LITERATURE SUMMARY: Evidence describing use of NAC in virus-associated acute liver injury hepatitis A, hepatitis B, dengue fever .... Based on similar mechanisms, NAC shows promise in pr
Summary statement of the proposal for inclusion, change or deletion
We propose adding a new indication to the EML for N-acetylcysteine (NAC), a medicine already listed, to manage non-acetaminophen-induced acute liver failure (ALF) caused by etiologies associated with glutathione depletion Grounded in trial and observational evidence, this indication supports NAC’s safety and its ability to prevent progression of hepatic failure in both adults and children By replenishing intracellular glutathione and exerting antioxidant effects, NAC mitigates hepatic injury and its sequelae across ALF etiologies linked to glutathione depletion This request targets the complementary EML, recognizing that ALF patients are typically treated in hospital or specialized settings.
N-acetylcysteine (NAC) is known for its hepatoprotective effects by increasing intracellular glutathione, especially in the liver, and for its antioxidant properties that counteract oxidative stress and inflammation Since the 1960s, NAC has been widely used and is considered safe and well tolerated; its role as the antidote for acetaminophen toxicity—where oral and intravenous NAC are equally effective in preventing and minimizing hepatotoxicity—is well established and it is listed on the Essential Medicines List for this use Building on similar mechanisms, NAC also shows promise in protecting the liver against non-acetaminophen–induced acute liver injury caused by glutathione depletion, including virus-induced hepatic failure, mushroom toxin–induced liver failure, acute alcoholic hepatitis, and heat stroke–induced acute liver failure.
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
5 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 We propose a new use for N-acetylcysteine (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 the presence of hepatic injury, as indicated by rising liver function tests The goal of this strategy, supported by the evidence described here, is to prevent or limit the severity of acute liver failure and reduce related morbidity and mortality.
N-acetylcysteine (NAC) has been evaluated as an adjunct to conventional supportive care for acute liver failure (ALF) arising from non‑acetaminophen etiologies, including heat‑stroke–related ALF, acute alcoholic hepatitis, mushroom poisoning, and acute viral hepatitis The literature supports NAC’s safety and efficacy in this setting, showing at least a meaningful incremental gain over supportive care alone with potential improvements in morbidity and a reduced likelihood of transplantation in some patients In addition, NAC’s long‑standing use in acetaminophen-induced liver injury provides a robust safety data base for both children and adults, underpinning its clinical use across diverse ALF etiologies.
There is precedent for using NAC as an antidote to acetaminophen toxicity, reflected in past EML committee decisions that real-world data were compelling enough to support its use A 2008 review notes that subsequent human investigations have been largely observational due to ethical concerns about withholding a potentially lifesaving treatment, and consequently there are no randomized controlled trials evaluating NAC for prevention of acetaminophen-induced hepatotoxicity, nor any randomized efficacy trials in children, with many studies relying on historical control groups to assess efficacy.
Relevant WHO technical department and focal point (if applicable) 3 Name of organization(s) consulted and/or supporting the application
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.
International Nonproprietary Name (INN) and Anatomical Therapeutic Chemical (ATC) code of the medicine
Dose forms(s) and strength(s) proposed for inclusion
Acetylcysteine, the nonproprietary name for the N-acetyl derivative of L-cysteine, is a generic medicine widely available internationally, and NAC can be administered intravenously or orally The WHO 2008 review on pediatric acetaminophen toxicity notes that oral administration is preferred when there are no contraindications such as aspiration or persistent vomiting, whereas intravenous NAC is recommended in cases of fulminant hepatic failure; this guidance supports using intravenous NAC for the new indication of NAC in various types of acute liver failure, with oral NAC as an option when IV formulation is unavailable In overdose settings to prevent hepatotoxicity, both oral and IV NAC regimens are commonly used and well tolerated, with no significant differences in safety or efficacy.
Availability is supported because N-acetylcysteine (NAC) is on the Essential Medicines List (EML) in both injectable and oral forms, with injectable 200 mg/mL in a 10 mL ampoule and oral liquid strengths of 10% and 20% appropriate for the treatment approach described in Section 7; while the evidence base for NAC use in non‑acetaminophen–induced liver failure shows variation in dosage and administration schedules, these regimens generally mirror the NAC strategy used for acetaminophen overdose and are similar for patients with acute liver failure due to other causes.
