Collaboration in pharmacovigilance: lamotrigine and fatal severe cutaneous adverse reactions - a review of spontaneous reports.

Pharmacovigilance presents many challenges, particularly when managing unpredictable, rare conditions, eg, severe cutaneous adverse reactions (SCARs). Such rare events are often only detected from spontaneous reports, which present their own limitations, particularly during a prolonged global launch schedule. GlaxoSmithKline's routine pharmacovigilance includes regular reviews of global adverse event (AE) reports and aggregate data from a central safety database. Lamotrigine is one of the several antiepileptic drugs associated with SCARs. After identification of increased rates of fatal SCAR cases with lamotrigine in Japan between September and December 2014, this analysis investigated the global incidence of fatal SCARs with lamotrigine and explored whether known risk factors may have contributed to these cases. Global fatal SCAR cases reported with lamotrigine administration from launch until January 2015 were reviewed for evidence of temporal association with dosing and the presence of risk factors, including comorbidities, concomitant medications, and noncompliance with the prescribing information (PI). Worldwide, the estimated cumulative exposure to lamotrigine was >8.4 million patient-years. Globally, there were 54,513 AE reports for lamotrigine, of which 3,454 (6.3%) concerned SCARs. Of these, 122 (3.5%) had a fatal outcome (attributable and nonattributable to lamotrigine), equating to 0.01 fatal SCARs per 1,000 patient-years. In Japan (estimated cumulative exposure 141,000 patient-years), 17 fatal SCARs were reported (attributable and nonattributable), equating to 0.12 per 1,000 patient-years. Seventy-one percent of fatal SCAR cases in Japan showed evidence of noncompliance with the recommended dosing regimen; in 65% of the cases, a delay in discontinuation of lamotrigine after early signs of hypersensitivity was reported. Despite a number of limitations inherent in comparing spontaneous report data, this analysis highlights the need for adherence to the lamotrigine PI and emphasizes the importance of collaboration between global and local pharmacovigilance departments, to promptly identify and reduce the risk of rare and serious events, such as SCARs.

Lack of efficacy of the selective iNOS inhibitor GW274150 in prophylaxis of migraine headache.

INTRODUCTION: This study investigated the efficacy and tolerability of the highly selective iNOS inhibitor GW274150 in prophylaxis of migraine headache. SUBJECTS AND METHODS: The study was conducted in two parts, each comprising a 4-week baseline period, a 12-week, double-blind, parallel-group treatment period, and a 4-week follow-up period. The study had an adaptive design in that findings of Part 1 of the study were used to inform the conduct of Part 2. Following an interim analysis at the end of Part 1, the trial could be stopped for futility or continued in Part 2 to study the full-dose response or to increase sample size in case initial assumptions had been violated. The primary end-point in both parts of the study was the probability of the occurrence of a migraine headache day during the baseline period and the treatment period. RESULTS: In Part 1, adult male and female patients with migraine received GW274150 60 mg (n = 37), 120 mg (n = 37), or placebo (n = 38) once daily for 12 weeks. In Part 2, female patients with migraine received GW274150 60 mg (n= 160) or placebo (n = 154) once daily for 12 weeks. GW274150 was no more effective than placebo for the primary efficacy end-point or any secondary efficacy end-point in Part 1 or Part 2. GW274150 was generally well tolerated. CONCLUSIONS: GW274150 at doses predicted to inhibit iNOS >80% did not differ from placebo in the prophylaxis of migraine. The results do not support a role of iNOS inhibition in migraine prevention.

Decreased duration of mechanical ventilation when comparing analgesia-based sedation using remifentanil with standard hypnotic-based sedation for up to 10 days in intensive care unit patients: a randomised trial [ISRCTN47583497].

INTRODUCTION: This randomised, open-label, multicentre study compared the safety and efficacy of an analgesia-based sedation regime using remifentanil with a conventional hypnotic-based sedation regime in critically ill patients requiring prolonged mechanical ventilation for up to 10 days. METHODS: One hundred and five randomised patients received either a remifentanil-based sedation regime (initial dose 6 to 9 microg kg(-1) h(-1) (0.1 to 0.15 microg kg(-1) min(-1)) titrated to response before the addition of midazolam for further sedation (n = 57), or a midazolam-based sedation regime with fentanyl or morphine added for analgesia (n = 48). Patients were sedated to an optimal Sedation-Agitation Scale (SAS) score of 3 or 4 and a pain intensity (PI) score of 1 or 2. RESULTS: The remifentanil-based sedation regime significantly reduced the duration of mechanical ventilation by more than 2 days (53.5 hours, P = 0.033), and significantly reduced the time from the start of the weaning process to extubation by more than 1 day (26.6 hours, P < 0.001). There was a trend towards shortening the stay in the intensive care unit (ICU) by 1 day. The median time of optimal SAS and PI was the same in both groups. There was a significant difference in the median time to offset of pharmacodynamic effects when discontinuing study medication in patients not extubated at 10 days (remifentanil 0.250 hour, comparator 1.167 hours; P < 0.001). Of the patients treated with remifentanil, 26% did not receive any midazolam during the study. In those patients that did receive midazolam, the use of remifentanil considerably reduced the total dose of midazolam required. Between days 3 and 10 the weighted mean infusion rate of remifentanil remained constant with no evidence of accumulation or of a development of tolerance to remifentanil. There was no difference between the groups in SAS or PI score in the 24 hours after stopping the study medication. Remifentanil was well tolerated. CONCLUSION: Analgesia-based sedation with remifentanil was well tolerated; it reduces the duration of mechanical ventilation and improves the weaning process compared with standard hypnotic-based sedation regimes in ICU patients requiring long-term ventilation for up to 10 days.

