Hydrocodone Bitartrate and Homatropine Methylbromide

1 INDICATIONS AND USAGE Hydrocodone Bitartrate and Homatropine Methylbromide Oral Solution (Syrup) are 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, and misuse with opioids, even at recommended doses [see Warnings and Precautions ( 5.1 )], reserve Hydrocodone Bitartrate and Homatropine Methylbromide Oral Solution (Syrup) 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. Hydrocodone Bitartrate and Homatropine Methylbromide Oral Solution (Syrup) 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 ( 1 ) Not indicated for pediatric patients under 18 years of age. Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses, reserve Hydrocodone Bitartrate and Homatropine Methylbromide Oral Solution (Syrup) 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.

2 DOSAGE AND ADMINISTRATION 2.1 Important Dosage and Administration Instructions Administer Hydrocodone Bitartrate and Homatropine Methylbromide Oral Solution (Syrup) by the oral route only. Always use an accurate milliliter measuring device when administering Hydrocodone Bitartrate and Homatropine Methylbromide Oral Solution (Syrup) 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 (Syrup) 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 (Syrup) 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 (Syrup) 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 (Syrup) 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 24-72 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 (Syrup), the relative incidence of adverse reactions, and the development of addiction, abuse, or misuse [ see Warnings and Precautions ( 5.1 ) ]. Do not abruptly discontinue Hydrocodone Bitartrate and Homatropine Methylbromide Oral Solution (Syrup) 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 (Syrup) regularly and may be physically dependent no longer requires therapy with Hydrocodone Bitartrate and Homatropine Methylbromide Oral Solution (Syrup), 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. Adults 18 years of age and older : 5 mL Oral Solution (Syrup) 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 (Syrup) 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 )

4 CONTRAINDICATIONS Hydrocodone Bitartrate and Homatropine Methylbromide Oral Solution (Syrup) 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 (Syrup) [ 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 (Syrup). ( 4 )

5 WARNINGS AND PRECAUTIONS Life-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 ) Activities 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 ) Seizures in patients with seizure disorders : Monitor during therapy. ( 5.11 ) Severe hypotension : Monitor during initiation of therapy. Avoid use in patients with circulatory shock. ( 5.12 ) Adrenal 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 (Syrup) contains hydrocodone, a Schedule II controlled substance. As an opioid, Hydrocodone Bitartrate and Homatropine Methylbromide Oral Solution (Syrup) 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 (Syrup) 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 (Syrup), prescribe Hydrocodone Bitartrate and Homatropine Methylbromide Oral Solution (Syrup) 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 (Syrup). Addiction can occur at recommended dosages and if the drug is misused or abused. 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 (Syrup). 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 (Syrup). 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 respiratory depression includes discontinuation of Hydrocodone Bitartrate and Homatropine Methylbromide Oral Solution (Syrup), close observation, supportive measures, and use of opioid antagonists (e.g. naloxone), depending on the patient's clinical status [ see Overdosage ( 10 ) ]. 