استعرض مصدر Omeprazole – Selected Adverse Events


تعليق: تقرير رسمي من موقع هيئة الأدوية والأغذية الأمريكية. وبه تلاعب بالألفاظ واضح للخبراء.--احمد شوقي محمدين 21:40، 1 نوفمبر 2016 (ت ع م)

12.4 Visual Disturbances

12.4.1 Introduction

Evaluations of possible visual disturbances related to the use of parenteral formulations
of omeprazole were based on initial concerns expressed by the regulatory authority in
Germany. Scientific considerations of these adverse events by AstraZeneca LP (formerly
Astra Merck Inc.) and medical reviews of spontaneous reports of visual disturbances
formed the basis of several submissions to the FDA under PRILOSEC® NDA 19-810.
The content of these submissions, as well as that of a recently filed update of safety
information with a proposal for an amendment of the prescribing information for
PRILOSEC [filed 15 Nov. 99 to NDA 19-810] are summarized in this section. The
available data do not suggest that there is any medically significant ocular toxicity
associated with either short or long-term use of omeprazole in the general population.

12.4.2 Historical Review of Visual Disturbance Considerations for Omeprazole

BGA Findings and Astra Hässle Response

In March 1994, Astra Hässle (Sweden) was requested by the Bundesgesundheitsamt
(BGA) to address their concerns about reported cases of visual disturbances associated
with the use of omeprazole. Of principal concern to the BGA were several cases of
severe visual disturbances, including blindness, reported in severely ill patients receiving
an intravenous formulation of omeprazole. The BGA requested comment on 19 adverse
event case reports from post-marketing surveillance, 6 of them after administration of
intravenous omeprazole and the remaining cases after oral administration. The BGA also
suggested a series of prospective toxicological, pharmacological, and clinical studies to
further address their concerns.

Astra Hässle, in turn, compiled and submitted a report describing all available
information that was relevant to these cases, and included the results of studies and
analyses requested by the BGA to address their concerns. This report was submitted to
the BGA on 20-Mar-94 and organized into an 8 volume report by Astra Merck that was
submitted to FDA on 20-Apr-94.

The nonclinical information in the submission to the BGA consisted of the following: a
report of a state-of-the-art computerized electroretinography study in rabbits that had 
received injections of high intravenous doses; a report of a study in dogs after intravenous
infusion that included ophthalmoscopy, fundus photography and full histologic
evaluation, including of the eyes and optic nerves; a review of the ocular findings from
12 previous toxicology studies with omeprazole in mice, rats and dogs and an
autoradiographic distribution study in mice; and a report on the histological reevaluation
of the eyes from the animals in the two-year carcinogenicity/chronic toxicity study in
rats.
The conclusion from this extensive evaluation of nonclinical data was that there was no
evidence from any of the studies of any adverse effect of omeprazole on the visual or
vascular systems at high concentrations and over long periods, irrespective of the route of
administration.

The safety section of the report contained adverse event data from investigational clinical
trials, clinical pharmacological studies, and case reports arising during worldwide
commercial use. In all, there were no adverse events indicating any causal effect of
omeprazole on the visual systems.

In comparative clinical trials, the low frequency and mild nature of adverse events
suggested visual disturbance associated with omeprazole was comparable to that with
placebo as well as histamine-2 receptor antagonists.

The pharmacological data were from 177 studies involving 1,498 human volunteers and
patients, and included patients with hepatic and renal impairment. The frequency and
types of adverse events during omeprazole use were comparable to those with placebo,
irrespective of dose, route of administration or whether slow or fast metabolizers were
considered. No single case of impaired vision was reported in any of the studies, or
among the patients with Zollinger-Ellison syndrome who were treated long-term with
high doses of omeprazole.

The post-marketed adverse events were evaluated at that time against a background of
over 75 million patient treatment courses from which AstraZeneca LP had received
notification of a total of 5,942 adverse events reported for 3,937 patients.

A review of all safety data confirmed that there was no evidence for a causal relationship
between omeprazole and visual disturbances. In addition to the Astra Hässle assessment
of the adverse event reports cited by the BGA, evaluations were also provided by several
independent expert ophthalmologists. In the opinion of these experts, there was no
conclusive evidence for any causal relationship between omeprazole therapy and visual
disturbances.

