Slide

Executive Summary for
Bisphosphonates
Substantial Findings of Bisphosphonates from the AERS Analysis
On September 30, 2004, the FDA and Novartis AG notified healthcare professionals of the revisions to the precautions and adverse reactions sections of labeling, describing spontaneous reports of osteonecrosis of the jaw mainly in cancer patients, who have received bisphosphonates as a component of their therapy. This finding was substantiated in the AERS analysis given below Osteonecrosis affects approximately 20,000 new patients every year in the United States. Although individuals in almost any age group may develop the condition, most patients are between 20 and 50 years of age, with the average age in the late 30's. The infusion therapy, Zometa, recorded the highest number of cases (3,302) affected by osteonecrosis followed by its oral competitor Fosamax which went on to record 800 cases. While Zometa registered 189 deaths as a result of osteonecrosis, Fosamax recorded 23 deaths. The hospitalization rate was higher for Zometa and Fosamax, while both Actonel and Boniva were found to be relatively silent in the case of osteonecrosis.
Note: The above data correspond only to patients who reported osteonecrosis in the AERS database due to the consumption of the bisphosphonates. The data do not necessarily include all the patients in the nation who encountered these adverse reactions due to consuming bisphophonates. Additionally, while these drugs are either the primary suspect or secondary suspect for these cases, other drugs prescribed for the same cases may be the concomitants or interacting drugs. Concomitants and interacting drugs may be responsible for the cause of these adverse reactions to a certain degree. This study, however, only analyzed bisphosphonates. Source: Adverse Event Reporting System, USA FDA, 2004 Q1 to 2007 Q1 On March 15, 1996, cases were filed for the occurrence of esophagitis and esophageal ulceration in patients taking Fosamax. Merck & Company, Inc. revised the product circular and patient package insert to advise strict compliance with the dosage instructions. These reactions were also observed in the AERS analysis as given below.
Reactions
Reactions
The AERS findings, whereby Fosamax was found to be the causal factor for esophageal associated reactions, were in fact observed in clinical studies. A contradictory finding is that, although Zometa registered a higher number of cases in comparison to all 4 bisphosphonates, it recorded the least number of esophageal reactions.
Reactions
Reactions
Note: The above data correspond only to patients who reported esophagitis and its associated reactions in the AERS database due to consumption of bisphosphonates. The data do not necessarily include all the patients in the nation who encountered these adverse reactions due to consuming bisphosphonates. Additionally, while these drugs are either the primary suspect or secondary suspect for these cases, other drugs prescribed for the same cases may be the concomitants or interacting drugs. Concomitants and interacting drugs may be responsible for the cause of these adverse reactions to a certain degree. This study, however, only analyzed bisphosphonates.
Source: Adverse Event Reporting System, USA FDA, 2004 Q1 to 2007 Q1 To date, no FDA warning has been issued against the cardiovascular reaction atrial fibrillation for bisphosphonates, but clinical studies and AERS findings reveal the occurrence of these adverse reactions from the consumption of bisphosphonates.
In addition to the observed atrial fibrillation events in HORIZON (study involving Zometa), the results of the Fracture Intervention Trial (FIT), a randomized study with Fosamax, also reviewed a similar trend of increased risk of serious atrial fibrillation. A strong association between atrial fibrillation and treatment with Fosamax was considered unlikely by both the Data Safety Monitoring Board investigators and Merck & Company, Inc., the manufacturer of Fosamax.
Findings from AERS Analysis
Bisphosphonates
Atrial Fibrillation
Reactions Count
Outcomes
Hospitalization
Disability
For atrial fibrillation, Zometa recorded 7 deaths from the reported 18 cases, with 10 of the cases being hospitalized. For Fosamax, 13 cases were hospitalized from the reported14 cases. Additionally, the consumption of Actonel resulted in high rates of hospitalization.
Note: The above data correspond only to patients who reported atrial fibrillation in the AERS database due to consumption of bisphosphonates. The data do not necessarily include all the patients in the nation who encountered these adverse reactions due to consuming bisphophonates. Additionally, while these drugs are either the primary suspect or secondary suspect for these cases, other drugs prescribed for the same cases may be the concomitants or interacting drugs. Concomitants and interacting drugs may be responsible for the cause of these adverse reactions to a certain degree. This study, however, only analyzed bisphosphonates.
Source: Adverse Event Reporting System, USA FDA, 2004 Q1 to 2007 Q1 Outcomes for the Bone Drugs
The maximum percentage of deaths and disabilities were seen in patients consuming Fosamax (14% and 16%, respectively), while Actonel registered for maximum percentage of hospitalized cases (44%) and cases suffering from required impairment (3%).
Zometa recorded 13% deaths as a result of cancer-related reactions and 11% deaths due to bone-related reactions.
Zometa was found to be the causal factor for 7% deaths due to blood- Note: (1) The outcome percentages were calculated against the total number of distinct outcomes for all reported bisphosphonates cases (2) The total outcomes (6251) reported for Zometa is more than the total Zometa cases (5212) due to the fact that one case could have more than one outcome. Source: Adverse Event Reporting System, USA FDA, 2004 Q1 to 2007 Q1

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