Immediate-release Acetaminophen Research Articles

Nomogramın Uygulanamadığı Durumlarda Parasetamol Zehirlenmesi Riskinin Belirlenmesi

The Rumack-Matthew nomogram for acetaminophen toxicity was prepared using the acetaminophen levels of untreated patients and published in 1975. In order to determine the risk, the authors aimed to determine the acetaminophen levels that cause the aminotransferase level to increase to 1,000 IU/L and above (1). Thus, the line presenting the values above 200 was created. In the study published by Rumack et al. in 1981, the line representing values above 150 was suggested as a safer value (2). On the other hand, the nomogram was designed on the known intake times of single dose, immediate-release acetaminophen preparations. This causes significant limitations in clinical practice.

Acetaminophen Overdose with Altered Acetaminophen Pharmacokinetics and Hepatotoxicity Associated with Premature Cessation of Intravenous N-Acetylcysteine Therapy

To report a case of erratic absorption, double peak serum concentrations, and hepatotoxicity following premature cessation of intravenous N-acetylcysteine (NAC) treatment in the setting of a massive acetaminophen overdose. A 78-year-old man reportedly ingested approximately 96 immediate-release acetaminophen 500-mg tablets (48 g) over a one-hour period in an apparent suicide attempt. The acetaminophen concentration at 2.25 hours was 264 microg/mL. Intravenous NAC was initiated 5 hours postingestion. At 6.25 hours postingestion, the acetaminophen concentration was 281 microg/mL. Following administration of intravenous NAC for 21 hours, therapy was discontinued despite a residual acetaminophen concentration of 116 microg/mL. The patient experienced hepatotoxicity, coagulopathy, and renal injury. Pharmacokinetic analysis revealed significantly prolonged acetaminophen absorption and a second peak acetaminophen concentration of 228 microg/mL approximately 48 hours postingestion. Direct in-hospital monitoring of the patient made a second ingestion unlikely. Acetaminophen overdose is usually effectively managed with NAC. Patients with massive ingestions may have altered absorption kinetics due to acetaminophen's solubility being exceeded, physiologically or chemically altered gastrointestinal emptying or motility, or other factors. These patients may benefit from gastrointestinal decontamination and prolonged NAC therapy. In patients with massive acetaminophen ingestion, erratic absorption may occur, and toxic serum concentrations may persist beyond a standard 21-hour course of intravenous NAC therapy. Acetaminophen concentrations and aminotransferase levels should be evaluated at the completion of the intravenous NAC infusion to ensure complete elimination of acetaminophen and absence of hepatotoxicity and to exclude the need for prolonged treatment.

Acetaminophen Availability Increases in Canada with No Increase in the Incidence of Reports of Inpatient Hospitalizations with Acetaminophen Overdose and Acute Liver Toxicity

In September 1999, several Canadian provinces had place-of-sale restrictions lifted that had limited the sale of acetaminophen >325 mg and packages >24 tablets (any strength) to pharmacies only. This allowed the sale of all strengths of immediate-release acetaminophen in all package sizes in nonpharmacy locations. This study's purpose was to explore the effect that lifting restrictions on acetaminophen place of sale may have had on reported hospitalizations in Canada related to acetaminophen overdose toxicity. Using hospital discharge data, provinces with no preexisting restrictions on place of sale were compared with those in which restrictions were lifted in September 1999. Cases of reported APAP overdose included ICD-9/9-CM code 965.4, ICD-9 code E850.2, or ICD-9-CM code E850.4. Cases with reported acute liver toxicity included ICD-9/9-CM codes 570, 572.2, 572.4, V42.7, or procedure code 50.5. There were no significant differences between the 1.5-year periods pre- and post-September 1999 in annual incidence rates per 100,000 persons ages >/=12 years of hospitalizations reported with acetaminophen overdose, either overall or limited to those with death as an outcome, or in hospitalization reports with both acetaminophen overdose and acute liver toxicity, either overall (provinces with no restrictions: pre = 0.70, post = 0.80, P = 0.6328; provinces with restrictions lifted in September 1999: pre = 0.49, post = 0.47, P = 0.8649) or limited to those with death as an outcome (provinces with no restrictions: pre = 0.22, post = 0.12, P = 0.3030; provinces with restrictions lifted in September 1999: pre = 0.13, post = 0.09, P = 0.3589). In conclusion, the decision to lift Canadian place-of-sale restrictions increased acetaminophen availability and did not increase the rate of reported hospitalizations related to acetaminophen overdose toxicity.

