Immediate Release Paracetamol Research Articles

Prolonged use of paracetamol and the prescribing patterns on rehabilitation facilities.

The study investigated: (a) the usage patterns of paracetamol, and (b) the association between paracetamol use and patient outcomes such as liver and kidney functions among older people. Paracetamol is a well-known analgesic and antipyretic drug, with an excellent safety profile when used within its recommended dose. It is a commonly used drug by people aged over 65years to treat chronic pain. Prolonged use of paracetamol in the elderly is poorly understood. As such, there is a genuine risk among older people of unintentional overdose. A retrospective analysis of medical records in rehabilitation wards was undertaken from 1July 2016 to 30June 2017. Patients' paracetamol use, prescribing patterns and biochemical results were analysed to assess for differences in admission and discharge biochemistry results. The TREND Statement was utilised to guide study reporting (Enhancing the QUAlity and Transparency Of health Research, 2021). A total of 1119 patients were admitted for seven or more days in a metropolitan tertiary hospital in Melbourne. Almost three-quarters (74%) of patients were administered paracetamol; 76.1% received 'Immediate-Release Paracetamol' (IRP), and 23.9% were given 'Sustained-Release Paracetamol' (SRP). A proportion (4.5%) of patients in both the IRP and SRP groups received more than the daily recommended dose. There were limited statistically significant differences between patients' admission and discharge biochemistry results; group or time differences were observed, which were indicative of improvements within the paracetamol group. Paracetamol was a commonly used medication among long-stay elderly patients. Precaution to ensure paracetamol use does not exceed recommended daily doses is required. This study suggests that paracetamol used at a therapeutic level in older patients had limited, negative associations with liver and kidney function. The clinical practice regarding prolonged use of paracetamol is ambitious. The increased risk of paracetamol toxicity among the frail elderly is a concern. Optimising the dose adjustment in the elderly is important to avoid adverse outcomes.

Population pharmacokinetics of immediate-release and modified-release paracetamol and its major metabolites in a supratherapeutic dosing study

Objectives Overdose with paracetamol modified-release (MR) formulation, a bilayer tablet containing 69% slow-release component, has been increasing since its introduction to the market. However, little evidence exists for the management of MR paracetamol overdose. We aimed to develop a population pharmacokinetic (PK) model for immediate-release (IR) and MR paracetamol and its major metabolism, and quantitatively understand the formulation difference in toxicity assessment based on the nomogram line. Methods Data from a cross-over study design in nine healthy volunteers administered a single supratherapeutic oral dose (80 mg/kg) of either IR and MR paracetamol were available from a published study. Plasma concentrations for paracetamol and its metabolites glucuronide (APAPG) and sulfate conjugate (APAPS) for both formulations were measured and analysed with population pharmacokinetic (PK) method using NONMEM. Toxicity in both formulations was assessed by comparing the simulated paracetamol concentrations under different paracetamol dose levels with the 150 mg/L nomograms. The difference in the assessment was compared between the two formulations. Results Paracetamol concentrations for the IR formulation were described with a two-compartment model with first-order input and a lag time. The delayed time-course of MR paracetamol concentrations was best captured by a parallel absorption model in which the slow-release component was a serial zero-order then the first-order process. The formation of APAPG was linear, while APAPS concentrations were best fitted by a Michaelis-Menten process. The relative bioavailability of MR paracetamol compared to IR () was estimated as 0.81. The simulated probability of making different toxicity assessments based on nomogram line was increased with dose levels and was as high as 14.6% after 22 g IR or MR paracetamol ingested. Conclusions A joint parent-metabolite model to describe time-course profiles of both IR and MR paracetamol and its metabolites APAPG and APAPS concentrations was developed. Simulations from the model showed that toxicity assessment based on the 150 mg/L nomograms is not suitable in MR paracetamol overdoses.

