DailyMed Label: Hydrocodone Bitartrate and Aspirin

DailyMed Label: Hydrocodone Bitartrate and Aspirin

2024

DailyMed Prescription

Hydrocodone Bitartrate and Aspirin

Hydrocodone Bitartrate and Aspirin

LGM PHARMA SOLUTIONS, LLC

NDC: 79739-7182

NDC: 79739-7182

Hydrocodone Bitartrate and Aspirin Tablets are immediate-release tablets for oral administration only. Each Hydrocodone Bitartrate and Aspirin Tablet, 5 mg/500 mg contains: Hydrocodone Bitartrate ……………….. 5 mg Aspirin ……………………………................ 500 mg Hydrocodone Bitartrate is an opioid agonist and occurs as fine, white crystals or as a crystalline powder. It is affected by light. It is soluble in water, slightly soluble in alcohol, and insoluble in ether and chloroform. 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: Aspirin, acetylsalicylic acid, is a nonsteroidal anti-inflammatory drug which is an odorless white, needle-like crystalline or powdery substance. The aspirin component is 2-(acetyloxy)-, Benzoic acid. When exposed to moisture, aspirin hydrolyzes into salicylic and acetic acids, and gives off a vinegary-odor. It is highly lipid soluble and slightly soluble in water; freely soluble in alcohol; soluble in chloroform and in ether; sparingly soluble in absolute ether. Its structure is as follows: In addition, each tablet contains the following inactive ingredients: Microcrystalline Cellulose, Anhydrous Lactose, Corn Starch, Hypromellose, Crospovidone, Stearic Acid, Talc, Colloidal Silicon Dioxide. Hydrocodone Bitartrate SF aspirin sf

Hydrocodone Bitartrate and Aspirin 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, and misuse, with opioids, which can occur at any dosage or duration, reserve Hydrocodone Bitartrate and Aspirin Tablets 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 Aspirin Tablets should not be used for 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.

Hydrocodone Bitartrate and Aspirin 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 the individual patient treatment goals [see WARNINGS ]. Because the risk of overdose increases as opioid doses increase, reserve titration to higher doses of Hydrocodone Bitartrate with Aspirin Tablets for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using 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 addition, abuse, and misuse [see WARNINGS ]. Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increase with Hydrocodone Bitartrate and Aspirin Tablets. Consider the risk when selecting an initial dose and when making dose adjustments [see WARNINGS ]. Administer Hydrocodone Bitartrate and Aspirin Tablets with food or a full glass of water to minimize GI distress. 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 Aspirin Tablets [see WARNINGS ; Life-Threatening Respiratory Depression , PRECAUTIONS ; Information for Patients/Caregivers ]. Inform patients and caregivers about the various ways to obtain naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (e.g., by prescription, directly from a pharmacist, or as part of a community-based program). Consider prescribing naloxone, based on the patient’s risk factors for overdose, such as concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose. The presence of risk factors for overdose should not prevent the proper management of pain in any given patient [see WARNINGS ; Addiction, Abuse, and Misuse ; Life-Threatening Respiratory Depression ; Life-Threatening Respiratory Depression ; Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants ] . Consider prescribing naloxone when there are household members (including children) or other close contacts at risk for accidental ingestion or overdose . Initiating Treatment with Hydrocodone Bitartrate and Aspirin Tablets Initiate treatment with Hydrocodone Bitartrate and Aspirin Tablets using one (1) or two (2) tablets every four (4) to six (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 Aspirin Tablets. Conversion from Other Opioids to Hydrocodone Bitartrate and Aspirin Tablets There is inter-patient variability in the potency of opioid drugs and opioid formulations. Therefore, a conservative approach is advised when determining the total daily dosage of Hydrocodone Bitartrate and Aspirin Tablets. It is safer to underestimate a patient’s 24-hour Hydrocodone Bitartrate and Aspirin Tablets dosage than to overestimate the 24-hour Hydrocodone Bitartrate and Aspirin Tablets dosage and manage an adverse reaction due to an overdose. Conversion from Hydrocodone Bitartrate and Aspirin Tablets to Extended-Release Hydrocodone The relative bioavailability of Hydrocodone Bitartrate and Aspirin Tablets compared to extended-release hydrocodone is unknown, so conversion to extended-release hydrocodone may lead to increased risk of excessive sedation and respiratory depression. Individually titrate Hydrocodone Bitartrate and Aspirin Tablets to a dose that provides adequate analgesia and minimizes adverse reactions. Continually reevaluate patients receiving Hydrocodone Bitartrate and Aspirin Tablets to assess the maintenance of pain control, signs and symptoms of opioid withdrawal, and other adverse reactions, as well as reassess for the development of addiction, abuse, or misuse [see WARNINGS ]. Frequent communication is important among the prescriber, other members of the healthcare team, the patient, and the caregiver/family during periods of changing analgesic requirements, including initial titration. If the level of pain increases after dosage stabilization, attempt to identify the source of the increased pain before increasing the Hydrocodone Bitartrate and Aspirin Tablets dosage. If after increasing the dosage, unacceptable opioid-related adverse reactions are observed (including an increase in pain after dosage increase), consider reducing the dosage [see WARNINGS ]. Adjust the dosage to obtain an appropriate balance between management of pain and opioid-related adverse reactions. Do not abruptly discontinue Hydrocodone Bitartrate and Aspirin Tablets in patients who may be physically dependent on opioids. Rapid discontinuation of opioid analgesics in patients who are physically dependent on opioids has resulted in serious withdrawal symptoms, uncontrolled pain, and suicide. Rapid discontinuation has also been associated with attempts to find other sources of opioid analgesics, which may be confused with drug-seeking for abuse. Patients may also attempt to treat their pain or withdrawal symptoms with illicit opioids, such as heroin, and other substances. When a decision has been made to decrease the dose or discontinue therapy in an opioid-dependent patient taking Hydrocodone Bitartrate and Aspirin Tablets, there are a variety of factors that should be considered, including the total daily dose of opioid (including Hydrocodone Bitartrate and Aspirin Tablets) the patient has been taking, the duration of treatment, the type of pain being treated, and the physical and psychological attributes of the patient. It is important to ensure ongoing care of the patient and to agree on an appropriate tapering schedule and follow-up plan so that patient and provider goals and expectations are clear and realistic. When opioid analgesics are being discontinued due to a suspected substance use disorder, evaluate and treat the patient, or refer for evaluation and treatment of the substance use disorder. Treatment should include evidence-based approaches, such as medication assisted treatment of opioid use disorder. Complex patients with co-morbid pain and substance use disorders may benefit from referral to a specialist. There are no standard opioid tapering schedules that are suitable for all patients. Good clinical practice dictates a patient-specific plan to taper the dose of the opioid gradually. For patients on Hydrocodone Bitartrate and Aspirin Tablets who are physically opioid-dependent, initiate the taper by a small enough increment (e.g., no greater than 10% to 25% of the total daily dose) to avoid withdrawal symptoms, and proceed with dose-lowering at an interval of every 2 to 4 weeks. Patients who have been taking opioids for briefer periods of time may tolerate a more rapid taper. It may be necessary to provide the patient with lower dosage strengths to accomplish a successful taper. Reassess the patient frequently to manage pain and withdrawal symptoms, should they emerge. Common withdrawal symptoms include restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Other signs and symptoms also may develop, including irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate. If withdrawal symptoms arise, it may be necessary to pause the taper for a period of time or raise the dose of the opioid analgesic to the previous dose, and then proceed with a slower taper. In addition, evaluate patients for any changes in mood, emergence of suicidal thoughts, or use of other substances. When managing patients taking opioid analgesics, particularly those who have been treated for an extended period of time, and/or with high doses for chronic pain, ensure that a multimodal approach to pain management, including mental health support (if needed), is in place prior to initiating an opioid analgesic taper. A multimodal approach to pain management may optimize the treatment of chronic pain, as well as assist with the successful tapering of the opioid analgesic [see WARNINGS ; Withdrawal , DRUG ABUSE AND DEPENDENCE ].

