Depot-medroxyprogesterone acetate (DMPA-SC) Sayana Press WHO EML Application December 2016

Depot-medroxyprogesterone acetate (DMPA-SC) (Sayana® Press)

Application for Inclusion in the WHO Essential Medicines List

December 2016

1 090177e18a903a4c\Approved\Approved On: 18-Nov-2016 03:23 Depot-medroxyprogesterone acetate (DMPA-SC) Sayana Press WHO EML Application December 2016

Contents GENERAL ITEMS ...... 3 1. Summary statement of the proposal for inclusion, change or deletion...... 3 2. Name of the WHO technical department and focal point supporting the application (where relevant)...... 4 3. Name of organization(s) consulted and/or supporting the application...... 4 4. International Nonproprietary Name (INN) and Anatomical Therapeutic Chemical (ATC) code of the medicine...... 5 5. Formulation(s) and strength(s) proposed for inclusion; including adult and paediatric (if appropriate)...... 5 6. Whether listing is requested as an individual medicine or as representative of a pharmacological class...... 5 TREATMENT DETAILS, PUBLIC HEALTH RELEVANCE AND EVIDENCE APPRAISAL AND SYNTHESIS ...... 5 7. Treatment details (requirements for diagnosis, treatment and monitoring)...... 5 8. Information supporting the public health relevance (epidemiological information on disease burden, assessment of current use, target population)...... 9 9. Review of benefits: summary of comparative effectiveness in a variety of clinical settings...... 12 10. Review of harms and toxicity: summary of evidence on safety...... 15 11. Summary of available data on comparative cost and cost- effectiveness within the pharmacological class or therapeutic group...... 37 REGULATORY INFORMATION...... 41 12. Summary of regulatory status of the medicine...... 41 13. Availability of pharmacopoeial standards (British Pharmacopoeia, International Pharmacopoeia, United States Pharmacopoeia, European Pharmacopeia)...... 44 APPENDICES...... 45 Appendix I. Clinical Trial Exposure to DMPA-SC ...... 46 Appendix II. Safety Data from DMPA-SC Clinical Trials...... 48

2 090177e18a903a4c\Approved\Approved On: 18-Nov-2016 03:23 Depot-medroxyprogesterone acetate (DMPA-SC) Sayana Press WHO EML Application December 2016

REFERENCES...... 51

GENERAL ITEMS 1. Summary statement of the proposal for inclusion, change or deletion. The present application is to recommend the inclusion of medroxyprogesterone acetate for subcutaneous injection (104 mg/0.65 ml) (DMPA-SC) as a hormonal contraceptive on the WHO Essential Medicines List.

Subcutaneously-administered depot medroxyprogesterone acetate (DMPA-SC) has been included as a new method in the 5th edition of WHO’s ‘Medical eligibility criteria for contraceptive use’ (MEC)1 alongside DMPA for intramuscular administration (DMPA-IM). This application proposes to include DMPA-SC, in addition to the formulation for IM administration (150 mg/ml), in paragraph 18.3.2 (Injectable Hormonal Contraceptives) of the Essential Medicines List.

Pfizer produces DMPA-SC in two different presentations:

1. a pre-filled glass syringe

2. a pre-filled, single-use, non-reusable delivery system

Sayana/Sayana Press was developed to help provide women with more contraceptive options; these include, but are not limited to inherent compliance: 1 injection every three months rather than having to remember to take the pill every day, in addition to risk reduction of AEs occurring upon exposure to oestrogens, as found in combination oral contraceptives, particularly for young women. Both presentations of Sayana/Sayana Press (medroxyprogesterone acetate for subcutaneous injection) are approved for the therapeutic indications of “long-term female contraception” in all countries where they are registered.

For illustration purposes, we will focus most of this discussion on Sayana Press; with the exception of specific delivery system information, data on Sayana Press may be applied to the Sayana prefilled syringe. Both approved presentations use a 104 mg/0.65 mL suspension for SC injection contained in either a pre- filled glass syringe or in the pre-filled, single-dose, non-reusable delivery system and each represents an effective medication for female contraception when administered in accordance with the instructions for use.2

Each subcutaneous injection prevents ovulation and provides contraception for at least 13 weeks (+/- 1 week).

Sayana Press combines a reversible, long-acting contraceptive with an all-in-one prefilled, single-use, non-reusable delivery system that eliminates the need to prepare a needle and syringe. The use of this delivery system allows the contraceptive to be self-administered by women at home or in other convenient settings, following a basic and straightforward training from a health care provider.

3 090177e18a903a4c\Approved\Approved On: 18-Nov-2016 03:23 Depot-medroxyprogesterone acetate (DMPA-SC) Sayana Press WHO EML Application December 2016

Injectable contraceptives are a widely-used family planning method among women in developing countries where the lifetime risk for death due to a maternal cause can be as high as one in 15.4 In many developing countries, women must return to a clinic or health post every three months for a new injection from a skilled health care provider, limiting access to the product when living in remote and other hard-to-reach areas. Accordingly, experts have identified the need for a contraceptive method that can be administered in low- resource, non-clinic settings.3 Because of its delivery technology, expanding access to Sayana Press should help fill this gap.4

In July 2015, the UK Medicines and Healthcare Products Regulatory Agency (MHRA) approved an update to the Sayana® Press label, adding the option for self-injection by women when considered appropriate by a healthcare professional (HCP).5,6

Pfizer will continue its efforts to help bring this updated label to more countries across the globe, with an initial focus on those in the developing world where data show an unmet medical need.3

With the approval for home or self-injection, following proper training, women will have the opportunity to self-administer Sayana Press outside of a clinical setting, which will reduce the need and frequency of travelling to a clinic.3

The inclusion of DMPA-SC in the Essential Medicines List would help facilitate access to this new formulation and method of administration, providing women with contraceptive choices with expanded range and convenience.

2. Name of the WHO technical department and focal point supporting the application (where relevant).

Department of Reproductive Health and Research (RHR), focal point being Dr. Petrus Steyn email: [email protected]

3. Name of organization(s) consulted and/or supporting the application.

PATH 2201 Westlake Avenue, Suite 200 Seattle, WA 98121 USA

www.path.org

4 090177e18a903a4c\Approved\Approved On: 18-Nov-2016 03:23 Depot-medroxyprogesterone acetate (DMPA-SC) Sayana Press WHO EML Application December 2016

4. International Nonproprietary Name (INN) and Anatomical Therapeutic Chemical (ATC) code of the medicine.

International Nonproprietary Name (INN): medroxyprogesterone acetate (MPA)

Anatomical Therapeutic Chemical (ATC Code): G03AC06

5. Formulation(s) and strength(s) proposed for inclusion; including adult and paediatric (if appropriate).

104 mg medroxyprogesterone acetate (MPA) in 0.65 mL suspension for injection.

White to off-white homogeneous suspension for subcutaneous administration

6. Whether listing is requested as an individual medicine or as representative of a pharmacological class.

The request for inclusion is for an additional formulation of an existing medicine (medroxyprogesterone acetate Depot injection: 150 mg/mL in 1- mL vial)

The request is for: 1. the modification of the indication of the route of administration of DMPA- IM, from:  Depot injection: 150 mg/mL in 1- mL vial To:  Injection (intramuscular): 150 mg/mL in 1- mL vial

2. The inclusion of the formulation for subcutaneous injection:  Injection (subcutaneous): 104 mg/0.65 ml in a prefilled syringe and single dose pre-filled injection delivery system

TREATMENT DETAILS, PUBLIC HEALTH RELEVANCE AND EVIDENCE APPRAISAL AND SYNTHESIS 7. Treatment details (requirements for diagnosis, treatment and monitoring). Sayana Press may be administered by a healthcare professional (HCP) or, when considered appropriate by the HCP, and approved by the local regulatory authority, self-injected by the patient, with medical follow up as necessary in accordance with local clinical guidance, as well as the WHO Guideline on Medical eligibility criteria for contraceptive use.1

5 090177e18a903a4c\Approved\Approved On: 18-Nov-2016 03:23 Depot-medroxyprogesterone acetate (DMPA-SC) Sayana Press WHO EML Application December 2016

Administration of Sayana Press should be initiated under the supervision of a HCP. After proper training in injection technique and schedule of administration, patients may self-inject with Sayana Press if their HCP determines that it is appropriate and with medical follow-up, as necessary.

In preparation for administration, the Sayana Press user must ensure that the dose being given appears as a uniform suspension and the contents are completely sealed inside the reservoir of the injector. The liquid does not completely fill the reservoir; there is a small bubble of air above the liquid. The injector must be activated before use. The activation process pierces an internal seal so that the medication is able to move through the needle when the reservoir is squeezed. The dose is administered as a subcutaneous injection (SC) into the anterior thigh or abdomen. When the injection is being given, the injector must be held with the needle downwards. This helps ensure that the full dose of liquid is delivered through the needle. The medication should be injected slowly over 5-7 seconds. Slow injection is necessary because the subcutaneous DMPA formulation is a suspension, which has higher viscosity than a typical solution. If the patient or HCP attempts to inject very rapidly, there would be resistance to flow of the suspension through the needle. Slow injection (i.e., only modest injection pressure) will avoid that resistance to flow and the drug administration will proceed without difficulty. The single-dose container should be maintained at room temperature. It must be vigorously shaken just before use to create a uniform suspension.

Mixing the medicine

 Ensure that the SAYANA PRESS single- dose container is at room temperature.

 Hold the injector firmly by the port.  Shake the injector vigorously for at least 30 seconds to mix the medicine.

6 090177e18a903a4c\Approved\Approved On: 18-Nov-2016 03:23 Depot-medroxyprogesterone acetate (DMPA-SC) Sayana Press WHO EML Application December 2016

 The medicine should appear white and uniform. If it is not, discard the injector and use a new one.  If you see liquid leaking out or any other problem, discard the injector and use a new one.  If there is a delay before injecting, you must repeat the mixing step.

Activating the injector

 Hold the injector firmly by the port, making sure the needle shield is pointing upwards. Take care not to squeeze the reservoir.  Hold the needle shield with the other hand.

 Push the needle shield firmly towards the port until it will go no further. The injector is now activated.

 Pull the needle shield off, and discard it.

Adults

First Injection: To provide contraceptive cover in the first cycle of use, an injection of 104 mg SC should be given during the first five days of a normal

7 090177e18a903a4c\Approved\Approved On: 18-Nov-2016 03:23 Depot-medroxyprogesterone acetate (DMPA-SC) Sayana Press WHO EML Application December 2016

menstrual cycle. If the injection is carried out according to these instructions, no additional contraceptive measure is required.

Further doses: The second and subsequent injections should be given at 13 week intervals, as long as the injection is given no later than seven days after this time, no additional contraceptive measures (e.g. barrier) are required. If the interval from the preceding injection is greater than 14 weeks (13 weeks plus 7 days) for any reason, then pregnancy should be excluded before the next injection is given. The efficacy of Sayana Press depends on adherence to the recommended dosage schedule of administration.

Women should be re-evaluated by a health care provider periodically as clinically appropriate or at least every year to determine if Sayana Press is still the best option for them.

Postpartum: If the patient is not breast-feeding, the injection should be given within 5 days postpartum (to increase assurance that the patient is not pregnant). If the injection is to be given at another time then the pregnancy should be excluded.

If the patient is breast-feeding, the injection should be given no sooner than six weeks postpartum, when the infant’s enzyme system is more developed (see section 4.6).

There is evidence that women prescribed Sayana Press in the immediate puerperium can experience prolonged and heavy bleeding. Because of this, the drug should be used with caution in the puerperium. Women who are considering use of the product immediately following delivery or termination should be advised that the risk of heavy or prolonged bleeding may be increased. Doctors are reminded that in the non breast-feeding, postpartum patient, ovulation may occur as early as week 4.

Switching from other Methods of Contraception: When moving from other contraception methods, Sayana Press should be given in a manner that ensures continuous contraceptive coverage based upon the mechanism of action of both methods, (e.g. patients moving from oral contraceptives to Sayana Press should have their first injection of Sayana Press within 7 days after their last active pill).

