Safety Monitoring of COVID-19 Vaccines in Persons with Prior SARS-CoV-2 Infection: A European Multi-Country Study.

In all pivotal trials of COVID-19 vaccines, the history of previous SARS-CoV-2 infection was mentioned as one of the main exclusion criteria. In the absence of clinical trials, observational studies are the primary source for evidence generation. This study aims to describe the patient-reported adverse drug reactions (ADRs) following the first COVID-19 vaccination cycle, as well as the administration of booster doses of different vaccine brands, in people with prior SARS-CoV-2 infection, as compared to prior infection-free matched cohorts of vaccinees. A web-based prospective study was conducted collecting vaccinee-reported outcomes through electronic questionnaires from eleven European countries in the period February 2021-February 2023. A baseline questionnaire and up to six follow-up questionnaires collected data on the vaccinee's characteristics, as well as solicited and unsolicited adverse reactions. Overall, 3886 and 902 vaccinees with prior SARS-CoV-2 infection and having received the first dose or a booster dose, respectively, were included in the analysis. After the first dose or booster dose, vaccinees with prior SARS-CoV-2 infection reported at least one ADR at a higher frequency than those matched without prior infection (3470 [89.6%] vs. 2916 [75.3%], and 614 [68.2%] vs. 546 [60.6%], respectively). On the contrary side, after the second dose, vaccinees with a history of SARS-CoV-2 infection reported at least one ADR at a lower frequency, compared to matched controls (1443 [85.0%] vs. 1543 [90.9%]). The median time to onset and the median time to recovery were similar across all doses and cohorts. The frequency of adverse reactions was higher in individuals with prior SARS-CoV-2 infection who received Vaxzevria as the first dose and Spikevax as the second and booster doses. The frequency of serious ADRs was low for all doses and cohorts. Data from this large-scale prospective study of COVID-19 vaccinees could be used to inform people as to the likelihood of adverse effects based on their history of SARS-CoV-2 infection, age, sex, and the type of vaccine administered. In line with pivotal trials, the safety profile of COVID-19 vaccines was also confirmed in people with prior SARS-CoV-2 infection.

Frequency and timing of adverse reactions to COVID-19 vaccines; A multi-country cohort event monitoring study.

INTRODUCTION: During the COVID-19 pandemic, EMA set-up a large-scale cohort event monitoring (CEM) system to estimate incidence rates of patient-reported adverse drug reactions (ADRs) of different COVID-19 vaccines across the participating countries. This study aims to give an up to date and in-depth analysis of the frequency of patient-reported ADRs after the 1st, 2nd, and booster vaccination, to identify potential predictors in developing ADRs and to describe time-to-onset (TTO) and time-to-recovery (TTR) of ADRs. METHODS: A CEM study was rolled out in a period ranging from February 2021 to February 2023 across multiple European countries; The Netherlands, Belgium, France, the United Kingdom, Italy, Portugal, Romania, Slovakia and Spain. Analysis consisted of a descriptive analyses of frequencies of COVID-19 vaccine-related ADRs for 1st, 2nd and booster vaccination, analysis of potential predictors in developing ADRs with a generalized linear mixed-effects model, analysis of TTO and TTR of ADRs and a sensitivity analysis for loss to follow-up (L2FU). RESULTS: A total of 29,837 participants completed at least the baseline and the first follow-up questionnaire for 1st and 2nd vaccination and 7,250 participants for the booster. The percentage of participants who reported at least one ADR is 74.32% (95%CI 73.82-74.81). Solicited ADRs, including injection site reactions, are very common across vaccination moments. Potential predictors for these reactions are the brand of vaccine used, the patient's age, sex and prior SARS-CoV-2 infection. The percentage of serious ADRs in the study is low for 1st and 2nd vaccination (0.24%, 95%CI 0.19--0.31) and booster (0.26%, 95%CI 0.15, 0.41). The TTO was 14 h (median) for dose 1 and slightly longer for dose 2 and booster dose. TTR is generally also within a few days. The effect of L2FU on estimations of frequency is limited. CONCLUSION: Despite some limitations due to study design and study-roll out, CEM studies can allow prompt and almost real-time observations of the safety of medications directly from a patient-centered perspective, which can play a crucial role for regulatory bodies during an emergency setting such as the COVID-19 pandemic.

Impact of the COVID-19 pandemic on cancer screenings in Portugal.

