RSV Prefusion F Protein-Based Maternal Vaccine - Preterm Birth and Other Outcomes.

BACKGROUND: Vaccination against respiratory syncytial virus (RSV) during pregnancy may protect infants from RSV disease. Efficacy and safety data on a candidate RSV prefusion F protein-based maternal vaccine (RSVPreF3-Mat) are needed. METHODS: We conducted a phase 3 trial involving pregnant women 18 to 49 years of age to assess the efficacy and safety of RSVPreF3-Mat. The women were randomly assigned in a 2:1 ratio to receive RSVPreF3-Mat or placebo between 24 weeks 0 days and 34 weeks 0 days of gestation. The primary outcomes were any or severe medically assessed RSV-associated lower respiratory tract disease in infants from birth to 6 months of age and safety in infants from birth to 12 months of age. After the observation of a higher risk of preterm birth in the vaccine group than in the placebo group, enrollment and vaccination were stopped early, and exploratory analyses of the safety signal of preterm birth were performed. RESULTS: The analyses included 5328 pregnant women and 5233 infants; the target enrollment of approximately 10,000 pregnant women and their infants was not reached because enrollment was stopped early. A total of 3426 infants in the vaccine group and 1711 infants in the placebo group were followed from birth to 6 months of age; 16 and 24 infants, respectively, had any medically assessed RSV-associated lower respiratory tract disease (vaccine efficacy, 65.5%; 95% credible interval, 37.5 to 82.0), and 8 and 14, respectively, had severe medically assessed RSV-associated lower respiratory tract disease (vaccine efficacy, 69.0%; 95% credible interval, 33.0 to 87.6). Preterm birth occurred in 6.8% of the infants (237 of 3494) in the vaccine group and in 4.9% of those (86 of 1739) in the placebo group (relative risk, 1.37; 95% confidence interval [CI], 1.08 to 1.74; P = 0.01); neonatal death occurred in 0.4% (13 of 3494) and 0.2% (3 of 1739), respectively (relative risk, 2.16; 95% CI, 0.62 to 7.56; P = 0.23), an imbalance probably attributable to the greater percentage of preterm births in the vaccine group. No other safety signal was observed. CONCLUSIONS: The results of this trial, in which enrollment was stopped early because of safety concerns, suggest that the risks of any and severe medically assessed RSV-associated lower respiratory tract disease among infants were lower with the candidate maternal RSV vaccine than with placebo but that the risk of preterm birth was higher with the candidate vaccine. (Funded by GlaxoSmithKline Biologicals; ClinicalTrials.gov number, NCT04605159.).

Challenges and lessons learned from four years of planning and implementing pharmacovigilance enhancement in sub-Saharan Africa.

Pharmacovigilance (PV) systems in many countries in sub-Saharan Africa (SSA) are not fully functional. The spontaneous adverse events (AE) reporting rate in SSA is lower than in any other region of the world, and healthcare professionals (HCPs) in SSA countries have limited awareness of AE surveillance and reporting procedures. The GSK PV enhancement pilot initiative, in collaboration with PATH and national PV stakeholders, aimed to strengthen passive safety surveillance through a training and mentoring program of HCPs in healthcare facilities in three SSA countries: Malawi, Côte d'Ivoire, and Democratic Republic of Congo (DRC). Project implementation was country-driven, led by the Ministry of Health via the national PV center or department, and was adapted to each country's needs. The implementation phase for each country was scheduled to last 18 months. At project start, low AE reporting rates reflected that awareness of PV practices was very low among HCPs in all three countries, even if a national PV center already existed. Malawi did not have a functional PV system nor a national PV center prior to the start of the initiative. After 18 months of PV training and mentoring of HCPs, passive safety surveillance was enhanced significantly as shown by the increased number of AE reports: from 22 during 2000-2016 to 228 in 18 months to 511 in 30 months in Malawi, and ~ 80% of AE reports from trained healthcare facilities in Côte d'Ivoire. In DRC, project implementation ended after 7 months because of the SARS-CoV-2 pandemic. Main challenges encountered were delayed AE report transmission (1-2 months, due mainly to remoteness of healthcare facilities and complex procedures for transmitting reports to the national PV center), delayed or no causality assessment due to lack of expertise and/or funding, negative perceptions among HCPs toward AE reporting, and difficulties in engaging public health programs with the centralized AE reporting processes. This pilot project has enabled the countries to train more HCPs, increased reporting of AEs and identified KPIs that could be flexibly replicated in each country. Country ownership and empowerment is essential to sustain these improvements and build a stronger AE reporting culture.

