Acetaminophen and Codeine

BOXED WARNING

WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; ULTRA-RAPID METABOLISM OF CODEINE AND LIFE-THREATENING RESPIRATORY DEPRESSION IN CHILDREN; NEONATAL OPIOID WITHDRAWAL SYNDROME; HEPATOTOXICITY; INTERACTIONS WITH DRUGS AFFECTING CYTOCHROME P450 ISOENZYMES; and RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS

Addiction, Abuse, and Misuse

Acetaminophen and codeine phosphate tablets 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 acetaminophen and codeine phosphate tablets, and monitor all patients regularly for the development of these behaviors and conditions [see WARNINGS].

Life-Threatening Respiratory Depression

Serious, life-threatening, or fatal respiratory depression may occur with use of acetaminophen and codeine phosphate tablets. Monitor for respiratory depression, especially during initiation of acetaminophen and codeine phosphate tablets or following a dose increase [see WARNINGS].

Accidental Ingestion

Accidental ingestion of acetaminophen and codeine phosphate tablets, especially by children, can result in a fatal overdose of acetaminophen and codeine phosphate tablets [see WARNINGS].

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 cases following tonsillectomy and/or adenoidectomy, and many of the children had evidence of being an ultra-rapid metabolizers of codeine due to a CYP2D6 polymorphism. Codeine is contraindicated in children younger than twelve years of age and in children of any age who are undergoing tonsillectomy and/or adenoidectomy. Avoid the use of acetaminophen and codeine phosphate tablets 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 acetaminophen and codeine phosphate tablets during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated. 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].

Hepatotoxicity

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].

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 acetaminophen and codeine phosphate tablets requires careful consideration of the effects on the parent drug, codeine, and the active metabolite, morphine.

• Cytochrome P450 3A4 Interaction

  The concomitant use of acetaminophen and codeine phosphate tablets with all cytochrome P450 3A4 inhibitors or discontinuation of a cytochrome P450 3A4 inducer may result in an increase in codeine plasma concentrations with subsequently greater metabolism by cytochrome P450 2D6, resulting in greater morphine levels, which could increase or prolong adverse reactions and may cause potentially fatal respiratory depression.

  The concomitant use of acetaminophen and codeine phosphate tablets with all cytochrome P450 3A4 inducers or discontinuation of a cytochrome P450 3A4 inhibitor may result in lower codeine levels, greater norcodeine levels, and less metabolism via 2D6 with resultant lower morphine levels. This may be associated with a decrease in efficacy, and in some patients, may result in signs and symptoms of opioid withdrawal.

  Follow patients receiving acetaminophen and codeine phosphate tablets and any CYP3A4 inhibitor or inducer for signs and symptoms that may reflect opioid toxicity and opioid withdrawal when acetaminophen and codeine phosphate tablets are used in conjunction with inhibitors and inducers of CYP3A4 [see WARNINGS and PRECAUTIONS, Drug Interactions].

• Cytochrome P450 2D6 Interaction

The concomitant use of acetaminophen and codeine phosphate tablets with all cytochrome P450 2D6 inhibitors may result in an increase in codeine plasma concentrations and a decrease in the plasma concentration of the active metabolite, morphine, which could result in an analgesic efficacy reduction or symptoms of opioid withdrawal.

The discontinuation of a cytochrome P450 2D6 inhibitor may result in a decrease in codeine plasma concentrations and an increase in the plasma concentration of the active metabolite, morphine, which could increase or prolong adverse reactions and may cause potentially fatal respiratory depression.

Follow patients receiving acetaminophen and codeine phosphate tablets and any CYP2D6 inhibitor for signs and symptoms that may reflect opioid toxicity and opioid withdrawal when acetaminophen and codeine phosphate tablets are used in conjunction with inhibitors of CYP2D6 [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 acetaminophen and codeine phosphate 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.