Federal Institute for Drugsand Medical Devices

Main Office and Mailing Address:Kurt-Georg-Kiesinger-Allee 3D-53175 Bonnhttp://www.bfarm.deTelephone: +49-228-207-30

+49-228-99307-0Telefax: +49-228-207-5207

+49-228-99307-5207e-mail: poststelle@bfarm.de

P-RMS FinalASSESSMENT REPORT

Procedure number DE/H/PSUR/0041/001

Active substanceLevonorgestrel (IUS and implant)

Innovator name of products MirenaJadelle implants

<for MRP products also procedure number> National ProcedurePharmaceutical form(s)/strength IUS 20µg/24h MAH(s) Bayer HealthCareHBD and DLP 16.12.1982 19900509PSUR period Mirena: 28.09.2005 – 23.12.2010

Jadelle implants: 24.12.2008 – 23.12.2010P-RMS GermanyAssessor Dr. Ellen Pantke / Prof. Dr. B. Sachs (draft FAR)Contact point psur@bfarm.de

TIME TABLE Procedure Start Date 01.05.2011Date of preliminary AR 10.06.2011Deadline for comments to P-RMS 10.07.2011Clockstop/ RFI / LoQ RFI: 14.07.2011Procedure Restart Date 1 February 2012Date of Draft Final AR 1 February 2012Deadline for comments to P-RMS 5 March 2012Date of Draft (2) Final AR 7 September 2012Deadline of comments to P-RMS 5 October 2012Final AR 22 November 2012DLP of the next PSUR submission and period of PSUR

According to DLP: 23 December 2014

The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health.

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The following PSURs of products not authorised in the P-RMS have been submitted as part of the worksharing procedure.MAHs Product/ MR procedure number

(if applicable)Period covered by the PSUR

Bayer Health Care Jadelle sine inserter, 2 x 75 mg implants; Jadelle, 2 x 75 mg implants

24 Dec 2008 to 23 Dec 2010

INDICATIONS AUTHORISED IN THE P-RMS (INNOVATOR): Mirena: Contraception, Hypermenorrhoea

Although the active ingredient levonorgestrel (LNG) is the same in Mirena IUS and Jadelle implants, theadministration route of the active ingredient is totally different, leading to important differences in the mechanism of action as well as the systemic concentrations of the active ingredient.

In Mirena IUS, the LNG is released locally into the uterine cavity, and the main mechanism of action is based on the high local concentration of LNG in the uterus. Although LNG from Mirena is also absorbed by the blood vessels of the uterus and transported into the systemic circulation, the serum LNG concentration is approximately 1000-fold lower than the LNG concentration in the uterine cavity. After insertion of Mirena, LNG is detectable in serum. In correspondence with the declining release rate, the median serum concentration of LNG declines from 206 pg/ml (25th to 75th percentiles: 151 pg/ml to 264 pg/ml) at 6 months to 194 pg/ml (146 mg/ml to 266 pg/ml) at 12 months, and to 131 pg/ml (113 pg/ml to 161 pg/ml) at 60 months in women of reproductive age weighing above 55 kg.

In Jadelle implants, the LNG is absorbed from subdermal tissue of the upper arm into the blood circulation, and the mechanism of action is based on the systemic concentration of LNG, similarly as with oral LNG-only pills.

The different administration routes for Mirena and Jadelle result in important differences in the possible adverse reactions associated with the administration and are specific to each method. The difference in the systemic LNG concentration also contributes to differences in the type and/or frequency of adverse reactions.

The MAH presented separate yearly PSURs/SBRs/Addendum reports for Mirena (overall period 28 Sep 2005 to 23 Dec 2010, PSUR 21-25, SBR, Addendum report) and Jadelle (overall period 24 Dec 2008 to 23 Dec 2010, PSUR 13-14, SBR, Addendum report). Additionally, because of the above mentioned differences the MAH proposed separate CSPs for Mirena and Jadelle. Since the risks are not identical and in several regards not comparable, it makes no sense to create one common Core safety profile. The Assessment report will discuss the several topics separate for Mirena and Jadelle. Also the tables of adverse reactions will be presented separately for Mirena and Jadelle.

For Jadelle a CSP was approved in a PSUR WSP in 2009 (P-RMS: Finland; procedure number: FI/H/PSUR/0012/001). After this PSUR Worksharing procedure the P-RMS has changed. Please note, that in Germany Jadelle implants are not authorised.

WORLDWIDE MARKETING AUTHORISATION STATUS AND UPDATE OF REGULATORY ACTIONS TAKEN FOR SAFETY REASONS (MAH, AUTHORITIES)

Has there been a change to the marketing authorisation status or have regulatory actions been taken for

safety reasons? Yes No

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If yes, specify:

Mirena:- Recalls of selected batches in Romania due to outdated local labelling information and of one batch in

Australia because of a product quality finding (the root cause was identified and corrective actions were implemented) were performed.

- The MAH complied with a request from Health Canada to issue a Healthcare Provider Communication (HPC) and a Public Communication (PC) in Canada, as a reminder of the potential risk of uterine perforation in patients using Mirena. The background for the request was an observed increase in the absolute number of spontaneously reported post-marketing adverse reaction reports for uterine perforations. The increased number of reports was in accordance with an increased use of Mirena in Canada. The reporting rate of uterine perforations with Mirena determined on the basis of spontaneously reported post-marketing adverse reaction reports has remained stable in Canada since launch.

- Following these postings, requests for DHPCs were received from the regulatory authorities of Belgium, Malaysia, New Zealand and Turkey. The MAH replied by explaining the background for the Canadian HPC / PC, that uterine perforation rates had not changed in Canada since launch and that the Company is of the opinion that a DHPC is not warranted at this time. The Malaysian Health Authority insisted on distribution of a DHPC ‘to inform all Malaysian healthcare professionals so that they are informed about this issue’. In Belgium and New Zealand, the responses of the respective regulatory authorities are currently pending.

Jadelle:No changes for safety reasons.

SUMMARY OF PREVIOUS RELEVANT PhVWP/CHMP DISCUSSIONS *, IF ANY: Mirena:The following topics are discussed in the PhVWP:Risk of uterine perforation, ectopic pregnancies and breast cancer.The 5th interim results of EURAS-IUD will be discussed in the PhVWP June 2011.

* During the period under review

CHANGES TO REFERENCE SAFETY INFORMATION

Is the CCDS the reference document? Mirena: Yes No Jadelle: Yes No

If not, please indicate which document is used as reference document:Jadelle: Corporate Core Text (CCT) Date of the last reference document : Mirena: 7 Oct 2008 Jadelle: 18 February 2003

Which sections of the reference safety document have been changed during the period covered by the PSUR?

Mirena: Jadelle: no changes posology and method of administration (4.2) contraindications(4.3) special warnings and precautions for use(4.4) interaction with other medicinal products and other forms of interaction(4.5) pregnancy and lactation (4.6) effects on ability to drive and use machines(4.7)

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undesirable effects(4.8) overdose (4.9)

Please specify the safety relevant changes:

During the interval of the 21 st PSUR (28 Sep 2005 – 27 Sept 2006):

An analysis of all available data on the topics breast cancer, uterine perforation and ectopic pregnancy in the context of a BfArM graduated step plan led to the following CCDS updates:

As a precaution and in an effort to harmonize the Mirena Core Safety Information with labels of progestin-only preparations approved in the EU, the section “Contraindications” was updated to include “Progestogen-dependent tumors”. In the section "Special warnings and special precautions for use", a paragraph summarizing available epidemiological data on breast cancer risk and COC and progestin-only preparations was added, and the following sentence was included in the “Undesirable effects” section: "In addition, cases of breast cancer have been reported in Mirena users (frequency unknown, see section 4.4 Special warnings and special precautions for use)".

In the sections “Dosage and method of administration” and “Special warnings and special precautions for use”, warnings regarding a possibly increased risk of uterine perforations in post-partum insertions, insertion in lactating women and in women with fixed retroverted uterus, were added.

In the case of method failure and an accidental pregnancy with Mirena in situ, the relative risk of ectopic pregnancy is increased. This information was included in the “Special warnings and special precautions for use” and "Undesirable effects" section.

To contribute to a consistent and correct use of Mirena, the following paragraph was added in Section 4. ‘Dosage and method of administration’: “Mirena, when inserted according to the insertion instructions, has a failure rate of approximately 0.1 % per year. The failure rate may increase in case of expulsion or perforation.”

The statement was based on the publication of Trussell 1998.

In Germany, these changes were implemented in 2007 by way of a Dear Doctor Letter ("Rotehandbrief") together with the introduction of a procedure for obtaining the patient's written consent.

During the interval of the 23rd PSUR (28 Sep 2007 – 27 Sept 2008), the CCDS was updated with the following:

- Relevant new clinical data concerning the failure rate of Mirena- New evaluations of clinical data leading to a correction of the ectopic pregnancy rate of Mirena, and- New pharmacokinetic data on administration, distribution, biotransformation and elimination.

During the interval of the 24th PSUR (28 Sept 2008 – 27 Sept 2009), the CCDS was updated with the following:In order to provide advice to the healthcare professional with regard to the rare occurrence of displacement of the hormone cylinder over the arms of the T-frame of the intrauterine system (IUS) upon removal of Mirena, new text was included in section 4.2 ‘Dosage and administration’.

Selected differences between RSI and proposed CSP:The MAH presented a comparison between Mirena CCDS and the proposed Mirena CSP. Regarding the sections relevant for the CSP, all important information of the CCDS is included into the proposed CSP.

Furthermore, the MAH presented a comparison between Jadelle CCT and the proposed CSP. For Jadelle sine inserter/Jadelle, the proposed CSP reflects all safety-relevant information covered by the MRP EU SmPCs.

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Mirena: SUSPECTED ADVERSE DRUG REACTIONS (INNOVATOR) DURING THE PERIOD (29   Sept   2005 to 23 Dec 2010)

SERIOUS CASES AND ADRs (medically confirmed)Total number of serious cases, incl. fatalities 6,956Number of fatal cases 15

Mirena: SUSPECTED ADVERSE DRUG REACTIONS, overview (28 Sept 2005 – 23 Dec 2010)

TABLE OF ADVERSE DRUG REACTIONS (ADRs)

 Serious

 Non-serious

  Total

System Organ Class (SOC) Listed Unlisted Listed Unlisted  

Blood and lymphatic system disorders 1 51 2 95 149Cardiac disorders 0 111 1 190 302Congenital and familial and genetic disorders 1 34 0 3 38Ear and labyrinth disorders 0 35 2 109 146Endocrine disorders 2 14 3 63 82Eye disorders 0 110 5 292 407Gastrointestinal disorders 119 134 5.628 939 6820General disorders and administration site conditions 2.444 258 20.691 4.628 28.021Hepatobiliary disorders 1 75 0 26 102Immune system disorders 16 32 45 109 202Infections and infestations 305 231 573 1.019 2.128Injury poisoning and procedural complications 2.376 79 3.424 614 6.493Investigations 51 172 1.241 999 2463Metabolism and nutrition disorders 5 21 88 191 305Musculoskeletal and connective tissue disorders 13 101 864 1.113 2.091Neoplasms benign, malignant and unspecified 1 556 10 227 794Nervous system disorders 211 439 1.758 1.146 3.554Pregnancy, puerperium and perinatal conditions 1.464 137 2.599 152 4.352Psychiatric disorders 60 283 1.512 1.206 3.061Renal and urinary disorders 1 56 9 188 254Reproductive system and breast disorders 466 331 20.612 3.598 25.007Respiratory thoracic and mediastinal disorders 1 124 2 199 326Social circumstances 0 12 2 21 35Skin and subcutaneous tissue disorders 107 78 2.859 1.146 4.190Surgical and medical procedure 15 99 44 51 209Vascular disorders 9 204 95 389 697

Mirena: TABLE OF SELECTED* SERIOUS UNLISTED ADRs:

Serious unlisted ADRs(MedDRA PT in agreed SOC order)

Number of serious unlisted ADRs

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Myocardial infarction 21Blindness unilateral 8Anaphylactic shock 5Sepsis 10Septic shock 12Breast cancer 145Breast cancer female 100Breast cancer in situ 22Endometrial cancer 19Meningeoma 9Cerebrovascular accident 33Loss of consciousness 26Syncope 38Transient ischaemic attack 20Depression 73Depression suicidal 14Suicidal ideation 37Suicidal attempt 5Pulmonary embolism 55Deep vein thrombosis 46Pelvic vein thrombosis 11

* Selection is within the discretion of the P-RMS

Jadelle: SUSPECTED ADVERSE DRUG REACTIONS (INNOVATOR) DURING THE PERIOD (24   Dec   2008 to 23 Dec 2010)

SERIOUS CASES AND ADRs (medically confirmed)Total number of serious cases, incl. fatalities 16Number of fatal cases 0

Jadelle: SUSPECTED ADVERSE DRUG REACTIONS, overview

TABLE OF ADVERSE DRUG REACTIONS (ADRs)

 Serious

 Non-serious

  Total

System Organ Class (SOC) Listed Unlisted Listed Unlisted  

Blood and lymphatic system disorders 0 0 0 0 0Cardiac disorders 0 0 0 0 0Congenital and familial and genetic disorders 0 0 0 0 0Ear and labyrinth disorders 0 0 0 0 0Endocrine disorders 0 0 0 0 0Eye disorders 0 0 0 0 0Gastrointestinal disorders 0 0 2 6 8General disorders and administration site conditions 3 0 19 7 29Hepatobiliary disorders 0 0 0 0 0Immune system disorders 0 0 1 0 1Infections and infestations 1 0 2 0 3Injury poisoning and procedural complications 0 1 2 0 3Investigations 1 0 5 0 6

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Metabolism and nutrition disorders 0 0 1 1 2Musculoskeletal and connective tissue disorders 0 1 0 0 1Neoplasms benign, malignant and unspecified 0 0 0 0 0Nervous system disorders 0 4 10 2 16Pregnancy, puerperium and perinatal conditions 4 6 20 0 27Psychiatric disorders 0 0 4 1 5Renal and urinary disorders 0 0 0 1 1Reproductive system and breast disorders 2 0 21 2 25Respiratory thoracic and mediastinal disorders 0 0 0 0 0Social circumstances 0 0 0 0 0Skin and subcutaneous tissue disorders 1 0 4 4 9Surgical and medical procedure 0 0 0 0 0Vascular disorders 1 0 0 1 2Total 13 12 96 26 148

Jadelle: TABLE OF SELECTED* SERIOUS UNLISTED ADRs :

Serious unlisted ADRs(MedDRA PT in agreed SOC order)

Number of serious unlisted ADRs

Peripheral nerve lesion 3

* Selection is within the discretion of the P-RMS

OVERALL ASSESSOR COMMENTS ON CASE REPORTS (INCL. LITERATURE CASES)Fatal cases - MirenaThe following cases with fatal outcome were reported and discussed in the respective PSURs:

PSUR 21 (28 Sep 2005 -27 Sep 2006):- 1 case of fatal Group A streptococcal sepsis- 1 case of fatal hepatic necrosis

PSUR 22 (28 Sep 2006 – 27 Sep 2007)- 1 case of acute brain circulation disturbance and severe comatose condition- 1 case of ruptured cerebral aneurysm

PSUR 23 (28 Sep 2007 – 27 Sep 2008)- 2 cases concern the death of prematurely delivered newborns of mothers who have been using Mirena- 1 case of streptococcal infection with septic shock- 1 case of pulmonary embolism

PSUR 24 (28 Sep 2008 – 27 Sep 2009)- 2 cases of completed suicide (in one case 6 weeks after removal of Mirena)- 1 case of necrotising fasciitis- 1 case of sudden death- 1 case of fatal aortic dissection- 1 case of premature delivery (23rd gestational week) resulting in death of the newborn - 1 additional non-medically confirmed ADR report with fatal outcome

PSUR 25 (28 Sep 2009 – 27 Sep 2010)- 1 case of fatal cardiac arrest

Addendum report (28 Sep 2010 – 23 Dec 2010)- 1 non-medically confirmed case: completed suicide

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Fatal cases – Jadelleno cases with fatal outcome were reported

Assessor`s comment:In future WSPs the MAH should give an overview of all cases with fatal outcome from the overall reporting period and should discuss these cases in detail.