Dose Can Help to Achieve Effective Pain Relief for Acute Mild to Moderate Pain with Over-the-Counter Paracetamol

Background:Paracetamol (acetaminophen) is one of the most widely used Over-The-Counter (OTC) analgesics for the self-treatment of mild to moderate acute pain. Different dosages are used in different countries and, in some of them, a large proportion of adults are using low doses (325 mg to 500 mg).Objectives:The objective of the study was to review information from published research studies to answer the question: is there a dose-dependent analgesic effect of paracetamol in the treatment of mild to moderate acute pain?Methods:A detailed assessment of available systematic reviews, meta-analyses and single randomised trials was undertaken based on an electronic literature search focusing on studies comparing higher and lower doses of paracetamol in the management of mild to moderate acute pain.Results:Reviews and comparative trials generally showed greater efficacy with higher dose paracetamol (1000 mg) than with lower doses (500 mg or 650 mg) in achieving clinically significant pain relief with comparable tolerability in different types of pain.ConclusionsThe nature and intensity of the pain are two key elements of the therapeutic choice.Higher dose immediate-release paracetamol (1000 mg), used for a short duration of time (4-5 days) and adhering to recommendations within the label for risk groups, delivers safe and more effective analgesia than lower doses for adults with mild to moderate acute pain.Strengths and Limitations of this Study:• Paracetamol is one of the most widely used OTC analgesics for the self- treatment of mild to moderate acute pain and this study aims to explore the practical question of whether the use of low doses, which is common in some countries, provides suboptimal pain relief.• This review provides an overview of previous studies focusing on comparing the analgesic efficacy of different doses of paracetamol rather than comparing the effect of different OTC analgesics.• This review details a narrative assessment of available systematic reviews, meta-analysis and randomised trials but does not offer a quantitative analysis of pain relief achieved with different doses of paracetamol.• The review does not provide an overview of studies focusing on different forms of paracetamol.• The focus for this review is immediate release paracetamol. Combined and slow release paracetamol formulations were not considered of relevance. The latter are in the process of being suspended across the European Union due to safety concerns with overdosing [1].

Bioequivalence and Safety of Twice-Daily Sustained-Release Paracetamol (Acetaminophen) Compared With 3- and 4-Times-Daily Paracetamol: A Repeat-Dose, Crossover Pharmacokinetic Study in Healthy Volunteers.

Twice‐daily sustained‐release (SR) paracetamol (acetaminophen) offers convenient administration to chronic users. This study investigated at steady state (during the last 24 hours of a 3‐day dosing period) the pharmacokinetics, bioequivalence, and safety of twice‐daily SR paracetamol compared with extended‐release (ER) and immediate‐release (IR) paracetamol. In this open‐label, randomized, multidose, 3‐way crossover study, 28 healthy subjects received paracetamol SR (2 × 1000 mg twice daily), ER (2 × 665 mg 3 times daily), and IR (2 × 500 mg 4 times daily). At steady state, twice‐daily SR paracetamol was bioequivalent to ER and IR paracetamol. The 90% confidence intervals for the ratios of geometric means were within the acceptance interval for SR/ER paracetamol (AUC0–t, 0.973–1.033; AUC0–24, 0.974–1.034; AUC0–∞, 0.948–1.011; Cmax, 1.082–1.212; Cav, 1.011–1.106) and SR/IR paracetamol (AUC0–t, 0.969–1.029; AUC0–24, 0.968–1.027; AUC0–∞, 0.963–1.026; Cmax, 0.902–1.010; Cav, 1.004–1.098). Given twice daily, the SR formulation demonstrated SR properties as expected. Mean time at or above a 4 μg/mL plasma concentration of paracetamol from 2 daily doses of the SR formulation was significantly longer than that from 4 daily doses of IR paracetamol. SR formulation also had a greater Tmax, a longer half‐life, and lower Cmin compared with ER and IR paracetamol. All formulations were well tolerated.

The standard treatment protocol for paracetamol poisoning may be inadequate following overdose with modified release formulation: a pharmacokinetic and clinical analysis of 53 cases

