Hydrocodone Bitartrate and Acetaminophen (hydrocodone bitartrate 7.5 mg acetaminophen 325 mg) Dailymed

CIIRx Only

Warning: Serious And Life-threatening Risks From Use Of Hydrocodone Bitartrate And Acetaminophen Tablets

Addiction, Abuse, and Misuse

Because the use of hydrocodone bitartrate and acetaminophen tablets expose patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death, assess each patient's risk prior to prescribing and reassess all patients regularly for the development of these behaviors and conditions [seeWARNINGS].

Life-Threatening Respiratory Depression

Serious, life-threatening, or fatal respiratory depression may occur with use of hydrocodone bitartrate and acetaminophen tablets, especially during initiation or following a dosage increase. To reduce the risk of respiratory depression, proper dosing and titration of hydrocodone bitartrate and acetaminophen tablets are essential [seeWARNINGS].

Accidental Ingestion

Accidental ingestion of even one dose of hydrocodone bitartrate and acetaminophen tablets, especially by children, can result in a fatal overdose of hydrocodone [seeWARNINGS].

Risks From Concomitant Use With Benzodiazepines Or Other CNS Depressants

Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing of hydrocodone bitartrate and acetaminophen tablets and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate [see WARNINGS;PRECAUTIONS, Drug Interactions].

Neonatal Opioid Withdrawal Syndrome (NOWS)

If opioid use is required for an extended period of time in a pregnant woman, advise the patient of the risk of NOWS, which may be life-threatening if not recognized and treated. Ensure that management by neonatology experts will be available at delivery [seeWARNINGS].

Opioid Analgesic Risk Evaluation and Mitigation Strategy (REMS)

Healthcare providers are strongly encouraged to complete a REMS-compliant education program and to counsel patients and caregivers on serious risks, safe use, and the importance of reading the Medication Guide with each prescription [seeWARNINGS].

Cytochrome P450 3A4 Interaction

The concomitant use of hydrocodone bitartrate and acetaminophen tablets with all Cytochrome P450 3A4 inhibitors may result in an increase in hydrocodone plasma concentrations, which could increase or prolong adverse reactions and may cause potentially fatal respiratory depression. In addition, discontinuation of a concomitantly used Cytochrome P450 3A4 inducer may result in an increase in hydrocodone plasma concentrations. Monitor patients receiving hydrocodone bitartrate and acetaminophen tablets and any Cytochrome P450 3A4 inhibitor or inducer for signs of respiratory depression or sedation [seeCLINICAL PHARMACOLOGY;WARNINGS;PRECAUTIONS, Drug Interactions].

Hepatotoxicity

Acetaminophen has been associated with cases of acute liver failure, at times resulting in liver transplant and death. Most of the cases of liver injury are associated with the use of acetaminophen at doses that exceed 4,000 milligrams per day, and often involve more than one acetaminophen-containing product [seeWARNINGS;OVERDOSAGE].

Description

Hydrocodone bitartrate and acetaminophen is available in tablet 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:
C₁₈H₂₁NO₃∙C₄H₆O₆∙2½H₂O              MW = 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:
C₈H₉NO₂                 MW = 151.16
Each Hydrocodone Bitartrate and Acetaminophen Tablet, USP, 5 mg/ 325 mg contains:

Hydrocodone Bitartrate	5 mg
Acetaminophen	325 mg

Each Hydrocodone Bitartrate and Acetaminophen Tablet, USP, 7.5 mg/ 325 mg contains:

Hydrocodone Bitartrate	7.5 mg
Acetaminophen	325 mg

Each Hydrocodone Bitartrate and Acetaminophen Tablet, USP, 10 mg/ 325 mg contains:

Hydrocodone Bitartrate	10 mg
Acetaminophen	325 mg

In addition, each tablet contains the following inactive ingredients: colloidal silicon dioxide, pregelatinized starch, crospovidone, magnesium stearate, povidone, and stearic acid.

Meets USP Dissolution Test 1.

Clinical Pharmacology

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.

Pharmacodynamics

Effects on the Central Nervous System

The principal therapeutic action of hydrocodone is analgesia. Hydrocodone produces respiratory depression by direct action on brain stem respiratory centers. The respiratory depression involves a reduction in the responsiveness of the brain stem respiratory centers to both increases in carbon dioxide tension and electrical stimulation.

Hydrocodone causes miosis, even in total darkness. Pinpoint pupils are a sign of opioid overdose but are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origins may produce similar findings). Marked mydriasis rather than miosis may be seen due to hypoxia in overdose situations.

