Acetaminophen and codeine

Name: Acetaminophen and codeine

What is the most important information I should know about acetaminophen and codeine?

MISUSE OF THIS MEDICINE CAN CAUSE ADDICTION, OVERDOSE, OR DEATH, especially in a child or other person using the medicine without a prescription.

You should not use this medicine if you have recently used alcohol, sedatives, tranquilizers, or other narcotic medications.

This medicine is not for use in children younger than 12 years old, and is not for use in anyone under 18 who recently had surgery to remove the tonsils or adenoids.

Taking this medicine during pregnancy may cause life-threatening withdrawal symptoms in the newborn.

Fatal side effects can occur if you use this medicine with alcohol, or with other drugs that cause drowsiness or slow your breathing.

What should I avoid while taking acetaminophen and codeine?

This medication may impair your thinking or reactions. Avoid driving or operating machinery until you know how the medicine will affect you. Dizziness or severe drowsiness can cause falls or other accidents.

Do not drink alcohol. Dangerous side effects or death could occur.

Ask a doctor or pharmacist before using any other cold, allergy, pain, or sleep medication. Acetaminophen (sometimes abbreviated as APAP) is contained in many combination medicines. Taking certain products together can cause you to get too much acetaminophen which can lead to a fatal overdose. Check the label to see if a medicine contains acetaminophen or APAP.

Warnings

Addiction, Abuse, and Misuse

Acetaminophen and Codeine phosphate tablets contain codeine, a Schedule II controlled substance. As an opioid, Acetaminophen and Codeine phosphate tablets expose 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 proper use of Acetaminophen and Codeine phosphate tablets along with intensive monitoring for signs of addiction, abuse, 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/Caregivers). 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 of Acetaminophen and Codeine phosphate tablets during 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 and Pregnancy).

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 and 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 and 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/Caregivers  and 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, Cachetic, 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, Life-Threatening 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.

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 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 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).

Drug Abuse and Dependence

Controlled Substance

Acetaminophen and Codeine phosphate tablets contain codeine, a Schedule II controlled substance.

Abuse

Acetaminophen and Codeine phosphate tablets contain codeine, a substance with a high potential for abuse similar to other opioids, including fentanyl, hydrocodone, hydromorphone, methadone, morphine, oxycodone, oxymorphone, and tapentadol. Acetaminophen and Codeine phosphate tablets can be abused and are subject to misuse, addiction, and criminal diversion (see WARNINGS).

All patients treated with opioids require careful monitoring for signs of abuse and addiction, because use of opioid analgesic products carries the risk of addiction even under appropriate medical use.

Prescription drug abuse is the intentional non-therapeutic use of a prescription drug, even once, for its rewarding psychological or physiological effects.

Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that develop after repeated substance use and includes: a strong desire to take the drug, difficulties in controlling its use, persisting in its use despite harmful, or potentially harmful, consequences, a higher priority given to drug use than to other activities and obligations, increased tolerance, and sometimes a physical withdrawal.

“Drug-seeking” behavior is very common in persons with substance use disorders. Drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing, or referral, repeated “loss” of prescriptions, tampering with prescriptions and reluctance to provide prior medical records or contact information for other treating health care providers. “Doctor shopping” (visiting multiple prescribers to obtain additional prescriptions) is common among drug abusers and people suffering from untreated addiction. Preoccupation with achieving adequate pain relief can be appropriate behavior in a patient with poor pain control.

Abuse and addiction are separate and distinct from physical dependence and tolerance. Health care providers should be aware that addiction may not be accompanied by concurrent tolerance and symptoms of physical dependence in all addicts. In addition, abuse of opioids can occur in the absence of true addiction.

Acetaminophen and Codeine phosphate tablets, like other opioids, can be diverted for non-medical use into illicit channels of distribution. Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests, as required by state and federal law, is strongly advised.

Proper assessment of the patient, proper prescribing practices, periodic re-evaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs.

