Public Assessment Report - GOV.UK · PAR Levosert 20microgram/24 hours Intrauterine Delivery System UK/H/ 3030/001/DC 1. Public Assessment Report . Decentralised Procedure . LEVOSERT

PAR Levoser t 20microgram/24 hours Intrauter ine Delivery System UK/H/3030/001/DC

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Public Assessment Report

Decentralised Procedure

LEVOSERT 20MICROGRAM/24 HOURS INTRAUTERINE DELIVERY SYSTEM

(levonorgestrel)

Procedure No: UK/H/3030/001/DC

UK Licence No: PL 30306/0438

ACTAVIS GROUP PTC ehf


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LAY SUMMARY

Levosert 20 microgram/24 hours Intrauterine Delivery System (levonorgestrel, intrauterine delivery system, 52mg (20 micrograms/24 hours))

This is a summary of the Public Assessment Report (PAR) for Levosert 20 microgram/24 hours Intrauterine Delivery System (PL 30306/0438; UK/H/3030/001/DC, previously PL 34096/0003; UK/H/3030/001/DC). It explains how Levosert 20 microgram/24 hours Intrauterine Delivery System was assessed and its authorisation recommended, as well as its conditions of use. It is not intended to provide practical advice on how to use Levosert 20 microgram/24 hours Intrauterine Delivery System. For practical information about using Levosert 20 microgram/24 hours Intrauterine Delivery System, patients should read the package leaflet or contact their doctor or pharmacist. Levosert 20 microgram/24 hours Intrauterine Delivery System may be referred to as Levosert in this report. What is Levosert and what is it used for? Levosert is an intrauterine delivery system (IUS) for insertion in the womb. It can be used in the following ways: • as an effective method of contraception (prevention of pregnancy); • for heavy menstrual bleeding (heavy periods). Levosert is also useful for reducing menstrual blood

flow, so it can be used if you suffer from heavy menstrual bleeding (periods). This is called menorrhagia.

Levosert is a ‘hybrid generic medicine’. This means that Levosert is similar to a reference medicine already authorised in the European Union (EU) and it is a locally acting product, available as a Levonorgestrel Intrauterine delivery system (IUS). The reference medicine is Mirena, 52 mg – 20 µg/24h Intrauterine Delivery System, which was first granted in Finland to Bayer Schering Pharma Oy on 05 May 1990. Mirena is an intrauterine system (IUS) placed inside the womb (uterus) where it slowly releases the hormone levonorgestrel. It can be used in the following three ways: 1. As an effective long-term and reversible method of contraception. 2. For reducing menstrual blood flow, if the patient suffers from heavy periods (heavy menstrual bleeding). It can be used for contraception and heavy menstrual bleeding until it is removed or up to a maximum of 5 years. How does Levosert work? Levosert prevents pregnancy by controlling the monthly development of the womb lining so that it is not thick enough for pregnancy to occur; by making the normal mucus in the opening to the womb (the cervical canal) thicker so that the sperm cannot get through to fertilise the egg; by preventing the release of eggs (ovulation) in some women. There are also local effects on the lining of the womb caused by the presence of the T-shaped frame. The hormone in Levosert, levonorgestrel, acts by controlling the monthly development of the womb lining, making it thinner, so that there is less bleeding every month.


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How is Levosert used? Levosert 20 microgram/24 hours Intrauterine Delivery System is fitted by a doctor or specially trained nurse into the uterus (womb) where it slowly releases the hormone levonorgestrel over a period of 3 years or until it is removed. Please read section 3 of the Patient Information Leaflet (available on the MHRA website) for detailed information on dosing recommendations, the route of administration, and the duration of treatment. Levosert can only be obtained with a prescription. What benefits of Levosert have been shown in studies? As Levosert is a hybrid application and is considered to be therapeutically equivalent, to the reference product Mirena, the benefits and risks are taken as being the same as those of the reference medicine. What are the possible side effects from Levosert? Like all medicines, this medicine can cause side effects, although not everybody gets them. With Levosert, side effects are most common during the first months after the system is fitted and decrease as time goes on. Severe pain or fever developing shortly after insertion may mean that the patient has a severe infection which must be treated immediately. In rare cases very severe infection (sepsis) can occur. The doctor should be contacted immediately if you experience such side effects (see Patient Information Leaflet, Section 2 Warnings and Precautions). Very common (affects more than 1 in 10 women) side effects can include: - menstrual changes. You might experience spotting, shorter or longer periods, painful periods. Though

Levosert usually achieves a significant reduction in menstrual blood loss in 3 to 6 months of treatment, you may have an increase in bleeding, usually in the first 2 to 3 months, before a reduction in blood loss is achieved. Periods can totally disappear. If a significant reduction in blood loss is not achieved after 3 to 6 months, alternative treatments should be considered.

- ovarian cysts. They are fluid-filled sacs in the ovary. Common (may affect up to 1 in 10 women) side effects can include: - bloating or swelling of your legs or ankles; - weight gain; - depression, nervousness or other mood changes; - headache; - abdominal, pelvic or back pain; - feeling sick (nausea); - spots (acne); - painful periods; - increased vaginal discharge; - inflammation of the neck of the womb (cervicitis); - tender, painful breasts; or - Levosert coming out by itself. Uncommon (may affect up to 1 in 100 women) side effects can include: - genital infections that may cause: vaginal itching; pain on passing urine; or lower abdominal (tummy)

pain from inflammation of the womb, ovaries or Fallopian tubes; - increased growth of hair on the face and body; - hair loss; or - itchy skin (pruritus).


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Rare (may affect up to 1 in 1000 women) side effects can include: - reduced sex drive; - migraine; - bloated abdomen; - rashes, itching, eczema; or - the wall of the womb torn when Levosert is fitted. Why is Levosert approved? It was concluded that, in accordance with EU requirements, Levosert has been shown to have comparable quality and to be therapeutically equivalent to Mirena 52mg - 20 micrograms/24 hours Intrauterine Delivery System (Schering). It was therefore considered that, as for Mirena 52mg - 20 micrograms/24 hours Intrauterine Delivery System (Schering), the benefits outweigh the identified risks and the grant of the Marketing Authorisation was recommended. What measures are being taken to ensure the safe and effective use of Levosert? A Risk Management Plan has been developed to ensure that Levosert is used as safely as possible. Based on this plan, safety information has been included in the Summary of Product Characteristics and the package leaflet for Levosert, including the appropriate precautions to be followed by healthcare professionals and patients. Known side effects are continuously monitored. Furthermore new safety signals reported by patients/healthcare professionals will be monitored/reviewed continuously as well. Other information about Levosert. A Marketing Authorisation (Levosert 20 microgram/24 hours Intrauterine Delivery System (PL 34096/0003; UK/H/3030/001/DC) was granted in the UK on 28 December 2012. Subsequent to a Change of Ownership procedure, the Marketing Authorisation (PL 30306/0438; UK/H/3030/001/DC) was granted in the UK to Actavis Group PTC ehf on 18 September 2013. The full PAR for Levosert follows this summary. For more information about treatment with Levosert read the package leaflet, or contact your doctor or pharmacist. This summary was last updated in December 2014.


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TABLE OF CONTENTS

Module 1: Information about initial procedure Page 6 Module 2: Summary of Product Characteristics Page7 Module 3: Patient Information Leaflets Page 8 Module 4: Labelling Page 9 Module 5: Scientific Discussion Page 11 I Introduction II About the Product III Scientific Overview and Discussion III.1 Quality aspects III.2 Non-clinical aspects III.3 Clinical aspects IV Overall conclusions Module 6 Steps taken after initial procedure Page 21 Annex 1 Page 22


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Module 1 Information about the initial procedure

Product Name

Levosert 20 microgram/24 hours Intrauterine Delivery System

Type of Application

Hybrid, Article 10(3)

Active Substance

Levonorgestrel

Form

Intrauterine delivery system

Strength

52mg levonorgestrel

MA Holder

Mithra Pharmaceuticals SA, rue Saint Georges 5-7, Liege, B-400, Belgium

Reference Member State (RMS)

UK

Concerned Member States (CMS)

Bulgaria, Czech Republic, Hungary, Lithuania, Latvia, Poland, Romania, Slovakia

Procedure Number

UK/H/3030/001/DC

Timetable

Day 210 – 14 November 2012


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Module 2 Summary of Product Characteristics

The current approved UK version of the Summary of Product Characteristics (SmPC) for this product is available on the MHRA website.


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Module 3 Patient Information Leaflet

The current approved UK version of the Patient Information Leaflet (PIL) for this product is available on the MHRA website.


