ABSTRACT 740 ACADEMIC EMERGENCY MEDICINE AUG 1996 VOL 3/NO 8

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1 740 ACADEMIC EMERGENCY MEDICINE AUG 1996 VOL 3/NO 8 A Pharmacokinetic Comparison of Acetaminophen Products (Tylenol d Extended Relief vs Regular Tylenol) Daniel R. Douglas, MD, James B. Sholal; MD, Martin J. Smilkstein, MD I ABSTRACT... Obiedive: To compare the pharmacokinetics of Tylenol Extended Relief (ER APAP) with those of immediaterelease acetaminophen (IR APAP) at supratherapeutic doses. Methods: A prospective, double-blind, randomized, crossover comparison trial involving 14 adult volunteers. Each subject ingested 75 mgkg 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] (TmaK); the maximum [APAP] values (CmaK); the elimination half-lives 4-16 hours postingestion (tin), and the areas under the [APAP] vs time curve (AUC) for ER APAP and IR APAP were compared using the paired t-test. Results: All the subjects completed both study phases. The mean APAP dose ingested was 5.6 g (range, g). Both the AUC and the C,, 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: Parameter (mean t SD) IR APAP ER APAP v-value % t t <O.OOOI 0.1Ooo Conclusion: 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. Key words: acetaminophen; pharmacokinetic; area under curve; serum levels; toxicity; poisoning. Acad. Emerg. Med. 1996; 3: From the Oregon Health Sciences University, Oregon Poison Center; Poriland. OR, Department of Emergency Medicine (DRD, JBS. MJS). Received: December 6, 1995; revision received: February 26, 1996; accepted: March 3, 1996; updated: March 20, Prior presentation: SAEM annual meeting, San Antonio, TX, May Address for correspondence and reprints: Martin J. Smilkstein. MD, Oregon Healrh Sciencer Vniversiv, Oregon Poison Centec CSB-550, 3181 SW Sam Jackson Park Road, Portland, OR Fax: : smilkste@ohsu.edu I Acetaminophen (APAP) continues to be the most common pharmaceutical agent involved in overdosage. In 1993, U.S. poison control centers received >100,000 calls following APAP exposures.' Until recently, all cases involved immediate-release APAP (IR APAP), and a well-established approach to screening these patients has been established. A single plasma APAP concentration ([APAP]), obtained 2 4 hours after ingestion, plotted on the APAP treatment nomogram has proven to be a sensitive method of screening for potential hepatotoxicity after acute overdose of IR APAP.2-6

2 Pharmacokinetic Comparison of Acetaminophen Products, Douglas et al In 1994, a new bilayered formulation of APAP, Tylenol Extended Relief (ER APAP), became available to the public. While regular-strength IR APAP contains 325 mg of APAP per tablet, a single bilayered caplet of ER APAP contains a total of 650 mg of APAP, with each layer containing 325 mg. The outermost layer is designed to immediately release APAP, while the innermost layer provides delayed APAP dissolution. The potential for altered pharmacokinetics with ER APAP. as compared with IR APAP, has raised the concern that the traditional screening approach may be inadequate. The only available guideline for screening after ER APAP overdose recommends that if an initial [APAP] 2 4 hours after ingestion is detectable, but below the lower nomogram treatment line, then a second [APAP] should be obtained 4-6 hours later. If this second [APAP] is still below the lower nomogram line, then treatment with n- acetylcysteine is not required. However, these guidelines have been based on unstudied assumptions. The objective of this study was to compare relevant pharmacokinetics of ER APAP with those of IR APAP after supratherapeutic doses to determine whether an alternative approach to managing overdoses of ER APAP is necessary. I METHODS Study Design This study was a prospective, randomized, doubleblind, crossover controlled comparison of the pharmacokinetics of ER APAP and IR MAP after each preparation was taken in supratherapeutic doses by healthy adult volunteers. The study protocol was approved by our institutional review board, and written informed consent was obtained from each subject. Setting and Population The study was conducted through the Clinical Research Center of the Oregon Health Sciences University between January and May The subjects consisted of 7 male and 7 female adult volunteers. Exclusion criteria included an allergy to APAP, current pregnancy, hepatic or renal disease, alcohol abuse, the use of any medication 24 hours prior to the study, and the chronic use of medications that affect the P-450 hepatic enzyme system (e.g., alcohol, carbamazepine, cimetidine, isoniazid, and