1

Annex 4, continued

Annex4

toProcedureforSurveillanceoverAdverseReactionstoMedicinalProductsPermittedforMedicalUse

FORMATofPeriodicsafetyupdatereportoNmedicinalproductPermittedformediclause

І. Cover page

Periodicsafetyupdatereportonmedicinalproduct (periodic report)______

(serialnumber)

International name, АТС: Code(s)

Tradenameofmedicinalproduct / Composition of medicinal product / Number of registration certificate
(in Ukraine) /

Date ofissueofregistrationcertificate

(inUkraine)

/ Holder of registration certificate
1 / 2 / 3 / 4 / 5

Statusofmedicinalproductinukraine: Registration/re-registration

AUTHORIZATION procedure in EС:Centralized/mutual recognition/national

International birth date (IBD): Date

Reportingperiod:FromDate> – toDate

Date of reporting:Date

Volume:Number/total number of volumes

Otherinformation:Other descriptive information

data lock point of next report:

Date

Applicant’SName and ADDRESS:

Name

Address

Authorizedperson, responsibleforpharmacovigilance (includingthat inUkraine), contactDETAILS:

Full name

Address

Phone/fax

E-mail

Signature:

List of serial numbers

Serialnumber / Period covered by thisreport

Distribution list

Regulatory authority / Number of copies

ІІ. Report’s content

Listofabbreviations(if necessary)

  1. Basicstatements/explanatorynote(abriefdescriptionofeachsafetyreportintheformofexplanatorynotewhichincludessummary;licensingstatusintheworld; importantregulatoryinformation(e.g., informationaboutanyurgentsafetyrestrictionsrelatedtouseofmedicinalproduct); data about use, number of new reportsreceived during reporting period, as well as summarized data).
  2. Introduction.
  3. World-wide market authorization status(tableformat: country, registration certificate’snumber, dateofissueofmarketingauthorizationandsubsequent re-registration; any restrictions of license conditions; indications for use; date of entering the market; trade name(s)).
  4. Updateof actions taken by regulatoryauthoritiesorregistration certificate holderfor safetyreasons(marketingauthorization withdrawal or suspension; rejection in re-registration; restrictions for use; change of dosage regimen; change of indications for use; formulationchanges, etc. The safety-relatedreasons that caused the appropriate decision being taken should be indicated and the required documentation submitted; with copies of relevant reports).
  5. Changesto referencesafetyinformation (the applicant may use list of applicant’s core data together with the applicant’s core safety dataas reference safety information). The changes toapplicant’s safetydatarelatedtocontraindications, warningsandadversereactionstomedicinalproductorduetoitsinteractionwithothermedicinalproductsalready made duringreporting period shouldbeclearly described with submission of the modified sections. When essential differencesexist between the instructionsformedical useandECsafetydataofmedicinalproduct (orofficialdatasheets/product informationdocument approvedinUkraine), a brief comment should be prepared by the applicantdescribing the present differencesand their consequences to the overall safety evaluation and actions proposed or initiated. Thiscommentshallbeprovidedas acoverletteroraddendumtotheperiodicalreport).

6. Patient exposure(an estimate ofthe numberofpatientsexposed should be provided along with the methodused to derive the estimate: patient-days, number of prescriptions or number of dosage units of medicinal product, etc. Iftheseorother moreprecisemeasuresarenot availablethebulk sales (packaging, presentation unit or tonnage)maybeused. Ifthenumberofpatientsis impossible to estimatethe appropriate explanations and justifications shall be presented. Theestimationofpatientexposureandestimationmethodusedtoderivetheestimate (adversereactionincidenceduringmedical useofthismedicinalproduct, etc.) shouldbepresented. When data reportedindicateapotentialproblem,detailsbycountries(locallyrecommendeddailydose)or other segmentations (e.g., indications, pharmaceutical forms) shouldbepresented.

7. Presentation of individual casehistories(description and analysis of cases which contain new and/or important safety information related to medicinal product. SuchcasesshouldbeclassifiedaccordingtoMedDRAterminology by System Organ Classes (SOC). Theinclusioncriteriausedforanalysisshallbedescribed).

7.1. Casesofadversereactionstomedicinalproductare to be presentedaslinelistings.

The line listingsshouldinclude:

а) allseriousadversereactionsandnon-seriousunregisteredadversereactionsreceived through spontaneous reporting;

b) allseriousadversereactions(whichinvestigatororsponsorrelatesto the useofmedicinalproduct), whichhavebeenreceivedfromsafetyorotherstudies(includingthosebeingapartofriskmanagementplan) or programs for use of medicinal product in exceptional circumstances (use of product by specific patient);

c) allseriousadversereactionsandnon-seriousunregisteredadversereactions;

d) allseriousadversereactions submitted to the applicant by the country regulatory authorities.

Alltypesofcasespresentedbelowshouldbeannexedtothe periodicreport:

а) allnon-seriousregisteredadversereactionsreceivedthroughspontaneousreporting;

b) allseriousandnon-seriousregisteredadversereactionsreportedbypatientsand other non-health workers(not proved by health worker/physician).

Thesuspectedtransmissionofanyinfectiousagentduringuseofmedicinalproductshall be considered as serious adverse reaction.

The line listingsshouldincludeeachpatientonly once, regardless of how many adverse reactiontermsare reported for the case. Ifthereismorethanonereaction, theyshouldallbementionedbutthecaseshouldbelistedunderthemostseriousADR(symptom,diagnose) asjudgedbythe applicant.

Cases should be classified (summarized in table-list) according to MedDRAterminology by System Organ Classes (SOC).