A Model for Monitoring Spontaneously Reported Medication Errors Using the Adjuvanted Recombinant Zoster Vaccine as an Example.

A European legislation was put in place for the reporting of medication errors, and guidelines were drafted to help stakeholders in the reporting, evaluation, and, ultimately, minimization of these errors. As part of pharmacovigilance reporting, a proper classification of medication errors is needed. However, this process can be tedious, time-consuming, and resource-intensive. To fulfill this obligation regarding medication errors, we developed an algorithm that classifies the reported errors in an automated way into four categories: potential medication errors, intercepted medication errors, medication errors without harm (i.e., not associated with adverse reaction(s)), and medication errors with harm (i.e., associated with adverse reaction(s)). A fifth category ("conflicting category") was created for reported cases that could not be unambiguously classified as either potential or intercepted medication errors. Our algorithm defines medication error categories based on internationally accepted terminology using the Medical Dictionary for Regulatory Activities (MedDRA®) preferred terms. We present the algorithm and the strengths of this automated way of reporting medication errors. We also give examples of visualizations using spontaneously reported vaccination error data associated with the adjuvanted recombinant zoster vaccine. For this purpose, we used a customized web-based platform that uses visualizations to support safety signal detection. The use of the algorithm facilitates and ensures a consistent way of categorizing medication errors with MedDRA® terms, thereby saving time and resources and avoiding the risk of potential mistakes versus manual classification. This allows further assessment and potential prevention of medication errors. In addition, the algorithm is easy to implement and can be used to categorize medication errors from different databases.

Safety of medicines and vaccines - building next generation capability.

The systematic safety surveillance of real-world use of medicinal products and related activities (pharmacovigilance) started in earnest as a scientific field only in the 1960s. While developments have occurred over the past 50 years, adding to its complexity and sophistication, the extent to which some of these advances have positively impacted the capability for ensuring patient safety is questionable. We review how the conduct of safety surveillance has changed, highlight recent scientific advances, and argue how they need to be harnessed to enhance pharmacovigilance in the future. Specifically, we describe five changes that we believe should and will need to happen globally in the coming years: (i) better, more diverse data used for safety; (ii) the switch from manual activities to automation; (iii) removal of limited value, extraneous transactional activities and replacement with sharpened focus on scientific efforts to improve patient safety; (iv) patient-involved and focussed safety; and (v) personalised safety.

An Analysis of Spontaneously Reported Data of Vesicular and Bullous Cutaneous Eruptions Occurring Following Vaccination with the Adjuvanted Recombinant Zoster Vaccine.

