BMJ Open: first published as 10.1136/bmjopen-2019-030373 on 7 October 2019. Downloaded from BMJ Open is committed to open peer review. As part of this commitment we make the peer review history of every article we publish publicly available. When an article is published we post the peer reviewers’ comments and the authors’ responses online. We also post the versions of the paper that were used during peer review. These are the versions that the peer review comments apply to. The versions of the paper that follow are the versions that were submitted during the peer review process. They are not the versions of record or the final published versions. They should not be cited or distributed as the published version of this manuscript. BMJ Open is an open access journal and the full, final, typeset and author-corrected version of record of the manuscript is available on our site with no access controls, subscription charges or pay-per-view fees (http://bmjopen.bmj.com). If you have any questions on BMJ Open’s open peer review process please email [email protected] http://bmjopen.bmj.com/ on September 26, 2021 by guest. Protected copyright. BMJ Open BMJ Open: first published as 10.1136/bmjopen-2019-030373 on 7 October 2019. Downloaded from A Scoping Review To Map Evidence On Mechanism Of Action, Pharmacokinetics, Effectiveness And Side Effects Of Centchroman As A Contraceptive Pill ForJournal: peerBMJ Open review only Manuscript ID bmjopen-2019-030373 Article Type: Research Date Submitted by the 11-Mar-2019 Author: Complete List of Authors: Kabra, Rita ; World Health Organization, Reproductive Health and Research Allagh, Komal Preet; World Health Organization, Reproductive Health and Research (Consultant) Ali, Moazzam; World Health Organization, Reproductive health and Research Jayathilaka, C. Anoma; World Health Organization Regional Office for South-East Asia Mwinga, Kasonde; World Health Organisation Country Office for India Kiarie, James; World Health Organization, Reproductive Health and Research Keywords: centchroman, safety, effectiveness, oral pill, contraception, ormeloxifene http://bmjopen.bmj.com/ on September 26, 2021 by guest. Protected copyright. For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 1 of 33 BMJ Open 1 2 3 TITLE PAGE BMJ Open: first published as 10.1136/bmjopen-2019-030373 on 7 October 2019. Downloaded from 4 5 6 7 A Scoping Review To Map Evidence On Mechanism Of Action, 8 Pharmacokinetics, Effectiveness And Side Effects Of Centchroman As A 9 10 Contraceptive Pill 11 12 13 14 Author names and affiliations: 15 1. Dr Rita Kabraa Email- [email protected] 16 17 2. Dr Komal Preet Allaghb,* Email- [email protected] 18 For peer review only 19 3. Dr Moazzam Ali a Email- [email protected] 20 c 21 4. Dr C. Anoma Jayathilaka Email- [email protected] 22 5. Dr Kasonde Mwingad E-mail: [email protected] 23 24 6. Dr James Kiariea Email- [email protected] 25 * 26 Corresponding author: Dr Komal Preet Allagh 27 Present/permanent address: 30-Avenue Wendt, Geneva-1203, Switzerland 28 29 a Department of Reproductive Health and Research, World Health Organization, 20 30 31 Avenue Appia, 1211 Geneva 27, Switzerland 32 b 33 Consultant- Independent consultant 34 c World Health Organization, Regional office for South East Asia, World Health 35 36 House, Indraprastha estate, Mahatma Gandhi Marg, New Delhi- 110002, India 37 http://bmjopen.bmj.com/ 38 d World Health Organization, Nirman Bhawan, Maulana Azad road, New Delhi- 39 40 110011, India 41 42 43 44 45 on September 26, 2021 by guest. Protected copyright. 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 1 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 2 of 33 1 2 3 ABSTRACT BMJ Open: first published as 10.1136/bmjopen-2019-030373 on 7 October 2019. Downloaded from 4 5 Objective: To systematically identify and map the available evidence on 6 7 effectiveness, side effects, pharmacokinetics and mechanism of action of centchroman 8 as a contraceptive pill (weekly and post-coital). 9 10 Introduction 11 12 Centchroman was introduced in the Indian National family planning program in 2016 13 14 as a once a week short-term oral contraceptive pill. At present there are no WHO 15 recommendations on this method of contraception. We examined the available 16 17 evidence through a scoping review. 18 For peer review only 19 Methods 20 21 A search was conducted inclusive to the years 1970 to 2019 on electronic databases, 22 grey literature sources and reference lists of included studies to identify studies. The 23 24 five stages of Arksey and O’Malley’s scoping review framework were applied in 25 26 undertaking this scoping review. 