Patients with hepatic impairment: The effect of hepatic disease on the pharmacokinetics of Sayana Press is unknown. As Sayana Press largely undergoes hepatic elimination it may be poorly metabolised in patients with severe hepatic insufficiency (see section 4.3).

Patients with renal impairment: The effect of renal disease on the pharmacokinetics of Sayana Press is unknown. No dosage adjustment should be necessary in women with renal insufficiency, since Sayana Press is almost exclusively eliminated by hepatic metabolism.

8 090177e18a903a4c\Approved\Approved On: 18-Nov-2016 03:23 Depot-medroxyprogesterone acetate (DMPA-SC) Sayana Press WHO EML Application December 2016

Paediatric population

Sayana Press is not indicated before menarche (see section 4.1). Data in adolescent females (12-18 years) is available for IM administration of MPA (see sections 4.4 and 5.1). Other than concerns about loss of BMD, the safety and effectiveness of Sayana Press is expected to be the same for adolescents after menarche and adult females.

8. Information supporting the public health relevance (epidemiological information on disease burden, assessment of current use, target population) Contraceptive measures can either be administered as planned prophylaxis (e.g. OC pills, patches, injectables, implants, vaginal or intrauterine devices, barrier foams, spermicides, tubal ligation, vasectomy) or postcoitally for emergency contraception (i.e. high-dose oestrogen-containing OC pills, high-dose progestin pills, or progesterone antagonist, intrauterine devices). The most commonly used form of contraception is combination contraceptives containing an oestrogen and progestin.7 However, consensus views arising from the 49th United Kingdom Royal College of Obstetricians and Gynaecologist (RCOG) study group recommends that women with conditions that may be exacerbated by oestrogen should use progestin-only rather than combined methods.8 Oral combination contraceptives are taken daily whereas other formulations of combined contraception such a vaginal rings and patches are effective over a course of one to 3 weeks. DMPA, an injectable progestin, provides long-acting contraception for 3 months.

As identified by Kahn et al9, an increase in the access to, and use of, contraceptive methods has resulted in steep declines in fertility since the 1960s. Additionally, modeling estimates indicate that contraceptive use averted 44% of (or 272,040) maternal deaths in 2008.10 The same modeling exercise projects that a further 29% of maternal deaths could be averted annually if unmet needs for contraception were met.10 An estimated 222 million women in low-income countries have an unmet need for modern contraception.11 It has been estimated that this unmet need contributes to 7.4 million disability-adjusted life years.9 The number of women who have an unmet need for modern contraception in 2012 is 222 million. This number declined slightly between 2008 and 2012 in the developing world overall, but increased in some subregions, as well as in the 69 poorest countries.11 Medroxyprogesterone acetate can help meet this unmet medical need.

Impact of Modern Techniques on Contraception Prevalence in the Modern and the Developing World

The prevalence of contraceptive use in the EU has been estimated in a few population-based surveys. A Commission Report on the state of women's health in the European Community reported contraceptive use rates between 71% and 81% in most member states, except for Spain (59%) and Portugal (66%).12

9 090177e18a903a4c\Approved\Approved On: 18-Nov-2016 03:23 Depot-medroxyprogesterone acetate (DMPA-SC) Sayana Press WHO EML Application December 2016

A European survey was performed to investigate contraceptive use in randomly selected European women aged 15 to 49 years. The survey was conducted among 12,138 randomly selected women from five countries (France, Germany, Italy, Spain, and United Kingdom [UK]) in 2003 to investigate contraceptive use in European women aged 15 to 49 years.13 Overall, 77% of the women were using a contraceptive method with country specific rates ranging from 71% in Spain to 82% in Germany. The EU sponsored another survey conducted during 1991 to 1993 in Denmark, Germany, Poland, Italy and Spain among 5,266 women “at risk of pregnancy” (women who were involved in a steady sexual relationship, were fertile, were not pregnant and had not delivered in the previous 2 months).14 At the time of interview, 83.7% of these women were using contraceptives. Prevalence of contraceptive use ranged from 73.3% in Poland to 91.2% in southern Italy.

In 2010, 146 million (130 to 166 million) women worldwide aged 15 to 49 years who were married or in a union had an unmet need for family planning.15 A systematic and comprehensive analysis of the national, regional, and global rates and trends in contraceptive prevalence and unmet need for family planning found that worldwide, contraceptive prevalence increased from 54.8% (95% uncertainty interval 52.3–57.1) in 1990, to 63.3% (60.4–66.0) in 2010. This increase was driven mainly by a rise in contraceptive prevalence in developing countries, from 51.8% (48.8–54.6) in 1990, to 62.0% (58.7–65.0) in 2010.15 The largest absolute increases in contraceptive prevalence were in southern Asia and three subregions of Africa (eastern, northern, and southern Africa). However, in two subregions of Africa, contraceptive prevalence still remained low: by 2010, fewer than one in five married women of reproductive age (MWRA) used any contraceptive method in middle and western Africa. Seventeen countries of Africa had contraceptive prevalence levels below 20 percent. This group includes Nigeria, where contraceptive use was at less than half the level in Ethiopia (16 percent and 36 percent, respectively). Less than 10 percent of married or in-union women of reproductive age were using contraception in Chad, Guinea, and South Sudan in 2015. Five countries in Eastern Africa (Kenya, Malawi, Rwanda, Zambia, and Zimbabwe) also had contraceptive prevalence levels of 50 percent or more in 2015.16

Most increases in contraceptive prevalence that occurred between 1990 and 2010 were attributable to a rise in the use of modern methods, including injectable contraceptives. The prevalence of modern method use in 2010 ranged from 8.3 percent in middle Africa to more than 70 percent in eastern Asia, northern America, and northern Europe.15 Overall, as reported in a recent survey published by the United Nations in 2015, among women aged 15 to 49, the estimate of contraceptive prevalence using any method was 63.6% worldwide vs 39.5% in the least developed countries. However, the prevalence estimate for injectable contraceptives in the least developed countries (12.9%) was found to be more than twice that worldwide (4.6%).16 The target population for DMPA SC is represented by women who are seeking long-term contraception.

10 090177e18a903a4c\Approved\Approved On: 18-Nov-2016 03:23 Depot-medroxyprogesterone acetate (DMPA-SC) Sayana Press WHO EML Application December 2016

Benefit of Modern Contraception Techniques: Maternal Mortality

Increasing contraceptive use in developing countries has cut the number of maternal deaths by 40 percent over the past 20 years by reducing the number of unintended pregnancies.17 By preventing high-risk pregnancies, especially in women of high parities and those that would have ended in unsafe abortion, increased contraceptive use has reduced the maternal mortality rate by about 26 percent in little more than a decade. A further 30 percent of maternal deaths could be avoided by fulfilment of unmet need for contraception.17

Benefit of Modern Contraception Techniques: Children and Neonates

Further benefit of modern contraception methods are evident in developing countries where the risk of prematurity and low birth-weight doubles when conception occurs within six months of a previous birth, and children born within two years of an elder sibling are 60 percent more likely to die in infancy than are those born more than two years after their sibling.17 Use of family planning spaces births and mitigates these perinatal and child survival risks.

11 090177e18a903a4c\Approved\Approved On: 18-Nov-2016 03:23 Depot-medroxyprogesterone acetate (DMPA-SC) Sayana Press WHO EML Application December 2016

Benefit of DMPA-SC in Treating Endometriosis

In addition to the impact provided by contraception use, DMPA-SC has been shown to benefit women suffering from endometriosis. Two 18-month Phase 3 clinical studies, were each randomized, evaluator-blinded, parallel group, comparator-controlled, multinational studies designed to assess the safety and efficacy of DMPA-SC (104 mg subcutaneously every 3 months) in women between ages of 18 and 49 with endometriosis.18,19

Both these studies met their primary efficacy objective - clinical equivalence between treatment groups at 6 months - by demonstrating statistical equivalence between the DMPA-SC and the leuprolide comparator groups in at least 4 of the 5 endometriosis-associated pain categories in the ITT-OC analysis.19

9. Review of benefits: summary of comparative effectiveness in a variety of clinical settings.

Medroxyprogesterone acetate (MPA) is a synthetic analogue of 17 -hydroxyprogesterone, which has antiestrogenic, antiandrogenic, and antigonadotropic effects. It is a synthetic progestin (structurally related to the endogenous hormone progesterone), which has been demonstrated to possess several pharmacological actions on the endocrine system:

 Inhibition of pituitary gonadotropins (follicle-stimulating hormone [FSH] and luteinizing hormone [LH])

 Decrease of adrenocorticotropic hormone (ACTH) and hydrocortisone blood levels

 Decrease of circulating testosterone

 Decrease of circulating oestrogen levels (as the result of both FSH inhibition and enzymatic induction of hepatic reductase, resulting in increased clearance of testosterone and consequent decreased conversion of androgens to oestrogens)20

A 2010 systematic review of contraceptive efficacy across methods found that injectable contraceptives are highly effective compared with other methods. The review determined that injectable contraceptives have a Pearl Index of 0 and life-table range of 0 to 1.1. Comparatively, as explained in the review, injectable contraceptives are more effective than oral contraceptives, the patch, vaginal ring, and barrier methods.21

Depot (injectable)-MPA has been marketed since 1960 as intramuscular (IM) formulations for contraception (DEPO-PROVERA contraceptive injection). The drug has a well-known pharmacologic profile and a wide therapeutic safety margin.

12 090177e18a903a4c\Approved\Approved On: 18-Nov-2016 03:23 Depot-medroxyprogesterone acetate (DMPA-SC) Sayana Press WHO EML Application December 2016

Pfizer (the Applicant) has developed DMPA-SC to offer an alternative option to women who wish to use a contraceptive that does not require frequent administration and is available at a lower dose and volume of injection compared with the currently available presentations.

The clinical programme for the development of DMPA-SC for long-term female contraception is comprised of 6 completed studies, including three Phase 1/2 clinical pharmacology studies and three Phase 3 efficacy and safety studies. These studies were conducted using the DMPA-SC pre-filled syringe presentation.

The clinical pharmacology studies included a dose-finding study (Study 265), a pharmacokinetic (PK)/pharmacodynamic (PD) study in Asian women (Study 271)2, and a comprehensive PK/PD study in which PD of DMPA-SC was compared to that of DMPA-IM (Study 272).2 The Phase 3 studies included 2 open-label, non-comparative, multinational, 1-year trials (Studies 267 and 269) to evaluate the efficacy and safety of DMPA-SC when administered at a dose of 104 mg every 3 months.23 A sub-study of Study 267 (Study 267 BMD) in a separate population was directed at comparing bone mineral density (BMD) over a 2-year period in women randomized to DMPA-SC or DMPA-IM. 22 Studies 267 and 269 included an option for subjects to self-administer DMPA-SC in the practitioner’s office or independently after appropriate training.

The efficacy of DMPA-SC was established in the 2 pivotal Phase-3, open-label, non-comparative, multinational 1 year studies.