INTRODUCTION: With the approval of the adjuvanted recombinant zoster vaccine (RZV; Shingrix, GSK) in October 2017, GSK established enhanced safety surveillance measures to allow prompt identification of potential safety signals not observed during clinical development. In Germany, cases of vesicular and bullous cutaneous eruptions following RZV vaccination were reported. OBJECTIVE: Our objective was to search and analyse 2.5 years of worldwide spontaneously reported post-marketing data for vesicular and bullous cutaneous eruptions, represented by adverse events suggestive of (1) herpes zoster (HZ) and (2) non-HZ vesicular and bullous cutaneous eruptions, that occurred following RZV vaccination. METHODS: We conducted a descriptive analysis of all identified reports of HZ and non-HZ vesicular and bullous cutaneous eruptions following RZV vaccination and an observed versus expected (O/E) analysis of reports of HZ that met criteria of varicella zoster virus (VZV) reactivations following RZV vaccination (i.e., time to onset [TTO] of the event < 30 days or missing after any dose). RESULTS: Until the data lock point, 32,597,779 RZV doses had been distributed globally. There were 2423 reports of HZ (including complications) identified, of which 645 met the criteria of possible vaccination failure (i.e., TTO of the event ≥ 30 days or missing following a complete RZV vaccination schedule). The O/E analysis of 1928 reports assessed as possible VZV reactivations indicated that the observed number of cases was lower than that expected in the general population. Additionally, 810 reports of non-HZ vesicular and bullous cutaneous eruptions were identified, including injection site rashes attributed to the vaccine's reactogenicity. CONCLUSION: This review of spontaneously reported post-marketing data did not raise safety concerns regarding the occurrence of vesicular and bullous cutaneous eruptions following vaccination with RZV.

Shingles is a disease caused by reactivation of the chickenpox virus. It mostly affects adults aged 50 years and older and patients of all ages who have an impaired immune system. Diagnosis of shingles is often based only on the presence of symptoms such as a typical rash and pain. However, rashes can have various other causes (e.g., allergies, autoimmune diseases, and infections). Consequently, rashes with other causes may be misdiagnosed as shingles. Adults at increased risk of shingles and/or aged 50 years and older may be vaccinated with Shingrix (GSK, Belgium) to protect them from shingles and its complications. Since Shingrix became available in Germany, blister-like skin rashes have been reported that occurred shortly after vaccination. We searched the GSK safety database for reports of blister-like skin rashes that occurred following vaccination with Shingrix and that were spontaneously reported from countries where Shingrix was first marketed. To analyse these reports of rashes, we described the reports that we retrieved, we performed a statistical analysis to quantify whether the number of events assessed as reactivations of the chickenpox virus following Shingrix vaccination was higher than the number of reactivations that would be expected in the general population, and we described possible explanations for the observed rashes and underlying disease mechanisms. Our analyses did not raise safety concerns related to the onset of these rashes after vaccination with Shingrix. This paper raises awareness about the varying causes of rashes since a shingles-like rash that onsets shortly after vaccination with Shingrix is not necessarily caused by vaccination. In conclusion, this analysis shows that caution is needed when evaluating rashes in older adults and that all potential contributing factors (e.g., pre-existing diseases, medication, vaccination) should be considered.

Post-Marketing Safety Surveillance for the Adjuvanted Recombinant Zoster Vaccine: Methodology.

A diligent, systematic, regular review of aggregate safety data is essential, particularly early after vaccine introduction, as this is when safety signals not identified during clinical development may emerge. In October 2017, the US Centers for Disease Control and Prevention Advisory Committee on Immunization Practices recommended the adjuvanted recombinant zoster vaccine (RZV; Shingrix, GSK) as the preferred vaccine for preventing herpes zoster (HZ) and related complications in immunocompetent adults aged ≥ 50 years. Subsequently, GSK experienced an unprecedented high demand for RZV. In this methodology paper, we summarize the enhanced measures undertaken to assess RZV safety during its early post-marketing experience in the USA, Canada and Germany. In addition to the routine signal-detection methods already in place for all vaccines, GSK established tailored and enhanced safety monitoring for RZV based on aggregate data of spontaneous reports and manufacturing data. Proactive, near real-time detection and evaluation of signals was a key objective. A dedicated in-house signal-detection tool customized for RZV was employed on a weekly (rather than the routine monthly) basis, allowing for a centralized, more frequent review of data on a single web-based platform. We also identified the background incidence rates of preselected medical events of interest in the first countries to introduce RZV (USA, Canada and Germany) to perform observed-to-expected analyses. This approach may offer a solution to the challenges associated with the assessment and monitoring of vaccine safety in an efficient and timely manner in the context of high vaccine uptake.

Enhancing Pharmacovigilance in Sub-Saharan Africa Through Training and Mentoring: A GSK Pilot Initiative in Malawi.

