Download Osteoporosis treatment with Bisphosphonates

The AdverseEvents Monitor:
Osteoporosis treatment with Bisphosphonates
A response to the FDA’s concerns and
a detailed analysis of adverse events within the drug class.
Background
The FDA has called a meeting to “discuss the benefits and risks of long-term bisphosphonate use for the treatment
and prevention of osteoporosis (thinning and weakening of bones that increases the chance of having a broken
bone) in light of the emergence of the safety concerns of osteonecrosis of the jaw (jawbone death) and atypical
femur fractures (unusual broken thigh bone) that may be associated with the long-term use of bisphosphonates.”1
Goal
Provide timely and relevant adverse event analysis in response to the FDA’s “Joint Meeting of the Reproductive
Health Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee Meeting
Announcement”, noted above.
Context
Osteoporosis is a widespread condition associated with low bone density and mass, resulting in increased risks of
bone fractures. The US National Institutes of Health estimates that “in the United States today, more than 40
million people either already have osteoporosis or are at high risk due to low bone mass”2. The condition is more
common in women than in men, and occurs predominately in persons 50 years and older. For many years, drugs
from the class known as bisphosphonates have been used to decrease fracture rates in at-risk patients. The most
popular bisphosphonates are Fosamax (alendronate), Actonel (risedronate), Reclast (zoledronic acid), and Boniva
(ibandronate). These drugs are widely prescribed to patients with osteoporosis due to their significant efficacy
record. While their overall safety record appears favorable, they have been linked to a number of very serious side
effects. Due to the fact that these drugs stay active in patients for years after dosing, many of the adverse events
associated with these compounds may not have been properly captured in their time-constrained clinical trial
testing phases. Therefore, detailed surveillance of post-marketing adverse events associated with FDA-approved
bisphosphonates is of vital importance.
Objectives
1) To identify and analyze post-approval adverse event reports that implicate prescription bisphosphonate
medications as a trigger for femur and jaw fractures, osteonecrosis (bone death), kidney failure, osteomyelitis
(acute or chronic infection of bone), and various muscle and tendon disorders. 2) To determine if associations
between bisphosphonate drugs and such side effects warrant greater attention from regulatory bodies, healthcare
providers, and consumers. 3) To determine if the rates and/or severity of such adverse events differ among drugs
within the bisphosphonate class.
Methodology
RxFilterTM, a proprietary 17-step data refinement process developed by AdverseEvents, Inc., was used to perform a
comprehensive analysis of bisphosphonate-linked adverse event case reports found in the FDA Adverse Event
Reporting System (AERS) database. Drugs were included that had cases reported to the FDA within the seven year
time period of January 1, 2004 to March 31, 2011. The bisphosphonate drugs examined were: Fosamax, Actonel,
Reclast, and Boniva, and included generic equivalents and foreign designations. A detailed search of the AERS
database, and accompanying case report forms, was performed in order to identify potentially important
medication-related adverse events, with special emphasis placed on current FDA concerns such as atypical femur
fractures, osteonecrosis of the jaw, jaw fractures, and kidney failure (please see methods section for further
details).
Results
Analysis using the RxFilterTM process identified thousands of case reports, across numerous adverse event
categories, linked to bisphosphonates in the FDA AERS database. What we found most compelling in these results
are the apparent differences in side effect risks between the four distinct bisphosphonate drugs. To our knowledge,
no other analysis of this scope has been conducted regarding post-marketing adverse events linked to the
bisphosphonates. Of the twenty separate adverse event categories we searched, Reclast (injectable) had the highest
percentage risk in fourteen categories, while Fosamax had the highest risk in six. In short, some of the concerns
noted in the literature concerning Reclast appeared to be supported by our study, but not all. Interestingly,
Fosamax appeared to be consistently linked to higher adverse event risks than the two other oral bisphosphonates
(Actonel and Boniva), neither of which showed the highest risk in any of the twenty adverse event categories
analyzed.
Conclusions
Femur and jaw fractures, bone death, kidney failure, bone infections, and various muscle and tendon disorders are
serious adverse events associated with the top selling bisphosphonate class of drugs used to treat osteoporosis
(Fosamax, Actonel, Reclast, and Boniva). Such side effects appear to be on the rise in consumer populations, likely
because many do not fully manifest until years after bisphosphonate treatment begins. Because of this significant
latency, it is likely that these adverse events were not properly evaluated during time-constrained clinical testing
phases associated with each drug. Post-approval adverse event analysis with the RxFilterTM process in large, post
drug approval, consumer populations indicates that these side effects may be more common than currently
appreciated, and that drugs within the bisphosphonate class show varied risk rates. Prospective studies, however,
are needed to establish the exact incidence rates for these adverse events. This analysis warrants the attention of all
healthcare providers and patients associated with bisphosphonate and other bone anti-resorptive medications.
Adverse Events, Inc.
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Introduction
Osteoporosis
As we age, the natural processes of bone remodeling
and recycling are gradually disrupted by decreased
physical activity and changes in hormone levels.
These transformations selectively increase bone
resorption over production rates, resulting in both
decreased bone mass and strength. In patients with
osteoporosis, such imbalances have reached levels
where bone fracture risks become significantly
increased.
The incidence rate of osteoporosis continues to grow,
seemingly in parallel to the general increases in
average life span. In fact, “in the United States today,
more than 40 million people either already have
osteoporosis or are at high risk due to low bone
mass.”2 The risk for developing osteoporosis is
greater for women, especially for non-Hispanic
whites and Asians, and increases with advancing age.
In addition to very significant financial costs,
complications associated with osteoporosis cause
considerable reductions in quality of life for those
affected. One particularly devastating consequence
of osteoporosis is hip fractures, as they are
responsible for medical complications that oftentimes
result in death. Of those that survive, approximately
half of affected patients can no longer walk without
significant assistance. Osteoporosis also significantly
increases one’s risk for various other fractures.
Many patients with confirmed osteoporosis are
currently being successfully treated with a class of
compounds known as bisphosphonates. These drugs,
however, are increasingly being linked to serious side
effects. The FDA is investigating, in particular, links
between the bisphosphonates and: i) atypical femur
fractures, ii) jaw fractures, iii) jaw death, and iv)
renal failure.
The primary goals of the study described herein were
to estimate bisphosphonate side effect rates for the
four categories above and to determine if meaningful
safety differences might exist between the four main
bisphosphonate drugs. While other authors have
Adverse Events, Inc.
analyzed controlled clinical trials undertaken with
this class of drugs, we wanted to assess links between
these drugs and side effects in large, heterogonous,
non-controlled, patient populations. Accordingly, the
data we analyzed consisted of seven-years worth of
FDA adverse event case reports from the wide
consumer populations that are prescribed
bisphosphonate medications.
We used RxFilterTM, a proprietary 17-step data
refinement process developed by AdverseEvents,
Inc., to broadly assess adverse event case reports
associated with the four main FDA-approved
bisphosphonate drugs.
Bisphosphonate Drugs - General
Bisphosphonates are a class of a drugs widely
prescribed to protect against bone fractures in
osteoporosis patients. The drugs localize to areas of
bone undergoing active resorption (Rodan and
Fleisch, 1996) and they exert their positive effects
(Silverman et al., 2007; Favus, 2010; Charopoulos et
al., 2010; Rizzoli, 2011) by inhibiting the natural
resorption of bone from its surface. This mechanism
is especially helpful to those suffering from
osteoporosis because their production of new bone
gradually lags behind resorption processes, resulting
in weaker bones as they age. The bisphosphonates
inhibit such imbalances and thereby generate gains in
bone strength, mass, and density. Due to these
favorable attributes, bisphosphonate usage has
dramatically increased over the last few years and
continues to grow.
Some bisphosphonates are taken orally while others
are taken intravenously. Of the bisphosphonates
analyzed in this study, Fosamax, Actonel, and Boniva
are administered orally, while Reclast is given via
injection. The bisphosphonates are also used to treat
various cancer malignancies that have metastasized
to bone (usually at much higher doses than those used
for osteoporosis patients), as well as glucocorticoidinduced osteoporosis.
In summary, the drug class has demonstrated a solid
efficacy record for various disorders caused by
excessive bone resorption. While most side effects
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linked to the bisphosphonate dosages typically given
to osteoporosis patients are mild, some are very
serious and require close medical scrutiny.
Bisphosphonates - Potential Problems Introduction
Prior to being introduced into large consumer
populations, members of the bisphosphonate class of
drugs, like all FDA-approved medications, were
subjected to rigorous preclinical and clinical tests.
The testing regimes are designed to demonstrate both
efficacy and safety. In general, they work very well.
However, due to financial and logistical constraints,
it is not realistic to expect these evaluations to
identify all potential side effects that might occur in
large, post-approval, patient populations. Demands
for evidence of safety that do not recognize these
constraints would severely retard the timely
introduction of valuable new medicines.
A key dynamic of clinical testing is that drug
developers enroll subjects that are relatively
homogenous in order to increase the likelihood that
drug efficacy signals can be readily detected. This
procedural step, while vital for achieving robust
statistical descriptions of a compound’s effects,
necessarily leaves open the possibility that the test
drug will have unexpected actions in particular
subgroups of a heterogeneous population of users.
It follows that careful post-approval monitoring for
adverse events is vital to the drug evaluation process.
Ideally, this should begin immediately after a drug is
approved and introduced into a broad patient
population. The FDA’s AERS database and the
process described here for analyzing it, the
RxFilterTM, are tools designed to do just that.
The gradual evolution of the side effect profile for
bisphosphonate drugs serves to underscore the
preceding arguments. Clinical testing uncovered side
effects such as gastrointestinal discomfort and acute,
flu-like illness. However, adverse events that were
not exposed during the screening programs became
evident after approval. These include atypical femur
fractures, osteonecrosis (bone death), osteomyelitis
(acute or chronic infection of bone), jaw fractures
Adverse Events, Inc.
and/or jaw death, and various muscle and tendon
disorders. A further complication in evaluating
adverse events for the bisphosphonate drug class is
that the medications can remain active in a patient for
years after dosing (Khan et al. 1997); this again
emphasizes the need for careful, long term, and
meaningful post-approval monitoring.
For a concise review of suspected adverse events
across the bisphosphonate class of drugs please see
Lewiecki (2011).
Potential Problems - Atypical Femur Fractures
Concerns continue to grow that a rare form of bone
breakage called an “atypical femur fracture” may be a
side effect of currently prescribed bisphosphonates.
According to the FDA, “atypical subtrochanteric
femur fractures are fractures in the bone just below
the hip joint. Diaphyseal femur fractures occur in the
long part of the thigh bone. These fractures are very
uncommon and appear to account for less than 1% of
all hip and femur fractures overall. Although it is not
clear if bisphosphonates are the cause, these unusual
femur fractures have been predominantly reported in
patients taking bisphosphonates.”3
The rates of such atypical fractures are rare
(Abrahamsen, 2010b; Black et al., 2010; Charopoulos
et al., 2010). A review of three placebo-controlled
and randomized bisphosphonate clinical trials was
performed by Black et al. (2010). They concluded
that not only were such fractures quite uncommon,
but they also could not find a significant link to
bisphosphonate usage in the three trials. The authors
noted a number of limitations to their study,
including: they only had limited access to
radiographic data, the trials only documented a low
number of actual fractures to examine, the clinical
trial participants were enrolled only after specific
selection criteria (please see preceding sections for
more detail on potential consequences associated
with clinical trial selection), and the duration of time
that the tested patients were taking bisphosphonates
was only 3 to 4.5 years.
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Case reports, however, generally link such atypical
femur fractures to patients that have been on
bisphosphonates for an average of 4-5 years, or more
(Abrahamsen, 2010a).
Potential Problems - Osteonecrosis of the Jaw
The causes of osteonecrosis of the jaw (ONJ) are not
well understood, and its incidence in the general
population is not known. In fact, it is likely that mild
cases of ONJ are neither acknowledged nor reported
by dentists and physicians (Abrahamsen, 2010b). It is
commonly recognized, however, in cancer patients
who receive much higher doses of bisphosphonates
than those typically prescribed for osteoporosis
patients (Abrahamsen, 2010a). ONJ has also been
linked to a monoclonal antibody that targets bone
resorption processes via a completely different
mechanism than the bisphosphonates (Aghaloo et al.,
2010), further strengthening the link between
resorption inhibitors and ONJ.
