Hydromet

1 INDICATIONS AND USAGE Hydrocodone bitartrate and homatropine methylbromide oral solution is indicated for the symptomatic relief of cough in adult patients 18 years of age and older. Limitations of Use: Not indicated for pediatric patients under 18 years of age [see Use in Specific Populations ( 8.4 )] . Contraindicated in pediatric patients less than 6 years of age [see Contraindications ( 4 )] . 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 and Precautions ( 5.1 )] , reserve hydrocodone bitartrate and homatropine methylbromide oral solution for use in adult patients for whom alternative treatment options are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of cough. Hydrocodone bitartrate and homatropine methylbromide oral solution is a combination of hydrocodone, an opioid agonist; and homatropine, a muscarinic antagonist, indicated for the symptomatic relief of cough in adult patients 18 years of age and older. ( 1 ) Limitations of Use Not indicated for pediatric patients under 18 years of age. ( 1 ) 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, reserve hydrocodone bitartrate and homatropine methylbromide oral solution for use in adult patients for whom alternative treatment options are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of cough. ( 1 , 5.1 )

2 DOSAGE AND ADMINISTRATION A du l ts 18 years of age and older: 5 mL of the oral solution every 4 to 6 hours as needed; not to exceed 30 mL in 24 hours. ( 2.2 ) Measure hydrocodone bitartrate and homatropine methylbromide oral solution with an accurate milliliter measuring device. ( 2.1 , 5.5 ) Do not increase the dose or dosing frequency. ( 2.1) Prescribe for the shortest duration consistent with treatment goals. ( 2.3 ) Reevaluate patients with unresponsive cough in 5 days or sooner for possible underlying pathology. ( 2.3 ) Reevaluate patient prior to refilling. ( 2.3 ) Do not rapidly reduce or abruptly discontinue in a physically-dependent patient. ( 2.3 ) 2.1 Important Dosage and Administration Instructions Administer hydrocodone bitartrate and homatropine methylbromide oral solution by the oral route only. Always use an accurate milliliter measuring device when administering hydrocodone bitartrate and homatropine methylbromide oral solution to ensure that the dose is measured and administered accurately. A household teaspoon is not an accurate measuring device and could lead to overdosage [see Warnings and Precautions ( 5.5 )] . For prescriptions where a measuring device is not provided, a pharmacist can provide an appropriate measuring device and can provide instructions for measuring the correct dose. Do not overfill. Rinse the measuring device with water after each use. Advise patients not to increase the dose or dosing frequency of hydrocodone bitartrate and homatropine methylbromide oral solution because serious adverse events such as respiratory depression may occur with overdosage [see Warnings and Precautions ( 5.2 ), Overdosage ( 10 )] . The dosage of hydrocodone bitartrate and homatropine methylbromide oral solution should not be increased if cough fails to respond; an unresponsive cough should be reevaluated for possible underlying pathology [see Dosage and Administration ( 2.3 ), Warnings and Precautions ( 5.4 )] . 2.2 Recommended Dosage Adults 18 years of age and older: 5 mL of the oral solution every 4 to 6 hours as needed; not to exceed 30 mL in 24 hours. 2.3 Monitoring, Maintenance, and Discontinuation of Therapy Prescribe hydrocodone bitartrate and homatropine methylbromide oral solution for the shortest duration that is consistent with individual patient treatment goals [see Warnings and Precautions ( 5.1 )] . Monitor patients closely for respiratory depression, especially within the first 24 to 72 hours of initiating therapy [see Warnings and Precautions ( 5.2 )] . Reevaluate patients with unresponsive cough in 5 days or sooner for possible underlying pathology, such as foreign body or lower respiratory tract disease [see Warnings and Precautions ( 5.4 )] . If a patient requires a refill, reevaluate the cause of the cough and assess the need for continued treatment with hydrocodone bitartrate and homatropine methylbromide oral solution, the relative incidence of adverse reactions, and the development of addiction, abuse, or misuse [see Warnings and Precautions ( 5.1) ] . Do not rapidly reduce or abruptly discontinue hydrocodone bitartrate and homatropine methylbromide oral solution in a physically-dependent patient [see Drug Abuse and Dependence ( 9.3 )] . When a patient who has been taking hydrocodone bitartrate and homatropine methylbromide oral solution regularly and may be physically dependent no longer requires therapy with hydrocodone bitartrate and homatropine methylbromide oral solution, taper the dose gradually, by 25% to 50% every 2 to 4 days, while monitoring carefully for signs and symptoms of withdrawal. If the patient develops these signs or symptoms, raise the dose to the previous level and taper more slowly, either by increasing the interval between decreases, decreasing the amount of change in dose, or both.

