Drug Interactions

Acetaminophen is metabolized extensively in the liver by conjugation with glucuronide and sulfate, and via the CYP2E1 isoenzyme. CYP2E1 is the isoenzyme responsible for the formation of acetaminophen’s toxic metabolite NAPQI (N-acetyl-p-benzoquinoneimine). Acetaminophen is also a minor substrate of CYP1A2, CYP2A6, CYP2D6 and CYP3A4. Drugs that induce or inhibit these enzymes are likely to interact with acetaminophen.

Drug-Drug Interactions

Alcohol (ethanol)

Alcohol is both a substrate and inducer of CYP2E1, the enzyme responsible for the formation of acetaminophen’s toxic metabolite NAPQI. Regular and excessive consumption of both alcohol and acetaminophen increases risk of hepatotoxicity. Avoid regular or excessive use of either acetaminophen or alcohol. Patients who drink ≥3 drinks/day should consider an alternative analgesic.

Anticoagulants

Oral Administration of acetaminophen may potentiate the anticoagulant effect of warfarin. This interaction may be more likely with higher doses of acetaminophen but may occur with short-term use of lower doses. Patients stabilized on warfarin should be made aware of this potential interaction and additional monitoring of INR may be indicated.
New oral anticoagulants are not known to interact with acetaminophen.

Cholestyramine

Cholestyramine reduces the absorption of acetaminophen. Oral doses of cholestyramine and acetaminophen should be given at least 1 hour apart.

Enzyme Inducers

Barbiturates and other enzyme inducers such as carbamazepine, isoniazid, phenytoin or rifampin may enhance the metabolism of acetaminophen. This can result in increased clearance and diminished therapeutic effect of acetaminophen, or increased hepatotoxicity. Appropriate monitoring (for therapeutic effect and hepatotoxicity) is indicated if these agents are used concurrently. Patients taking enzyme-inducing drugs should limit self-medication with acetaminophen.

Lamotrigine

Acetaminophen use for several concurrent days has resulted in decreased serum concentrations of lamotrigine If repeated dosing of acetaminophen is required, consider alternative analgesics/antipyretics.

Phenylephrine

Acetaminophen may inhibit sulfation of phenylephrine in the intestinal wall, resulting in increased serum levels and increased risk of hypertension. Monitor patient for adverse effects of phenylephrine. This interaction may be more significant with higher doses of acetaminophen (500–1000 mg).

Tyrosine kinase inhibitors (e.g., dasatinib, imatinib, sunitinib)

Increased risk of hepatotoxicity Maximum acetaminophen dose of 1300 mg/day when combined with imatinib; use higher doses with caution when combined with dasatinib or sunitinib.

Vaccines

Potentially decreased efficacy of vaccine when acetaminophen is administered prophylactically Consider avoiding prophylactic use of acetaminophen for post-vaccine fever/pain. This interaction does not appear significant for the influenza vaccine, nor for acetaminophen use for treatment of pain/fever after administration of vaccine.

Drug-Food Interactions

Food delays the absorption of acetaminophen. For rapid onset of action, avoid taking acetaminophen with food, particularly carbohydrates. Cabbage may increase the glucoronidation of acetaminophen.High fat-foods can delay the time to peak concentration for up to one hour. Extended-release tablets should be swallowed whole and taken with water on an empty stomach.

Drug-Herb Interactions

Concurrent use of acetaminophen with potentially hepatotoxic herbs may increase the risk of hepatotoxicity. Examples of these herbs include black cohosh, cassia cinnamon and comfrey.

Drug-Laboratory Test Interactions

• False positive for urinary 5-hydroxyindolacetic acid
• Increased serum uric acid level in tests using the chemical phosphotungstic method; consider using the ezymatic uricase method.

Drug-Lifestyle Interactions

Cigarette smoking may induce CYP1A1, CYP1A2, and CYP2E1, increasing the metabolism of acetaminophen. When smoking is increased/decreased, this may have a subsequent effect on acetaminophen efficacy and toxicity.