phenobarbital), because the toxic metabolite of APAP is formed via the P-450 pathway. Experimental Protocol All female subjects underwent a urine &human chorionic gonadotropin (P-hCG) test prior to commencing each phase of the study. Following a 6-hour overnight fast, each subject began the first phase by ingesting a single oral dose of 75 mgkg of either ER APAP (Tylenol Extended Relief caplets, McNeil Consumer Products Co., Fort Washington, PA) or IR APAP (Tylenol 325-mg caplets, McNeil Consumer Products Co.) with 3 mug of tap water in a double-blind fashion. To use only intact, whole tablets, the final APAP dose was obtained by rounding either up or down to the multiple of 650 mg closest to 75 mgkg. No further oral intake was allowed for 6 hours after the APAP ingestion. Phase 2 of the study followed 1 week later, during which each subject ingested 75 mgkg of the other APAP preparation in the same manner and at the same time of day as before. Measurements The measured data consisted of 9 serial [APAP] values obtained 0.5, 1, 2, 3, 4, 6, 8, 12, and 16 hours after ingestion. Blood samples were drawn through an 18- gauge indwelling venous catheter, collected in additivefree red-top tubes, allowed to sit at room temperature for 1 hour, and then stored at 2-8 C. Within 24 hours of collection, [APAP] was determined for each blood sample using an ultraviolet spectrophotometric device (Beckman CX-7 multi-analyte random access analyzer, model #2600, Brea, CA). Data Analysis For each subject the following pharmacokinetic parameters were determined for both ER APAP and IR APAP: maximum measured [APAP] (C,,,), time to maximum measured [APAP] (T,,,,,), elimination half-life 4-16 hours postingestion (t,,2) using the formula ti12 = 0.693k (where k, is the first order rate constant), and the area under the drug concentration vs time curve (AUC) using the trapezoidal rule. Mean pharmacokinetic parameters were compared using a paired t-test, and statistical significance was defined as a p-value < The above computations were performed using SPSS/PC+ software (SPSS Inc., Chicago, IL). Post-hoc power analysis revealed that 10 subjects were necessary to detect a difference of 0.5 hour in the tli2 and a difference of 100 pg/ml/hr* in the AUC between ER APAP and IR APAP, with a power of I RESULTS... All 14 subjects completed both study phases. The mean age was 26 years (range, years) and the mean weight was 67.8 kg (range, kg). The mean... *The units of measure for [APAP] were left in pg/ml to be consistent with the units used in the nomogram. Usually, Academic Emergency Medicine prefers SI (SystPme International) units.

3 742 ACADEMIC EMERGENCY MEDICINE AUG 1996 VOL 3/NO 8 I TABLE 1 Summary of Pharmacokinetic Parameters*... Parameter (mean t SD) IR APAP ER APAP p-value Cm, (CLglmL) 100.2? t 16.8 < Tma, (hours) 0.9 t ? fjl2 (hours) 2.6? ? AUC (pg/ml/hr) * IR APAP = immediate-release acetaminophen; ER APAP = Tylenol Extended Relief; C., = the maximum acetaminophen concentration ([APAP]) value; T.,. = the time to maximum [APAP]; t,,? = the elimination half-life 4-16 hours postingestion; AUC = the area under the [APAP] vs time curve. APAP dose ingested was 5.6 g (range, g). This dose was generally well tolerated, with nausea reported for 3 subjects (21%) and light-headedness for 1 subject (7%). No ill effect was reported after completion of the study. The mean pharmacokinetic parameters for the 2 APAP preparations are shown in Table 1. Both the AUC and the, C, for ER APAP were less than that for IR APAP (p < and p = 0.02, respectively). For the remaining pharmacokinetic parameters, there was no statistically significant difference between the 2 preparations. When the mean [APAP] values for both ER APAP and IR APAP are plotted, ER APAP yielded a flatter, plateau-shaped curve before 4 hours (Figs. 1 and 2). After 4 hours postingestion, the 2 curves closely resembled one another. I DISCUSSION To determine whether an alternative management approach is required for acute ER APAP overdoses, one must first review and evaluate the current approach for IR APAP overdoses. Since its development in 1974,3 the APAP nomogram has been used in the management of hundreds of thousands of acute IR APAP overdoses. Despite the large number of cases (including many involving coingestants, little historical information, patients with alcoholism, and other high-risk groups), there have been surprisingly few anecdotal or published cases in which serious hepatotoxicity developed following an [APAP] below the lower nomogram treatment line. In a large national multicenter study, approximately 4% of n- acetylcysteine-treated subjects with [APAP] below the lower treatment line developed hepatotoxicity (aspartate aminotransferase or alanine aminotransferase > 1,000 IU/L).