Aspirin has been associated with elevated hepatic enzymes, blood urea nitrogen and serum creatinine, hyperkalemia, proteinuria, and prolonged bleeding time. Aspirin may increase the likelihood of hemorrhage due to its effect on the gastric mucosa and platelet function (prolongation of bleeding time). Salicylates should be used with caution in the presence of peptic ulcer or coagulation abnormalities. Hydrocodone and other morphine-like opioids have been shown to decrease bowel motility. Ileus is a common postoperative complication, especially after intra-abdominal surgery with use of opioid analgesia. Caution should be taken to monitor for decreased bowel motility in postoperative patients receiving opioids. Standard supportive therapy should be implemented. Renal Toxicity Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of an NSAID may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, dehydration, hypovolemia, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors or ARBs, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state. No information is available from controlled clinical studies regarding the use of Hydrocodone Bitartrate and Aspirin Tablets in patients with advanced renal disease. The renal effects of Hydrocodone Bitartrate and Aspirin Tablets may hasten the progression of renal dysfunction in patients with pre-existing renal disease. Correct volume status in dehydrated or hypovolemic patients prior to initiating Hydrocodone Bitartrate and Aspirin Tablets. Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia during use of Hydrocodone Bitartrate and Aspirin Tablets (see PRECAUTIONS ; Drug Interactions ]. Avoid the use of Hydrocodone Bitartrate and Aspirin Tablets in patients with advanced renal disease unless the benefits are expected to outweigh the risk of worsening renal function. If Hydrocodone Bitartrate and Aspirin Tablets is used in patients with advanced renal disease, monitor patients for signs of worsening renal function. Hyperkalemia Increases in serum potassium concentration, including hyperkalemia, have been reported with use of NSAIDs, even in some patients without renal impairment. In patients with normal renal function, these effects have been attributed to a hyporeninemic-hypoaldosteronism state. Aspirin may cause premature closure of the fetal ductus arteriosus. Avoid use of NSAIDs, including Hydrocodone Bitartrate and Aspirin Tablets, in pregnant women starting at 30 weeks of gestation (third trimester) [see PRECAUTIONS ]. 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 Aspirin Tablets 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 Aspirin Tablets 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 Aspirin Tablets 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. Addiction, Abuse, and Misuse Inform patients that the use of Hydrocodone Bitartrate and Aspirin Tablets, 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 Aspirin Tablets with others and to take steps to protect Hydrocodone Bitartrate and Aspirin Tablets 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 Aspirin Tablets or when the dosage is increased, and that it can occur even at recommended dosages [see WARNINGS ]. Advise patients how to recognize respiratory depression and to seek medical attention if breathing difficulties develop. 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. Accidental Ingestion Inform patients that accidental ingestion, especially by children, may result in respiratory depression or death [see WARNINGS ]. Instruct patients to take steps to store Hydrocodone Bitartrate and Aspirin Tablets securely and to dispose of unused Hydrocodone Bitartrate and Aspirin Tablets by flushing down the toilet. Interactions with Benzodiazepines and Other CNS Depressants Inform patients and caregivers that potentially fatal additive effects may occur if Hydrocodone Bitartrate and Aspirin Tablets are used with benzodiazepine and/or other CNS depressants, including alcohol, and not to use these concomitantly unless supervised by a healthcare provider [see WARNINGS , PRECAUTIONS ; Drug Interactions ]. Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose Discuss with the patient and caregiver the availability of naloxone for the emergency treatment of opioid overdose, both when initiating and renewing treatment with Hydrocodone Bitartrate and Aspirin Tablets. Inform patients and caregivers about the various ways to obtain naloxone as permitted by individual state naloxone dispensing and prescribing regulations (e.g., by prescription, directly from a pharmacist, or as part of a community-based program) [see WARNINGS ; Life-Threatening Respiratory Depression , DOSAGE AND ADMINISTRATION ; Initial Dosage ]. Educate patients and caregivers on how to recognize the signs and symptoms of an overdose. Explain to patients and caregivers that naloxone’s effects 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 naloxone is administered [see OVERDOSAGE ]. If naloxone is prescribed, also advise patients and caregivers: How to treat with naloxone in the event of an opioid overdose To tell family and friends about their naloxone 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 their naloxone 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 opioids 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 Aspirin Tablets while using any drugs that inhibit monoamine oxidase. Patients should not start MAOIs while taking Hydrocodone Bitartrate and Aspirin Tablets [see PRECAUTIONS ; Drug Interactions ]. Important Administration Instructions Instruct patients how to properly take Hydrocodone Bitartrate and Aspirin Tablets. The usual dosage is one or two tablets every four to six hours as needed for pain. The maximum daily dose of aspirin should not exceed 4 grams [see DOSAGE AND ADMINISTRATION , PRECAUTIONS ]. Important Discontinuation Instructions In order to avoid developing withdrawal symptoms, instruct patients not to discontinue Hydrocodone Bitartrate and Aspirin Tablets without first discussing a tapering plan with the prescriber [see DOSAGE AND ADMINISTRATION ]. Driving or Operating Heavy Machinery Inform patients that Hydrocodone Bitartrate and Aspirin Tablets may impair the ability to perform potentially hazardous activities such as driving a car or operating heavy machinery. Advise patients not to perform such tasks until they know how they will react to the medication [see WARNINGS ]. Constipation Advise patients of the potential for severe constipation, including management instructions and when to seek medical attention [see ADVERSE REACTIONS , CLINICAL PHARMACOLOGY ].   