Hydrocodone Bitartrate and Acetaminophen

INDICATIONS AND USAGE Hydrocodone Bitartrate and Acetaminophen Oral Solution is 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 Oral Solution for use in patients for whom alternative treatment options (e.g., non-opioid analgesics): 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 Oral Solution 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 Ensure accuracy when prescribing, dispensing, and administering Hydrocodone Bitartrate and Acetaminophen Oral Solution to avoid dosing errors due to confusion between mg and mL, and with other hydrocodone bitartrate and acetaminophen oral solutions of different concentrations, which could result in accidental overdose and death. Ensure the proper dose is communicated and dispensed. When writing prescriptions, include both the total dose in mg and the total dose in volume. Instruct patients and caregivers on how to accurately measure and take the correct dose of hydrocodone bitartrate and acetaminophen oral solution. Strongly advise patients and caregivers to always use a graduated oral syringe or measuring cup, with metric units of measurements (i.e., mL), to correctly measure the prescribed amount of medication. Inform patients and caregivers that oral dosing devices may be obtained from their pharmacy and to never use household teaspoons or tablespoons to measure hydrocodone bitartrate and acetaminophen oral solution. Hydrocodone Bitartrate and Acetaminophen Oral Solution 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 Oral Solution 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 Oral Solution. Consider this risk when selecting an initial dose and when making dose adjustments [see WARNINGS ]. Patient Access to an Opioid Overdose Reversal Agent for the Emergency Treatment of Opioid Overdose Inform patients and caregivers about opioid overdose reversal agents (e.g., naloxone, nalmefene). Discuss the importance of having access to an opioid overdose reversal agent, especially if the patient has risk factors for overdose (e.g., concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose) or if there are household members (including children) or other close contacts at risk for accidental ingestion or opioid overdose. The presence of risk factors for overdose should not prevent the management of pain in any patient [see WARNINGS ; Addiction, Abuse, and Misuse ; Life-Threatening Respiratory Depression; Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants ]. Discuss the options for obtaining an opioid overdose reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program). There are important differences among the opioid overdose reversal agents, such as route of administration, product strength, approved patient age range, and pharmacokinetics. Be familiar with these differences, as outlined in the approved labeling for those products, prior to recommending or pres …

CONTRAINDICATIONS Hydrocodone bitartrate and acetaminophen oral solution is contraindicated in patients with: • Significant respiratory depression [see WARNINGS ] • Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment [see WARNINGS ] • Known or suspected gastrointestinal obstruction, including paralytic ileus [see WARNINGS ] • Hypersensitivity to hydrocodone or acetaminophen (e.g., anaphylaxis) [see WARNINGS , ADVERSE REACTIONS ]

ADVERSE REACTIONS The following adverse reactions have been identified during post approval use of Hydrocodone Bitartrate and Acetaminophen Oral Solution. 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: Cardio-Renal: Bradycardia, cardiac arrest, circulatory collapse, renal toxicity, renal tubular necrosis, hypotension. Central Nervous System/Psychiatric: Anxiety, dizziness, drowsiness, dysphoria, euphoria, fear, general malaise, impairment of mental and physical performance, lethargy, light-headedness, mental clouding, mood changes, psychological dependence, sedation, somnolence progressing to stupor or coma. Endocrine: Hypoglycemic coma. Gastrointestinal System: Abdominal pain, constipation, gastric distress, heartburn, hepatic necrosis, hepatitis, occult blood loss, nausea, peptic ulcer, and vomiting. Genitourinary System: Spasm of vesical sphincters, ureteral spasm, and urinary retention. Hematologic: Agranulocytosis, hemolytic anemia, iron deficiency anemia, prolonged bleeding time, thrombocytopenia. Hypersensitivity: Allergic reactions. Musculoskeletal: Skeletal muscle flaccidity. Respiratory Depression: Acute airway obstruction, apnea, dose-related respiratory depression [see OVERDOSAGE ] , shortness of breath. Special Senses: Cases of hearing impairment or permanent loss have been reported predominantly in patients with chronic overdose. Skin: Cold and clammy skin, diaphoresis, pruritus, rash. 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 Oral Solution. 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). Opioid-induced esophageal dysfunction (OIED): Cases of OIED have been reported in patients taking opioids, and may occur more frequently in patients taking higher doses of opioids, and/or in patients taking opioids longer term [see WARNINGS ] . Adverse Reactions from Observational Studies A prospective, observational cohort study estimated the risks of addiction, abuse, and misuse in patients initiating long-term use of Schedule II opioid analgesics between 2017 and 2021. Study participants included in one or more analyses had been enrolled in selected insurance plans or health systems for at least one year, were free of at least one outcome at baseline, completed a minimum number of follow-up assessments, and either: 1) filled multiple extended-release/long-acting opioid analgesic prescriptions during a 90 day period (n=978); or 2) filled any Schedule II opioid analgesic prescriptions covering at least 70 of 90 days (n=1,244). Those included also had no dispensing of the qualifying opioids in the previous 6 months. Over 12 months: approximately 1% to 6% of participants across the two cohorts newly met criteria for addiction, as assessed with two validated interview-based measures of moderate-to-severe opioid use disorder based on Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria, and approximately 9% and 22% of participant …

