Acetylcysteine (N-acetylcysteine, NAC) for the management of non

Acetylcysteine (N-acetylcysteine, NAC) for the

management of non-acetaminophen-induced acute

liver failure

Submitted by:

Jill M. Pulley, MBA, Executive Director, and Rebecca Jerome, MLIS, MPH,

Manager, Translational Research

Vanderbilt Institute for Clinical and Translational Research

Vanderbilt University Medical Center, Nashville Tennessee, USA

(see Appendix 1 for a list of additional contributors)

Submission Date: November 30, 2020

Project | Remedi aims to uncover new therapeutic uses for hundreds of medicines

on the Essential Medicines List, seek approval to add them to the EML, and amplify

availability of new uses to benefit priority populations.

2 
 
Contents 
1. Summary statement of the proposal for inclusion, change or deletion ........................................................ 4 
2. Relevant WHO technical department and focal point (if applicable).  
3. Name of organization(s) consulted and/or supporting the application. ........................................................ 6 
4. International Nonproprietary Name (INN) and Anatomical Therapeutic Chemical (ATC) code of the 
medicine. ............................................................................................................................................................ 6 
5. Dose forms(s) and strength(s) proposed for inclusion ................................................................................... 6 
6. Whether listing is requested as an individual medicine or as representative of a pharmacological class. ... 6 
7. Treatment details (requirements for diagnosis, treatment and monitoring). ............................................... 7 
8. Information supporting the public health relevance. .................................................................................... 8 
9. Review of benefits: summary of evidence of comparative effectiveness. ..................................................... 9 
Identification of clinical evidence (search strategy, systematic reviews identified, reasons for 
selection/exclusion of particular data) ........................................................................................................... 9 
Summary of available data (appraisal of quality, outcome measures, summary of results) ......................... 9 
Summary of available estimates of comparative effectiveness ................................................................... 12 
10. Review of harms and toxicity: summary of evidence of safety. ................................................................. 12 
Estimate of total patient exposure to date: ................................................................................................. 12 
Description of the adverse effects/reactions when used in non-acetaminophen induced acute liver 
failure: ........................................................................................................................................................... 12 
Description of the adverse effects/reactions and estimates of their frequency (drawn from the broader 
NAC literature on human use) ...................................................................................................................... 12 
Summary of available data ........................................................................................................................... 13 
Identification of variation in safety that may relate to health systems and patient factors ....................... 15 
11. Summary of available data on comparative cost and cost-effectiveness of the medicine. ....................... 16 
12. Summary of regulatory status and market availability of the medicine. ................................................... 16 
13. Availability of pharmacopoeial standards (British Pharmacopoeia, International Pharmacopoeia, United 
States Pharmacopoeia, European Pharmacopeia). Summary of available data on comparative cost and cost-
effectiveness of the medicine. ......................................................................................................................... 17 
Literature summaries: non-acetaminophen acute liver failure, organized by precipitating 
exposure/condition .......................................................................................................................................... 18 
LITERATURE SUMMARY: Evidence describing use of NAC in general non-acetaminophen-induced acute 
liver injury ..................................................................................................................................................... 18 
LITERATURE SUMMARY: Evidence describing use of NAC in heatstroke-associated acute liver injury ....... 24 
LITERATURE SUMMARY: Evidence describing use of NAC in alcohol poisoning-associated acute liver injury
 ...................................................................................................................................................................... 25 
LITERATURE SUMMARY: Evidence describing use of NAC in mushroom toxin-induced acute liver injury.. 25 

3 
 
LITERATURE SUMMARY: Evidence describing use of NAC in virus-associated acute liver injury (hepatitis A, 
hepatitis B, dengue fever) ............................................................................................................................ 26 
14. Comprehensive reference list and in-text citations. .................................................................................. 31 
Appendix 1: Additional contributors ................................................................................................................ 41 
Appendix 2: Evidence describing hepatic effects of N- acetylcysteine in other conditions (excluding 
acetaminophen toxicity) ................................................................................................................................... 42 
Appendix 3: Summary of adverse events reported in systematic reviews, by indication................................ 51 
 
 
   

1. Summary statement of the proposal for inclusion, change or deletion

We propose a new listing to the EML to add an additional use of a medicine already on the EML, N-

acetylcysteine (NAC). The new indication is for the management of non-acetaminophen-induced

acute liver failure (ALF) caused by etiologies that deplete glutathione (see Figure 1). This

indication leverages a sound foundation of trial and observational evidence supporting the safety and

utility of NAC in preventing further progression of liver failure in adults and children. This indication

includes a range of etiologies for ALF with known connection to glutathione depletion which leads to

hepatic injury; NAC replenishes intracellular glutathione and exerts antioxidant effects which help to

ameliorate the adverse consequences of the hepatic insult and its sequelae. This request is being sought

for the complementary EML, as patients with ALF are typically cared for in a hospital/specialized setting.

Generally, N-acetylcysteine (NAC) is known via preclinical and clinical studies for its hepatoprotective

effects by increasing intracellular glutathione particularly in the liver and by its antioxidant properties

which counteract oxidative stress and inflammation.(1) NAC has been in widespread use since the 1960s

and has been proven to be safe and well tolerated; its use as an antidote for acetaminophen toxicity (a

use in which oral and intravenous NAC have been shown to be equally effective in preventing and

minimizing hepatotoxicity), and is already represented on the EML for this use. Based on similar

mechanisms, NAC shows promise in protecting the liver against the effects of and response to

insults precipitating non-acetaminophen induced acute liver injury due to glutathione depletion,

including virus-induced acute hepatic failure; mushroom toxin-induced liver failure; acute

alcoholic hepatitis; and heat stroke-induced ALF (Figure 1). In addition to the range of studies

reporting the benefit and safety of NAC use in these indications (see section 9 and 10, Literature

Summary table), a body of literature describing NAC use in heterogeneous populations of non-

acetaminophen induced ALF(2–4) further supports this new indication for NAC. (see Literature

Summary section for a synthesis of relevant systematic reviews, trials, and observational studies).

Briefly, various insults (e.g. hepatitis A virus, dengue virus, toxic mushroom consumption, excess alcohol

intake, heat stroke) directly deplete glutathione, which is a necessary enzyme for proper liver

function. Each of these etiologies for ALF has supporting data indicating that glutathione depletion plays

an important role in development of ALF; the mechanisms of acute liver dysfunction and failure in these

conditions are believed to result directly from hepatocyte apoptosis/necrosis, hypoxic damage due to

impaired liver perfusion resulting from fluid leakage, as well as oxidative stress and immune mediated

injury. (5–17) NAC, through enhancing glutathione S-transferase activity, affects several of these

mechanisms (Figure 2).(1,18–21) In addition, NAC has antioxidative, anti-inflammatory, and

vasodilatory effects,(22) which can help counteract the adverse effects of impaired liver perfusion and

reducing hepatocytes apoptosis due to oxidative stress and immune-mediated injury.

While ALF remains relatively rare, it

affects children and adults across

the world and confers significant

morbidity and mortality. (23,24)

Care for ALF associated with these

etiologies is supportive in nature,

with no targeted options for

minimizing further injury to the

liver. To address an unmet medical

need with an existing, safe therapy,

we propose a new use for NAC in the

treatment of ALF caused by

hepatitis A, dengue virus, heat

stroke, acute alcohol poisoning, and

mushroom toxicity. NAC should be

administered to affected patients as

soon as possible based on presence

of hepatic injury (i.e. laboratory data

indicating increase in liver function

test results). The goal of this

strategy, based on the evidence

described below, is to prevent or

limit severity of acute liver failure

and related morbidity and

mortality.

The literature describing clinical use of NAC in general non-acetaminophen-induced ALF patients, as

well as those with ALF due to heat stroke, acute alcoholic hepatitis, mushroom poisoning, or acute viral

hepatitis, supports the safety and efficacy of this therapeutic approach in complementing usual

supportive care for patients affected by these types of ALF. The literature indicates that use of NAC

represents at least a significant incremental gain over supportive care alone, with a reasonable

expectation of direct effects on morbidity, including averting the need for transplantation in some

patients. In addition, with its long-standing history of use in acetaminophen-induced acute liver injury,

NAC has a strong foundation of data supporting its safety in children and adults.

There is precedent for this approach with the use of NAC from past EML committee decision related to

use as an antidote to acetaminophen toxicity, as real-world data was deemed sufficiently compelling.

The relevant excerpt from 2008 review states: “…subsequent human investigations have consisted

mostly of observational studies due to ethical concerns of withholding a potential lifesaving treatment.

Thus, there are no randomized controlled trials that evaluate NAC therapy for prevention of

acetaminophen-induced hepatotoxicity. Likewise, no randomized efficacy trials have been conducted in

children. Many of the trials evaluate efficacy based on the outcomes of historical control patients.”(25)

2. Relevant WHO technical department and focal point (if applicable).

Department of Neglected Tropical Diseases

Other interested groups may include Alcohol, Drugs and Addictive Behaviors Unit, Global HIV Hepatitis

and STIs Programme

3. Name of organization(s) consulted and/or supporting the application.

Dr. Robert Wallis, MD; Chief Scientific Officer, AURUM was consulted and reviewed this submission.

Dr. Gordon Bernard, MD; Executive Vice President for Research, Vanderbilt University Medical Center

was consulted and reviewed this submission.

4. International Nonproprietary Name (INN) and Anatomical Therapeutic

Chemical (ATC) code of the medicine.

INN: Acetylcysteine

A05: Bile and liver therapy

5. Dose forms(s) and strength(s) proposed for inclusion

This request is for the inclusion of NAC in intravenous or oral form for the EML. [Acetylcysteine is the

nonproprietary name for the N-acetyl derivative of the naturally occurring amino acid, L-cysteine (N-

acetyl-L cysteine)]. NAC is a generic medicine and is widely available internationally. Regarding

formulation, the WHO 2008 review of use of NAC in pediatric acetaminophen toxicity notes that oral

administration is preferred when there are not contraindications to its use (e.g. aspiration, persistent

vomiting)(25); intravenous use is recommended in this guidance when fulminant hepatic failure is

present, thus we suggest following this recommendation for the new indication of NAC use in various

types of acute liver failure, with use of intravenous NAC. Oral NAC may be considered when the i.v.

formulation is not available. In its use in the overdose setting to prevent hepatotoxicity, both oral and

i.v. NAC regimens are commonly used and well-tolerated, with no significant differences in safety or

efficacy.

Availability is supported given NAC is already on EML (in both injectable and oral forms) with

strengths (Injection: 200 mg/mL in 10- mL ampoule; oral liquid: 10%; 20%) appropriate for the detailed

treatment approach described below in Section 7. While the existing evidence base on use of NAC in

various types of non-acetaminophen-induced liver failure represents some variation in dosage and

administration schedules, these plans generally paralleled the NAC strategy used in acetaminophen

overdose and are similar for patients with acute liver failure due to other causes.

6. Whether listing is requested as an individual medicine or as

representative of a pharmacological class.

Individual medicine

7. Treatment details (requirements for diagnosis, treatment and

monitoring).

NAC administration should be initiated intravenously in patients with significant acute liver injury as

soon as ALF is detected, typically via presence of one of the precipitating conditions (e.g. acute viral

hepatitis, heat stroke, dengue, acute alcoholic hepatitis, mushroom toxicity) combined with alterations

in clinical status and liver function tests indicating acute liver failure as per local clinical standards.

The recommended IV protocol described in a previous review by WHO, focused on NAC use in

paracetamol toxicity in pediatrics,(25) adapted to incorporate regimen provisions in the literature

describing use of NAC in non-acetaminophen ALF, includes:

• Loading dose: administer 150 mg/kg IV over 1 hour

• Maintenance: followed by 50 mg/kg over 4 hours, then 100 mg/kg over 16 hours, then

100 mg/kg/day until up to 7 days after initial start of NAC depending on clinical

response.

• Modified IV dosing in those weighing less than 40 kg is recommended to avoid fluid

overload.

