Hydrocodone Bitartrate

6 ADVERSE REACTIONS The following serious adverse reactions are described elsewhere in the labeling: Addiction, Abuse, and Misuse [see Warnings and Precautions ( 5.1 )] Life-Threatening Respiratory Depression [see Warnings and Precautions ( 5.3 )] Neonatal Opioid Withdrawal Syndrome [see Warnings and Precautions ( 5.4 )] Interactions with Benzodiazepine or Other CNS Depressants [see Warnings and Precautions ( 5.6 )] Adrenal Insufficiency [see Warnings and Precautions ( 5.8 )] Severe Hypotension [see Warnings and Precautions ( 5.9 )] Gastrointestinal Adverse Reactions [see Warnings and Precautions ( 5.12 , 5.13 )] Seizures [see Warnings and Precautions ( 5.14 )] Withdrawal [see Warnings and Precautions ( 5.15 )] Most common treatment-emergent adverse events (incidence ≥ 5%) are constipation, nausea, vomiting, fatigue, upper respiratory tract infection, dizziness, headache, and somnolence. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Alvogen, Inc. at 1-866-770-3024 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. A total of 1,827 patients were treated with hydrocodone bitartrate extended-release tablets in controlled and open-label chronic pain clinical trials. Five hundred patients were treated for 6 months and 364 patients were treated for 12 months. The clinical trial population consisted of opioid-naïve and opioid-experienced patients with persistent moderate to severe chronic pain. The common adverse reactions (≥2%) reported by patients in clinical trials comparing hydrocodone bitartrate extended-release tablets (20 mg/day to 120 mg/day) with placebo are shown in Table 2 below: Table 2: Adverse Reactions Reported in ≥2% of Patients during the Open-Label Titration Period and Double-Blind Treatment Period: Opioid-Naïve and Opioid-Experienced Patients Open-label Titration Period Double-blind Treatment Period MedDRA Preferred Term (N=905) (%) Placebo (N=292) (%) Hydrocodone Bitartrate Extended-Release Tablets (N=296) (%) Nausea 16 5 8 Constipation 9 2 3 Vomiting 7 3 6 Dizziness 7 2 3 Headache 7 2 2 Somnolence 5 1 1 Fatigue 4 1 1 Pruritus 3 <1 0 Tinnitus 2 1 2 Insomnia 2 2 3 Decreased appetite 1 1 2 Influenza 1 1 3 The adverse reactions seen in controlled and open-label chronic pain studies are presented below in the following manner: most common (≥5%), common (≥1% to <5%), and less common (<1%). The most common adverse reactions (≥5%) reported by patients treated with hydrocodone bitartrate extended-release tablets in the chronic pain clinical trials were constipation, nausea, vomiting, fatigue, upper respiratory tract infection, dizziness, headache, somnolence. The common (≥1% to <5%) adverse events reported by patients treated with hydrocodone bitartrate extended-release tablets in the chronic pain clinical trials organized by MedDRA (Medical Dictionary for Regulatory Activities) System Organ Class were: Ear and labyrinth disorders tinnitus Gastrointestinal disorders abdominal pain, abdominal pain upper, diarrhea, dry mouth, dyspepsia, gastroesophageal reflux disease General disorders and administration site conditions chest pain, chills, edema peripheral, pain, pyrexia Infections and infestations bronchitis, gastroenteritis, gastroenteritis viral, influenza, nasopharyngitis, sinusitis, urinary tract infection Injury, poisoning and procedural complications fall, muscle strain Metabolism and nutrition disorders decreased appetite Musculoskeletal and connective tissue disorders arthralgia, back pain, muscle spasms, musculoskeletal pain, myalgia, pain in extremity Nervous system disorders lethargy, migraine, sedation Psychiatric disorders anxiety, depression, insomnia Respiratory, thoracic and mediastinal disorders cough, nasal congestion, oropharyngeal pain Skin and subcutaneous tissue disorders hyperhidrosis, pruritus, rash Vascular disorders hot flush, hypertension Other less common adverse reactions that were seen in <1% of the patients in the hydrocodone bitartrate extended-release chronic pain clinical trials include the following in alphabetical order: abdominal discomfort, abdominal distention, agitation, asthenia, choking, confusional state, depressed mood, drug hypersensitivity, drug withdrawal syndrome, dysphagia, dyspnea, esophageal obstruction, flushing, hypogonadism, hypotension, hypoxia, irritability, libido decreased, malaise, mental impairment, mood altered, muscle twitching, edema, orthostatic hypotension, palpitations, presyncope, retching, syncope, thinking abnormal, thirst, tremor, and urinary retention. 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of hydrocodone. Because these reactions are 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. 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 extended-release tablets. Androgen deficiency : Cases of androgen deficiency have occurred with chronic use of opioids [see Clinical Pharmacology ( 12.2 )] .

4 CONTRAINDICATIONS Hydrocodone bitartrate extended-release tablets are contraindicated in patients with: Significant respiratory depression [see Warnings and Precautions ( 5.3 )] Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment [see Warnings and Precautions ( 5.7 )] Known or suspected gastrointestinal obstruction, including paralytic ileus [see Warnings and Precautions ( 5.12 , 5.13 )] Hypersensitivity to hydrocodone or any component of hydrocodone bitartrate extended-release tablets. Significant respiratory depression ( 4 ) Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment (4) Known or suspected gastrointestinal obstruction, including paralytic ileus (4) Hypersensitivity to hydrocodone or to any other components of hydrocodone bitartrate extended-release tablets (4)

11 DESCRIPTION Hydrocodone bitartrate extended-release tablets are supplied in 20 mg, 30 mg, 40 mg, 60 mg, 80 mg, 100 mg and 120 mg film-coated tablets for oral administration. The tablet strengths describe the amount of hydrocodone per tablet as the bitartrate salt. Hydrocodone bitartrate is an opioid agonist. Its chemical name is 4,5α-epoxy-3-methoxy-17-­methylmorphinan-6-one tartrate (1:1) hydrate (2:5). Its structural formula is: Empirical formula: C 18 H 21 NO 3 • C 4 H 6 O 6 • 2½H 2 O; Molecular weight: 494.49. Hydrocodone bitartrate exists as fine white crystals or a crystalline powder. It is affected by light. It is soluble in water, slightly soluble in alcohol, and insoluble in ether and chloroform. The 20 mg, 30 mg, 40 mg, 60 mg, 80 mg, 100 mg and 120 mg tablets contain the following inactive ingredients: hydroxypropyl cellulose, magnesium stearate, microcrystalline cellulose, polyethylene glycol (PEG), polyethylene oxide, polysorbate 80, polyvinyl alcohol, talc, and titanium dioxide. The 30 mg tablets also contain iron oxide red and iron oxide yellow. The 40 mg tablets also contain iron oxide red. The 60 mg tablets also contain FD&C Blue #2. The 80 mg tablets also contain D&C Red #27 and FD&C Blue #1. The 100 mg tablets also contain FD&C Blue #2 and iron oxide yellow. The 120 mg tablets also contain iron oxide yellow. The tablet imprinting ink contains ammonium hydroxide, butyl alcohol, iron oxide black, isopropyl alcohol, propylene glycol, and shellac.

2 DOSAGE AND ADMINISTRATION To be prescribed only by healthcare providers knowledgeable in use of potent opioids for management of chronic pain. ( 2.1 ) Daily doses of hydrocodone bitartrate extended-release tablets greater than or equal to 80 mg are only for use in patients in whom tolerance to an opioid of comparable potency has been established. Patients considered opioid-tolerant are those taking, for one week or longer, at least 60 mg oral morphine per day, 25 mcg transdermal fentanyl per hour, 30 mg oral oxycodone per day, 8 mg oral hydromorphone per day, 25 mg oral oxymorphone per day, 60 mg oral hydrocodone per day, or an equianalgesic dose of another opioid. ( 2.1 ) Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals. ( 2.1 ) Individualize dosing based on the severity of pain, patient response, prior analgesic experience, and risk factors for addiction, abuse, and misuse. ( 2.1 ) Instruct patients to swallow hydrocodone bitartrate extended-release tablets intact, and not to crush, chew, or dissolve the tablets (risk of potentially fatal overdose). ( 2.1 , 5.1 ) Instruct patients to take tablets one at a time, with enough water to ensure complete swallowing immediately after placing in the mouth. ( 2.1 , 5.12 ) Discuss availability of naloxone with the patient and caregiver and assess each patient’s need for access to naloxone, both when initiating and renewing treatment with hydrocodone bitartrate extended-release tablets. Consider prescribing naloxone based on the patient’s risk factors for overdose. ( 2.2 , 5.1 , 5.3 , 5.6 ). For opioid-naïve patients, initiate with 20 mg tablets orally every 24 hours. ( 2.3 ) To convert to hydrocodone bitartrate extended-release tablets from another opioid, follow the conversion instructions to obtain an estimated dose. ( 2.3 ) Dose titration of hydrocodone bitartrate extended-release tablets may occur every 3 to 5 days. ( 2.4 ) Patients with Severe Hepatic Impairment : Initiate dosing with one half of the recommended starting dosage and titrate carefully. Monitor for respiratory depression, sedation, and hypotension. ( 2.5 ) Patients with Moderate to Severe Renal Impairment and End-Stage Renal Disease : Initiate dosing at one half the recommended starting dosage and titrate carefully. Monitor for signs of respiratory depression, sedation, and hypotension. ( 2.6 ) Do not abruptly discontinue hydrocodone bitartrate extended-release tablets in a physically dependent patient because rapid discontinuation of opioid analgesics has resulted in serious withdrawal symptoms, uncontrolled pain, and suicide. ( 2.7 ) 2.1 Important Dosage and Administration Information Hydrocodone bitartrate extended-release tablets should be prescribed only by healthcare professionals who are knowledgeable in the use of potent opioids for the management of chronic pain. Daily doses of hydrocodone bitartrate extended-release tablets greater than or equal to 80 mg are only for use in patients in whom tolerance to an opioid of comparable potency has been established. Patients who are opioid tolerant are those receiving, for one week or longer, at least 60 mg oral morphine per day, 25 mcg transdermal fentanyl per hour, 30 mg oral oxycodone per day, 8 mg oral hydromorphone per day, 25 mg oral oxymorphone per day, 60 mg oral hydrocodone per day, or an equianalgesic dose of another opioid. Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals [see Warnings and Precautions ( 5 )]. Initiate the dosing regimen for each patient individually; taking into account the patient's severity of pain, patient response, prior analgesic treatment experience, and risk factors for addiction, abuse, and misuse [see Warnings and Precautions ( 5.1 )] . Monitor patients closely for respiratory depression, especially within the first 24 to 72 hours of initiating therapy and following dosage increases with hydrocodone bitartrate extended-release tablets and adjust the dosage accordingly [see Warnings and Precautions ( 5.3 )] . Instruct patients to swallow hydrocodone bitartrate extended-release tablets whole, one tablet at a time, with enough water to ensure complete swallowing immediately after placing in the mouth [see Patient Counseling Information ( 17 )] . Instruct patients not to pre-soak, lick, or otherwise wet the tablet prior to placing in the mouth [see Warnings and Precautions ( 5.12 )] . Crushing, chewing, or dissolving hydrocodone bitartrate extended-release tablets will result in uncontrolled delivery of hydrocodone and can lead to overdose or death [see Warnings and Precautions ( 5.1 )] . Hydrocodone bitartrate extended-release tablets are administered orally once daily (every 24 hours). Multiple tablets of lower dose strengths that provide the desired total daily dose can be taken as a once daily dose. 2.2 Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose Discuss the availability of naloxone for the emergency treatment of opioid overdose with the patient and caregiver and assess the potential need for access to naloxone, both when initiating and renewing treatment with hydrocodone bitartrate extended-release tablets [see Warnings and Precautions ( 5.3 ), Patient Counseling Information ( 17 )] . 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 and Precautions ( 5.1 , 5.3 , 5.6 )] . Consider prescribing naloxone if the patient has household members (including children) or other close contacts at risk for accidental ingestion or overdose. 2.3 Initial Dosage Use of Hydrocodone Bitartrate Extended-Release Tablets as the First Opioid Analgesic (opioid-naïve patients) Initiate therapy with 20 mg hydrocodone bitartrate extended-release tablets orally every 24 hours. Use of Hydrocodone Bitartrate Extended-Release Tablets in Patients who are not Opioid Tolerant (opioid non-tolerant patients) The starting dose for patients who are not opioid tolerant is 20 mg hydrocodone bitartrate extended-release tablets orally every 24 hours. Use of higher starting doses in patients who are not opioid tolerant may cause fatal respiratory depression [see Warnings and Precautions ( 5.3 )] . Conversion from Oral Hydrocodone Formulations to Hydrocodone Bitartrate Extended-Release Tablets Patients receiving other oral hydrocodone-containing formulations may be converted to hydrocodone bitartrate extended-release tablets by administering the patient's total daily oral hydrocodone dose as hydrocodone bitartrate extended-release tablets once daily. Conversion from Other Oral Opioids to Hydrocodone Bitartrate Extended-Release Tablets Discontinue all other around-the-clock opioid drugs when hydrocodone bitartrate extended-release therapy is initiated. There is inter-patient variability in the relative potency of opioid drugs and formulations. Therefore, a conservative approach is advised when determining the total daily dosage of hydrocodone bitartrate extended-release tablets. It is safer to underestimate a patient’s 24-hour oral hydrocodone dosage and provide rescue medication (e.g., immediate-release opioid) than to overestimate the 24-hour oral hydrocodone dosage and manage an adverse reaction due to an overdose. In a hydrocodone bitartrate extended-release tablets clinical trial with an open-label titration period, patients were converted from their prior opioid to hydrocodone bitartrate extended-release tablets using Table 1 as a guide for the initial hydrocodone bitartrate extended-release tablets dose. To obtain the initial hydrocodone bitartrate extended-release tablets dose, first use Table 1 to convert the prior oral opioids to a total hydrocodone daily dose and then reduce the calculated daily hydrocodone dose by 25% to account for interpatient variability in relative potency of different opioids. Consider the following when using the information found in Table 1. This is not a table of equianalgesic doses. The conversion factors in this table are only for the conversion from one of the listed oral opioid analgesics to hydrocodone bitartrate extended-release tablets. The table cannot be used to convert from hydrocodone bitartrate extended-release tablets to another opioid. Doing so will result in an over-estimation of the dose of the new opioid and may result in fatal overdose. Table 1. Conversion factors to hydrocodone bitartrate extended-release tablets (Not Equianalgesic Doses) Opioid Oral dose (mg) Approximate oral conversion factor Codeine 133 0.15 Hydromorphone 5 4 Methadone 13.3 1.5 Morphine 40 0.5 Oxycodone 20 1 Oxymorphone 10 2 Tramadol 200 0.1 To calculate the estimated total hydrocodone daily dose using Table 1: For patients on a single opioid, sum the current total daily dose of the opioid and then multiply the total daily dose by the approximate oral conversion factor to calculate the approximate oral hydrocodone daily dose. For patients on a regimen of more than one opioid, calculate the approximate oral hydrocodone dose for each opioid and sum the totals to obtain the approximate oral hydrocodone daily dose. For patients on a regimen of fixed-ratio opioid/non-opioid analgesic products, use only the opioid component of these products in the conversion. Reduce the calculated daily oral hydrocodone dose by 25%. Always round the dose down, if necessary, to the nearest hydrocodone bitartrate extended-release tablet strength available and initiate therapy with that dose. If the converted hydrocodone bitartrate extended-release tablets dose using Table 1 is less than 20 mg, initiate therapy with 20 mg hydrocodone bitartrate extended-release tablets. Example conversion from a single opioid to hydrocodone bitartrate extended-release tablets: For example, a total daily dose of oxycodone 50 mg would be converted to hydrocodone 50 mg based on the table above, and then multiplied by 0.75 (i.e., take a 25 % reduction) resulting in a dose of 37.5 mg hydrocodone. Round this down to the nearest dose strength available, 30 mg hydrocodone bitartrate extended-release tablets, to initiate therapy. Close observation and frequent titration are warranted until pain management is stable on the new opioid. Monitor patients for signs and symptoms of opioid withdrawal or for signs of over-sedation/toxicity after converting patients to hydrocodone bitartrate extended-release tablets. Conversion from Methadone to Hydrocodone Bitartrate Extended-Release Tablets Close monitoring is of particular importance when converting from methadone to other opioid agonists. The ratio between methadone and other opioid agonists may vary widely as a function of previous dose exposure. Methadone has a long half-life and can accumulate in the plasma. Conversion from Transdermal Fentanyl to Hydrocodone Bitartrate Extended-Release Tablets Eighteen hours following the removal of the transdermal fentanyl patch, hydrocodone bitartrate extended-release tablet treatment can be initiated. For each 25 mcg/hr fentanyl transdermal patch, a dose of 20 mg hydrocodone bitartrate extended-release tablets every 24 hours represents a conservative initial dose. Follow the patient closely during conversion from transdermal fentanyl to hydrocodone bitartrate extended-release tablets, as there is limited experience with this conversion. Conversion from Transdermal Buprenorphine to Hydrocodone Bitartrate Extended-Release Tablets All patients receiving transdermal buprenorphine (≤ 20 mcg/hr) should initiate therapy with 20 mg hydrocodone bitartrate extended-release tablets every 24 hours. Follow the patient closely during conversion from transdermal buprenorphine to hydrocodone bitartrate extended-release tablets, as there is limited experience with this conversion. 2.4 Titration and Maintenance of Therapy Individually titrate hydrocodone bitartrate extended-release tablets to a dose that provides adequate analgesia and minimizes adverse reactions. Continually reevaluate patients receiving hydrocodone bitartrate extended-release 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 and Precautions ( 5.1 )]. 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. During chronic therapy, periodically reassess the continued need for the use of opioid analgesics. Patients who experience breakthrough pain may require a dosage adjustment of hydrocodone bitartrate extended-release tablets, or may need rescue medication with an appropriate dose of an immediate-release analgesic. If the level of pain increases after dose stabilization, attempt to identify the source of increased pain before increasing the hydrocodone bitartrate extended-release tablets dosage. Adjust the dose of hydrocodone bitartrate extended-release tablets in increments of 10 mg to 20 mg every 3 to 5 days as needed to achieve adequate analgesia. 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. 2.5 Dosage Modifications in Patients with Severe Hepatic Impairment Patients with severe hepatic impairment may have higher plasma concentrations of hydrocodone than those with normal function. Initiate therapy with one half the initial dose of hydrocodone bitartrate extended-release tablets in these patients and monitor closely for respiratory depression, sedation, and hypotension [see Clinical Pharmacology ( 12.3 )] . 2.6 Dosage Modifications in Patients with Moderate to Severe Renal Impairment Patients with moderate to severe renal impairment, and end-stage renal disease may have higher plasma concentrations than those with normal function. Initiate therapy with one half the initial dose of hydrocodone bitartrate extended-release tablets in these patients and monitor closely for respiratory depression, sedation, and hypotension [see Clinical Pharmacology ( 12.3 )] . 2.7 Safe Reduction or Discontinuation of Hydrocodone Bitartrate Extended-Release Tablets Do not abruptly discontinue hydrocodone bitartrate extended-release 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 extended-release tablets, there are a variety of factors that should be considered, including the dose of hydrocodone bitartrate extended-release 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 comorbid 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 extended-release 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 and Precautions ( 5.15 ), Drug Abuse and Dependence ( 9.3 )] .