Drug Interactions Inhibitors of CYP3A4 and CYP2D6 The concomitant use of hydrocodone bitartrate and acetaminophen oral solution 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 hydrocodone from hydrocodone bitartrate and acetaminophen oral solution, resulting in increased or prolonged opioid effects. These effects could be more pronounced with concomitant use of hydrocodone bitartrate and acetaminophen oral solution and both CYP3A4 and CYP2D6 inhibitors, particularly when an inhibitor is added after a stable dose of hydrocodone bitartrate and acetaminophen oral solution is achieved [see WARNINGS ] . After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, 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 oral solution. If concomitant use is necessary, consider dosage reduction of hydrocodone bitartrate and acetaminophen oral solution 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 oral solution dosage until stable drug effects are achieved. Assess patients for signs or symptoms of opioid withdrawal. Inducers of CYP3A4 The concomitant use of hydrocodone bitartrate and acetaminophen oral solution 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 bitartrate and acetaminophen oral solution [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 oral solution dosage until stable drug effects are achieved [see DOSAGE AND ADMINISTRATION ]. Assess for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider hydrocodone bitartrate and acetaminophen oral solution 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, gabapentinoids (gabapentin or pregabalin) other opioids, and 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 recommending or prescribing an opioid overdose reversal agent [see WARNINGS , DOSAGE AND ADMINISTRATION ] . 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 …

Mechanism of Action Hydrocodone is a semi-synthetic opioid agonist with relative selectivity for the mu-opioid (μ) receptor, although it can interact with other opioid receptors at higher doses. Hydrocodone acts as a full agonist, binding to and activating opioid receptors at sites in the peri-aquaductal and peri-ventricular gray matter, the ventro-medial medulla and the spinal cord to produce analgesia. The analgesia, as well as the euphoriant, respiratory depressant and physiologic dependence properties of μ agonist opioids like hydrocodone, result principally from agonist action at the μ receptors. The precise mechanism of the analgesic properties of acetaminophen is not established but is thought to involve central actions.

DESCRIPTION Hydrocodone bitartrate and acetaminophen are available in liquid form for oral administration. Hydrocodone bitartrate is an opioid analgesic and occurs as fine, white crystals or as a crystalline powder. It is affected by light. The chemical name is 4,5α-epoxy-3-methoxy-17-methylmorphinan-6-one tartrate (1:1) hydrate (2:5). It has the following structural formula: C 18 H 21 NO 3 • C 4 H 6 O 6 • 21⁄2H 2 O M. W. 494.490 Acetaminophen, 4’-hydroxyacetanilide, a slightly bitter, white, odorless, crystalline powder, is a non- opiate, non- salicylate analgesic and antipyretic. It has the following structural formula: C 8 H 9 NO 2 M. W. 151.16 Hydrocodone bitartrate and acetaminophen oral solution contains: Per 5 mL Per 15 mL Hydrocodone Bitartrate 2.5 mg 7.5 mg Acetaminophen 108.0 mg 325.0 mg Ethyl Alcohol, USP (190 Proof) 7% 7% In addition, the liquid contains the following inactive ingredients: citric acid anhydrous, ethyl maltol, glycerin, methylparaben, propylene glycol, propylparaben, purified water, saccharin sodium, sorbitol solution, sucrose, with D&C Red #33 and FD&C Red #40 as coloring and natural and artificial flavoring. Hydrocodone Bitartrate Structural Formula Acetaminophen Structural Formula