Administration should continue for a minimum of three days but longer as needed based on

assessment of the patient’s clinical status, laboratory testing of liver function and related measures

such as international normalized ratio (INR), and the time course of the underlying medical condition

(e.g. mushroom toxicity follows a shorter time course than dengue fever, which has a longer disease

course). To avoid fluid overload, the volume of diluent should be reduced whenever clinically needed.

The literature does not indicate that the dose of NAC in infected patients with hepatic impairment should

be reduced. Reduced clearance of NAC was observed in seven patients affected by chronic liver disease

as compared with six healthy controls, suggesting that it is possible that cirrhotic patients may be at

increased risk of hypersensitivity reactions.(26) The existing NAC literature indicates that

hypersensitivity reactions may be managed by decreasing the infusion rate or discontinuing the infusion

altogether.

If IV NAC is not available/feasible, oral NAC could be substituted using the protocol noted in the WHO

NAC review,(25) 140 mg/kg followed in 4 hours by a maintenance dose of 70 mg/kg orally given every

4 hours for up to 5 days, tailored to the condition of the patient under treatment.

Use in Children: NAC has a well-established safety profile, including extensive safety data in children

due to its use in acetaminophen toxicity. Use of NAC in ALF associated with the indications described in

this application, which each may affect this age group, would be appropriate in children.

Use in Pregnancy: The US Food and Drug Administration lists NAC as a Pregnancy Category B agent,

noting: “Limited case reports of pregnant women exposed to acetylcysteine during various trimesters

did not report any adverse maternal, fetal or neonatal outcomes.”(27) No significant adverse effects

involving the mother or fetus were observed in a prospective comparative study (n=80) of oral NAC for

treatment of recurrent unexplained pregnancy loss;(28) an RCT of oral NAC in women with severe early

onset preeclampsia or HELLP syndrome (hemolysis, elevated liver enzymes, and low platelets);(29) an

RCT of IV NAC in maternal chorioamnionitis;(30) and an RCT of oral NAC in pregnant women with low

antioxidant status.(31) A randomized, double-blind, placebo-controlled trial of oral NAC for prevention

of recurrent preterm birth found no major maternal or fetal adverse effects; approximately 11% of

participants discontinued NAC due to nausea and vomiting.(32)

8. Information supporting the public health relevance.

While a relatively rare condition, acute liver failure is a serious clinical condition irrespective of country

and region, with high morbidity, as well as high mortality in the absence of supportive clinical care and

potentially liver transplantation. (23,24) ALF affects all age groups, and the causes of ALF are

heterogeneous; as noted above, we focus this application on ALF subsets with known involvement of

glutathione, given the targeting of this protein by NAC.

Acute viral hepatitis infections are responsible for most ALF cases globally, with variation in causative

viral pathogen in various regions (e.g. hepatitis A, B, E; dengue virus). (33) Considering dengue virus as

one key cause of acute liver injury and failure, the data suggests notable impact in some regions. Among

an estimated 390 million people infected with dengue each year, the WHO further estimates that 500

000 people with severe dengue require hospitalization and there is a 2.5% case fatality annually.(34) In

addition, there are growing reports of links between climate variations and the emergence of “climate-

sensitive infectious diseases”, which would include all of the mosquito-borne diseases dengue,

chikungunya, and Zika,(35) suggesting the global burden could be worsening. In the last 50 years,

incidence has been reported to have increased 30-fold. Although only nine countries had experienced

severe dengue epidemics prior to 1970, the disease is now endemic in over 120 countries resulting in

~3.9 billion people are at risk of infection.(36) Further, liver injury and failure may complicate the

disease course in a significant portion of individuals affected by dengue infection; in an analysis of 347

patients hospitalized for dengue fever during one outbreak in Thailand, 63% (n=219) had hepatic

failure.(37) The WHO notes:(34) “Dengue is increasing at a higher rate than any other communicable

disease, with 400% increase over 13 years (2000-2013). Annual dengue incidence is estimated to be in

the order of 100 million symptomatic cases a year, with another ~300 million asymptomatic infections.

The greatest burden is seen in Asia (75%) followed by Latin America and Africa.”

Heat stroke is another important cause of ALF. Incidence is difficult to estimate globally due to lack of

an accepted system for capture and reporting. In the US, for example, one study estimated over 4100

emergency department visits per year for heat stroke, an annual national incidence rate of 1.34

visits/100,000 people; this analysis noted a case fatality rate of 3.4%.(38) A 2015 report by the WHO

notes that heat waves are an emerging public health problem as climate change worsens, (39) which

further suggests that conditions such as heat stroke and its sequelae may become more common in the

future. This report also points to existing supportive evidence regarding increased mortality and

morbidity during past heat waves in Europe and other regions.(39)

Amatoxin toxicity due to consumption of poisonous mushrooms is a global problem, though difficult to

estimate incidence to do high likelihood of underreporting; while more common in some regions such

as Europe, the literature includes reports of mushroom poisoning in numerous regions around the

world and those with poisoning who develop ALF have a poor prognosis in the absence of significant

supportive care and potentially liver transplantation.(40,41)

ALF caused by excess alcohol intake is another serious condition, with estimated 30 day mortality of

30%.(42) Its exact incidence is unknown, but some have estimated that its incidence in alcoholics may

be up to 20%.(43) Providing global context, a WHO report in 2018 estimated that the prevalence of

heavy episodic drinking was around 18% in 2016 globally, and more common in some areas such as

Eastern Europe and sub-Saharan Africa,(44) suggesting that some regions may be at risk of increased

prevalence of this type of ALF.

Despite the prevalence of a range of conditions precipitating ALF in countries around the world and the

potentially catastrophic nature of ALF for affected child and adults, the EML does not contain any

specific, targeted treatment for this condition, outside of use of NAC specifically for

acetaminophen-induced toxicity. The literature indicates growing use of across a range of subtypes

of non-acetaminophen-induced liver failure, with significant off label use and supportive prospective

and retrospective data, described further below and suggesting that this intervention would provide a

valuable addition to the supportive care provided to these patients. Adding this information to the EML

would also provide critical guidance to health workers regarding standard dosing and administration of

NAC as supplemental treatment.

9. Review of benefits: summary of evidence of comparative effectiveness.

Identification of clinical evidence (search strategy, systematic reviews identified, reasons for

selection/exclusion of particular data)

The studies from the literature for this analysis were identified by a trained information scientist

searching the PubMed and Web of Science databases, as well as a broad Google search to identify

unindexed and grey literature. The search terms used were: “acute liver failure”, “acute liver injury”,

“acetylcysteine”, “N-acetylcysteine” and “acetylcysteine”. This search was not date limited; studies were

assessed without restriction by a publication date threshold to ensure inclusiveness. The reference lists

of reviewed articles were also assessed, to identify any studies not found by the initial search and to

better clarify preclinical and mechanistic underpinnings of both the disease and the therapy. No studies

investigating the use of NAC in treatment of ALF with the specified etiologies (selected due to

glutathione involvement, including hepatitis A or B, dengue fever, heat stroke, alcohol poisoning, and

mushroom toxicity) were excluded from this exploration; we further included any studies examining

general non-acetaminophen-induced ALF to complement the evidence pool identified related to the

specified ALF etiologies. Evidence was systemically extracted (see Literature Summary); when

comprehensive systematic reviews and meta-analyses were identified, additional primary evidence was

extracted from other papers to represent 1) data not covered in those reviews/meta-analysis and 2)

nuances of data to complement the data summarized in the systematic reviews. This review also

identified studies evaluating hepatic effects of NAC beyond the selected indications described in the

current application to aid in contextualization; this broader evidence is provided for additional context

in Appendix 2.

Summary of available data (appraisal of quality, outcome measures, summary of results)

Full details of the literature describing each of the subsets of literature described in this section are

included in the evidence tables represented in the Literature Summary section later in this application.

Here, we focus on key characteristics of the primary and secondary literature supporting each of the

ALF subsets proposed in the current application, including the literature describing use of NAC in

general non-acetaminophen-induced ALF as these studies typically represent a number of the narrower

populations we propose.

General non-acetaminophen-induced acute liver failure: Three systematic reviews, published in

2004,(2) 2013,(3) and 2015(4) provide useful insights into the evolution of evidence regarding the use

of NAC in non-acetaminophen-induced ALF. While the two older articles note potential utility of NAC in

this subset of ALF based on data pools comprised primarily of retrospective case reports and series,(2,3)

the 2015 review included four RCTs and concluded significant benefit with use of NAC as compared with

control in terms of transplant-free survival and post-transplantation survival. All three systematic

reviews noted that adverse effects in this population were consistent with those observed in its use in

acetaminophen-induced ALF and that no hepatotoxic effects were seen with the dose used for

acetaminophen toxicity. One additional RCT in non-acetaminophen-induced ALF (n=80) published in

2017, after the 2015 review, also found positive effects of NAC administration; more patients (72.5%)

survived in the NAC group than in the control group (47.5%) (p=0.025) and among those who survived,

hospital length of stay was approximately 2.5 days shorter in the NAC-treated group (p=0.002).(45)

Further, a large prospective multisite cohort in the US found increasing use of NAC over time suggesting

significant acceptance of this agent as a clinically attractive off-label use across centers, with almost 70%

of patients with non-acetaminophen-induced ALF receiving this intervention in an 8-year time period

through 2013, further paralleling an increase in survival rates during this time.(46)

Heat stroke associated acute liver failure: In addition to representation of this ALF population in the

general ALF studies described above, we identified 3 case reports suggesting improvement in liver

function and other clinical outcomes associated with use of IV NAC in patients with heat-related

ALF.(47–49) No adverse effects discordant with use of NAC in other indications were identified.

Severe acute alcoholic hepatitis: Severe acute alcoholic hepatitis is somewhat unique among the

causes of ALF, in that it represents an acute event likely embedded within chronic disease; NAC has

been used with success during this acute event, thus we include it here. In addition to representation of

this subgroup of patients in the general ALF studies summarized above, a systematic review in 2015

analyzed the literature regarding use of various therapies in treatment of acute alcoholic hepatitis

requiring hospitalization.(50) This review identified 22 RCTs comprising a total of 2621 patients and

including 5 different interventions. A network meta-analysis of this moderate quality evidence pool

found that the use of corticosteroids alone (relative risk [RR], 0.54; 95% credible interval [CrI], 0.39-

0.73) or in combination with NAC (RR, 0.15; 95% CI, 0.05-0.39), to reduce short-term mortality. No trials

published since the date of this literature review have been identified in the literature.

Mushroom-induced acute liver failure: In addition to representation in the general ALF studies

described above, acute liver injury and failure are a common and severe consequence of mushroom

poisoning. A 2020 systematic review examine the literature on use of NAC in this population, identifying

13 studies including a total of 506 patients.(51) Mortality in patients treated with NAC was 8-11%, liver

transplantation rate was 4.3%. Various laboratory values related to liver function and coagulopathy

improved over 4-7 days after ingestion. Anaphylactoid reactions occurred in 5%. The review concludes

that NAC appears to be safe and beneficial in this type of poisoning.

Acute viral hepatitis: In addition to representation in the ALF studies described above, two small

retrospective case series of NAC use in children with ALF in the context of acute viral hepatitis have been

published, including 40(52) and 12(53) patients respectively. Hepatitis A appeared to be the most

common etiology. Both reports indicate improvement of liver enzymes and coagulation parameters and

satisfactory medication tolerance with use of NAC in the population.

Dengue fever: Given the size of the literature describing use in dengue virus-associated liver injury and

failure, we elected to describe these data separately from the studies of acute viral hepatitis, in which

hepatitis A was most common as the precipitating viral infection. The data collected from various

studies of dengue-infected patients do not include a large, randomized, double-blind, controlled trial.