Uterine perforations - MirenaAs a national measure in Germany, the MAH was requested to perform a prospective cohort study, which should address the risk of uterine perforation associated with Mirena use compared to the use of copper-IUDs. The study protocol of this study was approved by the PhVWP in 2007. This study is currently ongoing in Austria, Sweden, Finland, Poland, the UK and Germany. The MAH provides interim reports every 6 months and the final study report is expected for April 2012.

Assessor`s comment:BfArM presented an assessment of the 4th interim report to the PhVWP in August 2010. Based on this assessment a List of Questions (LoQ) was sent to the MAH. In June 2011 BfArM will provide an assessment of the 5th interim report from January 2011 and the responses to the submitted LoQ (see PhVWP PAR).The risk of uterine perforation is mentioned in section 4.4 and 4.8 of the proposed CSP.

Breast cancerMirenaThe MAH presented a cumulative overview of breast cancer cases in PSUR 25 (period 28 Sep 2009 – 27 Sep 2010). The cumulative number of reports of breast cancer present in the MAH`s database at the time of PSUR 25 was 480 (including non-medically confirmed cases). The reporting frequency of breast cancer cases was comparable during the last PSUR periods (0.6 (PSUR 25), 0.7 (PSUR24), 0.7 (PSUR 23), 1.1 (PSUR 22), 0.9 (PSUR 21) per 100 000 woman-years for all cases). The mean exposure at the time of diagnosis is 2.9 years (ranging from the day of insertion to 14 years, median 2.5 years). In a large proportion of cases the diagnosis was made shortly after insertion of Mirena, which suggests that malignant changes were already present at the time of Mirena insertion, and diagnostic work-up was initiated or ongoing. The average age of the patients was 42.8 years, and in about one third of the cases with information on age the patients were between 41 and 45 years old, i.e., belonging to the age group in which the incidence of breast cancer starts to increase in the general population. It is not possible to estimate the age distribution of all Mirena users based on available sales data, however, the mean age of Mirena users reporting ADRs to the MAH is considerably lower at 34.2 years (mean age derived from all relevant reports with Mirena that were received by the MAH as of 04 Oct 2010 and that contain information on the user's age).

During the period of the PSUR 25, the results of a case-control study on breast cancer risk of Mirena versus copper intrauterine devices were published as a conference abstract (Voigt K et al., 2009). This large study included more than 5000 cases and 20 000 controls, and information on confounding factors was gathered in all cases and controls. In brief, the study demonstrated that in women <50 years, current use, or ever use of Mirena was not associated with a higher risk of breast cancer than current use, or ever use of Cu IUDs.

Assessors comment:Section 4.8 of the proposed CSP lists that cases of breast cancer have been reported (frequency unknown). Additionally, the proposed CSP includes a general warning regarding the potential risk of breast cancer in contraceptives. This is endorsed by the P-RMS. The MAH should continue to monitor cases with breast cancer and present an overview in the next PSUR.For the discussion of the topic breast cancer in 2006, please see the final minutes of the PhVWP.

JadelleNo cases of breast cancer were reported.

Assessors comment:Section 4.4 of the proposed CSP includes a general warning regarding the topic breast cancer. In the next PSUR the MAH should state if cases of breast cancer have been reported and if an inclusion of this ADR into section 4.8 of the CSP would be appropriate.

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Endometrial carcinoma - MirenaIn the summary tabulation of all ADRs of the current PSUR-period endometrial carcinoma was mentioned with the frequency 19. In PSUR 25 it is stated that case details of this period do not provide any evidence of a causal association with Mirena.

Assessors comment:In future PSURs the MAH should present a cumulative overview on this topic.

Depression/SuicidalityMirena/JadelleA cumulative analysis of all pertinent data on Mirena and depression was last performed in September 2009 and presented in the Mirena PSUR 24. The conclusion of this analysis was the same as in earlier analyses. Based on the literature, clinical trials, and postmarketing data, there is no evidence that treatment with Mirena may be causally related to the occurrence or aggravation of clinically-relevant depression, and the current labelling of Mirena is adequate with regard to this topic. Due to the medical significance of depression and suicidality, the MAH will continue to monitor this topic.

Assessors comment:In the presented summary tabulation of Mirena (period 28 Sep 2005 – 23 Dec 2010) the following serious unlisted ADRs are mentioned: depression (n=73), depression suicidal (n=14), suicidal ideation (n=37), suicidal attempt (n=5). Additionally, the following non-serious unlisted ADR are listed: depression (n=287), suicidal ideation (n=1). The summary tabulation of Jadelle includes the following non-serious listed ADRs: depression (n=1), mood swings (n=3).The last cumulative analysis of this topic was performed in 2009. Therefore, the MAH should provide an updated cumulative overview of all cases which include PTs of the MedDRA-SMQ “Depression and suicide/self-injury”. Cases of suicide should be described in detail. In addition the MAH should provide a comprehensive overview of literature reports on this topic.Depressed mood and altered mood are listed ADRs in section 4.8 of the proposed CSP of Mirena. Mood changes and depression are listed in section 4.8 of the proposed CSP of Jadelle. The MAH should discuss if additional terms should be included in section 4.8 of the Mirena CSP.In the proposed CSP of Jadelle the following warning in section 4.4 is already included: “Removal of Jadelle should also be considered in women who become significantly depressed, since the symptom may be hormone-related. Women with a history of depression should be carefully monitored and removal of Jadelle

considered if clear symptoms develop.” Because of the medical significance of depression/suicidality, it should be discussed if an inclusion of a warning into the CSP of Mirena would be appropriate.

EUG – MirenaIn the presented summary tabulation (period 28 Sep 2005 – 23 Dec 2010) of Mirena the ADR ectopic pregnancy is mentioned with a frequency of 411. The reporting frequency for ectopic pregnancies (calculated from gathered women-years as estimated from sales data) has remained constant during the PSUR-periods.

Assessors comment:In section 4.8 of the proposed CSP includes the information that when a woman becomes pregnant with Mirena in situ, the relative risk of ectopic pregnancy is increased. Additionally, in section 4.4. of the proposed CSP includes a warning regarding the risk ectopic pregnancies. No further action is required.

MeningiomaMirenaA cumulative analysis of literature and cases of meningioma in Mirena users was performed during the period covered by the 24th PSUR. It was concluded that there is no evidence of a causal association of Mirena use with the development of meningioma, nor evidence of a growth-promoting effect.Five medically confirmed cases of meningioma were received during the reporting interval of PSUR 25. The analysis of case details provided no new evidence which would change the overall assessment of this condition in association with Mirena use provided in the 24th PSUR.

Assessors comment:In the summary tabulation of all ADRs 9 cases of meningioma are mentioned. Given the annual background incidence of 2 per 100.000 for symptomatic meningioma the reporting frequency is considered low.

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However, the MAH should continue to closely monitor cases with meningioma.

JadelleNo cases of Meningioma are listed in the summary tabulation of all ADRs.

Sepsis (Mirena)In PSUR 25 it is stated, that since launch, cases of sepsis in Mirena users have been received at a very rare reporting frequency, i.e., <1 per 100 000 Mirena units sold, and <1 per one million woman-years of estimated post-marketing exposure.As mentioned in section 4.4 of the proposed Mirena CSP, the risk of pelvic inflammatory disease is increased in the first few weeks after insertion of an IUD. A warning regarding implication of serious consequences of PID is included and aseptic precautions when handling and inserting Mirena are advised.

Assessors comment:The argumentation of the MAH is acceptable.

Venous thromboembolic events (VTE)MirenaCumulative analyses of all pertinent data with regard to venous thromboembolism were last presented in the 21st and 22nd PSURs, respectively. These analyses concluded that there is no indication for an increased risk of VTE. The published studies identified during the PSUR interval of PSUR 25 that investigated the VTE risk in non-oral contraceptive users, the effects of Mirena on haemostasis, and menstrual blood loss and endothelial effects of Mirena respectively, do not indicate that Mirena has a prothrombotic effect, or that users of Mirena are at increased risk for venous thromboembolic events.

JadelleIn PSUR 14 it was stated that a signal investigation of Jadelle use and venous thromboembolism was performed upon request of the Swedish Health Authority to consider whether an update to the current SPC was required. It was concluded that a further warning above and beyond what is currently included in the SPC is not considered warranted. No new safety issue arose from this investigation.

Assessors comment:The proposed CSP of Mirena includes a warning in section 4.4 that in women using progestogen-only pills some recent epidemiological studies indicated that there may be a slightly increased risk of venous thromboembolism. The CSP of Jadelle states that “Thromboembolic and cardiovascular undesirable effects have been reported in users of other levonorgestrel implants …” Based on the VTE-cases in the MAH`s database the MAH should discuss if the inclusion of the ADR VTE into section 4.8 of the CSP would be appropriate.

Cerebrovascular disorders/Myocardial infarctionMirenaCumulative analyses of all pertinent data with regard to cerebrovascular disorders and myocardial infarction were presented in the 21st and 22nd PSURs, respectively. These analyses concluded that there is no indication for an increased risk in Mirena users.

JadelleThe summary tabulation of all ADRs in the reporting period lists no cases of cerebrovascular disorders or myocardial infarction.

Assessors comment:Since the last cumulative analysis was performed in 2007, the MAH should present a cumulative overview of all cases with myocardial infarction and cerebrovascular disorders. Additionally, the MAH should provide a comprehensive overview of literature reports on these topics.

Androgenic effects of levonorgestrel on skin and hairMirenaOn request of the Belgian Health Authority, a cumulative analysis was presented in PSUR 25 of all available safety data relating to Mirena and androgenic side effects on skin and hair. Based on an analysis of clinical trial data, postmarketing spontaneous reporting and other published evidence the following was concluded:Androgenic side effects of levonorgestrel have been known for some time, and appear to be triggered by

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the intrinsic activity of levonorgestrel on the androgen receptor. In a clinical context, androgenic side effects of levonorgestrel are experienced by some in the form of acne, hirsutism and hair loss, but these side effects are seldom cause for premature removal in studies with Mirena. The overall occurrence of these side effects especially in trials using symptom-specific questionnaires should be considered in relation to the high background frequency of these conditions in a population of women of fertile age. The proposed CSP for Mirena includes acne, hirsutism and alopecia in section 4.8, which is considered adequate by the MAH.

Assessors comment:The argumentation of the MAH is acceptable.

JadelleSection 4.8 of the proposed CSP includes the following ADRs: acne, alopecia, hypertrichosis.

Beside the above mentioned topics the MAH should discuss the cases with blindness, anaphylactic shock, loss of consciousness and syncope.

OVERALL ASSESSOR COMMENTS ON MAH SPONSORED STUDIESMirena:The following post-authorization safety studies or other studies specifically examining a safety concern were being conducted during the interval of the SBR (28 Sep 2005 – 27 Sep 2010; PSUR 21 – 25):

Breast cancer case-control study: ongoing during 22nd & 23rd PSUR, newly-analyzed during 24th PSUR:The results of a community-based case-control study on breast cancer risk of Mirena versus copper intrauterine devices became available during the interval of the 24th PSUR (28 Sep 2008 – 27 Sep 2009) The study was conducted by the Center for Epidemiology and Health Research (ZEG), as an independent research institute in Berlin, Germany, and funded by the MAH with an unrestricted research grant. The study was carried out in Finland and Germany with cases drawn from cancer registries. Women had to be ≤ 50 years with a breast cancer diagnosis between 2000 and 2007. Controls matched by age and region (in a ratio of 1:4) were obtained from randomly selected households (Germany) and the population register (Finland), respectively. Data were collected by using questionnaires as well as electronic information provided by the cancer registries/tumor centers. A total of 5,113 cases and 20,452 matched controls were analyzed.

Conclusions:

The results suggest that within the limitations of observational research:

- Ever use of Mirena is not associated with a higher risk of breast cancer than ever use of copper IUDs or the use of other hormonal contraceptives or the non-use of hormonal contraceptives methods

- Current use of Mirena is not associated with a higher risk of breast cancer

- Use of Mirena is not associated with a higher risk of invasive breast cancer with regional or distant metastasis

Thus, the study does not show evidence of tumor induction or promotion.

The results were presented to an independent scientific advisory board which supported the investigators’ conclusions. It was observed that the study was well-designed to minimize information bias, selection bias and confounding factors. All relevant information about established prognostic factors was obtained directly from the subjects. Reduction of structural inconsistencies and the implementation of appropriate procedures for the handling of residual inconsistencies was achieved by matching of cases and controls, by documentation and stratification for important confounders (e.g., age groups, country, duration of use), and by the circumspect construction of the statistical models.