OBJECTIVES: This study aimed to evaluate the impact of the COVID-19 pandemic on cancer screening in Portugal, and its consequences on cancer morbidity and mortality. METHODS: The pre-pandemic and pandemic periods were compared using publicly available data on performance and health outcomes indicators of the Portuguese NHS, namely the numbers and proportions of eligible individuals who underwent cancer screening (breast, cervical or colorectal). Pre-pandemic data were modelled to project hypothetical scenarios without a pandemic using an exponential smoothing algorithm, and then compared with data collected during the COVID-19 pandemic. A Markov model was developed to estimate years of life lost (YLL) due the reduction in the number of cancer screenings during the pandemic. The MS Excel and the PRISM symbolic model checker software were used. RESULTS: There was a decrease in the number of breast (13 %), cervical (15 %) and colorectal (9-11 %) cancers screenings during the first two years of the pandemic. The model projections are 506, 41, and 148 additional deaths, losses of 11, 6, and 4 months of life per patient, and 12.8 thousand, 576, and 4 thousand YLL by the population due to breast, cervical, and colorectal cancer, respectively, over a 25-year time horizon in Portugal. CONCLUSIONS: The disruption in cancer screening may contribute to increase cancer morbidity and mortality, with significant YLL. The long-term implications of the impaired cancer screening should be assessed, and proactive measures put in place to mitigate the increase in cancer morbidity, and mortality associated with the COVID-19 pandemic.

The effectiveness of ibandronate in reducing the risk of nonvertebral fractures in women with osteoporosis: systematic review and meta-analysis of observational studies.

BACKGROUND: Ibandronate is effective in reducing the risk of vertebral fractures, but experimental evidence offers conflicting results regarding nonvertebral fractures. Real-world evidence has been published evaluating the anti-nonvertebral fracture effect of ibandronate. AIM: This meta-analysis of observational studies assessed the effectiveness of ibandronate in reducing the risk of nonvertebral fractures in women with osteoporosis. METHOD: Pubmed/Embase databases were searched for observational studies. Risks of nonvertebral fractures and hip fractures were the outcomes. Meta-analyses were performed pooling rate ratios (RRs), using random-effects models. Data were reanalysed in sensitivity analyses considering Knapp-Hartung method and Bayesian random-effects. RESULTS: Six cohort studies were included. Overall, once-monthly 150 mg oral ibandronate reduced the risk of nonvertebral fractures (RR 0.84; 95% CI 0.76-0.94). Similar results were obtained when the comparison was restricted to once-monthly 150 mg risedronate, but no differences were found when the comparator was other oral bisphosphonates (weekly alendronate/risedronate). Ibandronate didn't significantly change the risk of hip fractures (RR 1.25; 95% CI 0.89-1.76). The risk of hip fracture was comparable between once monthly, 150 mg oral ibandronate and other oral bisphosphonates. Intravenous ibandronate was not effective in reducing hip fractures comparing to intravenous zoledronate. The low number of studies diminished the robustness of sensitivity analyses. CONCLUSION: Results suggest that once-monthly 150 mg oral ibandronate may be as effective as other oral bisphosphonates in reducing the risk of nonvertebral fractures. However, uncertainty associated to the small number of included studies, which are characterized by heterogeneous demographics and methodologies, precluded definitive conclusions.

Topical Janus kinase inhibitors in atopic dermatitis: a safety network meta-analysis.

BACKGROUND: Topical Janus kinase (JAK) inhibitors are being developed for the treatment of mild to moderate atopic dermatitis. However, comparative evidence on their safety profiles is still limited. AIM: This study aimed to compare the relative safety of topic JAK inhibitors in patients with atopic dermatitis. METHOD: Phase 2 and 3 clinical trials (RCTs) evaluating the efficacy and safety of topical JAK inhibitors in atopic dermatitis were searched on Medline, EMBASE and clinicaltrials.gov. The following outcomes were considered: any adverse event (AE), serious AEs, AEs leading to treatment discontinuation, any infection, any application site reaction. RESULTS: Ten RCTs were included in this network meta-analysis. Tofacitinib was associated with a reduced risk of any AE when compared with ruxolitinib (OR 0.18, 95% CrI 0.03-0.92). The analyses for the remaining outcomes did not identify other statistically significant risk differences between the topical JAK inhibitors. CONCLUSION: Although tofacitinib seems to present a reduced risk of any adverse event compared with ruxolitinib, this was the only statistically significant result found between JAK inhibitors. Therefore, such findings should be interpreted with caution considering the scarce data available and the heterogeneity between the studies, and there is no robust evidence allowing pointing out clinically important differences between the safety profiles of the existing topical JAK inhibitors. Further pharmacovigilance activities are needed to confirm the safety profile of these drugs.