* It is unlikely that these patients were representative because they were all treated with n-acetylcysteine despite subtoxic [APAP], indicating that suspected erroneous histories or some other reasons for treatment were involved. There is only 1 reported case that we are aware of in the English literature of failure of the lower nomogram treatment line, and the validity of this case has been questi~ned.. ~ On the basis of information to date, it appears safe to conclude that the lower nomogram treatment line is adequately sensitive to detect the presence of potential risk for hepatotoxicity after an acute overdose of IR APAP. The next question is whether ER APAP s bilayered design alters the pharmacokinetics of APAP in such a way that the risk of hepatotoxicity is increased or in a way that would invalidate the APAP nomogram after an acute overdose. Critical to the development of hepatotoxicity is the amount of hepatic glutathione (GSH) available to detoxify the toxic metabolite formed after an overdose of APAP. Although not a direct measure of relative toxic metabolite formation or GSH depletion, comparison of pharmacokinetic parameters provides insight. An excessively high peak [APAP] or sustained [APAP] elevations, best demonstrated by C,,,, AUC, and tin, might reflect an increased risk of GSH depletion. In the current study, however, ER APAP had a lower C,,, and overall AUC and a similar tln as compared with IR APAP. On the basis of these data, despite its unique bilayered design, ER APAP would not be expected to increase the risk of hepatotoxicity (increase GSH depletion) beyond that of IR APAP when taken in similar doses. Based on this study, markedly delayed APAP absorption does not seem likely. In all cases, peak [APAP] values for ER APAP were reached before 4 hours (Table l), and after 4 hours, kinetics were nearly identical between the products (Figs. 1 and 2). Following acute ER APAP overdoses, 1 case series (n = 5) reported a mean tln of hours and no late [APAP] rise; there was 1 case with a delayed elimination phase. A controlled volunteer study cannot predict the range of variations in actual ER APAP-overdosed patients, but IR APAP is subject to wide variations as well. Massive ingestion, slowed absorption by coingested food or drug, and other factors are likely to be important. Thus far, 1 case of a late [APAP] rise after an acute ER APAP overdose has been described. This case involved a massive APAP ingestion (potentially g) as well as coingestion of dextromethorphan, doxylamine, and pseudoephedrine. l3 Other information must be considered to place these observations in context. ER APAP s bilayered design results in the release of 2 doses of IR APAP separated in time. An overdose of ER APAP, therefore, most closely resembles an overdose of IR APAP in which 22 doses of APAP are ingested within a few hours. Traditionally, such overdoses have been treated as a single ingestion, with the earliest time representing time zero. This represents a conservative approach because an [RPAP] obtained 4 hours from the earliest estimated time of ingestion may increase the likelihood of the [APAPI s ex-

4 Pharmacokinetic Comparison of Acetaminophen Products, Douglas et al. 743 ceeding the APAP nomogram treatment line. Although multiple ingestions of IR APAP within a few hours represent a common and well-represented occurrence in IR APAP experience, we are not aware of anecdotal or published reports of APAP nomogram failure to identify serious toxicity using this conservative approach. Thus, based on the lack of clinically significant pharmacokinetic differences between ER APAP and IR APAP, the conservative nature of the APAP nomogram, and the successful experience with the APAP nomogram after repeated short-term IR APAP ingestions, we believe that the standard approach (a single 4 hour or later [APAP] and the lower nomogram treatment line) may be safely used to determine risk of toxicity after most acute ingestions of ER APAP. However, as with any general management guideline, each case must be individualized. In light of early reports and until further data are available, clinical suspicion of unusual circumstances (massive ingestion, coingestants capable of slowing absorption, poor histories, etc.) should prompt longer observation and a second [APAP]. Furthermore, this approach cannot be generalized to chronic ingestion or future formulations, which may have entirely different pharmacokinetic