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Module 4 Labelling


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Module 5 Scientific discussion during the initial procedure

I INTRODUCTION Based on the review of the data on quality, safety and efficacy, the member states considered that the application for Levosert 20 microgram/24 hours Intrauterine Delivery System (PL 34096/0003; UK/H/3030/001/DC) could be approved. This application was submitted via the Decentralised Procedure, with the UK as Reference Member State (RMS), and Bulgaria, Czech Republic, Hungary, Lithuania, Latvia, Poland, Romania, and Slovakia as Concerned Member States (CMS). This is a prescription-only medicine, indicated for heavy menstrual bleeding. This was an application made under the Decentralised Procedure (DCP), according to Article 10(3) of Directive 2001/83/EC, as amended, claiming to be a hybrid medicinal product of the originator product Mirena 52mg – 20microgram/24 hours Intrauterine Device, which was initially granted in Finland to Bayer Schering Pharma Oy in May 1990. Levosert is a levonorgestrel-releasing Intrauterine System (LNG-IUS) containing 52 mg of levonorgestrel in a cylindrical-shaped silastic reservoir. The reservoir is mounted on the vertical arm of a T-shaped polyethylene frame and is covered with a release-rate-controlling polydimethylsiloxane membrane. This drug delivery system releases LNG at an initial release-rate of approximately 20 µg per day in vivo. After insertion in the uterus, the product will release LNG directly and continuously for up to five years. No new non-clinical studies were conducted, which is acceptable given that this is a hybrid application cross-referring to a product that has been licensed for over 10 years. With the exception of the bioequivalence study, no new clinical studies were conducted and none are required for this application. A single study was submitted to show the therapeutic equivalence of the proposed product to Mirena 52mg - 20microgram/24 hours Intrauterine Device (Bayer SA, Belgium). The RMS has been assured that acceptable standards of Good Manufacturing Practice are in place for these product types at all sites responsible for the manufacture, assembly and batch release of this product. The RMS and CMS considered that the application could be approved with the end of procedure (Day 210) on 14 November 2012. After a subsequent national phase, the licence was granted in the UK on 28 December 2012. Subsequent to a Change of Ownership procedure, the Marketing Authorisation (PL 30306/0438; UK/H/3030/001/DC) was granted in the UK to Actavis Group PTC ehf on 18 September 2013.


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II. ABOUT THE PRODUCT Name of the product in the Reference Member State

Levosert 20microgram/24 hours Intrauterine Delivery System

Name(s) of the active substance(s) (INN) Levonorgestrel Pharmacotherapeutic classification (ATC code)

Intrauterine contraceptives (G02 BA)

Pharmaceutical form and strength(s) 52mg levonorgestrel Reference numbers for the Mutual Recognition Procedure

UK/H/3030/001/DC

Reference Member State United Kingdom Member States concerned Bulgaria, Czech Republic, Hungary,

Lithuania, Latvia, Poland, Romania, and Slovakia

Marketing Authorisation Number(s) PL 34096/0003 Name and address of the authorisation holder Mithra Pharmaceuticals SA, rue Saint

Georges 5-7, Liege, B-4000, Belgium


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III SCIENTIFIC OVERVIEW AND DISCUSSION III.1 QUALITY ASPECTS S. Active substance – Levonorgestrel rINN: Levonorgestrel Chemical name: 13β-ethyl-17β-hydroxy-18,19-dinor-17α-pregn-4-en-20-yn-3-one Structure:

Molecular formula: C21H28O2 Molecular weight: 312.45 g.mol-1 Appearance: A white to almost-white crystalline powder Solubility: Practically insoluble in water, sparingly soluble in methylene chloride, slightly

soluble in alcohol Levonorgestrel is the subject of a European Pharmacopoeia monograph. With the exception of the packaging and the retest period, all aspects of the manufacture and control of the active substance is covered by a European Directorate for the Quality of Medicines Certificate of Suitability. Suitable specifications have been provided for all packaging used. The primary packaging has been shown to comply with current guidelines concerning contact with food. Appropriate stability data have been generated supporting a suitable retest period when stored in the proposed packaging. P. Medicinal Product Other Ingredients Other ingredients consist of the pharmaceutical excipients, namely silicon base, tetra-n-propyl silicate, stannous octoate, polydimethylsiloxane elastomer, polydimethylsiloxane tubing, polyethylene T-frame (with 20-24% barium sulphate), polypropylene thread, copper phthalocyanine blue. All excipients comply with suitable in-house specifications. Suitable batch analysis data have been provided for all excipients, showing compliance with their respective specifications. None of the excipients are sourced from animal or human origin. No genetically modified organisms (GMO) have been used in the preparation of this product. Pharmaceutical Development The objective of the development programme was to formulate a globally acceptable, stable and bioequivalent product to the originator product Mirena 52mg – 20microgram/24 hours Intrauterine Device (Bayer Schering Pharma Oy, Finland). A satisfactory account of the pharmaceutical development has been provided. Comparative physico-chemical characteristics have been provided for the proposed product versus the originator product.


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Manufacturing Process Satisfactory batch formulae have been provided for the manufacture of the finished product. The manufacturing process has been validated using industrial-scale batches and has shown satisfactory results. Finished Product Specification The finished product specification proposed is acceptable. Test methods have been described and have been adequately validated. Batch data have been provided and comply with the release specifications. Certificates of analysis have been provided for all working standards used. Container-Closure System The product is individually packed with an inserter device into a thermoformed blister (polyester) package with a peelable lid (TYVEK-Polyethylene). Satisfactory specifications and Certificates of Analysis have been provided for all packaging components. All primary packaging complies with current European regulations. Stability of the product Stability studies were performed in accordance with current guidelines on batches of finished product packed in the packaging proposed for marketing. The data from these studies support a shelf-life of 48 months, with the storage conditions “Store in the original package.” Bioequivalence/bioavailability A single study was submitted to show the therapeutic equivalence of the proposed product to Mirena 52mg - 20microgram/24 hours Intrauterine Device (Bayer SA, Belgium). Summary of Product Characteristics (SmPC), Patient Information Leaflet (PIL) and Labels The SmPC, PIL and labels are acceptable from a pharmaceutical perspective. A package leaflet has been submitted to the MHRA along with results of consultations with target patient groups (‘user testing’), in accordance with Article 59 of Council Directive 2001/83/EC, as amended. The results indicate that the package leaflet is well-structured and organised, easy to understand and written in a comprehensive manner. The test shows that the patients/users are able to act upon the information that it contains. Marketing Authorisation Application (MAA) form The MAA form is satisfactory from a pharmaceutical perspective. Quality Overall Summary (Expert report) The pharmaceutical expert report has been written by an appropriately qualified person and is a suitable summary of the pharmaceutical dossier. Conclusion The grant of a Marketing Authorisation is recommended. III.2 NON-CLINICAL ASPECTS As the pharmacodynamic, pharmacokinetic and toxicological properties of levonorgestrel are well-known, no further non-clinical studies are required and none have been provided. The applicant’s non-clinical expert report has been written by an appropriately qualified person and is satisfactory, providing an appropriate review of the product’s pharmacology and toxicology. The environmental risk assessment has concluded that the finished product does not appear to cause a


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significant environmental concern because the estimated amount of levonorgestrel to be released in the environment by each patient following use of the product is extremely low. Further, it also states that levonorgestrel is a well-established progestogen drug that has undergone thorough toxicological evaluation. The non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction. This is acceptable. There are no objections to the approval of this product from a non-clinical viewpoint. III.3 CLINICAL ASPECTS Clinical Pharmacology and Efficacy With the exception of the below bioequivalence study, no clinical studies have been conducted to support the application. A multicenter, randomised, parallel-group, single-blind, 12-month clinical trial, to assess the therapeutic equivalence of efficacy and safety of test product (Levosert 20 microgram/24 hours Intrauterine Delivery System) and reference product (Mirena 52mg – 20microgram/24 hours Intrauterine Device) in subjects with menorrhagia. Each subject entered a 99-day (three completed menstrual cycles) run-in period to check they met inclusion criteria, followed by a treatment period of 12 months (using either the test or reference product). Some subjects were further enrolled into a 24-month extension period. The primary efficacy endpoint was the mean change in menstrual blood loss from baseline to Visit 5 (54 weeks) for each treatment group, using the previously validated modified Wyatt pictogram. The secondary efficacy and safety endpoints were: • Residual levonorgestrel amount in the intrauterine devices in the two treatment groups, given as

diffusion rate • Serum level of levonorgestrel in the two treatment groups. • Mean change from baseline to Visit 5 in weight in the two treatment groups • Mean change from baseline to Visit 5 in hemoglobin in the two treatment groups • Mean change from baseline to Visit 5 in ferritin in the two treatment groups • Occurrence of evaluable untoward drug reactions in the two treatment groups • Contraception level in the two treatment groups and contraceptive effect of Levosert • Mean reduction in blood loss from baseline to intermediate cycle in the two treatment groups The Intent-to-Treat (ITT) population included all randomized patients who underwent the insertion of Levosert or Mirena and had at least one study related evaluation. The Per Protocol (PP) population included all randomized patients included in the ITT population and who did not have any major protocol deviation. That is all ITT subjects who: (1) met all the inclusion criteria; (2) not met any of the exclusion criteria; (3) completed the study without any major protocol deviations. The Safety Population included all patients who had at least one insertion attempt of study treatment.


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Results Primary efficacy variable – Mean blood loss The individual blood loss values for all the patients were listed by cycles. The last observation carried forward (LOCF) technique was employed to handle missing data up to Visit 5. Mean change from baseline to Visit 5 (Week 52) in blood loss for the ITT and PP populations is presented below.

The one-sided hypothesis of non-inferiority was tested a significance level of 0.025. For both populations, the null hypothesis was rejected in favour of the alternative hypothesis. The estimated significance (p-value) for PP population was 0.00067, and for ITT population was 0.00391. These are presented in the table below.

Points estimates and 95% confidence intervals for ratio are presented in the below figure.

