DailyMed Label: Hycodan

DailyMed Label: Hycodan

2021

DailyMed Prescription

Hycodan

Hydrocodone Bitartrate and Homatropine Methylbromide

Genus Lifesciences Inc.

NDC: 64950-342

NDC: 64950-342

NDC: 64950-342

NDC: 64950-205

NDC: 64950-205

NDC: 64950-205

NDC: 64950-205

NDC: 64950-205

NDC: 64950-342

NDC: 64950-342

HYCODAN tablets and oral solution contain hydrocodone, an opioid agonist; and homatropine, a muscarinic antagonist. Each tablet or spoonful (5 mL) of HYCODAN contains 5 mg of hydrocodone bitartrate, USP and 1.5 mg of homatropine methylbromide, USP, for oral administration. HYCODAN tablets also contain: calcium phosphate dibasic, colloidal silicon dioxide, lactose, magnesium stearate, pregelatinized starch and stearic acid. HYCODAN oral solution also contains: anhydrous citric acid, FD&C Red 40, methylparaben, natural and artificial cherry flavor, propylparaben, purified water, sorbitol solution, sodium citrate dihydrate and sucrose. Hydrocodone Bitartrate The chemical name for hydrocodone bitartrate is morphinan-6-one, 4,5-epoxy-3-methoxy-17-methyl-, (5α)-, [R-(R*,R*)]-2,3-dihydroxybutanedioate (1:1), hydrate (2:5). It is also known as 4,5α-Epoxy-3-methoxy-17-methylmorphinan-6-one tartrate (1:1) hydrate (2:5). It occurs as a fine white crystal or crystalline powder, which is derived from the opium alkaloid, thebaine. It has a molecular weight of 494.50 and has the following chemical structure: C 18 H 21 NO 3 ∙ C 4 H 6 O 6 ∙ 2½H2O     MW 494.490 Chemical Structure Homatropine Methylbromide The chemical name for homatropine methylbromide is 8-Azoniabicyclo [3.2.1]octane,3-[(hydroxyphenyl-acetyl)oxy]-8,8-dimethyl-,bromide, endo-. It occurs as a white crystal or fine white crystalline powder. It has a molecular weight of 370.29 and has the following chemical structure: C 17 H 24 BrNO 3 HOMATROPINE METHYLBROMIDE Chemical Structure

HYCODAN is indicated for the symptomatic relief of cough in adult patients 18 years of age and older. HYCODAN 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 HYCODAN 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. 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 HYCODAN 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.

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 HYCODAN 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 ) Administer HYCODAN by the oral route only. Always use an accurate milliliter measuring device when administering HYCODAN 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 HYCODAN because serious adverse events such as respiratory depression may occur with overdosage [see Warnings and Precautions (5.2) , Overdosage (10) ] . The dosage of HYCODAN 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) ] . 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. Prescribe HYCODAN for the shortest duration that is consistent with individual patient treatment goals [see Warnings and Precautions (5.1) ]. Monitor patients closely for respiratory depression, especially within the first 24 to 72 hours of initiating therapy [see Warnings and Precautions (5.2) ]. Reevaluate patients with unresponsive cough in 5 days or sooner for possible underlying pathology, such as foreign body or lower respiratory tract disease [see Warnings and Precautions (5.4) ]. If a patient requires a refill, reevaluate the cause of the cough and assess the need for continued treatment with HYCODAN, the relative incidence of adverse reactions, and the development of addiction, abuse, or misuse [see Warnings and Precautions (5.1) ] . Do not abruptly discontinue HYCODAN in a physically-dependent patient [see Drug Abuse and Dependence (9.3) ] . When a patient who has been taking HYCODAN regularly and may be physically dependent no longer requires therapy with HYCODAN, 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.

