Addiction, Abuse, And Misuse; Life-Threatening Respiratory Depression; Accidental Ingestion; Ultra- Rapid Metabolism Of Codeine and Other Risk Factors For Life-Threatening Respiratory Depression in Children; Neonatal Opioid Withdrawal Syndrome; Interactions with Drugs Affecting Cytochrome P450 Isoenzymes; and Risks From Concomitant Use with Benzodiazepines Or Other CNS Depressants; Risk Evaluation and Mitigation Strategy (REMS)  

Addiction, Abuse, and Misuse 

• Codeine sulfate tablets 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 codeine sulfate tablets, and monitor all patients regularly for the development of these behaviors and conditions [see Warnings and Precautions]
• 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. 

Life-Threatening Respiratory Depression 

• Serious, life-threatening, or fatal respiratory depression may occur with use of codeine sulfate tablets. Monitor for respiratory depression, especially during initiation of codeine sulfate tablets or following a dose increase [see Warnings and Precautions].
• 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 codeine sulfate tablets, especially by children, can result in a fatal overdose of codeine [see Warnings and Precautions].

Neonatal Opioid Withdrawal Syndrome 

• Prolonged use of codeine sulfate tablets 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 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 [see Warnings and Precautions].

Death Related to Ultra-Rapid Metabolism of Codeine to Morphine 

• Respiratory depression and death have occurred in children who received codeine following tonsillectomy and/or adenoidectomy and had evidence of being ultra-rapid metabolizers of codeine due to a CYP2D6 polymorphism[see Warnings and Precautions].

Interactions with Drugs Affecting Cytochrome P450 Isoenzymes 

• The effects of concomitant use or discontinuation of cytochrome P450 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors with codeine are complex.  Use of cytochrome P450 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors with codeine sulfate tablets requires careful consideration of the effects on the parent drug, codeine, and the active metabolite, morphine. [See Warnings and Precautions, Drug Interactions].

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, Drug Interactions].

• Reserve concomitant prescribing of codeine sulfate tablets and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate. 
• Limit dosages and durations to the minimum required.
• Follow patients for signs and symptoms of respiratory depression and sedation.

Death Related to Ultra-Rapid Metabolism of Codeine to Morphine

• Respiratory depression and death have occurred in children who received codeine following tonsillectomy and/or adenoidectomy and had evidence of being ultra-rapid metabolizers of codeine due to a CYP2D6 polymorphism.

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. 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:

• complete a REMS-compliant education program,
• counsel patients and/or their caregivers, with every prescription, on safe use, serious risks, storage, and disposal of these products,
• emphasize to patients and their caregivers the importance of reading the Medication Guide every time it is provided by their pharmacist, and
• consider other tools to improve patient, household, and community safety.