One of these pivotal studies was a Phase 3, open-label, multinational, and multicentre study (Phase III Contraception Study of Depot Subcutaneous Injection (DMPA-SC) in Women of Childbearing Potential in the Americas (Study 267)). Patients (N=722; aged between 18 and 49 years) received contraceptive injection given every 3 months for up to 1 year. The primary efficacy variable was the treatment failure cumulative pregnancy rate at 1 year. This was defined as a positive pregnancy test prior to the next scheduled injection. This incidence of treatment failure pregnancy for each treatment group was assessed by calculating the rate and 95% confidence interval (CI) using the life table method and the Pearl Index. In this study, there were 5616 woman-cycles of exposure to DMPA-SC, excluding the months when barrier contraception was used or no intercourse occurred. No unintended pregnancies were reported in the 722 women with data who had been treated in this study. DMPA-SC was found to be highly effective.23

The second pivotal efficacy study was a Phase 3, open-label, non-comparator, multinational, multi-centre study (One-year Contraception Study of Depot Medroxyprogesterone Acetate Subcutaneous Injection (DMPA-SC) in Women of Childbearing Potential in Europe and Asia, including Substudy Assessments of Endometrial Biopsy and Endometrial Thickness (Study 269). Patients (N=1065; aged between 18 and 49 years) received contraceptive injection given every 3 months for up to 1 year. The primary efficacy endpoint was the treatment

13 090177e18a903a4c\Approved\Approved On: 18-Nov-2016 03:23 Depot-medroxyprogesterone acetate (DMPA-SC) Sayana Press WHO EML Application December 2016

failure cumulative pregnancy rate at 1 year. This was defined as a positive pregnancy test prior to next scheduled dose. This incidence of treatment failure pregnancy for each treatment group was assessed by calculating the rate and 95% CI using the life table method and the Pearl Index. This study included 10,407 woman-cycles of exposure to DMPA-SC, excluding the months when barrier contraception was used or no intercourse occurred. No pregnancies were reported in the 1065 women who were treated and had follow-up data. Thus, DMPA-SC was highly effective.23

A smaller comparative study was performed of DMPA-SC (104 mg SC MPA) with the original DMPA-IM (150 mg IM MPA) with regard to efficacy and duration of ovulation suppression and the return to ovulation at 12 months was performed in a prospective, blinded, randomized, single-center, single-dose trial.2 The primary efficacy endpoint was the cumulative rate of ovulation at 12 months following a single injection of DMPA-IM or DMPA-SC. Ovulation was defined primarily by serum progesterone concentrations 4.7 ng/mL and confirmed by urinary Pd-3-G levels that were three times the mean baseline level for at least three consecutive urine samples. While delivering a 30% lower total dose than the intramuscular formulation, the lower-dose formulation of Depo-Provera suppressed ovulation for more than 13 weeks in all subjects and was not affected by body mass index or race. Median time for return to ovulation was 30 weeks, with a 97.4% cumulative rate of return to ovulation at 12 months. An immediate and sustained suppression of ovulation with the lower-dose formulation was achieved and was independent of differences in body weight or race, which suggests that the lower-dose formulation is appropriate for a wide range of women2, and that DMPA-SC provides women with an effective, reversible contraception option.

An abbreviated clinical programme was conducted in order to establish the utility of the pre-filled, single-dose, non-reusable delivery system, and provide a link to the clinical efficacy and safety data generated with DMPA-SC in the pre-filled syringe. This abbreviated programme was comprised of 2 studies, A6791030 (Phase 1 PK study) and A6791034 (injection volume delivery study). A comparison of the safety profiles of DMPA-IM and DMPA-SC did not identify any additional safety concerns for the SC formulation (Sayana Press) other than those already established for the IM formulation.

14 090177e18a903a4c\Approved\Approved On: 18-Nov-2016 03:23 Depot-medroxyprogesterone acetate (DMPA-SC) Sayana Press WHO EML Application December 2016

10. Review of harms and toxicity: summary of evidence on safety. Introduction

As presented in item 9, above, MPA is a synthetic progestin (structurally related to the endogenous hormone progesterone), which has been demonstrated to possess several pharmacological actions on the endocrine system.

Depot (injectable)-MPA has been marketed since 1960 as intramuscular (IM) formulations for contraception (DEPO-PROVERA contraceptive injection). In 2015, the cumulative patient exposure in contraception was estimated to be 29,939,428 patient years, of which more than 90% occurred in Europe and North America.

MPA is also indicated for the treatment of endometriosis, menopausal vasomotor symptoms, and oncology indications, including recurrent and/or metastatic endometrial and renal cell carcinoma and metastatic prostate cancer (DEPO-PROVERA Sterile Aqueous Suspension). In addition it is provided as an oral formulation for the diagnosis of primary and secondary amenorrhea, the treatment of secondary amenorrhea, dysfunctional (anovulatory) uterine bleeding, endometriosis, opposition of endometrial effects of oestrogen in menopausal women being treated with oestrogen and menopausal vasomotor symptoms (low dose tablets) and the treatment of recurrent and/or metastatic breast, endometrial and renal cancer, metastatic prostate cancer, anorexia and cachexia syndrome (high dose tablets). The drug has a well-known pharmacologic profile and a wide therapeutic safety margin.20

DMPA-IM

DMPA injectable suspension for IM administration is indicated for contraception.24 When administered at the recommended dose of 150 mg every 3 months for contraception, the average annual pregnancy rate for women using DMPA-IM is less than 1 for every 100 women.25 The most common adverse events (AEs) in women who use the drug are irregular bleeding, spotting and amenorrhea. DMPA-IM is an appropriate choice for women who prefer a highly effective contraceptive that does not require frequent administration.20

Depot medroxyprogesterone acetate subcutaneous acetate injection (DMPA-SC)

The dose of DMPA-SC for use in contraception was established in a Phase 1/2 dose-finding study, which showed that 100 mg was the minimum dose that would reliably suppress ovulation for the planned dosing interval of 13 weeks (plus a 1-week margin to extend the allowable compliance window [i.e., 12-14 weeks]).26 The initial SC formulation that was developed for the clinical programme had a concentration of 100 mg MPA per 0.625 mL, the injection volume was rounded to 0.65 mL for practical reasons, thereby providing the dose of 104 mg MPA per 0.65 mL injection volume, which is the approved dose.

15 090177e18a903a4c\Approved\Approved On: 18-Nov-2016 03:23 Depot-medroxyprogesterone acetate (DMPA-SC) Sayana Press WHO EML Application December 2016

DMPA-SC in a pre-filled syringe (PFS) was approved in the USA in December 2004 and has been marketed in the USA since 2005 under the trade name depo-subQ provera 10427. DMPA-SC in a PFS, under the trade name SAYANA, was first approved in the UK in October 2005 and subsequently approved in additional EU markets through the European Union (EU) mutual recognition procedure (MRP) in July 2007.28

Sayana Press is available in the Uniject® system, a container closure system that is designed for single use and immediate disposal. Sayana Press was first approved in the UK on 21 June 2011 through the decentralized procedure as an extension application to Sayana and was first marketed in Belgium on 04 January 2013. Two Phase 3 studies included an option for subjects to self- administer DMPA-SC in the practitioner’s office or independently after appropriate training. An investigator-initiated, non-randomized, independent study compared the self-injection of DMPA-SC in prefilled syringes versus administration of DMPA-IM by a healthcare professional in the clinic. This study was partially supported by Pfizer as an investigator-initiated research project (DMPA-SC study drug, in pre-filled syringes, was supplied to the Investigators by Pfizer). Pfizer gained approval for the Type II variation for Sayana Press to enable patients the option of self-injection following successful supervised injection under guidance of a healthcare professional.29

Overview of Development Programme for DMPA-SC2,20,23,28,29,30,31,33,35

The safety of DMPA-SC for contraception was demonstrated primarily through three Phase 3 contraception studies. Study 839-FEH-0012-267 and Study 839- FEH-0012-269a were large, 1-year contraceptive efficacy studies, while Study 839-FEH-0012-267BMD was a smaller, 3-year safety study focusing on bone mineral density (BMD) changes; these three studies constitute the primary safety studies for DMPA-SC. Six additional clinical studies, all conducted with DMPA-SC, provide supportive safety data. Additionally, four Phase 1/2 clinical pharmacology studies (Studies 265, 271, 272 and A6791030) and two Phase 3 studies (Studies 268 and 270) were carried out in patients with the signs and symptoms of endometriosis. Finally, three Phase 4 studies conducted with only the intramuscular formulation (IM) of DMPA (DMPA-IM; Depo-Provera) provide safety information that is relevant to the bone effects of DMPA-SC, since the bone effects of the intramuscular and subcutaneous formulations of DMPA have been shown to be substantially similar (Study M/5400/0234; Study A6791022 aka Study Z/5400/0261; Study A6791032).

Studies 267, 269, and 267BMD were Phase 3, multinational, contraception studies conducted in the indicated population for DMPA-SC: healthy women seeking contraception. Studies 267 and 269 were single-arm, open-label studies

aFor ease of reference, a clinical study numbered 839-FEH-0012-XXX or M/5400/XXX, according to the original Pharmacia numbering, will be referred to as Study XXX. For example, clinical Study 839-FEH-0012- 267 will be referred to as Study 267. Study Z/5400/0261 was given a Pfizer number (A6791022) because it was ongoing at the time the study was acquired by Pfizer.

16 090177e18a903a4c\Approved\Approved On: 18-Nov-2016 03:23 Depot-medroxyprogesterone acetate (DMPA-SC) Sayana Press WHO EML Application December 2016

that assessed the efficacy, safety, and subject satisfaction of DMPA-SC administered every 3 months for 1 year. Self-injection was performed, to a limited extent, by a sub-set of patients in Studies 267 and 269. Study 267BMD was originally a 2-year, randomized, evaluator-blinded comparison of DMPA-SC and DMPA-IM that was primarily designed to evaluate changes in BMD; an amendment extended the study for a third year, and subjects who completed 2- years of treatment were given the opportunity to continue on for a third year of the study either with the same treatment they had received or with no treatment. Data from Study 267BMD for subjects participating through 2 years and data for subjects opting to continue through 3 years are presented in this summary; data from subjects treated with DMPA-SC are further compared with those from subjects treated with DMPA-IM. In the summary of clinical safety, data from all of the subjects treated with DMPA-SC in Studies 267, 269, and 267BMD were combined, as appropriate, for analyses and discussions.

Studies 265, 271, 272, and A6791030 were Phase 1/2, single-site, clinical pharmacology studies conducted in healthy subjects. Study 265 was an open- label, randomised (4 different dose levels), single-dose, parallel-group, dose- finding study of DMPA administered subcutaneously. Study 271 was an open- label, randomised (2 different injection sites: anterior leg vs. abdomen), single- dose (104 mg), parallel-group study designed to examine the effects of DMPA-SC on ovulation in Asian women. Study 272 was an evaluator-blinded, randomized comparison of single doses of DMPA-SC and DMPA-IM that was designed to examine the effects of both formulations on ovulation suppression, duration of ovulation suppression, and return to ovulation. Study A6791030 was a randomised, open-label parallel group study in healthy female subjects to assess the pharmacokinetics of DMPA-SC administered using the Uniject delivery system versus DMPA-SC administered using the pre-filled syringe

Studies 268 and 270 were Phase 3, multinational, randomised, parallel-group, investigator-blinded, comparator-controlled studies that were designed to compare the effects of DMPA-SC and leuprolide in the treatment of patients with the signs and symptoms of endometriosis. Both were 18-month studies that contained a 6-month treatment period and a 12-month follow-up period when neither drug was used. Group BMD data for the 2 studies combined from patients randomized to DMPA-SC were analysed and included in this summary as supportive safety data.

As mentioned above, the following 3 studies involved only the intramuscular formulation of DMPA (DMPA-IM) but are included here because they provide information about bone safety that is relevant to the subcutaneous formulation.

Study 234 was a prospective, long-term, single-arm study of BMD changes in adult women using DMPA-IM for contraception, while Study A6791022 was a prospective, long-term, single-arm study of BMD changes in adolescent women using DMPA-IM for contraception. Both studies included BMD assessment after study drug was discontinued in order to examine BMD recovery after treatment. Study A6791032 was conducted as a post-approval safety commitment (PASS)

17 090177e18a903a4c\Approved\Approved On: 18-Nov-2016 03:23 Depot-medroxyprogesterone acetate (DMPA-SC) Sayana Press WHO EML Application December 2016

required by MHRA following the marketing approval of Sayana (DMPA-SC) in 2005. The purpose of Study A6791032 was to assess the effect of DMPA versus other hormonal contraception (primarily oral contraceptive pills) on fractures due to low BMD (osteoporotic fractures). This retrospective cohort study utilized the General Practice Research Database (UK) (GPRD). One additional clinical study is included in this presentation of safety results: study GA67815 was an independent clinical study that was sponsored and conducted by investigators in the U.K.; it was not sponsored by Pfizer. Subsequently, a clinical study report suitable for regulatory submission and review was produced by Pfizer in cooperation with the investigators. This study evaluated each woman’s experience with self–injection of DMPA-SC (using the pre-filled syringe) over a 1-year period through use of a questionnaire and provides additional supportive safety data. The study also involved a second, parallel, non-randomized arm in which women received DMPA-IM administered in the clinic by an HCP. Finally, Study A6791035 was a device usability study of DMPA-SC in the Uniject delivery system that assessed the ability of representative users of the device (volunteer participants) to understand the Instructions for Use (IFU) and demonstrate proper use of the delivery device. As a usability study, it did not involve any administration of study drug to the study participants and, therefore, does not provide any relevant drug safety findings.