European Active Surveillance Study for Intrauterine Devices (EURAS IUD): ongoing since interval of

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22nd PSUREURAS IUD is a large, controlled, prospective, non-interventional cohort study with new users of two different types of IUDs: LNG and copper (Cu) IUDs. Its objective is to assess the risks of Mirena use and Cu IUD use in a study population that is representative of the real users of the individual IUDs. This includes an estimate of the absolute risk of rare serious adverse outcomes. The primary clinical outcome of interest is the uterine perforation rate. The combined cohort will include approximately 60,000 women in six European countries (Germany, Finland, Austria, UK, Sweden and Poland). Enrolment began at the end of 2006. Women and their gynaecologists will receive a follow-up questionnaire one year after enrolment. Patient-reported outcomes of interest are validated by the women’s treating physicians.

The final study report is expected in April 2012, and in total, six interim reports are planned. In June 2011 BfArM will provide an assessment of the 5th interims report from January 2011 and the responses to the submitted LoQ (see PhVWP PAR).

Breast cancer ISS: ongoing during 24th & 25th PSURsOne investigator-sponsored study was ongoing during the interval of the 24th & 25th PSURs for which interim data became available to the MAH. This study is performed by a Belgian study group who had published results of a previous, retrospective cohort analysis studying LNG-IUS in breast cancer patients (Trinh 2007, see 22nd Mirena PSUR for discussion). As this retrospective analysis was significantly limited by uncontrolled confounding, the investigators initiated a prospective controlled cohort analysis. The objective of this study is to compare recurrence and disease-free survival of premenopausal breast cancer patients under the age of 50, who have a Mirena at the time of diagnosis and those who never had a Mirena. The study includes premenopausal patients with invasive, but not metastatic breast cancer at the time of diagnosis.

An analysis of a total of 124 patients (37 current Mirena users and 87 never users) showed that there was no difference in the prognostic histopathological factors of breast cancer (tumor size, histological grade, receptor status, or lymph node invasion) between the Mirena users and never users. While these results appear reassuring, they need to be interpreted with caution as numbers are low, and a longer observation period is needed.

Jadelle:No MAHs sponsored studies were performed during the period covered by the SBR.

OVERALL ASSESSOR COMMENTS ON NEW INFORMATION REGARDING

Special populations:Mirena/Jadelle: no new information

Pregnancy/lactation:Unintended intrauterine pregnancies/Abnormal pregnancy outcomesMirena:Approximately 4100 cases of unintended intrauterine pregnancy in association with Mirena use have been reported to the MAH by the end of September 2010. The cumulative exposure to Mirena since launch as estimated from sales data is about 57.4 million woman years. The overall reporting frequency for unintended intrauterine pregnancies lies, therefore, around 0.007 per 100 woman-years. The Pearl Index for Mirena, derived from clinical trial experience and mentioned in the product labeling, is 0.2 per 100 woman-years. It can, therefore, be assumed that only a small proportion of all pregnancies occurring with Mirena are reported to the company. In this setting a selective reporting of unfavourable pregnancy outcomes to the company would seem likely. The assumed high degree of underreporting of pregnancies, and a probable reporting bias are reasons why the gathered spontaneously-reported ADR data may not be suitable for exact calculations of the outcomes of the pregnancies.The MAH attempts to follow-up all pregnancies which occur in association with Mirena use and of which the company becomes aware. The cumulative number of reported live births to the data lock point of PSUR 25 (including follow-up information from previous intervals) is approximately 760. About 990 spontaneous abortions have been reported in association with Mirena use. Spontaneous abortion and pre-term labour are known risks for pregnancies with IUD in situ, and are accordingly mentioned in the proposed Mirena CSP.

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In some of the remaining cases of reported intrauterine pregnancies, women opted for elective termination of the unintended pregnancy. Despite efforts made by the company to obtain details on the further course of a pregnancy, outcome information was not available for many of the cases.In most of the known pregnancies that have ended in live births, the newborn has reportedly been healthy. In a small minority of cases, however, there has been an abnormality of some kind in the newborn. Some of the reported anomalies are relatively common and a purely coincidental occurrence is a likely explanation. In some cases an apparent more plausible etiology for the disorder has been identified. No clear trend towards disorders of any kind has been observed and the reported cases can be considered as occasional single cases. In none of the cases of congenital anomalies has a causal relationship between exposure to Mirena and the disorder been verified. A pharmacological mechanism between intrauterine exposure to hormone and the observed defect in the newborn could be stipulated in 2 cases, which reported on slightly disturbed development of external genitals of female newborns; in both cases, Mirena had been inserted during early pregnancy, and the outcome was reported retrospectively and is likely to have triggered the report. A causal association could formally not be excluded in these cases, although other causes independent of Mirena exposure remain a possibility.It seems reasonable to assume that the cases with abnormal outcome are reported more frequently than the normal outcomes; accordingly, a number of cases relating to an abnormal outcome in pregnancies with verified exposure to Mirena have been reported retrospectively. Therefore, this spontaneously-reported data apparently do not reflect the frequency of occurrence of abnormal pregnancy outcomes subsequent to exposure to Mirena in the uterus.

Assessors comment:Section 4.6 of the proposed CSP lists that because of the intrauterine administration and the local exposure to the hormone in case of a pregnancy the possible occurrence of virilising effect in the fetus should be taken into consideration. Further it is stated that there is no evidence of birth defects caused by mirena use in cases where pregnancy continues to term with Mirena in place.In the next PSUR the MAH should continue to present a cumulative overview on abnormal pregnancy outcomes.

JadelleThe MAH presented cumulative trends of pregnancy reports in Jadelle users in PSUR 14. With an estimated cumulative market experience with Jadelle® of more than 6.4 million woman-years since launch, the cumulative reporting rate for all pregnancy cases for Jadelle (including inadvertent exposure) is 0.0009 per 100 woman-years. The Pearl Index for Jadelle observed in clinical studies was 0.17 per 100 woman-years. Relative to the estimated exposure during this reporting period, as estimated from the sales data, the frequency of pregnancy reports has remained constant (0.0004 vs. 0.0006 per 100 woman-years during the previous PSUR period). The majority of case reports concerning pregnancy continue to originate from Colombia. This is considered a result of the close cooperation of the company with inserting health care professionals due to the insertion training measures in Colombia described in the 12th PSUR for Jadelle. Colombia accounts for more than 10% of the worldwide exposure gathered during this PSUR interval.The Core Safety Information of Jadelle states that Jadelle should be inserted within seven days from the onset of menstrual bleeding. If the implants are inserted at any other time, pregnancy must be reliably excluded before insertion and an additional non-hormonal contraceptive method used for at least seven days after the insertion. In PSUR 13 (period 24 Dec 2008 – 23 Dec 2009) it was mentioned that relative to the estimated exposure during this reporting period, as estimated from the sales data, the frequency of pregnancy reports has decreased (0.0006 vs. 0.0014 per 100 woman years during the previous PSUR period).The company continues to monitor the frequency of pregnancy reports to assure the effectiveness of the re-training measures.

Assessors comment:The MAH should continue to monitor the frequency of pregnancy reports to assure the effectiveness of the re-training measures undertaken in Columbia. A cumulative analysis of pregnancy reports in Jadelle users is expected in next PSUR as well. Additionally, the MAH should give an overview of all cases with abnormal pregnancy outcomes.

Drug interaction:Mirena/Jadelle: no new information

Overdose:

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Mirena/Jadelle: no new information

Abuse or misuse:Mirena/Jadelle: no new information

Medication errors:Mirena/Jadelle: no new information

Long-term treatment:Mirena/Jadelle: no new information

Off label use:Mirena/Jadelle: no new information

COMMENTS ON ANY CHANGE OF THE RISK BENEFIT BALANCE

MAH conclusion:The benefit-risk balance for both Mirena and Jadelle remain favourable.

Assessors conclusions and comments:The benefit-risk balance for Mirena and Jadelle remains favourable.

ACTION PLAN AND CONCLUSIONS

A CHANGES OF THE BENEFIT RISK BALANCE

Has the benefit risk balance changed?

No

Yes , please specify:

B CHANGES REQUIRED IN THE CSP

Mirena:

The proposed CSP reflects the "Iowest common denominator" of the MRP EU SmPC (RMS. Portugal) and all respective national SmPCs in EU countries with MAs for Mirena. It reflects all safety-relevant information covered in the MRP EU SmPC (dated 20 April 2009).

Is the CSP acceptable?

Yes No

If not, specify the necessary changes (specific wordings):

Beside the above discussed points, the German SmPC includes the following additional warning:

- Mirena may be used with caution or removal of the system should be considered if any of the

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following conditions exist or arise for the first time: … Venous or arterial thromboembolic events, e.g. deep vein thrombosis of the leg, pulmonary embolism, stroke, myocardial infarction, retinal thrombosis (stroke and myocardial infarction are mentioned in the proposed CSP)

The P-RMS is of the opinion that this warning should also be included into section 4.4 of the CSP. The MAH should discuss this point.

The proposed CSP the contraindication “Progestogen-dependent tumors” is listed. The P-RMS is of the opinion that an example for this contraindication should be added: “Progestogen-dependent tumors, e.g. breast cancer”. The MAH should comment on this.

Additionally, the German SmPC includes the following recommendation for action in section 4.4: “If a sex hormone-dependent tumor (e.g. breast cancer) occurs in Mirena users, Mirena must be removed.” In the view of the P-RMS this recommendation should be included into section 4.4 of the CSP.

Jadelle:

The proposed CSP is based on the EU SmPCs which were approved as CSP in the Jadelle PSUR WS in 2009 (P-RMS. Finland; procedure number. FI/H/PSUR/0012/001). The format was adapted to the CSP format (sections 4.3-4.9 and safety-relevant information from section 4.2).

Is the CSP acceptable?

Yes No

If not, specify the necessary changes (specific wordings):

The above mentioned topics should be discussed after response of the MAH.

C REGULATORY ACTIONS * PROPOSED, IF ANY

* Regulatory options may include urgent safety restrictions, variations, suspension or revocation. Topics for close monitoring should be mentioned below in section E.

D SUMMARY OF COMMENTS FROM OTHER MSsMember State

Comment Agreed action e.g. updating CSP, close monitoring

AT Ectopic pregnancyThe ectopic pregnancy rate with Mirena is approximately 0.1% per year. This rate is lower than the rate in women not using any contraception (0,3-0,5% per year). The absolute risk of ectopic pregnancy in Mirena users is low. However, when a woman becomes pregnant with Mirena in situ, the relative likelihood of ectopic pregnancy is increased.

This text part might be misleading – another wording or deletion should be discussed.

Assessor`s comment:The MAH should discuss the wording.

MAH’s response: The MAH proposes to maintain the marked passages since it is considered non-ambigious and clearly understandable. The MAH only proposes a rewording of the last sentence for a better readability. "… The absolute risk of ectopic pregnancy in Mirena users is low. However , when a woman becomes pregnant with Mirena in situ, the relative likelihood of this ectopic pregnancy being ectopic is increased.”

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Assessor’s comment: The P-RMS is of the opinion that the misleading wording commented by AT has not been adequately addressed by the MAH. However, the rewording of the last sentence of this paragraph is acknowledged.

To address the comment made by AT the P-RMS proposes the following wording for section 4.4:

The absolute risk of ectopic pregnancy with Mirena users is low due to the overall reduced likelihood of pregnancy in Mirena users compared to non-users of any contraception. The absolute rate of ectopic pregnancies with Mirena is approximately 0.1% per year, compared to 0.3-0.5 % per year in women not using any contraception. However, if a woman becomes pregnant with Mirena in situ, the relative likelihood of this pregnancy being ectopic is increased.”

In addition, with regard to the post-tabular wording in section 4.8 a cross-reference to section 4.4 is added:

When a woman becomes pregnant with Mirena in situ, the relative risk of ectopic pregnancy is increased (see section 4.4 Special warnings and precautions of use).

Issue resolved.IE Section 4.4 The Irish SPC

contains information under pelvic infection that not only may PID include impairment of fertility, increase in the risk of ectopic pregnancy, and on rare occasions, hysterectomy

The P-RMS is asked to consider the inclusion of information on hysterectomy in the CSP in this section

Assessor`s comment:The MAH should discuss the risk of hysterectomy as a possible consequence of pelvic infection.

MAH’s response: The Mirena CSP lists 'current or recurrent pelvic inflammatory disease' as contraindication in section 4.3, and section 4.4 under the heading 'Pelvic infection' contains the warning that 'Pelvic infection may have serious consequence and itmay impair fertility and increase the risk of ectopic pregnancy.'The MAH is of the opinion that the current wording adequately addresses the possible risks of a pelvic infection. Listing here a number of medically known, rarely observed, possible complications involving surgical interventions, whichmay include but may not be limited to hysterectomy, is not considered helpful information to the healthcare provider. The MAH, therefore, does not agree to a change of the wording in the proposed Mirena CSP.In the “Guidance document for marketing authorisation holders on submissions of PSURs under the EU PSUR work sharing scheme, version July 2010” the requirements for generating a CSP are detailed under item 4, pages 2/3 “…This document should be generated according to the latest SmPC guidelines and include common information from sections 4.3 - 4.9 present in all SmPCs withinthe EU and any relevant safety information from section 4.2…”.When generating the proposed Mirena CSP, these rules were strictly followed and only common safety relevant information

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present in all SmPCs within the EU was considered (principle of “lowest common denominator”).With reference to the current CSP rules and the principle of “lowest common denominator” as specified above, the MAH proposes not to change the CSP and specify “hysterectomy” under the serious consequences of pelvic inflammatorydisease.According to the CSP guidance, countries where additional information is already nationally approved do not need to delete this information.

Assessor’s comment: The P-RMS agrees with the MAH that hysterectomy is already indirectly covered by the current wording ‘serious consequences’ also covering other surgical procedures. The P-RMS is of the opinion that healthcare professionals are aware of hysterectomy as a potential rare consequence of pelvic infections. According to the CSP guidance, countries where additional information is already nationally approved do not need to delete this information.Issue resolved.

Section 4.4 contains a warning that discontinuation of Mirena should also be considered in case of long-term immobilisation due to surgery or illness. Women with a history of thrombo-embolic disorders should be made aware of the possibility of a recurrence.

The P-RMS is asked to consider the inclusion of information in the CSP in this section.

Assessor`s comment:The MAH should comment on the inclusion of this warning.

