HYDROCODONE BITARTRATE

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.

Hydrocodone bitartrate extended-release tablets are indicated for the management of severe and persistent pain that requires an extended treatment period with a daily opioid analgesic and for which alternative treatment options are inadequate. Limitations of Use Because of the risks of addiction, abuse, and misuse with opioids, which can occur at any dosage or duration, and because of the greater risks of overdose and death with extended-release/long-acting 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 severe and persistent pain that requires an extended period with a daily opioid analgesic and for which alternative treatment options are inadequate. ( 1 ) Limitations of Use ( 1 ) Because of the risks of addiction, abuse, and misuse with opioids, which can occur at any dosage or duration, and because of the greater risks of overdose and death with extended-release/long-acting 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. Hydrocodone bitartrate extended-release tablets are not indicated as an as-needed (prn) analgesic.

Hydrocodone bitartrate extended-release tablets should be prescribed only by healthcare professionals who are knowledgeable about the use of extended-release/long-acting opioids and how to mitigate the associated risks. ( 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 of time consistent with individual patient treatment goals. (2.1) Reserve titration to higher doses of hydrocodone bitartrate extended-release tablets for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks. ( 2.1 , 5 ) Initiate the dosing regimen for each patient individually, taking into account the patient’s underlying cause and severity of pain, prior analgesic treatment and response, and risk factors for addiction, abuse, and misuse. ( 2.1 , 5.1 ) Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with hydrocodone bitartrate extended-release tablets. Consider this risk when selecting an initial dose and when making dose adjustments. ( 2.1 , 5.2 ) 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 , 5.2 , 5.3 ) 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 , 5.13 ) 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. Regularly evaluate 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. Regularly evaluate 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 Instructions Hydrocodone bitartrate extended-release tablets should be prescribed only by healthcare professionals who are knowledgeable about the use of extended-release/long-acting opioids and how to mitigate the associated risks. 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 of time consistent with individual patient treatment goals [see Warnings and Precautions ( 5 )] . Because the risk of overdose increases as opioid doses increase, reserve titration to higher doses of hydrocodone bitartrate extended-release tablets for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks. Initiate the dosing regimen for each patient individually, taking into account the patient's underlying cause and severity of pain, prior analgesic treatment and response, and risk factors for addiction, abuse, and misuse [see Warnings and Precautions ( 5.1 )] . Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with hydrocodone bitartrate extended-release tablets. Consider this risk when selecting an initial dose and when making dose adjustments [see Warnings and Precautions ( 5.2 )] . 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. Instruct patients not to pre-soak, lick, or otherwise wet the tablet prior to placing in the mouth [see Warnings and Precautions ( 5.13 )] . 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 ( 5.2 )] . 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 , 5.2, 5.3) ] . 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 treatment with hydrocodone bitartrate extended-release tablets at a dose of 20 mg 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 hydrocodone bitartrate extended-release tablets 20 mg 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 ( 5.2 )]. 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 Opioids to Hydrocodone Bitartrate Extended-Release Tablets When hydrocodone bitartrate extended-release tablets therapy is initiated, discontinue all other opioid analgesics other than those used on an as needed basis for breakthrough pain when appropriate. 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 hydrocodone bitartrate extended-release tablets 20 mg. 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, hydrocodone bitartrate extended-release tablets 30 mg, 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 Regular evaluation 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 hydrocodone bitartrate extended-release tablets 20 mg 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 hydrocodone bitartrate extended-release tablets 20 mg 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, signs and symptoms of opioid withdrawal, and other relative incidence of adverse reactions, as well as to reassess for the development of addiction, abuse, or misuse [see Warnings and Precautions ( 5.1 , 5.16 )] . 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 use of opioid therapy for an extended period of time, 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. If after increasing the dosage, unacceptable opioid-related adverse reactions are observed (including an increase in pain after a dosage increase), consider reducing the dosage [see Warnings and Precautions ( 5 )] . Adjust the dosage to obtain an appropriate balance between management of pain and opioid-related adverse reactions. 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. 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 regularly evaluate 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 regularly evaluate 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 total daily dose opioid (including 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, evaluate patients for any changes in mood, emergence of suicidal thoughts, or use of other substances. When managing patients taking opioid analgesics, particularly those who have been treated for an extended period of time, and/or with high doses for chronic pain, ensure that a multimodal approach to pain management, including mental health support (if needed), is in place prior to initiating an opioid analgesic taper. A multimodal approach to pain management may optimize the treatment of chronic pain, as well as assist with the successful tapering of the opioid analgesic [see Warnings and Precautions ( 5.16 ), Drug Abuse and Dependence ( 9.3 )]. 2.3 Initial Dosage Use of Hydrocodone Bitartrate Extended-Release Tablets as the First Opioid Analgesic (opioid-naïve patients) Initiate treatment with hydrocodone bitartrate extended-release tablets at a dose of 20 mg 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 hydrocodone bitartrate extended-release tablets 20 mg 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 ( 5.2 )]. 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 Opioids to Hydrocodone Bitartrate Extended-Release Tablets When hydrocodone bitartrate extended-release tablets therapy is initiated, discontinue all other opioid analgesics other than those used on an as needed basis for breakthrough pain when appropriate. 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 hydrocodone bitartrate extended-release tablets 20 mg. 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, hydrocodone bitartrate extended-release tablets 30 mg, 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 Regular evaluation 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 hydrocodone bitartrate extended-release tablets 20 mg 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 hydrocodone bitartrate extended-release tablets 20 mg 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, signs and symptoms of opioid withdrawal, and other relative incidence of adverse reactions, as well as to reassess for the development of addiction, abuse, or misuse [see Warnings and Precautions ( 5.1 , 5.16 )] . 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 use of opioid therapy for an extended period of time, 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. If after increasing the dosage, unacceptable opioid-related adverse reactions are observed (including an increase in pain after a dosage increase), consider reducing the dosage [see Warnings and Precautions ( 5 )] . Adjust the dosage to obtain an appropriate balance between management of pain and opioid-related adverse reactions. 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. 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 regularly evaluate 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 regularly evaluate 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 total daily dose opioid (including 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, evaluate patients for any changes in mood, emergence of suicidal thoughts, or use of other substances. When managing patients taking opioid analgesics, particularly those who have been treated for an extended period of time, and/or with high doses for chronic pain, ensure that a multimodal approach to pain management, including mental health support (if needed), is in place prior to initiating an opioid analgesic taper. A multimodal approach to pain management may optimize the treatment of chronic pain, as well as assist with the successful tapering of the opioid analgesic [see Warnings and Precautions ( 5.16 ), Drug Abuse and Dependence ( 9.3 )].