Performance of Aptima-HPV in the cervical cancer screening program of Portugal: a cost-analysis.

BACKGROUND: Cervical cancer is a major concern to women's health, being the fourth most common cancer worldwide. A great percentage of these cancer is consequence of an HPV infection, namely from specific genotypes such as 16/18. Portuguese screening program subjects women to a reflex cytology triage every 5 years. Aptima® HPV is a screening test which presents better specificity than other tests which are used in Portugal (Hybrid Capture® 2 and Cobas® 4800) and still have a comparable sensitivity. The present study aims to estimate the number of diagnostic tests and costs that are avoided using Aptima® HPV compared to the use of two other tests, Hybrid Capture® 2 and Cobas® 4800, within the cervical cancer screening programme in Portugal. METHODS: A model, consisting of a decision-tree, was developed to represent the full Portuguese screening program for cervical cancer. This model is used to compare the costs resulting from using Aptima® HPV test versus the other tests used in Portugal, during 2 years. Other outcomes such as the number of additional tests and exams were also computed. This comparison considers the performance of each test (sensitivity and specificity) and assumes an equal price for every test compared. RESULTS: Cost savings resulting from the use of Aptima® HPV are estimated at approximately €382 million versus Hybrid Capture® 2 and €2.8 million versus Cobas® 4800. Moreover, Aptima® HPV prevents 265,443 and 269,856 additional tests and exams when compared with Hybrid Capture® 2 and Cobas® 4800. CONCLUSIONS: The use of Aptima® HPV resulted in lower costs as well as less additional test and exams. These values result from the greater specificity of Aptima® HPV, which signals less false positive cases and consequently avoids carrying out additional tests.

Ibandronate in the Prevention of Vertebral and Nonvertebral Osteoporotic Fractures: A Systematic Review of Experimental and Observational Studies.

BACKGROUND/OBJECTIVE: This study aims to evaluate ibandronate clinical effectiveness in the prevention of osteoporosis-related vertebral fractures (VFs) and nonvertebral fractures (NVFs) in the treatment of postmenopausal osteoporosis. METHODS: This systematic review was conducted in accordance with the Centre for Reviews and Dissemination's guidance and reporting in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis statement 2020. A literature search was performed in PubMed and EMBASE since their inception until February 7, 2022. Randomized controlled trials (RCTs), meta-analysis, experimental, and observational studies evaluating adult patients treated with ibandronate and assessed to osteoporotic fractures prevention were included. The risk of bias was assessed according to study design. Data were analyzed using descriptive statistics. RESULTS: Eight references from 4 RCTs, 7 meta-analyses, and 6 observational studies were included. In RCTs, oral ibandronate was superior to placebo in the prevention of VF. However, the doses were lower than those approved. The meta-analyses confirmed these results and showed that adequate doses of oral ibandronate reduce the risk of NVF compared with insufficient doses. In observational studies, oral ibandronate (in approved doses) reduced the risk of VF compared with no treatment or risedronate or alendronate and the risk of NVF versus risedronate or alendronate; the risk of hip fractures was similar between ibandronate and other oral bisphosphonates. CONCLUSIONS: There is strong evidence that ibandronate reduces the risk of VF in postmenopausal osteoporosis. The available evidence further suggests that ibandronate may reduce the risk of NVF versus insufficient doses of ibandronate, as well as risedronate or alendronate.

The safety of systemic Janus kinase inhibitors in atopic dermatitis: a systematic review and network meta-analysis.

