e 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 regulations (e.g., by prescription, directly from a pharmacist, or as part of a community-based program). consider prescribing naloxone, based on the patients 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 the patient has household members (including children) or other close contacts at risk for accidental ingestion or overdose. initial dosage initiating treatment with hydrocodone bitartrate and acetaminophen tablets 2.5 mg/325 mg the usual adult dosage is one or two tablets every four to six hours as needed for pain. the total daily dosage should not exceed 8 tablets. 5 mg/325 mg the usual adult dosage is one or two tablets every four to six hours as needed for pain. the total daily dosage should not exceed 8 tablets. 7.5 mg/325 mg, 10 mg/325 mg the usual adult dosage is one tablet every four to six hours as needed for pain. the total daily dosage should not exceed 6 tablets. conversion from other opioids to hydrocodone bitartrate and acetaminophen 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 acetaminophen tablets. it is safer to underestimate a patient’s 24-hour hydrocodone bitartrate and acetaminophen tablets dosage than to overestimate the 24-hour hydrocodone bitartrate and acetaminophen tablets dosage and manage an adverse reaction due to overdose. conversion from hydrocodone bitartrate and acetaminophen tablets to extended-release hydrocodone the relative bioavailability of hydrocodone from hydrocodone bitartrate and acetaminophen 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 acetaminophen tablets to a dose that provides adequate analgesia and minimizes adverse reactions. continually reevaluate patients receiving hydrocodone bitartrate and acetaminophen 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 increased pain before increasing the hydrocodone bitartrate and acetaminophen 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 acetaminophen tablets do not abruptly discontinue hydrocodone bitartrate and acetaminophen tablets in patients who may be physically dependent on opioids. rapid discontinuation of opioid analgesics in patients who are physically dependent on opioids has resulted in serious withdrawal symptoms, uncontrolled pain, and suicide. rapid discontinuation has also been associated with attempts to find other sources of opioid analgesics, which may be confused with drug-seeking for abuse. patients may also attempt to treat their pain or withdrawal symptoms with illicit opioids, such as heroin, and other substances. when a decision has been made to decrease the dose or discontinue therapy in an opioid-dependent patient taking hydrocodone bitartrate and acetaminophen tablets, there are a variety of factors that should be considered, including the dose of hydrocodone bitartrate and acetaminophen 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 acetaminophen 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].

reactions. hematological: thrombocytopenia, agranulocytosis. serotonin syndrome: cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of opioids with serotonergic drugs. adrenal insufficiency: cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. anaphylaxis: anaphylaxis has been reported with ingredients contained in hydrocodone bitartrate and acetaminophen tablets. androgen deficiency: cases of androgen deficiency have occurred with chronic use of opioids [see clinical pharmacology].

esia. hydrocodone produces respiratory depression by direct action on brain stem respiratory centers. the respiratory depression involves a reduction in the responsiveness of the brain stem respiratory centers to both increases in carbon dioxide tension and electrical stimulation. hydrocodone causes miosis, even in total darkness. pinpoint pupils are a sign of opioid overdose but are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origins may produce similar findings). marked mydriasis rather than miosis may be seen due to hypoxia in overdose situations. therapeutic doses of acetaminophen have negligible effects on the cardiovascular or respiratory systems; however, toxic doses may cause circulatory failure and rapid, shallow breathing. effects on the gastrointestinal tract and other smooth muscle hydrocodone causes a reduction in motility associated with an increase in smooth muscle tone in the antrum of the stomach and duodenum. digestion of food in the small intestine is delayed and propulsive contractions are decreased. propulsive peristaltic waves in the colon are decreased, while tone may be increased to the point of spasm, resulting in constipation. other opioid-induced effects may include a reduction in biliary and pancreatic secretions, spasm of sphincter of oddi, and transient elevations in serum amylase. effects on the cardiovascular system hydrocodone produces peripheral vasodilation which may result in orthostatic hypotension or syncope. manifestations of histamine release and/or peripheral vasodilation may include pruritus, flushing, red eyes, sweating, and/or orthostatic hypotension. effects on the endocrine system opioids inhibit the secretion of adrenocorticotropic hormone (acth), cortisol, and luteinizing hormone (lh) in humans [see adverse reactions]. they also stimulate prolactin, growth hormone (gh) secretion, and pancreatic secretion of insulin and glucagon. 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]. pharmacokinetics the behavior of the individual components is described below. hydrocodone following a 10 mg oral dose of hydrocodone administered to five adult male subjects, the mean peak concentration was 23.6 ± 5.2 ng/ml. maximum serum levels were achieved at 1.3 ± 0.3 hours and the half-life was determined to be 3.8 ± 0.3 hours. hydrocodone exhibits a complex pattern of metabolism including o-demethylation, n-demethylation and 6-keto reduction to the corresponding 6-α- and 6-β-hydroxymetabolites. see overdosage for toxicity information. cyp3a4 mediated n-demethylation to norhydrocodone is the primary metabolic pathway of hydrocodone with a lower contribution from cyp2d6 mediated o-demethylation to hydromorphone. hydromorphone is formed from the o-demethylation of hydrocodone and may contribute to the total analgesic effect of hydrocodone. therefore, the formation of these and related metabolites can, in theory, be affected by other drugs [see precautions; drug interactions]. n-demethylation of hydrocodone to form norhydrocodone via cyp3a4 while o-demethylation of hydrocodone to hydromorphone is predominantly catalyzed by cyp2d6 and to a lesser extent by an unknown low affinity cyp enzyme. hydrocodone and its metabolites are eliminated primarily in the kidneys. acetaminophen acetaminophen is rapidly absorbed from the gastrointestinal tract and is distributed throughout most body tissues. a small fraction (10-25%) of acetaminophen is bound to plasma proteins. the plasma half-life is 1.25 to 3 hours, but may be increased by liver damage and following overdosage. elimination of acetaminophen is principally by liver metabolism (conjugation) and subsequent renal excretion of metabolites. acetaminophen is primarily metabolized in the liver by first-order kinetics and involves three principal separate pathways: conjugation with glucuronide; conjugation with sulfate; and oxidation via the cytochrome, p450-dependent, mixed-function oxidase enzyme pathway to form a reactive intermediate metabolite, which conjugates with glutathione and is then further metabolized to form cysteine and mercapturic acid conjugates. the principal cytochrome p450 isoenzyme involved appears to be cyp2e1, with cyp1a2 and cyp3a4 as additional pathways. approximately 85% of an oral dose appears in the urine within 24 hours of administration, most as the glucuronide conjugate, with small amounts of other conjugates and unchanged drug. see overdosage for toxicity information.

ay, nj 08854 revised: 05/21