The adverse event cases cited by the BGA, in addition to the Astra Hässle preclinical and
clinical data, were reviewed by an independent Expert Advisory Group composed of
18 leading German and international experts. This group unanimously concluded that
there were no data to support a causal role of omeprazole in the cases of visual

disturbance. Based on the preclinical and clinical data, the group dismissed an overall
causal relationship to omeprazole.

In summary, Astra Hässle concluded that there was no evidence to suggest a causal
relationship between omeprazole and the visual symptoms in the cases cited by the BGA.
This was in complete accordance with the unanimous conclusions of a number of
independent scientists.

Analysis of the BGA Concern over the Intravenous Injectable Form of Omeprazole
After review of the BGA findings, Astra Merck identified a number of inaccuracies in the
conclusions derived from the BGA analysis of adverse event reports of visual
disturbances and omeprazole.

Scientifically sound evidence for a causal relationship was lacking mainly because the
concept of temporal relationship in cases of optic neuropathy was addressed in an
indiscriminate manner. That is, optic neuropathy was observed following hemorrhage
and other disorders which result in significant hemodynamic compromise. In this
scenario, the precipitating event is commonly followed by a latent period prior to
symptomatic presentation. Application of temporal relationships was used in the
assessment of these cases without an understanding of the pathophysiologic course of the
actual events.

The BGA reported an increase in reporting frequency. This phenomenon was more likely
to be an artifact resulting from the publicity that followed the BGA inquiry in addition to
related publications that specifically solicited adverse event reports.
Extrapolation of the fact that blurred vision appears in the International Data Sheet for
omeprazole by Astra Hässle and therefore is evidence of a causal association between
omeprazole and more severe visual disturbances was not logical. Events such as blurred
vision occur quite commonly in the general population, the events occurred in
uncontrolled situations, and the addition of blurred vision to the international data sheet
was simply an attempt to acknowledge the occurrence of the events and not to convey a
finding of causal association.

In addition, use of the intravenous injection formulation of drugs in Germany has
historically been a cultural preference. The dose of intravenous drug has been much
higher in Germany than would be considered medically appropriate in the US
environment. The BGA has been concerned about off-label use of omeprazole including
dosing in excess of local labeling recommendations (10-20 mg daily), prescription for
non-approved indications, and excessive use of the intravenous injection form. It was
more likely that these concerns had actually influenced the BGA’s action rather than a
concern about a relationship between adverse reactions and intravenous omeprazole in
critically-ill patients. 

European CPMP Response to the BGA’s concerns
On 25-Jul-94, the European Committee for Proprietary Medicinal Products (CPMP)
discussed concerns about visual impairment that were identified by the BGA. The
content of these discussions were included in a submission to the FDA on 4-Aug-94. a

In addition to the previously mentioned data evaluations, a presentation of epidemiologic
data was discussed. A group associated with the Boston Collaborative Drug Surveillance
Programme had retrospectively studied a cohort using the VAMP database in the United
Kingdom with the objective to estimate and compare the incidence of serious visual
disorders associated with the use of omeprazole and four other ulcer-healing drugs. The
source population for the study was derived from 444 practices in England and Wales
from almost three years and encompassed almost four million registered individuals. The
study cohort included all subjects who received at least one prescription for a histamine-2
receptor antagonist or omeprazole during the study period.

Incidence rates and relative risk estimates for all the study outcomes (visual descriptors)
were calculated. The group found no evidence of an increased risk associated with use of
omeprazole as compared to non-use, nor was there any difference in risk across the study
drugs. It was demonstrated that there were no differences among the frequencies of
serious visual disorders during clinical use of omeprazole or histamine-2 receptor
antagonists, or with non-use.

Dr. Ralph Edwards of the World Health Organization also conducted an epidemiologic
study using the database maintained by the WHO Collaborating Centre for International
Drug Monitoring. The study findings did not show an increased risk of visual
disturbance with omeprazole exposure.