Overall Extent of Exposure

All subjects in Studies 267, 269, and 267BMD who received at least 1 dose of study medication were included in the safety analyses. Across studies, the ITT population consisted of 2,053 subjects who received at least 1 injection of DMPA-SC and 268 subjects who received at least 1 injection of DMPA-IM. Supporting data and subject populations are discussed in the sections that follow. Exposure data are available in Table 1 of Appendix I.

Exposure to DMPA-SC and to DMPA-IM in Studies 267, 269, and 267BMD is summarized in Table 2 of Appendix I. In the 1-year Studies 267 and 269, subjects could receive up to 4 injections of DMPA-SC (i.e. 1 injection every 3 months), while in Study 267BMD, up to 12 injections could be received by subjects who continued in the third year.30

In Studies 267 and 269, adequately trained subjects were allowed to perform self-injection, either at the physician’s office or independently. Over half (58.2%, 1040/1787) of the subjects in Studies 267 and 269 performed at least 1 self-injection: 53.2% (384/722) of the subjects in Study 267 and 61.6% (656/1065) of the subjects in Study 269. At least 1 self-injection was performed by 15.6% (278/1787) of the subjects in Studies 267 and 269, which included 10.1% (73/722) of the subjects in Study 267 and 19.2% (205/1065) of the subjects in Study 269.

18 090177e18a903a4c\Approved\Approved On: 18-Nov-2016 03:23 Depot-medroxyprogesterone acetate (DMPA-SC) Sayana Press WHO EML Application December 2016

Study GA6781528

All subjects in Study GA67815 received at least 1 dose of study medication and were included in the safety analyses.

Treatment duration for each treatment group is summarized in Table 3 of Appendix 1. The total number of injections received by subjects during the study group was similar in each group (235 and 228 in the DMPA-SC and DMPA- IM groups, respectively). The majority of subjects (79.7%) in each group received 4 injections.

Study 23430

A total of 608 patients were enrolled in the study: 248 subjects in the DMPA-IM Group and 360 subjects in the Control Group. The ITT population consisted of subjects who had been enrolled into the study and had a measure at screening or baseline and at least one post-baseline measurement for any efficacy variable, and included 228 subjects in the DEPO-PROVERA Group and 310 subjects in the Control Group. In the DEPO-PROVERA Group 42 subjects completed the 240 weeks of treatment, and 44 subjects who entered the post- treatment phase completed the 96 week follow-up. In the Control Group 118 subjects completed the treatment phase and 87 subjects completed the 96 week follow-up.

Study A679102231

The study enrolled 389 adolescent women, with 169 electing DMPA-IM treatment at baseline and 220 electing abstinence or non-hormonal contraception. Since the choice of contraceptive was always up to the subject, some subjects elected to change contraceptive methods during the study. Therefore, over the course of the study a total of 191 subjects received 1 or more injections of DMPA-IM (range: 1 to 20 injections). DMPA-IM (150 mg) was administered every 3 months for up to 240 weeks (approximately 4.6 years). The dosing phase of the study, for the DMPA users, was stopped by the DSMB in 2003 because the DSMB judged the accumulated data to be sufficient to describe the loss of BMD while subjects were taking DMPA-IM, but follow-up bone measurements (post- treatment) were continued until 2006 so that post-treatment recovery of BMD could be studied more fully.

Study A679103232,33

Study A6791032 was a non-randomized, retrospective cohort study. Fractures were recorded from the General Practice Research Database (GPRD) records of 312,395 women, for up to 2 years prior to the index date and for up to 15 years after the index date, where the index date was the date of the woman’s first contraceptive prescription (DMPA or other contraceptive) in the system. Among all women in the study, N=79,065 had recorded use of DMPA and contributed a total of 173,713 person-years of observation time; 41,876 of these women had at least 6 months of records prior to the index date. A total of 233,330 women

19 090177e18a903a4c\Approved\Approved On: 18-Nov-2016 03:23 Depot-medroxyprogesterone acetate (DMPA-SC) Sayana Press WHO EML Application December 2016

were included in the non-user control group (women who used a hormonal contraceptive other than DMPA, mostly oral pills) and contributed 744,242 person-years of observation time; 124,491 of these women had at least 6 months of records prior to the index date. Note that adverse events other that fracture were not collected in this study.

Overview of Comparative Safety Data from Clinical Development Programme

Adverse Events

Analysis of Adverse Events

At least 1 AE was reported in 59.5% (1216/2043) of the subjects who received at least 1 injection of DMPA-SC in the prospective clinical trials. Note that AE data were not available for 10 DMPA-SC-treated subjects (including 3 in Study 267BMD) and 2 DMPA-IM-treated subjects. AEs were coded using the Medical Dictionary for Regulatory Activities (MedDRA) version 2.3.

Summaries of treatment-emergent AEs are available in Table 1.

Table 1. Summary of Subject Reporting Treatment-Emergent Adverse Events (ITT Population) ------267BMD ------All DMPA-SC DMPA-SC DMPA-IM N = 2053 N = 266a N = 268 n % n % n % Total subjects reportedb 2043 100 263 100 266 100 Adverse events 1216 59.5 214 81.4 207 77.8 Serious adverse events 34 1.7 10 3.8 6 2.3 Drug-related adverse events 805 39.4 144 54.8 149 56 Adverse events leading to 203 9.9 47 17.9 59 22.2 discontinuation Deaths 1 <0.1 0 0 0 0 Percentages are based on the total subjects reported. aThese subjects are included in the all DMPA-SC column. bNote that data were unavailable for 10 subjects of the total treated with DMPA-SC (5 from 269, 2 form 267 and 3 from 267BMD) and for 2 subjects treated with DMPA-IM. “All DMPA-SC” includes subjects from studies 266, 267BMD, and 268. Abbreviations: BMD=bone mineral density; DMPA=depot medroxyprogesterone acetate; IM=intramuscular; ITT = intent-to-treat; SC=subcutaneous.

20 090177e18a903a4c\Approved\Approved On: 18-Nov-2016 03:23 Depot-medroxyprogesterone acetate (DMPA-SC) Sayana Press WHO EML Application December 2016

Study GA6781528,34

For treatment-emergent AEs (all-causality), 21 out of 64 DMPA-SC subjects (32.8%) reported a total of 41 AEs. In the DMPA-IM group, there was a lower incidence of AEs reported: 12 subjects (18.8%) reported a total of 15 AEs.

For treatment-related AEs, 15 out of 64 DMPA-SC subjects (23.4%) reported a total of 30 AEs. In the DMPA-IM group, there was a lower incidence of AEs reported: 6 subjects (9.4%) reported a total of 9 AEs.

One severe AE was reported in the DMPA-IM group; all other AEs were mild or moderate in severity. Overall 9 (7.0%) subjects were discontinued from the study due to AEs, but there was no important difference between the 2 treatment groups (5 [7.8%] subjects who received DMPA-SC and 4 [6.3%] subjects who received DMPA-IM).

There were no deaths or SAEs reported during the study.

Study 234

This study in adult women focused on the change in BMD from baseline during DMPA use and after discontinuation of DMPA use. Results from this study are discussed in the BMD sub-section.

Study A6791022

This study in adolescents focused on the change in BMD from baseline during DMPA use and after discontinuation of DMPA use. Results from this study are discussed in the BMD sub-section.

Study A6791032

This retrospective cohort study focused solely on the association between the use of DMPA and bone fractures and did not report any other AE data. Results from this study are discussed in the BMD sub-section.

Common Adverse Events

In Studies 267, 267BMD, and 269 and with DMPA-IM in Study 267BMD, and data from case report forms (CRFs), AEs were reported in 59.5% (1216/2043) of all subjects treated with DMPA-SC. Few were serious (1.7%). One subject died due to a motor vehicle accident during Study 267; this death was not attributed to treatment with DMPA-SC. Treatment group assignment in Study 267BMD did not appear to influence the rate of reported AEs.

Overall, the most frequently reported AEs were headache NOS (8.5%, 173/2043), intermenstrual bleeding (7.1%, 145/2043), weight increased (6.9%, 140/2043), and amenorrhea NOS (6.4%, 130/2043). These were the only AEs

21 090177e18a903a4c\Approved\Approved On: 18-Nov-2016 03:23 Depot-medroxyprogesterone acetate (DMPA-SC) Sayana Press WHO EML Application December 2016

that were reported in at least 5% of the subjects. Most AEs were mild to moderate in severity.

Table 1 of Appendix II summarizes relatedness of AEs to study medication based on a 1% or greater cut-point for all subjects treated with DMPA-SC. At least 1 drug-related AE was reported in 39.4% (805/2043) of all DMPA-SC-treated subjects. The most frequently reported drug-related AEs were intermenstrual bleeding (7.0%, 143/2043), weight increased (6.7%, 136/2043), and amenorrhea NOS (6.3%, 129/2043).35

Study GA67815

The incidence of treatment related AEs is presented in Table 2 of Appendix II.28

Overall, AEs were reported more frequently in the DMPA-SC self-injection group in Study GA67815 compared with the DMPA-IM clinic group. This was the case for all-causality AEs and for treatment-related AEs.

The most notable differences in the reported AEs were for injection site reactions (14 reports for DMPA-SC; no reports for DMPA-IM), although there was a trend for greater AE incidence in the DMPA-SC group across most categories of AEs.

Deaths35

One subject died during the 1-year study period of Study 267 as a result of trauma sustained in a motor vehicle accident. Her death was considered unrelated to the study medication. No other deaths were reported among the interventional clinical studies.

Discontinuations Due to Adverse Events35

Overall, 9.9% (203/2043) of all subjects treated with DMPA-SC discontinued from the study because of one or more AEs. Higher percentages of subjects in Study 267BMD than in Study 267 or 269 discontinued because of AEs; this was true for subjects in both treatment groups. This could be attributed to the longer duration of Study 267BMD.

The most frequently reported (ie, at least 1% of subjects) AEs leading to discontinuation in subjects treated with DMPA-SC were increased weight (2.0%, 40/2043), intermenstrual bleeding (1.2%, 24/2043), decreased libido (1.1%, 22/2043), and acne NOS (1.0%, 20/2043).

Injection Site Reactions35

Sixteen preferred terms relating to possible injection site reactions were listed in the MedDRA System Organ Class General Disorders and Administrative Site Disorders and 6 preferred terms are listed in the Skin and Subcutaneous Tissue

22 090177e18a903a4c\Approved\Approved On: 18-Nov-2016 03:23 Depot-medroxyprogesterone acetate (DMPA-SC) Sayana Press WHO EML Application December 2016

Disorder System Organ Class. These preferred terms were grouped into 4 composite terms: injection site atrophy/dimpling, injection site nodule/lump, injection site pain/tenderness, and injection site reaction general.

Of the subjects who received treatment with DMPA-SC, 6.1% (124/2043) experienced injection site reactions that were reported as AEs; the overwhelming majority of subjects recovered from them. Some subjects had multiple occurrences of the same AE (preferred term) and/or had more than 1 type of injection site reaction. The descriptive terms often imply a more severe AE than was actually observed, since most of the events were of mild intensity: few subjects (0.5%, 11/2043) withdrew from study participation because of an injection site reaction. Approximately half were reported at the time of the first injection. Only 2 injection site reactions were reported after home self-injection: 1 in Study 267 and 1 in Study 269 (one injection site reaction was reported in a subject who was administered DMPA-IM).