Therapeutic doses of acetaminophen have negligible effects on the cardiovascular or respiratory systems; however, toxic doses may cause circulatory failure and rapid, shallow breathing.

Effects on the Gastrointestinal Tract and Other Smooth Muscle

Hydrocodone causes a reduction in motility associated with an increase in smooth muscle tone in the antrum of the stomach and duodenum. Digestion of food in the small intestine is delayed and propulsive contractions are decreased. Propulsive peristaltic waves in the colon are decreased, while tone may be increased to the point of spasm, resulting in constipation. Other opioid-induced effects may include a reduction in biliary and pancreatic secretions, spasm of sphincter of Oddi, and transient elevations in serum amylase.

Effects on the Cardiovascular System

Hydrocodone produces peripheral vasodilation which may result in orthostatic hypotension or syncope. Manifestations of histamine release and/or peripheral vasodilation may include pruritus, flushing, red eyes, sweating, and/or orthostatic hypotension.

Effects on the Endocrine System

Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing hormone (LH) in humans [see ADVERSE REACTIONS ]. They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagon.

Use of opioids for an extended period of time may influence the hypothalamic-pituitary-gonadal axis, leading to androgen deficiency that may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility. The causal role of opioids in the syndrome of hypogonadism is unknown because the various medical, physical, lifestyle, and psychological stressors that may influence gonadal hormone levels have not been adequately controlled for in studies conducted to date [see ADVERSE REACTIONS ].

Effects on the Immune System

Opioids have been shown to have a variety of effects on components of the immune system. The clinical significance of these findings is unknown. Overall, the effects of opioids appear to be modestly immunosuppressive.

ConcentrationEfficacy Relationships

The minimum effective analgesic concentration will vary widely among patients, especially among patients who have been previously treated with opioid agonists. The minimum effective analgesic concentration of hydrocodone for any individual patient may increase over time due to an increase in pain, the development of a new pain syndrome, and/or the development of analgesic tolerance [see DOSAGE AND ADMINISTRATION ].

ConcentrationAdverse Reaction Relationships

There is a relationship between increasing hydrocodone plasma concentration and increasing frequency of dose-related opioid adverse reactions such as nausea, vomiting, CNS effects, and respiratory depression. In opioid-tolerant patients, the situation may be altered by the development of tolerance to opioid-related adverse reactions [see DOSAGE AND ADMINISTRATION ].

Pharmacokinetics

The behavior of the individual components is described below.

Hydrocodone

Following a 10 mg oral dose of hydrocodone administered to five adult male subjects, the mean peak concentration was 23.6 ± 5.2 ng/mL. Maximum serum levels were achieved at 1.3 ± 0.3 hours and the half-life was determined to be 3.8 ± 0.3 hours.

Hydrocodone exhibits a complex pattern of metabolism including O-demethylation, N-demethylation, and 6-keto reduction to the corresponding 6-α- and 6-β-hydroxymetabolites. See OVERDOSAGE for toxicity information.

CYP3A4 mediated N-demethylation to norhydrocodone is the primary metabolic pathway of hydrocodone with a lower contribution from CYP2D6 mediated O-demethylation to hydromorphone. Hydromorphone is formed from the O-demethylation of hydrocodone and may contribute to the total analgesic effect of hydrocodone. Therefore, the formation of these and related metabolites can, in theory, be affected by other drugs [see PRECAUTIONS, Drug Interactions ]. N-demethylation of hydrocodone to form norhydrocodone via CYP3A4 while O-demethylation of hydrocodone to hydromorphone is predominantly catalyzed by CYP2D6 and to a lesser extent by an unknown low affinity CYP enzyme. Hydrocodone and its metabolites are eliminated primarily in the kidneys.

Acetaminophen

Acetaminophen is rapidly absorbed from the gastrointestinal tract and is distributed throughout most body tissues. A small fraction (10 to 25%) of acetaminophen is bound to plasma proteins. The plasma half-life is 1.25 to 3 hours, but may be increased by liver damage and following overdosage. Elimination of acetaminophen is principally by liver metabolism (conjugation) and subsequent renal excretion of metabolites. Acetaminophen is primarily metabolized in the liver by first-order kinetics and involves three principal separate pathways: conjugation with glucuronide; conjugation with sulfate; and oxidation via the cytochrome, P450-dependent, mixed-function oxidase enzyme pathway to form a reactive intermediate metabolite, which conjugates with glutathione and is then further metabolized to form cysteine and mercapturic acid conjugates. The principal cytochrome P450 isoenzyme involved appears to be CYP2E1, with CYP1A2 and CYP3A4 as additional pathways. Approximately 85% of an oral dose appears in the urine within 24 hours of administration, most as the glucuronide conjugate, with small amounts of other conjugates and unchanged drug [see OVERDOSAGE for toxicity information].