Whether listing is requested as an individual medicine or as representative of a pharmacological class
Treatment details (requirements for diagnosis, treatment and monitoring)
Intravenous N-acetylcysteine (NAC) should be initiated in patients with significant acute liver injury as soon as acute liver failure (ALF) is detected, typically when a precipitating condition—such as acute viral hepatitis, heat stroke, dengue, acute alcoholic hepatitis, or mushroom toxicity—is present in combination with clinical deterioration and abnormal liver function tests that meet local ALF criteria.
Building on a previous WHO review that described an intravenous N-acetylcysteine (NAC) protocol for pediatric acetaminophen toxicity, the protocol has been adapted to reflect regimen provisions drawn from studies of NAC use in non-acetaminophen acute liver failure This integrated approach unifies pediatric paracetamol toxicity management with broader NAC regimens applied in diverse etiologies of acute liver failure.
• 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 of N-acetylcysteine should continue for a minimum of three days and longer as needed based on the patient’s clinical status, liver function test results and related measures such as INR, and the time course of the underlying condition (for example, mushroom toxicity typically has a shorter course than dengue fever) To avoid fluid overload, reduce the volume of diluent as clinically indicated The literature does not indicate that NAC dosing should be reduced in infected patients with hepatic impairment Reduced clearance of NAC has been observed in seven patients with chronic liver disease compared with six healthy controls, suggesting that cirrhotic patients may be at increased risk of hypersensitivity reactions Hypersensitivity reactions to NAC may be managed by decreasing the infusion rate or discontinuing the infusion altogether.
If IV NAC is not available or feasible, oral NAC could be substituted using the protocol noted in the WHO NAC review: 140 mg/kg followed in 4 hours by a maintenance dose of 70 mg/kg orally given every 4 hours.
4 hours for up to 5 days, tailored to the condition of the patient under treatment
N-acetylcysteine (NAC) has a well-established safety profile in children, supported by extensive safety data from its use in acetaminophen toxicity Use of NAC in acute liver failure (ALF) associated with the indications described in this application, each of which may affect this age group, would be appropriate in children.
In pregnancy, the FDA lists NAC as a Pregnancy Category B agent, noting that limited case reports of acetylcysteine exposure during various trimesters did not report any adverse maternal, fetal, or neonatal outcomes Across clinical studies, no significant adverse effects on the mother or fetus were observed in a prospective comparative study of oral NAC for recurrent unexplained pregnancy loss, in randomized trials of oral NAC for severe early-onset preeclampsia or HELLP syndrome, in IV NAC for maternal chorioamnionitis, or in oral NAC for pregnant women with low antioxidant status A randomized, double-blind, placebo-controlled trial of oral NAC for prevention of recurrent preterm birth found no major maternal or fetal adverse effects, though approximately 11% of participants discontinued NAC due to nausea and vomiting.
Information supporting the public health relevance
Acute liver failure (ALF) is a relatively rare but serious global condition characterized by high morbidity and mortality in the absence of timely supportive care and, when needed, liver transplantation ALF affects people of all ages and has heterogeneous etiologies; this review focuses on ALF subsets with known involvement of glutathione, reflecting the rationale for targeting this pathway with N-acetylcysteine (NAC).
Acute viral hepatitis infections account for the majority of acute liver failure (ALF) cases worldwide, with regional variation in the causative viral pathogens, including hepatitis A, B, and E in many regions and dengue virus in others Given dengue as a key cause of acute liver injury and failure, data show a notable regional impact An estimated 390 million people are infected with dengue each year, and the World Health Organization (WHO) estimates that about 500,000 of these develop severe dengue annually, highlighting the potential for dengue-related hepatic involvement and progression to ALF in affected areas.
Severe dengue requires hospitalization for a substantial number of patients, with an annual case fatality rate of about 2.5% Growing evidence links climate variations to the emergence of climate-sensitive infectious diseases, including dengue, chikungunya, and Zika, suggesting the global burden could worsen Over the past five decades, dengue incidence has risen roughly 30-fold Before 1970 only a handful of countries experienced severe dengue epidemics, but today the disease is endemic in more than 120 countries, underscoring its expanding health and economic impact.
