codeine/acetaminophen (Tylenol with Codeine, Tylenol #3, Tylenol #4)

Dosing and uses of Tylenol with Codeine, Tylenol #3 (codeine/acetaminophen)

• Adult
• Pediatric

 

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)