Hydrocodone Bitartrate

Q: What should I know before taking Hydrocodone Bitartrate?

5 WARNINGS 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 evalu

Q: Is Hydrocodone Bitartrate available over the counter?

Hydrocodone Bitartrate is a prescription medication. You will need a valid prescription from a licensed healthcare provider.

Prescription

ब्रांड नाम: Hydrocodone Bitartrate

खुराक रूप

Capsule

मार्ग

ORAL

निर्माता

Alvogen Inc.

About This Medication

11 DESCRIPTION Hydrocodone bitartrate extended-release capsules are hard gelatin capsules for oral administration. Hydrocodone bitartrate is an opioid agonist and occurs as fine, white crystals, or as a crystalline powder. The chemical name is 4,5(alpha)-epoxy-3-methoxy-17-methylmorphinan-6-one tartrate (1:1) hydrate (2:5) or morphinan-6-one, 4,5-epoxy-3-methoxy-17-methyl-, (5 alpha)-, [R (R*, R*)]-2,3-dihydroxybutanedioate (1:1), hydrate (2:5). It has the following structural formula: Each hydrocodone bitartrate extended-release capsule contains either 10 mg, 15 mg, 20 mg, 30 mg, 40 mg, or 50 mg of hydrocodone bitartrate USP. All capsule strengths include the following inactive ingredients: ammonio methacrylate copolymer Type B, copovidone, gelatin, silicon dioxide, sodium lauryl sulfate, sugar spheres, and talc. The capsule shells contain the following colorants: black iron oxide (50 mg capsule), D&C yellow #10 (all capsule strengths), FD&C blue #1 (10 mg, 15 mg, and 30 mg capsules), FD&C red #3 (15 mg and 30 mg capsules), FD&C red #40 (30 mg capsule), FD&C yellow #6 (all capsule strengths) and titanium dioxide (all capsule strengths). The imprinting ink for all capsule strengths contains: black iron oxide, D&C yellow #10, FD&C blue #1, FD&C blue #2, FD&C red # 40, n-butyl alcohol, propylene glycol and shellac.

