HYDROCODONE: 47,828 Adverse Event Reports & Safety Profile

DESCRIPTION Each hydrocodone bitartrate and ibuprofen tablet contains either: Hydrocodone Bitartrate, USP 2.5 mg, 5 mg, 7.5 mg, or 10 mg and Ibuprofen, USP 200 mg Hydrocodone bitartrate and ibuprofen tablets are supplied in a fixed combination tablet form for oral administration. Hydrocodone bitartrate and ibuprofen tablets combine the opioid agonist, hydrocodone bitartrate, USP, with the nonsteroidal anti-inflammatory (NSAID) agent, ibuprofen, USP. Hydrocodone bitartrate, USP is a semisynthetic opioid agonist. Its chemical name is: 4,5 α-epoxy-3-methoxy-17-methylmorphinan-6-one tartrate (1:1) hydrate (2:5). Its chemical formula is: C 18 H 21 NO 3

• C 4 H 6 O 6
• 2½H 2 O, and the molecular weight is 494.50. Its structural formula is: Ibuprofen, USP is a nonsteroidal anti-inflammatory agent [non-selective COX inhibitor] with analgesic and antipyretic properties. Its chemical name is: (±)-2-( p -isobutylphenyl) propionic acid. Its chemical formula is: C 13 H 18 O 2 , and the molecular weight is: 206.29. Its structural formula is: Inactive ingredients in hydrocodone bitartrate and ibuprofen 2.5 mg/200 mg, 5 mg/200 mg and 7.5 mg/200 mg tablets include: carnauba wax, colloidal silicon dioxide, croscarmellose sodium, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polydextrose, pregelatinized starch and titanium dioxide. Inactive ingredients in hydrocodone bitartrate and ibuprofen 10 mg/200 mg tablets include: colloidal silicon dioxide, croscarmellose sodium, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polydextrose, pregelatinized starch, titanium dioxide, triacetin and D&C Yellow #10 Aluminum Lake. 893afda7-figure-01 893afda7-figure-02

AND USAGE Hydrocodone bitartrate extended-release capsules 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 capsules 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 capsules are not indicated as an as-needed (prn) analgesic. Hydrocodone bitartrate extended-release capsules are an opioid agonist 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. ( 1 ) 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, reserve hydrocodone bitartrate extended-release capsules 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 capsules are not indicated as an as-needed (prn) analgesic. ( 1 )

AND ADMINISTRATION 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 <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5 )]</span> . 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&apos;s underlying cause and severity of pain, prior analgesic treatment and response, and risk factors for addiction, abuse, and misuse <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.1 )]</span> . 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 <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.2 )]</span> . 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 <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.13 )]</span> . Crushing, chewing, or dissolving hydrocodone bitartrate extended-release tablets will result in uncontrolled delivery of hydrocodone and can lead to overdose or death <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.1 )]</span> . 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 <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.2 )]</span> . 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 <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.1 , 5.2, 5.3) ]</span> . 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 <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.2 )]</span>. 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&apos;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 <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.1 , 5.16 )]</span> . 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 <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5 )]</span> . 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 <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span> .

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 <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span> .

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 <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.16 ), Drug Abuse and Dependence ( 9.3 )]</span>.

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 <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.2 )]</span>. 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&apos;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 <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.1 , 5.16 )]</span> . 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 <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5 )]</span> . 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 <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span> .

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 <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span> .

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 <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.16 ), Drug Abuse and Dependence ( 9.3 )]</span>.

CONTRAINDICATIONS Hydrocodone bitartrate and ibuprofen tablets are contraindicated in patients with: Significant respiratory depression (see WARNINGS: Life-Threatening Respiratory Depression ) . Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment (see WARNINGS: Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients ) . Known or suspected gastrointestinal obstruction, including paralytic ileus (see WARNINGS: Risks of Use in Patients with Gastrointestinal Conditions ) . Known hypersensitivity (e.g., anaphylactic reactions, serious skin reactions) to hydrocodone, ibuprofen, or any components of the drug product (see WARNINGS: Anaphylactic Reactions, Serious Skin Reactions ) . Patients known to be hypersensitive to other opioids may exhibit cross-sensitivity to hydrocodone. History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs. Severe, sometimes fatal, anaphylactic reactions to NSAIDs have been reported in such patients (see WARNINGS: Anaphylactic Reactions, Exacerbation of Asthma Related to Aspirin Sensitivity ) . In the setting of coronary artery bypass graft (CABG) surgery (see WARNINGS: Cardiovascular Thrombotic Events ) .

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 ( 5.2 )] 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 <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.2 )]</span> . Hyperalgesia and Allodynia : Cases of hyperalgesia and allodynia have been reported with opioid therapy of any duration <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.7 )]</span> . 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 <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.2 )]</span> . Hyperalgesia and Allodynia : Cases of hyperalgesia and allodynia have been reported with opioid therapy of any duration <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.7 )]</span> . 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).

AND PRECAUTIONS Opioid-Induced Hyperalgesia and Allodynia: Opioid-Induced Hyperalgesia (OIH) occurs when an opioid analgesic paradoxically causes an increase in pain, or an increase in sensitivity to pain. If OIH is suspected, carefully consider appropriately decreasing the dose of the current opioid analgesic, or opioid rotation. ( 5.7 ) Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients : Regularly evaluate, particularly during initiation and titration. ( 5.8 )

Adrenal

Insufficiency : If diagnosed, treat with physiologic replacement of corticosteroids, and wean patient off of the opioid. ( 5.9 )

Severe

Hypotension : Regularly evaluate during dosage initiation and titration. Avoid use of hydrocodone bitartrate extended-release tablets in patients with circulatory shock. ( 5.10 ) QTc Prolongation : Avoid use in patients with congenital long QTc syndrome. In patients who develop QTc prolongation, consider reducing the dose. ( 5.11 , 12.2 ) Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness : Monitor for sedation and respiratory depression. Avoid use of hydrocodone bitartrate extended-release tablets in patients with circulatory shock. ( 5.12 ) Risk of Obstruction in Patients who have Difficulty Swallowing or have Underlying GI Disorders that may Predispose them to Obstruction : Consider use of an alternative analgesic. ( 5.14 )

5.1 Addiction, Abuse, and Misuse Hydrocodone bitartrate extended-release tablets contain hydrocodone, a Schedule II controlled substance. As an opioid, hydrocodone bitartrate extended-release tablets expose users to the risks of addiction, abuse, and misuse. Because extended-release products such as hydrocodone bitartrate extended-release tablets deliver the opioid over an extended period of time, there is a greater risk for overdose and death due to the larger amount of hydrocodone present <span class="opacity-50 text-xs">[see Drug Abuse and Dependence ( 9 )]</span>. Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed hydrocodone bitartrate extended-release tablets. Addiction can occur at recommended doses and if the drug is misused or abused. Assess each patient’s risk for opioid addiction, abuse, or misuse prior to prescribing hydrocodone bitartrate extended-release tablets, and reassess all patients receiving hydrocodone bitartrate extended-release tablets for the development of these behaviors and conditions. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). The potential for these risks should not, however, prevent the prescribing of hydrocodone bitartrate extended-release tablets for the proper management of pain in any given patient. Patients at increased risk may be prescribed opioids such as hydrocodone bitartrate extended-release tablets, but use in such patients necessitates intensive counseling about the risks and proper use of hydrocodone bitartrate extended-release tablets along with frequent reevaluation for signs of addiction, abuse, and misuse. Consider prescribing naloxone for the emergency treatment of opioid overdose <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.2 ), Warnings and Precautions ( 5.2 )]</span>. Abuse or misuse of hydrocodone bitartrate extended-release tablets by crushing, chewing, snorting, or injecting the dissolved product will result in the uncontrolled delivery of the hydrocodone and can result in overdose and death <span class="opacity-50 text-xs">[see Drug Abuse and Dependence ( 9.2 ), and Overdosage ( 10 )]</span> . Opioids are sought for nonmedical use and are subject to diversion from legitimate prescribed use. Consider these risks when prescribing or dispensing hydrocodone bitartrate extended-release tablets. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on careful storage of the drug during the course of treatment and the proper disposal of unused drug. Contact local state professional licensing board or state-controlled substances authority for information on how to prevent and detect abuse or diversion of this product.

5.2 Life-Threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient’s clinical status <span class="opacity-50 text-xs">[see Overdosage ( 10 )]</span> . Carbon dioxide (CO 2 ) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids. While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of hydrocodone bitartrate extended-release tablets, the risk is greatest during the initiation of therapy or following a dosage increase. To reduce the risk of respiratory depression, proper dosing and titration of hydrocodone bitartrate extended-release tablets are essential <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.1 , 2.3 )]</span> . Overestimating the hydrocodone bitartrate extended-release tablets dosage when converting patients from another opioid product can result in fatal overdose with the first dose. Accidental ingestion of even one dose of hydrocodone bitartrate extended-release tablets, especially by children, can result in respiratory depression and death due to an overdose of hydrocodone. 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. Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the opioid dosage using best practices for opioid taper <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.4 )]</span> .