Adrenal Insufficiency Inform patients that the opioids could cause adrenal insufficiency, a potentially life-threatening condition. Adrenal insufficiency may present with non-specific symptoms and signs such as nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. Advise patients to seek medical attention if they experience a constellation of these symptoms [see WARNINGS ]. Hypotension Inform patients that Hydrocodone Bitartrate and Aspirin Tablets may cause orthostatic hypotension and syncope. Instruct patients how to recognize symptoms of low blood pressure and how to reduce the risk of serious consequences should hypotension occur (e.g., sit or lie down, carefully rise from a sitting or lying position) [see WARNINGS ]. Anaphylaxis Inform patients that anaphylaxis has been reported with ingredients contained in Hydrocodone Bitartrate and Aspirin Tablets. Advise patients how to recognize such a reaction and when to seek medical attention [see CONTRAINDICATIONS , ADVERSE REACTIONS ]. Serious Skin Reactions, including DRESS Advise patients to stop taking Hydrocodone Bitartrate and Aspirin Tablets immediately if they develop any type of rash or fever and to contact their healthcare provider as soon as possible [see WARNINGS ]. Aspirin Allergy Patients should be informed that Hydrocodone Bitartrate and Aspirin Tablets contain aspirin and should not be taken by patients with an aspirin or NSAID allergy. Pregnancy Neonatal Opioid Withdrawal Syndrome Inform female patients of reproductive potential that the use of Hydrocodone Bitartrate and Aspirin Tablets for an extended period of time during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated [see WARNINGS , PRECAUTIONS ; Pregnancy ]. Embryo-Fetal Toxicity Inform female patients of reproductive potential that Hydrocodone Bitartrate and Aspirin Tablets can cause fetal harm and to inform their healthcare provider of a known or suspected pregnancy. Avoid use of Hydrocodone Bitartrate and Aspirin Tablets and other NSAIDs starting at 30 weeks gestation because of the risk of the premature closing of the fetal ductus arteriosus [see WARNINGS ; Premature Closure of the Ductus Arteriosus, PRECAUTIONS ; Pregnancy ]. Inform pregnant women to avoid use of aspirin and other NSAIDs starting at 30 weeks gestation because of the risk of the premature closing of the fetal ductus arteriosus. If treatment with Hydrocodone Bitartrate and Aspirin Tablets is needed for a pregnant woman between about 20 to 30 weeks gestation, advise her that she may need to be monitored for oligohydramnios, if treatment continues for longer than 48 hours [see WARNINGS ; Fetal Toxicity , PRECAUTIONS ; Pregnancy ]. Lactation Advise nursing mothers to carefully observe infants for increased sleepiness (more than usual), breathing difficulties, or limpness. Instruct nursing mothers to seek immediate medical care if they notice these signs [see PRECAUTIONS ; Nursing Mothers (Lactation) ]. Infertility Inform patients that use of opioids for extended period of time may cause reduced fertility. It is not known whether these effects on fertility are reversible [see ADVERSE REACTIONS ]. Advise females of reproductive potential who desire pregnancy that NSAIDs, including Hydrocodone Bitartrate and Aspirin Tablets, may be associated with a reversible delay in ovulation [see Use in Specific Populations ( PRECAUTIONS ; Carcinogenesis, Mutagenesis, Impairment of Fertility ) ]. Risk of Bleeding Inform patients about the signs and symptoms of bleeding. Tell patients to notify their physician if they are prescribed any drug which may increase risk of bleeding. Counsel patients who consume three or more alcoholic drinks daily about the bleeding risks involved with chronic, heavy alcohol use while taking aspirin [see WARNINGS ]. Avoid Concomitant Use of NSAIDs Inform patients that the concomitant use of Hydrocodone Bitartrate and Aspirin Tablets with NSAIDs or other salicylates (e.g., diflunisal, salsalate) is not recommended due to the increased risk of gastrointestinal toxicity, and little or no increase in efficacy [see WARNINGS , PRECAUTIONS ; Drug Interactions ]. Alert patients that NSAIDs may be present in "over the counter" medications for treatment of colds, fever, or insomnia. Aspirin has been associated with elevated hepatic enzymes, blood urea nitrogen and serum creatinine, hyperkalemia, proteinuria, and prolonged bleeding time. In patients with severe hepatic or renal disease, effects of therapy should be followed with serial liver and/or renal function tests. Hypersensitivity to aspirin cannot be detected by skin testing or radioimmunoassay procedure. Table 1: Clinically Significant Drug Interactions with Hydrocodone Bitartrate and Aspirin Tablets Inhibitors of CYP3A4 and CYP2D6 Clinical Impact: The concomitant use of Hydrocodone Bitartrate and Aspirin Tablets and CYP3A4 inhibitors can increase the plasma concentration of hydrocodone, resulting in increased or prolonged opioid effects. These effects could be more pronounced with concomitant use of Hydrocodone Bitartrate and Aspirin Tablets and CYP2D6 and CYP3A4 inhibitors, particularly when an inhibitor is added after a stable dose of Hydrocodone Bitartrate and Aspirin Tablets is achieved [see WARNINGS ]. After stopping 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. Intervention: If concomitant use is necessary, consider dosage reduction of Hydrocodone Bitartrate and Aspirin 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 Aspirin Tablets dosage until stable drug effects are achieved. Evaluate for signs of opioid withdrawal. Examples: Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), protease inhibitors (e.g., ritonavir) CYP3A4 Inducers Clinical Impact: The concomitant use of Hydrocodone Bitartrate and Aspirin Tablets and CYP3A4 inducers 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. Intervention: If concomitant use is necessary, consider increasing the Hydrocodone Bitartrate and Aspirin Tablets dosage until stable drug effects are achieved. Evaluate for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider Hydrocodone Bitartrate and Aspirin Tablets dosage reduction and evaluate patients at frequent intervals for signs of respiratory depression and sedation. Examples: Rifampin, carbamazepine, phenytoin Benzodiazepines and other Central Nervous System (CNS) Depressants Clinical Impact: Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants including alcohol, increases the risk of respiratory depression, profound sedation, coma, and death. Intervention: Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Inform patients and caregivers of this potential interaction, educate them on the signs and symptoms of respiratory depression (including sedation). If concomitant use is warranted, consider prescribing naloxone for the emergency treatment of opioid overdose [see WARNINGS ]. Examples: Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol. Serotonergic Drugs Clinical Impact: The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. Intervention: If concomitant use is warranted, frequently evaluate the patient, particularly during treatment initiation and dose adjustment. Discontinue Hydrocodone Bitartrate and Aspirin Tablets if serotonin syndrome is suspected. Examples: Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that effect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants ( i.e. , cyclobenzaprine, metaxalone), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). Monoamine Oxidase Inhibitors (MAOIs) Clinical Impact: MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma) [see WARNINGS ]. Intervention: The use of Hydrocodone Bitartrate and Aspirin Tablets is not recommended for patients taking MAOIs or within 14 days of stopping such treatment. If urgent use of an opioid is necessary, use test doses and frequent titration of small doses to treat pain while closely evaluating blood pressure and signs and symptoms of CNS and respiratory depression. Examples: Phenelzine, tranylcypromine, linezolid Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics Clinical Impact: May reduce the analgesic effect of Hydrocodone Bitartrate and Aspirin Tablets and/or precipitate withdrawal symptoms Intervention: Avoid concomitant use. Examples: Butorphanol, nalbuphine, pentazocine, buprenorphine Muscle Relaxants Clinical Impact: Hydrocodone may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression. Intervention: Because respiratory depression may be greater than otherwise expected, decrease the dosage of Hydrocodone Bitartrate and Aspirin Tablets and/or the muscle relaxant as necessary. Due to the risk