Given that jaw bones are an area of high remodeling
activity, and that bisphosphonates are preferentially
deposited in such tissues, it is perhaps not surprising
that the jaw suffers from an increased risk of
bisphosphonate-induced osteonecrosis (see Ruggiero,
2010 for a detailed review of this issue).
Additionally, the FDA stated that the revised drug
label “recommends that healthcare professionals
screen patients prior to administering Reclast in order
to identify at-risk patients. Healthcare professionals
should also monitor renal function in patients who
are receiving Reclast.”4
Potential Problems - Osteomyelitis
Osteomyelitis commonly refers to acute or chronic
infections of the bone, caused by bacteria or fungi.
Such infections may spread from almost anywhere in
the body, but commonly originate in skin, muscles, or
tendons. Injury or surgery increases the risk of
contracting osteomyelitis. Vertebrae, hips, and feet
are most commonly affected in adults. Risk factors
typically include a history of: diabetes, hemodialysis,
and IV drug usage. Symptoms include: fever, bone
pain swelling, and back pain.
While osteomyelitis has been linked to
bisphosphonate use (Mortensen et al. 2007; Bertoldo
et al., 2007; Wimalawansa, 2008; Vestergaard et al.,
2011), our analysis indicates that this adverse event
may be more common than previously recognized.
Osteomyelitis risk rates may also vary significantly
across members of the bisphosphonate class of drugs.
Potential Problems - Muscles and Joints
Patients that have a history of dental issues,
especially inflammation-related disorders, have a
seven-fold risk of developing ONJ (Papapetrou,
2009). Additionally, surgical procedures or traumatic
events that expose jaw bones to bacterial infection
may precipitate localized osteonecrosis in subjects
who have been treated with bisphosphonates.
Potential Problems - Kidney Failure
In September 2011, the FDA “approved an update to
the drug label for Reclast (zoledronic acid) to better
inform healthcare professionals and patients of the
risk of kidney (renal) failure. Kidney failure is a rare,
but serious, condition associated with the use of
Reclast in patients with a history of or risk factors for
renal impairment. Cases of acute renal failure
requiring dialysis or having a fatal outcome following
Reclast use have been reported to FDA.” 4
Adverse Events, Inc.
In January 2008, the FDA warned that the
bisphosphonates might be linked to the “possibility of
severe and sometimes incapacitating bone, joint,
and/or muscle (musculoskeletal). Although severe
musculoskeletal pain is included in the prescribing
information for all bisphosphonates, the association
between bisphosphonates and severe musculoskeletal
pain may be overlooked by healthcare professionals,
delaying diagnosis, prolonging pain and/or
impairment, and necessitating the use of analgesics.
The severe musculoskeletal pain may occur within
days, months, or years after starting a
bisphosphonate.”5
Potential Problems - Summary
Bisphosphonates suppress bone turnover and are
believed to inhibit angiogenesis. Over time, the
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former likely results in changes to the normal mineral
content, flexibility, and microarchitecture of bone.
Such transformation may render bone more
susceptible to certain fractures currently linked to the
drug class. The inhibition of angiogenesis may
contribute to the impaired jaw healing and
osteonecrotic adverse events associated with the
bisphosphonates.
of Oral and Maxillofacial Surgeons (AAOMS), who
suggested that oral bisphosphonates be discontinued
for 3 months prior and post invasive oral surgery6.
Bisphosphonate Drugs - Potential Safeguards
Adding another level of guidance to prescribing
physicians is the growing literature that associates
concomitant use of corticosteroids, proton-pump
inhibitors, and other anti-resorptive medications to
the incidence and severity of many of the adverse
events linked to the bisphosphonates.
Due to extended exposure times, harm-benefit
considerations are especially important to evaluate
for drugs intended to treated chronic conditions such
as osteoporosis.
Additionally, “drug holidays” appear to be becoming
standard procedure for most physicians prescribing
long-term bisphosphonates. Such measures are
designed, in part, to help lessen adverse event risks.
Given the serious side effects linked to
bisphosphonates, it is becoming generally accepted
that their use should be reserved only for those with
demonstrable elevations in the risk of osteoporosisdriven fractures.
Finally, careful post-approval vigilance is vital to
identify, track, and analyze adverse events, from mild
to severe. Tools like the RxFilterTM are helping to
enable the exploration and careful analysis of the
vast, heretofore mostly uncharted, archive that is the
FDA AERS database.
To that end, the World Health Organization has
produced a useful risk assessment algorithm (FRAX)
designed to enable clinicians to accurately estimate
fracture risk in low bone mass patients
(http://www.shef.ac.uk/FRAX/). The widespread
adoption of this, and other similar tools, can help to
ensure that only those truly at risk of osteoporosisgenerated fractures are prescribed bisphosphonates
(Kennel and Drake, 2009). Additionally, prodromal
pain appears to precede many of these femur
fractures up to several months, potentially serving as
an actionable warning to healthcare providers
(Papapetrou, 2009; Charopoulos et al., 2010; Giusti
et al., 2010; Lewiecki, 2011).
With regard to osteonecrosis of the jaw, actions by
the FDA as far back as 2005 highlighted potential
links to bisphosphonate medications. Not only is
careful patient selection important for the drug class,
but clinicians should also pay special attention to the
oral hygiene habits of their patients. The modulation
of bisphosphonates dosing schedules before and after
elective oral surgery, or other invasive treatments,
coupled with rigorous bactericidal treatments may
also help lower the risk of ONJ. Guidelines to this
effect have been issued by the American Association
Adverse Events, Inc.
Methods
Data Source and Date Range: Data were obtained
from the FDA AERS database from case reports
received by the FDA between January 1, 2004 and
March 31, 2011, a total of over seven years.
Drugs Selected: Fosamax, Actonel, Reclast, and
Boniva (and their associated generic equivalents and
foreign designations). With regard to Reclast in
particular, case reports for Zometa were omitted
because, while it is the same compound as Reclast, it
is used at much higher doses, typically for cancer
patients.
Searching and Analysis: RxFilterTM, a proprietary 17step data refinement process developed by
AdverseEvents, Inc., was used to perform a
comprehensive analysis of bisphosphonate-linked
adverse events found in AERS. A detailed search of
the AERS database, and accompanying case report
forms, was performed on these drugs in order to
identify potentially important treatment-related side
effects.
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Drug Name(s) Reorganization: One aspect of the
RxFilterTM entails reorganization of the AERS
database in order to accurately identify and aggregate
all case reports for each marketed drug. Each drug
name variant that includes words such as the generic
name, name outside the United States, misspellings,
dosage description, etc., as originally entered in the
AERS database, is consolidated into one singular
“Brand Name” by the RxFilterTM. For example, in
the AERS database, Fosamax has 496 separate
designations, all of which are consolidated into a
single “Brand Name” by the RxFilterTM process. The
analysis herein included all such variants for each of
the four drugs (please see Appendix A for full name
listings).
Finding Adverse Event Case Reports: To determine
the number of case reports associated with each drug,
we used the advanced searching tools of the
RxFilterTM to cross-reference the consolidated Brand
Name as the primary suspect in causing suspected
adverse events found in the FDA AERS database.
Estimated Number of Patients Taking a Given Drug:
To estimate the number of patients taking each drug
during the applicable time period, we used U.S.
patient figures as estimated by BioMedTracker, a
leading provider of information services and drug
revenue modeling for the healthcare industry. The
peak annual patient figure for each drug between
2004 and 2011, as provided by BioMedTracker, was
used as the estimated total number of patients
exposed during the period, as most bisphosphonate
patients are prescribed this drug class for several
years.
The number of patients estimated to have been
exposed to bisphosphonates from January 1, 2004 to
March 31, 2011 was: Fosamax, 2,220,167; Actonel,
1,337,250; Boniva, 647,538; and Reclast, 321,574.
Note: searches were not refined by condition or
outcome type, as those fields are often left blank in
the FDA AERS case reports as filed.
Potential Limitations of this Study
The FDA AERS database is only as accurate as the
information inputted into it from various sources. By
design, it does not filter, correct, or make any
analysis of the quality or potential bias of the inputted
data. The FDA has also estimated that only
approximately 10% of all adverse events that are
potentially triggered by post-marketed drugs are
recorded into AERS.
Accordingly, while we believe that the RxFilterTM
process employed by AdverseEvents, Inc. represents
an exceptionally useful tool for searching and
analyzing AERS data, the output is constrained by
the raw data that can be queried from AERS. For
example, case reports that are submitted to FDA
often contain mistakes including: spelling errors
leading to misclassifications, important data either
missing or inadequately reported, and duplicate
reports. RxFilterTM utilizes multiple processing steps,
safeguards, and manual oversight to lessen the impact
of such complications, but not all data issues can be
completely fixed.
With regard to atypical femur fractures in particular,
the FDA AERS database does not list the specific
type of fracture. Accordingly, the RxFilterTM process
can only assay the adverse event categories termed:
1) “femur fractures”, which does not distinguish
between typical and “atypical” (subtrochanteric and
diaphyseal) breaks, and 2) “femoral neck fractures”.
Additionally, the literature indicates that Fosamax
may be considered by many physicians to be a more
powerful drug that Actonel. Fosamax, therefore,
could be disproportionately prescribed to patients
with more serious cases of osteoporosis. Such a
patient subgroup would be more likely to have femur
breaks in general, due to their lower bone densities.
We do not believe, however, that such potential drug
selection choices could have significantly affected
other adverse event categories analyzed here.
Finally, Fosamax has been on the market longer than
the other bisphosphonates examined here, a factor
that could potentially explain part of the increased
risk percentages linked to it in this study.
Adverse Events, Inc.
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Results
The RxFilterTM was used to analyze both single
adverse events as well as multiple events grouped
into a search list. Such side effect categories are
listed below, along with exact adverse event search
terms used. Duplicate case report forms were
omitted.
The displayed data are the amount of case report
forms that link the specific Adverse Events (AEs)
with the noted bisphosphonate drug as both
“primary” and “all” suspect (as listed in the FDA
AERS database).
The “percent risk” calculations are based upon the
number of “primary suspect” adverse events linked to
each bisphosphonate, divided by an estimated
number of patients exposed to the drug over the
January 2004 to March 2011 time period. The
estimated amounts of exposed patients were:
Fosamax, 2,220,167; Actonel, 1,337,250; Reclast,
321,574; and Boniva, 647,538.
In order to facilitate within-drug comparisons, we
used a “ranked risk” measure that is a normalization
that sets the bisphosphonate with the highest “percent
risk” in each adverse event category to 100. The
remaining 3 drugs are comparison ranked to that
drug.
Of the twenty separate adverse event categories
searched, Reclast (injectable) had the highest percent
risk in fourteen, while Fosamax had the highest risk
in six. In short, some of the concerns noted in the
literature concerning Reclast appeared to be
supported by our study, but not all.
Interestingly, Fosamax appeared to be consistently
linked to higher adverse event risks than the other
two oral bisphosphonates (Actonel and Boniva),
neither of which showed the highest risk in any of the
twenty adverse event categories we analyzed.
All Adverse Events linked to Bisphosphonates,
General
Adverse event searched: any and all AEs reported for
Adverse Events, Inc.
the four bisphosphonate drugs analyzed in this study.
Cases: there were a total of 28,083 “primary” and
53,526 “all” suspect case reports listed in AERS. Of
those, individual bisphosphonate numbers were:
AEs
Primary / All
Percent Risk
Ranked Risk
11,620 / 27,242
0.523%
27
Actonel
2,213 / 9,530
0.165%
8
Reclast
6,349 / 6,573
1.974%
100
Boniva
7,901 / 10,181
1.220%
62
Fosamax
Femur Fracture
Adverse event searched: “femur fracture”. There
were a total of 3,303 cases listed in AERS, across all
drugs in the database. The case reports linked to
bisphosphonates were:
AEs
Primary / All
Percent Risk
Ranked Risk
1,591 / 1,727
0.072%
100
Actonel
84 / 160
0.006%
9
Reclast
53 / 62
0.016%
23
Boniva
128 / 231
0.020%
28
Fosamax
Femoral “Neck” Fracture
Adverse event searched: “femoral neck fracture”.
