odone bitartrate and aspirin tablets until stable drug effects are achieved. monitor patients for respiratory depression and sedation at frequent intervals. if a cyp3a4 inhibitor is discontinued, consider increasing the hydrocodone bitartrate and aspirin tablets dosage until stable drug effects are achieved. monitor 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. monitor for signs of opioid withdrawal. if a cyp3a4 inducer is discontinued, consider hydrocodone bitartrate and aspirin tablets dosage reduction and monitor for signs of respiratory depression. 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. follow patients closely for signs of respiratory depression and 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, carefully observe 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 monitoring 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: monitor patients for signs of respiratory depression that may be greater than otherwise expected and 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 skeletal muscle relaxants and opioids, consider prescribing naloxone for the emergency treatment of opioid overdose [see warnings ]. 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: monitor 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: monitor 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.

not, however, prevent the proper management of pain in any given patient. patients at increased risk may be prescribed opioids such as hydrocodone bitartrate and aspirin tablets, but use in such patients necessitates intensive counseling about the risks and proper use of hydrocodone bitartrate and aspirin tablets along with intensive monitoring for signs of addiction, abuse, and misuse. consider prescribing naloxone for the emergency treatment of opioid overdose [see warnings; life-threatening respiratory depression , dosage and administration; patient access to naloxone for the emergency treatment of opioid overdose ] . opioids are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. consider these risks when prescribing or dispensing hydrocodone bitartrate and aspirin tablets. strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on the proper disposal of unused drug [see precautions; information for patients/caregivers ]. contact local state professional licensing board or state controlled substances authority for information on how to prevent and detect abuse or diversion of this product. opioid analgesic risk evaluation and mitigation strategy (rems) to ensure that the benefits of opioid analgesics outweigh the risks of addiction, abuse, and misuse, the food and drug administration (fda) has required a risk evaluation and mitigation strategy (rems) for these products. under the requirements of the rems, drug companies with approved opioid analgesic products must make rems-compliant education programs available to healthcare providers. prescribers are strongly encouraged to do all of the following: • complete a rems-compliant education program offered by an accredited provider of continuing education (ce) or another education program that includes all the elements of the fda education blueprint for health care providers involved in the management or support of patients with pain. • discuss the safe use, serious risks, and proper storage and disposal of opioid analgesics with patients and/or their caregivers every time these medicines are prescribed. the patient counseling guide (pcg) can be obtained at this link: www.fda.gov/opioidanalgesicremspcg . • emphasize to patients and their caregivers the importance of reading the medication guide that they will receive from their pharmacist every time an opioid analgesic is dispensed to them. • consider using other tools to improve patient, household, and community safety, such as patient-prescriber agreements that reinforce patient-prescriber responsibilities. to obtain further information on the opioid analgesic rems and for a list of accredited rems cme/ce, call 800-503-0784, or log on to www.opioidanalgesicrems.com . the fda blueprint can be found at www.fda.gov/opioidanalgesicremsblueprint . life-threatening respiratory depression serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended. respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient's clinical status [see overdosage ]. carbon dioxide (co 2 ) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids. while serious, life-threatening, or fatal respiratory depression can occur at any time during the use of hydrocodone bitartrate and aspirin tablets, the risk is greatest during the initiation of therapy or following a dosage increase. monitor patients closely for respiratory depression, especially within the first 24-72 hours of initiating therapy with and following dosage increases of hydrocodone bitartrate and aspirin tablets. to reduce the risk of respiratory depression, proper dosing and titration of hydrocodone bitartrate and aspirin tablets are essential [see dosage and administration ]. overestimating the hydrocodone bitartrate and aspirin tablets dosage when converting patients from another opioid product can result in a fatal overdose. accidental ingestion of hydrocodone bitartrate and aspirin tablets, especially by children, can result in respiratory depression and death due to an overdose of hydrocodone bitartrate and aspirin tablets. educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help right away in the event of a known or suspected overdose [see precautions; information for patients/caregivers ]. opioids can cause sleep-related breathing disorders including central sleep apnea (csa) and sleep-related hypoxemia. opioid use increases the risk of csa in a dose-dependent