Given the sporadic and epidemic nature of the disease, such a study would be time-consuming and

costly. We have assembled the existing evidence base on this use, comprising retrospective cohort

studies, case series, and case reports and totaling 43 patients with dengue infection receiving NAC in

addition to usual care. Dengue-related illnesses ranged in severity (but none appeared to be affected by

mild disease). Outcome measures included liver function testing, mortality, measures of morbidity such

as need for transplant, length of stay, and other laboratory measures relevant for dengue fever and its

sequelae. Observed adverse effects were consistent with the broader evidence base on NAC use in

humans, and all patients recovered except 3 patients, with disease level III–IV who already had dengue-

associated ALF prior to treatment, who died. Notably, in one case with dengue associated severe

hepatitis in a 53 year old, prior to NAC treatment, liver enzymes reached peak values of AST 16261 U/L

and ALT 4545 U/L on 4

day of admission (7

day of illness).(54) Authors note marked improvement

in liver enzyme values, and AST and ALT levels dropped by more than half by 48 hours of treatment. In

a retrospective case series, 13 people with moderate to severe hepatitis received NAC and had hepatic

recovery faster than less sick patients who did not receive NAC.(55) Data from case series and case

reports, gradual normalization of liver function tests was noted in 26 other patients (15 adults; 11

infants and children) receiving NAC in moderate to severe dengue illness. (56–67)

PheWAS data: We also reviewed a set of data in which a phenome-wide association study (PheWAS)

analysis was undertaken. PheWAS can identify diseases or conditions (phenotypes) that are associated

with a specific gene/genetic variant.(68) PheWAS leverages existing data from the Exomechip

genotyping platform (~250,000 coding variants across the protein coding region of the genome) and

electronic health records for approximately 35,000 patients. Because the logic of PheWAS can be

extended to predict phenotypic manifestations of pharmacological targeting (such as with NAC) of a

given gene product in humans, we use these methods for drug repurposing.(69) As a glutathione

synthetase (gene: GSS) ‘stimulator’, NAC is hepatoprotective. This is established in its use in

acetaminophen overdose. The phenotypes associated with a missense single nucleotide polymorphism

(SNP) (R418Q) in the GSS gene are risk causing, so in this regard we can say the SNP is behaving like a

glutathione synthetase inhibitor (the opposite of the drug). Thus, the variety of liver phenotypes in the

below analysis (Table 1) strengthen, with human data, that decreased glutathione synthetase is

associated with a broad range of liver injury, as is true in the ALF etiologies represented in the current

application for a new NAC indication on the EML.

Table 1: PheWAS results, GSS variation and liver disease

Note: The SNP in this table appears to be functioning as a glutathione synthetase inhibitor (GSS ↓); thus,

a glutathione synthetase stimulator such as NAC (GSS ↑) is indicated for management of relevant

phenotypes.

rsID (Mutation)

Gene

Phecode

Phenotype

Cases

(n)

Controls

(n)

Odds

ratio

(OR)

AFF_11

AFF_12

rs150141794

(Missense_R418Q)

GSS

530.2

Esophageal bleeding

(varices/hemorrhage)

394

18594

5.9300

0.002337

rs150141794

(Missense_R418Q)

GSS

261.2

Vitamin B-complex

deficiencies

557

21366

4.5910

0.00661

rs150141794

(Missense_R418Q)

GSS

571.8

Liver abscess and

sequelae of chronic

liver disease

598

22795

4.2490

0.008865

rs150141794

(Missense_R418Q)

GSS

573.7

Abnormal results of

function study of liver

890

22795

3.4230

0.01187

rs150141794

(Missense_R418Q)

GSS

571

Chronic liver disease

and cirrhosis

1312

22795

2.7070

0.02196

rs150141794

(Missense_R418Q)

GSS

571.51

Cirrhosis of liver

without mention of

alcohol

769

22795

3.3010

0.02317

rs150141794

(Missense_R418Q)

GSS

571.5

Other chronic

nonalcoholic liver

disease

1092

22795

2.7880

0.0282

rs150141794

(Missense_R418Q)

GSS

573.2

Liver replaced by

transplant

368

22795

4.1420

0.04077

rs150141794

(Missense_R418Q)

GSS

571.81

Portal hypertension

399

22795

3.8190

0.04958

Key: GSS glutathione synthetase gene; AFF_11 cases carrying two copies of the variant minor allele; AFF_12 cases carrying

one copy of the variant minor allele

Summary of available estimates of comparative effectiveness

With typical comparators in this literature on use of NAC in various types of non-acetaminophen-

induced ALF including either supportive care alone or placebo, the evidence indicates that use of NAC

represents at least an incremental benefit over usual care alone. The literature does not include head-

to-head comparisons with other “active” interventions, precluding a more thorough and quantified

estimate of the comparative effectiveness of NAC. The safety profile reported in this use is consistent

with published adverse effects of NAC use for other indications, suggesting that the risk benefit for this

approach is not weakened by a disparate safety signal.

10. Review of harms and toxicity: summary of evidence of safety.

Estimate of total patient exposure to date:

The WHO EML currently lists N-acetylcysteine as an antidote for the treatment of acetaminophen

overdose.(70) Based on exposure reported in the literature, and given that both oral and IV NAC have

been approved as a first-line therapy for acetaminophen overdose for 40+ years, it is estimated that

hundreds of thousands of patients have been exposed to date (likely many more worldwide).

Description of the adverse effects/reactions when used in non-acetaminophen induced

acute liver failure:

The safety data collected for studies of NAC in non-acetaminophen induced liver failure is captured from

clinical trials, retrospective cohorts, case series, and case reports, comprising data from approximately

2500 patients.(3,4,45–49,51–54,57–59,61,63–65,67,71–81) The adverse effects observed in this

literature are consistent with the broader evidence base on NAC use in humans showing that it is safe

and well tolerated. Investigators report an adverse effect profile observed with use of NAC in non-

acetaminophen induced ALF (general, heat stroke, acute alcoholic hepatitis, mushroom poisoning, acute

viral hepatitis, dengue fever) concordant with the established safety profile of this agent in its use for

acetaminophen induced ALF. Review of adverse effects observed in studies exploring therapeutic use

of NAC in other liver-related conditions and indications (see Appendix 3) also indicates risks similar to

those observed during NAC use for acetaminophen overdose.

Description of the adverse effects/reactions and estimates of their frequency (drawn from

the broader NAC literature on human use)

- Oral administration of NAC is documented to be safe and well-tolerated. The most common side

effects include nausea and vomiting, which is reported to occur in up to 23% of patients(82)

(this may be attributed to its distasteful odor). Oral NAC is rarely associated with more severe

side effects like angioedema.(83,84)

- IV administration of NAC is also usually well-tolerated but is associated with a higher risk of

adverse effects, the most common include:

o Nausea, vomiting – occurs at a frequency of up to 9%(82)

o Anaphylactoid reactions (rash, pruritis, angioedema, bronchospasm) – occurs at a

frequency of 8.2% (out of 6455 treatment courses). 75% of anaphylactoid reactions

were cutaneous(85)

▪ Risk factors for anaphylactoid reactions:

• Females(86) and patients with asthma(87) appear to be at higher risk of

developing the anaphylactoid response and both are associated with a

more severe reaction(85)

• Anaphylactoid reactions occur more commonly with lower

acetaminophen levels rather than high levels (this may be because

acetaminophen decreases the histamine released from mast cells and

mononuclear cells, proportionate to the dose ingested). (88)

▪ It is noted that hypersensitivity reactions may be managed by decreasing the

infusion rate or discontinuing the infusion.(83,89)

o Serious adverse reactions and fatalities are rare but have occurred with IV treatment

(these patients also had a history of asthma)(90)

o A tabular summary of the results of systematic reviews of NAC safety when used in non-

dengue indications is included in Appendix 3 .

o While thorough analyses of pharmacovigilance databases (e.g. US FDA FAERS, WHO

Vigibase) are not currently available in the published literature for NAC, the package

inserts for NAC benefit from the long-standing use of this agent for management of

acetaminophen overdose. Post marketing events summarized in these

materials(27,91) include:

▪ Adverse effects identified through post-marketing experience for NAC injection:

rash, urticaria, and pruritus. The frequency of adverse reactions have been

reported to be between 0.2% and 21%, and they most commonly occur during

the initial loading dose of acetylcysteine.

▪ Adverse effects identified through post-marketing experience for oral NAC:

nausea and vomiting, other gastrointestinal symptoms, and rash with or without

fever, and upper GI hemorrhage. (Frequency not reported.)

Summary of available data

- NAC therapies, given via various routes of administration (oral, IV, or inhaled), have been

marketed in the US (and other countries) for over 40 years. Systematic reviews of NAC treatment

for approved and non-approved indications are abundant and suggest that it is a safe and well-

tolerated drug in both pediatric(75,92) and adult populations(83,85,93–96), although particular

attention should be paid to dosing per body weight in pediatric populations to avoid toxicity

related to dosing errors.(97)

- Side effects associated with NAC treatment are typically mild and while nausea and vomiting is

the most common side effect with both IV and oral routes, the rate of nausea and vomiting is

higher with oral NAC. Anaphylactoid reactions are more common with IV NAC and typically

subside upon ceasing treatment. Symptoms characteristic of anaphylactoid reactions include

flushing, pruritus, and rash and can also include angioedema, bronchospasm, and hypotension.

Severe adverse reactions and fatalities are rare.(82)

- NAC drugs are available internationally.(89,98) For example regarding availability of various

formulations, there are 7 drugs currently on the market in the US given via IV route of

administration, 4 given orally (effervescent tablet or oral solution), and 3 given via inhaled

solution.(99)

- Safety information from package inserts for example NAC therapies is presented below (Table

2; adverse events for various routes of NAC administration including oral, IV, and inhaled

routes).

- Several randomized control trials of NAC for acetaminophen overdose have also been reported.

One relatively small randomized control trial (n = 50) randomized patients with hepatic failure

after acetaminophen overdose to either IV NAC in addition to standard liver care or standard

liver care alone.(100) The NAC regimen in this study included: 150 mg/kg body weight in 200

ml 5% dextrose over 15 minutes, followed by 50 mg/kg in 500 ml 5% dextrose over four hours,

then 100 mg/kg in 1 L over 16 hour. The final infusion rate was continued until recovery from

encephalopathy or death. The rate of survival was higher in patients receiving NAC. No adverse

side effects were reported in this study.

- Another larger trial(101) that randomized 223 patients to different 150 mg/kg N-acetylcysteine

loading infusion rates (15 minutes or 60 minutes) reported adverse event rates of 75% and 61%

for the 15 minute and 60-minute arms, respectively. Anaphylactoid reactions were the most

reported adverse reactions in both arms, occurring in 18% in the 15-minute arm and 15% in the

60-minute arm. Two patients (one in each arm) experienced a severe anaphylactoid reaction

and were withdrawn from the study. Nausea and vomiting, classified within the broader GI

disorders category in study analyses, were experienced by 13% of patients. The difference

between the drug-related adverse events was not statistically significant and no deaths were

reported

- The remaining body of clinical trial literature is comprised of prospective, non-randomized,

observational trials.(83,85,93,94) Nevertheless, the data from these studies support the RCTs

above showing that both oral and IV NAC are safe and well tolerated. Case reports have also

described other rarer features of anaphylactoid reactions like ECG abnormalities(102), status

epilepticus(103), and a serum sickness-like illness(104), however these are not commonly

reported in larger trials.