1 INDICATIONS AND USAGE Hydrocodone bitartrate extended-release tablets are indicated for the management of pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate. Limitations of Use Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses, and because of the greater risks of overdose and death with extended-release opioid formulations [see Warnings and Precautions ( 5.1 )] , reserve hydrocodone bitartrate extended-release tablets for use in patients for whom alternative treatment options (e.g., non-opioid analgesics or immediate-release opioids) are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain. Hydrocodone bitartrate extended-release tablets are not indicated as an as-needed (prn) analgesic. Hydrocodone bitartrate extended-release tablets are an opioid agonist indicated for the management of pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate. ( 1 ) Limitations of Use Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses, and because of the greater risks of overdose and death with extended-release opioid formulations, reserve hydrocodone bitartrate extended-release tablets for use in patients for whom alternative treatment options (e.g., non-opioid analgesics or immediate-release opioids) are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain. ( 1 ) Hydrocodone bitartrate extended-release tablets are not indicated as an as-needed (prn) analgesic. ( 1 )

9.2 Abuse Hydrocodone bitartrate extended-release tablets contain hydrocodone, a substance with a high potential for abuse similar to other opioids, including fentanyl, hydromorphone, methadone, morphine, oxycodone, oxymorphone, and tapentadol. Hydrocodone bitartrate extended-release tablets can be abused and is subject to misuse, addiction, and criminal diversion [see Warnings and Precautions ( 5.1 )] . The high drug content in the extended-release formulation adds to the risk of adverse outcomes from abuse and misuse. All patients treated with opioids require careful monitoring for signs of abuse and addiction because use of opioid analgesic products carries the risk of addiction even under appropriate medical use. Prescription drug abuse is the intentional non-therapeutic use of a prescription drug, even once, for its rewarding psychological or physiological effects. Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that develop after repeated substance use and includes: a strong desire to take the drug, difficulties in controlling its use, persisting in its use despite harmful consequences, a higher priority given to drug use than to other activities and obligations, increased tolerance, and sometimes a physical withdrawal. "Drug-seeking" behavior is very common in persons with substance use disorders. Drug seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing, or referral, repeated “loss” of prescriptions, tampering with prescriptions, and reluctance to provide prior medical records or contact information for other treating healthcare provider(s). “Doctor shopping” (visiting multiple prescribers to obtain additional prescriptions) is common among drug abusers and people with untreated addiction. Preoccupation with achieving adequate pain relief can be appropriate behavior in a patient with poor pain control. Abuse and addiction are separate and distinct from physical dependence and tolerance. Healthcare providers should be aware that addiction may not be accompanied by concurrent tolerance and symptoms of physical dependence in all addicts. In addition, abuse of opioids can occur in the absence of true addiction. Hydrocodone bitartrate extended-release tablets, like other opioids, can be diverted for non-medical use into illicit channels of distribution. Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests, as required by state and federal law, is strongly advised. Proper assessment of the patient, proper prescribing practices, periodic re-evaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs. Risks Specific to Abuse of Hydrocodone Bitartrate Extended-Release Tablets Hydrocodone bitartrate extended-release tablets are for oral use only. Abuse of hydrocodone bitartrate extended-release tablets poses a risk of overdose and death. Abuse may occur by taking intact tablets in quantities greater than prescribed or without legitimate purpose, by crushing and chewing or snorting the crushed formulation, or by injecting a solution made from the crushed formulation. The risk is increased with concurrent use of hydrocodone bitartrate extended-release tablets with alcohol or other central nervous system depressants. Taking cut, broken, chewed, crushed, or dissolved hydrocodone bitartrate extended-release tablets increases the risk of overdose and death. With parenteral abuse, the inactive ingredients in hydrocodone bitartrate extended-release tablets can result in local tissue necrosis, infection, pulmonary granulomas, increased risk of endocarditis and valvular heart injury, embolism, and death. Parenteral drug abuse is commonly associated with transmission of infectious diseases, such as hepatitis and HIV. Abuse Deterrence Studies Hydrocodone bitartrate extended-release tablets are formulated with physicochemical properties intended to make the tablet more difficult to manipulate for misuse and abuse, and maintains some extended release characteristics even if the tablet is physically compromised. To evaluate the ability of these physicochemical properties to reduce the potential for abuse of hydrocodone bitartrate extended-release tablets, a series of in vitro laboratory studies, pharmacokinetic studies and clinical abuse potential studies was conducted. A summary is provided at the end of this section. In Vitro Testing In vitro physical and chemical tablet manipulation studies were performed to evaluate the success of different extraction methods in defeating the extended-release formulation. Results support that hydrocodone bitartrate extended-release tablets resists crushing, breaking, and dissolution using a variety of tools and solvents and retains some extended-release properties despite manipulation. When subjected to an aqueous environment, hydrocodone bitartrate extended-release tablets gradually forms a viscous hydrogel (i.e., a gelatinous mass) that resists passage through a hypodermic needle. Clinical Abuse Potential Studies Studies in Non-dependent Opioid Abusers: Two randomized, double-blind, placebo and active-comparator studies in non-dependent opioid abusers were conducted to characterize the abuse potential of hydrocodone bitartrate extended-release tablets following physical manipulation and administration via the intranasal and oral routes. For both studies, drug liking was measured on a bipolar drug liking scale of 0 to 100 where 50 represents a neutral response of neither liking nor disliking, 0 represents maximum disliking, and 100 represents maximum liking. Response to whether the subject would take the study drug again was measured on a unipolar scale of 0 to 100 where 0 represents the strongest negative response (“definitely would not take drug again”) and 100 represents the strongest positive response (“definitely would take drug again”). Intranasal Abuse Potential Study: In the intranasal abuse potential study, 31 subjects were dosed and 25 subjects completed the study. Treatments studied included intranasally administered tampered 60 mg hydrocodone bitartrate extended-release tablets, powdered hydrocodone bitartrate 60 mg, and placebo. Incomplete dosing due to granules falling from the subjects’ nostrils occurred in 82% (n = 23) of subjects receiving tampered hydrocodone bitartrate extended-release tablets compared to no subjects with powdered hydrocodone or placebo. The intranasal administration of tampered hydrocodone bitartrate extended-release tablets was associated with statistically significantly lower mean and median scores for drug liking and take drug again ( P <0.001 for both), compared with powdered hydrocodone as summarized in Table 4. Table 4. Summary of Maximum Scores (E max ) on Drug Liking and Take Drug Again VAS Following intranasal Administration of Hydrocodone Bitartrate Extended-Release Tablets and Hydrocodone Powder in Non-dependent Opioid Abusers VAS Scale (100 point) Hydrocodone Bitartrate Extended-Release Tablets Hydrocodone Intranasal (n=25) Manipulated Powder Drug Liking Bipolar scale (0=maximum negative response, 50=neutral response, 100=maximum positive response) Mean (SE) 65.4 (3.7) 90.4 (2.6) Median (Range) 56 (50–100) 100 (51–100) Take Drug Again Unipolar scale (0=maximum negative response, 100=maximum positive response) Mean (SE) 36.4 (8.2) 85.2 (5.0) Median (Range) 14 (0-100) 100 (1-100) Figure 1 demonstrates a comparison of peak drug liking scores for tampered hydrocodone bitartrate extended-release tablets compared with powdered hydrocodone in subjects (n = 25) who received both treatments intranasally. The Y-axis represents the percent of subjects attaining a percent reduction in peak drug liking scores for tampered hydrocodone bitartrate extended-release tablets vs. hydrocodone powder greater than or equal to the value on the X-axis. Approximately 80% (n = 20) of subjects had some reduction in drug liking with tampered hydrocodone bitartrate extended-release tablets relative to hydrocodone powder. Sixty-eight percent (n = 17) of subjects had a reduction of at least 30% in drug liking with tampered hydrocodone bitartrate extended-release tablets compared with hydrocodone powder, and approximately 64% (n = 16) of subjects had a reduction of at least 50% in drug liking with tampered hydrocodone bitartrate extended-release tablets compared with hydrocodone powder. Approximately 20% (n = 5) of subjects had no reduction in liking with tampered hydrocodone bitartrate extended-release tablets relative to hydrocodone powder. Figure 1: Percent Reduction Profiles for E max of Drug Liking VAS for Manipulated Hydrocodone Bitartrate Extended-Release Tablets vs. Hydrocodone Powder, N = 25 Following Intranasal Administration Oral Abuse Potential Study: In the oral abuse potential study, 40 subjects were dosed and 35 subjects completed the study. Treatments studied included oral administrations of chewed 60 mg hydrocodone bitartrate extended-release tablets, intact 60 mg hydrocodone bitartrate extended-release tablets, 60 mg aqueous hydrocodone bitartrate solution, and placebo. The oral administration of chewed and intact hydrocodone bitartrate extended-release tablets was associated with statistically lower mean and median scores on scales that measure drug liking and desire to take drug again (P<0.001), compared to hydrocodone solution as summarized in Table 5. Table 5. Summary of Maximum Scores (E max ) on Drug Liking and Take Drug Again VAS Following Oral Administration of Hydrocodone Bitartrate Extended-Release Tablets and Hydrocodone Solution in Non-dependent Recreational Opioid Users VAS Scale (100 point) Hydrocodone Bitartrate Extended-Release Tablets Hydrocodone Oral (n=35) Intact Chewed Solution Drug Liking Bipolar scale (0=maximum negative response, 50=neutral response, 100=maximum positive response) Mean (SE) 63.3 (2.7) 69.0 (3.0) 94.0 (1.7) Median (Range) 58 (50–100) 66 (50–100) 100 (51–100) Take Drug Again Unipolar scale (0=maximum negative response, 100=maximum positive response) Mean (SE) 34.3 (6.1) 44.3 (6.9) 89.7 (3.6) Median (Range) 24 (0-100) 55 (0-100) 100 (1-100) Figure 2 demonstrates a comparison of peak drug liking scores for chewed hydrocodone bitartrate extended-release tablets compared with hydrocodone solution in subjects who received both treatments orally. The Y-axis represents the percent of subjects attaining a percent reduction in peak drug liking scores for chewed hydrocodone bitartrate extended-release tablets vs. hydrocodone solution greater than or equal to the value on the X-axis. Approximately 80% (n = 28) of subjects had some reduction in drug liking with chewed hydrocodone bitartrate extended-release tablets relative to hydrocodone solution. Approximately 69% (n = 24) of subjects had a reduction of at least 30% in drug liking with chewed hydrocodone bitartrate extended-release tablets compared with hydrocodone solution, and approximately 60% (n = 21) of subjects had a reduction of at least 50% in drug liking with chewed hydrocodone bitartrate extended-release tablets compared with hydrocodone solution. Approximately 20% (n = 7) of subjects had no reduction in drug liking with chewed hydrocodone bitartrate extended-release tablets relative to hydrocodone solution. Figure 2. Percent Reduction Profiles for E max of Drug Liking VAS for Chewed Hydrocodone Bitartrate Extended-Release Tablets vs. Hydrocodone Solution, N = 35 Following Oral Administration The results of a similar analysis of drug liking for intact hydrocodone bitartrate extended-release tablets relative to hydrocodone solution were comparable to the results of chewed hydrocodone bitartrate extended-release tablets relative to hydrocodone solution. Approximately 83% (n = 29) of subjects had some reduction in drug liking with intact hydrocodone bitartrate extended-release tablets relative to hydrocodone solution. Eighty-three percent (n = 29) of subjects had a reduction of at least 30% in peak drug liking scores with intact hydrocodone bitartrate extended-release tablets compared to hydrocodone solution, and approximately 74% (n = 26) of subjects had a reduction of at least 50% in peak drug liking scores with intact hydrocodone bitartrate extended-release tablets compared with hydrocodone solution. Approximately 17% (n = 6) had no reduction in drug liking with intact hydrocodone bitartrate extended-release tablets relative to hydrocodone solution. Summary The in vitro data demonstrate that hydrocodone bitartrate extended-release tablets have physical and chemical properties that are expected to deter intranasal and intravenous abuse. The data from the clinical abuse potential studies, along with support from the in vitro data, also indicate that hydrocodone bitartrate extended-release tablets have physicochemical properties that are expected to reduce intranasal abuse and oral abuse when chewed. However, abuse of hydrocodone bitartrate extended-release tablets by the intravenous, intranasal, and oral routes is still possible. Additional data, including epidemiological data, when available, may provide further information on the impact of hydrocodone bitartrate extended-release tablets on the abuse liability of the drug. Accordingly, this section may be updated in the future as appropriate.