PURPOSE: Janus kinase (JAK) inhibitors have been developed to treat moderate to severe atopic dermatitis, but there is little evidence comparing the safety profile of these drugs. The aim of this study is to compare the relative safety of the different systemic JAK inhibitors in atopic dermatitis. METHODS: Medline, EMBASE, and clinicaltrials.gov were searched to identify phase 2/3, clinical trials (RCTs) designed to evaluate the efficacy and safety of systemic JAK inhibitors in atopic dermatitis. Outcomes were the risk of any adverse event (AE), serious AEs, AEs leading to treatment discontinuation, any infection, serious infections, herpes zoster infection, and any cardiac or vascular event. RESULTS: Eighteen RCTs were included. Compared with placebo, baricitinib (odds ratio [OR] 1.25, 95% credible interval [CrI] 1.03-1.55), abrocitinib (OR 1.54, 95% CrI 1.25-1.90), and upadacitinib (OR 1.46, 95% CrI 1.19-1.81) increase the risk of any adverse event. Abrocitinib (OR 1.62, 95% CrI 1.7-2.72), upadacitinib (OR 1.67, 95% CrI 1.19-2.43), and dupilumab (OR 1.69, 95% CrI 1.02-2.79) increase the risk of infections when compared with placebo. Dupilumab has a reduced risk of herpes zoster infection when compared with upadacitinib (OR 0.23; 95% CrI 0.08-0.81) No further statistically significant risk differences between treatments were identified. CONCLUSIONS: The results suggest systemic JAK inhibitors for atopic dermatitis have a similar safety profile. However, as current data present limitations, postmarketing safety evidence will be crucial to draw definitive conclusions regarding the safety of JAK inhibitors.

Classification of Pharmaceutical Policy Measures During the Portuguese Financial Crisis.

BACKGROUND: A rise in pharmaceutical expenses in Portugal led to the introduction of policy measures aimed at controlling outpatient public costs. This research examines and categorizes the most common pharmaceutical measures implemented during the Troika intervention, as well as comparing this period of time to prior ones. METHODS: A hierarchical structure of descriptors was built to classify and group measures over a 20-year period, including whether they might be deemed austerity measures. The nature, relative weight, and frequency of measures, along with the evolution of public drug expenditure, were assessed. RESULTS: Although there were fluctuations, frequency tended to increase. The highest number of policy changes per year was in 2010, a year before the financial assistance. The Troika intervention was characterized by a strong emphasis on pricing and prescription-related initiatives. Generic medicines played a significant role in the effort to reduce public drug expenditure. CONCLUSIONS: During the Troika intervention, outpatient public drug expenditure was consistently reduced through a comprehensive "package of measures" aimed at both the demand and supply sides. The effectiveness of some previous independent measures, if any, was temporary.

Development of medicines consumption in Portugal before and during the financial crisis.

BACKGROUND: In May 2011, the Portuguese Government signed a Memorandum of Understanding with the European Commission, the European Central Bank and the International Monetary Fund, including detailed measures to control health costs, allowing Portugal to receive a financial rescue package. This study aims to investigate medicines utilization in the outpatient sector during Troika's financial rescue. METHODS: Using Defined Daily Dose per million inhabitants per year as a measurement unit, we compared medicines utilization with other relevant indicators over 5-year intervals for a total period of 20 years, based on a built-in inventory of national outpatient drug use using the Intercontinental Medical Statistics Health and Anatomical Therapeutic Chemical index of the World Health Organization databases. The calculation was made on the basis of both compound and year-on-year growth rates. RESULTS: With the exception of the interval 2009-11, an absolute rise in consumption was observed over the 20-year period. The downturn occurred prior to financial rescue, when expenditure management mechanisms were already in place, and coincided with an increase in out-of-pocket spending. With the decline of cost for patients, the access trend returned to being positive, but at a slower pace. CONCLUSION: The rise in out-of-pocket and austerity measures may have led to decreased access to medicines. The findings of this study suggest that this impact was influenced by public cost-saving policies implemented even before the financial rescue. The results show that price reduction attenuated the repercussion of the measures.

Real-world intensive safety monitoring of biosimilars rituximab and trastuzumab in a Portuguese oncology hospital.

