See Boxed WARNINGS Interactions with CNS depressants: Concomitant use may cause profound sedation, respiratory depression, and death. If coadministration is required, consider dose reduction of one or both drugs. (5.4) Elderly, cachectic, debilitated patients, and those with chronic pulmonary disease: Monitor closely because of increased risk for life-threatening respiratory depression. (5.5, 5.6) Hypotensive effects: Monitor during dose initiation and titration. (5.7) Patients with head injury or increased intracranial pressure: Monitor for sedation and respiratory depression. Avoid use of ZOHYDRO ER in patients with impaired consciousness or coma susceptible to intracranial effects of CO2 retention. (5.8) Concomitant use of CYP3A4 inhibitors may increase opioid effects. (5.13) 5.1 Addiction, Abuse, and Misuse ZOHYDRO ER contains hydrocodone, a Schedule II controlled substance. As an opioid, ZOHYDRO ER exposes users to the risks of addiction, abuse, and misuse [see Drug Abuse and Dependence (9)]. As modified-release products such as ZOHYDRO ER deliver the opioid over an extended period of time, there is a greater risk for overdose and death due to the larger amount of hydrocodone present. Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed ZOHYDRO ER and in those who obtain the drug illicitly. Addiction can occur at recommended doses and if the drug is misused or abused. Assess each patient’s risk for opioid addiction, abuse, or misuse prior to prescribing ZOHYDRO ER, and monitor all patients receiving ZOHYDRO ER for the development of these behaviors or conditions. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol addiction or abuse) or mental illness (e.g., major depression). The potential for these risks should not, however, prevent the prescribing of ZOHYDRO ER for the proper management of pain in any given patient. Patients at increased risk may be prescribed modified-release opioid formulations such as ZOHYDRO ER, but use in such patients necessitates intensive counseling about the risks and proper use of ZOHYDRO ER along with intensive monitoring for signs of addiction, abuse, and misuse. Abuse or misuse of ZOHYDRO ER by crushing, chewing, snorting, or injecting the dissolved product will result in the uncontrolled delivery of the hydrocodone and can result in overdose and death [see Overdosage (10)]. Opioid agonists such as ZOHYDRO ER are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Consider these risks when prescribing or dispensing ZOHYDRO ER. 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- T hreatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression has been reported with the use of modified-release opioids, even when used as recommended. Respiratory depression from opioid use, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient’s clinical status [see Overdosage (10)]. Carbon dioxide (CO2) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids. While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of ZOHYDRO ER, the risk is greatest during the initiation of therapy or following a dose increase. Closely monitor patients for respiratory depression when initiating therapy with ZOHYDRO ER and following dose increases. To reduce the risk of respiratory depression, proper dosing and titration of ZOHYDRO ER are essential [see Dosage and Administration (2)]. Overestimating the ZOHYDRO ER dose when converting patients from another opioid product can result in fatal overdose with the first dose. Accidental ingestion of even one dose of ZOHYDRO ER, especially by children, can result in respiratory depression and death due to an overdose of hydrocodone. 5.3 Neonatal Opioid Withdrawal Syndrome Prolonged use of ZOHYDRO ER during pregnancy can result in withdrawal signs 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. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available. 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. 5.4 Interactions with Central Nervous System Depressants Patients must not consume alcoholic beverages, or prescription or non-prescription products containing alcohol, while on ZOHYDRO ER therapy. The co-ingestion of alcohol with ZOHYDRO ER may result in increased plasma levels and a potentially fatal overdose of hydrocodone [see Clinical Pharmacology (12.3)]. Hypotension, profound sedation, coma, respiratory depression, and death may result if ZOHYDRO ER is used concomitantly with alcohol or other central nervous system (CNS) depressants (e.g., sedatives, anxiolytics, hypnotics, neuroleptics, other opioids). When considering the use of ZOHYDRO ER in a patient taking a CNS depressant, assess the duration of use of the CNS depressant and the patient’s response, including the degree of tolerance that has developed to CNS depression. Additionally, evaluate the patient’s use of alcohol or illicit drugs that cause CNS depression. If the decision to begin ZOHYDRO ER is made, start with a lower ZOHYDRO ER dose than usual (i.e., 20%-30% less), monitor patients for signs of sedation and respiratory depression, and consider using a lower dose of the concomitant CNS depressant [see Drug Interactions (7.2)]. 