About 3.9 billion people are at risk of dengue infection, and liver injury or hepatic failure can complicate the disease; in a Thai outbreak, 63% of 347 hospitalized dengue patients experienced hepatic failure The World Health Organization notes that dengue is spreading faster than any other communicable disease, with roughly a 400% increase over 2000–2013 Annual incidence is on the order of 100 million symptomatic cases worldwide, plus about 300 million asymptomatic infections The greatest burden falls on Asia (about 75%), with the remainder in Latin America and Africa.
Heat stroke is a significant cause of acute liver failure (ALF) Global incidence is difficult to estimate due to the lack of a standardized capture and reporting system In the United States, one study estimated more than 4,100 emergency department visits per year for heat stroke, an incidence rate of about 1.34 visits per 100,000 people, and a case fatality rate of 3.4% A 2015 World Health Organization report notes that heat waves are an emerging public health problem as climate change intensifies, suggesting that heat stroke and its sequelae may become more common in the future, with evidence of increased mortality and morbidity during past heat waves in Europe and other regions.
Amatoxin poisoning from poisonous mushrooms is a global health concern, with incidence estimates hampered by underreporting Although Europe reports higher frequencies, mushroom poisoning has been documented in numerous regions worldwide Those who develop acute liver failure after amatoxin exposure have a poor prognosis without intensive supportive care and may require liver transplantation.
Alcohol-related acute liver failure (ALF) is a serious condition with an estimated 30-day mortality of about 30% The exact incidence is unknown, but estimates among individuals with heavy alcohol use suggest it could be as high as 20% WHO data from 2018 indicate that heavy episodic drinking was about 18% globally in 2016, with higher rates in Eastern Europe and sub-Saharan Africa, suggesting that these regions may face a greater risk of developing this form of ALF.
Acute liver failure (ALF) affects people worldwide due to a range of precipitating conditions and can be catastrophic for both children and adults; however, the Essential Medicines List (EML) does not prescribe any specific, targeted treatment for ALF, aside from the use of N-acetylcysteine (NAC).
Acetaminophen-induced toxicity remains a critical concern, while the literature indicates growing use of NAC across a range of subtypes of non-acetaminophen-induced liver failure, with substantial off-label use supported by prospective and retrospective data This evidence suggests that NAC would provide a valuable addition to the supportive care provided to these patients Incorporating this information into the Essential Medicines List (EML) would also provide critical guidance to health workers on standard dosing and administration of NAC as supplemental treatment.
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)
To identify the studies underpinning this analysis, a trained information scientist conducted a comprehensive search of PubMed and Web of Science and augmented it with a broad Google search to locate unindexed and grey literature The search terms included "acute liver failure" and "acute liver injury" to ensure broad coverage of relevant evidence This multi-database, multi-source approach aimed to capture both indexed and non-indexed sources, providing a robust evidence base for examining acute liver conditions.
An exhaustive search for “acetylcysteine,” “N-acetylcysteine,” and “acetylcysteine” was conducted without date restrictions to capture all relevant evidence on NAC use in acute liver failure (ALF) across etiologies linked to glutathione depletion—such as hepatitis A or B, dengue fever, heat stroke, alcohol poisoning, and mushroom toxicity—and to include non-acetaminophen-induced ALF to broaden the evidence base Reference lists of reviewed articles were screened to identify additional studies and to clarify the preclinical and mechanistic underpinnings of both the disease and the therapy No eligible studies were excluded from this exploration; data were systematically extracted (see Literature Summary), and when comprehensive systematic reviews and meta-analyses were identified, supplementary primary evidence was drawn from other papers to capture data not covered by those reviews and to reflect nuances beyond their summaries The review also catalogs hepatic effects of NAC beyond the selected indications to provide broader context, with this expanded context detailed in Appendix 2.
This section presents a concise summary of available data on acute liver failure (ALF), focusing on quality appraisal, outcome measures, and overall results across the proposed ALF subsets Full details of the literature describing each subset are documented in the evidence tables within the Literature Summary section of this application We emphasize the key characteristics of both primary and secondary literature underpinning each ALF subset, including studies on the use of N-acetylcysteine (NAC) in general non–acetaminophen–induced ALF, since these investigations often reflect the broader populations represented by our proposed categories.