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. Inform patients and caregivers about the various ways to obtain naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (e.g., by prescription, directly from a pharmacist, or as part of a community-based program). Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help, even if naloxone is administered. Consider prescribing naloxone, based on the patient’s risk factors for overdose, such as concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose. The presence of risk factors for overdose should not prevent the proper management of pain in any given patient. Also consider prescribing naloxone if the patient has household members (including children) or other close contacts at risk for accidental ingestion or overdose. If naloxone is prescribed, educate patients and caregivers on how to treat with naloxone [see Dosage and Administration ( 2.2 ), Warnings and Precautions ( 5.1 , 5.3 ), Overdosage ( 10 )].

5.3 Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants Profound sedation, respiratory depression, coma, and death may result from the concomitant use of hydrocodone bitartrate extended-release tablets with benzodiazepines and/or other CNS depressants, including alcohol (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids). Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioid analgesics alone. Because of similar pharmacological properties, it is reasonable to expect similar risk with the concomitant use of other CNS depressant drugs with opioid analgesics [ see Drug Interactions ( 7 )] . If the decision is made to prescribe a benzodiazepine or other CNS depressant concomitantly with an opioid analgesic, prescribe the lowest effective dosages and minimum durations of concomitant use. In patients already receiving an opioid analgesic, prescribe a lower initial dose of the benzodiazepine or other CNS depressant than indicated in the absence of an opioid, and titrate based on clinical response. If an opioid analgesic is initiated in a patient already taking a benzodiazepine or other CNS depressant, prescribe a lower initial dose of the opioid analgesic, and titrate based on clinical response. 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 <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.2 ), Warnings and Precautions ( 5.2 ), Overdosage ( 10 ) ]</span>. Advise both patients and caregivers about the risks of respiratory depression and sedation when hydrocodone bitartrate extended-release tablets are used with benzodiazepines or other CNS depressants (including alcohol and illicit drugs). Advise patients not to drive or operate heavy machinery until the effects of concomitant use of the benzodiazepine or other CNS depressant have been determined. Screen patients for risk of substance use disorders, including opioid abuse and misuse, and warn them of the risk for overdose and death associated with the use of additional CNS depressants including alcohol and illicit drugs <span class="opacity-50 text-xs">[see Drug Interactions ( 7 )]</span> .

5.4 Neonatal Opioid Withdrawal Syndrome Use of hydrocodone bitartrate extended-release tablets for an extended period of time during pregnancy can result in withdrawal in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly. Advise pregnant women using opioids for an extended period of time of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available <span class="opacity-50 text-xs">[see Use in Specific Populations ( 8.1 )]</span> .

5.5 Opioid Analgesic Risk Evaluation and Mitigation Strategy (REMS) To ensure that the benefits of opioid analgesics outweigh the risks of addiction, abuse, and misuse, the Food and Drug Administration (FDA) has required a Risk Evaluation and Mitigation Strategy (REMS) for these products. Under the requirements of the REMS, drug companies with approved opioid analgesic products must make REMS-compliant education programs available to healthcare providers. Healthcare providers are strongly encouraged to do all of the following: Complete a REMS-compliant education program offered by an accredited provider of continuing education (CE) or another education program that includes all the elements of the FDA Education Blueprint for Health Care Providers Involved in the Management or Support of Patients with Pain. Discuss the safe use, serious risks, and proper storage and disposal of opioid analgesics with patients and/or their caregivers every time these medicines are prescribed.

The Patient Counseling

Guide (PCG) can be obtained at this link: www.fda.gov/OpioidAnalgesicREMSPCG. Emphasize to patients and their caregivers the importance of reading the Medication Guide that they will receive from their pharmacist every time an opioid analgesic is dispensed to them. Consider using other tools to improve patient, household, and community safety, such as patient-prescriber agreements that reinforce patient-prescriber responsibilities. To obtain further information on the opioid analgesic REMS and for a list of accredited REMS CME/CE, call 1-800-503-0784, or log on to www.opioidanalgesicrems.com. The FDA Blueprint can be found at www.fda.gov/OpioidAnalgesicREMSBlueprint

5.6 Risks of Concomitant Use or Discontinuation of Cytochrome P450 3A4 Inhibitors and Inducers Concomitant use of hydrocodone bitartrate extended-release tablets with a CYP3A4 inhibitor, such as macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), and protease inhibitors (e.g., ritonavir), may increase plasma concentrations of hydrocodone and prolong opioid adverse reactions, which may cause potentially fatal respiratory depression <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.2 )]</span> , particularly when an inhibitor is added after a stable dose of hydrocodone bitartrate extended-release tablets are achieved. Similarly, discontinuation of a CYP3A4 inducer, such as rifampin, carbamazepine, and phenytoin, in hydrocodone bitartrate extended-release tablet-treated patients may increase hydrocodone plasma concentrations and prolong opioid adverse reactions. When using hydrocodone bitartrate extended-release tablets with CYP3A4 inhibitors or discontinuing CYP3A4 inducers in hydrocodone bitartrate extended-release tablet-treated patients, evaluate patients at frequent intervals and consider dosage reduction of hydrocodone bitartrate extended-release tablets until stable drug effects are achieved <span class="opacity-50 text-xs">[see Drug Interactions ( 7 ) ]</span> . Concomitant use of hydrocodone bitartrate extended-release tablets with CYP3A4 inducers or discontinuation of an CYP3A4 inhibitor could decrease hydrocodone plasma concentrations, decrease opioid efficacy or, possibly, lead to a withdrawal syndrome in a patient who had developed physical dependence to hydrocodone. When using hydrocodone bitartrate extended-release tablets with CYP3A4 inducers or discontinuing CYP3A4 inhibitors, monitor patients closely at frequent intervals and consider increasing the opioid dosage if needed to maintain adequate analgesia or if symptoms of opioid withdrawal occur <span class="opacity-50 text-xs">[see Drug Interactions ( 7 )]</span> .

5.7 Opioid-Induced Hyperalgesia and Allodynia Opioid-Induced Hyperalgesia (OIH) occurs when an opioid analgesic paradoxically causes an increase in pain, or an increase in sensitivity to pain. This condition differs from tolerance, which is the need for increasing doses of opioids to maintain a defined effect <span class="opacity-50 text-xs">[see Dependence ( 9.3 )]</span> . Symptoms of OIH include (but may not be limited to) increased levels of pain upon opioid dosage increase, decreased levels of pain upon opioid dosage decrease, or pain from ordinarily non-painful stimuli (allodynia). These symptoms may suggest OIH only if there is no evidence of underlying disease progression, opioid tolerance, opioid withdrawal, or addictive behavior. Cases of OIH have been reported, both with short-term and longer-term use of opioid analgesics. Though the mechanism of OIH is not fully understood, multiple biochemical pathways have been implicated. Medical literature suggests a strong biologic plausibility between opioid analgesics and OIH and allodynia. If a patient is suspected to be experiencing OIH, carefully consider appropriately decreasing the dose of the current opioid analgesic, or opioid rotation (safely switching the patient to a different opioid moiety) <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.7 ), Warnings and Precautions ( 5.16 )]</span>.

5.8 Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients The use of hydrocodone bitartrate extended-release tablets in patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment is contraindicated. Patients with Chronic Pulmonary Disease : Hydrocodone bitartrate extended-release tablet-treated patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression are at increased risk of decreased respiratory drive including apnea, even at recommended dosages of hydrocodone bitartrate extended-release tablets <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.2 )]</span> . Elderly, Cachectic, or Debilitated Patients: Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients because they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.3 )]</span> . Regularly evaluate patients, particularly when initiating and titrating hydrocodone bitartrate extended-release tablets and when hydrocodone bitartrate extended-release tablets are given concomitantly with other drugs that depress respiration <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.2 , 5.3 ), Drug Interactions ( 7 )]</span> . Alternatively, consider the use of non-opioid analgesics in these patients.

5.9 Adrenal Insufficiency Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Presentation of adrenal insufficiency may include non-specific symptoms and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. If adrenal insufficiency is suspected, confirm the diagnosis with diagnostic testing as soon as possible. If adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids. Wean the patient off of the opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers. Other opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency. The information available does not identify any particular opioids as being more likely to be associated with adrenal insufficiency.

5.10 Severe Hypotension Hydrocodone bitartrate extended-release tablets may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients. There is an increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume, or after concurrent administration of certain CNS depressant drugs (e.g., phenothiazines or general anesthetics) <span class="opacity-50 text-xs">[see Drug Interactions ( 7 )]</span> . Regularly evaluate these patients for signs of hypotension after initiating or titrating the dosage of hydrocodone bitartrate extended-release tablets. In patients with circulatory shock, hydrocodone bitartrate extended-release tablets may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of hydrocodone bitartrate extended-release tablets in patients with circulatory shock.