of respiratory depression with concomitant use of muscle relaxants and opioids, consider prescribing naloxone for the emergency treatment of opioid overdose. Diuretics Clinical Impact: Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. The effectiveness of diuretics in patients with underlying renal or cardiovascular disease may be diminished by the concomitant administration of aspirin due to inhibition of renal prostaglandins, leading to decreased renal blood flow and salt and fluid retention. Intervention: Evaluate patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed. Anticholinergic Drugs Clinical Impact: The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Intervention: Evaluate patients for signs of urinary retention or reduced gastric motility when Hydrocodone Bitartrate and Aspirin Tablets is used concomitantly with anticholinergic drugs. Anticoagulants Clinical Impact: Aspirin may enhance the effects of anticoagulants. Concurrent use may increase the risk of bleeding. Aspirin can also displace warfarin from protein binding sites, leading to prolongation of both the prothrombin time and the bleeding time. Intervention: Follow patients for signs of bleeding. Examples: Warfarin, heparin, enoxaparin, clopidogrel, prasugrel, rivaroxaban, apixaban Uricosuric Agents Clinical Impact: Aspirin inhibits the uricosuric effects of uricosuric agents. Intervention: Avoid concomitant use. Examples: Probenecid Carbonic Anhydrase Inhibitors Clinical Impact: Concurrent use with aspirin can lead to high serum concentrations of the carbonic anhydrase inhibitor and cause toxicity due to competition at the renal tubule for secretion. Intervention: Consider reducing the dose of the carbonic anhydrase inhibitor and follow patient for any adverse effects from the carbonic anhydrase inhibitor. Examples: Acetazolamide, methazolamide Methotrexate Clinical Impact: Aspirin may enhance the toxicity of methotrexate by displacing it from its plasma protein binding sites and/or reducing its renal clearance. Intervention: Use caution if using concomitantly, especially in elderly patients or patients with renal impairment. Follow patients for methotrexate toxicity. Nephrotoxic Agents Clinical Impact: Concomitant use with aspirin may lead to additive nephrotoxicity due to the inhibition of renal prostaglandins by aspirin. Also, the plasma concentration of aspirin is increased by conditions that reduce the glomerular filtration rate or tubular secretion. Intervention: Use Hydrocodone Bitartrate and Aspirin Tablets with caution if used concomitantly with nephrotoxic agents. Closely follow the renal function of patients. Examples: Aminoglycosides, amphotericin B, systemic bacitracin, cisplatin, cyclosporine, foscarnet, or parenteral vancomycin Angiotensin Converting Enzyme (ACE) Inhibitors Clinical Impact: The hyponatremic and hypotensive effects of ACE inhibitors may be diminished by the concomitant administration of aspirin due to its indirect effect on the renin-angiotensin conversion pathway. Intervention: Use caution if using concomitantly. Follow the blood pressure and renal function of patients. Examples: Ramipril, captopril Beta Blockers Clinical Impact: The hypotensive effects of beta blockers may be diminished by the concomitant administration of aspirin due to inhibition of renal prostaglandins, leading to decreased renal blood flow, and salt and fluid retention. Intervention: Use caution if using concomitantly. Follow the blood pressure and renal function of patients. Examples: Metoprolol, propranolol Hypoglycemic Agents Clinical Impact: Aspirin may increase the serum glucose-lowering action of insulin and sulfonylureas leading to hypoglycemia. Intervention: Patients should be advised to consult a physician if any signs or symptoms of hypoglycemia occur. Examples: Insulin, glimepiride, glipizide Anticonvulsants Clinical Impact: Aspirin can displace protein-bound phenytoin and valproic acid, leading to a decrease in the total concentration of phenytoin and an increase in serum valproic acid levels. Intervention: Use caution if using concomitantly. Examples: Phenytoin, valproic acid Nonsteroidal Anti-inflammatory Drugs (NSAIDs) Clinical Impact: Concurrent use of aspirin with other NSAIDs may increase the risk of bleeding or lead to decreased renal function. Aspirin may enhance serious side effects and toxicity of ketorolac by displacing it from its plasma protein binding sites and/or reducing its renal clearance. Intervention: Avoid concomitant use. Examples: Ketoralac, ibuprofen, naproxen, diclofenac Corticosteroids Clinical Impact: In patients receiving concomitant corticosteroids and chronic use of aspirin, withdrawal of corticosteroids may result in salicylism because corticosteroids enhance renal clearance of salicylates and their withdrawal is followed by return to normal rates of renal clearance. Intervention: Avoid concomitant use. Depending on the sensitivity/specificity and the test methodology, the individual components of Hydrocodone Bitartrate and Aspirin Tablets may cross-react with assays used in the preliminary detection of cocaine (primary urinary metabolite, benzoylecgonine) or marijuana (cannabinoids) in human urine. A more specific alternate chemical method must be used in order to obtain a confirmed analytical result. The preferred confirmatory method is gas chromatography/mass spectrometry (GC/MS). Moreover, clinical considerations and professional judgment should be applied to any drug-of-abuse test result, particularly when preliminary positive results are used. Salicylates may increase the protein bound iodine (PBI) result by competing for the protein binding sites on pre-albumin and possibly thyroid-binding globulins. Aspirin Aspirin may interfere with the following laboratory determinations: In blood: serum amylase, fasting blood glucose, carbon dioxide, cholesterol, protein, protein bound iodine, uric acid, prothrombin time, bleeding time, and spectrophotometric detection of barbiturates. In urine: glucose, 5-hydroxyindoleacetic acid, Gerhardt ketone, vanillylmandelic acid (VMA), protein, uric acid, and diacetic acid. Carcinogenesis Long-term studies to evaluate the carcinogenic potential of the combination of Hydrocodone Bitartrate and Aspirin Tablets have not been conducted. Administration of aspirin for 68 weeks at 0.5 percent in the feed of rats was not carcinogenic. Mutagenesis The combination of hydrocodone and aspirin has not been evaluated for mutagenicity. In the Ames Salmonella assay, aspirin was not mutagenic; however, aspirin did induce chromosome aberrations in cultured human fibroblasts. Impairment of Fertility Animal studies to evaluate the effects of hydrocodone on fertility have not been conducted. Aspirin has been shown to inhibit ovulation in rats. Risk Summary Use of NSAIDs, including aspirin, can cause premature closure of the fetal ductus arteriosus and fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. Because of these risks, limit dose and duration of Hydrocodone Bitartrate and Aspirin Tablets use between about 20 weeks of gestation, and avoid Hydrocodone Bitartrate and Aspirin Tablets use at about 30 weeks of gestation and later in pregnancy [see WARNINGS ; Fetal Toxicity ]. Premature Closure of Fetal Ductus Arteriosus Use of NSAIDs, including aspirin, at about 30 weeks gestation or later in pregnancy increases the risk of premature closure of the fetal ductus arteriosus. Oligohydramnios/Neonatal Renal Impairment Use of NSAIDs at about 20 weeks gestation or later in pregnancy has been associated with cases of fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. Data