Cases: 559 total in AERS. Bisphosphonate case
reports:
AEs
Primary / All
Percent Risk
Ranked Risk
Fosamax
24 / 43
0.001%
43
Actonel
3 / 12
0.000%
9
Reclast
8/9
0.002%
100
Boniva
3/5
0.000%
19
Jaw Fracture
Adverse event search term: “jaw fracture”. Cases:
320 total in AERS.
AEs
Primary / All
Percent Risk
Ranked Risk
Fosamax
78 / 87
0.004%
100
Actonel
6 / 16
0.000%
13
Reclast
3/3
0.001%
27
Boniva
7 / 12
0.001%
31
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Jaw Osteonecrosis
Osteonecrosis, General
AE searched: “osteonecrosis of jaw”. Cases: 1,341
total in AERS.
AE searched: “osteonecrosis”. Cases: 12,061 total in
AERS.
AEs
Primary / All
Percent Risk
Ranked Risk
207 / 233
0.009%
64
Actonel
15 / 45
0.001%
8
Reclast
47 / 48
0.015%
100
Boniva
29 / 71
0.004%
31
Fosamax
AEs
Primary / All
Percent Risk
Ranked Risk
3,114 / 3,321
0.140%
100
Actonel
130 / 258
0.010%
7
Reclast
113 / 116
0.035%
25
Boniva
266 / 402
0.041%
29
Fosamax
Osteomyelitis, General
Renal (Kidney Failure)
AEs searched: “renal failure, renal failure acute, renal
failure chronic”. Cases: 45,280 total in AERS.
Fosamax
AEs
Primary / All
Percent Risk
Ranked Risk
AEs searched: “osteomyelitis chronic, osteomyelitis”.
Cases: 2,771 total in AERS.
Fosamax
AEs
Primary / All
Percent Risk
Ranked Risk
638 / 703
0.029%
100
128 / 477
0.006%
13
Actonel
54 / 93
0.004%
14
Actonel
33 / 180
0.002%
6
Reclast
34 / 34
0.011%
37
Reclast
140 / 148
0.044%
100
Boniva
38 / 68
0.006%
20
Boniva
62 / 114
0.010%
22
Pain and Inflammation of the Jaw, General
All Renal Issues
AEs searched: “jaw inflammation, jaw osteitis, pain
in jaw”. Cases: 3,143 total in AERS.
AEs searched: (please see Appendix B). Cases:
23,948 total in AERS.
AEs
Primary / All
Percent Risk
Ranked Risk
Fosamax
278 / 338
0.013%
28
AEs
Primary / All
Percent Risk
Ranked Risk
Actonel
106 / 139
0.008%
18
Fosamax
88 / 312
0.004%
12
Reclast
143 / 144
0.044%
100
Actonel
33 / 125
0.002%
7
Boniva
186 / 204
0.029%
65
Reclast
110 / 112
0.034%
100
Boniva
65 / 87
0.010%
29
All Nephropathy
Muscle and Tendon Disorders, General
AEs searched: (please see Appendix B). Cases:
200,217 total cases in AERS.
AEs searched: (please see Appendix B). Cases:
11,320 total in AERS.
Percent Risk
Ranked Risk
AEs
Primary / All
1,429 / 3,513
0.064%
12
Percent Risk
Ranked Risk
Actonel
701 / 1,751
0.052%
10
Fosamax
84 / 206
0.004%
29
Reclast
1,678 / 1,729
0.522%
100
Actonel
21 / 81
0.002%
12
Boniva
1,563 / 1,936
0.241%
46
Reclast
42 / 45
0.013%
100
Boniva
29 / 37
0.004%
34
Adverse Events, Inc.
Fosamax
AEs
Primary / All
www.AdverseEvents.com
9
Throat Cancer
All Bone Fractures (Non-Osteoporosis)
AEs searched: (please see Appendix B). Cases: 818
total in AERS.
AEs searched: (please see Appendix B). Cases:
11,844 total cases in AERS.
AEs
Primary / All
Percent Risk
Ranked Risk
64 / 70
0.003%
100
Actonel
7/8
0.001%
Reclast
1/1
Boniva
10 / 12
Fosamax
AEs
Primary / All
Percent Risk
Ranked Risk
Fosamax
535 / 859
0.024%
28
18
Actonel
63 / 207
0.005%
6
0.000%
11
Reclast
272 / 280
0.085%
100
0.002%
54
Boniva
161 / 226
0.025%
29
Head and Neck Cancer
Teeth-Related Inflammation
AEs searched: (please see Appendix B). Cases: 679
total in AERS.
AEs searched: “alveolar osteitis, necrotising
ulcerative periodontitis, osteitis, periodontitis,
pulpitis dental”. Cases: 792 total cases in AERS.
AEs
Primary / All
Percent Risk
Ranked Risk
10 / 14
0.000%
48
Actonel
2/5
0.000%
16
Reclast
3/3
0.001%
100
Fosamax
Boniva
3/5
0.000%
50
Atrial Fibrillation
Percent Risk
Ranked Risk
114 / 133
0.005%
100
Actonel
22 / 37
0.002%
32
Reclast
8/9
0.002%
48
Boniva
20 / 35
0.003%
60
Fosamax
All Oral Inflammation (without Teeth)
AEs searched: “atrial fibrillation, atrial flutter”.
Cases: 12,684 total cases in AERS.
AEs
Primary / All
Percent Risk
Ranked Risk
Fosamax
148 / 336
0.007%
26
Actonel
38 / 132
0.003%
11
Reclast
83 / 87
0.026%
100
Boniva
59 / 79
0.009%
35
All Abnormal Heart Rhythms (without Atrial
Fibrillation)
AEs searched: (please see Appendix B). Cases:
40,447 total cases in AERS.
AEs
Primary / All
Percent Risk
Ranked Risk
Fosamax
85 / 375
0.004%
11
Actonel
35 / 172
0.003%
7
Reclast
113 / 116
0.035%
100
Boniva
72 / 99
0.011%
32
Adverse Events, Inc.
AEs
Primary / All
AEs searched: (please see Appendix B). Cases: 9,156
total in AERS.
AEs
Primary / All
Percent Risk
Ranked Risk
184 / 288
0.008%
81
Actonel
35 / 92
0.003%
26
Reclast
33 / 35
0.010%
100
Boniva
43 / 66
0.007%
65
Fosamax
All Bone-Related Inflammation
AEs searched: (please see Appendix B). Cases: 3,132
total in AERS.
AEs
Primary / All
Percent Risk
Ranked Risk
Fosamax
91 / 143
0.004%
38
Actonel
18 / 52
0.001%
12
Reclast
35 / 37
0.011%
100
Boniva
27 / 49
0.004%
38
www.AdverseEvents.com
10
Hypocalcemia
and was not devised with any consideration to
specific drugs.
AEs searched: “Hypocalcaemia”. Cases: 2,127 total
in AERS.
AEs
Primary / All
Percent Risk
Ranked Risk
Fosamax
24 / 42
0.001%
4
Actonel
13 / 23
0.001%
3
Reclast
96 / 96
0.030%
100
Boniva
17 / 19
0.003%
9
Discussion
The overall efficacy of the bisphosphonate drug class
is generally regarded as very favorable, and they
form a key part of osteoporosis and bone malignancy
treatments. Most of the data that healthcare
practitioners rely upon to judge the safety of the
bisphosphonates, however, are based upon clinical
trial results that likely did not accurately estimate rare
adverse event rates for a variety of reasons. Some of
these include: i) strict inclusion and exclusion criteria
resulting in comparatively homogenous clinical test
populations, ii) most clinical trials were of the 2-4
year duration while rare side effects linked to the
drugs appear to be most common after 4 years of
treatment, and iii) the bisphosphonates have extended
(up to years) retention times within bone tissue.
Accordingly, the present examination was designed
to address some of the shortcomings listed above by
providing insight into numerous side effects that are
linked to bisphosphonates in large, heterogeneous,
consumer patient populations.
Our analysis was based on the significant volume of
individual case reports in the FDA AERS database
that associate individual bisphosphonates with
various adverse events. We examined adverse events
linked to each individual drug with no exclusion or
inclusion criteria, other than the omission of
duplicate case reports and the fact that we did not
include Zometa (the version of Reclast given to
cancer-patients at a significantly increased dosage as
compared with osteoporosis patients).
To further guard against bias, the generation of our
adverse event “search lists” was based solely on
suspected side effects of bisphosphonates as a class,
Adverse Events, Inc.
Given that the FDA estimates that only 10% of
adverse events linked to post-marketed drugs are
successfully logged into AERS, the percent risk
findings in this study may be up to 10X lower than
the actual rates of these side effects in broad
consumer populations. Accordingly, we believe that
the risk rates disclosed here are likely to only
represent a small percentage of the true incidence
rates in osteoporosis patients.
What we find most compelling in these results are the
apparent differences in side effect risks between the
four distinct bisphosphonate drugs. To our
knowledge, no other analysis of this scope has been
conducted regarding FDA AERS post-marketing
adverse events linked to the bisphosphonates.
Cartsos et al., 2008 performed a medical claims study
with data from 2000-2006 and indicated that
injectable bisphosphonates are associated with higher
jaw-related adverse event risks than their oral
counterparts. Other authors reached similar
conclusions with regard to jaw disorders and
bisphosphonate treatment (Skrepnek et al., 2010).
Our analysis of the FDA AERS database case reports
from 2004-2011, however, only supports such a
differentiation between oral and injectable
bisphosphonates with regard to specific adverse event
categories. In our study, the injectable Reclast was
indeed associated most strongly (out of the four
bisphosphonates studied herein) with select adverse
events, but it did not appear to have higher side effect
rates than the oral bisphosphonates across a number
of other categories.
In a review of 141 case reports from the literature,
Giusti et al., 2010, presented data that linked
Fosamax (alendronate) to the majority of atypical
femur fractures. They assumed this within class
difference was “more likely to be due to the generally
more frequent use of alendronate, rather than to
specific pharmacological properties”. In order to test
assumptions of this type we estimated the amount of
www.AdverseEvents.com
11
patients exposed to each of the four main
bisphosphonates.
Our results demonstrate potential adverse events rate
differences between the three largest selling oral
bisphosphonates. In general, Fosamax appeared to be
linked to higher adverse event risks than Actonel and
Boniva across most of the side effect categories we
analyzed.
It should be noted that while these findings indicate
areas of potential concern, prospective studies are
needed to establish the exact incidence of these
adverse events.
We believe that these results warrant the attention of
healthcare providers, drug developers, patients, and
regulatory professionals involved with
bisphosphonates or other bone resorption inhibitors.
References
1. http://www.fda.gov/AdvisoryCommittees/Calendar/ucm262477.htm
Jan;139(1):23-30.
Charopoulos I, Orme S, Giannoudis PV. Fracture risk associated with chronic
use of bisphosphonates: evidence today. Expert Opin Drug Saf. 2011
Jan;10(1):67-76. Epub 2010 Dec 2.
Favus MJ. Bisphosphonates for osteoporosis. N Engl J Med. 2010 Nov
18;363(21):2027-35.
Giusti A, Hamdy NA, Papapoulos SE. Atypical fractures of the femur and
bisphosphonate therapy: A systematic review of case/case series studies. Bone.
2010 Aug;47(2):169-80. Epub 2010 May 20.
Kennel KA, Drake MT. Adverse effects of bisphosphonates: implications for
osteoporosis management. Mayo Clin Proc. 2009 Jul;84(7):632-7
Khan SA, et al. Elimination and biochemical responses to intravenous
alendronate in postmenopausal osteoporosis. J Bone Miner Res. 1997
Oct;12(10):1700-7.
Lewiecki EM. Safety of long-term bisphosphonate therapy for the management
of osteoporosis. Drugs. 2011 Apr 16;71(6):791-814.
Mortensen M, Lawson W, Montazem A. Osteonecrosis of the jaw associated
with bisphosphonate use: Presentation of seven cases and literature review.