fashion. in patients who present with csa, consider decreasing the opioid dosage using best practices for opioid taper [see dosage and administration ]. patient access to naloxone for the emergency treatment of opioid overdose discuss the availability of naloxone for the emergency treatment of opioid overdose with the patient and caregiver and assess the potential need for personal access to naloxone, 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 requirements or guidelines (e.g., by prescription, directly from a pharmacist, or as part of a community-based program). educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help, even if naloxone is administered [see precautions; information for patients/caregivers ]. consider prescribing naloxone, based on the patient’s risk factors for overdose, such as concomitant use of cns depressants, a history of opioid use disorder, or prior opioid overdose. the presence of risk factors for overdose should not prevent the proper management of pain in any given patient. also consider prescribing naloxone when there are household members (including children) or other close contacts at risk for accidental ingestion or overdose. if naloxone is prescribed, educate patients and caregivers on how to treat with naloxone [see warnings ; addiction, abuse, and misuse ; risks from concomitant use with benzodiazepines or other cns depressants , precautions; information for patients/caregivers ]. neonatal opioid withdrawal syndrome prolonged use of hydrocodone bitartrate and aspirin tablets hydrocodone bitartrate and aspirin tablets during pregnancy can result in withdrawal in the neonate. neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly. advise pregnant women using opioids for a prolonged period of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [see precautions ; information for patients/caregivers ; pregnancy ]. risks of concomitant use for discontinuation of cytochrome p450 3a4 inhibitors and inducers concomitant use of hydrocodone bitartrate and aspirin tablets with a cyp3a4 inhibitor, such as macrolide antibiotics (e.g., erythromycin), azote-antifungal agents (e.g., ketoconazole), and protease inhibitors (e.g., ritonavir), may increase plasma concentrations of hydrocodone bitartrate and aspirin tablets and prolong opioid adverse reactions, and which may cause potentially fatal respiratory depression [see warnings ], particularly when an inhibitor is added after a stable dose of hydrocodone bitartrate and aspirin tablets is achieved. similarly, discontinuation of a cyp3a4 inducer, such as rifampin, carbamazepine, and phenytoin, in hydrocodone bitartrate and aspirin tablet-treated patients may increase hydrocodone plasma concentrations and prolong opioid adverse reactions. when adding cyp3a4 inhibitors or discontinuing cyp3a4 inducers in hydrocodone bitartrate and aspirin tablet-treated patients, follow patients at frequent intervals and consider dosage reduction of hydrocodone bitartrate and aspirin tablets until stable drug effects are achieved [see precautions; drug interactions ]. concomitant use of hydrocodone bitartrate and aspirin tablets with cyp3a4 inducers or discontinuation of a cyp3a4 inhibitor could decrease hydrocodone plasma concentrations, decrease opioid efficacy or, possibly, lead to a withdrawal syndrome in a patient who had developed physical dependence to hydrocodone. when using hydrocodone bitartrate and aspirin tablets with cyp3a4 inducers or discontinuing cyp3a4 inhibitors, monitor patients closely at frequent intervals and consider increasing the opioid dosage if needed to maintain adequate analgesia or if symptoms of opioid withdrawal occur [see precautions; drug interactions ]. risks from concomitant use with benzodiazepines or other cns depressants profound sedation, respiratory depression, coma, and death may result from the concomitant use of hydrocodone bitartrate and aspirin tablets with benzodiazepines or other cns depressants (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol). because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioid analgesics alone. because of similar pharmacological properties, it is reasonable to expect similar risk with the concomitant use of other cns depressant drugs with opioid analgesics [see precautions; drug interactions ]. if the decision is made to prescribe a benzodiazepine or other cns depressant concomitantly with an opioid analgesic, prescribe the lowest effective dosages and minimum durations of concomitant use. in patients already receiving an opioid analgesic, prescribe a lower initial dose of the benzodiazepine or other cns depressant than indicated in the absence of an opioid, and titrate based on clinical response. if an opioid analgesic is initiated in a patient already taking a benzodiazepine or other cns depressant, prescribe a lower initial dose of the opioid analgesic, and titrate based on clinical response. follow patients closely for signs and symptoms of respiratory depression and sedation. if concomitant use is warranted, consider prescribing naloxone for the emergency treatment of opioid overdose [see dosage and administration; patient access to naloxone for the emergency treatment of opioid overdose , warnings ; life-threatening respiratory depression ]. advise both patients and caregivers about the risks of respiratory depression and sedation when hydrocodone bitartrate and aspirin tablets are used with benzodiazepines or other cns depressants (including alcohol and illicit drugs). advise patients not to drive or operate heavy machinery until the effects of concomitant use of the benzodiazepine or other cns depressant have been determined. screen patients for risk of substance use