Table 2: Adverse event summary for various NAC formulations

Drug (route)

Population

Indication

Adverse event (and frequency, if

reported)

Reference

CETYLEV (oral

effervescent tablet)

Adults and

children, though

pediatric

approval is not

based on

adequate or

well-controlled

studies

Acetaminophen

overdose

- Allergic reaction

- Nausea and vomiting (up to 30% of

patients)

- Rash (with or without fever)

- GI problems

- May aggravate vomiting as a

symptom of acetaminophen

overdose

- May aggravate vomiting and

increase risk of upper GI

hemorrhage in at risk patients

(those with esophageal varices,

peptic ulcers)

- Hypersensitivity reactions,

including generalized urticaria

U.S package

insert(91)

ACETADOTE (IV)

Adults

Acetaminophen

overdose

- Pruritis (4.3%)

- Urticaria/facial flushing (6.1%)

- Respiratory symptoms (1.9%)

- Edema (1.6%)

U.S package

insert(27)

Children

Acetaminophen

overdose

- Urticaria/facial flushing (7.6%)

- Pruritis (4.1%)

- Respiratory symptoms (2.2%)

- Edema (1.2%)

Geriatric

Acetaminophen

overdose

- Clinical studies do not provide

sufficient number of geriatric

subjects to determine whether the

elderly respond differently

- There are not adequate and well-

controlled studies in pregnant

women, but limited case reports do

not include any adverse maternal,

fetal, or neonatal outcomes

Acetylcysteine 200

mg/mL injection (IV)

Adults and

children

Acetaminophen

overdose

- The most common AEs are nausea,

vomiting, flushing, and skin rash

- Less commonly, more serious

anaphylactoid reactions have been

reported (angioedema,

bronchospasm, hypotension,

tachycardia, or hypertension)

- AEs usually occur between 15 and

60 min after start of infusion (many

Europe/UK

package

insert(105)

symptoms are relieved by ceasing

infusion)

- Other reported AEs include:

infection site reaction, pruritus,

cough, chest tightness or pain, puffy

eyes, sweating, malaise, raised

temperature, vasodilation, blurred

vision, bradycardia, facial or eye

pain, syncope, acidosis,

thrombocytopenia, respiratory or

cardiac arrest, stridor, anxiety,

extravasation, arthropathy,

arthralgia, deterioration of liver

function, generalized seizure,

cyanosis, lowered blood urea

- Fatalities are very rare

- Hypokalemia and ECG changes have

been noted in patients with

acetaminophen overdose,

monitoring of plasma potassium

concentration is recommended

Acetylcysteine

solution, USP

(inhaled)

Adults and

children

Chronic or acute

bronchopulmonary

disease, pulmonary

complications of

cystic fibrosis, and

other conditions

associated with

abnormal, viscid, or

inspissated mucous

secretions

- Stomatitis, nausea, vomiting, fever,

rhinorrhea, drowsiness,

clamminess, chest tightness and

bronchoconstriction.

- Clinically overt bronchospasm

occurs infrequently and

unpredictably even in patients with

asthmatic bronchitis or bronchitis

complicating bronchial asthma

Package

insert(106)

Acetaminophen

overdose

- Oral administration of the large

doses needed to treat

acetaminophen overdose may

result in nausea, vomiting, and

other GI disorders

- Rash, with or without fever, has

been reported but rarely

Parvolex (200 mg/ml

concentrate solution

for infusion)

Adults and

children

Acetaminophen

overdose

- Swelling of the face, lips or tongue

- Wheezing, difficulty breathing

- Irritation at the injection site

- Skin rash, itching

- Flushing

- Low blood pressure resulting in

dizziness

- Rapid heartbeat or increased blood

pressure (rarely)

- Other rare side effects include

coughing, noisy breathing,

respiratory arrest, chest tightness

or pain, puffy eyes, blurred vision,

sweating, raised temperature, liver

problems, slow heartbeat, fainting

or collapsing, reduction in blood

platelets

Package

insert(107)

Identification of variation in safety that may relate to health systems and patient factors

- Studies using IV NAC for acetaminophen overdose have shown that females(86) and those with

a history of asthma or atrophy(87) are particularly susceptible to anaphylactoid reactions.

- The package insert for CETYLEV (oral, effervescent NAC tablets) states that it may aggravate

vomiting as a symptom of acetaminophen overdose and may aggravate vomiting and increase

risk of upper GI hemorrhage in at risk patients (those with esophageal varices, peptic

ulcers).(91)

- Reduced clearance of NAC in seven patients affected by chronic liver disease as compared with

six healthy controls, suggesting that it is possible that cirrhotic patients may be at increased risk

of hypersensitivity reactions.(26)

- As NAC is a nitrogenous substance, a theoretical risk of hepatic encephalopathy (HE) is noted in

some NAC package inserts, which further note that there is no clinical data suggesting that

acetylcysteine influences on hepatic failure.

11. Summary of available data on comparative cost and cost-effectiveness

of the medicine.

NAC is already on the EML, with a widespread availability in most countries of the world at very low

cost. The current application is not a request to add a medication for which pricing would be needed, as

there would be no change to the existing pricing data expected from adding this new use of NAC.

Considering one of the more extreme outcomes of ALF, liver transplantation has varied costs and

availability in different settings; in the United States, for example, a recent report noted that the average

liver transplant was billed at over $800,000 per patient(108); while it is likely that the US is on the upper

end of the global spectrum of costs for this procedure,(109) the resources required for transplant and

follow-up are likely intensive in most settings, compounded further by the limited availability of organs

for transplant. The estimated cost for NAC is US$70. Given the extremely low NAC price per dose and

the potential for averting significant downstream outcomes such as need for liver transplantation, its

use would have substantial cost effectiveness.

12. Summary of regulatory status and market availability of the medicine.

NAC is approved by many health authorities for prevention of liver injury in acetaminophen overdose

or as a mucolytic. To our knowledge, no health authority currently has NAC formally listed for a liver

indication outside of acetaminophen overdose despite it being used in this setting. The lack of financial

incentives for the pharma manufacturing industry to pursue new regulatory approvals for a medication

that is no longer proprietary likely prevents this from happening. Examples of NAC approval for use in

various countries are as follows:

Regulatory Agency

Indication

US Food and Drug Administration (FDA)

- To prevent or lessen liver injury after

acetaminophen overdose

- Mucolytic in patients with cystic fibrosis

(or other conditions associated with

abnormal or viscid mucous secretions)

European Medicines Agency (EMA)

- To prevent or lessen liver injury after

acetaminophen overdose

- Mucolytic in patients with cystic fibrosis

(or other conditions associated with

abnormal or viscid mucous secretions)

Australian Government, Department of Health,

Therapeutic Goods Administration

- To prevent or lessen liver injury after

acetaminophen overdose

- Mucolytic in patients with cystic fibrosis

(or other conditions associated with

abnormal or viscid mucous secretions)

Japanese Pharmaceuticals and Medical Devices

Agency

- To prevent or lessen liver injury after

acetaminophen overdose

- Mucolytic in patients with cystic fibrosis

(or other conditions associated with

abnormal or viscid mucous secretions)

Health Canada

- To prevent or lessen liver injury after

acetaminophen overdose

- Mucolytic in patients with cystic fibrosis

(or other conditions associated with

abnormal or viscid mucous secretions)

Further, there is widespread market availability of NAC and multiple generic manufacturers including

Fresenius Kabi, Auro Medics Pharma, Cadila Healthcare, Zydus Pharmaceuticals, Roxane Laboratories

Inc., Sagent Pharmaceuticals, and Pfizer, among many others in various countries. Given that NAC is in

widespread use globally as an acetaminophen overdose antidote and as a mucolytic, it is anticipated that

the currently proposed expanded use for this agent would leverage the existing supply chains

established in various regions.

13. Availability of pharmacopeial standards (British Pharmacopoeia,

International Pharmacopoeia, United States Pharmacopoeia, European

Pharmacopeia). Summary of available data on comparative cost and cost-

effectiveness of the medicine.

Acetylcysteine is included in several pharmacopeial standards, including the British Pharmacopoeia; the

United States Pharmacopoeia; and the European Pharmacopoeia.

Literature summaries: non-acetaminophen acute liver failure, organized by precipitating

exposure/condition

LITERATURE SUMMARY: Evidence describing use of NAC in general non-acetaminophen-induced acute liver injury

First author, year

country

Design

Condition

Sample

size

NAC dose, frequency,

duration, route of

administration; comparator

Findings

Outcome

Hu, 2015(4)

Meta-analysis

Non-

acetaminophen

induced acute liver

failure

4 clinical

trials

(total n

331 NAC,

285

control)

NAC as administered in

original clinical trials,

compared to control arm

No statistical difference was identified

between NAC group and control group for

overall survival [236/331 (71%) vs

191/285 (67%); 95% CI 1.16 (0.81-1.67);

P=0.42].

There were significant differences between

NAC group and control group regarding the

survival with native liver [112/273 (41%)

vs 68/226 (30%); 95% CI 1.61 (1.11-2.34);

P=0.01] and post-transplantation survival

[78/91 (85.7%) vs 50/70 (71.4%); 95% CI

2.44 (1.11-5.37); P=0.03].

Side effects included nausea, vomiting, and

diarrhea or constipation; rarer effects

included rashes, fever, headache,

drowsiness, low blood pressure, and

elevated serum transaminase levels in a

patient with cystic fibrosis.

No hepatotoxic effects observed at the dose

used for acetaminophen toxicity.

Positive

effect

Sales, 2013(3)

Systematic

review

Non-

acetaminophen

induced acute liver

failure

articles

included

(8 case

reports, 2

retrospec

tive trials,

1 RCT)

NAC as administered in

original report

The 2 retrospective studies suggested

survival benefit in adults and children; RCT

suggested benefit in terms of transplant-

free survival.

Oral and IV NAC well tolerated.

Authors concluded marginal benefit of NAC

Suggests

positive effect

Sklar 2004(2)

Systematic

review

Non-

acetaminophen

7 studies

NAC as administered in

original report

Investigators commented: “All of the

studies found were small and do not

provide conclusive evidence that

Suggests

positive effect

related to

induced acute liver

failure

acetylcysteine benefits this subgroup of

patients. Microvascular regional benefits

were seen, but clinical outcomes have not

been studied.”

microvascular

regional

benefit

Nabi, 2017(45)

Randomized

study

Non-

acetaminophen-

induced liver

failure (etiology

included

undetermined,

hepatitis E, other

drugs and toxins,

Wilson disease,

autoimmune

disease, CMV, HSV)

IV NAC initial loading dose of

150 mg/kg over 1 hour,

followed by 12.5 mg/kg/h for

4 hours and continuous

infusion of 6.25 mg/kg/h for

remaining 67 hours.

Control patients received 5%

dextrose infusion for 72 hours.

Incidence of renal failure was not

significantly different between the two

groups. Mannitol for increased ICP was

used more often in the control group as

compared with the NAC group (92.5 vs

75%, p=0.037). Among the patients who

survived, mean hospital length of stay was

shorter in the NAC group (8.241 ± 2.115 vs

10.737 ± 3.106, p=0.002).

A total of 32 of 80 (40%) patients died with

ALF complications; 11 (27.5%) patients

belonged to the NAC group and 21 (52.5%)

patients to the control group (chi‑square =

5.208; P = 0.023) and the mean time to

death from diagnosis was 9.3 days.

More patients (72.5%) survived in the NAC

group than in the control group (47.5%)

(p=0.025) Stratification by etiology

suggested that patients with drug‑induced

ALF showed improved outcomes..

No adverse effects attributable to NAC were

observed.

Positive

effect

Lee, 2009(71),

Stravitz,

2013(73)and Singh,

2013(72)

USA

RCT

Non-

acetaminophen-

induced liver

failure

Majority fell into 4

etiologies: drug-

induced liver

injury (n=45),

autoimmune

hepatitis (n=26),

hepatitis B (n=37)

and

indeterminate (n=

41)

173

NAC infusion in 5% dextrose:

an initial loading dose of 150

mg/kg/h of NAC over 1 hour,

followed by 12.5 mg/kg/h for

4 hours, then continuous

infusions of 6.25 mg/kg NAC

for the remaining 67 hours (3

days total) (81 assigned, 48

completed 72h trial, 33

received less than full

treatment because of death,

withdrawal of support,

transplantation, or side effects

of drugs (4 thought to be due

to NAC specifically))

Transplant-free survival was significantly

better for NAC patients (40%) than for

those given placebo (27%; 1-sided P =

.043).

The transplantation rate was lower in the

NAC group but was not significantly

different between groups (32% vs 45%; P =

.093).

Adverse effects: Nausea and vomiting

occurred significantly more frequently in

the NAC group (14% vs 4%; P=0.031).

