Hydrocodone Bitartrate and Ibuprofen

INDICATIONS AND USAGE Hydrocodone Bitartrate and Ibuprofen Tablets are indicated for the short-term management of acute pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate. Limitations of Use Carefully consider the potential benefits and risks of Hydrocodone Bitartrate and Ibuprofen Tablets and other treatment options before deciding to use Hydrocodone Bitartrate and Ibuprofen Tablets Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals (see WARNINGS: Cardiovascular Thrombotic Events, Gastrointestinal Bleeding, Ulceration, and Perforation ). Do not use Hydrocodone Bitartrate and Ibuprofen Tablets for the treatment of conditions such as osteoarthritis or rheumatoid arthritis. Because of the risks of addiction, abuse, misuse, overdose and death, which can occur at any dosage or duration and persist over the course of therapy (see WARNINGS ), reserve opioid analgesics, including Hydrocodone Bitartrate and Ibuprofen Tablets for use in patients for whom alternative treatment options are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.

DOSAGE AND ADMINISTRATION Hydrocodone Bitartrate and Ibuprofen Tablets should be prescribed only by healthcare professionals who are knowledgeable about the use of opioids and how to mitigate the associated risks. Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals [see Warnings]. Because the risk of overdose increases as opioid doses increase, reserve titration to higher doses of Hydrocodone Bitartrate and Ibuprofen 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. Many acute pain conditions (e.g., the pain that occurs with a number of surgical procedures or acute musculoskeletal injuries) require no more than a few days of an opioid analgesic. Clinical guidelines on opioid prescribing for some acute pain conditions are available. There is variability in the opioid analgesic dose and duration needed to adequately manage pain due both to the cause of pain and to individual patient factors. 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]. Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with Hydrocodone Bitartrate and Ibuprofen Tablets. Consider this risk when selecting an initial dose and when making dose adjustments [see Warnings]. 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. The presence of risk factors for overdose should not prevent the management of pain in any patient [see WARNINGS; Addiction, Abuse, and Misuse; Life-Threatening Respiratory Depression; Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants]. Discuss the options for obtaining an opioid overdose reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program). There are important differences among the opioid overdose reversal agents, such as route of administration, product strength, approved patient age range, and pharmacokinetics. Be familiar with these differences, as outlined in the approved labeling for those products, prior to recommending or prescribing such an agent. Initial Dosage Use of Hydrocodone Bitartrate and Ibuprofen Tablets as the First Opioid Analgesic Initiate treatment with Hydrocodone Bitartrate and Ibuprofen Tablets at a dose of one tablet every 4 to 6 hours as needed for pain, at the lowest dose necessary to achieve adequate analgesia. Titrate the dose based upon the individual patient’s response to their initial dose of Hydrocodone Bitartrate and Ibuprofen Tablets. Dosage should not exceed 5 tablets in a 24-hour period. The lowest effective dose or the longest dosing interval should be sought for each patient (see WARNINGS), especially in the elderly. After observing the initial response to therapy with hydrocodone bitartrate and ibuprofen tablets, the dose and frequency of dosing should be adjusted to suit the individual patient's need, without exceeding the total daily dose recommended. Titration and Maintenance of Therapy Individually titrate Hydrocodone Bitartrate and Ibuprofen Tablets to a dose that provides adequate analgesia and minimizes adverse reactions. Continually reevaluate patients receiving Hydrocodone Bitartrate …

WARNINGS Hydrocodone Component Addiction, Abuse, and Misuse Hydrocodone Bitartrate and Ibuprofen Tablets contains hydrocodone, a Schedule II controlled substance. As an opioid- containing product, Hydrocodone Bitartrate and Ibuprofen Tablets exposes users to the risks of addiction, abuse, and misuse (see DRUG ABUSE AND DEPENDENCE). Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed Hydrocodone Bitartrate and Ibuprofen Tablets. Addiction can occur at recommended dosages and if the drug is misused or abused.The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. In post-marketing studies, addiction, abuse, misuse, and fatal and non-fatal opioid overdose were observed in patients with long-term opioid use [ADVERSE REACTIONS]. Assess each patient’s risk for opioid addiction, abuse, or misuse prior to prescribing Hydrocodone Bitartrate and Ibuprofen Tablets, and reassess all patients receiving Hydrocodone Bitartrate and Ibuprofen 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 proper management of pain in any given patient. Patients at increased risk may be prescribed opioid such as Hydrocodone Bitartrate and Ibuprofen Tablets, but use in such patients necessitates intensive counseling about the risks and proper use of Hydrocodone Bitartrate and Ibuprofen Tablets along with frequent reevaluation for signs of addiction, abuse, and misuse. Consider recommending or prescribing an opioid overdose reversal agent (WARNINGS, DOSAGE AND ADMINISTRATION. Opioids are sought for nonmedical use and are subject to diversion from legitimate prescribed use. Consider these risks when prescribing or dispensing Hydrocodone Bitartrate and Ibuprofen Tablets. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient 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. 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 overdose reversal agents, depending on the patient’s clinical status (see OVERDOSAGE). Carbon dioxide (CO2) 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 and Ibuprofen 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 and Ibuprofen Tablets are essential (see DOSAGE AND ADMINISTRATION). Overestimating the Hydrocodone Bitartrate and Ibuprofen Tablets dosage when converting patients from another opioid product can result in a fatal overdose with the first dose. Accidental ingestion of even one dose of Hydrocodone Bitartrate and Ibuprofen Tablets, especially by children, can result in respiratory depression and death due to an overdose of Hydrocodone Bitartrate and Ibuprofen Tablets. Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting eme…