5.11 QTc Interval Prolongation QTc prolongation has been observed with hydrocodone bitartrate extended-release tablets following daily doses of 160 mg <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.2 )]</span> . This observation should be considered in making clinical decisions regarding patient monitoring when prescribing hydrocodone bitartrate extended-release tablets in patients with congestive heart failure, bradyarrhythmias, electrolyte abnormalities, or who are taking medications that are known to prolong the QTc interval. Hydrocodone bitartrate extended-release tablets should be avoided in patients with congenital long QT syndrome. In patients who develop QTc prolongation, consider reducing the dose by 33% to 50%, or changing to an alternate analgesic.

5.12 Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness In patients who may be susceptible to the intracranial effects of CO 2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors), hydrocodone bitartrate extended-release tablets may reduce respiratory drive, and the resultant CO 2 retention can further increase intracranial pressure. Monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy with hydrocodone bitartrate extended-release tablets. Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of hydrocodone bitartrate extended-release tablets in patients with impaired consciousness or coma.

5.13 Gastrointestinal Obstruction, Dysphagia, and Choking In the clinical studies with specific instructions to take hydrocodone bitartrate extended-release tablets with adequate water to swallow the tablet, 11 out of 2,476 subjects reported difficulty swallowing hydrocodone bitartrate extended-release tablets. These reports included esophageal obstruction, dysphagia, and choking, one of which had required medical intervention to remove the tablet <span class="opacity-50 text-xs">[see Adverse Reactions ( 6 )]</span> . Instruct patients not to pre-soak, lick, or otherwise wet hydrocodone bitartrate extended-release tablets prior to placing in the mouth, and to take one tablet at a time with enough water to ensure complete swallowing immediately after placing in the mouth. Patients with underlying gastrointestinal disorders such as esophageal cancer or colon cancer with a small gastrointestinal lumen are at greater risk of developing these complications. Consider use of an alternative analgesic in patients who have difficulty swallowing and patients at risk for underlying gastrointestinal disorders resulting in a small gastrointestinal lumen. 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 <span class="opacity-50 text-xs">[see Use in Specific Populations ( 8.4 )]</span> .

5.14 Risks of Use in Patients with Gastrointestinal Conditions Hydrocodone bitartrate extended-release tablets are contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus. The hydrocodone in hydrocodone bitartrate extended-release tablets may cause spasm of the sphincter of Oddi. Opioids may cause increases in serum amylase. Regularly evaluate patients with biliary tract disease, including acute pancreatitis, for worsening symptoms.

5.15 Increased Risk of Seizures in Patients with Seizure Disorders The hydrocodone in hydrocodone bitartrate extended-release tablets may increase the frequency of seizures in patients with seizure disorders, and may increase the risk of seizures occurring in other clinical settings associated with seizures. Regularly evaluate patients with a history of seizure disorders for worsened seizure control during hydrocodone bitartrate extended-release tablet therapy.

5.16 Withdrawal Do not abruptly discontinue hydrocodone bitartrate extended-release tablets in a patient physically dependent on opioids. When discontinuing hydrocodone bitartrate extended-release tablets in a physically dependent patient, gradually taper the dosage. Rapid tapering of hydrocodone in a patient physically dependent on opioids may lead to a withdrawal syndrome and return of pain <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.7 ), Drug Abuse and Dependence ( 9.3 )]</span> . Additionally, avoid the use of mixed agonist/antagonist analgesics (e.g., pentazocine, nalbuphine, and butorphanol) or partial agonist (e.g., buprenorphine) analgesics in patients who are receiving a full opioid agonist analgesic, including hydrocodone bitartrate extended-release tablets. In these patients, mixed agonist/antagonist and partial agonist analgesics may reduce the analgesic effect and/or may precipitate withdrawal symptoms <span class="opacity-50 text-xs">[see Drug Interactions ( 7 )]</span> .

5.17 Risks of Driving and Operating Machinery Hydrocodone bitartrate extended-release tablets may impair the mental and physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery. Peak blood levels of hydrocodone may occur 14 to 16 hours (range 6 to 30 hours) after initial dosing of hydrocodone bitartrate extended-release tablet administration. Blood levels of hydrocodone, in some patients, may be high at the end of 24 hours after repeated-dose administration. Warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects of hydrocodone bitartrate extended-release tablets and know how they will react to the medication.

5.1 Addiction, Abuse, and Misuse Hydrocodone bitartrate extended-release tablets contain hydrocodone, a Schedule II controlled substance. As an opioid, hydrocodone bitartrate extended-release tablets expose users to the risks of addiction, abuse, and misuse. Because extended-release products such as hydrocodone bitartrate extended-release tablets deliver the opioid over an extended period of time, there is a greater risk for overdose and death due to the larger amount of hydrocodone present <span class="opacity-50 text-xs">[see Drug Abuse and Dependence ( 9 )]</span>. Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed hydrocodone bitartrate extended-release tablets. Addiction can occur at recommended doses and if the drug is misused or abused. Assess each patient’s risk for opioid addiction, abuse, or misuse prior to prescribing hydrocodone bitartrate extended-release tablets, and reassess all patients receiving hydrocodone bitartrate extended-release tablets for the development of these behaviors and conditions. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). The potential for these risks should not, however, prevent the prescribing of hydrocodone bitartrate extended-release tablets for the proper management of pain in any given patient. Patients at increased risk may be prescribed opioids such as hydrocodone bitartrate extended-release tablets, but use in such patients necessitates intensive counseling about the risks and proper use of hydrocodone bitartrate extended-release tablets along with frequent reevaluation for signs of addiction, abuse, and misuse. Consider prescribing naloxone for the emergency treatment of opioid overdose <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.2 ), Warnings and Precautions ( 5.2 )]</span>. Abuse or misuse of hydrocodone bitartrate extended-release tablets by crushing, chewing, snorting, or injecting the dissolved product will result in the uncontrolled delivery of the hydrocodone and can result in overdose and death <span class="opacity-50 text-xs">[see Drug Abuse and Dependence ( 9.2 ), and Overdosage ( 10 )]</span> . Opioids are sought for nonmedical use and are subject to diversion from legitimate prescribed use. Consider these risks when prescribing or dispensing hydrocodone bitartrate extended-release tablets. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on careful storage of the drug during the course of treatment and the proper disposal of unused drug. Contact local state professional licensing board or state-controlled substances authority for information on how to prevent and detect abuse or diversion of this product.

5.2 Life-Threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient’s clinical status <span class="opacity-50 text-xs">[see Overdosage ( 10 )]</span> . Carbon dioxide (CO 2 ) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids. While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of hydrocodone bitartrate extended-release tablets, the risk is greatest during the initiation of therapy or following a dosage increase. To reduce the risk of respiratory depression, proper dosing and titration of hydrocodone bitartrate extended-release tablets are essential <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.1 , 2.3 )]</span> . Overestimating the hydrocodone bitartrate extended-release tablets dosage when converting patients from another opioid product can result in fatal overdose with the first dose. Accidental ingestion of even one dose of hydrocodone bitartrate extended-release tablets, especially by children, can result in respiratory depression and death due to an overdose of hydrocodone. 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. Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the opioid dosage using best practices for opioid taper <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.4 )]</span> .

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. Inform patients and caregivers about the various ways to obtain naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (e.g., by prescription, directly from a pharmacist, or as part of a community-based program). Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help, even if naloxone is administered. Consider prescribing naloxone, based on the patient’s risk factors for overdose, such as concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose. The presence of risk factors for overdose should not prevent the proper management of pain in any given patient. Also consider prescribing naloxone if the patient has household members (including children) or other close contacts at risk for accidental ingestion or overdose. If naloxone is prescribed, educate patients and caregivers on how to treat with naloxone [see Dosage and Administration ( 2.2 ), Warnings and Precautions ( 5.1 , 5.3 ), Overdosage ( 10 )].

5.4 Neonatal Opioid Withdrawal Syndrome Use of hydrocodone bitartrate extended-release tablets for an extended period of time during pregnancy can result in withdrawal in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly. Advise pregnant women using opioids for an extended period of time of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available <span class="opacity-50 text-xs">[see Use in Specific Populations ( 8.1 )]</span> .

5.6 Risks of Concomitant Use or Discontinuation of Cytochrome P450 3A4 Inhibitors and Inducers Concomitant use of hydrocodone bitartrate extended-release tablets with a CYP3A4 inhibitor, such as macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), and protease inhibitors (e.g., ritonavir), may increase plasma concentrations of hydrocodone and prolong opioid adverse reactions, which may cause potentially fatal respiratory depression <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.2 )]</span> , particularly when an inhibitor is added after a stable dose of hydrocodone bitartrate extended-release tablets are achieved. Similarly, discontinuation of a CYP3A4 inducer, such as rifampin, carbamazepine, and phenytoin, in hydrocodone bitartrate extended-release tablet-treated patients may increase hydrocodone plasma concentrations and prolong opioid adverse reactions. When using hydrocodone bitartrate extended-release tablets with CYP3A4 inhibitors or discontinuing CYP3A4 inducers in hydrocodone bitartrate extended-release tablet-treated patients, evaluate patients at frequent intervals and consider dosage reduction of hydrocodone bitartrate extended-release tablets until stable drug effects are achieved <span class="opacity-50 text-xs">[see Drug Interactions ( 7 ) ]</span> . Concomitant use of hydrocodone bitartrate extended-release tablets with CYP3A4 inducers or discontinuation of an CYP3A4 inhibitor could decrease hydrocodone plasma concentrations, decrease opioid efficacy or, possibly, lead to a withdrawal syndrome in a patient who had developed physical dependence to hydrocodone. When using hydrocodone bitartrate extended-release tablets with CYP3A4 inducers or discontinuing CYP3A4 inhibitors, monitor patients closely at frequent intervals and consider increasing the opioid dosage if needed to maintain adequate analgesia or if symptoms of opioid withdrawal occur <span class="opacity-50 text-xs">[see Drug Interactions ( 7 )]</span> .

