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Two key features limited broad acceptance by patients and physicians.   Each dose had to be taken at least ½ hour prior to the first food or beverage of the day, due to an interaction that greatly reduced bioavailability. Second, each tablet had to be followed by a full glass of water and patients had to remain upright before eating to reduce the risk of esophagitis due to either esophageal tablet retention or reflux.  While esophagitis was not common in phase 3 studies, case reports of esophagitis that was more severe than observed in phase 3 trials appeared (published in NEJM) shortly after launch.   Moreover, these events were often associated with incorrect administration (e.g., while supine, without water, after the onset of esophageal symptoms).

These limitations were addressed in 3 ways.

·         Physician and patient education on the importance of carefully following dosing instructions

·         Non-clinical studies of the mechanism of esophageal irritation

·         Alternative dose forms and regimens

New, non-clinical studies indicated that a single exposure to alendronate resulted in little or no esophageal injury.  However, multiple daily exposures to alendronate resulted in mucosal injury and acidic solutions were much more irritating than solutions with a neutral pH.  Alendronate and other nitrogen-containing bisphosphonates were shown to inhibit farnesyl-diphosphate synthase in epithelial cells in vitro, suggesting that esophageal injury was not due a simple physicochemical phenomenon.  These findings led to the hypothesis that a higher, less frequent dose of alendronate (or another nitrogen-containing bisphosphonate) would have a lower potential for esophageal injury than a lower daily dose.  In the absence of these new studies, “intuition” would have indicated the opposite. 

The Fosamax once-weekly dosing program was based on these unexpected non-clinical safety findings and the knowledge that the half-life of alendronate on bone surfaces was approximately 3 to 5 weeks.  Bone mineral density of the lumbar spine was chosen as the clinically relevant efficacy endpoint, and two-year clinical trials  with adequate size and statistical power to demonstrate therapeutic equivalence between Fosamax 70 mg once weekly and 10 mg daily after one year of treatment were successfully conducted.  Safety was similar in these studies.  Independent patient preference studies showed preference for the weekly formulation and calendar-like product packaging was designed to reduce the potential for medication error.  One year after introduction of the once-weekly product, approximately 90 to 95% of new Fosamax prescriptions were for the 70 mg once-weekly product.  Pharmacovigilance data indicated that the proportion of spontaneous gastrointestinal event reports that were “serious” (regulatory definition) was approximately 50% lower with the weekly formulation versus the daily formulation.  While not proof of superior safety, the data are reassuring.

 

 

 

Pasteur quote (source is Wikipedia):

 

Dans les champs de l'observation le hasard ne favorise que les esprits préparés.

 

 

In the fields of observation chance favours only prepared minds.