WARNINGS

Addiction, Abuse, and Misuse An acetaminophen and codeine phosphate tablet contains codeine, a Schedule II controlled substance.

As an opioid, acetaminophen and codeine phosphate tablets exposes users to the risks of addiction, abuse, and misuse [see DRUG ABUSE AND DEPENDENCE ].

Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed acetaminophen and codeine phosphate tablets.

Addiction can occur at recommended dosages and if the drug is misused or abused.

Assess each patient’s risk for opioid addiction, abuse, or misuse prior to prescribing acetaminophen and codeine phosphate tablets, and monitor all patients receiving acetaminophen and codeine phosphate tablets for the development of these behaviors and conditions.

Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression).

The potential for these risks should not, however, prevent the proper management of pain in any given patient.

Patients at increased risk may be prescribed opioids such as acetaminophen and codeine phosphate tablets but use in such patients necessitates intensive counseling about the risks and misuse.

Opioids are sought by drug abusers and people with addiction disorders and are subject to criminal diversion.

Consider these risks when prescribing or dispensing acetaminophen and codeine phosphate tablets.

Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on the proper disposal of unused drug [see PRECAUTIONS ; Information for Patients].

Contact local state professional licensing board or state controlled substances authority for information on how to prevent and detect abuse or diversion of this product.

Life-Threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended.

Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death.

Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient’s clinical status [see OVERDOSAGE ].

Carbon dioxide (CO2) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.

While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of acetaminophen and codeine phosphate tablets the risk is greatest during the initiation of therapy or following a dosage increase.

Monitor patients closely for respiratory depression, especially within the first 24 to 72 hours of initiating therapy with and following dosage increases of acetaminophen and codeine phosphate tablets.

To reduce the risk of respiratory depression, proper dosing and titration of acetaminophen and codeine phosphate tablets are essential [see DOSAGE AND ADMINISTRATION ].

Overestimating the acetaminophen and codeine phosphate tablets dosage when converting patients from another opioid product can result in a fatal overdose with the first dose.

Accidental ingestion of acetaminophen and codeine phosphate tablets, especially by children, can result in respiratory depression and death due to an overdose of codeine.

Neonatal Opioid Withdrawal Syndrome Prolonged use ofacetaminophen and codeine phosphate tabletsduring pregnancy can result in withdrawal in the neonate.

Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts.

Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly.

Advise pregnant women using opioids for a prolonged period of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [see PRECAUTIONS , Information for Patients/Caregivers, Pregnancy].

Codeine Phosphate 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 [CYP2D6] 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, 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 , 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 depressant 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 ; 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 ; Respiratory Depression].

Monitor such patients closely, particularly when initiating and titrating Acetaminophen and Codeine Phosphate Tablets and when Acetaminophen and Codeine Phosphate Tablets is given concomitantly with other drugs that depress respiration [see ; Life Threatening-Respiratory Depression].

Alternatively, consider the use of non-opioid analgesics in these patients.

Interaction with Monoamine Oxidase Inhibitors Monoamine oxidase inhibitors (MAOIs) may potentiate the effects of morphine, codeine’s active metabolite including respiratory depression, coma, and confusion.

Acetaminophen and Codeine Phosphate Tablets should not be used in patients taking MAOIs or within 14 days of stopping such treatment.

Adrenal Insufficiency Cases of adrenal insufficiency have been reported with opioid use, more often following greater than 1 month of use.

Presentation of adrenal insufficiency may include non-specific symptoms and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure.

If adrenal insufficiency is suspected, confirm the diagnosis with diagnostic testing as soon as possible.

If adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids.

Wean the patient off of the opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers.

Other opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency.

The information available does not identify any particular opioids as being more likely to be associated with adrenal insufficiency.

Severe Hypotension Acetaminophen and Codeine Phosphate Tablets may cause severe hypotension including hypotension and syncope in ambulatory patients.

There is increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs (e.g., phenothiazines or general anesthetics) [see PRECAUTIONS; Drug Interactions].

Monitor these patients for signs of hypotension after initiating or titrating the dosage of Acetaminophen and Codeine Phosphate Tablets.

In patients with circulatory shock Acetaminophen and Codeine Phosphate Tablets may cause vasodilatation that can further reduce cardiac output and blood pressure.

Avoid the use of Acetaminophen and Codeine Phosphate Tablets with circulatory shock.

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.

The excessive intake of acetaminophen may be intentional to cause self-harm or unintentional as patients attempt to obtain more pain relief or unknowingly take other acetaminophen-containing products.

The risk of acute liver failure is higher in individuals with underlying liver disease and in individuals who ingest alcohol while taking acetaminophen.

Instruct patients to look for acetaminophen or APAP on package labels and not to use more than one product that contains acetaminophen.

Instruct patients to seek medical attention immediately upon ingestion of more than 4,000 milligrams of acetaminophen per day, even if they feel well.

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 postmarketing reports of hypersensitivity and anaphylaxis associated with use of acetaminophen.

Clinical signs include 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.

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 CO2 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 CO2 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.

Sulfite Sensitivity Acetaminophen and Codeine Phosphate Tablets contain sodium metabisulfite, a sulfite that may cause allergic-type reactions including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people.

The overall prevalence of sulfite sensitivity in the general population is unknown and probably low.

Sulfite sensitivity is seen more frequently in asthmatic than in nonasthmatic people.

Increased Risk of Seizures in Patients with Seizure Disorders The codeine in Acetaminophen and Codeine Phosphate Tablets may increase the frequency of seizures in patients with seizure disorders, and may increase the risk of seizures occurring in other clinical settings associated with seizures.

Monitor patients with a history of seizure disorders for worsened seizure control during Acetaminophen and Codeine Phosphate Tablets therapy.

Withdrawal Avoid the use of mixed agonist/antagonist (e.g, pentazocine, nalbuphine, and butorphanol) or partial agonist (e.g., buprenorphine) analgesics in patients who are receiving a full opioid agonist analgesic, including Acetaminophen and Codeine Phosphate Tablets.

In these patients, mixed agonist/antagonist and partial analgesics may reduce the analgesic effect and/or precipitate withdrawal symptoms.

When discontinuing Acetaminophen and Codeine Phosphate Tablets, gradually taper the dosage [see DOSAGE AND ADMINISTRATION].

Do not abruptly discontinue Acetaminophen and Codeine Phosphate Tablets [see DRUG ABUSE AND DEPENDENCE ].