9.1 Controlled Substance Hydrocodone bitartrate extended-release tablets contain hydrocodone bitartrate, a Schedule II controlled substance.

9.3 Dependence Both tolerance and physical dependence can develop during chronic opioid therapy. Tolerance is the need for increasing doses of opioids to maintain a defined effect such as analgesia (in the absence of disease progression or other external factors). Tolerance may occur to both the desired and undesired effects of drugs, and may develop at different rates for different effects. Physical dependence is a physiological state in which the body adapts to the drug after a period of regular exposure, resulting in withdrawal symptoms after abrupt discontinuation or a significant dosage reduction of a drug. Withdrawal also may be precipitated through the administration of drugs with opioid antagonist activity (e.g., naloxone, nalmefene), mixed agonist/antagonist analgesics (e.g., pentazocine, butorphanol, nalbuphine), or partial agonists (e.g., buprenorphine). Physical dependence may not occur to a clinically significant degree until after several days to weeks of continued opioid usage. Do not abruptly discontinue hydrocodone bitartrate extended-release tablets in a patient physically dependent on opioids. Rapid tapering of hydrocodone bitartrate extended-release tablets in a patient physically dependent on opioids may lead to 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. When discontinuing hydrocodone bitartrate extended-release tablets, gradually taper the dosage using a patient specific plan that considers the following: the dose of hydrocodone bitartrate extended-release tablets the patient has been taking, the duration of treatment, and the physical and psychological attributes of the patient. To improve the likelihood of a successful taper and minimize withdrawal symptoms, it is important that the opioid tapering schedule is agreed upon by the patient. In patients taking opioids for a long duration at high doses, ensure that a multimodal approach to pain management, including mental health support (if needed), is in place prior to initiating an opioid analgesic taper [see Dosage and Administration ( 2.7 ), Warnings and Precautions ( 5.15 )] . Infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal signs [see Use in Specific Populations ( 8.1 )].

9 DRUG ABUSE AND DEPENDENCE 9.1 Controlled Substance Hydrocodone bitartrate extended-release tablets contain hydrocodone bitartrate, a Schedule II controlled substance. 9.2 Abuse Hydrocodone bitartrate extended-release tablets contain hydrocodone, a substance with a high potential for abuse similar to other opioids, including fentanyl, hydromorphone, methadone, morphine, oxycodone, oxymorphone, and tapentadol. Hydrocodone bitartrate extended-release tablets can be abused and is subject to misuse, addiction, and criminal diversion [see Warnings and Precautions ( 5.1 )] . The high drug content in the extended-release formulation adds to the risk of adverse outcomes from abuse and misuse. All patients treated with opioids require careful monitoring for signs of abuse and addiction because use of opioid analgesic products carries the risk of addiction even under appropriate medical use. Prescription drug abuse is the intentional non-therapeutic use of a prescription drug, even once, for its rewarding psychological or physiological effects. Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that develop after repeated substance use and includes: a strong desire to take the drug, difficulties in controlling its use, persisting in its use despite harmful consequences, a higher priority given to drug use than to other activities and obligations, increased tolerance, and sometimes a physical withdrawal. "Drug-seeking" behavior is very common in persons with substance use disorders. Drug seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing, or referral, repeated “loss” of prescriptions, tampering with prescriptions, and reluctance to provide prior medical records or contact information for other treating healthcare provider(s). “Doctor shopping” (visiting multiple prescribers to obtain additional prescriptions) is common among drug abusers and people with untreated addiction. Preoccupation with achieving adequate pain relief can be appropriate behavior in a patient with poor pain control. Abuse and addiction are separate and distinct from physical dependence and tolerance. Healthcare providers should be aware that addiction may not be accompanied by concurrent tolerance and symptoms of physical dependence in all addicts. In addition, abuse of opioids can occur in the absence of true addiction. Hydrocodone bitartrate extended-release tablets, like other opioids, can be diverted for non-medical use into illicit channels of distribution. Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests, as required by state and federal law, is strongly advised. Proper assessment of the patient, proper prescribing practices, periodic re-evaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs. Risks Specific to Abuse of Hydrocodone Bitartrate Extended-Release Tablets Hydrocodone bitartrate extended-release tablets are for oral use only. Abuse of hydrocodone bitartrate extended-release tablets poses a risk of overdose and death. Abuse may occur by taking intact tablets in quantities greater than prescribed or without legitimate purpose, by crushing and chewing or snorting the crushed formulation, or by injecting a solution made from the crushed formulation. The risk is increased with concurrent use of hydrocodone bitartrate extended-release tablets with alcohol or other central nervous system depressants. Taking cut, broken, chewed, crushed, or dissolved hydrocodone bitartrate extended-release tablets increases the risk of overdose and death. With parenteral abuse, the inactive ingredients in hydrocodone bitartrate extended-release tablets can result in local tissue necrosis, infection, pulmonary granulomas, increased risk of endocarditis and valvular heart injury, embolism, and death. Parenteral drug abuse is commonly associated with transmission of infectious diseases, such as hepatitis and HIV. Abuse Deterrence Studies Hydrocodone bitartrate extended-release tablets are formulated with physicochemical properties intended to make the tablet more difficult to manipulate for misuse and abuse, and maintains some extended release characteristics even if the tablet is physically compromised. To evaluate the ability of these physicochemical properties to reduce the potential for abuse of hydrocodone bitartrate extended-release tablets, a series of in vitro laboratory studies, pharmacokinetic studies and clinical abuse potential studies was conducted. A summary is provided at the end of this section. In Vitro Testing In vitro physical and chemical tablet manipulation studies were performed to evaluate the success of different extraction methods in defeating the extended-release formulation. Results support that hydrocodone bitartrate extended-release tablets resists crushing, breaking, and dissolution using a variety of tools and solvents and retains some extended-release properties despite manipulation. When subjected to an aqueous environment, hydrocodone bitartrate extended-release tablets gradually forms a viscous hydrogel (i.e., a gelatinous mass) that resists passage through a hypodermic needle. Clinical Abuse Potential Studies Studies in Non-dependent Opioid Abusers: Two randomized, double-blind, placebo and active-comparator studies in non-dependent opioid abusers were conducted to characterize the abuse potential of hydrocodone bitartrate extended-release tablets following physical manipulation and administration via the intranasal and oral routes. For both studies, drug liking was measured on a bipolar drug liking scale of 0 to 100 where 50 represents a neutral response of neither liking nor disliking, 0 represents maximum disliking, and 100 represents maximum liking. Response to whether the subject would take the study drug again was measured on a unipolar scale of 0 to 100 where 0 represents the strongest negative response (“definitely would not take drug again”) and 100 represents the strongest positive response (“definitely would take drug again”). Intranasal Abuse Potential Study: In the intranasal abuse potential study, 31 subjects were dosed and 25 subjects completed the study. Treatments studied included intranasally administered tampered 60 mg hydrocodone bitartrate extended-release tablets, powdered hydrocodone bitartrate 60 mg, and placebo. Incomplete dosing due to granules falling from the subjects’ nostrils occurred in 82% (n = 23) of subjects receiving tampered hydrocodone bitartrate extended-release tablets compared to no subjects with powdered hydrocodone or placebo. The intranasal administration of tampered hydrocodone bitartrate extended-release tablets was associated with statistically significantly lower mean and median scores for drug liking and take drug again ( P <0.001 for both), compared with powdered hydrocodone as summarized in Table 4. Table 4. Summary of Maximum Scores (E max ) on Drug Liking and Take Drug Again VAS Following intranasal Administration of Hydrocodone Bitartrate Extended-Release Tablets and Hydrocodone Powder in Non-dependent Opioid Abusers VAS Scale (100 point) Hydrocodone Bitartrate Extended-Release Tablets Hydrocodone Intranasal (n=25) Manipulated Powder Drug Liking Bipolar scale (0=maximum negative response, 50=neutral response, 100=maximum positive response) Mean (SE) 65.4 (3.7) 90.4 (2.6) Median (Range) 56 (50–100) 100 (51–100) Take Drug Again Unipolar scale (0=maximum negative response, 100=maximum positive response) Mean (SE) 36.4 (8.2) 85.2 (5.0) Median (Range) 14 (0-100) 100 (1-100) Figure 1 demonstrates a comparison of peak drug liking scores for tampered hydrocodone bitartrate extended-release tablets compared with powdered hydrocodone in subjects (n = 25) who received both treatments intranasally. The Y-axis represents the percent of subjects attaining a percent reduction in peak drug liking scores for tampered hydrocodone bitartrate extended-release tablets vs. hydrocodone powder greater than or equal to the value on the X-axis. Approximately 80% (n = 20) of subjects had some reduction in drug liking with tampered hydrocodone bitartrate extended-release tablets relative to hydrocodone powder. Sixty-eight percent (n = 17) of subjects had a reduction of at least 30% in drug liking with tampered hydrocodone bitartrate extended-release tablets compared with hydrocodone powder, and approximately 64% (n = 16) of subjects had a reduction of at least 50% in drug liking with tampered hydrocodone bitartrate extended-release tablets compared with hydrocodone powder. Approximately 20% (n = 5) of subjects had no reduction in liking with tampered hydrocodone bitartrate extended-release tablets relative to hydrocodone powder. Figure 1: Percent Reduction Profiles for E max of Drug Liking VAS for Manipulated Hydrocodone Bitartrate Extended-Release Tablets vs. Hydrocodone Powder, N = 25 Following Intranasal Administration Oral Abuse Potential Study: In the oral abuse potential study, 40 subjects were dosed and 35 subjects completed the study. Treatments studied included oral administrations of chewed 60 mg hydrocodone bitartrate extended-release tablets, intact 60 mg hydrocodone bitartrate extended-release tablets, 60 mg aqueous hydrocodone bitartrate solution, and placebo. The oral administration of chewed and intact hydrocodone bitartrate extended-release tablets was associated with statistically lower mean and median scores on scales that measure drug liking and desire to take drug again (P<0.001), compared to hydrocodone solution as summarized in Table 5. Table 5. Summary of Maximum Scores (E max ) on Drug Liking and Take Drug Again VAS Following Oral Administration of Hydrocodone Bitartrate Extended-Release Tablets and Hydrocodone Solution in Non-dependent Recreational Opioid Users VAS Scale (100 point) Hydrocodone Bitartrate Extended-Release Tablets Hydrocodone Oral (n=35) Intact Chewed Solution Drug Liking Bipolar scale (0=maximum negative response, 50=neutral response, 100=maximum positive response) Mean (SE) 63.3 (2.7) 69.0 (3.0) 94.0 (1.7) Median (Range) 58 (50–100) 66 (50–100) 100 (51–100) Take Drug Again Unipolar scale (0=maximum negative response, 100=maximum positive response) Mean (SE) 34.3 (6.1) 44.3 (6.9) 89.7 (3.6) Median (Range) 24 (0-100) 55 (0-100) 100 (1-100) Figure 2 demonstrates a comparison of peak drug liking scores for chewed hydrocodone bitartrate extended-release tablets compared with hydrocodone solution in subjects who received both treatments orally. The Y-axis represents the percent of subjects attaining a percent reduction in peak drug liking scores for chewed hydrocodone bitartrate extended-release tablets vs. hydrocodone solution greater than or equal to the value on the X-axis. Approximately 80% (n = 28) of subjects had some reduction in drug liking with chewed hydrocodone bitartrate extended-release tablets relative to hydrocodone solution. Approximately 69% (n = 24) of subjects had a reduction of at least 30% in drug liking with chewed hydrocodone bitartrate extended-release tablets compared with hydrocodone solution, and approximately 60% (n = 21) of subjects had a reduction of at least 50% in drug liking with chewed hydrocodone bitartrate extended-release tablets compared with hydrocodone solution. Approximately 20% (n = 7) of subjects had no reduction in drug liking with chewed hydrocodone bitartrate extended-release tablets relative to hydrocodone solution. Figure 2. Percent Reduction Profiles for E max of Drug Liking VAS for Chewed Hydrocodone Bitartrate Extended-Release Tablets vs. Hydrocodone Solution, N = 35 Following Oral Administration The results of a similar analysis of drug liking for intact hydrocodone bitartrate extended-release tablets relative to hydrocodone solution were comparable to the results of chewed hydrocodone bitartrate extended-release tablets relative to hydrocodone solution. Approximately 83% (n = 29) of subjects had some reduction in drug liking with intact hydrocodone bitartrate extended-release tablets relative to hydrocodone solution. Eighty-three percent (n = 29) of subjects had a reduction of at least 30% in peak drug liking scores with intact hydrocodone bitartrate extended-release tablets compared to hydrocodone solution, and approximately 74% (n = 26) of subjects had a reduction of at least 50% in peak drug liking scores with intact hydrocodone bitartrate extended-release tablets compared with hydrocodone solution. Approximately 17% (n = 6) had no reduction in drug liking with intact hydrocodone bitartrate extended-release tablets relative to hydrocodone solution. Summary The in vitro data demonstrate that hydrocodone bitartrate extended-release tablets have physical and chemical properties that are expected to deter intranasal and intravenous abuse. The data from the clinical abuse potential studies, along with support from the in vitro data, also indicate that hydrocodone bitartrate extended-release tablets have physicochemical properties that are expected to reduce intranasal abuse and oral abuse when chewed. However, abuse of hydrocodone bitartrate extended-release tablets by the intravenous, intranasal, and oral routes is still possible. Additional data, including epidemiological data, when available, may provide further information on the impact of hydrocodone bitartrate extended-release tablets on the abuse liability of the drug. Accordingly, this section may be updated in the future as appropriate. 9.3 Dependence Both tolerance and physical dependence can develop during chronic opioid therapy. Tolerance is the need for increasing doses of opioids to maintain a defined effect such as analgesia (in the absence of disease progression or other external factors). Tolerance may occur to both the desired and undesired effects of drugs, and may develop at different rates for different effects. Physical dependence is a physiological state in which the body adapts to the drug after a period of regular exposure, resulting in withdrawal symptoms after abrupt discontinuation or a significant dosage reduction of a drug. Withdrawal also may be precipitated through the administration of drugs with opioid antagonist activity (e.g., naloxone, nalmefene), mixed agonist/antagonist analgesics (e.g., pentazocine, butorphanol, nalbuphine), or partial agonists (e.g., buprenorphine). Physical dependence may not occur to a clinically significant degree until after several days to weeks of continued opioid usage. Do not abruptly discontinue hydrocodone bitartrate extended-release tablets in a patient physically dependent on opioids. Rapid tapering of hydrocodone bitartrate extended-release tablets in a patient physically dependent on opioids may lead to 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. When discontinuing hydrocodone bitartrate extended-release tablets, gradually taper the dosage using a patient specific plan that considers the following: the dose of hydrocodone bitartrate extended-release tablets the patient has been taking, the duration of treatment, and the physical and psychological attributes of the patient. To improve the likelihood of a successful taper and minimize withdrawal symptoms, it is important that the opioid tapering schedule is agreed upon by the patient. In patients taking opioids for a long duration at high doses, ensure that a multimodal approach to pain management, including mental health support (if needed), is in place prior to initiating an opioid analgesic taper [see Dosage and Administration ( 2.7 ), Warnings and Precautions ( 5.15 )] . Infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal signs [see Use in Specific Populations ( 8.1 )].