INTRODUCTION: Pharmacovigilance (PV) systems to monitor drug and vaccine safety are often inadequate in sub-Saharan Africa. In Malawi, a PV enhancement initiative was introduced to address major barriers to PV. OBJECTIVE: The objective of this initiative was to improve reporting of adverse events (AEs) by strengthening passive safety surveillance via PV training and mentoring of local PV stakeholders and healthcare providers (HCPs) at their own healthcare facilities (HCFs). METHODS: An 18-month PV training and mentoring programme was implemented in collaboration with national stakeholders, and in partnership with the Ministry of Health, GSK and PATH. Two-day training was provided to Expanded Programme on Immunisation coordinators, identified as responsible for AE reporting, and four National Regulatory Authority representatives. Abridged PV training and mentoring were provided regularly to HCPs. Support was given in upgrading the national PV system. Key performance indicators included the number of AEs reported, transmission of AE forms, completeness of reports, serious AEs reported and timeliness of recording into VigiFlow. RESULTS: In 18 months, 443 HCPs at 61 HCFs were trained. The number of reported AEs increased from 22 (January 2000 to October 2016) to 228 (November 2016 to May 2018), enabling Malawi to become a member of the World Health Organization Programme for International Drug Monitoring. Most (98%) AE report forms contained mandatory information on reporter, event, patient and product, but under 1% were transmitted to the national PV office within 48 h. CONCLUSION: Regular PV training and mentoring of HCPs were effective in enhancing passive safety surveillance in Malawi, but the transmission of reports to the national PV centre requires further improvement.

When a medicine or vaccine is made available for use, healthcare organisations maintain regular surveillance to confirm that the medicinal product is safe and effective. The efficiency of this surveillance depends mainly on the healthcare system and medical practices in place in each country. An important element is an effective procedure for identifying and reporting any unwanted medical occurrences (adverse events) after taking a medicinal product. In countries where regular safety surveillance has not been maintained, it is important to train and mentor healthcare providers on the need to be aware of adverse events and the importance of adhering to safety reporting procedures. GSK and partners conducted a pilot project in Malawi with the aim of improving adverse event reporting by training and mentoring healthcare providers. Training sessions and continuous mentoring were conducted over 18 months, involving 443 healthcare providers at 61 healthcare facilities. There was a large increase in the number of adverse events reported: from 22 in the 16-year period before the project started to 228 during the 18-month project period. This project showed that the training and mentoring programme for healthcare providers was effective in increasing the number of adverse events reported. This enabled Malawi to join the World Health Organization's international safety reporting scheme. Other countries facing similar challenges in safety surveillance systems could benefit from a similar approach.

Review of the initial post-marketing safety surveillance for the recombinant zoster vaccine.

BACKGROUND: The adjuvanted recombinant zoster vaccine (RZV) received its first marketing authorization in October 2017, for prevention of herpes zoster in individuals aged ≥50 years. METHODS: We summarized safety information, following RZV administration, received by GSK via spontaneous adverse event (AE) reports submitted by healthcare providers, vaccine recipients and other reporters. Observed-to-expected (O/E) analyses were performed for selected outcomes: reports of death, Guillain-Barré syndrome and Bell's palsy. Standard case definitions were used to assess individual case reports. Data mining, using proportional reporting ratio and time-to-onset signal detection methods, was employed to identify RZV-AE pairs with disproportionate reporting or unexpected time-to-onset distribution. RESULTS: Between October 13, 2017 and February 10, 2019, an estimated 9.3 million doses were distributed and GSK received 15,638 spontaneous AE reports involving RZV. Most reports were classified as non-serious (95.3%) and originated from the United States (81.7%), where the majority of doses were distributed. Among reports with age or sex reported, individuals were mainly 50-69-year-olds (62.1%) and female (66.7%). Of all reports, 3,579 (22.9%) described vaccination errors, of which 82.7% were without associated symptoms. Of all vaccination error reports, most described errors of vaccine preparation and reconstitution (29.7%), inappropriate schedule or incomplete course of administration (26.7%), incorrect route of administration (16.4%), and storage errors (12.9%). The most commonly reported symptoms were consistent with the known RZV reactogenicity profile observed in clinical trials, including injection site reactions, pyrexia, chills, fatigue, headache. O/E analyses for selected outcomes and data mining analyses for all reported AEs did not identify any unexpected patterns. CONCLUSIONS: Review of the initial data from the post-marketing safety surveillance showed that the safety profile of RZV is consistent with that previously observed in pre-licensure clinical trials. Other studies are ongoing and planned, to continue generating real-world safety data and further characterize RZV.

