N-acetylcysteine

Registered South African indications:

• Paracetamol overdose

Contraindications

South African recommendations

• Hypersensitivity to acetylcysteine or any excipients in the preparation

Recommendations in other jurisdictions

• No contraindications to the treatment of paracetamol overdose with N-acetylcysteine

Cautions

• Pregnancy
• Breastfeeding
• Renal impairment
• Hepatic impairment
• History of atopy
• History of asthma
• Children
• Patients requiring fluid restriction
• Patients weighing <40kg
• Coagulopathy
• Sodium controlled diet

Forms avail. in SA and covered in this monograph: inj

Dosages below include:

• South African registered indications and dosages
• Indications and dosages registered in other jurisdictions

South African registered indications and dosages

Paracetamol overdose

• IV: Initial: 150mg/kg body mass, as a 200ml infusion over 15mins; Then: 50mg/kg body mass, as a 500ml continuous infusion over 4hrs; Then: 100mg/kg body mass, as a 1000ml infusion over 16hrs

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N-acetylcysteine must be diluted with one of the following infusion fluids: 5% dextrose, 0.9% sodium chloride, 0.3% potassium chloride with 5% glucose, or 0.3% potassium chloride with 0.9% sodium chloride

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N-acetylcysteine is for single use only. Any unused portion of the solution/diluted solution should be discarded. Administration should commence within 3 hours after dilution

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N-acetylcysteine should be administered to all cases of suspected overdose as soon as possible, preferably within 8 hours of overdosage, although treatment up to 36 hours after ingestion may still be of benefit, especially if more than 150mg/kg of paracetamol was taken

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Indications and dosages registered in other jurisdictions

Paracetamol overdose
- Staggered overdose (ingested over 1hr or more) irrespective of plasma paracetamol level
- Where there is any doubt over the time of the overdose, irrespective of plasma paracetamol level
- Plasma paracetamol level on or above a line joining points of 100mg/l at 4hrs and 15mg/l at 15hrs

• IV: First infusion: Initial loading dose: 150mg/kg body mass, as a 200ml infusion over 1hr; Second infusion: 50mg/kg body mass, as a 500ml infusion over 4hrs; Third infusion: 100mg/kg body mass, as a 1000ml infusion over 16hrs; Total dose: 300mg/kg/21hrs

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The full course of treatment with acetylcysteine comprises 3 consecutive intravenous infusions as above

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Continued treatment with acetylcysteine (given at the dose and rate as used in the third infusion) may be necessary depending on the clinical evaluation of the individual patient

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The injection should be administered by intravenous infusion preferably using glucose 5% as the infusion fluid. Sodium chloride 0.9% solution may be used if glucose 5% is not suitable

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Dosage should be calculated using the patient's actual weight

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A ceiling weight of 110kg should be used when calculating the dosage for obese patients

Paed. forms avail in SA and covered in this monograph: inj

Paed. dosages below include:

• South African registered indications and dosages
• Indications and dosages registered in other jurisdictions

South African registered indications and dosages

Paracetamol overdose

• See adult dosage

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The quantity of intravenous fluid used in children should be modified to take into account age and mass

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Indications and dosages registered in other jurisdictions

Paracetamol overdose

• IV: First infusion: Initial loading dose: 150mg/kg body mass, as an infusion over 1hr (150mg/kg/hr) given as a 50mg/ml solution at a rate of 3ml/kg/hr; Second infusion: 50mg/kg body mass, as an infusion over 4hrs (12.5mg/kg/hr) given as a 6.25mg/ml solution at a rate of 2ml/kg/hr; Third infusion: 100mg/kg body mass, as an infusion over 16hrs (6.25mg/kg/hr) given as a 6.25mg/ml solution at a rate of 1ml/kg/hr

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Children should be treated with the same doses and regimen as adults; however, the quantity of intravenous fluid used should be modified to take into account age and weight, as fluid overload is a potential danger

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N-acetylcysteine should be administered by intravenous infusion preferably using glucose 5% as the infusion fluid. Sodium chloride 0.9% solution may be used if glucose 5% is not suitable

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Doses should be administered using an appropriate infusion pump

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The full course of treatment with N-acetylcysteine comprises 3 consecutive intravenous infusions as above

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Doses should be administered sequentially with no break between the doses

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Preparation of the solution
Dose 1: Prepare a 50mg/ml solution. Dilute each 10ml ampoule of N-acetylcysteine (200mg/ml) with 30ml glucose 5% or sodium chloride 0.9% to give a total volume of 40ml
Dose 2: Prepare a 6.25mg/ml solution. Dilute each 10ml ampoule of N-acetylcysteine (200mg/ml) with 310ml glucose 5% or sodium chloride 0.9% to give a total volume of 320ml
Dose 3: Prepare a 6.25mg/ml solution. Dilute each 10ml ampoule of N-acetylcysteine (200mg/ml) with 310ml glucose 5% or sodium chloride 0.9% to give a total volume of 320ml
Any unused solution should be disposed of in accordance with local requirements

Pregnancy

• Caution; no evidence of risk in studies
• The safety of N-acetylcysteine in pregnancy has not been investigated in formal prospective clinical trials. However, clinical experience indicates that use of N-acetylcysteine in pregnancy for the treatment of paracetamol overdose is effective. Prior to use in pregnancy, the potential risks should be balanced against the potential benefits