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 Homatropine Methylbromide Oral Solution (Syrup), the risk is greatest during the initiation of therapy, when Hydrocodone Bitartrate and Homatropine Methylbromide Oral Solution (Syrup) are used concomitantly with other drugs that may cause respiratory depression [ see Warnings and Precautions ( 5.8 ) ], in patients with chronic pulmonary disease or decreased respiratory reserve, and in patients with altered pharmacokinetics or altered clearance (e.g. elderly, cachectic, or debilitated patients) [ see Warnings and Precautions ( 5.4 ) ]. To reduce the risk of respiratory depression, proper dosing of Hydrocodone Bitartrate and Homatropine Methylbromide Oral Solution (Syrup) are essential [ see Dosage and Administration ( 2.1 ), Warnings and Precautions ( 5.5 ) ]. Monitor patients closely, especially within the first 24 to 72 hours of initiating therapy or when used in patients at higher risk. Overdose of hydrocodone in adults has been associated with fatal respiratory depression, and the use of hydrocodone in pediatric patients younger than 6 years of age has been associated with fatal respiratory depression when used as recommended. Accidental ingestion of even one dose of Hydrocodone Bitartrate and Homatropine Methylbromide Oral Solution (Syrup), especially by children, can result in respiratory depression and death. 5.3 Risks with Use in Pediatric Populations Pediatric patients are particularly sensitive to the respiratory depressant effects of hydrocodone [ see Warnings and Precautions ( 5.2 ) ]. Because of the risk of life-threatening respiratory depression and death, Hydrocodone Bitartrate and Homatropine Methylbromide Oral Solution (Syrup) is contraindicated in pediatric patients less than 6 years of age [ see Contraindications ( 4 ) ]. Use of Hydrocodone Bitartrate and Homatropine Methylbromide Oral Solution (Syrup) in pediatric patients also exposes them to the risks of addiction, abuse, and misuse [ see Drug Abuse and Dependence ( 9 ) ], which can lead to overdose and death [ see Warnings and Precautions ( 5.1 ), Overdosage ( 10 ) ]. Because the benefits of symptomatic treatment of cough associated with allergies or the common cold do not outweigh the risks of use of hydrocodone in pediatric patients, Hydrocodone Bitartrate and Homatropine Methylbromide Oral Solution (Syrup) is not indicated for use in patients younger than 18 years of age [ see Indications ( 1 ), Use in Specific Populations ( 8.4 ) ]. 5.4 Risks with Use in Other At-Risk Populations Unresponsive Cough The dosage of Hydrocodone Bitartrate and Homatropine Methylbromide Oral Solution (Syrup) should not be increased if cough fails to respond; an unresponsive cough should be reevaluated in 5 days or sooner for possible underlying pathology, such as foreign body or lower respiratory tract disease [ see Dosage and Administration ( 2.3 ) ]. Asthma and Other Pulmonary Disease The use of Hydrocodone Bitartrate and Homatropine Methylbromide Oral Solution (Syrup) in patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment is contraindicated [ see Contraindications ( 4 ) ]. Opioid analgesics and antitussives, including hydrocodone, one of the active ingredients in Hydrocodone Bitartrate and Homatropine Methylbromide Oral Solution (Syrup), should not be used in patients with acute febrile illness associated with productive cough or in patients with chronic respiratory disease where interference with ability to clear the tracheobronchial tree of secretions would have a deleterious effect on the patient's respiratory function. Hydrocodone Bitartrate and Homatropine Methylbromide Oral Solution (Syrup)-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 and Homatropine Methylbromide Oral Solution (Syrup) [ see Warnings and Precautions ( 5.2 ) ]. 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 [ see Warnings and Precautions ( 5.2 ) ]. Because of the risk of respiratory depression, avoid the use of opioid antitussives, including Hydrocodone Bitartrate and Homatropine Methylbromide Oral Solution (Syrup) in patients with compromised respiratory function, patients at risk of respiratory failure, and in elderly, cachectic, or debilitated patients. If Hydrocodone Bitartrate and Homatropine Methylbromide Oral Solution (Syrup) are prescribed, monitor such patients closely, particularly when initiating Hydrocodone Bitartrate and Homatropine Methylbromide Oral Solution (Syrup) and when Hydrocodone Bitartrate and Homatropine Methylbromide Oral Solution (Syrup) are given concomitantly with other drugs that depress respiration [ see Warnings and Precautions ( 5.8 ) ]. 