5.8 Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients The use of hydrocodone bitartrate extended-release tablets in patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment is contraindicated. Patients with Chronic Pulmonary Disease : Hydrocodone bitartrate extended-release tablet-treated patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression are at increased risk of decreased respiratory drive including apnea, even at recommended dosages of hydrocodone bitartrate extended-release tablets <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.2 )]</span> . Elderly, Cachectic, or Debilitated Patients: Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients because they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.3 )]</span> . Regularly evaluate patients, particularly when initiating and titrating hydrocodone bitartrate extended-release tablets and when hydrocodone bitartrate extended-release tablets are given concomitantly with other drugs that depress respiration <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.2 , 5.3 ), Drug Interactions ( 7 )]</span> . Alternatively, consider the use of non-opioid analgesics in these patients.

5.9 Adrenal Insufficiency Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Presentation of adrenal insufficiency may include non-specific symptoms and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. If adrenal insufficiency is suspected, confirm the diagnosis with diagnostic testing as soon as possible. If adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids. Wean the patient off of the opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers. Other opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency. The information available does not identify any particular opioids as being more likely to be associated with adrenal insufficiency.

5.10 Severe Hypotension Hydrocodone bitartrate extended-release tablets may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients. There is an increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume, or after concurrent administration of certain CNS depressant drugs (e.g., phenothiazines or general anesthetics) <span class="opacity-50 text-xs">[see Drug Interactions ( 7 )]</span> . Regularly evaluate these patients for signs of hypotension after initiating or titrating the dosage of hydrocodone bitartrate extended-release tablets. In patients with circulatory shock, hydrocodone bitartrate extended-release tablets may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of hydrocodone bitartrate extended-release tablets in patients with circulatory shock.

5.11 QTc Interval Prolongation QTc prolongation has been observed with hydrocodone bitartrate extended-release tablets following daily doses of 160 mg <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.2 )]</span> . This observation should be considered in making clinical decisions regarding patient monitoring when prescribing hydrocodone bitartrate extended-release tablets in patients with congestive heart failure, bradyarrhythmias, electrolyte abnormalities, or who are taking medications that are known to prolong the QTc interval. Hydrocodone bitartrate extended-release tablets should be avoided in patients with congenital long QT syndrome. In patients who develop QTc prolongation, consider reducing the dose by 33% to 50%, or changing to an alternate analgesic.

5.12 Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness In patients who may be susceptible to the intracranial effects of CO 2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors), hydrocodone bitartrate extended-release tablets may reduce respiratory drive, and the resultant CO 2 retention can further increase intracranial pressure. Monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy with hydrocodone bitartrate extended-release tablets. Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of hydrocodone bitartrate extended-release tablets in patients with impaired consciousness or coma.

5.13 Gastrointestinal Obstruction, Dysphagia, and Choking In the clinical studies with specific instructions to take hydrocodone bitartrate extended-release tablets with adequate water to swallow the tablet, 11 out of 2,476 subjects reported difficulty swallowing hydrocodone bitartrate extended-release tablets. These reports included esophageal obstruction, dysphagia, and choking, one of which had required medical intervention to remove the tablet <span class="opacity-50 text-xs">[see Adverse Reactions ( 6 )]</span> . Instruct patients not to pre-soak, lick, or otherwise wet hydrocodone bitartrate extended-release tablets prior to placing in the mouth, and to take one tablet at a time with enough water to ensure complete swallowing immediately after placing in the mouth. Patients with underlying gastrointestinal disorders such as esophageal cancer or colon cancer with a small gastrointestinal lumen are at greater risk of developing these complications. Consider use of an alternative analgesic in patients who have difficulty swallowing and patients at risk for underlying gastrointestinal disorders resulting in a small gastrointestinal lumen. 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 <span class="opacity-50 text-xs">[see Use in Specific Populations ( 8.4 )]</span> .

5.14 Risks of Use in Patients with Gastrointestinal Conditions Hydrocodone bitartrate extended-release tablets are contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus. The hydrocodone in hydrocodone bitartrate extended-release tablets may cause spasm of the sphincter of Oddi. Opioids may cause increases in serum amylase. Regularly evaluate patients with biliary tract disease, including acute pancreatitis, for worsening symptoms.

5.15 Increased Risk of Seizures in Patients with Seizure Disorders The hydrocodone in hydrocodone bitartrate extended-release tablets may increase the frequency of seizures in patients with seizure disorders, and may increase the risk of seizures occurring in other clinical settings associated with seizures. Regularly evaluate patients with a history of seizure disorders for worsened seizure control during hydrocodone bitartrate extended-release tablet therapy.

5.16 Withdrawal Do not abruptly discontinue hydrocodone bitartrate extended-release tablets in a patient physically dependent on opioids. When discontinuing hydrocodone bitartrate extended-release tablets in a physically dependent patient, gradually taper the dosage. Rapid tapering of hydrocodone in a patient physically dependent on opioids may lead to a withdrawal syndrome and return of pain <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.7 ), Drug Abuse and Dependence ( 9.3 )]</span> . Additionally, avoid the use of mixed agonist/antagonist analgesics (e.g., pentazocine, nalbuphine, and butorphanol) or partial agonist (e.g., buprenorphine) analgesics in patients who are receiving a full opioid agonist analgesic, including hydrocodone bitartrate extended-release tablets. In these patients, mixed agonist/antagonist and partial agonist analgesics may reduce the analgesic effect and/or may precipitate withdrawal symptoms <span class="opacity-50 text-xs">[see Drug Interactions ( 7 )]</span> .

5.17 Risks of Driving and Operating Machinery Hydrocodone bitartrate extended-release tablets may impair the mental and physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery. Peak blood levels of hydrocodone may occur 14 to 16 hours (range 6 to 30 hours) after initial dosing of hydrocodone bitartrate extended-release tablet administration. Blood levels of hydrocodone, in some patients, may be high at the end of 24 hours after repeated-dose administration. Warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects of hydrocodone bitartrate extended-release tablets and know how they will react to the medication.

PRECAUTIONS Masking of Inflammation and Fever The pharmacological activity of hydrocodone bitartrate and ibuprofen tablets in reducing inflammation, and possibly fever, may diminish the utility of diagnostic signs in detecting infections.

Ophthalmological Effects

Blurred or diminished vision, scotomata, and changes in color vision have been reported with oral ibuprofen. Discontinue ibuprofen if a patient develops such complaints, and refer the patient for an ophthalmologic examination that includes central visual fields and color vision testing. Information for Patients Advise the patient to read the FDA-approved patient labeling (Medication Guide) that accompanies each prescription dispensed. Patients, families, or their caregivers should be informed of the following information before initiating therapy with hydrocodone bitartrate and ibuprofen tablets and periodically during the course of ongoing therapy. 1. Storage and Disposal : Because of the risks associated with accidental ingestion, misuse, and abuse, advise patients to store Hydrocodone Bitartrate and Ibuprofen Tablets securely, out of sight and reach of children, and in a location not accessible by others, including visitors to the home . Inform patients that leaving Hydrocodone Bitartrate and Ibuprofen Tablets unsecured can pose a deadly risk to others in the home. (see WARNINGS, DRUG ABUSE AND DEPENDENCE) Advise patients and caregivers that when medicines are no longer needed, they should be disposed of promptly. Expired, unwanted, or unused Hydrocodone Bitartrate and Ibuprofen 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. 2. Addiction, Abuse, and Misuse Inform patients that the use of Hydrocodone Bitartrate And Ibuprofen Tablets, even when taken as recommended, can result in addiction, abuse, and misuse, which can lead to overdose and death (see WARNINGS: Addiction, Abuse, and Misuse) . Instruct patients not to share hydrocodone bitartrate and ibuprofen tablets with others and to take steps to protect hydrocodone bitartrate and ibuprofen tablets from theft or misuse. 3. L ife-Threatening Respiratory Depression Inform patients of the risk of life-threatening respiratory depression, including information that the risk is greatest when starting hydrocodone bitartrate and ibuprofen tablets or when the dosage is increased, and that it can occur even at recommended dosages. Advise patients how to recognize respiratory depression and to seek medical attention if breathing difficulties develop. Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help right away in the event of a known or suspected overdose (see WARNINGS, Life Threatening Respiratory Depression). 4.