disorders, including opioid abuse and misuse, and warn them of the risk for overdose and death associated with the use of additional cns depressants including alcohol and illicit drugs [see precautions ; drug interactions ; information for patients/caregivers ]. life-threatening respiratory depression in patients with chronic pulmonary disease or in elderly, cachectic, or debilitated patients the use of hydrocodone bitartrate and aspirin tablets in patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment is contraindicated. patients with chronic pulmonary disease : hydrocodone bitartrate and aspirin tablet-treated patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression are at increased risk of decreased respiratory drive including apnea, even at recommended dosages of hydrocodone bitartrate and aspirin tablets [see warnings ; life-threatening respiratory depression ]. elderly, cachectic, or debilitated patients : life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients because they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients [see warnings ; life-threatening respiratory depression ]. follow such patients closely, particularly when initiating and titrating hydrocodone bitartrate and aspirin tablets and when hydrocodone bitartrate and aspirin tablets is given concomitantly with other drugs that depress respiration [see warnings ; life-threatening respiratory depression ]. alternatively, consider the use of non-opioid analgesics in these patients. adrenal insufficiency cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. presentation of adrenal insufficiency may include non-specific symptoms and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. if adrenal insufficiency is suspected, confirm the diagnosis with diagnostic testing as soon as possible. if adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids. wean the patient off of the opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers. other opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency. the information available does not identify any particular opioids as being more likely to be associated with adrenal insufficiency. severe hypotension hydrocodone bitartrate and aspirin tablets may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients. there is increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain cns depressant drugs (e.g., phenothiazines or general anesthetics) [see precautions ; drug interactions ]. monitor these patients for signs of hypotension after initiating or titrating the dosage of hydrocodone bitartrate and aspirin tablets. in patients with circulatory shock hydrocodone bitartrate and aspirin tablets may cause vasodilatation that can further reduce cardiac output and blood pressure. avoid the use of hydrocodone bitartrate and aspirin tablets with circulatory shock. risks of use in patients with increased intracranial pressure, brain tumors, head injury, or impaired consciousness in patients who may be susceptible to the intracranial effects of co 2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors), hydrocodone bitartrate and aspirin tablets may reduce respiratory drive, and the resultant co 2 retention can further increase intracranial pressure. monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy with hydrocodone bitartrate and aspirin tablets. opioids may also obscure the clinical course in a patient with a head injury. avoid the use of hydrocodone bitartrate and aspirin tablets in patients with impaired consciousness or coma. risks of use in patients with gastrointestinal conditions hydrocodone bitartrate and aspirin tablets are contraindicated in patients with gastrointestinal obstruction, including paralytic ileus. hydrocodone may cause spasm of the sphincter of oddi. opioids may cause increases in serum amylase. monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms. gastrointestinal bleeding, ulceration, and perforation the aspirin in hydrocodone bitartrate and aspirin tablets can cause gi side effects including stomach pain, heartburn, nausea, vomiting, and gross gi bleeding. although minor upper gi symptoms, such as dyspepsia, are common and can occur anytime during therapy, physicians should remain alert for signs of ulceration and bleeding, even in the absence of previous gi symptoms. physicians should inform patients about the signs and symptoms of gi side effects and what steps to take if they occur. risk factors for gi bleeding, ulceration, and perforation patients with a prior history of peptic ulcer disease and/or gi bleeding who used nsaids had a greater than 10-fold increased risk for developing a gi bleed compared to patients without these risk factors. other factors that increase the risk for of gi bleeding in patients treated with nsaids include longer duration of nsaid therapy; concomitant use of oral corticosteroids, aspirin, anticoagulants, or selective serotonin reuptake inhibitors (ssris); smoking; use of alcohol; older age; and poor general health status. most postmarketing reports of fatal gi events occurred in elderly or debilitated patients. additionally, patients with advanced liver disease and/or coagulopathy are at increased risk for gi bleeding. strategies to minimize the gi risks in nsaid-treated patients • use the lowest effective dosage for the shortest possible duration. • avoid administration of more than one nsaid at a time. • avoid use in patients at higher risk unless benefits are expected to outweigh the increased risk of bleeding. for high risk such patients, as well as those with active gi bleeding, consider alternate therapies other than nsaids. • remain alert for signs and symptoms of gi ulceration and bleeding during nsaid therapy. • if a serious