The incidences of injection site reactions (by composite term, with 1 or more occurrences per subject) were: injection site nodule/lump (1.9%, 38/2043), injection site atrophy/dimpling (1.5%, 30/2043), injection site pain/tenderness (1.4%, 28/2043), and injection site reaction general (1.4%, 28/2043). As expected, most injection site reactions were considered drug (or device) related. One-hundred and ten subjects (5.4%, 110/2043) experienced injection site reaction events that were considered drug related. None was classified as serious.

Return to Ovulation,25,35

Following a single dose of DMPA-SC or DMPA-IM in Study 272, return to ovulation was determined based on the first occurrence of serum progesterone levels that were at least 4.7 ng/mL. The cumulative rate of ovulation at the end of 12 months post-injection in evaluable subjects was 97.4% (38/39) in the DMPA-SC group and 94.7% (18/19) in the DMPA-IM group. Further analyses of these data showed no apparent effect of BMI or race on the cumulative rate of ovulation by the end of 12 months in either group.

Based on the progesterone levels defined above, the median time to return of ovulation was 212 days for subjects in the DMPA-SC group and 183 days for subjects in the DMPA-IM group. Ovulation of all subjects in the DMPA-SC group was suppressed through at least 106 days; the majority of subjects returned to ovulation between 198 and 225 days after DMPA-SC administration. Ovulation of all subjects in the DMPA-IM group was suppressed through at least 70 days; the majority of subjects returned to ovulation between 170 and 197 days after DMPA-IM administration.35 A sub-study of Study 267 examined the return to ovulation (using weekly blood sampling for progesterone levels) following 3 injections of DMPA-SC in 15 subjects from a single U.S. centre. Twelve of the 15 (80%) subjects returned to ovulation (progesterone level 4.7 ng/mL) within one year following the last dose of DMPA-SC. In those subjects returning to ovulation, the median time taken was 291 days. Of the 3 subjects who didn’t

23 090177e18a903a4c\Approved\Approved On: 18-Nov-2016 03:23 Depot-medroxyprogesterone acetate (DMPA-SC) Sayana Press WHO EML Application December 2016

ovulate, one did not complete the 12-month follow-up period due to the occurrence of non-treatment-related AEs. These data are consistent with results collected in Study 272, which determined the suppression and duration of ovulation, and return to ovulation following a single injection of DMPA-SC.25

The return to ovulation after stopping DMPA-SC is expected to be similar to after stopping DMPA-IM. In clinical trials of DMPA-IM, an overall mean of 5.3 months from last injection to return of ovulation or normal menses was observed.36

Description of the adverse effects/reactions and estimates of their frequency

Loss of Bone Mineral Density (BMD)

Use of DMPA injection reduces serum oestrogen levels in premenopausal women and is associated with a statistically significant loss of BMD as bone metabolism accommodates to a lower oestrogen level. Bone loss may be greater with increasing duration of use and may not be completely reversible in some women. It is unknown if use of DMPA injection during adolescence and early adulthood, a critical period of bone accretion, will reduce peak bone mass. In both adult and adolescent females the decrease in BMD during treatment appears to be substantially reversible after DMPA injection is discontinued and ovarian oestrogen production increases.

After discontinuing Depo-Provera injection in adolescents, full recovery of mean BMD required 1 year at the lumbar spine, 4.6 years at the total hip and 3.4 years at the femoral neck.31,37

In adults, BMD was observed for a period of 2 years after DMPA injection was discontinued and partial recovery of mean BMD towards baseline was observed at total hip, femoral neck and lumbar spine. A large observational study of female contraceptive users showed that use of Depo-Provera injection has no effect on a woman’s risk for osteoporotic or non-osteoporotic fractures, as shown in the following Table 2.32,33

24 090177e18a903a4c\Approved\Approved On: 18-Nov-2016 03:23 Depot-medroxyprogesterone acetate (DMPA-SC) Sayana Press WHO EML Application December 2016

Table 2. Incidence of Fracture Before and After Use of DMPA in Subcohort of 166,367 Women With 6-24 Months of Preindex History32,33

Before Starting Contraceptive After Starting Contraceptive

DMPA Ever Number Person- Fractures Number of Person-years Fractures IRR Use of Years per 1,000 Fractures per 1,000 After/Before Fractures person- person- (95% CI) years years

DMPA users 582 64,737 9.0 1,574 173,713 9.1 1.01 (0.92- 1.11) Nonusers 1,320 192,748 6.8 4,939 672,052 7.3 1.07 (1.01-1.14) Crude IRR 1.31 (1.19- 1.23 (1.16-1.30) (95% CI) for 1.45) DMPA vs. nonuse IRR = incident rate ratio. CI = confidence interval; DMPA = depot medroxyprogesterone acetate; Note: Number of DMPA users = 41,876; number of nonusers = 124,491. A total of 72,190 post–index date, pre-DMPA person-years were omitted from the before/after analysis.

25 090177e18a903a4c\Approved\Approved On: 18-Nov-2016 03:23 Depot-medroxyprogesterone acetate (DMPA-SC) Sayana Press WHO EML Application December 2016

Menstrual Irregularities

Most women using DMPA-SC experienced alteration of menstrual bleeding patterns. Patients should be appropriately counseled concerning the likelihood of menstrual disturbance and the potential delay in return to ovulation. As women continued using DMPA-SC, fewer experienced irregular bleeding and more experienced amenorrhea. During months 6 and 12, 39% and 56.5% of women, respectively, experienced amenorrhea. The changes in menstrual patterns from the three contraception trials are presented in Figures 1 and 2. Figure 1 shows the increase in the percentage of women experiencing amenorrhea over the 12 month study. Figure 2 presents the percentage of women experiencing spotting only, bleeding only, and bleeding and spotting over the same time period. In addition to amenorrhea, altered bleeding patterns included intermenstrual bleeding, menorrhagia and metrorrhagia. If abnormal bleeding associated with DMPA subcutaneous injection persists or is severe, appropriate investigation and treatment should be instituted.

Figure 1. Percent of DMPA subcutaneous injection -Treated Women with Amenorrhea per 30-Day Month Contraception Studies (ITT Population, N=2053)

26 090177e18a903a4c\Approved\Approved On: 18-Nov-2016 03:23 Depot-medroxyprogesterone acetate (DMPA-SC) Sayana Press WHO EML Application December 2016

Figure 2. Percent of DMPA subcutaneous injection -Treated Women with Bleeding and/or Spotting per 30-Day Month Contraception Studies (ITT Population, N=2053) Cancer Risks

Long-term case-controlled surveillance of DMPA-IM 150 mg users found no overall increased risk of ovarian, liver, or cervical cancer and a prolonged, protective effect of reducing the risk of endometrial cancer in the population of users.38,39,40,41,42,43

Breast cancer is rare among women under 40 years of age whether or not they use hormonal contraceptives.36

In several epidemiologic studies no overall increased risk for breast cancer was found among users of injectable depot progestogens in comparison to non- users.39,44,45 However, an increased relative risk (e.g. 2.0 in one study) was found for women who currently used injectable depot progestogens or had used them only a few years before.38

It is not possible to infer from these data whether this increased rate of breast cancer diagnosis among current users is due to increased surveillance among current users, the biological effects of injectable progestogens, or a combination of reasons.44,45

Thromboembolic Disorders

Although MPA has not been causally associated with the induction of thrombotic or thromboembolic disorders, MPA is not recommended in any patient with a history of venous thromboembolism (VTE). Discontinuation of MPA is recommended in patients who develop VTE while undergoing therapy with MPA.

27 090177e18a903a4c\Approved\Approved On: 18-Nov-2016 03:23 Depot-medroxyprogesterone acetate (DMPA-SC) Sayana Press WHO EML Application December 2016

Anaphylaxis and Anaphylactoid Reaction

MPA is contraindicated in women with known hypersensitivity to MPA or any component of the drug. If an anaphylactic reaction occurs, appropriate therapy should be instituted. Serious anaphylactic reactions require emergency medical treatment.46

Ocular Disorders

Medication should not be re-administered pending examination if there is a sudden partial or complete loss of vision or if there is a sudden onset of proptosis, diplopia, or migraine. If examination reveals papilledema or retinal vascular lesions, medication should not be re-administered.36

Weight Changes

Weight changes are common but unpredictable. In the phase 3 studies body weight was followed over 12 months. Half (50%) of women remained within 2.2 Kg of their initial body weight. 12% of women lost more than 2.2 Kg, and 38% of women gained more than 2.3 Kg.36

Fluid Retention

There is evidence that progestogens may cause some degree of fluid retention, and as a result, caution should be exercised in treating any patient with a pre- existing medical condition that might be adversely affected by fluid retention.36

Psychiatric Disorders

Patients with a history of treatment for clinical depression should be carefully monitored while receiving Sayana Press.36

Protection Against Sexually Transmitted Diseases

Patients should be counselled that Sayana Press does not protect against HIV infection (AIDS) or other sexually transmitted diseases.36

Carbohydrate/Metabolism

Some patients receiving progestogens may exhibit a decrease in glucose tolerance. Diabetic patients should be carefully observed while receiving such therapy.36

Liver Function

If jaundice develops in any woman receiving Sayana Press, consideration should be given to not re-administer the medication.36

Interaction with other medicinal products and other forms of interaction

28 090177e18a903a4c\Approved\Approved On: 18-Nov-2016 03:23 Depot-medroxyprogesterone acetate (DMPA-SC) Sayana Press WHO EML Application December 2016

No interaction studies have been performed with Sayana Press.

Interactions with other medical treatments (including oral anticoagulants) have rarely been reported, but causality has not been determined. The possibility of interactions should be borne in mind in patients receiving concurrent treatment with other drugs.

MPA is metabolized in-vitro primarily by hydroxylation via the CYP3A4. Specific drug-drug interaction studies evaluating the clinical effects with CYP3A4 inducers or inhibitors on MPA have not been conducted and therefore the clinical effects of CYP3A4 inducers or inhibitors are unknown.

Fertility, pregnancy and lactation

Fertility

Sayana Press is indicated for the prevention of pregnancy.

Women may experience a delay in return to fertility (conception) following discontinuation of Sayana Press.

Pregnancy

Sayana Press is contraindicated in women who are pregnant. Some reports suggest an association between intrauterine exposure to progestational drugs in the first trimester of pregnancy and genital abnormalities in male and female fetuses. If Sayana Press is used during pregnancy, or if the patient becomes pregnant while using this drug, the patient should be warned of the potential hazard to the fetus.

One study found that infants from unintentional pregnancies that occurred 1 to 2 months after injection of medroxyprogesterone acetate Injection 150 mg IM were at an increased risk of low birth weight; this, in turn, has been associated with an increased risk of neonatal death. However, the overall risk of this is very low because pregnancies while on medroxyprogesterone acetate Injection 150 mg IM are uncommon.

Children exposed to MPA in utero and followed to adolescence showed no evidence of any adverse effects on their health including their physical, intellectual, sexual or social development.

Lactation

Low detectable amounts of drug have been identified in the milk of mothers receiving MPA. In nursing mothers treated with medroxyprogesterone acetate injection 150 mg IM, milk composition, quality, and amount are not adversely affected. Neonates and infants exposed to MPA from breast milk have been studied for developmental and behavioural effects through puberty. No adverse effects have been noted. However, due to limitations of the data regarding the

29 090177e18a903a4c\Approved\Approved On: 18-Nov-2016 03:23 Depot-medroxyprogesterone acetate (DMPA-SC) Sayana Press WHO EML Application December 2016

effects of MPA in breastfed infants less than six weeks old, Sayana Press should be given no sooner than six weeks postpartum when the infant's enzyme system is more developed.

Effects on ability to drive and use machines

Sayana Press has no influence on the ability to drive and use machines.

Adverse reactions

The table below provides a listing of adverse drug reactions for DMPA-SC from clinical trials or post-marketing experience with DMPA-IM or DMPA-SC. Their frequency is based on all-causality data from clinical studies that enrolled 2053 women who received DMPA-SC for contraception. The most frequently (>5%) reported adverse drug reactions were headache (8.9%), metrorrhagia (7.1%), weight increased (6.9%), amenorrhoea (6.3%) and injection site reactions (any type, 6.1%).

