Addiction, Abuse, and Misuse, Risk Evaluation and Mitigation Strategy (REMS), Lifethreatening Respiratory Depression; Accidental Ingestion; Neonatal Opioid Withdrawal Syndrome; Hepatotoxicity, Cytochrome P450 3A4 Interaction, and Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants

Addiction, Abuse, and Misuse

• APADAZ exposes patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death. Assess each patient’s risk prior to prescribing APADAZ, and monitor all patients regularly for the development of these behaviors and conditions [see Warnings and Precautions (5.1)]. 
• Patients at increased risk may be prescribed opioids, but use in such patients necessitates intensive counseling about the risks and proper use along with intensive monitoring for signs of addiction, abuse, and misuse. Consider prescribing naloxone for the emergency treatment of opioid overdose. 

Opioid Analgesic Risk Evaluation and Mitigation Strategy (REMS)

• To ensure that the benefits of opioid analgesics outweigh the risks of addiction, abuse, and misuse, the Food and Drug Administration (FDA) has required a REMS for these products [see Warnings and Precautions (5.2)]. Under the requirements of the REMS, drug companies with approved opioid analgesic products must make REMS-compliant education programs available to healthcare providers. Healthcare providers are strongly encouraged to:
       1. complete a REMS-compliant education program,
       2. counsel patients and/or their caregivers, with every prescription, on safe use, serious risks, storage, and disposal of these products,
       3. emphasize to patients and their caregivers the importance of reading the Medication Guide every time it is provided by their pharmacist, and
       4. consider other tools to improve patient, household, and community safety.

Life-Threatening Respiratory Depression

• Serious, life-threatening, or fatal respiratory depression may occur with use of APADAZ. Monitor for respiratory depression, especially during initiation of APADAZ or following a dose increase [see Warnings and Precautions (5.3)].
• Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the opioid dosage using best practices for opioid taper.

Accidental Ingestion

• Accidental ingestion of even one dose of APADAZ, especially by children, can result in a fatal overdose of hydrocodone [see Warnings and Precautions (5.3)].

Neonatal Opioid Withdrawal Syndrome

• Prolonged use of APADAZ during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. If prolonged opioid use is required in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [see Warnings and Precautions (5.4)].

Cytochrome P450 3A4 Interaction

• The concomitant use of APADAZ with all cytochrome P450 3A4 inhibitors may result in an increase in hydrocodone plasma concentrations, which could increase or prolong adverse reactions and may cause potentially fatal respiratory depression. In addition, discontinuation of a concomitantly used cytochrome P450 3A4 inducer may result in an increase in hydrocodone plasma concentration. Monitor patients receiving APADAZ and any CYP3A4 inhibitor or inducer [see Warnings and Precautions (5.5), Drug Interactions (7), Clinical Pharmacology (12.3)].

Hepatotoxicity

• APADAZ contains acetaminophen. Acetaminophen has been associated with cases of acute liver failure, at times resulting in liver transplant and death. Most of the cases of liver injury are associated with the  use  of  acetaminophen  at  doses  that  exceed  4000 milligrams per day, and often involve more than one acetaminophen-containing product [see Warnings and Precautions (5.6)].

Risks From Concomitant Use With Benzodiazepines Or Other CNS Depressants

• Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death [see Warnings and Precautions (5.7), Drug Interactions (7)].
       1. Reserve concomitant prescribing of APADAZ and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate.
       2. Limit dosages and durations to the minimum required.
       3. Follow patients for signs and symptoms of respiratory depression and sedation.