5.5 Risks of Accidental Overdose and Death due to Medication Errors Dosing errors can result in accidental overdose and death. To reduce the risk of overdose and respiratory depression, ensure that the dose of Hydrocodone Bitartrate and Homatropine Methylbromide Oral Solution (Syrup) are communicated clearly and dispensed accurately [ see Dosage and Administration ( 2.1 ) ]. Advise patients to always use an accurate milliliter measuring device when measuring and administering Hydrocodone Bitartrate and Homatropine Methylbromide Oral Solution (Syrup). Inform patients that household teaspoon is not an accurate measuring device and such use could lead to overdosage and serious adverse reactions [ see Overdosage ( 10 ) ]. For prescriptions where a measuring device is not provided, a pharmacist can provide an appropriate calibrated measuring device and can provide instructions for measuring the correct dose. 5.6 Activities Requiring Mental Alertness: Risks of Driving and Operating Machinery Hydrocodone, one of the active ingredients in Hydrocodone Bitartrate and Homatropine Methylbromide Oral Solution (Syrup), may produce marked drowsiness and impair the mental and/or physical abilities required for the performance of potentially hazardous tasks such as driving a car or operating machinery. Advise patients to avoid engaging in hazardous tasks requiring mental alertness and motor coordination after ingestion of Hydrocodone Bitartrate and Homatropine Methylbromide Oral Solution (Syrup). Avoid concurrent use of Hydrocodone Bitartrate and Homatropine Methylbromide Oral Solution (Syrup) with alcohol or other central nervous system depressants because additional impairment of central nervous system performance may occur [ see Warnings and Precautions ( 5.8 ) ]. 5.7 Risks from Concomitant Use or Discontinuation of Cytochrome P450 3A4 Inhibitors and Inducers Concomitant use of Hydrocodone Bitartrate and Homatropine Methylbromide Oral Solution (Syrup) 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 and Homatropine Methylbromide Oral Solution (Syrup) are achieved. Similarly, discontinuation of a CYP3A4 inducer, such as rifampin, carbamazepine, and phenytoin, in Hydrocodone Bitartrate and Homatropine Methylbromide Oral Solution (Syrup) -treated patients may increase hydrocodone plasma concentrations and prolong opioid adverse reactions. Concomitant use of Hydrocodone Bitartrate and Homatropine Methylbromide Oral Solution (Syrup) with CYP3A4 inducers or discontinuation of a 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. Avoid the use of Hydrocodone Bitartrate and Homatropine Methylbromide Oral Solution (Syrup) in patients who are taking a CYP3A4 inhibitor or inducer. If concomitant use of Hydrocodone Bitartrate and Homatropine Methylbromide Oral Solution (Syrup) with a CYP3A4 inhibitor or inducer is necessary, monitor patients for signs and symptoms that may reflect opioid toxicity and opioid withdrawal [ see Drug Interactions ( 7.2 , 7.3 ) ]. 5.8 Risks from Concomitant Use with Benzodiazepines or other CNS Depressants Concomitant use of opioids, including Hydrocodone Bitartrate and Homatropine Methylbromide Oral Solution (Syrup), with benzodiazepines, or other CNS depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Because of these risks, avoid use of opioid cough medications in patients taking benzodiazepines, other CNS depressants, or alcohol [see Drug Interactions ( 7.1 , 7.4 )]. Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioids alone. Because of similar pharmacologic properties, it is reasonable to expect similar risk with concomitant use of opioid cough medications and benzodiazepines, other CNS depressants, or alcohol. Advise both patients and caregivers about the risks of respiratory depression and sedation if Hydrocodone Bitartrate and Homatropine Methylbromide Oral Solution (Syrup) are used with benzodiazepines, alcohol, or other CNS depressants [see Patient Counseling Information ( 17 )]. Patients must not consume alcoholic beverages, or prescription or non-prescription products containing alcohol, while on Hydrocodone Bitartrate and Homatropine Methylbromide Oral Solution (Syrup) therapy. The co-ingestion of alcohol with Hydrocodone Bitartrate and Homatropine Methylbromide Oral Solution (Syrup) may result in increased plasma levels and a potentially fatal overdose of hydrocodone [see Drug Interactions ( 7.1 )]. 