from observational studies regarding other potential embryofetal risks of NSAID use in women in the first or second trimesters of pregnancy are inconclusive. Based on animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization. In animal studies, administration of prostaglandin synthesis inhibitors such as aspirin, resulted in increased pre- and post-implantation loss. Prostaglandins also have been shown to have an important role in fetal kidney development. In published animal studies, prostaglandin synthesis inhibitors have been reported to impair kidney development when administered at clinically relevant doses. The estimated background risk of major birth defects and miscarriage for the indicated population(s) is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20% respectively. Clinical Considerations 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 ]. Premature Closure of Fetal Ductus Arteriosus: Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy, because NSAIDs, including Hydrocodone Bitartrate and Aspirin Tablets, can cause premature closure of the fetal ductus arteriosus [see WARNINGS ; Fetal Toxicity ]. Oligohydramnios/Neonatal Renal Impairment If an NSAID is necessary at about 20 weeks gestation or later in pregnancy, limit the use to the lowest effective dose and shortest duration possible. If Hydrocodone Bitartrate and Aspirin Tablets treatment extends beyond 48 hours, consider monitoring with ultrasound for oligohydramnios. If oligohydramnios occurs, discontinue Hydrocodone Bitartrate and Aspirin Tablets and follow up according to clinical practice [see WARNINGS ; Fetal Toxicity ]. Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. An opioid antagonist, such as naloxone must be available for reversal of opioid-induced respiratory depression in the neonate. Hydrocodone Bitartrate and Aspirin Tablets is not recommended for use in women during and immediately prior to labor, when use of shorter acting analgesics or other analgesic techniques are more appropriate. Occasionally, opioid analgesics, including Hydrocodone Bitartrate and Aspirin Tablets, can prolong labor through actions which temporarily reduce the strength, duration, and frequency of uterine contractions. However this effect is not consistent and may be offset by an increased rate of cervical dilation, which tends to shorten labor. Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression. Aspirin should be avoided one week prior to and during labor and delivery because it can result in excessive blood loss at delivery. Prolonged gestation and prolonged labor due to prostaglandin inhibition have been reported. Data Human Data Premature Closure of Fetal Ductus Arteriosus: Published literature reports that the use of NSAIDs at about 30 weeks of gestation and later in pregnancy may cause premature closure of the fetal ductus arteriosus. Oligohydramnios/Neonatal Renal Impairment: Published studies and postmarketing reports describe maternal NSAID use at about 20 weeks gestation or later in pregnancy associated with fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently as soon as 48 hours after NSAID initiation. In many cases, but not all, the decrease in amniotic fluid was transient and reversible with cessation of the drug. There have been a limited number of case reports of maternal NSAID use and neonatal renal dysfunction without oligohydramnios, some which were irreversible. Some cases of neonatal renal dysfunction required treatment with invasive procedures, such as exchange transfusion or dialysis. Methodological limitations of these postmarketing studies and reports include lack of a control group; limited information regarding dose, duration, and timing of drug exposure; and concomitant use of other medications. These limitations preclude establishing a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal NSAID use. Because the published safety data on neonatal outcomes involved mostly preterm infants, the generalizability of certain reported risks to the full-term infant exposed to NSAIDs through maternal use is uncertain. Animal Data Animal reproduction studies with the combination of hydrocodone and aspirin or the individual drugs alone are not available. Risk Summary Hydrocodone is present in human milk. Salicylic acid has been detected in breast milk. Adverse effects on platelet function in the nursing infant exposed to aspirin in breast milk may be a potential risk. Furthermore, the risk of Reye’s Syndrome caused by salicylate in breast milk is unknown. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Hydrocodone Bitartrate and Aspirin Tablets and any potential adverse effects on the breastfed infant from Hydrocodone Bitartrate and Aspirin Tablets or from the underlying maternal condition. Clinical Considerations Monitor infants exposed to Hydrocodone Bitartrate and Aspirin Tablets through breast milk 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. Infertility Use of opioids for extended period of time may cause reduced fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible [see ADVERSE REACTIONS ]. Females Based on the mechanism of action, the use of prostaglandin-mediated NSAIDs, including aspirin, may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility in some women. Published animal studies have shown that administration of prostaglandin synthesis inhibitors has the potential to disrupt prostaglandin-mediated follicular rupture required for ovulation. Small studies in women treated with NSAIDs have also shown a reversible delay in ovulation. Consider withdrawal of NSAIDs, including aspirin, in women who have difficulties conceiving or who are undergoing investigation of infertility. Hydrocodone Bitartrate and Aspirin Tablets should not be administered to pediatric patients. Reye’s Syndrome is a rare but serious disease which can follow flu or chicken pox in children and teenagers. While the cause of Reye’s Syndrome is unknown, some reports claim aspirin (or salicylates) may increase the risk of developing this disease. Elderly patients (aged 65 years or older) may have increased sensitivity to Hydrocodone Bitartrate and Aspirin Tablets. 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 Aspirin Tablets slowly in geriatric patients and frequently reevaluate the patient for signs of central nervous system and respiratory depression [see WARNINGS ]. Hydrocodone and aspirin 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. Elderly patients, compared to younger patients, are at greater risk for NSAID-associated serious cardiovascular, gastrointestinal, and/or renal adverse reactions. If the anticipated benefit for the elderly patient outweighs these potential risks, dose selection should start at the low end of the dosing range, and follow patients for adverse effects [see WARNINGS , PRECAUTIONS ]. Patients with hepatic impairment may have higher plasma hydrocodone concentrations than those with normal function. Use a low initial dose of Hydrocodone Bitartrate and Aspirin Tablets in patients with hepatic impairment and follow closely for adverse events such as respiratory depression and sedation. Avoid aspirin in patients with severe hepatic impairment. Patients with renal impairment may have higher plasma hydrocodone concentrations than those with normal function. Use a low initial dose Hydrocodone Bitartrate and Aspirin Tablets in patients with renal impairment and follow closely for adverse events such as respiratory depression and sedation. Avoid aspirin in patients with severe renal impairment (glomerular filtration rate less than 10 mL/minute).