सक्रिय तत्व

घटक	शक्ति
Hydrocodone Bitartrate	-

संकेत और उपयोग

1 INDICATIONS 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 )

यह कैसे काम करता है

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

खुराक और प्रशासन

2 DOSAGE AND ADMINISTRATION Hydrocodone bitartrate extended-release capsules 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 capsules, a single dose greater than 40 mg, or a total daily dose greater than 80 mg are only for use in patients in whom tolerance to an opioid of comparable potency has been established. ( 2.1 ) 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. Reserve titration to higher doses of hydrocodone bitartrate extended-release capsules 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 capsules. Consider this risk when selecting an initial dose and when making dose adjustments ( 2.1 , 5.2 ) Instruct patients to swallow hydrocodone bitartrate extended-release capsules intact and not to cut, break, chew, crush, or dissolve the capsules (risk of potentially fatal overdose). ( 2.1 , 5.1 ) 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 capsules. Consider prescribing naloxone based on the patient’s risk factors for overdose. ( 2.2 , 5.1 , 5.2 , 5.3 ) For opioid-naïve and opioid non-tolerant patients, initiate with 10 mg capsules orally every 12 hours. ( 2.3 ) To convert to hydrocodone bitartrate extended-release capsules from another opioid, use available conversion factors to obtain estimated dose. ( 2.3 ) Dose titration of hydrocodone bitartrate extended-release capsules may occur every 3 to 7 days, using increments of 10 mg every 12 hours (i.e., 20 mg per day). ( 2.4 ) Patients with Severe Hepatic Impairment: Initiate dosing with 10 mg every 12 hours and titrate carefully, while monitoring for respiratory depression, sedation, and hypotension. No adjustment in starting dose with hydrocodone bitartrate extended-release capsules is required in patients with mild or moderate hepatic impairment. ( 2.5 ) Do not abruptly discontinue hydrocodone bitartrate extended-release capsules in a physically dependent patient. ( 2.6 ) 2.1 Important Dosage and Administration Information Hydrocodone bitartrate extended-release capsules 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 capsules, a single dose of greater than 40 mg, or a total daily dose of greater than 80 mg, are only for use in patients in whom tolerance to an opioid of comparable potency has been established. Patients who are opioid tolerant are those receiving, for one week or longer, at least 60 mg oral morphine per day, 25 mcg transdermal fentanyl per hour, 30 mg oral oxycodone per day, 8 mg oral hydromorphone per day, 25 mg oral oxymorphone per day, 60 mg oral hydrocodone per day, or an equianalgesic dose of another opioid. Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals [see Warnings and Precautions ( 5 )] . Because the risk of overdose increases as opioid doses increase, reserve titration to higher doses of hydrocodone bitartrate extended-release capsules for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks. Initiate the dosing regimen for each patient individually, taking into account the patient's underlying cause and severity of pain, prior analgesic treatment and response, and risk factors for addiction, abuse, and misuse [see Warnings and Precautions ( 5.1 )] . Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with hydrocodone bitartrate extended-release capsules. Consider this risk when selecting an initial dose and when making dose adjustments [see Warnings and Precautions ( 5 )] . Instruct patients to swallow hydrocodone bitartrate extended-release capsules whole [see Patient Counseling Information ( 17 )] . Crushing, chewing, or dissolving the beads in hydrocodone bitartrate extended-release capsules will result in uncontrolled delivery of hydrocodone and can lead to overdose or death [see Warnings and Precautions ( 5.1 )] . Hydrocodone bitartrate extended-release capsules are administered orally twice daily (every 12 hours). 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 capsules [see Warnings and Precautions ( 5.2 ), Patient Counseling Information ( 17 )] . Inform patients and caregivers about the various ways to obtain naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (e.g., by prescription, directly from a pharmacist, or as part of a community-based program). Consider prescribing naloxone, based on the patient’s risk factors for overdose, such as concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose. The presence of risk factors for overdose should not prevent the proper management of pain in any given patient [see Warnings and Precautions ( 5.1 , 5.2 , 5.3 )] . Consider prescribing naloxone if the patient has household members (including children) or other close contacts at risk for accidental ingestion or overdose. 