Objective: The use of the standard procedure for managing overdoses with immediate release (IR) paracetamol is questionable when applied to overdoses with modified release (MR) formulations. This study describes the pharmacokinetics of paracetamol and the clinical outcomes following overdoses with a MR formulation.Methods: Medical records including laboratory analyses concerning overdoses of MR paracetamol from 2009 to 2015 were collected retrospectively. Inclusion criteria were ingestion of a toxic dose, known time of intake and documented measurements of serum paracetamol and liver function tests. Graphical analysis, descriptive statistics and population pharmacokinetic modelling were used to describe data.Results: Fifty-three cases were identified. Median age was 26 years (range 13–68), median dose was 20 g (range 10–166) and 74% were females. The pharmacokinetic analysis showed a complex, dose dependent serum versus time profile with prolonged absorption and delayed serum peak concentrations with increasing dose. Ten patients had persistently high serum levels for 24 h or more, six of them had a second peak 8–19 h after ingestion. Seven of 34 patients receiving N-acetylcysteine (NAC) within 8 h had alanine aminotransferase (ALT) above reference range. Three of them developed hepatotoxicity (ALT >1000 IU/l).Discussion and conclusions: The pharmacokinetic and clinical analysis showed that the standard treatment protocol, including risk assessment and NAC regimen, used for IR paracetamol poisoning not appear suitable for MR formulation. Individual and tailored treatment may be valuable but further studies are warranted to determine optimal regimen of overdoses with MR formulation.

Massive paracetamol overdose: an observational study of the effect of activated charcoal and increased acetylcysteine dose (ATOM-2)

Context: Paracetamol is commonly taken in overdose, with increasing concerns that those taking “massive” overdoses have higher rates of hepatotoxicity and may require higher doses of acetylcysteine. The objective was to describe the clinical characteristics and outcomes of “massive” (≥ 40 g) paracetamol overdoses.Methods: Patients were identified through the Australian Paracetamol Project, a prospective observational study through Poisons Information Centres in NSW and Queensland, over 3 and 1.5 years, respectively, and retrospectively from three clinical toxicology unit databases (over 2.5 to 20 years). Included were immediate-release paracetamol overdoses ≥ 40 g ingested over ≤ 8 h. Outcomes measured included paracetamol ratio[defined as the ratio of the first paracetamol concentration taken 4–16 h post-ingestion to the standard (150 mg/L at 4 h) nomogram line at that time] and hepatotoxicity (ALT >1000 U/L).Results: Two hundred paracetamol overdoses were analysed, reported median dose ingested was 50 g (interquartile range (IQR): 45–60 g) and median paracetamol ratio 1.9 (IQR: 1.4–2.9, n = 173). One hundred and ninety-three received acetylcysteine at median time of 6.3 h (IQR: 4–9.3 h) post-ingestion. Twenty-eight (14%) developed hepatotoxicity, including six treated within 8 h of ingestion. Activated charcoal was administered to 49(25%), at median of 2 h post-ingestion (IQR:1.5-5 h). Those receiving activated charcoal (within 4 h of ingestion), had significantly lower paracetamol ratio versus those who did not: 1.4 (n = 33, IQR: 1.1–1.6) versus 2.2 (n = 140, IQR: 1.5–3.0) (p < .0001) (paracetamol concentration measured ≥ 1 h after charcoal). Furthermore, they had lower rates of hepatotoxicity [unadjusted OR: 0.12 (95% CI: <0.001–0.91); adjusted for time to acetylcysteine OR: 0.20 (95%CI: 0.002–1.74)].Seventy-nine had a paracetamol ratio ≥2, 43 received an increased dose of acetylcysteine in the first 21 h; most commonly a double dose in the last bag (100 to 200 mg/kg/16 h). Those receiving increased acetylcysteine had a significant decrease risk of hepatotoxicity [OR:0.27 (95% CI: 0.08–0.94)]. The OR remained similar after adjustment for time to acetylcysteine and paracetamol ratio.Conclusion: Massive paracetamol overdose can result in hepatotoxicity despite early treatment. Paracetamol concentrations were markedly reduced in those receiving activated charcoal within 4 h. In those with high paracetamol concentrations, treatment with increased acetylcysteine dose within 21 h was associated with a significant reduction in hepatotoxicity.

