nhibitors of cyp3a4 and cyp2d6 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. 7.3 cyp3a4 inducers 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. 7.4 benzodiazepines, and other cns depressants due to additive pharmacologic effect, the concomitant use of benzodiazepines or other cns depressants, including alcohol, other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, and other opioids, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death. avoid the use of 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) ] . 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 hycodan if serotonin syndrome is suspected. 7.6 monoamine oxidase inhibitors (maois) 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) . 7.7 muscle relaxants hydrocodone may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression. avoid the use of 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. 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 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.

mended 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.

hedule 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. 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 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. 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, 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) ] . 5.4 risks with use in other at-risk populations 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) ] . 5.5 risk of accidental overdose and death due to medication errors dosing errors can result in accidental overdose and death. to reduce the risk of overdose and respiratory depression, ensure that the dose of 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. 5.6 activities requiring mental alertness: risks of driving and operating machinery 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) ] . 5.7 risks from concomitant use or discontinuation of cytochrome p450 3a4 inhibitors and inducers 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) ] . 5.8 risks from concomitant use with benzodiazepines or other cns depressants 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) ] . 5.9 risks of use in patients with gastrointestinal conditions 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. 5.10 risks of use in patients with head injury, impaired consciousness, increased intracranial pressure, or brain tumors 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. 5.11 increased risk of seizures in patients with seizure disorders 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. 5.12 severe hypotension 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. 5.13 neonatal opioid withdrawal syndrome 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) ] . 5.14 adrenal insufficiency cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. presentation of adrenal insufficiency may include non-specific symptoms and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. if adrenal insufficiency is suspected, confirm the diagnosis with diagnostic testing as soon as possible. if adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids. wean the patient off of the opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers. other opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency. the information available does not identify any particular opioids as being more likely to be associated with adrenal insufficiency. 5.15 drug/laboratory test interactions because opioid agonists may increase biliary tract pressure, with resultant increase in plasma amylase or lipase levels, determination of these enzyme levels may be unreliable for 24 hours after administration of a dose of hycodan.

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) ] . 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 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.

nd 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 hycodan 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 hycodan. 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. 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 pharm-olam at 1-866-511-6754 or fda at 1-800-fda-1088 or www.fda.gov/medwatch.

nhibitors of cyp3a4 and cyp2d6 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. 7.3 cyp3a4 inducers 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. 7.4 benzodiazepines, and other cns depressants due to additive pharmacologic effect, the concomitant use of benzodiazepines or other cns depressants, including alcohol, other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, and other opioids, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death. avoid the use of 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) ] . 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 hycodan if serotonin syndrome is suspected. 7.6 monoamine oxidase inhibitors (maois) 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) . 7.7 muscle relaxants hydrocodone may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression. avoid the use of 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. 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 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.

redients 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. 8.2 lactation 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. 8.3 females and males of reproductive potential 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) ]. 8.4 pediatric use 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) ] . 8.5 geriatric use 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. 8.6 renal impairment 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. 8.7 hepatic impairment 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.

al 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.

f 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. 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.

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.

hydrocodone have not been conducted. homatropine carcinogenicity, mutagenicity, and fertility studies with homatropine have not been conducted.

conducted. homatropine carcinogenicity, mutagenicity, and fertility studies with homatropine have not been conducted.

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.

o 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) ] . life-threatening respiratory depression inform patients of the risk of life-threatening respiratory depression, including information that the risk is greatest when starting hycodan and that it can occur even at recommended dosages [see warnings and precautions (5.2) ] . advise patients how to recognize respiratory depression and to seek medical attention if breathing difficulties develop. accidental ingestion inform patients that accidental ingestion, especially by children, may result in respiratory depression or death [see warnings and precautions (5.2) ] . instruct patients to take steps to store hycodan securely and to properly dispose of unused hycodan in accordance with the local state guidelines and/or regulations. activities requiring mental alertness advise patients to avoid engaging in hazardous tasks that require mental alertness and motor coordination such as operating machinery or driving a motor vehicle as hycodan may produce marked drowsiness [see warnings and precautions (5.6) ] . interactions with benzodiazepines and other central nervous system depressants, including alcohol inform patients and caregivers that potentially fatal additive effects may occur if hycodan is used with benzodiazepines or other cns depressants, including alcohol. advise patients to avoid concomitant use of hycodan with benzodiazepines or other cns depressants and instruct patients not to consume alcoholic beverages, as well as prescription and over-the-counter products that contain alcohol, during treatment with hycodan [see warnings and precautions (5.8) , drug interactions (7.1 , 7.4) ] . constipation advise patients of the potential for severe constipation [see warnings and precautions (5.9) , adverse reactions (6) ] . anaphylaxis inform patients that anaphylaxis has been reported with ingredients contained in hycodan. advise patients how to recognize such a reaction and when to seek medical attention [see contraindications (4) , adverse reactions (6) ] . maoi interaction inform patients not to take hycodan while using or within 14 days of stopping any drugs that inhibit monoamine oxidase. patients should not start maois while taking hycodan [see drug interactions (7.6) ] . hypotension inform patients that hycodan may cause orthostatic hypotension and syncope. instruct patients how to recognize symptoms of low blood pressure and how to reduce the risk of serious consequences should hypotension occur (e.g., sit or lie down, carefully rise from a sitting or lying position) [see warnings and precautions (5.12) ] . pregnancy advise patients that use of hycodan is not recommended during pregnancy [see use in specific populations (8.1) ] . neonatal opioid withdrawal syndrome inform female patients of reproductive potential that use of hycodan during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated [see warnings and precautions (5.13) , use in specific populations (8.1) ]. embryo-fetal toxicity inform female patients of reproductive potential that hycodan can cause fetal harm and to inform their healthcare provider of a known or suspected pregnancy [see use in specific populations (8.1) ]. lactation advise women that breastfeeding is not recommended during treatment with hycodan [see use in specific populations (8.2) ] . infertility inform patients that chronic use of opioids, such as hydrocodone, a component of hycodan, may cause reduced fertility. it is not known whether these effects on fertility are reversible [see use in specific populations (8.3) ]. adrenal insufficiency inform patients that hycodan could cause adrenal insufficiency, a potentially life-threatening condition. adrenal insufficiency may present with non-specific symptoms and signs such as nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. advise patients to seek medical attention if they experience a constellation of these symptoms [see warnings and precautions (5.14) ] . serotonin syndrome inform patients that hycodan could cause a rare but potentially life-threatening condition resulting from concomitant administration of serotonergic drugs. warn patients of the symptoms of serotonin syndrome and to seek medical attention right away if symptoms develop. instruct patients to inform their physicians if they are taking, or plan to take serotonergic medications [see adverse reactions (6) , drug interactions (7.5) ] . disposal of unused hycodan advise patients to properly dispose of unused hycodan. advise patients to throw the drug in the household trash following these steps. 1) remove them from their original containers and mix them with an undesirable substance, such as used coffee grounds or kitty litter (this makes the drug less appealing to children and pets, and unrecognizable to people who may intentionally go through the trash seeking drugs). 2) place the mixture in a sealable bag, empty can, or other container to prevent the drug from leaking or breaking out of a garbage bag, or to dispose of in accordance with local state guidelines and/or regulations.