profiles. Finally, as with IR APAP overdoses, if there is any doubt about the need for treatment, the better part of valor is to err on the side of treatment. I LIMITATIONS AND FUTURE QUESTIONS... This study has a few important limitations. First, although approximately 5 times the therapeutic APAP dose was given, it was still only about 75% of what is reported to be a minimum adult toxic dose.2 Second, unlike most overdoses, the subjects in this study fasted prior to ingesting APAP and thus this model was not complicated by the presence of coingestants or food in the gastrointestinal tract, which may interfere with the pharmacokinetic profile. Finally, measurement of toxic APAP metabolites was not performed, but instead a comparison of pharmacokinetic parameters between the 2 preparations was used as an indirect way of assessing potential differences in toxicity risk. The most obvious question that remains is whether the pharmacokinetic similarities of these 2 APAP preparations will hold true when an overdose involves toxic doses, coingestants, or recent food intake. Further studies may help answer this question (i.e., a large prospective/ clinical observational study or possibly a carefully modeled animal study). I CONCLUSION... Despite speculation that ER APAP pharmacokinetics would necessitate a new overdose treatment approach, L Hours Postingestion I FIGURE 1. Mean acetaminophen (APAP) concentration ([APAP]) vs time graph (SD represented by error bars). IR APAP = immediaterelease acetaminophen and ER APAP = Tylenol Extended Relief. n g 1000 \ u) - =L W 100 ER APAP r a n a Y 10 c m Z l.c u) -I 0 Hours Post ingestion I FIGURE 2. Log of mean acetaminophen (APAP) concentration ([APAP]) vs time graph (SD represented by error bars). IR APAP = immediate-release acetaminophen and ER APAP = Tylenol Extended Relief. our results do not indicate this. There is no evidence that, in most cases, delayed absorption or altered elimination of this product would lead to underdiagnosis using the traditional risk assessment methods (i.e., APAP nomogram). Recommendations to observe patients and obtain a second APAP concentration after several hours appear unwarranted. As for IR APAP (and with similar exceptions for unusual circumstances), a single APAP plasma concentration obtained after 4 hours or later and plotted on the APAP nomogram is adequate to assess the risk of hepatotoxicity and the need for antidotal treatment after an acute overdose with this formulation of ER APAP. Supported in part by PHS grant 5 M01 RR Dr. Smilkstein has received payment from McNeil Consumer Products for consultative services unrelated to this project. The current study was designed,

5 744 ACADEMIC EMERGENCY MEDICINE AUG 1996 VOL 3/NO 8 implemented, completed, analyzed. written. and edited without involvement from any representative of McNeil Consumer Products. Clay Mann. PhD, provided assistance with the statistical analysis. I REFERENCES I. Litovitz TL, Clark LR, Soloway RA annual report of the American Association of Poison Control Centers toxic exposure surveillance system. Am J Emerg Med. 1994; 12: Anker AL, Smilkstein MJ. Acetaminophen concepts and controversies. Emerg Med Clin North Am. 1994; 12: Rumack BH, Matthew H. Acetaminophen poisoning and toxicity. Pediatrics. 1974; 55: Rumack BH, Peterson RC, Koch GG. Amara IA. Acetaminophen overdose, 662 cases with evaluation of oral acetylcysteine treatment. Arch Intern Med. 1981; 141: Prescott LF. Paracetamol overdose, pharmacological considerations and clinical management. Drugs. 1983; 25: Smilkstein MJ, Knapp GL, Kulig KW, Rumack BH. Efficacy of oral n-acetylcysteine in the treatment of acetaminophen overdose, analysis of the National Multicenter Study ( ). N Engl J Med. 1988; 319: Temple AR. "Dear Doctor" letter. Fort Washington, PA: McNeil Consumer Products Company, Jan 3, Smilkstein MJ. Knapp GL, Kulig KW, Rumack BH. Acetaminophen overdose: do levels predict outcome [abstract]? Vet Hum Toxicol. 1987; 29: Cheung L, Potts RG, Meyer KC. Acetaminophen treatment nomogram [letter]. N Engl J Med. 1994; 330: Smilkstein MJ, Douglas DR, Daya MR. Acetaminophen poisoning and liver function [letter]. N Engl J Med. 1994; 331: Mitchell JR, Jollow DJ, Potter WZ, Gillette JR, Brodie BB. Acetaminophen-induced hepatic necrosis. IV. Protective role of glutathione. Pharmacol Exp Ther. 1973; 187: Cetaruk EW. Dart R, Horowitz RS, Hurlbut KM. Extended-relief acetaminophen overdose [letter]. JAMA. 1996; 275: Bizovi K. Keys N, Rivas J, Aks S, Gross R, Paloucek F. Tylenol@ ER, late rise in APAP level after overdose [abstract]. Clin Toxicol. 1995;