Dosage and Administration

Dosing Considerations

• Acetaminophen should not be used in adults or children for self-medication of marked fever (greater than 39.5°C), fever persisting longer than 3 days, or recurrent fever, unless directed by a physician, since such fevers may indicate serious illness requiring prompt medical attention.
• Acetaminophen should not be used for self-medication of pain for longer than 10 days in adults or 5 days in children, unless directed by a physician, since pain of such intensity and duration may indicate a pathological condition requiring medical evaluation.
• Acetaminophen should not be used for self-medication of sore throat for longer than 2 days in adults and children.
• For the treatment of headache, limit use to <15 days/month to prevent medication overuse headache.
• Because of the risk of toxicity, dosing for children must not exceed 5 doses in 24 hours unless under the advice of a physician (see Serious Warnings and Precautions).
• Rectal administration results in erratic absorption. Some experts recommend that rectal formulations should not be used in children unless under healthcare provider supervision.
• Calibrated measuring devices and weight-based dosing should always be used in children to prevent overdose and toxicity.
• Acetaminophen in oral drop formulations may be more concentrated than other liquid formulations. Pay careful attention to acetaminophen concentration when dosage volumes are calculated for liquid preparations.

Recommended Dose and Dosage Adjustment

Adults

Mild-moderate pain; fever
Route: Oral or rectal
Immediate-release dosage form: 325–1000 mg Q4–6H
Extended-release tablets: 1300 mg Q8H
Maximum: 4000 mg/day
Consider dosage reduction in patients at risk of hepatotoxicity (e.g., liver dysfunction, malnourishment, heavy alcohol consumption).

Pediatrics

[a] The Canadian Paediatric Society recommends consultation with a physician for infants under 6 months.

Overdosage

For management of a suspected drug overdose, contact your regional Poison Control Centre. See the eCPS Directory section for a list of Poison Control Centres. In adults, hepatotoxicity may occur after ingestion of a single dose of more than 7.5 g (adults) or 150 mg/kg (children) of acetaminophen; a dose of 10 g or more is potentially fatal. However, reports have indicated hepatic necrosis with a single dose of 6 g and death occurring with a single dose of 13 g. Nonfatal overdoses of 12.5–31.5 g have also been reported.

Signs and Symptoms

Early symptoms (nausea, vomiting, weakness, diaphoresis) usually occur after acute ingestion of an acetaminophen overdose large enough to cause hepatic toxicity. However, since some patients may exhibit few or none of these early signs, in cases of suspected acetaminophen overdose, antidotal therapy should begin as soon as possible. A latent period of 24–36 hours exists between ingestion and the onset of symptoms of hepatic injury. Laboratory evidence usually appears within 24–48 hours if severe hepatotoxicity is to occur. Therefore, liver function tests (AST or ALT) should be monitored for up to 48 hours after an acute ingestion. Following the latent period, vomiting, pain in the upper right quadrant and manifestations of hepatic failure including the onset of coma, may ensue. Maximum hepatic necrosis appears 2–5 days following overdose. Signs include gross elevation of ALT, AST, increased bilirubin, hypoglycemia and increased prothrombin time. Renal dysfunction following acetaminophen overdose is rare overall but quite common in cases where liver injury or failure occurs.

In addition to hepatic and renal damage, there are rare reports of pancreatitis, clotting defects, and myocardial damage with ST segment abnormalities, T wave flattening and pericarditis.

Recommended Management

• In cases of acute overdose, consultation with a Poison Control Centre is recommended. In cases of hepatotoxicity associated with subacute acetaminophen overdose, consultation with a toxicologist is recommended.
• Treatment of acute acetaminophen overdose includes supportive measures, gut decontamination with activated charcoal, and prompt administration of acetylcysteine as an antidote. For detailed information on acetylcysteine dosing and administration, see the Acetylcysteine (CPhA Monograph) monograph.
• Laboratory determinations include plasma acetaminophen levels, AST, ALT, prothrombin time, bilirubin, creatinine, urea, blood glucose and electrolyte concentrations. A single dose of activated charcoal is recommended, ideally within 1 hour of ingestion of overdose, and may be of benefit if given up to 4 hours postingestion. Hemodialysis may be helpful in certain cases, e.g., massive overdoses or acute renal failure.

Storage and Stability

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p style=”text-align: justify;”>Store at room temperature (15–30°C); protected from high heat and humidity. Liquid formulations should be protected from light and freezing. Suppositories should be stored at room temperature or in the refrigerator.