Acetaminophen and Codeine

Pronunciation

(a seet a MIN oh fen & KOE deen)

U.S. Brand Names

Capital® and Codeine; Tylenol® With Codeine

Synonyms

Codeine and Acetaminophen

Generic Available

Yes

Canadian Brand Names

ratio-Emtec; ratio-Lenoltec; Triatec-8; Triatec-8 Strong; Triatec-30; Tylenol Elixir with Codeine; Tylenol No. 1; Tylenol No. 1 Forte; Tylenol No. 2 with Codeine; Tylenol No. 3 with Codeine; Tylenol No. 4 with Codeine

Use

Relief of mild to moderate pain

Use - Dental

Treatment of postoperative pain

Restrictions

C-III; C-V

Note: In countries outside of the U.S., some formulations of Tylenol® with Codeine (eg, Tylenol® No. 3) include caffeine.

Pregnancy Risk Factor

Lactation

Enters breast milk/use caution

Contraindications

Hypersensitivity to acetaminophen, codeine, or any component of the formulation; significant respiratory depression (in unmonitored settings); acute or severe bronchial asthma; hypercapnia; paralytic ileus

Warnings/Precautions

Use with caution in patients with hypersensitivity reactions to other phenanthrene derivative opioid agonists (morphine, hydrocodone, hydromorphone, levorphanol, oxycodone, oxymorphone); tablets contain metabisulfite which may cause allergic reactions. Tolerance or drug dependence may result from extended use.

Limit total acetaminophen dose to <4 g/day. May cause severe hepatic toxicity on acute overdose; in addition, chronic daily dosing in adults has resulted in liver damage in some patients. Use with caution in patients with alcoholic liver disease; consuming 3 alcoholic drinks/day may increase the risk of liver damage. Use caution in patients with known G6PD deficiency.

This combination should be used with caution in elderly or debilitated patients, hypotension, adrenocortical insufficiency, thyroid disorders, prostatic hyperplasia, urethral stricture, seizure disorder, CNS depression, head injury or increased intracranial pressure. Causes sedation; caution must be used in performing tasks which require alertness (eg, operating machinery or driving). Safety and efficacy in pediatric patients have not been established.

Note: Some non-U.S. formulations (including most Canadian formulations) may contain caffeine as an additional ingredient. Caffeine may cause CNS and cardiovascular stimulation, as well as GI irritation in high doses. Use with caution in patients with a history of peptic ulcer or GERD; avoid in patients with symptomatic cardiac arrhythmias.

Adverse Reactions

>10%:

Central nervous system: Lightheadedness, dizziness, sedation

Gastrointestinal: Nausea, vomiting

Respiratory: Dyspnea

1% to 10%:

Central nervous system: Euphoria, dysphoria

Dermatologic: Pruritus

Gastrointestinal: Constipation, abdominal pain

Miscellaneous: Histamine release

<1%: Palpitations, hypotension, bradycardia, peripheral vasodilation, increased intracranial pressure, antidiuretic hormone release, biliary tract spasm, urinary retention, miosis, respiratory depression, physical and psychological dependence

Overdosage/Toxicology

Symptoms of overdose include hepatic necrosis, blood dyscrasias, respiratory depression.

Acetylcysteine 140 mg/kg orally (loading) followed by 70 mg/kg every 4 hours for 17 doses; therapy should be initiated based upon laboratory analysis suggesting high probability of hepatotoxic potential.

Naloxone 2 mg I.V. (0.01 mg/kg for children) with repeat administration as necessary up to a total of 10 mg; can also be used to reverse the toxic effects of the opiate.

Activated charcoal is effective at binding certain chemicals, and this is especially true for acetaminophen (use within 2 hours of ingestion).

Drug Interactions

Acetaminophen: Substrate (minor) of CYP1A2, 2A6, 2C8/9, 2D6, 2E1, 3A4; Inhibits CYP3A4 (weak)

Increased toxicity: CNS depressants, phenothiazines, tricyclic antidepressants, guanabenz, MAO inhibitors (may also decrease blood pressure); effect of warfarin may be enhanced

Ethanol/Nutrition/Herb Interactions

Ethanol: Excessive intake of ethanol may increase the risk of acetaminophen-induced hepatotoxicity. Avoid ethanol or limit to <3 drinks/day.

