Olgotrelvir as a Single-Agent Treatment of Nonhospitalized Patients with Covid-19.

BACKGROUND: Olgotrelvir is an oral antiviral with dual mechanisms of action targeting severe acute respiratory syndrome coronavirus 2 main protease (i.e., Mpro) and human cathepsin L. It has potential to serve as a single-agent treatment of coronavirus disease 2019 (Covid-19). METHODS: We conducted a phase 3, double-blind, randomized, placebo-controlled trial to evaluate the efficacy and safety of olgotrelvir in 1212 nonhospitalized adult participants with mild to moderate Covid-19, irrespective of risk factors, who were randomly assigned to receive orally either 600 mg of olgotrelvir or placebo twice daily for 5 days. The primary and key secondary end points were time to sustained recovery of a panel of 11 Covid-19-related symptoms and the viral ribonucleic acid (RNA) load. The safety end point was incidence of treatment-emergent adverse events. RESULTS: The baseline characteristics of 1212 participants were similar in the two groups. In the modified intention-to-treat population (567 patients in the placebo group and 558 in the olgotrelvir group), the median time to symptom recovery was 205 hours in the olgotrelvir group versus 264 hours in the placebo group (hazard ratio, 1.29; 95% confidence interval [CI], 1.13 to 1.46; P<0.001). The least squares mean (95% CI) changes of viral RNA load from baseline were -2.20 (-2.59 to -1.81) log10 copies/ml in olgotrelvir-treated participants and -1.40 (-1.79 to -1.01) in participants receiving placebo at day 4. Skin rash (3.3%) and nausea (1.5%) were more frequent in the olgotrelvir group than in the placebo group; there were no treatment-related serious adverse events, and no deaths were reported. CONCLUSIONS: Olgotrelvir as a single-agent treatment significantly improved symptom recovery. Adverse effects were not dose limiting. (Funded by Sorrento Therapeutics, a parent company of ACEA Therapeutics; ClinicalTrials.gov number, NCT05716425.).

Dose safety and pharmacodynamics of subcutaneous bupivacaine in a novel extended-release microparticle formulation: A phase 1, dose-ascending study in male volunteers.

A novel microparticle-based extended-release local anaesthetic containing a bupivacaine/poly-lactic-co-glycolic acid (PLGA; LIQ865A) or plain bupivacaine (LIQ865B) was examined in a first-in-human trial. The objectives were to examine the dose safety/tolerability and pharmacodynamics. Randomized subcutaneous injections of LIQ865A (n = 16) or LIQ865B (n = 12) and diluent, contralaterally, were administered in a dose-ascending manner (150- to 600-mg bupivacaine). Subjects were admitted 24 h post-injection and followed for 30 days post-injection. The risk ratios (RRs; 95% CI) of erythematous reactions for LIQ865A versus diluent was 9.00 (1.81-52.23; P = 0.006) and for LIQ865B versus diluent 2.50 (0.69-9.94; P = 0.37). The RR for the development of hematomas (LIQ865A versus diluent) were 3.25 (1.52-8.16; P = 0.004) and 4.00 (0.72-24.89; P = 0.32) (LIQ865B versus diluent). Subcutaneous indurations persisting for 4-13 weeks were seen in 6/16 subjects receiving LIQ865A. One subject receiving LIQ865A (600-mg bupivacaine) developed intermittent central nervous system (CNS) symptoms of local anaesthetic systemic toxicity (85 min to 51 h post-injection) coinciding with plasma peak bupivacaine concentrations (490-533 ng/ml). Both LIQ865 formulations demonstrated dose-dependent hypoesthesia and hypoalgesia. The duration of analgesia ranged between 37 and 86 h. The overall number of local adverse events, however, prohibits clinical application without further pharmacological modifications.

Population pharmacokinetic-pharmacodynamic model of subcutaneous bupivacaine in a novel extended-release microparticle formulation.

