Note: This document contains side effect information about acetaminophen / codeine. Some dosage forms listed on this page may not apply to the brand name Tylenol with Codeine #4.
Applies to acetaminophen / codeine: oral elixir, oral solution, oral tablet.
Warning
Oral route (Tablet)
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 or conditions.
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.
Opioid Analgesic Risk Evaluation and Mitigation Strategy (REMS)
: To ensure that the benefits of opioid analgesics outweigh the risks of addiction, abuse, and misuse, the Food and Drug Administration (FDA) has required a REMS for these products. Under the requirements of the REMS, drug companies with approved opioid analgesic products must make REMS-compliant education programs available to healthcare providers. Healthcare providers are strongly encouraged to; complete a REMS-compliant education program, counsel patients and/or their caregivers, with every prescription, on safe use, serious risks, storage, and disposal of these products, emphasize to patients and their caregivers the importance of reading the Medication Guide every time it is provided by their pharmacist, and consider other tools to improve patient, household, and community safety.
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.
Ultra-Rapid Metabolism of Codeine and Other Risk Factors for Life-Threatening Respiratory Depression in Children
Life-threatening respiratory depression and death have occurred in children who received codeine. Most of the reported cases occurred following tonsillectomy and/or adenoidectomy and many of the children had evidence of being ultra-rapid metabolizers of codeine due to CYP2D6 polymorphism. Acetaminophen and codeine phosphate tablets are contraindicated in children younger than 12 years of age and in children younger than 18 years of age following tonsillectomy and/or adenoidectomy. Avoid the use of acetaminophen and codeine phosphate tablets in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of codeine.
Neonatal Opioid Withdrawal Syndrome
Prolonged use of acetaminophen and codeine phosphate tablets during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated, 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.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 with codeine requires careful consideration of the effects on the parent drug, codeine, and the active metabolite, morphine.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 4000 milligrams per day, and often involve more than one acetaminophen-containing product.
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. 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. Follow patients for signs and symptoms of respiratory depression and sedation.
Oral route (Solution)
of Medication Errors: Ensure accuracy when prescribing, dispensing, and administering acetaminophen and codeine phosphate oral solution. Dosing errors due to confusion between mg and mL, and other codeine containing oral products of different concentrations can result in accidental overdose and death.Addiction, Abuse, and Misuse
Acetaminophen and codeine phosphate oral solution 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 oral solution, 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 and codeine phosphate oral solution. Monitor for respiratory depression, especially during initiation of acetaminophen and codeine phosphate oral solution or following a dose increase.
Opioid Analgesic Risk Evaluation and Mitigation Strategy (REMS)
: To ensure that the benefits of opioid analgesics outweigh the risks of addiction, abuse, and misuse, the Food and Drug Administration (FDA) has required a REMS for these products. Under the requirements of the REMS, drug companies with approved opioid analgesic products must make REMS-compliant education programs available to healthcare providers. Healthcare providers are strongly encouraged to; complete a REMS-compliant education program, counsel patients and/or their caregivers, with every prescription, on safe use, serious risks, storage, and disposal of these products, emphasize to patients and their caregivers the importance of reading the Medication Guide every time it is provided by their pharmacist, and consider other tools to improve patient, household, and community safety.
Accidental Ingestion
Accidental ingestion of acetaminophen and codeine phosphate oral solution, especially by children, can result in a fatal overdose of acetaminophen and codeine phosphate oral solution.
Ultra-Rapid Metabolism of Codeine and Other Risk Factors for Life-Threatening Respiratory Depression in Children
Life-threatening respiratory depression and death have occurred in children who received codeine. Most of the reported cases occurred following tonsillectomy and/or adenoidectomy and many of the children had evidence of being ultra-rapid metabolizers of codeine due to CYP2D6 polymorphism. Acetaminophen and codeine phosphate oral solution are contraindicated in children younger than 12 years of age and in children younger than 18 years of age following tonsillectomy and/or adenoidectomy. Avoid the use of acetaminophen and codeine phosphate oral solution in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of codeine.
Neonatal Opioid Withdrawal Syndrome
Prolonged use of acetaminophen and codeine phosphate oral solution 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.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 with codeine oral solution requires careful consideration of the effects on the parent drug, codeine, and the active metabolite, morphine.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 4000 milligrams per day, and often involve more than one acetaminophen-containing product.
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. Reserve concomitant prescribing of acetaminophen and codeine phosphate oral solution and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate. Follow patients for signs and symptoms of respiratory depression and sedation.
Serious side effects
Along with its needed effects, acetaminophen / codeine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.