Efficacy and tolerability of tapentadol immediate release and oxycodone HCl immediate release in patients awaiting primary joint replacement surgery for end-stage joint disease: a 10-day, phase III, randomized, double-blind, active- and placebo-controlled study.

OBJECTIVES: The primary objective of this study was to assess the efficacy and tolerability of tapentadol immediate release (IR) in patients who were candidates for joint replacement surgery due to end-stage joint disease. A secondary objective was to compare tapentadol IR with oxycodone HCl IR with respect to efficacy and prespecified tolerability end points. METHODS: This 10-day, Phase III, randomized, double-blind, active- and placebo-controlled study compared the efficacy and tolerability of tapentadol IR, oxycodone HCl IR, and placebo in patients with uncontrolled osteoarthritis pain who were candidates for primary replacement of the hip or knee as a result of end-stage degenerative joint disease. Patients received tapentadol IR 50 mg, tapentadol IR 75 mg, oxycodone HCl IR 10 mg, or placebo every 4 to 6 hours during waking hours. The primary end point was the sum of pain intensity difference (SPID) over 5 days. Secondary efficacy end points included 2- and 10-day SPID; 2-, 5-, and 10-day total pain relief (TOTPAR); and the sum of total pain relief and pain intensity difference (SPRID). Prespecified noninferiority comparisons with oxycodone HCl IR were performed with respect to efficacy (based on 5-day SPID) and tolerability (based on incidence of the reported adverse events (AEs) of nausea and/or vomiting and constipation). RESULTS: Of 666 patients originally enrolled, 659 were included in the efficacy analysis (51% male; 91% white; mean age, 61.2 years; mean weight, 97 kg). Five-day SPID was significantly lower in those treated with tapentadol IR (tapentadol IR 50 mg: least squares mean difference [LSMD] = 101.2 [95% CI, 54.58- 147.89]; tapentadol IR 75 mg: LSMD = 97.5 [95% CI, 51.81-143.26]) or oxycodone HCl IR (LSMD = 111.9 [95% CI, 66.49-157.38]) (all, P < 0.001). Tapentadol IR 50 and 75 mg and oxycodone HCl IR 10 mg were associated with significant reductions in pain intensity compared with placebo, based on 2- and 10-day SPID and 2-, 5-, and 10-day TOTPAR and SPRID (all, P < 0.001). The efficacy of tapentadol IR 50 and 75 mg was noninferior to that of oxycodone HCl IR 10 mg; however, the incidence of selected gastrointestinal AEs (nausea, vomiting, and constipation) was significantly lower for both doses of tapentadol IR compared with oxycodone HCl IR 10 mg (nominal P < 0.001). The odds ratios for nausea and/or vomiting for tapentadol IR 50 and 75 mg relative to oxycodone HCl IR 10 mg were 0.21 (95% CI, 0.128-0.339) and 0.32 (95% CI, 0.204-0.501), respectively; for constipation, the corresponding odds ratios were 0.13 (95% CI, 0.057-0.302) and 0.20 (95% CI, 0.098-0.398). Rates of treatment discontinuation were 18% (28/157) in the tapentadol IR 50-mg group, 26% (43/168) in the tapentadol IR 75-mg group, 35% (60/172) in the oxycodone HCl IR 10-mg group, and 10% (17/169) in the placebo group. In a post hoc analysis, tapentadol IR 50 mg was associated with a significantly lower incidence of treatment discontinuation than was oxycodone HCl IR 10 mg (P < 0.001). CONCLUSIONS: In these patients with uncontrolled osteoarthritis pain who were awaiting joint replacement surgery, tapentadol IR 50 and 75 mg were associated with analgesia that was noninferior to that provided by oxycodone HCl IR 10 mg. Tapentadol treatment was associated with improved gastrointestinal tolerability.