The following serious adverse reactions are described, or described in greater detail, in other sections:

Table 1: Clinically Significant Drug Interactions with Hydrocodone Bitartrate and Aspirin Tablets Inhibitors of CYP3A4 and CYP2D6 Clinical Impact: The concomitant use of Hydrocodone Bitartrate and Aspirin Tablets and CYP3A4 inhibitors can increase the plasma concentration of hydrocodone, resulting in increased or prolonged opioid effects. These effects could be more pronounced with concomitant use of Hydrocodone Bitartrate and Aspirin Tablets and CYP2D6 and CYP3A4 inhibitors, particularly when an inhibitor is added after a stable dose of Hydrocodone Bitartrate and Aspirin Tablets is achieved [see WARNINGS ]. After stopping 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. Intervention: If concomitant use is necessary, consider dosage reduction of Hydrocodone Bitartrate and Aspirin 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 Aspirin Tablets dosage until stable drug effects are achieved. Evaluate for signs of opioid withdrawal. Examples: Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), protease inhibitors (e.g., ritonavir) CYP3A4 Inducers Clinical Impact: The concomitant use of Hydrocodone Bitartrate and Aspirin Tablets and CYP3A4 inducers 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. Intervention: If concomitant use is necessary, consider increasing the Hydrocodone Bitartrate and Aspirin Tablets dosage until stable drug effects are achieved. Evaluate for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider Hydrocodone Bitartrate and Aspirin Tablets dosage reduction and evaluate patients at frequent intervals for signs of respiratory depression and sedation. Examples: Rifampin, carbamazepine, phenytoin Benzodiazepines and other Central Nervous System (CNS) Depressants Clinical Impact: Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants including alcohol, increases the risk of respiratory depression, profound sedation, coma, and death. Intervention: Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Inform patients and caregivers of this potential interaction, educate them on the signs and symptoms of respiratory depression (including sedation). If concomitant use is warranted, consider prescribing naloxone for the emergency treatment of opioid overdose [see WARNINGS ]. Examples: Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol. Serotonergic Drugs Clinical Impact: The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. Intervention: If concomitant use is warranted, frequently evaluate the patient, particularly during treatment initiation and dose adjustment. Discontinue Hydrocodone Bitartrate and Aspirin Tablets if serotonin syndrome is suspected. Examples: Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that effect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants ( i.e. , cyclobenzaprine, metaxalone), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). Monoamine Oxidase Inhibitors (MAOIs) Clinical Impact: MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma) [see WARNINGS ]. Intervention: The use of Hydrocodone Bitartrate and Aspirin Tablets is not recommended for patients taking MAOIs or within 14 days of stopping such treatment. If urgent use of an opioid is necessary, use test doses and frequent titration of small doses to treat pain while closely evaluating blood pressure and signs and symptoms of CNS and respiratory depression. Examples: Phenelzine, tranylcypromine, linezolid Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics Clinical Impact: May reduce the analgesic effect of Hydrocodone Bitartrate and Aspirin Tablets and/or precipitate withdrawal symptoms Intervention: Avoid concomitant use. Examples: Butorphanol, nalbuphine, pentazocine, buprenorphine Muscle Relaxants Clinical Impact: Hydrocodone may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression. Intervention: Because respiratory depression may be greater than otherwise expected, decrease the dosage of Hydrocodone Bitartrate and Aspirin Tablets and/or the muscle relaxant as necessary. Due to the risk of respiratory depression with concomitant use of muscle relaxants and opioids, consider prescribing naloxone for the emergency treatment of opioid overdose. Diuretics Clinical Impact: Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. The effectiveness of diuretics in patients with underlying renal or cardiovascular disease may be diminished by the concomitant administration of aspirin due to inhibition of renal prostaglandins, leading to decreased renal blood flow and salt and fluid retention. Intervention: Evaluate patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed. Anticholinergic Drugs Clinical Impact: The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Intervention: Evaluate patients for signs of urinary retention or reduced gastric motility when Hydrocodone Bitartrate and Aspirin Tablets is used concomitantly with anticholinergic drugs. Anticoagulants Clinical Impact: Aspirin may enhance the effects of anticoagulants. Concurrent use may increase the risk of bleeding. Aspirin can also displace warfarin from protein binding sites, leading to prolongation of both the prothrombin time and the bleeding time. Intervention: Follow patients for signs of bleeding. Examples: Warfarin, heparin, enoxaparin, clopidogrel, prasugrel, rivaroxaban, apixaban Uricosuric Agents Clinical Impact: Aspirin inhibits the uricosuric effects of uricosuric agents. Intervention: Avoid concomitant use. Examples: Probenecid Carbonic Anhydrase Inhibitors Clinical Impact: Concurrent use with aspirin can lead to high serum concentrations of the carbonic anhydrase inhibitor and cause toxicity due to competition at the renal tubule for secretion. Intervention: Consider reducing the dose of the carbonic anhydrase inhibitor and follow patient for any adverse effects from the carbonic anhydrase inhibitor. Examples: Acetazolamide, methazolamide Methotrexate Clinical Impact: Aspirin may enhance the toxicity of methotrexate by displacing it from its plasma protein binding sites and/or reducing its renal clearance. Intervention: Use caution if using concomitantly, especially in elderly patients or patients with renal impairment. Follow patients for methotrexate toxicity. Nephrotoxic Agents Clinical Impact: Concomitant use with aspirin may lead to additive nephrotoxicity due to the inhibition of renal prostaglandins by aspirin. Also, the plasma concentration of aspirin is increased by conditions that reduce the glomerular filtration rate or tubular secretion. Intervention: Use Hydrocodone Bitartrate and Aspirin Tablets with caution if used concomitantly with nephrotoxic agents. Closely follow the renal function of patients. Examples: Aminoglycosides, amphotericin B, systemic bacitracin, cisplatin, cyclosporine, foscarnet, or parenteral vancomycin Angiotensin Converting Enzyme (ACE) Inhibitors Clinical Impact: The hyponatremic and hypotensive effects of ACE inhibitors may be diminished by the concomitant administration of aspirin due to its indirect effect on the renin-angiotensin conversion pathway. Intervention: Use caution if using concomitantly. Follow the blood pressure and renal function of patients. Examples: Ramipril, captopril Beta Blockers Clinical Impact: The hypotensive effects of beta blockers may be diminished by the concomitant administration of aspirin due to inhibition of renal prostaglandins, leading to decreased renal blood flow, and salt and fluid retention. Intervention: Use caution if using concomitantly. Follow the blood pressure and renal function of patients. Examples: Metoprolol, propranolol Hypoglycemic Agents Clinical Impact: Aspirin may increase the serum glucose-lowering action of insulin and sulfonylureas leading to hypoglycemia. Intervention: Patients should be advised to consult a physician if any signs or symptoms of hypoglycemia occur. Examples: Insulin, glimepiride, glipizide Anticonvulsants Clinical Impact: Aspirin can displace protein-bound phenytoin and valproic acid, leading to a decrease in the total concentration of phenytoin and an increase in serum valproic acid levels. Intervention: Use caution if using concomitantly. Examples: Phenytoin, valproic acid Nonsteroidal Anti-inflammatory Drugs (NSAIDs) Clinical Impact: Concurrent use of aspirin with other NSAIDs may increase the risk of bleeding or lead to decreased renal function. Aspirin may enhance serious side effects and toxicity of ketorolac by displacing it from its plasma protein binding sites and/or reducing its renal clearance. Intervention: Avoid concomitant use. Examples: Ketoralac, ibuprofen, naproxen, diclofenac Corticosteroids Clinical Impact: In patients receiving concomitant corticosteroids and chronic use of aspirin, withdrawal of corticosteroids may result in salicylism because corticosteroids enhance renal clearance of salicylates and their withdrawal is followed by return to normal rates of renal clearance. Intervention: Avoid concomitant use.

