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