SummaryObjectivePerampanel, a selective, noncompetitive α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA) glutamate receptor antagonist, is indicated for adjunctive treatment of partial seizures in patients ≥12 years based on three phase III clinical studies. The perampanel U.S. Prescribing Information includes a boxed warning for serious psychiatric and behavioral adverse reactions. To provide context for this warning, detail on psychiatric and behavioral safety data from perampanel clinical studies is presented.MethodsAn analysis of pooled safety data from three phase III studies in patients with partial seizures is presented. Data from phase I and phase II studies in patients with and without epilepsy were also analyzed. Psychiatric and behavioral treatment‐emergent adverse events (TEAEs) were evaluated according to Medical Dictionary for Regulatory Activities (MedDRA) terms, using “narrow” and “narrow‐and‐broad” standardized MedDRA queries (SMQs) for TEAEs suggestive of hostility/aggression.ResultsFrom the three phase III partial‐seizure studies, the overall rate of psychiatric TEAEs was higher in the 8 mg (17.2%) and 12 mg (22.4%) perampanel groups versus placebo (12.4%). In the “narrow” SMQ, hostility/aggression TEAEs were observed in 2.8% for 8 mg and 6.3% for 12 mg perampanel groups, versus 0.7% of placebo patients. “Narrow‐and‐broad” SMQs for hostility/aggression TEAE rates were 12.3% for 8 mg and 20.4% for 12 mg perampanel groups, versus 5.7% for placebo; rates for events resulting in discontinuation were perampanel = 1.6% versus placebo = 0.7%. For events reported as serious AEs (SAEs), rates were perampanel = 0.7% versus placebo = 0.2%. In nonepilepsy patients, psychiatric TEAEs were similar between patients receiving perampanel and placebo. In phase I subjects/volunteers, all psychiatric TEAEs were mild or moderate. These analyses suggest that psychiatric adverse effects are associated with use of perampanel.SignificancePatients and caregivers should be counseled regarding the potential risk of psychiatric and behavioral events with perampanel in patients with partial seizures; patients should be monitored for these events during treatment, especially during titration and at higher doses.
clinicaltrials.gov Identifiers: Study 304: NCT00699972; 305: NCT00699582; 306: NCT00700310; Study 307: NCT00735397.
Objective:Evaluate the impact of concomitant enzyme (CYP3A4)-inducer antiepileptic drugs (EIAEDs) on the efficacy and safety of perampanel in patients from the 3 phase-III clinical trials.Methods:Patients with pharmacoresistant partial-onset seizures in the 3 phase-III clinical studies were aged 12 years and older and receiving 1 to 3 concomitant antiepileptic drugs. Following 6-week baseline, patients were randomized to once-daily, double-blind treatment with placebo or perampanel 8 or 12 mg (studies 304 and 305) or placebo or perampanel 2, 4, or 8 mg (study 306).Results:Treatment response assessed by median percent reduction in seizure frequency and responder rates improved with perampanel compared with placebo. However, at 8 and 12 mg, the treatment response was significantly greater in patients receiving non-EIAEDs. The treatment effect (perampanel–placebo) also demonstrated a dose-dependent increase in all patients. The overall incidence of treatment-emergent adverse events was similar regardless of the presence of EIAEDs. Occurrence of some adverse events, such as fatigue, somnolence, dizziness, irritability, was greater in patients receiving non-EIAEDs, as was discontinuation because of adverse events.Conclusions:Perampanel shows efficacy and safety in the presence and absence of EIAEDs. As systemic exposure to perampanel increases, so does efficacy. Given the extensive metabolism of perampanel, systemic exposure is clearly reduced with concomitant administration of CYP3A4 inducers. This supports the strategy of dosing perampanel to clinical effect. Recognition of these pharmacokinetic interactions will be important in the optimization of this novel medication.Classification of evidence:This study provides Class II evidence that 2 to 12 mg/d doses of perampanel reduced seizure frequency and improved responder rate in the presence and absence of EIAEDs.