Three systematic reviews (2004, 2013, and 2015) chart the evolving evidence on N-acetylcysteine (NAC) for non–acetaminophen-induced acute liver failure (ALF) Early reviews largely drew on retrospective case reports and series suggesting potential NAC utility in this ALF subset, whereas the 2015 review, which encompassed four randomized controlled trials, demonstrated a significant benefit of NAC over control in transplant-free survival and post-transplant survival Across all reviews, adverse effects were similar to those seen with NAC in acetaminophen-induced ALF, and no hepatotoxicity was observed at the acetaminophen-dose NAC regimen An additional randomized controlled trial examining NAC in non–acetaminophen-induced ALF was published.
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,
Among patients with acute liver failure treated with N-acetylcysteine (NAC), hospital length of stay was approximately 2.5 days shorter in the NAC-treated group (p=0.002) A large prospective multisite cohort in the United States showed NAC use increasing over time, reflecting broad acceptance of this off-label therapy across centers, with about 70% of patients with non-acetaminophen-induced acute liver failure receiving NAC through 2013, a period that coincided with rising survival rates.
Heat-stroke–associated acute liver failure has been represented in the broader ALF literature, and three case reports (47–49) suggest that intravenous N-acetylcysteine can improve liver function and other clinical outcomes in heat-related ALF No adverse effects discordant with NAC use in other indications were identified.
Severe acute alcoholic hepatitis is somewhat unique among ALF etiologies, representing an acute event embedded within chronic disease, and N-acetylcysteine (NAC) has been used during this acute phase; a 2015 systematic review analyzed therapies for acute alcoholic hepatitis requiring hospitalization, identifying 22 randomized controlled trials (RCTs) totaling 2,621 patients across five interventions A network meta-analysis of this moderate-quality evidence pool found that corticosteroids alone reduced short-term mortality (relative risk [RR], 0.54; 95% CrI, 0.39–0.73) and corticosteroids plus NAC reduced short-term mortality even more (RR, 0.15; 95% CI, 0.05–0.39) No trials published since the date of this literature review have been identified.
Mushroom-induced acute liver failure is a serious complication of mushroom poisoning and is discussed alongside broader ALF patterns in the literature A 2020 systematic review evaluated the use of N-acetylcysteine (NAC) for mushroom-related liver injury, identifying limited and inconsistent evidence and a need for more robust research to clarify NAC’s role in this specific population.
An analysis of 13 studies including 506 patients treated with N-acetylcysteine (NAC) for this poisoning reports a mortality rate of 8–11% and a liver transplantation rate of 4.3% Liver function and coagulation abnormalities improved within 4–7 days after ingestion, and anaphylactoid reactions occurred in about 5% of patients Overall, the review concludes that NAC is safe and beneficial for this type of poisoning.
Acute viral hepatitis: in addition to the ALF studies mentioned earlier, two small retrospective case series have examined the use of N-acetylcysteine (NAC) in children with acute liver failure secondary to acute viral hepatitis These series included 40 and 12 patients, respectively, with hepatitis A identified as the most common underlying cause Both reports describe improvements in liver enzymes and coagulation parameters and good tolerance of NAC in this pediatric population.
Dengue fever–related liver injury has been described separately from acute viral hepatitis, in which hepatitis A is often the precipitating infection, and there is currently no large randomized, double‑blind trial of N‑acetylcysteine (NAC) for dengue‑associated liver injury due to the disease’s sporadic and epidemic nature The existing evidence base consists of retrospective cohort studies, case series, and case reports documenting 43 dengue patients who received NAC in addition to usual care, with outcomes including liver function tests, mortality, transplant requirements, length of stay, and other dengue‑relevant laboratory measures; adverse effects were consistent with NAC’s broader safety profile, and all patients recovered except three who already had dengue‑associated acute liver failure prior to treatment and died Notably, a 53‑year‑old with dengue‑associated severe hepatitis showed peak AST of 16,261 U/L and ALT of 4,545 U/L on day 4 of admission, butAST and ALT dropped by more than half within 48 hours of NAC treatment, indicating marked biochemical improvement In a retrospective case series, 13 people with moderate to severe hepatitis received NAC.