Adverse reactions are listed according to the CIOMS frequency categories. These are as follows:

Very Common (≥1/10) Common (≥1/100 to <1/10) Uncommon (≥1/1,000 to <1/100) Rare (≥1/10,000 to <1/1,000) Frequency not known (cannot be estimated from the available data)

30 090177e18a903a4c\Approved\Approved On: 18-Nov-2016 03:23 Depot-medroxyprogesterone acetate (DMPA-SC) Sayana Press WHO EML Application December 2016

Table 3. Adverse reactions listed according to CIOMS frequency categories System organ Very Common Uncommon Rare Not known class Common Neoplasms benign, Breast cancer malignant and (see section unspecified 4.4) (including cysts and polyps) Immune system Drug hypersensitivity Anaphylactic disorders reaction, Anaphylactoid reaction, Angioedema Metabolism and Fluid retention, Increased nutrition disorders appetite, Decreased appetite Psychiatric disorders Depression, Insomnia, Nervousness, Emotional Anxiety, Affective disorder, Anorgasmia disorder, Irritability, Libido decreased Nervous system Dizziness, Headache Migraine, Somnolence Seizure disorders Ear and labyrinth Vertigo disorders Cardiac disorders Tachycardia Vascular disorders Hypertension, Varicose vein, Pulmonary Hot flush embolism, Embolism, and thrombosis (see section 4.4)

31 090177e18a903a4c\Approved\Approved On: 18-Nov-2016 03:23 Depot-medroxyprogesterone acetate (DMPA-SC) Sayana Press WHO EML Application December 2016

thrombophlebitis Gastrointestinal Abdominal pain, Nausea Abdominal distension disorders Hepatobiliary Jaundice, Hepatic disorders function abnormal (see section 4.4)

32 090177e18a903a4c\Approved\Approved On: 18-Nov-2016 03:23 Depot-medroxyprogesterone acetate (DMPA-SC) Sayana Press WHO EML Application December 2016

Table 3. Adverse reactions listed according to CIOMS frequency categories (cont.) System organ Very Common Uncommon Rare Not known class Common Skin and Acne Alopecia, Hirsutism, Lipodystrophy Skin striae subcutaneous tissue Dermatitis, Ecchymosis, acquired disorders Chloasma, Rash, Pruritus, Urticaria Musculoskeletal and Back pain, Pain in extremity Arthralgia, Muscle Osteoporosis, connective tissue spasms Osteoporotic disorders fractures Reproductive Menometrorrhagia, Ovarian cyst, Uterine system & breast Metrorrhagia, Menorrhagia haemorrhage (irregular, disorders (see section 4.4), increase, decrease), Dysmenorrhoea, Vaginal discharge, Amenorrhoea, Vaginitis, Breast Dyspareunia, pain Galactorrhoea, Vulvovaginal dryness, Premenstrual syndrome, Breast tenderness, Breast enlargement General disorders Fatigue, Injection site reaction, Pyrexia Asthenia and administration Injection site persistent site conditions atrophy/Indentation/dimpling, Injection site nodule/lump, Injection site pain/ tenderness Investigations Weight increased (see section Bone density decreased Weight 4.4), Smear cervix abnormal (see section 4.4), decreased (see Glucose tolerance section 4.4) decreased (see section

33 090177e18a903a4c\Approved\Approved On: 18-Nov-2016 03:23 Depot-medroxyprogesterone acetate (DMPA-SC) Sayana Press WHO EML Application December 2016

4.4), Hepatic enzyme abnormal

34 090177e18a903a4c\Approved\Approved On: 18-Nov-2016 03:23 Depot-medroxyprogesterone acetate (DMPA-SC) Sayana Press WHO EML Application December 2016

Safety in special populations36

Patients with hepatic impairment

The effect of hepatic disease on the pharmacokinetics of Sayana Press is unknown. As Sayana Press largely undergoes hepatic elimination it may be poorly metabolised in patients with severe hepatic insufficiency.

Patients with renal impairment

The effect of renal disease on the pharmacokinetics of Sayana Press is unknown. No dosage adjustment should be necessary in women with renal insufficiency, since Sayana Press is almost exclusively eliminated by hepatic metabolism.

Paediatric population

Sayana Press is not indicated before menarche. Data in adolescent females (12- 18 years) is available for IM administration of MPA. Other than concerns about loss of BMD, the safety and effectiveness of Sayana Press is expected to be the same for adolescents after menarche and adult females.

Elderly population

Use of DMPA-SC is not expected in the elderly population as the indication is contraception.

CONCLUSIONS

 DMPA-SC is a well-tolerated drug with a good safety profile. The overall safety profile of DMPA-SC shown in the Phase 3 contraception studies is consistent in most respects with that of the marketed DMPA-IM formulation and reflects the known physiological effects of MPA.

 Following a single DMPA-SC injection, the median time to ovulation was 212 days. Based on a single-dose study and a Phase 3 clinical study, 80% to 97.4% of the study participants returned to ovulation within the 12-month post-treatment observation period.

 In both adult and adolescent females, DMPA by any route (intramuscular or subcutaneous) causes a statistically significant decrease in BMD of about 5%, on average. There appears to be no significant difference in BMD loss in subjects who use DMPA-SC compared to DMPA-IM. This BMD loss is reversible, and has not been shown to have any effect on a woman’s risk for bone fracture.

 With the exception of injection site reactions, the types of AEs seen with DMPA-SC are similar to those of DMPA-IM. The higher rate of injection site reactions is not unexpected, since in general subcutaneous injections result in

35 090177e18a903a4c\Approved\Approved On: 18-Nov-2016 03:23 Depot-medroxyprogesterone acetate (DMPA-SC) Sayana Press WHO EML Application December 2016

more pain, swelling, and induration than intramuscular injections. Most of these events were of mild intensity and fewer than 1% of the subjects withdrew from their studies because of an injection site reaction.

 A majority of subjects experience bleeding irregularities on DMPA-SC, which generally progress to amenorrhoea on long-term treatment. Menstrual cycles gradually return to normal following discontinuation of treatment. The risk of subjects experiencing reproductive system and breast disorders due to DMPA-SC appears to be minimal based on AE data in the contraception studies.

 Although DMPA-SC is extensively metabolized by liver P450 enzymes, clinically significant drug-drug interactions due to induction of metabolic enzymes are considered unlikely. No clinically relevant drug interactions were demonstrated in the clinical studies.

 The available data for home self-injection do not suggest that these AEs, including injection site reactions, are likely to occur at a different frequency when the drug is self-administered as compared with having the injection given by a HCP.

 In summary, safety results of the Phase 3 studies show no evidence of significant health risk with the use of DMPA-SC. The profile of adverse effects reported with DMPA-SC use is comparable to that of DMPA-IM.

36 090177e18a903a4c\Approved\Approved On: 18-Nov-2016 03:23 Depot-medroxyprogesterone acetate (DMPA-SC) Sayana Press WHO EML Application December 2016

11. Summary of available data on comparative cost and cost- effectiveness within the pharmacological class or therapeutic group. Pricing of Sayana Press

Injectable contraceptives are a widely-used family planning method, particularly among women in developing countries. In November 2014, Pfizer Inc., the Bill & Melinda Gates Foundation and the Children’s Investment Fund Foundation (CIFF) entered into a collaboration to help broaden access to Sayana Press for women most in need in 69 of the world’s poorest countries, with the support of a consortium of public and private sector supporters. Through this collaboration, the Sayana Press presentation is currently (December 2016) being sold for US $1 per dose to qualified purchasers, who help enable the poorest women in these countries to have access to the contraceptive at reduced or no cost.47

For populations and countries that are not included in this agreement, Pfizer will continue to price based on a differential pricing structure and take into consideration local economic conditions and family planning climates. Prices in higher income countries will reflect the innovation and value that Sayana Press, and in particular Sayana Press Self-Injection, can bring; we will continue to explore access optimizations in all settings as appropriate.

37 090177e18a903a4c\Approved\Approved On: 18-Nov-2016 03:23 Depot-medroxyprogesterone acetate (DMPA-SC) Sayana Press WHO EML Application December 2016

Range of costs and patient preference of the proposed medicine

Table 4. Range of types of costs and patient preference of proposed medicine in low resource settings

Injection by Additional Medication Patient healthcare syringe needed price to preference (in provider (cost of qualified low resource needed syringe and purchasers (in settings) (requiring additional low resource costs of procurement) settings) transportation to visit and/or cost of injection) DMPA IM Yes Yes USAID Catalog: Fewer than 20% $0.80/vial of current DMPA IM patients preferred DMPA IM over SP in Uganda & Senegal at 3- month follow- up48 Sayana Yes No $1/unit to The majority Press qualified (>80%) of purchasers with current DMPA IM partnership patients consortium preferred SP to DMPA IM in Uganda & Senegal at 3- month follow- up48

Sayana No No $1/unit to Stated Press w/ qualified acceptability: A self purchasers with fifth to a half of injection partnership women were indication consortium moderately or very much willing to try independent self injection in Senegal and Uganda48

Study in Uganda: Nearly all of those who gave two injections (98%)

38 090177e18a903a4c\Approved\Approved On: 18-Nov-2016 03:23 Depot-medroxyprogesterone acetate (DMPA-SC) Sayana Press WHO EML Application December 2016

expressed a desire to continue with self-injection 3- months post- training (secondary objective)49

Current pricing in developed countries for Sayana Press includes: Belgium (€30.69/unit50), Netherlands (€ 13.50/unit51 and UK (£6.90/unit52).

Cost effectiveness

The cost effectiveness of Sayana Press, and particularly its self-injectable form, is the subject of growing exploration. Long acting reversible contraceptive agents (LARCs) as a class have a well-established body of literature demonstrating their cost-effectiveness comparative to other contraceptives; methods that require action by the user less frequently are both less costly and more effective than methods requiring actions on a daily basis.53,54,55 DMPA-IM has also been reviewed in cost utility and cost effectiveness studies, with favourable cost savings found comparative to many other methods.56,57 UK NICE guidelines support the cost effective nature of LARCs compared to many other contraceptive methods.58 Of the LARCs reviewed in their 2005 assessment, DMPA IM had room for further improvement; in particular with levers impacting consistency of use, compliance, and continuation.56 Similar to other cost effectiveness models though to date, the UK assessment is situated in developed settings; explorations continue in developing nations (details further remarked at the end of this section).

As a reformulation of DMPA-IM, Sayana Press is intended for subcutaneous administration. It has high efficacy under perfect use conditions, is generally well tolerated, and is a lower dose (104 mg MPA/0.65 mL) compared with DMPA- IM 150 mg.2,23 The option of administration through Uniject adds potential advantages including: (a) minimization of wastage as single prefilled dose, (b) an all-in-one presentation that eliminates the need for bundled vials and syringes that might lead to potential mismatches at service delivery point, (c) a non-reusable delivery system that may help minimize pathogen transmission through needle reuse, (d) compact size for easy transport, storage and disposal, and (e) ease of administration, which includes potential for self-injection.

Sayana Press self-injection offers an extended value profile for patients that could result in cost savings. Self-injection can lead to fewer needed clinic visits, and associative costs such as transportation, productivity/absent time lost from work and wages, and direct costs associated with clinic care. Implications for better adherence due to convenience are additional exploratory factors for cost savings.

39 090177e18a903a4c\Approved\Approved On: 18-Nov-2016 03:23 Depot-medroxyprogesterone acetate (DMPA-SC) Sayana Press WHO EML Application December 2016

PATH has remained committed in exploring this in real world settings.59 Operational feasibility studies, launched in 2015 in Senegal and Uganda, have early results that indicate most women readily attain proficiency in self-injection. Cost effectiveness analyses comparative to DMPA-IM are also continuing to more fully describe the above mentioned benefits anticipated with self-injected Sayana Press compared to provider-administered DMPA-IM.

40 090177e18a903a4c\Approved\Approved On: 18-Nov-2016 03:23 Depot-medroxyprogesterone acetate (DMPA-SC) Sayana Press WHO EML Application December 2016

REGULATORY INFORMATION 12. Summary of regulatory status of the medicine.