Laryngoscope. 2007 Jan;117(1):30-4.
Papapetrou PD. Bisphosphonate-associated adverse events. Hormones (Athens).
2009 Apr-Jun;8(2):96-110.
Rizzoli R. Bisphosphonates for post-menopausal osteoporosis: are they all the
same? QJM. 2011 Apr;104(4):281-300. Epub 2011 Jan 21.
2.www.niams.nih.gov/Health_Info/Bone/Osteoporosis/osteoporosis_hoh.asp
Rodan GA, Fleisch HA. Bisphosphonates: mechanisms of action. J Clin Invest.
1996 Jun 15;97(12):2692-6.
3.www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMe
dicalProducts/ucm229244.htm
Ruggiero SL. Bisphosphonate-related osteonecrosis of the jaw: an overview.
Ann N Y Acad Sci. 2011 Feb;1218:38-46. Epub 2010 Sep 28.
4.www.fda.gov/Drugs/DrugSafety/ucm270199.htm
Shane E. Evolving data about subtrochanteric fractures and bisphosphonates. N
Engl J Med. 2010 May 13;362(19):1825-7. Epub 2010 Mar 24.
5.www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatients
andProviders/ucm124165.htm)
6. www.aaoms.org/docs/position_papers/bronj_update.pdf
Abrahamsen B. Adverse effects of bisphosphonates. Calcif Tissue Int. 2010
Jun;86(6):421-35. Epub 2010 Apr 21. “2010a”
Silverman SL, Watts NB, Delmas PD, Lange JL, Lindsay R. Effectiveness of
bisphosphonates on nonvertebral and hip fractures in the first year of therapy:
the risedronate and alendronate (REAL) cohort study. Osteoporos Int. 2007
Jan;18(1):25-34. Epub 2006 Nov 15.
Abrahamsen B. Bisphosphonate adverse effects, lessons from large databases.
Curr Opin Rheumatol. 2010 Jul;22(4):404-9. “2010b”
Skrepnek GH, Seal B, Tangirala M, Jeffcoat MK, Watts NB, Hay JW. Adverse
events and intravenous versus oral bisphosphonate use in patients with
osteoporosis and cancer in the U.S. Gen Dent. 2010 Nov-Dec;58(6):484-92;
quiz 493-4.
Aghaloo TL, Felsenfeld AL, Tetradis S. Osteonecrosis of the jaw in a patient on
Denosumab. J Oral Maxillofac Surg. 2010 May;68(5):959-63. Epub 2010 Feb
10.
Vestergaard P, et al., Oral Bisphosphonate Use Increases the Risk for
Inflammatory Jaw Disease: A Cohort Study. J Oral Maxillofac Surg. 2011 Jul
[Epub]
Bertoldo F, Santini D, Lo Cascio V. Bisphosphonates and osteomyelitis of the
jaw: a pathogenic puzzle. Nat Clin Pract Oncol. 2007 Dec;4(12):711-21.
Wimalawansa SJ. Bisphosphonate-associated osteomyelitis of the jaw:
guidelines for practicing clinicians. Endocr Pract. 2008 Dec;14(9):1150-68.
Bilezikian JP, Grbic JT. Bisphosphonates and osteonecrosis of the jaw:
proceedings of an international conference. Ann N Y Acad Sci. 2011
Feb;1218:1-2.
Sales Contact
Black DM, Kelly MP, Genant HK, Palermo L, Eastell R, Bucci-Rechtweg C,
Cauley J, Leung PC, Boonen S, Santora A, de Papp A, Bauer DC; Fracture
Intervention Trial Steering Committee; HORIZON Pivotal Fracture Trial
Steering Committee. Bisphosphonates and fractures of the subtrochanteric or
diaphyseal femur. N Engl J Med. 2010 May 13;362(19):1761-71. Epub 2010
Mar 24.
Adriana Palomino-Scott
V.P. Sales and Business Development
[email protected]
(858) 945-4879
Cartsos VM, Zhu S, Zavras AI. Bisphosphonate use and the risk of adverse jaw
outcomes: a medical claims study of 714,217 people. J Am Dent Assoc. 2008
Adverse Events, Inc.
www.AdverseEvents.com
12
Appendix A
Fosamax, Actonel, Reclast, and Boniva
Separate designations listed in the FDA AERS database, aggregated into single “Brand Names”.
Fosamax
Other names:
Alendronate Sodium (and Alendronate Sodium/cholecalciferol); Fosavance (EU), Adrovance (France)
FDA listed names (606):
(alendronate), (alendronic Acid), (foxamax), Acide Alendronique Arrow, Acide Alendronique Sel Monosodique (alendronic Acid), Acido Alendronico, Acidum
Alendronicum, Adendronate, Adendronic Acid, Adronat, Adronat 70, Adrovance, Adrovance (alendronic Acid), Aklendronate Sodium (alendronate Sodium), Albndronate
Sodium, Aldendronage Sodium, Aldendronat, Aldendronate, Aldendronate 70mg, Barr Laboratories, Aldendronate Sodium, Aldendronate Sodium (alendronate Sodium),
Aldendronate Sodium Tablets 70mg Teva Pharmaceuticals Usa, Aldendrone Sodium, Aldenronic Acid (alendronic Acid), Aldronate, Aleandronic Acid, Aledron Acid,
Aledronate, Aledronate 70mg, Aledronate Sodium (alendronate Sodium), Aledronic Acid, Aledronic Acid (alendronic Acid), Alemdronate [alendronate], Alenat
(alendronate Sodium), Alend, Alend (alendronate Sodium), Alenddronate 70 Mg Cobalt Laboratories, Alendionde, Alendonate, Alendornate, Alendornate Sodim
(alendronate Sodium), Alendornate Sodium, Alendornate Sodium (alendronate Sodium), Alendornate Sodium (alendornate Sodium), Alendornate Sodium (alendronate
Sodium), Alendornate Sodum, Alendoronate Sodium (alendronate Sodium), Alendranate, Alendranic Acid(alendronic Acid), Alendraonate Sodium, Alendrate, Alendrate
(alendronate Sodium), Alendrate (alendronate Sodium), Alendrinate, Alendrnate Sodium, Alendro-q 70 Mg (alendronate), Alendroante Sodium, Alendroat Ratiopharm,
Alendroate, Alendroate Sodium, Alendroic Acid, Alendromate, Alendron, Alendron Acid, Alendron Beta, Alendron Beta (alendronate Sodium), Alendron Beta
(alendronate) Tablets 70 Mg, Alendron Beta Einmal Wochentlich 70 Mg Tabletten, Alendron Beta Einmal Wochentlich 70 Mg Tabletten (alendronic Acid), Alendron
Mepha, Alendron-hexal (alendronic Acid), Alendron-hexal (alendronic Acid), Alendron-hexal (ngx) (alendronic Acid) Tablet, 70mg, Alendron-sandoz (alendronate) Tablets
70 Mg, Alendronaat, Alendronae Sodium, Alendronae Sodium (alendronate Sodium), Alendronage Sodium, Alendronagte Sodium (alendronate Sodium), Alendronale,
Alendronat, Alendronat (alendronate) Tablets 70 Mg, Alendronat (alendronate Sodium), Alendronat (alendronate) Tablets 70 Mg, Alendronat 70, Alendronat Arrow,
Alendronat Ratiopharm, Alendronat Sodium (alendronate Sodium), Alendronat Sodium, Tablets, 5mg, 10mg, 40mg, 35mg, 70mg, Alendronate, Alendronate (alendronate
Sodium), Alendronate (alendronate Sodium), Alendronate (alednronate Sodium), Alendronate (alendroante Sodium), Alendronate (alendronate Acid), Alendronate
(alendronate Ion), Alendronate (alendronate Sodium (alendronate Sodium), Alendronate (alendronate Sodium), Alendronate (alendronate Sodium) Tablets, Alendronate
(alendronate Sodoum), Alendronate (alendronate Soidum), Alendronate (alendronate), Alendronate (alendronic Acid), Alendronate (con.), Alendronate (fosalan),
Alendronate (generic), Alendronate (laendronate Sodium), Alendronate (ngx) (alendronate) Unknown, Alendronate (tablet), Alendronate -generic Foxamax- 70mg Tenu ?,
Alendronate 2008 - 2010, Alendronate 35mg Teva Pharmaceuticals Usa, Alendronate 40 Mg Teva, Alendronate 5 Mg. Apotex Corp.-weston, Fl., Alendronate 50 D,
Alendronate 70 Mg, Alendronate 70 Mg Cobalt Laboratories, Alendronate 70 Mg Cobalt Labs, Alendronate 70 Mg For Osteoporosis, Alendronate 70 Mg Generic,
Alendronate 70 Mg Not Available, Alendronate 70 Mg Various, Alendronate 70 Mg Watson Laboritories, Alendronate 70 Mgmgm Teva, Alendronate 70mg, Alendronate
70mg Alendronate, Alendronate 70mg Barr, Mylan, Alendronate 70mg Cobalt Laboratories, Alendronate 70mg Generic, Alendronate 70mg Mylan, Alendronate 70mg Pills,
Alendronate 70mg Watson, And Arrow Pharm, Alendronate Acid, Alendronate Acid (alendronate Acid), Alendronate Acid (alendronic Acid), Alendronate Allendronate
70mg Cobalt Laboratories, Alendronate Calcium, Alendronate Dorium (alendronate Sodium), Alendronate Hydrate Sodium, Alendronate Merck Nm (alendronic Acid),
Alendronate Monosodc, Alendronate Monosodic, Alendronate Monosodium, Alendronate Monosodium Trihydrate, Alendronate Na, Alendronate Sandoz, Alendronate
Sdoium (alendronate Sodium), Alendronate Sod, Alendronate Sod., Alendronate Sodiuim, Alendronate Sodium, Alendronate Sodium (mfr: Unknown), Alendronate Sodium
70ng Teva, Alendronate Sodium (+) Cholecalciferol (msd) (unknown), Alendronate Sodium (alandronate Sodium), Alendronate Sodium (alenddronate), Alendronate
Sodium (alendeonate Sodium), Alendronate Sodium (alendornate Sodium), Alendronate Sodium (alendornate Sodum), Alendronate Sodium (alendroante Sodim),
Alendronate Sodium (alendromate Sodium), Alendronate Sodium (alendronae Sodium), Alendronate Sodium (alendronate Dosium), Alendronate Sodium (alendronate
Sodium), Alendronate Sodium (alendronate Sodium) `, Alendronate Sodium (alendronate Sodium) (alendronate Sodium), Alendronate Sodium (alendronate Sodium) (nr),
Alendronate Sodium (alendronate Sodium0, Alendronate Sodium (alendronate), Alendronate Sodium (alendronatre Sodium), Alendronate Sodium (alendronic Acid),
Alendronate Sodium (bonalon) (alendronate, Alendronate Sodium (bonalon) (alendronate Sodium), Alendronate Sodium (bonaton) (alendronate Sodium), Alendronate
Sodium (con.), Alendronate Sodium (formulation Unknown), Alendronate Sodium (fosmax), Alendronate Sodium (mfr: Unknown), Alendronate Sodium (watson
Laboratories, Alendronate Sodium (watson Laboratories), Alendronate Sodium 35 Mg Tablets Teva Pharmaceuticals, Alendronate Sodium 70 Mg Apotex Usa Inc,
Alendronate Sodium 70 Mg Northstar Llc/aurobindo, Alendronate Sodium 70 Mg Tab Watson Pharma, Inc., Alendronate Sodium 70 Mg Tatev Teva, Usa, Alendronate
Sodium 70 Mg Teva, Alendronate Sodium 70mg, Alendronate Sodium 91.37 Mg Mylan, Alendronate Sodium And Cholecalciferol, Alendronate Sodium Hydrate,
Alendronate Sodium Hydrate (alendronate Sodium), Alendronate Sodium Hydrate (alendronate Sodium), Alendronate Sodium Hydrate 9alendronate Sodium), Alendronate
Sodium Qw, Alendronate Sodium Tab, Alendronate Sodium Tablets, Alendronate Sodium Tablets (alendronate Sodium), Alendronate Sodium Tablets Us, Alendronate
Sodium Tablets Usp 70 Mg, Alendronate Sodium Tablets Usp 70 Mg Teva, Alendronate Sodium Tablets Usp 70mg, Alendronate Sodium Tablets, 35 Mg. Watson, Distrib.