This pooled analysis of the phase III BLOOM and BLOSSOM trials shows that lorcaserin 10 mg twice daily, in combination with diet and exercise, is safe and tolerable, and is associated with statistically significant weight loss and clinically relevant improvements in cardiometabolic parameters.
Objective Opioid analgesics are a mainstay for acute pain management, but postoperative opioid administration has risks. We examined the prevalence, risk factors, and consequences of opioid-related adverse drug events (ORADEs) in a previously opioid-free surgical population. Methods A retrospective, observational, cohort study using administrative, billing, clinical, and medication administration data from two hospitals. Data were collected for all adult patients who were opioid-free at admission, underwent surgery between October 1, 2015, and September 30, 2016, and received postoperative opioids. Potential ORADEs were determined based on inpatient billing codes or postoperative administration of naloxone. We determined independent predictors of ORADE development using multivariable logistic regression. We measured adjusted inpatient mortality, hospital costs, length of hospital stay, discharge destination, and readmission within 30 days for patients with and without ORADEs. Results Among 13,389 hospitalizations where opioid-free patients had a single qualifying surgery, 12,218 (91%) received postoperative opioids and comprised the study cohort. Of these, we identified 1111 (9.1%) with a potential ORADE. Independent predictors of ORADEs included older age, several markers of disease severity, longer surgeries, and concurrent benzodiazepine use. Opioid-related adverse drug events were strongly associated with the route and duration of opioids administered postoperatively: 18% increased odds per day on intravenous opioids. In analyses adjusted for several covariates, presence of an ORADE was associated with 32% higher costs of hospitalization, 45% longer postoperative length of stay, 36% lower odds of discharge home, and 2.2 times the odds of death. Conclusions We demonstrate a high rate and severe consequences of potential ORADEs in previously opioid-free patients receiving postoperative opioids. Knowledge of risk factors and predictors of ORADEs can help develop targeted interventions to minimize the development of these potentially dangerous and costly events.
ç ois Haas. Effect of naloxone on perceived exertion and exercise capacity during maximal cycle ergometry. J Appl Physiol 93: 2023-2028, 2002. First published August 23, 2002 10.1152/japplphysiol.00521.2002We assessed the effects of naloxone, an opioid antagonist, on exercise capacity in 13 men and 5 women (mean age ϭ 30.1 yr, range ϭ 21-35 yr) during a 25 W/min incremental cycle ergometer test to exhaustion on different days during familiarization trial and then after 30 mg (iv bolus) of naloxone or placebo (Pl) in a double-blind, crossover design. Minute ventilation (V E), O2 consumption (V O2), CO2 production, and heart rate (HR) were monitored. Perceived exertion rating (0-10 scale) and venous samples for lactate were obtained each minute. Lactate and ventilatory thresholds were derived from lactate and gas-exchange data. Blood pressure was obtained before exercise, 5 min postinfusion, at maximum exercise, and 5 min postexercise. There were no control-Pl differences. The naloxone trial demonstrated decreased exercise time (96% Pl; P Ͻ 0.01), total cumulative work (96% Pl; P Ͻ 0.002), peak V O2 (94% Pl; P Ͻ 0.02), and HR (96% Pl; P Ͻ 0.01). Other variables were unchanged. HR and V E were the same at the final common workload, but perceived exertion was higher (8.1 Ϯ 0.5 vs. 7.1 Ϯ 0.5) after naloxone than Pl (P Ͻ 0.01). The threshold for effort perception amplification occurred at ϳ60 Ϯ 4% of Pl peak V O2. Thus we conclude that peak work capacity was limited by perceived exertion, which can be attenuated by endogenous opioids rather than by physiological limits. peak oxygen consumption; lactate threshold; endogenous opioids; physiological fatigue THE DISCOMFORT ASSOCIATED with skeletal muscle activity and/or with increased breathing during exercise in healthy fit people may determine when the exercise is terminated (8, 9). Surbey et al. (22) have speculated that effort sensation, in turn, may be modulated by endogenous opioid release.The ventilatory component of discomfort is due, in part, to the disproportionate increase in minute ventilation (V E) relative to the increase in workload, which results from stimulation by H ϩ and CO 2 formed during buffering of lactic acid released during high levels of exercise (24, 25). The ventilatory threshold (VT) denotes the work rate at which this disproportionate increase occurs. Robertson (16) speculated that during high-intensity, continuous exercise above VT, discomfort becomes a limiting factor. This level of work has also been associated with endogenous opioid release (23). Endogenous opioids, in turn, have been shown to reduce V E (15, 27) for a given workload, thereby diminishing respiratory discomfort. Similarly, these endogenous opioids would also diminish discomfort originating from exercising muscles (18,19).Although a small number of investigations have assessed the role of opioid blockade on maximum exercise capacity (5,12,20,22), the effect in healthy subjects has not been thoroughly defined. To assess the possible impact of endogenous opioids on effort pe...