Positive

effect

Subjects in the placebo group

received infusion of 5%

dextrose only (92 assigned, 58

completed 72h trial, 34

received less than full

treatment)

Treatment group and day of study in

models including bilirubin or ALT were

predictors of transplantation or death

(maximum p < 0.03). Those patients with

early coma grade who were treated with

NAC showed significant improvement in

bilirubin and ALT levels when compared to

the other three groups (maximum p < 0.02

for NAC 1-2 vs. the 3 other treatments)

when predicting death or transplantation.

Treatment group, day of study, and

bilirubin were predictors of transplantation

(maximum p < 0.03) in ALF patients.

Stepwise multivariate logistic regression

analysis identified only NAC administration

and lower IL-17 concentrations as

independent predictors of transplant-free

survival. In patients with detectable IL-17

concentrations on admission, 78% of those

who received NAC vs. 44% of those who

received placebo had undetectable levels by

day 3-5 (P = 0.042), and the mean decrease

in IL-17 concentrations between admission

and late samples was significantly greater

in patients who received NAC vs. placebo (P

= 0.045).

Squires, 2013(110)

USA

Double-blind,

placebo-

controlled RCT

Pediatric acute

liver failure not

believed to be

caused by

acetaminophen

(discharge

diagnoses included

autoimmune,

infection,

metabolic

disorders, and

other conditions; 1

patient had

acetaminophen

overdose and

approximately

184

150 mg/kg/d NAC infusion in

5% dextrose infused over 24

hours for up to 7 consecutive

days (92 subjects)

92 received placebo (dextrose

and water alone)

The 1-year survival did not differ

significantly (p=0.19) between the NAC

(73%) and placebo (82%) treatment

groups.

*The 1-year transplant-free survival was

significantly lower (p=0.03) in those who

received NAC (35%) than those who

received placebo (53%).

There were no significant differences

between treatment arms for hospital or ICU

length of stay, organ systems failing, or

highest recorded grade of HE.

Metabolic disease was more common in the

NAC arm (13 NAC vs 5 placebo) with

Reduced

efficacy?

60% had unknown

cause)

Wilson disease (7 NAC vs 3 placebo) being

more common in the NAC arm than the

placebo arm.

Darweesh 2017(74)

Egypt

Prospective

and

retrospective

observational

study

Non-

acetaminophen-

induced liver acute

liver failure

155

IV NAC 150 mg/kg in 100 ml

dextrose 5% over 30 min, then

70 mg/kg in 500 ml dextrose

5% over 4 hr., then 70 mg/kg

in 500 ml dextrose 5% over 16

hr., then continuous infusion

over 24 hr. of 150 mg/kg in

500 ml dextrose 5% until up to

two consecutive normalized

INRs were obtained.

Control group included those

who did not receive NAC

The incidence of transplant-free survival

was 96.4% (n=82) in the NAC-treated

group (p<0.01 compared with control

group); among the 3 remaining patients, 2

received a liver transplant and 1 died.

These 3 patients did not receive the full

dose of NAC, two due to a severe allergic

reaction to NAC (both were transplanted)

In the control group, 17 (23.3%) recovered;

among the remaining 53 patients, 37

(53.3%) received a liver transplant and 16

(23.3%) died.

NAC treated patients had significantly

shorter hospital stays (p<0.001), less

encephalopathy (p=0.02), and less bleeding

(p<0.01) as compared with control patients.

Control patients had higher incidence of

ICU admission (p=0.01) and increased

incidence of abnormal creatine and

electrolytes (p=0.002 and p<0.01,

respectively).

Bilirubin was significantly increased among

controls (p=0.02); AST and INR were

significantly increased among NAC-treated

patients (p<0.001 for both). ALT was not

significantly different between the groups.

Positive

effect

Adverse events attributed to NAC included

prolonged cholestasis in 82; bilirubin

showed a steady but slow decrease over 2-3

months; patients not treated with NAC did

not develop this sign. Fever and allergic

reaction were observed in 3 patients and

dyspepsia in 11 patients. No bronchospasm

was observed.

Reuben, 2016(46)

Prospective

observational

Acute liver failure

of all causes except

previous liver

transplant; ~46%

acetaminophen

toxicity, the rest

due to

heterogeneous

causes

2070

NAC protocol varied from site

to site; not detailed

Two time periods, 1998-2005, 2006-2013

Use of NAC increased in the 2

time period

(69.3% vs 48.9% in the first time period,

p<0.001) in patients with ALF not due to

acetaminophen toxicity

Overall survival and transplant free

survival increased during the 16 year

period

Other changes in the 2

vs. 1

period

included reduced RBC and plasma infusion,

mechanical ventilation, and use of

vasopressors.

Suggests

positive effect

+ significant

off label use in

the US

Mumtaz, 2009(76)

Pakistan

Prospective

non-blinded

study with

historical

controls

Acute liver failure

not caused by

acetaminophen

(majority were due

to hepatitis E or B

virus, but some

due to

antituberculosis

treatment)

Oral NAC dose of 140 mg/kg

followed by 70 mg/kg, for a

total of 17 doses 4 hours apart

within 6 hours of admission

(47 subjects prospectively

enrolled)

44 subjects received standard

care only (historical controls

from hospital database)

A total of 34 (37.36%) patients survived; 22

(47%) in group 1 (NAC group) and 12

(27%) in group 2 (controls) (P = 0.05),

indicating NAC causes a significant

reduction in mortality. (no liver specific

outcome measures)

On multivariable regression analysis,

patients not given NAC (odds ratio

[OR] = 10.3, 95% confidence interval

[CI] = 1.6–65.7), along with age older than

40 years, patients requiring mechanical

ventilation, and interval between jaundice

and hepatic encephalopathy were

independent predictors of mortality.

Presumed

positive effect

Kortsalioudaki,

2008(75)

Retrospective

review

Pediatric acute

liver failure not

believed to be

caused by liver

failure

170

Continuous IV infusion NAC

100 mg/kg/24 hours until INR

normalization, death, or liver

transplant. Median duration 5

days (range 1-77)

Compared with historical

group receiving supportive

care without NAC

Length of hospital stay, length of ICU stay,

and incidence of death without liver

transplant were not significantly different

between the two groups. The 10 year

actuarial survival was 50% in the

supportive care group and 75% in the NAC

treated group (n=0.009). Survival with

native liver was observed in 13 (22%) of

the supportive care group and 48 (43%) of

the NAC-treated group. Death after

transplantation occurred in 15 (39%) of the

supportive care group as compared with 8

(16%) of the NAC treated group (p=0.02).

Among NAC-treated patients, side effects

were noted in 8 (10.8%), including rash

(n=3) resolving with no treatment;

bradycardia (n=2) or tachycardia (n=1)

attributed to underlying disease; dizziness

and peripheral edema (n=1) with NAC

tolerated at lower dose; and bronchospasm

and florid maculopapular rash attributed as

an allergic reaction to NAC requiring

discontinuation.

Presumed

positive effect

Ben-Ari, 2000(77)

Retrospective

observational

Acute liver failure

not caused by

acetaminophen

NAC administered at

presentation

Clinically, 3 patients who initially had grade

O/II encephalopathy, did not progress, and

have fully recovered. The mean peak

prothrombin time, serum factor V,

aspartate aminotransferase and alanine

aminotransferase levels, all significantly

improved. Four patients (57%) have

recovered fully (1 patient, although fully

recovered, died later from an unrelated

cause). Two patients required orthotopic

liver transplantation and 1 patient died. N-

acetylcysteine administration may have

prevented progression to grade III/IV

encephalopathy and improved serum

coagulation factors.

Presumed

positive effect

Harrison 1991(78)

Case series

Acute liver failure

12 due to

acetamin

ophen

and 8 due

NAC was given in a dose of 150

mg per kilogram of body

weight in 250 ml of 5 percent

dextrose over a period of 15

minutes and then in a dose of

Positive effects in patients with non

acetaminophen induced liver failure were

similar to those observed in the

acetaminophen group.

Presumed

positive effect

to other

causes

50 mg per kilogram in 500 ml

of 5 percent dextrose over a

period of 4 hours

LITERATURE SUMMARY: Evidence describing use of NAC in heatstroke-associated acute liver injury

First author, year

country

Design

Condition

Sample

size

NAC dose, frequency,

duration, route of

administration; comparator

Findings

Outcome

Monzon 2020(47)

Case report

Heatstroke-

associated ALF

NAC IV initiated hospital day 2

for ALI. NAC was infused at

15,000 mg IV over one hour,

followed by 5000 mg IV over

four hours, then 10,000 mg IV

over 16 h without continuation

of therapy.

24-year-old unresponsive male without

significant past medical history presented

to the emergency department with heat

stroke; his initial temperature was 107.4 °F.

During his hospital course, he developed

ALI with significant elevation in aspartate

aminotransferase, alanine

aminotransferase, and total bilirubin. These

laboratory findings peaked by hospital day

two, but improved prior to discharge on

hospital day five and throughout his follow

up clinic visits. His treatment course

included cooling measures, supportive care,

supplemental oxygen and airway

management, seizure control, and

intravenous NAC therapy.

Suggest

positive effect

Will 2019(49)

Case report

Heatstroke

associated ALF

Starting hospital day 3, loading

dose of NAC at 150 mg/kg was

given over one hour. NAC

therapy was continued at a

dose of 12.5 mg/kg/hr for four

hours with steady clinical

improvement. Following

stabilization, he was

transferred back to the

military treatment facility,

where he completed a 72-hour

total course of NAC continued

at 6.25 mg/kg/hr.

27-year-old basic combat trainee presented

with altered mental status, renal

insufficiency, rhabdomyolysis, and a core

temp of 107.9 °F after collapsing during a

run, leading to the diagnosis of heat stroke.

While the patient's azotemia and creatinine

kinase levels rapidly improved with

aggressive intravenous hydration,

transaminases continued to increase to

nearly 155 times the upper limit of normal.

Further laboratory evaluation revealed

coagulopathy and thrombocytopenia

suggestive of acute liver failure (ALF).

Liver function improved on NAC; patient

discharged after 3 days of NAC and

laboratory values returned to normal by 8

weeks.

Suggests

positive effect

Aquilina 2018(48)

Malta

Case report

Heatstroke

associated ALF

NAC dose not reported;

initiated day 6 and continued

until day 29

31 year old collapsed during a race, had

ALF at admission and liver function

continued to deteriorate. Liver transplant

considered

NAC discontinued at day 29 due to

improvement in liver function; discharged

on day 31.

Suggests

positive effect

LITERATURE SUMMARY: Evidence describing use of NAC in alcohol poisoning-associated acute liver injury

First author, year

country

Design

Condition

Sample

size

NAC dose, frequency,

duration, route of

administration; comparator

Findings

Outcome

Singh 2015(50)

Systematic

review and

meta analysis

Severe acute

alcoholic hepatitis

22 RCTs,

2621

patients,

interventi

ons

NAC as used in original reports

in a direct meta-analysis, only

corticosteroids decreased risk of short-

term mortality. In a network meta-analysis,

moderate quality evidence supported the

use of corticosteroids alone (relative risk

[RR], 0.54; 95% credible interval [CrI],

0.39-0.73) or in combination with

pentoxifylline (RR, 0.53; 95% CrI, 0.36-

0.78) or NAC (RR, 0.15; 95% CI, 0.05-0.39),

to reduce short-term mortality; low quality

evidence showed that pentoxifylline also

decreased short-term mortality (RR, 0.70;

95% CrI, 0.50-0.97). The addition of NAC,

but not pentoxifylline, to corticosteroids

may be superior to corticosteroids alone for

reducing short-term mortality.