+ Merck, Manufact, Alendronate Sodium Trihydrate, Alendronate Sodium Watson Laboratories (alendroate Sodium), Alendronate Sodium(alendro Sodium) Tablet, Unk,
Alendronate Sodium, 70 Mg, 1 In 1 Wk, Alendronate Sodium/vitamin D3, Alendronate Sodlum (alendronate Sodium), Alendronate Soduim, Alendronate Solution Tabs,usp
10 Mg, Substitute For Fosamax, Alendronate Tablets (unknown Manufacturer + Strength), Alendronate Tablets 70 Mg (arrow Pharm Malta), Alendronate Tablets 70 Mg
(mfr: Arrow Pharm Malta), Alendronate Tablets 70 Mg (mfr: Arrow Pharm Malta), Alendronate Tablets 70 Mg (unknown Manufacturer), Alendronate(alendronate
Sodium), Alendronate, 35 Mg, Barr, Alendronate-matching Placebo, Alendronate/calcium, Alendronato, Alendronato (alendronate Sodium), Alendronato Sodico, Alendrone
Acid, Alendronhexal, Alendronic, Alendronic Acid (alendronic Acid), Alendronic Acid, Alendronic Acid (alendronic Acid), Alendronic Acid (mfr. Unknown), Alendronic
Acid (alendronic Acid), Alendronic Acid (mfr. Unknown), Alendronic Acid (alendronic Acid), Alendronic Acid (alendronic Acid) Unknown, Alendronic Acid (alendronic
Acid), Alendronic Acid (mfr. Unknown), Alendronic Acid (mfr: Unknown), Alendronic Acid (alendronic Acid) Unknown, Alendronic Acid (alendronic Acid), Alendronic
Acid (alendronic Acid), Alendronic Acid (alendronate Acid), Alendronic Acid (alendronate Sodium), Alendronic Acid (alendronic Acid), Alendronic Acid (alendronic
Acid) (70 Mg), Alendronic Acid (alendronic Acid) (alendronic Acid), Alendronic Acid (alendronic Acid) (tablets), Alendronic Acid (alendronic Acid) Tablet, Alendronic
Acid (alendronic Acid) Unknown, Alendronic Acid (alendronic Acid, ), Alendronic Acid (alendronic Acid, , 0), Alendronic Acid (alendronic Acid0, Alendronic Acid
(arrow Generics Ltd), Alendronic Acid (con.), Alendronic Acid (fosamax), Alendronic Acid (mfr Unknown), Alendronic Acid (mfr. Unknown), Alendronic Acid (mfr:
Unknown), Alendronic Acid (ngx), Alendronic Acid (ngx) (alendronic Acid), Alendronic Acid (ngx) (alendronic Acid) Tablet, 70mg, Alendronic Acid (ngx) (alendronic
Acid) Unknown, Alendronic Acid (ngx) (alendroniuc Acid) Unknown, Alendronic Acid 10 Mg, (alendronic Acid), Alendronic Acid 10 Mg, Capsules (alendronic Acid),
Adverse Events, Inc.
www.AdverseEvents.com
13
Alendronic Acid 10mg Tablets, Alendronic Acid 70 Mg, Alendronic Acid 70mg Tablets, Alendronic Acid Sandoz (ngx) (alendronic Acid) Tablet, 70 Mg, Alendronic Acid
Tablets, Alendronic Acid Tablets 10 Mg (mah: Arrow Generics Ltd.), Alendronic Acid [alendronic Acid], Unknown, Alendronic Acid(alendronic Acid), Alendronic
Acid(tablets) (alendronic Acid), Alendronic Anhydre Acid, Alendronicacid (alendronic Acid), Alendronine Acid Pch, Alendroninezur, Alendroninezuur, Alendroninezuur
Actavis, Alendroninezuur Kr, Alendroninezuur Mylan, Alendronsacure, Alendronsaeure, Alendronsaeure (70 Mg), Alendronsaeure Abz, Alendronsaeure Stada,
Alendronsaeure Tablets, Alendronsaure, Alendros, Alendrosorineacid, Alenedronate Sodium (alendronate Sodium), Alenfronate Generic For 70mg Teva, Alenoronic Acid
(ngx) (alendronac Acid) Tablet, Alenronate (alendronate Sodium), Alenronic Acid (alendronic Acid), Allendronat (alendronate Sodium), Allendronate 70 Milligrams Teva
Pharmaceuticals, Allendronate Sodium, Allendronate Sodium (alendronate Sodium), Allendronate Sodium Tablets Usp 70 Mg, 91.363 Alendronate Sodi Aurobin,
Alndronate Sodium, Alndronate Sodium (alendronate Sodium), Alnedronate, Alodronate 70 Mg Teva Pharmaceuticals, Alondrate, Alondrenate 70mg Teva, Alondronate,
Alondronate (a Bisphospha, Alondronate 70mgm Sun Phamaceutical Industries, Apo-alendronate, Blinded Alendronate Sodium Comp-als+, Blinded Alendronic Acid,
Bonalen, Bonalen /01220302/, Bonalno (alendronate Sodium Hydrate), Bonalog, Bonaloln (alendronic Acid), Bonalon, Bonalon (alendronic Acid), Bonalon /01220301/,
Bonalon /01220302/, Bonalon (alendronate Sodium) Tablet, Bonalon (alendronic Acid), Bonalon (alendronic Acid), Bonalon (alendronic Acid), Bonalon (alendronic Acid),
Bonalon (alendronate Sodium), Bonalon (alendronic Acid), Bonalon (alendronate Sodium), Bonalon (alendronic Acid), Bonalon (alendronic Acid) Tablet, Bonalon
Alendronic Acid) Tablet, Bonalon (aledronic Acid), Bonalon (alendreonic Acid), Bonalon (alendroante Sodium) Per Oral Nos, Bonalon (alendroic Acid) Tablet, Bonalon
(alendronate Sodium Hydrate), Bonalon (alendronate Sodium Hydrate) (alendronate Sodium), Bonalon (alendronate Sodium Hydrate) Tablet, Bonalon (alendronate
Sodium), Bonalon (alendronate Sodium) Formulation Unknown, Bonalon (alendronate Sodium) Per Oral Nos, Bonalon (alendronate Sodium) Per Oral Nos. 35 Mg, Bonalon
(alendronate Sodium) Tabelt, Bonalon (alendronate Sodium) Tablet, Bonalon (alendronate Sodium) Unknown, Bonalon (alendronate Sodium)tablet, Bonalon (alendronic
Acid), Bonalon (alendronic Acid) Per Oral Nos, Bonalon (alendronic Acid) Tablet, Bonalon (alendronic Acid) Tablet, 5 Mg, Bonalon (alendronic Acid) Tablet, 5mg,
Bonalon (alnedronic Acid), Bonalon / 01220301/, Bonalon /01220301/, Bonalon /01220301/ (bonalon - Alendronate Sodium Hydrate), Bonalon /01220301/ (bonalon Alendronate Sodium Hydrate) 5 Mg (not Sp, Bonalon /01220301/(alendronic Acid) 5mg, Bonalon /01220302/, Bonalon /01220302/ (alendronate Sodium), Bonalon 35 Mg
(alendronate Sodium), Bonalon 35mg, Bonalon 35mg (alendronate Sodium), Bonalon 35mg (alendronate Sodium) Tablet, Bonalon 5mg, Bonalon 5mg (alendronate Sodium
Hydrate) Tablet, Bonalon Tablet, Bonalon(alendronate Sodium), Bonalon(alendronic Acid), Bonalon(alendronic Acid) Form, Bonalon/alendronate Sodium Hydrate,
Bonaron (alendronate Sodium), Co-alendronate, Diphosphonate (alendronate Sodium), Diphosphonates (alendronate Sodium), Dosamax (alendronate Sodiam), Dosamax
(alendronate Sodiam), Fab Fosamax Unk, Fasamax, Fasomax, Fasomax (alendronate Sodium), Foramax (alendronate Sodium), Fos0max Td, Fosafax, Fosalan, Fosalan
(alendronate Sodium), Fosalan (alendronate Sodium), Fosalan (alendronate Sodium) Unspecified, Fosalan(alendronate Sodium), Fosamac, Fosamac (alendronate Sodium)
Tablet, Fosamac (alendronate Sodium), Fosamac (alendronate Sodium), Fosamac (alendronate Sodium), Fosamac (alendronate Sodium) Formulation Unknown, Fosamac
(alendronate Sodium) Tablet, Fosamac (alendronate Sodium), Fosamac (alendronate Sodium) (alendronate Sodium), Fosamac (alendronate Sodium) (tablets), Fosamac
(alendronate Sodium) Formulation, Fosamac (alendronate Sodium) Formulation Unknown, Fosamac (alendronate Sodium) Per Oral Nos, Fosamac (alendronate Sodium)
Tablet, Fosamac (alendronate Sodium)(tablets), Fosamac (con.), Fosamac 35mg, Fosamac 5 Mg (alendronate Sodium Hydrate), Fosamac 5mg, Fosamac Tablets,
Fosamac(alendronate Sodium Hydrate), Fosamac(alendronate Sodium), Fosamac(alendronate Sodium) 5mg, Fosamas, Fosamax, Fosamax /ita/, Fosamax (alendroanate
Sodium), Fosamax /ita/ (alendronate Sodium), Fosamax (alendronate Socium), Fosamax /ita/(alendronate Sodium), Fosamax (alendronate Sodium) (alendronate Sodium),
Fosamax /ita/(alendronate Sodium), Fosamax (alendornate Sodium), Fosamax (alendronae Sodium), Fosamax /ita/, Fosamax /ita/ (alendronate Sodium), Fosamax
/ita/(alendronate Sodium), Fosamax (70 Milligram), Fosamax (alandronate Sodium), Fosamax (aldendronate Sodium), Fosamax (aldendronate), Fosamax (aldendronatte
Sodium), Fosamax (aldenronate Sodium), Fosamax (alebndronate Sodium), Fosamax (alednronate Sodium), Fosamax (alendcronate Sodium), Fosamax (alenderonate
Sodium), Fosamax (alendornate Sodium), Fosamax (alendornate Sodum), Fosamax (alendoronate Sodum), Fosamax (alendraonate Sodium), Fosamax (alendroane Sodium),
Fosamax (alendroane Sodium) Talbet, Fosamax (alendroantae Sodium), Fosamax (alendroante Sodum), Fosamax (alendroate Sodium), Fosamax (alendrona Sodium),
Fosamax (alendronade Sodium), Fosamax (alendronae Sodium), Fosamax (alendronafe Sodium), Fosamax (alendronat Sodium), Fosamax (alendronate Soldium), Fosamax
(alendronate Calcium), Fosamax (alendronate Odium), Fosamax (alendronate S0dium), Fosamax (alendronate Sdoium), Fosamax (alendronate Sodim), Fosamax
(alendronate Sodiu, Fosamax (alendronate Sodiuim), Fosamax (alendronate Sodium) (70 Milligram), Fosamax (alendronate Sodium) (70 Milligram, Tablets), Fosamax
(alendronate Sodium) (alendronate Sodium), Fosamax (alendronate Sodium) (alendronic Acid), Fosamax (alendronate Sodium) (capsules), Fosamax (alendronate Sodium)
(ta), Fosamax (alendronate Sodium) (tablets), Fosamax (alendronate Sodium) (unknown), Fosamax (alendronate Sodium) Ampule, Fosamax (alendronate Sodium)
Capsules, Fosamax (alendronate Sodium) Tablet, 5 Mg, Fosamax (alendronate Sodium) Tablets, Fosamax (alendronate Sodium) Unspecified, Fosamax (alendronate
Sodium)q, Fosamax (alendronate Sodium0, Fosamax (alendronate Sodum), Fosamax (alendronate Soidium), Fosamax (alendronate Soidum), Fosamax (alendronate Soium),
Fosamax (alendronate Sopium), Fosamax (alendronate4 Sodium), Fosamax (alendronatye Sodium), Fosamax (alendronic Acid), Fosamax (alendronic Acid) 70 Mg,
Fosamax (alendronte Sodium), Fosamax (alendrote Sodium), Fosamax (alendrpmate Spdoi,_, Fosamax (allendronate Sodium), Fosamax (alnedronate Sodium), Fosamax