Accidental Ingestion

Inform patients that accidental ingestion, especially by children, may result in respiratory depression or death (see WARNINGS: Life-Threatening Respiratory Depression) . 5. I nteractions with Benzodiazepines and OtherCNS Depressants Inform patients and caregivers that potentially fatal additive effects may occur if hydrocodone bitartrate and ibuprofen tablets are used with benzodiazepines or other CNS depressants, including alcohol,(e.g., non-benzodiazepine sedative/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, gabapentinoids [gabapentin or pregabalin], and other opioids) and not to use these concomitantly unless supervised by a healthcare provider (see WARNINGS: Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants, PRECAUTIONS: Drug Interactions) .

Patient

Access to an Opioid Overdose Reversal Agent for the Emergency Treatment of Opioid Overdose Inform patients and caregivers about opioid overdose reversal agents (e.g., naloxone, nalmefene). Discuss the importance of having access to an opioid overdose reversal agent, especially if the patient has risk factors for overdose (e.g., concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose) or if there are household members (including children) or other close contacts at risk for accidental ingestion or opioid overdose. Discuss with the patient the options for obtaining an opioid overdose reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program) [see WARNINGS, DOSAGE AND ADMINISTRATION]. Educate patients and caregivers on how to recognize the signs and symptoms of an overdose. Explain to patients and caregivers that effects of opioid overdose reversal agents like naloxone and nalmefene 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 an opioid overdose reversal agent is administered (see OVERDOSAGE). Advise patients and caregivers:

• how to treat with the overdose reversal agent in the event of an opioid overdose
• to tell family and friends about their opioid overdose reversal agent 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 opioid overdose reversal agent. Emphasize the importance of doing this before an opioid emergency happens, so the patient and caregiver will know what to do. Hyperalgesia and Allodynia Inform patients and caregivers not to increase opioid dosage without first consulting a clinician. Advise patients to seek medical attention if they experience symptoms of hyperalgesia, including worsening pain, increased sensitivity to pain, or new pain [see Warnings; Adverse Reactions]. 8. S er otonin Syndrome Inform patients that opioids could cause a rare but potentially life-threatening condition resulting from concomitant administration of serotonergic drugs. Warn patients of the symptoms of serotonin syndrome and to seek medical attention right away if symptoms develop. Instruct patients to inform their healthcare providers if they are taking, or plan to take serotonergic medications (see PRECAUTIONS: Drug Interactions) . 9.

Maoi

Interaction Inform patients to avoid taking hydrocodone bitartrate and ibuprofen tablets while using any drugs that inhibit monoamine oxidase. Patients should not start MAOIs while taking hydrocodone bitartrate and ibuprofen tablets (see PRECAUTIONS: Drug Interactions) . 10. I mportant Administration Instructions Instruct patients how to properly take Hydrocodone Bitartrate and Ibuprofen Tablets. For the short-term (generally less than 10 days) management of acute pain, the recommended dose of hydrocodone bitartrate and ibuprofen tablets are one tablet every 4 to 6 hours, as necessary. Inform patients that the dosage should not exceed 5 tablets in a 24-hour period (see DOSAGE AND ADMINISTRATION) . 11.

Important Discontinuation

Instructions In order to avoid developing withdrawal symptoms, instruct patients not to discontinue Hydrocodone Bitartrate and Ibuprofen Tablets without first discussing a tapering plan with the prescriber (see DOSAGE AND ADMINISTRATION) 12. Driving or Operating Heavy Machinery Inform patients that hydrocodone bitartrate and ibuprofen tablets may impair the ability to perform potentially hazardous activities such as driving a car or operating heavy machinery. Advise patients not to perform such tasks until they know how they will react to the medication (see WARNINGS: Risks of Driving and Operating Machinery) . 13. C onstipation Advise patients of the potential for severe constipation, including management instructions and when to seek medical attention (see ADVERSE REACTIONS: Clinical Trials Experience) . 14. C ar diovascular Thrombotic Events Advise patients to be alert for the symptoms of cardiovascular thrombotic events, including chest pain, shortness of breath, weakness, or slurring of speech, and to report any of these symptoms to their healthcare provider immediately (see WARNINGS: Cardiovascular Thrombotic Events) . 15.

Gastrointestinal

Bleeding, Ulceration, and Perforation Advise patients to report symptoms of ulcerations and bleeding, including epigastric pain, dyspepsia, melena, and hematemesis to their healthcare provider. In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, inform patients of the increased risk for and the signs and symptoms of GI bleeding (see WARNINGS: Gastrointestinal Bleeding, Ulceration, and Perforation) . 16.

Hepatotoxicity

Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, diarrhea, jaundice, right upper quadrant tenderness, and "flu-like" symptoms). If these occur, instruct patients to stop hydrocodone bitartrate and ibuprofen tablets and seek immediate medical therapy (see WARNINGS: Hepatotoxicity) . 17.

Heart

Failure and Edema Advise patients to be alert for the symptoms of congestive heart failure including shortness of breath, unexplained weight gain, or edema and to contact their healthcare provider if such symptoms occur (see WARNINGS: Heart Failure and Edema) . 18.

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: Adrenal Insufficiency) . 19. H y potension Inform patients that hydrocodone bitartrate and ibuprofen 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: Severe Hypotension) . 20.

Anaphylaxis

Inform patients that anaphylaxis has been reported with ingredients contained in Hydrocodone Bitartrate and Ibuprofen Tablets. Advise patients how to recognize such a reaction and when to seek medical attention (see CONTRAINDICATIONS, WARNINGS: Anaphylactic Reactions) . 21. P re g n a ncy N e onatal Opioid Withdrawal Syndrome Inform female patients of reproductive potential that use of hydrocodone bitartrate and ibuprofen tablets for an extended period of time during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated (see Boxed Warning, WARNINGS: Neonatal Opioid Withdrawal Syndrome, PRECAUTIONS: Pregnancy) .

Fetal Toxicity

Inform female patients of reproductive potential that hydrocodone bitartrate and ibuprofen tablets can cause fetal harm and to inform the prescriber of a known or suspected pregnancy. Inform pregnant women to avoid use of hydrocodone bitartrate and ibuprofen tablets and other NSAIDs starting at 30 weeks gestation because of the risk of premature closing of the fetal ductus arteriosus Inform pregnant women to avoid use of Hydrocodone Bitartrate and Ibuprofen Tablets and other NSAIDs starting at 30 weeks gestation because of the risk of the premature closing of the fetal ductus arteriosus. If treatment with Hydrocodone Bitartrate and Ibuprofen Tablets is needed for a pregnant woman between about 20 to 30 weeks gestation, advise her that she may need to be monitored for oligohydramnios, if treatment continues for longer than 48 hours (see WARNINGS; Fetal Toxicity, PRECAUTIONS; Pregnancy ). 22. L a c tation Advise nursing mothers to carefully observe infants for increased sleepiness (more than usual), breathing difficulties, or limpness. Instruct nursing mothers to seek immediate medical care if they notice these signs (see PRECAUTIONS: Nursing Mothers) . 23. I n fer tility Inform patients that use of opioids for an extended period of time may cause reduced fertility. It is not known whether these effects on fertility are reversible [see Adverse Reaction]. Advise female patients of reproductive potential who desire pregnancy that NSAIDs, including Hydrocodone Bitartrate And Ibuprofen Tablets, may be associated with a reversible delay in ovulation (see PRECAUTIONS: Carcinogenicity, Mutagenicity, Impairment of Fertility) . 24.

Serious Skin

Reactions, including DRESS. Advise patients to stop taking Hydrocodone Bitartrate and Ibuprofen Tablets immediately if they develop any type of rash or fever and to contact their healthcare provider as soon as possible (see Warnings) . 25.

Avoid

Concomitant use of NSAIDs Inform patients that the concomitant use of hydrocodone bitartrate and ibuprofen tablets with other NSAIDs or salicylates (e.g., diflunisal, salsalate) is not recommended due to the increased risk of gastrointestinal toxicity, and little or no increase in efficacy (see WARNINGS: Gastrointestinal Bleeding, Ulceration, and Perforation, PRECAUTIONS: Drug Interactions) . Alert patients that NSAIDs may be present in “over the counter” medications for treatment of colds, fever, or insomnia. 26. Use of NSAIDS and Low-Dose Aspirin Inform patients not to use low-dose aspirin concomitantly with hydrocodone bitartrate and ibuprofen tablets until they talk to their healthcare provider (see PRECAUTIONS: Drug Interactions) . 27.

Ophthalmological Effects

Instruct patients to report any signs of blurred vision or other eye symptoms (s ee PRECAUTIONS: Ophthalmological Effects) .

Laboratory Monitoring

Because serious GI bleeding, hepatotoxicity, and renal injury can occur without warning symptoms or signs, consider monitoring patients with a CBC and a chemistry profile periodically (see WARNINGS : Gastrointestinal Bleeding, Ulceration, and Perforation, Renal Toxicity and Hyperkalemia, Hepatotoxicity).