Positive

effect with

corticosteroi

LITERATURE SUMMARY: Evidence describing use of NAC in mushroom toxin-induced acute liver injury

First author, year

country

Design

Condition

Sample

size

NAC dose, frequency,

duration, route of

administration; comparator

Findings

Outcome

Liu 2020(51)

Systematic

review

Mushroom

poisoning

studies,

506

patients

Not detailed; all studies

included NAC intervention

The mortality rate (including liver

transplant patients) of amatoxin-poisoning

patients with NAC treatment was 11%

(57/506), and a the mortality rate

(excluding transplant patients) 7.9%

(40/506) and a liver transplantation rate of

Positive

effect

4.3% (22/506). Transaminase

concentrations generally peaked around 3

days after ingestion, prothrombin

time/International Normalized Ratio

(PT/INR) generally worsened during the

first 3-4 days after ingestion before

returning to normal four to 7 days after

ingestion, and Factor V levels normalized in

about 4-5 days after ingestion in patients

treated with NAC. Renal failure was

reported in 3% (3/101) and acute kidney

injury was reported in 19% (5/27).

Gastrointestinal bleeding occurred in 21%

(15/71). Anaphylactoid reactions were the

principle adverse reaction to NAC

treatment in amatoxin-poisoning patients

with an incidence of 5% (4/73).

Authors concluded that NAC appears to be

beneficial and safe.

Karvellas 2016(79)

North America

Registry cohort

Mushroom-

induced ALF and

ALI

18, 13

with ALF

Not detailed

N-acetylcysteine used in nearly all patients

88% of nonspontaneous survivors and 80%

of spontaneous survivors.

No efficacy

inferences

possible;

significant off

label use.

Vanooteghem

2014(80)

Belgium

Case series

Mushroom-

induced ALF

Not detailed

All patients survived without need for liver

transplant.

Suggests

positive effect

Montaninia

1999(81)

Italy

Case series

Mushroom-

induced ALF

Not detailed, notes “high dose”

All patients survived, 1 with preceding liver

disease required liver transplant

Suggests

positive effect

LITERATURE SUMMARY: Evidence describing use of NAC in virus-associated acute liver injury (hepatitis A, hepatitis B,

dengue fever)

First author, year

country

Design

Condition

Sample

size

NAC dose, frequency,

duration, route of

administration; comparator

Findings

Outcome

Saleem 2015(52)

Pakistan

Case series

Children age 1

month to 16 years

with ALF and acute

viral hepatitis

Not detailed

There was significant statistical difference

in liver enzymes and prothrombin time on

admission comparing at discharge in

Suggests

positive

effect

children received NAC (p < 0.001). Fifteen

(38%) children died.

Sotelo 2009(53)

Mexico

Case series

Children with

acute viral

hepatitis and acute

hepatic failure

12 (10

with

hepatitis

All received oral NAC, six

patients for a week and the

remaining six for 9-36 days.

Treatment was not ceased

until patients showed clinical

and laboratory improvement.

Significant improvement in liver function

and coagulation parameters compared with

initial values. Investigators note good

tolerance to medication and satisfactory

clinical course

Suggests

positive

effect

Arboviral infections

Paramasivam

2013(55)

Malaysia

Retrospective

cohort

Dengue fever with

moderate or

severe hepatitis

13 of 85

treated

with NAC

NAC administered over 1 hour

followed by maintenance until

AST < 300 mmol/L (NAC dose

not detailed)

Mean (SD) duration of NAC

administration was 2.4 (2.9)

days.

Comparison group: those not

treated with NAC

7 patients had moderate hepatitis (AST

300-9999 mmol/l) and 6 had severe

hepatitis (AST>1000 mmol/l).

Time to ALT reduction to < 300 mmol/l was

3.8 days in patients receiving NAC

compared with those who did not receive

NAC (4.7 days, p=0.003). Length of hospital

stay was significantly longer in those

receiving NAC vs. those not receiving NAC

(6.0 vs. 4.7 days, p=0.009). Authors note

that NAC was given to patients who were

more ill.

Positive

effect

Tan 2013(57)

Malaysia

Retrospective

case series

Severe dengue

fever by WHO

2009

classifications

7 of 8

treated

with NAC

IV NAC infusion 100-150

mg/kg/day for a minimum of 5

days

The maximum grade of hepatic

encephalopathy was grade III in five

patients and grade II in three patients, all

occurring within one to four days of

admission.

All patients discharged well after a median

of 13.5 (5, 35) hospital days; all seven

patients with longer term follow up had

normalization of ALT.

No adverse effects of NAC observed

Presumed

positive

effect

Kumarasena,

2010(58)

Sri Lanka

Retrospective

case series

Dengue-associate

acute liver failure

in the setting of

severe disease (six

patients had

dengue shock

syndrome)

Intravenous NAC at 150 mg/kg

loading dose over 15 min

followed by 12.5 mg/kg/h for

4 hours, then 6.25 mg/kg/h for

up to 72 hours

All received other supportive

management

All five patients with hepatic

encephalopathy coma grades I–II recovered

completely and were well at follow-up after

at least 2 months, whereas the three

patients with coma grades III–IV died.

No patients had adverse effects attributable

to NAC.

Presumed

positive

effect

Senanayake

2013(59)

Sri Lanka

Retrospective

case series

Dengue-associated

acute liver failure

(pediatric; age 6

months – 12 years)

IV NAC 100 mg/kg over 24

hours, continued up to 72

hours in patients with hepatic

encephalopathy at the end of

the first dose

Following the first dose of NAC (100 mg/kg

over 24 hours) four patients showed rapid

clinical improvement of encephalopathy.

Remaining three responded after

second (2) and third (1) doses. In all seven

patients, biochemical profiles showed

improvement from first dose onwards. No

side effects of NAC were noted. All seven

made complete recovery without residual

hepatic or neuro-developmental damage.

Presumed

positive

effect

Kularatne, 2018(60)

Sri Lanka

Retrospective

case series

Dengue-associated

acute liver failure

in adults (age 22

and age 39)

2 of 10

received

NAC

IV NAC (in one case, at 150

mg/hour, duration not noted;

NAC regimen details not

provided for 2

patient)

Case 1: discharged at day 12 with near

normal liver transaminases; follow-up at 21

days indicated normal liver biochemistry

Case 2: symptoms resolved within the next

few days

Presumed

positive

effect

Tan 2016(61)

Singapore

Retrospective

case series

Dengue-associated

liver failure in

pediatrics (age 5

months to 6 years)

2 of 4

received

NAC

IV NAC (100 mg/kg/day) for 1

week

All patients recovered fully. No adverse

effects of NAC observed.

Presumed

positive

effect

Lewis 2019(62)

Case report

Dengue shock

syndrome (age 23)

NAC (details not given)

Exchange student arrived from India 3 days

before hospital admission, treated with

platelets, NAC, and other supportive care.

Progressed to acute liver failure including

hepatic encephalopathy and was listed for

liver transplant. 24 hours after listing, liver

tests began to improve and mental status

normalized over the next 48 hours, along

with resolution of fever and tachycardia.

Patient was delisted.

Presumed

positive

effect

Dalugama 2018(56)

Sri Lanka

Case report

Dengue fever with

acute liver failure

and acute kidney

injury (age 43)

IV NAC 100 mg/hour for five

days

Transaminases gradually declined, lactate

normalized, serum creatinine reduced and

normalized, urine output gradually

increased and CVVHD was terminated after

138 hours of dialysis. Discharged on 9

day

after admission.

Presumed

positive

effect

Dalugama,

2017(63)

Sri Lanka

Case report

Dengue fever

(age 53)

Intravenous NAC at a rate of

100 mg/hour (in addition to

packed cells transfusion) until

discharge (day 5)

Gradual reduction in AST and ALT,

prothrombin time and activated partial

thromboplastin time normalized. On day 5

of admission AST and ALT were less than

200 U/L and NAC infusion was terminated

and patient discharged.

Patient was in good in health with normal

liver enzymes, clotting profile, and albumin

Presumed

positive

effect

at follow up visits on day 7 and 2 weeks

later.

Habaragamuwa

2014(54)

Sri Lanka

Case report

Dengue associated

severe hepatitis

(age 54)

Intravenous NAC at 100

mg/kg/day infusion for 5 days

Prior to NAC treatment, liver enzymes

reached peak values of AST 16261 U/L and

ALT 4545 U/L, prothrombin

time/international normalized ratio

(PT/INR) 1.7, and total bilirubin 5.9 mg/dl

on 4

day of admission (7

day of illness).

NAC administration produced marked

improvement in liver enzyme values, and

AST and ALT levels dropped by more than

half by 48 hours of treatment. On the 9

day of admission liver function revealed

AST 300 U/L, ALT 223 U/L and PT/INR 1.2.

During follow up visit at 2 weeks after

discharge, patient had normal liver profile

and no evidence of chronic liver disease.

Presumed

positive

effect

Manoj 2014(67)

Sri Lanka

Case report

Dengue

hemorrhagic fever

with acute liver

failure and massive

bleeding (age 37)

IV NAC for 72 hours (dose not

detailed) along with

recombinant factor VIIa and

other supportive therapies

Patient was admitted after 3 days of illness

and moved to ICU after developing agitation

and drowsiness 36 hours after admission,

with intubation around day 5-6 of illness.

Transaminases showed a marked rise (AST

12500 U/L and ALT: 2700 U/L, bilirubin

1.8) in seventh day of illness; massive

hematemesis on day 8 and CVP rise at 9

day required furosemide. Transaminases

gradually declined over next several days.

Patient was extubated after 7 days of

ventilatory support and discharged after a

total hospital stay of 18 days (discharge

AST 96 U/L, ALT 109 U/L, bilirubin 16.8

mg/dL).

Presumed

positive

effect

Abeysekera

2012(64)

Sri Lanka

Case report

Dengue fever with

hepatic

encephalopathy

(age 52)

IV NAC initiated on day 6 of

fever, just after admission, 150

mg/kg in 100 ml normal saline

over 1 hr., 50 mg/kg in 500 ml

normal saline over 24 hrs. for

3 days

Patient had complete recovery and was

discharged home 10 days after admission

with all parameters returning to normal

levels.

Presumed

positive

effect

Lim 2011(65)

Singapore

Case report

Dengue fever

(pediatric age 6)

Intravenous NAC at 100

mg/kg/day as a continuous

infusion over 24h for 6 days

Rapid decrease in liver transaminases: AST

dropped to 5991 U/l and ALT 1789 U/l

after 3 days; AST to 1044 U/l and ALT to

635 U/l, respectively, after 6 days.

Presumed

positive

effect

Coagulation profile normalized: PT

improved to 18.0 s and INR 1.54 after 6

days.

Over the course of treatment with NAC,

there were no adverse effects such as

dysrhythmias, bronchospasm, dizziness,

vomiting and rashes.

Gan 2013(66)

Malaysia

Case report

Post-dengue fever

shock syndrome

with fulminant

liver failure

(pediatric age 8

months)

IV NAC 10 mg/kg/hr.

Infant with severe dengue given

paracetamol; developed fulminant liver

failure with encephalopathy,

gastrointestinal hemorrhage, and severe

coagulopathy. Serum paracetamol was 0.1

mmol/l above the treatment nomogram at

20 hours after last dose of paracetamol.

Patient received supportive care

(transfusion, IV vitamin K) and NAC;

discharged at day 25 with lingering left

hemiparesis. No residual neurological

deficit at two months after initial illness.