Accuracy of the paracetamol-aminotransferase multiplication product to predict hepatotoxicity in modified-release paracetamol overdose

Context: The paracetamol-aminotransferase multiplication product (APAP × ALT) is a risk predictor of hepatotoxicity that is somewhat independent of time and type of ingestion. However, its accuracy following ingestion of modified-release formulations is not known, as the product has been derived and validated after immediate-release paracetamol overdoses.Objective: The aim of this retrospective cohort study was to evaluate the accuracy of the multiplication product to predict hepatotoxicity in a cohort of patients with modified-release paracetamol overdose.Methods: We assessed all patients with modified-release paracetamol overdose presenting to our hospital network from October 2009 to July 2016. Ingestion of a modified-release formulation was identified by patient self-report or retrieval of the original container. Hepatotoxicity was defined as peak alanine aminotransferase ≥1000 IU/L, and acute liver injury (ALI) as a doubling of baseline ALT to more than 50 IU/L.Results: Of 1989 paracetamol overdose presentations, we identified 73 modified-release paracetamol exposures treated with acetylcysteine. Five patients developed hepatotoxicity, including one who received acetylcysteine within eight hours of an acute ingestion. No patient with an initial multiplication product <10,000 mg/L × IU/L developed hepatotoxicity (sensitivity 100% [95%CI 48%, 100%], specificity 97% [90%, 100%]). Specificity fell to 54% (95%CI: 34, 59%) at a product cut-off point <1500 mg/L × IU/L. When calculated within eight hours of ingestion, mild elevations of the multiplication product fell quickly on repeat testing in patients without ALI or hepatotoxicity.Conclusions: In modified-release paracetamol overdose treated with acetylcysteine, the paracetamol-aminotransferase multiplication product demonstrated similar accuracy and temporal profile to previous reports involving mostly immediate-release formulations. Above a cut-point of 10,000 mg/L × IU/L, it was very strongly associated with the development of acute liver injury and hepatotoxicity, especially when calculated more than eight hours post-ingestion. When below 1500 mg/L × IU/L the likelihood of developing hepatotoxicity was very low. Persistently high serial multiplication product calculations were associated with the greatest risk of hepatotoxicity.

The comparative pharmacokinetics of modified‐release and immediate‐release paracetamol in a simulated overdose model

Panadol Extend (PEx) is an over-the-counter, modified-release formulation of paracetamol. Each 665 mg tablet contains 69% slow-release and 31% immediate-release paracetamol. In simulated human overdose, PEx exhibits lower and later peak serum concentrations and a lower area-under-the-curve (AUC) than comparable doses of immediate-release paracetamol (APAP-IR). The lower AUC might result from incomplete absorption of paracetamol or simultaneous metabolism with absorption. Do differences in pharmacokinetics (PK) between PEx and APAP-IR result from incomplete absorption or simultaneous absorption and metabolism of paracetamol? Cross-over study of 80 mg/kg of PEx or APAP-IR in nine volunteers. Serial plasma paracetamol, glucuronide, sulphate and cysteine metabolite estimates performed over 24 h. Peak plasma concentration (Cmax), AUC((0-∞),) time to peak concentration (Tmax) and elimination half-life (t(1/2) ) were compared. PEx exhibited significantly lower paracetamol Cmax (252.33 µmol/L vs 565.56 µmol/L, P= 0.0421), AUC((0-∞)) (2133 µmol/h/L vs 2637 µmol/h/L, P= 0.0004) and delayed Tmax (2.889 h vs 1.389 h, P= 0.0189) than APAP-IR. Sulphate metabolite PK parameters for both preparations, PEx vs APAP-IR, showed similar AUC((0-∞)) (1369 µmol/h/L vs 1089 µmol/h/L), Tmax (3.889 h vs 4.444 h), Cmax (95.889 µmol/L vs 95.889 µmol/L) and t(1/2) (3.895 h vs 3.810 h). Glucuronide metabolite concentrations revealed that PEx produced a lower Cmax (257.44 µmol/L vs 335.22 µmol/L, P= 0.0239) than APAP-IR. All other pharmacokinetic parameters were similar. Cysteine metabolite was not detected. There were minor differences between the PK parameters of the two major paracetamol metabolites of these two preparations in simulated overdose. The variability in paracetamol AUC seen between the two preparations in moderate overdose might be explained by concurrent metabolism of paracetamol during slower absorption with PEx.