Sayana Press (medroxyprogesterone acetate for subcutaneous injection) is currently approved for contraceptive use. It is a highly effective and generally well-tolerated contraceptive.

To date, Pfizer has no information of other manufacturers having registered a formulation of DMPA for SC administration

A summary listing of the global regulatory approvals for Sayana Press®/Sayana®/Sayanaject® (medroxyprogesterone acetate) 104 mg/0.65 mL suspension for injection in the Uniject™ delivery system for contraception as of November 2016 is provided below.

41 090177e18a903a4c\Approved\Approved On: 18-Nov-2016 03:23 Depot-medroxyprogesterone acetate (DMPA-SC) Sayana Press WHO EML Application December 2016

Country Trade Name Presentation Aruba Sayana Single dose container Austria Sayana Press Single dose container Bangladesh Sayana Press Single dose container Belgium Sayana Press Single dose container Bolivia Sayana Single dose container Burkina Faso Sayana Press Single dose container Costa Rica Sayana Single dose container Curacao Sayana Single dose container Denmark Sayanaject Single dose container Democratic Republic of Sayana Press Single dose Congo container El Salvador Sayana Single dose container Ethiopia Sayana Press Single dose container Finland Sayanaject Single dose container France Sayana Press Single dose container Guatemala Sayana Single dose container Honduras Sayana Single dose container Hungary Sayana Press Single dose container Italy Sayanaject Single dose container India Sayana Press Single dose container Jamaica Sayana Single dose container Kenya Sayana Press Single dose container Madagascar Sayana Press Single dose container Malawi Sayana Press Single dose container Mali Sayana Press Single dose container

42 090177e18a903a4c\Approved\Approved On: 18-Nov-2016 03:23 Depot-medroxyprogesterone acetate (DMPA-SC) Sayana Press WHO EML Application December 2016

Country Trade Name Presentation Mexico Sayana Single dose container Morocco Sayana Press Single dose container Mozambique Sayana Press Single dose container Myanmar Sayana Press Single dose container Netherlands Sayana Press Single dose container Nicaragua Sayana Single dose container Niger Sayana Press Single dose container Nigeria Sayana Press Single dose container Panama Sayana Single dose container Romania Sayanaject Single dose container Senegal Sayana Press Single dose container Spain Sayanaject Single dose container Sweden Sayanaject Single dose container Tanzania Sayana Press Single dose container Trinidad & Tobago Sayana Single dose container Uganda Sayana Press Single dose container United Kingdom Sayana Press Single dose Sayanaject container Venezuela Sayana Single dose container

43 090177e18a903a4c\Approved\Approved On: 18-Nov-2016 03:23 Depot-medroxyprogesterone acetate (DMPA-SC) Sayana Press WHO EML Application December 2016

13. Availability of pharmacopoeial standards (British Pharmacopoeia, International Pharmacopoeia, United States Pharmacopoeia, European Pharmacopeia). The active ingredient of Sayana Press - medroxyprogesterone acetate - is in The European Pharmacopoeia and The United States Pharmacopoeia

44 090177e18a903a4c\Approved\Approved On: 18-Nov-2016 03:23 Depot-medroxyprogesterone acetate (DMPA-SC) Sayana Press WHO EML Application December 2016

APPENDICES Appendix I. Clinical Trial Exposure to DMPA-SC

Appendix II. Safety Data from DMPA-SC Clinical Trials

45 090177e18a903a4c\Approved\Approved On: 18-Nov-2016 03:23 Depot-medroxyprogesterone acetate (DMPA-SC) Sayana Press WHO EML Application December 2016

Appendix I. Clinical Trial Exposure to DMPA-SC

Table 1. Extent of Exposure to DMPA-SC and DMPA-IM (ITT Population)

Study ------Number of Subjects ------DMPA-SC DMPA-IM 267 722 0 269 1065 0 267BMD 266 268 TOTAL 2053 268 Abbreviations: BMD=bone mineral density; DMPA=depot medroxyprogesterone acetate; IM=intramuscular; ITT = intent-to-treat; SC=subcutaneous.

Table 2. Number of DMPA-SC and DMPA-IM Injections Received by Subjects (ITT Population) ------267BMD ------All DMPA-SC DMPA-SC DMPA-IM N = 2053 N = 266a N = 268 Number of n % n % n % Injections 1 177 8.6 21 7.9 35 13.1 2 213 10.4 37 13.9 26 9.7 3 117 5.7 24 9.0 23 8.6 4 1388 67.6 26 9.8 31 11.6 5 22 1.1 22 8.3 16 6.0 6 7 0.3 7 2.6 9 3.4 7 4 0.2 4 1.5 8 3.0 8 41 2.0 41 15.4 49 18.3 9 8 0.4 8 3.0 2 0.7 10 4 0.2 4 1.5 4 1.5 11 5 0.2 5 1.9 8 3.0 12 67 3.3 67 25.2 57 21.3 Total subjects 2053 100 266 100 268 100 reported aThese subjects are included in the all DMPA-SC column. Abbreviations: BMD=bone mineral density; DMPA=depot medroxyprogesterone acetate; IM=intramuscular; ITT = intent-to-treat; SC=subcutaneous.

46 090177e18a903a4c\Approved\Approved On: 18-Nov-2016 03:23 Depot-medroxyprogesterone acetate (DMPA-SC) Sayana Press WHO EML Application December 2016

Table 3. Treatment Duration in Study GA67815 Number of Injections DMPA-SC* DMPA-IM* N=64 N=64 1 2 (3.1) 3 (4.7) 2 4 (6.3) 9 (14.1) 3 7 (10.9) 1 (1.6) 4 51 (79.7) 51 (79.7) Total number of injections given during the study 235 228

*Values represent the number of subjects given one to four injections (% of N). Subjects SC004, SC045 and SC054 had to use a second syringe because the needle separated from the syringe during their first attempt to perform self-injection, but these subjects were counted only once. Abbreviations: DMPA-IM = Depot medroxyprogesterone acetate administered intra- muscularly; DMPA-SC = Depot medroxyprogesterone acetate administered subcutaneously; N = Total number of subjects.

47 090177e18a903a4c\Approved\Approved On: 18-Nov-2016 03:23 Depot-medroxyprogesterone acetate (DMPA-SC) Sayana Press WHO EML Application December 2016

Appendix II. Safety Data from DMPA-SC Clinical Trials Table 1. Drug-Related Adverse Events Reported in 1%* of Subjects (ITT Population) System/Organ Classa All DMPA-SC DMPA-SCb DMPA-IM Preferred Term N = 2053 N = 266 N = 268 n % n % n % Total subjects reported 2043 100 263 100 266 100 Subjects with at least 1 805 39.4 144 54.8 149 56 drug-related adverse event General disorders and administration site conditions Fatigue 30 1.5 4 1.5 2 0.8 Injection site atrophy 23 1.1 7 2.7 0 0 Injection site pain 26 1.3 4 1.5 0 0 Investigations Weight increased 136 6.7 32 12.2 38 14.3 Nervous system disorders Headache NOS 79 3.9 9 3.4 14 5.3 Psychiatric disorders Depression NOS 28 1.4 9 3.4 5 1.9 Irritability 21 1 6 2.3 3 1.1 Libido decreased 54 2.6 8 3 16 6 Reproductive system and breast disorders Amenorrhea NOS 129 6.3 2 0.8 5 1.9 Intermenstrual bleeding 143 7 15 5.7 15 5.6 Menometrorrhagia 48 2.3 9 3.4 10 3.8 Menorrhagia 32 1.6 0 0 3 1.1 Menstruation irregular 25 1.2 0 0 3 1.1 Vaginal hemorrhage 74 3.6 6 2.3 5 1.9 Skin and subcutaneous tissue disorders Acne NOS 61 3 18 6.8 17 6.4 *The 1% cut-point was based on all DMPA-SC-treated subjects. Both treatment groups in Study 267BMD are included as a comparison. “All DMPA-SC” includes subjects from studies 266, 267BMD, and 268. Note that data were not available for 10 subjects in the DMPA-SC group (5 from 269, 2 form 267 and 3 from 267BMD) and for 2 subjects in the DMPA-IM group. aMedDRA version 2.3 bThese subjects are included in the all DMPA SC column. Abbreviations: BMD=bone mineral density; DMPA=depot medroxyprogesterone acetate; IM=intramuscular; ITT = intent-to-treat; NOS=not otherwise specified; SC=subcutaneous. Source: Clinical study reports for Studies 266, 267BMD, and 268.

48 090177e18a903a4c\Approved\Approved On: 18-Nov-2016 03:23 Depot-medroxyprogesterone acetate (DMPA-SC) Sayana Press WHO EML Application December 2016

Table 2. Study GA67815 – Treatment-Related Treatment-Emergent Adverse Events TEAE (Treatment-Related) DMPA-SC (N = 64) DMPA-IM (N = 64) n % n % Gastrointestinal Disorders 4 6.3 1 1.6 Abdominal distension 0 1 1.6 Abdominal mass 1 1.6 0 Abdominal pain 1 1.6 0 Diarrhoea 1 1.6 0 Gastritis 0 1 1.6 Nausea 2 3.1 0 Vomiting 1 1.6 0 General Disorders and Administration Site 10 15.6 0 Conditions Feeling abnormal 1 1.6 0 Injection site induration 1 1.6 0 Injection site mass 1 1.6 0 Injection site pain 4 6.3 0 Injection site reaction 7 10.9 0 Injection site vesicles 1 1.6 0 Infections and Infestations 0 2 3.1 Candida infection 0 2 3.1 Investigations 0 1 1.6 Weight increased 0 1 1.6 Musculoskeletal and Connective Tissue Disorders 1 1.6 0 Pain in extremity 1 1.6 0

49 090177e18a903a4c\Approved\Approved On: 18-Nov-2016 03:23 Depot-medroxyprogesterone acetate (DMPA-SC) Sayana Press WHO EML Application December 2016

Table 2. Study GA67815 – Treatment-Related Treatment-Emergent Adverse Events (cont.)

TEAE (Treatment-Related) DMPA-SC (N = 64) DMPA-IM (N = 64) n % n % Nervous System Disorders 1 1.6 0 Tremor 1 1.6 0 Psychiatric Disorders 2 3.1 1 1.6 Emotional disorder 2 3.1 0 Irritability 0 1 1.6 Mood swings 0 1 1.6 Reproductive System and Breast Disorders 3 4.7 1 1.6 Breast tenderness 2 3.1 1 1.6 Premenstrual cramps 1 1.6 0 Vaginal discharge 1 1.6 0 Skin and Subcutaneous Tissue Disorders 0 1 1.6 Skin disorder 0 1 1.6 Vascular Disorders 1 1.6 0 Hot flush 1 1.6 0 Total Preferred Term Events 30 9 DMPA-IM = Depot medroxyprogesterone acetate Intramuscular; DMPA-SC = Depot medroxyprogesterone acetate subcutaneous; N = total number of subjects participated in study;TEAE = treatment emergent adverse events.

50 090177e18a903a4c\Approved\Approved On: 18-Nov-2016 03:23 Depot-medroxyprogesterone acetate (DMPA-SC) Sayana Press WHO EML Application December 2016

REFERENCES

1. Medical eligibility criteria for contraceptive use, Sexual and reproductive Health, 5th edition, 2015 World Health Org. Accessed at: http://www.who.int/reproductivehealth/publications/family_planning/Ex-Summ- MEC-5/en. 23 Aug 2015.

2. Jain J, Dutton C, Nicosia A. et al. Pharmacokinetics, ovulation suppression and return to ovulation following a lower dose subcutaneous formulation of Depo- Provera. Contracept 2004;70:11-18.

3. Making family planning accessible in resource-poor settings. Prata N. Phil Trans R Soc B. 2009;364:3093-9.

4. Family Planning 2020. Progress Report 2013-2014: Executive Summary. Available at: http://progress.familyplanning2020.org/executive-summary. Accessed: November 4, 2014.

