Should the dose of acetylcysteine (Acetadote) be capped in obese patients?

Comment by InpharmD Researcher

The prescribing information for acetylcysteine (Acetadote) does not specify a maximum dose for obese patients and states that no studies have evaluated the need for dose adjustments in those over 100 kg, with limited data available on dosing requirements for this population. The labeling provides fixed doses for patients ≥ 100 kg as follows: 15,000 mg, 5,000 mg, and 10,000 mg for the three-bag regimen.

Background

The UK Medicines and Healthcare Products Regulatory Agency (MHRA) advises that for obese patients, a ceiling weight of 110 kg should be used when calculating intravenous (IV) N-acetylcysteine (NAC) in the treatment of paracetamol overdose. The patient should receive a total dose of 300 mg/kg bodyweight over a 21-hour period. [1]

Editorials have explored the complexities of NAC dosing in obese patients with acetaminophen toxicity, particularly regarding the practice of dosage capping. The 2021 editorial examined historical and contemporary challenges in NAC administration, questioning the assumption that weight-based dosing should scale linearly with body weight given the lack of direct correlation between weight, organ size, and hepatic detoxification capacity. The discussion referenced pharmacokinetic studies of aminoglycosides that established correction factors for obese patients, influencing NAC dosing strategies. Additionally, the editorial highlighted evolving biochemical thresholds for defining hepatotoxicity, contrasting traditional ALT/AST cutoffs ≥1000 IU/L with more recent studies, such as Baum et al. (see Table 2), which used ≥100 IU/L. The authors emphasized the need for continued research to refine NAC dosing and optimize therapeutic strategies. The 2022 editorial built upon this discussion, critically evaluating the validity of NAC dose capping in patients exceeding 100 kg. Responding to Baum et al., the authors raised concerns about the study’s power and sample size, noting its inability to establish non-inferiority between capped and uncapped regimens. Financial analysis in Baum et al. was also scrutinized, with the editorial questioning cost-savings calculations based on vial utilization rather than a strictly linear dose-to-cost relationship. While acknowledging the relevance of NAC dose capping, the authors concluded that cost-effectiveness claims remain insufficiently supported, calling for further research with improved methodological clarity. Together, these editorials underscored the evolving nature of NAC dosing paradigms and the need for ongoing investigation to optimize treatment strategies for obese patients with acetaminophen toxicity. [2], [3]

References:

[1] Gov.UK. Intravenous N-acetylcysteine (NAC) for paracetamol overdose: reminder of authorised dose regimen; possible need for continued treatment with NAC. Published January 19, 2017. Accessed February 17, 2025. https://www.gov.uk/drug-safety-update/intravenous-n-acetylcysteine-nac-for-paracetamol-overdose-reminder-of-authorised-dose-regimen-possible-need-for-continued-treatment-with-nac
[2] Berland NG, Leonard J, Calello DP. Should the Dosage Cap Be Used in Patients Greater than 100 kg Receiving N-acetylcysteine for Acetaminophen Toxicity? Journal of Medical Toxicology. 2022;18(1):65-66. doi:10.1007/s13181-021-00871-2
[3] Paloucek FP, Kanter MZ. It’s been a long journey: do we know where we are going? Journal of Medical Toxicology. 2021;17(3):239-240. doi:10.1007/s13181-021-00843-6
Literature Review

A search of the published medical literature revealed 3 studies investigating the researchable question:

Should the dose of acetylcysteine (Acetadote) be capped in obese patients?

Level of evidence

C - Multiple studies with limitations or conflicting results  Read more→


Please see Tables 1-3 for your response.

Three-Bag Recommended ACETADOTE Dosage and Dilution for Patients 5 kg or greater
Body Weight Bag 1 (Loading Dose) Bag 2 (Second Dose) Bag 3 (Third Dose)
Loading Dose Diluent Volume* Infusion Time Second Dose  Diluent Volume* Infusion time Third Dose Diluent Volume* Infusion time
5 kg** to 20 kg 150 mg/kg 3 mL/kg Infused over 1 hour 50 mg/kg 7 mL/kg Infused over 4 hours  100 mg/kg 14 mL/kg Infused over 16 hours  
21 kg to 40 kg 150 mg/kg 100 mL 50 mg/kg 250 mL 100 mg/kg 500 mL
41 kg to 99 kg 150 mg/kg 200 mL 50 mg/kg 500 mL 100 mg/kg 1,000 mL
100 kg or greater*** 15,000 mg 200 mL  5,000 mg 500 mL  10,000 mg 1,000 mL 

*Dilute ACETADOTE in one of the following three solutions: sterile water for injection, 0.45% sodium chloride injection, or 5% dextrose in water.

**Recommended dosing for those less than 5 kg has not been studied.

***No specific studies have been conducted to evaluate the necessity of dose adjustments in patients weighing over 100 kg. Limited information is available regarding the dosing requirements of patients that weigh more than 100 kg.          

