Acetaminophen and Codeine

Acetaminophen and codeine is approved to treat mild to moderate pain when an opioid is appropriate and other treatments haven't worked well enough.

• Acetaminophen and Codeine Phosphate tablets: management of mild to moderate pain when non-opioid alternatives are inadequate or not tolerated
• Acetaminophen and Codeine tablets (including TYLENOL with Codeine): same mild to moderate pain indication under the same criteria
• Acetaminophen and Codeine Phosphate oral solution: mild to moderate pain management — not for use in children under 12, or in anyone under 18 following tonsillectomy or adenoidectomy
• All forms: should not be used long-term unless the pain continues to be severe enough to require an opioid and no adequate alternative exists

Codeine binds to opioid receptors in the brain and spinal cord — especially the mu-opioid receptor — to reduce the perception of pain. Much of its effect comes from the liver converting codeine into morphine, which is the more active pain-relieving form. Acetaminophen works through a separate pathway, most likely acting centrally in the brain, though the exact mechanism isn't fully established. Together, these two ingredients provide pain relief through complementary actions.

Because codeine is converted to morphine by a liver enzyme called CYP2D6, people who metabolize it very quickly ("ultra-rapid metabolizers") can build up dangerously high morphine levels — a particularly serious concern in children.

Both the tablet and oral solution forms are taken by mouth, generally every 4 hours as needed for pain. Your prescriber will determine the right dose and schedule for you — always follow those instructions precisely. For the oral solution, always measure your dose using a graduated syringe or measuring cup in mL; never use a kitchen spoon.

• Use the lowest effective dose for the shortest time possible
• Many acute pain situations require only a few days of treatment
• Do not stop abruptly after extended use without talking to your doctor — physical dependence can develop

The most common side effects of acetaminophen and codeine include:

• Drowsiness or sedation
• Dizziness or lightheadedness
• Nausea or vomiting
• Constipation
• Sweating
• Headache
• Dry mouth
• Abdominal pain or discomfort

Serious reactions requiring immediate medical attention include slowed or stopped breathing, extreme sedation, signs of liver injury (yellowing of skin or eyes, dark urine, severe stomach pain), severe allergic reactions, and signs of serotonin syndrome (agitation, rapid heartbeat, muscle twitching).

• Life-threatening respiratory depression: Codeine can slow breathing to a dangerous or fatal degree. Risk is highest when starting treatment or increasing the dose. Call 911 immediately if someone cannot be woken up or is breathing abnormally.
• Addiction and misuse: Codeine is a controlled opioid substance. Addiction can develop even at recommended doses. Risk is higher in people with a personal or family history of substance use disorder.
• Liver damage from acetaminophen: Taking too much acetaminophen — including from other products — can cause acute, sometimes fatal, liver failure. Do not exceed safe daily limits and check all other medications for acetaminophen content.
• Children and teens: The oral solution must not be used in children under 12. No form should be used in anyone under 18 after tonsil or adenoid surgery. Children who are ultra-rapid metabolizers of codeine face an especially high risk of fatal breathing problems.
• Pregnancy: Regular opioid use during pregnancy can cause neonatal opioid withdrawal syndrome in the newborn — a potentially life-threatening condition.
• Dosing errors with the oral solution: Confusion between mg and mL, or between different concentrations, can cause fatal overdose. Always verify the dose carefully.

Acetaminophen and codeine interacts with several important drug categories. Always tell your doctor and pharmacist everything you take, including supplements and over-the-counter products.

• Benzodiazepines and other sedatives (e.g., diazepam, alprazolam, sleep aids): can cause dangerous sedation, stopped breathing, coma, or death
• Alcohol: increases sedation and respiratory depression — avoid entirely while taking this medication
• MAO inhibitors (e.g., phenelzine, linezolid): can trigger serotonin syndrome or opioid toxicity; do not combine, and wait at least 14 days after stopping an MAOI
• CYP2D6 inhibitors (e.g., paroxetine, fluoxetine, bupropion, quinidine): alter how your body converts codeine to morphine, changing both effectiveness and risk
• CYP3A4 inhibitors (e.g., erythromycin, ketoconazole, ritonavir): can raise codeine levels and increase risk of side effects or respiratory depression
• CYP3A4 inducers (e.g., rifampin, carbamazepine, phenytoin): can lower codeine levels, reducing pain relief or causing withdrawal
• Serotonergic drugs (SSRIs, SNRIs, tricyclic antidepressants, triptans, tramadol): can cause serotonin syndrome
• Anticholinergic drugs: worsen constipation and may cause urinary retention
• Muscle relaxants: increase risk of respiratory depression when combined with codeine
• Diuretics: codeine may reduce their effectiveness

This is not a complete list of interactions. Always talk with your doctor or pharmacist before starting, stopping, or changing any medication.

• Tell your prescriber if you have ever had a substance use disorder, alcohol dependence, or a mental health condition such as depression
• Tell your prescriber about any breathing conditions — including asthma, COPD, or sleep apnea — as codeine can worsen respiratory problems
• Tell your prescriber if you have liver disease or drink alcohol regularly; acetaminophen carries a serious liver injury risk
• Tell your prescriber if you are pregnant — extended opioid use can cause life-threatening withdrawal in the newborn
• Tell your prescriber if you are breastfeeding — codeine passes into breast milk and can harm a nursing infant
• Do not use the oral solution if you are under 12 years of age
• Do not use any form of this medication if you are under 18 and have recently had tonsil or adenoid surgery
• Tell your prescriber about all other medications, especially any that contain acetaminophen, sedatives, antidepressants, or antibiotics
• Do not use this medication if you have significant respiratory depression, uncontrolled asthma, a bowel obstruction (including paralytic ileus), or a known allergy to codeine or acetaminophen
• Do not use within 14 days of taking a monoamine oxidase inhibitor (MAOI)

An overdose can be life-threatening and requires immediate emergency care. Codeine overdose can cause extremely slowed or stopped breathing, loss of consciousness, limpness, pinpoint pupils, and cold or clammy skin. Acetaminophen overdose may not cause obvious symptoms right away, but can lead to severe liver damage within 48 to 72 hours — early signs include nausea, vomiting, and abdominal pain. If you suspect an overdose, call 911 immediately; opioid overdose reversal agents such as naloxone can reverse codeine's effects, but emergency medical care is still essential even after a reversal agent is used.

Codeine acts on the brain's respiratory control centers, which is why it can slow breathing — a key risk at higher doses. It also slows movement through the digestive tract, which commonly causes constipation. It can cause a drop in blood pressure when standing up quickly (orthostatic hypotension) and may trigger the release of histamine, leading to flushing, itching, or sweating. With long-term use, codeine and other opioids can affect hormone levels, potentially causing sexual dysfunction, irregular periods, or reduced fertility.

Codeine is absorbed quickly from the gut after an oral dose. Pain relief typically begins within about 2 hours and lasts 4 to 6 hours. The liver converts codeine into morphine (via an enzyme called CYP2D6) and other byproducts; about 90% of the dose is cleared by the kidneys within 24 hours. Codeine's half-life — the time for half of it to leave the body — is roughly 3 hours. Acetaminophen is also rapidly absorbed, processed mainly by the liver, and largely eliminated in the urine within 24 hours; its half-life is about 1.25 to 3 hours, but can be longer in people with liver damage.

Store at 20° to 25°C (68° to 77°F) . Dispense in a tight, light-resistant container with a child-resistant closure. Store acetaminophen and codeine phosphate oral solution securely and dispose of properly .