Acetaminophen and codeine

Acetaminophen and codeine: Drug information
Copyright 1978-2011 Lexicomp, Inc. All rights reserved.
(For additional information see “Acetaminophen and codeine: Patient drug information” and see “Acetaminophen and codeine: Pediatric drug information”)

Special Alerts
Acetaminophen: Change in Maximum Content of Prescription Products and Labeling Changes January 2011
The Food and Drug Administration (FDA) is asking manufacturers to limit the strength of acetaminophen in prescription products to 325 mg per dosage unit. Drug manufacturers will have until January 14, 2014 to comply with the FDA’s request. The dosing instructions of prescription acetaminophen products will not change. For example, the instructions of 1-2 tablets every 4-6 hours for a combination product of acetaminophen 500 mg with an opioid can still be used for a combination product of acetaminophen 325 mg with an opioid.

The FDA is also notifying healthcare professionals of labeling changes for all prescription products that contain acetaminophen. A Boxed Warning will be required on all prescription acetaminophen products to describe the potential risk of severe liver injury. Additionally, the FDA has asked manufacturers to add a Warning regarding the potential for allergic reactions, including anaphylaxis.

Healthcare professionals should advise patients:

– not to exceed 4 g/day of acetaminophen

– not to take multiple acetaminophen-containing products (including over-the-counter products)

– not to consume alcohol while taking acetaminophen-containing products

– that severe liver injury and cases of hypersensitivity reactions (including anaphylaxis) have occurred with the use of acetaminophen

– to report taking more acetaminophen than directed

– to report any adverse events that may have occurred with the use of acetaminophen

Further information may be found at: file://www.fda.gov/Drugs/DrugSafety/ucm239821.htm

ALERT: U.S. Boxed Warning The FDA-approved labeling includes a boxed warning. See Warnings/Precautions section for a concise summary of this information. For verbatim wording of the boxed warning, consult the product labeling or www.fda.gov.
Brand Names: U.S. Capital® and Codeine; Tylenol® with Codeine No. 3; Tylenol® with Codeine No. 4
Brand Names: Canada ratio-Emtec; ratio-Lenoltec; Triatec-30; Triatec-8; Triatec-8 Strong; 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
Pharmacologic Category Analgesic, Opioid
Dosing: Adult 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.
Cough (Antitussive): Oral: Based on codeine (15-30 mg/dose) every 4-6 hours (maximum: 360 mg/24 hours based on codeine component)

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

1-2 tablets every 4 hours to a maximum of 12 tablets/24 hours

Dosing: Pediatric
(For additional information see “Acetaminophen and codeine: Pediatric drug information”)

Analgesic: Oral:

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

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

Dosing: Geriatric Doses should be titrated to appropriate analgesic effect.
One Tylenol® No. 3 tablet every 4 hours; do not exceed 4 g/day acetaminophen.

Dosing: Renal Impairment See individual agents.
Dosing: Hepatic Impairment Use with caution. Limited, low-dose therapy is usually well tolerated in hepatic disease/cirrhosis; however, cases of hepatotoxicity at daily acetaminophen dosages <4 g/day have been reported. Avoid chronic use in hepatic impairment.
Dosage Forms: U.S. Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution, 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%]

Suspension, oral [C-V] (Capital® and Codeine): Acetaminophen 120 mg and codeine phosphate 12 mg per 5 mL (480 mL) [alcohol free; contains propylene glycol, sodium benzoate; 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

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]

Dosage Forms: Canada Excipient information presented when available (limited, particularly for generics); consult specific product labeling. Note: In countries outside of the U.S., some formulations of Tylenol® with Codeine include caffeine.
Caplet:

ratio-Lenoltec No. 1, Tylenol No. 1: Acetaminophen 300 mg, codeine phosphate 8 mg, and caffeine 15 mg

Tylenol No. 1 Forte: Acetaminophen 500 mg, codeine phosphate 8 mg, and caffeine 15 mg

Solution, oral:

Tylenol Elixir with Codeine: Acetaminophen 160 mg and codeine phosphate 8 mg per 5 mL (500 mL) [contains alcohol 7%, sucrose 31%; cherry flavor]

Tablet:

ratio-Emtec, Triatec-30: Acetaminophen 300 mg and codeine phosphate 30 mg

ratio-Lenoltec No. 1: Acetaminophen 300 mg, codeine phosphate 8 mg, and caffeine 15 mg

ratio-Lenoltec No. 2, Tylenol No. 2 with Codeine: Acetaminophen 300 mg, codeine phosphate 15 mg, and caffeine 15 mg

ratio-Lenoltec No. 3, Tylenol No. 3 with Codeine: Acetaminophen 300 mg, codeine phosphate 30 mg, and caffeine 15 mg

ratio-Lenoltec No. 4, Tylenol No. 4 with Codeine: Acetaminophen 300 mg and codeine phosphate 60 mg

