OXYCODONE HYDROCHLORIDE

Oxycodone hydrochloride tablets, USP contains oxycodone, an opioid agonist. Each tablet for oral administration contains 5 mg, 10 mg, 15 mg, 20 mg, or 30 mg, of oxycodone hydrochloride USP. Oxycodone hydrochloride is a white, odorless crystalline powder derived from the opium alkaloid, thebaine. Oxycodone hydrochloride dissolves in water (1 g in 6 to 7 mL) and is considered slightly soluble in alcohol (octanol water partition coefficient is 0.7). Chemically, oxycodone hydrochloride is 4, 5α-epoxy-14-hydroxy-3-methoxy-17-methylmorphinan-6-one hydrochloride and has the following structural formula: Oxycodone hydrochloride tablets, USP contains inactive ingredients: corn starch; lactose monohydrate; microcrystalline cellulose; silicon dioxide; sodium starch glycolate; and stearic acid. The 10 mg tablet also contains D&C Red No. 27 aluminum lake. The 15 mg tablet also contains D&C Yellow No. 10 aluminum lake and FD&C Blue No. 2 aluminum lake. The 20 mg tablet also contains FD&C Blue No. 2 aluminum lake; FD&C Red No. 40 aluminum lake; and FD&C Yellow No. 6 aluminum lake. The 30 mg tablet also contains FD&C Blue No. 2 aluminum lake. The 5 mg, 10 mg, 15 mg, 20 mg and 30 mg tablets contain the equivalent of 4.5 mg, 9 mg, 13.5 mg 18 mg and 27 mg, respectively, of oxycodone free base. Chemical Structure

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 tablets are 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 tablets 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.

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 ) Initiate dosing with a range of 5 to 15 mg every 4 to 6 hours as needed for pain. ( 2.2 ) For control of chronic pain, administer oxycodone hydrochloride tablets on a regularly scheduled basis, at the lowest dosage level to achieve adequate analgesia. ( 2.2 ) Individually titrate oxycodone hydrochloride tablets to a dose that provides adequate analgesia and minimizes adverse reactions. ( 2.3 ) Do not stop oxycodone hydrochloride tablets abruptly in a physically dependent patient. ( 2.4 ) 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 Tablets and adjust the dosage accordingly [see Warnings and Precautions ( 5.2 )]. 2.2 Initial Dosage Use of Oxycodone Hydrochloride Tablets as the First Opioid Analgesic Initiate treatment with Oxycodone Hydrochloride Tablets in a dosing range of 5 to 15 mg every 4 to 6 hours as needed for pain. Titrate the dose based upon the individual patient’s response to their initial dose of Oxycodone Hydrochloride Tablets. 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, Oxycodone Hydrochloride Tablets should be administered on a regularly scheduled basis, every 4 to 6 hours, at the lowest dosage level that will achieve adequate analgesia. Although it is not possible to list every condition that is important to the selection of the initial dose of Oxycodone Hydrochloride Tablets, attention should be given to: 1) the daily dose, potency, and characteristics of a pure 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 needed, 3) the degree of opioid tolerance, 4) the general condition and medical status of the patient, and 5) the balance between pain control and adverse experiences. Conversion from Other Opioids to Oxycodone Hydrochloride Tablets There is inter-patient variability in the potency of opioid drugs and opioid formulations. Therefore, a conservative approach is advised when determining the total daily dosage of Oxycodone Hydrochloride Tablets. It is safer to underestimate a patient’s 24-hour Oxycodone Hydrochloride Tablets dosage than to overestimate the 24-hour Oxycodone Hydrochloride Tablets dosage and manage an adverse reaction due to overdose. If a patient has been receiving opioid-containing medications prior to taking Oxycodone Hydrochloride Tablets, the potency of the prior opioid relative to oxycodone should be factored into the selection of the total daily dose (TDD) of oxycodone. In converting patients from other opioids to Oxycodone Hydrochloride Tablets close observation and adjustment of dosage based upon the patient’s response to Oxycodone Hydrochloride Tablets is imperative. Administration of supplemental analgesia for breakthrough or incident pain and titration of the total daily dose of Oxycodone Hydrochloride Tablets may be necessary, especially in patients who have disease states that are changing rapidly. Conversion From Fixed-Ratio Opioid/Acetaminophen, Opioid/Aspirin, or Opioid/Nonsteroidal Combination Drugs When converting patients from fixed ratio opioid/non-opioid drug regimens a decision should be made whether or not to continue the non-opioid analgesic. If a decision is made to discontinue the use of non-opioid analgesic, it may be necessary to titrate the dose of Oxycodone Hydrochloride Tablets in response to the level of analgesia and adverse effects afforded by the dosing regimen. If the non-opioid regimen is continued as a separate single entity agent, the starting dose Oxycodone Hydrochloride Tablets should be based upon the most recent dose of opioid as a baseline for further titration of oxycodone. Incremental increases should be gauged according to side effects to an acceptable level of analgesia. Conversion from Oxycodone Hydrochloride Tablets to Extended-Release Oxycodone: The relative bioavailability of Oxycodone Hydrochloride Tablets 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 Oxycodone Hydrochloride Tablets to a dose that provides adequate analgesia and minimizes adverse reactions. Continually reevaluate patients receiving Oxycodone Hydrochloride Tablets 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 Oxycodone Hydrochloride Tablets dosage. 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 Discontinuation of Oxycodone Hydrochloride Tablets When a patient who has been taking Oxycodone Hydrochloride Tablets regularly and may be physically dependent no longer requires therapy with Oxycodone Hydrochloride Tablets, taper the dose gradually, by 25% to 50% every 2 to 4 days, while monitoring carefully for signs and symptoms of withdrawal. If the patient develops these signs or symptoms, raise the dose to the previous level and taper more slowly, either by increasing the interval between decreases, decreasing the amount of change in dose, or both. Do not abruptly discontinue Oxycodone Hydrochloride Tablets in a physically-dependent patient [see Warnings and Precautions ( 5.1 ), Drug Abuse and Dependence ( 9.3 )] .