(con.), Fosamax (fosamax), Fosamax (generic), Fosamax + D, Fosamax + D (alendronate Sodium), Fosamax /ita/, Fosamax /ita/ (alendronate Sodium), Fosamax
/ita/(alendronate Sodium), Fosamax 600 Plus D, Fosamax 61 Days, Fosamax 70 Mg Semanal, Fosamax 9alendronate Sodium), Fosamax Brandc=, Fosamax D, Fosamax D
(alendronate Sodium), Fosamax Generic, Fosamax Nos, Fosamax Once Weekly, Fosamax Plus, Fosamax Plus (alendronate Sodium), Fosamax Plus D, Fosamax Plus D
(alendronate Sodium Cholecalciferol), Fosamax Plus D (alendronate Sodium With Cholecalciferol), Fosamax Plus D (fosavance), Fosamax Plus(tablets), Fosamax Protonix,
Fosamax Semanal, Fosamax Unk, Fosamax Veckotablett, Fosamax W/d, Fosamax Weekly, Fosamax With Vitamin D, Fosamax(alendrnate Sodium), Fosamax(alendronate
Soidum), Fosamax+d, Fosamax+d (alendronate Sodium), Fosamax, Pretreatment, Fosamax-d, Fosamax. Mfr: Not Specified, Fosamax. Mfr: Merck Sharp + Dome,
Fosamax/ita (alendronate Sodium), Fosamax/ita/(alendronate Sodium), Fosamax/vitamin D (alendronate Sodium), Fosamax/vitamin D (alendronate Sodium), Fosamaz,
Fosamex, Fosamex (alendronate Sodium), Fosamox, Fosamx (alendornte Sodium) Unspecified, Fosamx (alendronate Sodium), Fosanax (alendronate Sodium), Fosdamax
(alendronate Sodium), Fosemax, Fosfomax, Fosimax, Fosimax (alendronate Sodium), Fosimax Plus, Fosmax, Fosmax (alendorate Sodium), Fosmax (alendronate Sodium),
Fosmax / Ita (alendronate Sodium), Fosomax, Fosomax ( ) Alendronate Sodium, Fosomax (alandronate Sodium), Fosomax (alendronate Sodium), Fosomax 70 Mg Watson
Labs, Fosomax With D, Fosomax With Vitamin D, Fosovance, Fossamax, Fostepor, Fosvance, Foxamax, Foxamax (alendoronate Sodium), Foxamax (alendornate Sodium),
Foxamax (alendornate Sodium) Unspecified, Foxamex, Foxomax, Foxomax 70mg Merck, Foxomax-d, Fozamax, Generic Alendronate 70 Mg Mylan Pharmaceutical,
Generic Fosamax, Generic Name: Alendronate, Ic Alendronate 70 Mg Apotex Corp., Lendornate Sodium (alendornate Sodium), Monosodium Alendronate, Monsodium
Alendronate (alendronate Sodium), Nasal Steroid Alendronate, Novo Alendronate, Novo-alendronate, Novo-alendronate 70mg Novopharm, Phosamax, Phosamax
(fosamax), Phosimex, Phosmax, Phosomax, Phosomex, Phostarac (alendronate Sodium) Tablet, Posamax (alendronate Sodium), Riva-alendronate, Romax (ngx), Sandozalendronate, Sodium Alendronate, Sodium Alendronate (alendronate Sodium), Sodium Alendronate, Alendronic Acid, Solumedrol (alendronate Sodium), Sonalon
(alendronic Acid), Tab Alendronate Sodium (+) Cholecalciferol, Tab Alendronic Acid, Tab Fosamax 35 Mg, 70 Mg, Tab Fosamax (alendronate Sodium), Tab Fosamax 10
Mg, Tab Fosamax 70 Mg, Tab Fosamax 35 Mg/70 Mg, Tab Fosamax 35 Mg, 70 Mg, Tab Fosamax 35 Mg, Tab Fosmax 70mg, Tab Fosamax 70 Mg, Tab Fosamax Unk, 5
Mg, 70 Mg, Tab Sofamax 10 Mg, Weekly Alendronate
Actonel
Other names : Risedronate Sodium Tablets, Benet, NE58095
FDA listed names (323):
(risedronate Sodium) - Unknown - Unit Dose : Unknown, Acetonel, Acetonel (risedronate), Acide Risedronique Sel Monosodique (risedronic Acid), Acidum
Risedronicum(risendronat), Acrel (risedronate Sodium 35 Mg) Tablet, 35 Mg, Acrel (risedronate Sodium) Tablet,, Acrel (risedronate Sodium) Tablet, 35mg, Acrel
Adverse Events, Inc.
www.AdverseEvents.com
14
(risedronate Sodium) Tablet, 75mg, Acrel(risedronate Sodium 35 Mg) Tablet, 35mg, Actenol 150 Mg P + G, Actenol 35mg Proctor And Gamble, Actoinel (risedronate
Sodium), Actokit (risedronate Sodiuim 35 Mg, Calcium (carbonate 1250 Mg)tablet,, Actokit (risedronate Sodium 35 Mg, Calcium Carbonate 1250 Mg) Tablet,, Acton Acth
Inj, Actone (risedronate Sodium), Actoneal (risedronate Sodium), Actonel, Actonel /usa/, Actonel /usa/ (risedronate Sodium), Actonel (risedronate Sosium) Tablet,
Unknownmg, Actonel /usa/(risedronate Sodium), Actonel (risederonate Sodium) (risedronate Sodium), Actonel (actonel), Actonel (atenolol), Actonel (capsules), Actonel
(con.), Actonel (con.) /01026402/ (con.), Actonel (proctor + Gamble), Actonel (residronate Sodium), Actonel (riedronate Sodium), Actonel (riesdronate Sodium), Actonel
(risdedronate Sodium), Actonel (risdedronate), Actonel (risderronate Sodium), Actonel (risdronae Sodium) Tablet, 35mg, Actonel (risdronate Sodium) Tablet, Actonel
(risederonate Sodium), Actonel (risedonate Sodium), Actonel (risedroante Sodium), Actonel (risedronage Sodium), Actonel (risedronate Acetate), Actonel (risedronate
Acid), Actonel (risedronate Chloride), Actonel (risedronate Sodiu, Actonel (risedronate Sodiuim), Actonel (risedronate Sodiuim)tablet, 35mg, Actonel (risedronate Sodium)
(35 Milligram), Actonel (risedronate Sodium) (35 Milligram) (risedronate Sodium), Actonel (risedronate Sodium) (nr), Actonel (risedronate Sodium) (risedronate Sodium),
Actonel (risedronate Sodium) (unknown), Actonel (risedronate Sodium) 2.5 Mg, Actonel (risedronate Sodium) Formulation Unknown, Actonel (risedronate Sodium) Per
Oral Nos, Actonel (risedronate Sodium) Tablets, Actonel (risedronate Sodium) Unknown, Actonel (risedronate Sodium)(risedronate Sodium), Actonel (risedronate
Sodium0, Actonel (risedronate Sodiuum), Actonel (risedronate Soidum) Tablet, 35mg, Actonel (risedronate Sosium) Tablet, Unknownmg, Actonel (risedronate0, Actonel
(risedronates Sodium) Tablet, Unknownmg, Actonel (risedroonate Sodium), Actonel (risedrpmate Sodium), Actonel (riseedronate), Actonel (risendronate Sodium), Actonel
(risendronate), Actonel (riserdronte Sodium), Actonel (risidronate Sodium), Actonel (risperidone Sodium), Actonel (risperonae Sodium), Actonel (rissedronate Sodium),
Actonel (sodium Risedronate Hydrate), Actonel (sodium Risedronate Hydrate) (risedronate Sodium), Actonel (ta), Actonel (tablet) (risedronate Sodium), Actonel (tablets),
Actonel (tablets) Risedronate Sodium, Actonel (talbets) Risedronate Sodium, Actonel + Calcium, Actonel /usa/, Actonel /usa/ (risedronate Sodium), Actonel
/usa/(risedronate Sodium), Actonel /usa/risedronate Sodium), Actonel 35 Plu (risedronate Acid, Calcium, Vitamin D), Actonel 35 Plus, Actonel 35mg Plus Calcium
(risedronate Sodium 35 Mg, Calcium Carbonate, Actonel 9risedronate Sodium), Actonel And Vitamin D, Actonel Code Not Broken, Actonel Combi, Actonel Combi
(risedronate Sodium 35 Mg, Calcium Carbonate 1250 Mg) Ta, Actonel Combi C, Actonel Combi D, Actonel Combi(risedronate Sodium 35 Mg, Calcium Carbonate 1250
Mg) Tab, Actonel Einmal W Chentlich(risedronate Sodium) Tablet, 35mg, Actonel Einmal Wa Chentlich(risedronate Sodium) Tablet, 35mg, Actonel Einmal Woechentlich,
Actonel Einmal Woechentlich (risedronic Acid), Actonel Generic, Actonel Plus, Actonel Plus Calcium, Actonel Plus Calcium (calcium Carbonate, Risedronate Sodium),
Actonel Plus Calcium /02223601/, Actonel Plus Calcium D, Actonel Plus Calcium D (risedronate Sodium 35 Mg, Calcium Carbonate 25, Actonel Plus Calcium
D(risedronate Sodium 35 Mg, Calcium Carbonate 250, Actonel Sachet Kit (risedroante Sodium 35 Mg, Calcium Carbonate 2500 M, Actonel Therapy, Actonel With
Calcium, Actonel With Calcium (copackaged), Actonel With Calcium(risedronate Sodium 35 Mg, Calcium Carbonate 1250, Actonel(risedronate Sodium) Tablet, 35mg,
Actonel(risedronate Sodum) Tablet, 35mg, Actonel(tablets), Actonel-calcium, Actonel-chlor, Actonel-chlorthal, Actonel/usa/, Actonel/usa/(risedronate Sodium),
Actonel/usa/(risedronate Soidum), Actonel/usa/risedronate Sodium), Actonell, Actoneol (risedronate Sodium), Actonol (risedronate Sodium), Atelvia, Atonel (risedronate
Sodium), Bene(risedronate Sodium) Tablet, 2.5mg, Benet, Benet (risedronate Sodium), Benet (risedronate Sodium), Benet (risedronate Sodium), Benet (rispedronate
Sodium), Benet (risedronate Sodium), Benet (risedronate Sodium), Benet (risedronate Sodium) Tablet,, Benet (risedronate Sodium), Benet (risedronate Sodium), Benet (all
Otehr Therapeutic Products) Tablets, Benet (all Other Therapeutic Prdoucts ) Unknonw, Benet (all Other Therapeutic Products), Benet (all Other Therapeutic Products)
Tablets, Benet (benet) (not Specified), Benet (con), Benet (con.), Benet (risedronat Sodium), Benet (risedronate Acid), Benet (risedronate Sodium), Benet (risedronate
Sodium) (risedronate Sodium), Benet (risedronate Sodium) (ta), Benet (risedronate Sodium) (tablet) (risedronate Sodium), Benet (risedronate Sodium) Per Oral Nos, Benet
(risedronate Sodium) Tablet, Benet (risedronate Sodium) Tablet 2.5 Mg, Benet (risedronate Sodium) Tablet 2.5mg, Benet (risedronate Sodium) Tablet Tablet, 17.5 Mg Mg,
Benet (risedronate Sodium) Tablet, 17.5 Mg, Benet (risedronate Sodium) Tablet, 17.5g, Benet (risedronate Sodium) Tablet, 17.5mg, Benet (risedronate Sodium) Tablet, 2.5
Mg, Benet (risedronate Sodium) Tablet, 2.5mg, Benet (risedronate Sodium) Tablet, Unknownmg, Benet (risedronate Sodium)tablet, 17.5 Mg, Benet (risedronate
Sodium)tablet, 2.5 Mg, Benet (risedronate Sodium0, Benet (risedronic Acid), Benet (risendronate Sodium), Benet (risendronate Sodium) Tablet, 17.5 Mg, Benet
(risendronate Sodium) Tablet, 2.5mg, Benet (riserdonate Sodium) (tablet) (risedronate Sodium), Benet (sodium Risedronae Hydrate), Benet (sodium Risedronae Hydrate)
Tablet, Benet (sodium Risedronate Hydrate), Benet (sodium Risedronate Hydrate) Tablet, Benet (sodium Risedronate Sodium Hydrate) Tablet 17.5mg, Benet (sodium