5 WARNINGS AND PRECAUTIONS L ife-threatening respiratory depression in patients with chronic pulmonary disease or in elderly, cachectic, or debilitated patients : Monitor closely, particularly during initiation of therapy. ( 5.4 ) A ctivities requiring mental alertness : Avoid engaging in hazardous tasks requiring mental alertness such as driving or operating machinery. ( 5.6 ) Risks of use in patients with head injury, impaired consciousness, increased intracranial pressure, or brain tumors : Avoid use. May increase intracranial pressure and obscure the clinical course of head injuries. ( 5.10 ) S e izures in patients with seizure disorders : Monitor during therapy. ( 5.11 ) S e v e r e hypotension : Monitor during initiation of therapy. Avoid use in patients with circulatory shock. ( 5.12 ) A d r e n al insufficiency : If diagnosed, treat with physiologic replacement of corticosteroids, and wean patient off of the opioid. ( 5.14) 5.1 Addiction, Abuse, and Misuse Hydrocodone bitartrate and homatropine methylbromide oral solution contains hydrocodone, a Schedule II controlled substance. As an opioid, hydrocodone bitartrate and homatropine methylbromide oral solution exposes users to the risks of addiction, abuse, and misuse [see Drug Abuse and Dependence ( 9 )], which can lead to overdose and death [see Overdosage ( 10 )]. Reserve hydrocodone bitartrate and homatropine methylbromide oral solution for use in adult patients for whom the benefits of cough suppression are expected to outweigh the risks, and in whom an adequate assessment of the etiology of the cough has been made. Assess each patient’s risk prior to prescribing hydrocodone bitartrate and homatropine methylbromide oral solution, prescribe hydrocodone bitartrate and homatropine methylbromide oral solution for the shortest duration that is consistent with individual patient treatment goals , monitor all patients regularly for the development of addiction or abuse, and refill only after reevaluation of the need for continued treatment. Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed hydrocodone bitartrate and homatropine methylbromide oral solution. Addiction can occur at recommended dosages and if the drug is misused or abused. T he 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 postmarketing studies, addiction, abuse, misuse, and fatal and non-fatal opioid overdose were observed in patients with long-term opioid use [see Adverse Reactions ( 6 )]. 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). Opioids are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Consider these risks when prescribing or dispensing hydrocodone bitartrate and homatropine methylbromide oral solution. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on the proper disposal of unused drug [see Patient Counseling Information ( 17 )] . 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, including hydrocodone, one of the active ingredients in hydrocodone bitartrate and homatropine methylbromide oral solution. Hydrocodone produces dose-related respiratory depression by directly acting on the brain stem respiratory center that controls respiratory rhythm and may produce irregular and periodic breathing. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respirat…

4 CONTRAINDICATIONS Hydrocodone bitartrate and homatropine methylbromide oral solution is contraindicated for: All pediatric patients younger than 6 years of age [see Warnings and Precautions ( 5.2 , 5.3 ), Use in Specific Populations ( 8.4 )]. 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 ( 5.4 )] . Known or suspected gastrointestinal obstruction, including paralytic ileus [see Warnings and Precautions ( 5.9 )] . Hypersensitivity to hydrocodone, homatropine, or any of the inactive ingredients in hydrocodone bitartrate and homatropine methylbromide oral solution [see Adverse Reactions ( 6 )] . Children younger than 6 years of age. ( 4 ) Significant respiratory depression. ( 4 ) Acute or severe bronchial asthma in an unmonitored setting or in absence of resuscitative equipment. ( 4 ) Known or suspected gastrointestinal obstruction, including paralytic ileus. ( 4 ) Hypersensitivity to hydrocodone, homatropine, or any of the inactive ingredients in hydrocodone bitartrate and homatropine methylbromide oral solution. ( 4 )