Breastfeeding

• Caution; not recommended
• No information is available on the excretion of N-acetylcysteine into breast milk. Breastfeeding is thus not advised during or immediately following the use of this agent

Renal Impairment

• Caution; no information available 

Hepatic Impairment

• Caution; no information available

Elderly

• No dose adjustment recommended

Porphyria Information

• Not yet classified (NC)

Drugs in Sport

• Permitted - No warnings

Central Nervous System Disorders

• Syncope
• Anxiety
• Generalised seizure
• Malaise

Cardiovascular Disorders

• Bradycardia
• Vasodilation
• Cardiac arrest
• Flushing
• ECG changes

Respiratory Disorders

• Respiratory arrest
• Cough
• Chest tightness or pain
• Cyanosis
• Stridor

Gastrointestinal Disorders

• Nausea and vomiting

Hepatobiliary Disorders

• Decreased hepatic function

Endocrine and Metabolic Disorders

• Hypokalaemia
• Acidosis
• Raised temperature
• Decreased blood urea

Musculoskeletal Disorders

• Arthropathy
• Arthralgia

Skin and Subcutaneous Tissue Disorders

• Skin rash
• Pruritus
• Injection site reactions
• Extravasation
• Sweating

Immune, Blood and Lymphatic System Disorders

• Anaphylactoid reactions
  - Angioedema
  - Bronchospasm/ respiratory distress
  - Hypotension
  - Tachycardia
  - Hypertension
• Thrombocytopenia

Sensory Disorders

• Blurred vision
• Facial or eye pain

Others

• Puffy eyes

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Click here for the management of adverse reactions to N-Acetylcysteine (NAC) 

None known

None routine. Specific cases may require

• Paracetamol levels
• Prothrombin time
• Hepatic function
• Bilirubin
• Blood urea nitrogen test
• Serum glucose
• Haemoglobin
• Haematocrit
• Electrolytes
• Serum creatinine

Additional observations

• Anaphylaxis or anaphylactoid reactions

Paracetamol overdose

• IV N-acetylcysteine, given within 24 hours of ingestion of a potentially hepatotoxic overdose of paracetamol, is indicated to prevent or reduce the severity of liver damage. It is most effective when administered within 8-10 hours of a paracetamol overdose. Although the efficacy of N-acetylcysteine diminishes between 10-24 hours post-overdose, it should be administered up to 24 hours as it can still be of benefit. It may still be administered after 24 hours in patients at risk of severe liver damage

Anaphylactoid reactions

• Anaphylactoid hypersensitivity reactions occur with N-acetylcysteine, particularly with the initial loading dose. The patient should be carefully observed during this period for signs of an anaphylactoid reaction. Nausea, vomiting, flushing, skin rash, pruritus and urticaria are the most common features, but more serious anaphylactoid reactions have been reported where the patient develops angioedema, bronchospasm, respiratory distress, tachycardia and hypotension. In very rare cases these reactions have been fatal. There is some evidence that patients with a history of atopy and asthma may be at increased risk of developing an anaphylactoid reaction
• Most anaphylactoid reactions can be managed by temporarily suspending the N-acetylcysteine infusion, administering appropriate supportive care and restarting at a lower infusion rate. Once an anaphylactoid reaction is under control, the infusion can normally be restarted at an infusion rate of 50 mg/kg over 4 hours, followed by the final 16 hour infusion (100 mg/kg over 16 hours)

Changes in colour

• A change in colour of the solution to light purple has sometimes been noted and is not thought to indicate significant impairment of safety or efficacy

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Click here for the management of adverse reactions to N-Acetylcysteine (NAC) 

N-acetylcysteine is considered to reduce the hepatic toxicity of NAPQI (n-acetyl-p-benzo-quinoneimine), the highly reactive intermediate metabolite following ingestion of a high dose of paracetamol, by at least two mechanisms. First, N-acetylcysteine acts as a precursor for the synthesis of glutathione and, therefore, maintains cellular glutathione at a level sufficient to inactivate NAPQI. This is thought to be the main mechanism by which N-acetylcysteine acts in the early stages of paracetamol toxicity.

N-acetylcysteine has been shown to still be effective when infusion is started at up to 12 hours after paracetamol ingestion, when most of the analgesic will have been metabolised to its reactive metabolite. At this stage, N-acetylcysteine is thought to act by reducing oxidised thiol groups in key enzymes.

When N-acetylcysteine treatment is begun more than 8-10 hours after paracetamol overdose, its efficacy in preventing hepatotoxicity (based on serum indicators) declines progressively with further lengthening of the overdose-treatment interval (the time between paracetamol overdose and start of treatment). However, there is now evidence that it can still be beneficial when given up to 24 hours after overdose. At this late stage of paracetamol hepatotoxicity, N-acetylcysteine's beneficial effects may be due to its ability to improve systematic haemodynamics and oxygen transport, although the mechanism by which this may occur has yet to be determined.

Injection (per ml) 200mg

• Parvolex (Pharmacare) originator
• Paradote (Equity)