codeine/acetaminophen (Tylenol with Codeine, Tylenol #3, Tylenol #4)
Classes: Analgesics, Opioid Combos
Dosing and uses of Tylenol with Codeine, Tylenol #3 (codeine/acetaminophen)
Adult dosage forms and strengths
tablet: Schedule III
- 15mg/300mg
- 30mg/300mg
- 60mg/300mg
oral suspension: Schedule V
- (12mg/120mg)/5mL
Mild to Moderately Severe Pain
Tablet: 30-60 mg codeine/dose PO q4-6hr; not to exceed 360 mg codeine/day or 4 g acetaminophen/day
Oral solution: 15 mL (36 mg/360 mg) PO q4hr PRN; not to exceed 4 g acetaminophen/day
Dosing considerations
- Based on the dosage strength selected and pain severity/tolerance, the prescriber must determine the number of tablets for each dose and frequency of administration (typically q4-6hr)
Cough
15-30 mg codeine/dose PO q4-6hr; not to exceed 360 mg codeine/day or 4 g acetaminophen/day
Dosage modifications
Renal impairment: Use caution
Hepatic impairment: May tolerate low-dose therapy in hepatic cirrhosis; avoid chronic use
Pediatric dosage forms and strengths
tablet: Schedule III
- 15mg/300mg
- 30mg/300mg
- 60mg/300mg
oral suspension: Schedule V
- (12mg/120mg)/5mL
Mild to Moderately Severe Pain
Tablet
- 7-12 years: 0.5-1 mg codeine/kg/dose PO q4-6hr (not to exceed 5 doses q24hr); 10-15 mg acetaminophen/kg/dose PO q4-6hr (not to exceed 2.6 g acetaminophen q24hr)
- >12 years: As adults; single dose range is 15-60 mg/dose for codeine (not to exceed 360 mg q24hr) and 300-1000 mg/dose for acetaminophen (not to exceed 4 g q24hr); may repeat dose q4hr
Oral suspension
- <3 years: Safety and efficacy not established
- 3-6 years: 5 mL (12 mg/120 mg) PO q6-8hr
- 7-12 years: 10 mL (24 mg/240 mg) PO q6-8hr
- >12 years: 15 mL (36 mg/360 mg) PO q4hr prn
Dosing Considerations
Maximum acetaminophen dose in children should not exceed the following
3 years: 800 mg/day
4-6 years: 1200 mg/day
6-8 years: 1600 mg/day
9-10 years: 2000 mg/day
11-12 years: 2400 mg/day
>12 years: 4000 mg/day
Tylenol with Codeine, Tylenol #3 (codeine/acetaminophen) adverse (side) effects
Frequency not defined (Codeine)
Constipation
Drowsiness
Hypotension
Tachycardia or bradycardia
Confusion
Dizziness
False feeling of well being
Headache
Lightheadedness
Malaise
Paradoxical CNS stimulation
Restlessness
Rash
Urticaria
Anorexia
Nausea
Vomiting
Xerostomia
Ureteral spasm
Decreased urination
Increased LFTs
Burning at injection site
Weakness
Blurred vision
Dyspnea
Histamine release
Frequency not defined (Acetaminophen)
Pruritic maculopapular rash
Urticaria
Laryngeal edema
Angioedema
Anaphylactoid reaction
Thrombocytopenia
Leukopenia
Pancytopenia
Neutropenia
Thrombocytopenic purpura
Agranulocytosis
Hepatotoxicity
Warnings
Black box warnings
Contains acetaminophen
Hepatotoxicity may occur with acetaminophen doses that exceed 4 g/day; take into account all acetaminophen-containing products that the patient is taking, including PRN doses and OTC products
Acetaminophen has been associated with cases of acute liver failure, at times resulting in liver transplantation or death
New dosage limit allows no more than 325 mg/dosage unit for prescription medications that contain acetaminophen
Healthcare professionals can direct patients to take 1 or 2 tablets, capsules, or other dosage units of a prescription product containing 325 mg of acetaminophen up to 6 times a day (12 dosage units) and still not exceed the maximum daily dose of acetaminophen of 4 g/day
Respiratory depression and death reported following tonsillectomy and/or adenoidectomy in patients that appeared to be rapid metabolizers of codeine due to CYP2D6 polymorphism
Contraindications
Hypersensitivity
Hepatitis or severe hepatic/renal impairment
Postoperative pain management in children who have undergone tonsillectomy and/or adenoidectomy
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 an 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 cuation in adrenal insufficiency, billiary 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
Pregnancy and lactation
Pregnancy category: C; may prolong delivery and cause respiratory depression/withdrawal symptoms in newborn
Lactation: Excreted in breast milk; caution advised
Pregnancy categories
A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.
C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.
D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.
X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.
NA: Information not available.
Pharmacology of Tylenol with Codeine, Tylenol #3 (codeine/acetaminophen)
Mechanism of action
Codeine: Opioid agonist; analgesia; blocks pain impulse generation and inhibits ascending pain pathways, thus altering the perception and response to pain; inhibits cough by acting centrally in the medulla; causes CNS depression
Acetaminophen: Nonopioid, nonsalicylate analgesic; may work peripherally to block pain impulse generation; acts on hypothalamus to produce antipyresis
Absorption
Bioavailability: Codeine (53%); acetaminophen (100%)
Onset: 0.5-1 hr
Duration: 4-6 hr
Peak effect: 1-1.5 hr
Distribution
Protein bound: Codeine (<25%); acetaminophen (10-25%), higher with toxic concentrations
Vd: Codeine (3-6 L/kg); acetaminophen (1 L/kg)
Metabolism
Codeine
- Via hepatic UGT2B7 and UGT2B4 to codeine-6-glucuronide
- 10% of codeine is metabolized in liver to morphine by CYP2D6; the active morphine metabolite has a higher affinity for opioid receptors; also via CYP3A4 to norcodeine
- CYPD2D6 poor metabolizers may not achieve adequate analgesia
- Ultrarapid metabolizers (up to 7% of whites and up to 30% of Asian and African populations) may experience increased toxicity due to rapid conversion to morphine
Acetaminophen
- Metabolized in liver by microsomal enzyme systems
- 80-85% conjugated principally with glucuronic acid and to a lesser extent with sulfuric acid and cysteine
- 4% metabolized by CYP450 to toxic metabolite (N acetyl-p-benzoquinoneimine, N-acetylimidoquinone [NAPQI]), which is further detoxified by conjugation with glutathione; high doses may deplete fixed amount of glutathione in body, causing NAPQI accumulation
Elimination
Codeine
- Half-life: 3 hr
- Excretion: Urine (90%)
Acetaminophen
- Half-life: 2-4 hr
- Excretion: Urine (90-100%; principally as acetaminophen glucuronide with acetaminophen sulfate/mercaptate)