Paracetamol (acetaminophen) overdose and hepatotoxicity: mechanism, treatment, prevention measures, and estimates of burden of disease.

INTRODUCTION: Paracetamol is one of the most used medicines worldwide and is the most common important poisoning in high-income countries. In overdose, paracetamol causes dose-dependent hepatotoxicity. Acetylcysteine is an effective antidote, however despite its use hepatotoxicity and many deaths still occur. AREAS COVERED: This review summarizes paracetamol overdose and toxicity (including mechanisms, risk factors, risk assessment, and treatment). In addition, we summarize the epidemiology of paracetamol overdose worldwide. A literature search on PubMed for poisoning epidemiology and mortality from 1 January 2017 to 26 October 2022 was performed to estimate rates of paracetamol overdose, liver injury, and deaths worldwide. EXPERT OPINION: Paracetamol is widely available and yet is substantially more toxic than other analgesics available without prescription. Where data were available, we estimate that paracetamol is involved in 6% of poisonings, 56% of severe acute liver injury and acute liver failure, and 7% of drug-induced liver injury. These estimates are limited by lack of available data from many countries, particularly in Asia, South America, and Africa. Harm reduction from paracetamol is possible through better identification of high-risk overdoses, and better treatment regimens. Large overdoses and those involving modified-release paracetamol are high-risk and can be targeted through legislative change.

A Cost-Effectiveness Analysis of Nintedanib in Idiopathic Pulmonary Fibrosis in the UK.

BACKGROUND: International guidelines recommend nintedanib (OFEV®) as an option for the treatment of idiopathic pulmonary fibrosis (IPF). OBJECTIVE: The objective of this study was to assess the cost effectiveness of nintedanib versus pirfenidone, N-acetylcysteine and best supportive care (BSC) for the treatment of IPF from a UK payer's perspective. METHODS: A Markov model was designed to capture the changes in the condition of adults with IPF. Efficacy outcomes included mortality, lung function decline and acute exacerbations. Treatment safety (serious adverse events) and tolerability (overall discontinuation) were also considered. The baseline risk of these events was derived from patient-level data from the placebo arms of nintedanib clinical trials (TOMORROW, INPULSIS-1, INPULSIS-2). A network meta-analysis (NMA) was conducted to estimate the relative effectiveness of the comparator treatments. Quality of life and healthcare resource use data from the clinical trials were also incorporated in the economic model. RESULTS: Nintedanib showed statistically significant differences against placebo on acute exacerbation events avoided and lung function decline. In the cost-effectiveness analysis, the results were split between two treatments with relative low costs and modest effectiveness (BSC and N-acetylcysteine) and two that showed improved effectiveness (lung function) and higher costs (nintedanib and pirfenidone). All comparators were assumed to have similar projected survival and the difference in quality-adjusted life-years (QALYs) was driven by the acute exacerbations and lung function estimates. In the base-case deterministic pairwise comparison with pirfenidone, nintedanib was found to have fewer acute exacerbations and resulted in less costs and more QALYs gained. CONCLUSIONS: Compared with BSC (placebo), nintedanib and pirfenidone were the only treatments to show statistical significance in the efficacy parameters. We found substantial uncertainty in the overall cost-effectiveness results between nintedanib and pirfenidone. N-Acetylcysteine was largely similar to BSC but with a worse survival profile. INPULSIS-1 and INPULSIS-2 ClinicalTrials.gov numbers, NCT01335464 and NCT01335477.

Preventive nebulization of mucolytic agents and bronchodilating drugs in invasively ventilated intensive care unit patients (NEBULAE): study protocol for a randomized controlled trial.