Hydrocodone Bitartrate and Aspirin Tablets are supplied as oval, bisected white tablets containing 5 mg Hydrocodone Bitartrate and 500 mg of Aspirin. Each tablet is debossed with “MLB” bisect “125” on one side and “5-500” on the other side. Bottles of 100 tablets – NDC 79739-7182-1 Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F). [See USP Controlled Room Temperature]. Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required). Protect from moisture. Store Hydrocodone Bitartrate and Aspirin Tablets securely and dispose of properly [see PRECAUTIONS ; Information for Patients/Caregivers ] Manufactured by: LGM Pharma Solutions, LLC, Irvine, CA 92614 7182-PD Rev 01/2024

Hydrocodone is 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. Aspirin is a nonsteroidal anti-inflammatory drug. Aspirin (acetylsalicylic acid) is a more potent inhibitor of both prostaglandin synthesis and platelet aggregation than other salicylic acid derivatives. The differences in activity between aspirin and salicylic acid are thought to be due to the acetyl group on the aspirin molecule. This acetyl group is responsible for the inactivation of cyclo-oxygenase via acetylation. Aspirin (acetylsalicylic acid) works by inhibiting the body's production of prostaglandins, including prostaglandins involved in inflammation. Prostaglandins cause pain sensations by stimulating muscle contractions and dilating blood vessels throughout the body. In the CNS, aspirin works on the hypothalamus heat-regulating center to reduce fever, however, other mechanisms may be involved. Aspirin affects platelet aggregation by irreversibly inhibiting prostaglandin cyclo-oxygenase. This effect lasts for the life of the platelet and prevents the formation of the platelet aggregating factor thromboxane A2. Nonacetylated salicylates do not inhibit this enzyme and have no effect on platelet aggregation. At somewhat higher doses, aspirin reversibly inhibits the formation of prostaglandin I2 (prostacyclin), which is an arterial vasodilator and inhibits platelet aggregation. At higher doses aspirin is an effective anti-inflammatory agent, partially due to inhibition of inflammatory mediators via cyclo-oxygenase inhibition in peripheral tissues. In vitro studies suggest that other mediators of inflammation may also be suppressed by aspirin administration, although the precise mechanism of action has not been elucidated. It is this nonspecific suppression of cyclo-oxygenase activity in peripheral tissues following large doses that leads to its primary side effect of gastric irritation. [see ADVERSE REACTIONS ]. Effects on the Central Nervous System 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. 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. Aspirin can produce gastrointestinal injury (lesions, ulcers) through a mechanism that is not yet completely understood, but may involve a reduction in eicosanoid synthesis by the gastric mucosa. Decreased production of prostaglandins may compromise the defenses of the gastric mucosa and the activity of substances involved in tissue repair and ulcer healing. 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 symptoms as low libido, impotence, erectile dysfunction, amenorrhea, or infertility. The casual 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. Concentration-Efficacy Relationships The minimum effective analgesic concentration will vary widely among patients, especially among patients who have been previously treated with agonist 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 ]. Concentration-Adverse 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 ]. The dose of Hydrocodone Bitartrate and Aspirin Tablets must be individualized because the effective analgesic dose for some patients will be too high to be tolerated by other patients [see DOSAGE AND ADMINISTRATION ]. The behavior of the individual components is described below. Hydrocodone Absorption: 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. Elimination: Metabolism 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. 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. Excretion Hydrocodone and its metabolites are eliminated primarily in the kidneys. Aspirin Absorption: In general, immediate release aspirin is well and completely absorbed from the gastrointestinal (GI) tract. Following absorption, aspirin is hydrolyzed to salicylic acid with peak plasma levels of salicylic acid occurring within 1-2 hours of dosing [see Pharmacokinetics — Metabolism ]. The rate of absorption from the GI tract is dependent upon the dosage form, the presence or absence of food, gastric pH (the presence or absence of GI antacids or buffering agents), and other physiologic factors. Distribution: Salicylic acid is widely distributed to all tissues and fluids in the body including the central nervous system (CNS), breast milk, and fetal tissues. The highest concentrations are found in the plasma, liver, renal cortex, heart, and lungs. The protein binding of salicylate is concentration-dependent, i.e., nonlinear. At low concentrations (<100 micrograms/milliliter ([micro]g/mL)), approximately 90 percent of plasma salicylate is bound to albumin while at higher concentrations (>400 [micro]g/mL), only about 75 percent is bound. Elimination: Metabolism Aspirin is rapidly hydrolyzed in the plasma to salicylic acid such that plasma levels of aspirin are essentially undetectable 1-2 hours after dosing. Salicylic acid is primarily conjugated in the liver to form salicyluric acid, a phenolic glucuronide, an acyl glucuronide, and a number of minor metabolites. Salicylic acid has a plasma half-life of approximately 6 hours. Salicylate metabolism is saturable and total body clearance decreases at higher serum concentrations due to the limited ability of the liver to form both salicyluric acid and phenolic glucuronide. Following toxic doses (10-20 grams (g)), the plasma half-life may be increased to over 20 hours. Excretion The elimination of salicylic acid follows zero order pharmacokinetics; ( i.e., the rate of drug elimination is constant in relation to plasma concentration). Renal excretion of unchanged drug depends upon urine pH. As urinary pH rises above 6.5, the renal clearance of free salicylate increases from <5 percent to >80 percent. Following therapeutic doses, approximately 10 percent is found excreted in the urine as salicylic acid, 75 percent as salicyluric acid, and 10 percent phenolic and 5 percent acyl glucuronides of salicylic acid.