2.3 Initial Dosage Use of Hydrocodone Bitartrate Extended-Release Capsules as the First Opioid Analgesic (opioid-naïve patients) Initiate therapy with hydrocodone bitartrate extended-release capsules with one 10 mg capsule every 12 hours. Use of Hydrocodone Bitartrate Extended-Release Capsules in Patients Who Are Not Opioid Tolerant The starting dose for patients who are not opioid tolerant is hydrocodone bitartrate extended-release capsules 10 mg orally every 12 hours. Use of higher starting doses in patients who are not opioid tolerant may cause fatal respiratory depression [see Warnings and Precautions ( 5.2 )] . Conversion from Oral Hydrocodone Formulations to Hydrocodone Bitartrate Extended-Release Capsules Patients receiving other oral hydrocodone-containing formulations may be converted to hydrocodone bitartrate extended-release capsules by dividing the patient’s total daily oral hydrocodone dose in half and administrating as hydrocodone bitartrate extended-release capsules every 12 hours. Conversion from Other Oral Opioids to Hydrocodone Bitartrate Extended-Release Capsules When hydrocodone bitartrate extended-release capsules 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 different opioid drugs and products. Therefore, a conservative approach is advised when determining the total daily dosage of hydrocodone bitartrate extended-release capsules. 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 capsules clinical trial with an open label titration period, patients were converted from their prior opioid to hydrocodone bitartrate extended-release capsules using Table 1 as a guide for the initial hydrocodone bitartrate extended-release capsules dose. To obtain the initial hydrocodone bitartrate extended-release capsules 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 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 capsules. The table cannot be used to convert from hydrocodone bitartrate extended-release capsules 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 Capsules (Not Equianalgesic Doses) Prior Oral Opioid Oral Dose (mg) Approximate Oral Conversion Factor The conversion ratios in this table are only to be used for the conversion from current opioid therapy to hydrocodone bitartrate extended-release capsules. Hydrocodone 10 1 Oxycodone 10 1 Methadone 10 1 Oxymorphone 5 2 Hydromorphone 3.75 2.67 Morphine 15 0.67 Codeine 100 0.10 To calculate the estimated daily hydrocodone bitartrate extended-release capsule 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. Divide the daily dose in half for administration every 12 hours. 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 approximate total hydrocodone daily dose. The daily dose should then be divided in half for administration every 12 hours. 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 capsule strength(s) available and initiate therapy with that dose. Example conversion from a single opioid to hydrocodone bitartrate extended-release capsules Step 1: Sum the total daily dose of the opioid (in this case, extended-release oxymorphone); 15 mg oxymorphone twice daily = 30 mg total daily dose of oxymorphone. Step 2: Calculate the approximate equivalent dose of oral hydrocodone based on the total daily dose of the current opioid using Table 1; 30 mg total daily dose of oxymorphone x 2 = 60 mg of oral hydrocodone daily. The daily dose should then be divided in half for administration every 12 hours. Step 3: Calculate the approximate starting dose which is 30 mg hydrocodone bitartrate extended-release capsules every 12 hours. Round down, if necessary, to the appropriate hydrocodone bitartrate extended-release capsule strengths available. 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 capsules. The dose of hydrocodone bitartrate extended-release capsules can be gradually adjusted preferably at increments of 10 mg every 12 hours every 3 to 7 days, until adequate pain relief and acceptable adverse reactions have been achieved. Conversion from Methadone to Hydrocodone Bitartrate Extended-Release Capsules Close monitoring is of particular importance when converting from methadone to other opioid agonists. The ratio between methadone and other opioid agonists may vary widely as a function of previous dose exposure. Methadone has a long half-life and tends to accumulate in the plasma. Conversion from Transdermal Fentanyl to Hydrocodone Bitartrate Extended-Release Capsules Hydrocodone bitartrate extended-release capsules treatment can be initiated 18 hours following the removal of the transdermal fentanyl patch. Although there has been no systematic assessment of such conversion, a conservative hydrocodone dose, approximately 10 mg every 12 hours of hydrocodone bitartrate extended-release capsules, should be initially substituted for each 25 mcg/hr fentanyl transdermal patch. Follow the patient closely during conversion from transdermal fentanyl to hydrocodone bitartrate extended-release capsules, as there is limited documented experience with this conversion. 