Hydrocodone Bitartrate and Acetaminophen

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, 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 oral solution, for use in patients for whom alternative treatment options are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.

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 ]

. Risk of Accidental Overdose and Death due to Medication Errors Dosing errors can result in accidental overdose and death. Avoid dosing errors that may result from confusion between mg and mL and confusion with hydrocodone bitartrate and acetaminophen oral solutions of different concentrations, when prescribing, dispensing, and administering hydrocodone bitartrate and acetaminophen oral solution. Ensure that the dose is communicated clearly and dispensed accurately. Instruct patients and caregivers on how to measure and administer the correct dose of hydrocodone bitartrate and acetaminophen oral solution and to use extreme caution when measuring the dose. Strongly advise patients and caregivers to obtain and always use a graduated device that can measure and deliver the prescribed dose accurately, and to never use household teaspoons or tablespoons to measure a dose because these are not accurate measuring devices. Addiction, Abuse, and Misuse Hydrocodone bitartrate and acetaminophen oral solution contains hydrocodone, a Schedule II controlled substance. As an opioid, hydrocodone bitartrate and acetaminophen oral solution exposes 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 oral solution. 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 oral solution, and reassess all patients receiving hydrocodone bitartrate and acetaminophen oral solution 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 oral solution, but use in such patients necessitates intensive counseling about the risks and proper use of hydrocodone bitartrate and acetaminophen oral solution along with frequent reevaluation for signs of addiction, abuse, and misuse. Consider recommending or prescribing an opioid overdose reversal agent [see WARNINGS , DOSAGE AND ADMINISTRATION ]. 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 oral solution. 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 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 oral solution, 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 oral solution are essential [see DOSAGE AND ADMINISTRATION ]. Overestimating the hydrocodone bitartrate and acetaminophen oral solution dosage when converting patients from another opioid product can result in a fatal overdose. Accidental ingestion of even one dose of hydrocodone bitartrate and acetaminophen oral solution especially by children, can result in respiratory depression and death due to an overdose of hydrocodone bitartrate and acetaminophen oral solution. Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help right away in the event of a known or suspected overdose [see PRECAUTIONS; Information for Patients/Caregivers ]. Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the opioid dosage using best practices for opioid taper [see DOSAGE AND ADMINISTRATION ]. 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 ]. 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. Educate patients and caregivers on how to recognize respiratory depression, and how to use an opioid overdose reversal agent for the emergency treatment of opioid overdose. Emphasize the importance of calling 911 or getting emergency medical help, even if an opioid overdose reversal agent is administered [see WARNINGS , OVERDOSAGE ]. Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants Profound sedation, respiratory depression, coma, and death may result from the concomitant use of hydrocodone bitartrate and acetaminophen oral solution with benzodiazepines and/or other CNS depressants, including alcohol (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, gabapentinoids [gabapentin or pregabalin], and other opioids). Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioid analgesics alone. Because of similar pharmacological properties, it is reasonable to expect similar risk with the concomitant use of other CNS depressant drugs with opioid analgesics [see PRECAUTIONS; Drug Interactions ]. […]

