impact of oxycodone on fertility have not been conducted.

  • 16 HOW SUPPLIED/STORAGE AND HANDLING

    OXAYDO (oxycodone HCl) 5 mg tablets are round, convex, white tablets debossed with the strength “5” on one side and the letter “O” on the other side and supplied as:

    NDC 69344-113-11 Bottles of 100 tablets

    OXAYDO 7.5 mg tablets are round, convex, white tablets debossed with the strength “7.5” on one side and the letter “O” on the other side and supplied as:

    NDC 69344-213-11 Bottles of 100 tablets

    Dispense in tight container as defined in the USP, with a child-resistant closure.

    Store at 25°C (77°F); with excursions permitted to 15°-30°C (59°-86°F) [See USP Controlled Room Temperature].

    Protect from moisture.

  • 17 PATIENT COUNSELING INFORMATION

    Advise the patient to read the FDA-approved patient labeling

    (Medication Guide).

    Storage and Disposal:

    Because of the risks associated with accidental ingestion, misuse, and abuse, advise patients to store OXAYDO securely, out of sight and reach of children, and in a location not accessible by others, including visitors to the home [ see Warnings and Precautions (5.1), Drug Abuse and Dependence (9.2) ]. Inform patients that leaving OXAYDO unsecured can pose a deadly risk to others in the home.

    Advise patients and caregivers that when medicines are no longer needed, they should be disposed of promptly. Expired, unwanted, or unused OXAYDO should be disposed of by flushing the unused medication down the toilet if a drug take-back option is not readily available. Inform patients that they can visit www.fda.gov/drugdisposal for a complete list of medicines recommended for disposal by flushing, as well as additional information on disposal of unused medicines.

    Addiction, Abuse, and Misuse

    Inform patients that the use of OXAYDO, even when taken as recommended, can result in addiction, abuse, and misuse, which can lead to overdose and death [see Warnings and Precautions (5.1)]. Instruct patients not to share OXAYDO with others and to take steps to protect OXAYDO from theft or misuse.

    Life-Threatening Respiratory Depression

    Inform patients of the risk of life-threatening respiratory depression, including information that the risk is greatest when starting OXAYDO or when the dosage is increased, and that it can occur even at recommended dosages [see Warnings and Precautions (5.3)]. Advise patients how to recognize respiratory depression and to seek medical attention if breathing difficulties develop.

    Accidental Ingestion

    Inform patients that accidental ingestion, especially by children, may result in respiratory depression or death [see Warnings and Precautions (5.3)].

    Interactions with Benzodiazepines and Other CNS Depressants

    Inform patients and caregivers that potentially fatal additive effects may occur if OXAYDO is used with benzodiazepines or other CNS depressants, including alcohol, and not to use these concomitantly unless supervised by a health care provider [see Warnings and Precautions (5.6), Drug Interactions (7)].

    Serotonin Syndrome

    Inform patients that opioids could cause a rare but potentially life-threatening condition resulting from concomitant administration of serotonergic drugs. Warn patients of the symptoms of serotonin syndrome and to seek medical attention right away if symptoms develop. Instruct patients to inform their healthcare providers if they are taking, or plan to take serotonergic medications. [see Drug Interactions (7)].

    MAOI Interaction

    Inform patients to avoid taking OXAYDO while using any drugs that inhibit monoamine oxidase. Patients should not start MAOIs while taking OXAYDO [see Drug Interactions (7)].

    Adrenal Insufficiency

    Inform patients that opioids could cause adrenal insufficiency, a potentially life-threatening condition. Adrenal insufficiency may present with non-specific symptoms and signs such as nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. Advise patients to seek medical attention if they experience a constellation of these symptoms [see Warnings and Precautions (5.8)].

    Important Administration Instructions

    Instruct patients how to properly take OXAYDO [see Dosage and Administration (2), Warnings and Precautions (5)]. Advise patients:

    • that OXAYDO is a narcotic pain reliever and must be taken only as directed.
    • not to pre-soak, lick or otherwise wet the tablet prior to placing in the mouth.
    • to take each tablet with enough water to ensure complete swallowing immediately after placing in the mouth.
    • that OXAYDO tablets must be swallowed whole and not crushed or dissolved.
    • that OXAYDO is not for administration via nasogastric, gastric or other feeding tubes as it may cause obstruction of feeding tubes.
    • that if they miss a dose to take it as soon as possible. If it is almost time for the next dose, advise to skip the missed dose and take the next dose at the regularly scheduled time. Advise patients not to take 2 doses at once unless instructed by their healthcare provider. If they are not sure about their dosing, call their healthcare provider.
    • not to adjust the dose of OXAYDO without consulting with a physician or other healthcare professional.