Eleven patients recovered faster than less sick patients who did not receive N-acetylcysteine (NAC) Data from case series and case reports show gradual normalization of liver function tests in 26 other patients—15 adults and 11 infants and children—who received NAC in moderate to severe dengue illness (56–67).
In this analysis we reviewed phenome-wide association study (PheWAS) data to identify phenotypes linked to a specific gene or genetic variant PheWAS leverages the Exomechip genotyping platform (~250,000 coding variants across the protein-coding genome) and electronic health records for about 35,000 patients to map genotype–phenotype associations Because the logic of PheWAS can be extended to predict phenotypic manifestations of pharmacologic targeting of a gene product, it supports drug repurposing efforts—for example, evaluating N-acetylcysteine (NAC) as a potential targeted agent for glutathione synthetase pathways NAC acts as a stimulator of glutathione synthetase and is hepatoprotective, a role established in acetaminophen overdose In particular, the missense SNP R418Q in GSS is risk-associated and behaves like a glutathione synthetase inhibitor, and the liver phenotypes linked to this SNP across the analysis (Table 1) reinforce that decreased glutathione synthetase is associated with a broad spectrum of liver injury, consistent with the ALF etiologies represented and supporting a new NAC indication on the EML.
Table 1: PheWAS results, GSS variation and liver disease
The SNP shown operates as a glutathione synthetase inhibitor (GSS ↓), which indicates that a glutathione synthetase stimulator such as NAC (GSS ↑) may be indicated for managing the relevant phenotypes The table lists rsID (Mutation), Gene, Phecode, Phenotype, and Cases to summarize the associations.
(Missense_R418Q) GSS 261.2 Vitamin B-complex deficiencies 557 21366 4.5910 0.00661 0 5 rs150141794
Liver abscess and sequelae of chronic liver disease 598 22795 4.2490 0.008865 0 5 rs150141794
(Missense_R418Q) GSS 573.7 Abnormal results of function study of liver 890 22795 3.4230 0.01187 0 6 rs150141794
(Missense_R418Q) GSS 571 Chronic liver disease and cirrhosis 1312 22795 2.7070 0.02196 0 7 rs150141794
Cirrhosis of liver without mention of alcohol 769 22795 3.3010 0.02317 0 5 rs150141794
Other chronic nonalcoholic liver disease 1092 22795 2.7880 0.0282 0 6 rs150141794
(Missense_R418Q) GSS 573.2 Liver replaced by transplant 368 22795 4.1420 0.04077 0 3 rs150141794
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
Evidence from studies of non–acetaminophen-induced acute liver failure shows that N-acetylcysteine (NAC) provides at least an incremental benefit over usual care, whether compared with supportive care or placebo Because there are no head-to-head trials against other active interventions, a precise, quantitative assessment of NAC’s relative effectiveness remains elusive The safety profile of NAC in this setting mirrors its known adverse effects in other indications, suggesting no unusual safety signals and a favorable overall risk-benefit when used for non–acetaminophen-induced ALF.
Review of harms and toxicity: summary of evidence of safety
Estimate of total patient exposure to date:
According to the World Health Organization Essential Medicines List, N-acetylcysteine is listed as an antidote for acetaminophen overdose Both oral and intravenous NAC have been approved as first-line therapies for acetaminophen overdose for more than 40 years, reflecting extensive clinical use Based on exposure reported in the literature, it is estimated that hundreds of thousands of patients have been exposed to acetaminophen overdose to date, with likely many more worldwide.
Description of the adverse effects/reactions when used in non-acetaminophen induced acute liver failure:
Safety data for N-acetylcysteine (NAC) in non‑acetaminophen–induced liver failure have been gathered from a range of study designs, including clinical trials, retrospective cohort studies, case series, and individual case reports, drawing on data from a broad patient population to illuminate NAC's safety profile in this setting.