5.9 Risks of Use in Patients with Gastrointestinal Conditions Hydrocodone Bitartrate and Homatropine Methylbromide Oral Solution (Syrup) are contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus [see Contraindications (4)]. The use of hydrocodone in Hydrocodone Bitartrate and Homatropine Methylbromide Oral Solution (Syrup) may obscure the diagnosis or clinical course of patients with acute abdominal conditions. The concurrent use of anticholinergics with Hydrocodone Bitartrate and Homatropine Methylbromide Oral Solution (Syrup) may produce paralytic ileus [see Drug Interactions (7.9)]. The hydrocodone in Hydrocodone Bitartrate and Homatropine Methylbromide Oral Solution (Syrup) may result in constipation or obstructive bowel disease, especially in patients with underlying intestinal motility disorders. Use with caution in patients with underlying intestinal motility disorders. The hydrocodone in Hydrocodone Bitartrate and Homatropine Methylbromide Oral Solution (Syrup) may cause spasm of the sphincter of Oddi, resulting in an increase in biliary tract pressure. Opioids may cause increases in serum amylase [see Warnings and Precautions (5.15)]. Monitor patients with biliary tract disease, including acute pancreatitis for worsening symptoms. 5.10 Risks of Use in Patients with Head Injury, Impaired Consciousness, Increased Intracranial Pressure, or Brain Tumors Avoid the use of Hydrocodone Bitartrate and Homatropine Methylbromide Oral Solution (Syrup) in patients with head injury, intracranial lesions, or a pre-existing increase in intracranial pressure. 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 and Homatropine Methylbromide Oral Solution (Syrup) may reduce respiratory drive, and the resultant CO 2 retention can further increase intracranial pressure. Furthermore, opioids produce adverse reactions that may obscure the clinical course of patients with head injuries. 5.11 Increased Risk of Seizures in Patients with Seizure Disorders The hydrocodone in Hydrocodone Bitartrate and Homatropine Methylbromide Oral Solution (Syrup) may increase the frequency of seizures in patients with seizure disorders, and may increase the risk of seizures occurring in other clinical settings associated with seizures. Monitor patients with a history of seizure disorders for worsened seizure control during Hydrocodone Bitartrate and Homatropine Methylbromide Oral Solution (Syrup) therapy. 5.12 Severe Hypotension Hydrocodone Bitartrate and Homatropine Methylbromide Oral Solution (Syrup) may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients. There is increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs (e.g., phenothiazines or general anesthetics) [ see Drug Interactions ( 7.4 ) ] . Monitor these patients for signs of hypotension after initiating Hydrocodone Bitartrate and Homatropine Methylbromide Oral Solution (Syrup). In patients with circulatory shock, Hydrocodone Bitartrate and Homatropine Methylbromide Oral Solution (Syrup) may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of Hydrocodone Bitartrate and Homatropine Methylbromide Oral Solution (Syrup) in patients with circulatory shock. 5.13 Neonatal Opioid Withdrawal Syndrome Hydrocodone Bitartrate and Homatropine Methylbromide Oral Solution (Syrup) are not recommended for use in pregnant women. Prolonged use of Hydrocodone Bitartrate and Homatropine Methylbromide Oral Solution (Syrup) 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 a prolonged period 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 ) ] 5.14 Adrenal Insufficiency Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Presentation of adrenal insufficiency may include non-specific symptoms and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. If adrenal insufficiency is suspected, confirm the diagnosis with diagnostic testing as soon as possible. If adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids. Wean the patient off of the opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers. Other opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency. The information available does not identify any particular opioids as being more likely to be associated with adrenal insufficiency. 5.15 Drug/Laboratory Test Interactions Because opioid agonists may increase biliary tract pressure, with resultant increase in plasma amylase or lipase levels, determination of these enzyme levels may be unreliable for 24 hours after administration of a dose of Hydrocodone Bitartrate and Homatropine Methylbromide Oral Solution (Syrup).