Tablets: 5 mg of hydrocodone bitartrate and 1.5 mg of homatropine methylbromide per tablet, white-colored, biconvex, one face bisected and debossed with "205", and the other face plain [see Description (11) ] . Oral solution: 5 mg of hydrocodone bitartrate and 1.5 mg of homatropine methylbromide per 5 mL, a clear red-colored, cherry-flavored [see Description (11) ] . Tablets: 5 mg of hydrocodone bitartrate and 1.5 mg of homatropine methylbromide per tablet. ( 3 ) Oral solution: 5 mg of hydrocodone bitartrate and 1.5 mg of homatropine methylbromide per 5 mL. ( 3 )

HYCODAN 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 HYCODAN [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 HYCODAN. ( 4 )

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 ) HYCODAN contains hydrocodone, a Schedule II controlled substance. As an opioid, HYCODAN 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 HYCODAN 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 HYCODAN, prescribe HYCODAN 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 HYCODAN. 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 HYCODAN. 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. Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, including hydrocodone, one of the active ingredients in HYCODAN. 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 HYCODAN, close observation, supportive measures, and use of opioid antagonists (e.g., naloxone), depending on the patient's clinical status [see Overdosage (10) ] . Carbon dioxide (CO 2 ) 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 HYCODAN, the risk is greatest during the initiation of therapy, when HYCODAN 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 HYCODAN 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 HYCODAN, especially by children, can result in respiratory depression and death. 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, HYCODAN is contraindicated in pediatric patients less than 6 years of age [see Contraindications (4) ] . Use of HYCODAN 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, HYCODAN is not indicated for use in patients younger than 18 years of age [see Indications (1) , Use in Specific Populations (8.4) ] . Unresponsive Cough The dosage of HYCODAN 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 HYCODAN 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 HYCODAN, 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. HYCODAN-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 HYCODAN [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 HYCODAN in patients with compromised respiratory function, patients at risk of respiratory failure, and in elderly, cachectic, or debilitated patients. If HYCODAN is prescribed, monitor such patients closely, particularly when initiating HYCODAN and when HYCODAN is given concomitantly with other drugs that depress respiration [see Warnings and Precautions (5.8) ] . Dosing errors can result in accidental overdose and death. To reduce the risk of overdose and respiratory depression, ensure that the dose of HYCODAN is 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 HYCODAN oral solution. 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. Hydrocodone, one of the active ingredients in HYCODAN, 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 HYCODAN. Avoid concurrent use of HYCODAN with alcohol or other central nervous system depressants because additional impairment of central nervous system performance may occur [see Warnings and Precautions (5.8) ] . Concomitant use of HYCODAN 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 HYCODAN is achieved. Similarly, discontinuation of a CYP3A4 inducer, such as rifampin, carbamazepine, and phenytoin, in HYCODAN-treated patients may increase hydrocodone plasma concentrations and prolong opioid adverse reactions. Concomitant use of HYCODAN 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 HYCODAN in patients who are taking a CYP3A4 inhibitor or inducer. If concomitant use of HYCODAN 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) ] . Concomitant use of opioids, including HYCODAN, 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 HYCODAN is 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 HYCODAN therapy. The co-ingestion of alcohol with HYCODAN may result in increased plasma levels and a potentially fatal overdose of hydrocodone [see Drug Interactions (7.1) ] . HYCODAN is contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus [see Contraindications (4) ] . The use of hydrocodone in HYCODAN may obscure the diagnosis or clinical course of patients with acute abdominal conditions. The concurrent use of anticholinergics with HYCODAN may produce paralytic ileus [see Drug Interactions (7.9) ] . The hydrocodone in HYCODAN 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 HYCODAN 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. Avoid the use of HYCODAN 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), HYCODAN 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. The hydrocodone in HYCODAN 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 HYCODAN therapy. HYCODAN 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 HYCODAN. In patients with circulatory shock, HYCODAN may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of HYCODAN in patients with circulatory shock. HYCODAN is not recommended for use in pregnant women. Prolonged use of HYCODAN 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) ] . 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. 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 HYCODAN.

