FDA label 4b7dcfa6-7247-2ad5-e054-00144ff8d46c

WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; NEONATAL OPIOID WITHDRAWAL SYNDROME; DEATH RELATED TO ULTRA-RAPID METABOLISM OF CODEINE TO MORPHINE; HEPATOTOXICITY; CYTOCHROME P450 2D6 INTERACTION; 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 ]. 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, 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 ]. 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 , PRECAUTIONS; Information for Patients/Caregivers , Nursing mothers ]. 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 , 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 , 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 , 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.

Serious Skin Reactions Rarely, acetaminophen may cause serious skin reactions such as acute generalized exanthematous pustulosis (AGEP), Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. Patients should be informed about the signs of serious skin reactions, and use of the drug should be discontinued at the first appearance of skin rash or any other sign of hypersensitivity.

Hypersensitivity/Anaphylaxis There have been post-marketing reports of hypersensitivity and anaphylaxis associated with the use of acetaminophen. Clinical signs included swelling of the face, mouth, and throat, respiratory distress, urticaria, rash, pruritus, and vomiting. There were infrequent reports of life-threatening anaphylaxis requiring emergency medical attention. Instruct patients to discontinue Acetaminophen and Codeine Phosphate Tablets immediately and seek medical care if they experience these symptoms. Do not prescribe Acetaminophen and Codeine Phosphate Tablets for patients with acetaminophen allergy [see PRECAUTIONS; Information for Patients/Caregivers ].

Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness In patients who may be susceptible to the intracranial effects of CO 2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors), Acetaminophen and Codeine Phosphate Tablets may reduce respiratory drive, and the resultant CO 2 retention can further increase intracranial pressure. Monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy with Acetaminophen and Codeine Phosphate Tablets. Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of Acetaminophen and Codeine Phosphate Tablets in patients with impaired consciousness or coma.

Risks of Use in Patients with Gastrointestinal Conditions Acetaminophen and Codeine Phosphate Tablets are contraindicated in patients with gastrointestinal obstruction, including paralytic ileus. The administration of Acetaminophen and Codeine Phosphate Tablets or other opioids may obscure the diagnosis or clinical course in patients with acute abdominal conditions. Acetaminophen and Codeine Phosphate Tablets may cause spasm of the sphincter of Oddi. Opioids may cause increases in serum amylase. Monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms.

ADVERSE REACTIONS The following adverse reactions have been identified during post approval use of Acetaminophen and Codeine Phosphate Tablets. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Addiction, Abuse, and Misuse [see WARNINGS ] Life-Threatening Respiratory Depression [see WARNINGS ] Neonatal Opioid Withdrawal Syndrome [see WARNINGS ] Ultra-rapid Metabolizers of Codeine [see WARNINGS ] Interactions with CNS Depressants [see WARNINGS ] Severe Hypotension [see WARNINGS ] Gastrointestinal Adverse Reactions [see WARNINGS ] Seizures [see WARNINGS ] Withdrawal [see WARNINGS ] Serious adverse reactions associated with codeine are respiratory depression and, to a lesser degree, circulatory depression, respiratory arrest, shock, and cardiac arrest. The most frequently observed adverse reactions with codeine administration include drowsiness, lightheadedness, dizziness, sedation, shortness of breath, nausea, vomiting, sweating, and constipation. Other adverse reactions include allergic reactions, euphoria, dysphoria, abdominal pain, pruritis, rash, thrombocytopenia, and agranulocytosis. Other less frequently observed adverse reactions expected from opioid analgesics, including Acetaminophen and Codeine Phosphate Tablets: Cardiovascular system : faintness, flushing, hypotension, palpitations, syncope Digestive System : abdominal cramps, anorexia, diarrhea, dry mouth, gastrointestinal distress, pancreatitis Nervous system : anxiety, drowsiness, fatigue, headache, insomnia, nervousness, shakiness, somnolence, vertigo, visual disturbances, weakness Skin and Appendages : rash, sweating, urticarial Serotonin syndrome : Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of opioids with serotonergic drugs. Adrenal insufficiency : Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Anaphylaxis : Anaphylaxis has been reported with ingredients contained in Acetaminophen and Codeine Phosphate Tablets. Androgen deficienc y: Cases of androgen deficiency have occurred with chronic use of opioids [see CLINICAL PHARMACOLOGY ].