Objective: To identify an early treatment milestone that optimizes sensitivity and specificity for predicting 5% weight loss at Week (W) 52 in patients with and without type 2 diabetes on lorcaserin or placebo. Methods: Post hoc area under the curve for receiver operating characteristic analyses of data from three phase 3 trials comparing lifestyle modification1placebo with lifestyle modification1lorcaserin. A total of 6897 patients (18-65 years; BMI, 30-45 or 27-29.9 kg/m 2 with 1 comorbidity) were randomized to placebo or lorcaserin 10 mg bid. Changes (baseline to W52) in cardiometabolic parameters were assessed. Results: Response (5% weight loss from baseline) at W12 was a strong predictor of W52 response. Lorcaserin patients with a W12 response achieved mean W52 weight losses of 10.6 kg (without diabetes) and 9.3 kg (with diabetes). Proportions achieving 5% and 10% weight loss at W52 were 85.5% and 49.8% (without diabetes), and 70.5% and 35.9% (with diabetes). Lorcaserin patients who did not achieve a W12 response lost 3.2 kg (without diabetes) and 2.8 kg (with diabetes) at W52. Responders had greater improvements in cardiometabolic risk factors than the modified intent-to-treat (MITT) population, consistent with greater weight loss. Conclusions: 5% weight loss by W12 predicts robust response to lorcaserin at 1 year.
Background and ObjectiveSeveral features favor paracetamol (acetaminophen) administration by the intravenous rather than the oral route in the postoperative setting. This study compared the pharmacokinetics and bioavailability of oral and intravenous paracetamol when given with or without an opioid, morphine.MethodsIn this randomized, single-blind, parallel, repeat-dose study in healthy adults, subjects received four repeat doses of oral or intravenous 1000 mg paracetamol at 6-h intervals, and morphine infusions (0.125 mg/kg) at the 2nd and 3rd intervals. Comparisons of plasma pharmacokinetic profiles were conducted before, during, and after opioid co-administrations.ResultsTwenty-two subjects were included in the pharmacokinetic analysis. Observed paracetamol peak concentration (C max) and area under the plasma concentration-time curve over the dosing interval (AUC0–6) were reduced when oral paracetamol was co-administered with morphine (reduced from 11.6 to 7.25 µg/mL and from 31.00 to 25.51 µg·h/mL, respectively), followed by an abruptly increased C max and AUC0–6 upon discontinuation of morphine (to 13.5 µg/mL and 52.38 µg·h/mL, respectively). There was also a significantly prolonged mean time to peak plasma concentration (T max) after the 4th dose of oral paracetamol (2.84 h) compared to the 1st dose (1.48 h). However, pharmacokinetic parameters of paracetamol were not impacted when intravenous paracetamol was co-administered with morphine.ConclusionsMorphine co-administration significantly impacted the pharmacokinetics of oral but not intravenous paracetamol. The abrupt release of accumulated paracetamol at the end of morphine-mediated gastrointestinal inhibition following oral but not intravenous administration of paracetamol suggests that intravenous paracetamol provides a better option for the management of postoperative pain.ClinicalTrials.gov IdentifierNCT02848729.
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