The objective of this study was to develop a population pharmacokinetic-pharmacodynamic model of subcutaneously administered bupivacaine in a novel extended-release microparticle formulation for postoperative pain management. Bupivacaine was administered subcutaneously in the lower leg to 28 healthy male subjects in doses from 150 to 600 mg in a phase 1 randomized, placebo-controlled, double-blind, dose-ascending study with two different microparticle formulations, LIQ865A and LIQ865B. Warmth detection threshold was used as a surrogate pharmacodynamic endpoint. Population pharmacokinetic-pharmacodynamic models were fitted to plasma concentration-effect-time data using non-linear mixed-effects modelling. The pharmacokinetics were best described by a two-compartment model with biphasic absorption as two parallel absorption processes: a fast, zero-order process and a slower, first-order process with two transit compartments. The slow absorption process was found to be dose-dependent and rate-limiting for elimination at higher doses. Apparent bupivacaine clearance and the transit rate constant describing the slow absorption process both appeared to decrease with increasing doses following a power function with a shared covariate effect. The pharmacokinetic-pharmacodynamic relationship between plasma concentrations and effect was best described by a linear function. This model gives new insight into the pharmacokinetics and pharmacodynamics of microparticle formulations of bupivacaine and the biphasic absorption seen for several local anaesthetics.

Olgotrelvir, a dual inhibitor of SARS-CoV-2 Mpro and cathepsin L, as a standalone antiviral oral intervention candidate for COVID-19.

BACKGROUND: Oral antiviral drugs with improved antiviral potency and safety are needed to address current challenges in clinical practice for treatment of COVID-19, including the risks of rebound, drug-drug interactions, and emerging resistance. METHODS: Olgotrelvir (STI-1558) is designed as a next-generation antiviral targeting the SARS-CoV-2 main protease (Mpro), an essential enzyme for SARS-CoV-2 replication, and human cathepsin L (CTSL), a key enzyme for SARS-CoV-2 entry into host cells. FINDINGS: Olgotrelvir is a highly bioavailable oral prodrug that is converted in plasma to its active form, AC1115. The dual mechanism of action of olgotrelvir and AC1115 was confirmed by enzyme activity inhibition assays and co-crystal structures of AC1115 with SARS-CoV-2 Mpro and human CTSL. AC1115 displayed antiviral activity by inhibiting replication of all tested SARS-CoV-2 variants in cell culture systems. Olgotrelvir also inhibited viral entry into cells using SARS-CoV-2 Spike-mediated pseudotypes by inhibition of host CTSL. In the K18-hACE2 transgenic mouse model of SARS-CoV-2-mediated disease, olgotrelvir significantly reduced the virus load in the lungs, prevented body weight loss, and reduced cytokine release and lung pathologies. Olgotrelvir demonstrated potent activity against the nirmatrelvir-resistant Mpro E166 mutants. Olgotrelvir showed enhanced oral bioavailability in animal models and in humans with significant plasma exposure without ritonavir. In phase I studies (ClinicalTrials.gov: NCT05364840 and NCT05523739), olgotrelvir demonstrated a favorable safety profile and antiviral activity. CONCLUSIONS: Olgotrelvir is an oral inhibitor targeting Mpro and CTSL with high antiviral activity and plasma exposure and is a standalone treatment candidate for COVID-19. FUNDING: Funded by Sorrento Therapeutics.

Research design considerations for single-dose analgesic clinical trials in acute pain: IMMPACT recommendations.

This article summarizes the results of a meeting convened by the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) on key considerations and best practices governing the design of acute pain clinical trials. We discuss the role of early phase clinical trials, including pharmacokinetic-pharmacodynamic (PK-PD) trials, and the value of including both placebo and active standards of comparison in acute pain trials. This article focuses on single-dose and short-duration trials with emphasis on the perioperative and study design factors that influence assay sensitivity. Recommendations are presented on assessment measures, study designs, and operational factors. Although most of the methodological advances have come from studies of postoperative pain after dental impaction, bunionectomy, and other surgeries, the design considerations discussed are applicable to many other acute pain studies conducted in different settings.