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.

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; ADVERSE REACTIONS ]

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.

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 prescribing naloxone for the emergency treatment of opioid overdose [see WARNINGS, Life-Threatening Respiratory Depression; DOSAGE AND ADMINISTRATION, Patient Access to Naloxone 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 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 antagonists, depending on the patient's clinical status [see OVERDOSAGE ]. Carbon dioxide (CO₂) 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 even one dose 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 tablets.

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 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 bitartrate and acetaminophen tablets. Inform patients and caregivers about the various ways to obtain naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (e.g., by prescription, directly from a pharmacist, or as part of a community-based program). Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help, even if naloxone is administered [see PRECAUTIONS, Information for Patients/Caregivers ].

Consider prescribing naloxone, based on the patient's risk factors for overdose, such as concomitant use of other 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. Also consider prescribing naloxone if the patient has household members (including children) or other close contacts at risk for accidental ingestion or overdose. If naloxone is prescribed, educate patients and caregivers on how to treat with naloxone [see WARNINGS, Addiction, Abuse, and Misuse, Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants; PRECAUTIONS, Information for Patients/Caregivers; 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 tablets with benzodiazepines and/or other CNS depressants, including alcohol (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, 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 ].

If the decision is made to prescribe a benzodiazepine or other CNS depressant concomitantly with an opioid analgesic, prescribe the lowest effective dosages and minimum durations of concomitant use. In patients already receiving an opioid analgesic, prescribe a lower initial dose of the benzodiazepine or other CNS depressant than indicated in the absence of an opioid, and titrate based on clinical response. If an opioid analgesic is initiated in a patient already taking a benzodiazepine or other CNS depressant, prescribe a lower initial dose of the opioid analgesic, and titrate based on clinical response. 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, Life-Threatening Respiratory Depression; DOSAGE AND ADMINISTRATION, Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose ].

Advise both patients and caregivers about the risks of respiratory depression and sedation when hydrocodone bitartrate and acetaminophen tablets are used with benzodiazepines or other CNS depressants (including alcohol and illicit drugs). Advise patients not to drive or operate heavy machinery until the effects of concomitant use of the benzodiazepine or other CNS depressant have been determined. Screen patients for risk of substance use disorders, including opioid abuse and misuse, and warn them of the risk for overdose and death associated with the use of additional CNS depressants including alcohol and illicit drugs [see PRECAUTIONS, Drug Interactions,Information for Patients/Caregivers ].

Neonatal Opioid Withdrawal Syndrome

Use of hydrocodone bitartrate and acetaminophen tablets for an extended period of time during pregnancy can result in withdrawal in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly. Advise pregnant women using opioids for an extended period of time of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [see PRECAUTIONS, Information for Patients/Caregivers, Pregnancy ].

Opioid Analgesic Risk Evaluation and Mitigation Strategy (REMS)

To ensure that the benefits of opioid analgesics outweigh the risks of addiction, abuse, and misuse, the Food and Drug Administration (FDA) has required a Risk Evaluation and Mitigation Strategy (REMS) for these products. Under the requirements of the REMS, drug companies with approved opioid analgesic products must make REMS-compliant education programs available to healthcare providers. Healthcare providers are strongly encouraged to do all of the following:

• Complete a REMS-compliant education program offered by an accredited provider of continuing education (CE) or another education program that includes all the elements of the FDA Education Blueprint for Health Care Providers Involved in the Management or Support of Patients with Pain.
• Discuss the safe use, serious risks, and proper storage and disposal of opioid analgesics with patients and/or their caregivers every time these medicines are prescribed. The Patient Counseling Guide (PCG) can be obtained at this link: www.fda.gov/OpioidAnalgesicREMSPCG.
• Emphasize to patients and their caregivers the importance of reading the Medication Guide that they will receive from their pharmacist every time an opioid analgesic is dispensed to them.
• Consider using other tools to improve patient, household, and community safety, such as patient-prescriber agreements that reinforce patient-prescriber responsibilities.

To obtain further information on the opioid analgesic REMS and for a ul of accredited REMS CME/CE, call 1-800-503-0784, or log on to www.opioidanalgesicrems.com. The FDA Blueprint can be found at www.fda.gov/OpioidAnalgesicREMSBlueprint.

