Hydrocodone Bitartrate and Acetaminophen

INDICATIONS AND USAGE Hydrocodone bitartrate and acetaminophen 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, misuse, overdose, and death, which can occur at any dosage or duration and persist over the course of therapy ( see WARNINGS ), reserve opioid analgesics, including hydrocodone bitartrate and acetaminophen tablets for use in patients for whom alternative treatment options are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.

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 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 prescribing such an agent. Initial Dosage Use of Hydrocodone Bitartrate and Acetaminophen Tablets as the First Opioid Analgesic 2.5 mg/300 mg 5 mg/300 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, 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/300 mg 10 mg/300 mg Initiate treatment with hydrocodone bitartrate and acetaminophen tablets with 1 tablet every 4 to 6 hours as needed for pain, 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-pati…

WARNINGS Addiction, Abuse, and Misuse Hydrocodone bitartrate and acetaminophen tablets contain hydrocodone, a Schedule II controlled substance. As an opioid, hydrocodone bitartrate and acetaminophen tablets expose users to the risks of addiction, abuse, and misuse ( see DRUG ABUSE AND DEPENDENCE ). Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed hydrocodone bitartrate and acetaminophen tablets. Addiction can occur at recommended dosages and if the drug is misused or abused. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. In postmarketing studies, addiction, abuse, misuse, and fatal and non-fatal opioid overdose were observed in patients with long-term opioid use ( see ADVERSE REACTIONS ). Assess each patient’s risk for opioid addiction, abuse, or misuse prior to prescribing hydrocodone bitartrate and acetaminophen tablets, and reassess all patients receiving hydrocodone bitartrate and acetaminophen tablets 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 hydrocodone bitartrate and acetaminophen tablets, but use in such patients necessitates intensive counseling about the risks and proper use of hydrocodone bitartrate and acetaminophen tablets along with frequent reevaluation for signs of addiction, abuse, and misuse. Consider recommending or prescribing an opioid overdose reversal agent ( see WARNINGS, Life-Threatening Respiratory Depression ; DOSAGE AND ADMINISTRATION, Patient Access to an Opioid Overdose Reversal Agent for the Emergency Treatment of Opioid Overdose ). Opioids are sought for nonmedical use and are subject to diversion from legitimate prescribed use. Consider these risks when prescribing or dispensing hydrocodone bitartrate and acetaminophen tablets. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on careful storage of the drug during the course of treatment and the proper disposal of unused drug. 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. 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 overdose reversal agents, depending on the patient’s clinical status ( see OVERDOSAGE ). Carbon dioxide (CO 2 ) 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 hydrocodone bitartrate and acetaminophen tablets, the risk is greatest during the initiation of therapy or following a dosage increase. To reduce the risk of respiratory depression, proper dosing and titration of hydrocodone bitartrate and acetaminophen tablets are essential ( see DOSAGE AND ADMINISTRATION ). Overestimating the hydrocodone bitartrate and acetaminophen tablets dosage when converting patients from another opioid product can result in a fatal overdose. Accidental ingestion of hydrocodone bitartrate and acetaminophen tablets, especially by children, can result in respiratory depression and death due to an overdose of hydrocodone bitartrate and acetaminophen …

CONTRAINDICATIONS Hydrocodone bitartrate and acetaminophen tablets are 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 and ADVERSE REACTIONS )

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, and tranquilizers, muscle relaxants, general anesthetics, antipsychotics, gabapentinoids (gabapentin or pregabalin), 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 recommending or prescribing an opioid overdose reversal agent ( 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 mon…

Pregnancy Teratogenic Effects Pregnancy Category C There are no adequate and well-controlled studies in pregnant women. Hydrocodone bitartrate and acetaminophen tablets should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nonteratogenic Effects Fetal/Neonatal Adverse Reactions Use of opioid analgesics for an extended period of time 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, 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 ).

Nursing Mothers Hydrocodone is present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for hydrocodone bitartrate and acetaminophen tablets and any potential adverse effects on the breastfed infant from hydrocodone bitartrate and acetaminophen tablets or from the underlying maternal condition. Infants exposed to hydrocodone bitartrate and acetaminophen tablets through breast milk should be monitored 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.

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 predominantly 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). 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 participants across the two cohorts newly met criteria for prescription opioid abuse and misuse (defined in DRUG ABUSE AND DEPENDENCE ), respectively, as measured with a validated self-reported instrument. A retrospective, observational cohort study estimated the risk of opioid-involved overdose or opioid overdose-related death in patients with new long-term use of Schedule II opioid analgesics from 2006 through 2016 (n=220,249). Included patients had been enrolled in either one of two commercial insurance programs, one managed care program, or one Medicaid program for at least 9 months. New long-term use was defined as having …