PURPOSE: The aim of this study was to assess the safety profiles of two biosimilar medicines (rituximab and trastuzumab) in the treatment of cancer patients within a Portuguese oncology hospital. METHODS: This hospital-based prospective observational study followed a cohort event monitoring approach focused on signalling suspected adverse drug reactions (ADRs). Patients undergoing treatment with rituximab biosimilar CT-P10 (Truxima®) or trastuzumab biosimilar CT-P6 (Herzuma®) were recruited over an 11-month and a 6-month period, respectively. Clinicians identified eligible patients and used paper-based forms to report all ADRs associated with biosimilar medicines. ADR case reports were assessed for seriousness, expectedness and causality in the Pharmacovigilance Unit of Coimbra. RESULTS: Ninety-four patients received biosimilar medicines (rituximab, n = 35; trastuzumab, n = 59). Of those, 4 patients (11.4%) experienced 16 ADRs with rituximab and 1 patient (1.7%) experienced 5 ADRs with trastuzumab. All case reports contained serious and expected ADRs that were at least probably related with biosimilar medicines under study. Based on the MedDRA PT coding, the most reported ADR for rituximab CT-P10 was chest discomfort (n = 4; 19.1%), followed by odynophagia (n = 2; 9.5%). Trastuzumab CT-P6 was associated with back pain, headache, pain in extremity, tachypnoea and tremor (each, n = 1; 4.8%). CONCLUSION: The results of this study suggest that using biosimilar rituximab and biosimilar trastuzumab to treat cancer patients in the real-world clinical setting is associated with acceptable safety profiles. No new safety problems were identified.

Rectus sheath hematoma in patients receiving subcutaneous enoxaparin: A case series of five patients.

Physicians must acknowledge the potential risk of RSH with enoxaparin. Switching home anticoagulation by enoxaparin upon hospital admission is common, but it may put patients at higher risk for RSH. Management guidelines are needed in this setting.

A Systematic Review of Economic Studies Evaluating Ophthalmic Drugs: An Analysis of the Health-state Utilities.

PURPOSE: To characterize the techniques used to derive health-state utilities (HSU) in the cost-utility studies (CUS) of ophthalmic drugs. METHODS: A systematic review was conducted in Pubmed/Embase until October 2019. CUS evaluating ophthalmic drugs were included. Therapeutic area, technique to derive HSU and sources of HSU were extracted. It was assessed if the HSU and the other parameters of CUS were collected from the same population. The techniques to derive HSU used in the CUS were compared to the techniques recommended by the country-specific economic evaluation guidelines. RESULTS: Seventy CUS were included. Forty-three (61.4%) used direct techniques to derive HSU, 19 (27.1%) used indirect, 1 (1.4%) used direct and indirect and the remaining (n = 7; 10.0%) used other or unknown techniques. Twelve (17.1%) CUS collected the HSU and the other parameters from the same population: nine (12.9%) retrieved utility data from experimental studies, two (2.9%) from observational and one (1.4%) from other sources. Forty-eight (68.6%) CUS collected the HSU and the other parameters from different populations: eight (11.4%) retrieved utility data from experimental studies, 33 (47.1%) from observational, one (1.4%) from both experimental and observational and six (8.6%) from other sources. It was not possible to identify the population from whom data were obtained in 10 (14.3%) CUS. Eleven (15.7%) CUS followed the recommendations of guidelines, 21 (30.0%) did not follow and for 38 (54.3%), it was not possible to assess. CONCLUSION: Choosing different techniques to derive HSU may result in different results, which can preclude the comparison between cost-utility studies.

Spontaneous reports of hypersensitivity adverse drug reactions in Portugal: a retrospective analysis.

BACKGROUND: Hypersensitivity adverse drug reactions (ADRs) are usually serious, unpredictable, and associated with high morbidity and mortality. This study describes cases of hypersensitivity ADRs spontaneously reported in Central Portugal. METHODS: Spontaneous reports (SRs) of ADRs received between 2010 and 2017 were reviewed to identify cases of hypersensitivity reactions, using a Standardized MedDRA Query (SMQ). Seriousness, expectedness, and causality were assessed. Descriptive statistics were used to analyze data. RESULTS: Among 2050 SRs, 598 (29.2%) contained 726 hypersensitivity ADRs: 657 (90.5%) serious, 569 (78.4%) unexpected, and 469 (64.6%) certainly related to drug exposure. Anaphylactic reactions (n = 93; 12.8%), rash maculopapular (n = 82; 11.3%), rash (n = 67; 9.2%) and DRESS (n = 54; 7.4%) were the most common reactions. Frequently implicated drug classes comprised antibiotics (n = 150; 23.0%), antineoplastic agents (n = 124; 19.0%), antigout preparations (n = 54; 8.3%), and anti-inflammatories (n = 44; 6.8%). Top-causative drugs were allopurinol (n = 54; 8.3%), docetaxel (n = 46; 7.1%), and trimethoprim/sulfamethoxazole (n = 26; 4.0%). CONCLUSIONS: Most hypersensitivity ADRs were serious, unexpected, and with strong causal relationship with suspected drugs. Allopurinol was the top-causative drug. Besides antibiotics and anti-inflammatories, antineoplastic agents were frequently cited. These results deserve further investigation.