2.4 Titration and Maintenance of Therapy Individually titrate hydrocodone bitartrate extended-release capsules to a dose that provides adequate analgesia and minimizes adverse reactions. Continually reevaluate patients receiving hydrocodone bitartrate extended-release capsules to assess the maintenance of pain control, signs and symptoms of opioid withdrawal, and other adverse reactions, as well as to reassess for the development of addiction, abuse, or misuse [see Warnings and Precautions ( 5.1 , 5.14 )] . 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 use of opioid analgesics. Patients who experience breakthrough pain may require a dosage adjustment of hydrocodone bitartrate extended-release capsules, or may need a 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 capsules dosage. Because steady-state plasma concentrations are approximated within 3 days, hydrocodone bitartrate extended-release capsules dosage adjustments, preferably at increments of 10 mg every 12 hours, may be done every 3 to 7 days. If after increasing the dosage, unacceptable opioid-related adverse reactions are observed (including an increase in pain after dosage increase), consider reducing the dosage [see Warnings and Precautions ( 5 )] . Adjust the dosage to obtain an appropriate balance between management of pain and opioid-related adverse reactions. 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. Therefore, initiate therapy with 10 mg every 12 hours and titrate carefully, while monitoring for respiratory depression, sedation, and hypotension. No adjustment in starting dose with hydrocodone bitartrate extended-release capsules is required in patients with mild or moderate hepatic impairment [see Clinical Pharmacology ( 12.3 )] . 2.6 Safe Reduction or Discontinuation of Hydrocodone Bitartrate Extended-Release Capsules Do not abruptly discontinue hydrocodone bitartrate extended-release capsules 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 capsules, there are a variety of factors that should be considered, including the total daily dose of opioid (including hydrocodone bitartrate extended-release capsules) the patient has been taking, the duration of treatment, the type of pain being treated, and the physical and psychological attributes of the patient. It is important to ensure ongoing care of the patient and to agree on an appropriate tapering schedule and follow-up plan so that patient and provider goals and expectations are clear and realistic. When opioid analgesics are being discontinued due to a suspected substance use disorder, evaluate and treat the patient, or refer for evaluation and treatment of the substance use disorder. Treatment should include evidence-based approaches, such as medication assisted treatment of opioid use disorder. Complex patients with co- morbid pain and substance use disorders may benefit from referral to a specialist. There are no standard opioid tapering schedules that are suitable for all patients. Good clinical practice dictates a patient-specific plan to taper the dose of the opioid gradually. For patients on hydrocodone bitartrate extended-release capsules who are physically opioid-dependent, initiate the taper by a small enough increment (e.g., no greater than 10% to 25% of the total daily dose) to avoid withdrawal symptoms, and proceed with dose-lowering at an interval of every 2 to 4 weeks. Patients who have been taking opioids for briefer periods of time may tolerate a more rapid taper. It may be necessary to provide the patient with lower dosage strengths to accomplish a successful taper. Reassess the patient frequently to manage pain and withdrawal symptoms, should they emerge. Common withdrawal symptoms include restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Other signs and symptoms also may develop, including irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate. If withdrawal symptoms arise, it may be necessary to pause the taper for a period of time or raise the dose of the opioid analgesic to the previous dose, and then proceed with a slower taper. In addition, evaluate patients for any changes in mood, emergence of suicidal thoughts, or use of other substances. When managing patients taking opioid analgesics, particularly those who have been treated for an extended period of time, and/or with high doses for chronic pain, ensure that a multimodal approach to pain management, including mental health support (if needed), is in place prior to initiating an opioid analgesic taper. A multimodal approach to pain management may optimize the treatment of chronic pain, as well as assist with the successful tapering of the opioid analgesic [see Warnings and Precautions ( 5.14 ), Drug Abuse and Dependence ( 9.3 )] .