Mechanism of Action

Inhibits the synthesis of prostaglandins in the central nervous system and peripherally blocks pain impulse generation; produces antipyresis from inhibition of hypothalamic heat-regulating center; binds to opiate receptors in the CNS, causing inhibition of ascending pain pathways, altering the perception of and response to pain; causes cough supression by direct central action in the medulla; produces generalized CNS depression. Caffeine (contained in some non-U.S. formulations) is a CNS stimulant; use with acetaminophen and codeine increases the level of analgesia provided by each agent.

Pharmacodynamics/Kinetics

See individual agents.

Dosage

Doses should be adjusted according to severity of pain and response of the patient. Adult doses

60 mg codeine fail to give commensurate relief of pain but merely prolong analgesia and are associated with an appreciably increased incidence of side effects. Oral:

Children: Analgesic:

Codeine: 0.5-1 mg codeine/kg/dose every 4-6 hours

Acetaminophen: 10-15 mg/kg/dose every 4 hours up to a maximum of 2.6 g/24 hours for children <12 years; alternatively, the following can be used:

3-6 years: 5 mL 3-4 times/day as needed of elixir

7-12 years: 10 mL 3-4 times/day as needed of elixir

>12 years: 15 mL every 4 hours as needed of elixir

Adults:

Antitussive: Based on codeine (15-30 mg/dose) every 4-6 hours (maximum: 360 mg/24 hours based on codeine component)

Analgesic: Based on codeine (30-60 mg/dose) every 4-6 hours (maximum: 4000 mg/24 hours based on acetaminophen component)

Dosing adjustment in renal impairment: See individual monographs for Acetaminophen and Codeine

Monitoring Parameters

Relief of pain, respiratory and mental status, blood pressure, bowel function

Dietary Considerations

May be taken with food.

Patient Education

See individual agents. Pregnancy/breast-feeding precautions: Inform prescriber if you are or intend to become pregnant. Consult prescriber if breast-feeding.

Nursing Implications

Observe patient for excessive sedation, respiratory depression, constipation

Cardiovascular Considerations

Codeine may cause constipation which may be problematic in patients with unstable angina, and patients after myocardial infarction. The hemodynamic responses to valsalva-like maneuvers due to straining may have adverse cardiovascular consequences in patients with critical coronary artery disease.

Dental Health: Effects on Dental Treatment

No significant effects or complications reported

Dental Health: Vasoconstrictor/Local Anesthetic Precautions

No information available to require special precautions

Dental Comment

Codeine products, as with other narcotic analgesics, are recommended only for acute dosing (ie, 3 days or less). The most common adverse effect you will see in your dental patients from codeine is nausea, followed by sedation and constipation. Codeine has narcotic addiction liability, especially when given long-term. Because of the acetaminophen component, this product should be used with caution in patients with alcoholic liver disease.

A study by Hylek, et al, suggested that the combination of acetaminophen with warfarin (Coumadin®) may cause enhanced anticoagulation. The following recommendations have been made by Hylek, et al, and supported by an editorial in JAMA by Bell.

Dose and duration of acetaminophen should be as low as possible, individualized and monitored.

The study by Hylek reported the following:

For patients who reported taking the equivalent of at least 4 regular strength (325 mg) tablets for longer than a week, the odds of having an INR >6.0 were increased 10-fold above those not taking acetaminophen. Risk decreased with lower intakes of acetaminophen reaching a background level of risk at a dose of 6 or fewer 325 mg tablets per week.

Mental Health: Effects on Mental Status

Sedation is common; less commonly, codeine may produce euphoria or dysphoria

Mental Health: Effects on Psychiatric Treatment

Codeine may produce physical and psychological dependence. Antipsychotics, TCAs, MAO inhibitors, barbiturates, benzodiazepines, and anticonvulsants may increase the toxicity of codeine. Barbiturates and carbamazepine may increase the hepatotoxic potential of acetaminophen. Diminution of pain relief may occur with the SSRIs.

Dosage Forms

[DSC] = Discontinued product; [CAN] = Canadian brand name

Caplet:

ratio-Lenoltec No. 1 [CAN], Tylenol No. 1 [CAN]: Acetaminophen 300 mg, codeine phosphate, 8 mg and caffeine 15 mg [not available in the U.S.]