IV acetaminophen: Efficacy of a single dose for postoperative pain after hip arthroplasty: subset data analysis of 2 unpublished randomized clinical trials.

Inadequate control of postoperative pain after orthopedic procedures may trigger complications that increase morbidity. Multimodal analgesia is used to manage pain effectively after surgical procedures and reduce the need for rescue analgesia. Intravenous (IV) acetaminophen (OFIRMEV; Cadence Pharmaceuticals, Inc.), an analgesic that has been studied and used in the multimodal management of acute pain after major orthopedic procedures, combines the safety seen with oral and rectal formulations with a preferred route of administration. Two double-blind, randomized, placebo-controlled clinical trials were conducted (total 130 patients) to determine the efficacy and safety of single-dose IV acetaminophen in patients following total hip arthroplasty. Although both studies were stopped prematurely, overlap in patient populations, study design, and methodologies in the single-dose phase of these studies allowed for analysis of their results to be presented concurrently. Both trials demonstrated IV acetaminophen having greater efficacy than placebo in terms of primary endpoints [pain intensity differences from T0.5 to T3 (P < 0.05 in both studies)]. The use of IV acetaminophen also reduced the need for rescue opioid consumption, with patients receiving IV acetaminophen consuming, on average, less than half the amount of rescue medication as those receiving placebo. IV acetaminophen was effective in treating moderate-to-severe pain after total hip arthroplasty and reduced the need for rescue opioid consumption.

Novel delivery systems for postoperative analgesia.

Moderate-to-severe postoperative pain is usually controlled using a multimodal approach, including opioids. Intravenously administered patient-controlled analgesia (IV PCA) with opioids, popular for over 40 years, enables patients to control their level of analgesia and has advantages over a nurse-administered approach, including more satisfied patients and improved pain relief. Unfortunately, IV PCA has drawbacks such as device programming errors, medication prescribing errors, pump malfunction, limitations on patient mobility, IV patency issues, and transmission of infection. Furthermore, the setup of an infusion pump is often complex, time-consuming, and requires witnessed confirmation. Complicating IV PCA is the problem of commonly used compounds, morphine and hydromorphone, having significantly reduced brain/effector-site permeability and active metabolites, both of which create the risk of delayed adverse events. Novel patient-controlled modalities that incorporate rapid effector site-permeating opioids and non-invasive routes of administration offer great promise to enhance both patient and caregiver experiences with postoperative analgesia systems.

Confusion: acetaminophen dosing changes based on NO evidence in adults.

Acetaminophen (paracetamol) plays a vital role in American health care, with in excess of 25 billion doses being used annually as a nonprescription medication. Over 200 million acetaminophen-containing prescriptions, usually in combination with an opioid, are dispensed annually. While acetaminophen is recognized as a safe and effective analgesic and antipyretic, it is also associated with significant morbidity and mortality (hepatotoxicity) if doses in excess of the therapeutic amount are ingested inappropriately. The maximum daily therapeutic dose of 3900-4000 mg was established in separate actions in 1977 and 1988, respectively, via the Food and Drug Administration (FDA) monograph process for nonprescription medications. The FDA has conducted multiple advisory committee meetings to evaluate acetaminophen and its safety profile, and has suggested (but not mandated) a reduction in the maximum daily dosage from 3900-4000 mg to 3000-3250 mg. In 2011, McNeil, the producer of the Tylenol® brand of acetaminophen, voluntarily reduced the maximum daily dose of its 500 mg tablet product to 3000 mg/day, and it has pledged to change the labeling of its 325 mg/tablet product to reflect a maximum of 3250 mg/day. Generic manufacturers have not changed their dosing regimens and they have remained consistent with the established monograph dose. Therefore, confusion will be inevitable as both consumers and health care professionals try to determine the proper therapeutic dose of acetaminophen. Which is the correct dose of acetaminophen: 3000 mg if 500 mg tablets are used, 3250 mg with 325 mg tablets, or 3900 mg when 650 mg arthritis-strength products are used?