Hydrocodone bitartrate extended-release tablets are contraindicated in patients with: Significant respiratory depression [see Warnings and Precautions ( 5.2 )] Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment [see Warnings and Precautions ( 5.8 )] Known or suspected gastrointestinal obstruction, including paralytic ileus [see Warnings and Precautions ( 5.13 , 5.14 )] 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 )

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 ( 5.2 )] Interactions with Benzodiazepine or Other CNS Depressants [see Warnings and Precautions ( 5.3 )] Neonatal Opioid Withdrawal Syndrome [see Warnings and Precautions ( 5.4 )] Opioid-Induced Hyperalgesia and Allodynia [see Warnings and Precautions ( 5.7 )] Adrenal Insufficiency [see Warnings and Precautions ( 5.9 )] Severe Hypotension [see Warnings and Precautions ( 5.10 )] Gastrointestinal Adverse Reactions [see Warnings and Precautions ( 5.13 , 5.14 )] Seizures [see Warnings and Precautions ( 5.15 )] Withdrawal [see Warnings and Precautions ( 5.16 )] 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 tablets 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 use of opioids for an extended period of time [see Clinical Pharmacology ( 12.2 )] . Hyperalgesia and Allodynia : Cases of hyperalgesia and allodynia have been reported with opioid therapy of any duration [see Warnings and Precautions ( 5.7 )] . Hypoglycemia : Cases of hypoglycemia have been reported in patients taking opioids. Most reports were in patients with at least one predisposing risk factor (e.g., diabetes). 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 tablets 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 use of opioids for an extended period of time [see Clinical Pharmacology ( 12.2 )] . Hyperalgesia and Allodynia : Cases of hyperalgesia and allodynia have been reported with opioid therapy of any duration [see Warnings and Precautions ( 5.7 )] . Hypoglycemia : Cases of hypoglycemia have been reported in patients taking opioids. Most reports were in patients with at least one predisposing risk factor (e.g., diabetes).

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 ( 5.6 )] . 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. Evaluate patients at frequent intervals for respiratory depression and sedation. If a CYP3A4 inhibitor is discontinued, consider increasing the hydrocodone bitartrate extended-release tablets dosage until stable drug effects are achieved. Assess 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 ( 5.6 )] . 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. Evaluate for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider hydrocodone bitartrate extended-release tablet dosage reduction and evaluate patients at frequent intervals for signs of respiratory depression and sedation. Examples: Rifampin, carbamazepine, phenytoin Benzodiazepines and Other Central Nervous System (CNS) Depressants Clinical Impact: Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death [see Warnings and Precautions ( 5.3 )] . Intervention: Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Inform patients and caregivers of this potential interaction and educate them on the signs and symptoms of respiratory depression (including sedation). If concomitant use is warranted, consider prescribing naloxone for the emergency treatment of opioid overdose [see Dosage and Administration ( 2.2 ), Warnings and Precautions ( 5.1 , 5.2 , 5.3 )] . Examples: Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol. Serotonergic Drugs Clinical Impact: The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. Intervention: If concomitant use is warranted, frequently evaluate the patient, particularly during treatment initiation and dose adjustment. Discontinue hydrocodone bitartrate 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 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: Because respiratory depression may be greater than otherwise expected, 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 ( 5.2 , 5.3 ) ] . Examples: Cyclobenzaprine, metaxalone Diuretics Clinical Impact: Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. Intervention: Evaluate patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed. Anticholinergic Drugs Clinical Impact: The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Intervention: Evaluate patients for signs of urinary retention or reduced gastric motility when hydrocodone bitartrate 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, regularly evaluate 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 )