What are the side effects of N-acetylcysteine (NAC)?

Side Effects of N-Acetylcysteine (NAC)

NAC is generally well-tolerated with primarily gastrointestinal side effects when taken orally, while intravenous administration carries a risk of anaphylactoid reactions in up to 10% of patients, particularly in females and those with asthma or atopy. 1, 2, 3

Oral NAC Side Effects

Gastrointestinal Effects (Most Common)

• Nausea, vomiting, and other gastrointestinal symptoms are the primary adverse effects of oral NAC, especially at the high doses used for acetaminophen overdose 1
• Diarrhea may also occur with oral administration 2
• Stomatitis (mouth inflammation) has been reported 1
• These GI effects are dose-dependent and more prominent at higher therapeutic doses 1

Other Oral Side Effects

• Rash with or without mild fever occurs rarely 1
• Drowsiness and clamminess have been reported 1
• Acquired sensitization to NAC is rare but has been documented 1

Intravenous NAC Side Effects

Anaphylactoid Reactions (Non-Immunological)

• Anaphylactoid reactions occur in up to 10% of patients receiving IV NAC, typically 15-60 minutes into infusion 2, 3
• These reactions include: angioedema, bronchospasm, flushing, hypotension, nausea/vomiting, rash, tachycardia, and respiratory distress 2
• Females and patients with asthma or atopy are at higher risk for these reactions 3
• These are non-immunological reactions mediated by histamine release, not true allergic responses 3
• Higher serum paracetamol concentrations paradoxically protect against anaphylactoid reactions 3

Respiratory Effects

• Transient bronchospasm occurs in 1-2% of patients 4
• Chest tightness and bronchoconstriction have been reported 1
• Rhinorrhea may occur 1

Dermatological Effects

• Skin rash occurs in less than 5% of patients 4
• Pruritus and angioedema are part of the anaphylactoid reaction spectrum 3

Serious Adverse Effects (Rare)

NAC Overdose Complications

• Excessive NAC dosage over short periods can cause hemolysis, thrombocytopenia, and acute renal failure, even in patients with normal glucose-6-phosphate dehydrogenase 5
• Fatalities have occurred following accidental intravenous overdosage 2
• Symptoms of NAC overdose include weakness, lethargy, extreme fatigue, nausea, and dizziness 5

Laboratory Effects

• NAC affects clotting factor activity and can cause minor disturbances in International Normalized Ratio (INR), which must be considered when interpreting coagulation studies in acetaminophen overdose 3

Context-Specific Safety Profile

COPD and Chronic Bronchitis Use

• At standard doses of 1200mg daily (600mg twice daily), NAC shows no significant difference in adverse events compared to placebo 6, 7
• Studies using up to 1800mg daily demonstrated no significant safety concerns 7
• NAC is well-tolerated in long-term use for COPD exacerbation prevention 6

Acetaminophen Overdose Treatment

• The loading dose of 140 mg/kg followed by 70 mg/kg every 4 hours (approximately 9,800mg loading dose for a 70kg person) is used safely in acute overdose management 7, 8
• Reducing the loading dose may decrease adverse reaction risk while maintaining efficacy 2

Clinical Pitfalls and Management

• Do not discontinue NAC due to anaphylactoid reactions in significant acetaminophen poisoning—temporary cessation with antihistamine treatment and slower re-infusion is preferred 3
• Oral NAC is contraindicated in patients with coma, active vomiting, or active gastrointestinal bleeding 7, 2
• Patients with asthma or atopic histories should preferentially receive oral rather than IV NAC when clinically appropriate to minimize bronchospasm and anaphylactoid reaction risk 7
• Most adverse reactions occur early in treatment when NAC concentrations are highest 3