Risks of Concomitant Use or Discontinuation of Cytochrome P450 3A4 Inhibitors and Inducers

Concomitant use of hydrocodone bitartrate and acetaminophen tablets with a CYP3A4 inhibitor, such as macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), and protease inhibitors (e.g., ritonavir), may increase plasma concentrations of hydrocodone bitartrate and acetaminophen tablets and prolong opioid adverse reactions, which may cause potentially fatal respiratory depression [see WARNINGS ], particularly when an inhibitor is added after a stable dose of hydrocodone bitartrate and acetaminophen tablets is achieved. Similarly, discontinuation of a CYP3A4 inducer, such as rifampin, carbamazepine, and phenytoin, in hydrocodone bitartrate and acetaminophen tablets-treated patients may increase hydrocodone plasma concentrations and prolong opioid adverse reactions. When adding CYP3A4 inhibitors or discontinuing CYP3A4 inducers in hydrocodone bitartrate and acetaminophen tablets-treated patients, evaluate patients at frequent intervals and consider dosage reduction of hydrocodone bitartrate and acetaminophen tablets until stable drug effects are achieved [see PRECAUTIONS, Drug Interactions ].

Concomitant use of hydrocodone bitartrate and acetaminophen tablets with CYP3A4 inducers or discontinuation of a CYP3A4 inhibitor could decrease hydrocodone plasma concentrations, decrease opioid efficacy or, possibly, lead to a withdrawal syndrome in a patient who had developed physical dependence to hydrocodone. When using hydrocodone bitartrate and acetaminophen tablets with CYP3A4 inducers or discontinuing CYP3A4 inhibitors, follow patients at frequent intervals and consider increasing the opioid dosage if needed to maintain adequate analgesia or if symptoms of opioid withdrawal occur [see PRECAUTIONS, Drug Interactions ].

Hepatotoxicity

Acetaminophen has been associated with cases of acute liver failure, at times resulting in liver transplant and death. Most of the cases of liver injury are associated with the use of acetaminophen at doses that exceed 4,000 milligrams per day, and often involve more than one acetaminophen-containing product. The excessive intake of acetaminophen may be intentional to cause self-harm or unintentional as patients attempt to obtain more pain relief or unknowingly take other acetaminophen-containing products.

The risk of acute liver failure is higher in individuals with underlying liver disease and in individuals who ingest alcohol while taking acetaminophen.

Instruct patients to look for acetaminophen or APAP on package labels and not to use more than one product that contains acetaminophen. Instruct patients to seek medical attention immediately upon ingestion of more than 4,000 milligrams of acetaminophen per day, even if they feel well.

Opioid-Induced Hyperalgesia and Allodynia

Opioid-Induced Hyperalgesia (OIH) occurs when an opioid analgesic paradoxically causes an increase in pain, or an increase in sensitivity to pain. This condition differs from tolerance, which is the need for increasing doses of opioids to maintain a defined effect [see DRUG ABUSE AND DEPENDENCE ]. Symptoms of OIH include (but may not be limited to) increased levels of pain upon opioid dosage increase, decreased levels of pain upon opioid dosage decrease, or pain from ordinarily non-painful stimuli (allodynia). These symptoms may suggest OIH only if there is no evidence of underlying disease progression, opioid tolerance, opioid withdrawal, or addictive behavior.

Cases of OIH have been reported, both with short-term and longer-term use of opioid analgesics. Though the mechanism of OIH is not fully understood, multiple biochemical pathways have been implicated. Medical literature suggests a strong biologic plausibility between opioid analgesics and OIH and allodynia. If a patient is suspected to be experiencing OIH, carefully consider appropriately decreasing the dose of the current opioid analgesic, or opioid rotation (safely switching the patient to a different opioid moiety) [see DOSAGE AND ADMINISTRATION; WARNINGS ].

Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients

The use of hydrocodone bitartrate and acetaminophen tablets in patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment is contraindicated.

Patients with Chronic Pulmonary Disease

Hydrocodone bitartrate and acetaminophen tablet-treated patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression are at increased risk of decreased respiratory drive including apnea, even at recommended dosages of hydrocodone bitartrate and acetaminophen tablets [see WARNINGS, Life-Threatening Respiratory Depression ].

Elderly, Cachectic, or Debilitated Patients

Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients because they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients [see WARNINGS, Life-Threatening Respiratory Depression ].