Assessor’s comment There was a significant decrease in mean menstrual blood loss for both treatment groups from baseline to Visit 5 (54 weeks). From the results obtained, the test product appears to be similar to the reference product in terms of efficacy. Secondary efficacy variables Residual amount of levonorgestrel As a measure for residual amount of levonorgestrel, diffusion rate was used (μg/24 hours). The two treatments showed equivalent diffusion rates in both PP and ITT populations, as shown in the tables below. The number of subjects for this endpoint was reduced for both populations: 70 patients from all randomized subjects (35 on test product and 35 on reference product) have been included in the study extension.


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ITT Population:

Per-Protocol Population:

Assessor’s comment The rate of diffusion appears to be similar in both the reference and test product. Serum levels of levonorgestrel The table below shows the statistical analysis output for comparison of levonorgestrel concentrations in the two arms. The mean difference at Visit 5 was -5.871 ng/l, which was not statistically significant (p=0.8485).

Assessor’s comment There appears to be no difference in serum levonorgestrel levels at the end of 52 weeks. Clinical Safety In the above study, 142 women were exposed to Levosert and 126 completed the 1-year treatment period in the study. The exposure was increased by 2 years in 70 women (35 with Levosert) participants in the extension phase and 27 completed the 36 months’ treatment period.


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The safety analysis was performed on the safety population of the bioequivalence study, which consisted of 280 subjects, 141 received test product Levosert and 139 received reference product Mirena. Additionally, as of 4 November 2011, 760 subjects had received test product Levosert and 159 subjects had received reference product Mirena in a separate US study. A total number of 628 adverse events were recorded in 229 patients (81.79% of overall 280) – 112 (48.91%) of them were randomised to test product Levosert and 117 (51.09%) to reference product Mirena. For the patients participating to the extension phase of the study, a total number of 276 adverse events in 65 patients (92.86% of overall 70) – 31(47.69%) of them were randomised to test product Levosert and 34 (52.31%) to reference product Mirena, were recorded during the entire study period (3 years). The most frequent drug-related adverse event in bioequivalence study was "prolonged menstrual cycle", followed by spotting between menses and amenorrhea. Ovarian cysts were reported by 21 subjects treated with test product Levosert and by 23 subjects treated with reference product Mirena. In the test product Levosert group, 12 subjects reported post procedural pain while 9 subjects reported this adverse event in the reference product Mirena group. In the separate US study, the most frequent drug-related adverse event was “acne”. In the bioequivalence study there were five serious adverse events reported during the main phase, all of them in the test product Levosert group, four were estimated as unrelated and one (ovarian cyst) was estimated as possibly related (but expected) to treatment. There were two serious adverse events reported during the 2-year extension of the trial. One of them (ovarian cyst) occurred in subject receiving test product Levosert. The other serious adverse event (submucous leiomyoma of uterus) occurred in a subject receiving the reference product Mirena and was considered as unlikely related to the study treatment. Both recovered completely. In the US study, there have been twenty-three serious adverse events in nineteen subjects by 04 November 2011; three subjects accounted for a total of 10 serious adverse events. Twenty of these serious adverse events were in the test product Levosert group and three in the reference product Mirena group. All serious adverse events were deemed as either not related or unlikely related to the intrauterine device/procedure by both the investigator and sponsor. Insertion-related problems There were no reported insertion related problems for either the test product Levosert or the reference product Mirena in the bioequivalence study. Although no data were directly captured for insertion-related problems, none were reported as adverse events. In the ongoing US study, some insertion related difficulties have been recorded. The IUD is more widely used almost everywhere in Europe than in the United States and one can conclude that a European investigator is likely to be more familiar using a two-handed insertion system than a US investigator. An active post marketing program on insertion related difficulties will be initiated with the launch of the product. SmPC, PIL and Labels The SmPC, PIL and labels are acceptable from a clinical perspective. The SmPC is consistent with that for the originator product. MAA Form The MAA form is acceptable from a clinical perspective.


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Pharmacovigilance System and Risk Management Plan The Pharmacovigilance System, as described by the applicant, fulfils the requirements and provides adequate evidence that the applicant has the services of a qualified person responsible for pharmacovigilance, and has the necessary means for the notification of any adverse reaction suspected of occurring either in the Community or in a third country. A satisfactory Risk Management Plan has been submitted for the product. The following list of safety concerns have been identified : Uterine perforations, Ectopic pregnancy, Insertion related difficulties, Pelvic inflammatory disease, Ovarian cysts, Menstrual changes, unintended pregnancy with IUS in situ, expulsion of device, breast cancer and off label use. Appropriate pharmacovigilance and risk minimisation activities have been addressed. Clinical Expert Report The clinical expert report has been written by an appropriately qualified physician and is a suitable summary of the clinical aspects of the dossier. Conclusion The grant of a Marketing Authorisation is recommended. IV OVERALL CONCLUSION AND BENEFIT-RISK ASSESSMENT QUALITY The important quality characteristics of Levosert 20 microgram/24 hours Intrauterine Delivery System (PL 34096/0003; UK/H/3030/001/DC) are well-defined and controlled. The specifications and batch analytical results indicate consistency from batch to batch. There are no outstanding quality issues that would have a negative impact on the benefit-risk balance. NON-CLINICAL No new non-clinical data were submitted and none are required for an application of this type. CLINICAL With the exception of the non-inferiority bioequivalence study, no new clinical data have been submitted in support of this application. This non-inferiority study was carried out to demonstrate therapeutic non-inferiority of test product Levosert 20 microgram/24 hours Intrauterine Delivery System versus Mirena 20microgram/24 hours Intrauterine Delivery System in the treatment of heavy menstrual bleeding; this is acceptable and in line with guidance. The results of the study showed a significant decrease in mean menstrual blood loss in both test and reference products, with the test product Levosert demonstrated to be statistically non-inferior to the reference product Mirena. The results also showed similar residual levels of levonorgestrel in both groups and similar serum levels of levonorgestrel, suggesting comparable pharmacokinetics up to 1 year. No new or unexpected safety concerns arose from this application. The SmPC, PIL and labelling are satisfactory and consistent with those for the reference product Mirena 20 microgram/24 hours Intrauterine Delivery System. BENEFIT-RISK ASSESSMENT The quality of the product is acceptable and no new non-clinical or clinical safety concerns have been identified. The bioequivalence (non-inferiority) study supports the claim that the applicant’s product Levosert 20 microgram/24 hours Intrauterine Delivery System and the reference product Mirena 20microgram/24 hours Intrauterine Delivery System are interchangeable. Extensive clinical experience


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with levonorgestrel is considered to have demonstrated the therapeutic value of the active substance. The benefit/risk ratio is considered to be positive.


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Module 6

STEPS TAKEN AFTER THE INITIAL PROCEDURE - SUMMARY

Date submitted Application

type Scope Outcome

08 November 2013 Type II To update sections 4.1, 4.2, 4.4, 4.8 and 5.1 of the Summary of Product Characteristics (SmPC) to align the indications with those of the reference product (Mirena) by adding the indication 'Contraception' based on new data from a pivotal, Phase 3 contraception study) to assess the long-term, reversible contraceptive efficacy and safety of the product. As a consequence, the Patient information Leaflet (PIL) has also been updated.

Approved on 23 October 2014


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ANNEX 1

Our Reference: PL 30306/0438, Application 0003 Product: Levosert 20 microgram/24 hours Intrauterine Delivery

System Marketing Authorisation Holder: Actavis Group PTC ehf. Active Ingredient(s): Levonorgestrel Type of Procedure: Mutual Recognition Submission Type: Variation Submission Category: Type II Submission Complexity: Complex EU Procedure Number (if applicable): UK/H/3030/001/II/002 Reason: To update sections 4.1, 4.2, 4.4, 4.8 and 5.1 of the Summary of Product Characteristics (SmPC) to align the indications with those of the reference product (Mirena) by adding the indication 'Contraception' based on new data from a pivotal, Phase 3 contraception study) to assess the long-term, reversible contraceptive efficacy and safety of the product. As a consequence, the Patient information Leaflet (PIL) has also been updated. Supporting Evidence: The results of a pivotal, Phase 3 contraception study. Revised SmPC Revised Patient Information Leaflet Evaluation:

RECOMMENDATION Based on the review of the data on efficacy and safety, the RMS considers that the variation application for Levosert currently indicated in the treatment of heavy menstrual bleeding to further align the indications with those of the reference product (Mirena) by adding the indication “Contraception” for Levosert based on new data from a pivotal, Phase 3 study (contraception study) is approvable.

EXECUTIVE SUMMARY

II.1 Scope of the variation Levosert is a generic form of the levonorgestrel (LNG) intrauterine system (IUS) licensed under Article 10(3) of Directive 2001/83/EC to the product marketed by Bayer Schering Pharma under the brand name Mirena®. The scope of this Type II variation is to further align the indications with those of the reference product (Mirena) by adding the indication “Contraception” for Levosert based on new data from a pivotal, Phase 3 study (contraception study) conducted to assess the long-term, reversible contraceptive efficacy and safety of the product. Although the contraception study is planned to continue for up to 5 years, the study report which forms the basis of this variation application is based on the interim analysis at 3 years of use to support the proposed contraceptive indication with 3 years duration of use. Levosert is currently approved for the indication of heavy menstrual bleeding, with 3 years duration of use. The Summary of Product Characteristics and Patient Information Leaflet have also been amended as a consequence of this Type II variation.