Plasma and cerebrospinal fluid pharmacokinetic parameters after single-dose administration of intravenous, oral, or rectal acetaminophen.

BACKGROUND: This is the first study to compare plasma and cerebrospinal fluid (CSF) pharmacokinetics of intravenous (IV), oral (PO), or rectal (PR) formulations of acetaminophen. METHODS: Healthy male subjects (N = 6) were randomized to receive a single dose of IV (OFIRMEV(®) ; Cadence) 1,000 mg (15 minute infusion), PO (2 Tylenol(®) 500 mg caplets; McNeil Consumer Healthcare), or PR acetaminophen (2 Feverall(®) 650 mg suppositories; Actavis) with a 1-day washout period between doses. The 1,300 mg PR concentrations were standardized to 1,000 mg. Acetaminophen plasma and CSF levels were obtained at T0, 0.25, 0.5, 0.75, 1, 2, 3, 4, and 6 hours. RESULTS: IV acetaminophen showed earlier and higher plasma and CSF levels compared with PO or PR administration. CSF bioavailability over 6 hours (AUC(0-6)) for IV, PO, and PR 1 g was 24.9, 14.2, and 10.3 µg·h/mL, respectively. No treatment-related adverse events were reported. One subject was replaced because of premature failure of his lumbar spinal catheter. The mean CSF level in the IV group was similar to plasma from 3 to 4 hours and higher from 4 hours on. Absorption phase, variability in plasma, and CSF were greater in PO and PR groups than variability with IV administration. CONCLUSIONS: These results demonstrate that earlier and greater CSF penetration occurs as a result of the earlier and higher plasma peak with IV administration compared with PO or PR.

Safety and efficacy of intravenous acetaminophen in the elderly after major orthopedic surgery: subset data analysis from 3, randomized, placebo-controlled trials.

As the number of patients aged 65 years and older increases, joint replacement has become a frequent procedure after progressive osteoarthritis or fractures. Although hip and knee arthroplasty has become a relatively commonplace procedure in this age-group, the advanced age in patients undergoing these procedures often is associated with comorbidities and potential complications that can present challenges and limit analgesic choices. This subset analysis is designed to determine the efficacy and safety of intravenous (IV) acetaminophen in the elderly subpopulation from 3 placebo-controlled studies conducted to document the safety and efficacy of IV acetaminophen. A total of 231 patients were enrolled in the 3 trials, and of these, a total of 107 patients (46%) were aged 65 years or older. Across the studies, safety and efficacy were well documented in the elderly subpopulation and were comparable with the subpopulation younger than 65 years. A review of the literature similarly demonstrates the efficacy and safety of IV acetaminophen used for postoperative analgesia after joint replacement.

Intravenous acetaminophen for pain after major orthopedic surgery: an expanded analysis.

BACKGROUND AND METHODS: From the time that Sinatra et al. (Anesthesiology. 2005;102:822) was published to FDA apaproval of intravenous (IV) acetaminophen, an expanded analysis of the original raw study data became necessary for the regulatory submission. The following analyses were conducted: (1) sum of pain intensity differences over 24 hours (SPID24) using currently accepted imputation methods to account for both missing data and the effects of rescue; (2) efficacy results after the first 6 hours; (3) effects of gender, race/ethnicity, age, weight, surgical site, ASA Class, and serotonin antagonists; and (4) a stepwise regression analysis of why adverse events of nausea and vomiting were numerically (although not statistically) higher in the IV acetaminophen group compared with placebo. RESULTS: Sum of pain intensity differences over 24 hours using a 0- to 100-mm visual analog scale was statistically significantly (P < 0.001) in favor of IV acetaminophen (n = 49) compared with placebo (n = 52). Time to rescue was found to be 3.9 and 2.1 hours, respectively, for total hip and knee arthroplasty compared with 0.8 hours for the placebo group. Rescue medication consumption, requests, and actual administration were all significantly lower in the IV acetaminophen group compared with placebo for each dosing interval, except in the 6- to 12-hours interval where a numerical trend was observed. Analysis of various subset variables demonstrated similar efficacy for each variable. A stepwise regression analysis demonstrated that AE reports of nausea and vomiting were most likely due to prerandomization events, particularly opioid consumption and presence of nausea prior to randomization. CONCLUSION: Repeated-dose 24-hours end points were found to be as robust as previously published results. IV acetaminophen efficacy and safety appeared to be unaffected by specific subset variables.▪