Tylenol Extended Relief Overdose

In this report we describe the toxicokinetics of the Tylenol Extended Relief (TER) preparation of acetaminophen in human overdose. We collected 41 cases of TER overdose from five regional poison centers. Patients who met the following criteria were studied: a single ingestion of TER alone; confirmed time of ingestion; at least four acetaminophen determinations; and normal concentrations of liver function enzymes. With the exception of standard decontamination measures, treatment with N-acetylcysteine (NAC) if any acetaminophen level was above the treatment line of the Rumack-Matthew nomogram, and additional acetaminophen determinations, no interventions were recommended. Our study group comprised 13 patients, 12 female and 1 male, with single overdoses of 10.4 to 65 g TER. The acetaminophen elimination half-life was 3.1±.8 hours (mean±SD; range, 1.3 to 4.0 hours; n=12). The elimination phase for patients 2, 3, 4, 6, 8, 9, 11, 13 was delayed until 8.0±2.8 hours (range, 5 to 14 hours) after ingestion. Patients 3, 8, and 11—who had initial acetaminophen levels below the “possible toxicity” line of the Rumack-Matthew nomogram—later had acetaminophen levels above this line. No patient demonstrated a late or second acetaminophen peak. We conclude that the elimination half-life of TER acetaminophen is similar to that reported in overdose of immediate-release acetaminophen overdose. In a subgroup of patients, drug absorption continued beyond the 2 to 4 hours previously reported in immediate-release acetaminophen overdose. On the basis of our data, the use of a single 4-hour acetaminophen determination may lead to failure to recognize patients with potentially toxic TER ingestion. Until more toxicokinetic data are available, a reasonable approach would be to obtain at least one additional acetaminophen determination at least 4 to 6 hours after the first, if the first is obtained 4 to 8 hours after ingestion. NAC treatment should be initiated if either level is above the nomogram line but not if both levels fall below the nomogram line. [Cetaruk EW, Dart RC, Hurlbut KM, Horowitz RS, Shih R: Tylenol Extended Relief overdose. Ann Emerg Med July 1997;30:104-108.]

Late Increase in Acetaminophen Concentration After Overdose of Tylenol Extended Relief

We report a case demonstrating a late increase in acetaminophen concentration after ingestion of Tylenol Extended Relief (extended-release acetaminophen; McNeil Consumer Products) along with drugs known to slow gastrointestinal motility. Coingestants that slow gastrointestinal motility are known to affect the interpretation of serum drug concentrations. However, this case illustrates potentially significant differences between extended-release and immediate-release acetaminophen and demonstrates an exception to the current manufacturer recommendation for the use of the Rumack-Matthew nomogram in this setting. [Bizovi KE, Aks SE, Paloucek F, Gross R, Keys N, Rivas J: Late increase in acetaminophen concentration after overdose of Tylenol Extended Relief. Ann Emerg Med November 1996;28: 549-551.]

A Pharmacokinetic Comparison of Acetaminophen Products (Tylenol Extended Relief vs Regular Tylenol)