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I. SCIENTIFIC DISCUSSION III.1 Quality aspects N/A III.2 Non clinical aspects N/A III.3 Clinical aspects III.3.1 Clinical pharmacology Pharmacokinetics Pharmacokinetics (PK) Sub-study A PK analysis was undertaken for a subset of the contraceptive study. The objectives and results of this analysis are presented below. The objective was to assess the plasma pharmacokinetics of levonorgestrel in a subset of approximately 60 subjects with serial sampling over the duration of use. Subjects had blood samples collected for plasma LNG concentrations on enrolment before IUS insertion and at Days 7 and 14, Months 1, 3, 6, 9, 12, 18, 24 or at early discontinuation. LNG concentrations in the plasma samples were determined by a validated LC-MS/MS method. The lower limit of quantification was 25 pg/ml. The pharmacokinetic parameters were derived from drug concentrations in plasma. For the pharmacokinetic reporting, only AUC(0-540) was included as an estimate of systemic exposure. The mean plasma LNG concentrations (pg/ml) are plotted against treatment duration in Figure 2.5.3.1-1 for non-obese Levosert users (n = 16; LNG 20 Non-obese), obese (BMI ≥ 30) Levosert users (n = 13; LNG 20 Obese) and non-obese Mirena users (n = 11). The data are included only for subjects that reached Day 540 (18 months) of treatment.

Conclusion of PK study The PK characteristics of Levosert have been characterised in the initial application. The results of this


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sub-study are comparable to those obtained in the heavy menstrual bleeding study. The plasma levels of levonorgestrel appear to be similar in both the Mirena and Levosert group (non-obese). However, the plasma levels in obese subjects are lower. This is not considered to be a significant concern as plasma levels of levonorgestrel do not always correlate with efficacy of the (intrauterine contraceptive device) IUCD. The local action is thought to be more relevant. Pharmacodynamics As part of the contraceptive study, the effect of Levosert on endometrial thickness (ET) was measured in a subset of the population. ET measurements were made in 59 Levosert 16-35 year-old subjects at baseline (most recent value prior to IUS insertion) and Month 12 [ET will be measured again after the full intended duration of study use (i.e. Month 60)]. Changes from baseline were also estimated.

At baseline, subjects had a median endometrial thickness of 4 mm, with a range of 1 to10 mm. At Month 12 a median change of zero was recorded, varying anywhere from a 7 mm decrease to a 3 mm increase. On average, no impact of the LNG20 on endometrial thickness after one year of use was noted. No adverse events or other findings for any subject were noted for any endometrial thickness measurements.


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These results suggest there was no increase in endometrial thickness but firm conclusions cannot be made on the action of Levosert on endometrial thickness.

III.3.2 Clinical efficacy Main study (ies) Contraception Study A Phase 3, Randomized, Multi-Centre, Open-Label Study of a Levonorgestrel-Releasing Intrauterine System (20 mcg/day) and Mirena for Long-Term, Reversible Contraception up to Five Years Method This phase III partially randomised, multi-centre, open-label was conducted to evaluate the efficacy of a levonorgestrel-releasing intrauterine system (Levosert). A marketed levonorgestrel-releasing intrauterine system (Mirena) is included as an informative comparator. The study is on-going and the intended study duration for participants is five years. Study assessments were performed at a clinic visit at Screening/Enrolment and months 1, 3, 6, 12, 18, 24 and 36. Additional assessments by telephone were made at 3-monthly intervals starting at Month 9. Unscheduled visits were permitted when subjects reported problems related to safety, the IUS, or study participation or for repeat laboratory tests. Study Participants Approximately 1,910 subjects were to be enrolled into the study. This includes approximately 1,760 women ages 16 to 35, inclusive, assigned to the LNG20 or Mirena IUS. At least 20% of women ages 16 to 35 were expected to be nulliparous. Additionally, a cohort of 150 women between the ages of 36 and 45 years were to be enrolled for treatment with the LNG20.

Inclusion criteria 1. Signed informed consent 2. Healthy females 16-45 years old inclusive at the time of enrolment (non-emancipated subjects under

18 years old were required to have written parental consent documented on the consent form) 3. Regularly sexually active and in a mutually monogamous relationship for at least 6 months at study

entry 4. Willing to rely on the study IUS as the primary method of contraception during study participation. 5. History of regular menstrual cycles defined as occurring every 21-35 days when not using hormones

and with a variation of typical cycle length of no more than 5 days 6. History of regular menstrual cycles defined as occurring every 21-35 days when not using hormones

and with a variation of typical cycle length of no more than 5 days 7. Willing to comply with study visit schedule and assessments, including diary completion

requirements 8. Planned to reside within a reasonable driving distance of a research site (approximately 150 miles)

for at least 2 years

Exclusion criteria Subjects were ineligible for participation in this study if they met any one of the following requirements: Currently pregnant; • Pregnant within 4 weeks prior to study entry; • Planning pregnancy within 24 months of study entry; • Currently breastfeeding; • History of ectopic pregnancy without a subsequent intrauterine pregnancy; • History of trophoblastic disease (benign or malignant gestational) without subsequent non-

trophoblastic intrauterine pregnancy;


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• Acute pelvic inflammatory disease or a history of pelvic inflammatory disease without subsequent intrauterine pregnancy;

• History of a positive HIV test or having a partner who is known to be HIV positive; • History of cervical or vaginal infection (unless successfully treated and considered clinically cured

for at least 7 days prior to study entry); • Postpartum or post-abortion endometritis unless symptoms resolved at least 4 weeks prior to study

entry; • Current persistent, abnormal vaginal bleeding; • Abnormal Pap test ; • History of malignancy of the genital tract (e.g. cervical cancer, ovarian cancer, endometrial cancer); • History of breast cancer, or suspicion of breast cancer until proven otherwise; • History of bicornuate uterus or any other abnormality of the uterus resulting in distortion of the

uterine cavity or cervical canal incompatible with insertion; • Known or suspected allergy to levonorgestrel or hypersensitivity to any component of the product; • Bleeding diathesis (inherited or acquired); • Use of anticoagulants within 30 days prior to study entry; • Body habitus, or history of lower genital tract abnormalities or prior surgeries which may prohibit

proper visualization of the cervix or not allow the uterus to be appropriately instrumented.

Treatments After written consent was obtained and eligibility established, subjects 16-35 years old were assigned to either LNG20 or Mirena. Under the original protocol and versions 2-4, subjects were randomized using a 4:1 LNG20 to Mirena ratio. Starting with protocol version 5, subjects were only assigned to LNG20. The assigned IUS could be used for up to 5 continuous years. With regards to LNG20, during the course of this study two inserters were employed; the THI-001 (Two-Handed Inserter) and the SHI-001 (Single-Handed Inserter). It would appear that significant amendments were made to the protocol after the start of the study. This is not considered to be an issue because a rationale has been provided. Mirena was changed from an active comparator to an informative comparator and a decision was taken by the applicant to discontinue enrolment into the Mirena arm because it was considered that sufficient safety data was available from the previously conducted heavy menstrual bleeding study. This is acceptable as it is agreed that there is no requirement for active comparators for contraceptive studies, in line with the guideline on Clinical Investigation of Steroid Contraceptives in Women (CPMP/EWP/519/98 Rev1). In terms of safety, it is also agreed that the guideline does not state the number of subjects required for comparative assessment. Therefore, it is agreed that this major change in the protocol does not affect the integrity of the study. Objectives The primary objective of this study was to assess the contraceptive efficacy of a levonorgestrel (LNG)-releasing intrauterine system (IUS: LNG20) in nulliparous and parous females of child-bearing potential who request long-term, reversible contraception. The secondary objectives of the study were to assess:

• The safety, tolerability, bleeding patterns, and continuation rates of LNG20; • The occurrence of menses and return to fertility after IUS discontinuation; • The plasma pharmacokinetics of levonorgestrel in a subset of approximately 60 subjects with

serial sampling over the duration of use; • Plasma levonorgestrel levels in a subset of 60 subjects (LNG20 16-35 year old arm only);

following IUS removal at 60 months with sampling at various time points up to 14 days post-IUS removal;

• Plasma levonorgestrel levels for all subjects at each visit starting with Month 36 to support a decision for extended duration of use of LNG20 beyond Month 60;


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• Analysis of an appropriate sampling of IUSs that were removed and, when available, expelled during the study;

• The safety and tolerability of LNG20 in a small cohort of women between ages 36 and 45 years; • Endometrial thickness in a subset of 60 LNG20 16-35 year old subjects at 1 year and 5 years of

LNG20 use. A number of a priori-defined subject subgroups were also to be evaluated for consistency of certain efficacy and safety findings in particular subgroups. These included age, parity, race, BMI, and inserter type. Outcomes/endpoints Primary efficacy endpoint: The primary efficacy variable was the Pearl Index, an estimation of the number of unintended pregnancies per 100 women-years of exposure. The Pearl Index was calculated as the number of "on treatment" pregnancies in the study divided by the total number of complete 28-day cycles of use in the study across all participating subjects, that result multiplied by 1300 (13 cycles x 100 years). For the definitive assessment of contraceptive efficacy, the Pearl Index and its 95% confidence interval were considered the primary result for inferences. Secondary efficacy endpoints: The Pearl Index was also calculated as a secondary efficacy variable as follows: • Modified intention-to-treat (MITT) with no cycle exclusions for other birth control method use

during a cycle. This calculation included all “on treatment” pregnancies in the numerator and all cycles of use in the denominator.