Triatec-8: Acetaminophen 325 mg, codeine phosphate 8 mg, and caffeine 30 mg

Triatec-8 Strong: Acetaminophen 500 mg, codeine phosphate 8 mg, and caffeine 30 mg

Generic Equivalent Available: U.S. Yes
Administration May be administered with food.
Use Relief of mild-to-moderate pain
Medication Safety Issues
Sound-alike/look-alike issues:
Tylenol® may be confused with atenolol, timolol, Tylox®

High alert medication:
The Institute for Safe Medication Practices (ISMP) includes this medication among its list of drug classes which have a heightened risk of causing significant patient harm when used in error.

Other safety concerns:
Duplicate therapy issues: This product contains acetaminophen, which may be a component of other combination products. Do not exceed the maximum recommended daily dose of acetaminophen.

T3 is an error-prone abbreviation (mistaken as liothyronine)

International issues:
Codex: Brand name for acetaminophen/codeine [Brazil], but also the brand name for saccharomyces boulardii [Italy]

Codex [Brazil] may be confused with Cedax brand name for ceftibuten [U.S. and multiple international markets]

Adverse Reactions Significant
>10%:

Central nervous system: Dizziness, lightheadedness, sedation

Gastrointestinal: Nausea, vomiting

Respiratory: Dyspnea

1% to 10%:

Central nervous system: Dysphonia, euphoria

Dermatologic: Pruritus

Gastrointestinal: Abdominal pain, constipation

Miscellaneous: Histamine release

<1% (Limited to important or life-threatening): Antidiuretic hormone release, biliary tract spasm, bradycardia, hypotension, intracranial pressure increased, miosis, palpitation, peripheral vasodilation, physical and psychological dependence, respiratory depression, urinary retention

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
Boxed warnings:

• Hepatotoxicity: See “Concerns related to adverse effects” below.

Concerns related to adverse effects:

• CNS depression: May cause CNS depression, which may impair physical or mental abilities; patients must be cautioned about performing tasks which require mental alertness (eg, operating machinery or driving).

• Hepatotoxicity: [U.S. Boxed Warning]: Acetaminophen may cause severe hepatotoxicity, potentially requiring liver transplant or resulting in death; hepatotoxicity is usually associated with excessive acetaminophen intake (>4 g/day). Risk is increased with alcohol use, pre-existing liver disease, and intake of more than one source of acetaminophen-containing medications. Chronic daily dosing in adults has also resulted in liver damage in some patients.

• Hypersensitivity/anaphylactic reactions: Hypersensitivity and anaphylactic reactions have been reported with acetaminophen use; discontinue immediately if symptoms of allergic or hypersensitivity reactions occur. Use with caution in patients with hypersensitivity reactions to other phenanthrene-derivative opioid agonists (hydrocodone, hydromorphone, levorphanol, oxycodone, oxymorphone).

• Hypotension: May cause hypotension; use with caution in patients with hypovolemia, cardiovascular disease (including acute MI), or drugs which may exaggerate hypotensive effects (including phenothiazines or general anesthetics).

Disease-related concerns:

• Abdominal conditions: May obscure diagnosis or clinical course of patients with acute abdominal conditions.

• Adrenal insufficiency: Use with caution in patients with adrenal insufficiency, including Addison’s disease.

• CNS depression/coma: Use with caution in patients with CNS depression or coma.

• Drug abuse: Use with caution in patients with a history of drug abuse or acute alcoholism; potential for drug dependency exists. Tolerance, psychological and physical dependence may occur with prolonged use.

• Ethanol use: Use with caution in patients with alcoholic liver disease; consuming ≥3 alcoholic drinks/day may increase the risk of liver damage.

• G6PD deficiency: Use with caution in patients with known G6PD deficiency.

• Head trauma: Use with extreme caution in patients with head injury, intracranial lesions, or elevated intracranial pressure; exaggerated elevation of ICP may occur.

• Hepatic impairment: Use with caution in patients with severe hepatic impairment.

• Prostatic hyperplasia/urinary stricture: Use with caution in patients with prostatic hyperplasia and/or urinary stricture.

• Renal impairment: Use with caution in patients with renal impairment.

• Respiratory disease: Use with caution in patients with pre-existing respiratory compromise (hypoxia and/or hypercapnia), COPD or other obstructive pulmonary disease, and kyphoscoliosis or other skeletal disorder which may alter respiratory function; critical respiratory depression may occur, even at therapeutic dosages.

• Seizure disorder: Use with caution in patients with a history of seizure disorder.

• Thyroid dysfunction: Use with caution in patients with thyroid dysfunction.

Concurrent drug therapy issues:

• Sedatives: Effects may be potentiated when used with other sedative drugs or ethanol.