Subsequent to all discussion, and once all the data were reviewed, the CPMP reached the
following conclusions: 1) A causal relationship between the reported reactions and the
use of omeprazole has not been established; 2) The preferred route of administration of
omeprazole is oral. If this is not possible, then intravenous administration can be used
taking into account the different pharmacokinetic profiles of the intravenous (IV) bolus
injection and the IV infusion when prescribing the intravenous form; 3) The infusion
form should be preferred over the bolus injection form because of the higher plasma
concentration peaks and remaining suspicions of adverse events related to special clinical
conditions and high doses of the latter; and 4) The summary of product characteristics
(SPC) for the intravenous presentations should be adjusted to include the following
statement: “Irreversible visual impairment has been reported in isolated cases of critically
ill patients who have received omeprazole intravenous injection, especially at high doses,
but no causal relationship has been established.”
a
 The findings of this report were included in the following submission to the FDA on 4-Aug-94:
NDA 19-810 General Correspondence, which provided an update of the activities of the BGA and
CPMP to that point in time. The reader is directed to those sections addressing the visual system. 

Despite the firm conclusions drawn by the CPMP regarding the lack of evidence for a
causal association, the BGA elected to take unilateral action with regard to marketing of
omeprazole within their national jurisdiction and gave notice to Astra’s German
subsidiary of the suspension of the registration for the injectable bolus formulation of
omeprazole. This action was not supported by any of the other Member States.

FDA Response to BGA’s Findings and Astra Hässle and Astra Merck Reviews

In August 1994, the FDA Division of Epidemiology and Surveillance, Postmarketing
Safety Branch, compiled their review of the visual disturbance issue based on the report
they received from Astra Merck in April 1994. In addition to the three adverse event data
sets evaluated in that report, this review also included a set of reports from the FDA
spontaneous reporting system (SRS) through May 1994. However, it should be noted
that the SRS set was not corrected for duplications. The cases were individually
reviewed, and it was determined that assessment of causality was not possible because of
the limited amount of information provided in many of the cases. Missing data included
the lack of ophthalmologic examination results, concomitant administration of multiple
drugs in some cases, the presence of confounding factors such as concurrent illnesses or
conditions, and the lack of a potential mechanism to explain a possible ocular toxicity.
The conclusion of this review was that if a relationship existed between omeprazole and
these ocular events, the currently available information from the SRS cases suggests that
the overall nature of such events is non-serious, of short-term onset and is reversible,
although three of the patients reported permanent vision loss.

Review of the Published Literature

The published medical literature includes letters, case reports and small case series
concerning visual disturbances associated with the use of omeprazole. These anecdotal
data are balanced by published rebuttals and review articles, and pharmacoepidemiology
studies.

Several anecdotal reports of visual disturbances associated with the use of omeprazole
have been published as editorial correspondence, case reports, or small case series. These
cases have been captured in SafeTNet and described in regulatory submissions to the
FDA (see above) or reflect similar visual aberrations described in cases reported in these
submissions. Some of this literature reflects the concerns raised by the BGA on this
issue.198-202 The concern of the German regulatory authority was mainly over case
reports of visual disturbances related to anterior ischemic optic neuropathy with the use
of omeprazole, but this suspected drug-event association was not scientifically validated.
A significant body of literature exists in which this condition is described in association
with a variety of medical conditions.203-212 Several additional references to medical news
articles and editorials describing the BGA inquiry and subsequent deliberations by other
expert panels are not included because these do not contribute any additional information
to the historical review presented earlier in this section. 

The following types of visual disturbances were reported: anterior ischemic optic
neuropathy213-214 perception of color changes or decreased visual acuity215 blurred
vision214-218 and transient blindness in association with seizures.219-220 Rebuttal
correspondence and review articles reported on the absence of scientific data to implicate
omeprazole as a cause of the described visual disturbances.221-226

12.4.3 Nonclinical Pharmacodynamic and Toxicology Studies

The potential of omeprazole to adversely affect the visual system has been evaluated
extensively in nonclinical pharmacodynamic and toxicology studies. Compelling
molecular biological evidence has clearly shown that the gastric H+
,K+
-ATPase is not
expressed in the human eye.227 Immunological results from animal studies also strongly
suggest that the gastric proton pump is not found in the eye; however, binding of
antibodies to the gastric H+
,K+
-ATPase in the rabbit and bovine eye may indicate the
presence of a closely related protein or cross reactivity with one of the ocular Na+
,K+
-
ATPases.227,228 Even if the gastric proton pump was present in the eye, the local pH is
not sufficiently low to concentrate and activate omeprazole. No evidence of adverse
effects on ocular structure or function have been observed in extensive pharmacodynamic
and toxicological studies in animals, including ones which involved high doses and/or
long-term exposure. Thus, the results from nonclinical studies regarding the eye do not
indicate a risk from the over-the-counter (OTC) use of omeprazole.