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 ).

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 mu…

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, ca…

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

ADVERSE REACTIONS The following adverse reactions are described below and elsewhere in the labeling including the WARNINGS section. Addiction, Abuse, and Misuse Life-Threatening Respiratory Depression Neonatal Opioid Withdrawal Syndrome Interactions with Cytochrome P450 3A4 Inhibitors and Inducers Interactions with Benzodiazepines or Other CNS Depressants Adrenal Insufficiency Severe Hypotension Seizures Withdrawal Cardiovascular Thrombotic Events Gastrointestinal Bleeding, Ulceration, and Perforation Hepatotoxicity Hypertension Heart Failure and Edema Renal Toxicity and Hyperkalemia Anaphylactic Reactions Exacerbation of Asthma Related to Aspirin Sensitivity Serious Skin Reactions Premature Closure of Fetal Ductus Arteriosus Hematologic Toxicity Aseptic Meningitis Opioid-Induced Hyperalgesia and Allodynia [See Warnings] Clinical Trials 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. Hydrocodone bitartrate and ibuprofen tablets were administered to approximately 300 pain patients in a safety study that employed dosages and a duration of treatment sufficient to encompass the recommended usage (see DOSAGE AND ADMINISTRATION ). Adverse event rates generally increased with increasing daily dose. The event rates reported below are from approximately 150 patients who were in a group that received one tablet of hydrocodone bitartrate and ibuprofen tablets an average of three to four times daily. The overall incidence rates of adverse experiences in the trials were fairly similar for this patient group and those who received the comparison treatment, acetaminophen 600 mg with codeine 60 mg. The following lists adverse events that occurred with an incidence of 1% or greater in clinical trials of Hydrocodone Bitartrate and Ibuprofen Tablets, without regard to the causal relationship of the events to the drug. To distinguish different rates of occurrence in clinical studies, the adverse events are listed as follows: name of adverse event = less than 3% adverse events marked with an asterisk * = 3% to 9% adverse event rates over 9% are in parentheses. Body as a Whole Abdominal pain*; Asthenia*; Fever; Flu syndrome; Headache (27%); Infection*; Pain. Cardiovascular Palpitations; Vasodilation. Central Nervous System Anxiety*; Confusion; Dizziness (14%); Hypertonia; Insomnia*; Nervousness*; Paresthesia; Somnolence (22%); Thinking abnormalities. Digestive Anorexia; Constipation (22%); Diarrhea*; Dry mouth*; Dyspepsia (12%); Flatulence*; Gastritis; Melena; Mouth ulcers; Nausea (21%); Thirst; Vomiting*. Metabolic and Nutritional Disorders Edema*. Respiratory Dyspnea; Hiccups; Pharyngitis; Rhinitis. Skin and Appendages Pruritus*; Sweating*. Special Senses Tinnitus. Urogenital Urinary frequency. Incidence less than 1% Body as a Whole Allergic reaction. Cardiovascular Arrhythmia; Hypotension; Tachycardia. Central Nervous System Agitation; Abnormal dreams; Decreased libido; Depression; Euphoria; Mood changes; Neuralgia; Slurred speech; Tremor, Vertigo. Digestive Chalky stool; "Clenching teeth"; Dysphagia; Esophageal spasm; Esophagitis; Gastroenteritis; Glossitis; Liver enzyme elevation. Metabolic and Nutritional Weight decrease. Musculoskeletal Arthralgia; Myalgia. Respiratory Asthma; Bronchitis; Hoarseness; Increased cough; Pulmonary congestion; Pneumonia; Shallow breathing; Sinusitis. Skin and Appendages Rash; Urticaria. Special Senses Altered vision; Bad taste; Dry eyes. Urogenital Cystitis; Glycosuria; Impotence; Urinary incontinence; Urinary retention. Post marketing 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 es…