BACKGROUND: Preventive nebulization of mucolytic agents and bronchodilating drugs is a strategy aimed at the prevention of sputum plugging, and therefore atelectasis and pneumonia, in intubated and ventilated intensive care unit (ICU) patients. The present trial aims to compare a strategy using the preventive nebulization of acetylcysteine and salbutamol with nebulization on indication in intubated and ventilated ICU patients. METHODS/DESIGN: The preventive nebulization of mucolytic agents and bronchodilating drugs in invasively ventilated intensive care unit patients (NEBULAE) trial is a national multicenter open-label, two-armed, randomized controlled non-inferiority trial in the Netherlands. Nine hundred and fifty intubated and ventilated ICU patients with an anticipated duration of invasive ventilation of more than 24 hours will be randomly assigned to receive either a strategy consisting of preventive nebulization of acetylcysteine and salbutamol or a strategy consisting of nebulization of acetylcysteine and/or salbutamol on indication. The primary endpoint is the number of ventilator-free days and surviving on day 28. Secondary endpoints include ICU and hospital length of stay, ICU and hospital mortality, the occurrence of predefined pulmonary complications (acute respiratory distress syndrome, pneumonia, large atelectasis and pneumothorax), and the occurrence of predefined side effects of the intervention. Related healthcare costs will be estimated in a cost-benefit and budget-impact analysis. DISCUSSION: The NEBULAE trial is the first randomized controlled trial powered to investigate whether preventive nebulization of acetylcysteine and salbutamol shortens the duration of ventilation in critically ill patients. TRIAL REGISTRATION: NCT02159196, registered on 6 June 2014.

Epidemiology, management and outcome of paracetamol poisoning in an inner city emergency department.

BACKGROUND: Paracetamol poisoning accounts for just under half of all self-poisoning cases that present to hospitals in England. Treatment with acetylcysteine is routine, yet recommendations regarding its use vary internationally and have recently been revised in England and Wales. METHODS: Data on all cases of paracetamol poisoning presenting to an adult inner city emergency department between May 2011 and April 2012 were prospectively collected using the Bristol Self-harm Surveillance Register. RESULTS: Paracetamol overdoses accounted for 44% of adult self-poisoning cases. A quarter (26.9%) of patients required treatment with acetylcysteine and it was estimated that recent changes in treatment guidelines would increase that proportion to 32.6%. Paracetamol concentration was positively associated with the risk of any adverse reaction to acetylcysteine. 22.5% of patients experienced anaphylactoid reactions to acetylcysteine. There was no clear evidence of an association between risk of anaphylactoid reaction and blood paracetamol levels. Patients presenting with blood paracetamol levels greater than 200 mg/L at 4 h post-ingestion were at greater risk of repeat self-harm (HR 2.17, 95% CI 1.11 to 4.21, p=0.033). DISCUSSION: The recent changes in UK treatment guidelines are expected to increase the proportion of our population requiring acetylcysteine by 5.7%. We found no clear evidence that risk of anaphylactoid or more general adverse reaction to acetylcysteine was increased in patients presenting with lower blood paracetamol concentrations. Blood paracetamol level was highlighted as a potentially useful clinical indicator for risk of repeat self-harm.

Incidence and management of N-acetylcysteine-related anaphylactoid reactions during the management of acute paracetamol overdose.

OBJECTIVE: Adverse drug reactions (ADRs) to N-acetylcysteine (NAC) treatment for paracetamol overdose are typically anaphylactoid in origin and occur in 2-48% of treated patients. We explored the incidence and management of NAC ADR in our unit. PATIENTS AND METHODS: Case notes of patients who presented with paracetamol overdose and had ADR to NAC between February 2005 and June 2011 were reviewed. A total of 1648 patients presented with suspected paracetamol overdose and 660 received NAC treatment. Within this group, 82 patients had documented NAC-related ADR. RESULTS: ADR developed in 12.4% (82/660) of patients receiving intravenous NAC and 59 had full documentation available and were included in this study (34 women, 25 men). ADR occurred in the 15-min (150 mg/kg) bag in 36 cases (61%), 22 in the 4-h (50 mg/kg) bag (37%) and one in the 16-h (100 mg/kg) bag (2%). Symptoms were classified as minimal (n=16, 27%), moderate (n=26, 44%) and severe (n=17, 29%). Asthma and female sex, which are reported risk factors for ADR, did not lead to the development of more severe ADR (P=0.771 and 0.330, respectively). Treatments administered included stopping the NAC infusion (n=32, 54%), administration of antiemetics (n=36, 61%), H1 antihistamines (n=26, 44%), steroids (n=16, 27%), inhaled B2 agonists (n=6, 10%) and adrenaline (n=3, 5%). CONCLUSION: The incidence of ADR to NAC was comparable with published studies, although there was no association of severity with asthma or female sex. The management of ADRs is variable, with frequent, inappropriate use of steroids. Education about the pathophysiology of these ADRs may improve management.

Relative bioavailability of generic and branded acetylcysteine effervescent tablets: A single-dose, open-label, randomized-sequence, two-period crossover study in fasting healthy Chinese male volunteers.