. Risks of Driving and Operating Machinery Hydrocodone bitartrate and acetaminophen oral solution may impair the mental or physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery. Warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects of hydrocodone bitartrate and acetaminophen oral solution and know how they will react to the medication [see PRECAUTIONS; Information for Patients/Caregivers ]. Information for Patients/Caregivers Advise the patient to read the FDA-approved patient labeling (Medication Guide). Storage and Disposal Because of the risks associated with accidental ingestion, misuse, and abuse, advise patients to store hydrocodone bitartrate and acetaminophen oral solution securely, out of sight and reach of children, and in a location not accessible by others, including visitors to the home. Inform patients that leaving hydrocodone bitartrate and acetaminophen oral solution unsecured can pose a deadly risk to others in the home [see WARNINGS , DRUG ABUSE AND DEPENDENCE ]. Advise patients and caregivers that when medicines are no longer needed, they should be disposed of promptly. Expired, unwanted, or unused hydrocodone bitartrate and acetaminophen oral solution should be disposed of by flushing the unused medication down the toilet if a drug take-back option is not readily available. Inform patients that they can visit www.fda.gov/drugdisposal for a complete list of medicines recommended for disposal by flushing, as well as additional information on disposal of unused medicines. Medication Errors 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 [see WARNINGS ]. If the prescribed concentration is changed, instruct patients on how to correctly measure the new dose to avoid errors which could result in accidental overdose and death. Addiction, Abuse, and Misuse Inform patients that the use of hydrocodone bitartrate and acetaminophen oral solution, even when taken as recommended, can result in addiction, abuse, and misuse, which can lead to overdose and death [see WARNINGS ]. Instruct patients not to share hydrocodone bitartrate and acetaminophen oral solution with others and to take steps to protect hydrocodone bitartrate and acetaminophen oral solution from theft or misuse. Life-Threatening Respiratory Depression Inform patients of the risk of life-threatening respiratory depression, including information that the risk is greatest when starting hydrocodone bitartrate and acetaminophen oral solution or when the dosage is increased, and that it can occur even at recommended dosages. Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help right away in the event of a known or suspected overdose [see WARNINGS; Life-Threatening Respiratory Depression ]. Accidental Ingestion Inform patients that accidental ingestion, especially by children, may result in respiratory depression or death [see WARNINGS ] . Interactions with Benzodiazepines and Other Central Nervous System (CNS) Depressants Inform patients and caregivers that potentially fatal additive effects may occur if hydrocodone bitartrate and acetaminophen oral solution is used with benzodiazepines and other CNS depressants, including alcohol (e.g., non-benzodiazepine sedative/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, gabapentinoids [gabapentin or pregabalin], and other opioids), and not to use these concomitantly unless supervised by a healthcare provider [see WARNINGS , PRECAUTIONS; Drug Interactions ]. 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. Discuss with the patient the options for obtaining an opioid overdose reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program) [see WARNINGS , DOSAGE AND ADMINISTRATION ]. Educate patients and caregivers on how to recognize the signs and symptoms of an overdose. Explain to patients and caregivers that effects of opioid overdose reversal agents like naloxone and nalmefene are temporary, and that they must call 911 or get emergency medical help right away in all cases of known or suspected opioid overdose, even if an opioid overdose reversal agent is administered [see OVERDOSAGE ]. Advise patients and caregivers: how to treat with the overdose reversal agent in the event of an opioid overdose to tell family and friends about their opioid overdose reversal agent and to keep it in a place where family and friends can access it in an emergency to read the Patient Information (or other educational material) that will come with the opioid overdose reversal agent. Emphasize the importance of doing this before an opioid emergency happens, so the patient and caregiver will know what to do. Hyperalgesia and Allodynia Inform patients and caregivers not to increase opioid dosage without first consulting a clinician. Advise patients to seek medical attention if they experience symptoms of hyperalgesia, including worsening pain, increased sensitivity to pain, or new pain [see WARNINGS , ADVERSE REACTIONS ]. Serotonin Syndrome Inform patients that hydrocodone bitartrate and acetaminophen oral solution could cause a rare but potentially life-threatening condition resulting from concomitant administration of serotonergic drugs. Warn patients of the symptoms of serotonin syndrome and to seek medical attention right away if symptoms develop. Instruct patients to inform their healthcare providers if they are taking, or plan to take serotonergic medications [see PRECAUTIONS; Drug Interactions ]. Monoamine Oxidase Inhibitor (MAOI) Interaction Inform patients to avoid taking hydrocodone bitartrate and acetaminophen oral solution while using any drugs that inhibit monoamine oxidase. Patients should not start MAOIs while taking hydrocodone bitartrate and acetaminophen oral solution [see PRECAUTIONS; Drug Interactions ]. Important Administration Instructions Instruct patients how to properly measure and take hydrocodone bitartrate and acetaminophen oral solution [see DOSAGE AND ADMINISTRATION , WARNINGS ]. Instruct patients and caregivers on how to accurately measure and administer the correct dose of hydrocodone bitartrate and acetaminophen oral solution. Strongly advise patients and caregivers to always use a graduated oral dosing syringe or measuring cup with metric units of measurements (i.e., mL) to correctly measure the prescribed amount of medication. [see WARNINGS ]. 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. Advise patients not to adjust the dose of hydrocodone bitartrate and acetaminophen oral solution without consulting with a physician or other healthcare professional. […]