7 DRUG INTERACTIONS No specific drug interaction studies have been conducted with hydrocodone bitartrate and homatropine methylbromide oral solution. Serotonergic Drugs : Concomitant use may result in serotonin syndrome. Discontinue if serotonin syndrome is suspected. ( 7.5 ) Monoamine Oxidase Inhibitors (MAOIs) : Can potentiate the effects of hydrocodone. Avoid concomitant use in patients receiving MAOIs or within 14 days of stopping an MAOI. ( 7.6 ) Mu s cle Relaxants : Avoid concomitant use. (7.7 ) D iuretics : Hydrocodone may reduce the efficacy of diuretics. Monitor for reduced effect. (7.8 ) A n ticholinergic drugs : Concurrent use may cause paralytic ileus. ( 5.9 , 7.9 ) 7.1 Alcohol Concomitant use of alcohol with hydrocodone bitartrate and homatropine methylbromide oral solution can result in an increase of hydrocodone plasma levels and potentially fatal overdose of hydrocodone. Instruct patients not to consume alcoholic beverages or use prescription or nonprescription products containing alcohol while on hydrocodone bitartrate and homatropine methylbromide oral solution therapy [see Warnings and Precautions ( 5.8 ), Clinical Pharmacology ( 12.3 )] . 7.2 Inhibitors of CYP3A4 and CYP2D6 The concomitant use of hydrocodone bitartrate and homatropine methylbromide oral solution and CYP3A4 inhibitors, such as macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), or 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 homatropine methylbromide oral solution and CYP2D6 and CYP3A4 inhibitors, particularly when an inhibitor is added after a stable dose of hydrocodone bitartrate and homatropine methylbromide is achieved [see Warnings and Precautions ( 5.7 )] . After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the hydrocodone plasma concentration will decrease [see Clinical Pharmacology ( 12.3 )] , resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to hydrocodone. Avoid the use of hydrocodone bitartrate and homatropine methylbromide oral solution while taking a CYP3A4 or CYP2D6 inhibitor. If concomitant use is necessary, monitor patients for respiratory depression and sedation at frequent intervals. 7.3 CYP3A4 Inducers The concomitant use of hydrocodone bitartrate and homatropine methylbromide oral solution and CYP3A4 inducers such as rifampin, carbamazepine, or phenytoin, can decrease the plasma concentration of hydrocodone [see Clinical Pharmacology ( 12.3) ] , resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to hydrocodone [see Warnings and Precautions ( 5.7 )] . After stopping a CYP3A4 inducer, as the effects of the inducer decline, the hydrocodone plasma concentration will increase [see Clinical Pharmacology ( 12.3)] , which could increase or prolong both the therapeutic effects and adverse reactions, and may cause serious respiratory depression. Avoid the use of hydrocodone bitartrate and homatropine methylbromide oral solution in patients who are taking CYP3A4 inducers. If concomitant use of a CYP3A4 inducer is necessary, follow the patient for reduced efficacy. 7.4 Benzodiazepines, and Other CNS Depressants Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, gabapentinoids (gabapentin or pregabalin), and other opioids, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death. Avoid the use of hydrocodone bitartrate and homatropine methylbromide oral solution in patients who are taking benzodiazepines, gabapentinoids, or other CNS depressa…

8.1 Pregnancy Risk Summary Hydrocodone bitartrate and homatropine methylbromide oral solution is not recommended for use in pregnant women, including during or immediately prior to labor. Prolonged use of opioids during pregnancy may cause neonatal opioid withdrawal syndrome [see Warnings and Precautions ( 5.13 ), Clinical Considerations] . There are no available data with hydrocodone bitartrate and homatropine methylbromide oral solution use in pregnant women to inform a drug-associated risk for adverse developmental outcomes. Published studies with hydrocodone have reported inconsistent findings and have important methodological limitations (see Data) . Reproductive toxicity studies have not been conducted with hydrocodone bitartrate and homatropine methylbromide oral solution; however, studies are available with individual active ingredients or related active ingredients (see Data) . In animal reproduction studies, hydrocodone administered by the subcutaneous route to pregnant hamsters during the period of organogenesis produced a teratogenic effect at a dose approximately 45 times the maximum recommended human dose (MRHD) (see Data) . Based on the animal data, advise pregnant women of the potential risk to a fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Prolonged use of opioid analgesics during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth. Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea and failure to gain weight. The onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination of the drug by the newborn. Observe newborns for symptoms of neonatal opioid withdrawal syndrome and manage accordingly [see Warnings and Precautions ( 5.13 )]. Labor or Delivery Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. An opioid overdose reversal agent, such as naloxone or nalmefene, must be available for reversal of opioid-induced respiratory depression in the neonate. Opioids, including hydrocodone bitartrate and homatropine methylbromide, can prolong labor through actions which temporarily reduce the strength, duration, and frequency of uterine contractions. However, this effect is not consistent and may be offset by an increased rate of cervical dilation, which tends to shorten labor. Monitor neonates exposed to opioids during labor for signs of excess sedation and respiratory depression. Data Human Data Hydrocodone A limited number of pregnancies have been reported in published observational studies and postmarketing reports describing hydrocodone use during pregnancy. However, these data cannot definitely establish or exclude any drug-associated risk during pregnancy. Methodological limitations of these observational studies include small sample size and lack of details regarding dose, duration and timing of exposure. Animal Data Reproductive toxicity studies have not been conducted with hydrocodone bitartrate and homatropine methylbromide; however, studies are available with individual active ingredients or related active ingredients. H y d r ocodone In an embryofetal development study in pregnant hamsters dosed on gestation day 8 during the period of organogenesis, hydrocodone induced cranioschisis, a malformation, at approximately 45 times the MRHD (on…