Oxycodone hydrochloride tablets are contraindicated in patients with: Significant respiratory depression [see Warnings and Precautions ( 5.2 )] Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment or hypercarbia [see Warnings and Precautions ( 5.6 )] Known or suspected gastrointestinal obstruction, including paralytic ileus [see Warnings and Precautions ( 5.10 )] 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 )

The following serious adverse reactions are described, or described in greater detail, in other sections: Addiction, Abuse, and Misuse [see Warnings and Precautions ( 5.1 )] Life-Threatening Respiratory Depression [see Warnings and Precautions ( 5.2 )] Neonatal Opioid Withdrawal Syndrome [see Warnings and Precautions ( 5.3 )] Interactions with Benzodiazepines or Other CNS Depressants [see Warnings and Precautions ( 5.5 )] Adrenal Insufficiency [see Warnings and Precautions ( 5.7 )] Severe Hypotension [see Warnings and Precautions ( 5.8 )] Gastrointestinal Adverse Reactions [see Warnings and Precautions ( 5.10 )] Seizures [see Warnings and Precautions ( 5.11 )] Withdrawal [see Warnings and Precautions ( 5.12 )] Most common adverse reactions (≥ 3%) were nausea, constipation, vomiting, headache, pruritus, insomnia, dizziness, asthenia, and somnolence. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact KVK-Tech, Inc. at 1-215-579-1842 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 tablets 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 tablets 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 tablets, the following adverse events were recorded in oxycodone hydrochloride tablets 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 tablets 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 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. General disorders and administrative site disorders: drug withdrawal syndrome neonatal [see Warnings and Precautions ( 5.3 )] Respiratory, thoracic and mediastinal disorders: pharyngeal edema Serotonin syndrome: Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of opioids with serotonergic drugs [see Drug Interactions ( 7 )]. Adrenal insufficiency: Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use [see Warnings and Precautions ( 5.7 )] . Anaphylaxis: Anaphylactic reaction has been reported with ingredients contained in ROXICODONE [see Contraindications ( 4 )]. Androgen deficiency: Cases of androgen deficiency have occurred with chronic use of opioids [see Clinical Pharmacology ( 12.2 )].

Table 1 includes clinically significant drug interactions with Oxycodone Hydrochloride Tablets. Table 1: Clinically Significant Drug Interactions with Oxycodone Hydrochloride Tablets Inhibitors of CYP3A4 and CYP2D6 Clinical Impact: The concomitant use of oxycodone hydrochloride tablets 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 tablets and CYP2D6 and CYP3A4 inhibitors, particularly when an inhibitor is added after a stable dose of oxycodone hydrochloride tablets is achieved [see Warnings and Precautions ( 5.4 )] . 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 tablets 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 tablets 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 tablets and CYP3A4inducers 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 ( 5.12 )] . 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 tablets dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider oxycodone hydrochloride tablets 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 increases 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 ( 5.5 )] . 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 Reaction ( 6.2 )]. Intervention: If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue oxycodone hydrochloride tablets 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 ( 5.2 )]. Intervention: The use of oxycodone hydrochloride tablets is not recommended for patients taking MAOIs or within 14 days of stopping such treatment. If urgent use of an opioid is necessary, use test doses and frequent titration of small doses to treat pain while closely monitoring blood pressure and signs and symptoms of CNS and respiratory depression. Examples: phenelzine, tranylcypromine, linezolid Mixed Agonist/Antagonist Opioid Analgesics Clinical Impact: May reduce the analgesic effect of oxycodone hydrochloride tablets and/or may precipitate withdrawal symptoms. Intervention: Avoid concomitant use Examples Butorphanol, nalbuphine, pentazocine, buprenorphine Muscle Relaxants Clinical Impact: Oxycodone may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression. Intervention: Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of oxycodone hydrochloride tablets 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 dismissed 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 result in increased 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 oxycodone hydrochloride tablets are used concurrently with anticholinergic drugs. Serotonergic Drugs: Concomitant use may result in serotonin syndrome. Discontinue oxycodone hydrochloride tablets if serotonin syndrome is suspected. ( 7 ) Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics: Avoid use with oxycodone hydrochloride tablets because they may reduce analgesic effect of oxycodone hydrochloride tablets or precipitate withdrawal symptoms. ( 7 ) Monoamine Oxidase Inhibitors (MAOIs): Can potentiate the effects of morphine. Avoid concomitant use in patients receiving MAOIs or within 14 days of stopping treatment with an MAOI. ( 7 )