Risks Specific to Abuse of Acetaminophen and Codeine Phosphate Tablets – Acetaminophen and Codeine phosphate tablets are for oral use only. Abuse of Acetaminophen and Codeine phosphate tablets poses a risk of overdose and death. The risk is increased with concurrent use of Acetaminophen and Codeine phosphate tablets with alcohol and other central nervous system depressants.

Parenteral drug abuse is commonly associated with transmission of infectious diseases such as hepatitis and HIV.

Dependence

Both tolerance and physical dependence can develop during chronic opioid therapy. Tolerance is the need for increasing doses of opioids to maintain a defined effect such as analgesia (in the absence of disease progression or other external factors). Tolerance may occur to both the desired and undesired effects of drugs, and may develop at different rates for different effects.

Physical dependence results in withdrawal symptoms after abrupt discontinuation or a significant dosage reduction of a drug. Withdrawal also may be precipitated through the administration of drugs with opioid antagonist activity (e.g., naloxone, nalmefene), mixed agonist/antagonist analgesics (e.g., pentazocine, butorphanol, nalbuphine), or partial agonists (e.g., buprenorphine). Physical dependence may not occur to a clinically significant degree until after several days to weeks of continued opioid usage.

Acetaminophen and Codeine phosphate tablets should not be abruptly discontinued (see DOSAGE AND ADMINISTRATION). If Acetaminophen and Codeine phosphate tablets are abruptly discontinued in a physically dependent patient, a withdrawal syndrome may occur. Some or all of the following can characterize this syndrome: restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Other signs and symptoms also may develop, including: irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate.

Infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal signs (see PRECAUTIONS, Pregnancy).

Overdosage

Following an acute overdosage, toxicity may result from codeine or acetaminophen.

Clinical Presentation

Codeine – Acute overdosage with codeine can be manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and, in some cases, pulmonary edema, bradycardia, hypotension, partial or complete airway obstruction, atypical snoring, and death. Marked mydriasis rather than miosis may be seen with hypoxia in overdose situations.

Acetaminophen – Dose-dependent, potentially fatal hepatic necrosis is the most serious adverse effect of acetaminophen. Renal tubular necrosis, hypoglycemic coma, and coagulation defects may also occur.

Early symptoms following a potentially hepatotoxic overdose may include anorexia, nausea, vomiting, diaphoresis, pallor and general malaise. Clinical and laboratory evidence of hepatic toxicity may not be apparent until 48 to 72 hours post-ingestion.

Treatment of Overdose

Codeine – In case of codeine overdose, priorities are the reestablishment of a patent and protected airway and institution of assisted or controlled ventilation, if needed. Employ other supportive measures (including oxygen and vasopressors) in the management of circulatory shock and pulmonary edema as indicated. Cardiac arrest or serious arrhythmias will require advanced life-support measures.

The opioid antagonists, naloxone or nalmefene, are specific antidotes to respiratory depression resulting from opioid overdose. For clinically significant respiratory or circulatory depression secondary to Acetaminophen and Codeine phosphate tablets overdose, administer an opioid antagonist. Only administer opioid antagonists in the presence of clinically significant respiratory, circulatory and/or central nervous system depression secondary to codeine overdose. In patients who are physically dependent on any opioid agonist including Acetaminophen and Codeine phosphate tablets, an abrupt or complete reversal of opioid effects may precipitate an acute withdrawal syndrome. The severity of the withdrawal syndrome produced will depend on the degree of physical dependence and the dose of the antagonist administered. Please see the prescribing information for the specific opioid antagonist for details of their proper use.

Because the duration of opioid reversal is expected to be less than the duration of action of Acetaminophen and Codeine phosphate tablets, carefully monitor the patient until spontaneous respiration is reliably reestablished. If the response to an opioid antagonist is suboptimal or only brief in nature, administer additional antagonist as directed by the product’s prescribing information.

Acetaminophen – Gastric decontamination with activated charcoal should be administered just prior to N-acetylcysteine (NAC) to decrease systemic absorption if acetaminophen ingestion is known or suspected to have occurred within a few hours of presentation.

