Hydrocodone Bitartrate and Aspirin Dailymed

Precautions

General

Aspirin has been associated with elevated hepatic enzymes, blood urea nitrogen and serum creatinine, hyperkalemia, proteinuria, and prolonged bleeding time.

Hemorrhage

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.

Ambulatory Surgery and Postoperative Use

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 and Hyperkalemia

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.

Premature Closure of Fetal Ductus Arteriosus

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 ].

Information for Patients/Caregivers

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Storage and Disposal

Because of the risks associated with accidental ingestion, misuse, and abuse, advise patients to store Hydrocodone Bitartrate and 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 ul 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.

Laboratory Tests

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.

Drug Interactions

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.

Drug/Laboratory Test Interactions

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, Mutagenesis, Impairment of Fertility

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.

Pregnancy

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 ].

Labor and Delivery

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.

Lactation

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.

Females and Males of Reproductive Potential

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.

Pediatric Use

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.

Geriatric Use

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 ].

Hepatic Impairment

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.

Renal 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).