Safety and efficacy of analgesia-based sedation with remifentanil versus standard hypnotic-based regimens in intensive care unit patients with brain injuries: a randomised, controlled trial [ISRCTN50308308].

INTRODUCTION: This randomised, open-label, observational, multicentre, parallel group study assessed the safety and efficacy of analgesia-based sedation using remifentanil in the neuro-intensive care unit. METHODS: Patients aged 18-80 years admitted to the intensive care unit within the previous 24 hours, with acute brain injury or after neurosurgery, intubated, expected to require mechanical ventilation for 1-5 days and requiring daily downward titration of sedation for assessment of neurological function were studied. Patients received one of two treatment regimens. Regimen one consisted of analgesia-based sedation, in which remifentanil (initial rate 9 microg kg(-1) h(-1)) was titrated before the addition of a hypnotic agent (propofol [0.5 mg kg(-1) h(-1)] during days 1-3, midazolam [0.03 mg kg(-1) h(-1)] during days 4 and 5) (n = 84). Regimen two consisted of hypnotic-based sedation: hypnotic agent (propofol days 1-3; midazolam days 4 and 5) and fentanyl (n = 37) or morphine (n = 40) according to routine clinical practice. For each regimen, agents were titrated to achieve optimal sedation (Sedation-Agitation Scale score 1-3) and analgesia (Pain Intensity score 1-2). RESULTS: Overall, between-patient variability around the time of neurological assessment was statistically significantly smaller when using remifentanil (remifentanil 0.44 versus fentanyl 0.86 [P = 0.024] versus morphine 0.98 [P = 0.006]. Overall, mean neurological assessment times were significantly shorter when using remifentanil (remifentanil 0.41 hour versus fentanyl 0.71 hour [P = 0.001] versus morphine 0.82 hour [P < 0.001]). Patients receiving the remifentanil-based regimen were extubated significantly faster than those treated with morphine (1.0 hour versus 1.93 hour, P = 0.001) but there was no difference between remifentanil and fentanyl. Remifentanil was effective, well tolerated and provided comparable haemodynamic stability to that of the hypnotic-based regimen. Over three times as many users rated analgesia-based sedation with remifentanil as very good or excellent in facilitating assessment of neurological function compared with the hypnotic-based regimen. CONCLUSIONS: Analgesia-based sedation with remifentanil permitted significantly faster and more predictable awakening for neurological assessment. Analgesia-based sedation with remifentanil was very effective, well tolerated and had a similar adverse event and haemodynamic profile to those of hypnotic-based regimens when used in critically ill neuro-intensive care unit patients for up to 5 days.

Remifentanil versus fentanyl for analgesia based sedation to provide patient comfort in the intensive care unit: a randomized, double-blind controlled trial [ISRCTN43755713].

INTRODUCTION: This double-blind, randomized, multicentre study was conducted to compare the efficacy and safety of remifentanil and fentanyl for intensive care unit (ICU) sedation and analgesia. METHODS: Intubated cardiac, general postsurgical or medical patients (aged >/= 18 years), who were mechanically ventilated for 12-72 hours, received remifentanil (9 microgram/kg per hour; n = 77) or fentanyl (1.5 microgram/kg per hour; n = 75). Initial opioid titration was supplemented with propofol (0.5 mg/kg per hour), if required, to achieve optimal sedation (i.e. a Sedation-Agitation Scale score of 4). RESULTS: The mean percentages of time in optimal sedation were 88.3% for remifentanil and 89.3% for fentanyl (not significant). Patients with a Sedation-Agitation Scale score of 4 exhibited significantly less between-patient variability in optimal sedation on remifentanil (variance ratio of fentanyl to remifentanil 1.84; P = 0.009). Of patients who received fentanyl 40% required propofol, as compared with 35% of those who received remifentanil (median total doses 683 mg and 378 mg, respectively; P = 0.065). Recovery was rapid (median time to extubation: 1.1 hours for remifentanil and 1.3 hours for fentanyl; not significant). Remifentanil patients who experienced pain did so for significantly longer during extubation (6.5% of the time versus 1.4%; P = 0.013), postextubation (10.2% versus 3.6%; P = 0.001) and post-treatment (13.5% versus 5.1%; P = 0.001), but they exhibited similar haemodynamic stability with no significant differences in adverse event incidence. CONCLUSION: Analgesia based sedation with remifentanil titrated to response provided effective sedation and rapid extubation without the need for propofol in most patients. Fentanyl was similar, probably because the dosing algorithm demanded frequent monitoring and adjustment, thereby preventing over-sedation. Rapid offset of analgesia with remifentanil resulted in a greater incidence of pain, highlighting the need for proactive pain management when transitioning to longer acting analgesics, which is difficult within a double-blind study but would be quite possible under normal circumstances.

