Drug shortages are a complex global challenge, and few studies have analyzed quantitative data on their impacts. In September 2019, detection of a nitrosamine impurity in ranitidine led to recalls and shortages.
The ranitidine shortage led to immediate and sustained shifts in H2RA utilization in both countries, potentially affecting hundreds of thousands of patients. Our results emphasize the need for future studies of the clinical and financial implications of the shortage, and the importance of ongoing work to mitigate and prevent drug shortages.
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On September 13, 2019, Health Canada and the United States Food and Drug Administration (US FDA) informed the public that the impurity N-nitrosodimethylamine (NDMA), a probable human carcinogen, had been detected in some ranitidine drug products [1, 2]. Within the same month, the first voluntary ranitidine recalls were announced in Canada and the US due to unacceptable NDMA levels [3, 4]. Over the following months, supply disruptions and ongoing recalls of ranitidine, and increased demand for alternatives, resulted in drug shortages in both countries [5, 6].
Ranitidine is a drug that inhibits gastric acid secretion [7]. The two classes of acid suppression drugs available in Canada and the US are histamine-2 receptor antagonists (H2RAs), which include ranitidine, and proton pump inhibitors (PPIs). H2RAs have been used for decades in the treatment of gastroesophageal reflux disease (GERD) and peptic ulcer disease (PUD) [7,8,9,10]. Compared to H2RAs, PPIs are newer, more potent, and more effective in the management of most GERD and PUD conditions [8, 9]. H2RAs and PPIs have both ranked consistently in the top 100 most-used drug classes in Canada and the US [11, 12]. Prior to the recalls and shortages, ranitidine was the most commonly used H2RA [13].
To our knowledge, the extent of the ranitidine shortage and its impact on the utilization of acid suppression drugs has not been studied. Our aim was to determine the impact of the ranitidine shortage on the utilization of H2RAs and PPIs in Canada and the US.
We conducted a repeated cross-sectional study over a 6-year period from January 2016 through December 2021 using monthly data for Canada and the US. We assessed the change in utilization of acid suppression drugs before and after the ranitidine recalls started in September 2019. We included all H2RA and PPI drug products available by prescription or over-the-counter in Canada or the US, including combination drug products containing an H2RA or PPI with one or more antacids (calcium carbonate, magnesium hydroxide or sodium bicarbonate). Combination products containing antibiotics were excluded because they are indicated for eradication of H. pylori infection, and not for acid suppression therapy.
We determined the utilization of acid suppression drugs by calculating the monthly number of units of all H2RA and PPI drug products purchased in Canada and the US. We adjusted the purchasing data for population size in each country using Statistics Canada and US Census Bureau population estimates [25,26,27]. We defined the purchasing rate as the monthly number of units purchased per 100,000 persons in the population. We categorized acid suppression drugs into three groups: (1) ranitidine, (2) non-ranitidine H2RAs (cimetidine, famotidine, and nizatidine), and (3) PPIs (dexlansoprazole, esomeprazole, lansoprazole, omeprazole, pantoprazole, and rabeprazole). Our primary outcome was the monthly purchasing rates for each of the three acid suppression drug groups. Secondary outcomes included purchasing rates for individual H2RA drugs and total H2RAs.
After the ranitidine recalls started, total purchasing rates for the H2RA drug class decreased and remained below pre-recall levels over the subsequent 2 years, with larger decreases in Canada (Supplemental Fig. 3). In both countries, famotidine accounted for the majority of non-ranitidine H2RA purchases before and after the ranitidine recalls started (Supplemental Figs. 4, 5).
The ranitidine recalls and shortages, which started in September 2019, led to immediate shifts in H2RA utilization which persisted throughout the remaining 2 years of our study period in Canada and the US. We observed shifts from ranitidine to non-ranitidine H2RAs in both countries; however, the patterns and timing of these shifts differed between countries. The broad impacts experienced in both countries highlight the potential clinical and financial implications of the ranitidine shortage.
Average ranitidine purchasing rates were similar in Canada and the US prior to the recalls. After the announcement of the NDMA impurity in ranitidine in September 2019, we observed immediate and long-term decreases in ranitidine utilization in both countries. These decreases likely resulted from the combined effects of several factors: ongoing recalls; shortages due to supply disruptions and product discontinuations; FDA and Health Canada alerts; and patient concerns about ranitidine safety [3, 33].