The list should include the following information: applicant’s case reference number; country, in whichcaseoccurred; sourceofreport; patient’sageandsex; dosageregimenofsuspectedmedicinalproduct; dateofonsetofadversereaction; dateofstartandendoftherapy(duration of treatment); descriptionofreactionas reported; patient outcome(e.g., fatal, resolved, complicated); comment (causal effect assessment, if the applicant disagrees with the reporter; concomitant medications, suspected to play a role in the reaction development; indications for prescription of the given medicinal product; dechallenge/rechallenge results, etc.

7.2.Cases presented in summarytabulations (providean aggregate summaryforeachcase of adverse reaction to medicinal product in line listings where serious and non-serious reactions being registered or not registeredare specified. Whenthereisa lackofinformationforsummarytabulationthedatashouldbepresentedin optional form. If necessary, the summary tabulations may be sorted by source of information or by country of report).

7.3. Analysisofindividualcasehistoriesby applicant (the comment to individualcasehistories shall be provided. Analysisofseriousorunexpectedadversereactionsshall be conducted – itscharacter, medical significance, mechanism, incidence, etc.).

8. Studies (informationaboutallstudies(nonclinical, clinical, epidemiological,whichcontainsafetydata(includinginformationaboutlackofefficacy) withpossibleeffecttoproductinformationshallbeprovided; speciallyplanned studies,those being conducted and published studies,where the safety issues are considered, should be included in discussion of any intermediate and final results. Thestudieswhichareapartofriskmanagementplanshallbeprovided).

8.1.Newlyanalyzedstudies(allstudiescontainingimportantsafetyinformationandreanalyzedduringthereportingperiodshouldbedescribedincludingdatafromepidemiological, toxicologicalorlaboratoryinvestigations. Addcopiesofcompletestudyreportswhichcontainsignificantsafetyandefficacyresults (ifnecessary).

8.2. Newtarget safetystudies (planned, initiated orongoing during the reporting period).

8.3. Publishedstudy data(notifications/reports in scientific and medical literature including appropriate published paper abstracts of workshops/conferences, which contain important safety results (positive or negative) with references to the appropriate publications).

8.4. Otherstudies(anyimportantinformationaboutdataobtainedfromregistersofpregnantexposureandthecommentonpositiveandnegativeexperienceofuseofmedicinalproductduringpregnancyshallbeprovided).

9. Otherinformation.

9.1. Efficacy-relatedinformation(information about cases of lack of efficacy shall be provided).

9.2. Late-breakinginformation(anyimportantnewinformationreceivedafterdata lock pointshall be submitted for study and report. Newdatashallalso beconsideredin“Overallsafetyevaluation”ofperiodicreport).

9.3. Riskmanagementplan(riskmanagementplanshallbediscussed ifitexists;the efficacy of risk management system shall be evaluated).

9.4. Reportonanalysisofrisk/benefitratio(provide summary of analysisofrisk/benefitratioorsafetyanalysisif suchanalysis had been conducted).

10. Overallsafetyevaluation.

10.1. The applicantshouldpresentaconciseanalysisof data along with assessment of significance of the datacollected during this period. Thecollecteddataaboutadversereactionsshouldbeanalyzedandthefollowinginformationshouldbepresented:

a)changesincharacteristicsof adversereactionsto medicinal product(severity, outcome, target population)registered by the applicant (specified in applicant’s core safety information);

b) numberofseriousadverse reactions to medicinal productnot registered by the applicant (notmentionedinapplicant’s core safety information);

c) numberofnon-seriousadverse reactions to medicinal product not registered by the applicant (notmentionedinapplicant’s core safety information);

d) anincreasedoccurrence of reportedadverse reactions to medicinal product registered by the applicant (mentionedinapplicant’s core safety information), includingcommentsonwhetherthe data arebelievedto reflect essential changes in adverse reaction frequency.

10.2.Informationshouldexplicitlyaddressanynewsafetyissuerelatedtothe useofmedicinalproductwithcommentandassessmentofsignificanceofsuchinformationregarding:

а) druginteractions;

b) experiencewithoverdose(deliberateoraccidental) and appropriate treatment;

c) drugabuse, accidentalorirrationaluseofmedicinalproduct;

d) experienceofusingmedicinalproductduringpregnancyorlactation;

e) experienceofusingmedicinalproductinspecialpatientgroups(children, elderly, organandsystemimpaired);

f) effectsoflong-termtreatment;

g) reportsfrompatientsandothernon-healthworkers(if necessary);

h) ifthereareerrorsinprescription/treatmentincludingerrorswithtradenamesorpackagingofmedicinalproductwhichaffectthesafetyofmedicinalproduct.

11. Conclusion:

а) indicatesafetydatawhichdonotcomplywiththe previouslyobtaineddata andwiththereferencesafetyinformationaboutuseofmedicinalproduct;

b) specifyandjustifyanyactionrecommendedorinitiated;

c) makeoverallconclusionaboutsafetyofmedicinalproductatmedicaluseduringreportingperiod.

Whendecisionistakenaboutintroductionofchangestoinstructionsformedicaluse of medicinalproduct, theapplicantshouldsubmitapplicationonintroductionofchangesalongwithperiodicalreportorif this is not possible presentascheduleofsubmissionofthesedocuments.

Note. IftheperiodicreporthasbeensubmittedinEnglish,sections4, 5 and 11 shall be provided in Ukrainian or Russian. Section10 ofperiodicreportshouldbeprovidedinUkrainianorRussian,if requested by the Center.