Side Effects Overview

6 ADVERSE REACTIONS The following serious adverse reactions are discussed elsewhere in the labeling: Addiction, Abuse, and Misuse [see Warnings and Precautions ( 5.1 )] Life-Threatening Respiratory Depression [see Warnings and Precautions ( 5.2 )] Risks from Concomitant Use with Benzodiazepines and 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 ( 5.12 )] Seizures [see Warnings and Precautions ( 5.13 )] Withdrawal [see Warnings and Precautions ( 5.14 )] Adverse reactions in ≥2% of patients in placebo-controlled trials include constipation, nausea, somnolence, fatigue, headache, dizziness, dry mouth, vomiting, pruritus, abdominal pain, edema peripheral, upper respiratory tract infection, muscle spasms, urinary tract infection, back pain, and tremor. ( 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 clinical practice. The safety of hydrocodone bitartrate extended-release capsules was evaluated in a total of 1,148 subjects in Phase 3 clinical trials. Table 2 lists the most frequently occurring adverse reactions occurring at a greater frequency than placebo from the placebo-controlled trial in subjects with moderate-to-severe chronic lower back pain. Table 2. Treatment-Emergent Adverse Events in ≥2% of Subjects During the Open-Label Titration Period and/or the Double-Blind Treatment Period, by Preferred Term — Number (%) of Treated Subjects (Placebo-Controlled Study in Opioid-Experienced Subjects with Moderate-to-Severe Chronic Lower Back Pain) Open-Label Titration Period Double-Blind Treatment Period Hydrocodone Bitartrate Extended-Release Capsules Hydrocodone Bitartrate Extended-Release Capsules Placebo Preferred Term (N = 510) (n = 151) (n = 151) Constipation 56 (11%) 12 (8%) 0 (0%) Nausea 50 (10%) 11 (7%) 5 (3%) Somnolence 24 (5%) 1 (1%) 0 (0%) Fatigue 21 (4%) 1 (1%) 2 (1%) Headache 19 (4%) 0 (0%) 2 (1%) Dizziness 17 (3%) 3 (2%) 1 (1%) Dry mouth 16 (3%) 0 (0%) 0 (0%) Vomiting 14 (3%) 7 (5%) 1 (1%) Pruritus 13 (3%) 0 (0%) 0 (0%) Abdominal pain 8 (2%) 4 (3%) 0 (0%) Edema peripheral 7 (1%) 4 (3%) 0 (0%) Upper respiratory tract infection 7 (1%) 5 (3%) 1 (1%) Muscle spasms 6 (1%) 4 (3%) 2 (1%) Urinary tract infection 4 (1%) 8 (5%) 3 (2%) Back pain 4 (1%) 6 (4%) 5 (3%) Tremor 1 (0%) 4 (3%) 1 (1%) The common (≥1% to <10%) adverse drug reactions reported at least once by subjects treated with hydrocodone bitartrate extended-release capsules in the Phase 3 clinical trials and not represented in Table 2 were: Gastrointestinal Disorders: abdominal discomfort, abdominal pain, gastroesophageal reflux disease General Disorders and Administration Site Conditions: non-cardiac chest pain, pain, peripheral edema, pyrexia Injury, Poisoning and Procedural Complications: contusion, fall, foot fracture, joint injury, joint sprain, muscle strain, skin laceration Investigations: increased blood cholesterol, increased gamma-glutamyltransferase Metabolism and Nutrition Disorders: dehydration, hypokalemia Musculoskeletal and Connective Tissue Disorders: arthralgia, musculoskeletal pain, myalgia, neck pain, osteoarthritis, pain in extremity Nervous System Disorders: lethargy, migraine, paresthesia Psychiatric Disorders: anxiety, depression, insomnia Respiratory, Thoracic, and Mediastinal Disorders: cough, dyspnea Skin and Subcutaneous Tissue Disorders: hyperhidrosis, night sweats, rash Vascular Disorders: hot flush 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 capsules. Androgen deficiency: Cases of androgen deficiency have occurred with use of opioids for an extended period of time [see Clinical Pharmacology ( 12.2 )] . Hyperalgesia and Allodynia: Cases of hyperalgesia and allodynia have been reported with opioid therapy of any duration [see Warnings and Precautions ( 5.7 )] . Hypoglycemia: Cases of hypoglycemia have been reported in patients taking opioids. Most reports were in patients with at least one predisposing risk factor (e.g., diabetes).

