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.

Death Related to Ultra-Rapid Metabolism of Codeine to Morphine Codeine-containing products are contraindicated for post-operative pain management in all pediatric patients undergoing tonsillectomy and/or adenoidectomy [see CONTRAINDICATIONS ]. Respiratory depression and death have occurred in children who received codeine in the postoperative period following tonsillectomy and/or adenoidectomy and had evidence of being ultra-rapid metabolizers of codeine (i.e., multiple copies of the gene for cytochrome P450 isoenzyme 2D6 or high morphine concentrations). Deaths have also occurred in nursing infants who were exposed to high levels of morphine in breast milk because their mothers were ultra-rapid metabolizers of codeine [see PRECAUTIONS; Information for Patients/Caregivers , Nursing Mothers ]. Some individuals may be ultra-rapid metabolizers because of a specific CYP2D6 genotype (gene duplications denoted as *1/*1xN or *1/*2xN). The prevalence of this CYP2D6 phenotype varies widely and has been estimated at 0.5 to 1% in Chinese and Japanese, 0.5 to 1% in Hispanics, 1 to 10% in Caucasians, 3% in African Americans, and 16 to 28% in North Africans, Ethiopians, and Arabs. Data are not available for other ethnic groups. These individuals convert codeine into its active metabolite, morphine, more rapidly and completely than other people. This rapid conversion results in higher than expected serum morphine levels. Even at labeled dosage regimens, individuals who are ultra-rapid metabolizers may have life-threatening or fatal respiratory depression or experience signs of overdose (such as extreme sleepiness, confusion, or shallow breathing) [see OVERDOSAGE ]. Children with obstructive sleep apnea who are treated with codeine for post-tonsillectomy and/or adenoidectomy pain may be particularly sensitive to the respiratory depressant effects of codeine that has been rapidly metabolized to morphine.

Risks of 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 , such as macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), and protease inhibitors (e.g., ritonavir) or discontinuation of a cytochrome P450 3A4 inducer such as rifampin, carbamazepine, and phenytoin, 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 ]. Risks of Concomitant Use or Discontinuation of Cytochrome P450 2D6 Inhibitors The concomitant use of Acetaminophen and Codeine Phosphate Tablets with all cytochrome P450 2D6 inhibitors (e.g., amiodarone, quinidine) may result in an increase in codeine plasma concentrations and a decrease in active metabolite morphine plasma concentration which could result in an analgesic efficacy reduction or symptoms of opioid withdrawal. Discontinuation of a concomitantly used cytochrome P450 2D6 inhibitor may result in a decrease in codeine plasma concentration and an increase in active metabolite morphine plasma concentration which could 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 PRECAUTIONS, Drug Interactions ].

Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants Profound sedation, respiratory depression, coma, and death may result from the concomitant use of Acetaminophen and Codeine Phosphate Tablets with benzodiazepines or other CNS depressants (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol). Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioid analgesics alone. Because of similar pharmacological properties, it is reasonable to expect similar risk with the concomitant use of other CNS depressant drugs with opioid analgesics [see PRECAUTIONS, Drug Interactions ]. If the decision is made to prescribe a benzodiazepine or other CNS depressant concomitantly with an opioid analgesic, prescribe the lowest effective dosages and minimum durations of concomitant use. In patients already receiving an opioid analgesic, prescribe a lower initial dose of the benzodiazepine or other CNS depressant than indicated in the absence of an opioid, and titrate based on clinical response. If an opioid analgesic is initiated in a patient already taking a benzodiazepine or other CNS depressant, prescribe a lower initial dose of the opioid analgesic, and titrate based on clinical response. Follow patients closely for signs and symptoms of respiratory depression and sedation. Advise both patients and caregivers about the risks of respiratory depression and sedation when Acetaminophen and Codeine Phosphate Tablets are used with benzodiazepines or other CNS depressants (including alcohol and illicit drugs). Advise patients not to drive or operate heavy machinery until the effects of concomitant use of the benzodiazepine or other CNS depressants have been determined. Screen patients for risk of substance use disorders, including opioid abuse and misuse, and warn them of the risk for overdose and death associated with the use of additional CNS depressants including alcohol and illicit drugs [see PRECAUTIONS, Information for Patients , Drug Interactions ].

Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or Elderly, Cachectic, or Debilitated Patients The use of Acetaminophen and Codeine Phosphate Tablets in patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment is contraindicated. Patients with Chronic Pulmonary Disease: Acetaminophen and Codeine Phosphate Tablets-treated patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression are at increased risk of decreased respiratory drive including apnea, even at recommended dosages of Acetaminophen and Codeine Phosphate Tablets [see WARNINGS; Life-Threatening Respiratory Depression ]. Elderly, Cachectic, or Debilitated Patients: Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients because they may have altered pharmacokinetics, including clearance, compared to younger, healthier patients [see WARNINGS; Respiratory Depression ]. Monitor such patients closely, particularly when initiating and titrating Acetaminophen and Codeine Phosphate Tablets and when Acetaminophen and Codeine Phosphate Tablets are given concomitantly with other drugs that depress respiration [see WARNINGS; Life Threatening-Respiratory Depression ]. Alternatively, consider the use of non-opioid analgesics in these patients.

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 ].