Safety of peanut (Arachis hypogaea) allergen powder-dnfp in children and teenagers with peanut allergy: Pooled summary of phase 3 and extension trials.

BACKGROUND: Peanut (Arachis hypogaea) allergen powder-dnfp (PTAH; previously known as AR101) is a daily oral immunotherapy approved to mitigate allergic reactions after accidental peanut exposure in peanut-allergic individuals aged 4-17 years. OBJECTIVE: We sought to comprehensively summarize the PTAH safety profile for up to ∼2 years of treatment. METHODS: Safety and adverse event (AE) data from participants aged 4-17 years from 3 controlled, phase 3 and 2 open-label extension trials were pooled and assessed. RESULTS: Of the 944 individuals receiving ≥1 PTAH dose, median exposure was ∼49 weeks; most participants experienced ≥1 treatment-related AE (TRAE; n = 853; 90.4%). A total of 829 participants experienced TRAEs with a maximum severity of mild (497, 52.6%) or moderate (332, 35.2%); 24 participants (2.5%) experienced TRAEs graded as severe. Overall, 80 participants (9.5%) discontinued as a result of AEs; most experienced gastrointestinal symptoms and discontinued during the first 6 months. When adjusted for exposure, AEs and TRAEs occurred at a rate of 76.4 and 58.7 events per participant-year of exposure (PYE), respectively, during updosing; AEs and TRAEs decreased to 23.0 and 14.2, respectively, during 300 mg maintenance. Overall, exposure-adjusted rates of systemic allergic reactions were 0.12 events/PYE (mild), 0.11 events/PYE (moderate), and 0.01 events/PYE (severe [anaphylaxis]). CONCLUSION: The safety profile of PTAH was consistent across trials, manageable, and improved over time. AEs were predominantly mild to moderate, and all grades declined in frequency with continued treatment. These data can be used to facilitate shared decision-making discussions with patients and families considering treatment with PTAH.

Final report on exposure during pregnancy from a pregnancy registry for quadrivalent human papillomavirus vaccine.

OBJECTIVE: To better describe the safety profile of pregnancy exposures to the qHPV vaccine by acquiring and analyzing post-marketing data on pregnancy outcomes. METHODS: This is a voluntary, post-marketing prenatal vaccine exposure registry. Enrollment criteria included an identifiable patient and health care provider from the United States, France, or Canada and exposure within 1 month before the date of onset of the last menstrual period or at any time during pregnancy. Outcomes of interest were pregnancy outcomes and birth defects. Prospectively reported cases were used for rate calculations. RESULTS: For the 1752 prospective reports with known outcome, 1518 (86.6%) were live births, including ten twin pregnancies. Of 1527 neonates, 1444 (94.6%) had no congenital anomalies. The overall rate of spontaneous abortion was 6.7 per 100 outcomes (95% confidence interval [CI] 5.5-8.2). The prevalence of major birth defects was 2.4 per 100 live-born neonates (95% CI 1.7-3.3). There were 12 fetal deaths (0.8 per 100 outcomes, 95% CI 0.4-1.4). CONCLUSION: Rates of spontaneous abortions and major birth defects were not greater than the general population rates. Although no adverse signals have been identified to date, the qHPV vaccine is not recommended for use in pregnant women.

Closure of varicella-zoster virus-containing vaccines pregnancy registry - United States, 2013.

Vaccines that contain live attenuated varicella-zoster virus (VZV) (Varivax, ProQuad, and Zostavax [all products of Merck & Co., Inc.]) are contraindicated during pregnancy. To monitor the pregnancy outcomes of women inadvertently vaccinated with VZV-containing vaccines immediately before or during pregnancy, Merck and CDC established the Merck/CDC Pregnancy Registry for VZV-Containing Vaccines in 1995. This report updates previously published summaries of registry data, provides the rationale for the closure of the registry, and describes plans for continued monitoring of the safety of these vaccines when inadvertently administered to pregnant women or immediately before pregnancy. From inception of the registry in 1995 through March 2012, no cases of congenital varicella syndrome and no increased prevalence of other birth defects have been detected among women vaccinated within 3 months before or during pregnancy. Although a small risk for congenital varicella syndrome cannot be ruled out, the number of exposures being registered each year (approximately two varicella-susceptible women exposed during the high-risk period for congenital varicella syndrome) is now too low to improve on the current estimate of the risk.

Measles, mumps, and rubella virus vaccine (M-M-R™II): a review of 32 years of clinical and postmarketing experience.