27 Results 28 29 The review identified 33 studies conducted between 1976 and 2017. Eight studies 30 31 reported on effectiveness ranging between 93-100%. Pregnancies due to user failure 32 33 ranged from 2.6 % to 10.2 %. Although side effects were reported in thirteen studies, 34 but the incidence varied greatly between the studies. Continuous bleeding and 35 36 prolonged cycles > 45 days were the most commonly reported side effects. All 37 http://bmjopen.bmj.com/ 38 studies conducted had a small sample size and the duration of follow up of women 39 40 was 12 months or less. Fifty five percent of studies were by the developers of the pill 41 (CDRI) and results of the phase IV clinical trial were unavailable. Insufficient 42 43 evidence exists on centchroman use as a post-coital contraceptive pill. 44 45 Conclusions on September 26, 2021 by guest. Protected copyright. 46 The scoping review provides a comprehensive review of currently available literature 47 48 on centchroman, as a contraceptive pill. It is noted that studies with robust designs 49 50 and in international context are lacking. The broad uncertainty in range of side effects 51 52 and effectiveness in the studies implies insufficient evidence to make global 53 recommendations on centchroman that is currently licensed as contraceptive and is in 54 55 use in India. 56 57 58 KEYWORDS: Centchroman, safety, effectiveness, oral pill, contraception, 59 60 Ormeloxifene. 2 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 3 of 33 BMJ Open 1 2 3 Strengths and Limitations of this study BMJ Open: first published as 10.1136/bmjopen-2019-030373 on 7 October 2019. Downloaded from 4 5 A strength of our study is that it is the first scoping review to explore the 6 7 mechanism of action, pharmacokinetics, effectiveness and side effects of 8 centchroman, when used as a weekly or post-coital contraceptive pill 9 10 The review was a comprehensive overview of sources covering peer-reviewed 11 12 studies and grey literature. 13 14 A limitation of our review was that we were likely to have missed studies on 15 mechanism of action of centchroman since animal studies were excluded from 16 17 the review. 18 For peer review only 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 http://bmjopen.bmj.com/ 38 39 40 41 42 43 44 45 on September 26, 2021 by guest. Protected copyright. 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 3 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 4 of 33 1 2 3 1. INTRODUCTION BMJ Open: first published as 10.1136/bmjopen-2019-030373 on 7 October 2019. Downloaded from 4 5 Centchroman acts as a selective estrogen receptor modulator (SERM) with tissue 6 7 selective estrogenic or anti-estrogenic effects [1]. It suppresses the estrogen receptors 8 in the reproductive organs, but stimulates those of other organs like the bones [1, 2]. 9 10 It is used as an oral contraceptive pill and in treatment of dysfunctional uterine 11 12 bleeding, mastalgia and fibroadenoma due to its estrogen antagonist effect [3]. Due to 13 14 its estrogen agonist effect, centchroman is used for management of osteoporosis and 15 its levo-isomer has been shown to have some cardioprotective effects [3]. The 16 17 reported advantages of centchroman over other oral contraceptive pills are: 1) it is 18 For peer review only 19 taken once a week, 2) it does not have any side effects seen with hormonal pills like 20 21 nausea, vomiting, weight gain; 3) it is considered safe for use among breast feeding 22 women [4]; 4) it can be taken by women of all ages. 23 24 In 1960’s, the Government of India called upon Indian laboratories to develop 25 26 alternate birth control pills. The team at Central Drug Research Institute (CDRI) took 27 up this challenge and synthesized [5, 3] Centchroman (3, 4 trans-2, 2-dimethyl-3- 28 29 phenyl 4-p (β- pyrrolidinoethoxy) phenyl 7-methoxychroman) in 1967 [6, 3]. Since it 30 31 was made at CDRI and belongs to the chroman family, it was named as Centchroman. 32 33 It is also known as Ormeloxifene [7]. Following pre-clinical and clinical studies 34 (phase 1 and 2) in 1989 the Drug Controller General of India approved centchroman 35 36 as an oral contraceptive pill in 1991 [6, 3]. It was available in the Indian market since 37 http://bmjopen.bmj.com/ 38 1992. It was first manufactured by Torrent pharmaceuticals, Ahmedabad and 39 40 marketed under brand name of Centron. Later Hindustan Latex and Life care Limited 41 (HLL Lifecare Limited); Thiruvananthapuram manufactured it under the brand names 42 43 Choice-7 and Saheli [8].