Safety profile of the RTS,S/AS01 malaria vaccine in infants and children: additional data from a phase III randomized controlled trial in sub-Saharan Africa.

A phase III, double-blind, randomized, controlled trial (NCT00866619) in sub-Saharan Africa showed RTS,S/AS01 vaccine efficacy against malaria. We now present in-depth safety results from this study. 8922 children (enrolled at 5-17 months) and 6537 infants (enrolled at 6-12 weeks) were 1:1:1-randomized to receive 4 doses of RTS,S/AS01 (R3R) or non-malaria control vaccine (C3C), or 3 RTS,S/AS01 doses plus control (R3C). Aggregate safety data were reviewed by a multi-functional team. Severe malaria with Blantyre Coma Score ≤2 (cerebral malaria [CM]) and gender-specific mortality were assessed post-hoc. Serious adverse event (SAE) and fatal SAE incidences throughout the study were 24.2%-28.4% and 1.5%-2.5%, respectively across groups; 0.0%-0.3% of participants reported vaccination-related SAEs. The incidence of febrile convulsions in children was higher during the first 2-3 days post-vaccination with RTS,S/AS01 than with control vaccine, consistent with the time window of post-vaccination febrile reactions in this study (mostly the day after vaccination). A statistically significant numerical imbalance was observed for meningitis cases in children (R3R: 11, R3C: 10, C3C: 1) but not in infants. CM cases were more frequent in RTS,S/AS01-vaccinated children (R3R: 19, R3C: 24, C3C: 10) but not in infants. All-cause mortality was higher in RTS,S/AS01-vaccinated versus control girls (2.4% vs 1.3%, all ages) in our setting with low overall mortality. The observed meningitis and CM signals are considered likely chance findings, that - given their severity - warrant further evaluation in phase IV studies and WHO-led pilot implementation programs to establish the RTS,S/AS01 benefit-risk profile in real-life settings.

Signal management in pharmacovigilance and human risk assessment of CpG 7909, integrating embryo-fetal and post-natal developmental toxicity studies in rats and rabbits.

The potential reproductive and developmental toxicity of the synthetic oligodeoxynucleotide (ODN) CpG 7909, a component of GSK's AS15 immunostimulant, was examined in rat and rabbit studies following intermittent intramuscular injections. Previous studies using subcutaneous and intraperitoneal injections in mice, rats and rabbits revealed that CpG ODNs induced developmental effects. To analyze the safety signal, GSK conducted additional animal studies using the intended clinical route of administration. CpG 7909 injections were administered intramuscularly to rats or rabbits 28 and 14days before pairing, on 4 or 5 occasions during gestation, and on lactation day 7. The No Observed Adverse Effect Level for female fertility, embryo-fetal and pre- and post-natal development was 4.2mg/kg in both species, approximately 500-fold higher than the anticipated human dose. In conclusion, the anticipated risk to humans is considered low for sporadic intramuscular exposure to CpG 7909.

Results on exposure during pregnancy from a pregnancy registry for AS04-HPV-16/18 vaccine.

