What are the toxic dosage levels for Paracetamol (Acetaminophen)?

Paracetamol (Acetaminophen) Toxicity Dosage Levels

For acute single ingestions, the toxic threshold is 150 mg/kg or approximately 10 grams in adults, though severe hepatotoxicity has been documented with doses as low as 4-5 grams per day in high-risk populations, particularly those with chronic alcohol use or malnutrition. 1, 2

Acute Single Ingestion Thresholds

• The FDA defines toxic dose as 150 mg/kg or greater in a single acute ingestion, which translates to approximately 10 grams or more for most adults 1
• Ingestions exceeding 10 grams (10,000 mg) in a 24-hour period are considered potentially toxic and require immediate medical evaluation 2
• Severe hepatotoxicity and mortality have been documented with ingestions ranging from 10-65 grams, with the mean dose causing severe hepatotoxicity in intentional overdose patients being 23 grams 2
• Use the Rumack-Matthew nomogram to assess risk when acetaminophen level is drawn 4-24 hours post-ingestion—levels above 200 mcg/mL at 4 hours or 50 mcg/mL at 12 hours indicate potential hepatotoxicity 1, 3

Repeated Supratherapeutic Ingestion (RSTI)

• Repeated ingestions totaling ≥10 grams or 200 mg/kg (whichever is less) over a single 24-hour period require medical evaluation 2
• Repeated ingestions of ≥6 grams or 150 mg/kg (whichever is less) per 24-hour period for 48 hours or longer are potentially toxic 2
• Severe hepatotoxicity has been documented with doses as low as 4-5 grams per day when taken repeatedly, particularly in patients with risk factors 2

High-Risk Populations with Lower Toxicity Thresholds

Chronic Alcohol Users

• Multiple case series demonstrate severe hepatotoxicity and mortality rates of 20-33% in chronic alcoholics taking 2.5-16.5 grams per day (median 6.4 grams per day) 2
• Severe hepatotoxicity has been reported with doses of 4-5 grams per day in patients with chronic alcohol consumption 2
• For high-risk individuals including chronic alcohol users, the threshold is lower at >4 grams or 100 mg/kg per day 2
• Maximum daily dose should be limited to 2-3 grams per day in patients with chronic alcohol use or pre-existing liver disease 2

Fasting and Malnourished Patients

• Severe hepatotoxicity can occur at recommended dosages (4 grams daily) in severely malnourished patients following periods of fasting 4
• Recent fasting and nutritional impairment have been identified as key precipitants for liver damage following moderate overdoses of 5-10 grams daily 4

Patients on Enzyme-Inducing Drugs

• Patients taking enzyme-inducing drugs (which increase cytochrome P450 2E1 activity) have increased susceptibility to toxicity 5
• These patients should be treated with N-acetylcysteine even with paracetamol levels in the "non-toxic" range 2

Therapeutic Dose Considerations

• The FDA recommends limiting daily acetaminophen intake to a maximum of 4 grams for the general population 2
• Even therapeutic doses of 4 grams per day for 14 days caused ALT elevations >3 times normal in 31-41% of healthy adults without risk factors 2
• For chronic administration, consider limiting doses to 3 grams or less per day to reduce hepatotoxicity risk 2
• For patients with risk factors (liver disease, chronic alcohol use), maximum daily dose should be 2-3 grams per day 2

Critical Clinical Pearls

• Very high aminotransferase levels (AST/ALT >3,500 IU/L) are highly correlated with acetaminophen poisoning and should raise suspicion even without clear overdose history 2
• Low or absent acetaminophen levels do NOT rule out acetaminophen poisoning if the ingestion was remote, occurred over several days, or timing is uncertain 2
• Combination products containing acetaminophen (with opioids like hydrocodone or codeine) significantly increase the risk of unintentional overdose because patients may not realize they are taking acetaminophen from multiple sources 2
• The nomogram does NOT apply to repeated supratherapeutic ingestions, extended-release formulations, or presentations >24 hours after ingestion 6

Treatment Initiation Thresholds

• N-acetylcysteine (NAC) should be initiated for any patient with acetaminophen levels above the treatment line on the nomogram (the line 25% below the "probable hepatotoxicity line") 2, 1
• NAC should be initiated for any patient with suspected acetaminophen ingestion with signs of liver injury (AST or ALT >50 IU/L) 2
• For repeated supratherapeutic ingestions, treat with NAC if serum acetaminophen ≥10 mg/mL or if AST or ALT >50 IU/L 6
• Treatment within 8 hours results in only 2.9% severe hepatotoxicity; this increases to 6.1% when treated within 10 hours and 26.4% when treated 10-24 hours post-ingestion 3, 6