Hydrocodone Bitartrate and Homatropine Methylbromide Oral Solution

INDICATIONS AND USAGE Hydrocodone bitartrate and homatropine methylbromide 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 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 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 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)

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) 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 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 rapidly reduce or 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.

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. 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 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. 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 overdose reversal agents (e.g. naloxone or nalmefene), 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, the risk is greatest during the initiation of therapy, when hydrocodone bitartrate and homatropine methylbromide is 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 is 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, 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 is contraindicated in pediatric patients less than 6 years of age [see Contraindications (4)] . Use of hydrocodone bitartrate and homatropine methylbromide 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 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 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 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, 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-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

CONTRAINDICATIONS Hydrocodone bitartrate and homatropine methylbromide 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 [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)

DRUG INTERACTIONS No specific drug interaction studies have been conducted with hydrocodone bitartrate and homatropine methylbromide. 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 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 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 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 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 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 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 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 in patients who are taking benzodiazepines, gabapentinoids, 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 [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 if serotonin syndrome is suspected. 7.6 Monoamine Oxidase Inhibitors (MAOIs) Avoid the use of hydrocodone bitartrate and homatropine methylbromide 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, 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 (e.g., cyclobenzaprine, metaxolone) and produce an increased degree of respiratory depression. Avoid the use of hydrocodone bitartrate and homatropine methylbromide in patients taking muscle relaxants. If concomitant use is necessary, monitor 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. Monitor 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 may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus [see Warnings and Precautions (5.9)] . Monitor patients for signs of urinary retention or reduced gastric motility when hydrocodone bitartrate and homatropine methylbromide is used concomitantly with anticholinergic drugs.

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). 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 opioids longer term. 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, Inc. at 1-800-862-3895 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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, transient elevations in serum amylase, and opioid-induced esophageal dysfunction (OIED). 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 immune system in in vitro and animal models. The clinical significance of these findings is unknown. Overall, the effects of opioids appear to be modestly immunosuppressive. Concentration–Adverse Reaction Relationships There is a relationship between increasing hydrocodone plasma concentration and increasing frequency of dose-related opioid adverse reactions such as nausea, vomiting, CNS effects, and respiratory depression. In opioid-tolerant patients, the situation may be altered by the development of tolerance to opioid-related adverse reactions. Homatropine Homatropine methylbromide has several mild but undesirable clinical properties resulting from its antisecretory effects. These can include: dry mouth, loss of visual accommodation, photophobia, and difficulty in urination. The extent of the above actions is dictated by dose, dose escalation, therefore, results in progressively aversive symptoms in patients. 12.3 Pharmacokinetics Absorption Following a 10 mg oral dose of hydrocodone administered to five adult male subjects, the mean peak concentration was 23.6 ± 5.2 ng/mL. Maximum serum levels were achieved at 1.3 ± 0.3 hours. Food has no significant effect on the extent of absorption of hydrocodone. Distribution Although the extent of protein binding of hydrocodone in human plasma has not been definitively determined, structural similarities to related opioid analgesics suggest that hydrocodone is not extensively protein bound. As most agents in the 5-ring morphinan group of semi-synthetic opioids bind plasma protein to a similar degree (range 19% [hydromorphone] to 45% [oxycodone]), hydrocodone is expected to fall within this range. Elimination Metabolism Hydrocodone exhibits a complex pattern of metabolism, including N-demethylation, O-demethylation, and 6keto reduction to the corresponding 6-α-and 6-β-hydroxy metabolites. CYP3A4 mediated N-demethylation to norhydrocodone is the primary metabolic pathway of hydrocodone with a lower contribution from CYP2D6-mediated O-demethylation to hydromorphone. Hydromorphone is formed from the O-demethylation of hydrocodone and may contribute to the total analgesic effect of hydrocodone. Therefore, the formation of these and related metabolites can, in theory, be affected by other drugs [see Drug Interactions (7.2)] . Published in vitro studies have shown that N-demethylation of hydrocodone to form norhydrocodone can be attributed to CYP3A4 while O-demethylation of hydrocodone to hydromorphone is predominantly catalyzed by CYP2D6 and to a lesser extent by an unknown low affinity CYP enzyme. Excretion Hydrocodone and its metabolites are eliminated primarily in the kidneys. The mean plasma half-life of hydrocodone is approximately 4 hours.