Drug Interactions

Inhibitors of CYP3A4 and CYP2D6 The concomitant use of hydrocodone bitartrate and ibuprofen tablets and CYP3A4 inhibitors, such as macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), protease inhibitors (e.g., ritonavir), can increase the plasma concentration of hydrocodone, resulting in increased or prolonged opioid effects. These effects could be more pronounced with concomitant use of hydrocodone bitartrate and ibuprofen tablets and CYP2D6 and CYP3A4 inhibitors, particularly when an inhibitor is added after a stable dose of hydrocodone bitartrate and ibuprofen tablets are achieved (see WARNINGS: Risks of Concomitant Use or Discontinuation of Cytochrome P450 3A4 Inhibitors and Inducers ). After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the hydrocodone plasma concentration will decrease (see CLINICAL PHARMACOLOGY: Pharmacokinetics ), resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to Hydrocodone Bitartrate and Ibuprofen Tablets. If concomitant use is necessary, consider dosage reduction of hydrocodone bitartrate and ibuprofen tablets until stable drug effects are achieved. Evaluate patients at frequent intervals for respiratory depression and sedation. If a CYP3A4 inhibitor is discontinued, consider a dosage increase of hydrocodone bitartrate and ibuprofen tablets until stable drug effects are achieved. Evaluate for signs of opioid withdrawal. CYP3A4 Inducers The concomitant use of hydrocodone bitartrate and ibuprofen tablets and CYP3A4 inducers, such as rifampin, carbamazepine, and phenytoin, can decrease the plasma concentration of hydrocodone (see CLINICAL PHARMACOLOGY: Pharmacokinetics ), resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to hydrocodone (see WARNINGS: Withdrawal ). After stopping a CYP3A4 inducer, as the effects of the inducer decline, the hydrocodone plasma concentration will increase (see CLINICAL PHARMACOLOGY: Pharmacokinetics ), which could increase or prolong both the therapeutic effects and adverse reactions, and may cause serious respiratory depression. If concomitant use is necessary, consider a dosage increase of hydrocodone bitartrate and ibuprofen tablets until stable drug effects are achieved. Evaluate for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider hydrocodone bitartrate and ibuprofen tablets dosage reduction and evaluate patients at frequent intervals for signs of respiratory depression and sedation. Benzodiazepines and Other Central Nervous System (CNS)

Depressants

Due to additive pharmacologic effect, the concomitant use of benzodiazepines and other CNS depressants, such as benzodiazepines and other sedative hypnotics, anxiolytics, and tranquilizers, muscle relaxants, general anesthetics, antipsychotics, gabapentinoids (gabapentin or pregabalin) and other opioids, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death. Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Inform patients and caregivers of this potential interaction, educate them on the signs and symptoms of respiratory depression (including sedation). If concomitant use is warranted, consider recommending or prescribing an opioid overdose reversal agent [see WARNINGS, DOSAGE AND ADMINISTRATION].

Serotonergic Drugs

The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system, such as selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that effect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e., cyclobenzaprine,metaxalone), and monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue), has resulted in serotonin syndrome (see PRECAUTIONS: Information for Patients ). If concomitant use is warranted, frequently evaluate the patient, particularly during treatment initiation and dose adjustment. Discontinue hydrocodone bitartrate and ibuprofen tablets if serotonin syndrome is suspected.

Monoamine Oxidase

Inhibitors (MAOIs) MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma). If urgent use of an opioid is necessary with MAOIs such as phenelzine, tranylcypromine, linezolid, use test doses and frequent titration of small doses to treat pain while closely monitoring blood pressure and signs and symptoms of CNS and respiratory depression. The use of hydrocodone bitartrate and ibuprofen tablets are not recommended for patients taking MAOIs or within 14 days of stopping such treatment.

Mixed

Agonist/Antagonist and Partial Agonist Opioid Analgesics Agonist/antagonist analgesics such as pentazocine, nalbuphine, butorphanol and buprenorphine may reduce the analgesic effect of hydrocodone bitartrate and ibuprofen tablets and/or precipitate withdrawal symptoms in these patients. Avoid concomitant use of these drugs.

Muscle Relaxants Hydrocodone

Bitartrate and Ibuprofen Tablets may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression. Because respiratory depression may be greater than otherwise expected, decrease the dosage of hydrocodone bitartrate and ibuprofen 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 recommending or prescribing an opioid overdose reversal agent (see WARNINGS, DOSAGE AND ADMINISTRATION). Examples: Cyclobenzaprine, metaxalone.

Anticholinergics

The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Evaluate patients for signs of urinary retention or reduced gastric motility when hydrocodone bitartrate and ibuprofen tablets are used concomitantly with anticholinergic drugs.

Drugs That Interfere With Hemostasis

Ibuprofen and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of ibuprofen and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. Monitor patients with concomitant use of hydrocodone bitartrate and ibuprofen tablets with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), SSRIs, and SNRIs for signs of bleeding (see WARNINGS: Hematologic Toxicity ).

Aspirin

Pharmacodynamic studies have demonstrated interference with the antiplatelet activity of aspirin when ibuprofen 400 mg, given three times daily, is administered with enteric coated low-dose aspirin. The interaction exists even following a once-daily regimen of ibuprofen 400 mg, particularly when ibuprofen is dosed prior to aspirin. The interaction is alleviated if immediate-release low-dose aspirin is dosed at least 2 hours prior to a once daily regimen of ibuprofen; however, this finding cannot be extended to enteric-coated low-dose aspirin [see Clinical Pharmacology/Pharmacodynamics ]. Because there may be an increased risk of cardiovascular events due to the interference of ibuprofen with the antiplatelet effect of aspirin, for patients taking low-dose aspirin for cardioprotection who require analgesics, consider use of an NSAID that does not interfere with the antiplatelet effect of aspirin, or non-NSAID analgesics, where appropriate. Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone (see WARNINGS: Gastrointestinal Bleeding, Ulceration, and Perforation ). Concomitant use of hydrocodone bitartrate and ibuprofen tablets and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding (see WARNINGS: Hematologic Toxicity ). ACE-Inhibitors, Angiotensin Receptor Blockers, and Beta-blockers NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). During concomitant use of hydrocodone bitartrate and ibuprofen tablets and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. Evaluate for signs of worsening renal function (see WARNINGS: Renal Toxicity and Hyperkalemia ). These effects are usually reversible. When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.

Diuretics

Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. During concomitant use of hydrocodone bitartrate and ibuprofen tablets with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects (see WARNINGS: Renal Toxicity and Hyperkalemia ).

Digoxin

The concomitant use of ibuprofen with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin. During concomitant use of hydrocodone bitartrate and ibuprofen tablets and digoxin, monitor serum digoxin levels. Lithium NSAIDs have produced elevations in plasma lithium concentration and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis. During concomitant use of hydrocodone bitartrate and ibuprofen tablets and lithium, evaluate patients for signs of lithium toxicity.

Methotrexate

Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). During concomitant use of hydrocodone bitartrate and ibuprofen tablets and methotrexate, evaluate patients for methotrexate toxicity.

Cyclosporine

Concomitant use of hydrocodone bitartrate and ibuprofen tablets and cyclosporine may increase cyclosporine’s nephrotoxicity. During concomitant use of hydrocodone bitartrate and ibuprofen tablets and cyclosporine, evaluate patients for signs of worsening renal function. NSAIDs and Salicylates Concomitant use of ibuprofen with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy (see WARNINGS: Gastrointestinal Bleeding, Ulceration, and Perforation). The concomitant use of ibuprofen with other NSAIDs or salicylates is not recommended.

Pemetrexed

Concomitant use of hydrocodone bitartrate and ibuprofen tablets and Pemetrexed may increase the risk of Pemetrexed associated myelosuppression, renal, and GI toxicity (see the Pemetrexed prescribing information). During concomitant use of hydrocodone bitartrate and ibuprofen tablets and Pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of Pemetrexed. In the absence of data regarding potential interaction between Pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following Pemetrexed administration. Carcinogenicity, Mutagenicity, Impairment of Fertility Carcinogenesis Long-term animal studies to evaluate the carcinogenic potential of the combination of hydrocodone and ibuprofen, ibuprofen alone, or hydrocodone alone have not been conducted.

Mutagenesis

The mutagenic potential of the combination of hydrocodone and ibuprofen or hydrocodone alone has not been investigated. In published studies, ibuprofen was not mutagenic in the in vitro bacterial reverse mutation assay (Ames assay). Impairment of Fertility Animal studies evaluating the impact of the combination of hydrocodone and ibuprofen or hydrocodone alone on fertility have not been conducted. In a published study, dietary administration of ibuprofen to male and female rats 8-weeks prior to and during mating at dose levels of 20 mg/kg (0.2-times the MRHD of 1000 mg ibuprofen based on body surface area comparison) did not impact male or female fertility or litter size. In other studies, adult mice were administered ibuprofen intraperitoneally at a dose of 5.6 mg/kg/day (0.03-times the MRHD based on body surface area comparison) for 35 or 60 days in males and 35 days in females. There was no effect on sperm motility or viability in males but decreased ovulation was reported in females. Based on the mechanism of action, the use of prostaglandin-mediated NSAIDs, including ibuprofen, may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility in some women. Small studies in women treated with NSAIDs have also shown a reversible delay in ovulation. Consider withdrawal of NSAID-containing products, including Hydrocodone Bitartrate and Ibuprofen Tablets, in women who have difficulties conceiving or who are undergoing investigation of infertility. Use of opioids for an extended period of time may cause reduced fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible (see ADVERSE REACTIONS: Postmarketing Experience) .