OBJECTIVE: To assess pregnancy outcomes after exposure to AS04-HPV-16/18 vaccine (Cervarix, GSK, Belgium) prior to, or during pregnancy, as reported to a pregnancy registry. METHODS: A pregnancy exposure registry was established to collect data in the United Kingdom and the United States. Exposure was defined as vaccination with AS04-HPV-16/18 within 60days before the estimated conception date and delivery. Reporting was voluntary. RESULTS: Between September 2007 and November 2015, 306 pregnancy exposure reports were received of which 181 were prospective, evaluable reports. From these 181 reports, 154 (85.1%) pregnancies resulted in a live birth, 14 (7.7%) in spontaneous abortion, one (0.5%) in stillbirth, and 12 (6.6%) were electively terminated. There was no clustering of outcomes with respect to the timing of exposure. There were 18 infants born with a congenital anomaly of which nine were minor structural defects, seven were major structural defects, one was a hereditary disorder and one was likely the result of a congenital infection. In three cases of structural defect (two minor and one major), there was a temporal association to vaccination during the critical developmental period of gestation. There was no cluster or constellation of congenital anomalies suggestive of possible teratogenesis. CONCLUSION: The pharmacovigilance plan to investigate the effects of inadvertent exposure to AS04-HPV-16/18 vaccine during pregnancy included assessment of pregnancy outcomes among women enrolled in clinical trials, evaluation of pregnancy exposure reports from all countries as part of routine passive safety surveillance, a large, well conducted post-authorization observational study, and the pregnancy registry. These registry data complement other data from clinical trials and post-marketing surveillance showing no evidence that vaccination with AS04-HPV-16/18 during the defined exposure period (within 60days before conception until delivery) increases the risk of teratogenicity.

Investigating Reports of Complex Regional Pain Syndrome: An Analysis of HPV-16/18-Adjuvanted Vaccine Post-Licensure Data.

Complex regional pain syndrome (CRPS) is a chronic pain disorder that typically follows trauma or surgery. Suspected CRPS reported after vaccination with human papillomavirus (HPV) vaccines led to temporary suspension of proactive recommendation of HPV vaccination in Japan. We investigated the potential CRPS signal in relation to HPV-16/18-adjuvanted vaccine (Cervarix®) by database review of CRPS cases with independent expert confirmation; a disproportionality analysis and analyses of temporality; an observed versus expected analysis using published background incidence rates; systematic reviews of aggregate safety data, and a literature review. The analysis included 17 case reports of CRPS: 10 from Japan (0.14/100,000 doses distributed) and seven from the United Kingdom (0.08/100,000). Five cases were considered by independent experts to be confirmed CRPS. Quantitative analyses did not suggest an association between CRPS and HPV-16/18-adjuvanted vaccine. Observed CRPS incidence after HPV-16/18 vaccination was statistically significantly below expected rates. Systematic database reviews using search terms varying in specificity and sensitivity did not identify new cases. No CRPS was reported during clinical development and no unexpected results found in the literature. There is not sufficient evidence to suggest an increased risk of developing CRPS following vaccination with HPV-16/18-adjuvanted vaccine. Post-licensure safety surveillance confirms the acceptable benefit-risk of HPV-16/18 vaccination.

Tapentadol immediate release: a new treatment option for acute pain management.

The undertreatment of acute pain is common in many health care settings. Insufficient management of acute pain may lead to poor patient outcomes and potentially life-threatening complications. Opioids provide relief of moderate to severe acute pain; however, therapy with pure µ-opioid agonists is often limited by the prevalence of side effects, particularly opioid-induced nausea and vomiting. Tapentadol is a novel, centrally acting analgesic with 2 mechanisms of action, µ-opioid receptor agonism and norepinephrine reuptake inhibition. The analgesic effects of tapentadol are independent of metabolic activation and tapentadol has no active metabolites; therefore, in theory, tapentadol may be associated with a low potential for interindividual efficacy variations and drug-drug interactions. Previous phase 3 trials in patients with various types of moderate to severe acute pain have shown that tapentadol immediate release (IR; 50 to 100 mg every 4 to 6 hours) provides analgesia comparable to that provided by the pure µ-opioid agonist comparator, oxycodone HCl IR (10 or 15 mg every 4 to 6 hours), with a lower incidence of nausea, vomiting, and constipation. Findings suggest tapentadol may represent an improved treatment option for acute pain.

