WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Bleeding is the main adverse drug reaction of warfarin use. • Several medicines, herbal products and dietary supplements may interact with warfarin. • A high percentage of patients on warfarin receive potentially interacting substances. WHAT THIS STUDY ADDS • Potentially interacting medicines were used in more than 50% of the warfarin‐associated bleeding events reported to the Norwegian spontaneous reporting system. • Only a minority of the concomitant medicines were reported as suspected or interacting in the reporters' assessments. • There was a higher degree of under‐reporting of pharmacokinetically than of pharmacodynamically interacting medicines. AIMS To study warfarin associated bleeding events reported to the Norwegian spontaneous reporting system and evaluate the differences in assessment of potentially interacting medicines between reporters and evaluators. METHODS Data on bleeding events on warfarin were retrieved from the Norwegian spontaneous reporting system database. Key measurements were time to bleeding, use of concomitant medications and the evaluation done by reporters. RESULTS In 289 case reports a total of 1261 medicines (median 4.0 per patient, range 1–17) was used. The evaluators (authors of this article) identified 546 medicines including warfarin (median 2.0 per patient, range 1–7) that could possibly cause bleeding alone or in combination. Reporters assessed 349 medicines (median 1.0 per patient, range 1–4) as suspect. Evaluators identified 156 pharmacokinetic and 101 pharmacodynamic interactions, compared with 19 pharmacokinetic and 56 pharmacodynamic interactions reported as suspected by the reporters. Time to bleeding was stated in 224 reports. Among the early bleeding events, the reports on warfarin without interacting medicines showed the highest INR (international normalized ratio). Heparin was used in 17/21 reported bleeding events during the first week on warfarin. Among the late bleeding events, reports with pharmacokinetic interacting medicines had the highest INR. CONCLUSIONS Concomitant use of potentially interacting medicines was involved in the majority of the warfarin‐associated bleeding events reported to the Norwegian spontaneous reporting system. Reporters assessed mostly warfarin as the only contributor to bleeding. In particular, pharmacokinetically interacting medicines were not suspected as contributing to bleeding.
Complying with good manufacturing practices (GMP) and ensuring a quality system is integral to production and supply of quality medicines and achieving universal health coverage. This study focus on the local production of medicines in Pakistan, a lower middle-income country that has observed considerable growth in the number of pharmaceutical companies over the past two decades. Against this background, we investigated: (1) How is quality assurance (QA) and GMP compliance understood and acted upon by local pharmaceutical manufacturers?; (2) What are the institutional barriers and enablers for QA and GMP compliance in the local pharmaceutical sector from the perspective of key stakeholders?; and (3) What are the institutional barriers and enablers for strengthening local regulatory capacity to improve QA in the industry in the long term? We used a qualitative study design involving 22 interviews of the drug regulatory bodies (n = 9), academia (n = 3) and local manufacturers (n = 10), identifying key themes in data by thematic analysis. Document analysis was used to collect additional information and supplement the interview data. We identified that manufacturing facilities operated under different GMP standards and interpretations, pointing towards an absence of harmonization in quality standards across the industry. Views diverged about the status of GMP compliance, with interviewees from academia presenting a more critical view compared with regulators who promoted a more positive story. Among the barriers explaining why companies struggled with quality standards, the lack of a mindset promoting quality and safety among profit-oriented manufacturers was prominent. At the federal level, DRAP’s establishment represented an institutional improvement aiming to promote QA through inspections and guidance. While some positive measures to promote quality have been observed, the need for DRAP to strengthen its technical and regulatory capacity, enhance its engagement in international collaboration and learning, and improve transparency and accountability were highlighted. Overall, since the challenges in Pakistan are shared with other low- and middle-income countries with local production, there is a need to commit to international collaborative mechanisms, such as those lead by WHO, on this issue.
In most hospitals, the addition of drugs to infusion fluids is carried out by nurses. The preparation involves certain hazards both microbiologically and pharmaceutically. Incompatibilities between drug and fluid or between drugs may result in admixtures which have reduced therapeutic activity or which are even hazardous to the patient.The all‐in‐one total parenteral nutrition mixtures represent a new way of administering nutrition and has achieved increased popularity both for in‐ and outpatients. During preparation, which takes place in the pharmacy, several precautions have to be taken to assure a product with acceptable stability. Some of the important incompatibilities are mentioned.
Non-warfarin-associated bleeding events are associated with substantial mortality. Old age, cerebral bleeds, number of drugs used, and use of fibrinolytics are all independently associated with increased mortality. The recognition of the bleeding risk of commonly used drugs such as acetylsalicylic acid and heparins may be insufficient among prescribers.
A 54-year-old man of Asian origin with major depression developed an asthma-like reaction during venlafaxine treatment. Two weeks after therapy was initiated, he experienced gradually worsening dry cough at night and periodically dyspnea during the daytime. After 5 weeks, clinical examination revealed marked signs of pulmonary obstruction and the forced expiratory volume (FEV1) was assessed to only 32% of the expected value. The venlafaxine medication was gradually decreased and eventually discontinued 9 weeks after its initiation, resulting in a successive improvement of the patient's respiratory complaints.
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