Codeine-Acetaminophen

Codeine/Acetaminophen is a prescription medication used for the treatment of Mild to Moderately Severe Pain. 

• Codeine/Acetaminophen is available under the following different brand names: Tylenol with Codeine, Tylenol #3, Tylenol #4

Adult and Pediatric dosage

Tablet: Schedule III

• 15mg/300mg
• 30mg/300mg
• 60mg/300mg

Oral suspension: Schedule V

Adult Dosages

• (12mg/120mg)/5mL

Pediatric Dosage

• 15 mL (36mg/360mg) orally every 4 hours as needed

Mild to Moderately Severe Pain

Adult Dosages

• Tablet: 15-60 mg codeine/dose orally every 4-6 hours, not to exceed 360 mg codeine per day or 4 g acetaminophen per day
• Oral solution: 15 mL (36mg/360 mg) orally every 4 hours as needed, not to exceed 4 g acetaminophen per day
• Based on the dosage strength selected and pain severity/tolerance, the prescribed must determine the number of tablets for each dose and frequency of administration (typically every 4-6 hours)

Pediatric Dosage

• Children older than 12 years of age: 0.5-1 mg codeine/kg orally every 4-6 hours (not to exceed 5 doses every 24 hours and 300-1000 mg/dose for acetaminophen (not to exceed 4 g every 24 hours); may repeat dose every 4 hours

Dosage Considerations – Should be Given as Follows: 

• See "Dosages."

Common side effects of Codeine/Acetaminophen include:

• drowsiness, 
• dizziness, 
• tiredness,
• nausea, 
• vomiting, 
• stomach pain, 
• constipation, and
• headache 

Serious side effects of Codeine/Acetaminophen include:

• hives, 
• difficulty breathing, 
• swelling of the face, lips, tongue, or throat, 
• slow breathing with long pauses, 
• blue colored lips, 
• difficult or hard to wake up, 
• skin redness, 
• rash that spreads and causes blistering and peeling, 
• noisy breathing, 
• sighing, 
• shallow breathing, 
• breathing that stops, 
• lightheadedness, 
• confusion, 
• severe drowsiness, 
• nausea, 
• upper stomach pain, 
• itching, 
• loss of appetite, 
• dark urine, 
• clay-colored stools, 
• yellowing of the skin or eyes (jaundice), 
• agitation, 
• hallucinations, 
• fever, 
• sweating, 
• shivering, 
• fast heart rate, 
• muscle stiffness, 
• twitching, 
• loss of coordination, 
• nausea, 
• vomiting, and 
• diarrhea 

Rare side effects of Codeine/Acetaminophen include:

• none 

This is not a complete list of side effects and other serious side effects or health problems may occur as a result of the use of this drug. Call your doctor for medical advice about serious side effects or adverse reactions. You may report side effects or health problems to FDA at 1-800-FDA-1088.

If your medical doctor is using this medicine to treat your pain, your doctor or pharmacist may already be aware of any possible drug interactions and may be monitoring you for them.  Do not start, stop, or change the dosage of any medicine before checking with your doctor, health care provider or pharmacist first

• Codeine/Acetaminophen has severe interactions with the following drugs:
  • alvimopan
• Codeine/Acetaminophen has serious interactions with at least 29 other drugs.
• Codeine/Acetaminophen has moderate interactions with at least 239 other drugs.
• Codeine/Acetaminophen has minor interactions with at least 71 other drugs.

This information does not contain all possible interactions or adverse effects.  Visit the RxList Drug Interaction Checker for any drugs interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use.  Keep a list of all your medications with you, and share this information with your doctor and pharmacist.  Check with your health care professional or doctor for additional medical advice, or if you have health questions, concerns.

Contraindications

• Hypersensitivity to codeine, acetaminophen, or ingredients
• Not indicated for children younger than 12 years of age
• Post-operative management in children <18 years following tonsillectomy and/or adenoidectomy
• Patients with significant respiratory depression, acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment
• Concurrent use of monoamine oxidase inhibitors (MAOIs) or use of MAOIs within last 14 days
• Known or suspected gastrointestinal obstruction, including paralytic ileus
• Hepatitis or severe hepatic/renal impairment. 

Effects of drug abuse

• None

Short-Term Effects

• See "What are Side Effects Associated with Using Codeine/Acetaminophen?"

Long-Term Effects

• See "What Are Side Effects Associated with Using Codeine/Acetaminophen?"