Tylenol No. 1 Forte [CAN]: Acetaminophen 500 mg, codeine phosphate 8 mg, and caffeine 15 mg [not available in the U.S.]

Elixir, oral [C-V]: Acetaminophen 120 mg and codeine phosphate 12 mg per 5 mL (5 mL, 10 mL, 12.5 mL, 15 mL, 120 mL, 480 mL) [contains alcohol 7%]

Tylenol® with Codeine [DSC]: Acetaminophen 120 mg and codeine phosphate 12 mg per 5 mL (480 mL) [contains alcohol 7%; cherry flavor]

Tylenol Elixir with Codeine [CAN]: Acetaminophen 160 mg and codeine phosphate 8 mg per 5 mL (500 mL) [contains alcohol 7%, sucrose 31%; cherry flavor; not available in the U.S.]

Suspension, oral [C-V] (Capital® and Codeine): Acetaminophen 120 mg and codeine phosphate 12 mg per 5 mL (480 mL) [alcohol free; fruit punch flavor]

Tablet [C-III]: Acetaminophen 300 mg and codeine phosphate 15 mg; acetaminophen 300 mg and codeine phosphate 30 mg; acetaminophen 300 mg and codeine phosphate 60 mg

ratio-Emtec [CAN], Triatec-30 [CAN]: Acetaminophen 300 mg and codeine phosphate 30 mg [not available in the U.S.]

ratio-Lenoltec No. 1 [CAN]: Acetaminophen 300 mg, codeine phosphate 8 mg, and caffeine 15 mg [Not available in the U. S.]

ratio-Lenoltec No. 2 [CAN], Tylenol No. 2 with Codeine [CAN]: Acetaminophen 300 mg, codeine phosphate 15 mg, and caffeine 15 mg [not available in the U.S.]

ratio-Lenoltec No. 3 [CAN], Tylenol No. 3 with Codeine [CAN]: Acetaminophen 300 mg, codeine phosphate 30 mg, and caffeine 15 mg [not available in the U.S.]

ratio-Lenoltec No. 4 [CAN], Tylenol No. 4 with Codeine [CAN]: Acetaminophen 300 mg and codeine phosphate 60 mg [not available in the U.S.]

Triatec-8 [CAN]: Acetaminophen 325 mg, codeine phosphate 8 mg, and caffeine 30 mg [not available in the U.S.]

Triatec-8 Strong [CAN]: Acetaminophen 500 mg, codeine phosphate 8 mg, and caffeine 30 mg [not available in the U.S.]

Tylenol® with Codeine No. 3: Acetaminophen 300 mg and codeine phosphate 30 mg [contains sodium metabisulfite]

Tylenol® with Codeine No. 4: Acetaminophen 300 mg and codeine phosphate 60 mg [contains sodium metabisulfite]

References

Dionne RA, "New Approaches to Preventing and Treating Postoperative Pain," J Am Dent Assoc , 1992, 123(6):26-34.

Dionne RA, Campbell RA, Cooper SA, et al, "Suppression of Postoperative Pain by Preoperative Administration of Ibuprofen in Comparison to Placebo, Acetaminophen, and Acetaminophen Plus Codeine," J Clin Pharmacol , 1983, 23(1):37-43.

Mokhlesi B, Leikin JB, Murray P, et al, "Adult Toxicology in Critical Care: Part II: Specific Poisonings," Chest , 2003, 123(3):897-922.

Forbes JA, Butterworth GA, Burchfield WH, et al, "Evaluation of Ketorolac, Aspirin, and an Acetaminophen-Codeine Combination in Postoperative Oral Surgery Pain," Pharmacotherapy , 1990, 10(6 Pt 2):77S-93S.

Gobetti JP, "Controlling Dental Pain," J Am Dent Assoc , 1992, 123(6):47-52.

International Brand Names

ratio-Emtec (CA); ratio-Lenoltec (CA); Triatec-8 (CA); Triatec-8 Strong (CA); Triatec-30 (CA); Tylenol Elixir with Codeine (CA); Tylenol No. 1 (CA); Tylenol No. 1 Forte (CA); Tylenol No. 2 with Codeine (CA); Tylenol No. 3 with Codeine (CA); Tylenol No. 4 with Codeine (CA)

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