Hydrocodone

Mechanism of Action Hydrocodone is a full opioid agonist with relative selectivity for the mu-opioid (µ) receptor, although it can interact with other opioid receptors at higher doses. The principal therapeutic action of hydrocodone is analgesia. Like all full opioid agonists, there is no ceiling effect for analgesia with hydrocodone. 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. The precise mechanism of the analgesic properties of acetaminophen is not established but is thought to involve central actions.

INDICATIONS AND USAGE Hydrocodone Bitartrate and Acetaminophen Tablets, USP 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, which can occur at any dosage or duration [see WARNINGS ] , reserve hydrocodone bitartrate and acetaminophen 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 Hydrocodone bitartrate and acetaminophen tablets should not be used for an extended period of time unless the pain remains severe enough to require an opioid analgesic and for which alternative treatment options continue to be inadequate.

DOSAGE AND ADMINISTRATION Important Dosage and Administration Instructions Hydrocodone bitartrate and acetaminophen tablets should be prescribed only by healthcare professionals who are knowledgeable about the use of opioids and how to mitigate the associated risks. Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals [see WARNINGS ] . Because the risk of overdose increases as opioid doses increase, reserve titration to higher doses of hydrocodone bitartrate and acetaminophen tablets for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks. Many acute pain conditions (e.g., the pain that occurs with a number of surgical procedures or acute musculoskeletal injuries) require no more than a few days of an opioid analgesic. Clinical guidelines on opioid prescribing for some acute pain conditions are available. There is variability in the opioid analgesic dose and duration needed to adequately manage pain due both to the cause of pain and to individual patient factors. Initiate the dosing regimen for each patient individually, taking into account the patient's underlying cause and severity of pain, prior analgesic treatment and response, and risk factors for addiction, abuse, and misuse [see WARNINGS ]. Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with hydrocodone bitartrate and acetaminophen tablets. Consider this risk when selecting an initial dose and when making dose adjustments [see WARNINGS ] . 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 hydrocodone and acetaminophen tablets [see WARNINGS, Life-Threatening Respiratory Depression ; PRECAUTIONS, Information for Patients/Caregivers ]. Inform patients and caregivers about the various ways to obtain naloxone as permitted by individual state naloxone dispensing and prescribing regulations (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, Addiction, Abuse, and Misuse , Life-Threatening Respiratory Depression , Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants ]. Consider prescribing naloxone when the patient has household members (including children) or other close contacts at risk for accidental ingestion or overdose. Initial Dosage Use of Hydrocodone Bitartrate and Acetaminophen Tablets as the First Opioid Analgesic 5 mg/325 mg Initiate treatment with hydrocodone bitartrate and acetaminophen tablets in a dosing range of 1 to 2 tablets every 4 to 6 hours as needed for pain, and at the lowest dose necessary to achieve adequate analgesia. Titrate the dose based upon the individual patient's response to their initial dose of hydrocodone bitartrate and acetaminophen tablets. The total daily dosage should not exceed 8 tablets. 7.5 mg/325 mg 10 mg/325 mg Initiate treatment with hydrocodone bitartrate and acetaminophen tablets with 1 tablet every 4 to 6 hours as needed for pain, and at the lowest dose necessary to achieve adequate analgesia. Titrate the dose based upon the individual patient's response to their initial dose of hydrocodone bitartrate and acetaminophen tablets. The total daily dosage should not exceed 6 tablets. Conversion from Other Opioids to Hydrocodone Bitartrate and Acetaminophen 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 hydrocodone bitartrate and acetaminophen tablets. It is safer to underestimate a patient's 24-hour hydrocodone bitartrate and acetaminophen tablets dosage than to overestimate the 24-hour hydrocodone bitartrate and acetaminophen tablets dosage and manage an adverse reaction due to overdose. Conversion from Hydrocodone Bitartrate and Acetaminophen Tablets to Extended-Release Hydrocodone The relative bioavailability of hydrocodone bitartrate and acetaminophen tablets compared to extended-release hydrocodone is unknown, so conversion to extended-release hydrocodone may lead to increased risk of excessive sedation and respiratory depression. Titration and Maintenance of Therapy Individually titrate hydrocodone bitartrate and acetaminophen tablets to a dose that provides adequate analgesia and minimizes adverse reactions. Continual