• Per Protocol (PP): A subset of the MITT population that excludes subjects with major protocol deviations (identified prior to data lock).

• LNG20 subjects 36-45 years old with no cycle exclusions. The "on-treatment" pregnancy rate and its associated 95% confidence interval were also estimated using life table methods with year of use serving as the principal life-table classification. Because the life-table method depends on a continuous exposure interval, it did not exclude 28-day cycles in which another birth control method was reported, i.e., all complete 28-day cycles were used in the calculations.

A Life Table analysis was conducted on the following populations: • MITT with no cycle exclusions • LNG20 subjects 36-45 years old with no cycle exclusions. An additional life table evaluation for the MITT and LNG20 36-45 year-old study populations was conducted as a secondary analysis that adjusts for cycles during which another birth control method was used. Specifically, it incorporated the calculation of an "absolute time"-based duration of use that adjusts for cycles where use of another birth control method (BCM) was reported. Duration of use was based on the total number of 28-day cycles of exposure adjusted downward to account for those cycles during which other BCM use was reported, the result converted into years of product use by multiplying by 28 (number of days per 28-day cycle) and then dividing by 364 (number of days in a 13 28-cycle year). Life table-derived and crude pregnancy rates are also provided for the MITT population by age, parity, BMI, race and by inserter type. Analysis sets The following subject populations were used for efficacy analyses:

• The Modified Intent-to-Treat (MITT) population included all subjects between 16 and 35 years of age at study entry for whom the assigned IUS was successfully placed in the uterus and for whom there was at least one assessment of pregnancy status after inserting the IUS.

For the primary Pearl Index outcome using exposure information through Year 3, the MITT population was used as the basis of exposure and all 28-day cycles (except the first 28-day cycle) where use of


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another birth control method reported in the daily diary were excluded from the total cycle count denominator. Use of another birth control method within the first 28-day cycle following insertion was not considered a basis for exclusion of that cycle since, per-protocol, the use of another birth control method was allowed as a back-up during the initial period following IUS insertion.

• The Per-Protocol (PP) population included subjects in the MITT population with no major protocol deviations (to be identified prior to database cut-off). [Note: following determination that 4 subjects (<0.3%) had major protocol deviations impacting efficacy, the PP population was considered redundant with regard to the MITT population already defined and, therefore, no PP population was analysed. That is, the PP population would have included all but 4 subjects from the MITT population].

The following populations were used for sub-study analyses: • The Treatment Pharmacokinetics (PK) population included all subjects enrolled in the sub-study and

who had at least one post-insertion PK assessment and no major protocol deviations. • The Endometrial Thickness (ET) population included all subjects enrolled in the ET sub-study who

had at least one post-insertion ET measurement. The safety population included all subjects enrolled who underwent the IUD insertion procedure, regardless of age and outcome. Treatment assignment was based on the treatment actually received.

Statistical methods Satisfactory details of the statistical methods used have been provided. Sample size Sample size was determined to achieve an acceptable Pearl Index through a minimum of five years of use. Eligible subjects 16-35 years of age included approximately 1,600 subjects using LNG20 and 160 subjects using Mirena. In the original study protocol, approximately 650 LNG20 and 160 Mirena subjects were to be randomized in a 4:1 ratio of LNG20 to Mirena. Subsequently, under the amended single-arm protocol versions 4- 5, the remaining 950 subjects were to be assigned to LNG20 only. The estimation of the number of subjects needed to evaluate the contraceptive efficacy of LNG20 was based on the Pearl Index, defined as the estimated rate of pregnancy per 100 women per year based on thirteen 28-day cycles of exposure per year. For this study, the following assumptions were made: • The Pearl Index was estimated to be less than 0.280 • The difference between the point estimate and the upper limit of the 95% confidence interval of the

Pearl Index calculated for each year of use was no larger than 1 unit (Benda 2004, Gerlinger 2003). • Early discontinuations due to dropouts, IUS expulsions, pregnancies, and other reasons would not

exceed 26% in year 1, 20% per year in year 2, 15% in year 3, and 10% per year in years 4 and 5 for a cumulative total over 5 years of 59.2%.

• Loss of women-months for use in calculating the Pearl Index would not exceed 0.6 months per subject in year 1 and 0.3 months per year in years 2, 3, 4, and 5.

With these assumptions, it was expected that, for the efficacy analysis, 1,600 LNG20 subjects (16-35 years old) would provide at least 10,000 woman-months (28-day cycles) of exposure in the first two years with at least 200 subjects having at least two years of LNG20 exposure within that total 28-day cycle calculation. In addition, the planned sample size assumed that at least 600 women would remain on treatment through the end of five years. For the purposes of calculating the Pearl Index, a minimum of 200 women must complete each year of study. Disposition The study is ongoing and subjects are still being enrolled. As of the 12 July 2013 3-year data cut-off date, a total of 1910 subjects had been enrolled, 1751 on Levosert (150 between the ages of ages of 36-45) and 159 on Mirena.


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383 subjects (16-35 years of age) had completed at least 2 years of treatment and 272 had completed 3 years of treatment. As of the 3-year data cut-off date, 269 subjects aged between 16 and 35 years; 41 Mirena 16-35 year old and 26 Levosert 36-45 year old subjects discontinued the study before one year. A total of 110 Levosert 16-35 year old subjects, 33 Mirena 16-35 year old and 9 Levosert 36-45 year old subjects have so far discontinued between the first and second year of treatment and a total of 64 Levosert 16-35 year old subjects, 18 Mirena 16-35 year old and 6 Levosert 36-45 year old subjects have discontinued after completing two years of treatment. Overall 108 subjects have been lost to follow up; 8.4% in the Levosert 16-35 age group; 9.5% in the Mirena group and 8.6% in the Levosert 36-45 years group. Therefore, at the 3-year data cut-off date, 1141 Levosert 16-35 year old subjects, 66 Mirena 16-35 year old and 109 Levosert 36-45 year old subjects were enrolled in the study. Patient disposition summary and details of subject discontinuation is presented in the tables below.

Disposition Summary (3 Year Data) Characteristic Levosert 16-

35 Years Old

Mirena 16-35

Years Old

Levosert 36-45 Years

Old Subjects Enrolled 1600 159 151 Subjects Completing 1 Year of Treatment 694 118 114

Subjects Completing 2 Years of Treatment 383 85 82

Subjects Completing 3 Years of Treatment 272 61 76

Subjects Known to be Ongoing Into Year 4 256 60 75

Total Subjects Ongoing 1141 66 109 Total Subjects Discontinued 459 93 42 Subjects Discontinued Before 1 Year Completion 269 41 26

Subjects Discontinued After Year 1 But Before Year 2 110 33 9

Subjects Discontinued After Year 2 But Before Year 3 64 18 6

Subjects Discontinued After Year 3 16 1 1


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Summary statistics for the number of 28-day cycles completed per subject and a breakdown of cumulative 28-day cycles of product use for 6, 12, 18, 24, 30, and 36 months of study participation is presented in the table below.

Number of 28-day cycles of Product use (3 Year data) all subjects[1]

The product duration of use for subjects who were lost to follow-up, according to the 3 year data cut is presented in the table below.


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Product duration of use (3 year data) subjects lost to follow-up

Study amendments There were six amendments (two significant) to the original protocol (dated October 19, 2009) prior to 12 July 2013 during the conduct of the study. The applicant has clarified why a number of significant amendments were made to the protocol after the start of the study. In particular, a decision was taken by the applicant to discontinue enrolment into the Mirena arm and change the Mirena arm to an informative comparator arm as it was considered that sufficient safety data was available from the previously conducted heavy menstrual bleeding study. It is agreed that there is no requirement for active comparators for contraceptive studies in line with the guideline on Clinical Investigation of Steroid Contraceptives in Women (CPMP/EWP/519/98 Rev1). In terms of safety it is also agreed that the guideline does not state the number of subjects required for comparative assessment. Therefore, it is agreed that this major change in the protocol does not affect the integrity of the study. Protocol deviations A total of 2,292 protocol deviations were reported. The most frequently reported deviations were related to out of window or missed visits. These represented 59.5% of all deviations. It should be noted that lost to follow-up subjects (108) were required to miss at least two consecutive study visits or contacts and so would account for at least 192 (60.6%) of the missed visits. For the per protocol (PP) population, major protocol deviations that could potentially affect the primary protocol outcome (efficacy) were identified prior to database cut-off. Less than 0.2% of patients in the LNG20 MITT population had major protocol deviations. Since the number was so small, efficacy summaries and analyses based on a PP population would have been virtually identical to those obtained for the MITT population. Therefore, no PP population was formulated nor were any analyses for that population pursued.


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Baseline data The table below presents Demographics and Baseline Characteristics in the (MITT Population.