Pregnancy Risk Summary

Use of NSAIDs, including Hydrocodone Bitartrate and Ibuprofen Tablets, can cause premature closure of the fetal ductus arteriosus and fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. Because of these risks, limit dose and duration of Hydrocodone Bitartrate and Ibuprofen Tablets use between about 20 and 30 weeks of gestation, and avoid Hydrocodone Bitartrate and Ibuprofen Tablets use at about 30 weeks of gestation and later in pregnancy (see WARNINGS; Fetal Toxicity ).

Premature

Closure of Fetal Ductus Arteriosus Use of NSAIDs, including Hydrocodone Bitartrate and Ibuprofen Tablets, at about 30 weeks gestation or later in pregnancy increases the risk of premature closure of the fetal ductus arteriosus.

Oligohydramnios/Neonatal

Renal Impairment Use of NSAIDs at about 20 weeks gestation or later in pregnancy has been associated with cases of fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. Data from observational studies regarding other potential embryofetal risks of NSAID use in women in the first or second trimesters of pregnancy are inconclusive. In animal reproduction studies, an increase in the percentage of litters and fetuses with any major abnormality and an increase in the number of litters and fetuses with one or more nonossified metacarpals was observed when the combination of hydrocodone and ibuprofen was administered orally to pregnant rabbits during organogenesis at 1.8 times the maximum daily dose. There are no animal reproductive and developmental toxicology studies with hydrocodone alone. In published animal reproduction studies testing ibuprofen alone, there were no clear developmental effects at doses up to 1.2 times the maximum recommended human dose (MRHD) in the rabbit and 1.8 times in the MRHD rat when dosed throughout gestation. In contrast, an increase in membranous ventricular septal defects was reported in rats treated on Gestation Days 9 & 10 with 3 times the MRHD. Based on animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization. In animal studies, administration of prostaglandin synthesis inhibitors such as ibuprofen, resulted in increased pre- and post-implantation loss. Prostaglandins also have been shown to have an important role in fetal kidney development. In published animal studies, prostaglandin synthesis inhibitors have been reported to impair kidney development when administered at clinically relevant doses. The estimated background risk of major birth defects and miscarriage for the indicated population(s) is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Clinical Considerations Fetal/Neonatal

Adverse Reactions Use of opioid analgesics for an extended period of time during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth. Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity 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: Neonatal Opioid Withdrawal Syndrome ).

Premature

Closure of Fetal Ductus Arteriosus: Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy, because NSAIDs, including Hydrocodone Bitartrate and Ibuprofen Tablets, can cause premature closure of the fetal ductus arteriosus (see WARNINGS; Fetal Toxicity ).

Oligohydramnios/Neonatal

Renal Impairment If an NSAID is necessary at about 20 weeks gestation or later in pregnancy, limit the use to the lowest effective dose and shortest duration possible.

If Hydrocodone

Bitartrate and Ibuprofen Tablets treatment extends beyond 48 hours, consider monitoring with ultrasound for oligohydramnios. If oligohydramnios occurs, discontinue Hydrocodone Bitartrate and Ibuprofen Tablets and follow up according to clinical practice (see WARNINGS; Fetal Toxicity ). Labor and Delivery Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. An opioid overdose reversal agent, such as naloxone, must be available for reversal of opioid-induced respiratory depression in the neonate. Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression. There are no studies on the effects of hydrocodone bitartrate and ibuprofen tablets during labor or delivery. In animal studies, NSAIDs, including ibuprofen, inhibit prostaglandin synthesis, cause delayed parturition, and increase the incidence of stillbirth. Hydrocodone bitartrate and ibuprofen tablets are not recommended for use in women during and immediately prior to labor, when use of shorter-acting analgesics or other analgesic techniques are more appropriate. Opioid analgesics, including Hydrocodone Bitartrate and Ibuprofen Tablets, can prolong labor through actions that 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 dilatation, which tends to shorten labor. Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression.

Data Human Data Premature

Closure of Fetal Ductus Arteriosus: Published literature reports that the use of NSAIDs at about 30 weeks of gestation and later in pregnancy may cause premature closure of the fetal ductus arteriosus.

Oligohydramnios/Neonatal

Renal Impairment: Published studies and postmarketing reports describe maternal NSAID use at about 20 weeks gestation or later in pregnancy associated with fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. In many cases, but not all, the decrease in amniotic fluid was transient and reversible with cessation of the drug. There have been a limited number of case reports of maternal NSAID use and neonatal renal dysfunction without oligohydramnios, some of which were irreversible. Some cases of neonatal renal dysfunction required treatment with invasive procedures, such as exchange transfusion or dialysis. Methodological limitations of these postmarketing studies and reports include lack of a control group; limited information regarding dose, duration, and timing of drug exposure; and concomitant use of other medications. These limitations preclude establishing a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal NSAID use. Because the published safety data on neonatal outcomes involved mostly preterm infants, the generalizability of certain reported risks to the full-term infant exposed to NSAIDs through maternal use is uncertain.

Animal Data

Pregnant rabbits were treated with 10, 33, or 95 mg/kg of 1:27 ratio of hydrocodone:ibuprofen (the high dose is 1.8 times the maximum daily dose of both compounds based on surface area) from Gestation Day 5 to 18. The dose of 95 mg/kg of the combination, which also produced maternal toxicity (44% decrease in body weight gain compared to control), resulted in an increase in the percentage of litters and fetuses with any major abnormality and an increase in the number of litters and fetuses with one or more nonossified metacarpals (a minor abnormality). Pregnant rats were treated with 50, 100, or 166 mg/kg of a 1:27 ratio of hydrocodone:ibuprofen (the high dose is 1.6 times the maximum daily dose of both compounds based on body surface area) from Gestation Day 5 to 15. No reproductive toxicity was noted despite the presence of maternal toxicity in the 100 and 166 mg/kg groups (21% and 60% decrease in body weight gain compared to control). In a published study, female rabbits given 7.5, 20, or 60 mg/kg ibuprofen (0.15, 0.39, or 1.2 times the maximum recommended human daily dose of 1000 mg of ibuprofen based on body surface area) from Gestation Days 1 to 29, no clear treatment-related adverse developmental effects were noted. This dose was associated with significant maternal toxicity (stomach ulcers, gastric lesions). In the same publication, female rats were administered 7.5, 20, 60, 180 mg/kg ibuprofen (0.07, 0.2, 0.6, 1.8 times the maximum daily dose) did not result in clear adverse developmental effects. Maternal toxicity (gastrointestinal lesions) was noted at 20 mg/kg and above. In a published study, rats were orally dosed with 300 mg/kg ibuprofen (3 times the maximum human daily dose of 1000 mg based on body surface area) during Gestation Days 9 and 10 (critical time points for heart development in rats). Ibuprofen treatment resulted in an increase in the incidence of membranous ventricular septal defects. This dose was associated with significant maternal toxicity including gastrointestinal toxicity (1 out of 20 animals). In the same study/publication rabbits were dosed on Gestation Day 9, 10 and 11 with 500 mg/kg (9.7 times the maximum human daily dose), and only one incidence each of a membranous ventricular septal defect and gastroschisis was noted in the rabbit fetuses. This dose was also associated with maternal toxicity.

Nursing Mothers 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. Limited published literature reports that, following oral administration, ibuprofen is present in human milk at relative infant doses of 0.06% to 0.6% of the maternal weight-adjusted daily dose. Lactation studies have not been conducted with Hydrocodone Bitartrate and Ibuprofen 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. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for hydrocodone bitartrate and ibuprofen tablets and any potential adverse effects on the breastfed infant from hydrocodone bitartrate and ibuprofen tablets or from the underlying maternal condition.

Clinical Considerations

Monitor infants exposed to hydrocodone bitartrate and ibuprofen tablets through breast milk for excess sedation and respiratory depression. Withdrawal symptoms can occur in breastfed infants when maternal administration of hydrocodone is stopped, or when breastfeeding is stopped Pediatric Use The safety and effectiveness of hydrocodone bitartrate and ibuprofen tablets in pediatric patients below the age of 16 have not been established.