gi adverse event is suspected, promptly initiate evaluation and treatment, and discontinue hydrocodone bitartrate and aspirin tablets until a serious gi adverse event is ruled out. • in the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, monitor patients more closely for evidence of gi bleeding [see drug interactions ]. increased risk of seizures in patients with seizure disorders the hydrocodone in hydrocodone bitartrate and aspirin tablets may increase the frequency of seizures in patients with seizure disorders, and may increase the risk of seizures occurring in other clinical settings associated with seizures. follow patients with a history of seizure disorders for worsened seizure control during hydrocodone bitartrate and aspirin tablet therapy. withdrawal do not abruptly discontinue hydrocodone bitartrate and aspirin tablets in a patient physically dependent on opioids. when discontinuing hydrocodone bitartrate and aspirin tablets in a physically-dependent patient, gradually taper the dosage. rapid tapering of hydrocodone in a patient physically dependent on opioids may lead to a withdrawal syndrome and return of pain [see dosage and administration , drug abuse and dependence ]. additionally, avoid the use of mixed agonist/antagonist (e.g., pentazocine, nalbuphine, and butorphanol) or partial agonist (e.g., buprenorphine) analgesics in patients who are receiving a full opioid agonist analgesic, including hydrocodone bitartrate and aspirin tablets. in these patients, mixed agonist/antagonist and partial analgesics may reduce the analgesic effect and/or precipitate withdrawal symptoms [see precautions ; drug interactions ]. fetal toxicity premature closure of fetal ductus arteriosus : avoid use of nsaids, including hydrocodone bitartrate and aspirin tablets, in pregnant women at about 30 weeks gestation and later. nsaids including hydrocodone bitartrate and aspirin tablets, increase the risk of premature closure of the fetal ductus arteriosus at approximately this gestational age. oligohydramnios/neonatal renal impairment : use of nsaids, including hydrocodone bitartrate and aspirin tablets, at about 20 weeks gestation or later in pregnancy may cause 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 reported as soon as 48 hours after nsaid initiation. oligohydramnios is often, but not always, reversible with treatment discontinuation. complications of prolonged oligohydramnios may, for example, include limb contractures and delayed lung maturation. in some postmarketing cases of impaired neonatal renal function, invasive procedures such as exchange transfusion or dialysis were required. if nsaid treatment is necessary between about 20 weeks and 30 weeks gestation, limit hydrocodone bitartrate and aspirin tablets use to the lowest effective dose and shortest duration possible. consider ultrasound monitoring of amniotic fluid if hydrocodone bitartrate and aspirin tablets treatment extends beyond 48 hours. discontinue hydrocodone bitartrate and aspirin tablets if oligohydramnios occurs and follow up according to clinical practice [see precautions ; pregnancy ]. risks of driving and operating machinery hydrocodone bitartrate and aspirin tablets may impair the mental or physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery. warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects of hydrocodone bitartrate and aspirin tablets and know how they will react to the medication [see precautions; information for patients/caregivers ]. hypersensitivity to hydrocodone or aspirin, (e.g. angioedema) hydrocodone bitartrate and aspirin tablets are contraindicated in patients with known hypersensitivity to hydrocodone or aspirin, and in any situation where opioids or aspirin are contraindicated. aspirin is contraindicated in patients with known allergy to nonsteroidal anti-inflammatory drug products (nsaids) and in patients with the syndrome of asthma, rhinitis, and nasal polyps. aspirin may cause severe urticaria, angioedema, or bronchospasm (asthma). coagulation abnormalities and bleeding risks even low doses of aspirin can inhibit platelet function leading to an increase in bleeding time. this can adversely affect patients with inherited (hemophilia) or acquired (liver disease or vitamin k deficiency) bleeding disorders. aspirin is contraindicated in patients with hemophilia. aspirin administered pre-operatively may prolong bleeding time. alcohol warning patients who consume three or more alcoholic drinks every day should be counseled about the bleeding risks involved with chronic, heavy alcohol use while taking aspirin. risk of reye’s syndrome when used for treatment of viral infections in children or teenagers aspirin should not be used in children or teenagers for viral infections, with or without fever, because of the risk of reye’s syndrome with concomitant use of aspirin in certain viral illnesses. drug rash with eosinophilia and systemic symptoms (dress) drug reaction with eosinophilia and systemic symptoms (dress) has been reported in patients taking nsaids such as hydrocodone bitartrate and aspirin tablets. some of these events have been fatal or life-threatening. dress typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling. other clinical manifestations may include hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis. sometimes symptoms of dress may resemble an acute viral infection. eosinophilia is often present. because this disorder is variable in its presentation, other organ systems not noted here may be involved. it is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. if such signs or symptoms are present, discontinue hydrocodone bitartrate and aspirin tablets and evaluate the patient immediately.