Demographics and Baseline Characteristics (MITT

Population)

By definition, all subjects in the MITT population were between the ages of 16 and 35 years. In the LNG20 group, 78.6% of subjects were white and 12.9% were African-American and 8.5 % other. Nulliparous subjects made up 61.7% of the LNG20 MITT population. Almost one-fourth (24.2%) were defined as overweight (BMI 25-29.9), one-fourth (24.3%) were defined as obese (BMI ≥ 30) and 5.0% morbidly obese (BMI≥40). 57.3% reported living with their partner. The mean age of LNG20 36-45 year old subjects was 39.6 years, or approximately 13 years older than the mean age of the 16-35 year old LNG20 and Mirena groups. A greater proportion of LNG20 36-45 year old subjects (36.4%) was obese. In addition, whereas the proportion of nulliparous LNG20 16-35


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year old and Mirena 16-35 year old subjects in the Safety population remained approximately the same as for the MITT population (61.8% and 56.6%, respectively), 14.6% of LNG20 36-45 year old subjects in the Safety Population were nulliparous. Results Primary efficacy results The primary efficacy variable was the Pearl Index, an estimation of the number of unintended pregnancies per 100 women-years of exposure. The 95% confidence interval for the Pearl Index (PI) was calculated using the methods described by Benda et al. and Gerlinger et al. (Benda, N et al., 2004-Gerlinger, C et al., 2003). Pearl Index (PI) calculations were performed accounting for other birth control methods (BCM) use during a study cycle. Use of another birth control method within the first 28- day cycle following insertion was not considered a basis for exclusion of that cycle since, per-protocol, the use of another birth control method is allowed as a back-up during the initial period following intrauterine device insertion. In addition, diary days when no information regarding the use of other birth control methods was reported were considered days when no other birth control method use took place. In line with requirements of current EU guidance, the Confidence Intervals and PIs at Year 1, 2 and 3 from 3-year data were based on cumulative on-treatment pregnancies, and all treatment cycles from the start of the study to end of Years 1, 2 and 3 respectively. The following table shows the Pearl Index (PI) and 95% confidence interval, excluding 28-day cycles where a subject reported one or more days of use of another birth control method for Years 1, 2 and 3 for the MITT group.


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The PI estimates and confidence intervals for Years 2 and 3 using only data accrued in each year is presented in the table below:

Pearl Index estimates by Year (3-year data point) for Study M360-L102

Secondary Efficacy Endpoints Pearl Index Analysis: LNG20 Subjects 36-45 Years Old and Mirena Since no pregnancies were reported among LNG20 subjects 36-45 years of age, the PI point estimate was equal to zero. Subsequent to the Protocol amendments 4-6, the PI of the Mirena group was no longer considered as a comparative group but as an informative group. The PI of this group was therefore no longer calculated, since the PI for Mirena is well documented from historical data in the literature. Life Table Derived Pregnancy Rates Overall LNG20 MITT Population Life table pregnancy rates for the LNG20 MITT population with no cycles excluded were the same as those observed when cycles were excluded for other BCM use (see tables below). The life table estimate derived for either case was associated with year 1, year 2 and year 3 pregnancy rates of 0.10% (95% CI: 0.0%-0.90%) 0.19% (95% CI: 0.05%-0.75%). A year of use was defined as 364 days (13 28-day cycles).

Life Table Derived Pregnancy Rates in LNG20 IUS Subjects: No Cycles Excluded (MITT Population)


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Life Table Derived Pregnancy Rates in LNG20 IUS Subjects: Cycles of other Reported BCM Use Excluded (MITT

Population)

LNG20 36-45 Year Olds There were no pregnancies reported among LNG20 subjects in the 36-45 year-old age group. As a result, the life table estimate of the rate of on-treatment pregnancies in this subgroup was zero. Clinical studies in special populations N/A Analysis performed across trials (pooled analyses and meta-analysis) N/A Supportive study(ies) N/A Study conclusion The Pearl Indices and associated confidence intervals for years 1 and 2 are reassuring. The confidence interval for year 3 implies that insufficient cycles have been observed to meet the criterion for approval in year 3 in the clinical setting. However, since there already exist data on the rate of release of levonorgestrel from the device, and levonorgestrel does not drop to sub-therapeutic levels over this time period, it can be agreed that the evidence available supports the use of the device for up to 3 years for contraception. Although the study was conducted in the US, the applicant provided suitable justification that the results of the study can be extrapolated to the EU population in accordance with the Note for Guidance on Ethnic Factors in the Acceptability of Foreign Clinical Data (CPMP/ICH/289/95). III.3.3 Clinical safety Patient exposure All subjects randomized to treatment and who had at least one insertion attempt were included in the safety population. Subject exposure is based on an average of 30.4 days per women-month (thirteen 28-day cycle of use and includes subjects in the safety population who had successful IUS insertion. Thus among the 1600 Levosert subjects 16-35 years old, 32 had discontinued from the study following a failed insertion attempt, leaving 1568 for consideration of exposure. Two hundred and seventy-two subjects of 16-35 years old with Levosert IUSs completed at least 3 years of product use, 348 with the higher age group of patients included.


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Adverse events Adverse event data were evaluated for all subjects in the safety population up to the 3-year data cut-off date. Adverse events with onset dates anytime from the initial insertion attempt date up to 30 days following a subject’s last date of product use (for those subjects who discontinued prior to the 3-year data cut-off date) were included in all incidence rate calculations. Diary-reported cramping/pain and/or vaginal bleeding were recorded and summarized separately from other adverse events. Adverse events were also summarized by age category, parity, race, BMI subgroups, and inserter type.

At least one TEAE was reported by 1349 (77.0%) Levosert-treated subjects and in 135 (84.9%) Mirena treated subjects. Most events were mild or moderate in severity with 161 (9.2%) Levosert subjects reporting severe events and 9 (0.5%) classified as life-threatening. There were more (25 [15.7%]) severe adverse events reported by Mirena treated subjects and one (0.6%) life-threatening event. Events considered by the investigator to be probably related/related to the IUS or IUS insertion procedure were observed in 435 (24.8%) Levosert treated subjects and in 53 (33.3%) Mirena treated subjects. Adverse events leading to IUS removal for safety reasons occurred in 5 Levosert and 3 Mirena subjects. For Levosert, these included uterine perforation, alteration in mood with suicidal ideation, ovarian cysts, uterine perforation, reported ectopic pregnancy and one subject with a partial expulsion of the IUS. For Mirena, these included a collapsing ovarian cyst, uterine perforation and worsening of depression.


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The most commonly reported TEAEs among Levosert-treated subjects (incidence >5%) were nasopharyngitis (13.5%), bacterial vaginitis (10.7%), urinary tract infections (UTI) (9.7%), acne (8.7%), vulvovaginal mycotic infection (9.3%), headache (6.6%), upper respiratory tract infections (URTI, 6.0%) and dyspareunia (5.7%). For Mirena, the most commonly reported TEAEs (incidence >10% among subjects) were vulvovaginal mycotic infection (14.5%), bacterial vaginitis (13.8%), UTI (13.8%), acne (12.0%), acne (12.0%), URTI (10.1%), sinusitis (8.8%), IUS expulsion (7.6%), anxiety (7.6%), headache (6.9%), nausea (6.9%), influenza (6.9%), dyspareunia (6.3%), breast tenderness (5.7%), pelvic pain (5.7%), weight increased (5.7%), vaginal discharge (5.7%), depression (5.05) and insomnia (5.0%). The most commonly reported treatment-possibly related/ related AEs for Levosert (TRAE) (as determined by the investigator, with an incidence of >2%) were acne (5.4%), IUS expulsion (2.8%) and dyspareunia (2.6%); for Mirena, it was IUS expulsion (7.6%), acne (6.3%), dysfunctional uterine bleeding (2.5%), and pelvic discomfort (3.1%) The most commonly reported TEAEs are summarised in the table below.


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The most common AEs associated with the IUS insertion procedure for Levosert subjects, occurring in less than 2% subjects, included pre-syncope (20 subjects). For Mirena, the most common events associated with the IUS procedure were 4 subjects with pre-syncope.

Four hundred and thirty-five (24.8%) Levosert subjects experienced one or more events considered related to the IUS with the distribution being similar between the 16-35 year old and the 36-45 year old groups. For Mirena, 53 (33.3%) of subjects had at least one event reported as related to the IUS. The


