Absence of Inhibitor Development in the Routine Clinical Use of Alphanate® in Patients with Severe Hemophilia A: Results From a Long-Term Post-Marketing Surveillance Study.
Charles L. SexauerYasmin AyobMadeline CantiniMiguel A. EscobarTamiko FukudaKristine HoltzPier Mannuccio ManucciKathryn MoynihanKapil SaxenaChristopher WalshAntonio PáezPaul P PinciaroMichael K. Woodward
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Onabotulinumtoxin A (onabotA) has shown efficacy in chronic migraine (CM), with good tolerability and a low rate of adverse effects, most of them not severe. The aim of this study is to evaluate tolerability and adverse effects of onabotA in clinical practice and to analyze if there is a relationship between tolerability to treatment administration, adverse effects' (AEs) occurrence and clinical response. We included patients with CM that received treatment with onabotA for the first time. Tolerability to treatment was evaluated by a 0-10 numeric rating scale (0: worst possible, 10: optimal tolerability). We assessed the presence of AEs by using a standardized questionnaire. Treatment response was based on the 50 and 75% responder rate between weeks 20 and 24, compared with the baseline, according to headache diaries. We analyzed whether the tolerability was associated with a higher frequency of AEs or a higher probability of clinical response. We included 105 patients, 87.7% female, with an age of 43.9 ± 10.7 years. Mean tolerability was 7.8/10 and 7.2/10 in the first and second onabotA administration, respectively. AEs were reported by (first-second) 71.4-68.6% patients. The percentage of patients with a 50% response was 56.3%. There was no association between tolerability and AEs' occurrence or clinical response.
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Objectives:GOAL (Gauging Osteoarthritis [OA] with Limbrel *Limbrel is manufactured by Primus Pharmaceuticals, Inc., Scottsdale, AZ, USA.), an open-label, post-marketing study was performed to determine the overall efficacy and gastrointestinal (GI) tolerability of flavocoxid, a novel, plant-based, anti-inflammatory medication, in a 'real world' clinical practice setting. To this end, the study enrolled several unique patient types including nonsteroidal anti-inflammatory drug (NSAID) naïve patients, those who had used NSAIDs in the past, regardless of outcome (positive or negative), and those who had previously taken a gastroprotective medication to improve GI tolerability or continued to take it as a precautionary measure to prevent NSAID-associated GI damage.
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Summary: Purpose: To evaluate the tolerability and safety of gabapentin (GBP) as add‐on therapy for seizure control. Methods: Conducted in an outpatient setting and reflecting usual practice, this study compared tolerability of GBP dosages ≤1,800 versus >1,800 mg/day, when these doses were required to achieve the most effective seizure control. Two analyses of adverse events are presented: tolerability and safety. In the tolerability analysis, each patient served as his or her own control to compare the occurrence of adverse events at GBP ≤1,800 versus >1,800 mg/day. The safety analysis required patients to receive at least one dose of GBP and have a follow‐up contact. Results: A total of 2,216 patients enrolled in this open‐label, 16‐week study and were evaluable for safety. Of these, 74.0% completed the 16‐week study, and 281 met the tolerability criteria. Within these 281 patients, two mutually exclusive groups were compared (a) those reporting adverse events at only ≤1,800 mg/day (low dose); and (b) those reporting adverse events at only >1,800 mg/day (high dose). Three adverse events (asthenia, headache, and dizziness) were observed in a statistically significantly larger number of patients at only the low dose than in the group reporting these same adverse events at only the high dose, suggesting that patients who tolerated GBP at ≤1,800 mg/day did not experience a significant increase in adverse events with dosages >1,800 mg/day. Overall, 10.6% of the 2,216 patients in the safety population prematurely withdrew because of adverse events, and 3.5% discontinued because of lack of efficacy. Safety and tolerability of GBP was rated as excellent or good for 78.5% of all patients. Conclusions: Gabapentin doses >1,800 mg/day were as well tolerated as doses ≤1,800 mg/day and were not associated with more adverse events.