चेतावनियाँ और सावधानियाँ

5 WARNINGS 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 capsules in patients with circulatory shock. ( 5.10 ) 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 capsules in patients with impaired consciousness or coma. ( 5.11 ) 5.1 Addiction, Abuse, and Misuse Hydrocodone bitartrate extended-release capsules contain hydrocodone, a Schedule II controlled substance. As an opioid, hydrocodone bitartrate extended-release capsules exposes users to the risks of addiction, abuse, and misuse. Because extended-release products such as hydrocodone bitartrate extended-release capsules 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 [see Drug Abuse and Dependence ( 9.1 )] . Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed hydrocodone bitartrate extended-release capsules. 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 capsules, and reassess all patients receiving hydrocodone bitartrate extended-release capsules 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 addiction or abuse) or mental illness (e.g., major depression). The potential for these risks should not, however, prevent the prescribing of hydrocodone bitartrate extended-release capsules for the proper management of pain in any given patient. Patients at increased risk may be prescribed opioids such as hydrocodone bitartrate extended-release capsules, but use in such patients necessitates intensive counseling about the risks and proper use of hydrocodone bitartrate extended-release capsules along with frequent reevaluation for signs of addiction, abuse, and misuse. Consider prescribing naloxone for the emergency treatment of opioid overdose [see Dosage and Administration ( 2.2 ), Warnings and Precautions ( 5.2 )] . Abuse or misuse of hydrocodone bitartrate extended-release capsules 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 [see Drug Abuse and Dependence ( 9.1 ), Overdosage ( 10 )] . 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 capsules. 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 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 [see Overdosage ( 10 )] . 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 capsules, 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 capsules are essential [see Dosage and Administration ( 2.4 )] . Overestimating the hydrocodone bitartrate extended-release capsules dose 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 capsules, 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 [see Patient Counseling Information ( 17 )] . Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the opioid dosage using best practices for opioid taper [see Dosage and Administration ( 2.6 )] . 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 capsules. Inform patients and caregivers about the various ways to obtain naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (e.g., by prescription, directly from a pharmacist, or as part of a community-based program). Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help, even if naloxone is administered [see Patient Counseling Information ( 17 )] . 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 capsules 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 duration 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, educate them on the signs and symptoms of respiratory depression (including sedation). If concomitant use is warranted, consider prescribing naloxone for the emergency treatment of opioid overdose [see Dosage and Administration ( 2.2 ), Warnings and Precautions ( 5.2 )] . Advise both patients and caregivers about the risks of respiratory depression and sedation when hydrocodone bitartrate extended-release capsules is 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 of overdose and death associated with the use of additional CNS depressants including alcohol and illicit drugs [see Drug Interactions ( 7 ) and Patient Counseling Information ( 17 )] . Patients must not consume alcoholic beverages, or prescription or non-prescription products containing alcohol, while on hydrocodone bitartrate extended-release capsules therapy. The co-ingestion of alcohol with hydrocodone bitartrate extended-release capsules may result in increased plasma levels and a potentially fatal overdose of hydrocodone [see Clinical Pharmacology ( 12.3 )] . 5.4 Neonatal Opioid Withdrawal Syndrome Use of hydrocodone bitartrate extended-release capsules 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 [see Use in Specific Populations ( 8.1 ), Patient Counseling Information ( 17 )] . 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 capsules 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 [see Warnings and Precautions ( 5.2 )] , particularly when an inhibitor is added after a stable dose of hydrocodone bitartrate extended-release capsules is achieved. Similarly, discontinuation of a CYP3A4 inducer, such as rifampin, carbamazepine, and phenytoin, in hydrocodone bitartrate extended-release capsule-treated patients may increase hydrocodone plasma concentrations and prolong opioid adverse reactions. When using hydrocodone bitartrate extended-release capsules with CYP3A4 inhibitors or discontinuing CYP3A4 inducers in hydrocodone bitartrate extended-release capsule-treated patients, evaluate patients at frequent intervals and consider dosage reduction of hydrocodone bitartrate extended-release capsules until stable drug effects are achieved [see Drug Interactions ( 7 )] . Concomitant use of hydrocodone bitartrate extended-release capsules 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 capsules with CYP3A4 inducers or discontinuing CYP3A4 inhibitors, monitor patients closely at frequent intervals and consider increasing the opioid dosage if needed to maintain adequate analgesia or if symptoms of opioid withdrawal occur [see Drug Interactions ( 7 )] . 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 [see Dependence ( 9.3 )] . 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) [see Dosage and Administration ( 2.6 ), Warnings and Precautions ( 5.14 )] . 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 capsules 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 capsule-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 capsules. 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. Regularly evaluate patients, particularly when initiating and titrating hydrocodone bitartrate extended-release capsules and when hydrocodone bitartrate extended-release capsules are given concomitantly with other drugs that depress respiration [see Warnings and Precautions ( 5 ), Drug Interactions ( 7 )] . 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 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 opioid as being more likely to be associated with adrenal insufficiency. 5.10 Severe Hypotension Hydrocodone bitartrate extended-release capsules may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients. There is an added 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) [see Drug Interactions ( 7 )] . Regularly evaluate these patients for signs of hypotension after initiating or titrating the dosage of hydrocodone bitartrate extended-release capsules. In patients with circulatory shock, hydrocodone bitartrate extended-release capsules may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of hydrocodone bitartrate extended-release capsules in patients with circulatory shock. 5.11 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 capsules 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 capsules. Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of hydrocodone bitartrate extended-release capsules in patients with impaired consciousness or coma. 5.12 Risks of Use in Patients with Gastrointestinal Conditions Hydrocodone bitartrate extended-release capsules are contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus. Hydrocodone in hydrocodone bitartrate extended-release capsules 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 of symptoms. 5.13 Increased Risk of Seizures in Patients with Seizure Disorders The hydrocodone in hydrocodone bitartrate extended-release capsules may increase the frequency of seizures in patients with seizure disorders, and may increase the risk 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 capsules therapy. 5.14 Withdrawal Do not abruptly discontinue hydrocodone bitartrate extended-release capsules in a patient physically dependent on opioids. When discontinuing hydrocodone bitartrate extended-release capsules in a physically dependent patient, gradually taper the dosage. Rapid tapering of hydrocodone in a patient physically dependent on opioids may lead to a withdrawal syndrome and return of pain [see Dosage and Administration ( 2.6 ), Drug Abuse and Dependence ( 9.3 )] . Additionally, avoid the use of mixed agonist/antagonist (e.g., pentazocine, nalbuphine, and butorphanol) or partial agonist (e.g., buprenorphine) analgesics in patients who are receiving a full opioid agonist analgesic, including hydrocodone bitartrate extended-release capsules. In these patients, mixed agonist/antagonist and partial agonist analgesics may reduce the analgesic effect and/or may precipitate withdrawal symptoms [see Drug Interactions ( 7 )] . 5.15 Risks of Driving and Operating Machinery Hydrocodone bitartrate extended-release capsules may impair the mental and physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery. Warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects of hydrocodone bitartrate extended-release capsules and know how they will react to the medication [see Clinical Pharmacology ( 12.3 ), Patient Counseling Information ( 17 )] .