Geriatric

Use In controlled clinical trials there was no difference in tolerability between patients < 65 years of age and those ≥ 65, apart from an increased tendency of the elderly to develop constipation. However, elderly patients are at greater risk for NSAID-associated serious cardiovascular, gastrointestinal, and renal adverse reactions as well as possible increased risk of respiratory depression with opioids. 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 (see WARNINGS: Cardiovascular Thrombotic Events, Gastrointestinal Bleeding, Ulceration, and Perforation, Renal Toxicity and Hyperkalemia ). Respiratory depression is the chief risk for elderly patients treated with opioids, and has occurred after large initial doses were administered to patients who were not opioid-tolerant or when opioids were co-administered with other agents that depress respiration. Titrate the dosage of hydrocodone bitartrate and ibuprofen tablets slowly in geriatric patients and frequently reevaluate the patient for signs of central nervous system and respiratory depression (see WARNINGS ). Both hydrocodone and ibuprofen are known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to regularly evaluate renal function.

Hepatic Impairment

Patients with hepatic impairment may have higher hydrocodone plasma concentrations than those with normal function. In patients with severe hepatic impairment, use a low initial dose. Monitor these patients closely for adverse events such as respiratory depression, sedation, and hypotension.

Renal Impairment

Patients with renal impairment may have higher hydrocodone plasma concentrations than those with normal function. Use a low initial dose in patients with renal impairment and monitor closely for adverse events such as respiratory depression, sedation, and hypotension.

Drug Interactions Inhibitors of CYP3A4 and CYP2D6 The concomitant use of hydrocodone bitartrate and ibuprofen tablets and CYP3A4 inhibitors, such as macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), protease inhibitors (e.g., ritonavir), can increase the plasma concentration of hydrocodone, resulting in increased or prolonged opioid effects. These effects could be more pronounced with concomitant use of hydrocodone bitartrate and ibuprofen tablets and CYP2D6 and CYP3A4 inhibitors, particularly when an inhibitor is added after a stable dose of hydrocodone bitartrate and ibuprofen tablets are achieved (see WARNINGS: Risks of Concomitant Use or Discontinuation of Cytochrome P450 3A4 Inhibitors and Inducers ). After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the hydrocodone plasma concentration will decrease (see CLINICAL PHARMACOLOGY: Pharmacokinetics ), resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to Hydrocodone Bitartrate and Ibuprofen Tablets. If concomitant use is necessary, consider dosage reduction of hydrocodone bitartrate and ibuprofen tablets until stable drug effects are achieved. Evaluate patients at frequent intervals for respiratory depression and sedation. If a CYP3A4 inhibitor is discontinued, consider a dosage increase of hydrocodone bitartrate and ibuprofen tablets until stable drug effects are achieved. Evaluate for signs of opioid withdrawal. CYP3A4 Inducers The concomitant use of hydrocodone bitartrate and ibuprofen tablets and CYP3A4 inducers, such as rifampin, carbamazepine, and phenytoin, can decrease the plasma concentration of hydrocodone (see CLINICAL PHARMACOLOGY: Pharmacokinetics ), resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to hydrocodone (see WARNINGS: Withdrawal ). After stopping a CYP3A4 inducer, as the effects of the inducer decline, the hydrocodone plasma concentration will increase (see CLINICAL PHARMACOLOGY: Pharmacokinetics ), which could increase or prolong both the therapeutic effects and adverse reactions, and may cause serious respiratory depression. If concomitant use is necessary, consider a dosage increase of hydrocodone bitartrate and ibuprofen tablets until stable drug effects are achieved. Evaluate for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider hydrocodone bitartrate and ibuprofen tablets dosage reduction and evaluate patients at frequent intervals for signs of respiratory depression and sedation. Benzodiazepines and Other Central Nervous System (CNS)

Depressants

Due to additive pharmacologic effect, the concomitant use of benzodiazepines and other CNS depressants, such as benzodiazepines and other sedative hypnotics, anxiolytics, and tranquilizers, muscle relaxants, general anesthetics, antipsychotics, gabapentinoids (gabapentin or pregabalin) and other opioids, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death. Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Inform patients and caregivers of this potential interaction, educate them on the signs and symptoms of respiratory depression (including sedation). If concomitant use is warranted, consider recommending or prescribing an opioid overdose reversal agent [see WARNINGS, DOSAGE AND ADMINISTRATION].

Serotonergic Drugs

The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system, such as selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that effect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e., cyclobenzaprine,metaxalone), and monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue), has resulted in serotonin syndrome (see PRECAUTIONS: Information for Patients ). If concomitant use is warranted, frequently evaluate the patient, particularly during treatment initiation and dose adjustment. Discontinue hydrocodone bitartrate and ibuprofen tablets if serotonin syndrome is suspected.

Monoamine Oxidase

Inhibitors (MAOIs) MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma). If urgent use of an opioid is necessary with MAOIs such as phenelzine, tranylcypromine, linezolid, use test doses and frequent titration of small doses to treat pain while closely monitoring blood pressure and signs and symptoms of CNS and respiratory depression. The use of hydrocodone bitartrate and ibuprofen tablets are not recommended for patients taking MAOIs or within 14 days of stopping such treatment.

Mixed

Agonist/Antagonist and Partial Agonist Opioid Analgesics Agonist/antagonist analgesics such as pentazocine, nalbuphine, butorphanol and buprenorphine may reduce the analgesic effect of hydrocodone bitartrate and ibuprofen tablets and/or precipitate withdrawal symptoms in these patients. Avoid concomitant use of these drugs.

Muscle Relaxants Hydrocodone

Bitartrate and Ibuprofen Tablets may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression. Because respiratory depression may be greater than otherwise expected, decrease the dosage of hydrocodone bitartrate and ibuprofen 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 recommending or prescribing an opioid overdose reversal agent (see WARNINGS, DOSAGE AND ADMINISTRATION). Examples: Cyclobenzaprine, metaxalone.

Anticholinergics

The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Evaluate patients for signs of urinary retention or reduced gastric motility when hydrocodone bitartrate and ibuprofen tablets are used concomitantly with anticholinergic drugs.

Drugs That Interfere With Hemostasis

Ibuprofen and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of ibuprofen and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. Monitor patients with concomitant use of hydrocodone bitartrate and ibuprofen tablets with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), SSRIs, and SNRIs for signs of bleeding (see WARNINGS: Hematologic Toxicity ).

Aspirin

Pharmacodynamic studies have demonstrated interference with the antiplatelet activity of aspirin when ibuprofen 400 mg, given three times daily, is administered with enteric coated low-dose aspirin. The interaction exists even following a once-daily regimen of ibuprofen 400 mg, particularly when ibuprofen is dosed prior to aspirin. The interaction is alleviated if immediate-release low-dose aspirin is dosed at least 2 hours prior to a once daily regimen of ibuprofen; however, this finding cannot be extended to enteric-coated low-dose aspirin [see Clinical Pharmacology/Pharmacodynamics ]. Because there may be an increased risk of cardiovascular events due to the interference of ibuprofen with the antiplatelet effect of aspirin, for patients taking low-dose aspirin for cardioprotection who require analgesics, consider use of an NSAID that does not interfere with the antiplatelet effect of aspirin, or non-NSAID analgesics, where appropriate. Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone (see WARNINGS: Gastrointestinal Bleeding, Ulceration, and Perforation ). Concomitant use of hydrocodone bitartrate and ibuprofen tablets and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding (see WARNINGS: Hematologic Toxicity ). ACE-Inhibitors, Angiotensin Receptor Blockers, and Beta-blockers NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). During concomitant use of hydrocodone bitartrate and ibuprofen tablets and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. Evaluate for signs of worsening renal function (see WARNINGS: Renal Toxicity and Hyperkalemia ). These effects are usually reversible. When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.

Diuretics

Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. During concomitant use of hydrocodone bitartrate and ibuprofen tablets with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects (see WARNINGS: Renal Toxicity and Hyperkalemia ).

Digoxin

The concomitant use of ibuprofen with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin. During concomitant use of hydrocodone bitartrate and ibuprofen tablets and digoxin, monitor serum digoxin levels. Lithium NSAIDs have produced elevations in plasma lithium concentration and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis. During concomitant use of hydrocodone bitartrate and ibuprofen tablets and lithium, evaluate patients for signs of lithium toxicity.

Methotrexate

Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). During concomitant use of hydrocodone bitartrate and ibuprofen tablets and methotrexate, evaluate patients for methotrexate toxicity.

Cyclosporine

Concomitant use of hydrocodone bitartrate and ibuprofen tablets and cyclosporine may increase cyclosporine’s nephrotoxicity. During concomitant use of hydrocodone bitartrate and ibuprofen tablets and cyclosporine, evaluate patients for signs of worsening renal function. NSAIDs and Salicylates Concomitant use of ibuprofen with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy (see WARNINGS: Gastrointestinal Bleeding, Ulceration, and Perforation). The concomitant use of ibuprofen with other NSAIDs or salicylates is not recommended.

Pemetrexed

Concomitant use of hydrocodone bitartrate and ibuprofen tablets and Pemetrexed may increase the risk of Pemetrexed associated myelosuppression, renal, and GI toxicity (see the Pemetrexed prescribing information). During concomitant use of hydrocodone bitartrate and ibuprofen tablets and Pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of Pemetrexed. In the absence of data regarding potential interaction between Pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following Pemetrexed administration.