To compare the pharmacokinetics of Tylenol Extended Relief (ER APAP) with those of immediate-release acetaminophen (IR APAP) at supratherapeutic doses. A prospective, double-blind, randomized, crossover comparison trial involving 14 adult volunteers. Each subject ingested 75 mg/kg of either ER APAP or IR APAP and 1 week later received the other APAP preparation. On both occasions plasma APAP concentration ([APAP]) was determined 0.5, 1, 2, 3, 4, 6, 8, 12, and 16 hours after ingestion. The times to maximum [APAP] (Tmax); the maximum [APAP] values (Cmax); the elimination half-lives 4-16 hours postingestion (t1/2), and the areas under the [APAP] vs time curve (AUC) for ER APAP and IR APAP were compared using the paired t-test. All the subjects completed both study phases. The mean APAP dose ingested was 5.6 g (range 4.2-7.8 g). Both the AUC and the Cmax were less after ER APAP than after IR APAP; otherwise, there was no evident difference in any measure. Graphically, ER APAP yielded a flatter, plateau-shaped curve initially, but after 4 hours the curve was nearly identical to that for IR APAP. Results are summarized in the table: [table: see text] In this model involving a single supratherapeutic dose, ER APAP evidenced no pharmacokinetic features that would suggest the need for an alternate poisoning screening strategy. When compared with IR APAP, ER APAP had a lower AUC, all peak [APAP] occurred in < 4 hours, and terminal eliminations were identical. The data suggest that, in most cases, the diagnostic approach to an overdose of ER APAP need not deviate from that used for an IR APAP overdose.

Relative bioavailability of a novel sustained-release acetaminophen molded tablet

An experimental easily swallowable oral sustained-release dosage form of acetaminophen (APAP) that can be administered to patients every 12 hours was formulated and evaluated in 8 healthy, adult volunteers. The test product was compared to a well-characterized, commercially available immediate-release acetaminophen caplet. Multiple doses of these two products were administered to 8 healthy human subjects in a two-way cross-over design. Saliva samples were collected over a period of 24–48 h depending upon the administered treatment. The time course of acetaminophen concentrations in saliva was analyzed using non-compartmental methods. Results indicate that it is possible to maintain the desired therapeutic concentration over a 12-h dosing interval using the molded tablet dosage form.

Extended-Release Acetaminophen Overdose

<h3>To the Editor.</h3> —There were 102 619 cases of ingestion of acetaminophen-containing products, including 100 deaths, reported in the United States in 1994.¹Management of acute acetaminophen overdose is guided by the Rumack-Matthew nomogram, which assumes acetaminophen absorption in acute overdose is complete by 4 hours after ingestion.²In August 1994, McNeil Pharmaceuticals (Fort Washington, Pa) introduced Tylenol Extended Relief, the first extended-release formulation of acetaminophen available in the United States. Patients presenting after overdose with extended release (ER) acetaminophen (Tylenol ER) which contains 325 mg of immediate-release acetaminophen and 325 mg of extended-release acetaminophen per tablet, pose a dilemma because the kinetics of acetaminophen ER in overdose are unknown, and it is not known whether physicians can rely on the nomogram to facilitate treatment. Douglas et al³found no difference in time to peak concentration between acetaminophen ER and immediate-release acetaminophen in volunteers who ingested 75

Automated analytical systems for drug development studies 3. Multivessel dissolution testing system based on microdialysis sampling

An automated system consisting of a six-vessel dissolution apparatus, microdialysis sampling, STT E6 multiposition switching valve and a liquid chromatograph was assembled to measure dissolution profiles of immediate and sustained-release tablets. A DL-5 microdialysis loop probe (BAS, Inc.) was immersed in each dissolution vessel and perfused with a suitable medium for sampling. The dialystate from each vessel was injected sequentially onto an on-line liquid chromatography (LC) system for automated analysis. The STT E6 multiposition switching valve was used to sample up to six vessels simultaneously. After addressing issues related to sample carry-over and between-probe variability, the automated system was used in a reproducible manner (RSD < 3%) to measure the dissolution of immediate-release acetaminophen tablets and Accutrim ® (containing 75 mg phenylpropanolamine HCl) 16 h Precision Release™ tablets. An uneven injection time sequence was used to monitor three acetaminophen tablets per dissolution run using the automated system and each vessel was sampled about every 6.5 min. However, with Accutrim ® 16 h Precision Release™ tablets, a longer sampling interval (10 min) was used, the six tablets could be tested in each dissolution run. The dissolution profiles of acetaminophen and Accutrim ® tablets measured using the automated multivessel dissolution system compared well with manual and automated single-vessel dissolution systems.