10 OVERDOSAGE Clinical Presentation Acute overdosage with hydrocodone bitartrate extended-release tablets can be manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and, in some cases, pulmonary edema, bradycardia, hypotension, partial or complete airway obstruction, atypical snoring, and death. Marked mydriasis rather than miosis may be seen with hypoxia in overdose situations [see Clinical Pharmacology (12.2)] . Treatment of Overdose In case of overdose, priorities are the re-establishment of a patent airway and institution of assisted or controlled ventilation, if needed. Employ other supportive measures (including oxygen and vasopressors) in the management of circulatory shock and pulmonary edema accompanying overdose as indicated. Cardiac arrest or arrhythmias will require advanced life support techniques. Opioid antagonists, such as naloxone, are specific antidotes to respiratory depression resulting from opioid overdosage. For clinically significant respiratory or circulatory depression secondary to opioid overdose, administer an opioid antagonist. Because the duration of opioid reversal is expected to be less than the duration of action of hydrocodone in hydrocodone bitartrate extended-release tablets, carefully monitor the patient until spontaneous respiration is reliably reestablished. Hydrocodone bitartrate extended-release tablets will continue to release hydrocodone and add to the hydrocodone load for 24 to 48 hours or longer following ingestion, necessitating prolonged monitoring. If the response to an opioid antagonist is suboptimal or only brief in nature, administer additional antagonist as directed by the product’s prescribing information. In an individual physically dependent on opioids, administration of the recommended dose of the antagonist will precipitate an acute withdrawal syndrome. The severity of the withdrawal syndrome produced will depend on the degree of physical dependence and the dose of the antagonist administered. If a decision is made to treat serious respiratory depression in the physically dependent patient, administration of the antagonist should be initiated with care and by titration with smaller than usual doses of the antagonist.

7 DRUG INTERACTIONS Table 3 includes clinically significant drug interactions with hydrocodone bitartrate extended-release tablets. ­­ Table 3: Clinically Significant Drug Interactions with Hydrocodone Bitartrate Extended-Release Tablets Inhibitors of CYP3A4 Clinical Impact: The concomitant use of hydrocodone bitartrate extended-release 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 extended-release tablets and CYP3A4 inhibitors, particularly when an inhibitor is added after a stable dose of hydrocodone bitartrate extended-release tablets is achieved [see Warnings and Precautions ( 5.5 )] . After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the hydrocodone plasma concentration will decrease [see Clinical Pharmacology ( 12.3 )] , 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 extended-release 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 extended-release 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 extended-release tablets and CYP3A4 inducers can decrease the plasma concentration of hydrocodone [see Clinical Pharmacology ( 12.3 )] , resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to hydrocodone [see Warnings and Precautions ( 5.5 )] . After stopping a CYP3A4 inducer, as the effects of the inducer decline, the hydrocodone plasma concentration will increase [see Clinical Pharmacology (12.3)] , 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 extended-release tablet dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider hydrocodone bitartrate extended-release tablet 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, can increase the risk of hypotension, 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 Dosage and Administration ( 2.2 ), Warnings and Precautions ( 5.1 , 5.3 , 5.6 )] . 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 extended-release 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 affect 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 and Precautions ( 5.3 )] . Intervention: The use of hydrocodone bitartrate extended-release tablets is not recommended for patients taking MAOIs or within 14 days of stopping such treatment. Examples: Phenelzine, tranylcypromine, linezolid Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics Clinical Impact: May reduce the analgesic effect of hydrocodone bitartrate extended-release 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 extended-release 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 Dosage and Administration ( 2.2 ), Warnings and Precautions ( 5.3 , 5.6 )] . Examples: Cyclobenzaprine, metaxalone Diuretics Clinical Impact: Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. 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 extended-release tablets are used concomitantly with anticholinergic drugs. Strong Laxatives Clinical Impact: Concomitant use of hydrocodone bitartrate extended-release tablets with strong laxatives that rapidly increase gastrointestinal motility, may decrease hydrocodone absorption and result in decreased hydrocodone plasma levels. Intervention: If hydrocodone bitartrate extended-release tablets are used in these patients, closely monitor for the development of adverse events as well as changing analgesic requirements. Example: lactulose Serotonergic Drugs : Concomitant use may result in serotonin syndrome. Discontinue hydrocodone bitartrate extended-release tablets if serotonin syndrome is suspected. ( 7 ) Mixed Agonists/Antagonists and Partial Agonist Opioid Analgesics : Avoid use with hydrocodone bitartrate extended-release tablets because they may reduce analgesic effect of hydrocodone bitartrate extended-release tablets or precipitate withdrawal symptoms. (7) Monoamine Oxidase Inhibitors (MAOIs) : Can potentiate the effects of hydrocodone. Avoid concomitant use in patients receiving MAOIs or within 14 days of stopping an MAOI. (7)