OVERDOSAGE Following an acute overdosage, toxicity may result from hydrocodone or acetaminophen. Clinical Presentation Acute overdosage with hydrocodone bitartrate and acetaminophen oral solution 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, hypoglycemia, 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 ]. Toxic leukoencephalopathy has been reported after opioid overdose and can present hours, days, or weeks after apparent recovery from the initial intoxication. Acetaminophen Dose-dependent, potentially fatal hepatic necrosis is the most serious adverse effect of acetaminophen overdosage. Renal tubular necrosis, hypoglycemic coma and coagulation defects may also occur. Early symptoms following a potentially hepatotoxic overdose may include: nausea, vomiting, diaphoresis and general malaise. Clinical and laboratory evidence of hepatic toxicity may not be apparent until 48 to 72 hours post-ingestion. Treatment of Overdose Hydrocodone 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 will require advanced life-support techniques. For clinically significant respiratory or circulatory depression secondary to hydrocodone bitartrate and acetaminophen oral solution overdose, administer an opioid overdose reversal agent such as naloxone or nalmefene. Because the duration of opioid reversal is expected to be less than the duration of action of hydrocodone in hydrocodone bitartrate and acetaminophen oral solution carefully monitor the patient until spontaneous respiration is reliably reestablished. If the response to an opioid overdose reversal agent is suboptimal or only brief in nature, administer additional reversal agent as directed by the product's prescribing information. In an individual physically dependent on opioids, administration of the recommended usual dosage of the opioid overdose reversal agent 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 reversal agent administered. If a decision is made to treat serious respiratory depression in the physically dependent patient, administration of the reversal agent should be initiated with care and by titration with smaller than usual doses of the reversal agent. Acetaminophen Gastric decontamination with activated charcoal should be administered just prior to N-acetylcysteine (NAC) to decrease absorption if acetaminophen is known or suspected to have occurred within a few hours of presentation. Serum acetaminophen levels should be obtained immediately if the patient presents 4 hours or more after ingestion to assess potential risk of hepatotoxicity; acetaminophen levels drawn less than 4 hours post-ingestion may be misleading. To obtain best possible outcome, NAC should be administered as soon as possible where impending or evolving liver injury is suspected. Intravenous NAC may be administered when circumstances preclude oral administration. Vigorous supportive therapy is required in severe intoxication. Procedures to limit the continuing absorption of the drug must be readily performed since the hepatic injury is dose-dependent and occurs in the course of intoxication.

HOW SUPPLIED Hydrocodone Bitartrate and Acetaminophen Oral Solution is a yellow-colored, fruit flavored liquid containing 7.5 mg hydrocodone bitartrate and 325 mg acetaminophen per 15 mL, with 6.7% alcohol. It is supplied in the following oral dosage forms: NDC 0121-4772-05: 5 mL unit dose cup. NDC 0121-4772-40: Case contains 40 unit dose cups of 5 mL (0121-4772-05) packaged in 4 trays of 10 unit dose cups each. NDC 0121-1544-10: 10 mL unit dose cup. NDC 0121-1544-40: Case contains 40 unit dose cups of 10 mL (0121-1544-10) packaged in 4 trays of 10 unit dose cups each. NDC 0121-2316-15: 15 mL unit dose cup. NDC 0121-2316-40: Case contains 40 unit dose cups of 15 mL (0121-2316-15) packaged in 4 trays of 10 unit dose cups each. NDC 0121-2316-50: Case contains 50 unit dose cups of 15 mL (0121-2316-15) packaged in 5 trays of 10 unit dose cups each.