प्रतिनिर्देश

4 CONTRAINDICATIONS Hydrocodone bitartrate extended-release capsules are contraindicated in patients with: Significant respiratory depression [see Warnings and Precautions ( 5.2 )] Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment [see Warnings and Precautions ( 5.8 )] Known or suspected gastrointestinal obstruction, including paralytic ileus [see Warnings and Precautions ( 5.12 )] Hypersensitivity (e.g., anaphylaxis) to hydrocodone or any other ingredients in hydrocodone bitartrate extended-release capsules Significant respiratory depression ( 4 ) Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment ( 4 ) Known or suspected gastrointestinal obstruction, including paralytic ileus ( 4 ) Hypersensitivity to hydrocodone or to any other components of hydrocodone bitartrate extended-release capsules ( 4 )

फार्माकोकाइनेटिक्स

12.3 Pharmacokinetics Absorption As compared to immediate-release hydrocodone combination products, hydrocodone bitartrate extended-release capsules at similar daily doses results in similar overall exposure but with lower maximum concentrations. The half-life is also longer due to the prolonged duration of absorption. Based on the half-life of hydrocodone, steady-state should be obtained after 3 days of dosing. Following 7 days of dosing, AUC and C max increase approximately two-fold as compared to the first day of dosing. The pharmacokinetics of hydrocodone bitartrate extended-release capsules have been shown to be independent of dose up to a dose of 50 mg. Hydrocodone bitartrate extended-release capsules exhibit peak plasma concentrations approximately 5 hours after dose administration. Food Effects Food has no significant effect on the extent of absorption of hydrocodone from hydrocodone bitartrate extended-release capsules. Although there was no evidence of dose dumping associated with this formulation under fasted and fed conditions, peak plasma concentration of hydrocodone increased by 27% when a hydrocodone bitartrate extended-release 20 mg capsule was administered with a high-fat meal. Distribution Although the extent of protein binding of hydrocodone in human plasma has not been definitively determined, structural similarities to related opioid analgesics suggest that hydrocodone is not extensively protein bound. As most agents in the 5-ring morphinan group of semi-synthetic opioids bind plasma protein to a similar degree (range 19% [hydromorphone] to 45% [oxycodone]), hydrocodone is expected to fall within this range. Elimination Metabolism Hydrocodone exhibits a complex pattern of metabolism, including N-demethylation, O-demethylation, and 6-keto reduction to the corresponding 6-α-and 6-β-hydroxy metabolites. CYP3A4 mediated N-demethylation to norhydrocodone is the primary metabolic pathway of hydrocodone with a lower contribution from CYP2D6 mediated O-demethylation to hydromorphone. Hydromorphone is formed from the O-demethylation of hydrocodone and may contribute to the total analgesic effect of hydrocodone. Therefore, the formation of these and related metabolites can, in theory, be affected by other drugs [see Drug Interactions ( 7 )] . Published in vitro studies have shown that N-demethylation of hydrocodone to form norhydrocodone can be attributed to CYP3A4 while O-demethylation of hydrocodone to hydromorphone is predominantly catalyzed by CYP2D6 and to a lesser extent by an unknown low affinity CYP enzyme. Excretion Hydrocodone and its metabolites are eliminated primarily in the kidneys, with a mean apparent plasma half-life after hydrocodone bitartrate extended-release capsules administration of approximately 8 hours. Special Populations Age: Geriatric Patients No significant pharmacokinetic differences by age were observed based on population pharmacokinetic analysis. Sex: No significant pharmacokinetic differences by sex were observed based on population pharmacokinetic analysis. Hepatic Impairment After a single dose of 20 mg hydrocodone bitartrate extended-release capsules in 20 patients with mild to moderate hepatic impairment based on Child-Pugh classifications, mean hydrocodone C max values were 25 ± 5 ng/mL, 24 ± 5 ng/mL, and 22 ± 3.3 ng/mL for moderate and mild impairment, and normal subjects, respectively. Mean hydrocodone AUC values were 509 ± 157 ng∙h/mL, 440 ± 124 ng∙h/mL, and 391 ± 74 ng∙h/mL for moderate and mild impairment, and normal subjects, respectively. Hydrocodone C max values were 8% to 10% higher in patients with mild or moderate hepatic impairment, respectively, while AUC values were 10% and 26% higher in patients with mild and moderate hepatic impairment, respectively. Severely impaired subjects were not studied [see Use in Specific Populations ( 8.6 )]. Renal Impairment After a single dose of 20 mg hydrocodone bitartrate extended-release capsules in 28 patients with mild, moderate, or severe renal impairment based on Cockcroft-Gault criteria, mean hydrocodone C max values were 26 ± 6.0 ng/mL, 28 ± 7.5 ng/mL, 21 ± 5.1 ng/mL and 19 ± 4.4 ng/mL for severe, moderate, mild renal impairment, and normal subjects, respectively. Mean hydrocodone AUC values were 487 ± 123 ng∙h/mL, 547 ± 184 ng∙h/mL, 391 ± 122 ng∙h/mL and 343 ± 105 ng∙h/mL for severe, moderate, mild renal impairment, and normal subjects, respectively. Hydrocodone C max values were 15%, 48%, and 41% higher and AUC values were 15%, 57% and 44% higher in patients with mild, moderate, and severe renal impairment, respectively [see Use in Specific Populations ( 8.7 )]. Drug Interaction Studies Interactions with Alcohol The rate of absorption of hydrocodone bitartrate extended-release capsules 50 mg was affected by co-administration with 40% alcohol in the fasted state, as exhibited by an increase in peak hydrocodone concentrations (on average 2.4-fold increase with maximum increase of 3.9-fold in one subject) and a decrease in the time to peak concentrations. The extent of absorption was increased on average 1.2-fold with maximum increase of 1.7-fold in one subject with 40% alcohol [see Warnings and Precautions ( 5.3 )] . Cytochrome P450 Enzymes While comprehensive PK drug-drug interaction studies (other than alcohol) have not been performed in humans receiving hydrocodone, published in vitro and human PK studies indicate that conversion of hydrocodone to its primary metabolite, norhydrocodone and lesser metabolite, hydromorphone, is mediated by the cytochrome P450 enzyme system. N-demethylation of hydrocodone to form norhydrocodone is attributed to CYP3A4 and O-demethylation of hydrocodone to hydromorphone is predominantly catalyzed by CYP2D6 and to a lesser extent by an unknown low affinity CYP enzyme. CYP3A4 Inhibitors and Inducers An increase in CYP3A4 activity by initiation of CYP3A4 inhibiting drugs or discontinuation of CYP3A4 inducing drugs could alter the metabolic profile of hydrocodone causing a slowing of hydrocodone clearance, and lead to elevated hydrocodone concentrations and effects, which could be more pronounced with concomitant use of cytochrome P450 CYP3A4 inhibitors. Initiation of a CYP3A4 inducing drug can lower hydrocodone plasma levels and may induce an opioid-withdrawal syndrome [see Warnings and Precautions ( 5.6 ) and Drug Interactions ( 7 )] .