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most frequently reported IUS-related events (≥2% for the Levosert 16-35 year old group was acne (5.7%), dyspareunia (2.8%) and IUS expulsion (2.8%) and for Mirena the rates in descending order were IUS expulsion (7.6%), acne (6.3%), pelvic discomfort (3.1%) and dysfunctional uterine bleeding (2.5%). In the Levosert 36-45 year old groups, the incidences in decreasing frequency consisted of breast tenderness (3.3%), dysfunctional uterine bleeding (2.7%), acne (2.7%), IUS expulsion (2.0%) and weight increase (2.0%). Adverse events related to the IUS insertion procedure were reported in 53 (3.9%) Levosert subjects. The most frequently reported procedure-related events were pre-syncope (11 subjects; 0.8%) and nausea (5 subjects; 0.4%). All other AEs considered related to the IUS procedure occurred in fewer than 5 subjects. For Mirena, 4 subjects (2.5%) reported presyncope and two subjects reported pelvic pain (1.3%). Adverse Events Associated with Levosert IUS Use The following such events were identified during the study period: pelvic pain: 50 (3.6%) of subjects; abdominal pain (general, upper, lower): 50 (3.6%) subjects; pelvic inflammatory disease: 6 (<0.1%) subjects; uterine perforation: 3 (<0.1%) subjects. Of these, only pelvic inflammatory disease in two Levosert subjects was classified as serious; these events in both patients resolved without sequelae and were considered unrelated to treatment. For pelvic pain, only 18 subjects reported events that the investigator considered were related to the Levosert IUS: only 7 of the reported events of abdominal pain in Levosert subjects were classified as treatment-related. Uterine perforation was considered related to the IUS in two Levosert subjects. Two instances of pelvic inflammatory disease were also considered related to the IUS. Serious adverse events and deaths Forty-three (2.3%) reported one or more SAEs: 34(2.1%) subjects in the Levosert 16-35 year old group, 4 (2.7%) in the Levosert 36-45 year old group, and 5 (3.1%) in the Mirena group. The most frequently reported serious events were infections and infestations (6 subjects) and psychiatric disorders (10 subjects); none was related to the IUS or IUS placement. Ectopic pregnancy was reported in two Ectopic pregnancy was reported in two Levosert 16-35 year old group subjects as was pelvic inflammatory. All other SAEs were single reported in no more than two subjects in any treatment group. One death, a suicide, was reported in the Levosert 16-35 year-old group during the study period. The case was considered by the Investigator to be unlikely related to the IUS. Eleven life-threatening events were reported in 5 Levosert subjects. Only one (ectopic pregnancy) was classified as treatment-related. Three SAEs on Levosert were considered to be probably related to the IUS: two ectopic pregnancies, an ovarian cyst. No SAEs were classified as related or probably related to the IUS placement procedure. Adverse Events Leading to IUS Removal IUS removal as an outcome of adverse events occurred in 183/1600 (11.4%) Levosert 16-35 year-old subjects, 17/151 (11.3%) Levosert 36-45 year-old subjects, and in 25/159 (15.7%) Mirena treated subjects. However, the IUS was removed for safety reasons in only 8 subjects, 5 in the Levosert 16-35 year old group (uterine perforation, ectopic pregnancy, suicidal ideation, ovarian cyst) and 3 in the Mirena group (uterine perforation, depression, ovarian cyst). [The determination of “removal for safety reasons” was made by the investigator based on the protocol definition of “an adverse event that put the subject at risk for a serious complication as a direct result of the AE if the IUS had not been removed.”]. In all other cases, the IUS was removed only as a result of the subject's decision to withdraw from the study.


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Expulsions and Perforations Forty-five (2.9%) Levosert 16-35 year-old subjects experienced an expulsion and 3 (0.2%) subjects experienced a uterine perforation. Four (2.7%) Levosert 36-45 year-olds also experienced an IUS expulsion. There were 12 expulsions (7.7%) and one (0.6%) perforation reported for Mirena. In the Levosert-treated groups, all three perforations and 28 (3.7%) expulsions were observed in association with the THI-001 inserter and 21 (2.1%) expulsions were seen for the SHI-001 inserter (largely reflecting the respective system usage). IUS Removal The great majority of Levosert IUS removals were accomplished without difficulty with 96.6% of subjects having removal accomplished by pulling on the strings. IUS removal could not be accomplished in the office in one subject in the Levosert 16-35 year old group and required removal in an operating theatre using hysteroscopy secondary to perforation of the IUS. No other subjects required a second visit for IUS removal. Most subjects (80.1%) did not experience bleeding during IUS removal; those who did, reported only spotting (15.6%). In addition, 61.3% of subjects reported no cramping related to removal; 1.8% of subjects reported severe cramping. Cramping/Pain The mean number of diary-reported cramping/pain days was greatest during the first 28 day period following insertion. That number dropped dramatically as during Cycle 2, falling to a mean of approximately 2.5 days at the end of 1 year, and remaining consistently below a mean of 2 days' duration thereafter. Levosert subjects 16-35 years old had a somewhat higher mean number of days of cramping/pain at Cycle 1 compared to older subjects but by Cycle 12 the mean number of cramping/pain days reported for Levosert 16-35 year old subjects was < 1 day greater than their older counterparts (2.3, 1.5 days, respectively). The majority of subjects who had an incidence of cramping reported it as lasting no more than 1-3 days within any given cycle. Bleeding Events The mean number of subject diary-reported bleeding and/or spotting days was summarized by 28-day cycle. For both Levosert subgroups, the mean numbers of reported days of bleeding and/or spotting were greatest during the first 28-day period following insertion and then consistently fell thereafter. The mean number of days of reported bleeding and/or spotting fell from about 14.8 days at Cycle 1 to under 11 days at Cycle 2 and then reached a relatively stable 3-4 days per cycle beginning at Cycle 9 and extending through the 2-year point (Cycle 26).


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Bleeding TEAEs were entered into the Adverse Events CRF only when the bleeding led to IUS discontinuation, qualified as a SAE, or was not related to the IUS. The cycle-to-cycle data on bleeding is considered a more representative description of the changes in bleeding experienced during LNG20 use and accounts for every day of use. Endometrial thickness This was evaluated in 50 Levosert 16-35 year old subjects with data both at baseline and month 12 as part of a sub-study conducted with the main protocol. At baseline, subjects had a median endometrial thickness of 4mm, with a range of 1 to 10mm. an endometrial thickness of 1mm was observed in 5 subjects at baseline. At month 12 a median change of zero was recorded, varying anywhere from a 7mm decrease to a 3mm increase. On average, no impact of Levosert on endometrial thickness after one year of use was noted. Laboratory findings Haemoglobin No marked differences in haemoglobin levels were observed among the two Levosert treatment and Mirena-treatment groups. Baseline mean haemoglobin was between 13.3 and 13.5 g/dl, well within the normal range. After 12 months, the mean haemoglobin levels remained virtually unchanged at 13.5 g/dl.

Adverse events of decreased haemoglobin was observed in one Levosert 16-35 year old subject and increased haemoglobin was observed in one Levosert 16-35 year old subject during the study; neither was considered to be related to the IUS or insertion procedure. Seven reports of anaemia and 1 report of iron-deficiency anaemia were also classified as not related to the study treatment.

Serum Chemistry Serum chemistry tests (alanine aminotransferase, aspartate aminotransferase, total bilirubin, and creatinine) were obtained only at baseline as part of the screening procedure. There was no further testing on treatment. 'Pap' Tests Baseline Pap results were clinically normal in 93.4% of Levosert 16-35 year-old subjects, 89.2% of Mirena subjects, and 95.9% of Levosert 36-45 year-old subjects. Considering the additional ASCUS, HPV negative findings at baseline, these normal percentages increased to 96.1%, 94.2%, and 98.0%, respectively. High-grade Pap findings (HSIL and ASC-H) were each observed in two Levosert subjects at baseline, respectively. No Pap tests performed at Months 12 and 24 showed high grade abnormal findings. Results were generally similar for all three treatment groups. Vital Signs Vital signs (systolic and diastolic blood pressure) were obtained at baseline and Months 1, 3, 6, 12, 18, and 24, 30 and 36. Subject temperature was obtained at baseline only. Median baseline systolic pressure was similar across the three treatment groups (Levosert 16- 35 year old group: 114.2 mmHg; Levosert 36-45 year old group: 118 mmHg). Median systolic blood pressure (SBP) at Month 36 for the two groups was virtually the same as it was at screening (-1 mmHg for the Levosert 16- 35 year old group and 0 for the Levosert 36-45 year old group). Median diastolic blood pressure (DBP) was 73.8 mmHg in the Levosert 16-35 year-old group, and 76.2 mmHg in the Levosert 36-45 year-old group. The distribution of DBP remained virtually unchanged in all treatment groups at Month 12, Month 24 and Month 36 with a median reduction of no more than 1-2 mmHg.


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"Elevated blood pressure" was reported as an AE during the study in eight subjects (five in the Levosert 16-35 year old group and three in the Levosert 36-45 year old group). Six cases were classified as mild and two as moderate in severity. All were considered unrelated to the IUS or the IUS insertion procedure. Safety in special populations No specific study has been conducted in special populations. Conclusion on safety In the study, 272 subjects aged between 16 and 45 years have had Levosert inserted for at least 3 years. The most frequently encountered treatment emergent adverse events were acne, IUD expulsion and dyspareunia in the Levosert group and in the Mirena group, they were intrauterine device expulsion, acne, dysfunctional uterine bleeding and pelvic discomfort. Generally, the adverse events and the frequency of occurrence were similar in both groups in this study and to those for other IUDs. Overall, there does not appear to be any cause for concern regarding the safety of Levosert. During the initial procedure, it was noted that a significant number of subjects had unsuccessful insertion of IUS especially in the Levosert group leading to a temporary suspension of recruitment. This issue was thought to be related to multiple factors including the design of the inserter, lack of familiarity of US physicians with the Levosert inserter, the parity of the women, age and possible cultural differences. Enrolment was resumed and a new “one handed” inserter was developed for use in the US market. A phase I study was conducted to assess the ease of use, the subject tolerance and performance of the SHI-001 inserter in placing the Levosert IUS. See below for further details of the study. Phase I study - SHI-001 inserter study The primary objective of the Phase I study, conducted in the United States, was to assess the subject safety and successful placement of the Levosert IUS utilising a novel singlehanded inserter (SHI-001) in women 18-45 years old.