5. National Health Service. The Contraceptive Injection. Available at: http://www.nhs.uk/conditions/contraception-guide/pages/contraceptive- injection.aspx. Accessed: September 8, 2015.

6. Electronic Medicines Compendium. Noristerat SPC. Available at: http://www.medicines.org.uk/emc/medicine/1835. Accessed: September 8, 2015.

7. Schimmer BP, Parker KL. Chapter 66. Contraception and Pharmacotherapy of Obstretrical and Gynecological Disorders. In: Brunton LL, Chabner BA, Knollmann BC, eds. Goodman and Gilman’s The Pharmacological Basis of Therapeutics. 12th ed. New York: McGraw-Hill; 2011. http://www.accessmedicine.com/content.aspx?aID=16682543. Accessed 28 Jan 2013.

8. Royal College of Obstreticians and Gynaecologists. Consensus views arising from the 49th Study Group: Contraception and Contraceptive Use. Available: http://www.rcog.org.uk/womens-health/clinical-guidance/contraception-and- contraceptive-use-studygroup-statement. Accessed on 29 Jan 2013.

9. Kahn S, Grady B, Tifft S. Estimating demand for a new contraceptive Method: Projections for the introduction of Sayana Press. Int J Gynecol Obstet 2015; 130:E21-24.

10. Ahmed S, Li Q, Liu L, Tsui AO. Maternal deaths averted by contraceptive use: an analysis of 172 countries. Lancet 2012;380(9837):111–25.

11. Singh S, Darroch JE. Adding It Up: Costs and Benefits of Contraceptive Services— Estimates for 2012. http://www.guttmacher.org/pubs/AIU-2012-estimates.pdf. Published June 2012. Accessed July 26, 2016.

51 090177e18a903a4c\Approved\Approved On: 18-Nov-2016 03:23 Depot-medroxyprogesterone acetate (DMPA-SC) Sayana Press WHO EML Application December 2016

12. Women’s Health. Activities of the European Union Summaries of Legislation, 1997. Last updated 4/5/2006. http://eur-lex.europa.eu/legal- content/EN/ALL/?uri=URISERV%3Ac11558. Accessed August 24, 2016.

13. Skouby SO. Contraceptive use and behaviour in the 21st century: a comprehensive study across five European countries. Eur J Contracept Health Care 2007;9:57-68.

14. Spinelli A, Talamanca IF, Lauria L, et al. Patterns of contraceptive use in 5 European countries. Am J Public Health 2000;90:1403-8.

15. Alkema L, Kantorova V, Menozzi C, et al. National, regional, and global rates and trends in contraceptive prevalence and unmet need for family planning between 1990 and 2015: a systematic and comprehensive analysis. Lancet 2013;381(9878):1642-52.

16. United Nations Department of Economic and Social Affairs Population Division. Trends in Contraceptive Use Worldwide 2015. United Nations [cited 2016 Aug 1]. Available from: http://www.un.org/en/development/desa/population/publications/pdf/family/trend sContraceptiveUse2015Report.pdf

17. Cleland J, Conde-Agudelo A, Peterson H, Ross J, Tsui A. Contraception and health. Lancet 2012;380(9837):149-56.

18. Schlaff WD, Carson SA, Luciano A, Ross D, Bergqvisy A. Subcutaneous injection of depot medroxyprogesterone acetate compared with leuprolide acetate in the treatment of endometriosis-associated pain. Fertil Steril. 2006;85(2):314-25.

19. Crosignani PG, Luciano A, Ray A, Bergqvist A. Subcutaneous depot medroxyprogesterone acetate versus leuprolide acetate in the treatment of endometriosis-associated pain. Hum Reprod. 2006;21(1):248-56.

20. Prescribing Information, Sayana (Medroxyprogesterone Acetate), 03 January 2011, Accessed at http://www.pharmaline.co.il/images/newsletterregistration/pfizer/11032011/sayan adr.pdf. 11 November 2016.

21. Mansour D, Inki P, Gemzell-Danielsson K. Efficacy of contraceptive methods: A review of the literature. Eur J Contracept Reprod Health Care 2010;15(1):4-16.

22. Kaunitz AM, Darney PD, Ross D, Wolter KD, Speroff L. Subcutaneous depot medroxyprogesterone acetate (DMPA) versus intramuscular DMPA: A 2-year randomized study of contraceptive efficacy and bone mineral density. Contracept 2009;80(1):7-17.

23. Jain J, Jakimiuk AJ, Bode FR, Ross D, Kaunitz AM. Contraceptive efficacy and safety of DMPA-SC. Contracept 2004;70:269-75.

24. Depo-Provera United States Prescribing Information Revision 1/2015 http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/020246s053lbl.pdf

52 090177e18a903a4c\Approved\Approved On: 18-Nov-2016 03:23 Depot-medroxyprogesterone acetate (DMPA-SC) Sayana Press WHO EML Application December 2016

25. Depo-subQ provera 104 United States Prescribing Information http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/021583s025lbl.pdf

26. Food Drug Administration NDA 21-583 Clinical Pharmacology and Biopharmaceutics Review(s) 17 December 2004 http://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/021583s000_ClinPhar mR.pdf

27. Food Drug Administration NDA 21-583 depo-subQ provera 104 Approval Letter http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2004/021583ltr.pdf

28. Medicines Healthcare Regulatory Agency Sayana Public Assessment Report Mutual Recognition Procedure UK/H/0960/001/MR http://www.mhra.gov.uk/home/groups/par/documents/websiteresources/con0881 09.pdf

29. Medicines Healthcare Regulatory Agency Sayana Press Public Assessment Report Mutual Recognition Procedure UK/H/0960/002/MR http://www.mhra.gov.uk/home/groups/par/documents/websiteresources/con1261 47.pdf

30. Food Drug Administration NDA 21-583 depo-subQ provera 104 Approval Medical Review 17 December 2014 http://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/021583s000_MedR_P1. pdf

31. Harel Z, Johnson CC, Gold MA, et al. Recovery of bone mineral density in adolescents following the use of depot medroxyprogesterone acetate contraceptive injections. Contracep 2010;81:281-91.

32. Lanza LL, McQuay LJ, Rothman KJ, et al. Use of depot medroxyprogesterone acetate contraception and incidence of bone fracture. Obstet Gynecol 2013;121:593–600.

33. Lanza LL, McQuay LJ, Rothman KJ, et al. Comment on journal review of ‘Use of depot medroxyprogesterone acetate contraception and incidence of bone fracture’. J Fam Plann Repro Health Care 2013;39:306.

34. Cameron ST, Glasier A, Johnstone A. Pilot study of home self-administration of subcutaneous depo-medroxyprogesterone acetate for contraception. Contracep 2012;85(5):458-64.

35. Medicines and Healthcare Regulatory Agency Elashine 104 mg Public Assessment Report UK/H/5503/001/DC http://www.mhra.gov.uk/home/groups/par/documents/websiteresources/con5151 36.pdf

36. Depo-Provera suspension for injection 150 mg/ml Summary of Product Characteristics United Kingdom https://www.medicines.org.uk/emc/medicine/11121

53 090177e18a903a4c\Approved\Approved On: 18-Nov-2016 03:23 Depot-medroxyprogesterone acetate (DMPA-SC) Sayana Press WHO EML Application December 2016

37. Johnson CC, Burkman RT, Gold MA, et al. Longitudinal study of depot medroxyprogesterone acetate (Depo-Provera®) effects on bone health in adolescents: study design, population characteristics and baseline bone mineral density. Contracep 2008;77:239-48.

38. WHO Collaborative Study of Neoplasia and Steroid Contraceptives. Breast cancer and depot-medroxyprogesterone acetate: a multi-national study. Lancet 1991;338:833-8.

39. Skegg DCG, Noonan EA, Paul C, Spears GFS, Meirik O, Thomas DB. Depot Medroxyprogesterone Acetate And Breast Cancer: A Pooled Analysis From The World Health Organization. JAMA 1995;273(10):799-804.

40. WHO Collaborative Study of Neoplasia and Steroid Contraceptives. Depotmedroxyprogesterone acetate (DMPA) and risk of epithelial ovarian cancer. Int J Cancer. 1991;49:191-5.

41. WHO Collaborative Study of Neoplasia and Steroid Contraceptives. Depot- medroxyprogesterone acetate (DMPA) and risk of liver cancer. Int J Cancer. 1991;49:182-5.

42. WHO Collaborative Study of Neoplasia and Steroid Contraceptives. Depotmedroxyprogesterone acetate (DMPA) and risk of invasive squamous-cell cervical cancer. Contracep 1992;45:299-312.

43. WHO Collaborative Study of Neoplasia and Steroid Contraceptives. Depotmedroxyprogesterone acetate (DMPA) and risk of endometrial cancer. Int J Cancer 1991;49:186-190.

44. Strom BL, Berlin JA, Weber AL, et al. Absence of an effect of injectable and implantable progestin-only contraceptives on subsequent risk of breast cancer. Contracep 2004;69(5):353-60.

45. Shapiro S, Rosenberg L, Hoffman M, et al. Risk of breast cancer in relation to the use of injectable progestogen contraceptives and combined estrogen/progestogen contraceptives. Am J Epidemiol 2000;151(4):396-403.

46. Summary of Product Characyteristics, Sayana Press 104mg/0.65 ml suspension for injection, Updated 08 August 2016. Accessed at https://www.medicines.org.uk/emc/medicine/27798/SPC/SAYANA+PR ESS+104+mg+0.65+ml+suspension+for+injection/.

47. Family Planning 2020. Available at: http: , 2014.//www.familyplanning2020.org/countries/all-countries. Accessed: November 5

48. Burke HM, Mueller MP, Perry B, et al. Observational study of the acceptability of Sayana Press among intramuscular DMPA users in Uganda and Senegal. Contracep 2014;89:361-7.

49. Cover J, Namagembe A, Tumusiime J, Lim J, Drake JK, Mbonye AK. A Prospective Cohort Study of the Feasibility and Acceptability of Depot Medroxyprogesterone

54 090177e18a903a4c\Approved\Approved On: 18-Nov-2016 03:23 Depot-medroxyprogesterone acetate (DMPA-SC) Sayana Press WHO EML Application December 2016

Acetate (DMPA) Administered Subcutaneously through Self-injection. Contraception 2016; doi:10.1016/j.contraception.2016.10.007. In Press.

50. http://www.cbip.be/fr/chapters/7?frag=18192&trade_family=24059 Accessed Aug 15, 2016

51. www.z-index.nl Accessed Aug 15, 2016 (requires subscription)

52. http://www.mims.co.uk/drugs/contraception/depot-contraceptives/sayana-press Accessed Aug 15, 2016

53. Foster, D.G., et al., Cost-savings from the provision of specific contraceptive methods in 2009, Womens Health Issues, 2013, 23(4), e265-71.

54. Trussell, J., Henry, N., Hassan, F., et al. Burden of unintended pregnancy in the United States: potential savings with increased use of long-acting reversible contraception. Contraception. 2013; 2(87):154-61.

55. Mavranezouli, I. Health economics of contraception. Best Pract Res Clin Obstet Gynaecol. 2009; 23:187-98.

56. Sonnenberg, F.A., et al., Costs and net health effects of contraceptive methods, Contraception, 2004, 69(6), 447-59.

57. Mavranezouli, I. The cost-effectiveness of long-acting reversible contraceptive methods in the UK: analysis based on a decision-analytic model developed for a National Institute for Health and Clinical Excellence (NICE) clinical practice guideline. Hum Reprod. 2008; 23:1338-45.

58. https://www.nice.org.uk/guidance/cg30/ chapter/1-Recommendations

59. http://www.path.org/publications/files/RH_sayana_press_self_inject_fs2016.pdf

55 090177e18a903a4c\Approved\Approved On: 18-Nov-2016 03:23 Document Approval Record

Document Name:     

Document Title:     

Signed By: Date(GMT) Signing Capacity

 !" #$%# &'&() *  %

 "     '#$%# +&+&, *  % 090177e18a903a4c\Approved\Approved On: 18-Nov-2016 03:23