Cautions

• Acetaminophen has been associated with cases of acute liver failure, at times resulting in liver transplantation and death; risk increases in individuals with underlying liver disease, alcohol ingestion, and/or use of more than 1 acetaminophen-containing product (see Black Box Warnings)
• Acetaminophen: Risk for rare, but serious skin reactions that can be fatal; these reactions include Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), and acute generalized exanthematous pustulosis (AGEP); symptoms may include skin redness, blisters and rash
• Acetaminophen may cause serious and potentially fatal skin reactions
• Patients with G6PD deficiency
• Use caution in repeated administration in patients with anemia or with cardiovascular, pulmonary, or renal disease
• Use caution in patients with history of porphyria
• May cause hypotension; use with caution in patients with hypovolemia
• Codeine may cause depression; avoid driving car or operating heavy machinery
• Use caution in patients with conditions associated with hypoxia, hypercapnia, upper respiratory obstruction, or debilitated patients
• May increase respiratory depressant effects; caution with head injury, COPD, or other conditions associated with decreased respiratory drive
• Use caution in patients with hypersensitivity reactions to other phenanthrene-derivative opioid agonists including oxymorphone, levorphanol, oxycodone, or hydrocodone
• Codeine may cause tolerance/dependency
• May obscure diagnosis or clinical course of patients with acute abdominal conditions and may worsen gastrointestinal ileus due to reduced GI motility
• Use caution in adrenal insufficiency, biliary tract impairment, patients susceptible to intracranial effects of CO2 retention, G6PD deficiency, head trauma, prostatic hyperplasia, hepatic/renal impairment, thyroid dysfunction, seizure disorder, or respiratory disease (COPD)
• Codeine may cause or exacerbate constipation; chronic use may result in obstructive bowel disease, especially in patients with existing intestinal motility disorders; reduce potential for constipation by taking preventive measures, including the increase of fiber intake and the use of stool softeners
• Long-term use in patients with adrenal insufficiency may cause secondary hypogonadism, which may lead to sexual dysfunction, infertility, mood disorders, and osteoporosis
• Use with caution in patients with biliary tract dysfunction, including pancreatitis; may increase amylase/lipase levels and may cause constriction of sphincter of Oddi
• Healthcare providers should choose lowest effective dose for shortest period of time and inform patients and caregivers about these risks and the signs of morphine overdose
• Death reported in nursing infant exposed to high levels of morphine in breast milk because mother was an ultra-rapid metabolizer of codeine; breastfeeding is not recommended during treatment
• May cause severe hypotension including orthostatic 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 (eg, phenothiazines or general anesthetics); monitor for signs of hypotension after initiating or titrating dosage; in patients with circulatory shock, drug may cause vasodilatation that can further reduce cardiac output and blood pressure; avoid use in circulatory shock
• Therapy may obscure diagnosis or clinical course in patients with acute abdominal conditions; therapy may cause spasm of sphincter of Oddi; opioids may cause increases in serum amylase; monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms
• Codeine may increase frequency of seizures in patients with seizure disorders, and may increase risk of seizures occurring in other clinical settings associated with seizures; monitor patients with a history of seizure disorders for worsened seizure control during therapy
• Do not abruptly discontinue drug in a patient physically dependent on opioids; when discontinuing therapy in a physically dependent patient, gradually taper the dosage
• Addiction potential
  • Therapy exposes users to the risks of addiction, abuse, and misuse; addiction can occur in patients appropriately prescribed therapy and can occur at recommended dosages; assess each patient’s risk for opioid addiction, abuse, or misuse prior to prescribing therapy; risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (eg, major depression)
  • Patients at increased risk may be prescribed opioids, but use in such patients necessitates intensive counseling about risks and proper use of drug along with intensive monitoring for signs of addiction, abuse, and misuse
• Adrenal insufficiency
  • Cases of adrenal insufficiency reported with opioid use, more often following over a 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 suspected, confirm diagnosis with diagnostic testing as soon as possible; if adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids; wean patient off of 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
• 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 patient’s clinical status; carbon dioxide (CO2) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids
  • Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related hypoxemia; opioid use increases risk of CSA in a dose dependent fashion; in patients who present with CSA, consider decreasing the opioid dosage using best practices for opioid taper
• 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; codeine is subject to variability in metabolism based upon CYP2D6 genotype, which can lead to an increased exposure to active metabolite morphine
  • Based upon post-marketing reports, children <12 years appear to be more susceptible to respiratory depressant effects of codeine, particularly if there are risk factors for respiratory depression; for example, many reported cases of death occurred in the post-operative period following tonsillectomy and/or adenoidectomy, and many of the children had evidence of being ultra-rapid metabolizers of codeine
  • Children with obstructive sleep apnea who are treated with codeine for post-tonsillectomy and/or adenoidectomy pain may be particularly sensitive to its respiratory depressant effects
  • Avoid use in adolescents 12-18 years of age who have other risk factors that may increase their sensitivity to respiratory depressant effects of codeine unless benefits outweigh risks; risk factors include conditions associated with hypoventilation, such as post-operative status, obstructive sleep apnea, obesity, severe pulmonary disease, neuromuscular disease, and concomitant use of other medications that cause respiratory depression
• Patient access to naloxone for emergency treatment of opioid overdose
  • Assess potential need for naloxone; consider prescribing for emergency treatment of opioid overdose
  • Consult on availability and ways to obtain naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines
  • Educate patients regarding the signs and symptoms of respiratory depression and to call 911 or seek immediate emergency medical help in the event of a known or suspected overdose
• Drug interaction overview
  • Concomitant use with all CYP3A4 inhibitors, such as macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (eg, ketoconazole), and protease inhibitors (e.g., ritonavir) or discontinuation of CYP3A4 inducer such as rifampin, carbamazepine, and phenytoin, may increase codeine plasma concentrations with subsequently greater metabolism by CYP2D6, resulting in greater morphine levels, which could increase or prolong adverse reactions and may cause potentially fatal respiratory depression
  • Concomitant use with all CYP3A4 inducers or discontinuation of a CYP3A4 inhibitor may result in lower codeine levels, greater norcodeine levels, and less metabolism via CYP2D6 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 the drug and any CYP3A4 inhibitor or inducer for signs and symptoms that may reflect opioid toxicity and opioid withdrawal when used in combination with inhibitors and inducers of CYP3A4
  • If concomitant use of a CYP3A4 inhibitor is necessary or if a CYP3A4 inducer is discontinued, consider dosage reduction until stable drug effects are achieved; monitor patients for respiratory depression and sedation at frequent intervals; if concomitant use of a CYP3A4 inducer is necessary or if a CYP3A4 inhibitor is discontinued, consider increasing the dosage of the drug until stable drug effects are achieved; monitor for signs of opioid withdrawal
  • Concomitant use with Codeine with all CYP2D6 inhibitors (eg, amiodarone, quinidine) may result in an increase in codeine plasma concentrations and a decrease in active metabolite morphine plasma concentration which could result in analgesic efficacy reduction or symptoms of opioid withdrawal; discontinuation of a concomitantly used CYP2D6 inhibitor may result in a decrease in codeine plasma concentration and an increase in active metabolite morphine plasma concentration which could increase or prolong adverse reactions and may cause potentially fatal respiratory depression
  • Follow patients receiving CYP2D6 inhibitor for signs and symptoms that may reflect opioid toxicity and opioid withdrawal when administered in conjunction with inhibitors of CYP2D6
  • If concomitant use with a CYP2D6 inhibitor necessary, follow patient for signs of reduced efficacy or opioid withdrawal and consider increasing
  • Dosage: after stopping use of a CYP2D6 inhibitor, consider reducing dosage and follow the patient for signs and symptoms of respiratory depression or sedation