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Drug tolerability refers to the degree to which drugs' overt adverse effects can be tolerated by patients. The tolerability profile is of comparative importance to its efficacy and safety, as it largely determines adherence to treatment and ultimately treatment success or failure. However, the term is frequently used imprecisely, and it is unclear if tolerability is limited to subjective patient-reported symptoms or also covers certain objective signs and findings. The aim of this systematic review was to assess how clinical studies define, evaluate and present drug tolerability.The study consisted of a systematic review of clinical studies in PubMed® reporting the term "tolerability".Eighty clinical studies were screened and 56 studies reporting drug tolerability were retained. None of the retained studies defined events encompassed by the term tolerability by making a distinction between safety and tolerability. Twenty-five studies claimed to evaluate tolerability, but none of them described how to evaluate tolerability from the patient perspective. Most studies (54 out of 56) concluded that the treatment was well tolerated, apparently implying favourable safety. However, none of them actually presented tolerability in terms of a contrast between safety and tolerability.Tolerability is used frequently, albeit incorrectly, to refer to a drug's favourable safety profile. Focused evaluation of drug tolerability (i.e., the patient perspective of adverse drug reactions) should become routine. Presentation in regulatory documents, such as risk management plan summaries, product information and patient leaflets should be a continuation of the process of patient-centred healthcare.
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Dalfampridine extended release tablets (dalfampridine-ER; prolonged-, modified, or sustained-release fampridine in some countries) were approved in the US to improve walking in patients with multiple sclerosis, as demonstrated by improvement in walking speed. Postmarketing safety experience is available from exposure of approximately 46,000 patients in the US from product approval through March 2011.To provide a descriptive analysis of all spontaneously reported postmarketing adverse events (AEs) for dalfampridine-ER since product launch.AE data were extracted from the safety database from product launch through March 31, 2011; AEs were classified using the Medical Dictionary for Regulatory Activities. Seizure cases were reviewed for patient demographics, time to event from treatment onset, and presence of additional risk factors.THE MOST FREQUENTLY REPORTED POSTMARKETING AES WERE SIMILAR TO THOSE REPORTED DURING CLINICAL DEVELOPMENT: dizziness, insomnia, balance disorder, headache, nausea, urinary tract infection, asthenia, and back pain (all included in US product labeling). New clinically significant findings are related to lack of efficacy and inappropriate dosing. Of the approximately 46,000 patients exposed, 85 seizures were reported (∼5.4/1000 patient-years), of which 82 were reported or confirmed by a health care practitioner (∼5.2/1000 patient-years). Beyond the intrinsic multiple sclerosis-related seizure risk, more than half of the 85 cases (62%) had an additional potential risk factor for seizure including a previous history of convulsions, renal impairment, incorrect dosing, or use of concurrent medications with a labeled seizure risk. Duration of treatment prior to the seizure ranged from one dose to 365 days; 26/85 (31%) patients suffered a seizure within a week of starting treatment.Spontaneous safety data from the US postmarketing experience were consistent with the safety profile seen during clinical development. Although first-year seizure incidence was not substantially different from that observed in dalfampridine-ER clinical trials, patients should be monitored for concomitant use of drugs that lower seizure threshold.
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To assess the use, and evaluate the usefulness, of non-interventional studies and routinely collected healthcare data in postmarketing assessments conducted by the European Medicines Agency (EMA).We reviewed and systematically assessed all referrals to the EMA made due to safety or efficacy concerns that were evaluated between 1 January 2013 and 30 June 2017. We extracted information from the assessment report and the referral notification. Two reviewers independently assessed the contribution of non-interventional evidence to decision-making.The preliminary evidence leading to the assessment in 52 eligible referrals was mostly from spontaneous reports (cited in 26 of 52 referrals) and randomised trials (22/52). In contrast, many evidence types were used for the full assessment. Non-interventional studies were frequently used in the full assessment for the evaluation of product safety (31/52) and product efficacy (18/52). In particular, non-interventional studies were relied on for the evaluation of safety and efficacy in subgroups, the evaluation of safety relating to a rare adverse event, understanding product usage and misuse and for evaluation of the effectiveness of risk minimisation measures. The most common recommendations were changes to product information (43/52) and marketing authorisation withdrawal or suspension (12/52). In the majority of referrals, non-interventional evidence was judged to contribute to the decision made (30/52) and in three referrals it was the primary source of evidence.European regulatory decision-making relies on multiple evidence types, particularly randomised trials, spontaneous reports and non-interventional studies. Non-interventional studies had an important role particularly for the characterisation and quantification of adverse events, the evaluation of product usage and for evaluating the effectiveness of regulatory action to minimise risk.
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