MAH’s response: As outlined in the MAH response to comment #4, the currently available data do not indicate an increased risk of VTE in Mirena users, or causal relationship between Mirena use and development of VTE.International guidelines, such as those of the WHO for eligibility of contraceptive use, do not restrict the use of Mirena in women with any risk factor for VTE, including prolonged immobilization due to surgery or illness (see Justification Document no. 38).Due to the lack of causal relationship between Mirena use and development of VTE, no incremental risk of VTE in women with any risk factor for VTE is expected. Thus the MAH does not agree to add a warning regarding consideration of removal in case of long-term immobilization due to surgery or illness in section 4.4.

Assessor’s comment:A new section addressing the risk of VTE is proposed for section 4.4 of the CSP. The following paragraph within this section referring to women with risk factors is considered to address this issue. National agencies may add information beyond this sentence:

Patients with risk factors for VTE In patients with risk factors for VTE (e.g. known thrombogenic mutations, history of VTE, prolonged immobilization) Mirena should only be used after careful assessment of the risk-benefit ratio and available alternatives.

This issue is finally addressed below in this AR (see 4. VTE

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cases).Irish SPC section 4.4 contains “chloasma may occasionally occur, especially in women with a history of chloasma gravidarum. Women with a tendency to chloasma should avoid exposure to the sun or ultraviolet radiation whilst using Mirena.

The P-RMS is requested to consider whether this should be included in the CSP section 4.4

Assessor`s comment:The MAH should discuss the risk of chloasma based on the MAHs study database and postmarketing data. It should be further discussed if an inclusion in section 4.8 and 4.4 of the CSP is appropriate.

MAH’s response   : A total of 32 clinical studies in the indications contraception, menorrhagia and endometrial protection during hormone replacement therapy (no approved indication) were performed with more than 5520 women exposed to Mirena. ‘Chloasma’ was reported as adverse event in 7 patients corresponding to a frequency of 0.1% (uncommon).

In the ADR database the MAH detected 185 reports of chloasma/skin hyperpigmentation, of which 6 were classified as serious due to medically significant or permanent cosmetic damage. 145 out of 185 reports were medically confirmed. The MAH stated that based on the estimated postmarketing exposure of Mirena the event ‘chloasma’ was reported at a very rare reporting frequency.

The MAH concluded that chloasma should not be included in section 4.4 and 4.8 of the CSP since there is currently no conclusive evidence that the use of Mirena would cause the occurrence of chloasma.

Assessor’s comment:During clinical trials the adverse event ‘chloasma’ was reported with uncommon frequency.

The MAH stated that from spontaneous reports the event occurred with very rare frequency. With regard to the well known underreporting of ADRs the calculation/estimation of ADR frequencies based on spontaneous reports is not considered appropriate. There are 185 reports of chloasma/ skin hyperpigmentation in the MAH’s safety database. Relevant concomitant medications were only reported in 3 cases (tamoxifen, retinoids 2x). In 11 cases sunlight exposure could be identified as a triggering factor. In the majority of cases no information regarding withdrawal of Mirena was provided but in 12 cases improvement after removal was reported.

From the presented data the P-RMS is of the opinion that ‘chloasma/skin hyperpigmentation’ should be added to the ADR table in section 4.8 of the CSP with the frequency uncommon under the SOC Skin and subcutaneous tissue disorder since a causal relationship between Mirena and chloasma is at least possible and patients should be informed that these events may occur during therapy. In addition the wording proposed by IE should be included in section 4.4 of the CSP. This issue is finally addressed below in this AR (see 15. chloasma).

UK Section 4.3 – The UK SPC Updating the CSP.

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includes the following:i) acute malignancies affecting the blood or leukaemias except when in remission;ii) recent trophoblastic disease while hCG levels remain elevatediii) confirmed or suspected hormone dependent tumours including breast canceriv) (active or previous severe arterial disease, such as stroke or myocardial infarction is a contraindication when Mirena is used in conjunction with an oestrogen for HRT use.)

Assessor`s comment:The MAH should discuss the inclusion of these contraindications.

MAH’s response   : i) ‘acute malignancies affecting the blood or leukaemias except when in remission’

The MAH stated that ‘conditions associated with increased susceptibility to infections’ are already included as contraindication and it adequately represent acute malignancies that are also associated with increased susceptibility to infections.

Assessor’s comment:Acute malignancies affecting the blood or leukaemias except when in remission may not only impact on the susceptibility of infections but also on the coagulation. Concerning the latter, the following text which is proposed for inclusion in section 4.4 of the CSP is considered adequate.

Patients with risk factors for VTE In patients with risk factors for VTE (e.g. known thrombogenic mutations, history of VTE, prolonged immobilization) Mirena should only be used after careful assessment of the risk-benefit ratio and available alternatives.

MAH’s response:ii) recent trophoblastic disease while hCG levels remain elevated Limited evidence suggests that women using intrauterine contraception following uterine evacuation for a molar pregnancy are not at increased risk of developingpost-molar trophoblastic disease when compared to women using other methods of contraception (Gaffield et al. 2009). In practice, the start of contraceptive method, including the insertion of intrauterine contraceptives (IUCs), occurs at the time of uterine evacuation, and the follow-up is based on β-hCG measurements. Postabortal insertion of IUCs has been proven safe and effective by a large body of evidence (Steenland et al. 2011). Elevation of β-hCG during follow-up is a sign of possibly malignant trophoblastic tumor, which is covered by the contraindication 'Uterine or cervical malignancy' in section 4.3 of the proposed Mirena CSP. Nochange of the proposed Mirena CSP is deemed necessary.

Assessor’s comment:The assessors feels that “recent trophoblastic disease while hCG levels remain elevated” is a specification of the already existing contraindication 'Uterine or cervical malignancy' and therefore does not see the need to add this specification to the CSP.

MAH’s response:iii) confirmed or suspected hormone dependent tumours including breast cancer.Please refer to the MAH response provided to # 8 above.

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Assessor’s comment:As stated below, e.g. progesterone-dependent cancers, e.g. breast cancer should be listed in the CSP. The assessor considers the issue therefore as resolved.

MAH’s response:iv) (active or previous severe arterial disease, such as stroke or myocardial infarction is a contraindication when Mirena is used in conjunction with an oestrogen for HRT use.)Please refer to the MAH response provided to # 5 above. The Mirena CSP includes a warning in section 4.4 that “Mirena may be used with caution after specialist consultation, or removal of the system should be considered if any of the following conditions exist or arise for the first time: ...Severe arterial disease such as stroke or myocardial infarction.”This point is considered to be adequately addressed with regard to Mirena use. Adding a contraindication to the Mirena CSP which is only based on the safety profile of estrogen is not considered warranted.

Assessor’s comment:The assessor agrees with the MAH that the current warning adequately addresses this issue.Issue resolved.

Section 4.4 – Conditions under which Mirena can be used with caution – The UK SPC contains the following additional bullet points: i) use of chronic corticosteroid therapy;ii) past history of symptomatic functional ovarian cysts, iii) active or previous severe arterial disease, such as stroke or myocardial infarction (see section 4.3 when Mirena is used in conjunction with an oestrogen for HRT use); iv) severe or multiple risk factors for arterial disease; thrombotic arterial or any current embolic disease; v) venous thromboembolism.

Assessor`s comment:The MAH should state on these warnings.

MAH’s response:i) Use of chronic corticosteroid therapyUse of chronic corticosteroid therapy may be associated with increased susceptibility to infections; 'conditions associated with increased susceptibility to infections' are included in section 4.3 of the Mirena CSP. The rationale for including this additional warning is unclear to the MAH. Since it is not considered to be in line with the “principle of lowest common denominator” for the CSP, inclusion in the CSP is not seen as necessary.

Assessor’s comment:The assessor agrees with the argumentation of the MAH. This issue is considered to be addressed by the general contraindication: 'conditions associated with increased susceptibility to infections'. Issue considered resolved.

ii) Past history of symptomatic functional ovarian cystsWomen using progestin-only contraception (implant, progestin-only pill, or Mirena) have an increased risk of development of functional ovarian cysts, most of which are asymptomatic and resolve spontaneously without treatment. Other known risk factors include tubal sterilization, elevated body mass index (BMI), early menarche, long or irregular menstrual cycle, and (inconsistently) smoking (Parazzini et al. 1996; Holt et al. 2005). The elevated risk of functional ovariancysts is due to the mechanism of action of progestin-only contraceptives, where the folliculogenesis is not affected but sometimes the rupture of the follicle is inhibited by the use of these methods. Based on this mechanism of action, there is

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no rationale why women with past history of symptomatic functional ovarian cysts would have a higher risk of development of functional symptomatic or asymptomatic cysts during the use of Mirena, compared to women without such history.International guidelines (WHO 2009, US CDC medical eligibility criteria contraception 2010, FSRH 2007) recommend unrestricted use of Levonorgestrel (LNG) IUS in women with benign ovarian tumors (including cysts). Inclusion of this warning into the Mirena CSP is, therefore, not warranted.

Assessor’s comment:It is understood that currently there is no data to state whether women with a history of functional ovarian cysts would have a higher risk of functional ovarian cysts compared to women without such a history. However, it would seem plausible that women with a history of such events are at a higher risk. Therefore, the following sentence in accordance with the UK SPC is proposed to be added in section 4.4 to the paragraph concerning delayed follicular atresia:“Mirena may be used with caution in women with past history of symptomatic functional ovarian cysts.”In addition, the heading has been changed from “delayed follicular atresia” to “enlarged follicels”.

iii) Active or previous severe arterial disease, such as stroke or myocardial infarction (see section 4.3 when Mirena is used in conjunction with an oestrogen for HRT use)The Mirena CSP includes a warning in section 4.4 that “Mirena may be used with caution after specialist consultation, or removal of the system should be considered if any of the following conditions exist or arise for the first time: ...Severe arterial disease such as stroke or myocardial infarction.”This point is considered to be adequately addressed. A further reference to use in conjunction with oestrogen is not considered warranted in the endometrial protection indication.The product labelling of the estrogen component used in conjuncture with Mirena should always be taken into consideration when Mirena is used in this indication.

Assessor’s comment:If Mirena is used in conjunction with an estrogen for HRT “active or recent arterial disease such as myocardial infarction” is considered an absolute contraindication with regard to the estrogen as stated in the actual valid HRT-core SPC. However, it would be difficult to incorporate the complete HRT-core SPC in the Mirena SPC in case Mirena is used for HRT. Rather it is proposed that a statement is added at a prominent place of the Mirena SPC (e.g. 4.1) that if Mirena is used in conjunction with an estrogen for HRT, the safety information of the estrogen also apply and should be followed.However, with regard to Mirena, the currently proposed wording in section 4.4 is considered adequate.

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iv) Severe or multiple risk factors for arterial diseaseMAH’s response:Please refer to the cumulative analysis for stroke and myocardial infarction (see response to question #5) for an assessment of the risk for arterial disease associatedwith LNG IUS. A warning referring to arterial disease beyond the one that is currently included in the Mirena CSP is not considered warranted.

Assessor’s comment:In accordance with the WHO-eligibility criteria, a warning concerning multiple risk factors for arterial disease is inserted in section 4.4:

“Mirena may be used with caution in women with multiple risk factors for cardiovascular disease (e.g. hypertension, smoking, diabetes, hypertension, older age).”

This issue is finally addressed below in this AR (see 5. myocardial infarction and cerebrovascular disorders).

v) Thrombotic arterial or any current embolic disease; venous thromboembolism

MAH’s response:Based on the evidence presented in the answers to questions #4 and #7 above, inclusion of this warning is not considered warranted.

Assessor’s comment:This issue is addressed below in section F.

Section 4.4 – Bacterial endocarditis – In line with guidance from the faculty of sexual and reproductive health, the UK has removed the statement regarding use of prophylactic antibiotics for the insertion or removal of Mirena.

Reconsider inclusion in the CSP.

Assessor`s comment:The MAH should state on this.

MAH’s response: The MAH agrees to the proposal to remove the statement on the use of prophylactic antibiotics for the insertion or removal of Mirena in patients at risk of infective endocarditis.

Assessor’s comment:Since national recommendations regarding antibiotic prophylaxis in patients at risk of infective endocarditis may differ the P-RMS agrees to delete this statement from the CSP. Inclusion of the statement in SPC should be considered on a national level.

Section 4.4 - Breast cancer: The UK SPC includes the following wording:The risk of having breast cancer diagnosed in users of progestogen-only methods (POPs, implants and injectables), including Mirena, is possibly of similar magnitude to that associated with COC. However, for progestogen only contraceptive preparations, the

The UK would suggest that the wording regarding risk in post-menopausal women included in our national SPC might be a useful optional addition to the CSP for those member states where Mirena is licensed for post-menopausal use.

Assessor`s comment:The MAH should discuss the inclusion of this warning regarding risk in post-menopausal women into the CSP.

MAH’s response (section 4,4): With respect to the wording from the UK SPC regarding breast cancer risk in postmenopausal women the MAH

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evidence is based on much smaller populations of users and so is less conclusive than that for COCs.

Risk in post-menopausal womenThe risk of breast cancer is increased in post-menopausal women using systemic (i.e. oral or transdermal) hormone replacement therapy (HRT). This risk is higher with combined oestrogen-progestogen HRT than with oestrogen only HRT. The risk of breast cancer when Mirena is prescribed to provide theprogestogen component of HRT is not yet known. The product information of the oestrogen component of the treatment should also be consulted for additional information.

proposes a complete new wording for section 4.4 of the CSP:

‘Due to the limited exposure in Mirena trials in the indication protection from endometrial hyperplasia during estrogen replacement therapy, the available data are not sufficient to confirm or refute a risk for breast cancer when Mirena is used in this indication.’

The MAH is of the opinion that a reference to the product labelling of the estrogen component used in conjuncture with Mirena during HRT is unnecessary.

Assessor’s comment:The proposed “new” wording for section 4.4 corresponds to the sentence: ‘The risk of breast cancer when Mirena is prescribed to provide the progestogen component of HRT is not yet known’ of the UK SPC. However, since an increased risk of breast cancer in users of estradiol plus LNG-IUS has been described1, the wording should read:“(…).The exact height of the risk of breast cancer when Mirena is prescribed to provide the progestogen component of HRT is not yet known.”.

MAH’s response (section 4,8): The MAH proposes the following change of section 4.8: 'In addition, cases of breast cancer have been reported (frequency unknown, see section 4.4 "Special warnings and special precautions of use"). The risk of breast cancer is unknown when Mirena is used in the indication protection from endometrial hyperplasia during estrogen replacement therapy. Cases of breast cancer have been reported frequency unknown, see Section 4.4 Special warnings and special precautions of use).'