8.3 Females and Males of Reproductive Potential Infertility Chronic use of opioids, such as hydrocodone, a component of hydrocodone bitartrate and homatropine methylbromide oral solution, may cause reduced fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible [see Adverse Reactions ( 6 ), Clinical Pharmacology ( 12.2 )] .

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in labeling: Addiction, abuse, and misuse [see Warnings and Precautions ( 5.1 ), Drug Abuse and Dependence ( 9.3)] Life-threatening respiratory depression [see Warnings and Precautions ( 5.2 , 5.3 , 5.4 , 5.8 ), Overdosage ( 10 )] Accidental overdose and death due to medication errors [see Warnings and Precautions ( 5.5 )] Decreased mental alertness with impaired mental and/or physical abilities [see Warnings and Precautions ( 5.6 )] Interactions with benzodiazepines and other CNS depressants [see Warnings and Precautions ( 5.8 ), Drug Interactions ( 7.1 , 7.4 )] Paralytic ileus, gastrointestinal adverse reactions [see Warnings and Precautions ( 5.9 )] Increased intracranial pressure [see Warnings and Precautions ( 5.10) ] Obscured clinical course in patients with head injuries [see Warnings and Precautions ( 5.10 )] Seizures [see Warnings and Precautions ( 5.11 )] Severe hypotension [see Warnings and Precautions ( 5.12 )] Neonatal Opioid Withdrawal Syndrome [see Warnings and Precautions ( 5.13 )] Adrenal insufficiency [see Warnings and Precautions ( 5.14) ] The following adverse reactions have been identified during clinical studies, in the literature, or during post-approval use of hydrocodone and/or homatropine. Because these reactions may be 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. The most common adverse reactions to hydrocodone bitartrate and homatropine methylbromide oral solution include: Sedation (somnolence, mental clouding, lethargy), impaired mental and physical performance, lightheadedness, dizziness, headache, dry mouth, nausea, vomiting, and constipation. Other reactions include: Anaphylaxis : Anaphylaxis has been reported with hydrocodone, one of the ingredients in hydrocodone bitartrate and homatropine methylbromide oral solution. Body as a whole : Coma, death, fatigue, falling injuries, lethargy. Cardiovascular : Peripheral edema, increased blood pressure, decreased blood pressure, tachycardia, chest pain, palpitation, syncope, orthostatic hypotension, prolonged QT interval, hot flush. Central Nervous System : Facial dyskinesia, insomnia, migraine, increased intracranial pressure, seizure, tremor. Dermatologic : Flushing, hyperhidrosis, pruritus, rash. Endocrine/Metabolic : Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of opioids with serotonergic drugs. Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Cases of androgen deficiency have occurred with chronic use of opioids. Gastrointestinal : Abdominal pain, bowel obstruction, decreased appetite, diarrhea, difficulty swallowing, dry mouth, GERD, indigestion, pancreatitis, paralytic ileus, biliary tract spasm (spasm of the sphincter of Oddi). Genitourinary : Urinary tract infection, ureteral spasm, spasm of vesicle sphincters, urinary retention. Laboratory : Increases in serum amylase. Musculoskeletal : Arthralgia, backache, muscle spasm. Ophthalmic : Miosis (constricted pupils), visual disturbances. Psychiatric : Agitation, anxiety, confusion, fear, dysphoria, depression. Reproductive : Hypogonadism, infertility. Respiratory : Bronchitis, cough, dyspnea, nasal congestion, nasopharyngitis, respiratory depression, sinusitis, upper respiratory tract infection. Other : Drug abuse, drug dependence, opioid withdrawal syndrome. 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). Opioid-induced esophageal dysfunction (OIED) : Cases of OIED have been reported in patients taking opioids and may occur more frequently in patients taking higher doses of opioids, and/or in patients taking op…