Visual disturbances during clinical trials have been rarely observed. For example, in a
multicenter clinical trial of 674 patients with dyspepsia, one vision adverse event was
reported in each of the omeprazole 10 and 20 mg treatment arms, and three such events
were reported in the antacid/alginate treatment arm.229

Four independent pharmacoepidemiology studies have been published. In a prescriptionevent
monitoring study of 16,204 patients treated with omeprazole, during the first year
following market authorization in the UK, no “signal” of visual disturbances was
detected when compared to the pattern of adverse events observed with four other drugs
(cisapride, misoprostol, famotidine, and nizatidine) used for similar indications.230 In an
independent analysis of adverse event data from 42 countries contained in the WHO
international adverse event database regarding visual disorders associated with the use of
omeprazole, it was concluded that the increased rate of reports from Germany was
possibly explained by solicited reporting artifact.231 A retrospective cohort study was
conducted using the General Practitioner’s Research Database in the UK, of which
94,063 individuals formed the study population. The findings showed no increased risk
for inflammatory or vascular disorders of the eye associated with omeprazole when
compared to that with four other anti-ulcer drugs (ranitidine, cimetidine, famotidine, and
nizatidine).232,233 The ocular safety of omeprazole and six histamine-2 receptor
antagonists (cimetidine, famotidine, niperotidine, nizatidine, ranitidine, and roxatidine)
was also demonstrated in a similarly designed study conducted in Italy using a large,
automated regional database sourced by hospital patient records and outpatient
prescriptions for a total of 71,108 study patients.234

12.4.4 Visual Disturbance Adverse Event Analysis

The AstraZeneca LP (AZLP) post-marketing safety surveillance database is called
SafeTNet. SafeTNet includes serious adverse events reported worldwide and non-serious
adverse events reported only in the United States (US). However, in 1994, reports of
visual AEs received by Astra from Germany (both serious and non-serious) were
included in the SafeTNet database and reported to FDA. Therefore, in this report, nonserious
adverse events represent those reported in the US as spontaneous postmarketing
reports, cases of nonserious AEs reported from Germany in 1994, and some nonserious
adverse events that may have accompanied reports of serious AEs from overseas.
A search of SafeTNet was conducted between the time frame of 1988 through April
1999. The serious and non-serious adverse events for both oral and intravenous
formulations of omeprazole were sought according to their categorization under all
preferred terms related to disturbed visual function, ocular structural pathology, or nonvisual
ocular symptoms. Therefore, preferred terms of several WHOART body system
categories (e.g., vision disorders, central nervous system, psychiatric disorders, and
others) were used to search the adverse event database to ensure capture of all ocular
events. This comprehensive medical review focused on adverse events categorized both
broadly (symptomatology versus structural pathology) and specifically under 41 different
preferred terms. Specific features of individual adverse event reports that suggest or
refute possible relatedness to the use of omeprazole were sought [filed 15 Nov. 99 to
NDA 19-810].

A total of 479 adverse events pertaining to visual disturbance were identified. Three
hundred and eighty-nine patients contributed to these 479 ocular adverse events.
Although only one eye-related adverse event was reported per patient for the majority of
patients, there were up to six adverse events for a single patient in several reports.
Medical review of all 479 adverse events led to classification of these events into one of
three general categories. These categories include events with 1) symptoms of visual
dysfunction without objective ophthalmologic diagnoses, 2) a specific diagnosis of ocular
pathology, or 3) ocular symptoms unrelated to any disturbances of vision.