Across roughly 2,500 patients studied, adverse effects attributed to N-acetylcysteine (NAC) align with the broader human safety data, indicating that NAC is safe and well tolerated Investigators report an adverse event profile for NAC in non–acetaminophen–induced acute liver failure—including cases of heat stroke, acute alcoholic hepatitis, mushroom poisoning, acute viral hepatitis, and dengue fever—that is consistent with NAC's established safety in acetaminophen-induced ALF Reviews of adverse effects seen in NAC used for other liver-related conditions and indications (see Appendix 3) also show risks similar to those observed with NAC used 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 N-acetylcysteine (NAC) is documented to be safe and well-tolerated The most common adverse effects are nausea and vomiting, reported to occur in up to 23% of patients (82), possibly related to its distasteful odor Oral NAC is rarely associated with more severe side effects such as angioedema (83,84).
Intravenous N-acetylcysteine (NAC) is generally well tolerated but carries a higher risk of adverse effects The most common adverse effects are nausea and vomiting, occurring in up to 9% of treatment courses, and anaphylactoid reactions (rash, pruritus, angioedema, bronchospasm) with an overall frequency of about 8.2% across 6,455 treatment courses; roughly 75% of these anaphylactoid reactions were cutaneous in nature.
▪ 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 at lower acetaminophen levels than at higher levels, a pattern that may reflect acetaminophen’s dose‑dependent suppression of histamine release from mast cells and mononuclear cells (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.)
N-acetylcysteine (NAC) therapies, delivered via oral, intravenous (IV), or inhaled routes, have been marketed in the United States and other countries for more than four decades Systematic reviews of NAC for both approved and off-label indications consistently find it to be safe and well tolerated in both children and adults, though pediatric dosing must be carefully matched to body weight to avoid toxicity from dosing errors.
N-acetylcysteine (NAC) side effects are typically mild, with nausea and vomiting being the most common adverse effects for both intravenous (IV) and oral NAC, though rates are higher with the oral form Anaphylactoid reactions occur more frequently with IV NAC and usually subside after treatment is stopped Symptoms may include flushing, pruritus, and rash and can also involve angioedema, bronchospasm, and hypotension Severe adverse reactions and fatalities are rare.
NAC drugs are available internationally, with a variety of formulations in circulation Specifically in the United States, seven NAC products are marketed for intravenous administration, four are available in oral forms (effervescent tablets or oral solutions), and three come as inhaled solutions, illustrating the range of delivery options for NAC therapies.
- 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 controlled trials have evaluated N-acetylcysteine (NAC) for acetaminophen overdose In a relatively small study (n = 50), patients with hepatic failure after acetaminophen overdose were randomized to receive intravenous NAC in addition to standard liver care or standard liver care alone The NAC regimen consisted of 150 mg/kg IV in 200 ml of 5% dextrose over 15 minutes, followed by 50 mg/kg in 500 ml of 5% dextrose over four hours, and then 100 mg/kg in 1 L over 16 hours.
14 encephalopathy or death The rate of survival was higher in patients receiving NAC No adverse side effects were reported in this study
In a larger randomized trial (n=223) comparing two 150 mg/kg N-acetylcysteine loading infusion rates—15-minute versus 60-minute—the adverse event rates were 75% and 61%, respectively Anaphylactoid reactions were the most reported adverse events, occurring in 18% of the 15-minute arm and 15% of the 60-minute arm Two patients (one in each arm) experienced a severe anaphylactoid reaction and were withdrawn from the study Nausea and vomiting, categorized within GI disorders in the analyses, affected 13% of patients The difference between the drug-related adverse events in the two arms was not statistically significant, and no deaths were reported.
The bulk of the remaining clinical trial literature consists of prospective, non-randomized observational studies Nevertheless, data from these studies support the randomized controlled trials cited above, showing that both oral and intravenous N-acetylcysteine (NAC) are safe and well tolerated Case reports have described rarer anaphylactoid reactions, including ECG abnormalities, status epilepticus, and a serum sickness-like illness, but these events 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)
Adults and children, though pediatric approval is not based on adequate or well-controlled studies
- Nausea and vomiting (up to 30% of patients)
- Rash (with or without fever)
- 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
- 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
15 symptoms are relieved by ceasing infusion)
Other reported adverse events 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, and lowered blood urea.