ADVERSE REACTIONS The following adverse reactions have been identified during post approval use of hydrocodone bitartrate and acetaminophen tablets. 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. The most frequently reported adverse reactions are light-headedness, dizziness, sedation, nausea, and vomiting. Other adverse reactions include: Central Nervous System - Drowsiness, mental clouding, lethargy, impairment of mental and physical performance, anxiety, fear, dysphoria, psychological dependence, mood changes. Gastrointestinal System - Constipation. Genitourinary System - Ureteral spasm, spasm of vesical sphincters, and urinary retention. Special Senses - Cases of hearing impairment or permanent loss have been reported predominately in patients with chronic overdose. Dermatological - Skin rash, pruritus, Stevens-Johnson syndrome, toxic epidermal necrolysis, allergic reactions. Hematological - Thrombocytopenia, agranulocytosis. 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 hydrocodone bitartrate and acetaminophen tablets. Androgen deficiency : Cases of androgen deficiency have occurred with use of opioids for an extended period of time [see CLINICAL PHARMACOLOGY ]. Hyperalgesia and Allodynia: Cases of hyperalgesia and allodynia have been reported with opioid therapy of any duration [see WARNINGS ] . Hypoglycemia: Cases of hypoglycemia have been reported in patients taking opioids. Most reports were in patients with at least one predisposing risk factor (e.g., diabetes).

Drug Interactions Inhibitors of CYP3A4 and CYP2D6 The concomitant use of hydrocodone bitartrate and acetaminophen tablets and CYP3A4 inhibitors, such as macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), and protease inhibitors (e.g., ritonavir), can increase the plasma concentration of the hydrocodone from hydrocodone bitartrate and acetaminophen tablets, resulting in increased or prolonged opioid effects. These effects could be more pronounced with concomitant use of hydrocodone bitartrate and acetaminophen tablets and both CYP3A4 and CYP2D6 inhibitors, particularly when an inhibitor is added after a stable dose of hydrocodone bitartrate and acetaminophen tablets is achieved [see WARNINGS ]. After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the hydrocodone plasma concentration will decrease [see CLINICAL PHARMACOLOGY ], resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to hydrocodone bitartrate and acetaminophen tablets. If concomitant use is necessary, consider dosage reduction of hydrocodone bitartrate and acetaminophen tablets until stable drug effects are achieved. Evaluate patients at frequent intervals for respiratory depression and sedation. If a CYP3A4 inhibitor is discontinued, consider increasing the hydrocodone bitartrate and acetaminophen tablets dosage until stable drug effects are achieved. Evaluate for signs or symptoms of opioid withdrawal. Inducers of CYP3A4 The concomitant use of hydrocodone bitartrate and acetaminophen tablets and CYP3A4 inducers, such as rifampin, carbamazepine, and phenytoin, can decrease the plasma concentration of hydrocodone [see CLINICAL PHARMACOLOGY ], resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to hydrocodone [see WARNINGS ]. After stopping a CYP3A4 inducer, as the effects of the inducer decline, the hydrocodone plasma concentration will increase [see CLINICAL PHARMACOLOGY ], which could increase or prolong both the therapeutic effects and adverse reactions, and may cause serious respiratory depression. If concomitant use is necessary, consider increasing the hydrocodone bitartrate and acetaminophen tablets dosage until stable drug effects are achieved. Assess the patient for signs and symptoms of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider hydrocodone bitartrate and acetaminophen tablets dosage reduction and evaluate patients at frequent intervals for signs of respiratory depression and sedation. Benzodiazepines and other CNS Depressants Due to additive pharmacologic effect, the concomitant use of benzodiazepines and other CNS depressants, such as benzodiazepines and other sedative hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, and other opioids, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death. Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Inform patients and caregivers of this potential interaction, educate them on the signs and symptoms of respiratory depression (including sedation). If concomitant use is warranted, consider prescribing naloxone for the emergency treatment of opioid overdose [see WARNINGS ] . Serotonergic Drugs The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system, such as selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), and monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue), has resulted in serotonin syndrome [see PRECAUTIONS, Information for Patients/Caregivers ]. If concomitant use is warranted, frequently evaluate the patient, particularly during treatment initiation and dose adjustment. Discontinue hydrocodone bitartrate and acetaminophen tablets immediately if serotonin syndrome is suspected. Monoamine Oxidase Inhibitors (MAOIs) The concomitant use of opioids and MAOIs, such as phenelzine, tranylcypromine, or linezolid, may manifest as serotonin syndrome, or opioid toxicity (e.g., respiratory depression, coma) [see WARNINGS ]. The use of hydrocodone bitartrate and acetaminophen 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 an