The following clinically significant adverse reactions are described elsewhere in labeling:

No specific drug interaction studies have been conducted with HYCODAN. 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 ) Concomitant use of alcohol with HYCODAN 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 HYCODAN therapy [see Warnings and Precautions (5.8) , Clinical Pharmacology (12.3) ] . The concomitant use of HYCODAN 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 HYCODAN and CYP2D6 and CYP3A4 inhibitors, particularly when an inhibitor is added after a stable dose of HYCODAN 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 HYCODAN while taking a CYP3A4 or CYP2D6 inhibitor. If concomitant use is necessary, monitor patients for respiratory depression and sedation at frequent intervals. The concomitant use of HYCODAN 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 HYCODAN in patients who are taking CYP3A4 inducers. If concomitant use of a CYP3A4 inducer is necessary, follow the patient for reduced efficacy. 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 HYCODAN 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 HYCODAN [see Drug Interactions (7.1) , Patient Counseling Information (17) ] . 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 HYCODAN if serotonin syndrome is suspected. Avoid the use of HYCODAN 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 HYCODAN, 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) . Hydrocodone may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression. Avoid the use of HYCODAN in patients taking muscle relaxants. If concomitant use is necessary, monitor patients for signs of respiratory depression that may be greater than otherwise expected. 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. The concomitant use of anticholinergic drugs with HYCODAN 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 HYCODAN is used concomitantly with anticholinergic drugs.

Pregnancy : Avoid use in pregnant women. May cause fetal harm. ( 8.1 ) Lactation : Breastfeeding not recommended. ( 8.2 ) Renal Impairment : Use with caution in patients with severe renal impairment. ( 8.6 ) Hepatic Impairment : Use with caution in patients with severe hepatic impairment. ( 8.7 ) Risk Summary HYCODAN is not recommended for use in pregnant women, including during or immediately prior to labor. Prolonged use of opioids during pregnancy may cause neonatal opioid withdrawal syndrome [see Warnings and Precautions (5.13) , Clinical Considerations ] . There are no available data with HYCODAN 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 HYCODAN; 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 HYCODAN, 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 HYCODAN; 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. Risk Summary Because of the potential for serious adverse reactions, including excess sedation, respiratory depression, and death in a breastfed infant, advise patients that breastfeeding is not recommended during treatment with HYCODAN. There are no data on the presence of HYCODAN in human milk, the effects of HYCODAN on the breastfed infant, or the effects of HYCODAN on milk production; however, data are available with hydrocodone and homatropine. Hydrocodone Hydrocodone is present in breast milk. Published cases report variable concentrations of hydrocodone and hydromorphone (an active metabolite) in breast milk with administration of immediate-release hydrocodone to nursing mothers in the early post-partum period with relative infant doses of hydrocodone ranging between 1.4% and 3.7%. There are case reports of excessive sedation and respiratory depression in breastfed infants exposed to hydrocodone. No information is available on the effects of hydrocodone on milk production. Homatropine No information is available on the levels of homatropine in breast milk or on milk production. The published literature suggests that homatropine may decrease milk production based on its anticholinergic effects ( see Clinical Considerations ). Clinical Considerations Infants exposed to HYCODAN through breast milk should be monitored for excess sedation and respiratory depression. Withdrawal symptoms can occur in breastfed infants when maternal administration of an opioid is stopped, or when breastfeeding is stopped. Infertility Chronic use of opioids, such as hydrocodone, a component of HYCODAN, may cause reduced fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible [see Adverse Reactions (6) , Clinical Pharmacology (12.2) ]. HYCODAN is contraindicated in pediatric patients younger than 6 years of age because of life-threatening respiratory depression and death have occurred in pediatric patients who received hydrocodone [see Contraindications (4) , Warnings and Precautions (5.2) ] . The safety and effectiveness of HYCODAN have not been established in patients younger than 18 years of age. HYCODAN is not recommended for use in patients younger than 18 years of age because the benefits of symptomatic treatment of cough associated with allergies or the common cold do not outweigh the risks for use of hydrocodone in these patients [see Indications (1) , Warnings and Precautions (5.3) ] . Clinical studies have not been conducted with HYCODAN in geriatric populations. Use caution when considering the use of HYCODAN in patients 65 years of age or older. Elderly patients may have increased sensitivity to hydrocodone; greater frequency of decreased hepatic, renal, or cardiac function; or concomitant disease or other drug therapy [see Warnings and Precautions (5.4) ] . Respiratory depression is the chief risk for elderly patients treated with opioids, including HYCODAN. Respiratory depression has occurred after large initial doses of opioids were administered to patients who were not opioid-tolerant or when opioids were co-administered with other agents that depress respiration [see Warnings and Precautions (5.4 , 5.8) ] . Hydrocodone is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, monitor these patients closely for respiratory depression, sedation, and hypotension. The pharmacokinetics of HYCODAN has not been characterized in patients with renal impairment. Patients with renal impairment may have higher plasma concentrations than those with normal function [see Clinical Pharmacology (12.3) ] . HYCODAN should be used with caution in patients with severe impairment of renal function, and patients should be monitored closely for respiratory depression, sedation, and hypotension. The pharmacokinetics of HYCODAN has not been characterized in patients with hepatic impairment. Patients with severe hepatic impairment may have higher plasma concentrations than those with normal hepatic function [see Clinical Pharmacology (12.3) ] . Therefore, HYCODAN should be used with caution in patients with severe impairment of hepatic function, and patients should be monitored closely for respiratory depression, sedation, and hypotension.