Serum acetaminophen levels should be obtained immediately if the patient presents
4 hours or more after ingestion to assess potential risk of hepatotoxicity; acetaminophen levels drawn less than 4 hours post-ingestion may be misleading. To obtain the best possible outcome, NAC should be administered as soon as possible where impending or evolving liver injury is suspected. Intravenous NAC may be administered when circumstances preclude oral administration.

Vigorous supportive therapy is required in severe intoxication. Procedures to limit the continuing absorption of the drug must be readily performed since the hepatic injury is dose-dependent and occurs early in the course of intoxication.

PACKAGE LABEL - PRINCIPAL DISPLAY PANEL - 300 mg/30 mg Bottle

NDC 0406-0484-10

1000 TABLETS

Acetaminophen and Codeine Phosphate
Tablets USP

CIII

300 mg/30 mg

Each tablet contains:
Acetaminophen USP . . . . . . . . . . . . 300 mg
Codeine Phosphate USP. . . . . . . . . . 30 mg

Rx only

This package is not for household use.

PHARMACIST: Dispense the Medication Guide provided separately to each patient.

Mallinckrodt™

L00A34
Rev 12/2016

Index Terms

  • Acetaminophen/Codeine
  • Codeine and Acetaminophen
  • Codeine Phos/Acetaminophen
  • Emtec
  • Tylenol #2
  • Tylenol #3
  • Tylenol Codeine

ALERT U.S. Boxed Warning

Risk of medication errors:

Ensure accuracy when prescribing, dispensing, and administering acetaminophen/codeine. Dosing errors due to confusion between mg and mL, and other acetaminophen/codeine oral suspensions of different concentrations can result in accidental overdose and death.

Addiction, abuse, and misuse:

Acetaminophen/codeine exposes patient 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/codeine, and monitor all patients regularly for the development of these behaviors or conditions.

Life-threatening respiratory depression:

Serious, life-threatening, or fatal respiratory depression may occur with use of acetaminophen/codeine. Monitor for respiratory depression, especially during initiation of acetaminophen/codeine or following a dose increase.

Accidental ingestion:

Accidental ingestion of even one dose of acetaminophen/codeine, especially by children, can result in a fatal overdose of codeine.

Neonatal opioid withdrawal syndrome:

Prolonged use of acetaminophen/codeine 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.

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 cytochrome P450 (CYP-450) 2D6 polymorphism.

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 dosages that exceed 4 g/day, and often involve more than one acetaminophen-containing product.

Interactions with drugs affecting cytochrome P450:

The effects of concomitant use or discontinuation of cytochrome P450 (CYP450) 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors with codeine are complex. Use of CYP450 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors with codeine requires careful consideration of the effects on the parent drug, codeine, and the active metabolite, morphine.

CYP450 3A4 Interaction: The concomitant use of codeine with all CYP450 3A4 inhibitors or discontinuation of a CYP450 3A4 inducer may result in an increase in codeine plasma concentrations with subsequently greater metabolism by CYP450 2D6, resulting in greater morphine levels, which could increase or prolong adverse reactions and may cause potentially fatal respiratory depression. The concomitant use of codeine with all CYP450 3A4 inducers or discontinuation of a CYP450 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/codeine and any CYP3A4 inhibitor or inducer for signs and symptoms that may reflect opioid toxicity and opioid withdrawal when acetaminophen/codeine are used in conjunction with inhibitors and inducers of CYP3A4.

CYP450 2D6 Interaction: The concomitant use of codeine with all CYP450 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 CYP450 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/codeine and any CYP2D6 inhibitor for signs and symptoms that may reflect opioid toxicity and opioid withdrawal when acetaminophen/codeine are used in conjunction with inhibitors of CYP2D6.

Risks from concomitant use with benzodiazepines or other CNS depressants:

Concomitant use of opioids with benzodiazepines or other CNS depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing of acetaminophen/codeine 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.