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Hydrocodone is a full opioid agonist with relative selectivity for the mu-opioid receptor, although it can interact with other opioid receptors at higher doses. The principal therapeutic action of hydrocodone is analgesia. Like all full opioid agonists, there is no ceiling effect for analgesia with hydrocodone. Clinically, dosage is titrated to provide adequate analgesia and may be limited by adverse reactions, including respiratory and CNS depression. The precise mechanism of the analgesic action is unknown. However, specific CNS opioid receptors for endogenous compounds with opioid-like activity have been identified throughout the brain and spinal cord and are thought to play a role in the analgesic effects of this drug. 12.2 Pharmacodynamics Cardiac Electrophysiology QTc interval prolongation was studied in a double-blind, placebo- and positive-controlled 3-treatment parallel-group, dose-escalating study of hydrocodone bitartrate extended-release tablets in 196 healthy subjects. QTc interval prolongation was observed following 160 mg hydrocodone bitartrate extended-release tablets per day. The maximum mean (90% upper confidence bound) difference in the QTc interval between hydrocodone bitartrate extended-release tablets and placebo (after baseline-correction) at steady state was 6 (9) milliseconds, 7 (10) milliseconds, and 10 (13) milliseconds at hydrocodone bitartrate extended-release tablet doses of 80 mg, 120 mg and 160 mg respectively. For clinical implications of the prolonged QTc interval, see Warnings and Precautions ( 5.10 ). Effects on the Central Nervous System Hydrocodone produces respiratory depression by direct action on brainstem 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 origin may produce similar findings). Marked mydriasis rather than miosis may be seen with hypoxia in overdose situations [see Overdosage ( 10 )] . 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 is 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 ( 6.2 )] . 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 low libido, impotence, erectile dysfunction, amenorrhea, or infertility. The causal role of opioids in the clinical 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 (6.2)] . Effects on the Immune System Opioids have been shown to have a variety of effects on components of the immune system in in vitro and animal models. 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 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 ( 2.1 , 2.4 )] . Concentration—Adverse Experience Relationships There is a relationship between increasing hydrocodone plasma concentration and increasing frequency of 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 ( 2.1 , 2.3 , 2.4 )] . 12.3 Pharmacokinetics Absorption Hydrocodone bitartrate extended-release tablets are a single-entity extended-release formulation of hydrocodone that yields a gradual increase in plasma hydrocodone concentrations with a median T max of 14 to 16 hours noted for different dose strengths. Peak plasma levels may occur in the range of 6 to 30 hours after single dose hydrocodone bitartrate extended-release tablets administration. Systemic exposure (AUC and C max ) increased linearly with doses from 20 to 120 mg. Both C max and AUC increased slightly more than dose proportionally (Table 6). The mean terminal half-life (t 1/2 ) was similar for all hydrocodone bitartrate extended-release tablets dose strengths ranging from 7 to 9 hours. Table 6 Mean (SD) Single-Dose Pharmacokinetic Parameters of Hydrocodone Bitartrate Extended-Release Tablets Dose Strength (mg) AUCinf (ng•h/mL) C max (ng/mL) T max median (minimum, maximum) (h) 20 284 (128) 14.6 (5.5) 16 (6, 24) 40 622 (252) 33.9 (11.8) 16 (6, 24) 60 1009 (294) 53.6 (15.4) 14 (10, 30) 80 1304 (375) 69.1 (17.2) 16 (10, 24) 120 1787 (679) 110 (44.1) 14 (6, 30) As compared to an immediate-release hydrocodone combination product, hydrocodone bitartrate extended-release tablets at the same daily dose results in similar bioavailability but with lower maximum concentrations at steady state (Figure 3). Figure 3. Mean Steady-State Plasma Hydrocodone Concentration Profile Steady-state plasma hydrocodone concentrations were confirmed on day 3 of once-daily dosing of hydrocodone bitartrate extended-release tablets. The extent of accumulation of systemic exposure was 1.3 and 1.1 fold with respect to AUC and C max at steady-state. The mean terminal half-life (t 1/2 ) at steady state was 7 hours. Median T max values were 14 hours (range: 12 to 24 hours) on both Day 1 and Day 5 following once daily administration of hydrocodone bitartrate extended-release tablets for five days. Daily fluctuation in peak to trough plasma levels of hydrocodone were higher at 80 mg and 120 mg doses of hydrocodone bitartrate extended-release tablets compared to 30 mg dose (Table 7). Table 7 Mean (SD) Steady-State Hydrocodone Pharmacokinetic Parameters Regimen AUC24,ss (ng•h/mL) C max ,ss (ng/mL) C min ,ss (ng/mL) %Fluctuation* Hydrocodone Bitartrate Extended-Release Tablets 30 mg q24h 443 (128) 26.4 (7.4) 16.7 (5.2) 61 (6.4, 113) 80 mg q24h 1252 (352) 82.6 (25.7) 28.2 (12) 105 (36, 214) 120 mg q24h 1938 (729) 135 (50) 63.6 (29) 97.9 (32, 250) * Mean (minimum, maximum); Percentage fluctuation in plasma concentration is derived as (C max ,ss – C min , ss)*100/Cavg,ss. Food Effects C max and AUC of 120 mg hydrocodone bitartrate extended-release tablets were similar under low fat conditions relative to fasting conditions (17% and 9% higher, respectively). C max was higher (54%) under high fat conditions relative to fasting conditions; however, AUC of 120 mg hydrocodone bitartrate extended-release tablets was only 20% higher when co-administered with a high fat meal. Hydrocodone bitartrate extended-release tablets may be administered without regard to meals. Distribution Following administration of hydrocodone bitartrate extended-release tablets, the typical (70 kg adult) value of apparent volume of distribution (V/F) is 402 L, suggesting extensive tissue distribution. The extent of in vivo binding of hydrocodone to human plasma proteins was minimal with a mean % bound at 36%. Elimination Metabolism Hydrocodone exhibits a complex pattern of metabolism, including N -demethylation, O -demethylation, and 6-keto reduction to the corresponding 6-α-and 6-β-hydroxy metabolites. CYP3A4 mediated N -demethylation to inactive norhydrocodone is the primary metabolic pathway of hydrocodone with a lower contribution from CYP2B6 and CYP2C19. The minor metabolite hydromorphone (<3% of the circulating parent hydrocodone) was mainly formed by CYP2D6 mediated O -demethylation with a smaller contribution by CYP2B6 and CYP2C19. Hydromorphone may contribute to the total analgesic effect of hydrocodone. Excretion Hydrocodone and its metabolites are cleared primarily by renal excretion. The percent of administered dose excreted unchanged as hydrocodone in urine was 6.5% in subjects with normal renal function, and 5.0%, 4.8%, and 2.3% in subjects with mild, moderate, and severe renal impairment, respectively. Renal clearance (CLr) of hydrocodone in healthy subjects was small (5.3 L/h) compared to apparent oral clearance (CL/F, 83 L/h); suggesting that non-renal clearance is the main elimination route. Ninety-nine percent of the administered dose is eliminated within 72 hours. The mean terminal half-life (t 1/2 ) was similar for all hydrocodone bitartrate extended-release tablets dose strengths ranging from approximately 7 to 9 hours across the range of doses. Specific Populations Age: Geriatric Patients Following administration of 40 mg hydrocodone bitartrate extended-release tablets, the pharmacokinetics of hydrocodone in healthy elderly subjects (65 to 77 years) are similar to the pharmacokinetics in healthy younger subjects (20 to 45 years). There were no clinically meaningful increase in C max (16%) and AUC (15%) of hydrocodone in elderly as compared with younger adult subjects [see Use in Specific Populations (8.5)] . Sex Systemic exposure of hydrocodone (C max and AUC) was similar between males and females. Hepatic Impairment After a single dose of 20 mg hydrocodone bitartrate extended-release tablets in subjects (8 each) with normal hepatic function, mild, moderate or severe hepatic impairment based on Child-Pugh classifications, mean hydrocodone C max values were 16 ng/mL, 15 ng/mL, 17 ng/mL, and 18 ng/mL, respectively. Mean hydrocodone AUC values were 342 ng.hr/mL, 310 ng.hr/mL, 390 ng.hr/mL, and 415 ng.hr/mL for subjects with normal hepatic function, mild, moderate or severe hepatic impairment, respectively. Geometric mean hydrocodone C max values were -6%, 5%, and 5% and AUC values were -14%, 13%, and 4% in patients with mild, moderate or severe hepatic impairment, respectively, when compared with subjects with normal hepatic function. The mean in vivo plasma protein binding of hydrocodone across the groups was similar, ranging from 33% to 37% [see Use in Specific Populations ( 8.6 )] . Renal Impairment After a single dose of 60 mg hydrocodone bitartrate extended-release tablets in subjects (8 each) with normal renal function, mild, moderate, or severe renal impairment based on Cockcroft-Gault criteria and end stage renal disease (with dialysis) patients, mean hydrocodone C max values were 40 ng/mL, 50 ng/mL, 51 ng/mL, 46 ng/mL, and 38 ng/mL, respectively. Mean hydrocodone AUC values were 754 ng.hr/mL, 942 ng.hr/mL, 1222 ng.hr/mL, 1220 ng.hr/mL, and 932 ng.hr/mL for subjects with normal renal function, mild, moderate or severe renal impairment and ESRD with dialysis, respectively. Hydrocodone C max values were 14%, 23%, 11% and -13% and AUC values were 13%, 61%, 57% and 4% higher in patients with mild, moderate or severe renal impairment or end stage renal disease with dialysis, respectively [see Use in Specific Populations ( 8.7 )] . Drug Interaction Studies CYP3A4 Co-administration of hydrocodone bitartrate extended-release tablets (20 mg single dose) and CYP3A4 inhibitor ketoconazole (200 mg BID for 6 days) increased mean hydrocodone AUC and C max by 135% and 78%, respectively [see Warnings and Precautions ( 5.5 ) and Drug Interactions ( 7 )] . CYP2D6 The 90% confidence interval (CI) of the geometric means for hydrocodone AUC inf (98% to 115%), AUC t (98% to 115%), and C max (93% to 121%) values were within the range of 80% to 125% when a single dose of 20 mg hydrocodone bitartrate extended-release tablets was co-administered with CYP2D6 inhibitor paroxetine (20 mg treatment each morning for 12 days). No differences in systemic exposure of hydrocodone were observed in the presence of paroxetine.

12.1 Mechanism of Action Hydrocodone is a full opioid agonist with relative selectivity for the mu-opioid receptor, although it can interact with other opioid receptors at higher doses. The principal therapeutic action of hydrocodone is analgesia. Like all full opioid agonists, there is no ceiling effect for analgesia with hydrocodone. Clinically, dosage is titrated to provide adequate analgesia and may be limited by adverse reactions, including respiratory and CNS depression. The precise mechanism of the analgesic action is unknown. However, specific CNS opioid receptors for endogenous compounds with opioid-like activity have been identified throughout the brain and spinal cord and are thought to play a role in the analgesic effects of this drug.

12.2 Pharmacodynamics Cardiac Electrophysiology QTc interval prolongation was studied in a double-blind, placebo- and positive-controlled 3-treatment parallel-group, dose-escalating study of hydrocodone bitartrate extended-release tablets in 196 healthy subjects. QTc interval prolongation was observed following 160 mg hydrocodone bitartrate extended-release tablets per day. The maximum mean (90% upper confidence bound) difference in the QTc interval between hydrocodone bitartrate extended-release tablets and placebo (after baseline-correction) at steady state was 6 (9) milliseconds, 7 (10) milliseconds, and 10 (13) milliseconds at hydrocodone bitartrate extended-release tablet doses of 80 mg, 120 mg and 160 mg respectively. For clinical implications of the prolonged QTc interval, see Warnings and Precautions ( 5.10 ). Effects on the Central Nervous System Hydrocodone produces respiratory depression by direct action on brainstem 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 origin may produce similar findings). Marked mydriasis rather than miosis may be seen with hypoxia in overdose situations [see Overdosage ( 10 )] . 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 is 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 ( 6.2 )] . 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 low libido, impotence, erectile dysfunction, amenorrhea, or infertility. The causal role of opioids in the clinical 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 (6.2)] . Effects on the Immune System Opioids have been shown to have a variety of effects on components of the immune system in in vitro and animal models. 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 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 ( 2.1 , 2.4 )] . Concentration—Adverse Experience Relationships There is a relationship between increasing hydrocodone plasma concentration and increasing frequency of 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 ( 2.1 , 2.3 , 2.4 )] .

12.3 Pharmacokinetics Absorption Hydrocodone bitartrate extended-release tablets are a single-entity extended-release formulation of hydrocodone that yields a gradual increase in plasma hydrocodone concentrations with a median T max of 14 to 16 hours noted for different dose strengths. Peak plasma levels may occur in the range of 6 to 30 hours after single dose hydrocodone bitartrate extended-release tablets administration. Systemic exposure (AUC and C max ) increased linearly with doses from 20 to 120 mg. Both C max and AUC increased slightly more than dose proportionally (Table 6). The mean terminal half-life (t 1/2 ) was similar for all hydrocodone bitartrate extended-release tablets dose strengths ranging from 7 to 9 hours. Table 6 Mean (SD) Single-Dose Pharmacokinetic Parameters of Hydrocodone Bitartrate Extended-Release Tablets Dose Strength (mg) AUCinf (ng•h/mL) C max (ng/mL) T max median (minimum, maximum) (h) 20 284 (128) 14.6 (5.5) 16 (6, 24) 40 622 (252) 33.9 (11.8) 16 (6, 24) 60 1009 (294) 53.6 (15.4) 14 (10, 30) 80 1304 (375) 69.1 (17.2) 16 (10, 24) 120 1787 (679) 110 (44.1) 14 (6, 30) As compared to an immediate-release hydrocodone combination product, hydrocodone bitartrate extended-release tablets at the same daily dose results in similar bioavailability but with lower maximum concentrations at steady state (Figure 3). Figure 3. Mean Steady-State Plasma Hydrocodone Concentration Profile Steady-state plasma hydrocodone concentrations were confirmed on day 3 of once-daily dosing of hydrocodone bitartrate extended-release tablets. The extent of accumulation of systemic exposure was 1.3 and 1.1 fold with respect to AUC and C max at steady-state. The mean terminal half-life (t 1/2 ) at steady state was 7 hours. Median T max values were 14 hours (range: 12 to 24 hours) on both Day 1 and Day 5 following once daily administration of hydrocodone bitartrate extended-release tablets for five days. Daily fluctuation in peak to trough plasma levels of hydrocodone were higher at 80 mg and 120 mg doses of hydrocodone bitartrate extended-release tablets compared to 30 mg dose (Table 7). Table 7 Mean (SD) Steady-State Hydrocodone Pharmacokinetic Parameters Regimen AUC24,ss (ng•h/mL) C max ,ss (ng/mL) C min ,ss (ng/mL) %Fluctuation* Hydrocodone Bitartrate Extended-Release Tablets 30 mg q24h 443 (128) 26.4 (7.4) 16.7 (5.2) 61 (6.4, 113) 80 mg q24h 1252 (352) 82.6 (25.7) 28.2 (12) 105 (36, 214) 120 mg q24h 1938 (729) 135 (50) 63.6 (29) 97.9 (32, 250) * Mean (minimum, maximum); Percentage fluctuation in plasma concentration is derived as (C max ,ss – C min , ss)*100/Cavg,ss. Food Effects C max and AUC of 120 mg hydrocodone bitartrate extended-release tablets were similar under low fat conditions relative to fasting conditions (17% and 9% higher, respectively). C max was higher (54%) under high fat conditions relative to fasting conditions; however, AUC of 120 mg hydrocodone bitartrate extended-release tablets was only 20% higher when co-administered with a high fat meal. Hydrocodone bitartrate extended-release tablets may be administered without regard to meals. Distribution Following administration of hydrocodone bitartrate extended-release tablets, the typical (70 kg adult) value of apparent volume of distribution (V/F) is 402 L, suggesting extensive tissue distribution. The extent of in vivo binding of hydrocodone to human plasma proteins was minimal with a mean % bound at 36%. Elimination Metabolism Hydrocodone exhibits a complex pattern of metabolism, including N -demethylation, O -demethylation, and 6-keto reduction to the corresponding 6-α-and 6-β-hydroxy metabolites. CYP3A4 mediated N -demethylation to inactive norhydrocodone is the primary metabolic pathway of hydrocodone with a lower contribution from CYP2B6 and CYP2C19. The minor metabolite hydromorphone (<3% of the circulating parent hydrocodone) was mainly formed by CYP2D6 mediated O -demethylation with a smaller contribution by CYP2B6 and CYP2C19. Hydromorphone may contribute to the total analgesic effect of hydrocodone. Excretion Hydrocodone and its metabolites are cleared primarily by renal excretion. The percent of administered dose excreted unchanged as hydrocodone in urine was 6.5% in subjects with normal renal function, and 5.0%, 4.8%, and 2.3% in subjects with mild, moderate, and severe renal impairment, respectively. Renal clearance (CLr) of hydrocodone in healthy subjects was small (5.3 L/h) compared to apparent oral clearance (CL/F, 83 L/h); suggesting that non-renal clearance is the main elimination route. Ninety-nine percent of the administered dose is eliminated within 72 hours. The mean terminal half-life (t 1/2 ) was similar for all hydrocodone bitartrate extended-release tablets dose strengths ranging from approximately 7 to 9 hours across the range of doses. Specific Populations Age: Geriatric Patients Following administration of 40 mg hydrocodone bitartrate extended-release tablets, the pharmacokinetics of hydrocodone in healthy elderly subjects (65 to 77 years) are similar to the pharmacokinetics in healthy younger subjects (20 to 45 years). There were no clinically meaningful increase in C max (16%) and AUC (15%) of hydrocodone in elderly as compared with younger adult subjects [see Use in Specific Populations (8.5)] . Sex Systemic exposure of hydrocodone (C max and AUC) was similar between males and females. Hepatic Impairment After a single dose of 20 mg hydrocodone bitartrate extended-release tablets in subjects (8 each) with normal hepatic function, mild, moderate or severe hepatic impairment based on Child-Pugh classifications, mean hydrocodone C max values were 16 ng/mL, 15 ng/mL, 17 ng/mL, and 18 ng/mL, respectively. Mean hydrocodone AUC values were 342 ng.hr/mL, 310 ng.hr/mL, 390 ng.hr/mL, and 415 ng.hr/mL for subjects with normal hepatic function, mild, moderate or severe hepatic impairment, respectively. Geometric mean hydrocodone C max values were -6%, 5%, and 5% and AUC values were -14%, 13%, and 4% in patients with mild, moderate or severe hepatic impairment, respectively, when compared with subjects with normal hepatic function. The mean in vivo plasma protein binding of hydrocodone across the groups was similar, ranging from 33% to 37% [see Use in Specific Populations ( 8.6 )] . Renal Impairment After a single dose of 60 mg hydrocodone bitartrate extended-release tablets in subjects (8 each) with normal renal function, mild, moderate, or severe renal impairment based on Cockcroft-Gault criteria and end stage renal disease (with dialysis) patients, mean hydrocodone C max values were 40 ng/mL, 50 ng/mL, 51 ng/mL, 46 ng/mL, and 38 ng/mL, respectively. Mean hydrocodone AUC values were 754 ng.hr/mL, 942 ng.hr/mL, 1222 ng.hr/mL, 1220 ng.hr/mL, and 932 ng.hr/mL for subjects with normal renal function, mild, moderate or severe renal impairment and ESRD with dialysis, respectively. Hydrocodone C max values were 14%, 23%, 11% and -13% and AUC values were 13%, 61%, 57% and 4% higher in patients with mild, moderate or severe renal impairment or end stage renal disease with dialysis, respectively [see Use in Specific Populations ( 8.7 )] . Drug Interaction Studies CYP3A4 Co-administration of hydrocodone bitartrate extended-release tablets (20 mg single dose) and CYP3A4 inhibitor ketoconazole (200 mg BID for 6 days) increased mean hydrocodone AUC and C max by 135% and 78%, respectively [see Warnings and Precautions ( 5.5 ) and Drug Interactions ( 7 )] . CYP2D6 The 90% confidence interval (CI) of the geometric means for hydrocodone AUC inf (98% to 115%), AUC t (98% to 115%), and C max (93% to 121%) values were within the range of 80% to 125% when a single dose of 20 mg hydrocodone bitartrate extended-release tablets was co-administered with CYP2D6 inhibitor paroxetine (20 mg treatment each morning for 12 days). No differences in systemic exposure of hydrocodone were observed in the presence of paroxetine.