Presumed

positive

effect

Key: ALF acute liver failure; ALI acute lung injury; ALP = alkaline phosphatase; ALT = alanine aminotransferase; ARDS acute respiratory distress syndrome; AST =

aspartate aminotransferase; AVH acute viral hepatitis; CABG coronary artery bypass grafting; COPD chronic obstructive pulmonary disease; CVVHD continuous veno-

venous hemodialysis; DF dengue fever; DIH drug induced hepatotoxicity; GGT gamma-glutamyl transferase; HCV = hepatitis C virus; ICU intensive care unit; IFN =

interferon; G-CSF granulocyte colony stimulating factor; ; INR international normalized ratio; MAP mean arterial pressure; MEGX = monoethylglycinexylidide; MET

metformin; NAC = N-acetylcysteine; NAFLD nonalcoholic fatty liver disease; PPC postoperative pulmonary complications; PT prothrombin time; RCT = randomized

controlled trial; SMT standard medical therapy; TB tuberculosis

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Appendix 1: Additional contributors

The following individuals contributed content, editing, and/or scientific review to the current

application:

Robert Wallis, M.D., FIDSA, Chief Scientific Officer, The AURUM Institute, Johannesburg, South Africa

Gordon Bernard, M.D., Executive Vice President for Research, Senior Associate Dean for Clinical

Sciences, Vanderbilt University Medical Center, Nashville, TN, USA,

Jana Shirey-Rice, Ph.D., Team Lead, Drug Repurposing, Vanderbilt Institute for Clinical and

Translational Research, Vanderbilt University Medical Center, Nashville, TN, USA

Nicole Zaleski, MA, MPH, Project Manager, Vanderbilt Institute for Clinical and Translational

Research, Vanderbilt University Medical Center, Nashville, TN, USA

Laura Zahn, M.S., Research Services Consultant, Vanderbilt Institute for Clinical and Translational

Research, Vanderbilt University Medical Center, Nashville, TN, USA

Nan Kennedy, Program Manager, Vanderbilt Institute for Clinical and Translational Research,

Vanderbilt University Medical Center, Nashville, TN, USA

Appendix 2: Evidence describing hepatic effects of N- acetylcysteine in other conditions (excluding

acetaminophen toxicity)

First author, year

country

Design

Condition

Sample

size

NAC dose, frequency,

duration, route of

administration;

comparator

Findings

Outcome

Other infections

Grant, 2000(111)

Double blind,

multicenter

RCT

Chronic

hepatitis C

147

Oral NAC 600 mg 3

times/day for 6 months

(1800 mg/day)

73 received 3MU IFN-

alpha 3 times/week by

subcutaneous injection +

NAC 3 times/day and 74

received IFN 3

times/week + placebo 3

times/day

No significant difference in sustained

virological response; Changes in serum ALT

levels correlated with virological outcome in

97% (n = 139) of cases; in 5 patients, serum

ALT remained normal despite virologic

relapse during 6 month post-treatment

window (paper does not report treatment

group data for these individuals).

no effect on

virologic response

Neri, 2000(112)

Italy

RCT

Chronic

hepatitis C

Participants were treated

with IFN (intramuscular

6,000,000 MU 3 times

each week for 6 months)

+ NAC (2400 mg/day in

two doses when fasting)

(n=38) or with IFN alone

(n=39)

No significant difference in viremia values

between the two groups. 7 patients from the

IFN only group and 6 patients from the

IFN+NAC group had no evidence of relapse

within 10 months after finishing therapy and

were excluded from further analysis.

Patients treated with IFN alone relapsed

earlier than patients treated with NAC + IFN

(22 vs. 31 weeks, p<0.05). Three cases of

breakthrough occurred in the IFN only group

and no cases in the IFN+NAC group.

Oxidase-reductase balance was significantly

higher during treatment in the IFN group as

compared with the IFN+NAC group (p<0.05),

which authors note suggests the presence of

oxidative stress in patients treated with IFN

alone. The difference waned over time after

cessation of treatment.

No adverse events requiring cessation of

either treatment.

Positive effect on

HCV relapse and

measures of

oxidative stress

no difference in

efficacy (ALT, liver

biopsy or

ultrasound)

Gunduz, 2003(113)

Turkey

Placebo

controlled RCT

Acute viral

hepatitis A or B

(hospitalized

patients)

Oral NAC 200 mg 3x daily

(600 mg/day) until

discharge

21 received placebo

tablets and 20 received

NAC

NAC administration did not significantly affect

the time necessary for ALT and total bilirubin

values to normalize (100 U/L and 2mg/dl,

respectively) or duration of hospitalization

“NAC was not harmful for AVH patients”

(given that hospital duration and time to

normalization of ALT and total bilirubin did

not get longer with use of NAC; no adverse

effects noted)

no effect on time

to normalization of

ALT or total

bilirubin; or

duration of

hospitalization

Look, 1999(114)

Germany

Prospective,

randomized

pilot trial

Chronic

hepatitis C

NAC effervescent tablets,

1800 mg/day for 24

weeks

8 received IFN alone, 8

received IFN + NAC +

sodium selenite, and 8

received IFN + NAC +

sodium selenite + vitamin

E544

NAC administration did not significantly affect

the response rate (normalization of ALT and

negative HCV RNA). No significant

improvement in liver histology or recurrence

rates.

no effect on

normalization of

ALT or negative

HCV RNA

Furtado 2017(115)

Portugal

Case report

Acute HBV and

coagulopathy

with non-

immune

hemolytic

anemia (age 41

years)

NAC for 5 days (protocol

not detailed), along with

entecavir, folic acid, and

vitamin K

Bilirubin and INR normalized progressively

during hospital stay.

Presumed positive

effect

Prevention and treatment of non-acetaminophen drug-induced acute liver injury and failure

Baniasadi,

2010(116)

Iran

Open-label,

RCT

Newly

diagnosed,

treatment

naïve,

pulmonary

tuberculosis

patients

beginning anti-

TB drug

regimen

600 mg NAC taken orally

twice a day

32 received standard anti-

TB drug therapy and 28

received standard drug

therapy + NAC

Hepatotoxicity occurred in 12 control patients

(37.5%) and none of the patients treated with

NAC.

After 1 and 2 weeks of treatment, mean ± SD

values of AST and ALT were significantly

higher in controls (week 1: 99.44±150.11,

65.78±88.64 and week 2: 57.22±75.81,

58.09±86.18) than those treated with NAC

(week 1: 27.68±13.79, 20.96±11.95, and week

2: 27.32±13.11, 21.53±9.56).

Positive effect

Cheng 2016(117)

Taiwan

Case control

Patients

receiving at

least 5 months

of an anti-TB

drug course

279

NAC 1200 mg/day plus

anti-TB regimen (n=82)

Anti-TB regimen only

(n=297)

11 patients (13.4%) were diagnosed with

drug-induced hepatotoxicity (DIH) in the NAC

group and 72 patients (24.2%) developed DIH

in the comparison group (p<0.05).

Positive effect

The mean duration of treatment before the

onset of hepatotoxicity was 28.6±14.9 days in

NAC group, as compared with 17.4±11.3 days

in the comparison group (p<0.01).

Liver function normalized 9.4 ±6.7 days after

stopping the anti-TB drugs in NAC group

compared with 19.2±11.5 days in the

comparison group (p<0.01).

Non-viral hepatitis

Oliveira, 2019(118)

Brazil

Open-label,

multicenter

RCT

Non-alcoholic

steatohepatitis

1200 mg/day of NAC

taken orally for 48 weeks

in combination with

metformin and/or

ursodeoxycholic acid

26 received metformin +

NAC + UDCA, 14 received

metformin + NAC, 13

received metformin +

UDCA

Significant improvements in the steatosis

degree (P=0.014), ballooning (0.027) and,

consequently, in the NAFLD Activity Score

(NAS) (P=0.005), and in the ALT levels at the

end of the treatment only in the metformin +

NAC group

No significant evidence of modification in the

liver fibrosis in any group (via baseline and

post-treatment liver biopsies)

Positive effect

Singh, 2018(119)

India

Open-label,

randomized

controlled pilot

study

Severe

alcoholic

hepatitis

Intravenous NAC for 5

days (day 1: NAC at 150,

50, and 100 mg/kg in 250,

500, and 1000 mL of 5%

glucose solution over 30

minutes, 4 hours, and 16

hours, respectively; days

2–5: 100 mg/kg/day in

1000 mL of 5% glucose

solution) in addition to

standard medical therapy

and G-CSF

20 received standard

medical therapy (SMT),

18 received SMT +

granulocyte colony-

stimulating factor (G-

CSF), and 19 received

SMT+ G-CSF + NAC

Both G-CSF and SMT+G-CSF + NAC improved

90-day survival compared to standard

medical therapy, but no significant difference

between this combination and G-CSF alone

*There was a significant increase in ALP on

day 6 compared with day 0 in the SMT+G-

CSF+NAC group and the G-CSF group; no

significant increase in ALP in the SMT alone

group.

There was significant improvement in the

clinical severity scores on day 6 compared

with day 0 in G-CSF group but not in the

SMT+G-CSF+NAC and the SMT group.

No effect

potential liver-

related safety issue

Hepatic surgical procedure (resection, transplant, biliary bypass)

Kakaei 2020(120)

Iran

RCT

Biliary bypass

for obstructive

jaundice

IV NAC 200 mg/kg/hour

first 8 hours after surgery,

then 100 mg/kg/hour for

40 hours

Control participants

received no infusion

The NAC group, as compared with control

patients, had significantly greater decline of

ALT (p=0.02), AST (p=0.01), ALP (p=0.01),

GGT (p=0.04), total bilirubin (p=0.02), direct

bilirubin (p=0.01). No significant differences

in decline of INR or creatinine or of hospital

stay duration, ICU admission, or ICU length of

stay were observed.

No adverse events due to NAC were observed

Positive effect

Li 2018(121)

China

RCT

Liver

transplantation

60 (42

included in

analysis)

Atomization inhalation of

3 mL NAC (10%) for 30

minutes before surgery

and 3 hours after

reperfusion

Control patients received

atomization inhalation of

3 ml sterile water for the

same periods of time.

Postoperative pulmonary complication as per

broad clinical definitions (atelectasis,

pneumothorax, pleural effusion, ALI, ARDS,

pneumonia) were similar between the two

groups. As measured by the Melbourne Group

Scale Version 2 score, there was a significantly

higher incidence of PPCs in the control group

as compared with the NAC group (73% vs.

40%, p=0.032).

30 participants developed at least one

respiratory infection within 1 month

postoperatively. Among these patients,

isolated bacterial infection was observed in 2

(11%) of 18 patients in the control group and

8 (67%) of 12 patients in the NAC group

(p=0.019), while investigators note that more

refractory infectious etiologies including

fungal, combined, or unknown infection

comprised the major pneumonia causes in the

control group but not the NAC group.

18 of the 22 control patients developed and

combined more than 3 kids of coexisting

pulmonary complications within 1 month

postoperatively, an incidence higher than that

of the NAC group (82% vs. 50%, p=0.028).

NAC group had significantly shorter ICU

(p=0.026) and hospital stay (p=0.029) and

hospitalization costs (p=0.020). 12 month

mortality related to pulmonary disease was

significantly lower in the NAC group

(p=0.012).

Positive effect

No side effects related to NAC inhalation were

observed.

Aliakbarian,

2017(122)

Iran

Double-blind

RCT

Orthotopic

liver transplant

115

After donor organ

retrieval, 2000 mg NAC

was added to 2 liters of

UW solution and perfused

through the mesenteric

vein (49 patients)

In 66 patients, standard

UW solution was used

No significant difference between the groups

regarding time to hepatic artery reperfusion,

hospital stay, vascular complications, inotrope

requirement before and after portal

declamping, and blood gas analysis. (no liver

specific measures)

*Hypotension after portal reperfusion was

significantly more common in experimental

group compared with control group (P =

.005).

Retransplant and in-hospital mortality were

comparable between the groups.

no effect

Grendar, 2016(123)

Canada

Open-label,

RCT (No

blinding was

performed)

Post-hepatic

resection

206

NAC infusion: 150 mg/kg

of NAC in 200 ml of 5%

glucose over 45 min upon

arrival in the post

anesthesia recovery room,

then 50 mg/kg of NAC in

500 ml of 5% glucose over

4 hr., followed by

100 mg/kg in 1000 ml of

5% glucose over the next

16 hr.; followed by

100 mg/kg in 1000 ml of

5% glucose per day over

the next 3 days, which

was administered in six

infusions of 50 mg/kg in

500 ml of 5% glucose,

given over 12 hr. each +

standard care (98

patients)

108 patients received the

usual postoperative

management without NAC

No significant differences were noted in

overall complications (32.7% and

45.7%, P = 0.06) or hepatic failure (3.6% and

5.4%, P = 0.537) between treatment groups.