Side Effects of Acetaminophen and Codeine

Serious side effects have been reported with acetaminophen/codeine. See "Drug Precautions" section.

Common side effects of acetaminophen/codeine include:

  • dizziness
  • lightheadedness
  • shortness of breath
  • drowsiness
  • nausea
  • vomiting
  • constipation

This is not a complete list of acetaminophen/codeine side effects. Ask your doctor or pharmacist for more information.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Acetaminophen and Codeine Food Interactions

Medicines can interact with certain foods. In some cases, this may be harmful and your doctor may advise you to avoid certain foods. In the case of acetaminophen/codeine, there are no specific foods that you must exclude from your diet when receiving acetaminophen/codeine.

Alcohol may intensify some of the side effects of this medication.

Acetaminophen and Codeine and Lactation

Tell your doctor if you are breastfeeding or plan to breastfeed.

The active ingredient in acetaminophen/codeine is excreted in human breast milk. The effect of acetaminophen/codeine on the nursing infant is not known.

Mothers using codeine should be told about when to seek immediate medical care and how to identify the signs and symptoms of infant toxicity, such as drowsiness or sedation, difficulty breastfeeding, breathing difficulties, and decreased tone, in their baby.

Usual Pediatric Dose for Pain

Less than 12 years: Contraindicated

12 to 18 years (postoperatively following a tonsillectomy and/or adenoidectomy): Contraindicated

12 to 18 years (with risk factors for respiratory depression): Avoid use

12 to 18 years: Use only if benefits outweigh potential risks
-Initial dose: Acetaminophen (300 to 600 mg) and codeine (15 to 60 mg) orally every 4 hours as needed for pain
Maximum doses: Acetaminophen 4000 mg/24 hours; Codeine: 360 mg/24 hours

Comments:
-Risk factors that increase sensitivity to the respiratory depressant effects of codeine include postoperative status, obstructive sleep apnea, obesity, and other conditions associated with hypoventilation syndromes (e.g., neuromuscular disease), concomitant use of other mediations that cause respiratory depression, and severe pulmonary disease.
-Initial doses should be individualized taking into account severity of pain, response, prior analgesic treatment experience, and risk factors for addiction, abuse, and misuse.
-Codeine doses higher than 60 mg have not been shown to improve pain relief and are associated with an increased incidence of adverse effects.
-Because of the risks of addiction, abuse and misuse, the lowest effective dose for the shortest duration consistent with individual patient treatment goals should be used.
-Monitor patients closely for respiratory depression within the first 24 to 72 hours of initiating therapy and following any increase in dose.

Use: For the management of mild to moderate pain where treatment with an opioid is appropriate and from which alternative treatments are inadequate.

Dialysis

Data not available

Other Comments

Administration advice:
-Take orally with or without food
-Patients should avoid use of more than one acetaminophen-containing product at a time.

Storage requirements:
-Protect from moisture and light

General:
-Because of the risks of addiction, abuse and misuse with codeine, the lowest dose for the shortest duration consistent with individual patient treatment goals should be used.
-Frequent communication between members of the healthcare team, patients, and their caregiver/family is important during periods of changing analgesic requirements; if the level of pain increases after dose stabilization, an attempt should be made to identify the source of increased pain before increasing the dose of pain medication.
-Patients who are ultra-rapid metabolizers of codeine due to a CYP450 2D6 polymorphism, will convert codeine more rapidly and completely to morphine resulting in unexpectedly high morphine levels, which may be life-threatening.
-Drug-induced hepatotoxicity due to acetaminophen use is preventable; all patients and caregivers need to be educated how to use acetaminophen safely and what to do if more than the recommended dose is consumed.
-Hypersensitivity reactions and serious rashes have been reported with acetaminophen use.