Risendronate Hydrate), Benet /jpn/, Benet Tablets (risedronate Sodium), Benet Tablets 17.5mg, Benet Tablets 17.5mg (risedronate Sodium), Benet Tablets 2.5 Mg
(risedronate Sodium) (tablets), Benet Tablets 2.5mg, Benet Tablets 2.5mg (risedronate Sodium) (tablets), Benet(risedronate Sodiuim)tablet, 2.5 Mg, Benet(risedronate
Sodium), Benet(risedronate Sodium) Tablet, 2.5 Mg, Benet(risedronate Sodium) Tablet, 2.5mg, Benet(risedronate Sodium) Tablet, Unknownmg, Benet(risedronate Sodium)
Talbet, 2.5mg, Benet(risedronate Sodium)tablet 2.5 Mg, Benet(risedronate Sodium)tablet, 2.5mg, Blinded Risedronic Acid, Calcium Carbonate And Risedronate Sodium,
Ctonel (risedronate Sodium), Generic Actonel 10 Mg, Monosodic Risedronate, Natrii Risedronas (risedronate Sodium), Optinata (risedronate Sodium), Optinate, Optinate
(risedronate Sodium), Optinate (risedronate Sodium), Optinate (risedronate Sodium), Optinate (risedronate Sodium) Tablet, 5mg, Optinate (risedronate Sodium), Optinate
(risedronate Sodium) Tablet, 30mg, Optinate (risedronate Sodium) Tablet, 35mg, Optinate (risedronate Sodium) Tablet, 5mg, Optinate (risedronate Sodium) Tablet, 75mg,
Optinate (risedronate Sodium)tablet, 35mg, Optinate Combi D, Optinate Septimum, Optinate Septimum (risedronate Sodium), Optinate Septimum (risedronate Sodium),
Optinate Septimum (risedronate), Optinate Septimum (risedronate Sodium), Optinate Septimum (risedronate), Optinate Septimum (risedronic Acid), Optinate Septimun,
Optinate Sodium (risedronate Sodium), Optinate(risedronate Sodium) Tablet, Optinate(risedronate Sodium) Tablet, 30mg, Optinate(risedronate Sodium) Tablet, 35mg,
Remodellin (alfacalcidol) (capsule) (risedronate Sodium), Resedronate Sodium, Residronate, Residronate Monosodium, Risdedronate, Risderonate (risedronate Soduim)
Tablet, 2.5mg, Risdronate Sodium, Risedromate, Risedronae Sodium (actonel ), Risedronat, Risedronate, Risedronate (risedronate), Risedronate (risedronic Acid),
Risedronate (risedronate Sodium), Risedronate (risedronic Acid), Risedronate -actonel-, Risedronate (risedromate Sodium), Risedronate (risedronate Ion), Risedronate
(risedronate Sodium), Risedronate (risedronate Sodium) (nr), Risedronate (risedronate Sodium) Tablet, Risedronate (risedronate Sodium) Tablet, 10 Mg, Risedronate
(risedronate Sodium) Tablet, 30mg, Risedronate (risedronate Sodium) Tablet, 35mg, Risedronate (risedronate Sodium) Tablet, Unknown, Risedronate (risedronate),
Risedronate (risedronic Acid), Risedronate (tablets), Risedronate (tablets_), Risedronate -actonel-, Risedronate Acid (risedronic Acid), Risedronate Lu#141370, Risedronate
Monosodic, Risedronate Monosodique, Risedronate Na, Risedronate Natrium, Risedronate Sodeium (risedronate Sodium), Risedronate Sodiium, Risedronate Sodijm
(risedronate Sodium), Risedronate Sodiuim, Risedronate Sodium, Risedronate Sodium (risedronate Sodium), Risedronate Sodium (risedronate Sodium), Risedronate
Sodium (risedronate Sodium), Risedronate Sodium (risedronate Sodium), Risedronate Sodium (residronate Sodium), Risedronate Sodium Tablet, 35mg, Risedronate
Sodium (risedronate Sodium), Risedronate Sodium (actonel), Risedronate Sodium (con.), Risedronate Sodium (ngx), Risedronate Sodium (residronate Sodium), Risedronate
Sodium (risedronate Sodium), Risedronate Sodium (risedronate Sodium) (con.), Risedronate Sodium (risedronate Sodium) (nr), Risedronate Sodium (risedronate Sodium)
(risedronate Sodium), Risedronate Sodium (risedronate Sodium0, Risedronate Sodium (risedronate Soidum), Risedronate Sodium (risedronate), Risedronate Sodium
(risendronate Sodium), Risedronate Sodium (rosiglitazone Maleate), Risedronate Sodium Hydrate, Risedronate Sodium Hydrate (risedronate Sodium), Risedronate Sodium
Hydrate (risedronate Sodium), Risedronate Sodium Tablet, 35mg, Risedronate Sodium Tablets, Risedronate Sodium( Risedronate Sodium), Risedronate Sodium(risedrnate
Sodium), Risedronate Soduim, Risedronate Sodum, Risedronate(risedronate Sodium) Tablet, 17.5mg, Risedronate(risedronate Sodium) Tablet, 5 Mg, Risedronato,
Risedrone Acid, Risedronic, Risedronic Acid, Risedronic Acid (risedronic Acid), Risedronic Acid, Risedronic Acid (risedronic Acid), Risedronic Acid Coated, Risedronic
Acid Sodium, Risedronic Acid/risedronate, Risendronate, Risendronate 35mg, Risendronate 35mg, Risendronate Sodium, Riserdronate, Risidronate, Risodronate,
Risodronate Sodium, Risofos (risedronate Sodium) 35 Mg Cipla Ltd, Risperidonate (risedronic Acid), Sodium Residronate Hydrate, Sodium Risedronate, Sodium
Risedronate Hydrate, Sodium Risedronate Hydrate (risedronate Sodium), Sodium Risedronate Hydrate (sodium Risedronate Hydrate), Sodium Risendronate Hydrate
Reclast
Other names: Aclasta; Zoledronic Acid
FDA listed names (42):
Adverse Events, Inc.
www.AdverseEvents.com
15
Aclasta, Aclasta (zoledronate) Solution For Injection, Aclasta (zoledronate) Unknown, 0.05mg/ml, Aclasta (zoledronate), 0.05mg/ml, Aclasta (zoledronic Acid), Aclasta
(zoledronic Acid) Solution For Infusion, 0.05mg/ml, Aclasta (zoledronic Acid) Vs Placebo, Aclasta (zoledronic Acid,), Aclasta Novartis, Aclasta/zoledronate,
Aclasta/zoledronate T29581+a+, Aclasta/zoledronate T29581+a++os, Aclasta/zoledronate T29581+a++pd, Aclasta/zoledronate T29581+a+solinj, Aclasta/zoledronate
T29581+a+solinj+os, Aclasta/zoledronate T29581+a+solinj+pd, Alcasta (zoledronic Acid) (injection) (zoledronic Acid), Annual Reclast Infusion, Blinded
Aclasta/zoledronate, Blinded Aclasta/zoledronate T29581+a++os, Blinded Aclasta/zoledronate T29581+a+solinj, Blinded Aclasta/zoledronate T29581+a+solinj+os, Iv
Reclast By Novartis - Zoledronic Acid - Iv, Reclast, Reclast (all Other Therapeutic Products), Reclast (zoledronate), Reclast (zoledronic Acid) (injection For Infusion),
Reclast (zoledronic Acid) (solution), Reclast (zoledronic Acid) (zoledronic Acid), Reclast 5 Mg/ 100 Ml Injection, Reclast 5mg/ 100ml Every Year Ivpb, Reclast Standard
Dose For Pt. Size, Reclast, 5mg/100ml , Novartis, Recreclast -zoledronic Acid- 5 Mg/100 Ml Novartis Pharmaceutical Corp, Zoledronate, Zoledronic, Zoledronic Acid,
Zoledronic Acid (aclasta) Or Placebo, Zoledronic Acid (aclasta) Vs Placebo Code Not Broken, Zoledronic Acid (reclast), Zoledronic Acid Vs Aledronate, Zometa,
Boniva
Other names: Ibandronate Sodium, Bonviva (extended Dosing), Bondronat (EU), Bondenza (EU), RG484, CT-064 (Oral)
FDA listed names (96):
Bandronate, Bandronate Sodium, Bandronic Acid), Blinded Ibandronic Acid, Bon Viva (ibandronate), Bonadronat, Bonavia, Bondenza, Bondeza (ibandronate Sodium)
(ibandronate Sodium), Bondronat, Bondronat (ibandronic Acid), Bondronat /01304701/, Bondronat (6 Milligram), Bondronat (bandronic Acid), Bondronat (ibandronic
Acid), Bondronat /01304701/, Bondronat [ibandronate Sodium], Bondronat ^orion^, Bondronat ^roche^, Bondronate, Boneva, Boniva, Boniva (1bandronic Acid), Boniva
(all Other Therapeutic Products), Boniva (bandronate Sodium), Boniva (con.), Boniva (ibandrinate Sodium) (150 Milligram), Boniva (ibandronate Sodium), Boniva
(ibandronate Sodium) (150 Milligram), Boniva (ibandronate Sodium) (150 Milligram, Tablets), Boniva (ibandronate Sodium) (intravenous Infusion), Boniva (ibandronate
Sodium) (pill), Boniva (ibandronate Sodium) (tablet) (ibandronate Sodium), Boniva (ibandronate Sodium) Injection, Boniva (ibandronate Sodium)`, Boniva (ibandronate),
Boniva (ibandronic Acid), Boniva (ibandronic Acid) 150 Mg, Boniva 9boniva), Boniva Calcium, Boniva Infusion, Boniva Inj (ibandronate Sodium), Boniva Injection Once
Every Three Months, Boniva R Cali/d3, Boniva(ibandronate Sodium), Boniva(ibandronate Sodium) (ibandronate Sodium), Bonivea, Bonivia (bandronate Sodium), Bonivia
(ibandronic Acid), Boniviva, Bonvia (ibandronate Sodium), Bonviva, Bonviva /01304701/, Bonviva (ibandronic Acid), Bonviva (ibandronic Acid), Bonviva (ibandronic
Acid) (ibandronic Acid), Bonviva /01304701/, Bonviva /01304701/ (bonviva - Ibandronic Acid) 150 Mg (not Specified), Bonviva/01304701/ (ibandronic Acid), Bovina
(ibandronate), Bovina (irbandronate), Hydrochloride Ibandronate Sodium, Ibandronae Sodium (ibandronae Sodium), Ibandronat, Ibandronate, Ibandronate 150mg (boniva),
Ibandronate (boniva), Ibandronate (ibandronate Sodium), Ibandronate 150 Mg (boniva), Ibandronate 150mg (boniva), Ibandronate 150mg Boniva, Ibandronate Monoso
(ibandronate Sodium), Ibandronate Sodium, Ibandronate Sodium (ibandronate Sodium), Ibandronate Sodium (bandronate Sodium), Ibandronate Sodium (boniva),
Ibandronate Sodium (ibandreonate Sodium), Ibandronate Sodium (ibandronate Sodium), Ibandronate Sodium (tablets), Ibandronic Acid, Ibandronic Acid (ibandronic Acid),
Ibandronic Acid (ibandronic Acid), Ibandronic Acid (injection For Infusion), Ibandronic Acid (bandronic Acid), Ibandronic Acid (ibandronic Acid), Ibandronic Acid (nonroche/non-comparator), Ibandronic Acid Senna (senna), Ibandronik Acid, Ibandronix Acid, Ibendronat, Ibendronate, Idrofos (ibandronate) -sun Pharma. Boneva Nda# 21455, Iibandronic Acid, Injections Of Boniva, Sodium Ibandronate, Tab Ibandronate Sodium 150 Mg
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Appendix B
Adverse event categories - search terms used
“All Renal Issues”
Cardiorenal syndrome, Inulin renal clearance decreased, Kidney enlargement, Kidney fibrosis, Kidney infection, Kidney perforation, Kidney rupture, Malignant renal