A randomized study of the efficacy and safety of intravenous acetaminophen compared to oral acetaminophen for the treatment of fever.

OBJECTIVES: The purpose of this study was to assess the safety and dynamics of the onset of antipyretic efficacy of intravenous (IV) acetaminophen versus oral (PO) acetaminophen in the treatment of endotoxin-induced fever. METHODS: This randomized, double-blind, double-dummy, single-dose study was conducted at a single center in the United States in healthy volunteer adult males with an endotoxin-induced fever to assess the antipyretic efficacy and safety of IV acetaminophen 1 g versus PO acetaminophen 1 g over 6 hours. Subjects who achieved a sufficient fever response to a test dose of reference standard endotoxin were randomly assigned to receive either IV acetaminophen and PO placebo (n = 54) or PO acetaminophen and IV placebo (n = 51). The primary efficacy outcome was the weighted sum of temperature differences from baseline at time T0 through T120 minutes. Safety evaluations included adverse event (AE), physical exam, and laboratory assessments. RESULTS: Of 105 subjects receiving study medication, 24 vomited within 2 hours postdose (PO acetaminophen, n = 15; and IV acetaminophen, n = 9) and were excluded from the modified intent-to-treat population that consisted of 36 and 45 subjects treated with PO and IV acetaminophen, respectively. While this was done to not confer an advantage to the IV formulation, a sensitivity analysis including these subjects did not change the overall efficacy results. Statistically significant results favoring IV acetaminophen were observed for the primary endpoint (weighted sum of temperature differences over 120 minutes, p = 0.0039) and also at each time point from T30 to T90 minutes, although the maximum mean observed temperature difference was only 0.3°C. The study drugs were well tolerated. The AE frequency was comparable between the IV and PO groups. CONCLUSIONS: A single dose of IV acetaminophen is as safe and effective in reducing endotoxin-induced fever as PO acetaminophen. IV acetaminophen may be useful where patients are unable to tolerate PO intake or when an earlier onset of action is desirable.

Safety and population pharmacokinetic analysis of intravenous acetaminophen in neonates, infants, children, and adolescents with pain or Fever.

OBJECTIVES: The administration of acetaminophen via the oral and rectal routes may be contraindicated in specific clinical settings. Intravenous administration provides an alternative route for fever reduction and analgesia. This phase 1 study of intravenous acetaminophen (Ofirmev, Cadence Pharmaceuticals, Inc., San Diego, CA) in inpatient pediatric patients with pain or fever requiring intravenous therapy was designed to assess the safety and pharmacokinetics of repeated doses over 48 hours. METHODS: Neonates (full-term to 28 days) received either 12.5 mg/kg every 6 hours or 15 mg/kg every 8 hours. Infants (29 days to <2 years), children (2 to <12 years) and adolescents (≥12 years) received either 12.5 mg/kg every 4 hours or 15 mg/kg every 6 hours. Both noncompartmental and population nonlinear mixed-effects modeling approaches were used. Urinary metabolite data were analyzed, and safety and tolerability were assessed. RESULTS: Pharmacokinetic parameters of acetaminophen were estimated using a two-compartment disposition model with weight allometrically expressed on clearances and central and peripheral volumes of distribution (Vds). Postnatal age, with a maturation function, was a significant covariate on clearance. Total systemic normalized clearance was 18.4 L/hr per 70 kg, with a plateau reached at approximately 2 years. Total central and peripheral Vds of acetaminophen were 16 and 59.5 L/70 kg, respectively. The drug was well tolerated based on the incidence of adverse events. The primary and minor pathways of elimination were acetaminophen glucuronidation, sulfation, and glutathione conjugate metabolites across all age groups. CONCLUSIONS: Intravenous acetaminophen in infants, children, and adolescents was well tolerated and achieved plasma concentrations similar to those achieved with labeled 15 mg/kg body weight doses by oral or rectal administration.