HYCODAN is supplied as a white-colored, biconvex tablet, one face bisected and debossed with "205", and the other face plain, available in: NDC 64950-205-03 Bottles of 30 NDC 64950-205-10 Bottles of 100 Store tablets at controlled room temperature 20°C to 25°C (68°F to 77°F) [See USP Controlled Room Temperature]. Dispense in a tight, light-resistant container, as defined in the USP, with a child-resistant closure. HYCODAN is available as a clear red-colored, cherry-flavored oral solution in:   NDC 64950-342-05: Unit Dose Cup of 5 mL   NDC 64950-342-45: Case contains 40 unit dose cups of 5 mL (NDC 64950-342-05), packaged in 4 trays of 10 unit dose cups each   NDC 64950-342-47: Bottle of 473 mL Store oral solution at controlled room temperature 20°C to 25°C (68°F to 77°F). [See USP Controlled Room Temperature.] Dispense in a tight, light-resistant container, as defined in the USP, with a child-resistant closure. Ensure that patients have an oral dosing dispenser that measures the appropriate volume in milliliters. Counsel patients on how to utilize an oral dosing dispenser and correctly measure the oral suspension as prescribed.

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. 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 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. 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.

Carcinogenicity, mutagenicity, and fertility studies have not been conducted with HYCODAN; however, published information is available for the individual active ingredients or related active ingredients. Hydrocodone Carcinogenicity studies were conducted with codeine, an opiate related to hydrocodone. Two-year studies in F344/N rats and B6C3F1 mice were conducted to assess the carcinogenic potential of codeine. No evidence of tumorigenicity was observed in male and female rats at codeine dietary doses up to 70 and 80 mg/kg/day (approximately equivalent to 40 and 45 times the MRHD of hydrocodone on a mg/m 2 basis, respectively). No evidence of tumorigenicity was observed in male and female mice at codeine dietary doses up to 400 mg/kg/day (approximately equivalent to 110 times the MRHD of hydrocodone on a mg/m 2 basis). Mutagenicity studies with hydrocodone have not been conducted. Fertility studies with hydrocodone have not been conducted. Homatropine Carcinogenicity, mutagenicity, and fertility studies with homatropine have not been conducted.

NDC 64950-205-03 HYCODAN ® CII (hydrocodone bitartrate and homatropine methylbromide) tablets 5 mg/1.5 mg "Dispense the accompanying Medication Guide to each patient." Rx Only 30 tablets Genus Lifesciences Inc. PRINCIPAL DISPLAY PANEL - 30 Tablet Bottle Label