- Hypokalemia and ECG changes have been noted in patients with acetaminophen overdose, monitoring of plasma potassium concentration is recommended
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
- 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
- Irritation at the injection site
- Low blood pressure resulting in dizziness
- Rapid heartbeat or increased blood pressure (rarely)
Summary of available data on comparative cost and cost-effectiveness of the medicine
N-acetylcysteine (NAC) is already listed on the Essential Medicines List (EML) and is widely available worldwide at a very low cost This request does not seek pricing for a new medication, as adding this new use would not alter the existing pricing data In the context of extreme outcomes like acute liver failure (ALF), liver transplantation incurs substantial variability in cost and availability across settings; for example, recent US data show the average liver transplant billed at over $800,000 per patient, and while the US is likely at the high end of global costs, transplantation and follow-up generally require intensive resources and are constrained by limited organ supply NAC is estimated at about $70 per dose, and because the price is so low and NAC has the potential to avert major downstream outcomes such as the need for transplantation, its use offers strong cost-effectiveness.
Summary of regulatory status and market availability of the medicine
N-acetylcysteine (NAC) is approved by many health authorities for preventing liver injury in acetaminophen overdose or for use as a mucolytic To our knowledge, no health authority currently lists NAC for a liver indication outside of acetaminophen overdose, despite its use in this setting The lack of financial incentives for the pharmaceutical 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:
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,
- 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
- 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)
- 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)
N-acetylcysteine (NAC) is widely available worldwide and produced by multiple generic manufacturers, including Fresenius Kabi, Auro Medics Pharma, Cadila Healthcare, Zydus Pharmaceuticals, Roxane Laboratories Inc., Sagent Pharmaceuticals, and Pfizer, among others in various countries Because NAC is already used globally as an antidote for acetaminophen overdose and as a mucolytic, the currently proposed expanded use for this agent would leverage the existing supply chains established across different regions, supporting broader access and scalable distribution.
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
Hu, 2015(4) Meta-analysis Non- acetaminophen induced acute liver failure
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);
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
Sales, 2013(3) Systematic review Non- acetaminophen induced acute liver failure
(8 case reports, 2 retrospec tive trials,
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
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
19 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)
80 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 intracranial pressure was used more often in the control group than in the NAC group (92.5% vs 75%, p=0.037) Among the patients who survived, the mean hospital length of stay was shorter in the NAC group (8.241 ± 2.115 days) compared with the control group (10.737 ± 3.106 days), p=0.002.
Among 80 patients with acute liver failure (ALF), 32 (40%) died from ALF complications Mortality was significantly lower in the N-acetylcysteine (NAC) group (11 of 40, 27.5%) compared with the control group (21 of 40, 52.5%), chi-square = 5.208, P = 0.023 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
RCT Non- acetaminophen- induced liver failure
Majority fell into 4 etiologies: drug- induced liver injury (nE), autoimmune hepatitis (n&), hepatitis B (n7) and indeterminate (n=
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
Participants were given an initial 4-hour period of treatment, followed by continuous infusions of N-acetylcysteine at 6.25 mg/kg for the remaining 67 hours (three days total) Of the 81 participants assigned, 48 completed the 72-hour trial, while 33 received less than the full treatment due to death, withdrawal of support, transplantation, or adverse drug effects, with four cases thought to be NAC-related.
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)
Subjects in the placebo group received infusion of 5% dextrose only (92 assigned, 58 completed 72h trial, 34 received less than full treatment)
Across models that included bilirubin or ALT, the treatment group and day of study emerged as predictors of transplantation or death (maximum p < 0.03) Among patients with early coma grade treated with N-acetylcysteine (NAC), there was a significant improvement in bilirubin and ALT levels compared with the other three treatment groups (maximum p < 0.02 for NAC 1–2 versus the 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 identified N-acetylcysteine (NAC) administration and lower IL-17 concentrations as independent predictors of transplant-free survival In patients with detectable IL-17 on admission, 78% of those who received NAC versus 44% of those who received placebo achieved undetectable IL-17 by day 3–5 (P = 0.042) The mean decrease in IL-17 between admission and late samples was significantly greater in the NAC group than in the placebo group.
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
60% had unknown cause) Wilson disease (7 NAC vs 3 placebo) being more common in the NAC arm than the placebo arm
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) in the NAC-treated group (p