Antinociceptive effects of systemic lidocaine: involvement of the spinal glycinergic system.

Beside their action on voltage-gated Na(+) channels, local anesthetics are known to exert a variety of effects via alternative mechanisms. The antinociceptive effect of lidocaine is well documented, yet the exact mechanism is not fully understood. Whether glycinergic mechanisms, which play a pivotal role in pain modulation, are involved in lidocaine-induced antinociception is hitherto unclear. In the present study, lidocaine was injected intravenously in rats using the formalin test for acute pain and the chronic constriction injury model for neuropathic pain. The effect of intrathecally administered d-serine (an agonist at the glycine-binding site at the NMDA-receptor), its inactive isomer l-serine, CGP 78608 (antagonist at the glycineB-site of the NMDA-receptor) and strychnine (antagonist at inhibitory glycine-receptors) on lidocaine-induced antinociception was examined. Systemically administered lidocaine was antinociceptive in both acute and chronic pain model. In the formalin test, the effect of lidocaine was antagonized by d-serine, but not by l-serine or strychnine. In the chronic constriction injury model, antinociception evoked by lidocaine was reduced by d-serine, strychnine and CGP 78608, while l-serine had no effect. These results indicate a modulatory effect of lidocaine on the NMDA-receptor. Additionally, since in our study lidocaine-induced antinociception was antagonized by both glycineB-site modulators and strychnine our results may favor the hypothesis of a general glycine-like action of lidocaine or some of its metabolites on inhibitory strychnine-sensitive receptors and on strychnine-insensitive glycine receptors.

A randomized, double-blind, placebo-controlled phase 3 study of the relative efficacy and tolerability of tapentadol IR and oxycodone IR for acute pain.

OBJECTIVE: To evaluate the relative efficacy and tolerability of tapentadol immediate release (IR) and oxycodone IR for management of moderate to severe pain following orthopedic surgery (bunionectomy). METHODS: Randomized patients (N = 901) received oral tapentadol IR 50 or 75 mg, oxycodone HCl IR 10 mg, or placebo every 4-6 h over a 72-h period following surgery. Acetaminophen (< or =2 g) was allowed in the first 12 h after the first dose of study drug. In the primary analysis, tapentadol IR (50 and 75 mg) was evaluated for efficacy superior to placebo and non-inferior to oxycodone HCl IR 10 mg (using sum of pain intensity difference [SPID] over 48 h), and tolerability superior to oxycodone IR (using incidence of treatment-emergent adverse events [TEAEs] of nausea and/or vomiting). RESULTS: Statistically significantly higher mean SPID(48) values were observed with tapentadol IR (50 and 75 mg) and oxycodone HCl IR 10 mg than placebo (all p < 0.001). The efficacy of tapentadol IR 50 mg and 75 mg was non-inferior to oxycodone HCl IR 10 mg. The incidence of TEAEs of nausea and/or vomiting was statistically significantly lower with tapentadol IR 50 mg versus oxycodone IR 10 mg (35 vs. 59%; p < 0.001). No statistically significant difference in the incidence of nausea and/or vomiting was observed between tapentadol IR 75 mg and oxycodone IR 10 mg (51 vs. 59%; p = 0.057). A possible limitation of this study was that the intense dose and patient monitoring may not represent real-world situations and may result in higher incidences of TEAEs than expected in a practice setting; this bias would be similar for all treatment groups. CONCLUSIONS: Clinically meaningful and statistically significant improvements were observed with tapentadol IR 50 mg and 75 mg compared with placebo for the relief of moderate-to-severe acute pain after orthopedic surgery. Tapentadol IR 50 mg and 75 mg were non-inferior to oxycodone HCl IR 10 mg for the treatment of acute pain based on the primary efficacy endpoint of SPID(48) and the pre-specified margin of 48 points. The incidence of nausea and/or vomiting was statistically significantly lower for tapentadol IR 50 mg and numerically lower for tapentadol IR 75 mg than for oxycodone HCl IR 10 mg.