An analysis of the effectiveness outcomes of economic studies evaluating ophthalmic drugs: a systematic review.

PURPOSE: To characterize the effectiveness measures of cost-effectiveness studies (CES) of ophthalmic drugs. METHODS: A systematic review was conducted in PubMed/Embase until October 2019. Cost-effectiveness studies (CES) evaluating ophthalmic drugs were included. Sources of effectiveness measures were extracted. Data on study design and study outcomes were extracted from sources of effectiveness measures. The adequacy of the sample size of the clinical studies used as sources of effectiveness measures was assessed. If CES have retrieved effectiveness data from multiple sources, the appropriateness of the method to combine the results was analysed. RESULTS: Forty-five CES were included. Thirty-one (68.9%) retrieved their effectiveness measures from experimental studies, five (11.1%) from observational studies and nine (20%) from other type of data sources. Eight (17.8%) CES used data from a primary outcome of a study as an effectiveness measure, eight (17.8%) used data from secondary outcomes, seven (15.6%) used data from the both primary and secondary outcomes and for 22 (48.9%) it was not possible to identify the outcomes used. From the 23 (51.1%) CES based on a single clinical study, three (6.7%) included data from clinical studies which had an adequate sample size to detect significant differences in the clinical outcomes used as effectiveness measures. From the 17 (37.8%) CES based on multiple clinical studies, only one (2.2%) used and/or reported an adequate method of quantitative synthesis (meta-analysis). CONCLUSION: A considerable number of CES in ophthalmology were not based on clinical studies with adequate sample sizes and report results from effectiveness measures not assessed as primary outcomes.

Risk of infections and cardiovascular and venous thromboembolic events associated with JAK inhibitors in rheumatoid arthritis: protocols of two systematic reviews and network meta-analyses.

INTRODUCTION: Janus kinases (JAK) inhibitors demonstrated to be effective in the treatment of adult patients with moderate-to-severe active rheumatoid arthritis (RA) but have been associated with serious cardiovascular and serious events. Two systematic reviews and network meta-analyses will be carried aiming to compare the relative safety of the different JAK inhibitors with regard to the risk of (1) cardiovascular and thromboembolic events and (2) serious infections in patients with RA. METHODS AND ANALYSIS: PUBMED, Embase, Cochrane Controlled Register of Trials and ClinicalTrials.gov will be searched in order to identify randomised controlled trials evaluating the efficacy and safety of JAK inhibitors in patients with RA. The following events will be assessed: (1) any cardiovascular event; major adverse cardiovascular events and venous thromboembolism and (2) any infection; serious infections; herpes zoster infection and tuberculosis. Search terms will comprise RA and drugs names, including the thesaurus terms and the International Nonproprietary Names. The assessment of the methodological quality of the included studies will be performed through the RoB 2 tool: a revised Cochrane risk of bias tool for randomised trials. Network meta-analyses will be performed using STATA V.13.0. For each outcome, treatments will be ranked according to the probability of being the safest (best) alternative using the surface under the cumulative ranking curve. ETHICS AND DISSEMINATION: Ethical approval is not required as no primary data are collected. This systematic review will be disseminated through peer-reviewed publications and at conference meetings.

Risk of nonarteritic ischaemic optic neuropathy with phosphodiesterase type 5 inhibitors: a systematic review and meta-analysis.