Assessor’s comment:The first sentence should be deleted. Therefore, it should read:Cases of breast cancer have been reported (frequency unknown, see Section 4.4 Special warnings and special precautions of use).

This issue is finally addressed below in this AR (see 19. Breast cancer during hormone replacement therapy).

Sections 4.4 & 4.8 – Chloasma – the UK considers that there is sufficient information to include this in the CSP.

Consideration of inclusion of appropriate statements in sections 4.4 and 4.8 of the CSP.

Assessor`s comment:See comment from IE.

Assessor’s comment:For discussion of this comment please see above. This issue is finally addressed below in this AR (see 15. Chloasma).

Section 4.6 – The UK SPC Possible amendment of CSP.

1 Lyytinen HK et al. A case-control study on hormone therapy as a risk factor for breast cancer in Finland: Intrauterine system carries a risk as well. Int J Cancer. 2010 Jan 15;126(2):483-9

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includes the following wording as the second sentence of this section: ‘…In case of accidental pregnancy with Mirena in situ, ectopic pregnancy should be excluded (see section 4.4) and then the system must be removed and termination of the pregnancy should be considered…’

Assessor`s comment:The MAH should discuss this wording.

MAH’s response:In the opinion of the MAH the sentence is already partly included in the CSP and in part misleading.

The following information is already included in the CSP: “If the woman becomes pregnant when using Mirena removal of the system is recommended, since any intrauterine contraceptive left in situ may increase the risk of abortion and preterm labor. Removal of Mirena or probing of the uterus may result in spontaneous abortion. If the intrauterine contraceptive cannot be gently removed, termination of the pregnancy may be considered. If the woman wishes to continue the pregnancy and the system cannot be withdrawn, she should be informed about the risks and the possible consequences of premature birth to the infant. The course of such a pregnancy should be closely monitored. Ectopic pregnancy should be excluded. The woman should be instructed to report all symptoms that suggest complications of the pregnancy, like cramping abdominal pain with fever.”

If the removal of Mirena was successful the MAH is of the opinion that pregnancy termination should not be considered in case the patient wishes to continue pregnancy after receiving consultation regarding the possible effects of LNG exposure: ‘Because of the intrauterine administration and the local exposure to the hormone, the possible occurrence of virilizing effects in the fetus should be taken into consideration’

From the submitted PSURs there is no evidence of birth defects caused by Mirena use in cases where pregnancy continues to term with Mirena in place.

Studies have shown that despite the initially higher risk of spontaneous abortion during a few days after successful removal of an intrauterine contraceptive during pregnancy, the rates of spontaneous abortion or premature delivery thereafter are only slightly elevated, and live birth rates approach 80% (Schiesser et al. 2004). International guidelines do not recommend consideration of pregnancy termination in case of accidental pregnancy with intrauterine contraceptive in situ (FSRH CEU 2007, NICE LARC Guideline 2005).

Assessor’s comment:The P-RMS agrees with the MAH that the information from the UK SPC is adequately covered by the CSP (see bold text above) and an amendment is not required.

E POINTS TO BE ADDRESSED IN THE NEXT PSURGeneral

In future WSPs the MAH should give an overview of all cases with fatal outcome from the overall

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reporting period and should discuss these cases in detail. The MAH should continue to monitor cases with breast cancer and present an overview in the next

PSUR. For Jadelle the MAH should state if cases of breast cancer have been reported and if an inclusion of this ADR into section 4.8 of the CSP would be appropriate.

The MAH should continue to closely monitor cases with meningioma.

Mirena In future PSURs the MAH should present a cumulative overview on the topic endometrial

carcinoma. In the next PSUR the MAH should continue to present a cumulative overview on abnormal

pregnancy outcomes.

Jadelle The MAH should continue to monitor the frequency of pregnancy reports to assure the effectiveness

of the re-training measures undertaken in Columbia. A cumulative analysis of pregnancy reports in Jadelle users is expected in next PSUR as well. Additionally, the MAH should give an overview of all cases with abnormal pregnancy outcomes.

F RFI / LoQ: REQUEST FOR FURTHER INFORMATION / LIST OF QUESTIONS

Questions to be addressed by the MAH:

1) Depression and suicide/self-injuryRFI:The MAH should provide an updated cumulative overview of all cases which include PTs of the MedDRA-SMQ “Depression and suicide/self-injury”. Cases of suicide should be described in detail. In addition the MAH should provide a comprehensive overview of literature reports on this topic.

MAH’s response: MirenaA cumulative analysis and review of clinical trial results, post-marketing data, and published literature on Mirena with regard to depression and suicidality is provided in attachment Mirena_cumulative_review_depression_suicidality.Based on all available data from clinical studies, literature and post-marketing reporting, there is no evidence that insertion/use of Mirena may be causally related to the occurrence or aggravation of major depression and any kind of suicidal depression.

JadelleA cumulative review of all adverse drug reaction (ADR) reports, case reports from the literature, and reports of serious adverse events (SAEs) from clinical trials received by the company which include PTs of the MedDRA-SMQ “Depression and suicide/self injury” for Jadelle is provided in attachment Jadelle_cumulative_review_depression_suicidality.

Assessor’s comment:See assessment of issue 3) below.

2) Depressed mood and altered mood

MirenaRFI:

Depressed mood and altered mood are listed ADRs in section 4.8 of the proposed CSP of Mirena. Mood changes and depression are listed in section 4.8 of the proposed CSP of Jadelle. The MAH should discuss if additional terms should be included in section 4.8 of the Mirena CSP.

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MAH’s response:

The MAH performed a re-analysis of clinical trial data for Mirena. It was concluded that ‘depressed mood’ and ‘depression’ should be included in the ADR section of the CCDS. Since the precise diagnosis of depression and depressive mood by gynaecologists is considered unlikely the MAH proposes to include ‘Depression’ in addition to ‘depressed mood’ with the frequency uncommon (assessor:?) to section 4.8 of the CSP. In addition the MAH proposes to delete ‘altered mood’ from the ADR table in section 4.8 because of insufficient evidence from clinical trial data.

Assessor’s comment:

It is understood that the (proposed) frequency of depression/depressed mood is common, as also stated in the proposed CSP.See assessment of issue 3) below.

3) Removal of Jadelle should be considered in women who become significantly depressedMirena

RFI:

In the proposed CSP of Jadelle the following warning in section 4.4 is already included: “ Removal of Jadelle should also be considered in women who become significantly depressed, since the symptom may be hormone-related. Women with a history of depression should be carefully monitored and removal of Jadelle considered if clear symptoms develop.” Because of the medical significance of depression/suicidality, it should be discussed if an inclusion of a warning into the CSP of Mirena would be appropriate

MAH’s response:

Based on all available data from the literature, clinical studies and post-marketing reports there is no evidence that insertion of Mirena may be causally related to the occurrence or aggravation of major depression and any kind of suicidal depression.The MAH, therefore, considers the current labelling of Mirena adequate with regard to this topic. Addition of a warning regarding occurrence or aggravation of clinically relevant depression is not justified.

Assessor’s comment:The assessor disagrees with the MAH. ‘Depression’ in addition to ‘depressed mood’ is an acknowledged ADR of Mirena and as such will be included in section 4.8 of the CSP with the frequency common.Since (severe) depression implies the risk of suicidality it appears justified to add a warning similar to the Jadelle CSP in section 4.4 of the Mirena CSP:

Mirena section 4.4Depression/depressed mood is commonly associated with Mirena use. Therefore, removal of Mirena should be considered in women with Mirena who become significantly depressed, since the depression may be related to Mirena use.

Women with a history of depression should carefully be monitored and removal of Mirena considered if clear symptoms develop.

MAH’s response dated April 2012:Please refer to the respective response document. The MAH concludes that addition of a warning regarding occurrence or aggravation of clinically relevant depression is not considered justified by the company.

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Assessor’s comment:

The proposed warning (see above) can be dealt with on a national basis by the MS. In the CSP “depression” in addition to “depressed mood” is listed in 4.8 with the frequency description common.

4) VTE-cases

RFI:Based on the VTE-cases in the MAH`s database the MAH should discuss if the inclusion of the ADR VTE into section 4.8 of the CSP would be appropriate.

MAH’s response:MirenaThe MAH proposes deleting the statement regarding the VTE risk of progestogen only pills from the Mirena CSP with the argumentation that new evidence pertaining specifically to Mirena has become available that indicates no increased risk of VTE in Mirena users. The MAH stated that the clinical program for Mirena was not designed to have sufficient statistical power to assess the risk of VTE. During clinical trials with Mirena including 5091 subjects no case of deep vein thrombosis and only one case of pulmonary embolism occurred, for which the causal relation was assessed as unlikely by the MAH. During clinical studies coagulation factors have not been systematically evaluated. In a Japanese contraception phase III study no clinically significant changes were found in coagulation and fibrinolysis system over time. In 2010 a case-control study investigating the VTE risk of Mirena and Depot Medroxyprogesterone acetate (DMPA) was published, including 446 women aged 18-50 with a first episode of VTE and 1146 controls. No increased risk of VTE could be shown for LNG IUS. In the Liedegaard study an increased risk of VTE among COC users as a class effect has been shown, which is dependent on the estrogen dose, but no evidence for an increased risk of VTE for Mirena and progestin-only pills (1.7 % of the woman-years in the study) could be shown when compared to non-hormonal contraceptive users. The WHO Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception (1998) found that the adjusted odds ratios for all cardiovascular diseases combined with current use of oral and injectable POCs and combined injectable contraceptives, respectively, were 1.14 (95%CI: 0.79–1.63), 1.02 (0.68 – 1.54), and 0.95 (0.49 –1.86) compared with nonusers, therefore suggesting no increased risk among POC user. Similarly, the POP-specific evaluation of the Transnational case-control study on oral contraceptives showed no increased risk for VTE in users of Pos compared to non-users (OR: 0,68; 95 % CI: 0.28 – 1.66) (Heinemann et al 1999). Goldstein et al (2007) performed a study on the risk of venous thrombosis associated with injectable progestogen-only contraceptives, using biomarkers (eg, coagulation factor levels, D-dimer, and activated partial thromboplastin time as markers of coagulation risk). They reported no adverse effects on these markers by use of progestin-only contraceptives. In summary, the available epidemiological and clinical data from these studies with higher systemic concentrations of progestins than those associated with Mirena use, do not show a significant relation between cardiovascular disease (and VTE in particular) and use of POC. Contemporary guidelines such as the WHO medical eligibility criteria for contraceptive use (2009) and the ACOG guideline Use of Hormonal Contraception in Women With Coexisting Medical Conditions (2006) recommend Mirena for women with risk factors for venous thromboembolism (VTE). In addition, Mirena is recommended (WHO medical eligibility criteria class 2) for women with VTE on anticoagulant therapy. The MAH concluded that the available evidence does not support a causal relationship between Mirena use and development of VTE. Apart from one case of pulmonary embolism occurring in a drug abuse user, no cases of VTE have occurred in the clinical development program in women not using concomitant estrogen replacement therapy. Current epidemiological trials do not support an increased risk of VTE during Mirena use. Clinical trials show no clinically relevant effects on coagulation factors by Mirena. Limited evidence supports use of Mirena in women using anticoagulant therapy for VTE, who are suffering from HMB as a consequence of their anticoagulant therapy. Current international contraceptive guidelines recommend the use of Mirena in women with risk factors for VTE. (…).

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The MAH stated that as outlined in response to question 4, the currently available data do not indicate an increased risk of VTE in Mirena users, or a causal relationship between Mirena use and development of VTE. The MAH arguments that international guidelines, such as those of the WHO for eligibility of contraceptive use, do not restrict the use of Mirena in women with a personal history of VTE or with current VTE established on anticoagulant therapy. Because up to two-thirds of women on anticoagulant therapy suffer from heavy menstrual bleeding and because of the known teratogenic nature of oral anticoagulants, reproductive aged women with VTE on anticoagulant therapy need contraceptives which are highly effective, do not exacerbate their bleeding problems and do not increase the risk of recurrence of VTE (Huq et al. 2011). Thus, the contraceptive options for these women are limited and most of the available contraceptive methods do not fulfil these criteria, either due to low contraceptive effectiveness and poor compliance (e.g. barrier methods) or due to an increased risk of exacerbation of bleeding problems (Cu-IUDs). A systematic review found overall positive effects of the use of Mirena in women with current VTE on anticoagulant therapy (Culwell and Curtis, 2009). A recent review concluded that Mirena appears to be safe and effective in the management of heavy menstrual bleeding in women on oral anticoagulant therapy for VTE (Huq et al. 2011). Based on these data the use of Mirena appears safe in women with current VTE on anticoagulant therapy.

Due to the reasons outlined above, the MAH is not in agreement to include venous thromboembolism (e.g. deep venous thromboembolism of the leg, pulmonary embolism, or retinal thrombosis) to section 4.4 of the Mirena CSP.

Assessor’s comment:The issue of VTE refers to different situations / sections.

- section 4.3 contraindication for women with risk factors- section 4.4 - data on VTE risk associated with Mirena use- warning for women with current VTE / with risk factors - section 4.8 summary of current data on VTE associated with Mirena use

a) section 4.3 MirenaIn the actual Mirena CSP thromboembolic disease is not stated as a contraindication. This is supported.

JadelleFor Jadelle, a contraindication is contained in section 4.3 (thromboembolic disease).This is supported in view of higher systemic plasma levels compared to Mirena.

b) section 4.4 MirenaIt is acknowledged that in the Lidegaard study (BMJ 2011) no increased VTE-risk for Mirena was found. However, this study was designed to address the VTE-risk of COCs and not the LNG-IUD. In view of the limitation of adequate epidemiological data and in the presence of case reports informing about VTE the following wording is proposed for section 4.4:

Venous thromboembolismIn a cohort study no increased risk of VTE was found based on 155.000 women years of Mirena exposure (RR: 0,83 [95% CI 0,63-1,08]; estimated crude incidence of 3.5 cases per 10.000 women years in Mirena-users) when comparing current users of Mirena to non-users of hormonal contraceptives. However, spontaneous reports of VTE associated with Mirena use have been reported.

Patients with current VTE:Removal of Mirena is recommended.