Special populations:

• CYP2D6 “ultrarapid metabolizers”: Use caution in patients with two or more copies of the variant CYP2D6*2 allele; may have extensive conversion to morphine and thus increased opioid-mediated effects.

• Debilitated patients: Use with caution in debilitated patients; there is a greater potential for critical respiratory depression, even at therapeutic dosages.

• Elderly: Use with caution in the elderly; may be more sensitive to adverse effects. Decrease initial dose.

Dosage form specific issues:

• Metabisulfite: Tablets contain metabisulfite which may cause allergic reactions.

• Non-U.S. formulations: 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.

Other warnings/precautions:

• Dosage limit: Limit acetaminophen dose from all sources (prescription and OTC) to <4 g/day.

• Withdrawal: Concurrent use of agonist/antagonist analgesics may precipitate withdrawal symptoms and/or reduced analgesic efficacy in patients following prolonged therapy with mu opioid agonists. Abrupt discontinuation following prolonged use may also lead to withdrawal symptoms.

Controlled Substance C-III; C-V
Metabolism/Transport Effects Acetaminophen: Substrate (minor) of CYP1A2, 2A6, 2C9, 2D6, 2E1, 3A4; Inhibits CYP3A4 (weak)
Drug Interactions
(For additional information: Launch Lexi-Interact™ Drug Interactions Program )
Alcohol (Ethyl): CNS Depressants may enhance the CNS depressant effect of Alcohol (Ethyl). Risk C: Monitor therapy

Alvimopan: Analgesics (Opioid) may enhance the adverse/toxic effect of Alvimopan. This is most notable for patients receiving long-term (i.e., more than 7 days) opiates prior to alvimopan initiation. Management: Alvimopan is contraindicated in patients receiving therapeutic doses of opioids for more than 7 consecutive days immediately prior to alvimopan initiation. Risk D: Consider therapy modification

Ammonium Chloride: May increase the excretion of Analgesics (Opioid). Risk C: Monitor therapy

Amphetamines: May enhance the analgesic effect of Analgesics (Opioid). Risk C: Monitor therapy

Anticonvulsants (Hydantoin): May increase the metabolism of Acetaminophen. This may 1) diminish the effect of acetaminophen; and 2) increase the risk of liver damage. Risk C: Monitor therapy

Antipsychotic Agents (Phenothiazines): May enhance the hypotensive effect of Analgesics (Opioid). Risk C: Monitor therapy

Barbiturates: May increase the metabolism of Acetaminophen. This may 1) diminish the effect of acetaminophen; and 2) increase the risk of liver damage. Risk C: Monitor therapy

CarBAMazepine: May increase the metabolism of Acetaminophen. This may 1) diminish the effect of acetaminophen; and 2) increase the risk of liver damage. Risk C: Monitor therapy

Cholestyramine Resin: May decrease the absorption of Acetaminophen. Effect is minimal if cholestyramine is administered 1 hour after acetaminophen. Risk D: Consider therapy modification

CNS Depressants: May enhance the adverse/toxic effect of other CNS Depressants. Exceptions: Levocabastine (Nasal). Risk C: Monitor therapy

Conivaptan: May increase the serum concentration of CYP3A4 Substrates (Low risk). Risk C: Monitor therapy

CYP2D6 Inhibitors (Moderate): May diminish the therapeutic effect of Codeine. These CYP2D6 inhibitors may prevent the metabolic conversion of codeine to its active metabolite morphine. Risk C: Monitor therapy

CYP2D6 Inhibitors (Strong): May diminish the therapeutic effect of Codeine. These CYP2D6 inhibitors may prevent the metabolic conversion of codeine to its active metabolite morphine. Risk D: Consider therapy modification

Cyproterone: May decrease the serum concentration of CYP1A2 Substrates. Risk C: Monitor therapy

Cyproterone: May decrease the serum concentration of CYP2E1 Substrates. Risk C: Monitor therapy

Dasatinib: Acetaminophen may enhance the hepatotoxic effect of Dasatinib. Dasatinib may increase the serum concentration of Acetaminophen. Risk D: Consider therapy modification

Desmopressin: Analgesics (Opioid) may enhance the adverse/toxic effect of Desmopressin. Risk C: Monitor therapy

Droperidol: May enhance the CNS depressant effect of CNS Depressants. Management: Consider dose reductions of droperidol or of other CNS agents (e.g., opioids, barbiturates) with concomitant use. Risk D: Consider therapy modification

HydrOXYzine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Imatinib: Acetaminophen may enhance the hepatotoxic effect of Imatinib. Imatinib may increase the serum concentration of Acetaminophen. Risk D: Consider therapy modification

Isoniazid: May enhance the adverse/toxic effect of Acetaminophen. Risk C: Monitor therapy