20210520

4

3 DOSAGE FORMS AND STRENGTHS 20 mg film-coated extended release tablets (white, round, film-coated tablet, “A392” printed in black ink on one side, blank on the other side) 30 mg film-coated extended release tablets (beige, round, film-coated tablet, “A393” printed in black ink on one side, blank on the other side) 40 mg film-coated extended release tablets (pink, round, film-coated tablet, “A394” printed in black ink on one side, blank on the other side) 60 mg film-coated extended release tablets (blue, round, film-coated tablet, “A395” printed in black ink on one side, blank on the other side) 80 mg film-coated extended release tablets (violet, round, film-coated tablet, “A396” printed in black ink on one side, blank on the other side) 100 mg film-coated extended release tablets (green, round, film-coated tablet, “A397” printed in black ink on one side, blank on the other side) 120 mg film-coated extended release tablets (yellow, round, film-coated tablet, “A398” printed in black ink on one side, blank on the other side) Extended-release tablets: 20 mg, 30 mg, 40 mg, 60 mg, 80 mg, 100 mg, and 120 mg ( 3 )

Hydrocodone Bitartrate Hydrocodone Bitartrate HYDROCODONE BITARTRATE HYDROCODONE MICROCRYSTALLINE CELLULOSE HYDROXYPROPYL CELLULOSE (90000 WAMW) POLYETHYLENE GLYCOL, UNSPECIFIED MAGNESIUM STEARATE POLYVINYL ALCOHOL, UNSPECIFIED TALC POLYSORBATE 80 TITANIUM DIOXIDE SHELLAC ISOPROPYL ALCOHOL FERROSOFERRIC OXIDE BUTYL ALCOHOL PROPYLENE GLYCOL AMMONIA POLYETHYLENE OXIDE 600000 POLYETHYLENE OXIDE 7000000 A392 Hydrocodone Bitartrate Hydrocodone Bitartrate HYDROCODONE BITARTRATE HYDROCODONE MICROCRYSTALLINE CELLULOSE HYDROXYPROPYL CELLULOSE (90000 WAMW) POLYETHYLENE GLYCOL, UNSPECIFIED MAGNESIUM STEARATE POLYVINYL ALCOHOL, UNSPECIFIED TALC POLYSORBATE 80 TITANIUM DIOXIDE SHELLAC ISOPROPYL ALCOHOL FERROSOFERRIC OXIDE BUTYL ALCOHOL PROPYLENE GLYCOL AMMONIA FERRIC OXIDE YELLOW FERRIC OXIDE RED POLYETHYLENE OXIDE 600000 POLYETHYLENE OXIDE 7000000 A393 beige Hydrocodone Bitartrate Hydrocodone Bitartrate HYDROCODONE BITARTRATE HYDROCODONE MICROCRYSTALLINE CELLULOSE HYDROXYPROPYL CELLULOSE (90000 WAMW) POLYETHYLENE GLYCOL, UNSPECIFIED MAGNESIUM STEARATE POLYVINYL ALCOHOL, UNSPECIFIED TALC POLYSORBATE 80 TITANIUM DIOXIDE SHELLAC ISOPROPYL ALCOHOL FERROSOFERRIC OXIDE BUTYL ALCOHOL PROPYLENE GLYCOL AMMONIA FERRIC OXIDE RED POLYETHYLENE OXIDE 600000 POLYETHYLENE OXIDE 7000000 A394 Hydrocodone Bitartrate Hydrocodone Bitartrate HYDROCODONE BITARTRATE HYDROCODONE MICROCRYSTALLINE CELLULOSE HYDROXYPROPYL CELLULOSE (90000 WAMW) POLYETHYLENE GLYCOL, UNSPECIFIED MAGNESIUM STEARATE POLYVINYL ALCOHOL, UNSPECIFIED TALC POLYSORBATE 80 TITANIUM DIOXIDE SHELLAC ISOPROPYL ALCOHOL FERROSOFERRIC OXIDE BUTYL ALCOHOL PROPYLENE GLYCOL AMMONIA FD&C BLUE NO. 2 POLYETHYLENE OXIDE 600000 POLYETHYLENE OXIDE 7000000 A395 Hydrocodone Bitartrate Hydrocodone Bitartrate HYDROCODONE BITARTRATE HYDROCODONE MICROCRYSTALLINE CELLULOSE HYDROXYPROPYL CELLULOSE (90000 WAMW) POLYETHYLENE GLYCOL, UNSPECIFIED MAGNESIUM STEARATE POLYVINYL ALCOHOL, UNSPECIFIED TALC POLYSORBATE 80 TITANIUM DIOXIDE SHELLAC ISOPROPYL ALCOHOL FERROSOFERRIC OXIDE BUTYL ALCOHOL PROPYLENE GLYCOL AMMONIA D&C RED NO. 27 FD&C BLUE NO. 1 POLYETHYLENE OXIDE 600000 POLYETHYLENE OXIDE 7000000 Violet A396 Hydrocodone Bitartrate Hydrocodone Bitartrate HYDROCODONE BITARTRATE HYDROCODONE MICROCRYSTALLINE CELLULOSE HYDROXYPROPYL CELLULOSE (90000 WAMW) POLYETHYLENE GLYCOL, UNSPECIFIED MAGNESIUM STEARATE POLYVINYL ALCOHOL, UNSPECIFIED TALC POLYSORBATE 80 TITANIUM DIOXIDE SHELLAC ISOPROPYL ALCOHOL FERROSOFERRIC OXIDE BUTYL ALCOHOL PROPYLENE GLYCOL AMMONIA FERRIC OXIDE YELLOW FD&C BLUE NO. 2 POLYETHYLENE OXIDE 600000 POLYETHYLENE OXIDE 7000000 A397 Hydrocodone Bitartrate Hydrocodone Bitartrate HYDROCODONE BITARTRATE HYDROCODONE MICROCRYSTALLINE CELLULOSE HYDROXYPROPYL CELLULOSE (90000 WAMW) POLYETHYLENE GLYCOL, UNSPECIFIED MAGNESIUM STEARATE POLYVINYL ALCOHOL, UNSPECIFIED TALC POLYSORBATE 80 TITANIUM DIOXIDE SHELLAC ISOPROPYL ALCOHOL FERROSOFERRIC OXIDE BUTYL ALCOHOL PROPYLENE GLYCOL AMMONIA FERRIC OXIDE YELLOW POLYETHYLENE OXIDE 600000 POLYETHYLENE OXIDE 7000000 A398 figure-1 figure-2 structure figure-3 figure-4 label-20mg label-30mg label-40mg label-60mg label-80mg label-100mg label-120mg

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Hydrocodone was evaluated for carcinogenic potential in rats and mice. In a two-year bioassay in rats, doses up to 25 mg/kg in males and females were administered orally and no treatment-related neoplasms were observed (exposure is equivalent to 0.2 times the human hydrocodone dose of 120 mg/day based on AUC exposure comparisons). In a two-year bioassay in mice, doses up to 200 mg/kg in males and 100 mg/kg in females were administered orally and no treatment-related neoplasms were observed (exposure is equivalent to 3.5 times and 3.0 times, respectively, the human hydrocodone dose of 120 mg/day based on AUC exposure comparisons). Mutagenesis Hydrocodone was genotoxic in the mouse lymphoma assay in the presence of rat S9 metabolic activation but not in the absence of rat metabolic activation. However, hydrocodone was not genotoxic in the mouse lymphoma assay with or without human S9 metabolic activation. There was no evidence of genotoxic potential with hydrocodone in an in vitro bacterial reverse mutation assay with Salmonella typhimurium and Escherichia coli with or without metabolic activation or in an in vivo mouse bone marrow micronucleus test with or without metabolic activation. Impairment of Fertility No effect on fertility or general reproductive performance was seen with oral administration of hydrocodone to male and female rats at doses up to 25 mg/kg/day (approximately 0.06 times and 0.08 times, respectively, the human hydrocodone dose of 120 mg/day based on AUC exposure comparisons).

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Hydrocodone was evaluated for carcinogenic potential in rats and mice. In a two-year bioassay in rats, doses up to 25 mg/kg in males and females were administered orally and no treatment-related neoplasms were observed (exposure is equivalent to 0.2 times the human hydrocodone dose of 120 mg/day based on AUC exposure comparisons). In a two-year bioassay in mice, doses up to 200 mg/kg in males and 100 mg/kg in females were administered orally and no treatment-related neoplasms were observed (exposure is equivalent to 3.5 times and 3.0 times, respectively, the human hydrocodone dose of 120 mg/day based on AUC exposure comparisons). Mutagenesis Hydrocodone was genotoxic in the mouse lymphoma assay in the presence of rat S9 metabolic activation but not in the absence of rat metabolic activation. However, hydrocodone was not genotoxic in the mouse lymphoma assay with or without human S9 metabolic activation. There was no evidence of genotoxic potential with hydrocodone in an in vitro bacterial reverse mutation assay with Salmonella typhimurium and Escherichia coli with or without metabolic activation or in an in vivo mouse bone marrow micronucleus test with or without metabolic activation. Impairment of Fertility No effect on fertility or general reproductive performance was seen with oral administration of hydrocodone to male and female rats at doses up to 25 mg/kg/day (approximately 0.06 times and 0.08 times, respectively, the human hydrocodone dose of 120 mg/day based on AUC exposure comparisons).

ANDA208269

Hydrocodone Bitartrate

Hydrocodone Bitartrate

47781-397

HUMAN PRESCRIPTION DRUG

ORAL

NDC 47781- 392 -60 Hydrocodone Bitartrate Extended-Release Tablets CII 20 mg Attention Dispenser: Accompanying Medication Guide must be provided to the patient upon dispensing. Swallow tablets whole. Do not cut, break, chew, crush, or dissolve. 60 Tablets Rx only

RECENT MAJOR CHANGES Dosage and Administration ( 2.2 ) 03/2021 Warnings and Precautions ( 5.1 , 5.3 , 5.6 ) 03/2021