Monitoring:
-Monitor for respiratory depression, especially during initiation and following any increase in dose; close monitoring will be necessary in patients at increased risk and/or those receiving concomitant medications that increase the risk of respiratory depression
-Monitor for signs of hypotension
-Monitor for signs of constipation
-Monitor for skin reactions
-Monitor for the development of behaviors indicative of addiction, abuse, or misuse

Patient advice:
-Patients should understand that this drug, even when taken as recommended can result in addiction, abuse, and misuse; instruct patients not to share their drug with others and protect their drug from theft or misuse.
-Patients should understand the risks of life-threatening respiratory depression and when this risk is greatest, patients should be aware that a genetic mutation may result in greater toxicity in some patients; patients and caregivers should be instructed to get emergency help right away if too much drug is taken or if breathing problems occur.
-Patients should understand this drug has potentially serious side effects including adrenal insufficiency, severe constipation, hepatotoxicity, and hypotension, as well as a number of potentially significant drug interactions; many of these events are avoidable with proper instructions and monitoring; patients should report stopping or starting any new medications and avoid alcohol during therapy.
-Breastfeeding is not recommended while taking this drug; nursing mothers should be instructed to seek immediate medical attention for infants experiencing increased sleepiness, difficulty breastfeeding, breathing difficulties, or limpness.
-Women of child bearing potential should understand that prolonged use during pregnancy can result in neonatal opioid withdrawal syndrome and that prompt recognition and treatment will be necessary.
-This drug may cause drowsiness, dizziness, or impair thinking or motor skills; patients should avoid driving or operating machinery until adverse effects are determined.
-Advise patients to store this drug safely out of the sight and reach of children; accidental use by a child is a medical emergency and can result in death.
-Patients should be instructed in proper disposal.

Response and Effectiveness

  • The analgesic effect of codeine reaches a peak in about two hours and the effects last for between four to six hours. Peak analgesic effects of acetaminophen are reached within 30 to 60 minutes of oral administration and last for three to four hours.
  • About 70-80% of a dose of codeine is metabolized by the liver into a number of metabolites, some active and some inactive. One of these active metabolites is morphine. About 5-10% of codeine is metabolized into morphine by the hepatic enzyme, CYP2D6. Experts believe some of the analgesic properties of codeine are due to it being converted into morphine. Note that up to 10% of Caucasians, 6% of Mexican-Americans, and 5% of African-Americans are poor metabolizers at CYP2D6 and are unlikely to metabolize codeine into morphine. 30% of Ethiopians, 20% of Saudis, 10% of Portuguese and Greeks, and 4% of North Americans are ultra-rapid metabolizers at CYP 2D6 and may experience excessive side effects, such as extreme sleepiness, confusion, and shallow breathing, even with normal dosages of acetaminophen/codeine.

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Acetaminophen / codeine Pregnancy Warnings

Both acetaminophen (paracetamol) and opioid analgesics cross the placenta. Epidemiologic studies have shown acetaminophen (paracetamol) has been used in humans without apparent harmful effects. Codeine has not shown teratogenic effects in rats and rabbits when administered during the period of organogenesis in doses ranging from 5 to 120 mg/kg. Doses of 120 mg/kg in the rat (toxic range) were associated with an increase in embryo resorption at the time of implantation. A single 100 mg/kg subcutaneous codeine dose resulted in delayed ossification in offspring. The use of codeine during labor may cause respiratory depression in the newborn infant. Prolonged use of opioids during pregnancy can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth. The onset, duration, and severity of the condition will vary based on use (duration of use, timing, and amount of last maternal use) and rate of elimination in the newborn. There are no controlled data in human pregnancy. Chronic use of opioids may cause reduced fertility; it is unknown whether these effects are reversible. AU TGA pregnancy category A: Drugs which have been taken by a large number of pregnant women and women of childbearing age without any proven increase in the frequency of malformations or other direct or indirect harmful effects on the fetus having been observed. US FDA pregnancy category C: Animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well-controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks.

Use is not recommended unless the benefit outweighs the risk to the fetus AU TGA pregnancy category: A US FDA pregnancy category: C Comments: Prolonged use of opioids during pregnancy can result in physical dependence in the neonate; women should be advised of the risk of neonatal abstinence syndrome and ensure that appropriate treatment will be available.

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