A literature review of randomized clinical trials of intravenous acetaminophen (paracetamol) for acute postoperative pain.

INTRODUCTION: This study's objective was to systematically review the literature to assess analgesic outcomes of intravenous (IV) acetaminophen for acute postoperative pain in adults. METHODS: We searched Medline and the Cochrane library (January 1, 2000 to January 17, 2010, date of last search) for prospective, randomized, controlled trials (RCTs) of IV acetaminophen vs. either an active comparator or placebo. RESULTS: Sixteen articles from 9 countries published between 2005 and 2010 met inclusion criteria and had a total of 1,464 patients. Median sample size=54 patients (range 25 to 165) and median follow-up=1 day (range 1 hour to 7 days). Four of the 16 articles had 3 arms in the study. One article had 4 arms. As a result, 22 study comparisons were analyzed: IV acetaminophen to an active comparator (n=8 studies) and IV acetaminophen to placebo (n=14 studies). The RCTs were of high methodological quality with Jadad median score=5. In 7 of 8 active comparator studies (IV parecoxib [n=3 studies], IV metamizol [n=4], oral ibuprofen [n=1]), IV acetaminophen had similar analgesic outcomes as the active comparator. Twelve of the 14 placebo studies found that IV acetaminophen patients had improved analgesia. Ten of those 14 studies reported less opioid consumption, a lower percentage of patients rescuing, or a longer time to first rescue with IV acetaminophen. Formal meta-analysis pooling was not performed because the studies had different primary end points, and the IV acetaminophen dosing regimens varied in dose, and duration and timing. CONCLUSION: In aggregate, these data indicate that IV acetaminophen is an effective analgesic across a variety of surgical procedures.

Safety of multiple-dose intravenous acetaminophen in adult inpatients.

BACKGROUND: Intravenous (IV) acetaminophen provides rapid and effective analgesia in the postoperative and inpatient settings. The utility and efficacy of acetaminophen is well established; however, due to chronic excessive dosing of over-the-counter acetaminophen products and prescription opioid combination products resulting in the potential for hepatic toxicity, concerns remain about acetaminophen safety. In order to evaluate the safety of IV acetaminophen 1,000mg q6h or 650mg q4h with repeated dosing for 5 days, a randomized, open-label study assessed the safety and tolerability of repeated doses used to treat acute pain or fever in 213 adult inpatients was conducted. METHODS: Subjects were randomized (3:3:1) to receive IV acetaminophen (1,000mg q6h or 650mg q4h) or standard-of-care treatment for pain or fever. Safety was assessed according to spontaneous reports of adverse events (AEs) and clinically meaningful changes from baseline laboratory parameters. RESULTS: Overall, IV acetaminophen was shown to be safe and well tolerated in adult inpatients when given as repeated doses for up to 5 days. Owing to the comorbidities in the study population, the frequency of AEs reported was high. However, the majority of treatment-emergent adverse events (TEAEs) were unrelated to treatment, and only 8% of the study population withdrew because of TEAEs. No major hepatic issues associated with IV acetaminophen warranted concern, and most hepatic events were likely related to underlying medical conditions or recent trauma/surgery. CONCLUSIONS: Consistent with the tolerability and safety results, both treatment groups (1,000mg q6h and 650mg q4h) demonstrated statistically significantly better ratings for the Subject Global Evaluations for the level of satisfaction with side effects related to study treatments as compared with the control group. The findings from this trial support the use of IV acetaminophen as a safe therapy in adult patients.