Check with your doctor immediately if any of the following side effects occur while taking acetaminophen / codeine:
More common
- Difficult or trouble breathing
- irregular, fast or slow, or shallow breathing
- pale or blue lips, fingernails, or skin
Incidence not known
- Black, tarry stools
- bleeding gums
- blood in the urine or stools
- cough
- difficulty with swallowing
- dizziness
- fast heartbeat
- fever with or without chills
- general feeling of tiredness or weakness
- hives, itching, skin rash
- hoarseness
- lower back or side pain
- painful or difficult urination
- pinpoint red spots on the skin
- puffiness or swelling of the eyelids or around the eyes, face, lips, or tongue
- sore throat
- sores, ulcers, or white spots on the lips or in the mouth
- tightness in the chest
- unusual bleeding or bruising
- unusual tiredness or weakness
Get emergency help immediately if any of the following symptoms of overdose occur while taking acetaminophen / codeine:
Symptoms of overdose
- Bloody or cloudy urine
- chills
- constricted, pinpoint, or small pupils (black part of the eye)
- dark urine
- headache
- increased sweating
- light-colored stools
- loss of appetite
- loss of consciousness
- nausea
- seizures
- stomach pain
- sudden decrease in the amount of urine
- unpleasant breath odor
- vomiting
- vomiting of blood
- yellow eyes or skin
Other side effects
Some side effects of acetaminophen / codeine may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects.
Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:
More common
- Drowsiness
- lightheadedness
- relaxed and calm feeling
- sleepiness
Incidence not known
- Difficulty having a bowel movement
- false or unusual sense of well-being
For Healthcare Professionals
Applies to acetaminophen / codeine: oral capsule, oral liquid, oral suspension, oral tablet.
General
The most frequently observed adverse reactions include drowsiness, lightheadedness, dizziness, sedation, shortness of breath, nausea, and vomiting.[Ref]
Nervous system
Acetaminophen-codeine:
Common (1% to 10%): Drowsiness, dizziness
Frequency not reported: Lightheadedness, sedation, medication over-use headache
Acetaminophen:
Frequency not reported: Drowsiness, impaired mental functions
Opioids:
Frequency not reported: Confusion, drowsiness, vertigo, dizziness, CNS excitation (restlessness/excitement), convulsions, headache, raised intracranial pressure[Ref]
Gastrointestinal
Acetaminophen-codeine:
Frequency not reported: Nausea, vomiting, constipation, abdominal pain
Acetaminophen:
Very rare (less than 0.01%): Pancreatitis
Frequency not reported: Dyspepsia
Opioids:
Frequency not reported: Constipation, GI irritation, biliary spasm, nausea, vomiting, loss of appetite, dry mouth, paralytic ileus, toxic megacolon[Ref]
Hepatic
Acetaminophen:
Frequency not reported: Acute liver failure, hepatotoxicity, chronic hepatic necrosis, cytolytic hepatitis[Ref]
Psychiatric
Acetaminophen-codeine:
Frequency not reported: Euphoria, dysphoria
Opioid:
Frequency not reported: Confusion, changes in mood, hallucinations, mental depression, trouble sleeping or nightmares, tolerance or dependence[Ref]
Renal
Acetaminophen-codeine:
Frequency not reported: Renal failure, uremia
Acetaminophen:
Frequency not reported: Nephrotoxicity, papillary necrosis[Ref]
Hypersensitivity
Acetaminophen-codeine:
Frequency not reported: Allergic reactions
Acetaminophen:
Rare (less than 0.1%): Allergic reactions including skin rash, drug fever, mucosal lesions
Postmarketing reports: Hypersensitivity including swelling of the face, mouth, and throat, respiratory distress, urticaria, rash, pruritus, and vomiting, anaphylaxis, angioedema
Opioids:
Frequency not reported: Rash, urticaria, difficulty breathing, increased sweating, redness, redness or flushed face[Ref]
Cardiovascular
Acetaminophen:
Frequency not reported: Toxic myocarditis, Kounis syndrome
Opioids:
Frequency not reported: Bradycardia, palpitations, hypotension[Ref]
Genitourinary
Acetaminophen-codeine:
Frequency not reported: Urinary retention or hesitance
Opioids:
Frequency not reported: Urinary retention, ureteral spasm, antidiuretic effect[Ref]
Hematologic
Acetaminophen-codeine:
Frequency not reported: Thrombocytopenia, agranulocytosis, anemia
Acetaminophen:
Very rare (less than 0.01%): Thrombocytopenia, neutropenia, leucopenia
Frequency not reported: Agranulocytosis, methemoglobinemia, pancytopenia, thrombocytopenia purpura, hemolytic anemia[Ref]
Dermatologic
Acetaminophen-codeine:
Frequency not reported: Pruritus, rash
Acetaminophen:
Rare (less than 0.1%): Serious skin reactions such as acute generalized exanthematous pustulosis (AGEP), Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN)
Frequency not reported: Sweating, fixed drug eruption[Ref]
Respiratory
Acetaminophen-codeine:
Frequency not reported: Shortness of breath
Acetaminophen:
Frequency not reported: Bronchospasm
Codeine:
Frequency not reported: Respiratory depression[Ref]
In patients with a tendency of analgesic asthma acetaminophen-use has triggered bronchospasms.[Ref]
Ocular
Opioids:
Frequency not reported: Blurred or double vision[Ref]