M-M-R™II (measles, mumps, and rubella virus vaccine live; Merck, Sharp, & Dohme Corp.) is indicated for simultaneous vaccination against measles, mumps, and rubella in individuals ≥ 12 months of age. Before the vaccine era, these viruses infected most exposed individuals, with subsequent morbidity and mortality. One of the greatest achievements of public health has been to eliminate these 3 diseases in large geographic areas. The safety profile of M-M-R™II is described using data from routine global postmarketing surveillance. Postmarketing surveillance has limitations (including incomplete reporting of case data), but allows collection of real-world information on large numbers of individuals, who may have concurrent medical problems excluding them from clinical trials. It can also identify rare adverse experiences (AEs). Over its 32-year history, ≈ 575 million doses of M-M-R™II have been distributed worldwide, with 17,536 AEs voluntarily reported for an overall rate of 30.5 AEs/1,000,000 doses distributed. This review provides evidence that the vaccine is safe and well-tolerated.

Clinical trial and post-licensure safety profile of a prophylactic human papillomavirus (types 6, 11, 16, and 18) l1 virus-like particle vaccine.

BACKGROUND: We describe the safety of the human papillomavirus (HPV)-6/11/16/18 vaccine using updated clinical trial data (median follow-up time of 3.6 years) and summarize up to 3 years of post-licensure surveillance. METHODS: In 5 clinical trials, 21,480 girls/women aged 9 to 26 years and boys aged 9 to 16 years received >or=1 dose of HPV-6/11/16/18 vaccine or placebo. All serious and non-serious adverse experiences (AEs) and new medical conditions were recorded for the entire study period(s). As of June 2009, >25 million doses of HPV-6/11/16/18 vaccine had been distributed in the United States with >50 million doses globally. Post-licensure safety as summarized by the Centers for Disease Control and Prevention using the United States Vaccine Adverse Event Reporting System database is also reported. RESULTS: Eight subjects experienced a treatment-related serious AE (0.05% vaccine; 0.02% placebo). Of 18 deaths (0.1% vaccine; 0.1% placebo), all were considered unrelated to study treatment. New medical conditions which were potentially consistent with autoimmune phenomena were reported in 2.4% of both vaccine and placebo recipients. Pain, the most common injection-site AE, occurred more frequently with vaccine (81% vaccine; 75% placeboaluminum; 45% placebo-saline). No differences were seen in the incidence of the most common non-serious AEs-headache and pyrexia. The Vaccine Adverse Event Reporting System has received 14,072 reports for the HPV-6/11/16/18 vaccine since licensure, with only 7% being serious AEs, about half the average reported for licensed vaccines in general. CONCLUSIONS: HPV-6/11/16/18 vaccination was associated with more injection-site pain than placebo but similar incidences of systemic and serious AEs and new medical conditions potentially consistent with autoimmune phenomena. Based on review of post-licensure safety information, the benefits of vaccination to prevent the majority of genital tract precancers and cancers continue to far outweigh its risks.

Pregnancy outcomes from the pregnancy registry of a human papillomavirus type 6/11/16/18 vaccine.

OBJECTIVE: To better describe the safety profile of pregnancy exposures to the human papillomavirus (HPV) type 6/11/16/18 vaccine by acquiring and analyzing postmarketing data on pregnancy outcomes (ie, live births, abortions, fetal deaths, and congenital anomalies). METHODS: Enrollment criteria included an identifiable patient and health care provider from the United States, France, or Canada and exposure within 1 month before the date of onset of the last menstrual period or at any time during pregnancy. Outcomes of interest were pregnancy outcomes and birth defects. Prospectively reported cases (reported before the outcome of the pregnancy was known) were used for rate calculations. RESULTS: For the 517 prospective reports with known outcome, 451 (87.2%) were live births, including three sets of twins. Of 454 neonates, 439 (96.7%) were normal. The overall rate of spontaneous abortion was 6.9 per 100 outcomes (95% confidence interval [CI] 4.8-9.6). The prevalence of major birth defects was 2.2 per 100 liveborn neonates (95% CI 1.05-4.05). There were seven fetal deaths (1.5 per 100 outcomes, 95% CI 0.60-3.09). CONCLUSION: Rates of spontaneous abortions and major birth defects were not greater than the unexposed population rates. Although no adverse signals have been identified to date, the HPV6/11/16/18 vaccine is not recommended for use in pregnant women. LEVEL OF EVIDENCE: III.

Randomized, open-label, comparative study of piperacillin-tazobactam administered by continuous infusion versus intermittent infusion for treatment of hospitalized patients with complicated intra-abdominal infection.