Pregnancy and Lactation

• There are no adequate and well-controlled studies in pregnant women; use during pregnancy only if potential benefit justifies potential risk to fetus
• Prolonged use of opioid analgesics during pregnancy for medical or nonmedical purposes can result in physical dependence in neonate and neonatal opioid withdrawal syndrome shortly after birth
• Inform female patients of reproductive potential that prolonged use of drug during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated
• Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea and failure to gain weight; onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination of drug by newborn; observe newborns for symptoms of neonatal opioid withdrawal syndrome and manage accordingly
• Inform female patients of reproductive potential that therapy can cause fetal harm and for patient to inform prescriber of a known or suspected pregnancy
• Inform patients that chronic use of opioids may cause reduced fertility; it is not known whether these effects on fertility are reversible
• Labor and delivery
  • Not recommended for use in pregnant women during or immediately prior to labor, when other analgesic techniques are more appropriate; opioid analgesics, including can prolong labor through actions which temporarily reduce strength, duration, and frequency of uterine contractions
  • Codeine and its active metabolite, morphine, are present in human milk; there are published studies and cases that have reported excessive sedation, respiratory depression, and death in infants exposed to codeine via breast milk; women who are ultra-rapid metabolizers of codeine achieve higher than expected serum levels of morphine, potentially leading to higher levels of morphine in breast milk that can be dangerous in their breastfed infants; in women with normal codeine metabolism (normal CYP2D6 activity)
  • The amount of codeine secreted into human milk is low and dose-dependent; there is no information on effects of codeine on milk production; because of potential for serious adverse reactions, including excess sedation, respiratory depression, and death in a breastfed infant, advise patients that breastfeeding is not recommended during treatment
  • Limited published studies report that acetaminophen passes rapidly into human milk with similar levels in milk and plasma; average and maximum neonatal doses of 1% and 2%, respectively, of weight-adjusted maternal dose are reported after a single oral administration of 1-gram APAP; there is one well documented report of rash in a breast-fed infant that resolved when mother stopped acetaminophen use and recurred when she resumed acetaminophen use
  • If infants are exposed to drug through breast milk, they should be monitored for excess sedation and respiratory depression; withdrawal symptoms can occur in breastfed infants when maternal administration of an opioid analgesic is stopped, or when breastfeeding is stopped