Adverse events were subsequently grouped into those related to symptoms of visual
dysfunction and all other events. The organization of adverse events divides the entire
group of 479 adverse events approximately in half for each of the two categories.
Although a due diligence review was performed on all events categorized according to
preferred terms, the grouping of events into these two major categories facilitated
consideration of adverse events, across preferred terms, which might be thought to be
associated with the use of omeprazole. A total of 235 adverse events related to symptoms
of visual dysfunction were categorized according to 11 select preferred terms (Table
12.1). A total of 244 adverse events related to structural abnormalities of the eye or other
non-visual ocular symptoms were categorized according to 30 select preferred terms
(Table 12.2).



TABLE 12.1

AZLP SAFETNET DATABASE SERIOUS AND NON SERIOUS POST-MARKETING REPORTS

SUMMARY OF ADVERSE EVENTS BY PREFERRED TERM VISION DISORDERS BODY SYSTEM AND EYE EVENTS IN OTHER BODY SYSTEMS

SYMPTOMS OF VISUAL DYSFUNCTION

PREFERRED SERIOUSNESS ROUTE

TERM

TOTAL

EVENTS SERIOUS NON-SERIOUS PARENTERAL OTHERa

Accommodation Abnormal 3 0 3 0 3


Blindness 18 16 2 7 11

Blindness Transient 5 3 2 0 5

Chromatopsia 1 0 1b 0 1

Diplopia 21 7 14 0 21

Myopia 2 0 2 0 2

Optic Atrophy 13 13 0 5 8

Optic Neuropathy 9 9c 0 2 7

Papilledema 6 5 1 1d 5

Vision Abnormal 141 39e 102 14 127

Vision Disorders NOS 16 2 14 0 16

TABLE TOTALS 235 94 141 29 206

a Oral form, combination of parenteral and oral forms, or unknown (but presumed oral form)

b
 Although the case summary report indicates the event is serious, sponsor review of available information leads to
categorization of the case as non-serious.

c
 One report of the AE, optic neuropathy, was reported as Serious = unknown; however, sponsor medical review
determined event to be medically significant. For the purposes of this cumulative review, this case is included in
the total of serious AEs.

d
 One report of the AE, papilledema, occurred while patient was taking parenteral formulation of
 omeprazole. Oral omeprazole was administered subsequent to the onset of the AE.

e
 Four reports of the AE, vision abnormal, were reported as Serious = unknown; however, they were also
 reported as medically significant. At the time the AEs were reported (1995), medical significance was not part of
 the definition of a serious AE. For the purposes of this cumulative review, these cases are
 included in the total of serious AEs. 



TABLE 12.2
AZLP SAFETNET DATABASE SERIOUS AND NON SERIOUS POST-MARKETING REPORTS
SUMMARY OF ADVERSE EVENTS BY PREFERRED TERM
VISION DISORDERS BODY SYSTEM AND EYE EVENTS IN OTHER BODY SYSTEMS
RELATED TO STRUCTURAL ABNORMALITIES OR OTHER NON-VISION SYMPTOMS
(PAGE 1 OF 2) 


12.4.5 Visual Disturbances — Summary

Relatively few reports of ocular adverse events have been received following approval of
omeprazole, for which surveillance has encompassed 10 years. This is despite the fact
that a variety of symptoms of visual dysfunction, ocular structural pathology, and nonvisual
ocular symptoms are quite common in the general population. With the exception
of the reports of patients who experienced nonspecific ocular symptoms that are often
self-limited, relatively mild, and interpreted medically as either “blurred vision” or “eye
irritation,” there is no evidence of an increased risk of specific ophthalmologic diseases in
patients who are treated with omeprazole.

The adverse event data do not establish a safety signal nor suggest an increased risk of
specific ophthalmologic disease associated with short or long-term use of omeprazole in
the general population.

In summary, information available in the published literature is consistent with data that
were presented in the regulatory submissions discussed above. Although there are
reports of individual cases of visual disturbances associated with the use of omeprazole,
pharmacoepidemiologic investigations do not reveal an increased rate of such adverse
reactions for omeprazole when compared to that of other antisecretory medications. 

http://www.fda.gov/ohrms/dockets/ac/00/backgrd/3650b1a_12.pdf


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