The purpose of this randomized, multicenter, open-label study was to compare the continuous infusion of piperacillin-tazobactam with the standard intermittent infusion in 262 hospitalized patients with complicated intra-abdominal infections. Within 1 day of surgical intervention, eligible patients were randomized (1:1) to piperacillin-tazobactam 12 g/1.5 g administered continuously over 24 h or 3 g/0.375 g administered over 30 min intermittently every 6 h for 4 to 14 days. The demographics of the patients in the groups were similar, with a median APACHE II score of 7 and a median length of hospitalization of 7 days. Among 167 clinically evaluable patients, 86.4% and 88.4% of the patients treated with the continuous infusion and the intermittent infusion, respectively, were clinically cured or improved at the test-of-cure visit (P = 0.817). Bacteriological success was observed in 83.9% and 87.9% of patients (P = 0.597) in the two groups, respectively, and no differences in bacteriological response by pathogen were noted. Defervesence and white blood cell count normalization occurred in the majority of patients within 3 days and were similar between patients receiving the continuous infusion and those receiving the intermittent infusion. Drug-related adverse events were generally mild and were reported in similar numbers of patients in each arm of the trial. The results of this study support continuous infusion as a safe and reasonable alternate mode of administration of piperacillin-tazobactam for the treatment of complicated intra-abdominal infection.

Population pharmacokinetics and pharmacodynamics of piperacillin/tazobactam in patients with complicated intra-abdominal infection.

OBJECTIVES: We investigated the population pharmacokinetics and pharmacodynamics of piperacillin and tazobactam in hospitalized patients. PATIENTS AND METHODS: A multicentre, randomized clinical trial was conducted in hospitalized patients with complicated intra-abdominal infection. Patients received piperacillin/tazobactam administered by either continuous infusion (13.5 g over 24 h, n = 130) or intermittent infusion (3.375 g every 6 h, n = 132). NONMEM was used to perform population pharmacokinetic analysis in a subset of patients (n = 56) who had serum samples obtained at steady-state for drug concentration analyses. Classification and regression tree analysis was used to identify the breakpoints of piperacillin PK-PD indexes in 94 patients with causative pathogen's MIC. RESULTS: A one-compartment model was applied to fit the data. Creatinine clearance and body weight were the most significant variables to explain patient variability in piperacillin and tazobactam clearance and volume of distribution. The infusion method had no influence on PK parameters. For patients (n = 30) receiving intermittent infusion in the pharmacokinetic study, mean Cmax and half-life were 122.22 mg/L and 1.17 h for piperacillin, and 15.74 mg/L and 1.81 h for tazobactam. For patients (n = 26) receiving continuous infusion in the pharmacokinetic study, mean steady-state concentration was 35.31 +/- 12.15 mg/L for piperacillin and 7.29 +/- 3.28 mg/L for tazobactam. As a result of a low rate of failures (<11%) observed in the trial and the low MICs for infecting pathogens, no association could be established between clinical/microbiological outcome and drug exposure. CONCLUSIONS: Intermittent infusion and continuous infusion of piperacillin and tazobactam provided sufficient drug exposure to treat those pathogens commonly implicated in intra-abdominal infections.

An open-label, randomized study comparing efficacy and safety of intravenous piperacillin/tazobactam and ampicillin/sulbactam for infected diabetic foot ulcers.

BACKGROUND: Soft tissue and bone infections of the lower limb continue to be a frequent and serious complication in patients with diabetes mellitus. The best choice of antimicrobial for the empiric treatment of moderate to severe diabetic foot infections has not been established clearly. METHODS: We conducted a prospective, randomized, open-label, multicenter trial comparing piperacillin/tazobactam (P/T) (4 g/0.5 g q8h) and ampicillin/sulbactam (A/S) (2 g/1 g q6h) as a parenteral treatment for 314 adult patients with moderate-to-severe infected diabetic foot ulcers. Patients with polymicrobial infections involving methicillin-resistant Staphylococcus aureus also received vancomycin 1 g q12h. RESULTS: Clinical efficacy rates (cure or improvement) were statistically equivalent overall (81% for P/T vs. 83.1% for A/S), and median duration of treatment was similar in the clinically evaluable populations (nine days for P/T, 10 days for A/S). Drug-related adverse events for both study drugs were comparable in frequency and type. CONCLUSIONS: Although both study drugs provide safe and effective empiric treatment for moderate-to-severe infected diabetic foot ulcers, piperacillin/tazobactam has the advantage of covering Pseudomonas aeruginosa (bacteriologic success rate of 85.7%), the most commonly isolated gram-negative pathogen in this study.