Regularly evaluate patients, particularly when initiating and titrating hydrocodone bitartrate and acetaminophen tablets and when hydrocodone bitartrate and acetaminophen tablets are given concomitantly with other drugs that depress respiration [see WARNINGS ]. Alternatively, consider the use of non-opioid analgesics in these patients.

Adrenal Insufficiency

Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Presentation of adrenal insufficiency may include non-specific symptoms and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. If adrenal insufficiency is suspected, confirm the diagnosis with diagnostic testing as soon as possible. If adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids. Wean the patient off the opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers. Other opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency. The information available does not identify any particular opioids as being more likely to be associated with adrenal insufficiency.

Severe Hypotension

Hydrocodone bitartrate and acetaminophen tablets may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients. There is increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs (e.g., phenothiazines or general anesthetics) [see PRECAUTIONS, Drug Interactions ]. Regularly evaluate patients for signs of hypotension after initiating or titrating the dosage of hydrocodone bitartrate and acetaminophen tablets. In patients with circulatory shock, hydrocodone bitartrate and acetaminophen tablets may cause vasodilatation that can further reduce cardiac output and blood pressure. Avoid the use of hydrocodone bitartrate and acetaminophen tablets with circulatory shock.

Serious Skin Reactions

Rarely, acetaminophen may cause serious skin reactions such as acute generalized exanthematous pustulosis (AGEP), Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. Patients should be informed about the signs of serious skin reactions, and use of the drug should be discontinued at the first appearance of skin rash or any other sign of hypersensitivity.

Hypersensitivity/Anaphylaxis

There have been post-marketing reports of hypersensitivity and anaphylaxis associated with use of acetaminophen. Clinical signs included swelling of the face, mouth, and throat, respiratory distress, urticaria, rash, pruritus, and vomiting. There were infrequent reports of life-threatening anaphylaxis requiring emergency medical attention. Instruct patients to discontinue hydrocodone bitartrate and acetaminophen tablets immediately and seek medical care if they experience these symptoms. Do not prescribe hydrocodone bitartrate and acetaminophen tablets for patients with acetaminophen allergy [see PRECAUTIONS, Information for Patients/Caregivers ].

Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness

In patients who may be susceptible to the intracranial effects of CO₂ retention (e.g., those with evidence of increased intracranial pressure or brain tumors), hydrocodone bitartrate and acetaminophen tablets may reduce respiratory drive, and the resultant CO₂ retention can further increase intracranial pressure. Follow such patients for signs of sedation and respiratory depression, particularly when initiating therapy with hydrocodone bitartrate and acetaminophen tablets.

Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of hydrocodone bitartrate and acetaminophen tablets in patients with impaired consciousness or coma.

Risks of Use in Patients with Gastrointestinal Conditions

Hydrocodone bitartrate and acetaminophen tablets are contraindicated in patients with gastrointestinal obstruction, including paralytic ileus.

The administration of hydrocodone bitartrate and acetaminophen tablets or other opioids may obscure the diagnosis or clinical course in patients with acute abdominal conditions.

Hydrocodone may cause spasm of the sphincter of Oddi. Opioids may cause increases in serum amylase. Regularly evaluate patients with biliary tract disease, including acute pancreatitis, for worsening symptoms.

Increased Risk of Seizures in Patients with Seizure Disorders

The hydrocodone in hydrocodone bitartrate and acetaminophen tablets may increase the frequency of seizures in patients with seizure disorders, and may increase the risk of seizures occurring in other clinical settings associated with seizures. Regularly evaluate patients with a history of seizure disorders for worsened seizure control during hydrocodone bitartrate and acetaminophen tablet therapy.

Withdrawal

Do not abruptly discontinue hydrocodone bitartrate and acetaminophen tablets in a patient physically dependent on opioids. When discontinuing hydrocodone bitartrate and acetaminophen tablets in a physically dependent patient, gradually taper the dosage. Rapid tapering of hydrocodone bitartrate and acetaminophen tablets in a patient physically dependent on opioids may lead to a withdrawal syndrome and return of pain [see DOSAGE AND ADMINISTRATION;DRUG ABUSE AND DEPENDENCE ] .

Additionally, avoid the use of mixed agonist/antagonist (e.g., pentazocine, nalbuphine, and butorphanol) or partial agonist (e.g., buprenorphine) analgesics in patients who are receiving a full opioid agonist analgesic, including hydrocodone bitartrate and acetaminophen tablets. In these patients, mixed agonist/antagonist and partial agonist analgesics may reduce the analgesic effect and/or precipitate withdrawal symptoms [see PRECAUTIONS, Drug Interactions ].