Frequently Asked Questions

1 INDICATIONS 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 …

2 DOSAGE AND ADMINISTRATION Hydrocodone bitartrate extended-release capsules 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 capsules, a single dose greater than 40 mg, or a total daily dose greater than 80 mg are only for use in patients in whom tolerance to an opioid of comparable potency has been established. ( 2.1 ) Patients considered …

5 WARNINGS 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, …

4 CONTRAINDICATIONS Hydrocodone bitartrate extended-release capsules are contraindicated in patients with: Significant respiratory depression [see Warnings and Precautions ( 5.2 )] Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment [see Warnings and Precautions ( 5.8 )] Known or suspected gastrointestinal obstruction, including paralytic ileus [see Warnings and Precautions ( 5.12 )] Hypersensitivity (e.g., anaphylaxis) to hydrocodone or any other ingredients in hydrocodone bitartrate extended-release capsules Significant respiratory depression ( 4 ) Acute …

Hydrocodone Bitartrate is a prescription medication. You will need a valid prescription from a licensed healthcare provider.

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References & Data Sources

• DailyMed — Hydrocodone Bitartrate drug label (National Library of Medicine)
• openFDA — Hydrocodone Bitartrate label data (U.S. Food & Drug Administration)
• RxNorm — RXCUI 1860491 (NLM Normalized Drug Names)
• NDC Directory — Hydrocodone Bitartrate (FDA National Drug Code)

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डेटा स्रोत: DailyMed (NLM), openFDA, MFDS