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Patients with VTE and established on anticoagulant therapy:Removal of the system should be considered or Mirena should only be used after careful assessment of the risk-benefit ratio and available alternatives.

Patients with risk factors for VTE: In patients with risk factors for VTE (e.g. known thrombogenic mutations, history of VTE, prolonged immobilization) Mirena should only be used after careful assessment of the risk-benefit ratio and available alternatives.

Measures:Appropriate diagnostic and therapeutic measures should be undertaken immediately if there are symptoms or signs of thrombosis.

JadelleThe current wording in the CSP can remain.

c) section 4.8:Mirena VTE should be added to the table in section 4.8 und the respective SOC with the frequency “unknown”. An asterisk should be placed to the “unknown” explaining that the frequency cannot be calculated from spontaneous reports.

JadelleCurrent wording can remain.

MAH’s response dated April 2012Please refer to the respective response document. The MAH concludes that given the above, the MAH does not agree to add any of the proposed warnings regarding VTE under section 4.4 or to mention VTE in section 4.8 in the CSP of Mirena.

Assessor's comment:MirenaIn line with the recently approved national variation in UK the following wording should be implemented in the CSP:

b) section 4.4 “Conditions under which Mirena can be used with cautionShould any of the following conditions exist or arise for the first time during treatment, removal of the system should be considered:………-Acute venous thromboembolism”

The other proposals concerning VTE can be dealt with on a national basis by the MS.

2nd Response of the MAH dated 18 October 2012:The Assessor refers to the UK national SPC that was recently updated following avariation filed by the MAH. During this variation procedure, the UK authority insistedon updating the UK SPC with the above wording. The MAH did not agree to theauthority's decision; however the MAH had to accept this request as a local, nationaldeviation in the UK. However, for the scientific and medical reasons outlined earlierduring this procedure, the MAH is of the opinion that such a warning is not justified and

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should not be included in the CSP.The MAH wishes to re-iterate that there is no evidence suggesting an increased risk ofVTE or increased recurrence of VTE in Mirena users and refers to the previous responseto the 1st draft Final Assessment Report for the detailed analysis of this data. The MAH´sposition is further strengthened by the recent meta-analysis (Mantha et al 2012) whichconcluded that progestin-only contraception was not associated with an increased risk ofvenous thromboembolism compared with non-users of hormonal contraception.Subgroup analysis confirmed there was no association between venous thromboembolicrisk and progestin-only pills (relative risk 0.90 (0.57 to 1.45)) or Mirena (0.61 (0.24 to1.53), while the relative risk of an injectable progestin versus non-users was 2.67 (1.29to 5.53). This highlights the fact that the risk may differ with different progestin-onlycontraceptives. The authors concluded that the study results “suggest that the relativesafety of progestin-only agents may be limited to oral and intrauterine formulations”while the results regarding injectable progestin needs confirmation due to possibleselection bias.The international guidelines give slightly conflicting advice with regards to “acuteVTE/PE”, a condition which is only mentioned in the WHO and US MEC. The WHO MEC gives category 3 for acute VTE/PE, whilst more recent US MEC from 2011 givescategory 2. With regards to the “(current) VTE/PE established on anticoagulants”, allthree guidelines (WHO, UK and US) give category 2 for Mirena use. The UK MEC haschanged the classification of use of Mirena in women with current VTE (onanticoagulants) from category 3 to 2 in the update from 2005/2006 to 2009 version,whilst no “acute VTE” is separately defined. It is thus fair to conclude that the newestevidence is reflected in the most recent guidelines and that the recommendations forprogestin-only contraceptive use in women with acute VTE have become less restrictive.From the clinical point of view, the MAH finds it difficult to justify why the” acuteVTE” would be considered as a condition where Mirena removal should be considered,since the definition of “acute VTE” may not be well understood if not given in thecontext of “(current) VTE/PE established on anticoagulant therapy” – where Mirena useis approved by all guidelines. Some clinicians would possibly incorrectly mistake “acuteVTE” for women with VTE on (long-term) anticoagulant therapy. The time intervalneeded for the development of “acute” VTE/PE to become “VTE/PE established onanticoagulant therapy” is nowadays very short as contemporary anticoagulants exerttheir effect rapidly – thus, a removal of Mirena upon presentation of an acute VTE, withre-insertion once established anticoagulation is achieved would not be justifiable due torepeat insertion procedure.In the absence of evidence to suggest an increased risk of VTE, or recurrence of VTE inMirena users, and according to the newest available guidelines, the MAH retains itsopinion not to include “acute VTE” under the conditions where Mirena should be usedwith caution or removal should be required.Please also refer to our previous argumentation above.

Assessor’s comment:The respective paragraph in 4.4 reads:

Mirena may be used with caution after specialist consultation, or removal of the system should be considered if any of the following conditions exist or arise for the first time:- (…)- acute venous thromboembolism.

Hence, Mirena may be used after specialist consultation.The proposal of the MAH cannot be followed.

5) myocardial infarction and cerebrovascular disordersRFI:

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The MAH should present a cumulative overview of all cases with myocardial infarction and cerebrovascular disorders. Additionally, the MAH should provide a comprehensive overview of literature reports on these topics.

MAH:MirenaA cumulative overview of Mirena cases reporting myocardial infarction or cerebrovascular disorders and an overview of the relevant literature can be found in attachment Mirena_myocard infarction_cerebrovascular disorders.The available safety data from clinical trials, and the cumulative data received from post-marketing ADR reporting, give no indication for an increased risk of myocardial infarction or cerebrovascular events in Mirena users. Published data do not indicate an increased risk of stroke or myocardial infarction with the use of LNG IUS.

Assessor’s comment:The MAH provided the requested data. The current information in the CSP is considered adequate with regard to MI and cerebrovascular disorders:Mirena may be used with caution after specialist consultation, or removal of the system should be considered if any of the following conditions exist or arise for the first time: Migraine, focal migraine with asymmetrical visual loss or other symptoms indicating transient

cerebral ischemia

● Exceptionally severe headache

● Marked increase of blood pressure

● Severe arterial disease such as stroke or myocardial infarction.

However, to be in line with the WHO elegibility criteria the following information should be added to section 4.4 with regard to cardiovascular risk factors:

Mirena may be used with caution in women with multiple risk factors for cardiovascular disease (e.g. hypertension, smoking, diabetes, hypertension, older age).

JadelleA retrieval of all Jadelle cases received by the company since launch until 29 June 2011 including at least one event coded under MedDRA HLGT Coronary artery disorders or MedDRA HLGT Central nervous system vascular disorders was performed with a data lock point of 29 June 2011. All together, 2 cases were identified. The first report describes a sinus thrombosis in a 32-year-old patient and was further analyzed in the last PSUR for Jadelle (reporting period 24 Dec 2009-23 Dec 2010; 201029796GPV). In the second case a 24-year-old woman experienced angina pectoris, atypical chest pain, left bundle branch block and J point elevation (CO-2005-010661). A causal relationship to Jadelle was not assumed by the reporting physician. This case is further analyzed in the 8th PSUR for Jadelle (reporting period 24 Dec 2004-23 Dec 2005, pages 15 and 26). No further cases meeting the criteria above were retrieved. From the spontaneous cases received for Jadelle, there is no evidence for an increased risk for myocardial infarction or cerebrovascular disorders. An overview of the relevant literature on LNG implants and myocardial infarction or cerebrovascular disorders for Jadelle can be found in attachment Mirena_myocard infarction_cerebrovascular disorders.

Assessor’s comment:The MAH provided the requested data. No new safety signal arises.The current information in the CSP is considered adequate:Section 4.4“The effects of JADELLE® on clotting factors have varied. In patients with a history of thromboembolic disease, JADELLE® should only be used if other contraceptive methods are unsuitable and after careful assessment of the risk-benefit ratio. Thromboembolic and cardiovascular undesirable effects have been reported in users of other levonorgestrel implants. Cases of stroke, myocardial infarction, pulmonary embolism and deep venous thrombosis have been reported in users of other levonorgestrel implants.

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Patients who develop thrombotic or embolic disease should have their JADELLE® implants removed (see also Large and small surgical procedures). Thrombophlebitis and superficial phlebitis have occurred more commonly in the arm of insertion. Some cases have been associated with trauma to that arm. Special caution should be observed in prescribing JADELLE® implants for patients with recognized risk factors for or any predisposition to arterial disease.”

Issue resolved.

MAH’s comment dated April 2012:Please refer to the respective document. In summary, the MAH states that the addition of a general warning regarding Mirena use in women with cardiovascular risk factors is not justified from a scientific point of view. Furthermore, such a warning potentially prevents Mirena use in patient populations in whom the benefit-risk ratio may be expected particularly favourable.

Assessor’s comment:In the UK there has recently been a variation concerning the Mirena SPC. The following wording has been approved.

Conditions under which Mirena can be used with caution

Should any of the following conditions exist or arise for the first time during treatment, removal of the system should be considered:

(…).Severe or multiple risk factors for arterial disease.

This is in accordance with the WHO-class 2 recommendation. Hence, it is proposed that on a national basis, the inclusion of the following wording in 4.4 could be considered:

Mirena may be used with caution in women with severe or multiple risk factors for cardiovascular disease (e.g. hypertension, smoking, diabetes, older age).

6) blindness, anaphylactic shock, loss of consciousness and syncopeRFI:The MAH should discuss the cases with blindness, anaphylactic shock, loss of consciousness and syncope.

MAH’s response:Blindness:MirenaBlindness was reported to the MAH at a very low reporting frequency. In all but 3 cases blindness was reported in the context of different underlying conditions, all of which represent a plausible alternative explanation for the occurrence of this event. De-challenge was observed in some patients who experienced blindness in association with migraine which is an expected ADR for Mirena. In conclusion, no new safety concern arose from the above-described reports.

JadelleCumulative retrieval on the company’s GPV database was performed with data

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cut-off 29 Jun 2011. Retrieval included case reports on Jadelle users with at least one event coded to MedDRA PTs included in the HLT Blindness (excluding colour blindness). No cases meeting the above described criteria were identified in the company’s safety database.

Assessor’s comment:The MAH provided the requested data. No new safety signal arises. Issue resolved.

Anaphylactic shockMirenaDue to the medical significance of anaphylaxis and severe hypersensitivity reactions, this topic is under close monitoring by the company. A cumulative review of the clinical trial data and post-marketing experience with Mirena with regard to anaphylaxis was last presented in the Mirena PSUR No. 23 (reporting period 28 Sep 2007-27 Sep 2008), based upon which it was concluded that available data do not conclusively indicate a causal relationship between Mirena use and anaphylaxis. It was announced that the company would continue to monitor all safety data relating to this topic. The same conclusion was drawn in the previous PSURs No. 24 (reporting period 28 Sep 2008-27 Sep 2009) and No. 25 (reporting period 28 Sep 2009-27 Sep 2010).

JadelleA search for cases reporting an adverse event coded to MedDRA HLT “Anaphylactic responses” revealed one case for Jadelle. In this case (2011-036067) a patient experienced an anaphylactic shock due to a local anaesthesia prior to a planned Jadelle insertion. Jadelle was not inserted. No additional cases were retrieved.

Assessor’s comment:The MAH provided the requested data. No new safety signal arises. Issue resolved.

Loss of consciousness and syncopeMirenaSyncope is a transient loss of consciousness and postural tone due to reduced cerebral blood flow. This transiently decreased cerebral blood flow is usually due to one of three general mechanisms: disorders of vascular tone or blood volume including reflex syncopes (neurocardiogenic syncopes) and orthostatic syncopes, cardiovascular disorders including obstructive lesions and cardiac arrhythmias, or cerebrovascular disease. In addition, metabolic and psychogenic disorders have been described as causes of syncopes.Neurocardiogenic syncopes (vasovagal and vasodepressor-sympathetic withdrawal (vasodilatation) and/or increased parasympathomimetic activity (bradycardia)) are the common faint that may be experienced by healthy persons; they account for approximately half of all episodes of syncope. Neurocardiogenic syncope is frequently recurrent and commonly precipitated by a hot or crowded environment, alcohol, extreme fatigue, severe pain, hunger, prolonged standing, and emotionalor stressful situations.It has been cited that syncope affects 12% to 48% of the population at some point in their lives. However, the etiology is established in only 50% to 75% of patients who present to a physician’s office or emergency department (Sud et al. 2009). Vasovagal syncope is considered to have a benign prognosis as patients with vasovagal syncope had no increased risk of death (Soteriades at al. 2002; Quinn et al. 2008).A retrieval of all adverse drug reaction (ADR) reports, case reports from the literature, and reports of serious adverse events (SAEs) from clinical trials received by the company since launch until 06 Jul 2011 (data lock point) including at least one event coded under MedDRA PT Syncope or under MedDRA PT Loss of consciousness was performed.In total, 351 cases reported at least one event that was coded to PT Syncope or to PT Loss of consciousness (264 cases with PT Syncope and 94 cases with PT Loss of consciousness with 7 cases reporting both). Of these 351 reports, 263 were medically confirmed, whereas 88 were non-medically confirmed cases. Based on a total cumulative exposure estimate from Mirena sales (more than 65.3 million woman-years of exposure by end of June 2011), this results in a reporting frequency of 0.4 per 100,000 woman-years of exposure as estimated on sales data for medically confirmed cases and in a reporting frequency of 0.5 per 100,000 woman-years for all cases.

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In 189 cases it was reported that the syncope/loss of consciousness occurred/or was suspected to have occurred in association with Mirena insertion. However, in many other cases the information provided was scarce and the time interval between insertion and the event was not reported. In almost all other cases providing meaningful information, the syncope/loss of consciousness occurred in relation to other serious events such as for example uterine perforation, ectopic pregnancy, severe pain or bleeding, cerebrovascular disorders such as epilepsy and stroke, and severe infections.

ConclusionAs mentioned in the proposed Mirena CSP in section 4.4, the insertion or removal procedure '..may precipitate fainting as a vasovagal reaction..' that might result in syncope. The information provided in the CSP is considered adequate.

JadelleA retrieval of all Jadelle cases received by the company since launch until 06 Jul 2011 including at least one event coded under MedDRA PT Syncope or under MedDRA PT Loss of consciousness was performed.All together, 3 cases were retrieved: Case CO-2006-013924 describes the occurrence of vomiting, nausea and blackout in a 32-year-old patient who was later diagnosed with a pregnancy.No additional information regarding the blackout could be obtained in this case. No new safety relevant information derives from this case.