    Important Discontinuation Instructions

    In order to avoid developing withdrawal symptoms, instruct patients not to discontinue OXAYDO without first discussing a tapering plan with the prescriber [see Dosage and Administration (2.4)]

    Hypotension

    Inform patients that OXAYDO may cause orthostatic hypotension and syncope. Instruct patients how to recognize symptoms of low blood pressure and how to reduce the risk of serious consequences should hypotension occur (e.g., sit or lie down, carefully rise from a sitting or lying position) [see Warnings and Precautions (5.9)].

    Anaphylaxis

    Inform patients that anaphylaxis has been reported with ingredients contained in OXAYDO. Advise patients how to recognize such a reaction and when to seek medical attention [see Contraindications (4), Adverse Reactions (6)].

    Pregnancy

    •   Neonatal Opioid Withdrawal Syndrome
      •   Inform female patients of reproductive potential that prolonged use of OXAYDO during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated [see Warnings and Precautions (5.4), Use in Specific Populations (8.1)].
    •   Embryo-Fetal Toxicity
      •   Inform female patients of reproductive potential that OXAYDO can cause fetal harm and to inform the healthcare provider of a known or suspected pregnancy [see Use in Specific Populations (8.1)].

    Lactation

    Advise nursing mothers to monitor infants for increased sleepiness (more than usual), breathing difficulties, or limpness. Instruct nursing mothers to seek immediate medical care if they notice these signs [see Use in Specific Populations (8.2)].

    Infertility

    Inform patients that chronic use of opioids may cause reduced fertility. It is not known whether these effects on fertility are reversible [see Use in Specific Populations (8.3)].

    Driving or Operating Heavy Machinery

    Inform patients that OXAYDO may impair the ability to perform potentially hazardous activities such as driving a car or operating heavy machinery. Advise patients not to perform such tasks until they know how they will react to the medication [see Warnings and Precautions (5.14)].

    Constipation

    Advise patients of the potential for severe constipation, including management instructions and when to seek medical attention [see Adverse Reactions (6), Clinical Pharmacology (12.2)].


    Distributed by:

    Zyla Life Sciences US Inc.
    Wayne, PA 19087

    © 2019 Zyla Life Sciences. All rights reserved.

    LBL #: 201.05
    10/2019



  • MEDICATION GUIDE

    This Medication Guide has been approved by the U.S. Food and Drug Administration.

    Issued: 10/2019

    Medication Guide

    OXAYDO (ox Ā doe)
    (oxycodone HCl, USP) Tablets for oral use only, CII

    OXAYDO is:

    • A strong prescription pain medicine that contains an opioid (narcotic) that is used to manage short term (acute) and long term (chronic) pain severe enough to require an opioid pain medicine, when other pain treatments such as non-opioid pain medicines do not treat your pain well enough or you cannot tolerate them.
    • An opioid pain medicine that can put you at risk for overdose and death. Even if you take your dose correctly as prescribed you are at risk for opioid addiction, abuse, and misuse that can lead to death.

    Important information about OXAYDO:

    • Get emergency help right away if you take too much OXAYDO (overdose). When you first start taking OXAYDO, when your dose is changed, or if you take too much (overdose), serious or life-threatening breathing problems that can lead to death may occur.
    • Taking OXAYDO with other opioid medicines, benzodiazepines, alcohol, or other central nervous system depressants (including street drugs) can cause severe drowsiness, decreased awareness, breathing problems, coma, and death.
    • Never give anyone else your OXAYDO. They could die from taking it. Store OXAYDO away from children and in a safe place to prevent stealing or abuse. Selling or giving away OXAYDO is against the law.

    Do not take OXAYDO if you have:

    • severe asthma, trouble breathing, or other lung problems.
    • a bowel blockage or have narrowing of the stomach or intestines.

    Before taking OXAYDO, tell your healthcare provider if you have a history of:

    • head injury, seizures
    • problems urinating
    • abuse of street or prescription drugs, alcohol addiction, or mental health problems.
    • liver, kidney, thyroid problems
    • pancreas or gallbladder problems

    Tell your healthcare provider if you are:

    • pregnant or planning to become pregnant. Prolonged use of OXAYDO during pregnancy can cause withdrawal symptoms in your newborn baby that could be life-threatening if not recognized and treated.
    • breastfeeding. Not recommended during treatment with OXAYDO. It may harm your baby.
    • taking prescription or over-the-counter medicines, vitamins, or herbal supplements. Taking OXAYDO with certain other medicines can cause serious side effects that could lead to death.