BACKGROUND: Acetylcysteine may be used as a muco- lytic agent for the treatment of chronic bronchitis, chronic obstructive pulmonary disease, and other pulmonary diseases complicated by the production of viscous mucus. However, little is known of its pharmacokinetic properties when given orally in healthy volunteers, particularly in a Chinese Han population. This study was conducted to provide support for the marketing of a generic product in China. OBJECTIVE: The purpose of this study was to compare the pharmacokinetics and relative bioavailability of a generic test formulation and a branded reference formulation of acetylcysteine in fasting healthy Chinese male volunteers. METHODS: A single-dose, open-label, randomized-sequence, 2-period crossover design with a 7-day washout period between doses was used in this study. Healthy Chinese male nonsmokers aged 18 to 40 years with a body mass index (BMI) of 19 to 25 kg/m(2) were selected. Eligible volunteers were randomly assigned to receive acetylcysteine 600 mg PO as either the test formulation (3 tablets of 200 mg each) or reference formulation (1 tablet of 600 mg) under fasting conditions. A total of 15 serial blood samples were collected over a 24-hour interval, and total plasma acetylcysteine concentrations were analyzed by a validated liquid chromatography-isotopic dilution mass spectrometry method. Pharmacokinetic parameters (C(max), T(max), t(½) AUC(0-t), and AUC(0-∞) were calculated and analyzed statistically. The 2 formulations were considered bioequivalent if the 90% CIs of the log-transformed ratios (test/reference) of C(max) and AUC were within the predetermined bioequivalence ranges (70%-143% for C(max); 80%-125% for AUC), as established by the State Food and Drug Administration of China. Tolerability was determined by vital signs, clinical laboratory tests, 12-lead ECGs, physical examinations, and interviews with the subjects about adverse events (AEs). RESULTS: A total of 24 healthy Chinese Han male volunteers were enrolled in and completed the study (mean [SD] age, 25.0 [2.4] years; height, 173.0 [5.6] cm; weight, 65.9 [6.4] kg; BMI, 22.0 [1.7] kg/m(2)). No formulation, period, or sequence effects were observed. The 90% CIs for the log-transformed C(max), AUC(0-t), and AUC(0-∞) were 89.7% to 103.8%, 86.7% to 101.7%, and 87.7% to 102.4%, respectively, which met the predetermined criteria for assuming bioequivalence. Two subjects (8.3%) experienced 2 mild AEs (increase in total bile acid and prolongation of the QT interval), which were not considered to be related to study drug administration. CONCLUSIONS: This single-dose study of acetylcysteine 600 mg PO found that the 3 tablets of the generic test formulation and 1 tablet of the branded reference formulation met the regulatory criteria for assuming bioequivalence in these fasting healthy Chinese male volunteers. Both formulations were generally well tolerated.

Effects of N-acetylcysteine on outcomes in chronic obstructive pulmonary disease (Bronchitis Randomized on NAC Cost-Utility Study, BRONCUS): a randomised placebo-controlled trial.

BACKGROUND: Increased oxidative stress is important in the pathogenesis of chronic obstructive pulmonary disease (COPD). We postulated that treatment with the antioxidant N-acetylcysteine would reduce the rate of lung-function decline, reduce yearly exacerbation rate, and improve outcomes. METHODS: In a randomised placebo-controlled study in 50 centres, 523 patients with COPD were randomly assigned to 600 mg daily N-acetylcysteine or placebo. Patients were followed for 3 years. Primary outcomes were yearly reduction in forced expiratory volume in 1 s (FEV1) and the number of exacerbations per year. Analysis was by intention to treat. FINDINGS: The yearly rate of decline in FEV1 did not differ between patients assigned N-acetylcysteine and those assigned placebo (54 mL [SE 6] vs 47 mL [6]; difference in slope between groups 8 mL [9]; 95% CI -25 to 10). The number of exacerbations per year did not differ between groups (1.25 [SD 1.35] vs 1.29 [SD 1.46]; hazard ratio 0.99 [95% CI 0.89-1.10, p=0.85]). Subgroup analysis suggested that the exacerbation rate might be reduced with N acetylcysteine in patients not treated with inhaled corticosteroids and secondary analysis was suggestive of an effect on hyperinflation. INTERPRETATION: N-acetylcysteine is ineffective at prevention of deterioration in lung function and prevention of exacerbations in patients with COPD.