Case 201029796GPV refers to a patient who experienced headache, sensibility change in right lower leg, and fainting, and was diagnosed with sinus thrombosis while using Jadelle. This case was analyzed in detail in the last PSUR for Jadelle (reporting period 24 Dec 2009-23 Dec 2010). A signal investigation of Jadelle use and venous thromboembolism was performed upon request of the Swedish Health Authority to consider whether an update to the current SmPC was required. No new safety issue arose from this investigation and results were presented in the last PSUR (reporting period 24 Dec 2009-23 Dec 2010).

Case ES-2004-034499 describes the occurrence of a vasovagal syncope with subsequent cardiorespiratory arrest and cerebral oedema in association with Jadelle insertion in a 36-year-old patient that resulted in the death of the patient. This case was further described and analyzed in detail in the 7th PSUR for Jadelle (reporting period 24 Dec 2003-23 Dec 2004; pages 13 and 24). It was concluded that the reported single case did not indicate a need for changes in the Jadelle Company Core Text (CCT)/SmPC. No further cases meeting the criteria above were retrieved.

Assessor’s comment:The MAH provided the requested data. No new safety signal arises. Issue resolved.

7) Additional warnings pertaining to certain conditionsRFI:The German SmPC includes the following additional warning: “Mirena may be used with caution or removal of the system should be considered if any of the following conditions exist or arise for the first time: … Venous or arterial thromboembolic events, e.g. deep vein thrombosis of the leg, pulmonary embolism, stroke, myocardial infarction, retinal thrombosis” (stroke and myocardial infarction are mentioned in the proposed CSP). The P-RMS is of the opinion that this warning should also be included into section 4.4 of the CSP. The MAH should discuss this point.

MAH’s response:As outlined in the MAH response to comment #4, the currently available data do not indicate an increased risk of VTE in Mirena users, or causal relationship between Mirena use and development of VTE. International guidelines, such as those of the WHO for eligibility of contraceptive use, do not restrict the use of Mirena in women with a personal history of VTE or with current VTE established on anticoagulant therapy (see Justification Document no. 38). Because up to two-thirds of women on anticoagulant therapy suffer from heavy menstrual bleeding and because of the known teratogenic

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nature of oral anticoagulants, reproductive aged women with VTE on anticoagulant therapy need contraceptives which are highly effective, do not exacerbate their bleeding problems and do not increase the risk of recurrence of VTE (Huq et al. 2011).Thus, the contraceptive options for these women are limited and most of the available contraceptive methods do not fulfill these criteria, either due to low contraceptive effectiveness and poor compliance (e.g. barrier methods) or due to an increased risk of exacerbation of bleeding problems (Cu-IUDs). A systematic review found overall positive effects of the use of Mirena in women with current VTE on anticoagulant therapy (Culwell and Curtis, 2009). A recent review concluded that Mirena appears to be safe and effective in the management of heavy menstrual bleeding in women on oral anticoagulant therapy for VTE (Huq et al. 2011). Based on these data the use of Mirena appears safe in women with current VTE on anticoagulant therapy.Due to the reasons outlined above, the MAH is not in agreement to include venous thromboembolism (e.g. deep venous thromboembolism of the leg, pulmonary embolism, or retinal thrombosis) to section 4.4 of the Mirena CSP.

Assessor’s comment:As described in the article by Culwell et al. (Contraception 2008), in the studies investigating women with the LNG-IUD with bleeding disorders or anticoagulation only a very limited number of women were included. In addition, the quality grade of the studies was limited. One case report of a thromboembolic complication during the use of the LNU-IUD while on anticoagulation therapy is listed (Schaedel et al. Am J Obstet Gynecol 2005). See also discussion referring to VTE above.

Assessor’s comment:Please refer to point 4.

8) Progestogen-dependent tumorsRFI:In the proposed CSP the contraindication “Progestogen-dependent tumors” is listed. The P-RMS is of the opinion that an example for this contraindication should be added: “Progestogen-dependent tumors, e.g. breast cancer”. The MAH should comment on this.

MAH’s response:In the “Guidance document for marketing authorisation holders on submissions of PSURs under the EU PSUR work sharing scheme, version July 2010” the requirements for generating a CSP are detailed under item 4, pages 2/3 “…This document should be generated according to the latest SmPC guidelines and include common information from sections 4.3 - 4.9 present in all SmPCs within the EU and any relevant safety information from section 4.2…”. When generating the proposed Mirena CSP, these rules were strictly followed and only common safety relevant information present in all SmPCs within the EU was considered (principle of “lowest common denominator”). With reference to the current CSP rules and the principle of “lowest common denominator” as specified above, the MAH proposes not to change the Mirena CSP and not to include reference to breast cancer as an example for the contraindication 'progestogen-dependent tumors'. According to the CSP guidance, countries where additional information is already nationally approved do not need to delete this information.

Assessor’s comment: The assessor considers the addition of the example as very helpful. Hence, e.g. breast cancer should be added.

MAH’s response dated April 2012:The MAH agrees to this request.

9) If a sex hormone-dependent tumor occurs, Mirena must be removedRFI:

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Additionally, the German SmPC includes the following recommendation for action in section 4.4: “If a sex hormone-dependent tumor (e.g. breast cancer) occurs in Mirena users, Mirena must be removed.” In the view of the P-RMS this recommendation should be included into section 4.4 of the CSP.

MAH’s response:In general, the 'Notice to Applicants, A Guideline on SmPC, September 2009, states in section 4.4 that 'Patient groups in which use of the medicinal product is contraindicated should be mentioned in section 4.3 only and not to be repeated here.' Furthermore, as summarized in the section “overall assessor comments on MAH sponsored studies”, in the preliminary assessment report from the P-RMS, dated 10.06.2011, the case-control study on risk of breast cancer in Mirena vs. Copper IUD users, conducted independently by the ZEG institute, concluded that there is “no indication of tumor induction or promotion” by Mirena use. An intermediate analysis of an ongoing investigator-sponsored trial on the risk of recurrence of breast cancer in Mirena users vs. never users, did not find a difference in breast cancer recurrence between the two groups. While non-hormonal contraceptive methods should always be recommended as first-line contraceptive methods in patients with breast cancer, some professional associations are of the opinion that Mirena can be considered by breast cancer survivors “if the unique contraceptive or non-contraceptive benefits outweigh the risk of an unknown effect on recurrence” (SOGC/GOC 2008). The currently available limited data is in agreement with the recommendation of the SOGC, rather than a recommendation for mandatory removal of Mirena in case of breast cancer. Therefore, the MAH is not in agreement to add the sentence 'If a sex hormone-dependent tumor (e.g. breast cancer) occurs in Mirena users, Mirena must be removed' into section 4.4. of the proposed Mirena CSP.

Assessor’s comment:Not agreed.Section 4.4 gives advice on what to do in certain situations, here, occurrence of breast cancer in a Mirena user. As such, this advise should be located here in section 4.4.In addition, according to the WHO eligibility criteria, the LNG-IUD should not be used in women with current breast cancer (category 4).

Therefore, the following statement should be included in the CSP in section 4. 4 (paragraph about breast cancer):“If a sex hormone-dependent tumor (e.g. breast cancer) occurs in Mirena users, Mirena must be removed.”In addition, the heading “breast cancer” was added to the respective paragraph and the paragraph was moved to a different location in section 4.4.Furtheron, certain sentences, which may suggest lack of a causal relationship or which are considered to be too reassuring have been removed. However, national agencies may add these sentences to the SPCs authorized in their countries.

These studies do not provide evidence for causation. The observed pattern of increased risk may be due to an earlier diagnosis of breast cancer in OC users, the biological effects of OCs or a combination of both. The breast cancers diagnosed in ever-users tend to be less advanced clinically than the cancers diagnosed in never-users.

MAH’s response dated April 2012Please refer to the respective response of the MAH. In summary, the MAH is not willing to include the statement in the CSP. The MAH would like to point out that this is consistent with the product information of other progestogen only long-acting reversible contraceptives such as for example Implanon or Jadelle which do not contain an additional warning for removal of the product in case this specific contraindication applies to the patient.

Assessor's comment:The current wording in the national German SPC will not be removed. However, BfArM could agree not to have such a statement in the CSP but as a requirement on a national basis.

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10) breast cancer warningPlease refer to the MAH's response document dated April 2012.In summary, the MAH proposes to delete the breast cancer warning in section 4.4 of the CSP. "Therefore, in line with the justifications provided in the justification documents #34 and #35, the MAH is of the opinion that the following paragraphs currently included in section 4.4 and 4.8 of the CSP must be deletedSection 4.4: “A meta-analysis from 54 epidemiological studies reported that there is a slightly increased relative risk (RR = 1.24) of having breast cancer diagnosed in women who are currently using combined oral contraceptives (COCs), mainly using estrogen-progestogen preparations. The excess risk gradually disappears during the course of the 10 years after cessation of COC use. Because breast cancer is rare in women under 40 years of age, the excess number of breast cancer diagnoses in current and recent COC users is small in relation to the overall risk of breast cancer. The risk of having breast cancer diagnosed in progestogen-only pill users is possibly of similar magnitude to that associated with COC. However, for progestogen-only preparations, the evidence is based on much smaller populations of users and so is less conclusive than that for COCs. These studies do not provide evidence for causation. The observed pattern of increased risk may be due to an earlier diagnosis of breast cancer in OC users, the biological effects of OCs or a combination of both. The breast cancers diagnosed in ever-users tend to be less advanced clinically than the cancers diagnosed in never-users.”

Deletion of the text in 4.8 (for women of fertile age):“Cases of breast cancer have been reported (frequency unknown, see section 4.4"Special warnings and special precautions of use").”

Assessor's comment:The proposal is declined. This wording has also been retained in the most recent UK variation.

MAH’s response dated 18 October 2012.The Assessor refers to the UK national SPC that was recently updated following avariation filed by the MAH. During this variation procedure, the UK authorityinsisted on updating the UK SPC with the above wording. The MAH did not agree tothe authority's decision; however the MAH had to accept this request as a local,national deviation in the UK. However, for the scientific and medical reasonsoutlined earlier during this procedure, the MAH is of the opinion that such a warningis not justified and should not be included in the CSP.Please also refer to our previous argumentation above.

Assessor's comment:Once again, the breast cancer warning represents a "class-effect" warning for hormonal contraceptives. There is not enough evidence to justify deletion of the warning.

15) chloasmaMAH's comment:Please refer to the respective document of the MAH. In summary, the MAH states that the inclusion of the warning as demanded by the PRMS is not considered adequate by the company. As there is currently no conclusive evidence that the use of Mirena would cause the occurrence of chloasma, chloasma should not be included in section 4.4 and 4.8 of the proposed CSP.

Assessor's comment:In view of the evidence gathered and the biological plausibility, chloasma is added to section 4.8 of the SPC. A respective warning in 4.4 (as within the Irish SPC) may be considered on a national basis.

16 ) Ovarian CystsMAH’s comment:Please refer to the respective response of the MAH. In summary, the MAH is not willing to include the following statement in the CSP.

“Mirena may be used with caution in women with past history of symptomatic functional ovarian cysts.”

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Assessor’s comment:The sentence was proposed in accordance with the UK SPC. However, it is proposed that this sentence can be dealt with on a national basis.

19) Breast cancer and protection from endometrial hyperplasia during estrogenreplacement therapy MAH’s comment dated April 2012:Please refer to the respective response of the MAH. In summary, the MAH states:The company agrees to include a warning regarding breast cancer in Section 4.4 of the CSP referring to post-menopausal women when Mirena is used in the indication protection from endometrial hyperplasia during estrogen replacement therapy. As pointed out in the response to item 9 in this document, there is no evidence to support a causal association between Mirena use and breast cancer induction or promotion in women of fertile age. This conclusion is based on the available epidemiological data onMirena use and breast cancer risk, which is consistent in showing no increased risk (justification documents #34 and #35).However, as stated in the provided justification document #33, in women using Mirena with concomitant estrogen replacement therapy for climacteric symptoms, the data is inconclusive. The company is of the opinion that section 4.8 of the CSP should contain the following information, to be included in the national labels if applicable:“The risk of breast cancer is unknown when Mirena is used in the indication protection from endometrial hyperplasia during estrogen replacement therapy. Cases of breast cancer have been reported (frequency unknown, see Section 4.4 Special warnings and special precautions of use).”

Assessor’s comment:The assessor is of the opinion that there is clear evidence that the risk of breast cancer is increased in post-menopausal women using systemic (i.e. oral or transdermal) hormone replacement therapy (HRT). In addition, this risk is higher with combined oestrogen-progestogen HRT than with oestrogen only HRT.

The assessor likes to point out that an increased risk of breast cancer has been shown in women using Mirena for endometrial protection during estrogen replacement therapy for climacteric symptoms (Estradiol plus LNG: RR 2,07 (1,78-2,41) compared to non-users2). It is acknowledged that there are some limitations with regard to the study, however, the assessor is of the opinion that an increased risk for Mirena cannot be excluded. A wording stating that the risk of Mirena is unknown when used in conjunction with estrogens for HRT implies that there may be a risk but there may also be no risk. This is not considered an adequate reflection of the current evidence.

Hence, the following wording is proposed with the sentence in brackets to be implemented on a national basis.

Risk in post-menopausal women (only if applicable, i.e. Mirena authorized for providing the progestogen component for HRT)The risk of breast cancer is increased in post-menopausal women using systemic (i.e. oral or transdermal) hormone replacement therapy (HRT). This risk is higher with combined oestrogen-progestogen HRT than with oestrogen only HRT. [The following sentence may be added on a national basis: The risk of breast cancer when Mirena is prescribed to provide the progestogen component of HRT is not yet known.] The product information of the oestrogen component of the treatment should also be consulted for additional information.

20) Previous (UK) comment on fertilityPrevious UK comment:The following wording is to be included in the UK SPC: “Studies have suggested that in women who discontinue Mirena for planned pregnancy the pregnancy rate at one year is similar to those who do not use contraception.”

2 Lyytinen HK et al. A case-control study on hormone therapy as a risk factor for breast cancer in Finland: Intrauterine system carries a risk as well. Int J Cancer. 2010 Jan 15;126(2):483-9.

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Assessor’s comment:The assessor feels that this comment is not related to safety in particular and proposes that this comment may be added on a national basis.