Alternative Regimen for Patients 41 kg or Greater: Two-Bag Recommended ACETADOTE Dosage and Dilution
Body Weight Bag 1 (Loading Dose) Bag 2 (Second Dose)
Loading Dose Diluent Volume* Infusion Time Second Dose  Diluent Volume* Infusion time
41 kg to 99 kg 200 mg/kg 1,000 mL Infused over 4 hours   100 mg/kg 500 mL Infused over 16 hours  
100 kg or greater*** 20,000 mg 1,000 mL  10,000 mg 500 mL 

*Dilute ACETADOTE in one of the following three solutions: sterile water for injection, 0.45% sodium chloride injection, or 5% dextrose in water.

**No specific studies have been conducted to evaluate the necessity of dose adjustments in patients weighing over 100 kg. Limited information is available regarding the dosing requirements of patients that weigh more than 100 kg.
References:

Adapted from: ACETADOTE ( acetylcysteine injection). Prescribing information. Cumberland Pharmaceuticals Inc.; 2024

 

Evaluation of Dosing Strategies of N-acetylcysteine for Acetaminophen Toxicity in Patients Greater than 100 Kilograms: Should the Dosage Cap Be Used?

Design

Retrospective, multi-center analysis

N= 83

Objective

To determine if a capped N-acetylcysteine (NAC) dosing scheme is similar to a non-capped dosing scheme in patients weighing over 100 kg

Study Groups

Traditional (n= 56)

Capped (n= 27)

Inclusion Criteria

Obese patients who received standard three-bag IV NAC treatment for acetaminophen overdose, weighed greater than 100 kg, aged ≥18 years

Exclusion Criteria

NAC used for non-acetaminophen toxicity, no acetaminophen concentrations or LFTs drawn after 24 hours, missing data, transferred from outside hospital where NAC was initiated, oral NAC

Methods

Patients were identified by ICD-9/ICD-10 codes for acetaminophen overdose. 

Duration

January 2009 to January 2016

Outcome Measures

Primary outcome: hepatic injury, defined as an AST or ALT ≥ 100 IU/L

Secondary outcomes: drug-related adverse events, occurrence of hepatotoxicity, cumulative NAC dose, regimen cost, length of hospital and intensive care unit stays, and in-hospital mortality

Baseline Characteristics

  

Traditional (n= 56)

Capped (n= 27)

 p-value

Age, years (IQR)

 36 (28-46.2) 44 (31-50) 0.147

Male

 53.6% 48.1% 0.819 

White

 80.4% 85.2%

0.129

Body mass index (BMI), kg/m2 

 40  38.8  0.629

Weight, kg (IQR)

 120 (109.7-135.2) 108.9 (104.9-118.6) 0.026 

Height, cm (IQR)

175.3 (167.6-182.9)

*n= 3

172.7 (165.1-177.8)

*n=0 

 0.235 
LOS, days (IQR)

3.7 (2-5.9)

3.5 (2.3-5)

 0.915
ICU length of stay, days (IQR)

3.5 (1.8-7.2)

*n=32

3 (2-4)

*n= 10

 0.406

*Missing observations

IQR: interquartile range, 25th-75th percentile

Results

Endpoint

Traditional (n= 56)

Capped (n= 27)

p-value

Hepatic injury

AST or ALT ≥100

AST ≥100

ALT ≥100

 

50%

46.4%

44.6%

 

48.1%

48.1%

40.7%

 

1.000

1.000

0.921

Hepatic injury

AST or ALT ≥1000

AST ≥1000

ALT ≥1000

 

28.6%

25%

28.6% 

 

33.3%

33.3%

29.6%

 

0.851

0.594

1.000

Deceased during admission

 7.1% 7.4% 1.000

Total cumulative NAC dose, mg/kg

 304.6 285.2 <0.001

Total cumulative NAC dose, mg (IQR)

40,800.0 (32,240-62,840.5)

*n= 1

30,000 (30,000-36,000)

*n= 0 

 <0.001 

Cost reduction, dollars (IQR)

2174.3 [1453.6-3649.3)

*n= 12

997 (667.9-1810.9)

*n= 4 

 <0.001

*Missing observations

IQR: interquartile range, 25th-75th percentile

Adverse Events

Adverse events included cutaneous symptoms (1.2%), gastrointestinal symptoms (3.6%), respiratory symptoms (0%), angioedema (1.2%), and cardiovascular instability (0%). No significant differences were found between the groups.

Study Author Conclusions

A capped NAC dosing scheme was not associated with higher rates of hepatic injury or hepatotoxicity in obese patients compared to a non-capped regimen. Further research is needed to verify these results.

InpharmD Researcher Critique

The study was limited by a small sample size and retrospective design, which may introduce biases and limit the generalizability of the findings. The study did not meet the required sample size calculation, and there were potential confounding factors not accounted for. However, the multi-center approach and focus on a specific patient population are strengths.