Childhood asthma and use during pregnancy of acetaminophen. A critical review.

The possible association between acetaminophen use during pregnancy and childhood asthma has been a subject of interest based on the theory that acetaminophen metabolism may deplete glutathione in the developing lung, leading to oxidative damage and inflammation. Epidemiology studies from eight centers have reported conflicting results. In some cases, end points of these studies have included wheezing in very young children, which is a poor predictor of asthma. Other study problems have included the common use of acetaminophen as the analgesic and antipyretic of choice during pregnancy. Because acetaminophen use may be a marker for infectious or inflammatory disorders, the results of the epidemiology studies may be influenced by confounding by indication. A placebo-controlled randomized trial of acetaminophen use during pregnancy would be helpful in resolving the question of whether acetaminophen use causes childhood asthma. At present, the evidence is inconclusive that any such association is causal.

A review of the literature on the effects of acetaminophen on pregnancy outcome.

Acetaminophen is commonly used during pregnancy. Experimental animal studies do not suggest increased malformations after therapeutic use of single-ingredient acetaminophen during pregnancy. Cohort studies in humans in which exposure is prospectively ascertained show no detectable increase in congenital malformation risk associated with single-ingredient acetaminophen use during pregnancy. A case-control study identified an association between acetaminophen use during pregnancy and risk of gastroschisis in the offspring, but the study was limited by recall bias, unblinded interviewers, possible misclassification of gastroschisis, confounding by indication, difficulty in separating out the effects of combination products, and possible selection bias. Two case-control studies failed to identify a statistically significant association between acetaminophen use during pregnancy and gastroschisis. No other malformation has been shown to be causally associated with single-ingredient acetaminophen. A reported association between pre-eclampsia, preterm birth, and acetaminophen may be explained by reverse causation. Concerns expressed about childhood asthma and prenatal acetaminophen use has been addressed in a separate review. The use of single-ingredient acetaminophen during pregnancy can be justified based on outcome data. Data on the effects of acetaminophen cannot necessarily be extended to acetaminophen combination products.

A randomized, double-blind, placebo-controlled, multicenter, repeat-dose study of two intravenous acetaminophen dosing regimens for the treatment of pain after abdominal laparoscopic surgery.