The development of nonarteritic anterior ischaemic optic neuropathy has been described to phosphodiesterase type 5 inhibitors. The aim of this systematic review and meta-analysis was to assess the risk of nonarteritic anterior ischaemic optic neuropathy associated with phosphodiesterase type 5 inhibitors exposure. A literature search was performed at MEDLINE, EMBASE, Toxline and VigiBase. Randomized controlled trials, observational studies, case reports and spontaneous reports describing nonarteritic anterior ischaemic optic neuropathy associated with phosphodiesterase type 5 inhibitors exposure were included. The risk of bias was assessed according to Centre for Reviews and Dissemination's (CRD) guidance. Data were analysed using descriptive statistics and meta-analysis. Four observational studies, 50 case reports and 608 spontaneous reports were identified. All observational studies evaluated males treated for erectile dysfunction. Treatment with phosphodiesterase type 5 inhibitors is not associated with an increased risk of definitive nonarteritic anterior ischaemic optic neuropathy [odds ratio (OR) 1.16; 95% CI 0.89, 1.52, p = 0.046; I2  = 62.6%]. The methodological quality was assessed as good for three studies. Among case reports, 12 (23%) patients did not have risk factors to develop nonarteritic anterior ischaemic optic neuropathy. Thirty-nine (78%) patients were treated for erectile dysfunction. A regular administration of phosphodiesterase type 5 inhibitors was observed in 24 (48%) case reports. All case reports were assessed as higher risk of bias. According to the available evidence, the treatment with phosphodiesterase type 5 inhibitors was not found to be associated with nonarteritic anterior ischaemic optic neuropathy. Further research is needed to study such association, including possible confounding factors.

Intensive safety monitoring program of antineoplastic medicines: A pilot study in a Portuguese oncology hospital.

PURPOSE: The aim of this study was to test the feasibility and the usefulness of an intensive safety monitoring program to identify adverse drug reactions for medicines under additional monitoring that are used to treat cancer patients within a Portuguese oncology hospital. METHODS: This pilot intensive safety monitoring program was a three-month prospective, observational study. Patients undergoing treatment with one of the following medicines were included: nivolumab, olaparib, palbociclib, pembrolizumab, pertuzumab, ramucirumab, ribociclib, trastuzumab emtansine, or trifluridine/tipiracil. Potential eligible patients were identified by pharmacists based on prescription data. Clinicians used proper paper-based reporting forms to record adverse drug reactions. Clinical secretariats sent those reports through an electronic platform to the pharmacovigilance department for analysis. RESULTS: Seventy-five patients were on treatment with selected medicines. Of those, 33 (44%) experienced adverse drug reactions: 23 (69.7%) cases were serious and 5 (15.2%) unexpected. Considering the number of patients exposed to each medicine and the number of patients experiencing adverse drug reactions, trifluridine/tipiracil (72.7%; 8/11) was associated with the highest rate of toxicity, followed by olaparib (66.7%; 2/3), trastuzumab emtansine (50.0%; 3/6), pertuzumab (47.8%; 11/23), pembrolizumab (45.5%; 5/11), palbociclib (25.0%; 1/4), and nivolumab (18.8%; 3/16). A total of 59 adverse drug reactions were identified (i.e. 1.8 adverse drug reactions/patient), mainly gastrointestinal disorders (n = 15; 25.4%), and blood and lymphatic system disorders (n = 14; 23.7%). CONCLUSION: This intensive safety monitoring program was feasible and allowed identifying serious and unexpected adverse drug reactions, adding value to pharmacovigilance and therefore contributing to improve patient safety. Further research is needed to confirm the findings of this pilot study.

Outcomes From the First 6 Years of Operation of the Central Portugal Pharmacovigilance Unit.

OBJECTIVES: The aim of this study was to analyze and characterize the outcomes of the Central Portugal Regional Pharmacovigilance Unit over a 6-year period. METHODS: Spontaneous reports received between January 2009 and December 2014 were considered. The annual reporting ratios were estimated. The cases were characterized according to their seriousness, previous description, causality assessment, reporting professional, pharmacotherapeutic groups of the suspected drugs, and type of adverse drug reactions most frequently reported. RESULTS: The Pharmacovigilance Unit received 1277 reports that contained 3222 adverse events. In 2014, the reporting rate was estimated at 124 reports per million inhabitants. Sixty-five percent of the reports were assessed as serious. Seventy-three percent of the cases were assessed as being at least possibly related with the suspected drug. Physicians reported 49% of the cases. The suspected drugs most frequently reported were "anti-infectives for systemic use" (n = 494, 38%). The most frequently reported adverse events were "general disorders and administration site conditions" (n = 667, 21%). CONCLUSIONS: Despite the continuous efforts carried out by the Central Portugal Regional Pharmacovigilance Unit in promoting spontaneous reports of suspected adverse drug reactions, the results, although representing a contribution to the postmarketing safety monitoring of drugs, are still modest illustrating the need to promote the adherence of health-care professionals to the pharmacovigilance system and to increase their reporting rates of suspected ADRs.