Prior to the recalls, over 20 million ranitidine units were purchased monthly in Canada and over 189 million units in the US on average. Assuming a typical 30- to 90-day supply of twice-daily ranitidine per prescription [34,35,36], we estimate that approximately 114,000 to 341,000 prescriptions were dispensed monthly in Canada and 1 to 3 million in the US. Therefore, hundreds of thousands of patients in each country were likely affected by the ranitidine shortage. This is not the first time that NDMA contamination of drug products has caused large-scale impacts; a Canadian study estimated that 160,000 patients were affected within 3 months of the NDMA-related recall of the antihypertensive drug valsartan in 2018 [37]. These examples highlight an ongoing need to address and prevent unacceptable levels of potentially carcinogenic impurities in medications [38, 39].
The patterns and timing of changes in ranitidine utilization differed between Canada and the US due to the different ways in which Health Canada and the FDA responded to the detection of NDMA in ranitidine. Immediately following the NDMA announcement in September 2019, Health Canada directed manufacturers to temporarily stop further distribution of ranitidine; after 3 months, ranitidine distribution was permitted to resume in Canada with increased NDMA testing requirements [40]. Accordingly, the ranitidine purchasing rate in Canada immediately dropped by over 99% from October through December 2019, followed by a slight increase (which remained below 30% of pre-recall purchasing rates) over the subsequent 2 years of our study period. In the US, distribution of ranitidine continued over the first 6 months after the NDMA announcement, with increased NDMA testing requirements for manufacturers [4]. The FDA requested the permanent withdrawal of ranitidine from the US market in April 2020, 7 months after the announcement of the NDMA impurity [41]. Accordingly, the ranitidine purchasing rate in the US initially declined to half of pre-recall levels in October 2019, and ultimately reached zero after April 2020.
While PPI purchasing rates increased somewhat over our study period, the changes after the start of the ranitidine recalls were not statistically significant in either country. It is surprising that we did not observe significant shifts toward PPI utilization. Guidelines for the management of GERD and PUD generally recommend PPIs as first-line therapy due to faster resolution of symptoms and higher healing rates, whereas the H2RAs have more limited roles as alternatives to PPIs or for the management of milder heartburn symptoms [8, 9, 43,44,45,46]. However, shifts toward PPIs may have been limited by increasing concerns about long-term safety, including risks of C. difficile and other enteric infections, and over-prescribing [8, 47]. National campaigns in Canada and the US have educated prescribers to reassess the need for long-term PPI therapy and titrate patients with GERD to the lowest effective dose [48, 49]. Whereas our study did not reveal shifts toward PPIs following the ranitidine recalls, a retrospective chart review of 210 patients in Cornwall, England found that 23% of patients formerly prescribed ranitidine were switched to PPIs; similar proportions were switched to non-ranitidine H2RAs (21.5%), stayed on ranitidine (24%), or tried various treatments (20%), while a minority (11.5%) stopped ranitidine and no replacement was prescribed [50]. While their study looked at prescribed acid suppression drugs in a primary care population, our study also captures broader drug utilization data, which may partly explain the different patterns observed, although future study is warranted.
In our results, between-country differences in acid suppression drug purchasing rates existed before the ranitidine recalls started and persisted throughout our study period. Purchasing rates for non-ranitidine H2RAs, primarily famotidine, were consistently higher in the US; conversely, purchasing rates for PPIs were consistently higher in Canada. We speculate that this could arise from differences in pharmaceutical policies and drug coverage restrictions between jurisdictions, as seen in another study comparing acid suppression drug utilization between Australia and Nova Scotia, Canada [51]. Future studies exploring the reasons for these between-country differences would be of interest.
Drug shortages negatively affect patients, healthcare providers and healthcare systems [14, 18]. Patients may fail to receive needed medications, or may experience delays in treatment [15, 52]. Medication errors and adverse drug events, including those involving serious patient harm or death, have occurred in the process of switching to replacement drugs [21, 53]. For healthcare systems, managing drug shortages can require substantial human and financial resources [15, 52]. In the ranitidine shortage, we observed major shifts in H2RA utilization within a short time period; the need to switch to replacement drugs likely put added strain on healthcare resources, and may have increased risks to patient health. Additionally, some patients might have discontinued ranitidine altogether, increasing the risk of symptoms due to untreated indications. Alternatively, the ranitidine shortage may have presented an opportunity to reassess the need for ongoing therapy and deprescribe unnecessary drugs [54]; a population-level study in the US revealed that over half of users of acid suppression drugs did not have a documented indication [13]. 152ee80cbc
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