References:

Baum RA, Woolum JA, Bailey AM, Howell MM, Weant KA, Geraghty L, Mohan S, Webb AN, Su MK, Akpunonu P; Collaborators. Evaluation of Dosing Strategies of N-acetylcysteine for Acetaminophen Toxicity in Patients Greater than 100 Kilograms: Should the Dosage Cap Be Used? J Med Toxicol. 2021 Jul;17(3):241-249. doi: 10.1007/s13181-021-00822-x. Epub 2021 Apr 21. PMID: 33884558; PMCID: PMC8206426.

 

Effects of N-acetylcysteine on aging cell and obesity complications in obese adults: a randomized, double-blind clinical trial

Design

Double-blind randomized clinical trial (RCT)

N= 40

Objective

To investigate the effects of N-acetylcysteine (NAC) on obesity complications and senescence of visceral adipose tissue in obese adults

Study Groups

NAC (n= 20)

Placebo (n= 20)

Inclusion Criteria

Age 25-50 years; obese (Body Mass Index [BMI] ≥ 35 kg/m2); candidates for bariatric surgery (abdominoplasty or liposuction)

Exclusion Criteria

History of various inflammatory, cancer, cardiovascular, liver, diabetes, kidney, infectious, and gastrointestinal diseases; use or history of use in the last 3 months of supplements or drugs affecting appetite, weight, or metabolism; receiving or following dietary and exercise treatments affecting weight during the last 6 months; use of alcohol or smoking

Methods

Patients were randomized to receive either 600 mg/day of NAC or a placebo for 4 weeks. All participants followed the same dietary recommendations, with caloric intake adjusted based on age, gender, and BMI, and macronutrient distribution set at 30% fat, 50% carbohydrates, and 20% protein.

Duration

Trial: 2022 to 2023

Intervention: 4 weeks

Outcome Measures

Primary: SA-β-gal activity test; substantial changes in the expression of the genes for tumor necrosis factor (TNF-α), IL-6, and p16; blood concentrations of TNF-α and IL-6 

Secondary: Weight, BMI, waist circumference (WC), fasting blood sugar (FBS), insulin, homeostatic model assessment of insulin resistance (HOMA-IR), total cholesterol (TC)

Baseline Characteristics

  

NAC (n= 20)

Placebo (n= 20)

  

Age, years

 40.21 ± 5.60 39.68 ± 6.91  

Female

52.6% 57.9%  

Weight, kg

 125.96 ± 13.05 127.21 ± 11.90  

BMI, kg/m2

 44.84 ± 3.05 44.31 ± 4.21  

Waist-circumference, cm

 137.55 ± 11.07 136.27 ± 10.39  

TC, mg/dL

 156.95 ± 34.53 157.07 ± 46.34  
FBS, mg/dL 124.43 ± 38.62 151.72 ± 40.06  
Insulin, μIU/mL 18.79 ± 3.62 20.39 ± 3.90  

IL-6, pg/mL

 3.97 ± 0.44  5.25 ± 2.91  
TNF-α, pg/mL 3.55 ± 0.28 3.69 ± 0.61  
HOMA-IR 5.66 ± 1.90 7.68 ± 2.45  

Results

Endpoint

NAC (n= 20)

Placebo (n= 20)

p-value

Weight, kg

 119.65± 11.82 121.68 ± 11.43 0.277

BMI, kg/m2

 42.16 ± 2.82  41.97 ± 3.90 0.147
Waist-circumference, cm 127.83 ± 9.88 128.86 ± 10.09 0.141
TC, mg/dL 149.94 ± 33.58 150.66 ± 44.41 0.528
FBS, mg/dL 111.92 ± 34.83 144.47 ± 39.50 <0.001
Insulin, μIU/mL 13.13 ± 3.27 16.83  ± 2.60 <0.001
IL-6, pg/mL 3.33 ± 0.46 4.90 ± 2.84 <0.001
TNF-α, pg/mL 3.26 ± 0.26 3.44 ± 0.62 0.079
HOMA-IR 3.55 ± 1.04 6.04 ± 1.89 <0.001

NAC significantly reduced SA-β-gal activity (as a marker of senescence) in the visceral adipose tissue compared to placebo in obese adults (p = 0.001). 

Adverse Events

Not disclosed.

Study Author Conclusions

Findings showed that NAC, in addition to having a potential beneficial effect on reducing some of the complications caused by obesity, seems to have synolytic/senomorphic potential as well.

InpharmD Researcher Critique

The small sample size of 40 participants may limit the generalizability of the findings. Obesity-related hormones and body fat percentage were not assessed. The absence of immunohistochemistry (IHC) as a gold standard for assessing inflammatory changes and the short intervention duration may have also influenced the findings.



References:

Sohouli MH, Eslamian G, Malekpour Alamdari N, et al. Effects of N-acetylcysteine on aging cell and obesity complications in obese adults: a randomized, double-blind clinical trial. Front Nutr. 2023;10:1237869. Published 2023 Sep 19. doi:10.3389/fnut.2023.1237869