Metyrapone: May increase the serum concentration of Acetaminophen. More importantly, by inhibiting the conjugative metabolism of acetaminophen, metyrapone may shift the metabolism towards the oxidative route that produces a hepatotoxic metabolite. Risk C: Monitor therapy

Mixed Agonist / Antagonist Opioids: May diminish the analgesic effect of Analgesics (Opioid). Management: Seek alternatives to mixed agonist/antagonist opioids in patients receiving pure opioid agonists, and monitor for symptoms of therapeutic failure/high dose requirements (or withdrawal in opioid-dependent patients) if patients receive these combinations. Risk D: Consider therapy modification

Peginterferon Alfa-2b: May decrease the serum concentration of CYP2D6 Substrates. Risk C: Monitor therapy

Pegvisomant: Analgesics (Opioid) may diminish the therapeutic effect of Pegvisomant. Risk C: Monitor therapy

Probenecid: May increase the serum concentration of Acetaminophen. Probenecid may also limit the formation of at least one major non-toxic metabolite, possibly increasing the potential for formation of the toxic NAPQI metabolite. Risk D: Consider therapy modification

Selective Serotonin Reuptake Inhibitors: Analgesics (Opioid) may enhance the serotonergic effect of Selective Serotonin Reuptake Inhibitors. This may cause serotonin syndrome. Risk C: Monitor therapy

Somatostatin Analogs: May decrease the metabolism of Codeine. The formation of two major codeine metabolites (morphine and norcodeine) may be impaired by somatostatin analogs. Risk C: Monitor therapy

SORAfenib: Acetaminophen may enhance the hepatotoxic effect of SORAfenib. SORAfenib may increase the serum concentration of Acetaminophen. Risk D: Consider therapy modification

Succinylcholine: May enhance the bradycardic effect of Analgesics (Opioid). Risk C: Monitor therapy

Thiazide Diuretics: Analgesics (Opioid) may enhance the orthostatic hypotensive effect of Thiazide Diuretics. Risk C: Monitor therapy

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy

Vitamin K Antagonists (eg, warfarin): Acetaminophen may enhance the anticoagulant effect of Vitamin K Antagonists. Most likely with daily acetaminophen doses >1.3 g for >1 week. Risk C: Monitor therapy

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.
Pregnancy Risk Factor C (show table)
Pregnancy Implications Refer to Codeine monograph.
Lactation Enters breast milk/use caution
Breast-Feeding Considerations Refer to Codeine monograph.
Dietary Considerations May be taken with food.
Pricing: U.S. (www.drugstore.com)
Solution (Acetaminophen-Codeine)

120-12 mg/5 mL (240): $19.99

Tablets (Acetaminophen-Codeine #2)

300-15 mg (30): $14.99

Tablets (Acetaminophen-Codeine #3)

300-30 mg (30): $15.99

Tablets (Acetaminophen-Codeine #4)

300-60 mg (30): $17.99

Tablets (Tylenol with Codeine #4)

300-60 mg (30): $45.99

Monitoring Parameters Relief of pain, respiratory and mental status, blood pressure, bowel function
International Brand Names Algimide (CO); Algimide F (CO); Citodon (SE); Claradol Codeine (FR); Co-Codamol (HK); Cod-Acamol 10/500 (IL); Cod-Acamol 15/325 (IL); Codabrol (IL); Codapane (AU); Codeipar (CN); Codicet (TH); Codilprane Enfant (FR); Codipar (GB, IE); Coditam (ID); Codoliprane (FR); Codoliprane Enfant (FR); Dafalgan Codeine (FR); Dolaforte (AU); Dolorol Forte (ZA); Efferalgan Codeine (PY); Maxadol (ZA); Nasa w/codeine (TH); Paceco (MY, SG); Panadeine (BB, BM, BS, BZ, CZ, GY, HK, HN, JM, MY, NL, NZ, SR, TT); Panadeine Co (AE, BH, CY, EG, IQ, IR, JO, KW, LB, LY, OM, QA, SA, SY, YE); Panadiene (BB, BM, BS, BZ, GY, HK, JM, JP, MY, NL, NZ, SR, TT); Panado-Co Caplets (ZA); Panadol Duo (FI); Paracodol (ZA); Paradine (MY); Paramax (EE); Parcono (TH); Parcoten (HK); Perdolan codeine (BE); Prodeine Forte (AU); Prodeine-15 (AU); Rokamol Plus (IL); Solpadeine (AE, BH, CY, EG, IQ, IR, JO, KW, LB, LY, OM, QA, SA, SY, YE); Solpadol (GB, IE); TWC 30 (IN); Tylex CD (CR, DO, GT, MX, NI, PA, SV); Uphamol Plus Codeine (MY); Winadeine (EC); Winadeine F (EC); Winadol Forte (CO); Zapain (GB, IE)
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.

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