7 DRUG INTERACTIONS No specific drug interaction studies have been conducted with Hydrocodone Bitartrate and Homatropine Methylbromide Oral Solution (Syrup). 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 ) Muscle Relaxants : Avoid concomitant use. ( 7.7 ) Diuretics : Hydrocodone may reduce the efficacy of diuretics. Monitor for reduced effect. ( 7.8 ) Anticholinergic 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 (Syrup) 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 (Syrup) 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 (Syrup) 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 (Syrup) and CYP2D6 and CYP3A4 inhibitors, particularly when an inhibitor is added after a stable dose of Hydrocodone Bitartrate and Homatropine Methylbromide Oral Solution (Syrup) are 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 (Syrup) while taking a CYP3A4 or CYP2D6 inhibitor. If concomitant use is necessary, evaluate patients for respiratory depression and sedation at frequent intervals. 7.3 CYP3A4 Inducers The concomitant use of Hydrocodone Bitartrate and Homatropine Methylbromide Oral Solution (Syrup) 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 (Syrup) 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, 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 (Syrup) in patients who are taking benzodiazepines or other CNS depressants [ see Warnings and Precautions ( 5.8 ) ], and instruct patients to avoid consumption of alcohol while on Hydrocodone Bitartrate and Homatropine Methylbromide Oral Solution (Syrup) [ see Drug Interactions ( 7.1 ) Patient Counseling Information ( 17 ) ]. 7.5 Serotonergic Drugs The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation. Discontinue Hydrocodone Bitartrate and Homatropine Methylbromide Oral Solution (Syrup) if serotonin syndrome is suspected. 7.6 Monoamine Oxidase Inhibitors (MAOIs) Avoid the use of Hydrocodone Bitartrate and Homatropine Methylbromide Oral Solution (Syrup) in patients who are taking monoamine oxidase inhibitors (MAOIs) or have taken MAOIs within 14 days. The use of MAOIs or tricyclic antidepressants with hydrocodone, one of the active ingredients in Hydrocodone Bitartrate and Homatropine Methylbromide Oral Solution (Syrup), may increase the effect of either the antidepressant or hydrocodone. MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma) . 7.7 Muscle Relaxants Hydrocodone may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression. Avoid the use of Hydrocodone Bitartrate and Homatropine Methylbromide Oral Solution (Syrup) in patients taking muscle relaxants. If concomitant use is necessary, evaluate patients for signs of respiratory depression that may be greater than otherwise expected. 7.8 Diuretics Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. Evaluate patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed. 7.9 Anticholinergic Drugs The concomitant use of anticholinergic drugs with Hydrocodone Bitartrate and Homatropine Methylbromide Oral Solution (Syrup) may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus [ see Warnings and Precautions ( 5.9 ) ]. Evaluate patients for signs of urinary retention or reduced gastric motility when Hydrocodone Bitartrate and Homatropine Methylbromide Oral Solution (Syrup) are used concomitantly with anticholinergic drugs.

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 (Syrup) 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 (Syrup). 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). Common adverse reactions include: Sedation (somnolence, mental clouding, lethargy), impaired mental and physical performance, lightheadedness, dizziness, headache, dry mouth, nausea, vomiting, and constipation.( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Novel Laboratories, Inc. at 866-403-7592 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

8.1 Pregnancy Risk Summary Hydrocodone Bitartrate and Homatropine Methylbromide Oral Solution (Syrup) are 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 (Syrup) 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 (Syrup); 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 antagonist, such as naloxone, must be available for reversal of opioid-induced respiratory depression in the neonate. Opioids, including Hydrocodone Bitartrate and Homatropine Methylbromide Oral Solution (Syrup), 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 Oral Solution (Syrup); however, studies are available with individual active ingredients or related active ingredients. Hydrocodone 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 a mg/m 2 basis with a maternal subcutaneous dose of 102 mg/kg). Reproductive toxicology studies were also conducted with codeine, an opiate related to hydrocodone. In an embryofetal development study in pregnant rats dosed throughout the period of organogenesis, codeine increased resorptions and decreased fetal weights at a dose approximately 65 times the MRHD of hydrocodone (on a mg/m 2 basis with a maternal oral dose of codeine at 120 mg/kg/day); however, these effects occurred in the presence of maternal toxicity. In embryofetal development studies with pregnant rabbits and mice dosed throughout the period of organogenesis, codeine produced no adverse developmental effects at doses approximately 30 and 160 times, respectively, the MRHD of hydrocodone (on a mg/m 2 basis with maternal oral doses of codeine at 30 mg/kg/day in rabbits and 600 mg/kg/day in mice). Homatropine Animal studies with homatropine are not available.