    When taking OXAYDO:

    • Do not change your dose. Take OXAYDO exactly as prescribed by your healthcare provider. Use the lowest dose possible for the shortest time needed.
    • Take your prescribed dose exactly as instructed by your healthcare provider. Your healthcare provider may adjust the dose until it is right for you. Do not take more than your prescribed dose. If you miss a dose, take your next dose at your usual time.
    • Call your healthcare provider if the dose you are taking does not control your pain.
    • If you have been taking OXAYDO regularly, do not stop taking OXAYDO without talking to your healthcare provider.
    • After you stop taking OXAYDO, destroy the unused tablets by flushing them down the toilet.

    While taking OXAYDO DO NOT:

    • Drive or operate heavy machinery, until you know how OXAYDO affects you. OXAYDO can make you sleepy, dizzy, or lightheaded.
    • Drink alcohol or use prescription or over-the-counter medicines that contain alcohol. Using products containing alcohol during treatment with OXAYDO may cause you to overdose and die.

    The possible side effects of OXAYDO:

    • constipation, nausea, sleepiness, vomiting, tiredness, headache, dizziness, abdominal pain. Call your healthcare provider if you have any of these symptoms and they are severe.

    Get emergency medical help if you have:

    • trouble breathing, shortness of breath, fast heartbeat, chest pain, swelling of your face, tongue, or throat, extreme drowsiness, light-headedness when changing positions, feeling faint, agitation, high body temperature, trouble walking, stiff muscles, or mental changes such as confusion.

    These are not all the possible side effects of OXAYDO. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. For more information go to fda.report


    Distributed by: Zyla Life Sciences US Inc., Wayne, PA, 19087; for more information go to www.oxaydo.com or call 1-800-518-1084

  • PRINCIPAL DISPLAY PANEL - NDC: 69344-113-11 - 5 mg 100-count Bottle Label

    5 mg 100-count Bottle Label

  • PRINCIPAL DISPLAY PANEL - NDC: 69344-213-11 - 7.5 mg 100-count Bottle Label

    7.5 mg 100-count Bottle Label

  • INGREDIENTS AND APPEARANCE
    OXAYDO 
    oxycodone hydrochloride tablet
    Product Information
    Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC: 69344-113
    Route of AdministrationORALDEA ScheduleCII    
    Active Ingredient/Active Moiety
    Ingredient NameBasis of StrengthStrength
    OXYCODONE HYDROCHLORIDE (UNII: C1ENJ2TE6C) (OXYCODONE - UNII:CD35PMG570) OXYCODONE HYDROCHLORIDE5 mg
    Product Characteristics
    ColorWHITEScoreno score
    ShapeROUND (convex) Size11mm
    FlavorImprint Code 5;O
    Contains    
    Packaging
    #Item CodePackage DescriptionMarketing Start DateMarketing End Date
    1NDC: 69344-113-11100 in 1 BOTTLE; Type 0: Not a Combination Product09/01/2015
    Marketing Information
    Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
    NDANDA20208009/01/2015
    OXAYDO 
    oxycodone hydrochloride tablet
    Product Information
    Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC: 69344-213
    Route of AdministrationORALDEA ScheduleCII    
    Active Ingredient/Active Moiety
    Ingredient NameBasis of StrengthStrength
    OXYCODONE HYDROCHLORIDE (UNII: C1ENJ2TE6C) (OXYCODONE - UNII:CD35PMG570) OXYCODONE HYDROCHLORIDE7.5 mg
    Product Characteristics
    ColorWHITEScoreno score
    ShapeROUND (convex) Size11mm
    FlavorImprint Code 7;5;O
    Contains    
    Packaging
    #Item CodePackage DescriptionMarketing Start DateMarketing End Date
    1NDC: 69344-213-11100 in 1 BOTTLE; Type 0: Not a Combination Product09/01/2015
    Marketing Information
    Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
    NDANDA20208009/01/2015
    Labeler - Zyla Life Sciences US Inc. (079581441)

    • Trademark Results [OXAYDO]

    Mark Image

    Registration | Serial
    Company
    Trademark
    Application Date
    OXAYDO
    OXAYDO
    86466673 4847742 Live/Registered
    Acura Pharmaceuticals, Inc.
    2014-11-27
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