Addiction, abuse, and misuse; risk evaluation and mitigation strategy (rems); life-threatening respiratory depression; accidental ingestion; risks from concomitant use with benzodiazepines or other cns depressants; 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 hepatotoxicity.

Addiction, Abuse, and Misuse

• Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules expose 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 Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules, and monitor all patients regularly for the development of these behaviors and conditions [see WARNINGS AND PRECAUTIONS (5.1)].

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 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.

Life-Threatening Respiratory Depression

• Serious, life-threatening, or fatal respiratory depression may occur with use of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules. Monitor for respiratory depression, especially during initiation of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules or following a dose increase [see WARNINGS AND PRECAUTIONS (5.3)].

Accidental Ingestion

• Accidental ingestion of even one dose of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules, especially by children, can result in a fatal overdose of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate [see WARNINGS AND PRECAUTIONS (5.3)].

Risks From Concomitant Use with Benzodiazepines or Other CNS Depressants

• Concomitant use of opioids or a barbiturate 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 (5.4), DRUG INTERACTIONS (7)].
• Reserve concomitant prescribing of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules 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.

Ultra-Rapid Metabolism of Codeine and Other Risk Factors for Life-threatening Respiratory Depression in Children

• Life-threatening respiratory depression and death have occurred in children who received codeine. Most of the reported cases occurred following tonsillectomy and/or adenoidectomy, and many of the children had evidence of being an ultra-rapid metabolizer of codeine due to a CYP2D6 polymorphism [see WARNINGS AND PRECAUTIONS (5.5)]. Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules are contraindicated in children younger than 12 years of age and in children younger than 18 years of age following tonsillectomy and/or adenoidectomy [see CONTRAINDICATIONS (4)]. Avoid the use of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of codeine.

Neonatal Opioid Withdrawal Syndrome

• Prolonged use of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules 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 (5.6)].

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 Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules requires careful consideration of the effects on codeine, and the active metabolite, morphine [see WARNINGS AND PRECAUTIONS (5.7)].

Hepatotoxicity

• Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules contain 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 4,000 milligrams per day, and often involve more than one acetaminophen-containing product [see WARNINGS AND PRECAUTIONS (5.8)].