17 PATIENT COUNSELING INFORMATION 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 extended-release tablets securely, out of sight and reach of children, and in a location not accessible by others, including visitors to the home [see Warnings and Precautions ( 5.1 , 5.3 ), Drug Abuse and Dependence ( 9.2 )] . Inform patients that leaving hydrocodone bitartrate extended-release tablets unsecured can pose a deadly risk to others in the home. Advise patients and caregivers that when medicines are no longer needed, they should be disposed of promptly. Expired, unwanted, or unused hydrocodone bitartrate extended-release tablets should be disposed of by flushing the unused medication down the toilet if a drug take-back option is not readily available. Inform patients that they can visit www.fda.gov/drugdisposal for a complete list of medicines recommended for disposal by flushing, as well as additional information on disposal of unused medicines. Addiction, Abuse, and Misuse Inform patients that the use of hydrocodone bitartrate extended-release tablets, even when taken as recommended, can result in addiction, abuse, and misuse, which can lead to overdose or death [see Warnings and Precautions ( 5.1 )] . Instruct patients not to share hydrocodone bitartrate extended-release tablets with others and to take steps to protect hydrocodone bitartrate extended-release 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 extended-release tablets or when the dosage is increased, and that it can occur even at recommended dosages. 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 Warnings and Precautions ( 5.3 )] . 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 extended-release 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) [see Dosage and Administration ( 2.2 ), Warnings and Precautions ( 5.3 )] . 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 ( 10 )] . 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. Accidental Ingestion Inform patients that accidental ingestion, especially by children, may result in respiratory depression or death [see Warnings and Precautions ( 5.3 )] . Interaction with Benzodiazepines and other CNS Depressants Inform patients and caregivers that potentially fatal additive effects may occur if hydrocodone bitartrate extended-release tablets are used with benzodiazepines or other CNS depressants, including alcohol, and not to use these concomitantly unless supervised by a health care provider [see Warnings and Precautions ( 5.6 ), Drug Interactions ( 7 )] . 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 Drug Interactions ( 7 )] . MAOI Interaction Inform patients to avoid taking hydrocodone bitartrate extended-release tablets while using any drugs that inhibit monoamine oxidase. Patients should not start MAOIs while taking hydrocodone bitartrate extended-release tablets [see Drug Interactions ( 7 )] . Adrenal Insufficiency Inform patients that 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 and Precautions ( 5.8 )] . Important Administration Instructions Instruct patients how to properly take hydrocodone bitartrate extended-release tablets, including the following: Use hydrocodone bitartrate extended-release tablets exactly as prescribed to reduce the risk of life-threatening adverse reactions (e.g., respiratory depression) [see Warnings and Precautions ( 5.3 )] . Swallow tablets whole, one tablet at a time, with enough water to ensure swallowing immediately after placing in the mouth [see Dosage and Administration ( 2.1 )] . Do not pre-soak, lick, or otherwise wet the tablet prior to placing in the mouth [see Dosage and Administration ( 2.1 )] . Do not chew, crush, or dissolve the tablets [see Dosage and Administration ( 2.1 )] . Important Discontinuation Instructions In order to avoid developing withdrawal symptoms, instruct patients not to discontinue hydrocodone bitartrate extended-release tablets without first discussing a tapering plan with the prescriber [see Dosage and Administration ( 2.7 )] . Hypotension Inform patients that hydrocodone bitartrate extended-release 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 and Precautions ( 5.9 )] . QTc interval prolongation Inform patients that QT prolongation has been observed with hydrocodone bitartrate extended-release tablets [see Clinical Pharmacology (12.2)] . Hydrocodone bitartrate extended-release tablets should be avoided in patients with congenital long QT syndrome. Instruct patients with a history of congestive heart failure or bradyarrhythmias, and patients at risk for electrolyte abnormalities or who are taking other medications known to prolong the QT interval, that periodic monitoring of electrocardiograms and electrolytes may be necessary during therapy with hydrocodone bitartrate extended-release tablets [see Warnings and Precautions ( 5.10 )] . Anaphylaxis Inform patients that anaphylaxis has been reported with ingredients contained in hydrocodone bitartrate extended-release tablets. Advise patients how to recognize such a reaction and when to seek medical attention [see Contraindications ( 4 ), Adverse Reactions ( 6 )] . Pregnancy Neonatal Opioid Withdrawal Syndrome Inform female patients of reproductive potential that prolonged use of hydrocodone bitartrate extended-release tablets during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated [see Warnings and Precautions ( 5.4 ), Use in Specific Populations ( 8.1 )] . Embryo-Fetal Toxicity Inform female patients of reproductive potential that hydrocodone bitartrate extended-release tablets can cause fetal harm and to inform their healthcare provider of a known or suspected pregnancy [see Use in Specific Populations ( 8.1 )] . Lactation Advise patients that breastfeeding is not recommended during treatment with hydrocodone bitartrate extended-release tablets [see Use in Specific Populations ( 8.2 )] . Infertility Inform patients that chronic use of opioids may cause reduced fertility. It is not known whether these effects on fertility are reversible [see Adverse Reactions ( 6.2 ), Use in Specific Populations ( 8.3 )] . Driving or Operating Heavy Machinery Inform patients that hydrocodone bitartrate extended-release tablets may impair the ability to perform potentially hazardous activities such as driving a car or operating heavy machinery. Blood levels of hydrocodone, in some patients, may be high at the end of 24 hours after repeated dose administration. Advise patients not to perform such tasks until they know how they will react to the medication [see Warnings and Precautions ( 5.16 )] . Constipation Advise patients of the potential for severe constipation, including management instructions and when to seek medical attention. Instruct patients to monitor their analgesic response following the use of strong laxatives and to contact the prescriber if changes are noted [see Adverse Reactions ( 6 ), Clinical Pharmacology ( 12.2 )] . Healthcare professionals can telephone Alvogen, Inc. at 1-866-770-3024 for information on this product. Product of USA Distributed by: Alvogen, Inc. Morristown, NJ 07960 USA PKG02865 PI392-01

Medication Guide Hydrocodone Bitartrate (hye'' droe koe' done bye tar' trate) Extended-Release Tablets , CII Hydrocodone bitartrate extended-release tablets are: A strong prescription pain medicine that contains an opioid (narcotic) that is used to manage pain severe enough to require daily, around-the-clock, long-term treatment with an opioid, when other pain treatments such as non-opioid pain medicines or immediate-release opioid medicines do not treat your pain well enough or you cannot tolerate them. A long-acting (extended-release) opioid pain medicine that can put you at risk for overdose and death. Even if you take your dose correctly as prescribed you are at risk for opioid addiction, abuse, and misuse that can lead to death. Not for use to treat pain that is not around-the-clock. Important information about hydrocodone bitartrate extended-release tablets : Get emergency help or call 911 right away if you take too many hydrocodone bitartrate extended-release tablets (overdose). When you first start taking hydrocodone bitartrate extended-release tablets, when your dose is changed, or if you take too much (overdose), serious or life-threatening breathing problems that can lead to death may occur. Talk to your healthcare provider about naloxone, a medicine for the emergency treatment of an opioid overdose. Taking hydrocodone bitartrate extended-release tablets with other opioid medicines, benzodiazepines, alcohol, or other central nervous system depressants (including street drugs) can cause severe drowsiness, decreased awareness, breathing problems, coma, and death. Never give anyone else your hydrocodone bitartrate extended-release tablets. They could die from taking it. Selling or giving away hydrocodone bitartrate extended-release tablets is against the law. Store hydrocodone bitartrate extended-release tablets securely, out of sight and reach of children, and in a location not accessible by others, including visitors to the home Do not take hydrocodone bitartrate extended-release tablets if you have: severe asthma, trouble breathing, or other lung problems. a bowel blockage or have narrowing of the stomach or intestines. Before taking hydrocodone bitartrate extended-release tablets, tell your healthcare provider if you have a history of: head injury, seizures liver, kidney, thyroid problems problems urinating pancreas or gallbladder problems heart rhythm problems (long QT syndrome) abuse of street or prescription drugs, alcohol addiction, opioid overdose, or mental health problems Tell your healthcare provider if you are: pregnant or planning to become pregnant . Prolonged use of hydrocodone bitartrate extended-release tablets during pregnancy can cause withdrawal symptoms in your newborn baby that could be life-threatening if not recognized and treated. breastfeeding . Not recommended during treatment with hydrocodone bitartrate extended-release tablets. It may harm your baby. living in a household where there are small children or someone who has abused street or prescription drugs. taking prescription or over-the-counter medicines, vitamins, or herbal supplements. Taking hydrocodone bitartrate extended-release tablets with certain other medicines can cause serious side effects and could lead to death. When taking hydrocodone bitartrate extended-release tablets: Do not change your dose. Take hydrocodone bitartrate extended-release tablets exactly as prescribed by your healthcare provider. Use the lowest dose possible for the shortest time needed. Take your prescribed dose every 24 hours, at the same time every day. Do not take more than your prescribed dose in 24 hours. If you miss a dose, take your next dose at your usual time the next day. Swallow hydrocodone bitartrate extended-release tablets whole. Do not cut, break, chew, crush, dissolve, snort, or inject hydrocodone bitartrate extended-release tablets because this may cause you to overdose and die. Hydrocodone bitartrate extended-release tablets should be taken 1 tablet at a time. Do not pre-soak, lick, or wet the tablet before placing it in your mouth to avoid choking on the tablet. Call your healthcare provider if the dose you are taking does not control your pain. Do not stop taking hydrocodone bitartrate extended-release tablets without talking to your healthcare provider. Dispose of expired, unwanted, or unused hydrocodone bitartrate extended-release tablets, by promptly flushing down the toilet, if a drug take-back option is not readily available. Visit www.fda.gov/drugdisposal for additional information on disposal of unused medicines. While taking hydrocodone bitartrate extended-release tablets, DO NOT: Drive or operate heavy machinery until you know how hydrocodone bitartrate extended-release tablets affect you. Hydrocodone bitartrate extended-release tablets can make you sleepy, dizzy, or lightheaded. Drink alcohol or use prescription or over-the-counter medicines that contain alcohol. Using products containing alcohol during treatment with hydrocodone bitartrate extended-release tablets may cause you to overdose and die. The possible side effects of hydrocodone bitartrate extended-release tablets are: constipation, nausea, sleepiness, vomiting, tiredness, headache, dizziness, abdominal pain. Call your healthcare provider if you have any of these symptoms and they are severe. Get emergency medical help or call 911 right away if you have: trouble breathing, shortness of breath, fast heartbeat, chest pain, swelling of your face, tongue or throat, extreme drowsiness, light-headedness when changing positions, feeling faint, agitation, high body temperature, trouble walking, stiff muscles, or mental changes such as confusion. These are not all the possible side effects of hydrocodone bitartrate extended-release tablets. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. For more information go to dailymed.nlm.nih.gov or call Alvogen, Inc. at 1-866-770-3024. Product of USA Distributed by: Alvogen, Inc., Morristown, NJ 07960 USA This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised: 05/2021 PL392-01 PKG02866

14 CLINICAL STUDIES 14.1 Moderate to Severe Chronic Lower Back Pain Study The efficacy and safety of hydrocodone bitartrate extended-release tablets was evaluated in a randomized double-blind, placebo-controlled, multi-center, 12-week clinical trial in both opioid-experienced and opioid-naïve patients with moderate to severe chronic low back pain. A total of 905 chronic low back pain patients (opioid naive and opioid-experienced) who were not responsive to their prior analgesic therapy entered an open-label conversion and dose- titration period for up to 45 days with hydrocodone bitartrate extended-release tablets. Patients were dosed once daily with hydrocodone bitartrate extended-release tablets (20 mg to 120 mg). Patients stopped their prior opioid analgesics and/or nonopioid analgesics prior to starting hydrocodone bitartrate extended-release tablet treatment. Optional use of rescue medication (immediate-release oxycodone 5 mg) up to 2 doses (2 tablets) was permitted during the dose titration period. For inadequately controlled pain, hydrocodone bitartrate extended-release tablets dose was allowed to be increased once every 3 to 5 days until a stabilized and tolerable dose was identified. During the dose-titration period, 65% of the patients achieved a stable hydrocodone bitartrate extended-release tablets dose and entered the double-blind treatment period. The remaining subjects discontinued from the dose-titration period for the following reasons: adverse events (10%); lack of therapeutic effect (5%); confirmed or suspected diversion (3%); subject’s choice (5%); lost to follow-up (2%); administrative reasons (2%); and failure to achieve protocol-defined reduction in pain score (7%). Following the dose titration period, 588 patients (65%) were randomized at a ratio of 1:1 into a 12-week double-blind treatment period with their fixed stabilized dose of hydrocodone bitartrate extended-release tablets (or matching placebo). These patients met the study randomization criteria of adequate analgesia (pain reduction of at least 2 points to a score of 4 or less on a 0 to 10 numerical rating scale) and acceptable tolerability of hydrocodone bitartrate extended-release tablets. Patients randomized to placebo were given a blinded taper of hydrocodone bitartrate extended-release tablets according to a pre-specified tapering schedule, 3 days on each step-down dose (reduced by 25% to 50% from the previous dose). Patients were allowed to use rescue medication (immediate-release oxycodone 5 mg) up to 6 doses (6 tablets) per day depending on their randomized hydrocodone bitartrate extended-release tablets dose. During the double-blind period, 229 treated patients (77%) completed the 12-week treatment with hydrocodone bitartrate extended-release tablets and 210 patients (72%) completed on placebo. Overall, 10% of patients discontinued due to lack of therapeutic effect (5% in hydrocodone bitartrate extended-release patients and 15% in placebo patients); 5% of patients discontinued due to adverse events (6% in hydrocodone bitartrate extended-release tablet treated patients and 3% in placebo patients). Hydrocodone bitartrate extended-release tablets provided greater analgesia compared with placebo. There was a statistically significant difference in the weekly average pain scores at Week 12 between the two groups. The percentage of patients (responders) in each group who demonstrated improvement in their weekly average pain scores at Week 12, as compared with screening is shown in Figure 4. The figure is cumulative, so that patients whose change from screening is, for example, 30%, are also included at every level of improvement below 30%. Patients who did not complete the study were classified as non-responders. Treatment with hydrocodone bitartrate extended-release tablets resulted in a higher proportion of responders, defined as patients with at least a 30% and 50% improvement, as compared with placebo. Figure 4. Percent Improvement in Pain Intensity

8.5 Geriatric Use In a controlled pharmacokinetic study, elderly subjects (greater than 65 years) compared to young adults had similar plasma concentrations of hydrocodone [see Clinical Pharmacology ( 12.3 )] . Of the 1827 subjects exposed to hydrocodone bitartrate extended-release tablets in the pooled chronic pain studies, 241 (13%) were age 65 and older (including those age 75 and older), while 42 (2%) were age 75 and older. In clinical trials with appropriate initiation of therapy and dose titration, no untoward or unexpected adverse reactions were seen in the elderly patients who received hydrocodone bitartrate extended-release 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 extended-release tablets slowly in geriatric patients and monitor closely for signs of central nervous system and respiratory depression [see Warnings and Precautions ( 5.3 )] . Hydrocodone is 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 monitor renal function.

8.2 Lactation Risk Summary Hydrocodone is present in human milk. A published lactation study reports variable concentrations of hydrocodone and hydromorphone (an active metabolite) in breast milk with administration of immediate-release hydrocodone to nursing mothers in the early post-partum period. This lactation study did not assess breastfed infants for potential adverse drug reactions. Lactation studies have not been conducted with hydrocodone bitartrate extended-release tablets, and no information is available on the effects of the drug on the breastfed infant or the effects of the drug on milk production. Because of the potential for serious adverse reactions, including excess sedation and respiratory depression in a breastfed infant, advise patients that breastfeeding is not recommended during treatment with hydrocodone bitartrate extended-release tablets. Clinical Considerations Monitor infants exposed to hydrocodone bitartrate extended-release 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.

8.3 Females and Males of Reproductive Potential Infertility Chronic use of opioids 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 ( 6.2 )].

