Oxycodone Hydrochloride

1 INDICATIONS AND USAGE Oxycodone hydrochloride tablets are indicated for the management of pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate. Limitations of Use Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses [see Warnings and Precautions (5.1)] , reserve oxycodone hydrochloride tablets for use in patients for whom alternative treatment options (e.g., non-opioid analgesics or opioid combination products): • Have not been tolerated or are not expected to be tolerated, • Have not provided adequate analgesia or are not expected to provide adequate analgesia. Oxycodone hydrochloride is an opioid agonist indicated for the management of pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate. (1) Limitations of Use (1) Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses, reserve oxycodone hydrochloride for use in patients for whom alternative treatment options (e.g., non-opioid analgesics or non-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 Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals. (2.1) Individualize dosing based on severity of pain, patient response, prior analgesic experience, and risk factors for addiction, abuse and misuse. (2.1) 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 hydrochloride. Consider prescribing naloxone based on the patient’s risk factors for overdose. (2.2, 5.1, 5.3, 5.6) Initiate dosing with a range of 5 to 15 mg every 4 to 6 hours as needed for pain. (2.3) For control of chronic pain, administer oxycodone hydrochloride on a regularly scheduled basis, at the lowest dosage level to achieve adequate analgesia. (2.3) Individually titrate oxycodone hydrochloride to a dose that provides adequate analgesia and minimizes adverse reactions. (2.4) Do not abruptly discontinue oxycodone hydrochloride 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 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 to 72 hours of initiating therapy and following dosage increases with oxycodone hydrochloride and adjust the dosage accordingly [see Warnings and Precautions (5.3)] . 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 hydrochloride tablets [see Warnings and Precautions (5.3), Patient Counseling Information (17)]. 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, 5.3, 5.6)]. 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 hydrochloride, 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 Oxycodone Hydrochloride as the First Opioid Analgesic Initiate treatment with oxycodone hydrochloride in a dosing range of 5 to 15 mg every 4 to 6 hours as needed for pain. Titrate the dos…

5 WARNINGS AND PRECAUTIONS Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients : Monitor closely, particularly during initiation and titration. (5.7) Adrenal Insufficiency: If diagnosed, treat with physiologic replacement of corticosteroids, and wean patient off of the opioid. (5.8) Severe Hypotension: Monitor during dosage initiation and titration. Avoid use of oxycodone hydrochloride in patients with circulatory shock. (5.9) Risks of Use in Patients with Increased Intracranial Pressure, BrainTumors, Head Injury, or Impaired Consciousness: Monitor for sedation and respiratory depression. Avoid use of oxycodone hydrochloride in patients with impaired consciousness or coma. (5.10) 5.1 Addiction, Abuse, and Misuse Oxycodone hydrochloride contains oxycodone, a Schedule II controlled substance. As an opioid, oxycodone hydrochloride exposes users to the risks of addiction, abuse, and misuse [see Drug Abuse and Dependence (9)] . Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed oxycodone hydrochloride. Addiction can occur at recommended dosages and if the drug is misused or abused. Assess each patient’s risk for opioid addiction, abuse, or misuse prior to prescribing oxycodone hydrochloride, and monitor all patients receiving oxycodone hydrochloride for the development of these behaviors and conditions. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). The potential for these risks should not, however, prevent the proper management of pain in any given patient. Patients at increased risk may be prescribed opioids such as oxycodone hydrochloride, but use in such patients necessitates intensive counseling about the risks and proper use of oxycodone hydrochloride along with intensive monitoring for signs of addiction, abuse, and misuse. Consider prescribing naloxone for the emergency treatment of opioid overdose [see Dosage and Administration (2.2), Warnings and Precautions (5.3)]. Opioids are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Consider these risks when prescribing or dispensing oxycodone hydrochloride. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on the proper disposal of unused drugs [see Patient Counseling Information (17)] . Contact local state professional licensing board or state controlled substances authority for information on how to prevent and detect abuse or diversion of this product. 5.2 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 di…

4 CONTRAINDICATIONS Oxycodone hydrochloride is contraindicated in patients with: • Significant respiratory depression [see Warnings and Precautions (5.3)]. • Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment or hypercarbia [see Warnings and Precautions (5.7)]. • Known or suspected gastrointestinal obstruction, including paralytic ileus [see Warnings and Precautions (5.11)] . • Known hypersensitivity (e.g., anaphylaxis) to oxycodone [see Adverse Reactions (6.2)]. Significant respiratory depression (4) Acute or severe bronchial asthma in an unmonitored setting or in absence of resuscitative equipment (4) Known or suspected gastrointestinal obstruction, including paralytic ileus (4) Hypersensitivity to oxycodone (4)

7 DRUG INTERACTIONS Table 1 includes clinically significant drug interactions with oxycodone hydrochloride. Table 1: Clinically Significant Drug Interactions with Oxycodone Hydrochloride Inhibitors of CYP3A4 and CYP2D6 Clinical Impact: The concomitant use of oxycodone hydrochloride 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 hydrochloride and CYP2D6 and CYP3A4 inhibitors, particularly when an inhibitor is added after a stable dose of oxycodone hydrochloride 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 oxycodone hydrochloride 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 oxycodone hydrochloride dosage until stable drug effects are achieved. Monitor 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 hydrochloride 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 (5.13)] . 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 hydrochloride dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider oxycodone hydrochloride dosage reduction and monitor for signs of respiratory depression. 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. 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)] . 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, 5.3, 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 [see Adverse Reactions (6.2)] . Intervention: If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue oxycodone hydrochloride if serotonin syndrome is suspected. Examples: Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricycl…

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