NDC 79739-7182-1 Hydrocodone Bitartrate and Aspirin Tablets CIII 5 mg/500 mg PHARMACIST: Dispense the Medication Guide provided separately to each patient. Rx only                                     100 TABLETS Manufactured by : LGM Pharma Solutions, LLC Irvine, CA 92614 EACH TABLET CONTAINS: Hydrocodone Bitartrate ………………………. 5 mg Aspirin………………………………………………. 500 mg Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F). [See USP Controlled Room Temperature]. Dispense in a tight, light-resistant containers as defined in the USP, with a child-resistant closure (as required). Protect from moisture. 7182-PD                                     Rev 05/2021 The usual adult dosage is one or two tablets every four to six hours as needed for pain. KEEP OUT OF THE REACH OF CHILDREN. NDC 79739-7182-1 Hydrocodone Bitartrate and Aspirin Tablets CIII 5 mg/500 mg PHARMACIST: Dispense the Medication Guide provided separately to each patient. Rx only 100 TABLETS Manufactured by : LGM Pharma Solutions, LLC Irvine, CA 92614 EACH TABLET CONTAINS: Hydrocodone Bitartrate ………………………. 5 mg Aspirin………………………………………………. 500 mg Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F). [See USP Controlled Room Temperature]. Dispense in a tight, light-resistant containers as defined in the USP, with a child-resistant closure (as required). Protect from moisture. 7182-PD Rev 05/2021 The usual adult dosage is one or two tablets every four to six hours as needed for pain. KEEP OUT OF THE REACH OF CHILDREN.