8.4 Pediatric Use The safety and effectiveness of hydrocodone bitartrate extended-release tablets in pediatric patients have not been established. Hydrocodone bitartrate extended-release tablets gradually forms a viscous hydrogel (i.e., a gelatinous mass) when exposed to water or other fluids. Pediatric patients may be at increased risk of esophageal obstruction, dysphagia, and choking because of a smaller gastrointestinal lumen if they ingest hydrocodone bitartrate extended-release tablets [see Warnings and Precautions ( 5.12 )] .

8.1 Pregnancy Risk Summary Prolonged use of opioid analgesics during pregnancy may cause neonatal opioid withdrawal syndrome [see Warnings and Precautions ( 5.4 )] . Available data with hydrocodone bitartrate extended-release tablets in pregnant women are insufficient to inform a drug-associated risk for major birth defects and miscarriage. In animal reproduction studies with hydrocodone in rats and rabbits no embryotoxicity or teratogenicity was observed. However, reduced pup survival rates, reduced fetal/pup body weights, and delayed ossification were observed at doses causing maternal toxicity. In all of the studies conducted, the exposures in animals were less than the human exposure [see Data] . The estimated background risk of major birth defects and miscarriage for the indicated population 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 and 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 and Precautions (5.4)] . 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 extended-release tablets are not recommended for use in pregnant women during or immediately prior to labor, when use of shorter-acting analgesics or other analgesic techniques are more appropriate. Opioid analgesics, including hydrocodone bitartrate extended-release 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. Data Animal Data No evidence of embryotoxicity or teratogenicity was observed after oral administration of hydrocodone throughout the period of organogenesis in rats and rabbits at doses up to 30 mg/kg/day (approximately 0.1 and 0.3 times, respectively, the human hydrocodone dose of 120 mg/day based on AUC exposure comparisons). However, in these studies, reduced fetal body weights and delayed ossification were observed in rat at 30 mg/kg/day and reduced fetal body weights were observed in rabbits at 30 mg/kg/day (approximately 0.1 and 0.3 times, respectively, the human hydrocodone dose of 120 mg/day based on AUC exposure comparisons). In a pre- and post-natal development study pregnant rats were administered oral hydrocodone throughout the period of gestation and lactation. At a dose of 30 mg/kg/day decreased pup viability, pup survival indices, litter size and pup body weight were observed. This dose is approximately 0.1 times the human hydrocodone dose of 120 mg/day based on AUC exposure comparisons.

8 USE IN SPECIFIC POPULATIONS Pregnancy : May cause fetal harm. ( 8.1 ) Lactation : Not recommended. ( 8.2 ) 8.1 Pregnancy Risk Summary Prolonged use of opioid analgesics during pregnancy may cause neonatal opioid withdrawal syndrome [see Warnings and Precautions ( 5.4 )] . Available data with hydrocodone bitartrate extended-release tablets in pregnant women are insufficient to inform a drug-associated risk for major birth defects and miscarriage. In animal reproduction studies with hydrocodone in rats and rabbits no embryotoxicity or teratogenicity was observed. However, reduced pup survival rates, reduced fetal/pup body weights, and delayed ossification were observed at doses causing maternal toxicity. In all of the studies conducted, the exposures in animals were less than the human exposure [see Data] . The estimated background risk of major birth defects and miscarriage for the indicated population 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 and 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 and Precautions (5.4)] . 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 extended-release tablets are not recommended for use in pregnant women during or immediately prior to labor, when use of shorter-acting analgesics or other analgesic techniques are more appropriate. Opioid analgesics, including hydrocodone bitartrate extended-release 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. Data Animal Data No evidence of embryotoxicity or teratogenicity was observed after oral administration of hydrocodone throughout the period of organogenesis in rats and rabbits at doses up to 30 mg/kg/day (approximately 0.1 and 0.3 times, respectively, the human hydrocodone dose of 120 mg/day based on AUC exposure comparisons). However, in these studies, reduced fetal body weights and delayed ossification were observed in rat at 30 mg/kg/day and reduced fetal body weights were observed in rabbits at 30 mg/kg/day (approximately 0.1 and 0.3 times, respectively, the human hydrocodone dose of 120 mg/day based on AUC exposure comparisons). In a pre- and post-natal development study pregnant rats were administered oral hydrocodone throughout the period of gestation and lactation. At a dose of 30 mg/kg/day decreased pup viability, pup survival indices, litter size and pup body weight were observed. This dose is approximately 0.1 times the human hydrocodone dose of 120 mg/day based on AUC exposure comparisons. 8.2 Lactation Risk Summary Hydrocodone is present in human milk. A published lactation study reports variable concentrations of hydrocodone and hydromorphone (an active metabolite) in breast milk with administration of immediate-release hydrocodone to nursing mothers in the early post-partum period. This lactation study did not assess breastfed infants for potential adverse drug reactions. Lactation studies have not been conducted with hydrocodone bitartrate extended-release tablets, and no information is available on the effects of the drug on the breastfed infant or the effects of the drug on milk production. Because of the potential for serious adverse reactions, including excess sedation and respiratory depression in a breastfed infant, advise patients that breastfeeding is not recommended during treatment with hydrocodone bitartrate extended-release tablets. Clinical Considerations Monitor infants exposed to hydrocodone bitartrate extended-release 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. 8.3 Females and Males of Reproductive Potential Infertility Chronic use of opioids 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 ( 6.2 )]. 8.4 Pediatric Use The safety and effectiveness of hydrocodone bitartrate extended-release tablets in pediatric patients have not been established. Hydrocodone bitartrate extended-release tablets gradually forms a viscous hydrogel (i.e., a gelatinous mass) when exposed to water or other fluids. Pediatric patients may be at increased risk of esophageal obstruction, dysphagia, and choking because of a smaller gastrointestinal lumen if they ingest hydrocodone bitartrate extended-release tablets [see Warnings and Precautions ( 5.12 )] . 8.5 Geriatric Use In a controlled pharmacokinetic study, elderly subjects (greater than 65 years) compared to young adults had similar plasma concentrations of hydrocodone [see Clinical Pharmacology ( 12.3 )] . Of the 1827 subjects exposed to hydrocodone bitartrate extended-release tablets in the pooled chronic pain studies, 241 (13%) were age 65 and older (including those age 75 and older), while 42 (2%) were age 75 and older. In clinical trials with appropriate initiation of therapy and dose titration, no untoward or unexpected adverse reactions were seen in the elderly patients who received hydrocodone bitartrate extended-release 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 extended-release tablets slowly in geriatric patients and monitor closely for signs of central nervous system and respiratory depression [see Warnings and Precautions ( 5.3 )] . Hydrocodone is 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 monitor renal function. 8.6 Hepatic Impairment No adjustment in starting dose with hydrocodone bitartrate extended-release tablets is required in patients with mild or moderate hepatic impairment. Patients with severe hepatic impairment may have higher plasma concentrations than those with normal hepatic function [see Clinical Pharmacology ( 12.3 )] . Therefore, a dosage reduction is recommended for these patients [see Dosage and Administration ( 2.5 )] . Monitor closely for respiratory depression, sedation, and hypotension. 8.7 Renal Impairment No dose adjustment is needed in patients with mild renal impairment. Patients with moderate or severe renal impairment or end stage renal disease have higher plasma concentrations than those with normal renal function [see Clinical Pharmacology ( 12.3 )] . Therefore, a dosage reduction is recommended for these patients [see Dosage and Administration ( 2.6 )] . Monitor closely for respiratory depression, sedation, and hypotension.

16 HOW SUPPLIED/STORAGE AND HANDLING Hydrocodone Bitartrate Extended-Release Tablets 20 mg are white, round, film-coated tablets, with “A392” printed in black ink on one side, and blank on the other side. They are supplied in opaque plastic bottles with a child-resistant closure. (NDC 47781-392-60, Bottle of 60 tablets). Hydrocodone Bitartrate Extended-Release Tablets 30 mg are beige, round, film-coated tablets, with “A393” printed in black ink on one side, and blank on the other side. They are supplied in opaque plastic bottles with a child-resistant closure. (NDC 47781-393-60, Bottle of 60 tablets). Hydrocodone Bitartrate Extended-Release Tablets 40 mg are pink, round, film-coated tablets, with “A394” printed in black ink on one side, and blank on the other side. They are supplied in opaque plastic bottles with a child-resistant closure. (NDC 47781-394-60, Bottle of 60 tablets). Hydrocodone Bitartrate Extended-Release Tablets 60 mg are blue, round, film-coated tablets, with “A395” printed in black ink on one side, and blank on the other side. They are supplied in opaque plastic bottles with a child-resistant closure. (NDC 47781-395-60, Bottle of 60 tablets). Hydrocodone Bitartrate Extended-Release Tablets 80 mg are violet, round, film-coated tablets, with “A396” printed in black ink on one side, and blank on the other side. They are supplied in opaque plastic bottles with a child-resistant closure. (NDC 47781-396-60, Bottle of 60 tablets). Hydrocodone Bitartrate Extended-Release Tablets 100 mg are green, round, film-coated tablets, with “A397” printed in black ink on one side, and blank on the other side. They are supplied in opaque plastic bottles with a child-resistant closure. (NDC 47781-397-60, Bottle of 60 tablets). Hydrocodone Bitartrate Extended-Release Tablets 120 mg are yellow, round, film-coated tablets, with “A398” printed in black ink on one side, and blank on the other side. They are supplied in opaque plastic bottles with a child-resistant closure. (NDC 47781-398-60, Bottle of 60 tablets). Store at 25°C (77°F); excursions permitted between 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Dispense in a tight, light-resistant container, as defined by the USP. Store Hydrocodone Bitartrate Extended-Release Tablets securely and dispose of properly [see Patient Counseling Information ( 17 )] .

WARNING: ADDICTION, ABUSE, AND MISUSE; RISK EVALUATION AND MITIGATION STRATEGY (REMS); LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; NEONATAL OPIOID WITHDRAWAL SYNDROME; CYTOCHROME P450 3A4 INTERACTION; and RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS Addiction, Abuse, and Misuse Hydrocodone bitartrate extended-release tablets expose patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death. Assess each patient’s risk prior to prescribing hydrocodone bitartrate extended-release tablets, and monitor all patients regularly for the development of these behaviors and conditions [see Warnings and Precautions ( 5.1 )] . 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 REMS for these products [see Warnings and Precautions ( 5.2 )] . Under the requirements of the REMS, drug companies with approved opioid analgesic products must make REMS-compliant education programs available to healthcare providers. Healthcare providers are strongly encouraged to • complete a REMS-compliant education program, • counsel patients and/or their caregivers, with every prescription, on safe use, serious risks, storage, and disposal of these products, • emphasize to patients and their caregivers the importance of reading the Medication Guide every time it is provided by their pharmacist, and • consider other tools to improve patient, household, and community safety. Life-Threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression may occur with use of hydrocodone bitartrate extended-release tablets. Monitor for respiratory depression, especially during initiation of hydrocodone bitartrate extended-release tablets or following a dose increase. Instruct patients to swallow hydrocodone bitartrate extended-release tablets whole; crushing, chewing, or dissolving hydrocodone bitartrate extended-release tablets can cause rapid release and absorption of a potentially fatal dose of hydrocodone [see Warnings and Precautions ( 5.3 )] . Accidental Ingestion Accidental ingestion of even one dose of hydrocodone bitartrate extended-release tablets, especially by children, can result in a fatal overdose of hydrocodone [see Warnings and Precautions ( 5.3 )] . Neonatal Opioid Withdrawal Syndrome Prolonged use of hydrocodone bitartrate extended-release tablets during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [see Warnings and Precautions ( 5.4 )] . Cytochrome P450 3A4 Interaction The concomitant use of hydrocodone bitartrate extended-release tablets with all cytochrome P450 3A4 inhibitors may result in an increase in hydrocodone plasma concentrations, which could increase or prolong adverse reactions and may cause potentially fatal respiratory depression. In addition, discontinuation of a concomitantly used cytochrome P450 3A4 inducer may result in an increase in hydrocodone plasma concentration. Monitor patients receiving hydrocodone bitartrate extended-release tablets and any CYP3A4 inhibitor or inducer [see Warnings and Precautions ( 5.5 ), Drug Interactions ( 7 ), and Clinical Pharmacology ( 12.3 )]. Risks From Concomitant Use With Benzodiazepines Or Other CNS Depressants Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death [see Warnings and Precautions ( 5.6 ), Drug Interactions ( 7 )]. Reserve concomitant prescribing of hydrocodone bitartrate extended-release tablets and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients for signs and symptoms of respiratory depression and sedation. WARNING: ADDICTION, ABUSE, AND MISUSE; RISK EVALUATION AND MITIGATION STRATEGY (REMS); LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; NEONATAL OPIOID WITHDRAWAL SYNDROME; CYTOCHROME P450 3A4 INTERACTION; and RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS See full prescribing information for complete boxed warning. Hydrocodone bitartrate extended-release tablets expose users to risks of addiction, abuse, and misuse, which can lead to overdose and death. Assess patient’s risk before prescribing, and monitor regularly for these behaviors and conditions. ( 5.1 ) 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. ( 5.2 ) Serious, life-threatening, or fatal respiratory depression may occur. Monitor closely, especially upon initiation or following a dose increase. Instruct patients to swallow hydrocodone bitartrate extended-release tablets whole to avoid exposure to a potentially fatal dose of hydrocodone. ( 5.3 ) Accidental ingestion of hydrocodone bitartrate extended-release tablets, especially by children, can result in fatal overdose of hydrocodone. ( 5.3) Prolonged use of hydrocodone bitartrate extended-release tablets during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated. If prolonged opioid use is required in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available. ( 5.4 ) Concomitant use with CYP3A4 inhibitors (or discontinuation of CYP3A4 inducers) can result in a fatal overdose of hydrocodone. ( 5.5 , 7 , 12.3 ) Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing for use in patients for whom alternative treatment options are inadequate; limit dosages and durations to the minimum required; and follow patients for signs and symptoms of respiratory depression and sedation. ( 5.6 , 7 )