No significant difference between groups in

biochemical markers of liver function except

INR (1.24 without NAC and 1.35 with NAC)

and creatinine (88.8 µmol/L without NAC and

72.6 µmol/L with NAC).

*There was significantly more delirium within

the NAC group (2.7% and 9.8%, P < 0.05) that

caused early trial termination.

Study had issues with randomization and

there were disproportional females in the

NAC group

no effect

potential safety

issue highlighted

Donadon 2016(124)

Italy

Double-blind

RCT

Hepatic

resection using

IV NAC 150 mg/kg as a

bolus for 1 hour before

surgery, then continuous

Morbidity was not significantly different

between the 3 groups.

Positive effect

Pringle

maneuver

infusion of 50 mg/kg/h

during the procedure

Compared to two other

regimens:

Methylprednisolone

(MET) 500 mg in 250 ml

glucose 5% as bolus 1 hr.

before surgery then

continuous infusion

Placebo infusion (glucose

5%)

Comparing across the 3 groups, ALT at

postoperative day 1 was significantly lower in

both the MET and NAC groups vs placebo

(p=0.039), and significantly lower in the NAC

group as compared with the MET group

(p=0.021). At postoperative day 3, the 3-

group difference was not significant, but the

NAC group ALT was lower than the MET

group (p=0.041).

Similarly, the NAC group had lower bilirubin

as compared with the MET group (p=0.03) at

postop day 1; the 3 group levels were not

significantly different and no significant

differences at day 3 in bilirubin were

observed.

D’Amico, 2013(125)

Italy

RCT

First liver

transplant for

chronic liver

disease

patients

140

15 minute NAC infusion

(30 mg/kg) 1 hour before

the start of organ retrieval

and a locoregional

infusion (150 mg/kg of

estimated liver weight for

a maximum dose 300 mg)

in the portal vein just

before cross-clamping (69

patients)

71 patients assigned to

standard protocol without

NAC

The NAC harvesting protocol significantly

improves graft survival (graft survival rates at

3 and 12 months were 93% and 90%,

respectively, in the NAC group and 82% and

70%, respectively, in the control group (P =

0.02).

Post-op day 15 AST levels were 31 U/L (range

= 15‑150 U/L) in the study group and 38 U/L

(range = 13‑326 U/L) in the control group

(P = 0.02). No significant differences in any

other liver specific measures.

The incidence of postoperative complications

was lower in the NAC group (23%) versus the

control group (51%, P < 0.01).

Positive effect

Robinson

2013(126)

Retrospective

cohort

Liver resection

IV NAC (10,000 mg/24 hr.

in 250 ml 5% dextrose)

starting at time of

parenchymal transaction

and continuing for 3 days

postoperatively or until a

fall in ALT in patients

operated on by one

surgeon

Comparison group:

patients resected by

NAC was associated with lower postoperative

ALT as compared with control (p=0.019); no

significant differences in serum bilirubin or

prothrombin time were observed between het

wo groups.

Grade A post-hepatectomy liver failure was

more common in the NAC group as compared

with controls (31.8% vs 9.1%, p=0.025);

incidence of no liver failure or grades B/C

post hepatectomy liver failure were not

significantly different between the NAC and

No effect

surgeons not using NAC

as part of their

perioperative regimen

control groups.

No statistically significant difference in

incidence of clinically important

complications between he two treatment

groups.

Regueira,

1997(127)

Spain

Retrospective

clinical study

Liver

transplant

Donor received IV of 6g of

NAC at least an hour

before extraction (25

patients)

In 37 transplants, the

donor did not receive any

specific treatment

Grafts that received NAC presented less

cytolysis and less elevation of transaminases

(AST maximum was 353.56 UI/L in NAC

group vs 825.97 UI/L in controls); (first day

post-transplant ALT 250.16 UI/L in NAC

group vs 440.54 UI/L in controls); bile

production and synthetic function were also

better.

Prothrombin time was significantly superior

in the first 5 days in the NAC group compared

to controls (P=.0062)

Patients in the NAC groups experienced acute

rejection significantly less than controls

(p=.0309)

Presumed positive

effect

Other operative procedures; not a complete list

El Hamamsy

2019(128)

Egypt

Double-blind,

placebo

controlled RCT

Patients

requiring ICU

admission and

total parenteral

nutrition for at

least 5 days

after colon

surgery

IV bolus NAC (100 mg/kg

dissolved in 5% dextrose)

infused over 15 minutes

then continuous infusion

50 mg/kg/day starting 1

hour before induction of

anesthesia and continuing

for 48 hours after the

operation

Comparison group

received infusion of

dextrose 5% at equal

volume and rate as the

NAC group

Most clinical and laboratory parameters did

not differ significantly between the two

groups, including MAP, heart rate,

temperature, respiratory rate, total leukocyte

count, platelets, serum creatinine, BUN, serum

sodium, serum potassium, TNF-α, and MDA.

Mean postoperative serum ALT was

significantly lower in the NAC-treated group

as compared with the control group (22.6±9.9

vs. 31.1±17.8, p=0.028).

Investigators note mild adverse effects of NAC

in 2 patients (6.6%), including hypotension

and tachycardia.

Positive effect

Onk, 2018(129)

Turkey

Prospective,

randomized

study

COPD patients

having

coronary artery

900 mg/day of NAC for 7

days until the day of

surgery (35 patients)

NAC pre-treatment has a stabilizing effect on

and nitrogen metabolism in COPD

patients undergoing CABG (postoperative

24th hour, and postoperative 48th hour

Positive effect

bypass grafting

surgery

35 patients received

standard care only

(respectively, 39.0±8.8 vs. 55.4±19.6 and

40.1±8.4 vs. 53.2±20.2 mcg/dl).

Patients with COPD who were started on N-

acetylcysteine before surgery tend to have

lower lactic acid levels (1.7±0.9 vs. 2.1±1.2

and 1.2±0.5 vs. 1.8±1.4 mmol/L; p<0.01),

authors infer that this indicates a protective

effect of N-acetylcysteine against renal and

hepatic tissue damage

Serum AST, ALT, ALP levels demonstrated no

significant difference between the 2 groups at

any of the 4 measurement time points

(preoperative, during cardiopulmonary

bypass, 24

postoperative hour, and

postoperative hour) (p>0.05)

Belgaumkar,

2016(130)

Single blinded,

RCT

Laparoscopic

sleeve

gastrectomy

NAC infusion at a

standard 150 mg/kg in

200 ml 5% dextrose over

15 min at induction of

anesthesia followed by an

infusion of 50 mg/kg in

500 ml of 5% dextrose

during surgical retraction

of the liver for a max of 4

hours (10 subjects)

10 control subjects

received standard

anesthetic medication

alone

NAC did not reduce intraoperative liver injury

No significant differences between liver

enzymes, rates of complications, length of

stay, white cell count, or liver injury scores:

The trial was not powered to detect

differences in clinical outcomes.

Authors comment: “The major drawback of

the study was a lack of a standardized,

reproducible toxic insult to the liver during

intraoperative liver retraction with the

Nathanson liver retractor. The pressure

applied to liver varied from patient to patient

depending on their body habitus,

intraabdominal dimensions and size and

texture of the liver. There are presently no

routine clinical methods of measuring tissue

oxygen tension or pressure within the liver.

This lack of uniformity lead the investigators

to conclude that a major study redesign would

be required to reach an robust conclusion.”

no effect

Septic shock

Rank, 2000(131)

Germany

Prospective,

double-blind,

placebo

controlled RCT

Septic shock

patients within

24 hours after

onset of sepsis

NAC infusion of 150

mg/kg in 250 mL of 5%

dextrose over a period of

15 mins, followed by a

continuous infusion of

12.5 mg/kg/hr. over 90

mins (30 patients)

(30 control patients

received 5% dextrose

only)

After NAC, a significant increase in absolute

liver blood flow index (2.7 vs. 3.3 L/min/m2;

p = .01) and cardiac index (5.0 vs. 5.7

L/min/m2; p = .02) was observed.

After NAC, microsomal liver function

improved, evidenced by a significant increase

in MEGX (p = .04). Liver blood flow index and

MEGX correlated significantly (r(s) = .57; p <

or = .01).

Positive effect

Appendix 3: Summary of adverse events reported in systematic reviews, by indication

Indication

Number of

participants

(studies)

Patient characteristics

Major adverse event(s) reported

Frequency

Acetaminophen

overdose(83)

1058 (8

prospective trials

of IV NAC)

Adult and pediatric

patients, males and

females

Anaphylactoid reactions including:

Up to 48% in prospective studies

Nausea and vomiting

From 4.5% to 70.4%

Cutaneous (rash, flushing, pruritis)

From 3.6% to 32%

Bronchospasm

From 4 to 18%

Hypotension

15.7% (only reported in one small study

with 27 patients)

Chest pain

6.5% (only reported in one small study of

11 patients)

Decrease in INR

One study(132) reported the effect in

100% of patients (of 87)

Acetaminophen

overdose(85)

6455 (1

retrospective

medical review of

patients treated

with IV NAC at 34

Canadian

hospitals)

Adult patients, males and

females

Anaphylactoid reactions including:

8.2%

Cutaneous only (rash, flushing, pruritis)

6.2%

Systemic only

.5%

Both cutaneous and systemic

1.5%

Respiratory effects and/or hypotension

Acetaminophen

overdose(82)

503 (multi-

center,

retrospective

chart review of

patients treated

with oral or IV

NAC)

Adult patients, males and

females

No serious adverse events reported.

Nausea and vomiting were mid and the

most common.

23% oral versus 9% IV

Anaphylactoid reactions

2% oral versus 6% IV

Psychiatric and

neurological

disorders(93)

~1300 (16

controlled studies

of patients

treated with oral

and IV NAC)

Adult and pediatric

patients, males and

females

Largest rate of AEs was seen in an open-

label cannabis study (24 patients)(133)

63% reported at least one AE

Abdominal discomfort

20.8%

Muscle pains/aches

20.8%

Insomnia

16.6%

Headache, nasal congestion, nausea,

weight decrease, restlessness, or

dizziness

12.5%

Idiopathic

pulmonary

fibrosis(95)

1003 (12 RCTs of

patients treated

with oral or

inhaled NAC

reported safety)

Adult patients, males and

females

Most commonly reported AEs were

cough, dyspnea, bacterial pneumonia,

diarrhea, headache, edema, abdominal

pain

No trial reported a significantly increased

risk of adverse events among patients

treated with NAC.

Contrast

neuropathy(96)

1776 (15,

prospective, case-

controlled studies

of patients

treated with oral

and IV NAC)

Adult patients, males and

females

No major treatment-related adverse

events were reported.

No trial reported a significantly increased

risk of adverse events among patients

treated with NAC.

Chronic

bronchitis(134)

2,540 (11

randomized,

controlled trials

of patients

treated with oral

NAC)

Adult patients, males, and

females

6 trials reported GI adverse effects

No trial reported a significant increase in

adverse events among patients treated

with NAC.

Acute liver

failure not

caused by

acetaminophen

overdose(75)

170 (1

retrospective

case-controlled

medical record

review, IV NAC

administered to

111 compared to

59 who did not

receive NAC)

Pediatric patients, males

and females

Adverse effects included rash, cardiac

reactions which were not attributed to

drug administration (3 children), mild

dizziness and peripheral edema (1

child), and bronchospasm (1 child)

which was attributed to an allergic

reaction (NAC was immediately

stopped)

Adverse events were reported in 11% of

patients but there was not a significant

increase in adverse events among patients

treated with NAC.

Psychiatric

conditions(135)

765 (12

randomized,

controlled trials

of oral NAC)

Pediatric patients, males

and females

Mild adverse effects were reported

including constipation (16.1%),

increased appetite (16.1%), fatigue

(12.9%), nervousness (12.9%), daytime

sleepiness (12.9%) in ASD studies,

headache and aggressive behavior in

nail biting, and headache (Tourette’s

syndrome)

No trial reported a significantly increased

risk of adverse events among patients

treated with NAC.