nd 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 ; 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 . initial dosage initiating treatment with hydrocodone bitartrate and aspirin tablets the usual adult usage is one or two tablets every four to six hours as needed for pain. 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 from hydrocodone bitartrate and aspirin tablets compared to extended-release hydrocodone products is unknown, so conversion to extended-release products must be accompanied by close observation for signs of excessive sedation and respiratory depression. titration and maintenance of therapy 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 and the relative incidence of adverse reactions, as well as monitoring 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 unacceptable opioid-related adverse reactions are observed, consider reducing the dosage. adjust the dosage to obtain an appropriate balance between management of pain and opioid-related adverse reactions. safe reduction or discontinuation of hydrocodone bitartrate and aspirin tablets 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 and aspirin tablets, there are a variety of factors that should be considered, including the dose of hydrocodone 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, monitor 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 a long duration 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 ].

tmarketing reports. because some of these reactions were reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. many adverse reactions due to aspirin ingestion are dose-related. the following is a list of adverse reactions that have been reported in the literature. [see warnings ]. body as a whole: fever, hypothermia, thirst. cardiovascular: dysrhythmias, hypotension, tachycardia. central nervous system: agitation, cerebral edema, coma, confusion, dizziness, headache, subdural or intracranial hemorrhage, lethargy, seizures. fluid and electrolyte: dehydration, hyperkalemia, metabolic acidosis, respiratory alkalosis. gastrointestinal: dyspepsia, gi bleeding, ulceration and perforation, nausea, vomiting, transient elevations of hepatic enzymes, hepatitis, reye's syndrome, pancreatitis. hematologic: prolongation of the prothrombin time, disseminated intravascular coagulation, coagulopathy, thrombocytopenia. hypersensitivity: acute anaphylaxis, angioedema, asthma, bronchospasm, laryngeal edema, urticaria. musculoskeletal: rhabdomyolysis. metabolism: hypoglycemia (in children), hyperglycemia. reproductive: prolonged pregnancy and labor, stillbirths, lower birth weight infants, antepartum and postpartum bleeding. respiratory: hyperpnea, pulmonary edema, tachypnea. special senses: hearing loss, tinnitus. patients with high frequency hearing loss may have difficulty perceiving tinnitus. in these patients, tinnitus cannot be used as a clinical indicator of salicylism. urogenital: interstitial nephritis, papillary necrosis, proteinuria, renal insufficiency and failure. serotonin syndrome : cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of opioids with serotonergic drugs. adrenal insufficiency : cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. anaphylaxis : anaphylaxis has been reported with ingredients contained in hydrocodone bitartrate and aspirin tablets. androgen deficiency : cases of androgen deficiency have occurred with chronic use of opioids [see clinical pharmacology ]. to report suspected adverse reactions, contact lgm pharma solutions, llc at 1-877-288-1495 or fda at 1-800-fda-1088 or www.fda.gov/medwatch.

odone bitartrate and aspirin tablets until stable drug effects are achieved. monitor patients for respiratory depression and sedation at frequent intervals. if a cyp3a4 inhibitor is discontinued, consider increasing the hydrocodone bitartrate and aspirin tablets dosage until stable drug effects are achieved. monitor 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. monitor for signs of opioid withdrawal. if a cyp3a4 inducer is discontinued, consider hydrocodone bitartrate and aspirin tablets dosage reduction and monitor for signs of respiratory depression. 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. follow patients closely for signs of respiratory depression and 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, carefully observe 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 monitoring 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: monitor patients for signs of respiratory depression that may be greater than otherwise expected and 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 skeletal muscle relaxants and opioids, consider prescribing naloxone for the emergency treatment of opioid overdose [see warnings ]. 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: monitor 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: monitor 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.

fetal 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 prolonged use of opioid analgesics 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 .

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. pharmacodynamics 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. chronic use of opioids 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 causal role of opioids in the syndrome of hypogonadism is unknown because the various medical, physical, lifestyle, and psychological stressors that may influence gonadal hormone levels have not been adequately controlled for in studies conducted to date [see adverse reactions ]. effects on the immune system opioids have been shown to have a variety of effects on components of the immune system. the clinical significance of these findings is unknown. overall, the effects of opioids appear to be modestly immunosuppressive. concentration-efficacy relationships the minimum effective analgesic concentration will vary widely among patients, especially among patients who have been previously treated with potent agonist opioids. 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 ]. pharmacokinetics 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.

ons ]. 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.