Homatropine

1 INDICATIONS AND USAGE Hydrocodone bitartrate and homatropine methylbromide is indicated for the symptomatic relief of cough in 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 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 is a combination of hydrocodone, an opioid agonist; and homatropine, a muscarinic antagonist, indicated for the symptomatic relief of cough in 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 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.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Hydrocodone Hydrocodone is an opioid agonist with relative selectivity for the mu-opioid receptor, although it can interact with other opioid receptors at higher doses. The precise mechanism of action of hydrocodone and other opiates is not known; however, hydrocodone is believed to act centrally on the cough center. In excessive doses, hydrocodone will depress respiration. Homatropine Homatropine is an anticholinergic that inhibits activity of the muscarinic acetylcholine receptor with less potency than atropine. 12.2 Pharmacodynamics Hydrocodone Effects on the Central Nervous System Hydrocodone produces respiratory depression by direct action on brain stem respiratory centers. The respiratory depression involves a reduction in the responsiveness of the brain stem respiratory centers to both increases in carbon dioxide tension and to electrical stimulation. Hydrocodone causes miosis, even in total darkness. Pinpoint pupils are a sign of opioid overdose but are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origins may produce similar findings). Marked mydriasis rather than miosis may be seen due to hypoxia in overdose situations. Effects on the Gastrointestinal Tract and Other Smooth Muscle Hydrocodone causes a reduction in motility associated with an increase in smooth muscle tone in the antrum of the stomach and duodenum. Digestion of food in the small intestine is delayed and propulsive contractions are decreased. Propulsive peristaltic waves in the colon are decreased, while tone may be increased to the point of spasm resulting in constipation. Other opioid-induced effects may include a reduction in biliary and pancreatic secretions, spasm of sphincter of Oddi, and transient elevations in serum amylase. Effects on the Cardiovascular System Hydrocodone produces peripheral vasodilation which may result in orthostatic hypotension or syncope. Manifestations of histamine release and/or peripheral vasodilation may include pruritus, flushing, red eyes and sweating and/or orthostatic hypotension. Effects on the Endocrine System Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing hormone (LH) in humans [see Adverse Reactions (6)] . They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagon. Chronic use of opioids may influence the hypothalamic-pituitary-gonadal axis, leading to androgen deficiency that may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility. The causal role of opioids in the clinical syndrome of hypogonadism is unknown because the various medical, physical, lifestyle, and psychological stressors that may influence gonadal hormone levels have not been adequately controlled for in studies conducted to date [see Adverse Reactions (6)] . Effects on the Immune System Opioids have been shown to have a variety of effects on components of the immu

2 DOSAGE AND ADMINISTRATION Adults 18 years of age and older: One (1) tablet or 5 mL of the oral solution every 4 to 6 hours as needed; not to exceed six (6) tablets or 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) 2.1 Important Dosage and Administration Instructions Administer hydrocodone bitartrate and homatropine methylbromide 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 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 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 : One (1) tablet or 5 mL of the oral solution every 4 to 6 hours as needed; not to exceed six (6) tablets or 30 mL in 24 hours. 2.3 Monitoring, Maintenance, and Discontinuation of Therapy Prescribe hydrocodone bitartrate and homatropine methylbromide 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, 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 in a physically dependent patient [see Drug Abuse and Dependence (9.3)] . When a patient who has been taking hydrocodone bitartrate and homatropine methylbromide regularly and may be physically dependent no longer requires therapy with hydrocodone bitartrate and homatropine methylbromide, 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.

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 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. 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 KVK-Tech,

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 contains hydrocodone, a Schedule II controlled substance. As an opioid, hydrocodone bitartrate and homatropine methylbromide 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 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, prescribe hydrocodone bitartrate and homatropine methylbromide 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. 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. 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. 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, 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

4 CONTRAINDICATIONS Hydrocodone bitartrate and homatropine methylbromide is contraindicated for: All children 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 [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. (4)

10 OVERDOSAGE Clinical Presentation Hydrocodone Acute overdose with hydrocodone is characterized by respiratory depression (a decrease in respiratory rate and/or tidal volume, Cheyne-Stokes respiration, cyanosis), extreme somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and, in some cases, pulmonary edema, bradycardia, partial or complete airway obstruction, atypical snoring, hypotension, circulatory collapse, cardiac arrest, and death. Hydrocodone may cause miosis, even in total darkness. Pinpoint pupils are a sign of opioid overdose but are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origin may produce similar findings). Marked mydriasis rather than miosis may be seen with hypoxia in overdose situations [see Clinical Pharmacology (12.2)] . Homatropine Homatropine has broad, nonspecific anticholinergic / antimuscarinic activity that similar to, although less potent than, atropine. Overdosage of homatropine can cause mydriasis and cycloplegia (fixed and dilated pupils), dry mouth and eyes, decreased sweating, hyperthermia, flushing, headache, visual blurring, gastrointestinal symptoms, constipation, urinary retention, tachycardia and palpitations, anxiety, restlessness, agitation, hallucinations, convulsions, cardiac arrhythmias and coma. Anticholinergic agents can also precipitate acute narrow angle glaucoma. Treatment of Overdose Treatment of overdosage is driven by the overall clinical presentation, and consists of discontinuation of hydrocodone bitartrate and homatropine methylbromide together with institution of appropriate therapy. Give primary attention to the reestablishment of adequate respiratory exchange through provision of a patent and protected airway and the institution of assisted or controlled ventilation. Employ other supportive measures (including oxygen and vasopressors) in the management of circulatory shock and pulmonary edema as indicated. Cardiac arrest or arrhythmias will require advanced life-support techniques. Gastric emptying may be useful in removing unabsorbed drug. The opioid antagonists, naloxone and nalmefene, are specific antidotes for respiratory depression resulting from opioid overdose. For clinically significant respiratory or circulatory depression secondary to hydrocodone overdose, administer an opioid antagonist. An antagonist should not be administered in the absence of clinically significant respiratory depression. Because the