BACKGROUND: Intravenous acetaminophen has been approved in Europe and elsewhere for the treatment of acute pain and fever, and was recently approved by the US Food and Drug Administration (FDA) for the management of mild to moderate pain, the management of moderate to severe pain with adjunctive opioid analgesics, and the reduction of fever. OBJECTIVE: The aim of this work was to evaluate the analgesic efficacy and safety of repeated doses of 2 dosing regimens of intravenous acetaminophen compared with placebo over 24 hours in subjects with moderate to severe pain after abdominal laparoscopic surgery. METHODS: This double-blind, placebo-controlled, parallel-group study was conducted at 17 sites in the United States and enrolled adult subjects (aged 18-80 years) who were randomized to 4 groups (IV acetaminophen 1000 mg [100 mL] q6h; IV acetaminophen 650 mg [65 mL] q4h; IV placebo 100 mL q6h; or IV placebo 65 mL q4h), each given as a 15-minute infusion after surgery for 24 hours. An open-label extension was offered to all subjects who remained in the hospital beyond the study period. Two subjects (1 in the placebo 100 mL q6h group and 1 in the IV acetaminophen 1000 mg q6h group) were enrolled in the open-label extension and were eligible to receive unblinded IV acetaminophen 1000 mg. Before randomization, the choice of opioid for patient-controlled analgesia (PCA) rescue was left to the investigator; however, acetaminophen-containing products, NSAIDs, and aspirin were not allowed. The morning after abdominal laparoscopic surgery procedure, subjects' PCA was withheld until pain intensity (PI) was moderate (2) or severe (3) on a categorical scale (range, 0-3) and between 40 and 70 mm, inclusive, on a 100-mm visual analog scale, at which point they were randomized. After the first dose of study medication, intravenous rescue was restricted to morphine or hydromorphone, and oral rescue was restricted to morphine or oxycodone immediate-release tablets. Efficacy analyses were performed using the modified intent-to-treat (mITT) population, defined as all randomized subjects who received ≥ 1 complete dose of study medication before requesting rescue medication, and who had ≥ 1 completed PI/pain relief (PR) assessment after baseline. The primary efficacy end point was the weighted sum of PI differences over 24 hours (SPID24) using an ANCOVA model. Time to meaningful PR was documented after the first dose of study medication using a double-stopwatch method: at T0, 2 stopwatches were started, and subjects were instructed to stop the first stopwatch when they felt perceptible PR and the second when it became meaningful. Safety was assessed via spontaneous adverse event (AE) reporting and laboratory tests. RESULTS: A total of 349 subjects were screened before elective surgery for eligibility. Of these, 244 subjects were randomized to a study arm (IV acetaminophen 1000 mg [n = 92]; IV acetaminophen 650 mg [n = 42]; IV placebo 100 mL [n = 43]; or IV placebo 65 mL [n = 67]) and included in the ITT population, of whom 81.1% (198/244) were women and 87.3% (213/244) were white; the mean (SD) age was 46.2 (12.51) years (range, 18-78 years), and the mean weight was 174.3 (35.7) lb (range, 103-284 lb). There was an allocation error in the contract research organization's program linking group assignment and kit randomization; therefore, the original randomization procedure was replaced with a modified randomization schedule created by an independent biostatistician under the supervision of the FDA. The mITT population included 241 subjects; of these, 227 completed 24 hours of treatment. Four subjects withdrew before completing treatment because of AEs (1 subject in the placebo group because of fever and 3 in the IV acetaminophen 1000 mg q6h group because of infusion-site pain [n = 1] or infiltration [n = 2]), 8 because of withdrawal of consent, 2 because of early discharge from the hospital, and 2 for other reasons. Only 2 subjects participated in the elective open-label extension. Both intravenous acetaminophen dosing regimens were associated with significantly reduced SPID24 compared with placebo (1000 mg q6h, P < 0.007; 650 mg q4h, P < 0.019). Among the mITT population, SPID24 (using nonimputed data after first rescue: 1000 mg q6h, P < 0.001; 650 mg q4h, P = 0.020), sum of PR scores over 24 hours (1000 mg q6h, P < 0.001; 650 mg q4h, P = 0.003) and 12 hours (1000 mg q6h, P < 0.001; 650 mg q4h, P = 0.001), and subjects' global evaluations at 24 hours (1000 mg q6h, P < 0.001; 650 mg q4h, P = 0.005) were statistically significant in favor of both acetaminophen dosing regimens compared with the combined placebo group. Time to meaningful PR (by double stopwatch method) after the first dose was significantly shorter among subjects who received IV acetaminophen 1000 mg compared with subjects in the placebo 100 mL group (median of 24.9 vs 53.9 minutes, respectively). The most common overall AEs (ie, those that occurred in >10% of any group) were constipation, flatulence, nausea, and headache. The frequency of treatment-emergent AEs (TEAEs) across the treatment groups was not statistically significant. Most TEAEs were deemed to be unrelated to study medication. There were 6 subjects with serious TEAEs (1 [0.9%] in the IV acetaminophen 1000 mg group, 3 [7.0%] in the IV acetaminophen 650 mg group, and 2 [1.8%] in the placebo group). There was 1 (2.3%) related hepatic TEAE (transaminase increased) in the placebo group. CONCLUSION: Both regimens of intravenous acetaminophen (1000 mg q6h and 650 mg q4h) were associated with statistically significant analgesic efficacy compared with placebo and were well tolerated in these adults after abdominal laparoscopic surgery. ClinicalTrials.gov identifier: NCT00564486.