Comparative pharmacokinetics of Panadol Extend and immediate‐release paracetamol in a simulated overdose model

Panadol Extend is a modified-release paracetamol formulation in which each 665 mg tablet contains 69% slow-release and 31% immediate-release paracetamol. There are no data on Panadol Extend pharmacokinetics in overdose. It is unknown whether the paracetamol treatment nomogram can be used to make decisions regarding the toxicity of this product in overdose. To compare the pharmacokinetics of Panadol Extend and immediate-release paracetamol (APAP-IR) in simulated overdose model in healthy volunteers. Cross-over study using a dose of 90 mg/kg ideal body weight of Panadol Extend or APAP-IR in seven healthy volunteers. Serum paracetamol concentrations were measured over 12 h. Maximal paracetamol concentration (Cmax), time to Cmax (Tmax), area under the curve (AUC) and elimination half-life (t(1/2)) were compared. Mean paracetamol dose was 73 mg/kg actual body weight. Panadol Extend produced lower Cmax (0.208 mmol/L +/- 0.02 vs 0.48 mmol/L +/- 0.02, P = 0.0001) and AUC(0-12 h) when compared with APAP-IR. Tmax was delayed with Panadol Extend (2.83 h +/- 0.26 vs 0.94 h +/- 0.17, P = 0.0001). Absorption was complete in all subjects by 4 h post ingestion in both study arms. Elimination t(1/2) was 1.69 +/- 0.09 h for APAP-IR and 1.65 +/- 0.13 h for Panadol Extend (not significant). Reductions in Panadol Extend Cmax and AUC(0-12 h) might be related to elimination occurring during the absorption phase. In this model of Panadol Extend moderate overdose, Tmax was significantly delayed. In larger overdoses, time to peak paracetamol levels might be further delayed, because of continuing absorption from the formulation. Therefore, the paracetamol treatment nomogram might not reliably predict hepatotoxicity from Panadol Extend if paracetamol levels are measured too early.

A study of the analgesic efficacy and safety of use of paracetomol formulations after third molar surgery

Objective To compare the analgesic efficacy and safety of a sustained release (SR) paracetamol formulation (Panadol Extend) with a standard immediate release (IR) formulation (Panadol) after third molar surgery. Design A multi-centre, double-blind, randomised clinical trial. Methods Patients received either a single oral dose of SR paracetamol or IR paracetamol for pain after the removal of at least one impacted third molar requiring bone removal under general anaesthesia. Post-operative pain and pain relief assessments were undertaken at time intervals up to 8 hours. Global assessments of effectiveness were made at 4 and 8 hours. Any adverse events were also recorded. Results Of 627 randomised patients, 314 were treated with SR paracetamol and 313 with IR paracetamol. In the per protocol population at 4 hours, 35.1% of the 252 patients on SR paracetamol rated the study medication as very good or excellent compared with 27.7% of the 258 patients on IR paracetamol. There were few statistically significant differences among the secondary parameters but where they did occur they favoured SR paracetamol. Trends in favour of SR paracetamol were observed among the secondary parameters and these tended to emerge at the later time points. For example, while there was no statistically significant difference in time to re-medication between the treatment groups, the estimated time to re-medication was longer for patients treated with SR paracetamol (4 hr 5 min) compared with IR paracetamol (3 hr 10 min). The high rate of re-medication observed is consistent with that reported for IR paracetamol using the post-operative dental pain model. No difference was observed between the SR paracetamol and IR paracetamol treatment groups in distribution, incidence or severity of adverse events. Conclusions SR paracetamol and IR paracetamol are clinically and statistically equivalent. While SR paracetamol and IR paracetamol were similar in terms of both onset of analgesia and peak analgesic effect, SR paracetamol had a longer duration of activity than IR paracetamol. The safety profiles of SR paracetamol and IR paracetamol were found to be very similar.

An attempt to establish an in vitro-in vivo correlation: case of paracetamol immediate-release tablets.

The purpose of this study was to investigate the possibility of developing different levels of in vitro-in vivo correlation for immediate-release paracetamol tablets using in vitro dissolution data obtained under various experimental conditions. The influence of agitation intensity and pH value of the dissolution media was investigated. The level B approach, using statistical moment analysis led to poor correlation results. The results obtained by numerical deconvolution in order to study level A correlation indicated that good correlation should be sought with moderate levels of agitation (beyond 50 rpm in rotating basket apparatus). Results obtained by numerical convolution showed the highest level of correlation, level A, with one-to-one relationship between observed and predicted in vivo profiles.