hypertension, Oedema due to renal disease, Pararenal pseudocyst, Pulmonary renal syndrome, Renal abscess, Renal adenoma, Renal amyloidosis, Renal aneurysm, Renal
arteriosclerosis, Renal arteritis, Renal artery arteriosclerosis, Renal artery atherosclerosis, Renal artery dissection, Renal artery hyperplasia, Renal artery occlusion, Renal
artery stenosis, Renal artery stent placement, Renal artery thrombosis, Renal atrophy, Renal bruit, Renal colic, Renal cortical necrosis, Renal cyst haemorrhage, Renal cyst
infection, Renal cyst ruptured, Renal cyst, Renal disorder, Renal embolism, Renal function test abnormal, Renal haematoma, Renal haemorrhage, Renal hydrocele, Renal
hypertension, Renal hypertrophy, Renal impairment, Renal infarct, Renal injury, Renal interstitial fibrosis, Renal ischaemia, Renal lipomatosis, Renal lymphocele, Renal
necrosis, Renal osteodystrophy, Renal pain, Renal papillary necrosis, Renal salt-wasting syndrome, Renal scan abnormal, Renal tubular acidosis, Renal tubular atrophy,
Renal tubular disorder, Renal tubular necrosis, Renal vasculitis, Renal vein embolism, Renal vein occlusion, Renal vein thrombosis, Renal vessel disorder, Renovascular
hypertension, Ultrasound kidney abnormal, Urea renal clearance decreased
“All Nephropathy”
Acute phosphate nephropathy, Bilateral hydronephrosis, Emphysematous pyelonephritis, Epidemic nephropathy, Glomerulonephropathy, Hydronephrosis, Hypercalcaemic
nephropathy, Hypertensive nephropathy, Iga nephropathy, Ischaemic nephropathy, Nephrectasia, Nephritic syndrome, Nephritis, Nephritis allergic, Nephritis haemorrhagic,
Nephritis interstitial, Nephroangiosclerosis, Nephrocalcinosis, Nephrogenic anaemia, Nephrolithiasis, Nephropathy, Nephropathy toxic, Nephrosclerosis, Nephrotic
syndrome, Perinephric abscess, Perinephric collection, Perinephric effusion, Pigment nephropathy, Pyelonephritis, Pyelonephritis acute, Pyelonephritis chronic,
Pyonephrosis, Reflux nephropathy, Urate nephropathy
“Muscle and Tendon Disorders, General”
Abasia, Abdominal Compartment Syndrome, Abdominal Rigidity, Akinaesthesia, Akinesia, Amimia, Amyotrophy, Arthralgia, Arthropathy, Asthenia, Ataxia, Athetosis,
Ballismus, Binocular Eye Movement Disorder, Blood Creatine Phosphokinase Abnormal, Blood Creatine Phosphokinase Mm Increased, Blood Creatine Phosphokinase
Mm, Blood Creatine Phosphokinase, Bradykinesia, Cachexia, Cerebellar Ataxia, Chorea, Choreoathetosis, Clonus, Cogwheel Rigidity, Coordination Abnormal, Cytotoxic
Cardiomyopathy, Dermatomyositis, Diaphragm Muscle Weakness, Diaphragmalgia, Diaphragmatic Abnormal Relaxation, Diaphragmatic Disorder, Diaphragmatic Injury,
Diaphragmatic Paralysis, Diplegia, Dyskinesia, Dysstasia, Dystonia, Extraocular Muscle Disorder, Extraocular Muscle Paresis, Eye Movement Disorder, Eye Muscle
Entrapment, Eye Muscle Tenotomy, Facial Paresis, Fibromuscular Dysplasia, Fibromyalgia, General Physical Condition Abnormal, Grip Strength Decreased, Grip Strength,
Gross Motor Delay, Hemiparesis, Hemiplegia Transient, Hemiplegia, Hyperkinesia, Hyperreflexia, Hypertonia, Hypokinesia, Hypophonesis, Hyporeflexia, Hypotonia,
Hypotonic-Hyporesponsive Episode, Immobilisation Prolonged, Inclusion Body Myositis, Intercostal Neuralgia, Intermittent Claudication, Joint Ankylosis, Joint
Contracture, Joint Destruction, Joint Hyperextension, Joint Injury, Joint Instability, Joint Ligament Rupture, Joint Lock, Joint Range Of Motion Decreased, Joint Sprain,
Joint Stiffness, Joint Swelling, Lagophthalmos, Latent Tetany, Levator Syndrome, Ligament Disorder, Ligament Laxity, Ligament Pain, Ligament Repair, Ligament
Rupture, Ligament Sprain, Ligamentitis, Limb Immobilisation, Locked-In Syndrome, Masked Facies, Meige'S Syndrome, Metatarsalgia, Monoparesis, Monoplegia,
Movement Disorder, Muscle Atrophy, Muscle Contracture, Muscle Cramp, Muscle Disorder, Muscle Enzyme Decreased, Muscle Enzyme Increased, Muscle Enzyme,
Muscle Fatigue, Muscle Fibrosis, Muscle Haemorrhage, Muscle Injury, Muscle Necrosis, Muscle Operation, Muscle Rigidity, Muscle Rupture, Muscle Spasms, Muscle
Spasticity, Muscle Strain, Muscle Swelling, Muscle Tightness, Muscle Twitching, Muscular Dystrophy, Muscular Weakness, Musculoskeletal Chest Pain, Musculoskeletal
Discomfort, Musculoskeletal Pain, Musculoskeletal Stiffness, Myalgia Intercostal, Myalgia, Myasthenia Gravis Crisis, Myasthenia Gravis, Myoclonus, Myoglobin Blood
Increased, Myoglobin Blood Present, Myoglobin Blood, Myoglobin Urine Present, Myoglobin Urine, Myoglobinuria, Myopathy Toxic, Myopathy, Myosclerosis, Myositis,
Myositis-Like Syndrome, Myotonia, Myotonic Dystrophy, Neuromuscular Toxicity, Neuromyopathy, Ocular Myasthenia, Ophthalmoplegia, Papillary Muscle Disorder,
Papillary Muscle Haemorrhage, Papillary Muscle Infarction, Papillary Muscle Rupture, Paralysis Flaccid, Paralysis, Paralytic Gait, Paralytic Lagophthalmos, Paraparesis,
Paraplegia, Paresis Anal Sphincter, Paresis Cranial Nerve, Paresis, Parkinsonian Gait, Pelvic Floor Muscle Weakness, Pelvic Muscles Inadequate, Peripheral Paralysis,
Peroneal Muscular Atrophy, Polymyalgia Rheumatica, Polymyalgia, Polymyositis, Progressive External Ophthalmoplegia, Progressive Muscular Atrophy, Purulent
Synovitis, Quadriparesis, Quadriplegia, Respiratory Muscle Weakness, Sarcopenia, Skeletal Muscle Enzymes, Spastic Diplegia, Spastic Paralysis, Spinal Muscular Atrophy,
Synovitis, Tendon Injury, Tendon Necrosis, Tendon Operation, Tendon Pain, Tendon Repair, Tendon Rupture, Tendonitis, Tenosynovitis Stenosans, Tenosynovitis, Tetany,
Trigger Finger.
“Throat Cancer”
Benign Oesophageal Neoplasm, Biopsy Oesophagus Abnormal, Oesophageal Cancer Metastatic, Oesophageal Carcinoma Recurrent, Oesophageal Carcinoma, Oesophageal
Dysplasia, Oesophageal Mass, Oesophageal Neoplasm, Oesophageal Squamous Cell Carcinoma Metastatic, Oesophageal Squamous Cell Carcinoma Stage I, Oesophageal
Squamous Cell Carcinoma Stage Ii, Oesophageal Squamous Cell Carcinoma Stage Iv, Oesophageal Squamous Cell Carcinoma, Throat Cancer
“Head and Neck Cancer”
benign laryngeal neoplasm, epiglottic mass, head and neck cancer, hypopharyngeal cancer, hypopharyngeal neoplasm benign, hypopharyngeal neoplasm, laryngeal cancer
recurrent, laryngeal cancer stage 0, laryngeal cancer stage ii, laryngeal cancer stage iii, laryngeal cancer stage iv, laryngeal cancer, laryngeal mass, laryngeal neoplasm,
nasopharyngeal cancer recurrent, nasopharyngeal cancer stage iv, nasopharyngeal cancer, nasopharyngeal neoplasm benign, neck mass, oropharyngeal cancer recurrent,
oropharyngeal cancer stage ii, oropharyngeal cancer stage iii, oropharyngeal cancer stage iv, oropharyngeal cancer stage unspecified, oropharyngeal neoplasm benign,
oropharyngeal neoplasm, pharyngeal cancer metastatic, pharyngeal cancer stage iii, pharyngeal cancer stage unspecified, pharyngeal mass, pharyngeal neoplasm benign,
pharyngeal neoplasm, postcricoid cancer, vocal cord neoplasm
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“All Abnormal Heart Rhythms (without Atrial Fibrillation)”
Agonal Rhythm, Arrhythmia Supraventricular, Arrhythmia, Atrial Tachycardia, Bradyarrhythmia, Bradycardia, Gallop Rhythm Present, Nodal Arrhythmia, Nodal Rhythm,
Pacemaker Generated Arrhythmia, Pacemaker Generated Rhythm, Paroxysmal Arrhythmia, Postural Orthostatic Tachycardia Syndrome, Rebound Tachycardia, Sinus
Arrhythmia, Sinus Bradycardia, Sinus Rhythm, Sinus Tachycardia, Supraventricular Tachyarrhythmia, Supraventricular Tachycardia, Tachyarrhythmia, Tachycardia
Paroxysmal, Tachycardia, Ventricular Arrhythmia, Ventricular Tachyarrhythmia, Ventricular Tachycardia
“All Bone Fractures (Non-Osteoporosis)”
Ankle Fracture, Clavicle Fracture, Epiphyseal Fracture, Facial Bones Fracture, Fibula Fracture, Foot Fracture, Forearm Fracture, Fracture Of Penis, Fractured Ischium,
Fractured Sacrum, Fractured Skull Depressed, Fractured Zygomatic Arch Elevation, Hand Fracture, Humerus Fracture, Ilium Fracture, Multiple Fractures, Patella Fracture,
Radius Fracture, Rib Fracture, Scapula Fracture, Skull Fracture, Skull Fractured Base, Sternal Fracture, Tibia Fracture, Tooth Fracture, Torus Fracture, Ulna Fracture, Upper
Limb Fracture, Wrist Fracture
“All Oral Inflammation (without Teeth)”
Acute Tonsillitis, Aphthous Stomatitis, Atrophic Glossitis, Cheilitis Granulomatosa, Cheilitis, Chronic Tonsillitis, Contact Stomatitis, Epiglottitis Obstructive, Epiglottitis,
Gingivitis Ulcerative, Gingivitis, Glossitis, Necrotising Ulcerative Gingivostomatitis, Palatitis, Parotitis, Peritonsillitis, Pharyngotonsillitis, Sialoadenitis, Stomatitis,
Stomatitis Haemorrhagic, Stomatitis Necrotising, Stomatitis Radiation, Tonsillitis, Uvulitis
“All Bone-Related Inflammation”
Ankylosing Spondylitis, Chondritis, Costochondritis, Epicondylitis, Intervertebral Discitis, Mastoiditis, Myositis Ossificans, Nodal Osteoarthritis, Osteitis Condensans,
Osteitis Deformans, Osteitis, Osteochondritis, Osteochondrosis, Perichondritis, Periostitis Hypertrophic, Periostitis, Polychondritis, Purulent Synovitis, Relapsing
Polychondritis, Spondylitis, Synovitis, Tenosynovitis Stenosans, Tenosynovitis, Trigger Finger
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