Efficacy and safety of remifentanil in coronary artery bypass graft surgery: a randomized, double-blind dose comparison study.

OBJECTIVES: To compare the efficacy and safety of 3 doses of remifentanil as part of a total intravenous anesthesia technique with low-dose propofol in patients undergoing coronary artery bypass graft (CABG) surgery. DESIGN: Multicenter, multinational, double-blind, randomized, dose comparison study. SETTING: Nine hospitals in 5 countries. PARTICIPANTS: One hundred forty-one patients undergoing first-time elective CABG surgery. INTERVENTIONS: Patients were premedicated with a short-acting oral benzodiazepine up to 2 h before surgery and randomized to receive continuous infusions of remifentanil 1.0 microg/kg/min (n = 45), 1.5 microg/kg/min (n = 44), or 2.0 microg/kg/min (n = 43), in combination with propofol 3 mg/kg/h. Nine patients received remifentanil 1.0 microg/kg/min on an open-label basis. Three different induction sequences (IS) were used. In IS 1 (n = 31), induction was started with remifentanil infusion followed 5 minutes later by propofol 0.5 mg/kg bolus and infusion at 3 mg/kg/h. Further bolus doses of propofol (10 mg) were given if loss of consciousness (LOC) was not attained after 5 minutes; pancuronium, 0.04 to 0.1 mg/kg, was administered at LOC. In IS 2 (n = 68), a priming dose of pancuronium, 0.015 mg/kg, was administered just before starting remifentanil. In IS 3 (n = 42), bolus doses of propofol, 10 mg every 10 seconds, were given until LOC, followed by pancuronium, 0.04 to 0.1 mg/kg, and the remifentanil and propofol infusions were started. MEASUREMENTS AND MAIN RESULTS: There were no significant differences among the remifentanil dose groups with regard to the primary outcome measure, responses to sternotomy/sternal spread/maximal sternal spread. Responses to these stimuli were recorded in 11%, 11%, and 14% of patients in the remifentanil 1.0, 1.5, and 2.0 microg/kg/min dose groups, respectively. Similarly, there were no significant differences in the responses to other surgical stimuli. There was a high incidence of muscle rigidity when remifentanil was used to induce anesthesia. CONCLUSIONS: All 3 remifentanil dose regimens provided profound suppression of responses to surgical stimuli in the majority of patients. There was no apparent advantage in starting the remifentanil infusion rate above 1.0 microg/kg/min. Remifentanil is not suitable for use as a sole induction agent.

Electrocatalytic reactions mediated by N,N,N',N'-Tetraalkyl-1,4-phenylenediamine redox liquid microdroplet-modified electrodes: chemical and photochemical reactions In, and At the surface of, femtoliter droplets.

The electro-oxidation of electrolytically unsupported ensembles of N,N-diethyl-N',N'-dialkyl-para-phenylenediamine (DEDRPD, R = n-butyl, n-hexyl, and n-heptyl) redox liquid femtoliter volume droplets immobilized on a basal plane pyrolytic graphite electrode is reported in the presence of aqueous electrolytes. Electron transfer at these redox liquid modified electrodes is initiated at the microdroplet-electrode-electrolyte three-phase boundary. Dependent on both the lipophilicity of the redox oil and that of the aqueous electrolyte, ion uptake into or expulsion from the organic deposits is induced electrolytically. In the case of hydrophobic electrolytes, redox-active ionic liquids are synthesized, which are shown to catalyze the oxidation of l-ascorbic acid over the surface of the droplets. In contrast, the photoelectrochemical reduction of the anaesthetic reagent halothane proceeds within the droplet deposits and is mediated by the ionic liquid precursor (the DEDRPD oil).

Remifentanil vs morphine for patients in intensive care unit who need short-term mechanical ventilation.

This randomized, double-blind study compared the safety and efficacy of remifentanil (9 microg/ kg/h) with morphine (0.045 mg/kg/h plus a bolus dose of 0.025 mg/kg). One hundred and eighty nine Intensive Care Unit (ICU) patients with normal renal function or mild renal impairment requiring mechanical ventilation were included in this study. A pre-defined dosing algorithm permitted initial titration of the opioids to predetermine the optimal level of sedation and pain score. Supplementary infusion of midazolam (0.03 mg/kg/h) was given when additional sedation was required. The duration of optimal sedation during the maintenance phase was 82.7 per cent and 84.3 per cent of the total time in the remifentanil and morphine groups respectively. There were no statistically significant differences in the between-subject variability in the duration of optimal sedation between the two treatment groups. Midazolam was not required in approximately 75 per cent of all patients. The patients in the morphine group required twice the amount of midazolam required by the remifentanil group. The dosing algorithm facilitated rapid extubation in both groups. Remifentanil provided comparable hemodynamic stability to morphine, and was not associated with an increase in cardiovascular adverse event. Remifentanil is therefore considered to be effective and well tolerated in ICU patients.