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, lightheadedness, 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 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 Schedule II opioid analgesic prescriptions covering at least 70 days’ supply over the 3 months prior to study entry and none during the preceding 6 months. Patients were excluded if they had an opioid-involved overdose in the 9 months prior to study entry. Overdose was measured using a validated medical code-based algorithm with linkage to the National Death Index database. The 5-year cumulative incidence estimates for opioid-involved overdose or opioid overdose-related death ranged from approximately 1.5% to 4% across study sites, counting only the first event during follow-up. Approximately 17% of first opioid overdoses observed over the entire study period (5-11 years, depending on the study site) were fatal. Higher baseline opioid dose was the strongest and most consistent predictor of opioid-involved overdose or opioid overdose-related death. Study exclusion criteria may have selected patients at lower risk of overdose, and substantial loss to follow-up (approximately 80%) also may have biased estimates. The risk estimates from the studies described above may not be generalizable to all patients receiving opioid analgesics, such as those with exposures shorter or longer than the duration evaluated in the studies.

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 [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, gabapenitoids (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 and 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 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, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue hydrocodone bitartrate and acetaminophen oral solution 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 oral solution 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. Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics The concomitant use of opioids with other opioid analgesics, such as butorphanol, nalbuphine, pentazocine, may reduce the analgesic effect of hydrocodone bitartrate and acetaminophen oral solution and/or precipitate withdrawal symptoms. Advise patient to avoid concomitant use of these drugs. Muscle Relaxants Hydrocodone may enhance the neuromuscular blocking action of skeletal muscle relaxants (e.g., cyclobenzaprine, metaxalone) and produce an increased degree of respiratory depression.Because respiratory depression may be greater than otherwise expected, decrease the dosage of hydrocodone bitartrate and acetaminophen oral solution and/or the muscle relaxant as necessary. Due to the risk of respiratory depression with concomitant use of skeletal muscle relaxants and opioids, consider recommending or prescribing an opioid overdose reversal agent [see WARNINGS , DOSAGE AND ADMINISTRATION ]. Diuretics Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. Evaluate patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed. Anticholinergic Drugs The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Evaluate patients for signs of urinary retention or reduced gastric motility when hydrocodone bitartrate and acetaminophen oral solution is used concomitantly with anticholinergic drugs.

Teratogenic Effects There are no adequate and well-controlled studies in pregnant women. Hydrocodone bitartrate and acetaminophen oral solution 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 and 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 ].

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 oral solution and any potential adverse effects on the breastfed infant from hydrocodone bitartrate and acetaminophen oral solution or from the underlying maternal condition. Infants exposed to hydrocodone bitartrate and acetaminophen oral solution 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 breast-feeding is stopped.

The safety and effectiveness of hydrocodone bitartrate and acetaminophen oral solution in the pediatric population below the age of two years have not been established. Use of hydrocodone bitartrate and acetaminophen oral solution in the pediatric patients over the age of 2 years is supported by evidence from adequate and well controlled studies of hydrocodone and acetaminophen combination products in adults, along with additional data which support the development of metabolic pathways in children two years of age and over [see DOSAGE AND ADMINISTRATION ] for pediatric dosage information.

Elderly patients (aged 65 years or older) may have increased sensitivity to hydrocodone bitartrate and acetaminophen oral solution. In general, use caution when selecting a dosage for an elderly patient, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy. Respiratory depression is the chief risk for elderly patients treated with opioids, and has occurred after large initial doses were administered to patients who were not opioid-tolerant or when opioids were co-administered with other agents that depress respiration. Titrate the dosage of hydrocodone bitartrate and acetaminophen oral solution slowly in geriatric patients and frequently reevaluate the patient for signs of central nervous system and respiratory depression [see WARNINGS ]. Hydrocodone and acetaminophen are known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to regularly evaluate renal function.

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.