Secondary objectives included the evaluation of the following endpoints: adjunctive procedures for IUS placement (cervical anaesthesia and cervical dilation), uterine perforation, IUS expulsion, ease of IUS placement into the uterus, and adverse events. Methodology A total of 53 potential subjects were screened, 50 subjects were enrolled, and 50 underwent IUS placement with the SHI-001 inserter. Inclusion criteria Healthy female subjects, age 18 to 45 years at enrolment, who signed an informed consent, who were in a mutually monogamous relationship for at least 3 months or were sexually abstinent, who, in the opinion of the investigator, were at low risk for sexually transmitted infection and were willing to comply with the study visit schedule were eligible for study participation. Exclusion criteria Pregnancy, desiring to be pregnant at the time of the study; pregnancy within 4 weeks of the study; pelvic inflammatory disease or postpartum or post-abortion endometritis within 12 weeks of study entry; clinically evident cervical or vaginal infection; current persistent, abnormal vaginal bleeding; inability to properly visualize the cervix; inability to sound the uterus or uterus sounds to less than 5.5 cm; a history of malignancy of the genital tract, uterine perforation from instrumentation, bicorunate uterus or uterine abnormalities incompatible with IUS placement, history of severe vasovagal reaction requiring


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treatment; use of anticoagulants within 30 days of study entry; or history of inability to have an IUS placed. Test Product The SHI-001 inserter containing the LNG20 intrauterine system The SHI-001 inserter consists of a symmetric, two-sided syringe handle integrated with a pre-curved high density polyethylene insertion tube. Each LNG20 inserter contains 52 mg of levonorgestrel in a cylindrical-shaped reservoir. Each LNG20 IUS is partially loaded into an SHI-001 inserter and packaged in a tray within a pouch as a single-use sterile system to be opened immediately before placement. LNG20 and SHI-001 was employed in this study.

The product package contains the LNG20 loaded at the top of the insertion tube with the vertical stem located within the tube and the arms in a horizontal position (so that the product is in a T-shape). The thread is pre-loaded through the insertion tube.

The IUS is loaded by pulling the threads while keeping the sliders in the most forward position, drawing the IUS into the tube. Once loaded, the threads are placed into the cleft at the end of the handle to hold the LNG20 in the loaded position within the insertion tube. When loaded correctly, the ends of the horizontal arms of the IUS form a rounded tip at the end of the tube.

Procedure After consent was obtained, screening procedures, including Chlamydia and gonorrhoea testing, were performed, and entry criteria were confirmed. Eligible subjects underwent the IUS placement procedure. The placement procedure (Study Day 1) could have occurred on the same day as the screening procedures or could have been scheduled for an alternate day.

However, the attempt was required to occur within 30 days of screening unless a waiver was obtained. In women using hormonal contraceptives, who were sexually abstinent, who were in an exclusively same sex relationship, or who were sterilized, the insertion attempt was permitted at any time during the subject’s menstrual cycle. In all other subjects, the placement attempt was required to occur within the first 7 days of the onset of the subject’s menstrual cycle.

The LNG20 was placed in the subject’s uterus by the study investigator using the SHI-001 inserter, with only a single placement attempt being allowed. Cervical anaesthesia and dilation (Pratt dilator or os finder) were allowed as needed, and ultrasound guidance was permitted. On successful placement of the IUS, the inserter was removed, and the tenaculum and speculum removed. Ultrasound verification that the LNG20 was within the uterus was performed.

The LNG20 was removed approximately 5 to 15 minutes after IUS placement if, in the opinion of the investigator, it was clinically safe to do so. After IUS removal, the subject was observed for approximately 15 minutes to monitor adverse events. The participant was discharged from the clinic when, in the opinion of the investigator, it was clinically safe to do so; per protocol, the IUS must have been removed prior to subject discharge from the clinic.

Description of Insertion Variables The following definitions were employed for the IUS placement procedure: • The IUS placement procedure was defined as beginning with speculum placement and ending with

removal of all instrumentation with an IUS placement attempt being made. • The IUS placement attempt was defined as beginning with the attempt to place the SHI-001 (with


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loaded LNG20) through the external cervical os and into the uterus. The IUS placement was considered complete after cutting of the string if the IUS was successfully placed or the procedure was terminated because of unsuccessful placement.

• Successful IUS placement was defined as the LNG20 being released from the inserter within the uterine cavity and remaining in the uterus upon removal of the inserter.

• The IUS removal procedure was defined as beginning with speculum placement with the intent to remove the IUS and ending when the speculum was removed.

Primary Insertion Analysis Variable The primary insertion analysis variable was the successful and safe placement of an LNG20 IUS utilizing a novel inserter into the uterus. A successful placement was defined as a “Yes” response to the question “Was the placement completed successfully?” on the IUS Placement Questionnaire CRF. A safe placement was defined as no adverse events (AEs) related to the IUS placement procedure. For AE causality, related was defined as “related”, ‘probably related”, or missing. Secondary Insertion and Removal Analysis Variables Secondary insertion analysis variables were responses to questions on the IUS Placement Questionnaire CRF and the IUS Removal Questionnaire CRF. • Adjunctive procedures for IUS placement based on responses on the IUS Placement Questionnaire

CRF: o Cervical anaesthesia based on “Yes” responses to all of the following questions: “Was

local anaesthesia used?”, “Given during procedure for clinical necessity?” and “If YES: Due to discomfort during IUS placement?”

o Cervical dilation based on responses to the question “Was rigid dilation performed?” Responses to the question “If YES: Largest dilator size used” were also presented.

• Uterine perforations based on the Adverse Event CRF. • IUS expulsions based on responses to the question “Did the IUS expel prior to removal attempt?” on

the IUS Removal Questionnaire CRF. • Investigator assessment of ease of IUS placement into the uterus based on responses to the question

“Rate the ease/difficulty of placing the IUS” on the IUS Placement Questionnaire CRF. • Difficulty with removal based on responses to the question “Was removal accomplished by pulling

on the string without difficulty?” and the “Difficulty with Removal” assessment on the IUS Removal Questionnaire CRF.


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Results Demographic and baseline data

Primary Analysis – Adverse event-free and Successful IUS Placement Successful IUS placement was reported in 48 subjects (96.0%) (Table 5). There were 2 (4%) unsuccessful placements reported. One unsuccessful placement was due to an unintended IUS removal at the time the inserter was removed from the uterus in a nulliparous subject.

The other occurred in a parous subject due to the inability of the sound to pass an anatomical ridge in the cervix after which no attempt to place the IUS into the uterus with the inserter was made (the protocol defined a placement attempt as beginning with any instrumentation of the cervix). Safe placement occurred in 41 of 50 (82.0%) subjects (83.9% nulliparous, 78.9% parous). All 48 subjects with reported successful insertions had ultrasound verification that the LNG20 was within the uterine cavity. Successful placement without serious adverse events occurred in 100% of these 48 women.

Overall, 39 subjects (78.0%) experienced a safe and successful IUS placement. Results were similar in the 2 parity groups, with 80.6% and 73.7% of nulliparous and parous subjects, respectively, experiencing a safe and successful IUS placement.


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Local anaesthesia was used for 28 (56.0%) subjects during IUS placement; all subjects receiving local anaesthesia were treated at the cervical lip for tenaculum placement. In addition, 3 nulliparous subjects (10.7%) received local anaesthesia for clinical necessity (discomfort during sounding or IUS placement).

Cervical dilation was reported in only 3 subjects (6.0%); an os finder was used in 1 subject and Pratt dilators in 2 subjects (largest sizes, 17 French and 19 French).

Other issues related to placement that were not adverse events were reported in only 3 subjects (6.0 %). These included the use of ultrasound guidance in 2 nulliparous subjects.

Additionally, in 1 parous subject, placement was successful but, per data entry, the procedure was not performed per the instructions, however, the investigator clarified that this was a clerical error identified after the database was locked and should not have been indicated as an issue.

The loading of the placement device was classified as being “easy” in 49 (98.0%) subjects and “neutral” in 1 (2.0%) subject; loading of the device was not considered “difficult” in any procedure. Placement of the IUS was classified as “easy” in 44 (88.0%) subjects, indicated as “neutral” in 2 (4.0%) of subjects, and was considered to be “difficult” in only 4 (8.0%) subjects. Conclusion of the SHI-001 inserter study This study was conducted to evaluate the ease of use of the one-handed one-handed inserter (SHI-001). Overall, it would appear that placement of the IUCD using the inserter was successfully in majority of cases both in nulliparous and parous women and the occurrence of adverse eventswas generally low in both groups The one-handed inserter (SHI-001) is not intended for use in the EU. It is also agreed that the efficacy of Levosert is independent of the inserter. However, it is considered that the inserter has a significant bearing on safety but it is accepted that the two-handed inserter (THI-002) is already approved for use as significant changes were made to the earlier version THI-001.


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Conclusion: The efficacy and safety data provided supports the use of the device for up to 3 years for contraception. The amendments to the SmPC and PIL are acceptable. In accordance with Directive 2010/84/EU the Summaries of Product Characteristics (SmPCs) and Patient Information Leaflets (PILs) for products granted Marketing Authorisations at a national level are available on the MHRA website. Decision: Approved on 23 October 2014.

Documents

Public Assessment Report - GOV.UK · PAR Levosert 20microgram/24 hours Intrauterine Delivery System UK/H/ 3030/001/DC 1. Public Assessment Report . Decentralised Procedure . LEVOSERT