5. 5 Use in Elderly, Cachectic, and Debilitated Patients Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients as they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients. Monitor such patients closely, particularly when initiating and titrating ZOHYDRO ER and when ZOHYDRO ER is given concomitantly with other drugs that depress respiration [see Warnings and Precautions (5.2)]. 5. 6 Use in Patients with Chronic Pulmonary Disease Monitor for respiratory depression in patients with significant chronic obstructive pulmonary disease or cor pulmonale, and patients having a substantially decreased respiratory reserve, hypoxia, hypercapnia, or preexisting respiratory depression, particularly when initiating therapy and titrating with ZOHYDRO ER, as in these patients, even usual therapeutic doses of ZOHYDRO ER may decrease respiratory drive to the point of apnea [see Warnings and Precautions (5.2)]. Consider the use of alternative non-opioid analgesics in these patients if possible. 5. 7 Hypotensive Effect ZOHYDRO ER may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients. There is an added risk to individuals whose ability to maintain blood pressure has been compromised by a depleted blood volume, or after concurrent administration with drugs such as phenothiazines or other agents which compromise vasomotor tone. Monitor these patients for signs of hypotension after initiating or titrating the dose of ZOHYDRO ER. In patients with circulatory shock, ZOHYDRO ER may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of ZOHYDRO ER in patients with circulatory shock. 5. 8 Use in Patients with Head Injury and Increased Intracranial Pressure Monitor patients taking ZOHYDRO ER who may be susceptible to the intracranial effects of CO2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors) for signs of sedation and respiratory depression, particularly when initiating therapy with ZOHYDRO ER. ZOHYDRO ER may reduce respiratory drive, and the resultant CO2 retention can further increase intracranial pressure. Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of ZOHYDRO ER in patients with impaired consciousness or coma. 5. 9 Use in Patients with Gastrointestinal Conditions ZOHYDRO ER is contraindicated in patients with known or suspected paralytic ileus. Opioids diminish propulsive peristaltic waves in the gastrointestinal tract and decrease bowel motility. Monitor for decreased bowel motility in post-operative patients receiving opioids. The administration of ZOHYDRO ER may obscure the diagnosis or clinical course in patients with acute abdominal conditions. Hydrocodone may cause spasm of the sphincter of Oddi. Monitor patients with biliary tract disease, including acute pancreatitis. 5. 10 Use in Patients with Convulsive or Seizure Disorders The hydrocodone in ZOHYDRO ER may aggravate convulsions in patients with convulsive disorders, and may induce or aggravate seizures in some clinical settings. Monitor patients with a history of seizure disorders for worsened seizure control during ZOHYDRO ER therapy. 5 .1 1 Avoidance of Withdrawal Avoid the use of mixed agonist/antagonist (i.e., pentazocine, nalbuphine, and butorphanol) or partial agonist (buprenorphine) analgesics in patients who have received, or are receiving, a course of therapy with a full opioid agonist analgesic, including ZOHYDRO ER. In these patients, mixed agonist/antagonist and partial agonist analgesics may reduce the analgesic effect and/or may precipitate withdrawal symptoms [see Drug Interactions (7.4) ] 5. 1 2 Driving and Operating Machinery ZOHYDRO ER may impair the mental and physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery. Warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects of ZOHYDRO ER and know how they will react to the medication. 5.13 Cytochrome P450 CYP3A4 Inhibitors and Inducers Since the CYP3A4 isoenzyme plays a major role in the metabolism of ZOHYDRO ER, drugs that alter CYP3A4 activity may cause changes in clearance of hydrocodone which could lead to changes in hydrocodone plasma concentrations. Inhibition of CYP3A4 activity by its inhibitors 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 effects. CYP3A4 inducers, such as rifampin, carbamazepine, and phenytoin, may induce the metabolism of hydrocodone and, therefore, may cause increased clearance of the drug which could lead to a decrease in hydrocodone plasma concentrations, lack of efficacy or, possibly, development of an abstinence syndrome in a patient who had developed physical dependence to hydrocodone. If co-administration is necessary, monitor patients closely who are currently taking, or discontinuing, CYP3A4 inhibitors or inducers. Evaluate these patients at frequent intervals and consider dose adjustments until stable drug effects are achieved [see Drug Interactions (7.3) and Clinical Pharmacology (12.3)].