21) Fatal streptococcus sepsisDuring the current assessment procedure disproportionate reporting concerning (fatal) cases of streptococcus sepsis has been observed in the UK database. Since cases with fatal outcome have been reported and sepsis is a serious condition the MAH is requested to look at this once again in some more detail. It is noted that this issue has been addressed by the MAH in the beginning of this procedure in 2011 (see page 10 of the AR). However, the disproportionate reporting was observed only recently and it is preferred to update the assessment concerning this issue and to finalize it in the ongoing PSUR-WS procedure.

There is considerable advice and information concerning the sterile insertion of Mirena and pelvic infection in the German SPC. Local infections (endometritis, PID) are labelled in the CSP whereas sepsis as a systemic infection is not labelled.

However, the MAH is also asked to comment in the MAH’s assessment whether changes to the CSP are considered necessary.

It is proposed that the MAH re-addresses this issue and sends his updated assessment until 5 October 2012.

MAH’s response dated October 2012

This topic has been under monitoring by the MAH and has repeatedly been discussed inthe PSURs for Mirena, including the 25th PSUR. Triggered by new information receivedwithin these monitoring activities, an update of the previous assessments including asystematic review of all available safety data on the topic has been performed by theMAH. The MAH considers that the available safety data indicates that an upper genitaltract infection occurring in association with the insertion of an IUD may be extremelyrarely complicated by a sepsis (including invasive group A streptococcal sepsis). Theevidence is based on isolated cases described in the medical literature and derived fromspontaneous postmarketing reports. The true incidence of this event cannot be estimatedbased on the available data.In light of the accumulated evidence from postmarketing data, the inclusion of a warningon sepsis in addition to the existing PID-related warning in section 4.4 of the MirenaCCDS is considered justified in order to raise the awareness of the health careprofessional to this particularly severe condition. In line with the applicable guidance forlabeling, information of the occurrence of sepsis, including group A streptococcal sepsis,should be included in the post marketing text of section 4.8 of the Mirena CCDS.The following changes are proposed in section 4.4 ‘Special warnings and precautions foruse’ and 4.8 ‘Undesirable effects’ of the CSP for Mirena:Section 4.4 Special warnings and precautions for usePelvic infectionThe insertion tube helps to prevent Mirena from contamination with micro-organismsduring the insertion and the Mirena inserter has been designed to minimize the risk ofinfections. In users of copper intrauterine devices (IUDs), the highest rate of pelvicinfections occurs during the first month after insertion and decreases later. Known riskfactors for pelvic inflammatory disease are multiple sexual partners. Pelvic infectionmay have serious consequences and it may impair fertility and increase the risk ofectopic pregnancy. As with other gynecological or surgical procedures, severe infectionor sepsis (including group A streptococcal sepsis) can occur following IUD insertion,although this is extremely rare.If the woman experiences recurrent endometritis or pelvic infections or if an acuteinfection is severe or does not respond to treatment within a few days, Mirena must beremoved.Section 4.8 Undesirable effects (4.8.3 Description of selected adverse reactions)

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Infections and InfestationsCases of sepsis (including group A streptococcal sepsis) have been reported followingIUD insertion (see section 4.4 Special warnings and precautions for use).Please refer to the JD #39 attachedThis update does not change the overall positive benefit - risk balance for Mirena.

Assessor’s comment:Agreed.

Additional comment by the assessor: 1) The following sentence has been added to section 4.2 of the CSP in order to ensure that only

experienced/trained health care professionals would insert Mirena: “It is strongly recommended that Mirena should only be inserted by physicians (midwifes/healt care professionals (as appropriate)) who are experienced with regard to the insertion of Mirena or who have been sufficiently trained”.

MAH’s response dated April 2012:The MAH agrees that only experienced/trained health care professionals should insert Mirena. It is also agreed that a respective statement should be included in 4.2 although this chapter is not necessarily part of the CSP. The MAH proposes to include the statement as included in the Core Data Sheet as this reflects the necessity for experience and training appropriately:

“It is strongly recommended that Mirena should only be inserted by physicians/health care professionals who are experienced in Mirena insertions and/or have undergone sufficient training for Mirena insertion.”

Assessor’s commentIssue resolved.

MAH’s response dated 18 October 2012:While the company and the Assessor mutually agree that the respective statement fromthe Core Data Sheet should be included in the CSP, the company wants to emphasizethat the suggested respective statement is slightly different worded.In order to prevent misunderstandings, the company wants to make the assessor aware of the exact statement intended to be included in the CSP:“It is recommended that Mirena should only be inserted by physicians /health careprofessionals who are experienced in Mirena insertions and/or have undergone sufficienttraining for Mirena insertion.”

Assessor's comment: The wording should contain the word "strongly" and should read:“It is strongly recommended that Mirena should only be inserted by physicians /health care professionals who are experienced in Mirena insertions and/or have undergone sufficient training for Mirena insertion.”

2) The contraindications in section 4.3 have been grouped (related contraindications) and the order has been changed according to the importance.

MAH’s response dated April 2012:The company agrees.

Assessor's comment:Issue resolved.

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3) The following sentence has been deleted from section 4.4 of the Mirena SPC since it was felt that this sentence does not contain relevant safety information: “Some studies suggest that the rate of pelvic infection in users of Mirena is lower than with copper IUDs.

MAH’s response dated April 2012:The company agrees.

Assessor's comment:Issue resolved.

4) The following sentence is contained in section 4.8 of the SPC: Very common undesirable effects ( 1/10) include uterine/vaginal bleeding including spotting, oligomenorrhea, amenorrhea and benign ovarian cysts.These ADRs are not listed in the ADR-table and should be included there with the frequency very common (respective column to be added). According to the SPC-GL all ADRs should be listed in the table. The MAH should provide sound reasoning in case of not including the ADRs also in the table. It is noted though, that ectopic pregnancy and breast cancer are addressed in a separate post-tabular text.

MAH’s response dated April 2012:The company agrees.

Assessor's comment:Issue resolved.

5) It would be difficult to incorporate the complete HRT-core SPC in the Mirena SPC in case Mirena is used for HRT. Rather it is proposed that a statement is added at a prominent place of the SPC (e.g. 4.1) that if Mirena is used in conjunction with an estrogen for HRT, the safety information of the estrogen also apply and should be followed.

MAH's response dated April 2012:The MAH agrees to this request. As this is safety related information important for use of Mirena, the MAH suggests to include a respective statement in section 4.4 of the CSP.“In case Mirena is used in conjunction with an estrogen for hormone replacement therapy, the safety information of the estrogen applies in addition and should be followed.”

Assessor’s comment:Issue resolved.

MAH response dated April 2012Correction of MistakeMAH's response dated April 2012:In the Mirena CSP section 4.6, subsection ‘Lactation’, the following paragraph was included by mistake:“Hormonal contraceptives are not recommended as first choice contraceptive method during lactation and progestogen-only methods are second choice after non-hormonal contraceptive methods.”

This wording is neither part of the common denominator of EU SPCs, the CCDS, nor is it based on any new data during the reporting period. The company apologizes for this mistake and wants to correct it in deleting this sentence from the Core Safety Profile. Further, current international contraceptive guidelines (WHO medical eligibility criteria for contraceptive use 2009) recommend the use of progestin-only methods, including Mirena, without restrictions after 3-4 weeks after delivery. There is convincing evidence from a randomized trial that use of Mirena does not affect lactation, or development and growth of the nursed infant, compared to non-hormonal method (Copper IUD, Shamaash et al 2005). Therefore the sentence of ‘hormonal methods not being recommended as first choice and progestin-only methods being recommended as second choice in lactating women’ is not applicable to Mirena and such statement should not be included in the CSP

Assessor’s comment:

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The WHO-elegibility criteria recommend use of Mirena in ≥ 4 weeks postpartum, irrespective whether the woman is breast feeding or not. In the SPC it is stated:“Postpartum insertions should be postponed until the uterus is fully involuted, however, not earlier than six weeks after delivery.”Therefore, the wording may be deleted from the CSP.

FINAL CONCLUSION (SUMMARY OF A-F)

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General In future WSPs the MAH should give an overview of all cases with fatal outcome from the overall

reporting period and should discuss these cases in detail. The MAH should continue to monitor cases with breast cancer and present an overview in the next

PSUR. For Jadelle the MAH should state if cases of breast cancer have been reported and if an inclusion of this ADR into section 4.8 of the CSP would be appropriate.

The MAH should continue to closely monitor cases with meningioma.

Mirena In future PSURs the MAH should present a cumulative overview on the topic endometrial carcinoma. In the next PSUR the MAH should continue to present a cumulative overview on abnormal pregnancy

outcomes. European Active Surveillance Study for Intrauterine Devices (EURAS IUD): ongoing since interval of

22nd PSUR. The MAH will provide the final results of this study in 2013. It cannot be excluded that depending on the study results further changes to the product information is deemed necessary.

It is noted that the Mirena CSP also encompasses section 4.2. In this respect the P-RMS would like to indicate that there is exhaustive information at the end of German Mirena SPC (section 11. (insertion)) concerning the insertion technique. These paragraphs have not been addressed in this procedure.

Fatal streptococcus sepsis

During the current assessment procedure disproportionate reporting concerning (fatal) cases of streptococcus sepsis has been observed in the UK database. Since cases with fatal outcome have been reported and sepsis is a serious condition the MAH is requested to look at this once again in some more detail. It is noted that this issue has been addressed by the MAH in the beginning of this procedure in 2011 (see page 10 of the AR). However, the disproportionate reporting was observed only recently and it is preferred to update the assessment concerning this issue and to finalize it in the ongoing PSUR-WS procedure.

There is considerable advice and information concerning the sterile insertion of Mirena and pelvic infection in the German SPC. Local infections (endometritis, PID) are labelled in the CSP whereas sepsis as a systemic infection is not labelled.

However, the MAH is also asked to comment in the MAH’s assessment whether changes to the CSP are considered necessary.

The MAH should re-address this issue and send his updated assessment until 5 October 2012. This is also the deadline of the comments of the CMS on the draft (2) final AR. Dependent on the comments of the CMS and the response of the MAH concerning the cases about streptococcus sepsis the P-RMS will inform about how to proceed.

Assessor’s comment:See item no. 21. Agreed.

Jadelle The MAH should continue to monitor the frequency of pregnancy reports to assure the effectiveness of

the re-training measures undertaken in Columbia. A cumulative analysis of pregnancy reports in Jadelle users is expected in next PSUR as well. Additionally, the MAH should give an overview of all cases with abnormal pregnancy outcomes.

CSPs: Changes to the CSP should be performed as outlined under F. Jadelle: It is noted that a CSP has been finalized for an etonogestrel implant (implanon) with the final

AR dated 10 May 2011. This etonogestrel implant is very similar to Jadelle (levonorgestrel implant). The MAH should perform a comparison of the final CSP for the etonogestrel implant with the proposed

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F Changes to the CSP of JadelleJadelle CSP / MAH’s response dated April 2012

Please refer to the respective response document.

Assessor’s comment:The assessor comments to selected aspects which are not agreed upon.

Liver diseaseJadelle CSP contraindication: Acute liver disease.Final CSP Etonogestrel implants: Presence or history of severe hepatic disease as long as liver function values have not returned to normal.

Assessor’s comment: Whereas the MAH does not see a difference contentwise the assessor is of the opinion that “acute liver disease” does not cover the situation of a history of severe hepatic disease as long as liver function values have not returned to normal. Therefore, the wording from the etonogestrel CSP should be implemented in the Jadelle CSP.

development of arterial hypertensionFinal CSP Etonogestrel implants: If a sustained hypertension develops during the use of <product name>, or if a significant increase in blood pressure does not adequately respond to antihypertensive therapy, the use of <product name> should be discontinued

Proposed Jadelle CSP: not addressed in 4.4 MAH: Suggest no change: hypertension is an expected ADR and therefore included in ADR table in 4.8., an additional warning is not warranted

Assessor’s comment:The respective wording should be implemented in the Jadelle CSP in 4.4. Reasoning: The warning is also contained in the Mirena CSP and Mirena has lower systemic plasma concentrations than Jadelle.

ChloasmaFinal CSP Etonogestrel implants: Chloasma may occasionally occur, especially in women with a history of chloasma gravidarum. Women with a tendency to chloasma should avoid exposure to the sun or ultraviolet radiation whilst using <product name>.

Jadelle CSP: currently not addressed in particular. However, skin discoloration is mentioned in 4.8.

MAH: Suggest no change: there is no evidence for an association of chloasma with levonorgestrel-only contraceptives. See also MAH's response on Mirena and chloasma.

Assessor’s comment:Section 4.4: In analogy with the Mirena CSP, a warning concerning chloasma can be dealt with on a national basis. Section 4.8: Chloasma should be added to the post-tabular text informing about ADRs (see CSP).“The occurrence of chloasma has been reported with the use of other levonorgestrel implants”.

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Reasoning: Chloasma has been observed with Mirena-use.

Gynecological cancersProposed Jadelle CSP: There is no confirmed evidence of an increased risk of gynecological cancers associated with the use of hormonal contraceptives. Clinical surveillance of all women using JADELLE® is, nevertheless, recommended.

Assessor’s comment:There is confirmed evidence of gynecological cancers associated with the use of hormonal contraceptives, e.g. with regard to breast cancer. Hence, this sentence is deleted. Furtheron, clinical surveillance of women using Jadelle is recommended in general anyway. Hence, this sentence is also deleted.

4.8 Frequently reported ADRsJadelle CSP: In the pre-tabular text it reads:Very common undesirable effects (occurring in more than 10% of users):Disturbance of menstrual bleeding patterns, such as frequent, irregular or prolonged menstrual bleeding, spotting, oligomenorrhea or amenorrhea, are the most common undesirable effects, occurring in the majority of users during the first year. 14% of users discontinued the use of JADELLE® because of bleeding pattern disturbances during five years. Other very common undesirable effects are: headache, nervousness, dizziness, nausea, cervicitis, vaginal discharge, genital pruritus, pelvic pain, breast pain, cervicitis, vaginal discharge, genital pruritus, pelvic pain, breast pain.

Assessor’s comment:These frequently occurring ADRs are currently not contained in the ADR table and are therefore added to the ADR table with the frequency description very common.

DATE AND CONCLUSION OF PHVWP DISCUSSION CONCERNING THIS PSUR, IF ANY:

Annex I : CSP Proposed CSP for Mirena and Jadelle

Annex III: COMMENTS ON THE PSUR (annex exclusively for innovator MAH)

Is the PSUR in accordance with international guidelines (CIOMS II, Volume 9A) ?

Yes No

If not, specify non-conformance with the guidelines

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